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Sample records for native atrial myocytes

  1. Sodium current kinetics in cat atrial myocytes.

    PubMed Central

    Follmer, C H; ten Eick, R E; Yeh, J Z

    1987-01-01

    1. Na+ current kinetics were studied in isolated atrial myocytes from the adult cat using the single suction-pipette voltage-clamp technique. 2. Current-voltage and conductance-voltage relationships were similar to those described in other cardiac myocyte preparations. 3. Analysis of Na+ current decay using single-pulse, double-pulse and tail current measurements were in agreement and demonstrate a second-order process of current decay. 4. Voltage dependence of steady-state inactivation curves was not symmetrical, having an inflexion at about -90 mV. These results suggest more than a single inactivation process for Na+ channel in the negative potential region. 5. Recovery of Na+ current from inactivation had a sigmoid time course: an initial slow component (delay) followed by a fast and then a second slow component. Increasing the pre-pulse duration slowed the time course of recovery. 6. Taken together, the results were consistent with the presence of multiple inactivated states for the atrial myocyte Na+ channel. PMID:2443658

  2. Functional Role and Mechanism of microRNA-28b in Atrial Myocyte in a Persistent Atrial Fibrillation Rat Model

    PubMed Central

    Wang, Yongbin; Kang, Weiqiang; Wang, Xu; Chen, Meina; Qin, Qiaoji; Guo, Minglei; Ge, Zhiming

    2016-01-01

    Background Persistent atrial fibrillation has been indicated to be related with microRNA-28b. However, the exact role of microRNA-28b in persistent atrial fibrillation needs to be further elucidated. Therefore, this study aimed to establish a rat model of persistent atrial fibrillation to investigate the level of microRNA-28b in atrial myocytes and to explore the molecular mechanism involved. Material/Methods A persistent atrial fibrillation model was established in rats by using chronic rapid atrial pacing induction. The size of the heart was measured by ultrasonic method. The expression of microRNA-28b in left atrial myocytes was quantified by RT-PCR. Cardiomyocytes were isolated and cultured to detect cell proliferation and apoptosis by MTT and flow cytometry, respectively. The specific inhibitor of ERK signaling pathway, PD98059, was used to further illustrate the role of ERK signaling pathway in the modulation of cardiomyocytes in persistent atrial fibrillation. Results MicroRNA-28b was up-regulated in the experimental rat model with persistent atrial fibrillation. The proliferation of cardiomyocytes was significantly inhibited with potentiated apoptosis. Blockage of the ERK pathway suppressed the microRNA-28b expression and inhibited cell apoptosis. Conclusions microRNA-28b-induced growth inhibition and cell apoptosis of atrial myocytes was observed in the rat model with persistent atrial fibrillation, via activation of the ERK signaling pathway. PMID:27574952

  3. Leptin modulates electrophysiological characteristics and isoproterenol-induced arrhythmogenesis in atrial myocytes

    PubMed Central

    2013-01-01

    Background Obesity is an important risk factor for atrial fibrillation (AF). Leptin is an important adipokine. However, it is not clear whether leptin directly modulates the electrophysiological characteristics of atrial myocytes. Results Whole cell patch clamp and indo-1 fluorescence were used to record the action potentials (APs) and ionic currents in isolated rabbit left atrial (LA) myocytes incubated with and without (control) leptin (100 nM) for 1 h to investigate the role of leptin on atrial electrophysiology. Leptin-treated LA myocytes (n = 19) had longer 20% of AP duration (28 ± 3 vs. 21 ± 2 ms, p < 0.05), but similar 50% of AP duration (51 ± 4 vs. 50 ± 3 ms, p > 0.05), and 90% of AP duration (89 ± 5 vs. 94 ± 4 ms, p > 0.05), as compared to the control (n = 22). In the presence of isoproterenol (10 nM), leptin-treated LA myocytes (n = 21) showed a lower incidence (19% vs. 54.2%, p < 0.05) of delayed afterdepolarization (DAD) than the control (n = 24). Leptin-treated LA myocytes showed a larger sodium current, but a smaller ultra-rapid delayed rectifier potassium current, and sodium-calcium exchanger current than the control. Leptin-treated and control LA myocytes exhibited a similar late sodium current, inward rectifier potassium current, transient outward current and L-type calcium current. In addition, the leptin-treated LA myocytes (n = 38) exhibited a smaller intracellular Ca2+ transient (0.21 ± 0.01 vs. 0.26 ± 0.01 R410/485, p < 0.05) and sarcoplasmic reticulum Ca2+ content (0.35 ± 0.02 vs. 0.43 ± 0.03 R410/485, p < 0.05) than the control LA myocytes (n = 42). Conclusions Leptin regulates the LA electrophysiological characteristics and attenuates isoproterenol-induced arrhythmogenesis. PMID:24354396

  4. Sick sinus syndrome and atrial fibrillation in older persons - A view from the sinoatrial nodal myocyte.

    PubMed

    Monfredi, O; Boyett, M R

    2015-06-01

    Sick sinus syndrome remains a highly relevant clinical entity, being responsible for the implantation of the majority of electronic pacemakers worldwide. It is an infinitely more complex disease than it was believed when first described in the mid part of the 20th century. It not only involves the innate leading pacemaker region of the heart, the sinoatrial node, but also the atrial myocardium, predisposing to atrial tachydysrhythmias. It remains controversial as to whether the dysfunction of the sinoatrial node directly causes the dysfunction of the atrial myocardium, or vice versa, or indeed whether these two aspects of the condition arise through some related underlying pathological mechanism, such as extracellular matrix remodeling, i.e., fibrosis. This review aims to shed new light on the myriad possible contributing factors in the development of sick sinus syndrome, with a particular focus on the sinoatrial nodal myocyte. This article is part of a Special Issue entitled CV Aging.

  5. Transverse tubules are a common feature in large mammalian atrial myocytes including human.

    PubMed

    Richards, M A; Clarke, J D; Saravanan, P; Voigt, N; Dobrev, D; Eisner, D A; Trafford, A W; Dibb, K M

    2011-11-01

    Transverse (t) tubules are surface membrane invaginations that are present in all mammalian cardiac ventricular cells. The apposition of L-type Ca(2+) channels on t tubules with the sarcoplasmic reticulum (SR) constitutes a "calcium release unit" and allows close coupling of excitation to the rise in systolic Ca(2+). T tubules are virtually absent in the atria of small mammals, and therefore Ca(2+) release from the SR occurs initially at the periphery of the cell and then propagates into the interior. Recent work has, however, shown the occurrence of t tubules in atrial myocytes from sheep. As in the ventricle, Ca(2+) release in these cells occurs simultaneously in central and peripheral regions. T tubules in both the atria and the ventricle are lost in disease, contributing to cellular dysfunction. The aim of this study was to determine if the occurrence of t tubules in the atrium is restricted to sheep or is a more general property of larger mammals including humans. In atrial tissue sections from human, horse, cow, and sheep, membranes were labeled using wheat germ agglutinin. As previously shown in sheep, extensive t-tubule networks were present in horse, cow, and human atrial myocytes. Analysis shows half the volume of the cell lies within 0.64 ± 0.03, 0.77 ± 0.03, 0.84 ± 0.03, and 1.56 ± 0.19 μm of t-tubule membrane in horse, cow, sheep, and human atrial myocytes, respectively. The presence of t tubules in the human atria may play an important role in determining the spatio-temporal properties of the systolic Ca(2+) transient and how this is perturbed in disease.

  6. Stimulatory action of protein kinase Cɛ isoform on the slow component of delayed rectifier K+ current in guinea-pig atrial myocytes

    PubMed Central

    Toda, H; Ding, W-G; Yasuda, Y; Toyoda, F; Ito, M; Matsuura, H; Horie, M

    2007-01-01

    Background and purpose: Protein kinase C (PKC) comprises at least twelve isoforms and has an isoform-specific action on cardiac electrical activity. The slow component of delayed rectifier K+ current (I Ks) is one of the major repolarizing currents in the hearts of many species and is also potentiated by PKC activation. Little is known, however, about PKC isoform(s) functionally involved in the potentiation of I Ks in native cardiac myocytes. Experimental approach: I Ks was recorded from guinea-pig atrial myocytes, using the whole-cell configuration of patch-clamp method. Key results: Bath application of phenylephrine enhanced I Ks concentration-dependently with EC50 of 5.4 μM and the maximal response (97.1±11.9% increase, n=16) was obtained at 30 μM. Prazosin (1 μM) almost totally abolished the potentiation of I Ks by phenylephrine, supporting the involvement of α1-adrenoceptors. The stimulatory action of phenylephrine was significantly, if not entirely, inhibited by the general PKC inhibitor bisindolylmaleimide I but was little affected by Gö-6976, Gö-6983 and rottlerin. Furthermore, this stimulatory effect was significantly reduced by dialyzing atrial myocytes with PKCɛ-selective inhibitory peptide ɛV1-2 but was not significantly affected by conventional PKC isoform-selective inhibitory peptide βC2-4. Phorbol 12-myristate 13-acetate (PMA) at 100 nM substantially increased I Ks by 64.2±1.3% (n=6), which was also significantly attenuated by an internal dialysis with ɛV1-2 but not with βC2-4. Conclusions and implications: The present study provides experimental evidence to suggest that, in native guinea-pig cardiac myocytes, activation of PKC contributes to α1-adrenoceptor-mediated potentiation of I Ks and that ɛ is the isoform predominantly involved in this PKC action. PMID:17339832

  7. Ageing is associated with deterioration of calcium homeostasis in isolated human right atrial myocytes

    PubMed Central

    Herraiz-Martínez, Adela; Álvarez-García, Jesus; Llach, Anna; Molina, Cristina E.; Fernandes, Jacqueline; Ferrero-Gregori, Andreu; Rodríguez, Cristina; Vallmitjana, Alexander; Benítez, Raúl; Padró, Josep M.; Martínez-González, José; Cinca, Juan; Hove-Madsen, Leif

    2015-01-01

    Aims Ageing-related cardiac disorders such as heart failure and atrial fibrillation often present with intracellular calcium homeostasis dysfunction. However, knowledge of the intrinsic effects of ageing on cellular calcium handling in the human heart is sparse. Therefore, this study aimed to analyse how ageing affects key mechanisms that regulate intracellular calcium in human atrial myocytes. Methods and results Whole membrane currents and intracellular calcium transients were measured in isolated human right atrial myocytes from 80 patients with normal left atrial dimensions and no history of atrial fibrillation. Patients were categorized as young (<55 years, n = 21), middle aged (55–74 years, n = 42), and old (≥75 years, n = 17). Protein levels were determined by western blot. Ageing was associated with the following electrophysiological changes: (i) a 3.2-fold decrease in the calcium transient (P < 0.01); (ii) reduction of the L-type calcium current (ICa) amplitude (2.4 ± 0.3 pA/pF vs. 1.4 ± 0.2 pA/pF, P < 0.01); (iii) lower levels of L-type calcium channel alpha-subunit (P < 0.05); (iv) lower rates of both fast (14.5 ± 0.9 ms vs. 20.9 ± 1.9, P < 0.01) and slow (73 ± 3 vs. 120 ± 12 ms, P < 0.001) ICa inactivation; and (v) a decrease in the sarcoplasmic reticulum calcium content (10.1 ± 0.8 vs. 6.4 ± 0.6 amol/pF, P < 0.005) associated with a significant decrease in both SERCA2 (P < 0.05) and calsequestrin-2 (P < 0.05) protein levels. In contrast, ageing did not affect spontaneous sarcoplasmic reticulum calcium release. Conclusion Ageing is associated with depression of SR calcium content, L-type calcium current, and calcium transient amplitude that may favour a progressive decline in right atrial contractile function with age. PMID:25712961

  8. Comparison of Detailed and Simplified Models of Human Atrial Myocytes to Recapitulate Patient Specific Properties.

    PubMed

    Lombardo, Daniel M; Fenton, Flavio H; Narayan, Sanjiv M; Rappel, Wouter-Jan

    2016-08-01

    Computer studies are often used to study mechanisms of cardiac arrhythmias, including atrial fibrillation (AF). A crucial component in these studies is the electrophysiological model that describes the membrane potential of myocytes. The models vary from detailed, describing numerous ion channels, to simplified, grouping ionic channels into a minimal set of variables. The parameters of these models, however, are determined across different experiments in varied species. Furthermore, a single set of parameters may not describe variations across patients, and models have rarely been shown to recapitulate critical features of AF in a given patient. In this study we develop physiologically accurate computational human atrial models by fitting parameters of a detailed and of a simplified model to clinical data for five patients undergoing ablation therapy. Parameters were simultaneously fitted to action potential (AP) morphology, action potential duration (APD) restitution and conduction velocity (CV) restitution curves in these patients. For both models, our fitting procedure generated parameter sets that accurately reproduced clinical data, but differed markedly from published sets and between patients, emphasizing the need for patient-specific adjustment. Both models produced two-dimensional spiral wave dynamics for that were similar for each patient. These results show that simplified, computationally efficient models are an attractive choice for simulations of human atrial electrophysiology in spatially extended domains. This study motivates the development and validation of patient-specific model-based mechanistic studies to target therapy. PMID:27494252

  9. Comparison of Detailed and Simplified Models of Human Atrial Myocytes to Recapitulate Patient Specific Properties

    PubMed Central

    Fenton, Flavio H.; Narayan, Sanjiv M.; Rappel, Wouter-Jan

    2016-01-01

    Computer studies are often used to study mechanisms of cardiac arrhythmias, including atrial fibrillation (AF). A crucial component in these studies is the electrophysiological model that describes the membrane potential of myocytes. The models vary from detailed, describing numerous ion channels, to simplified, grouping ionic channels into a minimal set of variables. The parameters of these models, however, are determined across different experiments in varied species. Furthermore, a single set of parameters may not describe variations across patients, and models have rarely been shown to recapitulate critical features of AF in a given patient. In this study we develop physiologically accurate computational human atrial models by fitting parameters of a detailed and of a simplified model to clinical data for five patients undergoing ablation therapy. Parameters were simultaneously fitted to action potential (AP) morphology, action potential duration (APD) restitution and conduction velocity (CV) restitution curves in these patients. For both models, our fitting procedure generated parameter sets that accurately reproduced clinical data, but differed markedly from published sets and between patients, emphasizing the need for patient-specific adjustment. Both models produced two-dimensional spiral wave dynamics for that were similar for each patient. These results show that simplified, computationally efficient models are an attractive choice for simulations of human atrial electrophysiology in spatially extended domains. This study motivates the development and validation of patient-specific model-based mechanistic studies to target therapy. PMID:27494252

  10. Fibroblast–myocyte electrotonic coupling: Does it occur in native cardiac tissue?☆

    PubMed Central

    Kohl, Peter; Gourdie, Robert G.

    2014-01-01

    Heterocellular electrotonic coupling between cardiac myocytes and non-excitable connective tissue cells has been a long-established and well-researched fact in vitro. Whether or not such coupling exists in vivo has been a matter of considerable debate. This paper reviews the development of experimental insight and conceptual views on this topic, describes evidence in favour of and against the presence of such coupling in native myocardium, and identifies directions for further study needed to resolve the riddle, perhaps less so in terms of principal presence which has been demonstrated, but undoubtedly in terms of extent, regulation, patho-physiological context, and actual relevance of cardiac myocyte–non-myocyte coupling in vivo. This article is part of a Special Issue entitled "Myocyte-Fibroblast Signalling in Myocardium." PMID:24412581

  11. Immunoreactive atrial natriuretic peptide and dopamine beta-hydroxylase in myocytes and chromaffin cells of the heart of the African lungfish, Protopterus aethiopicus.

    PubMed

    Larsen, T H; Helle, K B; Saetersdal, T

    1994-07-01

    The heart of the African lungfish, Protopterus aethiopicus, was examined for immunoreactive atrial natriuretic peptide (ANP) and dopamine beta-hydroxylase (D beta H) as markers for hormone secreting myocytes and chromaffin cells, respectively. Specific antibodies raised against rat alpha-ANP and rat D beta H were used for immunofluorescence microscopy and immunogold electron microscopy. D beta H-immunoreactive cells were restricted to subendocardial areas of the atrium whereas ANP immunoreactivity occurred throughout both the atrial and the ventricular myocardium, showing particularly strong staining intensity in the atrial myocytes. The granular ANP immunostaining in the atrial myocytes was frequently accumulated in the sarcoplasm. In the ventricular myocytes ANP immunoreactivity occurred as scattered granular staining throughout the sarcoplasm. ANP and D beta H immunofluorescence staining coincided with the presence of immunoreactive specific granules and secretory vesicles in the cardiac myocytes and chromaffin cells, respectively, as revealed by electron microscopy. The number of ANP-containing specific granules was generally high in the atrial myocytes, and they were frequently observed in clusters in subsarcolemmal areas. Granular frequency was considerably lower and the mean granular diameter was smaller (0.142 +/- 0.045 micron versus 0.213 +/- 0.049 micron) in the ventricular than in the atrial myocytes. The present results indicate that ANP and D beta H are phylogenetically highly conserved proteins from the dipnoi to the rat. The large amounts of ANP and of specific granules are consistent with an endocrine myocardium in the Protopterus heart. The presence of D beta H and secretory vesicles in the subendocardial chromaffin cells of the atrium suggests a local production of catecholamines from dopamine in the heart of this dipnoan. PMID:7926645

  12. Prevention of adenosine A2A receptor activation diminishes beat-to-beat alternation in human atrial myocytes.

    PubMed

    Molina, Cristina E; Llach, Anna; Herraiz-Martínez, Adela; Tarifa, Carmen; Barriga, Montserrat; Wiegerinck, Rob F; Fernandes, Jacqueline; Cabello, Nuria; Vallmitjana, Alex; Benitéz, Raúl; Montiel, José; Cinca, Juan; Hove-Madsen, Leif

    2016-01-01

    Atrial fibrillation (AF) has been associated with increased spontaneous calcium release from the sarcoplasmic reticulum and linked to increased adenosine A2A receptor (A2AR) expression and activation. Here we tested whether this may favor atrial arrhythmogenesis by promoting beat-to-beat alternation and irregularity. Patch-clamp and confocal calcium imaging was used to measure the beat-to-beat response of the calcium current and transient in human atrial myocytes. Responses were classified as uniform, alternating or irregular and stimulation of Gs-protein coupled receptors decreased the frequency where a uniform response could be maintained from 1.0 ± 0.1 to 0.6 ± 0.1 Hz; p < 0.01 for beta-adrenergic receptors and from 1.4 ± 0.1 to 0.5 ± 0.1 Hz; p < 0.05 for A2ARs. The latter was linked to increased spontaneous calcium release and after-depolarizations. Moreover, A2AR activation increased the fraction of non-uniformly responding cells in HL-1 myocyte cultures from 19 ± 3 to 51 ± 9 %; p < 0.02, and electrical mapping in perfused porcine atria revealed that adenosine induced electrical alternans at longer cycle lengths, doubled the fraction of electrodes showing alternation, and increased the amplitude of alternations. Importantly, protein kinase A inhibition increased the highest frequency where uniform responses could be maintained from 0.84 ± 0.12 to 1.86 ± 0.11 Hz; p < 0.001 and prevention of A2AR-activation with exogenous adenosine deaminase selectively increased the threshold from 0.8 ± 0.1 to 1.2 ± 0.1 Hz; p = 0.001 in myocytes from patients with AF. In conclusion, A2AR-activation promotes beat-to-beat irregularities in the calcium transient in human atrial myocytes, and prevention of A2AR activation may be a novel means to maintain uniform beat-to-beat responses at higher beating frequencies in patients with atrial fibrillation.

  13. Cellular Hypertrophy and Increased Susceptibility to Spontaneous Calcium-Release of Rat Left Atrial Myocytes Due to Elevated Afterload.

    PubMed

    Zhang, Haifei; Cannell, Mark B; Kim, Shang Jin; Watson, Judy J; Norman, Ruth; Calaghan, Sarah C; Orchard, Clive H; James, Andrew F

    2015-01-01

    Atrial remodeling due to elevated arterial pressure predisposes the heart to atrial fibrillation (AF). Although abnormal sarcoplasmic reticulum (SR) function has been associated with AF, there is little information on the effects of elevated afterload on atrial Ca2+-handling. We investigated the effects of ascending aortic banding (AoB) on Ca2+-handling in rat isolated atrial myocytes in comparison to age-matched sham-operated animals (Sham). Myocytes were either labelled for ryanodine receptor (RyR) or loaded with fluo-3-AM and imaged by confocal microscopy. AoB myocytes were hypertrophied in comparison to Sham controls (P<0.0001). RyR labeling was localized to the z-lines and to the cell edge. There were no differences between AoB and Sham in the intensity or pattern of RyR-staining. In both AoB and Sham, electrical stimulation evoked robust SR Ca2+-release at the cell edge whereas Ca2+ transients at the cell center were much smaller. Western blotting showed a decreased L-type Ca channel expression but no significant changes in RyR or RyR phosphorylation or in expression of Na+/Ca2+ exchanger, SR Ca2+ ATPase or phospholamban. Mathematical modeling indicated that [Ca2+]i transients at the cell center were accounted for by simple centripetal diffusion of Ca2+ released at the cell edge. In contrast, caffeine (10 mM) induced Ca2+ release was uniform across the cell. The caffeine-induced transient was smaller in AoB than in Sham, suggesting a reduced SR Ca2+-load in hypertrophied cells. There were no significant differences between AoB and Sham cells in the rate of Ca2+ extrusion during recovery of electrically-stimulated or caffeine-induced transients. The incidence and frequency of spontaneous Ca2+-transients following rapid-pacing (4 Hz) was greater in AoB than in Sham myocytes. In conclusion, elevated afterload causes cellular hypertrophy and remodeling of atrial SR Ca2+-release. PMID:26713852

  14. High-fat diet-dependent modulation of the delayed rectifier K(+) current in adult guinea pig atrial myocytes.

    PubMed

    Aromolaran, Ademuyiwa S; Colecraft, Henry M; Boutjdir, Mohamed

    2016-06-01

    Obesity is associated with hyperlipidemia, electrical remodeling of the heart, and increased risk of supraventricular arrhythmias in both male and female patients. The delayed rectifier K(+) current (IK), is an important regulator of atrial repolarization. There is a paucity of studies on the functional role of IK in response to obesity. Here, we assessed the obesity-mediated functional modulation of IK in low-fat diet (LFD), and high-fat diet (HFD) fed adult guinea pigs. Guinea pigs were randomly divided into control and obese groups fed, ad libitum, with a LFD (10 kcal% fat) or a HFD (45 kcal% fat) respectively. Action potential duration (APD), and IK were studied in atrial myocytes and IKr and IKs in HEK293 cells using whole-cell patch clamp electrophysiology. HFD guinea pigs displayed a significant increase in body weight, total cholesterol and total triglycerides within 50 days. Atrial APD at 30% (APD30) and 90% (APD90) repolarization were shorter, while atrial IK density was significantly increased in HFD guinea pigs. Exposure to palmitic acid (PA) increased heterologously expressed IKr and IKs densities, while oleic acid (OA), severely reduced IKr and had no effect on IKs. The data are first to show that in obese guinea pigs abbreviated APD is due to increased IK density likely through elevations of PA. Our findings may have crucial implications for targeted treatment options for obesity-related arrhythmias.

  15. Modulation of the muscarinic K+ channel by P2-purinoceptors in guinea-pig atrial myocytes.

    PubMed Central

    Matsuura, H; Ehara, T

    1996-01-01

    1. Activation of muscarinic K+ (KACh) channels by P2-purinergic agonists, such as ATP, decreases monotonically in the continued presence of agonist. We investigated the mechanisms underlying this process of decline in guinea-pig atrial myocytes using the patch-clamp technique. 2. External ATP reversibly depressed the acetylcholine (ACh, 5.5-11 microM)-induced KACh current in a concentration-dependent manner with a half-maximal inhibitory concentration (IC50) of 5.4 microM. 3. External ATP irreversibly reduced guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S)-induced KACh current both in control and pertussis toxin (PTX)-pretreated cells, suggesting (i) that the ATP-induced inhibition of KACh current occurred at some step(s) downstream from the activation of the PTX-sensitive G protein, GK, and (ii) that a PTX-insensitive G protein was involved in the signal transduction pathway. 4. The potency order of ATP analogues in reducing KACh current was ATP > or = 2-methylthio-ATP > or = alpha, beta-methylene-ATP, indicating involvement of a P2Y-type purinoceptor. 5. In the cell-attached patch recording, ATP (100 microM) applied to the bath solution reduced the activity of the KACh channels activated by ACh in the pipette, in two out of eight experiments, suggesting the possible involvement of cytosolic second messengers in the inhibition of KACh channels. 6. The ATP-induced reduction of KACh current was not affected by a protein kinase C inhibitor, 1-(5-isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride (H-7), suggesting that this response was not mediated by the activation of protein kinase C. 7. These results demonstrate that, in addition to the membrane-delimited activation through GK, external ATP causes an inhibition of the KACh channel probably by activating a PTX-insensitive G protein and cytosolic second messenger(s), which may underlie the monotonic decrease of the ATP-activated KACh current. PMID:8961182

  16. Cytosolic and nuclear calcium signaling in atrial myocytes: IP3-mediated calcium release and the role of mitochondria.

    PubMed

    Hohendanner, Felix; Maxwell, Joshua T; Blatter, Lothar A

    2015-01-01

    In rabbit atrial myocytes Ca signaling has unique features due to the lack of transverse (t) tubules, the spatial arrangement of mitochondria and the contribution of inositol-1,4,5-trisphosphate (IP3) receptor-induced Ca release (IICR). During excitation-contraction coupling action potential-induced elevation of cytosolic [Ca] originates in the cell periphery from Ca released from the junctional sarcoplasmic reticulum (j-SR) and then propagates by Ca-induced Ca release from non-junctional (nj-) SR toward the cell center. The subsarcolemmal region between j-SR and the first array of nj-SR Ca release sites is devoid of mitochondria which results in a rapid propagation of activation through this domain, whereas the subsequent propagation through the nj-SR network occurs at a velocity typical for a propagating Ca wave. Inhibition of mitochondrial Ca uptake with the Ca uniporter blocker Ru360 accelerates propagation and increases the amplitude of Ca transients (CaTs) originating from nj-SR. Elevation of cytosolic IP3 levels by rapid photolysis of caged IP3 has profound effects on the magnitude of subcellular CaTs with increased Ca release from nj-SR and enhanced CaTs in the nuclear compartment. IP3 uncaging restricted to the nucleus elicites 'mini'-Ca waves that remain confined to this compartment. Elementary IICR events (Ca puffs) preferentially originate in the nucleus in close physical association with membrane structures of the nuclear envelope and the nucleoplasmic reticulum. The data suggest that in atrial myocytes the nucleus is an autonomous Ca signaling domain where Ca dynamics are primarily governed by IICR. PMID:25891132

  17. Persistence of pro-arrhythmic spatio-temporal calcium patterns in atrial myocytes: a computational study of ping waves.

    PubMed

    Thul, Rüdiger; Coombes, Stephen; Bootman, Martin D

    2012-01-01

    Clusters of ryanodine receptors within atrial myocytes are confined to spatially separated layers. In many species, these layers are not juxtaposed by invaginations of the plasma membrane (transverse tubules; 'T-tubules'), so that calcium-induced-calcium signals rely on centripetal propagation rather than voltage-synchronized channel openings to invade the interior of the cell and trigger contraction. The combination of this specific cellular geometry and dynamics of calcium release can lead to novel autonomous spatio-temporal calcium waves, and in particular ping waves. These are waves of calcium release activity that spread as counter-rotating sectors of elevated calcium within a single layer of ryanodine receptors, and can seed further longitudinal calcium waves. Here we show, using a computational model, that these calcium waves can dominate the response of a cell to electrical pacing and hence are pro-arrhythmic. This highlights the importance of modeling internal cellular structures when investigating mechanisms of cardiac dysfunction such as atrial arrhythmia.

  18. Voltage-activated sodium current is inhibited by capsaicin in rat atrial myocytes.

    PubMed

    Milesi, V; Rebolledo, A; Alvis, A G; Raingo, J; Grassi de Gende, A O

    2001-04-13

    The effects of capsaicin, the active principle of hot pepper genus Capsicum, were studied on voltage-activated, tetrodotoxin-sensitive Na+ currents in isolated rat atrial cells using the patch clamp technique in the whole-cell configuration. 0.4 and 4 microM of capsaicin produced a significant tonic block on voltage-activated Na+ current (I(Na)) evoked by a depolarizing step to -40 mV from a holding potential of -100 mV (49 +/- 7% n = 11, P < 0.05 and 72 +/- 13% n = 4, P < 0.05 respectively). We didn't observe any use-dependent block of capsaicin in our experimental conditions. Capsaicin slowed the time decay of inactivation of I(Na), and increased the time constant of the recovery of inactivation. Capsaicin and tetrodotoxin (TTX) depressed contractility of isolated electrically driven left rat atria, being the depression of maximal velocity of force development (dF/dt(max)) with respect to control values of 19 +/- 3% at 1 microM of capsaicin and 22 +/- 2% at 1 microM of TTX. These results show an inhibitory effect of capsaicin on I(Na) in isolated atrial cells that may modify the electrical and contractile function of the rat heart. PMID:11352646

  19. Sarcoplasmic reticulum and L-type Ca²⁺ channel activity regulate the beat-to-beat stability of calcium handling in human atrial myocytes.

    PubMed

    Llach, Anna; Molina, Cristina E; Fernandes, Jacqueline; Padró, Josep; Cinca, Juan; Hove-Madsen, Leif

    2011-07-01

    Irregularities in intracellular calcium on a beat-to-beat basis can precede cardiac arrhythmia, but the mechanisms inducing such irregularities remain elusive. This study tested the hypothesis that sarcoplasmic reticulum (SR) and L-type calcium channel activity determine the beat-to-beat response and its rate dependency. For this purpose, patch-clamp technique and confocal calcium imaging was used to record L-type calcium current (ICa) and visualize calcium in human atrial myocytes subjected to increasing stimulation frequencies (from 0.2 to 2 Hz). The beat-to-beat response was heterogeneous among a population of 133 myocytes, with 30 myocytes responding uniformly at all frequencies, while alternating and irregular responses were induced in 78 and 25 myocytes, respectively. Myocytes with uniform responses had the lowest frequency of calcium wave-induced transient inward currents (ITI; 0.4 ± 0.2 min⁻¹), ICa density (1.8 ± 0.3 pA pF⁻¹) and caffeine-releasable calcium load (6.2 ± 0.5 amol pF⁻¹), while those with alternating responses had the highest ITI frequency (1.8 ± 0.3 min⁻¹,P =0.003) and ICa density (2.4 ± 0.2 pA pF⁻¹, P =0.04). In contrast, the calcium load was highest in myocytes with irregular responses (8.5 ± 0.7 amol pF⁻¹, P =0.01). Accordingly, partial ICa inhibition reduced the incidence (from 78 to 44%, P <0.05) and increased the threshold frequency for beat-to-beat alternation (from 1.3 ± 0.2 to 1.9 ± 0.2 Hz, P <0.05). Partial inhibition of SR calcium release reduced the ITI frequency, increased calcium loading and favoured induction of irregular responses, while complete inhibition abolished beat-to-beat alternation at all frequencies. In conclusion, the beat-to-beat response was heterogeneous among human atrial myocytes subjected to increasing stimulation frequencies, and the nature and stability of the response were determined by the SR and L-type calcium channel activities, suggesting that these mechanisms are key to

  20. Effects of temperature on intracellular Ca2+ in trout atrial myocytes.

    PubMed

    Shiels, Holly A; Vornanen, Matti; Farrell, Anthony P

    2002-12-01

    Acute temperature change can be cardioplegic to mammals, yet certain ectotherms maintain their cardiac scope over a wide temperature range. To better understand the acute effects of temperature on the ectothermic heart, we investigated the stimulus-induced change in intracellular Ca(2+) concentration ([Ca(2+)](i); cytosolic Ca(2+) transient) in isolated rainbow trout myocytes at 7 degrees C, 14 degrees C and 21 degrees C. Myocytes were voltage-clamped and loaded with Fura-2 to measure the L-type Ca(2+) channel current (I(Ca)) and [Ca(2+)](i) during physiological action potential (AP) pulses at frequencies that correspond to trout heart rates in vivo at 7 degrees C, 14 degrees C and 21 degrees C. Additionally, [Ca(2+)](i) and I(Ca) were examined with square (SQ) pulses at slow (0.2 Hz) and physiologically relevant contraction frequencies. The amplitude of [Ca(2+)](i) decreased with increasing temperature for both SQ and AP pulses, which may contribute to the well-known negative inotropic effect of warm temperature on contractile strength in trout hearts. With SQ pulses, [Ca(2+)](i) decreased from 474+/-53 nmol l(-1) at 7 degrees C to 198+/-21 nmol l(-1) at 21 degrees C, while the decrease in [Ca(2+)](i) with AP pulses was from 234+/-49 nmol l(-1) to 79+/-12 nmol l(-1), respectively. Sarcolemmal Ca(2+) influx was increased slightly at cold temperatures with AP pulses (charge transfer was 0.27+/-0.04 pC pF(-1), 0.19+/-0.03 pC pF(-1) and 0.13+/-0.03 pC pF(-1) at 7 degrees C, 14 degrees C and 21 degrees C, respectively). At all temperatures, cells were better able to maintain diastolic Ca(2+) levels at physiological frequencies with AP pulses compared with 500 ms SQ pulses. We suggest that temperature-dependent modulation of the AP is important for cellular Ca(2+) regulation during temperature and frequency change in rainbow trout heart.

  1. A new potassium ion current induced by stimulation of M2 cholinoreceptors in fish atrial myocytes.

    PubMed

    Abramochkin, Denis V; Tapilina, Svetlana V; Vornanen, Matti

    2014-05-15

    A novel potassium ion current induced by muscarinic stimulation (IKACh2) is characterized in atrial cardiomyocytes of teleost fishes (crucian carp, Carassius carassius; rainbow trout, Oncorhynchus mykiss) by means of the whole-cell patch-clamp technique. The current is elicited in atrial, but not ventricular, cells by application of carbamylcholine (CCh) in moderate to high concentrations (10(-7)-10(-4) mol l(-1)). It can be distinguished from the classic IKACh, activated by the βγ-subunit of the Gi-protein, because of its low sensitivity to Ba(2+) ions and distinct current-voltage relationship with a very small inward current component. Ni(2+) ions (5 mmol l(-1)) and KB-R7943 (10(-5) mol l(-1)), non-selective blockers of the sodium-calcium exchange current (INCX), strongly reduced and completely abolished, respectively, the IKACh2. Therefore, IKACh2 was initially regarded as a CCh-induced outward component of the INCX. However, the current is not affected by either exclusion of intracellular Na(+) or extracellular Ca(2+), but is completely abolished by intracellular perfusion with K(+)-free solution. Atropine (10(-6) mol l(-1)), a non-selective muscarinic blocker, completely eliminated the IKACh2. A selective antagonist of M2 cholinoreceptors, AF-DX 116 (2×10(-7) mol l(-1)) and an M3 antagonist, 4-DAMP (10(-9) mol l(-1)), decreased IKACh2 by 84.4% and 16.6%, respectively. Pertussis toxin, which irreversibly inhibits Gi-protein coupled to M2 receptors, reduced the current by 95%, when applied into the pipette solution. It is concluded that IKACh2, induced by stimulation of M2 cholinoceptors and subsequent Gi-protein activation, represents a new molecular target for the cardiac parasympathetic innervation. PMID:24526726

  2. Activation of f-channels by cAMP analogues in macropatches from rabbit sino-atrial node myocytes.

    PubMed Central

    Bois, P; Renaudon, B; Baruscotti, M; Lenfant, J; DiFrancesco, D

    1997-01-01

    1. The action of the two diastereometric phosphorothioate derivatives of cAMP, Rp-cAMPs and Sp-cAMPs, was investigated on hyperpolarization-activated 'pacemaker' current (i(f)) recorded in inside-out macropatches from rabbit sino-atrial (SA) node myocytes. 2. When superfused on the intracellular side of f-channels at the concentration of 10 microM, both cAMP derivatives accelerated i(f) activation; their action was moderately less pronounced than that due to the same concentration of cAMP. 3. The measurement of the i(f) conductance-voltage relation by voltage ramp protocols indicated that both cAMP analogues shift the activation curve of i(f) to more positive voltages with no change in maximal (fully activated) conductance. 4. Dose-response relationships of the shift of the i(f) activation curve showed that both Rp-cAMPs and Sp-cAMPs act as agonists in the cAMP-dependent direct f-channel activation. Fitting data to the Hill equation resulted in maximal shifts of 9.6 and 9.5 mV, apparent dissociation constants of 0.82 and 5.4 microM, and Hill coefficients of 0.82 and 1.12 for Sp-cAMPs and Rp-cAMPs, respectively. 5. The activating action of Rp-cAMPs, a known antagonist of cAMP in the activation of cAMP-dependent protein kinase, confirms previously established evidence that f-channel activation does not involve phosphorylation. These results also suggest that the cAMP binding site of f-channels may be structurally similar to the cyclic nucleotide binding site of olfactory receptor channels. PMID:9218217

  3. Voltage dependence of sodium-calcium exchange current in guinea-pig atrial myocytes determined by means of an inhibitor.

    PubMed Central

    Lipp, P; Pott, L

    1988-01-01

    1. Spontaneous transient inward currents (Iti) caused by cyclic release of Ca2+ ions from the sarcoplasmic reticulum were studied in cultured atrial myocytes from hearts of adult guinea-pigs. K+ channel currents were blocked by replacing K+ on both sides of the membrane by Cs+; the L-type Ca2+ current was inhibited by D600. 2. The voltage dependence of peak Iti and the background current displayed distinct outward-going rectification. The I-V curves for both currents approach each other at strongly positive membrane potentials but do not intersect. 3. 3'-4'Dichlorobenzamil (DCB) causes a concentration-dependent inhibition of peak Iti and a shift of the holding current (at -60 to -40 mV) in the inward direction. Inhibition of Iti is half-maximal at a concentration of 30 microM. 4. DCB reduces the outward-rectifying component of both peak Iti and the background current. The I-V curves of the control and DCB-inhibited currents intersect at ca. +10 mV (peak Iti) and negative to -75 mV (background current), suggesting the reversal potential of the DCB-inhibited current to be shifted by ca. 85 mV in the positive direction if Cai2+ rises following Ca2+ release. 5. The voltage dependence of the DCB-inhibited currents is highly compatible with the concept of Na+-Ca2+ exchange being the charge-carrying mechanism of the outward-rectifying background current. Ca2+ release from the SR alters the I-V curve of this current according to the shift of the thermodynamic driving force. PMID:2855345

  4. Left Atrial Wall Dissection: A Rare Sequela of Native-Valve Endocarditis

    PubMed Central

    Isbitan, Ahmad; Roushdy, Alaa; Shamoon, Fayez

    2015-01-01

    Left atrial wall dissection is a rare condition; most cases are iatrogenic after mitral valve surgery. A few have been reported as sequelae of blunt chest trauma, acute myocardial infarction, and invasive cardiac procedures. On occasion, infective endocarditis causes left atrial wall dissection. We report a highly unusual case in which a 41-year-old man presented with native mitral valve infective endocarditis that had caused left atrial free-wall dissection. Although our patient died within an hour of presentation, we obtained what we consider to be a definitive diagnosis of a rare sequela, documented by transthoracic and transesophageal echocardiography. PMID:25873836

  5. Left atrial wall dissection: a rare sequela of native-valve endocarditis.

    PubMed

    Saad, Marwan; Isbitan, Ahmad; Roushdy, Alaa; Shamoon, Fayez

    2015-04-01

    Left atrial wall dissection is a rare condition; most cases are iatrogenic after mitral valve surgery. A few have been reported as sequelae of blunt chest trauma, acute myocardial infarction, and invasive cardiac procedures. On occasion, infective endocarditis causes left atrial wall dissection. We report a highly unusual case in which a 41-year-old man presented with native mitral valve infective endocarditis that had caused left atrial free-wall dissection. Although our patient died within an hour of presentation, we obtained what we consider to be a definitive diagnosis of a rare sequela, documented by transthoracic and transesophageal echocardiography.

  6. Effects of α1-adrenoceptor agonist phenylephrine on swelling-activated chloride currents in human atrial myocytes.

    PubMed

    Li, Yetao; Du, Xinling

    2015-02-01

    Swelling-activated chloride currents (ICl.swell) play an important role in cardiac electrophysiology and arrhythmogenesis. However, the regulation of these currents has not been clarified to date. In this research, we focused on the function of phenylephrine, an α1-adrenoceptor agonist, in the regulation of I(Cl.swell) in human atrial myocytes. We recorded I(Cl.swell) evoked by a hypotonic bath solution with the whole-cell patch-clamp technique. We found that I(Cl.swell) increased over time, and it was difficult to achieve absolute steady state. Phenylephrine potentiated I(Cl.swell) from -1.00 ± 0.51 pA/pF at -90 mV and 2.58 ± 1.17 pA/pF at +40 mV to -1.46 ± 0.70 and 3.84 ± 1.67 pA/pF, respectively (P < 0.05, n = 6), and the upward trend in ICl.swell was slowed after washout. This effect was concentration-dependent, and the α1-adrenoceptor antagonist prazosin shifted the dose-effect curve rightward. Addition of prazosin or the protein kinase C (PKC) inhibitor bisindolylmaleimide (BIM) attenuated the effect of phenylephrine. The PKC activator phorbol 12,13-dibutyrate (PDBu) activated I(Cl.swell) from -1.69 ± 1.67 pA/pF at -90 mV and 5.58 ± 6.36 pA/pF at +40 mV to -2.41 ± 1.95 pA/pF and 7.05 ± 6.99 pA/pF, respectively (P < 0.01 at -90 mV and P < 0.05 at +40 mV; n = 6). In conclusion, the α1-adrenoceptor agonist phenylephrine augmented I(Cl.swell), a result that differs from previous reports in other animal species. The effect was attenuated by BIM and mimicked by PDBu, which indicates that phenylephrine might modulate I(Cl,swell) in a PKC-dependent manner.

  7. [Two-way concentration-dependent effect of H2O2 on I(Kur) and I(Ca,L) in human atrial myocytes.].

    PubMed

    Zhang, Guang-Wei; Gu, Tian-Xiang; Wang, Chun; Yu, Lei; Wen, Ti

    2008-12-25

    It has been shown that oxidative stress correlates with atrial fibrillation (AF). The purpose of the present study was to investigate the effects of reactive oxygen species (ROS) on the electrophysiological activity of human atrial myocytes. Right atrial appendages were obtained from patients with AF (AF group, n=12) and without AF (non-AF group, n=12). Single human atrial myocytes were isolated through enzymatic dissociation with type XXIV protease and type V collagenase, then divided into three subgroups: control group (n=12), H2O2 group (0.1, 0.2, 0.5, 0.75, 1, 2, 5, 10 mumol/L, n=7 at each concentration) and vitamin C (antioxidant) group (1 mumol/L, n=7). Ultrarapid delayed rectifier K(+) current (I(Kur)), L-type calcium current (I(Ca,L)) and action potential duration (APD) were recorded by whole-cell patch clamp. In AF control group, the maximum current densities of I(Kur) and I(Ca,L) were significantly lower than that in non-AF control group (both P<0.05) and APD(90) was significantly shorter as well (P<0.05). In both non-AF and AF groups, H2O2 showed two-way concentration-dependent effect on I(Kur) and I(Ca,L). The maximum current densities of I(Kur) and I(Ca,L) was significantly increased at lower H2O2 concentration, but was decreased at higher H2O2 concentration. In non-AF group, 0.2 mumol/L H2O2 caused a peak increase in the maximum current identities of I(Kur) [(8.92+/-0.51) pA/pF, P<0.05] and I(Ca,L) [(9.32+/-0.67) pA/pF, P<0.05]. H2O2 at a concentration higher than 0.75 mumol/L decreased I(Kur) and I(Ca,L). When the H2O2 concentrations were 0.2, 1, 2, 5 and 10 mumol/L, APD(90) was significantly shorter compared with that in non-AF control group (P<0.05), meanwhile it had no significant difference from that in AF control group. In AF group, the peak effective concentration of H2O2 was 0.5 mumol/L, and the turning concentration was 1 mumol/L. The H2O2 concentration-current density curve in AF group was similar to that in non-AF group, but the turning

  8. Inhibition of muscarinic K+ current in guinea-pig atrial myocytes by PD 81,723, an allosteric enhancer of adenosine binding to A1 receptors

    PubMed Central

    Brandts, B; Bünemann, M; Hluchy, J; Sabin, G V; Pott, L

    1997-01-01

    PD 81,723 has been shown to enhance binding of adenosine to A1 receptors by stabilizing G protein-receptor coupling (‘allosteric enhancement'). Evidence has been provided that in the perfused hearts and isolated atria PD 81,723 causes a sensitization to adenosine via this mechanism. We have studied the effect of PD 81,723 in guinea-pig isolated atrial myocytes by use of whole-cell measurement of the muscarinic K+ current (IK(ACh)) activated by different Gi-coupled receptors (A1, M2, sphingolipid). PD 81,273 caused inhibition of IK(ACh) (IC50≃5 μM) activated by either of the three receptors. Receptor-independent IK(ACh) in cells loaded with GTP-γ-S and background IK(ACh), which contributes to the resting conductance of atrial myocytes, were equally sensitive to PD 81,723. At no combination of concentrations of adenosine and PD 81,723 could an enhancing effect be detected. The compound was active from the outside only. Loading of the cells with PD 81,723 (50 μM) via the patch pipette did not affect either IK(ACh) or its sensitivity to adenosine. We suggest that PD 81,723 acts as an inhibitor of inward rectifying K+ channels; this is supported by the finding that ventricular IK1, which shares a large degree of homology with the proteins (GIRK1/GIRK4) forming IK(ACh) but is not G protein-gated, was also blocked by this compound. It is concluded that the functional effects of PD 81,723 described in the literature are not mediated by the A1 adenosine receptor-Gi-IK(ACh) pathway. PMID:9249260

  9. Characterization of the adenosine receptor in cultured embryonic chick atrial myocytes: Coupling to modulation of contractility and adenylate cyclase activity and identification by direct radioligand binding

    SciTech Connect

    Liang, B.T.

    1989-06-01

    Adenosine receptors in a spontaneously contracting atrial myocyte culture from 14-day chick embryos were characterized by radioligand binding studies and by examining the involvement of G-protein in coupling these receptors to a high-affinity state and to the adenylate cyclase and the myocyte contractility. Binding of the antagonist radioligand (3H)-8-cyclopentyl-1,3-diproylxanthine ((3H)CPX) was rapid, reversible and saturable and was to a homogeneous population of sites with a Kd value of 2.1 +/- 0.2 nM and an apparent maximum binding of 26.2 +/- 3 fmol/mg of protein (n = 10, +/- S.E.). Guanyl-5-yl-(beta, gamma-imido)diphosphate had no effect on either the Kd or the maximum binding and CPX reversed the N6-R-phenyl-2-propyladenosine-induced inhibition of adenylate cyclase activity and contractility, indicating that (3H) CPX is an antagonist radioligand. Competition curves for (3H) CPX binding by a series of reference adenosine agonists were consistent with labeling of an A1 adenosine receptor and were better fit by a two-site model than by a one-site model. ADP-ribosylation of the G-protein by the endogenous NAD+ in the presence of pertussis toxin shifted the competition curves from bi to monophasic with Ki values similar to those of the KL observed in the absence of prior pertussis intoxication. The adenosine agonists were capable of inhibiting both the adenylate cyclase activity and myocyte contractility in either the absence or the presence of isoproterenol. The A1 adenosine receptor-selective antagonist CPX reversed these agonist effects. The order of ability of the reference adenosine receptor agonists in causing these inhibitory effects was similar to the order of potency of the same agonists in inhibiting the specific (3H)CPX binding (N6-R-phenyl-2-propyladenosine greater than N6-S-phenyl-2-propyladenosine or N-ethyladenosine-5'-uronic acid).

  10. Characterization of the rapidly activating delayed rectifier potassium current, I (Kr), in HL-1 mouse atrial myocytes.

    PubMed

    Toyoda, Futoshi; Ding, Wei-Guang; Zankov, Dimitar P; Omatsu-Kanbe, Mariko; Isono, Takahiro; Horie, Minoru; Matsuura, Hiroshi

    2010-06-01

    HL-1 is the adult murine cardiac cell line that can be passaged repeatedly in vitro without losing differentiated phenotype. The present study was designed to characterize the rapidly activating delayed rectifier potassium current, I (Kr), endogenously expressed in HL-1 cells using the whole-cell patch-clamp technique. In the presence of nisoldipine, depolarizing voltage steps applied from a holding potential of -50 mV evoked the time-dependent outward current, followed by slowly decaying outward tail current upon return to the holding potential. The amplitude of the current increased with depolarizations up to 0 mV but then progressively decreased with further depolarizations. The time-dependent outward current as well as the tail current were highly sensitive to block by E-4031 and dofetilide (IC(50) of 21.1 and 15.1 nM, respectively) and almost totally abolished by micromolar concentrations of each drug, suggesting that most of the outward current in HL-1 cells was attributable to I (Kr). The magnitude of I (Kr) available from HL-1 cells (18.1 +/- 1.5 pA pF(-1)) was sufficient for reliable measurements of various gating parameters. RT-PCR and Western blot analysis revealed the expression of alternatively spliced forms of mouse ether-a-go-go-related genes (mERG1), the full-length mERG1a and the N-terminally truncated mERG1b isoforms. Knockdown of mERG1 transcripts with small interfering RNA (siRNA) dramatically reduced I (Kr) amplitude, confirming the molecular link of mERG1 and I (Kr) in HL-1 cells. These findings demonstrate that HL-1 cells possess I (Kr) with properties comparable to those in native cardiac I (Kr) and provide an experimental model suitable for studies of I (Kr) channels.

  11. Inhibitory effects of hesperetin on Kv1.5 potassium channels stably expressed in HEK 293 cells and ultra-rapid delayed rectifier K(+) current in human atrial myocytes.

    PubMed

    Wang, Huan; Wang, Hong-Fei; Wang, Chen; Chen, Yu-Fang; Ma, Rong; Xiang, Ji-Zhou; Du, Xin-Ling; Tang, Qiang

    2016-10-15

    In the present study, the inhibitory effects of hesperetin (HSP) on human cardiac Kv1.5 channels expressed in HEK 293 cells and the ultra-rapid delayed rectifier K(+) current (Ikur) in human atrial myocytes were examined by using the whole-cell configuration of the patch-clamp techniques. We found that hesperetin rapidly and reversibly suppressed human Kv1.5 current in a concentration dependent manner with a half-maximal inhibition (IC50) of 23.15 μΜ with a Hill coefficient of 0.89. The current was maximally diminished about 71.36% at a concentration of 300μM hesperetin. Hesperetin significantly positive shifted the steady-state activation curve of Kv1.5, while negative shifted the steady-state inactivation curve. Hesperetin also accelerated the inactivation and markedly slowed the recovery from the inactivation of Kv1.5 currents. Block of Kv1.5 currents by hesperetin was in a frequency dependent manner. However, inclusion of 30μM hesperetin in pipette solution produced no effect on Kv1.5 channel current, while the current were remarkable and reversibly inhibited by extracellular application of 30μM hesperetin. We also found that hesperetin potently and reversibly inhibited the ultra-repaid delayed K(+) current (Ikur) in human atrial myocytes, which is in consistent with the effects of hesperetin on Kv1.5 currents in HEK 293 cells. In conclusion, hesperetin is a potent inhibitor of Ikur (which is encoded by Kv1.5), with blockade probably due to blocking of both open state and inactivated state channels from outside of the cell.

  12. Differential control of the hyperpolarization-activated current (i(f)) by cAMP gating and phosphatase inhibition in rabbit sino-atrial node myocytes.

    PubMed Central

    Accili, E A; Redaelli, G; DiFrancesco, D

    1997-01-01

    1. The actions of the phosphatase inhibitor calyculin A on the hyperpolarization-activated cardiac 'pacemaker' current (i(f)) were determined in single cells isolated from the sino-atrial (SA) node of the rabbit. 2. Cells were incubated for 8 min in Tyrode solution containing calyculin A (0.5 microM) and then superfused with normal Tyrode solution. The mean normalized i(f) measured in eight cells at mid-activation voltages during and after exposure to calyculin A increased maximally by 47% with a time constant of 466 s, a time much longer than that required for cAMP-mediated i(f) stimulation (about 8 s). 3. In two-pulse protocols, calyculin A treatment increased i(f) at full as well as at mid-activation voltages, indicating a higher i(f) conductance. 4. Measurement of the conductance-voltage (gf(V)) relation by voltage ramp protocols confirmed a conductance increase by calyculin A, with no significant change in the position of the activation curve on the voltage axis. Data pooled together from ramp and two-pulse protocols yielded a calyculin A-induced increase in fully activated i(f) conductance of 39.6 +/- 6.4% (n = 16 cells). 5. The positive and negative shift of i(f) voltage dependence in response to beta-adrenergic (1 microM isoprenaline) and muscarinic stimulation (1 microM acetylcholine), respectively, was preserved after the calyculin A-induced increase in conductance. The shift of the i(f) activation curve induced by 1 microM isoprenaline was significantly larger in calyculin A-treated cells (8.8 vs. 5.8 mV). 6. These data indicate that phosphatase inhibition increases i(f) in a manner distinct from the direct cAMP pathway and potentiates the beta-adrenergic-mediated i(f) modulation. PMID:9161982

  13. Native valve disease in patients with non-valvular atrial fibrillation on warfarin or rivaroxaban

    PubMed Central

    Breithardt, Günter; Baumgartner, Helmut; Berkowitz, Scott D; Hellkamp, Anne S; Piccini, Jonathan P; Lokhnygina, Yuliya; Halperin, Jonathan L; Singer, Daniel E; Hankey, Graeme J; Hacke, Werner; Becker, Richard C; Nessel, Christopher C; Mahaffey, Kenneth W; Califf, Robert M; Fox, Keith A A; Patel, Manesh R

    2016-01-01

    Objective To compare the characteristics and outcomes of patients with atrial fibrillation (AF) and aortic stenosis (AS) with patients with AF with mitral regurgitation (MR) or aortic regurgitation (AR) and patients without significant valve disease (no SVD). Methods Using Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) data, we analysed efficacy and safety outcomes, adjusting hazard ratios (HRs) for potential confounders using Cox regression analysis. Results Among 14 119 intention-to-treat ROCKET AF trial patients, a trial that excluded patients with mitral stenosis or artificial valve prosthesis, 214 had AS with or without other valve abnormalities, 1726 had MR or AR and 12 179 had no SVD. After adjusting for prognostic factors, the composite of stroke, systemic embolism or vascular death increased approximately twofold in patients with AS (AS 10.84, MR or AR 4.54 and no SVD 4.31 events per 100 patient-years, p=0.0001). All-cause death also significantly increased (AS 11.22, MR or AR 4.90 and no SVD 4.39 events per 100 patient-years, p=0.0003). Major bleeding occurred more frequently in AS (adjusted HR 1.61, confidence intervals (CI) 1.03 to 2.49, p<0.05) and MR or AR (HR 1.30, 1.07 to 1.57, p<0.01) than in no SVD, but there was no difference between AS and MR or AR (HR 1.24, 0.78 to 1.97). The relative efficacy of rivaroxaban versus warfarin was consistent among patients with and without valvular disease. Rivaroxaban was associated with higher rates of major bleeding than warfarin in patients with MR or AR (HR 1.63, 1.15 to 2.31). Conclusions We found that patients with AF and AS on oral anticoagulants may have distinctly different efficacy and safety outcomes than patients with MR or AR or no SVD. Trial registration number NCT00403767; Post-results. PMID:26888572

  14. Atrial fibrillation in inherited cardiac channelopathies: From mechanisms to management.

    PubMed

    Enriquez, Andres; Antzelevitch, Charles; Bismah, Verdah; Baranchuk, Adrian

    2016-09-01

    Atrial fibrillation (AF) is prevalent in cardiac channelopathies and may be the presenting feature in some patients. The pathogenesis is related to the primary ion channel dysfunction in atrial myocytes that affects atrial conduction or repolarization. The development of AF is associated with adverse outcomes, and its management is challenging in these patients. In this article we review the current information on the prevalence, risk factors, pathophysiology, and treatment of AF in specific cardiac channelopathies. PMID:27291509

  15. A rabbit pulmonary vein myocyte isolation method based on simultaneous heart and pulmonary vein perfusion.

    PubMed

    Gao, Lin-Lin; Zhang, Miao-Miao; Zhang, Liang-Pin; Yang, Shu-Lin; Yao, Ke-Jun; Song, Yuan-Long

    2016-02-25

    Myocytes in the pulmonary veins (PV) play a pivotal role in the development of paroxysmal atrial fibrillation (AF). It is therefore important to understand physiological characteristics of these cells. Studies on these cells are, however, markedly impeded by the fact that single PV myocytes are very difficult to obtain due to lack of effective isolation methods. In this study, we described a novel PV myocyte isolation method. The key aspect of this method is to establish a combination of retrograde heart perfusion (via the aorta) and anterograde PV perfusion (via the pulmonary artery). With this simultaneous perfusion method, a better perfusion of the PV myocytes can be obtained. As results, the output and viability of single myocytes isolated by simultaneous heart and PV perfusion method were increased compared with those in conventional retrograde heart perfusion method. PMID:26915322

  16. Allicin inhibits transient outward potassium currents in mouse ventricular myocytes

    PubMed Central

    CAO, HONG; HUANG, CONGXIN; WANG, XIN

    2016-01-01

    Allicin is the active constituent of garlic, a widely used spice and food. The remedial properties of garlic have also been extensively researched and it has been demonstrated that allicin is able to inhibit the transient outward potassium current (Ito) in atrial myocytes. However, the direct effect of allicin on Ito in ventricular myocytes has yet to be elucidated. In the present study, the effects of allicin on Ito in ventricular myocytes isolated from mice were investigated, using the whole-cell patch recording technique. The results revealed that Ito current was not significantly suppressed by allicin in the low-dose group (10 µmol/l; P>0.05). However, Ito was significantly inhibited by higher doses of allicin (30, 100 and 300 µmol/l; P<0.05 vs. control; n=6) in a concentration-dependent manner (IC50=41.6 µmol/l). In addition, a high concentration of allicin (≥100 µmol/l) was able to accelerate the voltage-dependent inactivation of Ito in mouse ventricular myocytes. In conclusion, the present study revealed that allicin inhibited the Ito in mouse ventricular myocytes, which may be the mechanism through which allicin exerts its antiarrhythmic effect. PMID:27168824

  17. Cardiac melanocytes influence atrial reactive oxygen species involved with electrical and structural remodeling in mice.

    PubMed

    Hwang, Hayoung; Liu, Fang; Petrenko, Nataliya B; Huang, Jianhe; Schillinger, Kurt J; Patel, Vickas V

    2015-09-01

    Cardiac melanocyte-like cells (CMLCs) contribute to atrial arrhythmias when missing the melanin synthesis enzyme dopachrome tautomerase (Dct). While scavenging reactive oxygen species (ROS) in Dct-null mice partially suppressed atrial arrhythmias, it remains unclear if CMLCs influence atrial ROS and structure or if the electrical response of CMLCs to ROS differs from that of atrial myocytes. This study is designed to determine if CMLCs contribute to overall atrial oxidative stress or structural remodeling, and if ROS affects the electrophysiology of CMLCs differently than atrial myocytes. Immunohistochemical analysis showed higher expression of the oxidative marker 8-hydroxy-2'-deoxyguanosine in Dct-null atria versus Dct-heterozygous (Dct-het) atria. Exposing isolated CMLCs from Dct-het and Dct-null mice to hydrogen peroxide increased superoxide anion more in Dct-null CMLCs. Trichrome staining showed increased fibrosis in Dct-null atria, and treating Dct-null mice with the ROS scavenger Tempol reduced atrial fibrosis. Action potential recordings from atrial myocytes and isolated Dct-het and Dct-null CMLCs in response to hydrogen peroxide showed that the EC50 for action potential duration (APD) prolongation of Dct-null CMLCs was 8.2 ± 1.7 μmol/L versus 16.8 ± 2.0 μmol/L for Dct-het CMLCs, 19.9 ± 2.1 μmol/L for Dct-null atrial myocytes, and 20.5 ± 1.9 μmol/L for Dct-het atrial myocytes. However, APD90 was longer in CMLCs versus atrial myocytes in response to hydrogen peroxide. Hydrogen peroxide also induced more afterdepolarizations in CMLCs compared to atrial myocytes. These studies suggest that Dct within CMLCs contributes to atrial ROS balance and remodeling. ROS prolongs APD to a greater extent and induces afterdepolarizations more frequently in CMLCs than in atrial myocytes.

  18. Usefulness of New-Onset Atrial Fibrillation, as a Strong Predictor of Heart Failure and Death in Patients With Native Left-Sided Infective Endocarditis.

    PubMed

    Ferrera, Carlos; Vilacosta, Isidre; Fernández, Cristina; López, Javier; Sarriá, Cristina; Olmos, Carmen; Vivas, David; Sáez, Carmen; Sánchez-Enrique, Cristina; Ortiz-Bautista, Carlos; San Román, José Alberto

    2016-02-01

    Atrial fibrillation (AF) is the most common cardiac arrhythmia in adults and has been independently related to increased morbidity and mortality. AF is a frequent arrhythmia in infective endocarditis (IE). Nevertheless, there are no data on how AF affects the clinical outcome of patients with endocarditis. Our purpose was to investigate patient characteristics, microbiology, echocardiographic findings, in-hospital course, and prognosis of patients with IE who develop new-onset AF (NAF) and compare them with those who remained in sinus rhythm (SR) or had previous AF (PAF). From 1997 to 2014, 507 consecutive patients with native left-sided IE were prospectively recruited at 3 tertiary care centers. We distinguished 3 groups according to the type of baseline heart rhythm during hospitalization and previous history of AF: NAF group (n = 52), patients with no previous history of AF and who were diagnosed as having NAF during hospitalization; SR group (n = 380), patients who remained in SR; and PAF group (n = 75), patients with PAF. Patients with NAF were older than those who remained in SR (68.3 vs 59.6 years, p <0.001). At admission, heart failure was more common in NAF group (53% vs 34.3%, p <0.001), whereas stroke (p = 0.427) was equally frequent in all groups. During hospitalization, embolic events occurred similarly (p = 0.411). In the multivariate analysis, NAF was independently associated with heart failure (odds ratio 3.56, p <0.01) and mortality (odds ratio 1.91, p = 0.04). In conclusion, the occurrence of NAF in patients with IE was strongly associated with heart failure and higher in-hospital mortality independently from other relevant clinical variables. PMID:26762724

  19. Effects of spironolactone towards rabbit atrial remodeling with rapid pacing.

    PubMed

    Wang, Lian-Fa; Gu, Lei; Huang, Meng-Xun; Zhou, Wen-Bing; Li, Hua; Zhang, Bang-Zhu

    2016-01-01

    This study aimed to observe the effects of spironolactone towards the rabbit atrial remodeling with rapid atrial pacing (RAP). 30 rabbits were randomly divided into control group, RAP group and spironolactone group, with 10 rabbits in each group. RAP was performed at the speed of 800 beats/min for 8 h, atrial effective refractory period (AERP) was determined before and at the 1(st), 2(nd), 4(th), 6(th) and 8(th) of the pacing, the expressions of atrial muscular calcium channel α1C subunit and β1 subunit mRNA were performed the RT-PCR detection, and ultrastructural changes of atrial myocytes were observed. AERP of RAP group shortened, with poor frequency adaptability; the expressions of calcium channel α1C subunit and β1 subunit mRNA decreased 22% and 26%, respectively, when compared with the control group; ultrastructure of atrial myocytes changed significantly. AERP of spironotlactone group shortened less that RAP group, and the frequency adaptability was maintained, the decreased expressions of calcium channel α1C subunit and β1 subunit mRNA significantly reduced. RAP could cause atrial remodeling, while spironolactone could inhibit RAP-induced atrial remodeling. PMID:26826809

  20. The stimulus interval-tension relation in enzymatically isolated single myocytes of the frog heart.

    PubMed Central

    Cecchi, G; Colomo, F; Poggesi, C; Tesi, C

    1992-01-01

    1. Apparatus for recording the small tensions developed by electrically stimulated single intact myocytes of frog heart is described. A laser-light optoelectronic transducer was used. The compliance of the force probes was 10-20 nm/nN, with a frequency response of 600-900 Hz in Ringer solution. The myocyte shortening during an ordinary twitch contraction was no greater than 1% of the slack length. The overall sensitivity of the transducer system was 5-10 mV/nN, with a total noise of 0.5-1 nN peak to peak. The experiments were performed at 20-23 degrees C on either atrial or ventricular myocytes at 2.15-2.2 microns sarcomere length, in 1 mM-Ca2+ Ringer solution. 2. Isoprenaline (5 microM), increases in external Ca2+ concentration ([Ca2+]o), and shortening of stimulus interval potentiated the myocyte twitch tension. The dependence of twitch characteristics on these inotropic interventions for all the atrial and ventricular myocytes tested was comparable to that of multicellular preparations under similar experimental conditions. This implies that the enzymatic isolation procedure had not altered the physiological properties of the myocytes. 3. The stimulus interval-tension relation for premature twitches of atrial and ventricular myocytes showed (i) a very steep rising phase in the region of intervals just longer than 0.52 and 0.66 s (the duration of the mechanical refractoriness in atrial or ventricular cells), (ii) a peak, at intervals of 0.7-0.8 s, where the twitch tension was strongly potentiated compared to that of the controls, and (iii) as the stimulus interval was further increased, a progressive return to the control level. The stimulus interval-tension relation for steady-state conditions exhibited similar characteristics. 4. The degree of tension potentiation by isoprenaline was greater in the controls than in the earliest test twitches. The result was that the stimulus interval-tension relations for isoprenaline-treated myocytes showed a gentler rise and

  1. Gene Transfer into Cardiac Myocytes

    PubMed Central

    Lang, Sarah E.; Westfall, Margaret V.

    2016-01-01

    Traditional methods for DNA transfection are often inefficient and toxic for terminally differentiated cells, such as cardiac myocytes. Vector-based gene transfer is an efficient approach for introducing exogenous cDNA into these types of primary cell cultures. In this chapter, separate protocols for adult rat cardiac myocyte isolation and gene transfer with recombinant adenovirus are provided and are routinely utilized for studying the effects of sarcomeric proteins on myofilament function. PMID:25836585

  2. VAMP-1, VAMP-2, and syntaxin-4 regulate ANP release from cardiac myocytes.

    PubMed

    Ferlito, Marcella; Fulton, William B; Zauher, Mohamed A; Marbán, Eduardo; Steenbergen, Charles; Lowenstein, Charles J

    2010-11-01

    ANP is a peptide released by cardiac myocytes that regulates blood pressure and natriuresis. However, the molecular mechanisms controlling ANP release from cardiac myocytes are not defined. We now identify three components of the exocytic machinery that regulate ANP release from atrial myocytes. We found that cardiac myocytes express N-ethylmaleimide sensitive factor (NSF), soluble NSF attachment protein (α-SNAP), and SNAP receptors (SNAREs). Additionally we found that specific SNARE molecules, VAMP-1 and VAMP-2, both co-sediment and co-localize with ANP. Also, one SNARE molecule, syntaxin-4, partially co-sediments and partially co-localizes with ANP. Furthermore, these three SNAREs, syntaxin-4 and VAMP-1 and VAMP-2, form a SNARE complex inside cardiac myocytes. Finally, knockdown of VAMP-1, VAMP-2, or syntaxin-4 blocks regulated release of ANP. In contrast, silencing of VAMP-3 did not have an effect on ANP release. Our data suggest that three specific SNAREs regulate cardiac myocyte exocytosis of ANP. Pathways that modify the exocytic machinery may influence natriuresis and blood pressure.

  3. VAMP-1, VAMP-2 and Syntaxin-4 Regulate ANP Release from Cardiac Myocytes

    PubMed Central

    Ferlito, Marcella; Fulton, William B.; Zauher, A. M.; Marbán, Eduardo; Steenbergen, Charles; Lowenstein, Charles J.

    2010-01-01

    ANP is a peptide released by cardiac myocytes that regulates blood pressure and natriuresis. However, the molecular mechanisms controlling ANP release from cardiac myocytes are not defined. We now identify three components of the exocytic machinery that regulate ANP release from atrial myocytes. We found that cardiac myocytes express N-ethylmaleimide sensitive factor (NSF), soluble NSF attachment protein (α-SNAP), and SNAP receptors (SNAREs). Additionally we found that specific SNARE molecules, VAMP1 and VAMP-2, both co-sediment and co-localize with ANP. Also, one SNARE molecule, syntaxin-4, partially co-sediments and partially co-localizes with ANP. Furthermore, these three SNAREs, sytntaxin-4 and VAMP-1 and VAMP-2 form a SNARE complex inside cardiac myocytes. Finally, knockdown of VAMP1, VAMP-2 or syntaxin-4 blocks regulated release of ANP. In contrast, silencing of VAMP-3 did not have an effect on ANP release. Our data suggest that three specific SNAREs regulate cardiac myocyte exocytosis of ANP. Pathways that modify the exocytic machinery may influence natriuresis and blood pressure. PMID:20801128

  4. Isoform- and tissue-specific regulation of the Ca(2+)-sensitive transcription factor NFAT in cardiac myocytes and heart failure.

    PubMed

    Rinne, Andreas; Kapur, Nidhi; Molkentin, Jeffery D; Pogwizd, Steven M; Bers, Donald M; Banach, Kathrin; Blatter, Lothar A

    2010-06-01

    Nuclear factors of activated T cells (NFATs) are Ca(2+)-sensitive transcription factors that have been implicated in hypertrophy, heart failure (HF), and arrhythmias. Cytosolic NFAT is activated by dephosphorylation by the Ca(2+)-sensitive phosphatase calcineurin, resulting in translocation to the nucleus, which is opposed by kinase activity, rephosphorylation, and nuclear export. Four different NFAT isoforms are expressed in the heart. The activation and regulation of NFAT in adult cardiac myocytes, which may depend on the NFAT isoform and cell type, are not fully understood. This study compared basal localization, import, and export of NFATc1 and NFATc3 in adult atrial and ventricular myocytes to identify isoform- and tissue-specific regulatory mechanisms of NFAT activation under physiological conditions and in HF. NFAT-green fluorescent protein fusion proteins and NFAT immunocytochemistry were used to analyze NFAT regulation in adult cat and rabbit myocytes. NFATc1 displayed basal nuclear localization in atrial and ventricular myocytes, an effect that was attenuated by reducing intracellular Ca(2+) concentration and inhibiting calcineurin, and enhanced by the inhibition of nuclear export. In contrast, NFATc3 was localized to the cytoplasm but could be driven to the nucleus by angiotensin II and endothelin-1 stimulation in atrial, but not ventricular, cells. Inhibition of nuclear export (by leptomycin B) facilitated nuclear localization in both cell types. Ventricular myocytes from HF rabbits showed increased basal nuclear localization of endogenous NFATc3 and reduced responsiveness of NFAT translocation to phenylephrine stimulation. In control myocytes, Ca(2+) overload, leading to spontaneous Ca(2+) waves, induced substantial translocation of NFATc3 to the nucleus. We conclude that the activation of NFAT in adult cardiomyocytes is isoform and tissue specific and is tightly controlled by nuclear export. NFAT is activated in myocytes from HF animals and may be

  5. Optimisation of a generic ionic model of cardiac myocyte electrical activity.

    PubMed

    Guo, Tianruo; Al Abed, Amr; Lovell, Nigel H; Dokos, Socrates

    2013-01-01

    A generic cardiomyocyte ionic model, whose complexity lies between a simple phenomenological formulation and a biophysically detailed ionic membrane current description, is presented. The model provides a user-defined number of ionic currents, employing two-gate Hodgkin-Huxley type kinetics. Its generic nature allows accurate reconstruction of action potential waveforms recorded experimentally from a range of cardiac myocytes. Using a multiobjective optimisation approach, the generic ionic model was optimised to accurately reproduce multiple action potential waveforms recorded from central and peripheral sinoatrial nodes and right atrial and left atrial myocytes from rabbit cardiac tissue preparations, under different electrical stimulus protocols and pharmacological conditions. When fitted simultaneously to multiple datasets, the time course of several physiologically realistic ionic currents could be reconstructed. Model behaviours tend to be well identified when extra experimental information is incorporated into the optimisation.

  6. Cell contact as an independent factor modulating cardiac myocyte hypertrophy and survival in long-term primary culture

    NASA Technical Reports Server (NTRS)

    Clark, W. A.; Decker, M. L.; Behnke-Barclay, M.; Janes, D. M.; Decker, R. S.

    1998-01-01

    Cardiac myocytes maintained in cell culture develop hypertrophy both in response to mechanical loading as well as to receptor-mediated signaling mechanisms. However, it has been shown that the hypertrophic response to these stimuli may be modulated through effects of intercellular contact achieved by maintaining cells at different plating densities. In this study, we show that the myocyte plating density affects not only the hypertrophic response and features of the differentiated phenotype of isolated adult myocytes, but also plays a significant role influencing myocyte survival in vitro. The native rod-shaped phenotype of freshly isolated adult myocytes persists in an environment which minimizes myocyte attachment and spreading on the substratum. However, these conditions are not optimal for long-term maintenance of cultured adult cardiac myocytes. Conditions which promote myocyte attachment and spreading on the substratum, on the other hand, also promote the re-establishment of new intercellular contacts between myocytes. These contacts appear to play a significant role in the development of spontaneous activity, which enhances the redevelopment of highly differentiated contractile, junctional, and sarcoplasmic reticulum structures in the cultured adult cardiomyocyte. Although it has previously been shown that adult cardiac myocytes are typically quiescent in culture, the addition of beta-adrenergic agonists stimulates beating and myocyte hypertrophy, and thereby serves to increase the level of intercellular contact as well. However, in densely-plated cultures with intrinsically high levels of intercellular contact, spontaneous contractile activity develops without the addition of beta-adrenergic agonists. In this study, we compare the function, morphology, and natural history of adult feline cardiomyocytes which have been maintained in cultures with different levels of intercellular contact, with and without the addition of beta-adrenergic agonists

  7. Contractile reserve and calcium regulation are depressed in myocytes from chronically unloaded hearts

    NASA Technical Reports Server (NTRS)

    Ito, Kenta; Nakayama, Masaharu; Hasan, Faisal; Yan, Xinhua; Schneider, Michael D.; Lorell, Beverly H.

    2003-01-01

    BACKGROUND: Chronic cardiac unloading of the normal heart results in the reduction of left ventricular (LV) mass, but effects on myocyte contractile function are not known. METHODS AND RESULTS: Cardiac unloading and reduction in LV mass were induced by heterotopic heart transplantation to the abdominal aorta in isogenic rats. Contractility and [Ca(2+)](i) regulation in LV myocytes were studied at both 2 and 5 weeks after transplantation. Native in situ hearts from recipient animals were used as the controls for all experiments. Contractile function indices in myocytes from 2-week unloaded and native (control) hearts were similar under baseline conditions (0.5 Hz, 1.2 mmol/L [Ca(2+)](o), and 36 degrees C) and in response to stimulation with high [Ca(2+)](o) (range 2.5 to 4.0 mmol/L). In myocytes from 5-week unloaded hearts, there were no differences in fractional cell shortening and peak-systolic [Ca(2+)](i) at baseline; however, time to 50% relengthening and time to 50% decline in [Ca(2+)](i) were prolonged compared with controls. Severe defects in fractional cell shortening and peak-systolic [Ca(2+)](i) were elicited in myocytes from 5-week unloaded hearts in response to high [Ca(2+)](o). However, there were no differences in the contractile response to isoproterenol between myocytes from unloaded and native hearts. In 5-week unloaded hearts, but not in 2-week unloaded hearts, LV protein levels of phospholamban were increased (345% of native heart values). Protein levels of sarcoplasmic reticulum Ca(2+) ATPase and the Na(+)/Ca(2+) exchanger were not changed. CONCLUSIONS: Chronic unloading of the normal heart caused a time-dependent depression of myocyte contractile function, suggesting the potential for impaired performance in states associated with prolonged cardiac atrophy.

  8. Inactivation of calcium current in bull-frog atrial myocytes.

    PubMed Central

    Campbell, D L; Giles, W R; Hume, J R; Shibata, E F

    1988-01-01

    1. A single-microelectrode technique has been used to study the voltage dependence and the kinetics of inactivation and reactivation of a tetrodotoxin-resistant inward current (ICa) in single cells from bull-frog atrium. 2. In most cases the kinetics of both inactivation and reactivation can be well described as a single-exponential process. 3. Several different observations indicate that inactivation of ICa in these cells is controlled by both voltage-dependent and current-dependent processes, as has been demonstrated previously in heart (Kass & Sanguinetti, 1984; Lee, Marban & Tsien, 1985) and in other tissues (Hagiwara & Byerly, 1981; Tsien, 1983; Eckert & Chad, 1984). 4. Evidence in favour of a voltage-dependent inactivation mechanism included: (a) In paired-pulse measurements of steady-state inactivation ('f infinity') a 'conventional' steady-state f infinity vs. membrane potential (Vm) relationship was obtained in the range of membrane potentials from -60 to 0 mV. (b) Increasing [Ca2+]o from 2.5 to 7.5 mM, which resulted in a 2-3-fold increase in ICa, did not produce any significant increase in the amount of inactivation. (c) Using a 'gapped' double-pulse protocol non-monotonic U-shaped inactivation relationships were obtained, i.e. positive to approximately +20 mV some removal of inactivation occurred. However, f never approached a value near 1.00 at very depolarized potentials; it reached a maximum between 0.5 and 0.6. (d) In constant [Ca2+]o and at fixed Vm, the kinetics of ICa inactivation were independent of peak size of ICa. This was demonstrated by: (i) varying the holding potential (-90 to -30 mV), (ii) using paired-pulse 'recovery' protocols, and (iii) partial block by La3+ (1-10 microM) and Cd2+ (0.1 mM). (e) Influx of Ca2+ ions was not an obligatory prerequisite for development of inactivation. In all ionic conditions (Ca2+, Sr2+, Ba2+, Na+-free and Ca2+-free Ringer solutions) currents displayed inactivation phenomena, although the extent and kinetics of inactivation were dependent upon ionic conditions. Outward currents recorded above the reversal potential for ICa exhibited time- and voltage-dependent inactivation, and could be inactivated by brief depolarizing pre-pulses that produced no net inward current flow. Evidence against a possible role of the electrogenic Na+-Ca2+ exchanger in producing inactivation of these outward currents was obtained.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:2855343

  9. Atrial Fibrillation

    MedlinePlus

    ... with the speed or rhythm of the heartbeat. Atrial fibrillation (AF) is the most common type of arrhythmia. The ... the heart's electrical system. Often, people who have AF may not even feel symptoms. But you may ...

  10. Atrial Fibrillation.

    PubMed

    Goralnick, Eric; Bontempo, Laura J

    2015-08-01

    Atrial fibrillation (AF) is a supraventricular tachyarrhythmia that results from the chaotic depolarization of atrial tissue. AF is the most common sustained cardiac dysrhythmia and the most common dysrhythmia diagnosed in US emergency departments. All patients with AF must have their cardioembolic risk assessed, even if sinus rhythm is restored. Novel oral anticoagulants may be considered instead of vitamin K antagonists for anticoagulation in patients with nonvalvular AF. PMID:26226868

  11. Rat cardiac myocyte adenosine transport and metabolism

    SciTech Connect

    Ford, D.A.; Rovetto, M.J.

    1987-01-01

    Based on the importance of myocardial adenosine and adenine nucleotide metabolism, the adenosine salvage pathway in ventricular myocytes was studied. Accurate estimates of transport rates, separate from metabolic fllux, were determined. Adenosine influx was constant between 3 and 60 s. Adenosine metabolism maintained intracellular adenosine concentrations < 10% of the extracellular adenosine concentrations and thus unidirectional influx could be measured. Myocytes transported adenosine via saturable and nonsaturable processes. A minimum estimate of the V/sub max/ of myocytic adenosine kinase indicated the saturable component of adenosine influx was independent of adenosine kinase activity. Saturable transport was inhibited by nitrobenzylthioinosine and verapamil. Extracellular adenosine taken up myocytes was rapidly phosphorylated to adenine taken up by myocytes was rapidly phosphorylated to adenine nucleotides. Not all extracellular adenosine, though, was phosphorylated on entering myocytes, since free, as opposed to protein-bound, intracellular adenosine was detected after digitonin extraction of cells in the presence of 1 mM ethylene-diaminetetraacetic acid.

  12. Protective role of heme oxygenase-1 in atrial remodeling.

    PubMed

    Yeh, Yung-Hsin; Hsu, Lung-An; Chen, Ying-Hwa; Kuo, Chi-Tai; Chang, Gwo-Jyh; Chen, Wei-Jan

    2016-09-01

    Structural and electrical remodeling in the atrium constitutes the main feature of atrial fibrillation (AF), which is characterized by increased oxidative stress. Heme oxygenase-1 (HO-1) is a potent anti-oxidant system that may provide protection against various oxidative stress-related diseases. The aim of this study is to investigate whether HO-1 has a protective effect on AF-related remodeling. Cultured atrium-derived myocytes (HL-1 cell line) were used to evaluate tachypacing-induced oxidative stress, structural, and electrical remodeling. Transforming growth factor-β (TGF-β) was utilized to assess collagen (a main fibrosis-related protein) expression in atrial fibroblasts. Tachypacing in HL-1 myocytes and treatment of atrial fibroblasts with TGF-β enhanced the expression of HO-1, both of which were mediated by the activation of nuclear factor erythroid-2-related factor 2. Over-expression of HO-1 in HL-1 cells attenuated tachypacing-induced oxidative stress, myofibril degradation, down-regulation of L-type calcium channel, and shortening of action potential duration. Furthermore, HO-1 over-expression in atrial fibroblasts blocked the up-regulation of collagen by TGF-β, implicating a protective role of HO-1 in structural and electrical remodeling in the atrium. In vivo, HO-1(-/-) mice exhibited a higher degree of oxidative stress, myofibril degradation, and collagen deposit in their atria than wild-type mice. Moreover, burst atrial pacing induced a greater susceptibility to AF in HO-1(-/-) mice than in wild-type mice. In conclusion, a negative-feedback regulation of HO-1 in activated atrial myocytes and fibroblasts may provide protection against AF-related remodeling and AF development. PMID:27562817

  13. Modeling the isolated cardiac myocyte.

    PubMed

    Puglisi, Jose L; Wang, Fei; Bers, Donald M

    2004-01-01

    Computer modeling of cardiac myocytes has flourished in recent years. Models have evolved from mathematical descriptions of ionic channels alone to more sophisticated formulations that include calcium transport mechanisms, ATP production and metabolic pathways. The increased complexity is fueled by the new data available in the field. The continuous production of experimental data has led to the evolution of increasingly refined descriptions of the phenomena by modelers. Integrating the numerous systems involved in cardiac myocyte homeostasis makes the use of computer models necessary due to the unreliability of intuitive approaches. However the complexity of the model should not imply a cumbersome operation of the program. As with any tool, computer models have to be easy to operate or their strength will be diminished and potential users will not benefit fully from them. The contribution of the computer modeler to their respective biological fields will be more successful and enduring if modelers devote sufficient time to implement their equations into a model with user-friendly characteristics. PMID:15142742

  14. Arrhythmias, elicited by catecholamines and serotonin, vanish in human chronic atrial fibrillation.

    PubMed

    Christ, Torsten; Rozmaritsa, Nadiia; Engel, Andreas; Berk, Emanuel; Knaut, Michael; Metzner, Katharina; Canteras, Manuel; Ravens, Ursula; Kaumann, Alberto

    2014-07-29

    Atrial fibrillation (AF) is the most common heart rhythm disorder. Transient postoperative AF can be elicited by high sympathetic nervous system activity. Catecholamines and serotonin cause arrhythmias in atrial trabeculae from patients with sinus rhythm (SR), but whether these arrhythmias occur in patients with chronic AF is unknown. We compared the incidence of arrhythmic contractions caused by norepinephrine, epinephrine, serotonin, and forskolin in atrial trabeculae from patients with SR and patients with AF. In the patients with AF, arrhythmias were markedly reduced for the agonists and abolished for forskolin, whereas maximum inotropic responses were markedly blunted only for serotonin. Serotonin and forskolin produced spontaneous diastolic Ca(2+) releases in atrial myocytes from the patients with SR that were abolished or reduced in myocytes from the patients with AF. For matching L-type Ca(2+)-current (ICa,L) responses, serotonin required and produced ∼ 100-fold less cAMP/PKA at the Ca(2+) channel domain compared with the catecholamines and forskolin. Norepinephrine-evoked ICa,L responses were decreased by inhibition of Ca(2+)/calmodulin-dependent kinase II (CaMKII) in myocytes from patients with SR, but not in those from patients with AF. Agonist-evoked phosphorylation by CaMKII at phospholamban (Thr-17), but not of ryanodine2 (Ser-2814), was reduced in trabeculae from patients with AF. The decreased CaMKII activity may contribute to the blunting of agonist-evoked arrhythmias in the atrial myocardium of patients with AF. PMID:25024212

  15. Ca2+ Release Events in Cardiac Myocytes Up Close: Insights from Fast Confocal Imaging

    PubMed Central

    Shkryl, Vyacheslav M.; Blatter, Lothar A.

    2013-01-01

    The spatio-temporal properties of Ca2+ transients during excitation-contraction coupling and elementary Ca2+ release events (Ca2+ sparks) were studied in atrial and ventricular myocytes with ultra-fast confocal microscopy using a Zeiss LSM 5 LIVE system that allows sampling rates of up to 60 kHz. Ca2+ sparks which originated from subsarcolemmal junctional sarcoplasmic reticulum (j-SR) release sites in atrial myocytes were anisotropic and elongated in the longitudinal direction of the cell. Ca2+ sparks in atrial cells originating from non-junctional SR and in ventricular myocytes were symmetrical. Ca2+ spark recording in line scan mode at 40,000 lines/s uncovered step-like increases of [Ca2+]i. 2-D imaging of Ca2+ transients revealed an asynchronous activation of release sites and allowed the sequential recording of Ca2+ entry through surface membrane Ca2+ channels and subsequent activation of Ca2+-induced Ca2+ release. With a latency of 2.5 ms after application of an electrical stimulus, Ca2+ entry could be detected that was followed by SR Ca2+ release after an additional 3 ms delay. Maximum Ca2+ release was observed 4 ms after the beginning of release. The timing of Ca2+ entry and release was confirmed by simultaneous [Ca2+]i and membrane current measurements using the whole cell voltage-clamp technique. In atrial cells activation of discrete individual release sites of the j-SR led to spatially restricted Ca2+ release events that fused into a peripheral ring of elevated [Ca2+]i that subsequently propagated in a wave-like fashion towards the center of the cell. In ventricular myocytes asynchronous Ca2+ release signals from discrete sites with no preferential subcellular location preceded the whole-cell Ca2+ transient. In summary, ultra-fast confocal imaging allows investigation of Ca2+ signals with a time resolution similar to patch clamp technique, however in a less invasive fashion. PMID:23637847

  16. Engineering design of a cardiac myocyte

    NASA Astrophysics Data System (ADS)

    Adams, W. J.; Pong, T.; Geisse, N. A.; Sheehy, S. P.; Diop-Frimpong, B.; Parker, K. K.

    2007-04-01

    We describe a design algorithm to build a cardiac myocyte with specific spatial dimensions and physiological function. Using a computational model of a cardiac muscle cell, we modeled calcium (Ca2+) wave dynamics in a cardiac myocyte with controlled spatial dimensions. The modeled myocyte was replicated in vitro when primary neonate rat ventricular myocytes were cultured on micropatterned substrates. The myocytes remodel to conform to the two dimensional boundary conditions and assume the shape of the printed extracellular matrix island. Mechanical perturbation of the myocyte with an atomic force microscope results in calcium-induced calcium release from intracellular stores and the propagation of a Ca2+ wave, as indicated by high speed video microscopy using fluorescent indicators of intracellular Ca2+. Analysis and comparison of the measured wavefront dynamics with those simulated in the computer model reveal that the engineered myocyte behaves as predicted by the model. These results are important because they represent the use of computer modeling, computer-aided design, and physiological experiments to design and validate the performance of engineered cells. The ability to successfully engineer biological cells and tissues for assays or therapeutic implants will require design algorithms and tools for quality and regulatory assurance.

  17. Redox signaling in cardiac myocytes

    PubMed Central

    Santos, Celio X.C.; Anilkumar, Narayana; Zhang, Min; Brewer, Alison C.; Shah, Ajay M.

    2011-01-01

    The heart has complex mechanisms that facilitate the maintenance of an oxygen supply–demand balance necessary for its contractile function in response to physiological fluctuations in workload as well as in response to chronic stresses such as hypoxia, ischemia, and overload. Redox-sensitive signaling pathways are centrally involved in many of these homeostatic and stress-response mechanisms. Here, we review the main redox-regulated pathways that are involved in cardiac myocyte excitation–contraction coupling, differentiation, hypertrophy, and stress responses. We discuss specific sources of endogenously generated reactive oxygen species (e.g., mitochondria and NADPH oxidases of the Nox family), the particular pathways and processes that they affect, the role of modulators such as thioredoxin, and the specific molecular mechanisms that are involved—where this knowledge is available. A better understanding of this complex regulatory system may allow the development of more specific therapeutic strategies for heart diseases. PMID:21236334

  18. Atrial fibrillation.

    PubMed

    Essential facts Atrial fibrillation (AF) causes an abnormal, sometimes fast pulse, and is the most common heart rhythm disturbance. It occurs when electrical impulses controlling the heart's natural rhythm lose co-ordination. People with AF have a four or five times higher risk of stroke because it increases the risk of a blood clot forming in the chambers of the heart. The condition is responsible for 22,500 strokes a year in the UK, according to the British Heart Foundation (BHF). PMID:24593083

  19. Atrial fibrillation

    PubMed Central

    Munger, Thomas M.; Wu, Li-Qun; Shen, Win K.

    2014-01-01

    Atrial fibrillation is the most common arrhythmia affecting patients today. Disease prevalence is increasing at an alarming rate worldwide, and is associated with often catastrophic and costly consequences, including heart failure, syncope, dementia, and stroke. Therapies including anticoagulants, anti-arrhythmic medications, devices, and non-pharmacologic procedures in the last 30 years have improved patients' functionality with the disease. Nonetheless, it remains imperative that further research into AF epidemiology, genetics, detection, and treatments continues to push forward rapidly as the worldwide population ages dramatically over the next 20 years. PMID:24474959

  20. Role of ion channels in sepsis-induced atrial tachyarrhythmias in guinea pigs

    PubMed Central

    Aoki, Yuta; Hatakeyama, Noboru; Yamamoto, Seiji; Kinoshita, Hiroyuki; Matsuda, Naoyuki; Hattori, Yuichi; Yamazaki, Mitsuaki

    2012-01-01

    BACKGROUND AND PURPOSE Supraventricular tachyarrhythmias, including atrial fibrillation, are occasionally observed in patients suffering from sepsis. Modulation of cardiac ion channel function and expression by sepsis may have a role in the genesis of tachyarrhythmias. EXPERIMENTAL APPROACH Sepsis was induced by LPS (i.p.; 300 µg·kg−1) in guinea pigs. Membrane potentials and ionic currents were measured in atrial myocytes isolated from guinea pigs 10 h after LPS, using whole cell patch-clamp methods. KEY RESULTS In atrial cells from LPS-treated animals, action potential duration (APD) was significantly shortened. It was associated with a reduced L-type Ca2+ current and an increased delayed rectifier K+ current. These electrophysiological changes were eliminated when NG-nitro-l-arginine methyl ester (l-NAME) or S-ethylisothiourea was given together with LPS. In atrial tissues from LPS-treated animals, Ca2+ channel subunits (Cav1.2 and Cav1.3) decreased and delayed rectifier K+ channel subunits (Kv11.1 and Kv7.1) increased. However, L-NAME treatment did not substantially reverse such changes in atrial expression in LPS-treated animals, with the exception that Kv11.1 subunits returned to control levels. After LPS injection, inducible NOS in atrial tissues was up-regulated, and atrial NO production clearly increased. CONCLUSIONS AND IMPLICATIONS In atrial myocytes from guinea pigs with sepsis, APD was significantly shortened. This may reflect nitration of the ion channels which would alter channel functions, rather than changes in atrial expression of the channels. Shortening of APD could serve as one of the mechanisms underlying atrial tachyarrhythmia in sepsis. PMID:22050008

  1. Electrical consequences of cardiac myocyte: fibroblast coupling.

    PubMed

    McArthur, Lisa; Chilton, Lisa; Smith, Godfrey L; Nicklin, Stuart A

    2015-06-01

    Gap junctions are channels which allow electrical signals to propagate through the heart from the sinoatrial node and through the atria, conduction system and onwards to the ventricles, and hence are essential for co-ordinated cardiac contraction. Twelve connexin (Cx) proteins make up one gap junction channel, of which there are three main subtypes in the heart; Cx40, Cx43 and Cx45. In the cardiac myocyte, gap junctions are present mainly at the intercalated discs between neighbouring myocytes, and assist in rapid electrical conduction throughout the ventricular myocardium. Fibroblasts provide the structural skeleton of the myocardium and fibroblast numbers significantly increase in heart disease. Fibroblasts also express connexins and this may facilitate heterocellular electrical coupling between myocytes and fibroblasts in the setting of cardiac disease. Interestingly, cardiac fibroblasts have been demonstrated to increase Cx43 expression in experimental models of myocardial infarction and functional gap junctions between myocytes and fibroblasts have been reported. Therefore, in the setting of heart disease enhanced cardiac myocyte: fibroblast coupling may influence the electrical activity of the myocyte and contribute to arrhythmias.

  2. Optimisation of Ionic Models to Fit Tissue Action Potentials: Application to 3D Atrial Modelling

    PubMed Central

    Lovell, Nigel H.; Dokos, Socrates

    2013-01-01

    A 3D model of atrial electrical activity has been developed with spatially heterogeneous electrophysiological properties. The atrial geometry, reconstructed from the male Visible Human dataset, included gross anatomical features such as the central and peripheral sinoatrial node (SAN), intra-atrial connections, pulmonary veins, inferior and superior vena cava, and the coronary sinus. Membrane potentials of myocytes from spontaneously active or electrically paced in vitro rabbit cardiac tissue preparations were recorded using intracellular glass microelectrodes. Action potentials of central and peripheral SAN, right and left atrial, and pulmonary vein myocytes were each fitted using a generic ionic model having three phenomenological ionic current components: one time-dependent inward, one time-dependent outward, and one leakage current. To bridge the gap between the single-cell ionic models and the gross electrical behaviour of the 3D whole-atrial model, a simplified 2D tissue disc with heterogeneous regions was optimised to arrive at parameters for each cell type under electrotonic load. Parameters were then incorporated into the 3D atrial model, which as a result exhibited a spontaneously active SAN able to rhythmically excite the atria. The tissue-based optimisation of ionic models and the modelling process outlined are generic and applicable to image-based computer reconstruction and simulation of excitable tissue. PMID:23935704

  3. Cardioprotective Benefits of Adenosine Triphosphate: Sensitive Potassium Channel Opener Diazoxide Are Lost with Administration after the Onset of Stress in Mouse and Human Myocytes

    PubMed Central

    Janjua, M Burhan; Makepeace, Carol M; Anastacio, Melissa M; Schuessler, Richard B; Nichols, Colin G; Lawton, Jennifer S

    2014-01-01

    Background Adenosine triphosphate - sensitive (KATP) potassium channel opener diazoxide (DZX) maintains myocyte volume and contractility during stress via an unknown mechanism when administered at the onset of stress. This study was performed to investigate the cardioprotective potential of DZX when added after the onset of the stresses of hyperkalemic cardioplegia, metabolic inhibition, and hypo osmotic stress. Study Design Isolated mouse ventricular and human atrial myocytes were exposed to control Tyrode’s solution (TYR) for 10–20 min, test solution for 30 min (hypothermic hyperkalemic cardioplegia (CPG), CPG + 100uM diazoxide (CPG+DZX), metabolic inhibition (MI), MI+DZX, mild hypo osmotic stress (0.9T), or 0.9T + DZX) with DZX added after 10 or 20 min stress, followed by 20 min re-exposure to TYR (+/− DZX). Myocyte volume (human + mouse) and contractility (mouse) were compared. Results Mouse and human myocytes demonstrated significant swelling during exposure to CPG, MI, and hypo osmotic stress that was not prevented by DZX when administered either at 10 or 20 min after the onset of stress. Contractility following the stress of CPG in mouse myocytes significantly declined when DZX was administered 20 min after the onset of stress (p<0.05 vs. TYR). Contractility following hypo osmotic stress in mouse myocytes was not altered by the addition of DZX. Conclusions To maintain myocyte volume homeostasis and contractility during stress (hyperkalemic cardioplegia, metabolic inhibition, and hypo osmotic stress), KATP channel opener diazoxide requires administration at the onset of stress in this isolated myocyte model. These data have potential implications for any future clinical application of diazoxide. PMID:25158912

  4. Effect of ethanol and acetaldehyde at clinically relevant concentrations on atrial inward rectifier potassium current IK1: separate and combined effect.

    PubMed

    Horakova, Z; Matejovic, P; Pasek, M; Hosek, J; Simurdova, M; Simurda, J; Bebarova, M

    2016-06-01

    Atrial fibrillation is the most common arrhythmia at alcohol consumption. Its pathogenesis is complex, at least partly related to changes of cardiac inward rectifier potassium currents including IK1. Both ethanol and acetaldehyde have been demonstrated to considerably modify IK1 in rat ventricular myocytes. However, analogical data on the atrial IK1 are lacking. The present study aimed to analyse IK1 changes induced by ethanol and acetyldehyde in atrial myocytes. The experiments were performed by the whole cell patch-clamp technique at 23 ± 1°C on enzymatically isolated rat and guinea-pig atrial myocytes as well as on expressed human Kir2.3 channels. Ethanol (8 - 80 mM) caused a dual effect on the atrial IK1 showing the steady-state activation in some cells but inhibition in others in agreement with the ventricular data; on average, the activation was observed (at 20 mM by 4.3 and 4.5% in rat and guinea-pig atrial myocytes, respectively). The effect slightly increased with depolarization above -60 mV. In contrast, the current through human Kir2.3 channels (prevailing atrial IK1 subunit) was inhibited in all measured cells. Unlike ethanol, acetaldehyde (3 μM) markedly inhibited the rat atrial IK1 (by 15.1%) in a voltage-independent manner, comparably to the rat ventricular IK1. The concurrent application of ethanol (20 mM) and acetaldehyde (3 μM) resulted in the steady-state IK1 activation by 2.1% on average. We conclude that ethanol and even more acetaldehyde affected IK1 at clinically relevant concentrations if applied separately. Their combined effect did not significantly differ from the effect of ethanol alone. PMID:27511995

  5. Atrial Electrophysiological Remodeling and Fibrillation in Heart Failure

    PubMed Central

    Pandit, Sandeep V.; Workman, Antony J.

    2016-01-01

    Heart failure (HF) causes complex, chronic changes in atrial structure and function, which can cause substantial electrophysiological remodeling and predispose the individual to atrial fibrillation (AF). Pharmacological treatments for preventing AF in patients with HF are limited. Improved understanding of the atrial electrical and ionic/molecular mechanisms that promote AF in these patients could lead to the identification of novel therapeutic targets. Animal models of HF have identified numerous changes in atrial ion currents, intracellular calcium handling, action potential waveform and conduction, as well as expression and signaling of associated proteins. These studies have shown that the pattern of electrophysiological remodeling likely depends on the duration of HF, the underlying cardiac pathology, and the species studied. In atrial myocytes and tissues obtained from patients with HF or left ventricular systolic dysfunction, the data on changes in ion currents and action potentials are largely equivocal, probably owing mainly to difficulties in controlling for the confounding influences of multiple variables, such as patient’s age, sex, disease history, and drug treatments, as well as the technical challenges in obtaining such data. In this review, we provide a summary and comparison of the main animal and human electrophysiological studies to date, with the aim of highlighting the consistencies in some of the remodeling patterns, as well as identifying areas of contention and gaps in the knowledge, which warrant further investigation. PMID:27812293

  6. Integrative modeling of the cardiac ventricular myocyte

    PubMed Central

    Winslow, Raimond L.; Cortassa, Sonia; O'Rourke, Brian; Hashambhoy, Yasmin L.; Rice, John Jeremy; Greenstein, Joseph L.

    2011-01-01

    Cardiac electrophysiology is a discipline with a rich 50-year history of experimental research coupled with integrative modeling which has enabled us to achieve a quantitative understanding of the relationships between molecular function and the integrated behavior of the cardiac myocyte in health and disease. In this paper, we review the development of integrative computational models of the cardiac myocyte. We begin with a historical overview of key cardiac cell models that helped shape the field. We then narrow our focus to models of the cardiac ventricular myocyte and describe these models in the context of their subcellular functional systems including dynamic models of voltage-gated ion channels, mitochondrial energy production, ATP-dependent and electrogenic membrane transporters, intracellular Ca dynamics, mechanical contraction, and regulatory signal transduction pathways. We describe key advances and limitations of the models as well as point to new directions for future modeling research. PMID:20865780

  7. Novel Protective Role of Endogenous Cardiac Myocyte P2X4 Receptors in Heart Failure

    PubMed Central

    Yang, Tiehong; Shen, Jian-bing; Yang, Ronghua; Redden, John; Dodge-Kafka, Kimberly; Grady, James; Jacobson, Kenneth A.; Liang, Bruce T.

    2014-01-01

    Background Heart failure (HF), despite continuing progress, remains a leading cause of mortality and morbidity. P2X4 receptors (P2X4R) have emerged as potentially important molecules in regulating cardiac function and as potential targets for HF therapy. Transgenic P2X4R overexpression can protect against HF, but this does not explain the role of native cardiac P2X4R. Our goal is to define the physiological role of endogenous cardiac myocyte P2X4R under basal conditions and during HF induced by myocardial infarction or pressure overload. Methods and Results Mice established with conditional cardiac-specific P2X4R knockout were subjected to left anterior descending coronary artery ligation–induced postinfarct or transverse aorta constriction–induced pressure overload HF. Knockout cardiac myocytes did not show P2X4R by immunoblotting or by any response to the P2X4R-specific allosteric enhancer ivermectin. Knockout hearts showed normal basal cardiac function but depressed contractile performance in postinfarct and pressure overload models of HF by in vivo echocardiography and ex vivo isolated working heart parameters. P2X4R coimmunoprecipitated and colocalized with nitric oxide synthase 3 (eNOS) in wild-type cardiac myocytes. Mice with cardiac-specific P2X4R overexpression had increased S-nitrosylation, cyclic GMP, NO formation, and were protected from postinfarct and pressure overload HF. Inhibitor of eNOS, L-N5-(1-iminoethyl)ornithine hydrochloride, blocked the salutary effect of cardiac P2X4R overexpression in postinfarct and pressure overload HF as did eNOS knockout. Conclusions This study establishes a new protective role for endogenous cardiac myocyte P2X4R in HF and is the first to demonstrate a physical interaction between the myocyte receptor and eNOS, a mediator of HF protection. PMID:24622244

  8. Second-harmonic microscopy of unstained living cardiac myocytes: measurements of sarcomere length with 20-nm accuracy.

    PubMed

    Boulesteix, Thierry; Beaurepaire, Emmanuel; Sauviat, Martin-Pierre; Schanne-Klein, Marie-Claire

    2004-09-01

    We extend second-harmonic generation (SHG) microscopy to the measurement of sarcomere length in unstained living cardiac myocytes with 20-nm accuracy. We quantify individual sarcomere shortening in the presence of saxitoxin and find that it is in agreement with mechanical measurements of atrial tissue contracture. This functional application of SHG microscopy is generally applicable to quantify the physiological effects of drugs on contractile tissue. Our data also suggest that packed myosin heads in sarcomere thick filaments are responsible for the large second-harmonic endogenous signal in muscle tissue. PMID:15455770

  9. Mechanically induced orientation of adult rat cardiac myocytes in vitro

    NASA Technical Reports Server (NTRS)

    Samuel, J.-L.; Vandenburgh, H. H.

    1990-01-01

    The present study describes the spatial orientation of a population of freshly isolated adult rat cardiac myocytes using a computerized mechanical cell stimulator device for tissue cultured cells. A continuous unidirectional stretch of the substratum at 60 to 400 microns/min for 120 to 30 min, respectively, during the cell attachment period in a serum-free medium was found to induce a significant threefold increase in the number of rod-shaped myocytes oriented parallel to the direction of movement. The myocytes orient less well with unidirectional substratum stretching after their adhesion to the substratum. Adult myocytes plated onto a substratum undergoing continuous 10-percent stretch-relaxation cycling show no significant change in the myocyte orientation or cytoskeletal organization. In addition to the type of mechanical activity, orientation of rod-shaped myocytes is dependent on the speed of the substratum, the final stretch amplitude, and the timing between initiation of substratum stretching and adhesion of myocytes to the substratum.

  10. Mst1 inhibition rescues β1-adrenergic cardiomyopathy by reducing myocyte necrosis and non-myocyte apoptosis rather than myocyte apoptosis

    PubMed Central

    Lee, Grace J.; Yan, Lin; Vatner, Dorothy E.

    2015-01-01

    It is generally held that inhibition of mammalian sterile 20-like kinase 1 (Mst1) protects the heart through reducing myocyte apoptosis. We determined whether inhibition with a dominant-negative Mst1 (DN-Mst1) would protect against the cardiomyopathy induced by chronic β1-adrenergic receptor (β1-AR) stimulation by preventing myocyte apoptosis. DN-Mst1 mice were mated with β1-AR transgenic (Tg) mice and followed for 20 months. β1-AR Tg mice developed cardiomyopathy as they aged, as reflected by premature mortality and depressed cardiac function, which were rescued in β1-AR × DN-Mst1 bigenic mice. Surprisingly, myocyte apoptosis did not significantly decrease with Mst1 inhibition. Instead, Mst1 inhibition predominantly reduced non-myocyte apoptosis, e.g., fibroblasts, macrophages, neutrophils and endothelial cells. Fibrosis in the hearts with cardiomyopathy increased fivefold and this increase was nearly abolished in the bigenic mice with Mst1 inhibition. Regression analysis showed no correlation between myocyte apoptosis and cardiac function or myocyte number, whereas the latter two correlated significantly, p < 0.05, with fibrosis, which generally results from necrosis. To examine the role of myocyte necrosis, chronic β-AR stimulation with isoproterenol was induced for 24 h and myocyte necrosis was assessed by 1 % Evans blue dye. Compared to WT, DN-Mst1 mice showed significant inhibition, p < 0.05, of myocyte necrosis. We confirmed this result in Mst1-knockout mice, which also showed significant protection, p < 0.05, against myocyte necrosis compared to WT. These data indicate that Mst1 inhibition rescued cardiac fibrosis and myocardial dysfunction in β1-AR cardiomyopathy. However, this did not occur through Mst1 inhibition of myocyte apoptosis but rather by inhibition of cardiomyocyte necrosis and non-myocyte apoptosis, features of Mst1 not considered previously. PMID:25600225

  11. The increasing prevalence of atrial fibrillation among hemodialysis patients.

    PubMed

    Winkelmayer, Wolfgang C; Patrick, Amanda R; Liu, Jun; Brookhart, M Alan; Setoguchi, Soko

    2011-02-01

    A half million Americans have ESRD, which puts them at high risk for cardiovascular disease and poor outcomes. Little is known about the epidemiology of atrial fibrillation among patients with ESRD. We analyzed data from annual cohorts (1992 to 2006) of prevalent hemodialysis patients from the United States Renal Data System. In each cohort, we searched 1 year of medical claims for relevant diagnosis codes to determine the prevalence of atrial fibrillation. Among 2.5 million patient observations, 7.7% had atrial fibrillation, with the prevalence increasing 3-fold from 3.5% (1992) to 10.7% (2006). The number of affected patients increased from 3620 to 23,893 (6.6-fold) during this period. Older age, male gender, and several comorbid conditions were associated with increased risk for atrial fibrillation. Compared with otherwise similar Caucasians, the prevalence of atrial fibrillation rates was substantially lower for blacks, Asians, and Native Americans. One-year mortality was twice as high among hemodialysis patients with atrial fibrillation compared with those without (39% versus 19%), and this increased risk was constant during the 15 years of the study. In conclusion, the prevalence of diagnosed atrial fibrillation among patients receiving hemodialysis in the United States is increasing, varies by race, and remains associated with substantially increased mortality. Identifying potentially modifiable risk factors for incident atrial fibrillation requires further investigation.

  12. Atrial fibrillation.

    PubMed

    Bang, Casper N

    2013-10-01

    Atrial fibrillation (AF) is a common complication after myocardial infarction (MI) and new-onset AF has been demonstrated to be associated with adverse outcome and a large excess risk of death in both MI and aortic stenosis (AS) patients. Prevention of new-onset AF is therefore a potential therapeutic target in AS and MI patients. Lipid-lowering drugs, particularly statins, have anti-inflammatory and antioxidant properties that may prevent AF. Accordingly, statins are recommended as a class IIa recommendation for prevention of new-onset AF after coronary artery bypass grafting (CABG). However, this preventive effect has not been investigated on new-onset AF in asymptomatic patients with AS or a large scale first-time MI patient sample and data in patients not undergoing invasive cardiac interventions are limited. This PhD thesis was conducted at the Heart Centre, Rigshospitalet, Denmark, with the aim to investigate the three aforementioned questions and to add to the existing evidence of AF prevention with statins. This was done using three different settings: 1) a randomized patients sample of 1,873 from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, 2) a register patient sample of 97,499 with first-time MI, and 3) all published studies until beginning of June 2011 examining statin treatment on new-onset and recurrent AF in patients not undergoing cardiac surgery. This thesis revealed that statins did not lower the incidence or the time to new-onset AF in patients with asymptomatic AS. However, statin treatment showed an independently preventive effect on new-onset AF, including type-dependent effect and a trend to dosage-dependent effect. In addition, this thesis showed that good compliance to statin treatment was important to prevent new-onset AF. Finally, the meta-analysis in this PhD thesis showed a preventive effect in the observational studies although this effect was absent in the randomized controlled trials. Based on this PhD thesis

  13. Atrial Septal Defect (For Teens)

    MedlinePlus

    ... I Help a Friend Who Cuts? Atrial Septal Defect KidsHealth > For Teens > Atrial Septal Defect Print A ... Care of Yourself What Is an Atrial Septal Defect? Having a doctor listen to your heart is ...

  14. Organized Atrial Tachycardias after Atrial Fibrillation Ablation

    PubMed Central

    Castrejón-Castrejón, Sergio; Ortega, Marta; Pérez-Silva, Armando; Doiny, David; Estrada, Alejandro; Filgueiras, David; López-Sendón, José L.; Merino, José L.

    2011-01-01

    The efficacy of catheter-based ablation techniques to treat atrial fibrillation is limited not only by recurrences of this arrhythmia but also, and not less importantly, by new-onset organized atrial tachycardias. The incidence of such tachycardias depends on the type and duration of the baseline atrial fibrillation and specially on the ablation technique which was used during the index procedure. It has been repeatedly reported that the more extensive the left atrial surface ablated, the higher the incidence of organized atrial tachycardias. The exact origin of the pathologic substrate of these trachycardias is not fully understood and may result from the interaction between preexistent regions with abnormal electrical properties and the new ones resultant from radiofrequency delivery. From a clinical point of view these atrial tachycardias tend to remit after a variable time but in some cases are responsible for significant symptoms. A precise knowledge of the most frequent types of these arrhythmias, of their mechanisms and components is necessary for a thorough electrophysiologic characterization if a new ablation procedure is required. PMID:21941669

  15. Effect of overexpressed adenylyl cyclase VI on β1- and β2-adrenoceptor responses in adult rat ventricular myocytes

    PubMed Central

    Stark, Joalice C C; Haydock, Stephen F; Foo, Roger; Brown, Morris J; Harding, Sian E

    2004-01-01

    Adenylyl cyclase VI (ACVI) is one of the most abundantly expressed β adrenergic receptor (βAR)-coupled cyclases responsible for cyclic AMP (cAMP) production within the mammalian myocardium. We investigated the role of ACVI in the regulation of cardiomyocyte contractility and whether it is functionally coupled with β1 adrenergic receptor (β1AR). Recombinant adenoviruses were generated for ACVI and for antisense to ACVI (AS). Adult rat ventricular myocytes were transfected with ACVI virus, AS or both (SAS). Adenovirus for green fluorescent protein (GFP) served as control. Myocyte contraction amplitudes (% shortening) and relaxation times (R50) were analysed. ACVI function was determined using cAMP assays. ACVI-transfected cells demonstrated a strong 139 kDa ACVI protein band compared to controls. ACVI myocytes had higher steady-state intracellular cAMP levels than GFP myocytes when unstimulated (GFP vs ACVI=6.60±0.98 vs 14.2±2.1 fmol cAMP/viable cell, n=4, P<0.05) and in the presence of 1 μM isoprenaline or 10 μM forskolin. ACVI myocytes had increased basal contraction (% shortening: GFP vs ACVI: 1.90±1.36 vs 3.91±2.29, P<0.0001) and decreased basal R50 (GFP vs ACVI: 62.6±24.2 ms (n=50) vs 45.0±17.2 ms (n=248), P<0.0001). ACVI myocyte responses were increased for forskolin (Emax: GFP=6.70±1.59 (n=6); ACVI=9.06±0.69 (n=14), P<0.01) but not isoprenaline. ACVI myocyte responses were increased (Emax: GFP vs ACVI=3.16±0.77 vs 5.10±0.60, P<0.0001) to xamoterol (a partial β1AR-selective agonist) under β2AR blockade (+50 nM ICI 118, 551). AS decreased both control and ACVI-stimulated xamoterol responses (Emax: AS=2.59±1.42, SAS=1.38±0.5). ACVI response was not mimicked by IBMX. Conversely, response through β2 adrenergic receptor (β2AR) was decreased in ACVI myocytes. In conclusion, ACVI overexpression constitutively increases myocyte contraction amplitudes by raising cAMP levels. Native ACVI did not contribute to basal cAMP production or contraction

  16. Automatic quantitative analysis of t-tubule organization in cardiac myocytes using ImageJ.

    PubMed

    Pasqualin, Côme; Gannier, François; Malécot, Claire O; Bredeloux, Pierre; Maupoil, Véronique

    2015-02-01

    The transverse tubule system in mammalian striated muscle is highly organized and contributes to optimal and homogeneous contraction. Diverse pathologies such as heart failure and atrial fibrillation include disorganization of t-tubules and contractile dysfunction. Few tools are available for the quantification of the organization of the t-tubule system. We developed a plugin for the ImageJ/Fiji image analysis platform developed by the National Institutes of Health. This plugin (TTorg) analyzes raw confocal microscopy images. Analysis options include the whole image, specific regions of the image (cropping), and z-axis analysis of the same image. Batch analysis of a series of images with identical criteria is also one of the options. There is no need to either reorientate any specimen to the horizontal or to do a thresholding of the image to perform analysis. TTorg includes a synthetic "myocyte-like" image generator to test the plugin's efficiency in the user's own experimental conditions. This plugin was validated on synthetic images for different simulated cell characteristics and acquisition parameters. TTorg was able to detect significant differences between the organization of the t-tubule systems in experimental data of mouse ventricular myocytes isolated from wild-type and dystrophin-deficient mice. TTorg is freely distributed, and its source code is available. It provides a reliable, easy-to-use, automatic, and unbiased measurement of t-tubule organization in a wide variety of experimental conditions.

  17. Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation.

    PubMed

    Hodgson-Zingman, Denice M; Karst, Margaret L; Zingman, Leonid V; Heublein, Denise M; Darbar, Dawood; Herron, Kathleen J; Ballew, Jeffrey D; de Andrade, Mariza; Burnett, John C; Olson, Timothy M

    2008-07-10

    Atrial fibrillation is a common arrhythmia that is hereditary in a small subgroup of patients. In a family with 11 clinically affected members, we mapped an atrial fibrillation locus to chromosome 1p36-p35 and identified a heterozygous frameshift mutation in the gene encoding atrial natriuretic peptide. Circulating chimeric atrial natriuretic peptide (ANP) was detected in high concentration in subjects with the mutation, and shortened atrial action potentials were seen in an isolated heart model, creating a possible substrate for atrial fibrillation. This report implicates perturbation of the atrial natriuretic peptide-cyclic guanosine monophosphate (cGMP) pathway in cardiac electrical instability. PMID:18614783

  18. Atrial mass: a myxoma?

    PubMed

    Chatzis, Andrew C; Kostopanagiotou, Kostas; Kousi, Theofili; Mitropoulos, Fotios

    2016-08-01

    A middle-aged woman with a history of resected colorectal cancer and receiving chemotherapy presented with a right atrial mass and the provisional diagnosis of myxoma supported by echocardiography, computed tomography, and magnetic resonance imaging. Successful surgical removal revealed organized thrombus instead. Atrial thrombus may be mistaken for myxoma and long-term intracardiac indwelling catheters can be thrombogenic. PMID:27525099

  19. Electrophysiological Mechanisms of Atrial Flutter

    PubMed Central

    Tai, Ching- Tai; Chen, Shin-Ann

    2006-01-01

    Atrial flutter (AFL) is a common arrhythmia in clinical practice. Several experimental models such as tricuspid regurgitation model, tricuspid ring model, sterile pericarditis model and atrial crush injury model have provided important information about reentrant circuit and can test the effect of antiarrhythmic drugs. Human atrial flutter has typical and atypical forms. Typical atrial flutter rotates around tricuspid annulus and uses the crista terminalis and sometimes sinus venosa as the boundary. The IVC-tricuspid isthmus is a slow conduction zone and the target of radiofrequency ablation. Atypical atrial flutter may arise from the right or left atrium. Right atrial flutter includes upper loop reentry, free wall reentry and figure of eight reentry. Left atrial flutter includes mitral annular atrial flutter, pulmonary vein-related atrial flutter and left septal atrial flutter. Radiofrequency ablation of the isthmus between the boundaries can eliminate these arrhythmias. PMID:16943903

  20. Lifestyle and atrial fibrillation.

    PubMed

    Mattioli, Anna Vittoria

    2011-07-01

    Lifestyle factors, in particular dietary intake, have been recognized as important, modifiable risk factors for cardiovascular disease. Consuming a heart-healthy diet lowers the individual's risk for cardiovascular disease. Data on the relationship between lifestyle and atrial fibrillation are controversial; however, the strong association between obesity, atrial/ventricular dysfunction and a nonhealthy lifestyle and atrial fibrillation, suggests that a correction of nutritional habits could prevent the development of arrhythmias through a reduction of underlying cardiac diseases. Today, the Mediterranean diet is considered one of the most effective in terms of its prevention of cardiovascular disease.

  1. Atrial Fibrillation Medications

    MedlinePlus

    ... think you are pregnant If you notice red, dark brown or black urine or stools If you ... Fibrillation • Introduction • What is Atrial Fibrillation? • Why AFib Matters • Understand your Risk for AFib Children • Symptoms of ...

  2. Atrial fibrillation or flutter

    MedlinePlus

    ... the mitral valve) Hypertension Medicines Overactive thyroid gland ( hyperthyroidism ) Pericarditis Sick sinus syndrome Symptoms You may not ... procedures Heart attack Heart pacemaker High blood pressure Hyperthyroidism Pericarditis Pulse Stable angina Stroke Patient Instructions Atrial ...

  3. What Is Atrial Fibrillation?

    MedlinePlus

    ... regular beat. Certain cells in your heart make electric signals that cause the heart to contract and ... read your ECG to find out if the electric signals are normal. In atrial fibrillation (AFib), the ...

  4. Patterning, Prestress, and Peeling Dynamics of Myocytes

    PubMed Central

    Griffin, Maureen A.; Engler, Adam J.; Barber, Thomas A.; Healy, Kevin E.; Sweeney, H. Lee; Discher, Dennis E.

    2004-01-01

    As typical anchorage-dependent cells myocytes must balance contractility against adequate adhesion. Skeletal myotubes grown as isolated strips from myoblasts on micropatterned glass exhibited spontaneous peeling after one end of the myotube was mechanically detached. Such results indicate the development of a prestress in the cells. To assess this prestress and study the dynamic adhesion strength of single myocytes, the shear stress of fluid aspirated into a large-bore micropipette was then used to forcibly peel myotubes. The velocity at which cells peeled from the surface, Vpeel, was measured as a continuously increasing function of the imposed tension, Tpeel, which ranges from ∼0 to 50 nN/μm. For each cell, peeling proved highly heterogeneous, with Vpeel fluctuating between 0 μm/s (∼80% of time) and ∼10 μm/s. Parallel studies of smooth muscle cells expressing GFP-paxillin also exhibited a discontinuous peeling in which focal adhesions fractured above sites of strong attachment (when pressure peeled using a small-bore pipette). The peeling approaches described here lend insight into the contractile-adhesion balance and can be used to study the real-time dynamics of stressed adhesions through both physical detection and the use of GFP markers; the methods should prove useful in comparing normal versus dystrophic muscle cells. PMID:14747355

  5. Myocyte proliferation in the developing heart

    PubMed Central

    Sedmera, David; Thompson, Robert P.

    2012-01-01

    Regulation of organ growth is critical during embryogenesis. At the cellular level, mechanisms controlling the size of individual embryonic organs include cell proliferation, differentiation, migration, and attrition through cell death. All these mechanisms play a role in cardiac morphogenesis, but experimental studies have shown that the major determinant of cardiac size during prenatal development is myocyte proliferation. As this proliferative capacity becomes severely restricted after birth, the number of cell divisions that occur during embryogenesis limits the growth potential of the postnatal heart. We summarize here current knowledge concerning regional control of myocyte proliferation as related to cardiac morphogenesis and dysmorphogenesis. There are significant spatial and temporal differences in rates of cell division, peaking during the pre-septation period and then gradually decreasing towards birth. Analysis of regional rates of proliferation helps to explain the mechanics of ventricular septation, chamber morphogenesis, and the development of the cardiac conduction system. Proliferation rates are influenced by hemodynamic loading, and transduced by autocrine and paracrine signaling via growth factors. Understanding the biological response of the developing heart to such factors and physical forces will further our progress in engineering artificial myocardial tissues for heart repair and designing optimal treatment strategies for congenital heart disease. PMID:21538685

  6. Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial

    PubMed Central

    Breithardt, Günter; Baumgartner, Helmut; Berkowitz, Scott D.; Hellkamp, Anne S.; Piccini, Jonathan P.; Stevens, Susanna R.; Lokhnygina, Yuliya; Patel, Manesh R.; Halperin, Jonathan L.; Singer, Daniel E.; Hankey, Graeme J.; Hacke, Werner; Becker, Richard C.; Nessel, Christopher C.; Mahaffey, Kenneth W.; Fox, Keith A. A.; Califf, Robert M.

    2014-01-01

    Aims We investigated clinical characteristics and outcomes of patients with significant valvular disease (SVD) in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial. Methods and results ROCKET AF excluded patients with mitral stenosis or artificial valve prostheses. We used Cox regression to adjust comparisons for potential confounders. Among 14 171 patients, 2003 (14.1%) had SVD; they were older and had more comorbidities than patients without SVD. The rate of stroke or systemic embolism with rivaroxaban vs. warfarin was consistent among patients with SVD [2.01 vs. 2.43%; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.55–1.27] and without SVD (1.96 vs. 2.22%; HR 0.89, 95% CI 0.75–1.07; interaction P = 0.76). However, rates of major and non-major clinically relevant bleeding with rivaroxaban vs. warfarin were higher in patients with SVD (19.8% rivaroxaban vs. 16.8% warfarin; HR 1.25, 95% CI 1.05–1.49) vs. those without (14.2% rivaroxaban vs. 14.1% warfarin; HR 1.01, 95% CI 0.94–1.10; interaction P = 0.034), even when controlling for risk factors and potential confounders. In intracranial haemorrhage, there was no interaction between patients with and without SVD where the overall rate was lower among those randomized to rivaroxaban. Conclusions Many patients with ‘non-valvular atrial fibrillation’ have significant valve lesions. Their risk of stroke is similar to that of patients without SVD after controlling for stroke risk factors. Efficacy of rivaroxaban vs. warfarin was similar in patients with and without SVD; however, the observed risk of bleeding was higher with rivaroxaban in patients with SVD but was the same among those without SVD. Atrial fibrillation patients with and without SVD experience the same stroke-preventive benefit of oral anticoagulants. PMID:25148838

  7. Perturbed atrial calcium handling in an ovine model of heart failure: potential roles for reductions in the L-type calcium current.

    PubMed

    Clarke, Jessica D; Caldwell, Jessica L; Horn, Margaux A; Bode, Elizabeth F; Richards, Mark A; Hall, Mark C S; Graham, Helen K; Briston, Sarah J; Greensmith, David J; Eisner, David A; Dibb, Katharine M; Trafford, Andrew W

    2015-02-01

    Heart failure (HF) is commonly associated with reduced cardiac output and an increased risk of atrial arrhythmias particularly during β-adrenergic stimulation. The aim of the present study was to determine how HF alters systolic Ca(2+) and the response to β-adrenergic (β-AR) stimulation in atrial myocytes. HF was induced in sheep by ventricular tachypacing and changes in intracellular Ca(2+) concentration studied in single left atrial myocytes under voltage and current clamp conditions. The following were all reduced in HF atrial myocytes; Ca(2+) transient amplitude (by 46% in current clamped and 28% in voltage clamped cells), SR dependent rate of Ca(2+) removal (kSR, by 32%), L-type Ca(2+) current density (by 36%) and action potential duration (APD90 by 22%). However, in HF SR Ca(2+) content was increased (by 19%) when measured under voltage-clamp stimulation. Inhibiting the L-type Ca(2+) current (ICa-L) in control cells reproduced both the decrease in Ca(2+) transient amplitude and increase of SR Ca(2+) content observed in voltage-clamped HF cells. During β-AR stimulation Ca(2+) transient amplitude was the same in control and HF cells. However, ICa-L remained less in HF than control cells whilst SR Ca(2+) content was highest in HF cells during β-AR stimulation. The decrease in ICa-L that occurs in HF atrial myocytes appears to underpin the decreased Ca(2+) transient amplitude and increased SR Ca(2+) content observed in voltage-clamped cells. PMID:25463272

  8. Block of Na(+)/Ca(2+) exchanger by SEA0400 in human right atrial preparations from patients in sinus rhythm and in atrial fibrillation.

    PubMed

    Christ, Torsten; Kovács, Peter P; Acsai, Karoly; Knaut, Michael; Eschenhagen, Thomas; Jost, Norbert; Varró, András; Wettwer, Erich; Ravens, Ursula

    2016-10-01

    The Na(+)/Ca(2+) exchanger (NCX) plays a major role in myocardial Ca(2+) homoeostasis, but is also considered to contribute to the electrical instability and contractile dysfunction in chronic atrial fibrillation (AF). Here we have investigated the effects of the selective NCX blocker SEA0400 in human right atrial cardiomyocytes from patients in sinus rhythm (SR) and AF in order to obtain electrophysiological evidence for putative antiarrhythmic activity of this new class of drugs. Action potentials were measured in right atrial trabeculae using conventional microelectrodes. Human myocytes were enzymatically isolated. Rat atrial and ventricular cardiomyocytes were used for comparison. Using perforated-patch, NCX was measured as Ni(2+)-sensitive current during ramp pulses. In ruptured-patch experiments, NCX current was activated by changing the extracellular Ca(2+) concentration from 0 to 1mM in Na(+)-free bath solution (100mM Na(+) intracellular, "Hilgemann protocol"). Although SEA0400 was effective in rat cardiomyocytes, 10µM did not influence action potentials and contractility, neither in SR nor AF. SEA0400 (10μM) also failed to affect human atrial NCX current measured with perforated patch. With the "Hilgemann protocol" SEA0400 concentration-dependently suppressed human atrial NCX current, and its amplitude was larger in AF than in SR cardiomyocytes. Our results confirm higher NCX activity in AF than SR. SEA0400 fails to block Ni(2+)-sensitive current in human atrial cells unless unphysiological conditions are used. We speculate that block of NCX with SEA0400 depends on intracellular Na(+) concentration.

  9. Modeling gender effects on electrical activity of single ventricular myocytes.

    PubMed

    Cieniawa, Jerzy; Baszak, Jacek; Olchowik, Grazyna; Widomska, Justyna

    2013-09-01

    In this study we investigate the mechanisms underlying gender differences in the generation of arrhythmias in the long QT and Brugada syndromes. Simulations were conducted at the single myocyte level using a detailed mathematical model of human ventricular myocytes. Given the scarce human data on the gender-related differences in single cardiac cells, we assumed gender-related differences in five ionic-current systems: fast sodium current (INa), slowly inactivating late sodium current (INal), transient outward potassium current (Ito), slow delayed rectifier potassium current (IKs), and calcium current through the L-type channel (ICa(L)), based on experimental results obtained in canine myocytes. Our modeling results suggest that in left ventricular myocytes, enhanced INal under conditions of reduced repolarization reserve results in sex-dependent development of early afterdepolarizations (EADs) in the post-pause action potentials (APs). Moreover, this modeling study demonstrates increased propensity for the development of the loss of the AP dome in male epicardial myocytes of the right ventricle compared with other types of myocytes from the left and right ventricles. Finally, we also found a slight effect of INal on gender-dependent loss of AP dome in epicardial right ventricular myocytes. In conclusion, at the cellular level, gender differences in the development of EADs and the propensity to develop the loss of the AP dome can be attributed to male/female related differences in INa, INal, Ito, IKs, and ICa(L). PMID:23726761

  10. Physiological changes induced in cardiac myocytes by cytotoxic T lymphocytes

    SciTech Connect

    Hassin, D.; Fixler, R.; Shimoni, Y.; Rubinstein, E.; Raz, S.; Gotsman, M.S.; Hasin, Y.

    1987-01-01

    The lethal hit induced by viral specific, sensitized, cytotoxic T lymphocytes (CTL) attacking virus-infected heart cells is important in the pathogenesis of viral myocarditis and reflects the key role of CTL in this immune response. The mechanisms involved are incompletely understood. Studies of the physiological changes induced in mengovirus-infected, cultured, neonatal, rat heart cells by CTL that had been previously sensitized by the same virus are presented. The CTL were obtained from spleens of mengovirus-infected, major histocompatibility complex (MHC) matched adult rats. Cell wall motion was measured by an optical method, action potentials with intracellular microelectrodes, and total exchangeable calcium content by /sup 45/Ca tracer measurements after loading the myocytes with /sup 45/Ca and then exposing them to CTL. After 50 min (mean time) of exposing mengovirus-infected myocytes to the CTL, the mechanical relaxation of the myocyte was slowed, with a subsequent slowing of beating rate and a reduced amplitude of contraction. Impaired relaxation progressed, and prolonged oscillatory contractions lasting up to several seconds appeared, with accompanying oscillations in the prolonged plateau phase of the action potentials. Arrest of the myocyte contractions appeared 98 min (mean time) after exposure to CTL. It is concluded that infection of cultured myocytes with mengovirus predisposes them to attack by mengovirus specific CTL, and that persistent dysfunction of the myocyte is preceded by reversible changes in membrane potential and contraction. This is suggestive of an altered calcium handling by the myocytes possibly resulting in the cytotoxic effect.

  11. Isoproterenol-induced myocardial fibrosis in relation to myocyte necrosis

    SciTech Connect

    Benjamin, I.J.; Jalil, J.E.; Tan, L.B.; Cho, K.; Weber, K.T.; Clark, W.A. )

    1989-09-01

    Treatment of rats with the beta-adrenergic agonist isoproterenol results in cardiac hypertrophy, myocyte necrosis, and interstitial cell fibrosis. Our objectives in this study have been to examine whether hypertrophy and fibrosis occur in a compensatory and reparative response to myocyte loss or whether either process may be occurring independently of myocyte loss and thus be a reactive response to adrenergic hormone stimulation. We have examined this question by evaluating each of these responses in rats treated with different doses and forms of isoproterenol administration. Myocyte necrosis was evaluated using in vivo labeling with monoclonal antimyosin for identification of myocytes with permeable sarcolemma, which was indicative of irreversible injury. Myocardial fibrosis was evaluated by morphometric point counting of Gomori-stained tissue sections and by assessment of the stimulation of fibroblast proliferation by determination of increased levels of DNA synthesis. Stimulation of fibroblast DNA synthesis was determined from DNA specific radioactivities and radioautography after pulse labeling with (3H)thymidine. The evidence provided by this study suggests that the degree and timing of myocardial hypertrophy does not follow the course of myocyte loss and, thus, appears to be either a response to altered cardiac loading or a reactive response to beta-adrenergic hormone stimulation rather than a compensation for myocyte loss. Myocardial fibrosis, on the other hand, appears to be more closely related to myocyte necrosis with respect to collagen accumulation in the same areas of the heart, its dose-response relation to the amount of isoproterenol administered, and the timing of increased DNA synthesis, or fibroblast proliferation, after myocyte loss.

  12. Ultrastructural alterations in the atrial myocardium of pigs with acute monensin toxicosis.

    PubMed Central

    Van Vleet, J. F.; Ferrans, V. J.

    1984-01-01

    Monensin, A Na+-selective carboxylic ionophore, produces left atrial damage in pigs given toxic doses. Eight weanling pigs were given mycelial monensin orally (40 mg/kg body weight) and were killed on days 1, 2, 4, and 16 (two animals at each time interval) for ultrastructural study of the left atrial lesions. On days 1-4, extensive necrosis with contraction bands was present. Rapid macrophagic invasion and phagocytosis of sarcoplasmic debris was seen on days 2 and 4. Missing necrotic myocytes were outlined by persistent "tubes" of external laminas. In some surviving myocytes, sublethal injury was evident on day 1 by mitochondria with condensed conformation and on days 2, 4, and 16 by moderate to marked myofibrillar lysis and sarcoplasmic vacuolation. Monensin cardiotoxicity in pigs constitutes a unique example of selective injury to atrial myocardium. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 PMID:6696048

  13. MDIMP, a novel cardiac Ca(2+) channel blocker with atrial selectivity.

    PubMed

    Santamaria-Herrera, Mireille Aline; Ríos-Pérez, Erick Benjamín; de la Rosa, Juan Antonio Manuel; García-Castañeda, Maricela; Osornio-Garduño, Diana Stephanie; Ramos-Mondragón, Roberto; Mancilla-Percino, Teresa; Avila, Guillermo

    2016-06-15

    In cardiac muscle cells both T-and L-type Ca(2+) channels (TTCCs and LTCCs, respectively) are expressed, and the latter are relevant to a process known as excitation-contraction coupling (ECC). Evidence obtained from docking studies suggests that isoindolines derived from α-amino acids bind to the LTCC CaV1.2. In the present study, we investigated whether methyl (S)-2-(1,3-dihydroisoindol-2-yl)-4-methylpentanoate (MDIMP), which is derived from L-leucine, modulates both Ca(2+) channels and ECC. To this end, mechanical properties, as well as Ca(2+) transients and currents, were all investigated in isolated cardiac myocytes. The effects of MDIMP on CaV1.2 (transiently expressed in 293T/17 cells) were also studied. In this system, evidence was found for an inhibitory action that develops and recovers in min, with an IC50 of 450µM. With respect to myocytes: atrial-TTCCs, atrial-LTCCs, and ventricular-LTCCs were also inhibited, in that order of potency. Accordingly, Ca(2+) transients, contractions, and window currents of LTCCs were all reduced more strongly in atrial cells. Interestingly, while the modulation of LTCCs was state-independent in these cells, it was state-dependent, and dual, on the ventricular ones. Furthermore, practically all of the ventricular LTCCs were closed at resting membrane potentials. This could explain their resistance to MDIMP, as they were affected in only open or inactivated states. All these features in turn explain the preferential down-regulation of the atrial ECC. Thus, our results support the view that isoindolines bind to Ca(2+) channels, improve our knowledge of the corresponding structure-function relationship, and may be relevant for conditions where decreased atrial activity is desired. PMID:27089820

  14. Anticoagulation in atrial fibrillation

    PubMed Central

    Piccini, Jonathan P

    2014-01-01

    Atrial fibrillation increases the risk of stroke, which is a leading cause of death and disability worldwide. The use of oral anticoagulation in patients with atrial fibrillation at moderate or high risk of stroke, estimated by established criteria, improves outcomes. However, to ensure that the benefits exceed the risks of bleeding, appropriate patient selection is essential. Vitamin K antagonism has been the mainstay of treatment; however, newer drugs with novel mechanisms are also available. These novel oral anticoagulants (direct thrombin inhibitors and factor Xa inhibitors) obviate many of warfarin’s shortcomings, and they have demonstrated safety and efficacy in large randomized trials of patients with non-valvular atrial fibrillation. However, the management of patients taking warfarin or novel agents remains a clinical challenge. There are several important considerations when selecting anticoagulant therapy for patients with atrial fibrillation. This review will discuss the rationale for anticoagulation in patients with atrial fibrillation; risk stratification for treatment; available agents; the appropriate implementation of these agents; and additional, specific clinical considerations for treatment. PMID:24733535

  15. Exploiting periodicity to extract the atrial activity in atrial arrhythmias

    NASA Astrophysics Data System (ADS)

    Llinares, Raul; Igual, Jorge

    2011-12-01

    Atrial fibrillation disorders are one of the main arrhythmias of the elderly. The atrial and ventricular activities are decoupled during an atrial fibrillation episode, and very rapid and irregular waves replace the usual atrial P-wave in a normal sinus rhythm electrocardiogram (ECG). The estimation of these wavelets is a must for clinical analysis. We propose a new approach to this problem focused on the quasiperiodicity of these wavelets. Atrial activity is characterized by a main atrial rhythm in the interval 3-12 Hz. It enables us to establish the problem as the separation of the original sources from the instantaneous linear combination of them recorded in the ECG or the extraction of only the atrial component exploiting the quasiperiodic feature of the atrial signal. This methodology implies the previous estimation of such main atrial period. We present two algorithms that separate and extract the atrial rhythm starting from a prior estimation of the main atrial frequency. The first one is an algebraic method based on the maximization of a cost function that measures the periodicity. The other one is an adaptive algorithm that exploits the decorrelation of the atrial and other signals diagonalizing the correlation matrices at multiple lags of the period of atrial activity. The algorithms are applied successfully to synthetic and real data. In simulated ECGs, the average correlation index obtained was 0.811 and 0.847, respectively. In real ECGs, the accuracy of the results was validated using spectral and temporal parameters. The average peak frequency and spectral concentration obtained were 5.550 and 5.554 Hz and 56.3 and 54.4%, respectively, and the kurtosis was 0.266 and 0.695. For validation purposes, we compared the proposed algorithms with established methods, obtaining better results for simulated and real registers.

  16. Obesity and atrial fibrillation.

    PubMed

    Abed, H S; Wittert, G A

    2013-11-01

    Atrial fibrillation (AF) is an increasing public health problem, often described as the epidemic of the new millennium. The rising health economic impact of AF, its association with poor quality of life and independent probability of increased mortality, has recently been highlighted. Although population ageing is regarded as an important contributor to this epidemic, obesity and its associated cardiometabolic comorbidities may represent the principal driving factor behind the current and projected AF epidemic. Obesity-related risk factors, such as hypertension, vascular disease, obstructive sleep apnea and pericardial fat, are thought to result in atrial electro-structural dysfunction. In addition, insulin resistance, its associated abnormalities in nutrient utilization and intermediary metabolic by-products are associated with structural and functional abnormalities, ultimately promoting AF. Recent elucidation of molecular pathways, including those responsible for atrial fibrosis, have provided mechanistic insights and the potential for targeted pharmacotherapy. In this article, we review the evidence for an obesity-related atrial electromechanical dysfunction, the mechanisms behind this and its impact on AF therapeutic outcomes. In light of the recently described mechanisms, we illustrate proposed management approaches and avenues for further investigations.

  17. The antiarrhythmic peptide rotigaptide (ZP123) increases gap junction intercellular communication in cardiac myocytes and HeLa cells expressing connexin 43

    PubMed Central

    Clarke, Thomas C; Thomas, Dafydd; Petersen, Jørgen S; Evans, W Howard; Martin, Patricia E M

    2006-01-01

    We investigated the effects of rotigaptide (ZP123), a stable hexapeptide with antiarrhythmic properties, on gap junction mediated intercellular communication in contracting rat neonatal cardiac myocytes, HL-1 cells derived from cardiac atrium and in HeLa cells transfected with cDNA encoding Cx43-GFP, Cx32-GFP, Cx26-GFP, wild-type Cx43 or wild-type Cx26. Intercellular communication was monitored before and after treatment with rotigaptide following microinjection of small fluorescent dyes (MW<1 kDa). The communication-modifying effect of rotigaptide was confined to cells expressing Cx43 since the peptide had no effect on dye transfer in HeLa cells expressing Cx32-GFP, Cx26-GFP or wild-type Cx26. In contrast, HeLa cells expressing Cx43-GFP exposed to 50 nM rotigaptide for 5 h showed a 40% increase in gap junction mediated communication. Rotigaptide (50 nM) increased intercellular dye transfer in myocytes and atrial HL-1 cells, where Cx43 is the dominant connexin. However, it caused no change in cell beating rates of cardiac myocytes. Western blot analysis showed that rotigaptide did not modify the overall level of Cx43 expression and changes in the phosphorylation status of the protein were not observed. We conclude that the effects of rotigaptide were confined to cells expressing Cx43. PMID:16415913

  18. Measuring mitochondrial function in intact cardiac myocytes

    PubMed Central

    Dedkova, Elena N.; Blatter, Lothar A.

    2011-01-01

    Mitochondria are involved in cellular functions that go beyond the traditional role of these organelles as the power plants of the cell. Mitochondria have been implicated in several human diseases, including cardiac dysfunction, and play a role in the aging process. Many aspects of our knowledge of mitochondria stem from studies performed on the isolated organelle. Their relative inaccessibility imposes experimental difficulties to study mitochondria in their natural environment – the cytosol of intact cells – and has hampered a comprehensive understanding of the plethora of mitochondrial functions. Here we review currently available methods to study mitochondrial function in intact cardiomyocytes. These methods primarily use different flavors of fluorescent dyes and genetically encoded fluorescent proteins in conjunction with high-resolution imaging techniques. We review methods to study mitochondrial morphology, mitochondrial membrane potential, Ca2+ and Na+ signaling, mitochondrial pH regulation, redox state and ROS production, NO signaling, oxygen consumption, ATP generation and the activity of the mitochondrial permeability transition pore. Where appropriate we complement this review on intact myocytes with seminal studies that were performed on isolated mitochondria, permeabilized cells, and in whole hearts. PMID:21964191

  19. Characterization of a novel multifunctional resveratrol derivative for the treatment of atrial fibrillation

    PubMed Central

    Baczko, Istvan; Liknes, David; Yang, Wei; Hamming, Kevin C; Searle, Gavin; Jaeger, Kristian; Husti, Zoltan; Juhasz, Viktor; Klausz, Gergely; Pap, Robert; Saghy, Laszlo; Varro, Andras; Dolinsky, Vernon; Wang, Shaohua; Rauniyar, Vivek; Hall, Dennis; Dyck, Jason RB; Light, Peter E

    2014-01-01

    BACKGROUND AND PURPOSE Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with an increased risk for stroke, heart failure and cardiovascular-related mortality. Candidate targets for anti-AF drugs include a potassium channel Kv1.5, and the ionic currents IKACh and late INa, along with increased oxidative stress and activation of NFAT-mediated gene transcription. As pharmacological management of AF is currently suboptimal, we have designed and characterized a multifunctional small molecule, compound 1 (C1), to target these ion channels and pathways. EXPERIMENTAL APPROACH We made whole-cell patch-clamp recordings of recombinant ion channels, human atrial IKur, rat atrial IKACh, cellular recordings of contractility and calcium transient measurements in tsA201 cells, human atrial samples and rat myocytes. We also used a model of inducible AF in dogs. KEY RESULTS C1 inhibited human peak and late Kv1.5 currents, frequency-dependently, with IC50 of 0.36 and 0.11 μmol·L−1 respectively. C1 inhibited IKACh (IC50 of 1.9 μmol·L−1) and the Nav1.5 sodium channel current (IC50s of 3 and 1 μmol·L−1 for peak and late components respectively). C1 (1 μmol·L−1) significantly delayed contractile and calcium dysfunction in rat ventricular myocytes treated with 3 nmol·L−1 sea anemone toxin (ATX-II). C1 weakly inhibited the hERG channel and maintained antioxidant and NFAT-inhibitory properties comparable to the parent molecule, resveratrol. In a model of inducible AF in conscious dogs, C1 (1 mg·kg−1) reduced the average and total AF duration. CONCLUSION AND IMPLICATIONS C1 behaved as a promising multifunctional small molecule targeting a number of key pathways involved in AF. PMID:24102184

  20. Emergency management of atrial fibrillation

    PubMed Central

    Wakai, A; O'Neill, J

    2003-01-01

    Atrial fibrillation is the most common cardiac arrhythmia managed by emergency and acute general physicians. There is increasing evidence that selected patients with acute atrial fibrillation can be safely managed in the emergency department without the need for hospital admission. Meanwhile, there is significant variation in the current emergency management of acute atrial fibrillation. This review discusses evidence based emergency management of atrial fibrillation. The principles of emergency management of acute atrial fibrillation and the subset of patients who may not need hospital admission are reviewed. Finally, the need for evidence based guidelines before emergency department based clinical pathways for the management of acute atrial fibrillation becomes routine clinical practice is highlighted. PMID:12840118

  1. A new atrial septostomy technique.

    PubMed

    Park, S C; Zuberbuhler, J R; Neches, W H; Lenox, C C; Zoltun, R A

    1975-01-01

    Balloon atrial septostomy is usually ineffective if the atrial septum is thickened. A technique for incising the atrial septum is described. A no. 6 French catheter was modified to enclose a tiny surgical blade. The distal end of the blade was pivoted to the catheter tip, and the proximal end was attached to a guide wire in the catheter lumen. Advancing the guide wire protruded the blade through a slit in the long axis of the tip of the catheter. Atrial septostomy was performed in five newborn lambs in vivo and in adult dog hearts and human hearts in vitro by advancing the catheter tip across the atrial septum with the blade retracted and withdrawing it to the right atrium with the blade extended. Eight to 12 mm lacerations of the atrial septum were produced and could be extended by subsequent balloon septostomy. The technique may be useful when balloon septostomy has been ineffective.

  2. Changes in gene expression with iron loading and chelation in cardiac myocytes and non-myocytic fibroblasts.

    PubMed

    Parkes, J G; Liu, Y; Sirna, J B; Templeton, D M

    2000-02-01

    Iron overload is associated with long-term cardiac iron accumulation and tissue changes such as fibrosis. To determine short-term iron-dependent changes in expression of genes associated with iron homeostasis and fibrosis we measured mRNA on Northern blots prepared from cultured rat neonatal cardiomyocytes and non-myocytes (fibroblasts) as a function of iron loading and chelation. Transferrin receptor mRNA was reduced in myocytes exposed to various concentrations of iron for 3 days and this decline was associated with a 63% decline in iron-response element (IRE) binding of iron regulatory protein-1, indicating that myocytes utilize IRE-dependent mechanisms to modulate gene expression. In myocytes iron caused a dose-dependent decline in mRNAs coding for transforming growth factor- beta(1)(TGF- beta(1)), biglycan, and collagen type I while plasminogen activator inhibitor-1 mRNA was unaffected by iron loading and decorin mRNA doubled. Total TGF- beta bioactivity was also decreased by iron loading. Thus, the effects of iron loading on genes related to cardiac fibrosis are gene-specific. Addition of deferoxamine for 1 day did not have any significant effect on any of these genes. Parallel changes in gene expression were exhibited by non-myocytes (fibroblasts), where chelation also decreased TGF- beta(1)mRNA and activity, and mRNA for collagen type I and biglycan, and collagen synthesis. In addition to these changes in transcripts associated with matrix formation the mRNA of the metabolic enzyme glyceraldehyde-3-phosphate dehydrogenase was unaffected by iron loading but doubled in both cell types upon treatment with deferoxamine. These findings suggest that in both cardiac myocytes and non-myocyte fibroblasts gene expression is coupled to intracellular iron pools by gene-specific and IRE-dependent and idependent mechanisms. This linkage may influence matrix deposition, a significant component of cardiac injury.

  3. Clinical implications of atrial isomerism.

    PubMed Central

    Chiu, I S; How, S W; Wang, J K; Wu, M H; Chu, S H; Lue, H C; Hung, C R

    1988-01-01

    Right atrial isomerism or left atrial isomerism is frequently diagnosed as situs ambiguous without further discrimination of the specific morbid anatomy. Thirty six cases of right atrial isomerism and seven cases of left atrial isomerism were collected from the records and pathological museum at the National Taiwan University Hospital. There was a necropsy report for 18 cases. In all patients one or more of the following conditions was met: (a) isomeric bronchial anatomy, (b) echocardiographic and angiocardiographic evidence of isomerism, and (c) surgical or necropsy evidence of abnormal atrial anatomy. An anomalous pulmonary venous connection was present in 55% of patients with right atrial isomerism; in left atrial isomerism one case (14%) had a partial anomalous pulmonary venous connection. Forty per cent of cases of anomalous pulmonary venous connection with right atrial isomerism had obstruction. Six (86%) of seven cases with left atrial isomerism had an ambiguous biventricular atrioventricular connection. In contrast, univentricular atrioventricular connection (26 of 36, 72%) was significantly more common in right atrial isomerism. A common atrioventricular valve was the most frequent mode of connection in both forms. Two discrete atrioventricular valves were significantly more common in left atrial isomerism. Atrioventricular valve regurgitation was detected in 14 cases. Double outlet right ventricle was the most common type of ventriculoarterial connection. The most commonly cited causes of death after either palliative or definitive operation were undetected anomalous pulmonary venous connection, pulmonary venous stricture, and uncorrected atrioventricular valve or aortic regurgitation complicated by abnormal coagulation. Although the prognosis is poor, successful operation depends on knowledge of the precise anatomical arrangement associated with atrial isomerism. Images Fig 1 Fig 2 Fig 3 PMID:3408620

  4. Reactive γ-ketoaldehydes promote protein misfolding and preamyloid oligomer formation in rapidly-activated atrial cells.

    PubMed

    Sidorova, Tatiana N; Yermalitskaya, Liudmila V; Mace, Lisa C; Wells, K Sam; Boutaud, Olivier; Prinsen, Joseph K; Davies, Sean S; Roberts, L Jackson; Dikalov, Sergey I; Glabe, Charles G; Amarnath, Venkataraman; Barnett, Joey V; Murray, Katherine T

    2015-02-01

    Rapid activation causes remodeling of atrial myocytes resembling that which occurs in experimental and human atrial fibrillation (AF). Using this cellular model, we previously observed transcriptional upregulation of proteins implicated in protein misfolding and amyloidosis. For organ-specific amyloidoses such as Alzheimer's disease, preamyloid oligomers (PAOs) are now recognized to be the primary cytotoxic species. In the setting of oxidative stress, highly-reactive lipid-derived mediators known as γ-ketoaldehydes (γ-KAs) have been identified that rapidly adduct proteins and cause PAO formation for amyloid β1-42 implicated in Alzheimer's. We hypothesized that rapid activation of atrial cells triggers oxidative stress with lipid peroxidation and formation of γ-KAs, which then rapidly crosslink proteins to generate PAOs. To investigate this hypothesis, rapidly-paced and control, spontaneously-beating atrial HL-1 cells were probed with a conformation-specific antibody recognizing PAOs. Rapid stimulation of atrial cells caused the generation of cytosolic PAOs along with a myocyte stress response (e.g., transcriptional upregulation of Nppa and Hspa1a), both of which were absent in control, unpaced cells. Rapid activation also caused the formation of superoxide and γ-KA adducts in atriomyocytes, while direct exposure of cells to γ-KAs resulted in PAO production. Increased cytosolic atrial natriuretic peptide (ANP), and the generation of ANP oligomers with exposure to γ-KAs and rapid atrial HL-1 cell stimulation, strongly suggest a role for ANP in PAO formation. Salicylamine (SA) is a small molecule scavenger of γ-KAs that can protect proteins from modification by these reactive compounds. PAO formation and transcriptional remodeling were inhibited when cells were stimulated in the presence of SA, but not with the antioxidant curcumin, which is incapable of scavenging γ-KAs. These results demonstrate that γ-KAs promote protein misfolding and PAO formation as a

  5. Cytoskeletal prestress regulates nuclear shape and stiffness in cardiac myocytes

    PubMed Central

    Lee, Hyungsuk; Adams, William J; Alford, Patrick W; McCain, Megan L; Feinberg, Adam W; Sheeny, Sean P; Goss, Josue A

    2015-01-01

    Mechanical stresses on the myocyte nucleus have been associated with several diseases and potentially transduce mechanical stimuli into cellular responses. Although a number of physical links between the nuclear envelope and cytoplasmic filaments have been identified, previous studies have focused on the mechanical properties of individual components of the nucleus, such as the nuclear envelope and lamin network. The mechanical interaction between the cytoskeleton and chromatin on nuclear deformability remains elusive. Here, we investigated how cytoskeletal and chromatin structures influence nuclear mechanics in cardiac myocytes. Rapid decondensation of chromatin and rupture of the nuclear membrane caused a sudden expansion of DNA, a consequence of prestress exerted on the nucleus. To characterize the prestress exerted on the nucleus, we measured the shape and the stiffness of isolated nuclei and nuclei in living myocytes during disruption of cytoskeletal, myofibrillar, and chromatin structure. We found that the nucleus in myocytes is subject to both tensional and compressional prestress and its deformability is determined by a balance of those opposing forces. By developing a computational model of the prestressed nucleus, we showed that cytoskeletal and chromatin prestresses create vulnerability in the nuclear envelope. Our studies suggest the cytoskeletal–nuclear–chromatin interconnectivity may play an important role in mechanics of myocyte contraction and in the development of laminopathies by lamin mutations. PMID:25908635

  6. Myomaker mediates fusion of fast myocytes in zebrafish embryos

    SciTech Connect

    Landemaine, Aurélie; Rescan, Pierre-Yves; Gabillard, Jean-Charles

    2014-09-05

    Highlights: • Myomaker is transiently expressed in fast myocytes during embryonic myogenesis. • Myomaker is essential for fast myocyte fusion in zebrafish. • The function of myomaker is conserved among Teleostomi. - Abstract: Myomaker (also called Tmem8c), a new membrane activator of myocyte fusion was recently discovered in mice. Using whole mount in situ hybridization on zebrafish embryos at different stages of embryonic development, we show that myomaker is transiently expressed in fast myocytes forming the bulk of zebrafish myotome. Zebrafish embryos injected with morpholino targeted against myomaker were alive after yolk resorption and appeared morphologically normal, but they were unable to swim, even under effect of a tactile stimulation. Confocal observations showed a marked phenotype characterized by the persistence of mononucleated muscle cells in the fast myotome at developmental stages where these cells normally fuse to form multinucleated myotubes. This indicates that myomaker is essential for myocyte fusion in zebrafish. Thus, there is an evolutionary conservation of myomaker expression and function among Teleostomi.

  7. Dynamic investigation of Drosophila myocytes with second harmonic generation microscopy

    NASA Astrophysics Data System (ADS)

    Greenhalgh, Catherine; Stewart, Bryan; Cisek, Richard; Prent, Nicole; Major, Arkady; Barzda, Virginijus

    2006-09-01

    The functional dynamics and structure of both larval and adult Drosophila melanogaster muscle were investigated with a nonlinear multimodal microscope. Imaging was carried out using a home built microscope capable of recording the multiphoton excitation fluorescence, second harmonic generation, and third harmonic generation signals simultaneously at a scanning rate of up to ~12 frames/sec. The sample was excited by a home built femtosecond Ti:Sapphire laser at 840 nm, or by a Yb-ion doped potassium gadolinium tungstate (Yb:KGW) crystal based oscillator at 1042 nm. There was no observable damage detected in the myocyte after prolonged scanning with either of the lasers. Microscopic second harmonic generation (SHG) appears particularly strong in the myocytes. This allows the fast contraction dynamics of the myocytes to be followed. The larger sarcomere size observed in the larvae myocytes is especially well suited for studying the contraction dynamics. Microscopic imaging of muscle contractions showed different relaxation and contraction rates. The SHG intensities were significantly higher in the relaxed state of the myocyte compared to the contracted state. The imaging also revealed disappearance of SHG signal in highly stretched sarcomeres, indicating that SHG diminishes in the disordered structures. The study illustrates that SHG microscopy, combined with other nonlinear contrast mechanisms, can help to elucidate physiological mechanisms of contraction. This study also provides further insight into the mechanisms of harmonic generation in biological tissue and shows that crystalline arrangement of macromolecules has a determining factor for the high efficiency second harmonic generation from the bulk structures.

  8. Nuclear Morphology and Deformation in Engineered Cardiac Myocytes and Tissues

    PubMed Central

    Bray, Mark-Anthony; Adams, William J.; Geisse, Nicholas A.; Feinberg, Adam W.; Sheehy, Sean P.; Parker, Kevin Kit

    2010-01-01

    Cardiac tissue engineering requires finely-tuned manipulation of the extracellular matrix (ECM) microenvironment to optimize internal myocardial organization. The myocyte nucleus is mechanically connected to the cell membrane via cytoskeletal elements, making it a target for the cellular response to perturbation of the ECM. However, the role of ECM spatial configuration and myocyte shape on nuclear location and morphology is unknown. In this study, printed ECM proteins were used to configure the geometry of cultured neonatal rat ventricular myocytes. Engineered one- and two-dimensional tissue constructs and single-myocyte islands were assayed using live fluorescence imaging to examine nuclear position, morphology and motion as a function of the imposed ECM geometry during diastolic relaxation and systolic contraction. Image analysis showed that anisotropic tissue constructs cultured on microfabricated ECM lines possessed a high degree of nuclear alignment similar to that found in vivo; nuclei in isotropic tissues were polymorphic in shape with an apparently random orientation. Nuclear eccentricity was also increased for the anisotropic tissues, suggesting that intracellular forces deform the nucleus as the cell is spatially confined. During systole, nuclei experienced increasing spatial confinement in magnitude and direction of displacement as tissue anisotropy increased, yielding anisotropic deformation. Thus, the nature of nuclear displacement and deformation during systole appears to rely on a combination of the passive myofibril spatial organization and the active stress fields induced by contraction. Such findings have implications in understanding the genomic consequences and functional response of cardiac myocytes to their ECM surroundings under conditions of disease. PMID:20382423

  9. The Multi-Domain Fibroblast/Myocyte Coupling in the Cardiac Tissue: A Theoretical Study.

    PubMed

    Greisas, Ariel; Zlochiver, Sharon

    2016-09-01

    Cardiac fibroblast proliferation and concomitant collagenous matrix accumulation (fibrosis) develop during multiple cardiac pathologies. Recent studies have demonstrated direct electrical coupling between myocytes and fibroblasts in vitro, and assessed the electrophysiological implications of such coupling. However, in the living tissues, such coupling has not been demonstrated, and only indirect coupling via the extracellular space is likely to exist. In this study we employed a multi-domain model to assess the modulation of the cardiac electrophysiological properties by neighboring fibroblasts assuming only indirect coupling. Numerical simulations in 1D and 2D human atrial models showed that extracellular coupling sustains a significant impact on conduction velocity (CV) and a less significant effect on the action potential duration. Both CV and the slope of the CV restitution increased with increasing fibroblast density. This effect was more substantial for lower extracellular conductance. In 2D, spiral waves exhibited reduced frequency with increasing fibroblast density, and the propensity of wavebreaks and complex dynamics at high pacing rates significantly increased. PMID:27150222

  10. Verrucotoxin inhibits KATP channels in cardiac myocytes through a muscarinic M3 receptor-PKC pathway.

    PubMed

    Wang, Jian-Wu; Yazawa, Kazuto; Hao, Li-Ying; Onoue, Yoshio; Kameyama, Masaki

    2007-06-01

    Verrucotoxin is the major component of venom from the stonefish (Synanceia verrucosa). Stings from the dorsal spines of the stonefish produce intensive pain, convulsions, hypotension, paralysis, respiratory weakness and collapse of the cardiovascular system, occasionally leading to death. It has been reported that verrucotoxin might modulate ATP-sensitive K+ (KATP) current in frog atrial fibers. However, the mechanism by which verrucotoxin acts on KATP current remains unclear. In this study, we examined whether verrucotoxin inhibited KATP current in guinea pig ventricular myocytes, using the patch clamp method. Verrucotoxin suppressed KATP current induced by pinacidil (KATP channel opener) in a concentration-dependent manner, with a half maximum concentration of 16.3 microg/ml. The effect of verrucotoxin on KATP current was suppressed by atropine (1 microM), a muscarinic receptor antagonist, or by 4-diphenylacetoxy-N-methylpiperidine (100 nM), a muscarinic M3 receptor antagonist. Furthermore, the effect of verrucotoxin on KATP current was attenuated by the protein kinase C (PKC) inhibitor chelerythrine (10 microM) and calphostin C (10 microM), yet not by the cAMP-dependent protein kinase (PKA) inhibitor H-89 (0.5 microM). These results suggest that verrucotoxin inhibits KATP current through the muscarinic M3 receptor-PKC pathway. These findings enhance our understanding of the toxic effects of verrucotoxin from the stonefish. PMID:17362922

  11. The spatial pattern of atrial cardiomyocyte calcium signalling modulates contraction.

    PubMed

    Mackenzie, Lauren; Roderick, H Llewelyn; Berridge, Michael J; Conway, Stuart J; Bootman, Martin D

    2004-12-15

    We examined the regulation of calcium signalling in atrial cardiomyocytes during excitation-contraction coupling, and how changes in the distribution of calcium impacts on contractility. Under control conditions, calcium transients originated in subsarcolemmal locations and showed local regeneration through activation of calcium-induced calcium release from ryanodine receptors. Despite functional ryanodine receptors being expressed at regular (approximately 2 microm) intervals throughout atrial myocytes, the subsarcolemmal calcium signal did not spread in a fully regenerative manner through the interior of a cell. Rather, there was a diminishing centripetal propagation of calcium. The lack of regeneration was due to mitochondria and SERCA pumps preventing the inward movement of calcium. Inhibiting these calcium buffering mechanisms allowed the globalisation of action potential-evoked responses. In addition, physiological positive inotropic agents, such as endothelin-1 and beta-adrenergic agonists, as well as enhanced calcium current, calcium store loading and inositol 1,4,5-trisphosphate infusion also led to regenerative global responses. The consequence of globalising calcium signals was a significant increase in cellular contraction. These data indicate how calcium signals and their consequences are determined by the interplay of multiple subcellular calcium management systems.

  12. Phosphodiesterase4D (PDE4D)--A risk factor for atrial fibrillation and stroke?

    PubMed

    Jørgensen, Carina; Yasmeen, Saiqa; Iversen, Helle K; Kruuse, Christina

    2015-12-15

    Mutations in the gene encoding phosphodiesterase 4D (PDE4D) enzyme are associated with ischemic stroke; however the functional implications of such mutations are not well understood. PDE4D is part of a complex protein family modulating intracellular signalling by cyclic nucleotides. The PDE4 family includes subtypes A-D, all of which show unique intracellular, cellular and tissue distribution. PDE4D is the major subtype expressed in human atrial myocytes and involved in the pathophysiology of arrhythmias, such as atrial fibrillation. The PDE4D enzyme hydrolyses cyclic adenosine monophosphate (cAMP). Though diverging results are reported, several population based studies describe association of various PDE4D single nucleotide polymorphisms (SNP) with cardio-embolic stroke in particular. Functionally, a down regulation of PDE4D variants has been reported in stroke patients. The anti-inflammatory and vasodilator properties of PDE4 inhibitors make them suitable for treatment of stroke and cardiovascular disease. PDE4D has recently been suggested as factor in atrial fibrillation. This review summarizes the possible function of PDE4D in the brain, heart, and vasculature. Further, association of the described SNPs, in particular, with cardioembolic stroke, is reviewed. Current findings on the PDE4D mutations suggest functionality involves an increased cardiac risk factor as well as augmented risk of atrial fibrillation. PMID:26671126

  13. Hyperuricemia and Atrial Fibrillation.

    PubMed

    Maharani, Nani; Kuwabara, Masanari; Hisatome, Ichiro

    2016-07-27

    The importance of atrial fibrillation (AF) as a cause of mortality and morbidity has prompted research on its pathogenesis and treatment. Recognition of AF risk factors is essential to prevent it and reduce the risk of death. Hyperuricemia has been widely accepted to be associated with the incidence of paroxysmal or persistent AF, as well as to the risk of AF in post cardiovascular surgery patients. The possible explanations for this association have been based on their relation with either oxidative stress or inflammation. To investigate the link between hyperuricemia and AF, it is necessary to refer to hyperuricemia-induced atrial remodeling. So far, both ionic channel and structural remodeling caused by hyperuricemia might be plausible explanations for the occurrence of AF. Inhibition of xanthine oxidase and nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, or the use of antioxidants, along with serum uric acid (SUA) level reduction to prevent inflammation, might be useful. Uric acid transporters (UATs) play a key role in the regulation of intracellular uric acid concentration. Intracellular rather than serum uric acid level is considered more important for the pathogenesis of AF. Identification of UATs expressed in cells is thus important, and targeting UATs might become a potential strategy to reduce the risk of hyperuricemia-induced atrial fibrillation. PMID:27396561

  14. Electrical stimulation directs engineered cardiac tissue to an age-matched native phenotype

    PubMed Central

    Lasher, Richard A; Pahnke, Aric Q; Johnson, Jeffrey M; Sachse, Frank B

    2012-01-01

    Quantifying structural features of native myocardium in engineered tissue is essential for creating functional tissue that can serve as a surrogate for in vitro testing or the eventual replacement of diseased or injured myocardium. We applied three-dimensional confocal imaging and image analysis to quantitatively describe the features of native and engineered cardiac tissue. Quantitative analysis methods were developed and applied to test the hypothesis that environmental cues direct engineered tissue toward a phenotype resembling that of age-matched native myocardium. The analytical approach was applied to engineered cardiac tissue with and without the application of electrical stimulation as well as to age-matched and adult native tissue. Individual myocytes were segmented from confocal image stacks and assigned a coordinate system from which measures of cell geometry and connexin-43 spatial distribution were calculated. The data were collected from 9 nonstimulated and 12 electrically stimulated engineered tissue constructs and 5 postnatal day 12 and 7 adult hearts. The myocyte volume fraction was nearly double in stimulated engineered tissue compared to nonstimulated engineered tissue (0.34 ± 0.14 vs 0.18 ± 0.06) but less than half of the native postnatal day 12 (0.90 ± 0.06) and adult (0.91 ± 0.04) myocardium. The myocytes under electrical stimulation were more elongated compared to nonstimulated myocytes and exhibited similar lengths, widths, and heights as in age-matched myocardium. Furthermore, the percentage of connexin-43-positive membrane staining was similar in the electrically stimulated, postnatal day 12, and adult myocytes, whereas it was significantly lower in the nonstimulated myocytes. Connexin-43 was found to be primarily located at cell ends for adult myocytes and irregularly but densely clustered over the membranes of nonstimulated, stimulated, and postnatal day 12 myocytes. These findings support our hypothesis and reveal that the

  15. Remodelling of cellular excitation (reaction) and intercellular coupling (diffusion) by chronic atrial fibrillation represented by a reaction-diffusion system

    NASA Astrophysics Data System (ADS)

    Zhang, Henggui; Garratt, Clifford J.; Kharche, Sanjay; Holden, Arun V.

    2009-06-01

    Human atrial tissue is an excitable system, in which myocytes are excitable elements, and cell-to-cell electrotonic interactions are via diffusive interactions of cell membrane potentials. We developed a family of excitable system models for human atrium at cellular, tissue and anatomical levels for both normal and chronic atrial fibrillation (AF) conditions. The effects of AF-induced remodelling of cell membrane ionic channels (reaction kinetics) and intercellular gap junctional coupling (diffusion) on atrial excitability, conduction of excitation waves and dynamics of re-entrant excitation waves are quantified. Both ionic channel and gap junctional coupling remodelling have rate dependent effects on atrial propagation. Membrane channel conductance remodelling allows the propagation of activity at higher rates than those sustained in normal tissue or in tissue with gap junctional remodelling alone. Membrane channel conductance remodelling is essential for the propagation of activity at rates higher than 300/min as seen in AF. Spatially heterogeneous gap junction coupling remodelling increased the risk of conduction block, an essential factor for the genesis of re-entry. In 2D and 3D anatomical models, the dynamical behaviours of re-entrant excitation waves are also altered by membrane channel modelling. This study provides insights to understand the pro-arrhythmic effects of AF-induced reaction and diffusion remodelling in atrial tissue.

  16. Sinus Node and Atrial Arrhythmias.

    PubMed

    John, Roy M; Kumar, Saurabh

    2016-05-10

    Although sinus node dysfunction (SND) and atrial arrhythmias frequently coexist and interact, the putative mechanism linking the 2 remain unclear. Although SND is accompanied by atrial myocardial structural changes in the right atrium, atrial fibrillation (AF) is a disease of variable interactions between left atrial triggers and substrate most commonly of left atrial origin. Significant advances have been made in our understanding of the genetic and pathophysiologic mechanism underlying the development and progression of SND and AF. Although some patients manifest SND as a result of electric remodeling induced by periods of AF, others develop progressive atrial structural remodeling that gives rise to both conditions together. The treatment strategy will thus vary according to the predominant disease phenotype. Although catheter ablation will benefit patients with predominantly AF and secondary SND, cardiac pacing may be the mainstay of therapy for patients with predominant fibrotic atrial cardiomyopathy. This contemporary review summarizes current knowledge on sinus node pathophysiology with the broader goal of yielding insights into the complex relationship between sinus node disease and atrial arrhythmias.

  17. ErbB4 localization to cardiac myocyte nuclei, and its role in myocyte DNA damage response

    SciTech Connect

    Icli, Basak; Bharti, Ajit; Pentassuglia, Laura; Peng, Xuyang; Sawyer, Douglas B.

    2012-02-03

    Highlights: Black-Right-Pointing-Pointer ErbB4 localizes to cardiac myocyte nuclei as a full-length receptor. Black-Right-Pointing-Pointer Cardiac myocytes express predominantly JM-a/CYT-1 ErbB4. Black-Right-Pointing-Pointer Myocyte p53 activation in response to doxorubicin requires ErbB4 activity. -- Abstract: The intracellular domain of ErbB4 receptor tyrosine kinase is known to translocate to the nucleus of cells where it can regulate p53 transcriptional activity. The purpose of this study was to examine whether ErbB4 can localize to the nucleus of adult rat ventricular myocytes (ARVM), and regulate p53 in these cells. We demonstrate that ErbB4 does locate to the nucleus of cardiac myocytes as a full-length protein, although nuclear location occurs as a full-length protein that does not require Protein Kinase C or {gamma}-secretase activity. Consistent with this we found that only the non-cleavable JM-b isoform of ErbB4 is expressed in ARVM. Doxorubicin was used to examine ErbB4 role in regulation of a DNA damage response in ARVM. Doxorubicin induced p53 and p21 was suppressed by treatment with AG1478, an EGFR and ErbB4 kinase inhibitor, or suppression of ErbB4 expression with small interfering RNA. Thus ErbB4 localizes to the nucleus as a full-length protein, and plays a role in the DNA damage response induced by doxorubicin in cardiac myocytes.

  18. Novel Role for Vinculin in Ventricular Myocyte Mechanics and Dysfunction

    PubMed Central

    Tangney, Jared R.; Chuang, Joyce S.; Janssen, Matthew S.; Krishnamurthy, Adarsh; Liao, Peter; Hoshijima, Masahiko; Wu, Xin; Meininger, Gerald A.; Muthuchamy, Mariappan; Zemljic-Harpf, Alice; Ross, Robert S.; Frank, Lawrence R.; McCulloch, Andrew D.; Omens, Jeffrey H.

    2013-01-01

    Vinculin (Vcl) plays a key structural role in ventricular myocytes that, when disrupted, can lead to contractile dysfunction and dilated cardiomyopathy. To investigate the role of Vcl in myocyte and myocardial function, cardiomyocyte-specific Vcl knockout mice (cVclKO) and littermate control wild-type mice were studied with transmission electron microscopy (TEM) and in vivo magnetic resonance imaging (MRI) tagging before the onset of global ventricular dysfunction. MRI revealed significantly decreased systolic strains transverse to the myofiber axis in vivo, but no changes along the muscle fibers or in fiber tension in papillary muscles from heterozygous global Vcl null mice. Myofilament lattice spacing from TEM was significantly greater in cVclKO versus wild-type hearts fixed in the unloaded state. AFM in Vcl heterozygous null mouse myocytes showed a significant decrease in membrane cortical stiffness. A multiscale computational model of ventricular mechanics incorporating cross-bridge geometry and lattice mechanics showed that increased transverse systolic stiffness due to increased lattice spacing may explain the systolic wall strains associated with Vcl deficiency, before the onset of ventricular dysfunction. Loss of cardiac myocyte Vcl may decrease systolic transverse strains in vivo by decreasing membrane cortical tension, which decreases transverse compression of the lattice thereby increasing interfilament spacing and stress transverse to the myofibers. PMID:23561539

  19. Atrial Cardiopathy: A Broadened Concept of Left Atrial Thromboembolism Beyond Atrial Fibrillation

    PubMed Central

    Kamel, Hooman; Okin, Peter M.; Longstreth, W. T.; Elkind, Mitchell S.V.; Soliman, Elsayed Z.

    2016-01-01

    Atrial fibrillation (AF) has long been associated with a heightened risk of ischemic stroke and systemic thromboembolism, but recent data require a re-evaluation of our understanding of the nature of this relationship. New findings about the temporal connection between AF and stroke, alongside evidence linking markers of left atrial abnormalities with stroke in the absence of apparent AF, suggest that left atrial thromboembolism may occur even without AF. These observations undermine the hypothesis that the dysrhythmia that defines AF is necessary and sufficient to cause thromboembolism. In this commentary, we instead suggest that the substrate for thromboembolism may often be the anatomic and physiological atrial derangements associated with AF. Therefore, our understanding of cardioembolic stroke may be more complete if we shift our representation of its origin from AF to the concept of atrial cardiopathy. PMID:26021638

  20. Alpha-1, alpha-2, and beta adrenergic signal transduction in cultured uterine myocytes.

    PubMed

    Phillippe, M; Saunders, T; Bangalore, S

    1990-04-01

    The following studies were undertaken to develop a cultured uterine myocyte model which would allow further clarification of the adrenergic signal transduction mechanisms utilized by these myocytes. After mechanical removal of the endometrium, rabbit uterine myocytes were isolated by an overnight enzymatic disaggregation using collagenase and DNase I. The isolated myocytes were maintained in culture in 75-cm2 flasks containing Waymouth's MB 751/1 medium-10% fetal bovine serum along with 10(-8) M estradiol, penicillin, streptomycin, and Fungizone. The phase contrast and electron micrographic appearance of these cells was consistent with that previously reported for smooth muscle myocytes in culture. Immunocytochemical studies utilizing monoclonal anti-alpha-smooth muscle actin antibodies confirmed the presence of smooth muscle actin in these cultured myocytes. Western blot studies similarly confirmed the presence of alpha-smooth muscle actin in rabbit myometrial tissue and the cultured myocytes, both the primary and F1 generation. After prelabeling the myocytes with [3H]inositol, adrenergic stimulation experiments demonstrated alpha-1 receptor mediated stimulation of inositol phosphates. Beta receptor stimulation experiments confirmed cAMP production in these cultured myocytes, and the ability of clonidine, an alpha-2 agonist, to inhibit forskolin stimulated cAMP production confirmed the presence of functional alpha-2 adrenergic receptors in these myocytes. In conclusion, these cultured rabbit uterine myocytes have provided an in vitro model which can be utilized to further clarify the adrenergic receptor signal transduction mechanisms in genital tract smooth muscle.

  1. Telmisartan reduces atrial arrhythmia susceptibility through the regulation of RAS-ERK and PI3K-Akt-eNOS pathways in spontaneously hypertensive rats.

    PubMed

    Wang, Wei-Wei; Zhang, Fei-Long; Chen, Jian-Hua; Chen, Xue-Hai; Fu, Fa-Yuan; Tang, Mi-Rong; Chen, Liang-Long

    2015-08-01

    Telmisartan is an angiotensin II receptor blocker that displays unique PPAR-γ modulating activity. PPAR-γ agonists have been shown to decrease susceptibility to atrial fibrillation through their antioxidant and antiapoptotic effects. The aim of this study was to determine whether telmisartan would have a greater effect on susceptibility to atrial arrhythmia in a hypertensive rat model than valsartan, which is a traditional angiotensin II receptor blocker. In this study, spontaneously hypertensive rats were treated with 10 mg·(kg body mass)(-1)·d(-1) telmisartan (TEL group), 10 mg·(kg body mass)(-1)·d(-1) valsartan (VAL group), or vehicle (saline; SHR group) for 4 weeks. Age-matched Wistar-Kyoto rats (WKY) were used as normotensive controls. After 4 weeks of treatment, we performed echocardiographic assessment, electrophysiological analysis, histological evaluation, and Western blot analysis. Telmisartan decreased systolic blood pressure to a similar extent as valsartan. Relative to the WKY controls, atrial arrhythmia susceptibility was significantly increased in the SHR group, and was significantly decreased by both telmisartan and valsartan, albeit to a greater extent with telmisartan. Arrhythmogenic atrial remodeling, including enlargement of the left atrium, myocyte hypertrophy, interstitial fibrosis, and myocyte apoptosis, was observed in the SHR group, and was accompanied by activated RAS-ERK signaling and suppressed PI3K-Akt-eNOS signaling. The results suggest that telmisartan reduced susceptibility to atrial arrhythmia to a greater extent than valsartan, ameliorated atrial remodeling, and reversed imbalances in the RAS-ERK and PI3K-Akt-eNOS pathways. PMID:26158699

  2. Extracellular Ubiquitin: Role in Myocyte Apoptosis and Myocardial Remodeling.

    PubMed

    Scofield, Stephanie L C; Amin, Parthiv; Singh, Mahipal; Singh, Krishna

    2015-01-01

    Ubiquitin (UB) is a highly conserved low molecular weight (8.5 kDa) protein. It consists of 76 amino acid residues and is found in all eukaryotic cells. The covalent linkage of UB to a variety of cellular proteins (ubiquitination) is one of the most common posttranslational modifications in eukaryotic cells. This modification generally regulates protein turnover and protects the cells from damaged or misfolded proteins. The polyubiquitination of proteins serves as a signal for degradation via the 26S proteasome pathway. UB is present in trace amounts in body fluids. Elevated levels of UB are described in the serum or plasma of patients under a variety of conditions. Extracellular UB is proposed to have pleiotropic roles including regulation of immune response, anti-inflammatory, and neuroprotective activities. CXCR4 is identified as receptor for extracellular UB in hematopoietic cells. Heart failure represents a major cause of morbidity and mortality in western society. Cardiac remodeling is a determinant of the clinical course of heart failure. The components involved in myocardial remodeling include-myocytes, fibroblasts, interstitium, and coronary vasculature. Increased sympathetic nerve activity in the form of norepinephrine is a common feature during heart failure. Acting via β-adrenergic receptor (β-AR), norepinephrine is shown to induce myocyte apoptosis and myocardial fibrosis. β-AR stimulation increases extracellular levels of UB in myocytes, and UB inhibits β-AR-stimulated increases in myocyte apoptosis and myocardial fibrosis. This review summarizes intracellular and extracellular functions of UB with particular emphasis on the role of extracellular UB in cardiac myocyte apoptosis and myocardial remodeling. PMID:26756642

  3. Hypoxic-induced stress protein expression in rat cardiac myocytes

    SciTech Connect

    Howard, G.; Geoghegan, T.E.

    1986-05-01

    Mammalian stress proteins can be induced in cells and tissues exposed to a variety of conditions including hyperthermia and diminished O/sub 2/ supply. The authors have previously shown that the expression of three stress proteins (71, 85, and 95 kDa) was induced in cardiac tissue from mice exposed to hypoxic conditions. The expression of mRNAs coding for the 85 and 95 kDa proteins increase with time of exposure to hypoxia, while the mRNA coding for the 71 kDa protein is transiently induced. The authors extended these studies to investigate the expression of stress proteins in isolated rat cardiac myocytes. Freshly prepared myocytes were exposed to control, hypoxic, anoxic, or heat-shock environments for up to 16 h. The proteins were then labeled for 6 hours with (/sup 35/S)methionine. Analysis of the solubilized proteins by SDS-PAGE and autoradiography showed that there was a 6-fold increase in synthesis of the 85 kDa protein upon exposure to hypoxia but not heat-shock conditions. The 71 kDa protein was present at high levels in both control and treated myocyte protein preparations, and presumably had been induced during the isolation procedure. Total RNA isolated from intact rat heart and isolated myocytes was compared by cell-free translation analysis and showed induction of RNAs coding for several stress proteins in the myocyte preparation. The induced proteins at 85 and 95 kDa have molecular weights similar to reported cell stress and/or glucose-regulated proteins.

  4. PKCβII Modulation of Myocyte Contractile Performance

    PubMed Central

    Hwang, Hyosook; Robinson, Dustin A; Stevenson, Tamara K; Wu, Helen C; Kampert, Sarah E; Pagani, Francis D; Dyke, D. Brad; Martin, Jody L; Sadayappan, Sakthival; Day, Sharlene M; Westfall, Margaret V

    2012-01-01

    Significant up-regulation of the protein kinase CβII (PKCβII) develops during heart failure and yet divergent functional outcomes are reported in animal models. The goal here is to investigate PKCβII modulation of contractile function and gain insights into downstream targets in adult cardiac myocytes. Increased PKCβII protein expression and phosphorylation developed after gene transfer into adult myocytes while expression remained undetectable in controls. The PKCβII was distributed in a perinuclear pattern and this expression resulted in diminished rates and amplitude of shortening and re-lengthening compared to controls and myocytes expressing dominant negative PKCβII (PKCβDN). Similar decreases were observed in the Ca2+ transient and the Ca2+ decay rate slowed in response to caffeine in PKCβII-expressing myocytes. Parallel phosphorylation studies indicated PKCβII targets phosphatase activity to reduce phospholamban (PLB) phosphorylation at residue Thr17 (pThr17-PLB). The PKCβ inhibitor, LY379196 (LY) restored pThr17-PLB to control levels. In contrast, myofilament protein phosphorylation was enhanced by PKCβII expression, and individually, LY and the phosphatase inhibitor, calyculin A each failed to block this response. Further work showed PKCβII increased Ca2+- activated, calmodulin-dependent kinase IIδ (CaMKIIδ) expression and enhanced both CaMKIIδ and protein kinase D (PKD) phosphorylation. Phosphorylation of both signaling targets also was resistant to acute inhibition by LY. These later results provide evidence PKCβII modulates contractile function via intermediate downstream pathway(s) in cardiac myocytes. PMID:22587992

  5. Left atrial appendage occlusion.

    PubMed

    Alli, Oluseun; Holmes, David

    2015-06-01

    Left atrial appendage (LAA) occlusion for stroke and thromboembolism prevention in patients with atrial fibrillation (AF) represents a significant advancement in the field of cardiovascular disease. Prevention and avoidance of the devastating consequences of thromboembolic complications from AF continues to be central in the management of these patients. The role of LAA as a nidus for thrombus formation is well documented. Multiple approaches to exclude the LAA from the circulation either percutaneously or surgically have been described and are undergoing testing. Although pharmacological therapy for stroke prevention remains the cornerstone of treatment, device and surgical exclusion of the LAA have proven to be viable alternatives in carefully selected patients. Even though current evidence show that LAA occlusion is safe and effective, approval and adoption of this strategy has been quite difficult due to paucity of randomised clinical trial data on the risk and benefit ratio, cost effectiveness and the issues of procedural risk as well as longer-term outcome. This review aims to provide an update on the current status of LAA occlusion, specifically looking at interpretation of current clinical data, available techniques and devices, issues with current devices and future direction. PMID:25518846

  6. Effect of ethanol at clinically relevant concentrations on atrial inward rectifier potassium current sensitive to acetylcholine.

    PubMed

    Bébarová, Markéta; Matejovič, Peter; Pásek, Michal; Hořáková, Zuzana; Hošek, Jan; Šimurdová, Milena; Šimurda, Jiří

    2016-10-01

    Alcohol intoxication tends to induce arrhythmias, most often the atrial fibrillation. To elucidate arrhythmogenic mechanisms related to alcohol consumption, the effect of ethanol on main components of the ionic membrane current is investigated step by step. Considering limited knowledge, we aimed to examine the effect of clinically relevant concentrations of ethanol (0.8-80 mM) on acetylcholine-sensitive inward rectifier potassium current I K(Ach). Experiments were performed by the whole-cell patch clamp technique at 23 ± 1 °C on isolated rat and guinea-pig atrial myocytes, and on expressed human Kir3.1/3.4 channels. Ethanol induced changes of I K(Ach) in the whole range of concentrations applied; the effect was not voltage dependent. The constitutively active component of I K(Ach) was significantly increased by ethanol with the maximum effect (an increase by ∼100 %) between 8 and 20 mM. The changes were comparable in rat and guinea-pig atrial myocytes and also in expressed human Kir3.1/3.4 channels (i.e., structural correlate of I K(Ach)). In the case of the acetylcholine-induced component of I K(Ach), a dual ethanol effect was apparent with a striking heterogeneity of changes in individual cells. The effect correlated with the current magnitude in control: the current was increased by eth-anol in the cells showing small current in control and vice versa. The average effect peaked at 20 mM ethanol (an increase of the current by ∼20 %). Observed changes of action potential duration agreed well with the voltage clamp data. Ethanol significantly affected both components of I K(Ach) even in concentrations corresponding to light alcohol consumption.

  7. [Perioperative management of atrial fibrillation].

    PubMed

    Arguis, M J; Navarro, R; Regueiro, A; Arbelo, E; Sierra, P; Sabaté, S; Galán, J; Ruiz, A; Matute, P; Roux, C; Gomar, C; Rovira, I; Mont, L; Fita, G

    2014-05-01

    Atrial fibrillation is a frequent complication in the perioperative period. When it appears there is an increased risk of perioperative morbidity due to stroke, thromboembolism, cardiac arrest, myocardial infarction, anticoagulation haemorrhage, and hospital readmissions. The current article focuses on the recommendations for the management of perioperative atrial fibrillation based on the latest Clinical Practice Guidelines on atrial fibrillation by the European Society of Cardiology and the Spanish Society of Cardiology. This article pays special attention to the preoperative management, as well as to the acute perioperative episode. For this reason, the latest recommendations for the control of cardiac frequency, antiarrhythmic treatment and anticoagulation are included.

  8. Type 2 Diabetes Induces Prolonged P-wave Duration without Left Atrial Enlargement.

    PubMed

    Li, Bin; Pan, Yilong; Li, Xiaodong

    2016-04-01

    Prolonged P-wave duration has been observed in diabetes. However, the underlying mechanisms remain unclear. The aim of this study was to elucidate the possible mechanisms. A rat model of type 2 diabetes mellitus (T2DM) was used. P-wave durations were obtained using surface electrocardiography and sizes of the left atrium were determined using echocardiography. Cardiac inward rectifier K(+) currents (Ik1), Na(+) currents (INa), and action potentials were recorded from isolated left atrial myocytes using patch clamp techniques. Left atrial tissue specimens were analyzed for total connexin-40 (Cx40) and connexin-43 (Cx43) expression levels on western-blots. Specimens were also analyzed for Cx40 and Cx43 distribution and interstitial fibrosis by immunofluorescent and Masson trichrome staining, respectively. The mean P-wave duration was longer in T2DM rats than in controls; however, the mean left atrial sizes of each group of rats were similar. The densities of Ik1 and INa were unchanged in T2DM rats compared to controls. The action potential duration was longer in T2DM rats, but there was no significant difference in resting membrane potential or action potential amplitude compared to controls. The expression level of Cx40 protein was significantly lower, but Cx43 was unaltered in T2DM rats. However, immunofluorescent labeling of Cx43 showed a significantly enhanced lateralization. Staining showed interstitial fibrosis was greater in T2DM atrial tissue. Prolonged P-wave duration is not dependent on the left atrial size in rats with T2DM. Dysregulation of Cx40 and Cx43 protein expression, as well as fibrosis, might partly account for the prolongation of P-wave duration in T2DM.

  9. Atrial myxomas and coronary angiography.

    PubMed

    Rafiq, Isma; Parthasarthy, H; Clark, C Grahame

    2010-07-01

    Coronary angiography is not an only important component of preoperative evaluation of the patient with underlying coronary artery disease but also diagnostic tool for delineating cardiac myxomas. This also serve as an important surgical anatomical marker. We present two cases which presented with repeated episode of chest pain, were found to have atrial blushing on coronary angiography subsequent confirmation of diagnosis of atrial myxoma on echocardiography. PMID:20578102

  10. Rhythm control in atrial fibrillation.

    PubMed

    Piccini, Jonathan P; Fauchier, Laurent

    2016-08-20

    Many patients with atrial fibrillation have substantial symptoms despite ventricular rate control and require restoration of sinus rhythm to improve their quality of life. Acute restoration (ie, cardioversion) and maintenance of sinus rhythm in patients with atrial fibrillation are referred to as rhythm control. The decision to pursue rhythm control is based on symptoms, the type of atrial fibrillation (paroxysmal, persistent, or long-standing persistent), patient comorbidities, general health status, and anticoagulation status. Many patients have recurrent atrial fibrillation and require further intervention to maintain long term sinus rhythm. Antiarrhythmic drug therapy is generally recommended as a first-line therapy and drug selection is on the basis of the presence or absence of structural heart disease or heart failure, electrocardiographical variables, renal function, and other comorbidities. In patients who continue to have recurrent atrial fibrillation despite medical therapy, catheter ablation has been shown to substantially reduce recurrent atrial fibrillation, decrease symptoms, and improve quality of life, although recurrence is common despite continued advancement in ablation techniques. PMID:27560278

  11. Rate control in atrial fibrillation.

    PubMed

    Van Gelder, Isabelle C; Rienstra, Michiel; Crijns, Harry J G M; Olshansky, Brian

    2016-08-20

    Control of the heart rate (rate control) is central to atrial fibrillation management, even for patients who ultimately require control of the rhythm. We review heart rate control in patients with atrial fibrillation, including the rationale for the intervention, patient selection, and the treatments available. The choice of rate control depends on the symptoms and clinical characteristics of the patient, but for all patients with atrial fibrillation, rate control is part of the management. Choice of drugs is patient-dependent. β blockers, alone or in combination with digoxin, or non-dihydropyridine calcium-channel blockers (not in heart failure) effectively lower the heart rate. Digoxin is least effective, but a reasonable choice for physically inactive patients aged 80 years or older, in whom other treatments are ineffective or are contraindicated, and as an additional drug to other rate-controlling drugs, especially in heart failure when instituted cautiously. Atrioventricular node ablation with pacemaker insertion for rate control should be used as an approach of last resort but is also an option early in the management of patients with atrial fibrillation treated with cardiac resynchronisation therapy. However, catheter ablation of atrial fibrillation should be considered before atrioventricular node ablation. Although rate control is a top priority and one of the first management issues for all patients with atrial fibrillation, many issues remain. PMID:27560277

  12. Rhythm control in atrial fibrillation.

    PubMed

    Piccini, Jonathan P; Fauchier, Laurent

    2016-08-20

    Many patients with atrial fibrillation have substantial symptoms despite ventricular rate control and require restoration of sinus rhythm to improve their quality of life. Acute restoration (ie, cardioversion) and maintenance of sinus rhythm in patients with atrial fibrillation are referred to as rhythm control. The decision to pursue rhythm control is based on symptoms, the type of atrial fibrillation (paroxysmal, persistent, or long-standing persistent), patient comorbidities, general health status, and anticoagulation status. Many patients have recurrent atrial fibrillation and require further intervention to maintain long term sinus rhythm. Antiarrhythmic drug therapy is generally recommended as a first-line therapy and drug selection is on the basis of the presence or absence of structural heart disease or heart failure, electrocardiographical variables, renal function, and other comorbidities. In patients who continue to have recurrent atrial fibrillation despite medical therapy, catheter ablation has been shown to substantially reduce recurrent atrial fibrillation, decrease symptoms, and improve quality of life, although recurrence is common despite continued advancement in ablation techniques.

  13. Stroke prevention in atrial fibrillation.

    PubMed

    Freedman, Ben; Potpara, Tatjana S; Lip, Gregory Y H

    2016-08-20

    Atrial fibrillation is found in a third of all ischaemic strokes, even more after post-stroke atrial fibrillation monitoring. Data from stroke registries show that both unknown and untreated or under treated atrial fibrillation is responsible for most of these strokes, which are often fatal or debilitating. Most could be prevented if efforts were directed towards detection of atrial fibrillation before stroke occurs, through screening or case finding, and treatment of all patients with atrial fibrillation at increased risk of stroke with well-controlled vitamin K antagonists or non-vitamin K antagonist anticoagulants. The default strategy should be to offer anticoagulant thromboprophylaxis to all patients with atrial fibrillation unless defined as truly low risk by simple validated risk scores, such as CHA2DS2-VASc. Assessment of bleeding risk using the HAS-BLED score should focus attention on reversible bleeding risk factors. Finally, patients need support from physicians and various other sources to start anticoagulant treatment and to ensure adherence to and persistence with treatment in the long term. PMID:27560276

  14. Compromised redox homeostasis, altered nitroso–redox balance, and therapeutic possibilities in atrial fibrillation

    PubMed Central

    Simon, Jillian N.; Ziberna, Klemen; Casadei, Barbara

    2016-01-01

    Although the initiation, development, and maintenance of atrial fibrillation (AF) have been linked to alterations in myocyte redox state, the field lacks a complete understanding of the impact these changes may have on cellular signalling, atrial electrophysiology, and disease progression. Recent studies demonstrate spatiotemporal changes in reactive oxygen species production shortly after the induction of AF in animal models with an uncoupling of nitric oxide synthase activity ensuing in the presence of long-standing persistent AF, ultimately leading to a major shift in nitroso–redox balance. However, it remains unclear which radical or non-radical species are primarily involved in the underlying mechanisms of AF or which proteins are targeted for redox modification. In most instances, only free radical oxygen species have been assessed; yet evidence from the redox signalling field suggests that non-radical species are more likely to regulate cellular processes. A wider appreciation for the distinction of these species and how both species may be involved in the development and maintenance of AF could impact treatment strategies. In this review, we summarize how redox second-messenger systems are regulated and discuss the recent evidence for alterations in redox regulation in the atrial myocardium in the presence of AF, while identifying some critical missing links. We also examine studies looking at antioxidants for the prevention and treatment of AF and propose alternative redox targets that may serve as superior therapeutic options for the treatment of AF. PMID:26786158

  15. Compromised redox homeostasis, altered nitroso-redox balance, and therapeutic possibilities in atrial fibrillation.

    PubMed

    Simon, Jillian N; Ziberna, Klemen; Casadei, Barbara

    2016-04-01

    Although the initiation, development, and maintenance of atrial fibrillation (AF) have been linked to alterations in myocyte redox state, the field lacks a complete understanding of the impact these changes may have on cellular signalling, atrial electrophysiology, and disease progression. Recent studies demonstrate spatiotemporal changes in reactive oxygen species production shortly after the induction of AF in animal models with an uncoupling of nitric oxide synthase activity ensuing in the presence of long-standing persistent AF, ultimately leading to a major shift in nitroso-redox balance. However, it remains unclear which radical or non-radical species are primarily involved in the underlying mechanisms of AF or which proteins are targeted for redox modification. In most instances, only free radical oxygen species have been assessed; yet evidence from the redox signalling field suggests that non-radical species are more likely to regulate cellular processes. A wider appreciation for the distinction of these species and how both species may be involved in the development and maintenance of AF could impact treatment strategies. In this review, we summarize how redox second-messenger systems are regulated and discuss the recent evidence for alterations in redox regulation in the atrial myocardium in the presence of AF, while identifying some critical missing links. We also examine studies looking at antioxidants for the prevention and treatment of AF and propose alternative redox targets that may serve as superior therapeutic options for the treatment of AF.

  16. Current-Voltage Relationship for Late Na(+) Current in Adult Rat Ventricular Myocytes.

    PubMed

    Clark, R B; Giles, W R

    2016-01-01

    It is now well established that the slowly inactivating component of the Na(+) current (INa-L) in the mammalian heart is a significant regulator of the action potential waveform. This insight has led to detailed studies of the role of INa-L in a number of important and challenging pathophysiological settings. These include genetically based ventricular arrhythmias (LQT 1, 2, and 3), ventricular arrhythmias arising from progressive cardiomyopathies (including diabetic), and proarrhythmic abnormalities that develop during local or global ventricular ischemia. Inhibition of INa-L may also be a useful strategy for management of atrial flutter and fibrillation. Many important biophysical parameters that characterize INa-L have been identified; and INa-L as an antiarrhythmia drug target has been studied extensively. However, relatively little information is available regarding (1) the ion transfer or current-voltage relationship for INa-L or (2) the time course of its reactivation at membrane potentials similar to the resting or diastolic membrane potential in mammalian ventricle. This chapter is based on our preliminary findings concerning these two very important physiological/biophysical descriptors for INa-L. Our results were obtained using whole-cell voltage clamp methods applied to enzymatically isolated rat ventricular myocytes. A chemical agent, BDF 9148, which was once considered to be a drug candidate in the Na(+)-dependent inotropic agent category has been used to markedly enhance INa-L current. BDF acts in a potent, selective, and reversible fashion. These BDF 9148 effects are compared and contrasted with the prototypical activator of INa-L, a sea anemone toxin, ATX II. PMID:27586292

  17. Current-Voltage Relationship for Late Na(+) Current in Adult Rat Ventricular Myocytes.

    PubMed

    Clark, R B; Giles, W R

    2016-01-01

    It is now well established that the slowly inactivating component of the Na(+) current (INa-L) in the mammalian heart is a significant regulator of the action potential waveform. This insight has led to detailed studies of the role of INa-L in a number of important and challenging pathophysiological settings. These include genetically based ventricular arrhythmias (LQT 1, 2, and 3), ventricular arrhythmias arising from progressive cardiomyopathies (including diabetic), and proarrhythmic abnormalities that develop during local or global ventricular ischemia. Inhibition of INa-L may also be a useful strategy for management of atrial flutter and fibrillation. Many important biophysical parameters that characterize INa-L have been identified; and INa-L as an antiarrhythmia drug target has been studied extensively. However, relatively little information is available regarding (1) the ion transfer or current-voltage relationship for INa-L or (2) the time course of its reactivation at membrane potentials similar to the resting or diastolic membrane potential in mammalian ventricle. This chapter is based on our preliminary findings concerning these two very important physiological/biophysical descriptors for INa-L. Our results were obtained using whole-cell voltage clamp methods applied to enzymatically isolated rat ventricular myocytes. A chemical agent, BDF 9148, which was once considered to be a drug candidate in the Na(+)-dependent inotropic agent category has been used to markedly enhance INa-L current. BDF acts in a potent, selective, and reversible fashion. These BDF 9148 effects are compared and contrasted with the prototypical activator of INa-L, a sea anemone toxin, ATX II.

  18. VEGF-C/VEGFR-3 pathway promotes myocyte hypertrophy and survival in the infarcted myocardium

    PubMed Central

    Zhao, Tieqiang; Zhao, Wenyuan; Meng, Weixin; Liu, Chang; Chen, Yuanjian; Gerling, Ivan C; Weber, Karl T; Bhattacharya, Syamal K; Kumar, Rahul; Sun, Yao

    2015-01-01

    Background: Numerous studies have shown that in addition to angio/lymphangiogenesis, the VEGF family is involved in other cellular actions. We have recently reported that enhanced VEGF-C and VEGFR-3 in the infarcted rat myocardium, suggesting the paracrine/autocrine function of VEGF-C on cardiac remodeling. The current study was designed to test the hypothesis that VEGF-C regulates cardiomyocyte growth and survival in the infarcted myocardium. Methods and results: Gene profiling and VEGFR-3 expression of cardiomyocytes were assessed by laser capture microdissection/microarray and immunohistochemistry in the normal and infarcted myocardium. The effect of VEGF-C on myocyte hypertrophy and apoptosis during normoxia and hypoxia was detected by RT-PCR and western blotting in cultured rat neonatal cardiomyocytes. VEGFR-3 was minimally expressed in cardiomyocytes of the normal and noninfarcted myocardium, while markedly elevated in the surviving cardiomyocytes of the infarcted myocardium and border zone. Genes altered in the surviving cardiomyocytes were associated with the networks regulating cellular growth and survival. VEGF-C significantly increased the expression of atrial natriuretic factor (ANP), brain natriuretic factor (BNP), and β-myosin heavy chain (MHC), markers of hypertrophy, in neonatal cardiomyocytes. Hypoxia caused neonatal cardiomyocyte atrophy, which was prevented by VEGF-C treatment. Hypoxia significantly enhanced apoptotic mediators, including cleaved caspase 3, 8, and 9, and Bax in neonatal cardiomyocytes, which were abolished by VEGF-C treatment. Conclusion: Our findings indicate that VEGF-C/VEGFR-3 pathway exerts a beneficial role in the infarcted myocardium by promoting compensatory cardiomyocyte hypertrophy and survival. PMID:26064438

  19. Carbon nanotubes instruct physiological growth and functionally mature syncytia: nongenetic engineering of cardiac myocytes.

    PubMed

    Martinelli, Valentina; Cellot, Giada; Toma, Francesca Maria; Long, Carlin S; Caldwell, John H; Zentilin, Lorena; Giacca, Mauro; Turco, Antonio; Prato, Maurizio; Ballerini, Laura; Mestroni, Luisa

    2013-07-23

    Myocardial tissue engineering currently represents one of the most realistic strategies for cardiac repair. We have recently discovered the ability of carbon nanotube scaffolds to promote cell division and maturation in cardiomyocytes. Here, we test the hypothesis that carbon nanotube scaffolds promote cardiomyocyte growth and maturation by altering the gene expression program, implementing the cell electrophysiological properties and improving networking and maturation of functional syncytia. In our study, we combine microscopy, biological and electrophysiological methodologies, and calcium imaging, to verify whether neonatal rat ventricular myocytes cultured on substrates of multiwall carbon nanotubes acquire a physiologically more mature phenotype compared to control (gelatin). We show that the carbon nanotube substrate stimulates the induction of a gene expression profile characteristic of terminal differentiation and physiological growth, with a 2-fold increase of α-myosin heavy chain (P < 0.001) and upregulation of sarcoplasmic reticulum Ca(2+) ATPase 2a. In contrast, markers of pathological hypertrophy remain unchanged (β-myosin heavy chain, skeletal α-actin, atrial natriuretic peptide). These modifications are paralleled by an increase of connexin-43 gene expression, gap junctions and functional syncytia. Moreover, carbon nanotubes appear to exert a protective effect against the pathologic stimulus of phenylephrine. Finally, cardiomyocytes on carbon nanotubes demonstrate a more mature electrophysiological phenotype of syncytia and intracellular calcium signaling. Thus, carbon nanotubes interacting with cardiomyocytes have the ability to promote physiological growth and functional maturation. These properties are unique in the current vexing field of tissue engineering, and offer unprecedented perspectives in the development of innovative therapies for cardiac repair.

  20. Integrins and Integrin-Associated Proteins in the Cardiac Myocyte

    PubMed Central

    Ross, Robert S.

    2014-01-01

    Integrins are heterodimeric, transmembrane receptors that are expressed in all cells, including those in the heart. They participate in multiple critical cellular processes including adhesion, extracellular matrix organization, signaling, survival, and proliferation. Particularly relevant for a contracting muscle cell, integrins are mechanotransducers, translating mechanical to biochemical information. While it is likely that cardiovascular clinicians and scientists have highest recognition of integrins in the cardiovascular system from drugs used to inhibit platelet aggregation, the focus of this article will be on the role of integrins specifically in the cardiac myocyte. Following a general introduction to integrin biology, the manuscript will discuss important work on integrin signaling, mechanotransduction, and lessons learned about integrin function from a range of model organisms. Then we will detail work on integrin-related proteins in the myocyte, how integrins may interact with ion channels and mediate viral uptake into cells, and also play a role in stem cell biology. Finally, we will discuss directions for future study. PMID:24481847

  1. Biology of the cardiac myocyte in heart disease

    PubMed Central

    Peter, Angela K.; Bjerke, Maureen A.; Leinwand, Leslie A.

    2016-01-01

    Cardiac hypertrophy is a major risk factor for heart failure, and it has been shown that this increase in size occurs at the level of the cardiac myocyte. Cardiac myocyte model systems have been developed to study this process. Here we focus on cell culture tools, including primary cells, immortalized cell lines, human stem cells, and their morphological and molecular responses to pathological stimuli. For each cell type, we discuss commonly used methods for inducing hypertrophy, markers of pathological hypertrophy, advantages for each model, and disadvantages to using a particular cell type over other in vitro model systems. Where applicable, we discuss how each system is used to model human disease and how these models may be applicable to current drug therapeutic strategies. Finally, we discuss the increasing use of biomaterials to mimic healthy and diseased hearts and how these matrices can contribute to in vitro model systems of cardiac cell biology. PMID:27418636

  2. pH regulation in adult cardiac myocytes

    SciTech Connect

    Wallert, M.A.

    1989-01-01

    The purpose of this study is to examine the pH{sub i} regulatory mechanisms of adult ventricular myocytes, the cells that perform the pumping work of the heart. The cell system for this study was the ventricular myocyte, isolated by enzymatic dissociation from adult rate heart. In agreement with the findings on other cardiac model cells, I demonstrated the existence of a Cl{sup {minus}}/HCO{sub 3}{sup {minus}} exchanger and a Na{sup +}/H{sup +} exchanger in ventricular myocytes. The existence of the anion exchanger was demonstrated in {sup 36}Cl{sup {minus}} flux experiments and as stilbene disulfonate-inhibitable and Cl{sup {minus}} gradient-dependent intracellular pH shifts in the presence of bicarbonate. The fluorescein derivative BCECF served as a fluorescent probe of intracellular pH in the these experiments. The existence of the Na{sup +}/H{sup +} exchanger was demonstrated in pH{sub i} experiments using BCECF. Further experiments characterized the kinetics of the Na{sup +}/H{sup +} exchanger and its regulation. The steady-state pH{sub i} of ventricular myocytes was 7.16 {+-} 0.11 at pH{sub 0} = 7.4. Several agonists caused a rise in steady-state pH{sub i}: the protein kinase stimulator phorbol myristate acetate (PMA), the {alpha}{sub 1}-adrenergic agonist 6-fluoro-norepinephrine (6F-NE) and the {beta}-agonist UK14304, and ATP.

  3. Differential radiation response of cultured endothelial cells and smooth myocytes

    SciTech Connect

    Johnson, L.K.; Longenecker, J.P.; Fajardo, L.F.

    1982-09-01

    In vivo observations have suggested that endothelial cells are the most radiosensitive elements of the vascular wall. To test whether this represents an intrinsic differential sensitivity, the response of bovine aortic endothelial cells and smooth myocytes was investigated in confluent cell cultures exposed to single doses of gamma radiation (250, 500, 1,000 or 2,000 rad). Both cell types showed a dose-dependent decrease in attachment efficiency when dissociated and replated at six hours after radiation. However, the attachment efficiency in both cell types was similar when a 72-hour postirradiation incubation period was used prior to dissociation of the cells. Growth inhibition was significantly greater (7- to 10-fold) in endothelial cells than in myocytes when examined four days after attachment. Confluent endothelial monolayers showed a dose-dependent, progressive cell loss during the 72-hour postirradiation period (70% after 1,000 rad); the myocyte cultures showed no radiation effect on the cell numbers. In spite of the reduction in number, the endothelial cells maintained the continuity of their monolayer by compensation with an increase in mean cell size. Endothelial cells developed multiple structural lesions, including an increase in the number and size of residual and lysosomal bodies, electron-lucent cytoplasmic defects, interruptions in the plasma membrane and irregular aggregation of chromatin, causing electron-lucent nuclei. These changes increased in severity with time and dose and were most pronounced 24 to 72 hours after 1,000 rad. No significant ultrastructural alterations were detected in myocytes four days after 2,000 rad.

  4. Intermyofilament dynamics of myocytes revealed by second harmonic generation microscopy.

    PubMed

    Prent, Nicole; Green, Chantal; Greenhalgh, Catherine; Cisek, Richard; Major, Arkady; Stewart, Bryan; Barzda, Virginijus

    2008-01-01

    Drosophila melanogaster larva myocytes are imaged with second harmonic generation (SHG) microscopy undergoing forced stretching and rhythmic contractions to determine the nature of the SHG signal. During stretching, double peaked SHG profiles of the anisotropic (A-) bands evolve into single peaks with a higher SHG intensity. The dip in the intensity profile at the center of the A-band is attributed to destructive interference from out-of-phase second harmonic radiating myosin molecules that, in the central region of myofilaments, are arranged antiparallel. An intensity increase at the center of the A-band appears during forced stretching due to a small, less than 100 nm, intermyofilament separation of the antiparallel myosin molecules leading to constructive interference of the SHG radiation. In addition, the same phenomenon occurs during periodic contractions of the myocyte, where an SHG intensity increase with the lengthening of sarcomeres is observed. The SHG intensity dependence on sarcomere length can be used for imaging myocyte contractions with low resolution microscopy, and can be applied for the development of diagnostic tools where monitoring of muscle contraction dynamics is required.

  5. Nanoscale Three-Dimensional Imaging of the Human Myocyte

    PubMed Central

    Sulkin, Matthew S.; Yang, Fei; Holzem, Katherine M.; Van Leer, Brandon; Bugge, Cliff; Laughner, Jacob I.; Green, Karen; Efimov, Igor R.

    2014-01-01

    The ventricular human myocyte is spatially organized for optimal ATP and Ca2+ delivery to sarcomeric myosin and ionic pumps during every excitation-contraction cycle. Comprehension of three-dimensional geometry of the tightly packed ultrastructure has been derived from discontinuous two-dimensional images, but has never been precisely reconstructed or analyzed in human myocardium. Using a focused ion beam scanning electron microscope, we created nanoscale resolution serial images to quantify the three-dimensional ultrastructure of a human left ventricular myocyte. Transverse tubules (t-tubule), lipid droplets, A-bands, and mitochondria occupy 1.8, 1.9, 10.8, and 27.9% of the myocyte volume, respectively. The complex t-tubule system has a small tortuosity (1.04 ± 0.01), and is composed of long transverse segments with diameters of 317 ± 24 nm and short branches. Our data indicates that lipid droplets located well beneath the sarcolemma are proximal to t-tubules, where 59% (13 of 22) of lipid droplet centroids are within 0.50 μm of a t-tubule. This spatial association could have an important implication in the development and treatment of heart failure because it connects two independently known pathophysiological alterations, a substrate switch from fatty acids to glucose and t-tubular derangement. PMID:25160725

  6. Electrochemical properties and myocyte interaction of carbon nanotube microelectrodes.

    PubMed

    Fung, Andrew O; Tsiokos, Christos; Paydar, Omeed; Chen, Li Han; Jin, Sungho; Wang, Yibin; Judy, Jack W

    2010-11-10

    Arrays of carbon nanotube (CNT) microelectrodes (nominal geometric surface areas 20-200 μm(2)) were fabricated by photolithography with chemical vapor deposition of randomly oriented CNTs. Raman spectroscopy showed strong peak intensities in both G and D bands (G/D = 0.86), indicative of significant disorder in the graphitic layers of the randomly oriented CNTs. The impedance spectra of gold and CNT microelectrodes were compared using equivalent circuit models. Compared to planar gold surfaces, pristine nanotubes lowered the overall electrode impedance at 1 kHz by 75%, while nanotubes treated in O(2) plasma reduced the impedance by 95%. Cyclic voltammetry in potassium ferricyanide showed potential peak separations of 133 and 198 mV for gold and carbon nanotube electrodes, respectively. The interaction of cultured cardiac myocytes with randomly oriented and vertically aligned CNTs was investigated by the sectioning of myocytes using focused-ion-beam milling. Vertically aligned nanotubes deposited by plasma-enhanced chemical vapor deposition (PECVD) were observed to penetrate the membrane of neonatal-rat ventricular myocytes, while randomly oriented CNTs remained external to the cells. These results demonstrated that CNT electrodes can be leveraged to reduce impedance and enhance biological interfaces for microelectrodes of subcellular size. PMID:20954739

  7. Mechanical properties of adult feline ventricular myocytes in culture.

    PubMed

    Pollack, P S; Carson, N L; Nuss, H B; Marino, T A; Houser, S R

    1991-01-01

    The contractile and electrophysiological properties of cultured adult feline ventricular myocytes were studied. Cells were field stimulated and contraction was measured using a video-based edge detector. The magnitude of contraction decreased by 36% and the rate of contraction decreased by 52% 2 h after the cells were plated on laminin-coated cover slips. The magnitude and rate of contraction then remained stable for 1 wk. The duration of contraction prolonged and a second component to the twitch frequently, but not invariably, developed after 5 days in culture. This was associated with prolongation of the action potential duration. After 7 days in culture, cells could be divided into two groups based on resting membrane potential. Norepinephrine increased the magnitude of contraction for 5 days after plating. Cultured ventricular myocytes became unresponsive to the effects of norepinephrine after 7 days. Adult cardiac myocytes maintained in primary culture continue to respond to field stimulation and retain many contractile properties for up to 7 days; however, the functional characteristics of these cells do not remain uniform during this time period. PMID:1992803

  8. A unified theory of calcium alternans in ventricular myocytes

    PubMed Central

    Qu, Zhilin; Liu, Michael B.; Nivala, Michael

    2016-01-01

    Intracellular calcium (Ca2+) alternans is a dynamical phenomenon in ventricular myocytes, which is linked to the genesis of lethal arrhythmias. Iterated map models of intracellular Ca2+ cycling dynamics in ventricular myocytes under periodic pacing have been developed to study the mechanisms of Ca2+ alternans. Two mechanisms of Ca2+ alternans have been demonstrated in these models: one relies mainly on fractional sarcoplasmic reticulum Ca2+ release and uptake, and the other on refractoriness and other properties of Ca2+ sparks. Each of the two mechanisms can partially explain the experimental observations, but both have their inconsistencies with the experimental results. Here we developed an iterated map model that is composed of two coupled iterated maps, which unifies the two mechanisms into a single cohesive mathematical framework. The unified theory can consistently explain the seemingly contradictory experimental observations and shows that the two mechanisms work synergistically to promote Ca2+ alternans. Predictions of the theory were examined in a physiologically-detailed spatial Ca2+ cycling model of ventricular myocytes. PMID:27762397

  9. Imatinib Activates Pathological Hypertrophy by Altering Myocyte Calcium Regulation

    PubMed Central

    Barr, Larry; Makarewich, Catherine A.; Berretta, Remus M.; Gao, Hui; Troupes, Constantine D.; Woitek, Felix; Recchia, Fabio; Kubo, Hajime; Force, Thomas; Houser, Steven R.

    2014-01-01

    Background Imatinib mesylate is a selective tyrosine-kinase inhibitor used in the treatment of multiple cancers, most notably chronic myelogenous leukemia (CML). There is evidence that imatinib can induce cardiotoxicity in cancer patients. Our hypothesis is that imatinib alters calcium regulatory mechanisms and can contribute to development of pathological cardiac hypertrophy. Methods/Results Neonatal rat ventricular myocytes (NRVMs) were treated with clinical doses (Low: 2µM, High: 5µM) of imatinib and assessed for molecular changes. Imatinib increased peak systolic Ca2+ and Ca2+ transient decay rates and Western analysis revealed significant increases in phosphorylation of phospholamban (Thr-17) and the ryanodine receptor (Ser-2814), signifying activation of CaMKII. Imatinib significantly increased NRVM volume as assessed by Coulter counter, myocyte surface area and ANP abundance seen by Western. Imatinib induced cell death, but did not activate the classical apoptotic program as assessed by caspase-3 cleavage, indicating a necrotic mechanism of death in myocytes. We expressed AdNFATc3-GFP in NRVMS and showed imatinib treatment significantly increased NFAT translocation that was inhibited by the calcineurin inhibitor FK506 or CaMKII inhibitors. Conclusion These data show that imatinib can activate pathological hypertrophic signaling pathways by altering intracellular Ca2+ dynamics. This is likely a contributing mechanism for the adverse cardiac effects of imatinib. PMID:24931551

  10. Trophic effect of human pericardial fluid on adult cardiac myocytes. Differential role of fibroblast growth factor-2 and factors related to ventricular hypertrophy.

    PubMed

    Corda, S; Mebazaa, A; Gandolfini, M P; Fitting, C; Marotte, F; Peynet, J; Charlemagne, D; Cavaillon, J M; Payen, D; Rappaport, L; Samuel, J L

    1997-11-01

    Pericardial fluid (PF) may contain myocardial growth factors that exert paracrine actions on cardiac myocytes. The aims of this study were (1) to investigate the effects of human PF and serum, collected from patients undergoing cardiac surgery, on the growth of cultured adult rat cardiac myocytes and (2) to relate the growth activity of both fluids to the adaptive changes in overloaded human hearts. Both PF and serum increased the rate of protein synthesis, measured by [14C]phenylalanine incorporation in adult rat cardiomyocytes (PF, +71.9 +/- 8.2% [n = 17]; serum, +14.9 +/- 6.5% [n = 13]; both P < .01 versus control medium). The effects of both PF and serum on cardiomyocyte growth correlated positively with the respective left ventricular (LV) mass. However, the magnitude of change with PF was 3-fold greater than with serum (P < .01). These trophic effects of PF were mimicked by exogenous basic fibroblast growth factor (FGF2) and inhibited by anti-FGF2 antibodies and transforming growth factor-beta (TGF-beta), suggesting a relationship to FGF2. In addition, FGF2 concentration in PF was 20 times greater than in serum. On the other hand, the LV mass-dependent trophic effect, present in both fluids, was independent of FGF2 concentration or other factors, such as angiotensin II, atrial natriuretic factor, and TGF-beta. These data suggest that FGF2 in human PF is a major determining factor in normal myocyte growth, whereas unidentified LV mass-dependent factor(s), present in both PF and serum, participates in the development of ventricular hypertrophy. PMID:9351441

  11. Genetics Home Reference: familial atrial fibrillation

    MedlinePlus

    ... fibrillation also increases the risk of stroke and sudden death. Complications of familial atrial fibrillation can occur at ... beats , increasing the risk of syncope, stroke, and sudden death. Most cases of atrial fibrillation are not caused ...

  12. Left atrial myxoma masquerading as viral flu

    PubMed Central

    Chhabra, Lovely; Kiernan, Francis

    2016-01-01

    Atrial myxoma is a rare cardiac tumor that may be diagnosed incidentally on cardiac imaging or may present with life-threatening cardiac symptoms. We present a case of giant left atrial myxoma that presented as a flulike illness.

  13. Altered Na/Ca exchange distribution in ventricular myocytes from failing hearts

    PubMed Central

    Gadeberg, Hanne C.; Bryant, Simon M.; James, Andrew F.

    2015-01-01

    In mammalian cardiac ventricular myocytes, Ca efflux via Na/Ca exchange (NCX) occurs predominantly at T tubules. Heart failure is associated with disrupted t-tubular structure, but its effect on t-tubular function is less clear. We therefore investigated t-tubular NCX activity in ventricular myocytes isolated from rat hearts ∼18 wk after coronary artery ligation (CAL) or corresponding sham operation (Sham). NCX current (INCX) and l-type Ca current (ICa) were recorded using the whole cell, voltage-clamp technique in intact and detubulated (DT) myocytes; intracellular free Ca concentration ([Ca]i) was monitored simultaneously using fluo-4. INCX was activated and measured during application of caffeine to release Ca from sarcoplasmic reticulum (SR). Whole cell INCX was not significantly different in Sham and CAL myocytes and occurred predominantly in the T tubules in Sham myocytes. CAL was associated with redistribution of INCX and ICa away from the T tubules to the cell surface and an increase in t-tubular INCX/ICa density from 0.12 in Sham to 0.30 in CAL myocytes. The decrease in t-tubular INCX in CAL myocytes was accompanied by an increase in the fraction of Ca sequestered by SR. However, SR Ca content was not significantly different in Sham, Sham DT, and CAL myocytes but was significantly increased by DT of CAL myocytes. In Sham myocytes, there was hysteresis between INCX and [Ca]i, which was absent in DT Sham but present in CAL and DT CAL myocytes. These data suggest altered distribution of NCX in CAL myocytes. PMID:26566728

  14. Regulation of L-type calcium channel by phospholemman in cardiac myocytes.

    PubMed

    Zhang, Xue-Qian; Wang, JuFang; Song, Jianliang; Rabinowitz, Joseph; Chen, Xiongwen; Houser, Steven R; Peterson, Blaise Z; Tucker, Amy L; Feldman, Arthur M; Cheung, Joseph Y

    2015-07-01

    We evaluated whether phospholemman (PLM) regulates L-type Ca(2+) current (ICa) in mouse ventricular myocytes. Expression of α1-subunit of L-type Ca(2+) channels between wild-type (WT) and PLM knockout (KO) hearts was similar. Compared to WT myocytes, peak ICa (at -10 mV) from KO myocytes was ~41% larger, the inactivation time constant (τ(inact)) of ICa was ~39% longer, but deactivation time constant (τ(deact)) was similar. In the presence of isoproterenol (1 μM), peak ICa was ~48% larger and τ(inact) was ~144% higher in KO myocytes. With Ba(2+) as the permeant ion, PLM enhanced voltage-dependent inactivation but had no effect on τ(deact). To dissect the molecular determinants by which PLM regulated ICa, we expressed PLM mutants by adenovirus-mediated gene transfer in cultured KO myocytes. After 24h in culture, KO myocytes expressing green fluorescent protein (GFP) had significantly larger peak ICa and longer τ(inact) than KO myocytes expressing WT PLM; thereby independently confirming the observations in freshly isolated myocytes. Compared to KO myocytes expressing GFP, KO myocytes expressing the cytoplasmic domain truncation mutant (TM43), the non-phosphorylatable S68A mutant, the phosphomimetic S68E mutant, and the signature PFXYD to alanine (ALL5) mutant all resulted in lower peak ICa. Expressing PLM mutants did not alter expression of α1-subunit of L-type Ca(2+) channels in cultured KO myocytes. Our results suggested that both the extracellular PFXYD motif and the transmembrane domain of PLM but not the cytoplasmic tail were necessary for regulation of peak ICa amplitude. We conclude that PLM limits Ca(2+) influx in cardiac myocytes by reducing maximal ICa and accelerating voltage-dependent inactivation.

  15. The Heart: Mostly Postmitotic or Mostly Premitotic? Myocyte Cell Cycle, Senescence and Quiescence

    PubMed Central

    Siddiqi, Sailay; Sussman, Mark A

    2014-01-01

    The concept of myocyte division and myocyte-mediated regeneration has re-emerged in the past five years through development of sophisticated transgenic mice and carbon-dating of cells. Although, recently, a couple of studies have been conducted as an attempt to intervene in myocyte division, the efficiency in adult animals remains discouragingly low. Re-enforcing myocyte division is a vision that has been desired for decades, leading to years of experience in myocytes resistance to pro-proliferative stimuli. Previous attempts have indeed provided a platform for basic knowledge on molecular players and signaling in myocytes. However, natural biological processes such as hypertrophy and binucleation provide layers of complexity in interpretation of previous and current findings. A major hurdle in mediating myocyte division is a lack of insight in the myocyte cell cycle. To date, no knowledge is gained on myoycte cell cycle progression and/or duration. The current review will provide an overview of previous and current literature on myocytes cell cycle and division. Furthermore, this overview will point-out the limitations of current approaches and focus on re-igniting basic questions that may be essential in understand myocardial resistance to division. PMID:25442430

  16. Impaired sinoatrial node function and increased susceptibility to atrial fibrillation in mice lacking natriuretic peptide receptor C

    PubMed Central

    Egom, Emmanuel E; Vella, Kimberly; Hua, Rui; Jansen, Hailey J; Moghtadaei, Motahareh; Polina, Iuliia; Bogachev, Oleg; Hurnik, Rhea; Mackasey, Martin; Rafferty, Sara; Ray, Gibanananda; Rose, Robert A

    2015-01-01

    , function and arrhythmogenesis using NPR-C knockout (NPR-C−/−) mice. NPR-C−/− mice are characterized by sinoatrial node (SAN) dysfunction and a profound increase in susceptibility to atrial fibrillation. Increased susceptibility to arrhythmias in NPR-C−/− mice was associated with slowed electrical conduction in the SAN as well as the right and left atria due to enhanced collagen expression and deposition in the atria (structural remodelling), but without changes in action potential morphology (electrical remodelling) in isolated SAN or atrial myocytes. This study demonstrates a critical protective role for NPR-C in the heart. PMID:25641115

  17. Neutrophil adherence to isolated adult cardiac myocytes. Induction by cardiac lymph collected during ischemia and reperfusion.

    PubMed Central

    Youker, K; Smith, C W; Anderson, D C; Miller, D; Michael, L H; Rossen, R D; Entman, M L

    1992-01-01

    Canine neutrophils can be induced to adhere in vitro to isolated adult cardiac myocytes by stimulation of the neutrophils with chemotactic factors such as zymosan-activated serum (ZAS) only if the myocytes have been previously exposed to cytokines such as interleukin 1 (IL-1) or tumor necrosis factor-alpha. These cytokines induce synthesis and surface expression of intercellular adhesion molecule-1 (ICAM-1) on the myocyte, and neutrophil adhesion is almost entirely CD18 and ICAM-1 dependent. The present study examines cardiac-specific lymph collected from awake dogs during 1-h coronary occlusion and 3 d of reperfusion for its ability to induce both ICAM-1 expression in cardiac myocytes, and neutrophil-myocyte adherence. Reperfusion lymph induced ICAM-1 expression in isolated myocytes, and myocyte adherence to ZAS-stimulated neutrophils that was completely inhibited by anti-CD18 and anti-ICAM-1 monoclonal antibodies. This activity peaked at 90 min of reperfusion and persisted for up to 72 h. Preischemic lymph was not stimulatory. IL-1 appeared not to be a stimulating factor in lymph in that dilutions of lymph were found to inhibit the stimulatory effects of recombinant IL-1 beta. However, investigation of interleukin 6 (IL-6) revealed that recombinant IL-6 stimulated myocyte adhesiveness for ZAS-stimulated neutrophils (ED50 = 0.002 U/ml) and expression of ICAM-1 by isolated myocytes. IL-6 neutralizing antibody markedly reduced the ability of reperfusion lymph to stimulate adhesion and ICAM-1 expression, and estimates of levels of IL-6 in reperfusion lymph ranged from 0.035 to 0.14 U/ml. These results indicate that cytokines capable of promoting neutrophil-myocyte adhesion occur in extracellular fluid during reperfusion of ischemic myocardium, and that one of these cytokines is IL-6. Neutrophil-myocyte adhesion may be of pathogenic significance because it may enhance the cytotoxic activity of the neutrophil. Images PMID:1346618

  18. Dominant Frequency Increase Rate Predicts Transition from Paroxysmal to Long-Term Persistent Atrial Fibrillation

    PubMed Central

    Martins, Raphael P.; Kaur, Kuljeet; Hwang, Elliot; Ramirez, Rafael J.; Willis, B. Cicero; Filgueiras-Rama, David; Ennis, Steven R.; Takemoto, Yoshio; Ponce-Balbuena, Daniela; Zarzoso, Manuel; O’Connell, Ryan P.; Musa, Hassan; Guerrero-Serna, Guadalupe; Avula, Uma Mahesh R.; Swartz, Michael F.; Bhushal, Sandesh; Deo, Makarand; Pandit, Sandeep V.; Berenfeld, Omer; Jalife, José

    2014-01-01

    Background Little is known about the mechanisms underlying the transition from paroxysmal to persistent atrial fibrillation (AF). In an ovine model of long-standing persistent AF (LS-PAF) we tested the hypothesis that the rate of electrical and/or structural remodeling, assessed by dominant frequency (DF) changes, determines the time at which AF becomes persistent. Methods and Results Self-sustained AF was induced by atrial tachypacing. Seven sheep were sacrificed 11.5±2.3 days after the transition to persistent AF and without reversal to sinus rhythm (SR); 7 sheep were sacrificed after 341.3±16.7 days of LS-PAF. Seven sham-operated animals were in SR for 1 year. DF was monitored continuously in each group. RT-PCR, western blotting, patch-clamping and histological analyses were used to determine changes in functional ion channel expression and structural remodeling. Atrial dilatation, mitral valve regurgitation, myocyte hypertrophy, and atrial fibrosis occurred progressively and became statistically significant after the transition to persistent AF, with no evidence for left ventricular dysfunction. DF increased progressively during the paroxysmal-to-persistent AF transition and stabilized when AF became persistent. Importantly, the rate of DF increase (dDF/dt) correlated strongly with the time to persistent AF. Significant action potential duration (APD) abbreviation, secondary to functional ion channel protein expression changes (CaV1.2, NaV1.5 and KV4.2 decrease; Kir2.3 increase), was already present at the transition and persisted for one-year follow up. Conclusions In the sheep model of LS-PAF, the rate of DF increase predicts the time at which AF stabilizes and becomes persistent, reflecting changes in APD and densities of sodium, L-type calcium and inward rectifier currents. PMID:24463369

  19. Accelerated fibrosis and apoptosis with ageing and in atrial fibrillation: Adaptive responses with maladaptive consequences

    PubMed Central

    XU, GUO-JUN; GAN, TIAN-YI; TANG, BAO-PENG; CHEN, ZU-HENG; MAHEMUTI, AILIMAN; JIANG, TAO; SONG, JIAN-GUO; GUO, XIA; LI, YAO-DONG; MIAO, HAI-JUN; ZHOU, XIAN-HUI; ZHANG, YU; LI, JIN-XIN

    2013-01-01

    The aim of this study was to investigate whether abnormal expression of matrix metalloproteinase (MMP)-9/tissue inhibitors of MMPs (TIMP)-1 and B cell lymphoma 2 (BCL-2)/BCL-2-associated X protein (BAX) are correlated with the characteristic accelerated fibrosis and apoptosis during ageing and in atrial fibrillation (AF). Four groups of dogs were studied: adult dogs in sinus rhythm (SR), aged dogs in SR, adult dogs with AF induced by rapid atrial pacing and aged dogs with AF induced by rapid atrial pacing. The mRNA and protein expression levels of the target gene in the left atrium were measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. Pathohistological and ultrastructural changes were assessed by light and electron microscopy. The apoptotic indices of myocytes were detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL). The mRNA and protein expression levels of MMP-9 and BAX and those of TIMP-1 and BCL-2 were significantly upregulated and down-regulated, respectively, in the aged groups compared with the adult groups. Compared with the control groups, the adult and aged groups with AF exhibited significantly increased mRNA and protein expression levels of MMP-9 and BAX and decreased expression levels of TIMP-1 and BCL-2. Samples of atrial tissue demonstrated abnormal pathohistological and ultrastructural changes, accelerated fibrosis and apoptosis. MMP-9/TIMP-1 and BCL-2/BAX hold potential for use as substrates conducive to AF and their abnormal expression plays a major role in structural remodeling of the atrium. PMID:23403858

  20. Native Intelligence

    ERIC Educational Resources Information Center

    Seven, Richard

    2006-01-01

    Amid concerns from tribal leaders that No Child Left Behind testing is squeezing out electives that have traditionally covered their history and cultures, an ambitious brace of programs is making Native America part of the core curriculum at David Wolfle Elementary School and other schools in the western Washington State. By tapping into…

  1. [Panic disorder and atrial fibrillation].

    PubMed

    Olazabal Eizaguirre, N; Chavez, R; González-Torres, M A; Gaviria, M

    2013-10-01

    This paper studies the relationship between atrial fibrillation and panic disorder. There are often doubts on the differential diagnosis in emergency services and general medical settings. Panic disorder prevalence rates have been found to be high in patients suffering from atrial fibrillation. Various studies have observed that patients diagnosed with anxiety disorders frequently have higher cardiovascular disease rates compared to the general population. Usually, patients suffering from panic disorder exhibit somatic complaints suggesting coronary disease, such as chest pain or palpitations. The aim is to make the correct diagnosis and treatment for these different illnesses, and to decrease the costs due to misdiagnosis.

  2. CT findings of atrial myxoma

    SciTech Connect

    Tsuchiya, F.; Kohno, A.; Saitoh, R.; Shigeta, A.

    1984-04-01

    The computed tomographic (CT) appearance of six atrial myxomas was analyzed. Five of the myxomas were located in the left atrium and one was in the right atrium. The margin of the myxoma was at least slightly lobulated in five cases and the content was inhomogeneous in all. Calcification was demonstrated in three cases. The site of attachment of the myxoma was demonstrated by CT to be the arial septum in all cases. The CT finding correlated well with the operative findings. It is concluded that it is possible with CT to diagnose atrial myxoma by the location and nature of the intracardiac mass and to differentiate it from thrombus.

  3. [Atrial fibrillation and physical activity].

    PubMed

    Apor, Péter

    2013-03-31

    Atrial fibrillation is the most frequent arrhythmia. Its "lone" form (when underlying pathology is not discovered) can be detected in a small percentage of endurance sports participants, and in growing numbers among veterans, probably as a result of some cardiac or other irregularities. Enhanced vagal tone and sudden sympathetic impulse, repetitive oxidative stress, inflammatory processes, enlarged atria, electric instabilization can explain the higher occurrence. Treatment of atrial fibrillation enables the affected persons to participate in regular medium-intensity exercise, 3-5 hours a week, which offers a protective role against cardiovascular, metabolic and mental illnesses. PMID:23524234

  4. Genetics of Atrial Septal Defect

    PubMed Central

    Cascos, Andrés Sánchez

    1972-01-01

    Of 109 cases of atrial septal defect, cases with an isolated defect (92 cases) showed a female preponderance (sex ratio 0·64), but there was a higher risk to the sibs of the male patients, suggesting a multifactorial mechanism. Dermatoglyphs showed a large number of whorls on the fingers. In 17 cases there were multiple malformations, such as Holt-Oram syndrome (hypoplastic and triphalangic thumb, with ostium secundum atrial septal defect), polydactyly plus ostium primum defect, and tracheo-oesophageal fistula. ImagesFIG. 1.FIG. 2.FIG. 3. PMID:4261647

  5. Laser Atrial Septostomy: An Engineering Problem

    NASA Astrophysics Data System (ADS)

    Ben-Shachar, Giora; Cohen, Mark H.; Riemenschneider, Thomas A.; Beder, Stanley D.

    1987-04-01

    The purpose of this study was to develop a reproducible method for atrial septostomy in live animals, which would be independent of both atrial septal thickness and left atrial size. Seven mongrel dogs monitored electrocardiographically were anesthetized and instrumented with systemic and pulmonary arterial lines. A modified Mullin's transseptal sheath was advanced under fluoroscopic control to interrogate the left atrium and atrial septum. A 400 micron regular quartz or a laser heated metallic tip fiber was passed through the sheath up to the atrial septum. Lasing of the atrial septum was done with an Argon laser at power output of 5 watts. In three dogs, an atrial septosomy catheter was passed to the left atrium through the laser atrial septostomy and balloon atrial septostomy was performed. The laser atrial septostomy measured 3 x 5 mm in diameter. This interatrial communication could be enlarged with a balloon septostomy to over one cm in diameter. Hemodynamic and electrocardiographic monitoring were stable during the procedure. Engineering problems included: 1) radioluscency of the laser fibers thus preventing fluoroscopic localization of the fiber course; and 2) the inability to increase lateral vaporization of the atrial septum. It is concluded that further changes in the lasing fibers need to be made before the method can be considered for clinical use.

  6. HISTONE DEACETYLASE 7 (HDAC7) REGULATES MYOCYTE MIGRATION AND DIFFERENTIATION

    PubMed Central

    Gao, Chengzhuo; Liu, Yu; Lam, Minh; Kao, Hung-Ying

    2010-01-01

    Summary Class IIa HDACs including HDAC7 play a role in gene expression, cell differentiation, and animal development through their association with transcription factors such as myogenic enhancer factors 2 (MEF2s). In this study, we show that endogenous HDAC7 localizes to both the nucleus and the cytoplasm of C2C12 myoblasts, but is exclusively retained in the cytoplasm of myotubes after completion of differentiation process. To elucidate the role of differential distribution of HDAC7 during myogenesis, we examined the effects of stably expressed HDAC7 mutants on myogenesis. Expression of nuclear-retained HDAC7 mutants significantly inhibits myogenesis in C2C12 cells and reduces the expression of muscle-specific myosin heavy chain (MHC) and myogenin. The inhibition in myocyte differentiation can be partially relieved by introduction of a mutation disrupting HDAC7:MEF2 interaction. Since phosphorylation of HDAC7 plays an important role in its nucleocytoplasmic shuttling, we further investigated the expression and distribution of phosphorylated HDAC7. To our surprise, the phosphorylation levels of HDAC7 at S344 and S479 were slightly decreased upon differentiation, whereas the phosphorylation of S178 was unchanged. Interestingly, a significant fraction of pS344- and/or pS479-HDAC7 localizes to plasma membrane of myotubes. In addition, Ser178-phosphorylated (pS178) HDAC7 shows a predominant actin filament-like staining prior to muscle differentiation and cytoplasmic and plasma membrane staining after differentiation. Consistent with this notion, HDAC7 partially co-localizes with actin filaments; in particular, pS178-HDAC7 largely colocalizes with actin filaments as indicated by phalloidin counter staining in myocytes. Furthermore, C2C12 cells expressing nuclear-retained HDAC7 display defects in migration. Our results provide novel insight into the mechanisms that regulate myocyte differentiation and migration by controlling the subcellular distribution of HDAC7 in

  7. Myocyte Dedifferentiation Drives Extraocular Muscle Regeneration in Adult Zebrafish

    PubMed Central

    Saera-Vila, Alfonso; Kasprick, Daniel S.; Junttila, Tyler L.; Grzegorski, Steven J.; Louie, Ke'ale W.; Chiari, Estelle F.; Kish, Phillip E.; Kahana, Alon

    2015-01-01

    Purpose The purpose of this study was to characterize the injury response of extraocular muscles (EOMs) in adult zebrafish. Methods Adult zebrafish underwent lateral rectus (LR) muscle myectomy surgery to remove 50% of the muscle, followed by molecular and cellular characterization of the tissue response to the injury. Results Following myectomy, the LR muscle regenerated an anatomically correct and functional muscle within 7 to 10 days post injury (DPI). Following injury, the residual muscle stump was replaced by a mesenchymal cell population that lost cell polarity and expressed mesenchymal markers. Next, a robust proliferative burst repopulated the area of the regenerating muscle. Regenerating cells expressed myod, identifying them as myoblasts. However, both immunofluorescence and electron microscopy failed to identify classic Pax7-positive satellite cells in control or injured EOMs. Instead, some proliferating nuclei were noted to express mef2c at the very earliest point in the proliferative burst, suggesting myonuclear reprogramming and dedifferentiation. Bromodeoxyuridine (BrdU) labeling of regenerating cells followed by a second myectomy without repeat labeling resulted in a twice-regenerated muscle broadly populated by BrdU-labeled nuclei with minimal apparent dilution of the BrdU signal. A double-pulse experiment using BrdU and 5-ethynyl-2′-deoxyuridine (EdU) identified double-labeled nuclei, confirming the shared progenitor lineage. Rapid regeneration occurred despite a cell cycle length of 19.1 hours, whereas 72% of the regenerating muscle nuclei entered the cell cycle by 48 hours post injury (HPI). Dextran lineage tracing revealed that residual myocytes were responsible for muscle regeneration. Conclusions EOM regeneration in adult zebrafish occurs by dedifferentiation of residual myocytes involving a muscle-to-mesenchyme transition. A mechanistic understanding of myocyte reprogramming may facilitate novel approaches to the development of molecular

  8. Resveratrol reduces intracellular free calcium concentration in rat ventricular myocytes.

    PubMed

    Liu, Zheng; Zhang, Li-Ping; Ma, Hui-Jie; Wang, Chuan; Li, Ming; Wang, Qing-Shan

    2005-10-25

    Resveratrol (trans-3, 4', 5-trihydroxy stilbene), a phytoalexin found in grape skins and red wine, has been reported to have a wide range of biological and pharmacological properties. It has been speculated that resveratrol may have cardioprotective activity. The objective of our study was to investigate the effects of resveratrol on intracellular calcium concentration ([Ca(2+)](i)) in rat ventricular myocytes. [Ca(2+)](i) was detected by laser scanning confocal microscopy. The results showed that resveratrol (15~60 mumol/L) reduced [Ca(2+)](i) in normal and Ca(2+)-free Tyrode's solution in a concentration-dependent manner. The effects of resveratrol on [Ca(2+)](i) in normal Tyrode's solution was partially inhibited by pretreatment with sodium orthovanadate (Na3VO4, 1.0 mmol/L, P<0.01), an inhibitor of protein tyrosine phosphatase, or L-type Ca(2+) channel agonist Bay K8644 (10 mumol/L, P<0.05), but could not be antagonized by NO synthase inhibitor L-NAME (1.0 mmol/L). Resveratrol also markedly inhibited the ryanodine-induced [Ca(2+)](i) increase in Ca(2+)-free Tyrode's solution (P<0.01). When Ca(2+) waves were produced by increasing extracellular Ca(2+) concentration from 1 to 10 mmol/L, resveratrol (60 mumol/L) could reduce the velocity and duration of propagating waves, and block the propagating waves of elevated [Ca(2+)](i). These results suggest that resveratrol may reduce the [Ca(2+)](i) in isolated rat ventricular myocytes. The inhibition of voltage-dependent Ca(2+) channel and tyrosine kinase, and alleviation of Ca(2+) release from sarcoplasmic reticulum (SR) are possibly involved in the effects of resveratrol on rat ventricular myocytes. These findings could help explain the protective activity of resveratrol against cardiovascular disease. PMID:16220198

  9. Defining nonvalvular atrial fibrillation: A quest for clarification.

    PubMed

    Martins, Raphaël P; Galand, Vincent; Colette, Edouard; Behar, Nathalie; Pavin, Dominique; Leclercq, Christophe; Daubert, Jean-Claude; Mabo, Philippe

    2016-08-01

    Non-vitamin K oral anticoagulants (NOACs) are currently recommended for patients with nonvalvular atrial fibrillation since the publication of the 4 major pivotal trials evaluating the efficacy and safety of factor IIa and factor Xa inhibitors. The definition of nonvalvular atrial fibrillation is unclear, varying from one trial to another and even between North American and European guidelines, which is a source of uncertainties in clinical practice. However, many patients with atrial fibrillation present signs of valvular involvement, and clarification of this term is needed to not deny NOACs to patients based on the wrong perception that they may have valvular atrial fibrillation. The currently unique contraindications to NOACs are patients with mechanical heart valves and those with moderate-to-severe mitral stenosis, as stated by the recent 2015 position paper of the European Heart Rhythm Association. Patients with native heart valve involvement, regardless of their severity, are suitable for NOAC therapy. Patients with bioprosthetic heart valves and mitral valve repair may be suitable for NOACs except for the first 3 and the first 3-6 months postoperatively, respectively. Patients with transaortic valve implantation or percutaneous transluminal aortic valvuloplasty are also considered as being eligible for NOACs, although the bleeding risk has to be carefully considered in this population often requiring a combination with antiplatelet therapy. Future studies are warranted to increase the level of evidence of use of NOACs, particularly in patients with transaortic valve implantation and valvular surgery, and to determine whether they could be used in the future in the only 2 remaining contraindications. PMID:27502864

  10. Agrin regulation of alpha3 sodium-potassium ATPase activity modulates cardiac myocyte contraction.

    PubMed

    Hilgenberg, Lutz G W; Pham, Bryan; Ortega, Maria; Walid, Saif; Kemmerly, Thomas; O'Dowd, Diane K; Smith, Martin A

    2009-06-19

    Drugs that inhibit Na,K-ATPases, such as digoxin and ouabain, alter cardiac myocyte contractility. We recently demonstrated that agrin, a protein first identified at the vertebrate neuromuscular junction, binds to and regulates the activity of alpha3 subunit-containing isoforms of the Na,K-ATPase in the mammalian brain. Both agrin and the alpha3 Na,K-ATPase are expressed in heart, but their potential for interaction and effect on cardiac myocyte function was unknown. Here we show that agrin binds to the alpha3 subunit of the Na,K-ATPase in cardiac myocyte membranes, inducing tyrosine phosphorylation and inhibiting activity of the pump. Agrin also triggers a rapid increase in cytoplasmic Na(+) in cardiac myocytes, suggesting a role in cardiac myocyte function. Consistent with this hypothesis, spontaneous contraction frequencies of cultured cardiac myocytes prepared from mice in which agrin expression is blocked by mutation of the Agrn gene are significantly higher than in the wild type. The Agrn mutant phenotype is rescued by acute treatment with recombinant agrin. Furthermore, exposure of wild type myocytes to an agrin antagonist phenocopies the Agrn mutation. These data demonstrate that the basal frequency of myocyte contraction depends on endogenous agrin-alpha3 Na,K-ATPase interaction and suggest that agrin modulation of the alpha3 Na,K-ATPase is important in regulating heart function.

  11. Protective effect of eicosapentaenoic acid on ouabain toxicity in neonatal rat cardiac myocytes

    SciTech Connect

    Hallaq, H.; Leaf, A. ); Sellmayer, A. ); Smith, T.W. )

    1990-10-01

    Isolated neonatal cardiac myocytes have been utilized as a model for the study of cardiac arrhythmogenic factors. The myocytes respond to the toxic effects of a potent cardiac glycoside, ouabain at 0.1 mM, by an increase in their spontaneous beating rate and a reduction in amplitude of contractions resulting within minutes in a lethal state of contracture. Incubating the isolated myocytes for 3{endash}5 days in culture medium enriched with 5 {mu}M arachidonic acid had no effect on the development of lethal contracture after subsequent exposure to 0.1 mM ouabain. By contrast, incubating the myocytes for 3{endash}5 days with 5 {mu}M eicosapentaenoic acid completely prevented the toxic effects of ouabain at 0.1 mM. No differences in bumetanide-inhibitable {sup 86}Rb flux were observed between the three preparations. However, measurements with fura-2 of cytosolic free calcium levels indicated that control and arachidonic acid-enriched myocytes developed toxic cytosolic calcium concentrations of 845 {plus minus} 29 and 757 {plus minus} 64 nM, respectively, on exposure to 0.1 mM ouabain, whereas in eicosapentaenoic acid-enriched myocytes, physiologic calcium levels were preserved. Incubating the myocytes with eicosapentaenoic acid for 3{endash}5 days resulted in a small reduction of arachidonic acid and a small but significant increase of eicosapentaenoic acid in membrane phospolipids of the myocytes.

  12. Facilitation by intracellular carbonic anhydrase of Na+–HCO3− co-transport but not Na+/H+ exchange activity in the mammalian ventricular myocyte

    PubMed Central

    Villafuerte, Francisco C; Swietach, Pawel; Youm, Jae-Boum; Ford, Kerrie; Cardenas, Rosa; Supuran, Claudiu T; Cobden, Philip M; Rohling, Mala; Vaughan-Jones, Richard D

    2014-01-01

    Carbonic anhydrase enzymes (CAs) catalyse the reversible hydration of CO2 to H+ and HCO3− ions. This catalysis is proposed to be harnessed by acid/base transporters, to facilitate their transmembrane flux activity, either through direct protein–protein binding (a ‘transport metabolon’) or local functional interaction. Flux facilitation has previously been investigated by heterologous co-expression of relevant proteins in host cell lines/oocytes. Here, we examine the influence of intrinsic CA activity on membrane HCO3− or H+ transport via the native acid-extruding proteins, Na+–HCO3− cotransport (NBC) and Na+/H+ exchange (NHE), expressed in enzymically isolated mammalian ventricular myocytes. Effects of intracellular and extracellular (exofacial) CA (CAi and CAe) are distinguished using membrane-permeant and –impermeant pharmacological CA inhibitors, while measuring transporter activity in the intact cell using pH and Na+ fluorophores. We find that NBC, but not NHE flux is enhanced by catalytic CA activity, with facilitation being confined to CAi activity alone. Results are quantitatively consistent with a model where CAi catalyses local H+ ion delivery to the NBC protein, assisting the subsequent (uncatalysed) protonation and removal of imported HCO3− ions. In well-superfused myocytes, exofacial CA activity is superfluous, most likely because extracellular CO2/HCO3− buffer is clamped at equilibrium. The CAi insensitivity of NHE flux suggests that, in the native cell, intrinsic mobile buffer-shuttles supply sufficient intracellular H+ ions to this transporter, while intrinsic buffer access to NBC proteins is restricted. Our results demonstrate a selective CA facilitation of acid/base transporters in the ventricular myocyte, implying a specific role for the intracellular enzyme in HCO3− transport, and hence pHi regulation in the heart. PMID:24297849

  13. Facilitation by intracellular carbonic anhydrase of Na+ -HCO3- co-transport but not Na+ / H+ exchange activity in the mammalian ventricular myocyte.

    PubMed

    Villafuerte, Francisco C; Swietach, Pawel; Youm, Jae-Boum; Ford, Kerrie; Cardenas, Rosa; Supuran, Claudiu T; Cobden, Philip M; Rohling, Mala; Vaughan-Jones, Richard D

    2014-03-01

    Carbonic anhydrase enzymes (CAs) catalyse the reversible hydration of CO2 to H+ and HCO3- ions. This catalysis is proposed to be harnessed by acid/base transporters, to facilitate their transmembrane flux activity, either through direct protein-protein binding (a 'transport metabolon') or local functional interaction. Flux facilitation has previously been investigated by heterologous co-expression of relevant proteins in host cell lines/oocytes. Here, we examine the influence of intrinsic CA activity on membrane HCO3- or H+ transport via the native acid-extruding proteins, Na+ -HCO3- cotransport (NBC) and Na+ / H+ exchange (NHE), expressed in enzymically isolated mammalian ventricular myocytes. Effects of intracellular and extracellular (exofacial) CA (CAi and CAe) are distinguished using membrane-permeant and -impermeant pharmacological CA inhibitors, while measuring transporter activity in the intact cell using pH and Na+ fluorophores. We find that NBC, but not NHE flux is enhanced by catalytic CA activity, with facilitation being confined to CAi activity alone. Results are quantitatively consistent with a model where CAi catalyses local H+ ion delivery to the NBC protein, assisting the subsequent (uncatalysed) protonation and removal of imported HCO3- ions. In well-superfused myocytes, exofacial CA activity is superfluous, most likely because extracellular CO2/HCO3- buffer is clamped at equilibrium. The CAi insensitivity of NHE flux suggests that, in the native cell, intrinsic mobile buffer-shuttles supply sufficient intracellular H+ ions to this transporter, while intrinsic buffer access to NBC proteins is restricted. Our results demonstrate a selective CA facilitation of acid/base transporters in the ventricular myocyte, implying a specific role for the intracellular enzyme in HCO3- transport, and hence pHi regulation in the heart.

  14. Native Skies

    NASA Astrophysics Data System (ADS)

    Benningfield, Damond

    2001-03-01

    People native to North America practiced their own version of astronomy. They tracked the motions of the Sun to help them decide when to plant crops, move their camps, and stage sacred rituals. Some tribes built great circles of stones to help them predict the changing seasons. Others built great mounds of earth to reflect the patterns they saw in the heavens and to align their ceremonial centers with the Sun and the Moon.

  15. A Role for Myosin V Motor Proteins in the Selective Delivery of Kv Channel Isoforms to the Membrane Surface of Cardiac Myocytes

    PubMed Central

    Schumacher-Bass, Sarah M.; Vesely, Eileen D.; Zhang, Lian; Ryland, Katherine E.; McEwen, Dyke P.; Chan, Priscilla J.; Frasier, Chad R.; McIntyre, Jeremy C.; Shaw, Robin M.; Martens, Jeffrey R.

    2014-01-01

    Rationale Kv1.5 (KCNA5) mediates the IKur current that controls atrial action potential duration. Given its atrial-specific expression and alterations in human atrial fibrillation (AF), Kv1.5 has emerged as a promising target for the treatment of AF. A necessary step in the development of novel agents that selectively modulate trafficking pathways is the identification of the cellular machinery controlling Kv1.5 surface density, of which little is yet known. Objective To investigate the role of the unconventional myosin V (MYO5A and MYO5B) motors in determining the cell surface density of Kv1.5. Methods and Results Western Blot analysis showed MYO5A and MYO5B expression in the heart, while disruption of endogenous motors selectively reduced IKur current in adult rat cardiomyocytes. Dominant negative constructs and shRNA silencing demonstrated a role for MYO5A and MYO5B in the surface trafficking of Kv1.5 and Connexin-43 (Cx43), but not hERG (KCNH2). Live-cell imaging of Kv1.5-GFP and retrospective labeling of phalloidin demonstrated motility of Kv1.5 vesicles on actin tracts. MYO5A participated in anterograde trafficking, while MYO5B regulated post-endocytic recycling. Over-expression of mutant motors revealed a selective role for Rab11 in coupling MYO5B to Kv1.5 recycling. Conclusions MYO5A and MYO5B control functionally distinct steps in the surface trafficking of Kv1.5. These isoform-specific trafficking pathways determine Kv1.5-encoded IKur in myocytes to regulate repolarizing current, and consequently, cardiac excitability. Therapeutic strategies that manipulate Kv1.5 selective trafficking pathways may prove useful in the treatment of arrhythmias. PMID:24508725

  16. Continual electric field stimulation preserves contractile function of adult ventricular myocytes in primary culture.

    PubMed

    Berger, H J; Prasad, S K; Davidoff, A J; Pimental, D; Ellingsen, O; Marsh, J D; Smith, T W; Kelly, R A

    1994-01-01

    To model with greater fidelity the electromechanical function of freshly isolated heart muscle cells in primary culture, we describe a technique for the continual electrical stimulation of adult myocytes at physiological frequencies for several days. A reusable plastic cover was constructed to fit standard, disposable 175-cm2 tissue culture flasks and to hold parallel graphite electrodes along the long axis of each flask, which treated a uniform electric field that resulted in a capture efficiency of ventricular myocytes of 75-80%. Computer-controlled amplifiers were designed to be capable of driving a number of flasks concurrently, each containing up to 4 x 10(6) myocytes, over a range of stimulation frequencies (from 0.1 to 7.0 Hz) with reversal of electrode polarity after each stimulus to prevent the development of pH gradients around each electrode. Unlike quiescent, unstimulated myocytes, the amplitude of contraction, and velocities of shortening and relaxation did not change in myocytes paced at 3-5 Hz for up to 72 h. The maintenance of normal contractile function in paced myocytes required mechanical contraction per se, since paced myocytes that remained quiescent due to the inclusion of 2.5 microM verapamil in the culture medium for 48 h also exhibited a decline in contractility when paced after verapamil removal. Similarly, pacing increased peak calcium current compared with quiescent cells that had not been paced. Thus myocyte contraction at physiological frequencies induced by continual uniform electric field stimulation in short-term primary culture in defining medium maintains some biophysical parameters of myocyte phenotype that are similar to those observed in freshly isolated adult ventricular myocytes.

  17. Nitrate-containing beetroot enhances myocyte metabolism and mitochondrial content

    PubMed Central

    Vaughan, Roger A.; Gannon, Nicholas P.; Carriker, Colin R.

    2015-01-01

    Beetroot (甜菜 tián cài) juice consumption is of current interest for improving aerobic performance by acting as a vasodilator and possibly through alterations in skeletal muscle metabolism and physiology. This work explored the effects of a commercially available beetroot supplement on metabolism, gene expression, and mitochondrial content in cultured myocytes. C2C12 myocytes were treated with various concentrations of the beetroot supplement for various durations. Glycolytic metabolism and oxidative metabolism were quantified via measurement of extracellular acidification and oxygen consumption, respectively. Metabolic gene expression was measured using quantitative reverse transcription–polymerase chain reaction, and mitochondrial content was assessed with flow cytometry and confocal microscopy. Cells treated with beetroot exhibited significantly increased oxidative metabolism, concurrently with elevated metabolic gene expression including peroxisome proliferator-activated receptor gamma coactivator-1 alpha, nuclear respiratory factor 1, mitochondrial transcription factor A, and glucose transporter 4, leading to increased mitochondrial biogenesis. Our data show that treatment with a beetroot supplement increases basal oxidative metabolism. Our observations are also among the first to demonstrate that beetroot extract is an inducer of metabolic gene expression and mitochondrial biogenesis. These observations support the need for further investigation into the therapeutic and pharmacological effects of nitrate-containing supplements for health and athletic benefits. PMID:26870674

  18. Microfluidic partitioning of the extracellular space around single cardiac myocytes.

    PubMed

    Klauke, Norbert; Smith, Godfrey L; Cooper, Jonathan M

    2007-02-01

    This paper describes the partitioning of the extracellular space around an electrically activated single cardiac myocyte, constrained within a microfluidic device. Central to this new method is the production of a hydrophobic gap-structure, which divides the extracellular space into two distinct microfluidic pools. The content of these pools was controlled using a pair of concentric automated pipets (subsequently called "dual superfusion pipet"), each providing the ability to dispense (i.e., the source, inner pipet) and aspirate (the sink, outer pipet) a buffer solution (perfusate) into each of the two pools. For rapid solution switching around the cell, additional dual superfusion pipets were inserted into the microchannel for defined time periods using a piezostepper, enabling us to add a test solution, such as a drug. Three distinct areas of the cell were manipulated, namely, the microfluidic environment, the cellular membrane, and the intracellular space. Planar integrated microelectrodes enabled the electrical stimulation of the cardiomyocyte and the recording of the evoked action potential. The device was mounted on an inverted microscope to allow simultaneous sarcomere length and epifluorescence measurements during evoked electrical activity, including, for example, the response of the stimulated end of the cardiac myocyte in comparison with the untreated cell end.

  19. Nitrate-containing beetroot enhances myocyte metabolism and mitochondrial content.

    PubMed

    Vaughan, Roger A; Gannon, Nicholas P; Carriker, Colin R

    2016-01-01

    Beetroot ( tián cài) juice consumption is of current interest for improving aerobic performance by acting as a vasodilator and possibly through alterations in skeletal muscle metabolism and physiology. This work explored the effects of a commercially available beetroot supplement on metabolism, gene expression, and mitochondrial content in cultured myocytes. C2C12 myocytes were treated with various concentrations of the beetroot supplement for various durations. Glycolytic metabolism and oxidative metabolism were quantified via measurement of extracellular acidification and oxygen consumption, respectively. Metabolic gene expression was measured using quantitative reverse transcription-polymerase chain reaction, and mitochondrial content was assessed with flow cytometry and confocal microscopy. Cells treated with beetroot exhibited significantly increased oxidative metabolism, concurrently with elevated metabolic gene expression including peroxisome proliferator-activated receptor gamma coactivator-1 alpha, nuclear respiratory factor 1, mitochondrial transcription factor A, and glucose transporter 4, leading to increased mitochondrial biogenesis. Our data show that treatment with a beetroot supplement increases basal oxidative metabolism. Our observations are also among the first to demonstrate that beetroot extract is an inducer of metabolic gene expression and mitochondrial biogenesis. These observations support the need for further investigation into the therapeutic and pharmacological effects of nitrate-containing supplements for health and athletic benefits. PMID:26870674

  20. Myocyte repolarization modulates myocardial function in aging dogs.

    PubMed

    Sorrentino, Andrea; Signore, Sergio; Qanud, Khaled; Borghetti, Giulia; Meo, Marianna; Cannata, Antonio; Zhou, Yu; Wybieralska, Ewa; Luciani, Marco; Kannappan, Ramaswamy; Zhang, Eric; Matsuda, Alex; Webster, Andrew; Cimini, Maria; Kertowidjojo, Elizabeth; D'Alessandro, David A; Wunimenghe, Oriyanhan; Michler, Robert E; Royer, Christopher; Goichberg, Polina; Leri, Annarosa; Barrett, Edward G; Anversa, Piero; Hintze, Thomas H; Rota, Marcello

    2016-04-01

    Studies of myocardial aging are complex and the mechanisms involved in the deterioration of ventricular performance and decreased functional reserve of the old heart remain to be properly defined. We have studied a colony of beagle dogs from 3 to 14 yr of age kept under a highly regulated environment to define the effects of aging on the myocardium. Ventricular, myocardial, and myocyte function, together with anatomical and structural properties of the organ and cardiomyocytes, were evaluated. Ventricular hypertrophy was not observed with aging and the structural composition of the myocardium was modestly affected. Alterations in the myocyte compartment were identified in aged dogs, and these factors negatively interfere with the contractile reserve typical of the young heart. The duration of the action potential is prolonged in old cardiomyocytes contributing to the slower electrical recovery of the myocardium. Also, the remodeled repolarization of cardiomyocytes with aging provides inotropic support to the senescent muscle but compromises its contractile reserve, rendering the old heart ineffective under conditions of high hemodynamic demand. The defects in the electrical and mechanical properties of cardiomyocytes with aging suggest that this cell population is an important determinant of the cardiac senescent phenotype. Collectively, the delayed electrical repolarization of aging cardiomyocytes may be viewed as a critical variable of the aging myopathy and its propensity to evolve into ventricular decompensation under stressful conditions.

  1. Two Types of Calcium Channels in Guinea Pig Ventricular Myocytes

    NASA Astrophysics Data System (ADS)

    Mitra, Raman; Morad, Martin

    1986-07-01

    In cardiac muscle, Ca2+ plays a key role in regulation of numerous processes, including generation of the action potential and development of tension. The entry of Ca2+ into the cell is regulated primarily by voltage-gated channels in the membrane. Until recently, it was felt that only one type of Ca2+ channel existed in cardiac ventricular muscle. Experiments reported here suggest that in isolated guinea pig ventricular myocytes, there are two distinct types of Ca2+ channels with markedly different activation thresholds, inactivation kinetics, and sensitivities to inorganic and organic Ca2+ channel blockers. The channels were also distinguished based on their response to increased frequency of clamping such that the current through the low-threshold channel decreased while that through the high-threshold channel increased. In a few cells, the current through both channels was enhanced by isoproterenol, a β -adrenergic agonist, but only the high-threshold channel was enhanced by the Ca2+-channel agonist Bay K 8644. Thus, isolated guinea pig ventricular myocytes appear to have two types of Ca2+ channels distinguished by various criteria.

  2. Dioxin (TCDD) enhances triggered-afterdepolarizations in rat ventricular myocytes

    PubMed Central

    Xie, An; Walker, Nigel J.; Wang, Desuo

    2007-01-01

    The effects of TCDD (2,3,7,8-Tetrachlorodibenzo-p-dioxin) on action potential and afterdepolarizations were studied in rat ventricular myocytes using nystatin-perforated whole-cell patch-clamp technique. TCDD treatment, in the concentration range of 1 to 100 nM, significantly prolonged action potential duration measured at 90% of repolarization (APD90). The triggered delayed-afterdepolarizations (DADs) was observed in 6 out of 8 cells after exposure of TCDD (10 nM). In the presence of isoproterenol (ISO, 10 nM) or Bay K 8644 (1 μM), TCDD (10 nM) markedly augmented the amplitude and frequency of the arrhythmogenic DADs and triggered sustained spontaneous firings in ventricular myocytes. Voltage-clamp data indicated that TCDD (10 nM) exposure significantly enhanced the transient inward current (Iti). The triggered early-afterdepolarizations (EADs) were evoked only in cells simultaneously exposed to TCDD (10 nM) and ISO (or Bay K 8644). Further study indicated that TCDD treatment increased L-type Ca2+ current. These results indicate that activation of TCDD signaling pathway can prolong action potential duration and cause abnormal triggered afterdepolarizations. These effects may lead to clinically relevant ventricular arrhythmia especially when susceptible individuals are under elevated sympathetic stress or suffering from other myocardiopathies coincided with Ca2+-overload. PMID:17303918

  3. Calcium and IP3 dynamics in cardiac myocytes: experimental and computational perspectives and approaches.

    PubMed

    Hohendanner, Felix; McCulloch, Andrew D; Blatter, Lothar A; Michailova, Anushka P

    2014-01-01

    lays in quantitative differences of local [Ca(2+)] in the nuclear and cytosolic compartment. In this review, we discuss the state of knowledge regarding the origin and the physiological implications of nuclear Ca(2+) transients in different cardiac cell types (adult atrial and ventricular myocytes) as well as experimental and mathematical approaches to study Ca(2+) and IP3 signaling in the cytosol and nucleus. In particular, we focus on the concept that highly localized Ca(2+) signals are required to translocate and activate Ca(2+)-dependent transcription factors (e.g., nuclear factor of activated T-cells, NFAT; histone deacetylase, HDAC) through phosphorylation/dephosphorylation processes. PMID:24639654

  4. Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling

    PubMed Central

    Essick, Eric E.; Ouchi, Noriyuki; Wilson, Richard M.; Ohashi, Koji; Ghobrial, Joanna; Shibata, Rei; Pimentel, David R.

    2011-01-01

    Reactive oxygen species (ROS) induce matrix metalloproteinase (MMP) activity that mediates hypertrophy and cardiac remodeling. Adiponectin (APN), an adipokine, modulates cardiac hypertrophy, but it is unknown if APN inhibits ROS-induced cardiomyocyte remodeling. We tested the hypothesis that APN ameliorates ROS-induced cardiomyocyte remodeling and investigated the mechanisms involved. Cultured adult rat ventricular myocytes (ARVM) were pretreated with recombinant APN (30 μg/ml, 18 h) followed by exposure to physiologic concentrations of H2O2 (1–200 μM). ARVM hypertrophy was measured by [3H]leucine incorporation and atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) gene expression by RT-PCR. MMP activity was assessed by in-gel zymography. ROS was induced with angiotensin (ANG)-II (3.2 mg·kg−1·day−1 for 14 days) in wild-type (WT) and APN-deficient (APN-KO) mice. Myocardial MMPs, tissue inhibitors of MMPs (TIMPs), p-AMPK, and p-ERK protein expression were determined. APN significantly decreased H2O2-induced cardiomyocyte hypertrophy by decreasing total protein, protein synthesis, ANF, and BNP expression. H2O2-induced MMP-9 and MMP-2 activities were also significantly diminished by APN. APN significantly increased p-AMPK in both nonstimulated and H2O2-treated ARVM. H2O2-induced p-ERK activity and NF-κB activity were both abrogated by APN pretreatment. ANG II significantly decreased myocardial p-AMPK and increased p-ERK expression in vivo in APN-KO vs. WT mice. ANG II infusion enhanced cardiac fibrosis and MMP-2-to-TIMP-2 and MMP-9-to-TIMP-1 ratios in APN-KO vs. WT mice. Thus APN inhibits ROS-induced cardiomyocyte remodeling by activating AMPK and inhibiting ERK signaling and NF-κB activity. Its effects on ROS and ultimately on MMP expression define the protective role of APN against ROS-induced cardiac remodeling. PMID:21666115

  5. [Prophylaxis of thromboembolism in atrial fibrillation: new oral anticoagulants and left atrial appendage closure].

    PubMed

    Zeus, Tobias; Kelm, Malte; Bode, Christoph

    2015-08-01

    Thrombo-embolic prophylaxis is a key element within the therapy of atrial fibrillation/atrial flutter. Besides new oral anticoagulants the concept of left atrial appendage occlusion has approved to be a good alternative option, especially in patients with increased risk of bleeding. PMID:26261929

  6. Is there a relationship between atrial septal aneurysm and atrial tachycardia?

    PubMed

    Muser, Daniele; De Biasio, Marzia; Rebellato, Luca; Proclemer, Alessandro

    2011-09-01

    We describe the case of a 37-year-old woman with atrial tachycardia associated to atrial septal aneurysm. We consider a localized reentry mechanism as the pathogenetic mechanism of the arrhythmia as demostrated by means of electrophisiological evaluation and electroanatomical mapping. The treatment by radiofrequency appears as an effective and well tolerated treatment of this unusual left atrial tachycardia.

  7. Successful cryoablation of an incessant atrial tachycardia arising from the right atrial appendage

    PubMed Central

    Roshan, John; Gizurarson, Sigfus; Das, Moloy; Chauhan, Vijay S.

    2015-01-01

    The right atrial appendage can be the origin of focal atrial tachycardias. Their ablation can be challenging owing to the complexity of the appendage anatomy. To our knowledge, we describe the first successful solid tip cryoablation of a focal tachycardia within the right atrial appendage in a patient presenting with tachycardia-induced cardiomyopathy. PMID:26937112

  8. Evaluating the Atrial Myopathy Underlying Atrial Fibrillation: Identifying the Arrhythmogenic and Thrombogenic Substrate.

    PubMed

    Goldberger, Jeffrey J; Arora, Rishi; Green, David; Greenland, Philip; Lee, Daniel C; Lloyd-Jones, Donald M; Markl, Michael; Ng, Jason; Shah, Sanjiv J

    2015-07-28

    Atrial disease or myopathy forms the substrate for atrial fibrillation (AF) and underlies the potential for atrial thrombus formation and subsequent stroke. Current diagnostic approaches in patients with AF focus on identifying clinical predictors with the evaluation of left atrial size by echocardiography serving as the sole measure specifically evaluating the atrium. Although the atrial substrate underlying AF is likely developing for years before the onset of AF, there is no current evaluation to identify the preclinical atrial myopathy. Atrial fibrosis is 1 component of the atrial substrate that has garnered recent attention based on newer MRI techniques that have been applied to visualize atrial fibrosis in humans with prognostic implications regarding the success of treatment. Advanced ECG signal processing, echocardiographic techniques, and MRI imaging of fibrosis and flow provide up-to-date approaches to evaluate the atrial myopathy underlying AF. Although thromboembolic risk is currently defined by clinical scores, their predictive value is mediocre. Evaluation of stasis via imaging and biomarkers associated with thrombogenesis may provide enhanced approaches to assess risk for stroke in patients with AF. Better delineation of the atrial myopathy that serves as the substrate for AF and thromboembolic complications might improve treatment outcomes. Furthermore, better delineation of the pathophysiologic mechanisms underlying the development of the atrial substrate for AF, particularly in its earlier stages, could help identify blood and imaging biomarkers that could be useful to assess risk for developing new-onset AF and suggest specific pathways that could be targeted for prevention.

  9. Evaluating the Atrial Myopathy Underlying Atrial Fibrillation: Identifying the Arrhythmogenic and Thrombogenic Substrate.

    PubMed

    Goldberger, Jeffrey J; Arora, Rishi; Green, David; Greenland, Philip; Lee, Daniel C; Lloyd-Jones, Donald M; Markl, Michael; Ng, Jason; Shah, Sanjiv J

    2015-07-28

    Atrial disease or myopathy forms the substrate for atrial fibrillation (AF) and underlies the potential for atrial thrombus formation and subsequent stroke. Current diagnostic approaches in patients with AF focus on identifying clinical predictors with the evaluation of left atrial size by echocardiography serving as the sole measure specifically evaluating the atrium. Although the atrial substrate underlying AF is likely developing for years before the onset of AF, there is no current evaluation to identify the preclinical atrial myopathy. Atrial fibrosis is 1 component of the atrial substrate that has garnered recent attention based on newer MRI techniques that have been applied to visualize atrial fibrosis in humans with prognostic implications regarding the success of treatment. Advanced ECG signal processing, echocardiographic techniques, and MRI imaging of fibrosis and flow provide up-to-date approaches to evaluate the atrial myopathy underlying AF. Although thromboembolic risk is currently defined by clinical scores, their predictive value is mediocre. Evaluation of stasis via imaging and biomarkers associated with thrombogenesis may provide enhanced approaches to assess risk for stroke in patients with AF. Better delineation of the atrial myopathy that serves as the substrate for AF and thromboembolic complications might improve treatment outcomes. Furthermore, better delineation of the pathophysiologic mechanisms underlying the development of the atrial substrate for AF, particularly in its earlier stages, could help identify blood and imaging biomarkers that could be useful to assess risk for developing new-onset AF and suggest specific pathways that could be targeted for prevention. PMID:26216085

  10. Evaluating the Atrial Myopathy Underlying Atrial Fibrillation: Identifying the Arrhythmogenic and Thrombogenic Substrate

    PubMed Central

    Goldberger, Jeffrey J.; Arora, Rishi; Green, David; Greenland, Philip; Lee, Daniel C.; Lloyd-Jones, Donald M.; Markl, Michael; Ng, Jason; Shah, Sanjiv J.

    2015-01-01

    Atrial disease or myopathy forms the substrate for atrial fibrillation (AF) and underlies the potential for atrial thrombus formation and subsequent stroke. Current diagnostic approaches in patients with AF focus on identifying clinical predictors with evaluation of left atrial size by echocardiography serving as the sole measure specifically evaluating the atrium. Although the atrial substrate underlying AF is likely developing for years prior to the onset of AF, there is no current evaluation to identify the pre-clinical atrial myopathy. Atrial fibrosis is one component of the atrial substrate that has garnered recent attention based on newer MRI techniques that have been applied to visualize atrial fibrosis in humans with prognostic implications regarding success of treatment. Advanced ECG signal processing, echocardiographic techniques, and MRI imaging of fibrosis and flow provide up-to-date approaches to evaluate the atrial myopathy underlying AF. While thromboembolic risk is currently defined by clinical scores, their predictive value is mediocre. Evaluation of stasis via imaging and biomarkers associated with thrombogenesis may provide enhanced approaches to assess risk for stroke in patients with AF. Better delineation of the atrial myopathy that serves as the substrate for AF and thromboembolic complications might improve treatment outcomes. Furthermore, better delineation of the pathophysiologic mechanisms underlying the development of the atrial substrate for AF, particularly in its earlier stages, could help identify blood and imaging biomarkers that could be useful to assess risk for developing new onset AF and suggest specific pathways that could be targeted for prevention. PMID:26216085

  11. Neutrophil adherence to isolated adult canine myocytes. Evidence for a CD18-dependent mechanism.

    PubMed Central

    Entman, M L; Youker, K; Shappell, S B; Siegel, C; Rothlein, R; Dreyer, W J; Schmalstieg, F C; Smith, C W

    1990-01-01

    Cardiac myocytes were isolated from adult dogs and incubated with isolated canine neutrophils (PMN). Intercellular adhesion was low and unchanged by stimulation of the PMN with zymosan activated serum or platelet activating factor (PAF) at concentrations that significantly enhance PMN adhesion to protein-coated glass and canine endothelial cell monolayers. Intercellular adhesion was significantly increased only when both myocytes and PMN were stimulated (e.g., myocytes incubated with IL-1, tumor necrosis factor, or phorbol myristate acetate, and PMN were chemotactically stimulated). Inhibitors of protein synthesis diminished the IL-1 beta-induced effect by greater than 80%. The IL-1 beta, PAF-stimulated PMN-myocyte adhesion was associated with substantial H2O2 production. Under conditions with low PMN-myocyte adhesion (i.e., IL-1 beta alone, PAF alone, or no stimulus) H2O2 production was generally less than 5% of that occurring with high adhesion. An anti-CD18 monoclonal antibody (R15.7) inhibited stimulated PMN-myocyte adhesion by greater than 95% and reduced H2O2 production by greater than 90%. Control isotype-matched, binding, and nonbinding antibodies were without effect on adherence or H2O2 production. The results indicate that cytokine stimulation of adult myocytes induces expression of a ligand involved in CD18-dependent adherence of canine neutrophils. Images PMID:1970581

  12. Atrial Fibrillation - Multiple Languages: MedlinePlus

    MedlinePlus

    ... Atrial Fibrillation (Arabic) العربية Bilingual PDF Health Information Translations Chinese - Simplified (简体中文) Atrial Fibrillation 心房纤维颤动 - 简体中文 (Chinese - Simplified) Bilingual PDF Health Information Translations Chinese - Traditional (繁體中文) Atrial Fibrillation 心房纖維顫動 - 繁體中文 (Chinese - ...

  13. Almanac 2015: atrial fibrillation research in Heart

    PubMed Central

    Jawad-Ul-Qamar, Muhammad; Kirchhof, Paulus

    2016-01-01

    Atrial fibrillation continues to attract interest in the cardiovascular community and in Heart. Over 60 original research and review papers published in Heart in 2014–2015 cover various aspects of atrial fibrillation, from associated conditions and precipitating factors to new approaches to management. Here, we provide an overview of articles on atrial fibrillation published in Heart in 2014–2015, highlighting new developments, emerging concepts and novel approaches to treatment. PMID:26791994

  14. Stimulation of isolated ventricular myocytes within an open architecture microarray.

    PubMed

    Klauke, Norbert; Smith, Godfrey L; Cooper, Jonathan M

    2005-03-01

    This paper is concerned with the physiological responses of single heart cells within microfluidic chambers, in response to stimulation by integrated microelectrodes. To enable these investigations, which included the measurement of action potential duration, intracellular Ca2+ and cell shortening, a series of microfluidic chambers (50 microm wide, 180 microm long, 400 microm high, 500 microm pitch) and connecting channels (200 microm wide, 5000 microm long, 50 microm high, 500 microm pitch) were replica-moulded into the silicone elastomer, polydimethylsiloxane (PDMS). The structures were formed against a master of posts and lines, photolithograhically patterned into the high aspect ratio photoresist SU-8. The chambers within the slab of PDMS were aligned against pairs of stimulating gold microelectrodes (50 microm long, 20 microm wide, 0.1-10 microm thick, 180 microm apart) patterned on a microscope coverslip base, thus defining cavities of approximately 4 nL volume. The assembly was filled with physiological saline and single isolated rabbit ventricular myocytes were introduced by micropipetting, thus creating limited volumes of saline above individual myocytes that could be varied between 4 nL and > or = 4 microL. The application of transient current pulses to the cells via the electrodes caused transient contractions with constant amplitude (recorded as changes in sarcomere length), confirming that excitation contraction coupling (EC coupling) remained functional in these limited volumes. Continuous monitoring of the intracellular Ca2+ (using calcium sensitive dyes) showed, that in the absence of bath perfusion, the amplitude of the transients remained constant for approximately 3 min in the 4-nL volume and approximately 20 min for the 4 microL volume. Beyond this time, the cells became unexcitable until the bath was renewed. The action potential duration (APD) was recorded at stimulation frequencies of 1 Hz and 0.5 Hz using potential sensitive dyes and was

  15. Direct toxic effects of aqueous extract of cigarette smoke on cardiac myocytes at clinically relevant concentrations

    SciTech Connect

    Yamada, Shigeyuki; Zhang Xiuquan; Kadono, Toshie; Matsuoka, Nobuhiro; Rollins, Douglas; Badger, Troy; Rodesch, Christopher K.; Barry, William H.

    2009-04-01

    Aims: Our goal was to determine if clinically relevant concentrations of aqueous extract of cigarette smoke (CSE) have direct deleterious effects on ventricular myocytes during simulated ischemia, and to investigate the mechanisms involved. Methods: CSE was prepared with a smoking chamber. Ischemia was simulated by metabolic inhibition (MI) with cyanide (CN) and 0 glucose. Adult rabbit and mouse ventricular myocyte [Ca{sup 2+}]{sub i} was measured by flow cytometry using fluo-3. Mitochondrial [Ca{sup 2+}] was measured with confocal microscopy, and Rhod-2 fluorescence. The mitochondrial permeability transition (MPT) was detected by TMRM fluorescence and myocyte contracture. Myocyte oxidative stress was quantified by dichlorofluorescein (DCF) fluorescence with confocal microscopy. Results: CSE 0.1% increased myocyte contracture caused by MI. The nicotine concentration (HPLC) in 0.1% CSE was 15 ng/ml, similar to that in humans after smoking cigarettes. CSE 0.1% increased mitochondrial Ca{sup 2+} uptake, and increased the susceptibility of mitochondria to the MPT. CSE 0.1% increased DCF fluorescence in isolated myocytes, and increased [Ca{sup 2+}]{sub i} in paced myocytes exposed to 2.0 mM CN, 0 glucose (P-MI). These effects were inhibited by the superoxide scavenger Tiron. The effect of CSE on [Ca{sup 2+}]{sub i} during P-MI was also prevented by ranolazine. Conclusions: CSE in clinically relevant concentrations increases myocyte [Ca{sup 2+}]{sub i} during simulated ischemia, and increases myocyte susceptibility to the MPT. These effects appear to be mediated at least in part by oxidative radicals in CSE, and likely contribute to the effects of cigarette smoke to increase myocardial infarct size, and to decrease angina threshold.

  16. Aspirin Often Wrongly Prescribed for Atrial Fibrillation

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_159459.html Aspirin Often Wrongly Prescribed for Atrial Fibrillation Blood thinners -- not aspirin -- dramatically cut the risk of stroke, researchers say ...

  17. Vector-averaged gravity alters myocyte and neuron properties in cell culture

    NASA Technical Reports Server (NTRS)

    Gruener, Raphael; Hoeger, Glenn

    1991-01-01

    The effect of changes in the gravitational field of developing neurons and myocytes on the development of these cells was investigated using observations of rotated cultures of embryonic spinal neurons and myocytes in a horizontal clinostat, in which rotation produces, from the cells' perspective, a 'vector-free' gravity environment by continous averaging of the vector, thus simulating the microgravity of space. It was found that, at rotation rates between 1 and 50 rpm, cellular and nuclear areas of myocytes become significantly enlarged and the number of presumptive nucleoli increase; in neurons, frequent and large swellings appeared along neuritic shafts. Some of these changes were reversible after the cessation of rotation.

  18. Left Atrial Appendage Closure Devices

    PubMed Central

    Romero, Jorge; Perez, Irving E; Krumerman, Andrew; Garcia, Mario J; Lucariello, Richard J

    2014-01-01

    Atrial fibrillation (AF) increases the risk for thromboembolic stroke five-fold. The left atrial appendage (LAA) has been shown to be the main source of thrombus formation in the majority of strokes associated with AF. Oral anticoagulation with warfarin and novel anticoagulants remains the standard of care; however, it has several limitations, including bleeding and poor compliance. Occlusion of the LAA has been shown to be an alternative therapeutic approach to drug therapy. The purpose of this article is to review the different techniques and devices that have emerged for the purpose of occluding this structure, with a particular emphasis on the efficacy and safety studies published to date in the medical literature. PMID:24963274

  19. Trafficking of an endogenous potassium channel in adult ventricular myocytes

    PubMed Central

    Wang, Tiantian; Cheng, Yvonne; Dou, Ying; Goonesekara, Charitha; David, Jens-Peter; Steele, David F.; Huang, Chen

    2012-01-01

    The roles of several small GTPases in the expression of an endogenous potassium current, Ito,f, in adult rat ventricular myocytes have been investigated. The results indicate that forward trafficking of newly synthesized Kv4.2, which underlies Ito,f in these cells, requires both Rab1 and Sar1 function. Expression of a Rab1 dominant negative (DN) reduced Ito,f current density by roughly one-half relative to control, mCherry-transfected myocytes. Similarly, expression of a Sar1DN nearly halved Ito,f current density. Rab11 is not essential to trafficking of Kv4.2, as expression of a Rab11DN had no effect on Ito,f over the time frames investigated here. In a process dependent on intact endoplasmic reticulum (ER)-to-Golgi transport, however, overexpression of wild-type Rab11 resulted in a doubling of Ito,f density; block of ER-to-Golgi traffic by Brefeldin A completely abrogated the effect. Also implicated in the trafficking of Kv4.2 are Rab5 and Rab4. Rab5DN expression increased endogenous Ito,f by two- to threefold, nonadditively with inhibition of dynamin-dependent endocytosis. And, in a phenomenon similar to that previously reported for myoblast-expressed Kv1.5, Rab4DN expression roughly doubled endogenous peak transient currents. Colocalization experiments confirmed the involvement of Rab4 in postinternalization trafficking of Kv4.2. There was little role evident for the lysosome in the degradation of internalized Kv4.2, as overexpression of neither wild-type nor DN isoforms of Rab7 had any effect on Ito,f. Instead, degradation may depend largely on the proteasome; the proteasome inhibitor MG132 significantly increased Ito,f density. PMID:22914645

  20. Novel approaches for pharmacological management of atrial fibrillation.

    PubMed

    Ehrlich, Joachim R; Nattel, Stanley

    2009-01-01

    In the light of the progressively increasing prevalence of atrial fibrillation (AF), medical awareness of the need to develop improved therapeutic approaches for the arrhythmia has also risen over the last decade. AF reduces quality of life and is associated with increased morbidity and mortality. Despite several setbacks as a result of negative results from rhythm control trials, the potential advantages of sinus-rhythm (SR) maintenance have motivated continued efforts to design novel pharmacological options aiming to terminate AF and prevent its recurrence, with a hope that optimized medical therapy will improve outcomes in AF patients. Pathophysiologically, AF is associated with electrical and structural changes in the atria, which increase the propensity to arrhythmia perpetuation but may eventually allow for new modalities for therapeutic intervention. Antiarrhythmic drug therapy has traditionally targeted ionic currents that modulate excitability and/or repolarization of cardiac myocytes. Despite efficacious suppression of ventricular and supraventricular arrhythmias, traditional antiarrhythmic drugs present problematic risks of pro-arrhythmia, potentially leading to excess mortality in the case of Na+-channel blockers or IKr (IKr=the rapid component of the delayed rectifier potassium current) blockers. New anti-AF agents in development do not fit well into the classical Singh and Vaughan-Williams formulation, and are broadly divided into 'atrial-selective compounds' and 'multiple-channel blockers'. The prototypic multiple-channel blocker amiodarone is the most efficient presently available compound for SR maintenance, but the drug has extra-cardiac adverse effects and complex pharmacokinetics that limit widespread application. The other available drugs are not nearly as efficient for SR maintenance and have a greater risk of proarrhythmia than amiodarone. Two new antiarrhythmic drugs are on the cusp of introduction into clinical practice. Vernakalant affects

  1. Robotic-assisted left atrial ligation for stroke reduction in chronic atrial fibrillation: a case report.

    PubMed

    Kiaii, Bob; McClure, R Scott; Skanes, Alan C; Ross, Ian G; Spouge, Alison R; Swinamer, Stuart; Rayman, Reiza; Bainbridge, Daniel T; Iglesias, Ivan; Novick, Richard J

    2006-01-01

    Patients with atrial fibrillation are at significant risk for sustaining a thromboembolic stroke. More than 90% of thromboemboli form in the left atrial appendage. Ligation of the left atrial appendage to reduce the risk of stroke is often performed in connection with other cardiac surgical procedures. As a stand-alone procedure, however, left atrial ligation has generally been deemed too invasive and has gained little support as an alternative therapeutic option. We report a case of port-access robotic-assisted left atrial ligation as a stand-alone procedure in a patient with chronic atrial fibrillation in whom anticoagulation was a contraindication. To our knowledge, this is the first reported case of stand-alone robotic-assisted left atrial ligation in the literature. PMID:16387671

  2. The Scaffold Protein Muscle A-Kinase Anchoring Protein β Orchestrates Cardiac Myocyte Hypertrophic Signaling Required for the Development of Heart Failure

    PubMed Central

    Kritzer, Michael D.; Li, Jinliang; Passariello, Catherine L.; Gayanilo, Marjorie; Thakur, Hrishikesh; Dayan, Joseph; Dodge-Kafka, Kimberly; Kapiloff, Michael S.

    2014-01-01

    Background Cardiac myocyte hypertrophy is regulated by an extensive intracellular signal transduction network. In vitro evidence suggests that the scaffold protein muscle A-kinase anchoring protein β (mAKAPβ) serves as a nodal organizer of hypertrophic signaling. However, the relevance of mAKAPβ signalosomes to pathological remodeling and heart failure in vivo remains unknown. Methods and Results Using conditional, cardiac myocyte–specific gene deletion, we now demonstrate that mAKAPβ expression in mice is important for the cardiac hypertrophy induced by pressure overload and catecholamine toxicity. mAKAPβ targeting prevented the development of heart failure associated with long-term transverse aortic constriction, conferring a survival benefit. In contrast to 29% of control mice (n=24), only 6% of mAKAPβ knockout mice (n=31) died in the 16 weeks of pressure overload (P=0.02). Accordingly, mAKAPβ knockout inhibited myocardial apoptosis and the development of interstitial fibrosis, left atrial hypertrophy, and pulmonary edema. This improvement in cardiac status correlated with the attenuated activation of signaling pathways coordinated by the mAKAPβ scaffold, including the decreased phosphorylation of protein kinase D1 and histone deacetylase 4 that we reveal to participate in a new mAKAP signaling module. Furthermore, mAKAPβ knockout inhibited pathological gene expression directed by myocyte-enhancer factor-2 and nuclear factor of activated T-cell transcription factors that associate with the scaffold. Conclusions mAKAPβ orchestrates signaling that regulates pathological cardiac remodeling in mice. Targeting of the underlying physical architecture of signaling networks, including mAKAPβ signalosome formation, may constitute an effective therapeutic strategy for the prevention and treatment of pathological remodeling and heart failure. PMID:24812305

  3. The mechanism of PDT-induced electrical blockade: the dependence of time-lapse localization of talaporfin sodium on the cell death phenotypes in rat cardiac myocytes

    NASA Astrophysics Data System (ADS)

    Ito, A.; Matsuo, H.; Suenari, T.; Miyoshi, S.; Takatsuki, S.; Ogawa, S.; Arai, T.

    2009-02-01

    We have proposed a new type of atrial fibrillation treatment with the early state photodynamic therapy (PDT), in which the interval time between the photosensitizer injection and irradiation is shorter than that in conventional way. We had demonstrated the acute electrical blockade by the PDT with talaporfin sodium and a red (670 nm) diode laser in ex vivo and in vivo experiment using rat normal myocardial tissue. The previous study of intracellular Ca2+ concentration measurement in rat cardiac myocytes during the PDT indicated that Ca2+ influx induced by the plasma membrane damage might be the main cause of the acute reaction of myocardial tissue. We found that the cell damage of cardiac myocytes triggered by the PDT was mainly influenced by the site where the photosensitizer exists. In this study, we examined the relationship between the sites of talaporfin sodium existing and cell death phenotypes in response to the PDT, in order to clarify the mechanism of the acute electrical blockade induced by the PDT in myocardial tissue. The talaporfin sodium fluorescence was observed after the various incubation times to visualize the time-lapse intracellular photosensitizer localization. The distribution of the photosensitizer was dependent on the incubation time. The change in intracellular Ca2+ concentration during the PDT was examined with a fluorescent Ca2+ indicator by a high-speed Nipkow confocal laser microscope (CSU-X1, Yokogawa Electric Company). We obtained the Ca2+ dynamics during the PDT which can explain the PDT-induced cell death pathways. We concluded that the Ca2+ influx induced by plasma membrane damage is the possible mechanism of the electrical blockade by the early state PDT.

  4. Effects of troglitazone and pioglitazone on the action potentials and membrane currents of rabbit ventricular myocytes.

    PubMed

    Ikeda, S; Watanabe, T

    1998-09-18

    The effects of the antidiabetic thiazolidinediones troglitazone and pioglitazone on action potentials and membrane currents were studied in rabbit ventricular myocytes. Troglitazone (10 microM) reversibly reduced excitability of the myocytes and modified their action potential configuration. It significantly increased the stimulation threshold required to elicit action potentials and decreased action potential amplitude and the maximum upstroke velocity of the action potentials. The Inhibition of the maximum upstroke velocity by troglitazone was also significant at 1 microM. Voltage-clamp experiments revealed that troglitazone (10 microM) reversibly inhibited both the slow inward Ca2+ current and the steady-state K+ current. In contrast to troglitazone, pioglitazone (1-10 microM) had no significant effect on the excitability, action potential configuration, or membrane currents of myocytes. These results suggest that troglitazone, but not pioglitazone, modulates Na+, Ca2+ and K+ currents, leading to the changes in excitability and action potential configuration of ventricular myocytes. PMID:9797043

  5. Left atrial myxoma masquerading as viral flu

    PubMed Central

    Chhabra, Lovely; Kiernan, Francis

    2016-01-01

    Atrial myxoma is a rare cardiac tumor that may be diagnosed incidentally on cardiac imaging or may present with life-threatening cardiac symptoms. We present a case of giant left atrial myxoma that presented as a flulike illness. PMID:27695187

  6. A novel and simple atrial retractor.

    PubMed

    Kofidis, Theo; Lee, Chuen Neng

    2011-05-01

    Minimally invasive cardiac operations require specialized equipment. Atrial retractors are a frequently used tool to expose heart valves for minimally invasive and open procedures. The models currently available in the market are efficient; however, they may be complex, bulky, or expensive. We introduce a novel, very simple atrial retractor we designed using ubiquitously available materials.

  7. Atrial Arrhythmia Summit: Post Summit Report

    NASA Technical Reports Server (NTRS)

    Barr, Yael

    2010-01-01

    The Atrial Arrhythmia Summit brought together nationally and internationally recognized experts in cardiology, electrophysiology, exercise physiology, and space medicine in an effort to elucidate the mechanisms, risk factors, and management of atrial arrhythmias in the unique occupational cohort of the U.S. astronaut corps.

  8. Familial atrial fibrillation with fetal onset

    PubMed Central

    Tikanoja, T; Kirkinen, P; Nikolajev, K; Eresmaa, L; Haring, P

    1998-01-01

    A woman presented during two pregnancies (at 25 and 23 weeks' gestation, respectively) because the fetuses had rapid, irregular tachycardia and hydrops. After maternal drug treatment and achievement of slower fetal heart rates, the hydrops gradually resolved. Both babies were born full term with continuing atrial fibrillation. In the first, an ectopic atrial rhythm was temporarily achieved during high dose flecainide treatment but, in the younger sibling, all medications and repeated cardioversions failed even temporarily to convert the atrial fibrillation with an almost isoelectric baseline in ECG to sinus rhythm. Good rate control has been achieved with digoxin in both patients. No infective, immunological, or structural cause was found in either case, and thus an inherited aetiology is probable.

 Keywords: atrial fibrillation;  arrhythmias;  fetal atrial fibrillation;  familial arrhythmias PMID:9538316

  9. Minimally Invasive Surgical Therapies for Atrial Fibrillation

    PubMed Central

    Nakamura, Yoshitsugu; Kiaii, Bob; Chu, Michael W. A.

    2012-01-01

    Atrial fibrillation is the most common sustained arrhythmia and is associated with significant risks of thromboembolism, stroke, congestive heart failure, and death. There have been major advances in the management of atrial fibrillation including pharmacologic therapies, antithrombotic therapies, and ablation techniques. Surgery for atrial fibrillation, including both concomitant and stand-alone interventions, is an effective therapy to restore sinus rhythm. Minimally invasive surgical ablation is an emerging field that aims for the superior results of the traditional Cox-Maze procedure through a less invasive operation with lower morbidity, quicker recovery, and improved patient satisfaction. These novel techniques utilize endoscopic or minithoracotomy approaches with various energy sources to achieve electrical isolation of the pulmonary veins in addition to other ablation lines. We review advancements in minimally invasive techniques for atrial fibrillation surgery, including management of the left atrial appendage. PMID:22666609

  10. Stimulation of single isolated adult ventricular myocytes within a low volume using a planar microelectrode array.

    PubMed

    Klauke, Norbert; Smith, Godfrey L; Cooper, Jon

    2003-09-01

    Microchannels (40- microm wide, 10- microm high, 10-mm long, 70- microm pitch) were patterned in the silicone elastomer, polydimethylsiloxane on a microscope coverslip base. Integrated within each microchamber were individually addressable stimulation electrodes (40- microm wide, 20- microm long, 100-nm thick) and a common central pseudo-reference electrode (60- microm wide, 500- microm long, 100-nm thick). Isolated rabbit ventricular myocytes were introduced into the chamber by micropipetting and subsequently capped with a layer of mineral oil, thus creating limited volumes of saline around individual myocytes that could be varied from 5 nL to 100 pL. Excitation contraction coupling was studied by monitoring myocyte shortening and intracellular Ca(2+) transients (using Fluo-3 fluorescence). The amplitude of stimulated myocyte shortening and Ca(2+) transients remained constant for 90 min in the larger volume (5 nL) configuration, although the shortening (but not the Ca(2+) transient) amplitude gradually decreased to 20% of control within 60 min in the low volume (100 pL) arrangement. These studies indicate a lower limit for the extracellular volume required to stimulate isolated adult cardiac myocytes. Whereas this arrangement could be used to create a screening assay for drugs, individual microchannels (100 pL) can also be used to study the effects of limited extracellular volume on the contractility of single cardiac myocytes.

  11. Stimulation of Single Isolated Adult Ventricular Myocytes within a Low Volume Using a Planar Microelectrode Array

    PubMed Central

    Klauke, Norbert; Smith, Godfrey L.; Cooper, Jon

    2003-01-01

    Microchannels (40-μm wide, 10-μm high, 10-mm long, 70-μm pitch) were patterned in the silicone elastomer, polydimethylsiloxane on a microscope coverslip base. Integrated within each microchamber were individually addressable stimulation electrodes (40-μm wide, 20-μm long, 100-nm thick) and a common central pseudo-reference electrode (60-μm wide, 500-μm long, 100-nm thick). Isolated rabbit ventricular myocytes were introduced into the chamber by micropipetting and subsequently capped with a layer of mineral oil, thus creating limited volumes of saline around individual myocytes that could be varied from 5 nL to 100 pL. Excitation contraction coupling was studied by monitoring myocyte shortening and intracellular Ca2+ transients (using Fluo-3 fluorescence) . The amplitude of stimulated myocyte shortening and Ca2+ transients remained constant for 90 min in the larger volume (5 nL) configuration, although the shortening (but not the Ca2+ transient) amplitude gradually decreased to 20% of control within 60 min in the low volume (100 pL) arrangement. These studies indicate a lower limit for the extracellular volume required to stimulate isolated adult cardiac myocytes. Whereas this arrangement could be used to create a screening assay for drugs, individual microchannels (100 pL) can also be used to study the effects of limited extracellular volume on the contractility of single cardiac myocytes. PMID:12944291

  12. Baseline and post-atrial pacing release of atrial natriuretic factor in mitral stenosis.

    PubMed

    Malatino, L S; Stancanelli, B; Greco, G; Polizzi, G; Leonardi, C; Russo, G; Tamburino, C; Greco, G; Giuffrida, G; Tamburino, G

    1990-01-01

    To investigate the release of atrial natriuretic factor (ANF) in mitral stenosis and the influence of the increase on the frequency of atrial contraction or atrial distention on ANF secretion, we studied 10 patients with symptoms of congestive heart failure (New York Heart Association classes II and III) in sinus rhythm, who were undergoing cardiac catheterization as part of an evaluation workup for mitral stenosis. Echocardiographic tracings, repeat determinations of mean pulmonary artery wedge pressure (MPAWP) and mean right atrial pressure, and blood sampling from the pulmonary artery for measurements of ANF were performed at baseline, during atrial pacing (pacing rate of 125 beats/min for 5 minutes), and 5 minutes after the pacing protocol was completed. Baseline ANF levels were closely related to right atrial pressure (r = 0.89; p less than 0.001) and increased markedly after atrial pacing from 205.6 +/- 39.8 (SEM) to 343.9 +/- 57.9 (SEM) pg/ml. A similar pacing-induced increase was shown for MPAWP and left atrial size. Our data indicate that pacing-induced increases in atrial distention and intracavitary pressure further stimulate release of ANF. However, an independent effect of frequency of atrial pacing on plasma ANF in humans could not be identified. PMID:2136967

  13. Age-related atrial fibrosis.

    PubMed

    Gramley, Felix; Lorenzen, Johann; Knackstedt, Christian; Rana, Obaida R; Saygili, Erol; Frechen, Dirk; Stanzel, Sven; Pezzella, Francesco; Koellensperger, Eva; Weiss, Christian; Münzel, Thomas; Schauerte, Patrick

    2009-03-01

    Many age-related diseases are associated with, and may be promoted by, cardiac fibrosis. Transforming growth factor (TGF)-beta, hypoxia-induced factor (HIF), and the matrix metalloproteinase (MMP) system have been implicated in fibrogenesis. Thus, we investigated whether age is related to these systems and to atrial fibrosis. Right atrial appendages (RAA) obtained during heart surgery (n = 115) were grouped according to patients' age (<50 years, 51-60 years, 61-70 years, or >70 years). Echocardiographic ejection fractions (EF) and fibrosis using Sirius-red-stained histological sections were determined. TGF-beta was determined by quantitative RT-PCR and hypoxia-related factors [HIF1 alpha, the vascular endothelial growth factor (VEGF)-receptor, CD34 (a surrogate marker for microvessel density), the factor inhibiting HIF (FIH), and prolyl hydroxylase 3 (PHD 3)] were detected by immunostaining. MMP-2 and -9 activity were determined zymographically, and mRNA levels of their common tissue inhibitor TIMP-1 were determined by RT-PCR. Younger patients (<50 years) had significantly less fibrosis (10.1% +/- 4.4% vs 16.6% +/- 8.3%) than older individuals (>70 years). While HIF1 alpha, FIH, the VEGF-receptor, and CD34 were significantly elevated in the young, TGF-beta and PHD3 were suppressed in these patients. MMP-2 and -9 activity was found to be higher while TIMP-1 levels were lower in older patients. Statistical analysis proved age to be the only factor influencing fibrogenesis. With increasing age, RAAs develop significantly more fibrosis. An increase of fibrotic and decrease of hypoxic signalling and microvessel density, coupled with differential expression of MMPs and TIMP-1 favouring fibrosis may have helped promote atrial fibrogenesis. PMID:19234766

  14. Atrial fibrillation and physical activity

    PubMed Central

    Bosomworth, N. John

    2015-01-01

    Objective To review the evidence on the effects of various levels of physical activity (PA) on the incidence of atrial fibrillation (AF) in both the general population and in endurance athletes. Data sources A PubMed search was done initially using the MeSH headings or text words (with the search-field descriptor TIAB [title and abstract]) atrial fibrillation and exercise or physical activity or athlet* or sport*, without additional filters. Conclusions regarding quality and strength of evidence were based on the GRADE (grading of recommendations, assessment, development, and evaluation) system. Study selection No interventional studies were available. Observational studies were therefore considered acceptable, and, although larger long-term prospective cohort studies were preferred, case-control or cross-sectional trials were also included in this review. Synthesis Available evidence suggests a dose-response association linking increased exercise levels with reduced incident AF in women. The same is true in men at low and moderate levels of exertional activity. In men only, high levels of PA are associated with increased risk of AF in most, but not all, studies. This risk is moderate, with a hazard ratio of 1.29 in one of the better studies. The risk of AF for most people who exercise regularly is lower than that of a matched sedentary population. Conclusion Atrial fibrillation is probably less common as PA increases, with a demonstrable dose-response relationship. Exercise at any level should be promoted for its effect on physical well-being and mortality reduction. In men exercising at high levels, beneficial effects on AF might be lost and risk might exceed that of the sedentary population; however, the evidence is neither robust nor consistent. These men should be made aware of this modest increase in risk should they choose to continue to engage in high levels of PA. PMID:26668285

  15. An Experimental Model Using Cultured Cardiac Myocytes for a Study of the Generation of Premature Ventricular Contractions Under Ultrasound Exposure

    NASA Astrophysics Data System (ADS)

    Kudo, Nobuki; Yamamoto, Masaya

    2011-09-01

    It is known that use of a contrast agents in echocardiography increases the probability of generation of premature ventricular contractions (PVCs). As a basic study to elucidate the mechanisms and to reduce adverse effects, the generation of PVCs was investigated using cultured cardiac myocytes instead of the intact heart in vivo. Cardiac myocytes were isolated from neonatal rats and cultured on a cover slip. The myocyte sample was exposed to pulsed ultrasound with microbubbles adjacent to the myocytes, and generation of PVCs was examined with ultrasound exposure at various delay times after onset of myocyte contraction. The experimental results showed that generation of PVCs had a stable threshold delay time and that PVCs were generated only when myocytes were exposed to ultrasound with delay times longer than the threshold. The results indicate that the model used in this study is useful for revealing the mechanisms by which PVCs are induced by ultrasound exposure.

  16. Functional consequences of caspase activation in cardiac myocytes

    NASA Astrophysics Data System (ADS)

    Communal, Catherine; Sumandea, Marius; de Tombe, Pieter; Narula, Jagat; Solaro, R. John; Hajjar, Roger J.

    2002-04-01

    Cardiomyocyte apoptosis is present in many cardiac disease states, including heart failure and ischemic heart disease. Apoptosis is associated with the activation of caspases that mediate the cleavage of vital and structural proteins. However, the functional contribution of apoptosis to these conditions is not known. Furthermore, in cardiac myocytes, apoptosis may not be complete, allowing the cells to persist for a prolonged period within the myocardium. Therefore, we examined whether caspase-3 cleaved cardiac myofibrillar proteins and, if so, whether it affects contractile function. The effects of caspase-3 were studied in vitro on individual components of the cardiac myofilament including -actin, -actinin, myosin heavy chain, myosin light chain 1/2, tropomyosin, cardiac troponins (T, I, C), and the trimeric troponin complex. Exposure of the myofibrillar protein (listed above) to caspase-3 for 4 h resulted in the cleavage of -actin and -actinin, but not myosin heavy chain, myosin light chain 1/2, and tropomyosin, into three fragments (30, 20, and 15 kDa) and one major fragment (45 kDa), respectively. When cTnT, cTnI, and cTnC were incubated individually with caspase-3, there was no detectable cleavage. However, when the recombinant troponin complex was exposed to caspase-3, cTnT was cleaved, resulting in fragments of 25 kDa. Furthermore, rat cardiac myofilaments exposed to caspase-3 exhibited similar patterns of myofibrillar protein cleavage. Treatment with the caspase inhibitor DEVD-CHO or z-VAD-fmk abolished the cleavage. Myofilaments, isolated from adult rat ventricular myocytes after induction of apoptotic pathway by using -adrenergic stimulation, displayed a similar pattern of actin and TnT cleavage. Exposure of skinned fiber to caspase-3 decreased maximal Ca2+-activated force and myofibrillar ATPase activity. Our results indicate that caspase-3 cleaved myofibrillar proteins, resulting in an impaired force/Ca2+ relationship and myofibrillar ATPase activity

  17. Physiological pathway of magnesium influx in rat ventricular myocytes.

    PubMed

    Tashiro, Michiko; Inoue, Hana; Konishi, Masato

    2014-11-01

    Cytoplasmic free Mg(2+) concentration ([Mg(2+)]i) was measured in rat ventricular myocytes with a fluorescent indicator furaptra (mag-fura-2) introduced by AM-loading. By incubation of the cells in a high-K(+) (Ca(2+)- and Mg(2+)-free) solution, [Mg(2+)]i decreased from ? 0.9 mM to 0.2 to 0.5 mM. The lowered [Mg(2+)]i was recovered by perfusion with Ca(2+)-free Tyrode's solution containing 1 mM Mg(2+). The time course of the [Mg(2+)]i recovery was fitted by a single exponential function, and the first derivative at time 0 was analyzed as being proportional to the initial Mg(2+) influx rate. The Mg(2+) influx rate was inversely related to [Mg(2+)]i, being higher at low [Mg(2+)]i. The Mg(2+) influx rate was augmented by the high extracellular Mg(2+) concentration (5 mM), whereas it was greatly reduced by cell membrane depolarization caused by high K(+). Known inhibitors of TRPM7 channels, 2-aminoethoxydiphenyl borate (2-APB), NS8593, and spermine reduced the Mg(2+) influx rate with half inhibitory concentrations (IC50) of, respectively, 17 ?M, 2.0 ?M, and 22 ?M. We also studied Ni(2+) influx by fluorescence quenching of intracellular furaptra by Ni(2+). The Ni(2+) influx was activated by lowering intra- and extracellular Mg(2+) concentrations, and it was inhibited by 2-APB and NS8593 with IC50 values comparable with those for the Mg(2+) influx. Intracellular alkalization (caused by pulse application of NH4Cl) enhanced, whereas intracellular acidification (induced after the removal of NH4Cl) slowed the Mg(2+) influx. Under the whole-cell patch-clamp configuration, the removal of intracellular and extracellular divalent cations induced large inward and outward currents, MIC (Mg-inhibited cation) currents or IMIC, carried by monovalent cations likely via TRPM7 channels. IMIC measured at -120 mV was diminished to ? 50% by 100 ?M 2-APB or 10 ?M NS8593. These results suggest that TRPM7/MIC channels serve as a major physiological pathway of Mg(2+) influx in rat

  18. Atrial Fibrillation Ablation and Stroke.

    PubMed

    Aagaard, Philip; Briceno, David; Csanadi, Zoltan; Mohanty, Sanghamitra; Gianni, Carola; Trivedi, Chintan; Nagy-Baló, Edina; Danik, Stephan; Barrett, Conor; Santoro, Francesco; Burkhardt, J David; Sanchez, Javier; Natale, Andrea; Di Biase, Luigi

    2016-05-01

    Catheter ablation has become a widely available and accepted treatment to restore sinus rhythm in atrial fibrillation patients who fail antiarrhythmic drug therapy. Although generally safe, the procedure carries a non-negligible risk of complications, including periprocedural cerebral insults. Uninterrupted anticoagulation, maintenance of an adequate ACT during the procedure, and measures to avoid and detect thrombus build-up on sheaths and atheters during the procedure, appears useful to reduce the risk of embolic events. This is a review of the incidence, mechanisms, impact, and methods to reduce catheter ablation related cerebral insults. PMID:27150179

  19. Dronedarone for the treatment of atrial fibrillation and atrial flutter.

    PubMed

    Maund, E; McKenna, C; Sarowar, M; Fox, D; Stevenson, M; Pepper, C; Palmer, S; Woolacott, N

    2010-10-01

    This paper presents a summary of the evidence review group (ERG) report on the clinical effectiveness and cost-effectiveness of dronedarone for the treatment of atrial fibrillation (AF) or atrial flutter based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The population considered in the submission were adult clinically stable patients with a recent history of or current non-permanent AF. Comparators were the current available anti-arrhythmic drugs: class 1c agents (flecainide and propafenone), sotalol and amiodarone. Outcomes were AF recurrence, all-cause mortality, stroke, treatment discontinuations (due to any cause or due to adverse events) and serious adverse events. The main evidence came from four phase III randomised controlled trials, direct and indirect meta-analyses from a systematic review, and a synthesis of the direct and indirect evidence using a mixed-treatment comparison. Overall, the results from the different synthesis approaches showed that the odds of AF recurrence appeared statistically significantly lower with dronedarone and other anti-arrhythmic drugs than with non-active control, and that the odds of AF recurrence are statistically significantly higher for dronedarone than for amiodarone. However, the results for outcomes of all-cause mortality, stroke and treatment discontinuations and serious adverse events were all uncertain. A discrete event simulation model was used to evaluate dronedarone versus antiarrhythmic drugs and standard therapy alone. The incremental cost-effectiveness ratio of dronedarone was relatively robust and less than 20,000 pounds per quality-adjusted life-year. Exploratory work undertaken by the ERG identified that the main drivers of cost-effectiveness were the benefits assigned to dronedarone for all-cause mortality and stroke. Dronedarone is not cost-effective relative to its comparators when

  20. Tissue-Mimicking Geometrical Constraints Stimulate Tissue-Like Constitution and Activity of Mouse Neonatal and Human-Induced Pluripotent Stem Cell-Derived Cardiac Myocytes.

    PubMed

    Pilarczyk, Götz; Raulf, Alexandra; Gunkel, Manuel; Fleischmann, Bernd K; Lemor, Robert; Hausmann, Michael

    2016-01-01

    The present work addresses the question of to what extent a geometrical support acts as a physiological determining template in the setup of artificial cardiac tissue. Surface patterns with alternating concave to convex transitions of cell size dimensions were used to organize and orientate human-induced pluripotent stem cell (hIPSC)-derived cardiac myocytes and mouse neonatal cardiac myocytes. The shape of the cells, as well as the organization of the contractile apparatus recapitulates the anisotropic line pattern geometry being derived from tissue geometry motives. The intracellular organization of the contractile apparatus and the cell coupling via gap junctions of cell assemblies growing in a random or organized pattern were examined. Cell spatial and temporal coordinated excitation and contraction has been compared on plain and patterned substrates. While the α-actinin cytoskeletal organization is comparable to terminally-developed native ventricular tissue, connexin-43 expression does not recapitulate gap junction distribution of heart muscle tissue. However, coordinated contractions could be observed. The results of tissue-like cell ensemble organization open new insights into geometry-dependent cell organization, the cultivation of artificial heart tissue from stem cells and the anisotropy-dependent activity of therapeutic compounds. PMID:26751484

  1. Tissue-Mimicking Geometrical Constraints Stimulate Tissue-Like Constitution and Activity of Mouse Neonatal and Human-Induced Pluripotent Stem Cell-Derived Cardiac Myocytes

    PubMed Central

    Pilarczyk, Götz; Raulf, Alexandra; Gunkel, Manuel; Fleischmann, Bernd K.; Lemor, Robert; Hausmann, Michael

    2016-01-01

    The present work addresses the question of to what extent a geometrical support acts as a physiological determining template in the setup of artificial cardiac tissue. Surface patterns with alternating concave to convex transitions of cell size dimensions were used to organize and orientate human-induced pluripotent stem cell (hIPSC)-derived cardiac myocytes and mouse neonatal cardiac myocytes. The shape of the cells, as well as the organization of the contractile apparatus recapitulates the anisotropic line pattern geometry being derived from tissue geometry motives. The intracellular organization of the contractile apparatus and the cell coupling via gap junctions of cell assemblies growing in a random or organized pattern were examined. Cell spatial and temporal coordinated excitation and contraction has been compared on plain and patterned substrates. While the α-actinin cytoskeletal organization is comparable to terminally-developed native ventricular tissue, connexin-43 expression does not recapitulate gap junction distribution of heart muscle tissue. However, coordinated contractions could be observed. The results of tissue-like cell ensemble organization open new insights into geometry-dependent cell organization, the cultivation of artificial heart tissue from stem cells and the anisotropy-dependent activity of therapeutic compounds. PMID:26751484

  2. Stroke risk assessment in atrial fibrillation: risk factors and markers of atrial myopathy.

    PubMed

    Calenda, Brandon W; Fuster, Valentin; Halperin, Jonathan L; Granger, Christopher B

    2016-09-01

    Atrial fibrillation (AF) is a complex phenomenon associated with electrical, mechanical, and structural abnormalities of the atria. Ischaemic stroke in AF is only partially understood, but the mechanisms are known to be related to the atrial substrate as well as the atrial rhythm. The temporal dissociation between timing of AF and occurrence of stroke has led to the hypothesis that fibrotic, prothrombotic atrial tissue is an important cause of thrombus formation in patients with AF, independent of the atrial rhythm. Current stroke risk scores are practical, but limited in their capacity to predict stroke risk accurately in individual patients. Stroke prediction might be improved by the addition of emerging risk factors, many of which are expressions of atrial fibrosis. The use of novel parameters, including clinical criteria, biomarkers, and imaging data, might improve stroke risk prediction and inform on optimal treatment for patients with AF and perhaps individuals only at risk of AF. PMID:27383079

  3. Calcium binding to cardiac myocytes protected from proteolytic enzyme activity.

    PubMed

    Bailey, L E; Fawzi, A B

    1985-04-17

    Excitation-contraction coupling in cardiac muscle is dependent on extracellular calcium and calcium bound to the surface of the myocardial cell. In this study, we examined the physical characteristics of calcium binding to adult guinea pig ventricular myocytes disaggregated mechanically in oxygenated tissue culture medium containing a proteinase inhibitor (aprotinin), and separated from cellular debris by Cytodex beads. Cells prepared in this manner excluded Trypan blue and showed no evidence of spontaneous contraction or contracture. Scatchard plots of calcium binding determined by continuous flow equilibrium dialysis revealed a high-affinity, low-capacity pool, Ka = 65 X 10(3) M-1 and Bt = 1.3 nmol X mg-1 and a low-affinity, high-capacity pool, Ka = 141 M-1 and Bt = 138 nmol X mg-1. The low-affinity pool was not detectable after lanthanum, trypsin or collagenase treatment or in cells prepared without aprotinin in the isolation medium. Both neuraminidase and phospholipase C reduced Bt of the low-affinity pool by one half, but only neuraminidase affected the affinity constant of this pool. Ka was increased to 516.7 M-1, similar to the apparent affinity constant for calcium binding estimated from dP/dtmax measured at several extracellular calcium concentrations (470 M-1). The results suggest that calcium bound to sarcolemmal phospholipids represents the superficial calcium involved in excitation-contraction coupling in the heart.

  4. Syzygium aromaticum L. (Clove) extract regulates energy metabolism in myocytes.

    PubMed

    Tu, Zheng; Moss-Pierce, Tijuana; Ford, Paul; Jiang, T Alan

    2014-09-01

    The prevalence of metabolic syndrome and type 2 diabetes is increasing worldwide. Herbs and spices have been used for the treatment of diabetes for centuries in folk medicine. Syzygium aromaticum L. (Clove) extracts (SE) have been shown to perform comparably to insulin by significantly reducing blood glucose levels in animal models; however, the mechanisms are not well understood. We investigated the effects of clove on metabolism in C2C12 myocytes and demonstrated that SE significantly increases glucose consumption. The phosphorylation of AMP-activated protein kinase (AMPK), as well as its substrate, acetyl-CoA carboxylase (ACC) was increased by SE treatment. SE also transcriptionally regulates genes involved in metabolism, including sirtuin 1 (SIRT1) and PPARγ coactivator 1α (PGC1α). Nicotinamide, an SIRT1 inhibitor, diminished SE's effects on glucose consumption. Furthermore, treatment with SE dose-dependently increases muscle glycolysis and mitochondrial spare respiratory capacity. Overall, our study suggests that SE has the potential to increase muscle glycolysis and mitochondria function by activating both AMPK and SIRT1 pathways.

  5. Electrophysiological Determination of Submembrane Na(+) Concentration in Cardiac Myocytes.

    PubMed

    Hegyi, Bence; Bányász, Tamás; Shannon, Thomas R; Chen-Izu, Ye; Izu, Leighton T

    2016-09-20

    In the heart, Na(+) is a key modulator of the action potential, Ca(2+) homeostasis, energetics, and contractility. Because Na(+) currents and cotransport fluxes depend on the Na(+) concentration in the submembrane region, it is necessary to accurately estimate the submembrane Na(+) concentration ([Na(+)]sm). Current methods using Na(+)-sensitive fluorescent indicators or Na(+) -sensitive electrodes cannot measure [Na(+)]sm. However, electrophysiology methods are ideal for measuring [Na(+)]sm. In this article, we develop patch-clamp protocols and experimental conditions to determine the upper bound of [Na(+)]sm at the peak of action potential and its lower bound at the resting state. During the cardiac cycle, the value of [Na(+)]sm is constrained within these bounds. We conducted experiments in rabbit ventricular myocytes at body temperature and found that 1) at a low pacing frequency of 0.5 Hz, the upper and lower bounds converge at 9 mM, constraining the [Na(+)]sm value to ∼9 mM; 2) at 2 Hz pacing frequency, [Na(+)]sm is bounded between 9 mM at resting state and 11.5 mM; and 3) the cells can maintain [Na(+)]sm to the above values, despite changes in the pipette Na(+) concentration, showing autoregulation of Na(+) in beating cardiomyocytes. PMID:27653489

  6. Local regional stimulation of single isolated ventricular myocytes using microfluidics.

    PubMed

    Klauke, Norbert; Smith, Godfrey; Cooper, Jonathan M

    2009-08-01

    The regional manipulation of the microenvironment surrounding single adult cardiac myocytes in a microfluidic structure is described. The flow rates of laminar streams were adjusted such that the fluid interface between an injection flow and a perfusion flow was manipulated laterally to stimulate regions of the cell surface. Using this general principle, we were able to selectively expose defined regions of the cell to test solutions, with predefined pulse durations and frequencies. We demonstrate the transient depolarisation of the cardiomyocyte through the regional chemical stimulation of localized areas of the cell with elevated potassium concentrations (100 mM). The results show that chemical stimulation at frequencies < or = 0.25 Hz evoked Ca(2+) transients and cell shortening, comparable to those induced by electrical (field) stimulation. At higher frequencies the membrane potential failed to recover sufficiently from the depolarisation with the high K(+) solution, possibly because of the slow clearance of the ion from the t-tubular system. To test this hypothesis, the clearance of fluorescently labeled 10 kDa dextran from the t-system was measured and found to be approximately 0.5 s delayed compared to that of the bulk extracellular space, indicating the slow diffusion inside the confined space of the tubular membrane invaginations.

  7. Angiotensin II stimulates internalization and degradation of arterial myocyte plasma membrane BK channels to induce vasoconstriction

    PubMed Central

    Leo, M. Dennis; Bulley, Simon; Bannister, John P.; Kuruvilla, Korah P.; Narayanan, Damodaran

    2015-01-01

    Arterial smooth muscle cells (myocytes) express large-conductance Ca2+-activated K+ (BK) channel α and auxiliary β1 subunits that modulate arterial contractility. In arterial myocytes, β1 subunits are stored within highly mobile rab11A-positive recycling endosomes. In contrast, BKα subunits are primarily plasma membrane-localized. Trafficking pathways for BKα and whether physiological stimuli that regulate arterial contractility alter BKα localization in arterial myocytes are unclear. Here, using biotinylation, immunofluorescence resonance energy transfer (immunoFRET) microscopy, and RNAi-mediated knockdown, we demonstrate that rab4A-positive early endosomes traffic BKα to the plasma membrane in myocytes of resistance-size cerebral arteries. Angiotensin II (ANG II), a vasoconstrictor, reduced both surface and total BKα, an effect blocked by bisindolylmaleimide-II, concanavalin A, and dynasore, protein kinase C (PKC), internalization, and endocytosis inhibitors, respectively. In contrast, ANG II did not reduce BKα mRNA, and sodium nitroprusside, a nitric oxide donor, did not alter surface BKα protein over the same time course. MG132 and bafilomycin A, proteasomal and lysosomal inhibitors, respectively, also inhibited the ANG II-induced reduction in surface and total BKα, resulting in intracellular BKα accumulation. ANG II-mediated BK channel degradation reduced BK currents in isolated myocytes and functional responses to iberiotoxin, a BK channel blocker, and NS1619, a BK activator, in pressurized (60 mmHg) cerebral arteries. These data indicate that rab4A-positive early endosomes traffic BKα to the plasma membrane in arterial myocytes. We also show that ANG II stimulates PKC-dependent BKα internalization and degradation. These data describe a unique mechanism by which ANG II inhibits arterial myocyte BK currents, by reducing surface channel number, to induce vasoconstriction. PMID:26179602

  8. MicroRNA-214 protects cardiac myocytes against H2O2-induced injury.

    PubMed

    Lv, Guangwei; Shao, Suxia; Dong, Hua; Bian, Xiaohua; Yang, Xingwei; Dong, Shimin

    2014-01-01

    Reactive oxygen species (ROS)-induced cardiac myocyte injury resulting from changes in the expression levels of multiple genes plays a critical role in the pathogenesis of numerous heart diseases. The purpose of this study was to determine the potential roles of microRNA-214 (miR-214) in hydrogen peroxide (H2O2)-mediated gene regulation in cardiac myocytes. In this study, we used quantitative real-time RT-PCR (qRT-PCR) to demonstrate that miR-214 was upregulated in cardiac myocytes after treatment with H2O2. We transfected cells with pre-miR-214 to upregulate miR-214 expression and transfected cells with a miR-214 inhibitor (anti-miR-214) to downregulate miR-214 expression. H2O2-induced cardiac cell apoptosis was detected by flow cytometry. The level of apoptosis was increased by the miR-214 inhibitor and decreased by pre-miR-214. Therefore, we believe that miR-214 plays a positive role in H2O2-induced cardiac cell apoptosis. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is constitutively active and is considered to be the primary downregulator of the pro-oncogenic PI3K/Akt pathway. Western blot analysis revealed that the expression of the PTEN protein in cardiac myocytes decreased after H2O2 induction. Anti-miR-214 increased PTEN protein expression level, in contrast, pre-miR-214 decreased the PTEN protein expression level in cultured cardiac myocytes. These results indicate that PTEN is regulated by miR-214 and serves as an important target of miR-214 in cardiac myocytes. In conclusion, miR-214 is sensitive to H2O2 stimulation, and miR-214 protects cardiac myocytes against H2O2-induced injury via one of its targets, PTEN.

  9. Contractile reserve and intracellular calcium regulation in mouse myocytes from normal and hypertrophied failing hearts

    NASA Technical Reports Server (NTRS)

    Ito, K.; Yan, X.; Tajima, M.; Su, Z.; Barry, W. H.; Lorell, B. H.; Schneider, M. (Principal Investigator)

    2000-01-01

    Mouse myocyte contractility and the changes induced by pressure overload are not fully understood. We studied contractile reserve in isolated left ventricular myocytes from mice with ascending aortic stenosis (AS) during compensatory hypertrophy (4-week AS) and the later stage of early failure (7-week AS) and from control mice. Myocyte contraction and [Ca(2+)](i) transients with fluo-3 were measured simultaneously. At baseline (0.5 Hz, 1.5 mmol/L [Ca(2+)](o), 25 degrees C), the amplitude of myocyte shortening and peak-systolic [Ca(2+)](i) in 7-week AS were not different from those of controls, whereas contraction, relaxation, and the decline of [Ca(2+)](i) transients were slower. In response to the challenge of high [Ca(2+)](o), fractional cell shortening was severely depressed with reduced peak-systolic [Ca(2+)](i) in 7-week AS compared with controls. In response to rapid pacing stimulation, cell shortening and peak-systolic [Ca(2+)](i) increased in controls, but this response was depressed in 7-week AS. In contrast, the responses to both challenge with high [Ca(2+)](o) and rapid pacing in 4-week AS were similar to those of controls. Although protein levels of Na(+)-Ca(2+) exchanger were increased in both 4-week and 7-week AS, the ratio of SR Ca(2+)-ATPase to phospholamban protein levels was depressed in 7-week AS compared with controls but not in 4-week AS. This was associated with an impaired capacity to increase sarcoplasmic reticulum Ca(2+) load during high work states in 7-week AS myocytes. In hypertrophied failing mouse myocytes, depressed contractile reserve is related to an impaired augmentation of systolic [Ca(2+)](i) and SR Ca(2+) load and simulates findings in human failing myocytes.

  10. [Secondary pulmonary embolism to right atrial myxoma].

    PubMed

    Vico Besó, L; Zúñiga Cedó, E

    2013-10-01

    A case of pulmonary thromboembolism secondary to atrial myxoma right. The myxoma is a primary cardiac tumor, namely, has his origin in the cardiac tissue. Primary cardiac tumors are rare, including myxomas, the most common type. Have a predilection for females and the most useful tool for diagnosis is echocardiography. About 75% of myxomas occur in the left atrium of the heart and rest are in the right atrium. Right atrial myxomas in some sometimes associated with tricuspid stenosis and atrial fibrillation. The most common clinical manifestations include symptoms of this neoplasm constitutional, and embolic phenomena resulting from the obstruction to the flow intracavitary. The treatment of this condition is surgical.

  11. Detection of atrial-flutter and atrial-fibrillation waveforms by fetal magnetocardiogram.

    PubMed

    Kandori, A; Hosono, T; Kanagawa, T; Miyashita, S; Chiba, Y; Murakami, M; Miyashita, T; Tsukada, K

    2002-03-01

    Two cases of fetal tachycardia are reported: atrial flutter and fibrillation. The waveforms from each case were detected by fetal magnetocardiograms (FMCGs) using a 64-channel superconducting quantum interference device (SQUID) system. Because the magnitude of supraventricular arrhythmia signals is very weak, two subtraction methods were used to detect the fetal MCG waveforms: subtraction of the maternal MCG signal, and subtraction of the fetal ORS complex signal. It was found that atrial-flutter waveforms showed a cyclic pattern and that atrial-fibrillation waveforms showed f-waves with a random atrial rhythm. Fast Fourier transform analysis determined the main frequency of the atrial flutter to be about 7Hz, and the frequency distribution of atrial fibrillation consisted of small, broad peaks. To visualise the current pattern, current-arrow maps, which simplify the observation of pseudo-current patterns in fetal hearts, of the averaged atrial flutter and fibrillation waveforms were produced. The map of the atrial flutter had a circular pattern, indicating a re-entry circuit, and the map of the atrial fibrillation indicated one wavelet, which was produced by a micro-re-entry circuit. It is thus concluded that an FMCG can detect supraventricular arrhythmia, which can be characterised by re-entry circuits, in fetuses. PMID:12043803

  12. Native American Discursive Tactic

    ERIC Educational Resources Information Center

    Black, Jason Edward

    2013-01-01

    This essay derives from a course called ‘"The Rhetoric of Native America,’" which is a historical-critical survey of Native American primary texts. The course examines the rhetoric employed by Natives to enact social change and to build community in the face of exigencies. The main goal of exploring a native text (particularly, Simon Pokagon's…

  13. Left atrial appendage occlusion in atrial fibrillation after intracranial hemorrhage

    PubMed Central

    Horstmann, Solveig; Zugck, Christian; Krumsdorf, Ulrike; Rizos, Timolaos; Rauch, Geraldine; Geis, Nicolas; Hardt, Stefan

    2014-01-01

    Objective: To evaluate the safety and feasibility of percutaneous left atrial appendage occlusion (LAAO) in patients with atrial fibrillation (AF) and previous intracranial hemorrhage (ICH). Methods: In an explorative, prospective, single-center, observational study, LAAO was performed in patients with previous ICH and AF using the Amplatzer Cardiac Plug device. Risks of ischemic strokes and hemorrhagic complications were estimated using the CHA2DS2Vasc score and the HAS-BLED score. Before and 1, 6, 12, and 24 months after the procedure, clinical status and complications were recorded. Major complications were predefined as periprocedural stroke, death, pericardial effusion, and device embolism. Results: LAAO was performed in 20 patients. Based on CHA2DS2Vasc score (mean 4.5 ± 1.4) and HAS-BLED score (mean 4.7 ± 1.0), annual risks of stroke and hemorrhagic complications were 4.0%–6.7% and 8.7%–12.5%, respectively. No patient had a procedure-related complication. Minor postprocedural complications were observed in 4/20 patients (2 inguinal hematoma, 1 self-limiting asystole, and 1 thrombus formation on device). No ischemic or hemorrhagic stroke occurred during a mean follow-up of 13.6 ± 8.2 months. Conclusions: In this first study of LAAO in patients with previous ICH, LAAO appears feasible and safe. A larger, controlled trial is needed to assess the efficacy and safety of the procedure compared to other preventive measures. Classification of evidence: This study provides Class III evidence that in patients with a history of previous ICH and AF, percutaneous LAAO is safe and feasible. PMID:24319042

  14. Left atrial electrophysiologic feature specific for the genesis of complex fractionated atrial electrogram during atrial fibrillation.

    PubMed

    Hoshiyama, Tadashi; Yamabe, Hiroshige; Koyama, Junjiroh; Kanazawa, Hisanori; Ogawa, Hisao

    2016-05-01

    Complex fractionated atrial electrogram (CFAE) has been suggested to contribute to the maintenance of atrial fibrillation (AF). However, electrophysiologic characteristics of the left atrial myocardium responsible for genesis of CFAE have not been clarified. Non-contact mapping of the left atrium was performed at 37 AF onset episodes in 24 AF patients. Electrogram amplitude, width, and conduction velocity were measured during sinus rhythm, premature atrial contraction (PAC) with long- (L-PAC), short- (S-PAC) and very short-coupling intervals (VS-PAC). These parameters were compared between CFAE and non-CFAE regions. Unipolar electrogram amplitude was higher in CFAE than non-CFAE during sinus rhythm, L-, S- and VS-PAC (1.82 ± 0.73 vs. 1.13 ± 0.38, p < 0.001; 1.44 ± 0.54 vs. 0.92 ± 0.35, p < 0.001; 1.09 ± 0.40 vs. 0.70 ± 0.27, p < 0.001; 0.76 ± 0.30 vs. 0.53 ± 0.25 mV, p < 0.001). Laplacian bipolar electrogram amplitude was also higher in CFAE than non-CFAE during sinus rhythm, L-, S- and VS-PAC. Unipolar electrogram width was similar in CFAE and non-CFAE. Laplacian bipolar electrogram width was wider in CFAE than non-CFAE during L-, S- and VS-PAC (85.5 ± 6.8 vs. 79.6 ± 4.5, p < 0.001; 96.1 ± 9.7 vs. 84.5 ± 5.9, p < 0.001; 122.4 ± 16.0 vs. 99.6 ± 9.6 ms, p < 0.001), but not during sinus rhythm. The conduction velocity was slower in CFAE during sinus rhythm, L-, S- and VS-PAC than non-CFAE (1.7 ± 0.3 vs. 2.4 ± 0.4, p < 0.001; 1.4 ± 0.3 vs. 2.0 ± 0.5, p < 0.001; 1.2 ± 0.3 vs. 1.7 ± 0.5, p < 0.001; and 0.9 ± 0.3 vs. 1.4 ± 0.4 m/s, p < 0.001). CFAE was generated in the high amplitude atrial myocardium with slow and non-uniform conduction properties which were pronounced associated with premature activation, suggesting that heterogeneous conduction produced in high amplitude region contributes to the genesis of CFAE.

  15. MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling.

    PubMed

    Ahn, Byungyong; Soundarapandian, Mangala M; Sessions, Hampton; Peddibhotla, Satyamaheshwar; Roth, Gregory P; Li, Jian-Liang; Sugarman, Eliot; Koo, Ada; Malany, Siobhan; Wang, Miao; Yea, Kyungmoo; Brooks, Jeanne; Leone, Teresa C; Han, Xianlin; Vega, Rick B; Kelly, Daniel P

    2016-09-01

    Intramuscular lipid accumulation is a common manifestation of chronic caloric excess and obesity that is strongly associated with insulin resistance. The mechanistic links between lipid accumulation in myocytes and insulin resistance are not completely understood. In this work, we used a high-throughput chemical biology screen to identify a small-molecule probe, SBI-477, that coordinately inhibited triacylglyceride (TAG) synthesis and enhanced basal glucose uptake in human skeletal myocytes. We then determined that SBI-477 stimulated insulin signaling by deactivating the transcription factor MondoA, leading to reduced expression of the insulin pathway suppressors thioredoxin-interacting protein (TXNIP) and arrestin domain-containing 4 (ARRDC4). Depleting MondoA in myocytes reproduced the effects of SBI-477 on glucose uptake and myocyte lipid accumulation. Furthermore, an analog of SBI-477 suppressed TXNIP expression, reduced muscle and liver TAG levels, enhanced insulin signaling, and improved glucose tolerance in mice fed a high-fat diet. These results identify a key role for MondoA-directed programs in the coordinated control of myocyte lipid balance and insulin signaling and suggest that this pathway may have potential as a therapeutic target for insulin resistance and lipotoxicity. PMID:27500491

  16. Myocytic androgen receptor controls the strength but not the mass of limb muscles.

    PubMed

    Chambon, Céline; Duteil, Delphine; Vignaud, Alban; Ferry, Arnaud; Messaddeq, Nadia; Malivindi, Rocco; Kato, Shigeaki; Chambon, Pierre; Metzger, Daniel

    2010-08-10

    The anabolic effects of androgens on skeletal muscles are thought to be mediated predominantly through the androgen receptor (AR), a member of the ligand-dependent nuclear receptor superfamily. However, despite numerous studies performed in men and in rodents, these effects remain poorly understood. To characterize androgen signaling in skeletal muscles, we generated mice in which the AR is selectively ablated in myofibers. We show that myocytic AR controls androgen-induced insulin-like growth factor IEa (IGF-IEa) expression in the highly androgen-sensitive perineal muscles and that it mediates androgen-stimulated postnatal hypertrophy of these muscles. In contrast, androgen-dependent postnatal hypertrophy of limb muscle fibers is independent of myocytic AR. Thus, androgens control perineal and limb muscle mass in male mice through myocytic AR-dependent and -independent pathways, respectively. Importantly, we also show that AR deficiency in limb myocytes impairs myofibrillar organization of sarcomeres and decreases muscle strength, thus demonstrating that myocytic AR controls key pathways required for maximum force production. These distinct androgen signaling pathways in perineal and limb muscles may allow the design of screens to identify selective androgen modulators of muscle strength.

  17. Towards Low Energy Atrial Defibrillation.

    PubMed

    Walsh, Philip; Kodoth, Vivek; McEneaney, David; Rodrigues, Paola; Velasquez, Jose; Waterman, Niall; Escalona, Omar

    2015-01-01

    A wireless powered implantable atrial defibrillator consisting of a battery driven hand-held radio frequency (RF) power transmitter (ex vivo) and a passive (battery free) implantable power receiver (in vivo) that enables measurement of the intracardiac impedance (ICI) during internal atrial defibrillation is reported. The architecture is designed to operate in two modes: Cardiac sense mode (power-up, measure the impedance of the cardiac substrate and communicate data to the ex vivo power transmitter) and cardiac shock mode (delivery of a synchronised very low tilt rectilinear electrical shock waveform). An initial prototype was implemented and tested. In low-power (sense) mode, >5 W was delivered across a 2.5 cm air-skin gap to facilitate measurement of the impedance of the cardiac substrate. In high-power (shock) mode, >180 W (delivered as a 12 ms monophasic very-low-tilt-rectilinear (M-VLTR) or as a 12 ms biphasic very-low-tilt-rectilinear (B-VLTR) chronosymmetric (6ms/6ms) amplitude asymmetric (negative phase at 50% magnitude) shock was reliably and repeatedly delivered across the same interface; with >47% DC-to-DC (direct current to direct current) power transfer efficiency at a switching frequency of 185 kHz achieved. In an initial trial of the RF architecture developed, 30 patients with AF were randomised to therapy with an RF generated M-VLTR or B-VLTR shock using a step-up voltage protocol (50-300 V). Mean energy for successful cardioversion was 8.51 J ± 3.16 J. Subsequent analysis revealed that all patients who cardioverted exhibited a significant decrease in ICI between the first and third shocks (5.00 Ω (SD(σ) = 1.62 Ω), p < 0.01) while spectral analysis across frequency also revealed a significant variation in the impedance-amplitude-spectrum-area (IAMSA) within the same patient group (|∆(IAMSAS1-IAMSAS3)[1 Hz - 20 kHz] = 20.82 Ω-Hz (SD(σ) = 10.77 Ω-Hz), p < 0.01); both trends being absent in all patients that failed to cardiovert. Efficient

  18. Towards Low Energy Atrial Defibrillation

    PubMed Central

    Walsh, Philip; Kodoth, Vivek; McEneaney, David; Rodrigues, Paola; Velasquez, Jose; Waterman, Niall; Escalona, Omar

    2015-01-01

    A wireless powered implantable atrial defibrillator consisting of a battery driven hand-held radio frequency (RF) power transmitter (ex vivo) and a passive (battery free) implantable power receiver (in vivo) that enables measurement of the intracardiacimpedance (ICI) during internal atrial defibrillation is reported. The architecture is designed to operate in two modes: Cardiac sense mode (power-up, measure the impedance of the cardiac substrate and communicate data to the ex vivo power transmitter) and cardiac shock mode (delivery of a synchronised very low tilt rectilinear electrical shock waveform). An initial prototype was implemented and tested. In low-power (sense) mode, >5 W was delivered across a 2.5 cm air-skin gap to facilitate measurement of the impedance of the cardiac substrate. In high-power (shock) mode, >180 W (delivered as a 12 ms monophasic very-low-tilt-rectilinear (M-VLTR) or as a 12 ms biphasic very-low-tilt-rectilinear (B-VLTR) chronosymmetric (6ms/6ms) amplitude asymmetric (negative phase at 50% magnitude) shock was reliably and repeatedly delivered across the same interface; with >47% DC-to-DC (direct current to direct current) power transfer efficiency at a switching frequency of 185 kHz achieved. In an initial trial of the RF architecture developed, 30 patients with AF were randomised to therapy with an RF generated M-VLTR or B-VLTR shock using a step-up voltage protocol (50–300 V). Mean energy for successful cardioversion was 8.51 J ± 3.16 J. Subsequent analysis revealed that all patients who cardioverted exhibited a significant decrease in ICI between the first and third shocks (5.00 Ω (SD(σ) = 1.62 Ω), p < 0.01) while spectral analysis across frequency also revealed a significant variation in the impedance-amplitude-spectrum-area (IAMSA) within the same patient group (|∆(IAMSAS1-IAMSAS3)[1 Hz − 20 kHz] = 20.82 Ω-Hz (SD(σ) = 10.77 Ω-Hz), p < 0.01); both trends being absent in all patients that failed to cardiovert. Efficient

  19. Atrial Fibrillation During an Exploration Class Mission

    NASA Technical Reports Server (NTRS)

    Lipsett, Mark; Hamilton, Douglas; Lemery, Jay; Polk, James

    2011-01-01

    This slide presentation reviews a possible scenario of an astronaut having Atrial Fibrillation during a Mars Mission. In the case review the presentation asks several questions about the alternatives for treatment, medications and the ramifications of the decisions.

  20. [New antiarrhythmic drugs for atrial fibrillation].

    PubMed

    Drici, M-D

    2009-12-01

    The development of new antiarrhythmic drugs is mainly aimed to treat atrial fibrillation, because of its prevalence and major consequences in terms cerebral vascular thrombosis. Specific blockade of I(Na) et I(K), even if efficacious, have previously shown to be proarrhythmogenic, with a global impairment of the cardiac patient's outcome. This lead to the development of new drugs, selectively targeting atrial currents such as I(Kur) ou I(KAch). The efficacy of amiodarone in treatment of atrial fibrillation has also yielded a whole array of new antiarrhythmic drugs targeting both these atrial currents but also sharing amiodarone pharmacodynamics properties. This renders the Vaughan-Williams classification ill-adapted for such drugs.

  1. [Cardiac rehabilitation in patients with atrial fibrillation].

    PubMed

    Schlitt, Axel; Kamke, Wolfram; Guha, Manju; Haberecht, Olaf; Völler, Heinz

    2015-06-01

    The course of cardiac rehabilitation is often altered due to episodes of paroxysmal, predominantly postoperative atrial fibrillation. In symptomatic patients, a TEE-guided cardioversion - preferential DC shock - is indicated. In patients with persistent / permanent atrial fibrillation, a heart rate up to 110 / min and 170 / min at rest and during physical activity should, respectively, be tolerated. Therefore, training should not be quitted by heart rate but rather by load. The antithrombotic management is in addition a great task in treating patients with atrial fibrillation. With the exception of patients with a CHA2DS2-VASc-Score < 1, oral anticoagulation is indicated. Atrial fibrillation has little impact on social aspects, whereas the underlying heart disease and drug treatment (oral anticoagulation) has an important impact.

  2. Determinants and importance of atrial pressure morphology in atrial septal defect.

    PubMed Central

    Parikh, D N; Fisher, J; Moses, J W; Goldberg, H L; Levin, A R; Engle, M A; Borer, J S

    1984-01-01

    A prominent "v" wave relative to the "a" wave in the jugular vein and right atrial pressure tracing is considered to be a common haemodynamic sign of atrial septal defect. Since the prevalence, age relation, and haemodynamic determinants of the "v" greater than or equal to "a" wave configuration have not been studied the pressure recordings from 15 adults and 80 children with an isolated secundum atrial septal defect in sinus rhythm and from 40 adults and 55 children in sinus rhythm without structural cardiac abnormalities or with coronary and valvular heart disease were studied to assess the sensitivity and specificity of the "v" greater than or equal to "a" wave configuration in atrial septal defect. Only 20% of adults with an atrial septal defect had prominent right atrial "v" waves compared with 63% of children, although the specificity was quite high for each group. In adults "left atrialisation " of the right atrium ("v" greater than or equal to "a" wave) occurred in younger patients with higher right atrial and right ventricular end diastolic pressures. In contrast, in children no age related or haemodynamic determinants for the "v" greater than or equal to "a" pattern were found. In addition, most adults but few children with an atrial septal defect had "right atrialisation " of the left atrial wave configuration ("a" greater than "v"). This was found in older adults with lower right atrial and right ventricular end diastolic pressures and in older children with larger left to right shunts. Thus in contrast to children adults with an atrial septal defect rarely show a prominent "v" wave in the right atrium. The presence of a prominent right atrial "v" wave in adults with an atrial septal defect is associated with relatively higher left atrial and right heart pressures than is the absence of this sign and may be related to relatively higher systolic transatrial flow in these patients. The relative paucity of prominent right atrial "v" waves in older adults

  3. Atrial conduction delay predicts atrial fibrillation in paroxysmal supraventricular tachycardia patients after radiofrequency catheter ablation.

    PubMed

    Xu, Zhen-Xing; Zhong, Jing-Quan; Zhang, Wei; Yue, Xin; Rong, Bing; Zhu, Qing; Zheng, Zhaotong; Zhang, Yun

    2014-06-01

    This study aimed to assess whether intra- and inter-atrial conduction delay could predict atrial fibrillation (AF) for paroxysmal supraventricular tachycardia (PSVT) patients after successful treatment by radiofrequency catheter ablation (RFCA). Echocardiography examination was performed on 524 consecutive PSVT patients (15 patients were excluded). Left atrial dimension, right atrial diameter and intra- and inter-atrial conduction delay were measured before ablation. Patients were divided into group A (n = 32): occurrence of AF after the ablation and group B (n = 477): remained in sinus rhythm during follow-up. Receiver operating characteristic (ROC) curve analysis was performed to estimate the predictive value of intra- and inter-atrial conduction delay. Both intra- and inter-atrial conduction delay were higher in group A than in group B (4.79 ± 0.30 msec vs. 4.56 ± 0.32 msec; 21.98 ± 1.32 msec vs. 20.01 ± 1.33; p < 0.05). Binary logistic regression analysis showed that intra- and inter-atrial conduction were significant influential factors for the occurrence of AF (odds ratio [OR] = 13.577, 95% confidence interval [CI], 3.469-48.914; OR = 2.569, 95% CI, 1.909-3.459, p < 0.05). The ROC cure analysis revealed that intra-atrial conduction delay ≥ 4.45 msec and inter-atrial conduction delay ≥ 20.65 were the most optimal cut-off value for predicting AF in PSVT patients after RFCA. In conclusion, this is the first study to show that the intra- and inter-atrial conduction delay could effectively predict AF in post-ablation PSVT patients.

  4. Serum Soluble Semaphorin 4D is Associated with Left Atrial Diameter in Patients with Atrial Fibrillation

    PubMed Central

    Xiang, Li; You, Tao; Chen, Jianchang; Xu, Weiting; Jiao, Yang

    2015-01-01

    Background The aim of this study was to evaluate the serum soluble semaphorin 4D (sSema4D) in patients with atrial fibrillation and to investigate the relationship of serum sSema4D with left atrial diameter (LAD). Material/Methods We studied a total of 113 patients who were subdivided into paroxysmal and non-paroxysmal (included persistent and permanent) atrial fibrillation groups, respectively. Another 55 subjects without atrial fibrillation were enrolled as the healthy control group. Serum levels of soluble semaphorin 4D (Sema4D) were measured in all subjects using the enzyme-labeled immunosorbent assay method. We also evaluated the coagulation parameters and left atrial diameters. Results Patients with paroxysmal and non-paroxysmal atrial fibrillation had significantly higher sSema4D level compared with controls (8.50±2.19 ng/mL and 9.30±2.28 ng/mL vs. 6.56±1.27 ng/ml, P<0.05). Serum sSema4D concentrations were elevated in patients with non-paroxysmal atrial fibrillation compared to those with paroxysmal atrial fibrillation (P<0.001). The level of sSema4D was positively correlated with LAD (r=0.606, P<0.001). Multivariate logistic regression analysis revealed that serum sSema4D, LAD, male sex, heart rate, hypertension, and coronary artery disease were associated with atrial fibrillation (P<0.05). Conclusions Serum sSema4D levels are increased in patients with atrial fibrillation and are independently associated with atrial remodeling. PMID:26417899

  5. Multifocal atrial tachycardia caused by risperidone.

    PubMed

    Oner, Taliha; Akdeniz, Celal; Adaletli, Hilal

    2016-01-15

    Risperidone, an atypical antipsychotic drug, is one of the most frequently used atypical neuroleptic drugs for the treatment of symptoms of behavioral disorders seen in autism. Although various cardiovascular side effects have been reported with risperidone, to our knowledge, it has not yet been reported that it can also result in multifocal atrial tachycardia. Based on the case reported herein, our aim is to bring awareness that risperidone may cause multifocal atrial tachycardia.

  6. Atrial fibrillation precipitated by tyramine containing foods.

    PubMed Central

    Jacob, L H; Carron, D B

    1987-01-01

    Episodes of atrial fibrillation that occurred after meals developed in a 60 year old man with a history of ischaemic heart disease. The attacks were precipitated by precursors and metabolites of tyramine and tyramine containing foods and drinks, in the absence of monoamine oxidase inhibitors. The patient has remained free of atrial fibrillation for the past twelve months on a diet that does not contain tyramine. PMID:3814458

  7. Functional properties of K+ currents in adult mouse ventricular myocytes

    PubMed Central

    Brouillette, Judith; Clark, Robert B; Giles, Wayne R; Fiset, Céline

    2004-01-01

    Although the K+ currents expressed in hearts of adult mice have been studied extensively, detailed information concerning their relative sizes and biophysical properties in ventricle and atrium is lacking. Here we describe and validate pharmacological and biophysical methods that can be used to isolate the three main time- and voltage-dependent outward K+ currents which modulate action potential repolarization. A Ca2+-independent transient outward K+ current, Ito, can be separated from total outward current using an ‘inactivating prepulse’. The rapidly activating, slowly inactivating delayed rectifier K+ current, IKur, can be isolated using submillimolar concentrations of 4-aminopyridine (4-AP). The remaining K+ current, Iss, can be obtained by combining these two procedures: (i) inactivating Ito and (ii) eliminating IKur by application of low concentration of 4-AP. Iss activates relatively slowly and shows very little inactivation, even during depolarizations lasting several seconds. Our findings also show that the rate of reactivation of Ito is more than 20-fold faster than that of IKur. These results demonstrate that the outward K+ currents in mouse ventricles can be separated based on their distinct time and voltage dependence, and different sensitivities to 4-AP. Data obtained at both 22 and 32°C demonstrate that although the duration of the inactivating prepulse has to be adapted for the recording temperature, this approach for separation of K+ current components is also valid at more physiological temperatures. To demonstrate that these methods also allow separation of these K+ currents in other cell types, we have applied this same approach to myocytes from mouse atria. Molecular approaches have been used to compare the expression levels of different K+ channels in mouse atrium and ventricle. These findings provide new insights into the functional roles of IKur, Ito and Iss during action potential repolarization. PMID:15272047

  8. [Radiofrequency transcatheter ablation in atrial tachycardia].

    PubMed

    Velázquez Rodríguez, E; Morales Hernández, J A

    2000-01-01

    Incessant atrial tachycardia is an infrequent arrhythmia. Specially difficult to treat medically. Radiofrequency catheter ablation has been used successfully to cure a variety of supraventricular tachycardias. The purpose of this work is to report our initial experience in the treatment of atrial tachycardia. Ten patients, mean age 28.7 +/- 15 year with conventional drug-resistant symptomatic atrial tachycardia were treated with selective ablation of the focus using radiofrequency energy. It was found an abnormal automaticity in 10 tachycardias and in only one patient intra-atrial reentrant was supported. Radiofrequency energy was successful in 10 of 11 tachycardias with a mean of 9.3 +/- 6.8 applications using the technique of local atrial electrogram activation time with a mean value of -54 +/- -31 milliseconds at the successful ablation sites. No complications were observed and one patient had an early clinical recurrence. All patients with successful ablation are symptom-free, in sinus rhythm and without antiarrhythmic medications after 1 to 28 months of follow-up. Our initial experience support that radiofrequency catheter ablation is a safe and effective therapeutic option for incessant atrial tachycardia. PMID:10855411

  9. Antithrombotic treatment of atrial fibrillation: new insights.

    PubMed

    Le Heuzey, J Y

    2012-10-01

    The incidence and prevalence of atrial fibrillation are quickly increasing, mainly due to the ageing of the population. Atrial fibrillation is, to date, a problem of public health. Atrial fibrillation is associated to a five-fold risk of stroke, which may be identified by score risks, such as CHADS(2) score. The classical antithrombotic treatment of atrial fibrillation is based on vitamin K antagonists. Trials made in the 90's have clearly shown that vitamin K antagonists were able to decrease stroke risk by about 60%. New oral anticoagulants are now available on the market to treat patients with atrial fibrillation. These drugs are dabigatran which has demonstrated an interest in the RE-LY trial. Two doses may be prescribed, 110 mg bid and 150 mg bid. Anti Xa have also demonstrated an interest : rivaroxaban in the ROCKET AF trial and apixaban in the AVERROES (versus aspirin) and ARISTOTLE trials. In the future these drugs will have a major place in the armamentarium used to treat patients with atrial fibrillation. In all these trials a decrease in intra cranial haemorrhages has been demonstrated. In the everyday practice it will be necessary to be very cautious in patients with impaired renal function, as all these drugs are eliminated by kidneys. PMID:23026665

  10. Stimulation of polyunsaturated fatty acid oxidation in myocytes by regulating its cellular uptake

    SciTech Connect

    Abdel-aleem, S.; Frangakis, C. ); Badr, M. )

    1991-01-01

    In order to investigate the regulation of polyunsaturated fatty acid oxidation in the heart, the effect of the phosphodiesterase inhibitor enoximone on the oxidation of (1-{sup 14}C) arachidonic acid, and (1-{sup 14}C) arachidonyl-CoA, were studied in adult rat myocytes, and isolated rat heart mitochondria. Enoximone stimulated arachidonate oxidation by 94%, at a concentration of 0.25 mM. The apparent Vmax value of archidonate oxidation in the presence of enoximone was approximately 75% higher than the value observed with the control in isolated myocytes. Also, enoximone stimulated arachidonate uptake by 27% at a concentration of 0.25 mM. On the other hand, enoximone had no effect on the oxidation of (1-{sup 14}C) arachidonyl-CoA in isolated rat heart mitochondria. These results suggest that the oxidation of polyunsaturated fatty acids in myocytes is regulated by the rate of uptake of these acids across sarcolemmal membranes.

  11. Mature adipocyte-derived dedifferentiated fat cells can transdifferentiate into skeletal myocytes in vitro

    SciTech Connect

    Kazama, Tomohiko; Fujie, Masaki; Endo, Tuyoshi; Kano, Koichiro

    2008-12-19

    We have previously reported the establishment of preadipocyte cell lines, termed dedifferentiated fat (DFAT) cells, from mature adipocytes of various animals. DFAT cells possess long-term viability and can redifferentiate into adipocytes both in vivo and in vitro. Furthermore, DFAT cells can transdifferentiate into osteoblasts and chondrocytes under appropriate culture conditions. However, it is unclear whether DFAT cells are capable of transdifferentiating into skeletal myocytes, which is common in the mesodermal lineage. Here, we show that DFAT cells can be induced to transdifferentiate into skeletal myocytes in vitro. Myogenic induction of DFAT cells resulted in the expression of MyoD and myogenin, followed by cell fusion and formation of multinucleated cells expressing sarcomeric myosin heavy chain. These results indicate that DFAT cells derived from mature adipocytes can transdifferentiate into skeletal myocytes in vitro.

  12. Electrodeposition of anchored polypyrrole film on microelectrodes and stimulation of cultured cardiac myocytes.

    PubMed

    Nishizawa, Matsuhiko; Nozaki, Hyuma; Kaji, Hirokazu; Kitazume, Takahiro; Kobayashi, Noriyuki; Ishibashi, Takeshi; Abe, Takashi

    2007-03-01

    The electrically conducting polymer polypyrrole (PPy) was electrochemically deposited onto Pt microelectrodes on a polyimide (PI) substrate. Pre-modification of the PI surface with a self-assembled monolayer of octadecyltrichlorosilane-induced anisotropic lateral growth of PPy along the PI surface and enhanced adhesive strength of the PPy film. The lateral growth of PPy film around the electrode anchored the whole film to the substrate. External stimulation of cultured cardiac myocytes was carried out using the PPy-coated microelectrode. The myocytes on the microelectrode substrate were electrically conjugated to form a sheet, and showed synchronized beating upon stimulation. The threshold charge for effective stimulation of a 0.8 cm(2) sheet of myocytes was around 0.2 microC, roughly corresponding to a membrane depolarization of 250 mV.

  13. Numerical Simulations of Calcium Ions Spiral Wave in Single Cardiac Myocyte

    NASA Astrophysics Data System (ADS)

    Bai, Yong-Qiang; Zhu, Xing

    2010-04-01

    The calcium ions (Ca2+) spark is an elementary Ca2+ release event in cardiac myocytes. It is believed to buildup cell-wide Ca2+ signals, such as Ca2+ transient and Ca2+ wave, through a Ca2+-induced Ca2+ release (CICR) mechanism. Here the excitability of the Ca2+ wave in a single cardiac myocyte is simulated by employing the fire-diffuse-fire model. By modulating the dynamic parameters of Ca2+ release and re-uptake channels, we find three Ca2+ signaling states in a single cardiac myocyte: no wave, plane wave, and spiral wave. The period of a spiral wave is variable in the different regimes. This study indicates that the spiral wave or the excitability of the system can be controlled through micro-modulation in a living excitable medium.

  14. Carbon fiber technique for the investigation of single-cell mechanics in intact cardiac myocytes.

    PubMed

    Sugiura, Seiryo; Nishimura, Satoshi; Yasuda, Soichiro; Hosoya, Yumiko; Katoh, Kaoru

    2006-01-01

    This protocol describes a method for attaching single isolated cardiac myocytes to carbon fibers for mechanical manipulation and measurement. This method relies on cell-adhesive carbon fibers that attach easily to the cell membrane without causing damage, and is thus applicable to intact myocytes. To connect the carbon fiber to micromanipulators, a fiber holder with glass capillaries must first be fabricated. After connection of the fibers to the micromanipulators, firm attachment is easily established by gently pressing the fiber tip onto the cell membrane. Unlike other methods, this technique does not require vast technical expertise, and therefore greatly facilitates experiments. This method enables detection of the effect of drugs, genetic defects or the expression of exogenous proteins on both active and passive properties of cardiac myocytes. In combination with other experimental procedures, this technique can also be applied to the study of mechano-transduction. This protocol can be completed in 3.5 h.

  15. Genome-wide screening identifies a KCNIP1 copy number variant as a genetic predictor for atrial fibrillation

    PubMed Central

    Tsai, Chia-Ti; Hsieh, Chia-Shan; Chang, Sheng-Nan; Chuang, Eric Y.; Ueng, Kwo-Chang; Tsai, Chin-Feng; Lin, Tsung-Hsien; Wu, Cho-Kai; Lee, Jen-Kuang; Lin, Lian-Yu; Wang, Yi-Chih; Yu, Chih-Chieh; Lai, Ling-Ping; Tseng, Chuen-Den; Hwang, Juey-Jen; Chiang, Fu-Tien; Lin, Jiunn-Lee

    2016-01-01

    Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Previous genome-wide association studies had identified single-nucleotide polymorphisms in several genomic regions to be associated with AF. In human genome, copy number variations (CNVs) are known to contribute to disease susceptibility. Using a genome-wide multistage approach to identify AF susceptibility CNVs, we here show a common 4,470-bp diallelic CNV in the first intron of potassium interacting channel 1 gene (KCNIP1) is strongly associated with AF in Taiwanese populations (odds ratio=2.27 for insertion allele; P=6.23 × 10−24). KCNIP1 insertion is associated with higher KCNIP1 mRNA expression. KCNIP1-encoded protein potassium interacting channel 1 (KCHIP1) is physically associated with potassium Kv channels and modulates atrial transient outward current in cardiac myocytes. Overexpression of KCNIP1 results in inducible AF in zebrafish. In conclusions, a common CNV in KCNIP1 gene is a genetic predictor of AF risk possibly pointing to a functional pathway. PMID:26831368

  16. Role of Magnetic Resonance Imaging of Atrial Fibrosis in Atrial Fibrillation Ablation.

    PubMed

    Spragg, David D; Khurram, Irfan; Nazarian, Saman

    2013-11-01

    Atrial fibrillation (AF) likely involves a complex interplay between triggering activity, usually from pulmonary vein foci, and maintenance of the arrhythmia by an arrhythmogenic substrate. Both components of AF, triggers and substrate have been linked to atrial fibrosis and attendant changes in atrial electrophysiology. Recently, there has been a growing use of imaging modalities, particularly cardiac magnetic resonance (CMR), to quantify the burden of atrial fibrosis and scar in patients either undergoing AF ablation, or who have recently had the procedure. How to use the CMR derived data is still an open area of investigation. The aim of this article is to summarise what is known as atrial fibrosis, as assessed by traditional catheter-based techniques and newer imaging approaches, and to report on novel efforts from our group to advance the use of CMR in AF ablation patients.

  17. Cyclic GMP reduces ventricular myocyte stunning after simulated ischemia-reperfusion.

    PubMed

    Gandhi, A; Yan, L; Scholz, P M; Huang, M W; Weiss, H R

    1999-12-01

    We tested the hypothesis that the second messenger activated by nitric oxide, cyclic GMP, would reduce the effects of myocyte stunning following simulated ischemia-reperfusion and that this was related to cyclic GMP protein kinase. Ventricular cardiac myocytes were isolated from New Zealand White rabbits (n = 8). Cell shortening was measured by a video edge detector and protein phosphorylation was determined autoradiographically after SDS gel electrophoresis. Cell shortening data were acquired at: (i) baseline followed by 8-Bromo-cGMP 10(-6) M (8-Br-cGMP) and then KT 5823 10(-6) M (cyclic GMP protein kinase inhibitor) and (ii) simulated ischemia (20 min of 95% N(2)-5% CO(2) at 37 degrees C) followed by simulated reperfusion (reoxygenation) with addition of 8-Br-cGMP 10(-6) M followed by KT 5823 10(-6) M, (iii) addition of 8-Br-cGMP prior to ischemia followed by the addition of KT 5823 10(-6) M after 30 min of reoxygenation. In the control group, 8-Br-cGMP 10(-6) M decreased percentage shortening (%short) (5.0 +/- 0.6 vs 3.8 +/- 0. 4) and the maximum velocity (V(max), microm/s) (48.6 +/- 6.9 vs 40.2 +/- 6.4). KT 5823 10(-6) M added after 8-Br-cGMP partially restored %short (4.6 +/- 0.5) and V(max) (46.6 +/- 8.0). After stunning, baseline myocytes had decreased %short (3.4 +/- 0.2) and V(max) (36. 0 +/- 4.2). After the addition of 8-Br-cGMP, the %short (2.7 +/- 0. 2) and V(max) (27.6 +/- 2.5) decreased further. The addition of KT 5823 did not change either the %short or the V(max). The myocytes with 8-Br-cGMP during ischemia had increased %short (4.2 +/- 0.2) and V(max) (37.2 +/- 3.4) when compared to the stunned group. The addition of KT 5823 did not significantly alter %short (3.3 +/- 0.4) or V(max) (29.2 +/- 5.0) in the myocytes pretreated with 8-Br-cGMP. Protein phosphorylation was increased by 8-Br-cGMP in control and stunned myocytes. KT 5823 blocked this effect in control but not stunned myocytes, suggesting some change in the cyclic GMP protein kinase

  18. The relationship between contraction and intracellular sodium in rat and guinea-pig ventricular myocytes.

    PubMed Central

    Harrison, S M; McCall, E; Boyett, M R

    1992-01-01

    1. The contraction, measured optically, and the intracellular Na+ activity (aNai), measured with the Na(+)-sensitive fluorescent dye SBFI, have been recorded simultaneously in rat and guinea-pig ventricular myocytes. 2. In rat and guinea-pig ventricular myocytes at rest, aNai was 7.8 +/- 0.3 mM (n = 4) and 5.1 +/- 0.3 mM (n = 16), respectively. 3. When both rat and guinea-pig ventricular myocytes were stimulated at 1 Hz after a rest there was usually a gradual increase in twitch shortening (referred to as a 'staircase') over several minutes accompanied by an increase in aNai over a similar time course. Twitch shortening increased by 21 +/- 3% (n = 6) and 20 +/- 4% (n = 16) (of steady-state twitch shortening during 1 Hz stimulation) per millimolar rise in aNai in rat and guinea-pig ventricular myocytes, respectively. 4. When rat and guinea-pig ventricular myocytes were exposed to strophanthidin to block the Na(+)-K+ pump, there were increases in twitch shortening and aNai over similar time courses. Twitch shortening increased by 24 +/- 4% (n = 5) and 20 +/- 3% (n = 10) (of control twitch shortening) per millimolar rise in aNai in rat and guinea-pig ventricular myocytes respectively. 5. The inotropic effect of cardiac glycosides, such as strophanthidin, is widely regarded to be principally the result of the rise in aNai. The similarity of the relation between twitch shortening and aNai during the staircase and on application of strophanthidin suggests that the progressive increase in the strength of contraction during the staircase was also linked to the rise in aNai. 6. In guinea-pig, but not rat, ventricular myocytes there was hysteresis in the relation between twitch shortening and aNai on application and wash-off of strophanthidin. This indicates that strophanthidin has another inotropic action in guinea-pig ventricular myocytes. 7. A computer model of excitation-contraction coupling has been developed to simulate the staircase and the action of cardiac glycoside

  19. Applying non-linear dynamics to atrial appendage flow data to understand and characterize atrial arrhythmia

    SciTech Connect

    Chandra, S.; Grimm, R.A.; Katz, R.; Thomas, J.D.

    1996-06-01

    The aim of this study was to better understand and characterize left atrial appendage flow in atrial fibrillation. Atrial fibrillation and flutter are the most common cardiac arrhythmias affecting 15% of the older population. The pulsed Doppler velocity profile data was recorded from the left atrial appendage of patients using transesophageal echocardiography. The data was analyzed using Fourier analysis and nonlinear dynamical tools. Fourier analysis showed that appendage mechanical frequency ({ital f{sub f}}) for patients in sinus rhythm was always lower (around1 Hz) than that in atrial fibrillation (5-8 Hz). Among patients with atrial fibrillation spectral power below {ital f{sub f}} was significantly different suggesting variability within this group of patients. Results that suggested the presence of nonlinear dynamics were: a) the existence of two arbitrary peak frequencies {ital f{sub 1}, f{sub 2}}, and other peak frequencies as linear combinations thereof ({ital mf{sub 1}{+-}nf{sub 2}}), and b) the similarity between the spectrum of patient data and that obtained using the Lorenz equation. Nonlinear analysis tools, including Phase plots and differential radial plots, were also generated from the velocity data using a delay of 10. In the phase plots, some patients displayed a torus-like structure, while others had a more random-like pattern. In the differential radial plots, the first set of patients (with torus-like phase plots) showed fewer values crossing an arbitrary threshold of 10 than did the second set (8 vs. 27 in one typical example). The outcome of cardioversion was different for these two set of patients. Fourier analysis helped to: differentiate between sinus rhythm and atrial fibrillation, understand the characteristics of the wide range of atrial fibrillation patients, and provide hints that atrial fibrillation could be a nonlinear process. Nonlinear dynamical tools helped to further characterize and sub-classify atrial fibrillation.

  20. Outcomes after ablation for typical atrial flutter (from the Loire Valley Atrial Fibrillation Project).

    PubMed

    Clementy, Nicolas; Desprets, Laurent; Pierre, Bertrand; Lallemand, Bénédicte; Simeon, Edouard; Brunet-Bernard, Anne; Babuty, Dominique; Fauchier, Laurent

    2014-11-01

    Similar predisposing factors are found in most types of atrial arrhythmias. The incidence of atrial fibrillation (AF) among patients with atrial flutter is high, suggesting similar outcomes in patients with those arrhythmias. We sought to investigate the long-term outcomes and prognostic factors of patients with AF and/or atrial flutter with contemporary management using radiofrequency ablation. In an academic institution, we retrospectively examined the clinical course of 8,962 consecutive patients admitted to our department with a diagnosis of AF and/or atrial flutter. After a median follow-up of 934 ± 1,134 days, 1,155 deaths and 715 stroke and/thromboembolic (TE) events were recorded. Patients with atrial flutter undergoing cavotricuspid isthmus ablation (n = 875, 37% with a history of AF) had a better survival rate than other patients (hazard ratio [HR] 0.35, 95% confidence interval [CI] 0.25 to 0.49, p <0.0001). Using Cox proportional hazards model and propensity score model, after adjustment for main other confounders, ablation for atrial flutter was significantly associated with a lower risk of all-cause mortality (HR 0.55, 95% CI 0.36 to 0.84, p = 0.006) and stroke and/or TE events (HR 0.53, 95% CI 0.30 to 0.92, p = 0.02). After ablation, there was no significant difference in the risk of TE between patients with a history of AF and those with atrial flutter alone (HR 0.83, 95% CI 0.41 to 1.67, p = 0.59). In conclusion, in patients with atrial tachyarrhythmias, those with atrial flutter with contemporary management who undergo cavotricuspid isthmus radiofrequency ablation independently have a lower risk of stroke and/or TE events and death of any cause, whether a history of AF is present or not.

  1. Determinants of Left Atrial Volume in Patients with Atrial Fibrillation

    PubMed Central

    Hochgruber, Thomas; Krisai, Philipp; Zimmermann, Andreas J.; Aeschbacher, Stefanie; Pumpol, Katrin; Kessel-Schaefer, Arnheid; Stephan, Frank-Peter; Handschin, Nadja; Sticherling, Christian; Osswald, Stefan; Kaufmann, Beat A.; Paré, Guillaume; Kühne, Michael; Conen, David

    2016-01-01

    Introduction Left atrial (LA) enlargement is an important risk factor for incident stroke and a key determinant for the success of rhythm control strategies in patients with atrial fibrillation (AF). However, factors associated with LA volume in AF patients remain poorly understood. Methods Patients with paroxysmal or persistent AF were enrolled in this study. Real time 3-D echocardiography was performed in all participants and analyzed offline in a standardized manner. We performed stepwise backward linear regression analyses using a broad set of clinical parameters to determine independent correlates for 3-D LA volume. Results We included 210 patients (70.9% male, mean age 61±11years). Paroxysmal and persistent AF were present in 95 (45%) and 115 (55%) patients, respectively. Overall, 115 (55%) had hypertension, 11 (5%) had diabetes, and 18 (9%) had ischemic heart disease. Mean indexed LA volume was 36±12ml/m2. In multivariable models, significant associations were found for female sex (β coefficient -10.51 (95% confidence interval (CI) -17.85;-3.16), p = 0.0053), undergoing cardioversion (β 11.95 (CI 5.15; 18.74), p = 0.0006), diabetes (β 14.23 (CI 2.36; 26.10), p = 0.019), body surface area (BSA) (β 34.21 (CI 19.30; 49.12), p<0.0001), glomerular filtration rate (β -0.21 (CI -0.36; -0.06), p = 0.0064) and plasma levels of NT-pro brain natriuretic peptide (NT-proBNP) (β 6.79 (CI 4.05; 9.52), p<0.0001), but not age (p = 0.59) or hypertension (p = 0.42). Our final model explained 52% of the LA volume variability. Conclusions In patients with AF, the most important correlates with LA volume are sex, BSA, diabetes, renal function and NT-proBNP, but not age or hypertension. These results may help to refine rhythm control strategies in AF patients. PMID:27701468

  2. Atrial Ectopy as a Predictor of Incident Atrial Fibrillation

    PubMed Central

    Dewland, Thomas A.; Vittinghoff, Eric; Mandyam, Mala C.; Heckbert, Susan R.; Siscovick, David S.; Stein, Phyllis K.; Psaty, Bruce M.; Sotoodehnia, Nona; Gottdiener, John S.; Marcus, Gregory M.

    2014-01-01

    Background Atrial fibrillation (AF) prediction models have unclear clinical utility given the absence of AF prevention therapies and the immutability of many risk factors. Premature atrial contractions (PACs) play a critical role in AF pathogenesis and may be modifiable. Objective To investigate whether PAC count improves model performance for AF risk. Design Prospective cohort study. Setting 4 U.S. communities. Patients A random subset of 1260 adults without prevalent AF enrolled in the Cardiovascular Health Study between 1989 and 1990. Measurements The PAC count was quantified by 24-hour electrocardiography. Participants were followed for the diagnosis of incident AF or death. The Framingham AF risk algorithm was used as the comparator prediction model. Results In adjusted analyses, doubling the hourly PAC count was associated with a significant increase in AF risk (hazard ratio, 1.17 [95% CI, 1.13 to 1.22]; P < 0.001) and overall mortality (hazard ratio, 1.06 [CI, 1.03 to 1.09]; P < 0.001). Compared with the Framingham model, PAC count alone resulted in similar AF risk discrimination at 5 and 10 years of follow-up and superior risk discrimination at 15 years. The addition of PAC count to the Framingham model resulted in significant 10-year AF risk discrimination improvement (c-statistic, 0.65 vs. 0.72; P < 0.001), net reclassification improvement (23.2% [CI, 12.8% to 33.6%]; P < 0.001), and integrated discrimination improvement (5.6% [CI, 4.2% to 7.0%]; P < 0.001). The specificity for predicting AF at 15 years exceeded 90% for PAC counts more than 32 beats/h. Limitation This study does not establish a causal link between PACs and AF. Conclusion The addition of PAC count to a validated AF risk algorithm provides superior AF risk discrimination and significantly improves risk reclassification. Further study is needed to determine whether PAC modification can prospectively reduce AF risk. Primary Funding Source American Heart Association, Joseph Drown Foundation

  3. What Are the Signs and Symptoms of Atrial Fibrillation?

    MedlinePlus

    ... from the NHLBI on Twitter. What Are the Signs and Symptoms of Atrial Fibrillation? Atrial fibrillation (AF) ... the lungs and body. This can lead to signs and symptoms, such as: Palpitations (feelings that your ...

  4. Effect of phenylephrine infusion on atrial electrophysiological properties.

    PubMed Central

    Leitch, J. W.; Basta, M.; Fletcher, P. J.

    1997-01-01

    OBJECTIVE: To determine the effect of changes in autonomic tone induced by phenylephrine infusion on atrial refractoriness and conduction. DESIGN: Left and right atrial electrophysiological properties were measured before and after a constant phenylephrine infusion designed to increase sinus cycle length by 25%. SUBJECTS: 20 patients, aged 53 (SD 6) years, undergoing electrophysiological study for investigation of idiopathic paroxysmal atrial fibrillation (seven patients) or for routine follow up after successful catheter ablation of supraventricular tachycardia (13 patients). MAIN OUTCOME MEASURES: Changes in left and right atrial effective refractory periods, atrial activation times, and frequency of induction of atrial fibrillation. RESULTS: Phenylephrine (mean dose 69 (SD 18) mg/min) increased mean blood pressure by 22 (12) mm Hg (range 7 to 44) and lengthened sinus cycle length by 223 (94) ms (20 to 430). Left atrial effective refractory period lengthened following phenylephrine infusion from 250 (25) to 264 (21) ms (P < 0.001) but there was no significant change in right atrial effective refractory period: 200 (20) v 206 (29), P = 0.11. There was a significant relation between the effect of phenylephrine on sinus cycle length and on right atrial refractoriness (r = 0.6, P = 0.005) with shortening of right atrial refractoriness in patients with the greatest prolongation in sinus cycle length. During phenylephrine infusion, the right atrial stimulus to left atrial activation time at the basic pacing cycle length of 600 ms was unchanged, at 130 (18) v 131 (17) ms, but activation delay with a premature extrastimulus increased: 212 (28) v 227 (38) ms, P = 0.002. Atrial fibrillation was induced by two of 58 refractory period measurements at baseline and by 12 of 61 measurements during phenylephrine infusion (P < 0.01). Phenylephrine increased the difference between left and right atrial refractory periods by 22.8 (19.4) ms in the five patients with induced atrial

  5. A Case of Giant Right Atrial Aneurysm in a Child.

    PubMed

    Pawar, Ravindra S; Tiwari, Ashish; Suresh, P V; Raj, Vimal; Kaushik, Pradeepkumar

    2016-07-01

    Giant right atrial aneurysm is a rare entity in infants and children. It needs to be distinguished from an atrial diverticulum, which can have similar presentation. Generally, an incidental finding in children, it can present with varied symptoms. We report a case of a giant right atrial aneurysm in an asymptomatic child with a large clot in the dilated right atrium, who underwent successful resection of the atrial aneurysm. PMID:26884450

  6. Alaska Natives & the Land.

    ERIC Educational Resources Information Center

    Arnold, Robert D.; And Others

    Pursuant to the Native land claims within Alaska, this compilation of background data and interpretive materials relevant to a fair resolution of the Alaska Native problem seeks to record data and information on the Native peoples; the land and resources of Alaska and their uses by the people in the past and present; land ownership; and future…

  7. Native American Healing Traditions

    ERIC Educational Resources Information Center

    Portman, Tarrell A. A.; Garrett, Michael T.

    2006-01-01

    Indigenous healing practices among Native Americans have been documented in the United States since colonisation. Cultural encapsulation has deterred the acknowledgement of Native American medicinal practices as a precursor to folk medicine and many herbal remedies, which have greatly influenced modern medicine. Understanding Native American…

  8. The first case of atrial fibrillation-related graft kidney infarction following acute pyelonephritis.

    PubMed

    Tsai, Shang-Feng

    2014-01-01

    Native renal infarction is uncommon in patients with atrial fibrillation (AF)-related thromboembolism. Graft infarction is also rare, with such cases mostly occurring in the main graft artery postoperatively. To date, there have been no studies of AF-related graft kidney infarction. We herein describe the first case of AF-related graft kidney infarction. The clinical manifestations of this condition mimic and follow those of acute pyelonephritis; therefore, these diseases should be differentially diagnosed as early as possible using lactic dehydrogenase testing and computed tomography. Aggressive treatment with intravascular thrombolysis should be administered, even when the diagnosis is delayed, in order to restore a viable renal function.

  9. Displacement of Amplatzer septal occluder in a patient with atrial septal defects and an atrial septal aneurysm.

    PubMed

    Oda, Takeshi; Kato, Seiya; Suda, Kenji

    2016-10-01

    Transcatheter closure of atrial septal defects has become more common because of its high success rate and low morbidity; however, this treatment for patients with atrial septal aneurysms is still challenging. PMID:27434107

  10. Evidence for a further stimulation of atrial natriuretic factor release by atrial pacing in patients with mitral stenosis.

    PubMed

    Malatino, L S; Stancanelli, B; Greco, G; Polizzi, G; Leonardi, C; Russo, G; Tamburino, C; Greco, G; Giuffrida, G; Tamburino, G

    1989-12-01

    To investigate the release of atrial natriuretic factor (ANF) in mitral stenosis and the effect of an increased atrial contraction frequency on atrial distension and ANF secretion, we studied 14 patients [New York Heart Association (NYHA) grades II-III] in sinus rhythm, undergoing cardiac catheterization for mitral stenosis. Echocardiographic tracings, repeat determinations of mean pulmonary artery wedge pressure and blood samples from the pulmonary artery for ANF measurements were taken at baseline, during atrial pacing (125 beats/min for 5 min) and 5 min after pacing. After pacing, ANF levels rose markedly with a parallel increase in mean pulmonary artery wedge pressure and left atrial size. These data indicate that atrial pacing is capable of further stimulating ANF release, even in patients with elevated baseline ANF and left atrial pressure and an increased left atrial dimension. PMID:2534411

  11. Atrial fibrillation from the pathologist's perspective.

    PubMed

    Corradi, Domenico

    2014-01-01

    Atrial fibrillation (AF), the most common sustained cardiac arrhythmia encountered in clinical practice, is associated with increased morbidity and mortality. Electrophysiologically, it is characterized by a high rate of asynchronous atrial cell depolarization causing a loss of atrial contractile function and irregular ventricular rates. For a long time, AF was considered as a pure functional disorder without any structural background. Only in recent years, have new mapping and imaging techniques identified atrial locations, which are very often involved in the initiation and maintenance of this supraventricular arrhythmia (i.e. the distal portion of the pulmonary veins and the surrounding atrial myocardium). Morphological analysis of these myocardial sites has demonstrated significant structural remodeling as well as paved the way for further knowledge of AF natural history, pathogenesis, and treatment. This architectural myocardial disarrangement is induced by the arrhythmia itself and the very frequently associated cardiovascular disorders. At the same time, the structural remodeling is also capable of sustaining AF, thereby creating a sort of pathogenetic vicious circle. This review focuses on current understanding about the structural and genetic bases of AF with reference to their classification, pathogenesis, and clinical implications. PMID:24462196

  12. Dedifferentiation of atrial cardiomyocytes as a result of chronic atrial fibrillation.

    PubMed Central

    Ausma, J.; Wijffels, M.; van Eys, G.; Koide, M.; Ramaekers, F.; Allessie, M.; Borgers, M.

    1997-01-01

    Chronic atrial fibrillation was induced in goats by electrical pacing. After 9 to 23 weeks of sustained atrial fibrillation, the morphology of the atrial structures was examined. The majority of the cardiomyocytes exhibited marked changes in their cellular substructures, with the replacement of sarcomeres by glycogen as the main characteristic. Using immuno-histochemical staining procedures, we assessed the expression and organization of contractile and cytoskeletal proteins in these cases and compared them with the expression and organization of these proteins in normal atria. Part of the atrial cardiomyocytes acquired a dedifferentiated phenotype, as deduced from the re-expression of alpha-smooth muscle actin, the disappearance of cardiotin, and the staining patterns of titin, which resembled those of embryonic cardiomyocytes. From these results we conclude that chronic atrial fibrillation induces myocardial dedifferentiation. This model of chronic atrial fibrillation in goats offers the possibility to study the time course of changes in cardiac structure during sustained atrial fibrillation and after cardioversion. Images Figure 1 Figure 2 Figure 3 Figure 5 Figure 6 Figure 7 PMID:9327732

  13. Aorta-right atrial tunnel.

    PubMed

    Sai Krishna, Cheemalapati; Baruah, Dibya Kumar; Reddy, Gangireddy Venkateswara; Panigrahi, Nanda Kishore; Suman, Kalagara; Kumar, Palli Venkata Naresh

    2010-01-01

    Aorta-right atrial tunnel is a vascular channel that originates from one of the sinuses of Valsalva and terminates in either the superior vena cava or the right atrium. The tunnel is classified as anterior or posterior, depending upon its course in relation to the ascending aorta. An origin above the sinotubular ridge differentiates the tunnel from an aneurysm of the sinus of Valsalva, and the absence of myocardial branches differentiates it from a coronary-cameral fistula. Clinical presentation ranges from an asymptomatic precordial murmur to congestive heart failure. The embryologic background and pathogenesis of this lesion are attributable either to an aneurysmal dilation of the sinus nodal artery or to a congenital weakness of the aortic media. In either circumstance, progressive enlargement of the tunnel and ultimate rupture into the low-pressure right atrium could occur under the influence of the systemic pressure.The lesion is diagnosed by use of 2-dimensional echocardiography and cardiac catheterization. Computed tomographic angiography is an additional noninvasive diagnostic tool. The possibility of complications necessitates early therapy, even in asymptomatic patients or those with a hemodynamically insignificant shunt. Available treatments are catheter-based intervention, external ligation under controlled hypotension, or surgical closure with the patient under cardiopulmonary bypass.Herein, we discuss the cases of 2 patients who had this unusual anomaly. We highlight the outcome on follow-up imaging (patient 1) and the identification and safe reimplantation of the coronary artery (patient 2).

  14. Aging increases stiffness of cardiac myocytes measured by atomic force microscopy nanoindentation.

    PubMed

    Lieber, Samuel C; Aubry, Nadine; Pain, Jayashree; Diaz, Gissela; Kim, Song-Jung; Vatner, Stephen F

    2004-08-01

    It is well established that the aging heart exhibits left ventricular (LV) diastolic dysfunction and changes in mechanical properties, which are thought to be due to alterations in the extracellular matrix. We tested the hypothesis that the mechanical properties of cardiac myocytes significantly change with aging, which could contribute to the global changes in LV diastolic dysfunction. We used atomic force microscopy (AFM), which determines cellular mechanical property changes at nanoscale resolution in myocytes, from young (4 mo) and old (30 mo) male Fischer 344 x Brown Norway F1 hybrid rats. A measure of stiffness, i.e., apparent elastic modulus, was determined by analyzing the relationship between AFM indentation force and depth with the classical infinitesimal strain theory and by modeling the AFM probe as a blunted conical indenter. This is the first study to demonstrate a significant increase (P < 0.01) in the apparent elastic modulus of single, aging cardiac myocytes (from 35.1 +/- 0.7, n = 53, to 42.5 +/- 1.0 kPa, n = 58), supporting the novel concept that the mechanism mediating LV diastolic dysfunction in aging hearts resides, in part, at the level of the myocyte.

  15. EXPOSURE OF CULTURED MYOCYTES TO ZINC RESULTS IN ALTERED BEAT RATE AND INTERCELLULAR COMMUNICATION.

    EPA Science Inventory

    Exposure of cultured myocytes to zinc results in altered beat rate and intercellular communication

    Graff, Donald W, Devlin, Robert B, Brackhan, Joseph A, Muller-Borer, Barbara J, Bowman, Jill S, Cascio, Wayne E.

    Exposure to ambient air pollution particulate matter (...

  16. Effects of cannabidiol on contractions and calcium signaling in rat ventricular myocytes.

    PubMed

    Ali, Ramez M; Al Kury, Lina T; Yang, Keun-Hang Susan; Qureshi, Anwar; Rajesh, Mohanraj; Galadari, Sehamuddin; Shuba, Yaroslav M; Howarth, Frank Christopher; Oz, Murat

    2015-04-01

    Cannabidiol (CBD), a major nonpsychotropic cannabinoid found in Cannabis plant, has been shown to influence cardiovascular functions under various physiological and pathological conditions. In the present study, the effects of CBD on contractility and electrophysiological properties of rat ventricular myocytes were investigated. Video edge detection was used to measure myocyte shortening. Intracellular Ca(2+) was measured in cells loaded with the Ca(2+) sensitive fluorescent indicator fura-2 AM. Whole-cell patch clamp was used to measure action potential and Ca(2+) currents. Radioligand binding was employed to study pharmacological characteristics of CBD binding. CBD (1μM) caused a significant decrease in the amplitudes of electrically evoked myocyte shortening and Ca(2+) transients. However, the amplitudes of caffeine-evoked Ca(2+) transients and the rate of recovery of electrically evoked Ca(2+) transients following caffeine application were not altered. CBD (1μM) significantly decreased the duration of APs. Further studies on L-type Ca(2+) channels indicated that CBD inhibits these channels with IC50 of 0.1μM in a voltage-independent manner. Radioligand studies indicated that the specific binding of [(3)H]Isradipine, was not altered significantly by CBD. The results suggest that CBD depresses myocyte contractility by suppressing L-type Ca(2+) channels at a site different than dihydropyridine binding site and inhibits excitation-contraction coupling in cardiomyocytes.

  17. Interleukin 1 and Tumor Necrosis Factor Inhibit Cardiac Myocyte β -adrenergic Responsiveness

    NASA Astrophysics Data System (ADS)

    Gulick, Tod; Chung, Mina K.; Pieper, Stephen J.; Lange, Louis G.; Schreiner, George F.

    1989-09-01

    Reversible congestive heart failure can accompany cardiac allograft rejection and inflammatory myocarditis, conditions associated with an immune cell infiltrate of the myocardium. To determine whether immune cell secretory products alter cardiac muscle metabolism without cytotoxicity, we cultured cardiac myocytes in the presence of culture supernatants from activated immune cells. We observed that these culture supernatants inhibit β -adrenergic agonist-mediated increases in cultured cardiac myocyte contractility and intracellular cAMP accumulation. The myocyte contractile response to increased extracellular Ca2+ concentration is unaltered by prior exposure to these culture supernatants, as is the increase in myocyte intracellular cAMP concentration in response to stimulation with forskolin, a direct adenyl cyclase activator. Inhibition occurs in the absence of alteration in β -adrenergic receptor density or ligand binding affinity. Suppressive activity is attributable to the macrophage-derived cytokines interleukin 1 and tumor necrosis factor. Thus, these observations describe a role for defined cytokines in regulating the hormonal responsiveness and function of contractile cells. The effects of interleukin 1 and tumor necrosis factor on intracellular cAMP accumulation may be a model for immune modulation of other cellular functions dependent upon cyclic nucleotide metabolism. The uncoupling of agonist-occupied receptors from adenyl cyclase suggests that β -receptor or guanine nucleotide binding protein function is altered by the direct or indirect action of cytokines on cardiac muscle cells.

  18. Nicotinamide adenine dinucleotide fluorescence spectroscopy and imaging of isolated cardiac myocytes.

    PubMed Central

    Eng, J; Lynch, R M; Balaban, R S

    1989-01-01

    Nicotinamide adenine dinucleotide (NADH) plays a critical role in oxidative phosphorylation as the primary source of reducing equivalents to the respiratory chain. Using a modified fluorescence microscope, we have obtained spectra and images of the blue autofluorescence from single rat cardiac myocytes. The optical setup permitted rapid acquisition of fluorescence emission spectra (390-595 nm) or intensified digital video images of individual myocytes. The spectra showed a broad fluorescence centered at 447 +/- 0.2 nm, consistent with mitochondrial NADH. Addition of cyanide resulted in a 100 +/- 10% increase in fluorescence, while the uncoupler FCCP resulted in a 82 +/- 4% decrease. These two transitions were consistent with mitochondrial NADH and implied that the myocytes were 44 +/- 6% reduced under the resting control conditions. Intracellular fluorescent structures were observed that correlated with the distribution of a mitochondrial selective fluorescent probe (DASPMI), the mitochondrial distribution seen in published electron micrographs, and a metabolic digital subtraction image of the cyanide fluorescence transition. These data are consistent with the notion that the blue autofluorescence of rat cardiac myocytes originates from mitochondrial NADH. Images FIGURE 9 FIGURE 10 FIGURE 2 FIGURE 3 FIGURE 8 FIGURE 11 PMID:2720061

  19. Effects of cannabidiol on contractions and calcium signaling in rat ventricular myocytes.

    PubMed

    Ali, Ramez M; Al Kury, Lina T; Yang, Keun-Hang Susan; Qureshi, Anwar; Rajesh, Mohanraj; Galadari, Sehamuddin; Shuba, Yaroslav M; Howarth, Frank Christopher; Oz, Murat

    2015-04-01

    Cannabidiol (CBD), a major nonpsychotropic cannabinoid found in Cannabis plant, has been shown to influence cardiovascular functions under various physiological and pathological conditions. In the present study, the effects of CBD on contractility and electrophysiological properties of rat ventricular myocytes were investigated. Video edge detection was used to measure myocyte shortening. Intracellular Ca(2+) was measured in cells loaded with the Ca(2+) sensitive fluorescent indicator fura-2 AM. Whole-cell patch clamp was used to measure action potential and Ca(2+) currents. Radioligand binding was employed to study pharmacological characteristics of CBD binding. CBD (1μM) caused a significant decrease in the amplitudes of electrically evoked myocyte shortening and Ca(2+) transients. However, the amplitudes of caffeine-evoked Ca(2+) transients and the rate of recovery of electrically evoked Ca(2+) transients following caffeine application were not altered. CBD (1μM) significantly decreased the duration of APs. Further studies on L-type Ca(2+) channels indicated that CBD inhibits these channels with IC50 of 0.1μM in a voltage-independent manner. Radioligand studies indicated that the specific binding of [(3)H]Isradipine, was not altered significantly by CBD. The results suggest that CBD depresses myocyte contractility by suppressing L-type Ca(2+) channels at a site different than dihydropyridine binding site and inhibits excitation-contraction coupling in cardiomyocytes. PMID:25711828

  20. Effects of phytoestrogens on protein turnover in rainbow trout primary myocytes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Soybean-derived ingredients used in aquaculture feeds may contain phytoestrogens, but it is unknown if these compounds can mimic the catabolic effects of estradiol in fish muscle. Six day-old rainbow trout primary myocytes were exposed to increasing concentrations (10 nM – 100 µM) of either geniste...

  1. Atrial tachycardia originating from the atrial septum in a patient with dextrocardia and complex structural heart disease.

    PubMed

    Niu, Ya-Lei; Chang, Shih-Lin; Lin, Yenn-Jiang; Lo, Li-Wei; Hu, Yu-Feng; Lee, Pi-Chang; Chen, Shih-Ann

    2012-10-01

    We report a case with dextrocardia, corrected transposition of the great arteries. He also had an atrial septum defect (ASD) with patch repair. Activation map showed a centrifugal activation from a focal origin on the systemic lower left atrial ASD patch. Ablation of the origin can terminate the atrial tachycardia.

  2. Increased susceptibility to atrial fibrillation secondary to atrial fibrosis in transgenic goats expressing transforming growth factor - B1

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in people with significant morbidity and mortality. There is a strong association between atrial fibrosis and AF. Transforming growth factor B1 (TGF-B1) is an essential mediator of atrial fibrosis in animal models and human pat...

  3. Practice implications of the Atrial Fibrillation Guidelines.

    PubMed

    Curtis, Anne B

    2013-06-01

    Atrial fibrillation is one of the most common and complex cardiac arrhythmias. Using currently available evidence, leading medical societies have established recommendations for the optimal management of atrial fibrillation. These guidelines have recently been updated by 4 consensus groups: the European Society of Cardiology, the American College of Chest Physicians, the Canadian Cardiovascular Society, and a task force of 3 societies from the United States: the American College of Cardiology Foundation, the American Heart Association, and the Heart Rhythm Society. The present review focused on the similarities and differences among these recently updated guidelines. Key revisions included updated information on newer treatments for rhythm control, treatment options to reduce atrial fibrillation complications, and updated anticoagulant management for thromboprophylaxis.

  4. Ablation therapy for left atrial autonomic modification.

    PubMed

    Malcolme-Lawes, Louisa; Sandler, Belinda C; Sikkel, Markus B; Lim, Phang Boon; Kanagaratnam, Prapa

    2016-08-01

    The autonomic nervous system is implicated in the multifactorial pathogenesis of atrial fibrillation (AF) but few studies have attempted neural targeting for therapeutic intervention. We have demonstrated that short bursts of stimulation, at specific sites of left atrial ganglionated plexi (GPs), trigger fibrillation-inducing atrial ectopy and importantly continuous stimulation of these sites may not induce AV block, the 'conventional' marker used to locate GPs. We have shown that these ectopy-triggering GP (ET-GP) sites are anatomically stable and can be rendered inactive by either ablation at the site or by ablation between the site and the adjacent pulmonary vein (PV). This may have important implications for planning patient specific strategies for ablation of paroxysmal AF in the future. PMID:27595199

  5. Relationship between transient outward K+ current and Ca2+ influx in rat cardiac myocytes of endo- and epicardial origin

    PubMed Central

    Volk, Tilmann; Nguyen, Thi Hong-Diep; Schultz, Jobst-Hendrik; Ehmke, Heimo

    1999-01-01

    The transient outward K+ current (Ito) is a major repolarizing ionic current in ventricular myocytes of several mammals. Recently it has been found that its magnitude depends on the origin of the myocyte and is regulated by a number of physiological and pathophysiological signals. The relationship between the magnitude of Ito, action potential duration (APD) and Ca2+ influx (QCa) was studied in rat left ventricular myocytes of endo- and epicardial origin using whole-cell recordings and the action potential voltage-clamp method. Under control conditions, in response to a depolarizing voltage step to +40 mV, Ito averaged 12.1 ± 2.6 pA pF−1 in endocardial (n = 11) and 24.0 ± 2.6 pA pF−1 in epicardial myocytes (n = 12; P < 0.01). APD90 (90 % repolarization) was twice as long in endocardial myocytes, whereas QCa inversely depended on the magnitude of Ito. L-type Ca2+ current density was similar in myocytes from both regions. To determine the effects of controlled reductions of Ito on QCa, recordings were repeated in the presence of increasing concentrations of the Ito inhibitor 4-aminopyridine. Inhibition of Ito by as little as 20 % more than doubled QCa in epicardial myocytes, whereas it had only a minor effect on QCa in myocytes of endocardial origin. Further inhibition of Ito led to a progressive increase in QCa in epicardial myocytes; at 90 % inhibition of Ito, QCa was four times larger than the control value. We conclude that moderate changes in the magnitude of Ito strongly affect QCa primarily in epicardial regions. An alteration of Ito might therefore allow for a regional regulation of contractility during physiological and pathophysiological adaptations. PMID:10457095

  6. Myocyte morphology of free wall trabeculae in right ventricular pressure overload hypertrophy in rabbits.

    PubMed

    Hamrell, B B; Roberts, E T; Carkin, J L; Delaney, C L

    1986-02-01

    Right ventricular (RV) hypertrophy and changes in mechanical properties develop in response to sustained pulmonary artery construction in rabbits. We use basilar RV free wall trabeculae from rabbits for measurements of force, shortening and sarcomere length (diffraction and/or photomicrography). With enzymes we dispersed calcium tolerant myocytes from trabeculae similar to those used for the above mechanical studies. The average weight of the normal (N) rabbits (n = 16) was 2.21 +/- 0.16(1) kg and was 2.11 +/- 0.10 kg for the rabbits with RV hypertrophy (H; n = 16). The ratio of RV free wall to total ventricular weight was 0.17 +/- 0.01 in the N and 0.31 +/- 0.02 in H hearts (P less than 0.01). Average length and width were determined from digitized measures of the projected image of 42 +/- 3 Ca2+ tolerant myocytes from each N heart and 41 +/- 3 from each H heart. Average myocyte length increased from 102.9 +/- 0.9 in N to 109.8 +/- 1.0 micron in H (6.7% above N; P less than 0.05) and average width from 15.4 +/- 0.2 to 20.0 +/- 0.2 micron (29.9% above N; P less than 0.01). Sarcomere length in these quiescent myocytes was 1.92 +/- 0.003 micron in the N and 1.90 +/- 0.004 in H (P greater than 0.05); consequently, the restoring forces in the myocytes were the same as N in H. The greater addition of parallel myofibrils than of series sarcomeres in H is important for tension generation in the presence of the increased pressure load of pulmonary artery constriction. The addition of sarcomeres in series may be important to sustain muscle shortening in H and is consistent with our measures of sarcomere shortening in N and H trabeculae. PMID:2937924

  7. -Adrenergic receptors on rat ventricular myocytes: characteristics and linkage to cAMP metabolism

    SciTech Connect

    Buxton, I.L.O.; Brunton, L.L.

    1986-08-01

    When incubated with purified cardiomyocytes from adult rat ventricle, the 1-antagonist (TH)prazosin binds to a single class of sites with high affinity. Competition for (TH)prazosin binding by the 2-selective antagonist yohimbine and the nonselective -antagonist phentolamine demonstrates that these receptors are of the 1-subtype. In addition, incubation of myocyte membranes with (TH)yohimbine results in no measurable specific binding. Agonist competition for (TH)prazosin binding to membranes prepared from purified myocytes demonstrates the presence of two components of binding: 28% of 1-receptors interact with norepinephrine with high affinity (K/sub D/ = 36 nM), whereas the majority of receptors (72%) have a low affinity for agonist (K/sub D/ = 2.2 M). After addition of 10 M GTP, norepinephrine competes for (TH)prazosin binding to a single class of sites with lower affinity (K/sub D/ = 2.2 M). Incubation of intact myocytes for 2 min with 1 M norepinephrine leads to significantly less cyclic AMP (cAMP) accumulation than stimulation with either norepinephrine plus prazosin or isoproterenol. Likewise, incubation of intact myocytes with 10 W M norepinephrine leads to significantly less activation of cAMP-dependent protein kinase than when myocytes are stimulated by both norepinephrine and the 1-adrenergic antagonist, prazosin or the US -adrenergic agonist, isoproterenol. They conclude that the cardiomyocyte 1 receptor is coupled to a guanine nucleotide-binding protein, that 1-receptors are functionally linked to decreased intracellular cAMP content, and that this change in cellular cAMP is expressed as described activation of cAMP-dependent protein kinase.

  8. Diagnosis and Treatment of Atrial Fibrillation.

    PubMed

    Gutierrez, Cecilia; Blanchard, Daniel G

    2016-09-15

    Atrial fibrillation is a supraventricular arrhythmia that adversely affects cardiac function and increases the risk of stroke. It is the most common arrhythmia and a major source of morbidity and mortality; its prevalence increases with age. Pulse rate is sensitive, but not specific, for diagnosis, and suspected atrial fibrillation should be confirmed with 12-lead electrocardiography. Because normal electrocardiographic findings do not rule out atrial fibrillation, home monitoring is recommended if there is clinical suspicion of arrhythmia despite normal test results. Treatment is based on decisions made regarding when to convert to normal sinus rhythm vs. when to treat with rate control, and, in either case, how to best reduce the risk of stroke. For most patients, rate control is preferred to rhythm control. Ablation therapy is used to destroy abnormal foci responsible for atrial fibrillation. Anticoagulation reduces the risk of stroke while increasing the risk of bleeding. The CHA2DS2-VASc scoring system assesses the risk of stroke, with a score of 2 or greater indicating a need for anticoagulation. The HAS-BLED score estimates the risk of bleeding. Scores of 3 or greater indicate high risk. Warfarin, dabigatran, factor Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban), and aspirin are options for stroke prevention. Selection of therapy should be individualized based on risks and potential benefits, cost, and patient preference. Left atrial appendage obliteration is an option for reducing stroke risk. Two implantable devices used to occlude the appendage, the Watchman and the Amplatzer Cardiac Plug, appear to be as effective as warfarin in preventing stroke, but they are invasive. Another percutaneous approach to occlusion, wherein the left atrium is closed off using the Lariat, is also available, but data on its long-term effectiveness and safety are still limited. Surgical treatments for atrial fibrillation are reserved for patients who are undergoing

  9. Content in Native Literature Programs.

    ERIC Educational Resources Information Center

    Grant, Agnes

    Including Native literature in school curricula is an important way of enhancing the Native student's self-concept and providing accurate Native cultural knowledge to Native and non-Native students alike. Nevertheless, Canadian school literature programs generally contain neither contemporary nor traditional Native literature. Some programs…

  10. Bilateral Atrial Myxoma: A Case Report.

    PubMed

    Susupaus, Attapoom; Foofuengmonkolkit, Kumpoo

    2016-02-01

    Among the rare cardiac tumors, myxoma, which is mostly located in the left atrium, is the most common type. Bilateral atrial myxoma is extremely rare, and requires urgent surgery. The authors report the case of a 34-year-old male, who presented with one month of right hemiparesis and aphasia and subsequently diagnosed with bilateral atrial myxoma based on transthoracic echocardiography. An urgent operation for intra-cardiac tumor removal was performed with the biatrial approach. Once a diagnosis of myxoma has been made, an urgent operation for tumor removal is necessary due to the risk of serious complications, including sudden death from normal blood flow obstruction. PMID:27266240

  11. Left Atrial Myxoma Mimicking Mitral Stenosis

    PubMed Central

    Ojji, Dike B; Mamven, Manmak H; Omonua, Odiase; Habib, Zaiyad; Osaze, Hamamatu; Sliwa, Karen

    2012-01-01

    Cardiac myxoma is a benign (non-malignant) neoplasm that represents the most common primary tumour of the heart. We present the case of a 36 year old woman with background hypertension who presented with features of left ventricular failure and seizures, and was found during transthoracic echocardiography to have left atrial myxoma protruding through the mitral valve orifice. She subsequently had excision of the atrial myxoma. The usefulness of early transthoracic echocardiography in any patient presenting with features of heart failure even when the aetiology seems obvious cannot be over-emphasised. PMID:22844201

  12. Atrial Septal Defects and Cardioembolic Strokes.

    PubMed

    Leppert, Michelle; Poisson, Sharon N; Carroll, John D

    2016-05-01

    Atrial septal defects (ASDs) can be complicated by cardioembolic strokes, but the exact incidence is unknown. Patients with large and small shunts may present with a cardioembolic stroke. Patients with cryptogenic strokes should have cardiac ultrasound to see if an ASD is present. Cardioembolic strokes associated with ASD principally occur with 2 mechanisms. The first is paradoxic embolism involving a venous-based source of thrombus, which may subsequently pass through the ASD by right-to-left shunting, causing a cardioembolic stroke. The second is atrial fibrillation that can complicate the course of patients with ASDs, especially as they age. PMID:27150170

  13. A rare case of sinus of valsalva-right atrial fistula secondary to an abscess perforation from underlying aortic valve endocarditis

    PubMed Central

    2014-01-01

    Sinus of Valsalva-right atrial fistulas are abnormal connections between the aorta and the right atrium, and present challenging surgical conditions. An extremely rare etiology of aorto-right atrial fistula is infective endocarditis. This case report presents a 21 year old Caucasian female patient who had native aortic valve Staphylococcus aureus endocarditis complicated by sinus of Valsalva abscess perforation associated with an acute heart block, an aorto-right atrial fistula, severe heart failure, and cardiogenic shock. She underwent emergent aortic valve replacement and complex sinus of Valsalva fistula pericardial patch reconstruction and repair. This case report further explores the advantages and disadvantages of different valves for different patient populations, and evaluates the patient’s prosthesis mismatch and effective orifice area. PMID:25022608

  14. [Obesity as a risk factor for atrial fibrillation].

    PubMed

    Duraj, Iwona; Broncel, Marlena

    2016-01-01

    Atrial fibrillation (AF) and obesity is a growing problem of public health both in Poland and in the whole world. AF risk factors may be summarized as elderliness, male sex, smoking, hypertension, diabetes, obesity, coronary heart disease, heart failure, valvular heart disease, cardiac surgery. Once obesity is an independent, potentially modifiable risk factor for AF. The connection between obesity and atrial fibrillation is very up-to-date because of incremental prevalence, almost epidemic of obesity in the whole world. The probability of AF among obese patients increases with concomitant obstructive sleep apnea. Regardless many researches it hasn't been assessed yet how obesity itself predisposes to AF. It could be an effect of change in the atrial anatomy, the rise of atrial pressure, mechanical stretch, interstitial atrial fibrosis and disruption of atrial electric integrity. A great role is ascribed to inflammation, especially proinflammatory cytokines increased by adipocites of left atrial epicardial adiposity. PMID:26891428

  15. [Obesity as a risk factor for atrial fibrillation].

    PubMed

    Duraj, Iwona; Broncel, Marlena

    2016-01-01

    Atrial fibrillation (AF) and obesity is a growing problem of public health both in Poland and in the whole world. AF risk factors may be summarized as elderliness, male sex, smoking, hypertension, diabetes, obesity, coronary heart disease, heart failure, valvular heart disease, cardiac surgery. Once obesity is an independent, potentially modifiable risk factor for AF. The connection between obesity and atrial fibrillation is very up-to-date because of incremental prevalence, almost epidemic of obesity in the whole world. The probability of AF among obese patients increases with concomitant obstructive sleep apnea. Regardless many researches it hasn't been assessed yet how obesity itself predisposes to AF. It could be an effect of change in the atrial anatomy, the rise of atrial pressure, mechanical stretch, interstitial atrial fibrosis and disruption of atrial electric integrity. A great role is ascribed to inflammation, especially proinflammatory cytokines increased by adipocites of left atrial epicardial adiposity.

  16. Localized reentrant tachycardia in the aorta contiguity region mimicking perimitral atrial flutter in the context of atrial fibrillation ablation.

    PubMed

    Ejima, Koichiro; Shoda, Morio; Miyazaki, Shinsuke; Yashiro, Bun; Wakisaka, Osamu; Manaka, Tetsuyuki; Hagiwara, Nobuhisa

    2013-07-01

    We describe a case with a focal atrial tachycardia (AT) masquerading as perimitral atrial flutter revealed after circumferential pulmonary vein antral isolation for atrial fibrillation. It was successfully terminated and became noninducible by a point ablation on the left atrial anterior wall (LAAW) near the mitral annulus in contact with the aortic root and on the left superior pulmonary vein-left atrial appendage ridge, without any linear ablation, using electroanatomical mapping and conventional precise mapping with a maximum amplified gain within the low-voltage area. The AT revealed in our case was an LAAW-aorta contiguity area-related AT.

  17. Antithrombotic Therapy for Atrial Fibrillation

    PubMed Central

    You, John J.; Singer, Daniel E.; Howard, Patricia A.; Lane, Deirdre A.; Eckman, Mark H.; Fang, Margaret C.; Hylek, Elaine M.; Schulman, Sam; Go, Alan S.; Hughes, Michael; Spencer, Frederick A.; Manning, Warren J.; Halperin, Jonathan L.

    2012-01-01

    Background: The risk of stroke varies considerably across different groups of patients with atrial fibrillation (AF). Antithrombotic prophylaxis for stroke is associated with an increased risk of bleeding. We provide recommendations for antithrombotic treatment based on net clinical benefit for patients with AF at varying levels of stroke risk and in a number of common clinical scenarios. Methods: We used the methods described in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines article of this supplement. Results: For patients with nonrheumatic AF, including those with paroxysmal AF, who are (1) at low risk of stroke (eg, CHADS2 [congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischemic attack] score of 0), we suggest no therapy rather than antithrombotic therapy, and for patients choosing antithrombotic therapy, we suggest aspirin rather than oral anticoagulation or combination therapy with aspirin and clopidogrel; (2) at intermediate risk of stroke (eg, CHADS2 score of 1), we recommend oral anticoagulation rather than no therapy, and we suggest oral anticoagulation rather than aspirin or combination therapy with aspirin and clopidogrel; and (3) at high risk of stroke (eg, CHADS2 score of ≥ 2), we recommend oral anticoagulation rather than no therapy, aspirin, or combination therapy with aspirin and clopidogrel. Where we recommend or suggest in favor of oral anticoagulation, we suggest dabigatran 150 mg bid rather than adjusted-dose vitamin K antagonist therapy. Conclusions: Oral anticoagulation is the optimal choice of antithrombotic therapy for patients with AF at high risk of stroke (CHADS2 score of ≥ 2). At lower levels of stroke risk, antithrombotic treatment decisions will require a more individualized

  18. Atrial Tachycardias Arising from the Atrial Appendages and Aortic Sinus of Valsalva

    PubMed Central

    Taylor, Colleen M; Samardhi, Himabindu; Haqqani, Haris M

    2015-01-01

    Focal atrial tachycardias arising from the atrial appendages and the aortic sinuses of Valsalva are less frequently encountered in clinical practice. This review article describes the clinical presentation, surface P wave morphology, electrophysiologic characteristics and treatment of these arrhythmias. Catheter ablation of these focal tachycardias has a high success rate. It is however important to be aware of specific anatomic considerations in these locations for optimal treatment outcomes with low complication rates. PMID:25308812

  19. Computational models of atrial cellular electrophysiology and calcium handling, and their role in atrial fibrillation.

    PubMed

    Heijman, Jordi; Erfanian Abdoust, Pegah; Voigt, Niels; Nattel, Stanley; Dobrev, Dobromir

    2016-02-01

    The complexity of the heart makes an intuitive understanding of the relative contribution of ion channels, transporters and signalling pathways to cardiac electrophysiology challenging. Computational modelling of cardiac cellular electrophysiology has proven useful to integrate experimental findings, extrapolate results obtained in expression systems or animal models to other systems, test quantitatively ideas based on experimental data and provide novel hypotheses that are experimentally testable. While the bulk of computational modelling has traditionally been directed towards ventricular bioelectricity, increasing recognition of the clinical importance of atrial arrhythmias, particularly atrial fibrillation, has led to widespread efforts to apply computational approaches to understanding atrial electrical function. The increasing availability of detailed, atrial-specific experimental data has stimulated the development of novel computational models of atrial-cellular electrophysiology and Ca(2+) handling. To date, more than 300 studies have employed mathematical simulations to enhance our understanding of atrial electrophysiology, arrhythmogenesis and therapeutic responses. Future modelling studies are likely to move beyond current whole-cell models by incorporating new data on subcellular architecture, macromolecular protein complexes, and localized ion-channel regulation by signalling pathways. At the same time, more integrative multicellular models that take into account regional electrophysiological and Ca(2+) handling properties, mechano-electrical feedback and/or autonomic regulation will be needed to investigate the mechanisms governing atrial arrhythmias. A combined experimental and computational approach is expected to provide the more comprehensive understanding of atrial arrhythmogenesis that is required to develop improved diagnostic and therapeutic options. Here, we review this rapidly expanding area, with a particular focus on Ca(2+) handling, and

  20. Left atrial appendage closure for thromboembolism prevention in patients with atrial fibrillation: advances and perspectives

    PubMed Central

    Kong, Bin; Liu, Yu; Huang, He; Jiang, Hong

    2015-01-01

    Atrial fibrillation (AF) is a frequent cause of stroke. More than 90% of thrombi were found in the left atrial appendage (LAA) in non-valvular AF. Transcatheter LAA closure has been developed as a novel approach to reduce the risk of stroke in patients with AF over the last decade. In this article, we review the recent advances and propose the possible challenges regarding the LAA closure for thromboembolism prevention in patients with AF. PMID:25713737

  1. Effect of adenosine triphosphate on left atrial electrogram interval and dominant frequency in human atrial fibrillation☆

    PubMed Central

    Kogawa, Rikitake; Okumura, Yasuo; Watanabe, Ichiro; Kofune, Masayoshi; Nagashima, Koichi; Mano, Hiroaki; Sonoda, Kazumasa; Sasaki, Naoko; Iso, Kazuki; Takahashi, Keiko; Ohkubo, Kimie; Nakai, Toshiko; Hirayama, Atsushi

    2015-01-01

    Background Complex fractionated atrial electrograms (CFAEs) and high dominant frequency (DF) are targets for atrial fibrillation (AF) ablation. Although adenosine triphosphate (ATP) is known to promote AF by shortening the atrial refractory period, its role in the pathogenesis of CFAEs and DF during AF is not fully understood. Methods We recorded electrical activity from a 64-electrode basket catheter placed in the left atrium (LA) of patients with paroxysmal AF (PAF, n=18) or persistent AF (PerAF, n=19) before ablation. Atrial electrogram fractionation intervals (FIs) and DFs were measured from bipolar electrograms of each adjacent electrode pair. Offline mean atrial FIs and DFs were obtained before bolus injection of 30 mg ATP. Peak effect was defined as an R–R interval >3 s. Results With ATP, the mean FI decreased (from 110.4±29.1 ms to 90.5±24.7 ms, P<0.0001) and DF increased (from 6.4±0.6 Hz to 7.1±0.8 Hz, P<0.0001) in all patients. There was no difference in the FI decrease between the two groups (−20.3±20.5 ms vs. −19.6±14.5 ms, P=0.6032), but the increase in DF was significantly greater in PAF patients (1.1±0.8 Hz vs. 0.3±0.6 Hz, P=0.0051). Conclusions ATP shortens atrial FIs and increases DFs in both PAF and PerAF patients. The significant increase in DF in PAF patients suggests that pathophysiologic characteristics related to the frequency of atrial fractionation change as atrial remodeling progresses. PMID:26702319

  2. Percutaneous Left Atrial Appendage Ligation for Stroke Prevention in Atrial Fibrillation.

    PubMed

    Valderrábano, Miguel; Price, Matthew J

    2015-01-01

    Prevention of thromboembolic complications in atrial fibrillation remains a tremendous clinical challenge. Knowledge that the left atrial appendage (LAA) is the most common anatomical origin of cardioembolic strokes1 has been the main motivation to develop clinical and procedural strategies to exclude the LAA from the circulation, either surgically or percutaneously. This review discusses the rationale behind these strategies, their relative merits, and future prospects for LAA exclusion strategies. PMID:26306126

  3. Adjusted Left Atrial Emptying Fraction as a Predictor of Procedural Outcome after Catheter Ablation for Atrial Fibrillation

    PubMed Central

    Im, Sung Il; Kim, Sun Won; Choi, Cheol Ung; Kim, Jin Won; Yong, Hwan Seok; Kim, Eung Ju; Rha, Seung-Woon; Park, Chang Gyu; Seo, Hong Seog; Oh, Dong Joo; Lim, Hong Euy

    2015-01-01

    Structural remodeling of the left atrium is a risk factor for recurrent arrhythmia after catheter ablation for atrial fibrillation; however, data are sparse regarding the role of functional left atrial remodeling in predicting procedural outcomes. We evaluated whether left atrial transport function could be used to predict recurrent atrial fibrillation. From July 2008 through August 2010, we enrolled 202 consecutive patients who underwent catheter ablation for atrial fibrillation (paroxysmal=120, persistent=82). Left atrial volumes (LAVs) were measured by means of multislice computed tomography at every 10% of the R-R interval, and measurements were adjusted for body surface area to yield the LAV index (LAVI) at baseline. The left atrial emptying fraction (LAEF) was calculated according to LAV differences. During the mean follow-up period of 10 ± 4 months after a single ablation procedure, atrial fibrillation recurred in 59 patients (paroxysmal=19, persistent=40). Multivariate analysis revealed that persistent atrial fibrillation, early mitral inflow velocity, LAVImax, LAVImin, LAEF, LAVImax/LAEF, and LAVImin/LAEF were all independent predictors of atrial fibrillation, but the best predictor was LAVImin/LAEF (β=1.329, P=0.001). The cutoff value was 1.61 (mL/m2)/%, and the sensitivity and specificity were 74.6% and 62.2%, respectively (area under the curve=0.761). Our study shows that adjusted left atrial emptying fraction with use of multislice computed tomography might be a useful, noninvasive method to select patients for ablation. PMID:26175632

  4. Assessment of atrial fibrosis for the rhythm control of atrial fibrillation.

    PubMed

    Begg, Gordon A; Holden, Arun V; Lip, Gregory Y H; Plein, Sven; Tayebjee, Muzahir H

    2016-10-01

    Rhythm control of atrial fibrillation (AF) remains challenging, with modest long-term success rates. Atrial fibrosis has been associated with AF, but the clinical utility of assessment of this fibrosis has yet to be fully elucidated. In this paper we review the current state of understanding of the pathophysiology of atrial fibrosis in AF, and its impact upon the instigation and propagation of the arrhythmia. Fibrosis causes an increase in volume of dysfunctional extracellular matrix, and is associated with cellular alterations such as hypertrophy, apoptosis and membrane dysfunction within the atrial myocardium. In turn, these cause pathological alterations to atrial conduction, such as increased anisotropy, conduction block and re-entry, which can lead to AF. We review current methods of assessing atrial fibrosis and their impact upon the prediction of success of interventional rhythm control strategies such as ablation and cardioversion. We focus particularly on circulating biomarkers of fibrosis and scar formation; their role in the fibrotic process, and their value in the prediction of rhythm control success. We also review imaging and invasive electrocardiographic mapping techniques that may identify fibrosis, and again assess their potential predictive value. In this area there exist many unanswered questions, but further work will help to refine techniques to reliably identify and treat those patients who are most likely to benefit from rhythm control treatment strategies. PMID:27389440

  5. Role of inositol-1,4,5-trisphosphate receptor in the regulation of calcium transients in neonatal rat ventricular myocytes.

    PubMed

    Zeng, Zheng; Zhang, Heping; Lin, Na; Kang, Man; Zheng, Yuanyuan; Li, Chen; Xu, Pingxiang; Wu, Yongquan; Luo, Dali

    2014-01-01

    This study determined the regulatory effect of inositol 1,4,5-trisphosphate receptors (IP3Rs) on the basal Ca(2+) transients in cardiomyocytes. In cultured neonatal rat ventricular myocytes (NRVMs) at different densities, we used confocal microscopy to assess the effect of IP3Rs on the endogenous spontaneous Ca(2+) oscillations through specific activation of IP3Rs with myo-IP3 hexakis (butyryloxymethyl) ester (IP3BM), a membrane permeable IP3, and interference of IP3R expression with shRNA. We found that NRVMs at the monolayer state displayed coordinated Ca(2+) transients with less rate, shorter duration, and higher amplitude compared to single NRVMs. In addition, monolayer NRVMs exhibited 4 or 10 times more increased Ca(2+) transients in response to phenylephrine, an α-adrenergic receptor agonist, or IP3BM than single NRVMs did, while the transient pattern remained unaltered, suggesting that the sensitivity of intracellular Ca(2+) response to IP3R activation is different between single and monolayer NRVMs. However, interference of IP3R expression with shRNA reduced the frequency and amplitude of the spontaneous Ca(2+) fluctuates similarly in both densities of NRVMs, resembling the effects of ryanodine receptor inhibition by ryanodine or tetracaine. Our findings suggest that IP3Rs are involved, in part, in the regulation of native Ca(2+) transients, in profiles of their initiation and Ca(2+) release extent, in developing cardiomyocytes. In addition, caution should be paid in evaluating the behavior of Ca(2+) signaling in primary cultured cardiomyocytes at different densities. PMID:25242084

  6. Spontaneous atrial fibrillation in a freestyle skier.

    PubMed

    Whyte, G; Stephens, N; Sharma, S; Shave, R; Budgett, R; McKenna, W J

    2004-04-01

    A male freestyle skier was found to have atrial fibrillation during a routine physiological assessment. This was found to be associated with the consumption of an unusually large amount of alcohol. Athletes should be counselled about the potential dangers of alcohol consumption before exhaustive exercise.

  7. Right juxtaposition of the atrial appendages.

    PubMed

    Mathew, R; Replogle, R; Thilenius, O G; Arcilla, R A

    1975-04-01

    We present an infant with right-sided juxtaposition of atrial appendages who had open heart surgery for ventricular septal defect and patent ductus arteriosus. Of 12 cases thus far reported, ventricular d-loop was observed in nine, and normal position of great vessels in four. Contrary to previous views, this condition may not be accompanied by severe conotruncal anomalies.

  8. The cardiotoxicity and myocyte damage caused by small molecule anticancer tyrosine kinase inhibitors is correlated with lack of target specificity

    SciTech Connect

    Hasinoff, Brian B.

    2010-04-15

    The use of the new anticancer tyrosine kinase inhibitors (TKI) has revolutionized the treatment of certain cancers. However, the use of some of these results in cardiotoxicity. Large-scale profiling data recently made available for the binding of 7 of the 9 FDA-approved tyrosine kinase inhibitors to a panel of 317 kinases has allowed us to correlate kinase inhibitor binding selectivity scores with TKI-induced damage to neonatal rat cardiac myocytes. The tyrosine kinase selectivity scores, but not the serine-threonine kinase scores, were highly correlated with the myocyte damaging effects of the TKIs. Additionally, we showed that damage to myocytes gave a good rank order correlation with clinical cardiotoxicity. Finally, strength of TKI binding to colony-stimulating factor 1 receptor (CSF1R) was highly correlated with myocyte damage, thus possibly implicating this kinase in contributing to TKI-induced cardiotoxicity.

  9. Study of proliferative processes and nuclear estradiol and progesterone receptors in myocytes in pregnant and postpartum mouse uterus.

    PubMed

    Skurupiy, V A; Obedinskaya, K S

    2012-08-01

    Numerical densities of the nuclei were morhometrically evaluated in all myocytes and myocytes expressing nuclear estrogen- and progesterone-receptor complexes, which were revealed immunohistochemically with monoclonal antibodies in C57Bl/6 mice. It was shown that the above quantitative parameters of myometrial cells after the first pregnancy were similar to those in nonpregnant mice by day 10 after delivery. In the third pregnancy, especially developed after the second interrupted pregnancy, proliferation processes in the myometrium were not completed by postpartum day 10, but dramatically progressed. It was associated with a significant decrease in the fraction of myocytes carrying nuclear hormone-receptor complexes with estradiol and progesterone and their disturbed physiological relations in the myometrium during and after pregnancy probably due to dedifferentiation of a considerable part of myocytes.

  10. Implicit Attitudes towards Native and Non-Native Speaker Teachers

    ERIC Educational Resources Information Center

    Todd, R. Watson; Pojanapunya, Punjaporn

    2009-01-01

    The academic literature and educational principle suggest that native and non-native English speaking teachers should be treated equally, yet in many countries there is a broad social and commercial preference for native speaker teachers which may also involve racial issues. Attitudes towards native and non-native English speaking teachers have…

  11. Building Native Nations through Native Student's Commitment to Their Communities

    ERIC Educational Resources Information Center

    Lee, Tiffany S.

    2009-01-01

    One aspect of building Native nations entails motivating American Indian/Alaska Native youth to become committed to their communities so as to sustain and move forward with the goals of American Indian/Alaska Native nations. This study determined the impact of one Native American Studies department on its Native students' life goals. Through its…

  12. Diesterified nitrone rescues nitroso-redox levels and increases myocyte contraction via increased SR Ca(2+) handling.

    PubMed

    Traynham, Christopher J; Roof, Steve R; Wang, Honglan; Prosak, Robert A; Tang, Lifei; Viatchenko-Karpinski, Serge; Ho, Hsiang-Ting; Racoma, Ira O; Catalano, Dominic J; Huang, Xin; Han, Yongbin; Kim, Shang-U; Gyorke, Sandor; Billman, George E; Villamena, Frederick A; Ziolo, Mark T

    2012-01-01

    Nitric oxide (NO) and superoxide (O(2) (-)) are important cardiac signaling molecules that regulate myocyte contraction. For appropriate regulation, NO and O(2) (.-) must exist at defined levels. Unfortunately, the NO and O(2) (.-) levels are altered in many cardiomyopathies (heart failure, ischemia, hypertrophy, etc.) leading to contractile dysfunction and adverse remodeling. Hence, rescuing the nitroso-redox levels is a potential therapeutic strategy. Nitrone spin traps have been shown to scavenge O(2) (.-) while releasing NO as a reaction byproduct; and we synthesized a novel, cell permeable nitrone, 2-2-3,4-dihydro-2H-pyrrole 1-oxide (EMEPO). We hypothesized that EMEPO would improve contractile function in myocytes with altered nitroso-redox levels. Ventricular myocytes were isolated from wildtype (C57Bl/6) and NOS1 knockout (NOS1(-/-)) mice, a known model of NO/O(2) (.-) imbalance, and incubated with EMEPO. EMEPO significantly reduced O(2) (.-) (lucigenin-enhanced chemiluminescence) and elevated NO (DAF-FM diacetate) levels in NOS1(-/-) myocytes. Furthermore, EMEPO increased NOS1(-/-) myocyte basal contraction (Ca(2+) transients, Fluo-4AM; shortening, video-edge detection), the force-frequency response and the contractile response to β-adrenergic stimulation. EMEPO had no effect in wildtype myocytes. EMEPO also increased ryanodine receptor activity (sarcoplasmic reticulum Ca(2+) leak/load relationship) and phospholamban Serine16 phosphorylation (Western blot). We also repeated our functional experiments in a canine post-myocardial infarction model and observed similar results to those seen in NOS1(-/-) myocytes. In conclusion, EMEPO improved contractile function in myocytes experiencing an imbalance of their nitroso-redox levels. The concurrent restoration of NO and O(2) (.-) levels may have therapeutic potential in the treatment of various cardiomyopathies. PMID:23300588

  13. Altered distribution of ICa impairs Ca release at the t-tubules of ventricular myocytes from failing hearts

    PubMed Central

    Bryant, Simon M.; Kong, Cherrie H.T.; Watson, Judy; Cannell, Mark B.; James, Andrew F.; Orchard, Clive H.

    2015-01-01

    In mammalian cardiac ventricular myocytes, Ca influx and release occur predominantly at t-tubules, ensuring synchronous Ca release throughout the cell. Heart failure is associated with disrupted t-tubule structure, but its effect on t-tubule function is less clear. We therefore investigated Ca influx and release at the t-tubules of ventricular myocytes isolated from rat hearts ~ 18 weeks after coronary artery ligation (CAL) or corresponding Sham operation. L-type Ca current (ICa) was recorded using the whole-cell voltage-clamp technique in intact and detubulated myocytes; Ca release at t-tubules was monitored using confocal microscopy with voltage- and Ca-sensitive fluorophores. CAL was associated with cardiac and cellular hypertrophy, decreased ejection fraction, disruption of t-tubule structure and a smaller, slower Ca transient, but no change in ryanodine receptor distribution, L-type Ca channel expression, or ICa density. In Sham myocytes, ICa was located predominantly at the t-tubules, while in CAL myocytes, it was uniformly distributed between the t-tubule and surface membranes. Inhibition of protein kinase A with H-89 caused a greater decrease of t-tubular ICa in CAL than in Sham myocytes; in the presence of H-89, t-tubular ICa density was smaller in CAL than in Sham myocytes. The smaller t-tubular ICa in CAL myocytes was accompanied by increased latency and heterogeneity of SR Ca release at t-tubules, which could be mimicked by decreasing ICa using nifedipine. These data show that CAL decreases t-tubular ICa via a PKA-independent mechanism, thereby impairing Ca release at t-tubules and contributing to the altered excitation–contraction coupling observed in heart failure. PMID:26103619

  14. Cell-specific promoter in adenovirus vector for transgenic expression of SERCA1 ATPase in cardiac myocytes.

    PubMed

    Inesi, G; Lewis, D; Sumbilla, C; Nandi, A; Strock, C; Huff, K W; Rogers, T B; Johns, D C; Kessler, P D; Ordahl, C P

    1998-03-01

    Adenovirus-mediated transfer of cDNA encoding the chicken skeletal muscle sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA1) yielded selective expression in cultured chick embryo cardiac myocytes under control of a segment (-268 base pair) of the cell-specific cardiac troponin T (cTnT) promoter or nonselective expression in myocytes and fibroblasts under control of a constitutive viral [cytomegalovirus (CMV)] promoter. Under optimal conditions nearly all cardiac myocytes in culture were shown to express transgenic SERCA1 ATPase. Expression was targeted to intracellular membranes and was recovered in subcellular fractions with a pattern identical to that of the endogenous SERCA2a ATPase. Relative to control myocytes, transgenic SERCA1 expression increased up to four times the rates of ATP-dependent (and thapsigargin-sensitive) Ca2+ transport activity of cell homogenates. Although the CMV promoter was more active than the cTnT promoter, an upper limit for transgenic expression of functional enzyme was reached under control of either promoter by adjustment of the adenovirus plaque-forming unit titer of infection media. Cytosolic Ca2+ concentration transients and tension development of whole myocytes were also influenced to a similar limit by transgenic expression of SERCA1 under control of either promoter. Our experiments demonstrate that a cell-specific protein promoter in recombinant adenovirus vectors yields highly efficient and selective transgene expression of a membrane-bound and functional enzyme in cardiac myocytes.

  15. A force transducer and a length-ramp generator for mechanical investigations of frog-heart myocytes.

    PubMed

    Cecchi, G; Colomo, F; Poggesi, C; Tesi, C

    1993-04-01

    An apparatus for studying the mechanics of isolated frog heart myocytes is described. The cells are held horizontal in a through of Ringer solution by means of two suction micropipettes. Myocyte force is measured with an opto-electronic system recording the deflection of the tip of one micropipette, which acts as a cantilever force probe. The force probes are selected for compliance according to the force a myocyte is expected to develop in a given condition, so as to limit myocyte shortening during force development to no more than 1% of the slack cellular length (l0). The other micropipette, which is stiff relative to the forces measured, is mounted on an electromagnetic-loudspeaker motor by which controlled-velocity length changes, of preset size and in either direction, are imposed on myocytes. The force transducer has a sensitivity of 5-10 mV/nN, with a frequency response of 700-900 Hz in Ringer solution and a resolution of 0.5-1 nN. The motor with a suction micropipette can complete controlled-velocity length ramps within 1.5-2.0 ms, across a range of +/- 100 microns at a resolution of 8.0 nm. These values correspond, for frog-heart myocytes 200 microns and 400 microns long, to 25%-50% l0 and 0.002%-0.004% l0 respectively. PMID:8488085

  16. Legends of Native Americans.

    ERIC Educational Resources Information Center

    Flagg, Ann

    1999-01-01

    Presents a theme unit that includes elementary-level, cross-curricular lessons about lifestyle, belief systems, traditions, and history of Native Americans. The unit includes a poster which offers a traditional Cherokee story, literature on Native American legends, and a variety of cross-curricular activities. The unit ends with students writing…

  17. Native American Preparatory School.

    ERIC Educational Resources Information Center

    Native American Preparatory School, Rowe, NM.

    This booklet provides information on the Native American Preparatory School, a residential secondary school in Rowe, New Mexico, for high-achieving Native American students. The school sponsors two programs: a 5-week rigorously academic summer school for junior high school students and, beginning in fall 1995, a 4-year college preparatory program.…

  18. Traditional Native Poetry.

    ERIC Educational Resources Information Center

    Grant, Agnes

    1985-01-01

    While Native myths and legends were educational tools to transmit tribal beliefs and history, traditional American Indian poetry served a ritualistic function in everyday life. Few traditional Native songs, which all poems were, survive; only Mayan and Aztec poems were written, and most of these were burned by a Spanish bishop. In addition, many…

  19. Native American Entrepreneurship. Digest.

    ERIC Educational Resources Information Center

    Seymour, Nicole

    Although Native Americans have owned and started the fewest small businesses of all U.S. minority groups, entrepreneurship is considered to be an efficient tool for alleviating their economic problems. Barriers to Native American entrepreneurship include poverty, scarce start-up capital, poor access to business education and technical assistance,…

  20. Myocyte-specific enhancer factor 2C: a novel target gene of miR-214-3p in suppressing angiotensin II-induced cardiomyocyte hypertrophy

    PubMed Central

    Tang, Chun-Mei; Liu, Fang-zhou; Zhu, Jie-Ning; Fu, Yong-Heng; Lin, Qiu-Xiong; Deng, Chun-Yu; Hu, Zhi-Qin; Yang, Hui; Zheng, Xi-Long; Cheng, Jian-Ding; Wu, Shu-Lin; Shan, Zhi-Xin

    2016-01-01

    The role of microRNA-214-3p (miR-214-3p) in cardiac hypertrophy was not well illustrated. The present study aimed to investigate the expression and potential target of miR-214-3p in angiotensin II (Ang-II)-induced mouse cardiac hypertrophy. In mice with either Ang-II infusion or transverse aortic constriction (TAC) model, miR-214-3p expression was markedly decreased in the hypertrophic myocardium. Down-regulation of miR-214-3p was observed in the myocardium of patients with cardiac hypertrophy. Expression of miR-214-3p was upregulated in Ang-II-induced hypertrophic neonatal mouse ventricular cardiomyocytes. Cardiac hypertrophy was attenuated in Ang-II-infused mice by tail vein injection of miR-214-3p. Moreover, miR-214-3p inhibited the expression of atrial natriuretic peptide (ANP) and β-myosin heavy chain (MHC) in Ang-II-treated mouse cardiomyocytes in vitro. Myocyte-specific enhancer factor 2C (MEF2C), which was increased in Ang-II-induced hypertrophic mouse myocardium and cardiomyocytes, was identified as a target gene of miR-214-3p. Functionally, miR-214-3p mimic, consistent with MEF2C siRNA, inhibited cell size increase and protein expression of ANP and β-MHC in Ang-II-treated mouse cardiomyocytes. The NF-κB signal pathway was verified to mediate Ang-II-induced miR-214-3p expression in cardiomyocytes. Taken together, our results revealed that MEF2C is a novel target of miR-214-3p, and attenuation of miR-214-3p expression may contribute to MEF2Cexpressionin cardiac hypertrophy. PMID:27796324

  1. A systematic approach for assessing Ca²⁺ handling in cardiac myocytes.

    PubMed

    Sipido, Karin R; Macquaide, Niall; Bito, Virginie

    2015-05-01

    In cardiac myocytes, Ca(2+) release from the sarcoplasmic reticulum (SR) Ca(2+) store through the opening of ryanodine receptors (RyRs) is the major source of Ca(2+) for activation of myofilaments and contraction. Over the past 20 years, tools have become available to study this release process in detail, allowing new insights into the regulation of SR Ca(2+) release and RyR function. To assess these processes, we recommend and here review a systematic approach that evaluates the essential transport mechanisms and Ca(2+) fluxes in isolated single cardiac myocytes by using fluorescent Ca(2+) indicators and whole-cell recording of membrane voltage and ionic currents under voltage clamp. The approach includes an assessment of the L-type Ca(2+) current as a trigger for opening of RyRs and release of SR Ca(2+), of the SR Ca(2+) content, of intrinsic properties of RyRs, and of Ca(2+)-removal systems.

  2. Speckle based configuration for simultaneous in vitro inspection of mechanical contractions of cardiac myocyte cells

    NASA Astrophysics Data System (ADS)

    Golberg, Mark; Fixler, Dror; Shainberg, Asher; Zlochiver, Sharon; Micó, Vicente; Garcia, Javier; Beiderman, Yevgeny; Zalevsky, Zeev

    2013-04-01

    In this manuscript we propose optical lensless configuration for a remote non-contact measuring of mechanical contractions of vast number of cardiac myocytes. All the myocytes were taken from rats, and the measurements were done in an in vitro mode. The optical method is based on temporal analysis of secondary reflected speckle patterns generated in lensless microscope configuration. The processing involves analyzing the movement and the change in the statistics of the generated secondary speckle patterns that are created on top of the cell culture when it is illuminated by a spot of laser beam. The main advantage of the proposed system is the ability to measure many cells simultaneously (approximately one thousand cells) and to extract the statistical data of their movement at once. The presented experimental results also include investigation the effect of isoproteranol on cells contraction process.

  3. Erythropoietin protects cardiac myocytes from hypoxia-induced apoptosis through an Akt-dependent pathway.

    PubMed

    Tramontano, Anthony F; Muniyappa, Ranganath; Black, Aislinn D; Blendea, Mihaela C; Cohen, Inna; Deng, Lili; Sowers, James R; Cutaia, Michael V; El-Sherif, Nabil

    2003-09-01

    Apoptosis is a contributing cause of myocyte loss in ischemic heart disease. Recent work has shown that erythropoietin (EPO) offers protection against apoptosis in a wide variety of tissues. We demonstrate that the erythropoietin receptor (EPOR) is expressed in the neonatal rat ventricular myocyte (NRVM). Exposure of NRVMs to hypoxia, with recombinant human EPO, significantly decreased apoptosis as measured by TUNEL, flow cytometry, and caspase 3/7 like activity when compared to hypoxia treatment alone. EPO administered at the initiation of coronary artery occlusion in the rat significantly decreased apoptosis in the myocardial ischemic region. In the NRVM, EPO increased the activity of Akt. The anti-apoptotic effect of EPO was abrogated by co-treatment with LY294002, a specific blocker of phosphatidylinositol 3-kinase (PI3-K). Our study demonstrates that EPO inhibits apoptosis in the NRVM exposed to hypoxia, through an Akt-dependent pathway. EPO also inhibits apoptosis in the in vivo rat model of myocardial ischemia.

  4. Nonpharmacologic approaches to the treatment of atrial fibrillation and atrial flutter.

    PubMed

    Baker, B M; Smith, J M; Cain, M E

    1995-10-01

    The high prevalence of atrial fibrillation, the associated morbidity and mortality, the absence of safe and effective drug therapy, and an increased understanding of the pathophysiologic basis of atrial fibrillation and flutter have collectively led to the development of novel nonpharmacologic treatments for the management of these arrhythmias, including the CORRIDOR and MAZE surgical procedures, catheter-based ablation and modification of AV conduction, catheter-based ablation of atrial flutter and fibrillation, and internal atrial defibrillation. These surgical and catheter-based techniques offer potentially curative therapy while sparing the long-term risk of antiarrhythmic drug therapy. For patients with typical atrial flutter, catheter ablation affords to cure rate in excess of 70%. As technological innovations further facilitate identification and ablation of the critical isthmus in the floor of the right atrium, success rates should improve substantially. For patients with atrial fibrillation, AV junction ablation with implantation of a rate-responsive ventricular pacemaker should be considered palliative therapy, as should modification of AV junction conduction. The MAZE procedure offers very high cure rates, but because it currently involves open heart surgery, patient selection is critical. Catheter-based procedures emulating aspects of the MAZE procedure may one day offer cure rates comparable to those of the surgery itself, but additional research and technological development are necessary to further define and refine the minimal effective procedure, and then to facilitate the placement of contiguous, full-thickness lesions in precise three-dimensional configurations. In the interim, the implantable automatic atrial defibrillator may offer a means for rapidly restoring sinus rhythm without the risks of long-term antiarrhythmic drug therapy.

  5. Intra-atrial conduction block mimicking atrioventricular nodal block after multiple catheter ablation procedures for atrial tachycardia in a patient with cardiomyopathy.

    PubMed

    Chugh, Aman; Yokokawa, Miki; Baman, Timir; Bogun, Frank; Wu, Audrey

    2012-11-01

    A 42-year-old woman with a history of cardiomyopathy and multiple ablation procedures for atrial tachycardia developed intra-atrial conduction block that mimicked atrioventricular (AV) nodal block during radiofrequency ablation at the cavotricuspid isthmus. She was treated with atrial pacing (from the coronary sinus), which overcame intra-atrial conduction block and resulted in AV nodal conduction.

  6. Comparison of sarcolemmal calcium channel current in rabbit and rat ventricular myocytes.

    PubMed Central

    Yuan, W; Ginsburg, K S; Bers, D M

    1996-01-01

    1. Fundamental properties of Ca2+ channel currents in rat and rabbit ventricular myocytes were measured using whole cell voltage clamp. 2. In rat, as compared with rabbit myocytes, Ca2+ channel current (ICa) was half-activated at about 10 mV more negative potential, decayed slower, was half-inactivated (in steady state) at about 5 mV more positive potential, and recovered faster from inactivation. 3. These features result in a larger steady-state window current in rat, and also suggest that under comparable voltage clamp conditions, including action potential (AP) clamp, more Ca2+ influx would be expected in rat myocytes. 4. Ca2+ channel current carried by Na+ and Cs+ in the absence of divalent ions (Ins) also activated at more negative potential and decayed more slowly in rat. 5. The reversal potential for Ins was 6 mV more positive in rabbit, consistent with a larger permeability ratio (PNa/PCs) in rabbit than in rat. ICa also reversed at slightly more positive potentials in rabbit (such that PCa/PCs might also be higher). 6. Ca2+ influx was calculated by integration of ICa evoked by voltage clamp pulses (either square pulses or pulses based on recorded rabbit or rat APs). For a given clamp waveform, the Ca2+ influx was up to 25% greater in rat, as predicted from the fundamental properties of ICa and Ins. 7. However, the longer duration of the AP in rabbit myocytes compensated for the difference in influx, such that the integrated Ca2+ influx via ICa in response to the species-appropriate waveform was about twice as large as that seen in rat. PMID:8799895

  7. Comparison of SERCA1 and SERCA2a expressed in COS-1 cells and cardiac myocytes.

    PubMed

    Sumbilla, C; Cavagna, M; Zhong, L; Ma, H; Lewis, D; Farrance, I; Inesi, G

    1999-12-01

    Cultured COS-1 cells, as well as chicken embryonic and neonatal rat cardiac myocytes, were infected with recombinant adenovirus vectors to define limiting factors in the expression and Ca2+ transport function of recombinant sarcoplasmic-endoplasmic reticulum Ca(2+) (SERCA) isoforms. Titration experiments showed that all COS-1 cells and myocytes in culture could be infected by an adenovirus titer of 10 plaque-forming units (pfu) per seeded cell. Raising the adenovirus titer further yielded higher protein expression up to an asymptotic limit for functional, membrane-bound SERCA protein. The asymptotic behavior of SERCA expression was not transcription related but was due to posttranscriptional events. The minimal (-268) cardiac troponin T (cTnT) promoter was a convenient size for adenovirus vector construction and manifested tight muscle specificity. However, its efficiency was lower than that of the nonspecific cytomegalovirus (CMV) promoter. At any rate, identical maximal levels of SERCA expression were obtained with the CMV and the cTnT promoter, as long as the viral titer was adjusted to compensate for transcription efficiency. A maximal threefold increase of total SERCA protein expression over the level of the endogenous SERCA of control myocytes was reached (a sevenfold increase compared with the endogenous SERCA of the same infected myocytes due to reduction of endogenous SERCA after infection). In contrast with previous reports [Ji et al. Am. J. Physiol. 276 (Heart Circ. Physiol. 45): H89-H97, 1999], a higher kinetic turnover was demonstrated for the SERCA1 compared with the SERCA2a isoform as shown by a 5.0- versus 2.6-fold increase in calcium uptake rate accompanying maximal expression of recombinant SERCA1 or SERCA2a, respectively. This information is deemed necessary for studies attempting to modify myocardial cell function by manipulation of SERCA expression.

  8. In vitro characterization of HCN channel kinetics and frequency dependence in myocytes predicts biological pacemaker functionality.

    PubMed

    Zhao, Xin; Bucchi, Annalisa; Oren, Ronit V; Kryukova, Yelena; Dun, Wen; Clancy, Colleen E; Robinson, Richard B

    2009-04-01

    The pacemaker current, mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, contributes to the initiation and regulation of cardiac rhythm. Previous experiments creating HCN-based biological pacemakers in vivo found that an engineered HCN2/HCN1 chimeric channel (HCN212) resulted in significantly faster rates than HCN2, interrupted by 1-5 s pauses. To elucidate the mechanisms underlying the differences in HCN212 and HCN2 in vivo functionality as biological pacemakers, we studied newborn rat ventricular myocytes over-expressing either HCN2 or HCN212 channels. The HCN2- and HCN212-over-expressing myocytes manifest similar voltage dependence, current density and sensitivity to saturating cAMP concentrations, but HCN212 has faster activation/deactivation kinetics. Compared with HCN2, myocytes expressing HCN212 exhibit a faster spontaneous rate and greater incidence of irregular rhythms (i.e. periods of rapid spontaneous rate followed by pauses). To explore these rhythm differences further, we imposed consecutive pacing and found that activation kinetics of the two channels are slower at faster pacing frequencies. As a result, time-dependent HCN current flowing during diastole decreases for both constructs during a train of stimuli at a rapid frequency, with the effect more pronounced for HCN2. In addition, the slower deactivation kinetics of HCN2 contributes to more pronounced instantaneous current at a slower frequency. As a result of the frequency dependence of both instantaneous and time-dependent current, HCN2 exhibits more robust negative feedback than HCN212, contributing to the maintenance of a stable pacing rhythm. These results illustrate the benefit of screening HCN constructs in spontaneously active myocyte cultures and may provide the basis for future optimization of HCN-based biological pacemakers. PMID:19171659

  9. Minocycline suppresses oxidative stress and attenuates fetal cardiac myocyte apoptosis triggered by in utero cocaine exposure

    PubMed Central

    Sinha-Hikim, Indrani; Shen, Ruoqing; Nzenwa, Ify; Gelfand, Robert; Mahata, Sushil K.

    2015-01-01

    This study investigates the molecular mechanisms by which minocycline, a second generation tetracycline, prevents cardiac myocyte death induced by in utero cocaine exposure. Timed mated pregnant Sprague-Dawley (SD) rats received one of the following treatments twice daily from embryonic (E) day 15–21 (E15–E21): (i) intraperitoneal (IP) injections of saline (control); (ii) IP injections of cocaine (15 mg/kg BW); and (iii) IP injections of cocaine + oral administration of 25 mg/kg BW of minocycline. Pups were killed on postnatal day 15 (P15). Additional pregnant dams received twice daily IP injections of cocaine (from E15–E21) + oral administration of a relatively higher (37.5 mg/kg BW) dose of minocycline. Minocycline treatment continued from E15 until the pups were sacrificed on P15. In utero cocaine exposure resulted in an increase in oxidative stress and fetal cardiac myocyte apoptosis through activation of c-Jun-NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK)-mediated mitochondria-dependent apoptotic pathway. Continued minocycline treatment from E15 through P15 significantly prevented oxidative stress, kinase activation, perturbation of BAX/BCL-2 ratio, cytochrome c release, caspase activation, and attenuated fetal cardiac myocyte apoptosis after prenatal cocaine exposure. These results demonstrate in vivo cardioprotective effects of minocycline in preventing fetal cardiac myocyte death after prenatal cocaine exposure. Given its proven clinical safety and ability to cross the placental barrier and enter into the fetal circulation, minocycline may be an effective therapy for preventing cardiac consequences of in utero cocaine exposure. PMID:21424555

  10. Optimal range for parvalbumin as relaxing agent in adult cardiac myocytes: gene transfer and mathematical modeling.

    PubMed Central

    Coutu, Pierre; Metzger, Joseph M

    2002-01-01

    Parvalbumin (PV) has recently been shown to increase the relaxation rate when expressed in intact isolated cardiac myocytes via adenovirus gene transfer. We report here a combined experimental and mathematical modeling approach to determine the dose-response and the sarcomere length (SL) shortening-frequency relationship of PV in adult rat cardiac myocytes in primary culture. The dose-response was obtained experimentally by observing the PV-transduced myocytes at different time points after gene transfer. Calcium transients and unloaded mechanical contractions were measured. The results were as follows. At low estimated [PV] (approximately 0.01 mM), contractile parameters were unchanged; at intermediate [PV], relaxation rate of the mechanical contraction and the decay rate of the calcium transient increased with little effects on amplitude; and at high [PV] (approximately 0.1 mM), relaxation rate was further increased, but the amplitudes of the mechanical contraction and the calcium transient were diminished when compared with control myocytes. The SL shortening-frequency relationship exhibited a biphasic response to increasing stimulus frequency in controls (decrease in amplitude and re-lengthening time from 0.2 to 1.0 Hz followed by an increase in these parameters from 2.0 to 4.0 Hz). The effect of PV was to flatten this frequency response. This flattening effect was partly explained by a reduction in the variation in fractional binding of PV to calcium during beats at high frequency. In conclusion, experimental results and mathematical modeling indicate that there is an optimal PV range for which relaxation rate is increased with little effect on contractile amplitude and that PV effectiveness decreases as the stimulus frequency increases. PMID:11964244

  11. Intracellular tortuosity underlies slow cAMP diffusion in adult ventricular myocytes

    PubMed Central

    Richards, Mark; Lomas, Oliver; Jalink, Kees; Ford, Kerrie L.; Vaughan-Jones, Richard D.; Lefkimmiatis, Konstantinos; Swietach, Pawel

    2016-01-01

    Aims 3′,5′-Cyclic adenosine monophosphate (cAMP) signals in the heart are often confined to concentration microdomains shaped by cAMP diffusion and enzymatic degradation. While the importance of phosphodiesterases (degradative enzymes) in sculpting cAMP microdomains is well established in cardiomyocytes, less is known about cAMP diffusivity (DcAMP) and factors affecting it. Many earlier studies have reported fast diffusivity, which argues against sharply defined microdomains. Methods and results [cAMP] dynamics in the cytoplasm of adult rat ventricular myocytes were imaged using a fourth generation genetically encoded FRET-based sensor. The [cAMP]-response to the addition and removal of isoproterenol (β-adrenoceptor agonist) quantified the rates of cAMP synthesis and degradation. To obtain a read out of DcAMP, a stable [cAMP] gradient was generated using a microfluidic device which delivered agonist to one half of the myocyte only. After accounting for phosphodiesterase activity, DcAMP was calculated to be 32 µm2/s; an order of magnitude lower than in water. Diffusivity was independent of the amount of cAMP produced. Saturating cAMP-binding sites with the analogue 6-Bnz-cAMP did not accelerate DcAMP, arguing against a role of buffering in restricting cAMP mobility. cAMP diffused at a comparable rate to chemically unrelated but similar sized molecules, arguing for a common physical cause of restricted diffusivity. Lower mitochondrial density and order in neonatal cardiac myocytes allowed for faster diffusion, demonstrating the importance of mitochondria as physical barriers to cAMP mobility. Conclusion In adult cardiac myocytes, tortuosity due to physical barriers, notably mitochondria, restricts cAMP diffusion to levels that are more compatible with microdomain signalling. PMID:27089919

  12. Predicting changes in cardiac myocyte contractility during early drug discovery with in vitro assays

    SciTech Connect

    Morton, M.J.; Armstrong, D.; Abi Gerges, N.; Bridgland-Taylor, M.; Pollard, C.E.; Bowes, J.; Valentin, J.-P.

    2014-09-01

    Cardiovascular-related adverse drug effects are a major concern for the pharmaceutical industry. Activity of an investigational drug at the L-type calcium channel could manifest in a number of ways, including changes in cardiac contractility. The aim of this study was to define which of the two assay technologies – radioligand-binding or automated electrophysiology – was most predictive of contractility effects in an in vitro myocyte contractility assay. The activity of reference and proprietary compounds at the L-type calcium channel was measured by radioligand-binding assays, conventional patch-clamp, automated electrophysiology, and by measurement of contractility in canine isolated cardiac myocytes. Activity in the radioligand-binding assay at the L-type Ca channel phenylalkylamine binding site was most predictive of an inotropic effect in the canine cardiac myocyte assay. The sensitivity was 73%, specificity 83% and predictivity 78%. The radioligand-binding assay may be run at a single test concentration and potency estimated. The least predictive assay was automated electrophysiology which showed a significant bias when compared with other assay formats. Given the importance of the L-type calcium channel, not just in cardiac function, but also in other organ systems, a screening strategy emerges whereby single concentration ligand-binding can be performed early in the discovery process with sufficient predictivity, throughput and turnaround time to influence chemical design and address a significant safety-related liability, at relatively low cost. - Highlights: • The L-type calcium channel is a significant safety liability during drug discovery. • Radioligand-binding to the L-type calcium channel can be measured in vitro. • The assay can be run at a single test concentration as part of a screening cascade. • This measurement is highly predictive of changes in cardiac myocyte contractility.

  13. Heuristic problems in defining the three-dimensional arrangement of the ventricular myocytes.

    PubMed

    Anderson, Robert H; Ho, Siew Yen; Sanchez-Quintana, Damian; Redmann, Klaus; Lunkenheimer, Paul P

    2006-06-01

    There is lack of consensus concerning the three-dimensional arrangement of the myocytes within the ventricular muscle masses. Bioengineers are seeking to model the structure of the heart. Although the success of such models depends on the accuracy of the anatomic evidence, most of them have been based on concepts that are far from anatomical reality, which ignore many significant previous accounts of anatomy presented over the past 400 years. During the 19th century, Pettigrew emphasized that the heart was built on the basis of a modified blood vessel rather than in the form of skeletal muscles. This fact was reemphasized by Lev and Simkins as well as Grant in the 20th century, but the caveats listed by these authors have been ignored by proponents of two current concepts, which state either that the myocardium is arranged in the form of a "unique myocardial band," or that the walls of the ventricles are sequestrated in uniform fashion by laminar sheets of fibrous tissue extending from epicardium to endocardium. These two concepts are themselves incompatible and are further at variance with the majority of anatomic studies, which have emphasized the regional heterogeneity to be found in the three-dimensional packing of the myocytes within a supporting matrix of fibrous tissue. We reemphasize the significance of this three-dimensional muscular mesh, showing how the presence of intruding aggregates of myocytes extending in oblique transmural fashion also contends against the notion that all myocytes are orientated with their long axes parallel to the epicardial and enodcardial surfaces.

  14. Loading rat heart myocytes with Mg2+ using low-[Na+] solutions

    PubMed Central

    Almulla, Hasan A; Bush, Peter G; Steele, Michael G; Ellis, David; Flatman, Peter W

    2006-01-01

    The objective of our study was to investigate how Mg2+ enters mammalian cardiac cells. During this work, we found evidence for a previously undescribed route for Mg2+ entry, and now provide a preliminary account of its properties. Changes in Mg2+ influx into rat ventricular myocytes were deduced from changes in intracellular ionized Mg2+ concentration ([fMg2+]i) measured from the fluorescence of mag-fura-2 loaded into isolated cells. Superfusion of myocytes at 37°C with Ca2+-free solutions with both reduced [Na+] and raised [Mg2+] caused myocytes to load with Mg2+. Uptake was seen with solutions containing 5 mm Mg2+ and 95 mm Na+, and increased linearly with increasing extracellular [Mg2+] or decreasing extracellular [Na+]. It was very sensitive to temperature (Q10 > 9, 25–37°C), was observed even in myocytes with very low Na+ contents, and stopped abruptly when external [Na+] was returned to normal. Uptake was greatly reduced by imipramine or KB-R7943 if these were added when [fMg2+]i was close to the physiological level, but was unaffected if they were applied when [fMg2+]i was above 2 mm. Uptake was also reduced by depolarizing the membrane potential by increasing extracellular [K+] or voltage clamp to 0 mV. We suggest that initial Mg2+ uptake may involve several transporters, including reversed Na+–Mg2+ antiport and, depending on the exact conditions, reversed Na+–Ca2+ antiport. The ensuing rise of [fMg2+]i, in conjunction with reduced [Na+], may then activate a new Mg2+ transporter that is highly sensitive to temperature, is insensitive to imipramine or KB-R7943, but is inactivated by depolarization. PMID:16793904

  15. Cyclin D2 induces proliferation of cardiac myocytes and represses hypertrophy

    SciTech Connect

    Busk, Peter K. . E-mail: pkbu@novonordisk.com; Hinrichsen, Rebecca; Bartkova, Jirina; Hansen, Ane H.; Christoffersen, Tue E.H.; Bartek, Jiri; Haunso, Stig

    2005-03-10

    The myocytes of the adult mammalian heart are considered unable to divide. Instead, mitogens induce cardiomyocyte hypertrophy. We have investigated the effect of adenoviral overexpression of cyclin D2 on myocyte proliferation and morphology. Cardiomyocytes in culture were identified by established markers. Cyclin D2 induced DNA synthesis and proliferation of cardiomyocytes and impaired hypertrophy induced by angiotensin II and serum. At the molecular level, cyclin D2 activated CDK4/6 and lead to pRB phosphorylation and downregulation of the cell cycle inhibitors p21{sup Waf1/Cip1} and p27{sup Kip1}. Expression of the CDK4/6 inhibitor p16 inhibited proliferation and cyclin D2 overexpressing myocytes became hypertrophic under such conditions. Inhibition of hypertrophy by cyclin D2 correlated with downregulation of p27{sup Kip1}. These data show that hypertrophy and proliferation are highly related processes and suggest that cardiomyocyte hypertrophy is due to low amounts of cell cycle activators unable to overcome the block imposed by cell cycle inhibitors. Cell cycle entry upon hypertrophy may be converted to cell division by increased expression of activators such as cyclin D2.

  16. Mitochondria-Targeted Antioxidant Prevents Cardiac Dysfunction Induced by Tafazzin Gene Knockdown in Cardiac Myocytes

    PubMed Central

    He, Quan; Harris, Nicole; Ren, Jun; Han, Xianlin

    2014-01-01

    Tafazzin, a mitochondrial acyltransferase, plays an important role in cardiolipin side chain remodeling. Previous studies have shown that dysfunction of tafazzin reduces cardiolipin content, impairs mitochondrial function, and causes dilated cardiomyopathy in Barth syndrome. Reactive oxygen species (ROS) have been implicated in the development of cardiomyopathy and are also the obligated byproducts of mitochondria. We hypothesized that tafazzin knockdown increases ROS production from mitochondria, and a mitochondria-targeted antioxidant prevents tafazzin knockdown induced mitochondrial and cardiac dysfunction. We employed cardiac myocytes transduced with an adenovirus containing tafazzin shRNA as a model to investigate the effects of the mitochondrial antioxidant, mito-Tempo. Knocking down tafazzin decreased steady state levels of cardiolipin and increased mitochondrial ROS. Treatment of cardiac myocytes with mito-Tempo normalized tafazzin knockdown enhanced mitochondrial ROS production and cellular ATP decline. Mito-Tempo also significantly abrogated tafazzin knockdown induced cardiac hypertrophy, contractile dysfunction, and cell death. We conclude that mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes and suggest mito-Tempo as a potential therapeutic for Barth syndrome and other dilated cardiomyopathies resulting from mitochondrial oxidative stress. PMID:25247053

  17. Nuclear Compartmentalization of α1-Adrenergic Receptor Signaling in Adult Cardiac Myocytes

    PubMed Central

    Wu, Steven C.

    2015-01-01

    Abstract: Although convention dictates that G protein-coupled receptors localize to and signal at the plasma membrane, accumulating evidence suggests that G protein-coupled receptors localize to and signal at intracellular membranes, most notably the nucleus. In fact, there is now significant evidence indicating that endogenous alpha-1 adrenergic receptors (α1-ARs) localize to and signal at the nuclei in adult cardiac myocytes. Cumulatively, the data suggest that α1-ARs localize to the inner nuclear membrane, activate intranuclear signaling, and regulate physiologic function in adult cardiac myocytes. Although α1-ARs signal through Gαq, unlike other Gq-coupled receptors, α1-ARs mediate important cardioprotective functions including adaptive/physiologic hypertrophy, protection from cell death (survival signaling), positive inotropy, and preconditioning. Also unlike other Gq-coupled receptors, most, if not all, functional α1-ARs localize to the nuclei in adult cardiac myocytes, as opposed to the sarcolemma. Together, α1-AR nuclear localization and cardioprotection might suggest a novel model for compartmentalization of Gq-coupled receptor signaling in which nuclear Gq-coupled receptor signaling is cardioprotective. PMID:25264754

  18. Caveolae in Ventricular Myocytes are Required for Stretch-Dependent Conduction Slowing

    PubMed Central

    Pfeiffer, E.R.; Wright, A.T.; Edwards, A.G.; Stowe, J.C.; McNall, K.; Tan, J.; Niesman, I.; Patel, H.H.; Roth, D.M.; Omens, J.H.; McCulloch, A.D.

    2014-01-01

    Mechanical stretch of cardiac muscle modulates action potential propagation velocity, causing potentially arrhythmogenic conduction slowing. The mechanisms by which stretch alters cardiac conduction remain unknown, but previous studies suggest that stretch can affect the conformation of caveolae in myocytes and other cell types. We tested the hypothesis that slowing of action potential conduction due to cardiac myocyte stretch is dependent on caveolae. Cardiac action potential propagation velocities, measured by optical mapping in isolated mouse hearts and in micropatterned mouse cardiomyocyte cultures, decreased reversibly with volume loading or stretch, respectively (by 19±5% and 26±4%). Stretch-dependent conduction slowing was not altered by stretch-activated channel blockade with gadolinium or by GsMTx-4 peptide, but was inhibited when caveolae were disrupted via genetic deletion of caveolin-3 (Cav3 KO) or membrane cholesterol depletion by methyl-β-cyclodextrin. In wild-type mouse hearts, stretch coincided with recruitment of caveolae to the sarcolemma, as observed by electron microscopy. In myocytes from wild-type but not Cav3 KO mice, stretch significantly increased cell membrane capacitance (by 98±64%), electrical time constant (by 285±149%), and lipid recruitment to the bilayer (by 84±39%). Recruitment of caveolae to the sarcolemma during physiologic cardiomyocyte stretch slows ventricular action potential propagation by increasing cell membrane capacitance. PMID:25257915

  19. Predicting changes in cardiac myocyte contractility during early drug discovery with in vitro assays.

    PubMed

    Morton, M J; Armstrong, D; Abi Gerges, N; Bridgland-Taylor, M; Pollard, C E; Bowes, J; Valentin, J-P

    2014-09-01

    Cardiovascular-related adverse drug effects are a major concern for the pharmaceutical industry. Activity of an investigational drug at the L-type calcium channel could manifest in a number of ways, including changes in cardiac contractility. The aim of this study was to define which of the two assay technologies - radioligand-binding or automated electrophysiology - was most predictive of contractility effects in an in vitro myocyte contractility assay. The activity of reference and proprietary compounds at the L-type calcium channel was measured by radioligand-binding assays, conventional patch-clamp, automated electrophysiology, and by measurement of contractility in canine isolated cardiac myocytes. Activity in the radioligand-binding assay at the L-type Ca channel phenylalkylamine binding site was most predictive of an inotropic effect in the canine cardiac myocyte assay. The sensitivity was 73%, specificity 83% and predictivity 78%. The radioligand-binding assay may be run at a single test concentration and potency estimated. The least predictive assay was automated electrophysiology which showed a significant bias when compared with other assay formats. Given the importance of the L-type calcium channel, not just in cardiac function, but also in other organ systems, a screening strategy emerges whereby single concentration ligand-binding can be performed early in the discovery process with sufficient predictivity, throughput and turnaround time to influence chemical design and address a significant safety-related liability, at relatively low cost.

  20. Quantification of Myocyte Chemotaxis: A Role for FAK in Regulating Directional Motility

    PubMed Central

    Zajac, Britni; Hakim, Zeenat S.; Cameron, Morgan V.; Smithies, Oliver; Taylor, Joan M.

    2015-01-01

    Formation of a fully functional four-chambered heart involves an intricate and complex series of events that includes precise spatial–temporal regulation of cell specification, proliferation, and migration. The formation of the ventricular septum during mid-gestation ensures the unidirectional flow of blood, and is necessary for postnatal viability. Notably, a majority of all congenital malformations of the cardiovascular system in humans involve septal abnormalities which afflict 1 out of 100 newborn children in the United States. Thus, a clear understanding of the precise mechanisms involved in this morphogenetic event will undoubtedly reveal important therapeutic targets. The final step in valvuloseptal morphogenesis occurs, in part, by directed movement of flanking myocytes into the cushion mesenchyme. In order to identify the molecular mechanisms that regulate this critical myocyte function, we have developed two in vitro methodologies; a transwell assay to assess population changes in motility and a single-cell tracking assay to identify signals that drive the coordinated movement of these cells. These methods have proven effective to identify focal adhesion kinase (FAK) as an intracellular component that is critical for myocyte chemotaxis. PMID:22222526

  1. Pannexin 1 Constitutes the Large Conductance Cation Channel of Cardiac Myocytes

    PubMed Central

    Kienitz, Marie-Cecile; Bender, Kirsten; Dermietzel, Rolf; Pott, Lutz; Zoidl, Georg

    2011-01-01

    A large conductance (∼300 picosiemens) channel (LCC) of unknown molecular identity, activated by Ca2+ release from the sarcoplasmic reticulum, particularly when augmented by caffeine, has been described previously in isolated cardiac myocytes. A potential candidate for this channel is pannexin 1 (Panx1), which has been shown to form large ion channels when expressed in Xenopus oocytes and mammalian cells. Panx1 function is implicated in ATP-mediated auto-/paracrine signaling, and a crucial role in several cell death pathways has been suggested. Here, we demonstrate that after culturing for 4 days LCC activity is no longer detected in myocytes but can be rescued by adenoviral gene transfer of Panx1. Endogenous LCCs and those related to expression of Panx1 share key pharmacological properties previously used for identifying and characterizing Panx1 channels. These data demonstrate that Panx1 constitutes the LCC of cardiac myocytes. Sporadic openings of single Panx1 channels in the absence of Ca2+ release can trigger action potentials, suggesting that Panx1 channels potentially promote arrhythmogenic activities. PMID:21041301

  2. Effect of Transmurally Heterogeneous Myocyte Excitation-Contraction Coupling on Left Ventricular Electromechanics

    PubMed Central

    Campbell, Stuart G.; Howard, Elliot; Aguado-Sierra, Jazmin; Coppola, Benjamin A.; Omens, Jeffrey H.; Mulligan, Lawrence J.; McCulloch, Andrew D.; Kerckhoffs, Roy CP

    2009-01-01

    The excitation-contraction coupling properties of cardiac myocytes isolated from different regions of the mammalian left ventricular wall have been shown to vary considerably, with uncertain effects on ventricular function. We embedded a cell-level excitation-contraction coupling model with region-dependent parameters within a simple finite element model of left ventricular geometry to study effects of electromechanical heterogeneity on local myocardial mechanics and global hemodynamics. This model was compared with one in which heterogeneous myocyte parameters were assigned randomly throughout the mesh while preserving the total amount of each cell subtype. The two models displayed nearly identical transmural patterns of fibre and cross-fibre strains at end systole, but showed clear differences in fibre strains at earlier points during systole. Hemodynamic function, including peak left ventricular pressure, maximum rate of left ventricular pressure development, and stroke volume were essentially identical in the two models. These results suggest that in the intact ventricle heterogeneously distributed myocyte subtypes primarily impact local deformation of the myocardium, and that these effects are greatest during early systole. PMID:19251984

  3. Evidence for selective regulation of the phosphorylation of myocyte proteins by isoproterenol and prostaglandin E1.

    PubMed

    Hayes, J S; Bowling, N; King, K L; Boder, G B

    1982-01-12

    Both isoproterenol and prostaglandin E1 increased the activation state of cyclic AMP-dependent protein kinase in cultured myocytes; however, only isoproterenol enhanced phosphorylase activity and contractile state. Following the incubation of intact myocytes with 32PO3-(4), 32 phosphoproteins were resolved from total cellular proteins by electrophoresis in sodium dodecyl sulfate polyacrylamide gels followed by autoradiography. Isoproterenol stimulated 32PO3-(4) incorporation into 16 proteins, including 2 phosphoproteins not observed under control conditions. By contrast, prostaglandin E1 neither caused a measurable change in the protein phosphorylation pattern nor interfered with isoproterenol's capacity to do so. Isoproterenol stimulated myocyte protein phosphorylation in either the presence or absence of extracellular Ca2+. The results suggest that the regulation of protein phosphorylation following adenylate cyclase stimulation is: (1) an agonist-specific process and not due solely to a random accumulation of intracellular cycle AMP and activation of protein kinase; (2) the Ca2+ mobilization component of beta-receptor activation does not account for the paradoxical effects of isoproterenol and prostaglandin E1; (3) activation of cyclic AMP-dependent protein kinase does not always result in an enhancement of protein phosphorylation.

  4. A Computational Model of the Human Left-Ventricular Epicardial Myocyte

    PubMed Central

    Iyer, Vivek; Mazhari, Reza; Winslow, Raimond L.

    2004-01-01

    A computational model of the human left-ventricular epicardial myocyte is presented. Models of each of the major ionic currents present in these cells are formulated and validated using experimental data obtained from studies of recombinant human ion channels and/or whole-cell recording from single myocytes isolated from human left-ventricular subepicardium. Continuous-time Markov chain models for the gating of the fast Na+ current, transient outward current, rapid component of the delayed rectifier current, and the L-type calcium current are modified to represent human data at physiological temperature. A new model for the gating of the slow component of the delayed rectifier current is formulated and validated against experimental data. Properties of calcium handling and exchanger currents are altered to appropriately represent the dynamics of intracellular ion concentrations. The model is able to both reproduce and predict a wide range of behaviors observed experimentally including action potential morphology, ionic currents, intracellular calcium transients, frequency dependence of action-potential duration, Ca2+-frequency relations, and extrasystolic restitution/post-extrasystolic potentiation. The model therefore serves as a useful tool for investigating mechanisms of arrhythmia and consequences of drug-channel interactions in the human left-ventricular myocyte. PMID:15345532

  5. Heat stress activates AKT via focal adhesion kinase-mediated pathway in neonatal rat ventricular myocytes.

    PubMed

    Wei, Hongguang; Vander Heide, Richard S

    2008-08-01

    Heat stress (HS)-induced cardioprotection is associated with increased paxillin localization to the membrane fraction of neonatal rat ventricular myocytes (NRVM). The purpose of this study was 1) to examine the subcellular signaling pathways activated by HS; 2) to determine whether myocardial stress organizes and activates an integrated survival pathway; and 3) to investigate potential downstream cytoprotective proteins activated by HS. After HS, NRVM were subjected to chemical inhibitors (CI) designed to simulate ischemia by inhibiting both glycolysis and mitochondrial respiration. Protein kinase B (AKT) expression (wild type) was increased selectively with an adenoviral vector. Cell signaling was analyzed with Western blot analysis, while oncosis/apoptosis was assayed by measuring Trypan blue exclusion and/or terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining, respectively. HS increased phosphorylation of focal adhesion kinase (FAK) at tyrosine 397 but did not adversely affect the viability of NRVM before CI. HS increased association between FAK and phosphatidylinositol 3-kinase as well as causing a significant increase in AKT activity. Increased expression of wild-type AKT protected myocytes from both oncotic and apoptotic cell death. Increased expression of a FAK inhibitor, FRNK, reduced AKT phosphorylation in response to HS both at time 0 and after 10 min of CI compared with myocytes expressing empty virus. We conclude that myocardial stress activates cytoskeleton-based signaling pathways that are associated with protection from lethal cell injury.

  6. A prospective randomized study to assess the efficacy of rate and site of atrial pacing on long-term development of atrial fibrillation.

    PubMed

    Lau, Chu-Pak; Wang, Chun-Chieh; Ngarmukos, Tachapong; Kim, You-Ho; Kong, Chi-Woon; Omar, Razali; Sriratanasathavorn, Charn; Munawar, Muhammad; Kam, Ruth; Lee, Kathy Lf; Lau, Elizabeth Oi-Yan; Tse, Hung-Fat

    2009-09-01

    The Septal Pacing for Atrial Fibrillation Suppression Evaluation (SAFE) study is a single-blinded, parallel randomized designed multicenter study in pacemaker indicated patients with paroxysmal atrial fibrillation (AF). The objective is to evaluate whether the site of atrial pacing--conventional right atrial appendage versus low atrial septal--with or without atrial overdrive pacing will influence the development of persistent AF. The study will provide a definitive answer to whether a different atrial pacing site or the use of AF suppression pacing or both can give incremental antiarrhythmic benefit when one is implanting a device for a patient with a history of paroxysmal AF. PMID:19460078

  7. Aorto-left atrial tunnel: a rare entity.

    PubMed

    Paul, Sajiv K; Gajjar, Trushar P; Desai, Neelam B

    2013-05-01

    Aorto-left atrial tunnel (ALAT) is a vascular channel that originates from 1 of the sinuses of Valsalva and terminates in the left atrium. The aorto-left atrial tunnel is an extremely rare anomaly. We describe here a case of congenital aorto-left atrial tunnel in a 4-year-old child who underwent successful surgical ligation with good immediate and early results.

  8. Extreme variation in the atrial septation of caecilians (Amphibia: Gymnophiona).

    PubMed

    de Bakker, Desiderius M; Wilkinson, Mark; Jensen, Bjarke

    2015-01-01

    Caecilians (order Gymnophiona) are elongate, limbless, snake-like amphibians that are the sister-group (closest relatives) of all other recent amphibians (frogs and salamanders). Little is known of their cardiovascular anatomy and physiology, but one nearly century old study suggests that Hypogeophis (family Indotyphlidae), commonly relied upon as a representative caecilian species, has atrial septation in the frontal plane and more than one septum. In contrast, in other vertebrates there generally is one atrial septum in the sagittal plane. We studied the adult heart of Idiocranium (also Indotyphlidae) using immunohistochemistry and confirm that the interatrial septum is close to the frontal plane. Additionally, a parallel right atrial septum divides three-fourths of the right atrial cavity of this species. Idiocranium embryos in the Hill collection reveal that atrial septation initiates in the sagittal plane as in other tetrapods. Late developmental stages, however, see a left-ward shift of visceral organs and a concordant rotation of the atria that reorients the atrial septa towards the frontal plane. The gross anatomies of species from six other caecilian families reveal that (i) the right atrial septum developed early in caecilian evolution (only absent in Rhinatrematidae) and that (ii) rotation of the atria evolved later and its degree varies between families. In most vertebrates a prominent atrial trabeculation associates with the sinuatrial valve, the so-called septum spurium, and the right atrial septum seems homologous to this trabeculation but much more developed. The right atrial septum does not appear to be a consequence of body elongation because it is absent in some caecilians and in snakes. The interatrial septum of caecilians shares multiple characters with the atrial septum of lungfishes, salamanders and the embryonic septum primum of amniotes. In conclusion, atrial septation in caecilians is based on evolutionarily conserved structures but

  9. [PREVALENCE OF ATRIAL RHYTHM DISTURBANCES IN CARDIAC PATIENTS WITH COMORBIDITIES].

    PubMed

    Velichko, V L; Naychuk, O V; Lagoda, D O; Amirova, G U

    2015-01-01

    Atrial arrhythmias are the most common among all cardiac arrhythmias. The prevalence of atrial arrhythmias is increasing worldwide and has an impact on health indicators such as the loss of ability to work and mortality and increases the overall cardiovascular risk and/or heart disease occurence. This study indicates a high prevalence of atrial arthythmias in patients with ischemic heart disease and requires more detailed study in order to develop methods of preventing the onset of cardiac rhythm disorders.

  10. [PREVALENCE OF ATRIAL RHYTHM DISTURBANCES IN CARDIAC PATIENTS WITH COMORBIDITIES].

    PubMed

    Velichko, V L; Naychuk, O V; Lagoda, D O; Amirova, G U

    2015-01-01

    Atrial arrhythmias are the most common among all cardiac arrhythmias. The prevalence of atrial arrhythmias is increasing worldwide and has an impact on health indicators such as the loss of ability to work and mortality and increases the overall cardiovascular risk and/or heart disease occurence. This study indicates a high prevalence of atrial arthythmias in patients with ischemic heart disease and requires more detailed study in order to develop methods of preventing the onset of cardiac rhythm disorders. PMID:26118041

  11. Aorto-left atrial tunnel: a rare entity.

    PubMed

    Paul, Sajiv K; Gajjar, Trushar P; Desai, Neelam B

    2013-05-01

    Aorto-left atrial tunnel (ALAT) is a vascular channel that originates from 1 of the sinuses of Valsalva and terminates in the left atrium. The aorto-left atrial tunnel is an extremely rare anomaly. We describe here a case of congenital aorto-left atrial tunnel in a 4-year-old child who underwent successful surgical ligation with good immediate and early results. PMID:23608293

  12. Extreme variation in the atrial septation of caecilians (Amphibia: Gymnophiona).

    PubMed

    de Bakker, Desiderius M; Wilkinson, Mark; Jensen, Bjarke

    2015-01-01

    Caecilians (order Gymnophiona) are elongate, limbless, snake-like amphibians that are the sister-group (closest relatives) of all other recent amphibians (frogs and salamanders). Little is known of their cardiovascular anatomy and physiology, but one nearly century old study suggests that Hypogeophis (family Indotyphlidae), commonly relied upon as a representative caecilian species, has atrial septation in the frontal plane and more than one septum. In contrast, in other vertebrates there generally is one atrial septum in the sagittal plane. We studied the adult heart of Idiocranium (also Indotyphlidae) using immunohistochemistry and confirm that the interatrial septum is close to the frontal plane. Additionally, a parallel right atrial septum divides three-fourths of the right atrial cavity of this species. Idiocranium embryos in the Hill collection reveal that atrial septation initiates in the sagittal plane as in other tetrapods. Late developmental stages, however, see a left-ward shift of visceral organs and a concordant rotation of the atria that reorients the atrial septa towards the frontal plane. The gross anatomies of species from six other caecilian families reveal that (i) the right atrial septum developed early in caecilian evolution (only absent in Rhinatrematidae) and that (ii) rotation of the atria evolved later and its degree varies between families. In most vertebrates a prominent atrial trabeculation associates with the sinuatrial valve, the so-called septum spurium, and the right atrial septum seems homologous to this trabeculation but much more developed. The right atrial septum does not appear to be a consequence of body elongation because it is absent in some caecilians and in snakes. The interatrial septum of caecilians shares multiple characters with the atrial septum of lungfishes, salamanders and the embryonic septum primum of amniotes. In conclusion, atrial septation in caecilians is based on evolutionarily conserved structures but

  13. Association of Atrial Fibrillation with Morphological and Electrophysiological Changes of the Atrial Myocardium.

    PubMed

    Matějková, Adéla; Šteiner, Ivo

    2016-01-01

    Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. For long time it was considered as pure functional disorder, but in recent years, there were identified atrial locations, which are involved in the initiation and maintenance of this arrhythmia. These structural changes, so called remodelation, start at electric level and later they affect contractility and morphology. In this study we attempted to find a possible relation between morphological (scarring, amyloidosis, left atrial (LA) enlargement) and electrophysiological (ECG features) changes in patients with AF. We examined grossly and histologically 100 hearts of necropsy patients - 54 with a history of AF and 46 without AF. Premortem ECGs were evaluated. The patients with AF had significantly heavier heart, larger LA, more severely scarred myocardium of the LA and atrial septum, and more severe amyloidosis in both atria. Severity of amyloidosis was higher in LAs vs. right atria (RAs). Distribution of both fibrosis and amyloidosis was irregular. The most affected area was in the LA anterior wall. Patients with a history of AF and with most severe amyloidosis have more often abnormally long P waves. Finding of long P wave may contribute to diagnosis of a hitherto undisclosed atrial fibrillation. PMID:27526304

  14. Hemodynamic forces regulate developmental patterning of atrial conduction.

    PubMed

    Bressan, Michael C; Louie, Jonathan D; Mikawa, Takashi

    2014-01-01

    Anomalous action potential conduction through the atrial chambers of the heart can lead to severe cardiac arrhythmia. To date, however, little is known regarding the mechanisms that pattern proper atrial conduction during development. Here we demonstrate that atrial muscle functionally diversifies into at least two heterogeneous subtypes, thin-walled myocardium and rapidly conducting muscle bundles, during a developmental window just following cardiac looping. During this process, atrial muscle bundles become enriched for the fast conduction markers Cx40 and Nav1.5, similar to the precursors of the fast conduction Purkinje fiber network located within the trabeculae of the ventricles. In contrast to the ventricular trabeculae, however, atrial muscle bundles display an increased proliferation rate when compared to the surrounding myocardium. Interestingly, mechanical loading of the embryonic atrial muscle resulted in an induction of Cx40, Nav1.5 and the cell cycle marker Cyclin D1, while decreasing atrial pressure via in vivo ligation of the vitelline blood vessels results in decreased atrial conduction velocity. Taken together, these data establish a novel model for atrial conduction patterning, whereby hemodynamic stretch coordinately induces proliferation and fast conduction marker expression, which in turn promotes the formation of large diameter muscle bundles to serve as preferential routes of conduction.

  15. Coherex WAVECREST I Left Atrial Appendage Occlusion Study

    ClinicalTrials.gov

    2015-01-13

    Non-valvular Paroxysmal, Persistent, or Permanent Atrial Fibrillation; LAA Anatomy Amenable to Treatment by Percutaneous Technique; Anticoagulation Indication for Potential Thrombus Formation in the Left Atrium

  16. [Giant aneurysm of the inter-atrial septum].

    PubMed

    Akoudad, H; Cherti, M; Chaouki, S; Ztot, S; Haddour, L; el Mrabet, I; el Khadiri, A; Benmimoun, E G; Arharbi, A

    1999-01-01

    We report the case of a large atrial septal aneurysm and a review of the literature. Atrial septal aneurysm is found in 1-8% of normal subjects. Its prevalence is higher among patients with ischemic stroke. Transesophageal echocardiography is an optimal tool for the diagnosis of atrial septal aneurysm. The clinical course may be complicated by arterial embolism, but mechanical complications may also occur, as in this case. Due to the lack of general agreement, treatment options should be discussed on an individual basis for patients with atrial septal aneurysm. PMID:10093663

  17. Validation of an in vitro contractility assay using canine ventricular myocytes

    SciTech Connect

    Harmer, A.R. Abi-Gerges, N.; Morton, M.J.; Pullen, G.F.; Valentin, J.P.; Pollard, C.E.

    2012-04-15

    Measurement of cardiac contractility is a logical part of pre-clinical safety assessment in a drug discovery project, particularly if a risk has been identified or is suspected based on the primary- or non-target pharmacology. However, there are limited validated assays available that can be used to screen several compounds in order to identify and eliminate inotropic liability from a chemical series. We have therefore sought to develop an in vitro model with sufficient throughput for this purpose. Dog ventricular myocytes were isolated using a collagenase perfusion technique and placed in a perfused recording chamber on the stage of a microscope at ∼ 36 °C. Myocytes were stimulated to contract at a pacing frequency of 1 Hz and a digital, cell geometry measurement system (IonOptix™) was used to measure sarcomere shortening in single myocytes. After perfusion with vehicle (0.1% DMSO), concentration–effect curves were constructed for each compound in 4–30 myocytes taken from 1 or 2 dog hearts. The validation test-set was 22 negative and 8 positive inotropes, and 21 inactive compounds, as defined by their effect in dog, cynolomolgous monkey or humans. By comparing the outcome of the assay to the known in vivo contractility effects, the assay sensitivity was 81%, specificity was 75%, and accuracy was 78%. With a throughput of 6–8 compounds/week from 1 cell isolation, this assay may be of value to drug discovery projects to screen for direct contractility effects and, if a hazard is identified, help identify inactive compounds. -- Highlights: ► Cardiac contractility is an important physiological function of the heart. ► Assessment of contractility is a logical part of pre-clinical drug safety testing. ► There are limited validated assays that predict effects of compounds on contractility. ► Using dog myocytes, we have developed an in vitro cardiac contractility assay. ► The assay predicted the in vivo contractility with a good level of accuracy.

  18. [Progress of anticoagulation therapy in atrial fibrillation].

    PubMed

    Hernández Olmedo, Miguel; Suárez Fernández, Carmen

    2015-08-01

    Atrial fibrillation is currently a very prevalent disease and it represents one of the most common causes of disabling stroke. Antithrombotic therapies have reduced the incidence of this complication although they pose many limitations and difficulties. As a result, a large number of high risk patients do not receive an appropriate treatment. In recent years, four new oral anticoagulants (NOAC) with relevant advantages in comparison to vitaminK antagonists have been released. Four large phaseiii clinical trials have demonstrated that NOAC are at least as safe and efficacious as warfarin in stroke prevention in non-valve atrial fibrillation patients with moderate-high thrombotic risk, being their main advantage the reduction in intracranial hemorrhage. The arrival of these drugs has caused great expectations in the management of these patients but also new doubts. Lacking data in some subgroups of frail patients, the absence of specific antidotes available and specially their high cost represent nowadays the main limitations for their generalization.

  19. Propofol effects on atrial fibrillation wavefront delays.

    PubMed

    Cervigón, Raquel; Moreno, Javier; Millet, José; Pérez-Villacastín, Julián; Castells, Francisco

    2010-08-01

    Since the cardiac activity during atrial fibrillation (AF) may be influenced by autonomic modulations, in this study, a novel method to quantify the effects of the most common anesthetic agent (propofol) in AF ablation procedures is introduced. This study has two main objectives: first, to assess whether the sedation earlier to radio frequency ablation affects the arrhythmia itself, and second, to provide new information that contributes to a better understanding of the influence of the autonomic nervous system on AF. The methodology presented is based on the measurement of synchronization and delay indexes between two atrial activations at adjacent intracavitary electrodes. These parameters aim to estimate whether two activations at different sites may be caused by the same propagating wavefront, or otherwise, are the consequence of independent wavefronts. The results showed that the mentioned indexes have a different behavior at both atria: the right atrium becomes more synchronized with propofol administration, whereas the synchronization index decreases at the left atrium.

  20. Atrial fibrillation due to licorice root syrup.

    PubMed

    Erkuş, Musluhittin Emre; Altıparmak, İbrahim Halil; Demirbağ, Recep; Günebakmaz, Özgür

    2016-04-01

    While it is known that consumption of licorice may lead to cardiac arrhythmias, there have been no reports of atrial fibrillation resulting from the consumption of licorice root syrup. A 57-year-old male with no prior history of cardiovascular disease was admitted to the emergency department with palpitation. His electrocardiogram showed atrial fibrillation with a moderate to rapid ventricular rate. In laboratory assessment, potassium was 2.0 mmol/L and plasma renin activity and aldosterone level were suppressed (<300 ng/L/hour, 42 ng/L respectively). Volumes of the heart chambers were within normal range and functions and structures of the heart valves were normal in echocardiographic assessment. The arrhythmia was resolved with propafenone infusion. PMID:27138313

  1. Minimally invasive surgery for atrial fibrillation.

    PubMed

    Lancaster, Timothy S; Melby, Spencer J; Damiano, Ralph J

    2016-04-01

    The surgical treatment of atrial fibrillation (AF) has been revolutionized over the past two decades through surgical innovation and improvements in endoscopic imaging, ablation technology, and surgical instrumentation. These advances have prompted the development of the less complex and less morbid Cox-Maze IV procedure, and have allowed its adaptation to a minimally invasive right mini-thoracotomy approach that can be used in stand-alone AF ablation and in patients undergoing concomitant mitral and tricuspid valve surgery. Other minimally invasive ablation techniques have been developed for stand-alone AF ablation, including video-assisted pulmonary vein isolation, extended left atrial lesion sets, and a hybrid approach. This review will discuss the tools, techniques, and outcomes of minimally invasive surgical procedures currently being practiced for AF ablation.

  2. Atrial-like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial-selective pharmacology

    PubMed Central

    Devalla, Harsha D; Schwach, Verena; Ford, John W; Milnes, James T; El-Haou, Said; Jackson, Claire; Gkatzis, Konstantinos; Elliott, David A; Chuva de Sousa Lopes, Susana M; Mummery, Christine L; Verkerk, Arie O; Passier, Robert

    2015-01-01

    Drugs targeting atrial-specific ion channels, Kv1.5 or Kir3.1/3.4, are being developed as new therapeutic strategies for atrial fibrillation. However, current preclinical studies carried out in non-cardiac cell lines or animal models may not accurately represent the physiology of a human cardiomyocyte (CM). In the current study, we tested whether human embryonic stem cell (hESC)-derived atrial CMs could predict atrial selectivity of pharmacological compounds. By modulating retinoic acid signaling during hESC differentiation, we generated atrial-like (hESC-atrial) and ventricular-like (hESC-ventricular) CMs. We found the expression of atrial-specific ion channel genes, KCNA5 (encoding Kv1.5) and KCNJ3 (encoding Kir 3.1), in hESC-atrial CMs and further demonstrated that these ion channel genes are regulated by COUP-TF transcription factors. Moreover, in response to multiple ion channel blocker, vernakalant, and Kv1.5 blocker, XEN-D0101, hESC-atrial but not hESC-ventricular CMs showed action potential (AP) prolongation due to a reduction in early repolarization. In hESC-atrial CMs, XEN-R0703, a novel Kir3.1/3.4 blocker restored the AP shortening caused by CCh. Neither CCh nor XEN-R0703 had an effect on hESC-ventricular CMs. In summary, we demonstrate that hESC-atrial CMs are a robust model for pre-clinical testing to assess atrial selectivity of novel antiarrhythmic drugs. PMID:25700171

  3. Two functionally different Na/K pumps in cardiac ventricular myocytes

    PubMed Central

    1995-01-01

    The whole-cell patch-clamp technique was used to voltage clamp acutely isolated myocytes at -60 mV and study effects of ionic environment on Na/K pump activity. In quiescent guinea pig myocytes, normal intracellular Na+ is approximately 6 mM, which gives a total pump current of 0.25 +/- 0.09 pA/pF, and an inward background sodium current of 0.75 +/- 0.26 pA/pF. The average capacitance of a cell is 189 +/- 61 pF. Our main conclusion is the total Na/K pump current comprises currents from two different types of pumps, whose functional responses to the extracellular environment are different. Pump current was reversibly blocked with two affinities by extracellular dihydro-ouabain (DHO). We determined dissociation constants of 72 microM for low affinity (type-1) pumps and 0.75 microM for high affinity (type-h) pumps. These dissociation constants did not detectably change with two intracellular Na+ concentrations, one saturating and one near half- saturating, and with two extracellular K+ concentrations of 4.6 and 1.0 mM. Ion effects on type-h pumps were therefore measured using 5 microM DHO and on total pump current using 1 mM DHO. Extracellular K+ half- maximally activated the type-h pumps at 0.4 mM and the type-1 at 3.7 mM. Extracellular H+ blocked the type-1 pumps with half-maximal blockade at a pH of 7.71 whereas the type-h pumps were insensitive to extracellular pH. Both types of pumps responded similarly to changes in intracellular-Na+, with 9.6 mM causing half-maximal activation. Neither changes in intracellular pH between 6.0 and 7.2, nor concentrations of intracellular K+ of 140 mM or below, had any effect on either type of pump. The lack of any effect of intracellular K+ suggests the dissociation constants are in the molar range so this step in the pump cycle is not rate limiting under normal physiological conditions. Changes in intracellular-Na+ did not affect the half-maximal activation by extracellular K+, and vice versa. We found DHO-blockade of Na/K pump

  4. Fetal myocardium in the kidney capsule: an in vivo model of repopulation of myocytes by bone marrow cells.

    PubMed

    Zhang, Eric Y; Xiong, Qiang; Ye, Lei; Suntharalingam, Piradeep; Wang, Xiaohong; Astle, C Michael; Zhang, Jianyi; Harrison, David E

    2012-01-01

    Debate surrounds the question of whether the heart is a post-mitotic organ in part due to the lack of an in vivo model in which myocytes are able to actively regenerate. The current study describes the first such mouse model--a fetal myocardial environment grafted into the adult kidney capsule. Here it is used to test whether cells descended from bone marrow can regenerate cardiac myocytes. One week after receiving the fetal heart grafts, recipients were lethally irradiated and transplanted with marrow from green fluorescent protein (GFP)-expressing C57Bl/6J (B6) donors using normal B6 recipients and fetal donors. Levels of myocyte regeneration from GFP marrow within both fetal myocardium and adult hearts of recipients were evaluated histologically. Fetal myocardium transplants had rich neovascularization and beat regularly after 2 weeks, continuing at checkpoints of 1, 2, 4, 6, 8 and12 months after transplantation. At each time point, GFP-expressing rod-shaped myocytes were found in the fetal myocardium, but only a few were found in the adult hearts. The average count of repopulated myocardium with green rod-shaped myocytes was 996.8 cells per gram of fetal myocardial tissue, and 28.7 cells per adult heart tissue, representing a thirty-five fold increase in fetal myocardium compared to the adult heart at 12 months (when numbers of green rod-shaped myocytes were normalized to per gram of myocardial tissue). Thus, bone marrow cells can differentiate to myocytes in the fetal myocardial environment. The novel in vivo model of fetal myocardium in the kidney capsule appears to be valuable for testing repopulating abilities of potential cardiac progenitors.

  5. Hypertrophy, gene expression, and beating of neonatal cardiac myocytes are affected by microdomain heterogeneity in 3D

    PubMed Central

    Curtis, Matthew W.; Sharma, Sadhana; Desai, Tejal A.

    2011-01-01

    Cardiac myocytes are known to be influenced by the rigidity and topography of their physical microenvironment. It was hypothesized that 3D heterogeneity introduced by purely physical microdomains regulates cardiac myocyte size and contraction. This was tested in vitro using polymeric microstructures (G′=1.66 GPa) suspended with random orientation in 3D by a soft Matrigel matrix (G′=22.9 Pa). After 10 days of culture, the presence of 100 μm-long microstructures in 3D gels induced fold increases in neonatal rat ventricular myocyte size (1.61±0.06, p<0.01) and total protein/cell ratios (1.43± 0.08, p<0.05) that were comparable to those induced chemically by 50 μM phenylephrine treatment. Upon attachment to microstructures, individual myocytes also had larger cross-sectional areas (1.57±0.05, p<0.01) and higher average rates of spontaneous contraction (2.01±0.08, p<0.01) than unattached myocytes. Furthermore, the inclusion of microstructures in myocyte-seeded gels caused significant increases in the expression of beta-1 adrenergic receptor (β1-AR, 1.19±0.01), cardiac ankyrin repeat protein (CARP, 1.26±0.02), and sarcoplasmic reticulum calcium-ATPase (SERCA2, 1.59±0.12, p<0.05), genes implicated in hypertrophy and contractile activity. Together, the results demonstrate that cardiac myocyte behavior can be controlled through local 3D microdomains alone. This approach of defining physical cues as independent features may help to advance the elemental design considerations for scaffolds in cardiac tissue engineering and therapeutic microdevices. PMID:20668947

  6. Steroid hormone modulation of cAMP production in response to beta adrenergic receptor stimulation in genital tract myocytes.

    PubMed

    DiGiovanni, L; Austin, R; Phillippe, M

    1992-01-01

    beta-Adrenergic receptor stimulation results in smooth muscle relaxation through activation of adenylyl cyclase and subsequent cyclic AMP (cAMP) production. The present study was performed to evaluate the effects of steroid hormones (i.e. testosterone and hydrocortisone) on beta 2-adrenergic receptors and their signal transduction in the DDT1 MF-2 genital tract myocyte. Radioligand binding studies demonstrated that these two steroid hormones produced a 70 to 80% increase in the density of beta 2-adrenergic receptors in these myocytes. Stimulation of the beta 2-adrenergic receptors with isoproterenol resulted in a significant increase of cAMP in control myocytes; cells treated with testosterone for 24 h demonstrated a comparable response to isoproterenol, whereas hydrocortisone for 24 h resulted in a 50% greater cAMP response. In contrast to the response at 24 h, stimulation of myocytes after testosterone treatment for 48 h resulted in a cAMP response comparable to that seen in response to hydrocortisone at 24 h. Studies performed using theophylline demonstrated similar cAMP responses at 24 h between the control and testosterone-treated myocytes, thereby ruling out the possibility that the delayed increase of the cAMP response after testosterone was caused by stimulation of phosphodiesterase. Direct stimulation with forskolin resulted in greater cAMP production in the testosterone-treated myocytes compared to controls, thereby refuting the possibility that testosterone directly suppresses adenylyl cyclase activity at 24 h. These findings suggest that although both testosterone and hydrocortisone produce a twofold increase in beta 2-adrenergic receptor density in the DDT1 myocytes, beta 2-adrenergic receptors expressed in response to hydrocortisone appear functional at 24 h resulting in increased cAMP production, whereas those expressed in response to testosterone require 48 h to demonstrate increased functional activity.

  7. The exploitation of spatial topographies for atrial signal extraction in atrial fibrillation ECGs.

    PubMed

    Bonizzi, Pietro; Phlypo, Ronald; Zarzoso, Vicente; Meste, Olivier

    2008-01-01

    The accuracy in the extraction of the atrial activity (AA) from electrocardiogram (ECG) signals recorded during atrial fibrillation (AF) episodes plays an important role in the analysis and characterization of atrial arrhythmias. The present contribution puts forward a method for AA signal extraction based on a blind source separation (BSS) formulation. The latter exploits spatial information on the different components in the ECG related or not to AF. The source directions or spatial topographies of the components not related to AF are used to determine the nullspace of the AA, so that the topographies related to AA become more suitable to describe AF sources. The comparative performance of the method is evaluated on real data recorded from patients with noticeable AF. The AA extraction quality of the proposed technique is comparable to that of previous algorithms.

  8. Is percutaneous closure of the left atrial appendage comparable to anticoagulants for atrial fibrillation?

    PubMed

    Uslar, Thomas; Anabalón, Jaime

    2015-01-01

    For most atrial fibrillation patients oral anticoagulation constitutes the standard treatment to prevent stroke. However, they carry a risk of bleeding, which is why alternative treatments have been put into practice, such as percutaneous closure of the left atrial appendage. It is not clear whether this is as effective as the conventional treatment with anticoagulants. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified three systematic reviews including only one pertinent randomized controlled trial. We combined the evidence and generated a summary of findings following the GRADE approach. We concluded that percutaneous left atrial appendage occlusion may decrease stroke and mortality, but the certainty of the evidence is low. The effect on other outcomes is not clear because the certainty of the evidence is very low. PMID:26335602

  9. Is percutaneous closure of the left atrial appendage comparable to anticoagulants for atrial fibrillation?

    PubMed

    Uslar, Thomas; Anabalón, Jaime

    2015-08-17

    For most atrial fibrillation patients oral anticoagulation constitutes the standard treatment to prevent stroke. However, they carry a risk of bleeding, which is why alternative treatments have been put into practice, such as percutaneous closure of the left atrial appendage. It is not clear whether this is as effective as the conventional treatment with anticoagulants. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified three systematic reviews including only one pertinent randomized controlled trial. We combined the evidence and generated a summary of findings following the GRADE approach. We concluded that percutaneous left atrial appendage occlusion may decrease stroke and mortality, but the certainty of the evidence is low. The effect on other outcomes is not clear because the certainty of the evidence is very low.

  10. Ogilvie's Syndrome following Cardioversion for Atrial Fibrillation

    PubMed Central

    Al-Halawani, Moh'd; Thawabi, Mohammad; Abdeen, Yazan; Miller, Richard A.; Fedida, Andre A.

    2014-01-01

    Acute colonic pseudoobstruction, also known as Ogilvie's syndrome, is characterized by distension of the colon in the absence of a mechanical obstruction as evident by abdominal radiography. This syndrome is usually treated conservatively; however, medical or surgical therapies can be employed in refractory cases. Ogilvie's syndrome has been reported following cardiac events, such as myocardial infarction, heart failure, and cardiac bypass surgeries. We report the first case of Ogilvie's syndrome following synchronized electric cardioversion for atrial fibrillation. PMID:25214851

  11. Atrial fibrillation and microRNAs

    PubMed Central

    Santulli, Gaetano; Iaccarino, Guido; De Luca, Nicola; Trimarco, Bruno; Condorelli, Gianluigi

    2014-01-01

    Atrial fibrillation (AF) is the most common sustained arrhythmia, especially in the elderly, and has a significant genetic component. Recently, several independent investigators have demonstrated a functional role for small non-coding RNAs (microRNAs) in the pathophysiology of this cardiac arrhythmia. This report represents a systematic and updated appraisal of the main studies that established a mechanistic association between specific microRNAs and AF, focusing both on the regulation of electrical and structural remodeling of cardiac tissue. PMID:24478726

  12. Delay in diagnosis of right atrial myxoma

    SciTech Connect

    Northcote, R.J.; Sethia, B.; Ballantyne, D.

    1985-02-01

    Clinical, echocardiographic, and nuclear angiographic findings in a 51-year-old woman who presented with a history of dyspnea are discussed. Initial echocardiography revealed no abnormality. However, a subsequent radionuclide angiogram revealed a filling defect on the right side of the heart. This represented a right atrial myxoma. Radionuclide angiography can provide a useful noninvasive tool in the diagnosis of intracardiac tumors when echocardiography has not been helpful.

  13. Atrial Fibrillation During an Exploration Class Mission

    NASA Technical Reports Server (NTRS)

    Lipset, Mark A.; Lemery, Jay; Polk, J. D.; Hamilton, Douglas R.

    2010-01-01

    Background: A long-duration exploration class mission is fraught with numerous medical contingency plans. Herein, we explore the challenges of symptomatic atrial fibrillation (AF) occurring during an exploration class mission. The actions and resources required to ameliorate the situation, including the availability of appropriate pharmaceuticals, monitoring devices, treatment modalities, and communication protocols will be investigated. Challenges of Atrial Fibrillation during an Exploration Mission: Numerous etiologies are responsible for the initiation of AF. On Earth, we have the time and medical resources to evaluate and determine the causative situation for most cases of AF and initiate therapy accordingly. During a long-duration exploration class mission resources will be severely restricted. How is one to determine if new onset AF is due to recent myocardial infarction, pulmonary embolism, fluid overload, thyrotoxicosis, cardiac structural abnormalities, or CO poisoning? Which pharmaceutical therapy should be initiated and what potential side effects can be expected? Should anti-coagulation therapy be initiated? How would one monitor the therapeutic treatment of AF in microgravity? What training would medical officers require, and which communication strategies should be developed to enable the best, safest therapeutic options for treatment of AF during a long-duration exploration class mission? Summary: These questions will be investigated with expert opinion on disease elucidation, efficient pharmacology, therapeutic monitoring, telecommunication strategies, and mission cost parameters with emphasis on atrial fibrillation being just one illustration of the tremendous challenges that face a long-duration exploration mission. The limited crew training time, medical hardware, and drugs manifested to deal with such an event predicate that aggressive primary and secondary prevention strategies be developed to protect a multibillion-dollar asset like the

  14. Sequential Hybrid Procedure for Persistent Atrial Fibrillation

    PubMed Central

    Bulava, Alan; Mokracek, Ales; Hanis, Jiri; Kurfirst, Vojtech; Eisenberger, Martin; Pesl, Ladislav

    2015-01-01

    Background Catheter ablation of persistent atrial fibrillation yields an unsatisfactorily high number of failures. The hybrid approach has recently emerged as a technique that overcomes the limitations of both surgical and catheter procedures alone. Methods and Results We investigated the sequential (staged) hybrid method, which consists of a surgical thoracoscopic radiofrequency ablation procedure followed by radiofrequency catheter ablation 6 to 8 weeks later using the CARTO 3 mapping system. Fifty consecutive patients (mean age 62±7 years, 32 males) with long‐standing persistent atrial fibrillation (41±34 months) and a dilated left atrium (>45 mm) were included and prospectively followed in an unblinded registry. During the electrophysiological part of the study, all 4 pulmonary veins were found to be isolated in 36 (72%) patients and a complete box‐lesion was confirmed in 14 (28%) patients. All gaps were successfully re‐ablated. Twelve months after the completed hybrid ablation, 47 patients (94%) were in normal sinus rhythm (4 patients with paroxysmal atrial fibrillation required propafenone and 1 patient underwent a redo catheter procedure). The majority of arrhythmias recurred during the first 3 months. Beyond 12 months, there were no arrhythmia recurrences detected. The surgical part of the procedure was complicated by 7 (13.7%) major complications, while no serious adverse events were recorded during the radiofrequency catheter part of the procedure. Conclusions The staged hybrid epicardial–endocardial treatment of long‐standing persistent atrial fibrillation seems to be extremely effective in maintenance of normal sinus rhythm compared to radiofrequency catheter or surgical ablation alone. Epicardial ablation alone cannot guarantee durable transmural lesions. Clinical Trial Registration URL: www.ablace.cz Unique identifier: cz‐060520121617 PMID:25809548

  15. [Risk of thromboembolism in atrial fibrillation].

    PubMed

    Csanádi, Zoltán

    2016-09-01

    Atrial fibrillation is considered as one of the cardiovascular pandemics of our days due to its increasing prevalence and the significant burden on healthcare systems. Management, especially prevention of thromboembolism associated with the arrhythmia is still a challenge even with recently available treatment options. Herein, the author reviews the possibilities of risk stratification and stroke prevention, which are important to all medical professionals who potentially encounter patients with this arrhythmia. Orv. Hetil., 2016, 157(38), 1511-1515. PMID:27640617

  16. Native American Tribal Websites.

    ERIC Educational Resources Information Center

    Miller, Eric L.

    1999-01-01

    Lists Web sites maintained by 38 different Native American nations that deal with topics ranging from tribal history, news, arts and crafts, tourism, entertainment, and commerce. Represented nations include Apache, Blackfeet, Creek, Iroquois, Mohegan, and Sioux. (CMK)

  17. Native American Identity

    ERIC Educational Resources Information Center

    Horse, Perry G.

    2005-01-01

    Many issues and elements--including ethnic nomenclature, racial attitudes, and the legal and political status of American Indian nations and Indian people--influence Native American identity. (Contains 3 notes.)

  18. Native American Health

    MedlinePlus

    ... specific health concerns. Differences in the health of groups can result from: Genetics Environmental factors Access to care Cultural factors On this page, you'll find links to health issues that affect Native Americans.

  19. Atrial fibrillation pearls and perils of management.

    PubMed Central

    Kudenchuk, P J

    1996-01-01

    Atrial fibrillation, a common arrhythmia, is responsible for considerable cardiovascular morbidity. Its management demands more than antiarrhythmic therapy alone, but must address the causes and consequences of the arrhythmia. Although remediable causes are infrequently found, a thorough search for associated heart disease or its risk factors results in better-informed patient management. Controlling the ventricular response and protecting from thromboembolic complications are important initial goals of therapy and may include the administration of aspirin in younger, low-risk patients. Older patients and those with risk factors for systemic embolism are not adequately protected from stroke complications by aspirin therapy alone. It remains controversial whether all high-risk patients should receive warfarin and at what intensity. Whether and how sinus rhythm should be restored and maintained poses the greatest therapeutic controversy for atrial fibrillation. The mortal risk of antiarrhythmic therapy is substantially greater in patients with evidence of heart failure. In such persons, the risks and benefits of maintaining normal sinus rhythm with antiarrhythmic medications should be weighted carefully. A definitive cure for atrial fibrillation remains elusive, but promising surgical and catheter ablation therapies are being developed. PMID:8686300

  20. [Dilated cardiomyopathy induced by ectopic atrial tachycardia].

    PubMed

    Velázquez Rodríguez, E; Martínez Enríquez, A

    2000-01-01

    The deleterious effect of chronic or incessant supraventricular tachycardia on ventricular function is well-known and it has been demonstrated than can ultimately lead to dilated cardiomyopathy if unrecognized. Any variety of supraventricular tachycardia with chronic evolution may lead to left ventricular dysfunction, ectopic atrial tachycardia because of its persistent nature, often incessant and poorly responsive to antiarrhythmic drugs is a frequent cause of reversible congestive heart failure in patients without other demonstrable organic heart disease. Five patients (aged 14 to 52 years) were referred with symptoms of heart failure, NYHA functional class II (one patient), class III (one patient) and class IV (3 patients) associated with an incessant ectopic atrial tachycardia. Four patients underwent radiofrequency catheter ablation of the ectopic focus and one patient was treated with amiodarone. All patients were successfully treated and the echocardiographic assessment of left ventricular function indicated regression of the cardiomyopathy picture with recovery of systolic function, (mean left ventricular ejection fraction 39.2 +/- 6.1% before vs mean 62.4 +/- 4.8% after (p < 0.01). The clinical and echocardiographic picture of cardiomyopathy induced by incessant ectopic atrial tachycardia is reversible after successful treatment. This stresses the necessity of recognizing such arrhythmia as cause of primary heart failure. PMID:10959459

  1. Vernakalant. Too dangerous in atrial fibrillation.

    PubMed

    2012-05-01

    The usual aim of treatment for patients with symptomatic paroxysmal or recent-onset atrial fibrillation, including after cardiac surgery, is to slow the heart rate. Electrical and drug (amiodarone) cardioversion are other options. Vernakalant, an antiarrhythmic drug, has been authorised in the European Union for rapid reduction of recent-onset atrial fibrillation. It is only available in an injectable form. Vernakalant has not been compared in clinical trials with treatments slowing the heart rate, or with electrical cardioversion. The only available comparison with another antiarrhythmic agent is a clinical pharmacology study versus amiodarone, a slow-acting drug, based on the rate of cardioversion at 90 minutes in 240 patients. As expected, given the brief observation period, the rate was significantly higher with vernakalant (51.7% versus 5.2%). During clinical evaluation, 6 deaths occurred in the vernakalant groups versus none in the other groups (placebo or amiodarone). The main adverse effects of vernakalant are cardiac arrhythmias (ventricular arrhythmia, torsades de pointes, bradycardia) and severe hypotension. Altered taste, sneezing, paraesthesia, nausea and pruritus were frequent, and respiratory and neuropsychological effects were also reported. A trial in atrial flutter was interrupted when cases of cardiogenic shock occurred. Interactions are to be expected with drugs that prolong the QT interval, and also with drugs that lower the heart rate or the blood potassium concentration. In practice, it is better to continue to use amiodarone for drug cardioversion and to avoid using vernakalant. PMID:22827000

  2. Lone atrial fibrillation: Pathologic or not?

    PubMed

    Chambers, Patrick William

    2007-01-01

    Atrial fibrillation risk has been strongly associated with increasing age and visceral obesity. These characteristics are strongly associated with diabetes, decreased heart rate variability, and chronic inflammation. Lone atrial fibrillation (LAF) on the other hand exhibits a predilection for the physically fit and the middle aged, especially males. Given these opposing features it is postulated that pathologic AF is due to cardiac fibrosis and other age related changes while LAF is due to physiologic neurohormonal changes related to autonomic tone, insulin sensitivity, and electrolyte imbalance and that pathologic AF and LAF can be reliably differentiated via an anthropometric approach using weight, height, hip, and waist measurements. An anthropometric study is undertaken from an LAF database to test this hypothesis. Such individuals in addition to being younger and predominantly male appear to be taller with less central adiposity vs. those with pathologic AF. The ramifications of these findings with respect to insulin resistance, sympathetic tone, inflammation and hypertension, often associated with pathologic atrial fibrillation, are discussed. Speculation is drawn about possible etiologic link with mitral valve prolapse, which is commonly encountered in the tall and thin and which shares multiple clinical features with LAF. PMID:17005327

  3. Focal Atrial Tachycardia Surrounding the Anterior Septum

    PubMed Central

    Wang, Zulu; Ouyang, Jinge; Liang, Yanchun; Jin, Zhiqing; Yang, Guitang; Liang, Ming; Li, Shibei; Yu, Haibo

    2015-01-01

    Background— Focal atrial tachycardias (ATs) surrounding the anterior atrial septum (AAS) have been successfully ablated from the right atrial septum (RAS), the aortic cusps, and the aortic mitral junction. However, the strategy for mapping and ablation of AAS-ATs has not been well defined. Methods and Results— Of 227 consecutive patients with AT, 47 (20.7%; mean age, 56.3±11.6 years) with AAS-ATs were studied; among them, initial ablation was successful at RAS in only 5 of 14 patients and at noncoronary cusp (NCC) in 28 of 33 patients. In 45 of the 47 patients, the 46 of 48 AAS-ATs were eliminated at RAS in 8 patients, NCC in 35 patients (earliest activation time at NCC was later than that at RAS by 5–10 ms in 6 patients), and aortic mitral junction in 3 patients (all with negative P wave in lead aVL and positive P wave in the inferior leads), including 1 patient whose 2 ATs were eliminated separately from the NCC and the aortic mitral junction. Conclusions— Most of the ATs surrounding the AAS can be eliminated from within the NCC, which is usually the preferential ablation site. Ablation at the RAS and aortic mitral junction should be considered when supported by P-wave morphologies on surface ECG and results of activation mapping and ablation. PMID:25908691

  4. Atrial fibrillation: effects beyond the atrium?

    PubMed

    Wijesurendra, Rohan S; Casadei, Barbara

    2015-03-01

    Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is associated with significant morbidity, mostly secondary to heart failure and stroke, and an estimated two-fold increase in premature death. Efforts to increase our understanding of AF and its complications have focused on unravelling the mechanisms of electrical and structural remodelling of the atrial myocardium. Yet, it is increasingly recognized that AF is more than an atrial disease, being associated with systemic inflammation, endothelial dysfunction, and adverse effects on the structure and function of the left ventricular myocardium that may be prognostically important. Here, we review the molecular and in vivo evidence that underpins current knowledge regarding the effects of human or experimental AF on the ventricular myocardium. Potential mechanisms are explored including diffuse ventricular fibrosis, focal myocardial scarring, and impaired myocardial perfusion and perfusion reserve. The complex relationship between AF, systemic inflammation, as well as endothelial/microvascular dysfunction and the effects of AF on ventricular calcium handling and oxidative stress are also addressed. Finally, consideration is given to the clinical implications of these observations and concepts, with particular reference to rate vs. rhythm control.

  5. Atrial Fibrillation: The Science behind Its Defiance

    PubMed Central

    Czick, Maureen E.; Shapter, Christine L.; Silverman, David I.

    2016-01-01

    Atrial fibrillation (AF) is the most prevalent arrhythmia in the world, due both to its tenacious treatment resistance, and to the tremendous number of risk factors that set the stage for the atria to fibrillate. Cardiopulmonary, behavioral, and psychological risk factors generate electrical and structural alterations of the atria that promote reentry and wavebreak. These culminate in fibrillation once atrial ectopic beats set the arrhythmia process in motion. There is growing evidence that chronic stress can physically alter the emotion centers of the limbic system, changing their input to the hypothalamic-limbic-autonomic network that regulates autonomic outflow. This leads to imbalance of the parasympathetic and sympathetic nervous systems, most often in favor of sympathetic overactivation. Autonomic imbalance acts as a driving force behind the atrial ectopy and reentry that promote AF. Careful study of AF pathophysiology can illuminate the means that enable AF to elude both pharmacological control and surgical cure, by revealing ways in which antiarrhythmic drugs and surgical and ablation procedures may paradoxically promote fibrillation. Understanding AF pathophysiology can also help clarify the mechanisms by which emerging modalities aiming to correct autonomic imbalance, such as renal sympathetic denervation, may offer potential to better control this arrhythmia. Finally, growing evidence supports lifestyle modification approaches as adjuncts to improve AF control. PMID:27699086

  6. Atrial Fibrillation: The Science behind Its Defiance

    PubMed Central

    Czick, Maureen E.; Shapter, Christine L.; Silverman, David I.

    2016-01-01

    Atrial fibrillation (AF) is the most prevalent arrhythmia in the world, due both to its tenacious treatment resistance, and to the tremendous number of risk factors that set the stage for the atria to fibrillate. Cardiopulmonary, behavioral, and psychological risk factors generate electrical and structural alterations of the atria that promote reentry and wavebreak. These culminate in fibrillation once atrial ectopic beats set the arrhythmia process in motion. There is growing evidence that chronic stress can physically alter the emotion centers of the limbic system, changing their input to the hypothalamic-limbic-autonomic network that regulates autonomic outflow. This leads to imbalance of the parasympathetic and sympathetic nervous systems, most often in favor of sympathetic overactivation. Autonomic imbalance acts as a driving force behind the atrial ectopy and reentry that promote AF. Careful study of AF pathophysiology can illuminate the means that enable AF to elude both pharmacological control and surgical cure, by revealing ways in which antiarrhythmic drugs and surgical and ablation procedures may paradoxically promote fibrillation. Understanding AF pathophysiology can also help clarify the mechanisms by which emerging modalities aiming to correct autonomic imbalance, such as renal sympathetic denervation, may offer potential to better control this arrhythmia. Finally, growing evidence supports lifestyle modification approaches as adjuncts to improve AF control.

  7. Efficacy of anticoagulation in resolving left atrial and left atrial appendage thrombi: A transesophageal echocardiographic study

    NASA Technical Reports Server (NTRS)

    Jaber, W. A.; Prior, D. L.; Thamilarasan, M.; Grimm, R. A.; Thomas, J. D.; Klein, A. L.; Asher, C. R.

    2000-01-01

    BACKGROUND: Transesophageal echocardiography (TEE) is the gold standard for evaluation of the left atrium and the left atrial appendage (LAA) for the presence of thrombi. Anticoagulation is conventionally used for patients with atrial fibrillation to prevent embolization of atrial thrombi. The mechanism of benefit and effectiveness of thrombi resolution with anticoagulation is not well defined. METHODS AND RESULTS: We used a TEE database of 9058 consecutive studies performed between January 1996 and November 1998 to identify all patients with thrombi reported in the left atrium and/or LAA. One hundred seventy-four patients with thrombi in the left atrial cavity (LAC) and LAA were identified (1.9% of transesophageal studies performed). The incidence of LAA thrombi was 6.6 times higher than LAC thrombi (151 vs 23, respectively). Almost all LAC thrombi were visualized on transthoracic echocardiography (90.5%). Mitral valve pathology was associated with LAC location of thrombi (P <.0001), whereas atrial fibrillation or flutter was present in most patients with LAA location of thrombi. Anticoagulation of 47 +/- 18 days was associated with thrombus resolution in 80.1% of the patients on follow-up TEE. Further anticoagulation resulted in limited additional benefit. CONCLUSIONS: LAC thrombi are rare and are usually associated with mitral valve pathology. Transthoracic echocardiography is effective in identifying these thrombi. LAA thrombi occur predominantly in patients with atrial fibrillation or flutter. Short-term anticoagulation achieves a high rate of resolution of LAA and LAC thrombi but does not obviate the need for follow-up TEE.

  8. Underexpression of CACNA1C Caused by Overexpression of microRNA-29a Underlies the Pathogenesis of Atrial Fibrillation

    PubMed Central

    Zhao, Yujie; Yuan, Yiqiang; Qiu, Chunguang

    2016-01-01

    Background The objective of this study was to investigate the molecular mechanism of atrial fibrillation (AF), as well as the negative regulatory relationship between miR-29a-3p and CACNA1C. Material/Methods We searched the online miRNA database (www.mirdb.org) and identified the miR-29a-3p binding sequence within the 3′-UTR of the target gene, and then conducted luciferase assay to verify it. The cells were transfected with miR-29a-3p and ICa,L was determined in those cells. Results We validated CACNA1C to be the direct target gene of miR-29a-3p. We also established the negative regulatory relationship between miR-29a-3p and CACNA1C via studying the relative luciferase activity. We also conducted real-time PCR and Western blot analysis to study the mRNA and protein expression level of CACNA1C among different groups of cells treated with scramble control, 30nM miR-29a-3p mimics, and 60nM miR-29a-3p mimics, indicating a negative regulatory relationship between miR-29a-3p and CACNA1C. We next analyzed whether miR-29a-3p transfection in cardiomyocytes produced the effects on the ICa,L induced by electrical remodeling, and found a tonic inhibition of IBa by endogenous miR-29a-3p in atrial myocytes. Conclusions We validated the negative regulation between miR-29a-3p and CACNA1C, and found that miR-29a-3p might a potential therapeutic target in the treatment of AF. PMID:27341015

  9. Atrial natriuretic peptide inhibits cell cycle activity of embryonic cardiac progenitor cells via its NPRA receptor signaling axis.

    PubMed

    Hotchkiss, Adam; Feridooni, Tiam; Baguma-Nibasheka, Mark; McNeil, Kathleen; Chinni, Sarita; Pasumarthi, Kishore B S

    2015-04-01

    The biological effects of atrial natriuretic peptide (ANP) are mediated by natriuretic peptide receptors (NPRs), which can either activate guanylyl cyclase (NPRA and NPRB) or inhibit adenylyl cyclase (NPRC) to modulate intracellular cGMP or cAMP, respectively. During cardiac development, ANP serves as an early maker of differentiating atrial and ventricular chamber myocardium. As development proceeds, expression of ANP persists in the atria but declines in the ventricles. Currently, it is not known whether ANP is secreted or the ANP-NPR signaling system plays any active role in the developing ventricles. Thus the primary aims of this study were to 1) examine biological activity of ANP signaling systems in embryonic ventricular myocardium, and 2) determine whether ANP signaling modulates proliferation/differentiation of undifferentiated cardiac progenitor cells (CPCs) and/or cardiomyocytes. Here, we provide evidence that ANP synthesized in embryonic day (E)11.5 ventricular myocytes is actively secreted and processed to its biologically active form. Notably, NPRA and NPRC were detected in E11.5 ventricles and exogenous ANP stimulated production of cGMP in ventricular cell cultures. Furthermore, we showed that exogenous ANP significantly decreased cell number and DNA synthesis of CPCs but not cardiomyocytes and this effect could be reversed by pretreatment with the NPRA receptor-specific inhibitor A71915. ANP treatment also led to a robust increase in nuclear p27 levels in CPCs compared with cardiomyocytes. Collectively, these data provide evidence that in the developing mammalian ventricles ANP plays a local paracrine role in regulating the balance between CPC proliferation and differentiation via NPRA/cGMP-mediated signaling pathways.

  10. Rotigaptide (ZP123) improves atrial conduction slowing in chronic volume overload-induced dilated atria.

    PubMed

    Haugan, Ketil; Miyamoto, Takuya; Takeishi, Yasuchika; Kubota, Isao; Nakayama, Jun; Shimojo, Hisashi; Hirose, Masamichi

    2006-07-01

    Chronic atrial dilation is associated with atrial conduction velocity slowing and an increased risk of developing atrial tachyarrhythmias. Rotigaptide (ZP123) is a selective gap junction modifier that increases cardiac gap junctional intercellular communication. We hypothesised that rotigaptide treatment would increase atrial conduction velocity and reduce the inducibility to atrial tachyarrhythmias in a model of chronic volume overload induced chronic atrial dilatation characterized by atrial conduction velocity slowing. Chronic volume overload was created in Japanese white rabbits by arterio-venous shunt formation. Atrial conduction velocity and atrial tachyarrhythmias inducibility were examined in Langendorff-perfused chronic volume overload hearts (n=12) using high-resolution optical mapping before and after treatment with rotigaptide. Moreover, expression levels of atrial gap junction proteins (connexin40 and connexin43) were examined in chronic volume overload hearts (n=6) and compared to sham-operated controls (n=6). Rotigaptide treatment significantly increased atrial conduction velocity in chronic volume overload hearts, however, rotigaptide did not decrease susceptibility to the induction of atrial tachyarrhythmias. Protein expressions of Cx40 and Cx43 were decreased by 32% and 72% (P<0.01), respectively, in chromic volume overload atria compared to control. To conclude, rotigaptide increased atrial conduction velocity in a rabbit model of chromic volume overload induced atrial conduction velocity slowing. The demonstrated effect of rotigaptide on atrial conduction velocity did not prevent atrial tachyarrhythmias inducibility. Whether rotigaptide may possess antiarrhythmic efficacy in other models of atrial fibrillation remains to be determined.

  11. Atrial natriuretic peptide: water and electrolyte homeostasis.

    PubMed

    Kenyon, C J; Jardine, A G

    1989-08-01

    In the few years since its identification, a clear role for ANP in the regulation of water and electrolyte balance has emerged (Figure 3). The peptide is released in response to blood volume expansion, both acutely and gradually during changes in dietary sodium intake. Similarly, plasma levels are elevated in pathophysiological conditions such as cardiac and renal failure. It has become apparent that ANP has natriuretic, diuretic and vasorelaxant properties. Many of the original studies employed what we now know to be pharmacological doses of the peptide. However, recent reports have confirmed that small, sustained elevations in plasma ANP within or marginally above the 'normal' physiological range produce similar effects. A number of recent studies have tried to specifically address the physiological relevance of ANP. Although undoubtedly release by atrial distension and effective when infused to similar concentrations, atrial distension also has other effects via neural pathways. Thus, the demonstration that excretion of saline is impaired by atrial appendectomy (Benjamin et al, 1988) does not imply that this is only due to the absence of an atrial hormone. Goetz et al (1986) demonstrated that in the denervated heart, although ANP is still released, the excretion of a saline load is impaired. Similarly, in man, Richards et al (1988a) needed to infuse ANP to much higher plasma levels than those achieved by a saline load in order to reproduce the natriuresis. Although these experiments can be criticized, they confirm that ANP is not the sole mechanism for excreting a volume load, or for the natriuresis following atrial distension, but that these effects are likely to reflect the balance between ANP, AVP, the renin-angiotensin and autonomic nervous systems. In rats immunized against ANP (Greenwald et al, 1988), although the ability to excrete an acute saline load was impaired, long-term sodium balance was normal, suggesting that the rats were able to compensate for

  12. Preservation of high-energy phosphates in human myocardium. A phosphorus 31-nuclear magnetic resonance study of the effect of temperature on atrial appendages

    SciTech Connect

    Deslauriers, R.; Keon, W.J.; Lareau, S.; Moir, D.; Saunders, J.K.; Smith, I.C.; Whitehead, K.; Mainwood, G.W.

    1989-09-01

    After prolonged exposure to low temperatures (1 and 4{degrees}C), human atrial trabeculae show poor recovery of contraction. At somewhat higher temperatures (12 and 20{degrees}C), recovery is much better. Although better preservation of adenosine triphosphate and therefore improved contractile recovery might be expected after exposure to lower temperatures, it remained possible that, below a certain temperature, adenosine triphosphate-generating mechanisms could be slowed more than adenosine triphosphate utilization. To investigate this phenomenon further, we followed the time course of metabolic changes in human atrial appendages, harvested during cardiac bypass operations, at 1, 4, 12, and 20{degrees}C using high-resolution 31P and 1H nuclear magnetic resonance spectroscopy. The results are quantitated by correlation with data obtained from biochemical assays on quick-frozen tissues. Initial adenosine triphosphate levels in myocytes of human atrial appendages are 3.3 to 4.3 mumol.gm-1 tissue wet weight. At 20{degrees}C, adenosine triphosphate disappears after 6 hours; at 12{degrees}C, about half the initial adenosine triphosphate is still observable at this time; at 4{degrees}C or 1{degree}C, the decline is still slower. Only a small contribution toward adenosine triphosphate maintenance comes from creatine phosphate, since creatine phosphate, inorganic phosphate, and total creatine levels in the appendage are low (less than 2 mumol.gm-1 tissue wet weight). Glycolysis is active at all temperatures; the rate of glycolysis correlates positively with increasing temperature. Adenosine triphosphate generated by glycolysis falls just short of demand at all temperatures, but the difference is small at 1 and 4{degrees}C.

  13. Interferon-γ Causes Cardiac Myocyte Atrophy via Selective Degradation of Myosin Heavy Chain in a Model of Chronic Myocarditis

    PubMed Central

    Cosper, Pippa F.; Harvey, Pamela A.; Leinwand, Leslie A.

    2013-01-01

    Interferon-γ (IFN-γ), a proinflammatory cytokine, has been implicated in the pathogenesis of a number of forms of heart disease including myocarditis and congestive heart failure. In fact, overexpression of IFN-γ in mice causes dilated cardiomyopathy. However, the direct effects of IFN-γ on cardiac myocytes and the mechanism by which it causes cardiac dysfunction have not been described. Here, we present the molecular pathology of IFN-γ exposure and its effect on myofibrillar proteins in isolated neonatal rat ventricular myocytes. Treatment with IFN-γ caused cardiac myocyte atrophy attributable to a specific decrease in myosin heavy chain protein. This selective degradation of myosin heavy chain was not accompanied by a decrease in total protein synthesis or by an increase in total protein degradation. IFN-γ increased both proteasome and immunoproteasome activity in cardiac myocytes and their inhibition blocked myosin heavy chain loss and myocyte atrophy, whereas inhibition of the lysosome or autophagosome did not. Collectively, these results provide a mechanism by which IFN-γ causes cardiac pathology in the setting of chronic inflammatory diseases. PMID:23058369

  14. Characterization of L-type calcium channel activity in atrioventricular nodal myocytes from rats with streptozotocin-induced Diabetes mellitus.

    PubMed

    Yuill, Kathryn H; Al Kury, Lina T; Howarth, Frank Christopher

    2015-11-01

    Cardiovascular complications are common in patients with Diabetes mellitus (DM). In addition to changes in cardiac muscle inotropy, electrical abnormalities are also commonly observed in these patients. We have previously shown that spontaneous cellular electrical activity is altered in atrioventricular nodal (AVN) myocytes, isolated from the streptozotocin (STZ) rat model of type-1 DM. In this study, utilizing the same model, we have characterized the changes in L-type calcium channel activity in single AVN myocytes. Ionic currents were recorded from AVN myocytes isolated from the hearts of control rats and from those with STZ-induced diabetes. Patch-clamp recordings were used to assess the changes in cellular electrical activity in individual myocytes. Type-1 DM significantly altered the cellular characteristics of L-type calcium current. A reduction in peak ICaL density was observed, with no corresponding changes in the activation parameters of the current. L-type calcium channel current also exhibited faster time-dependent inactivation in AVN myocytes from diabetic rats. A negative shift in the voltage dependence of inactivation was also evident, and a slowing of restitution parameters. These findings demonstrate that experimentally induced type-1 DM significantly alters AVN L-type calcium channel cellular electrophysiology. These changes in ion channel activity may contribute to the abnormalities in cardiac electrical function that are associated with high mortality levels in patients with DM. PMID:26603460

  15. Prolonged and fractionated right atrial electrograms during sinus rhythm in patients with paroxysmal atrial fibrillation and sick sinus node syndrome.

    PubMed

    Tanigawa, M; Fukatani, M; Konoe, A; Isomoto, S; Kadena, M; Hashiba, K

    1991-02-01

    Intraatrial catheter mapping of the right atrium was performed during sinus rhythm in 92 patients: Group I = 43 control patients without paroxysmal atrial fibrillation or sick sinus node syndrome; Group II = 31 patients with paroxysmal atrial fibrillation but without sick sinus node syndrome; and Group III = 18 patients with both paroxysmal atrial fibrillation and sick sinus node syndrome. Atrial electrograms were recorded at 12 sites in the right atrium. The duration and number of fragmented deflections of the atrial electrograms were quantitatively measured. The mean duration and number of fragmented deflections of the 516 atrial electrograms in Group I were 74 +/- 11 ms and 3.9 +/- 1.3, respectively. The criteria for an abnormal atrial electrogram were defined as a duration of greater than or equal to 100 ms or eight or more fragmented deflections, or both. Abnormal atrial electrograms were observed in 10 patients (23.3%) in Group I, 21 patients (67.7%) in Group II and 15 patients (83.3%) in Group III (Group II versus Group I, p less than 0.001; Group III versus Group I, p less than 0.001). The mean number of abnormal electrograms per patient with an abnormal electrogram was 1.3 +/- 0.7 in Group I, 2.5 +/- 1.9 in Group II and 3.5 +/- 2.5 in Group III (Group I versus Group II, p less than 0.01; Group II versus Group III, p less than 0.05). A prolonged and fractionated atrial electrogram characteristic of paroxysmal atrial fibrillation can be closely related to the vulnerability of the atrial muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Native Knowledge in the Americas.

    ERIC Educational Resources Information Center

    Kidwell, Clara Sue

    1985-01-01

    Native American science is defined as activities of native peoples of the New World in observing physical phenomena and attempting to explain and control them. Problems in studying native science, ethnoscience and native science, archaeostronomy and ethnoastronomy, ethnobotany, agriculture, technology, and future directions are discussed. (JN)

  17. Effect of whiskey on atrial vulnerability and "holiday heart".

    PubMed

    Engel, T R; Luck, J C

    1983-03-01

    Vulnerability to atrial fibrillation and flutter was examined in 11 alcohol abusers who did not have cardiomyopathy or manifest heart failure. Atrial extrastimulation was done with rapid pacing (drive cycle length 500 ms) to facilitate induction of atrial vulnerability, seen in four alcohol abusers. The remaining seven were retested 30 minutes after drinking 60 to 120 ml of 86 proof whiskey (ethanol blood levels were 49 to 101 mg/100 ml but pulmonary capillary wedge pressure remained normal in all) and atrial fibrillation or flutter was induced in three of the drinkers. Three nondrinkers, symptomatic with sinus bradycardia but not in heart failure, were found not to be vulnerable to atrial fibrillation or flutter, but flutter was induced in two of the three after drinking whiskey. Whiskey did not alter atrial functional refractory periods (mean +/- standard error of the mean 297 +/- 14 to 290 +/- 12 ms) or widen the dispersion among three disparate right atrial sites (57 +/- 13 to 47 +/- 12 ms). Thus, whiskey enhanced vulnerability to atrial fibrillation and flutter in patients without heart failure or cardiomyopathy, substantiating the "holiday heart" syndrome.

  18. Hypertension and Atrial Fibrillation: Any Change with the New Anticoagulants.

    PubMed

    Ghiadoni, Lorenzo; Taddei, Stefano; Virdis, Agostino

    2014-01-01

    Hypertension and atrial fibrillation are the most common cardiovascular risk factors and clinically significant arrhythmia, respectively. These conditions frequently coexist and their prevalence increases rapidly with aging. Despite several different risk factors and clinical conditions predisposing to hypertension for its high prevalence in the population is still the main risk factor for the development of atrial fibrillation. Several pathophysiologic mechanisms (such as structural changes at the level of left ventricle and or atrium, neurohormonal activation, arterial stiffness, etc.) can contribute to the onset of atrial fibrillation. Some antihypertensive treatments have been shown to contribute to reduce the risk of new-onset atrial fibrillation. Atrial fibrillation is a major risk factor for stroke, which is further increased in the presence of hypertension. For this reason, hypertension is included as a major risk factor in the available models for the risk stratification and the prevention of thromboembolism in patients with atrial fibrillation. In this article we will review the relationship between atrial fibrillation and hypertension, looking at the possible specific indications of the antithrombotic treatment with new classes of anticoagulants in the prevention of thromboembolic events in hypertensive patients with atrial fibrillation.

  19. Calcified right atrial thrombus in HIV infected patient

    PubMed Central

    Mwita, Julius Chacha; Goepamang, Monkgogi; Mkubwa, Jack Joseph; Gunness, Teeluck Kumar; Reebye, Deshmukh; Motumise, Kelebogile

    2013-01-01

    Calcified right atrial thrombi are rare cardiac masses that may be complicated by pulmonary embolism. Although they can be discovered by a transthoracic echocardiography, they may need histological examination to differentiate them from other cardiac masses. We report a case of a 44-year-old woman who presented with a calcified right atrial thrombus and progressive dyspnoea. PMID:23819008

  20. Atrial Arrhythmias and Their Implications for Space Flight - Introduction

    NASA Technical Reports Server (NTRS)

    Polk, J. D.; Barr, Y. R.; Bauer, P.; Hamilton, D. R.; Kerstman, E.; Tarver, B.

    2010-01-01

    This panel will discuss the implications of atrial arrhythmias in astronauts from a variety of perspectives; including historical data, current practices, and future challenges for exploration class missions. The panelists will present case histories, outline the evolution of current NASA medical standards for atrial arrhythmias, discuss the use of predictive tools, and consider potential challenges for current and future missions.

  1. Novel Interventional Strategies for the Treatment of Atrial Fibrillation

    PubMed Central

    Siontis, Konstantinos C; Oral, Hakan

    2016-01-01

    The landscape of the invasive management of atrial fibrillation, the most common sustained arrhythmia in humans, has changed dramatically in the last decade owing to numerous advances in arrhythmia mapping and ablation technologies. The current review critically appraises novel interventional strategies for the treatment of atrial fibrillation with a focus on clinical effectiveness and safety. PMID:27403294

  2. Intramembrane charge movement in guinea-pig and rat ventricular myocytes.

    PubMed Central

    Hadley, R W; Lederer, W J

    1989-01-01

    1. Non-linear capacitative current (charge movement) was studied in isolated guinea-pig and rat ventricular myocytes. Linear capacitance was subtracted using standard procedures. Most of the experiments were done with guinea-pig myocytes, while rat myocytes were used for comparison. 2. When a myocyte was held at -100 mV, depolarizing clamp steps produced a rapid outward current transient, which was followed by an inward current transient upon repolarization. This current was identified as the movement of charged particles in the cell membrane, rather than ionic movement across the membrane, for the following reasons: (1) the current saturated at membrane potentials positive to +20 mV; (2) the current was capacitative in nature, having no reversal potential; (3) in general, the charge moved during depolarization (Qon) approximated the charge moved during repolarization (Qoff). 3. Qoff was significantly less than Qon for a depolarization from -100 mV to 0 mV. However, the Qoff/Qon ratio approached unity if the cell was instead repolarized to -140 mV. This was interpreted as being due to the immobilization of a fraction of the charge during the depolarization, which recovered rapidly enough to be measured at -140 mV, but recovered too slowly at -100 mV. 4. Charge movement in these cells had a sigmoidal dependence on the membrane potential, which could be empirically described by the two-state Boltzmann equation Q = Qmax/(1 + exp[-(V-V*)/kappa]), where Q is the charge movement at potential V, Qmax is the maximum charge, V* is the membrane potential at Q = Qmax/2, and kappa is a slope factor. Qmax was 11.7 nC/microF, V* was -18 mV and kappa was 16 mV in guinea-pig myocytes held at -100 mV, while the values in rat myocytes were 10.9 nC/microF, -32 mV and 13 mV. 5. The charge movement could be partially immobilized by a prior depolarization. This effect developed over a broad voltage range, from -120 to +20 mV. The fraction of charge that could be immobilized by a 10 s

  3. Left Atrial Remodeling Assessed by Transthoracic Echocardiography Predicts Left Atrial Appendage Flow Velocity in Patients With Paroxysmal Atrial Fibrillation.

    PubMed

    Watanabe, Atai; Suzuki, Shinya; Kano, Hiroto; Matsuno, Syunsuke; Takai, Hideaki; Kato, Yuko; Otsuka, Takayuki; Uejima, Tokuhisa; Oikawa, Yuji; Nagashima, Kazuyuki; Kirigaya, Hajime; Kunihara, Takashi; Sagara, Koichi; Yamashita, Naohide; Sawada, Hitoshi; Aizawa, Tadanori; Yajima, Junji; Yamashita, Takeshi

    2016-01-01

    Atrial fibrillation (AF) is associated with an increased risk of stroke and other thromboembolic events. Left atrial (LA) thrombus formation is closely related to LA dysfunction, particularly to decreased LA appendage flow velocity (LAA-FV) in patients with AF. We estimated LAA-FV using parameters noninvasively obtained by transthoracic echocardiography (TTE) in patients with paroxysmal AF.Echocardiographic and clinical parameters were assessed in 190 patients with nonvalvular paroxysmal AF showing sinus heart rhythm during transesophageal echocardiography (TEE) and TTE.LAA-FV (60 ± 22 cm/s) significantly correlated with the time interval between the initiation of the P-wave on ECG and that of the A-wave of transmitral flow on TTE (PA-TMF, correlation coefficient, -0.32; P < 0.001), LA dimension (LAD, -0.31; P < 0.001), septal a' velocity of tissue Doppler imaging (TDI, 0.35; P < 0.001), E/e' ratio (-0.28, P < 0.001), E velocity of transmitral flow (-0.20, P = 0.008), E/A ratio of transmitral flow (-0.18, P = 0.02), CHA2DS2-VASc score (-0.15, P = 0.04), and BNP plasma level (-0.32, P = 0.002). Multivariate analysis revealed that PA-TMF (standardized partial regression coefficient, -0.17; P = 0.03), a' velocity (0.24, P = 0.004), and LAD (-0.20, P = 0.01) were independent predictors of LAA-FV (multiple correlation coefficient R, 0.44; P < 0.001).Parameters of atrial remodeling, ie, decreased a' velocity, increased LAD, and PA-TMF during sinus rhythm may be useful predictors of LA blood stasis in patients with nonvalvular PAF. LAA-FV can be estimated using these TTE parameters instead of TEE.

  4. Atrial Arrhythmias in Astronauts. Summary of a NASA Summit

    NASA Technical Reports Server (NTRS)

    Barr, Yael; Watkins, Sharmila; Polk, J. D.

    2011-01-01

    This slide presentation reviews the findings of a panel of heart experts brought together to study if atrial arrhythmias more prevalent in astronauts, and potential risk factors that may predispose astronauts to atrial arrhythmias. The objective of the panel was to solicit expert opinion on screening, diagnosis, and treatment options, identify gaps in knowledge, and propose relevant research initiatives. While Atrial Arrhythmias occur in approximately the same percents in astronauts as in the general population, they seem to occur at younger ages in astronauts. Several reasons for this predisposition were given: gender, hypertension, endurance training, and triggering events. Potential Space Flight-Related Risk factors that may play a role in precipitating lone atrial fibrillation were reviewed. There appears to be no evidence that any variable of the space flight environment increases the likelihood of developing atrial arrhythmias during space flight.

  5. Global burden of atrial fibrillation in developed and developing nations.

    PubMed

    Chugh, Sumeet S; Roth, Gregory A; Gillum, Richard F; Mensah, George A

    2014-03-01

    Atrial fibrillation is the most common heart rhythm disorder in the world, with major public health impact especially due to increased risk of stroke and hospitalizations. The recently published results on epidemiology of atrial fibrillation from the Global Burden of Diseases, Injuries, and Risk Factors Study confirm the existence of a significant and progressive worldwide increase in the burden of atrial fibrillation. However, there appears to be regional variation in both the burden of atrial fibrillation and availability of epidemiological data regarding this condition. In this review, the authors identify issues that are unique to the developed versus developing regions and outline a road map for possible approaches to surveillance, management, and prevention of atrial fibrillation at the global level.

  6. Imaging Techniques in Percutaneous Cardiac Structural Interventions: Atrial Septal Defect Closure and Left Atrial Appendage Occlusion.

    PubMed

    Rodríguez Fernández, Antonio; Bethencourt González, Armando

    2016-08-01

    Because of advances in cardiac structural interventional procedures, imaging techniques are playing an increasingly important role. Imaging studies show sufficient anatomic detail of the heart structure to achieve an excellent outcome in interventional procedures. Up to 98% of atrial septal defects at the ostium secundum can be closed successfully with a percutaneous procedure. Candidates for this type of procedure can be identified through a systematic assessment of atrial septum anatomy, locating and measuring the size and shape of all defects, their rims, and the degree and direction of shunting. Three dimensional echocardiography has significantly improved anatomic assessments and the end result itself. In the future, when combined with other imaging techniques such as cardiac computed tomography and fluoroscopy, 3-dimensional echocardiography will be particularly useful for procedure guidance. Percutaneous closure of the left atrial appendage offers an alternative for treating patients with atrial fibrillation and contraindication for oral anticoagulants. In the future, the clinical focus may well turn to stroke prevention in selected patients. Percutaneous closure is effective and safe; device implantation is successful in 94% to 99% of procedures. However, the procedure requires an experienced cardiac structural interventional team. At present, 3-dimensional echocardiography is the most appropriate imaging technique to assess anatomy suitability, select device type and size, guide the procedure alongside fluoroscopy, and to follow-up the patient afterwards.

  7. Imaging Techniques in Percutaneous Cardiac Structural Interventions: Atrial Septal Defect Closure and Left Atrial Appendage Occlusion.

    PubMed

    Rodríguez Fernández, Antonio; Bethencourt González, Armando

    2016-08-01

    Because of advances in cardiac structural interventional procedures, imaging techniques are playing an increasingly important role. Imaging studies show sufficient anatomic detail of the heart structure to achieve an excellent outcome in interventional procedures. Up to 98% of atrial septal defects at the ostium secundum can be closed successfully with a percutaneous procedure. Candidates for this type of procedure can be identified through a systematic assessment of atrial septum anatomy, locating and measuring the size and shape of all defects, their rims, and the degree and direction of shunting. Three dimensional echocardiography has significantly improved anatomic assessments and the end result itself. In the future, when combined with other imaging techniques such as cardiac computed tomography and fluoroscopy, 3-dimensional echocardiography will be particularly useful for procedure guidance. Percutaneous closure of the left atrial appendage offers an alternative for treating patients with atrial fibrillation and contraindication for oral anticoagulants. In the future, the clinical focus may well turn to stroke prevention in selected patients. Percutaneous closure is effective and safe; device implantation is successful in 94% to 99% of procedures. However, the procedure requires an experienced cardiac structural interventional team. At present, 3-dimensional echocardiography is the most appropriate imaging technique to assess anatomy suitability, select device type and size, guide the procedure alongside fluoroscopy, and to follow-up the patient afterwards. PMID:27354151

  8. Dronedarone for the treatment of atrial fibrillation and atrial flutter: approval and efficacy

    PubMed Central

    Wolbrette, Deborah; Gonzalez, Mario; Samii, Soraya; Banchs, Javier; Penny-Peterson, Erica; Naccarelli, Gerald

    2010-01-01

    Dronedarone, a new Class III antiarrhythmic agent, has now been approved by the US Food and Drug Administration for use in patients with atrial fibrillation or atrial flutter. Approval came in March 2009 due to the positive results of the ATHENA trial showing significant reductions in all-cause mortality and cardiovascular hospitalization with dronedarone use. A post hoc analysis of the ATHENA data also suggested a decrease in stroke risk with this agent. However, due to safety concerns in the heart failure population in the earlier ANDROMEDA trial, dronedarone is not recommended for patients with an ejection fraction <35% and recent decompensated heart failure. Dronedarone is an amiodarone analog with multichannel blocking electrophysiologic properties similar to those of amiodarone, but several structural differences. Dronedarone’s lack of the iodine moiety reduces its potential for thyroid and pulmonary toxicity. Preliminary data from the DIONYSOS trial, and an indirect meta-analysis comparing amiodarone with dronedarone, showed amiodarone to be more effective in maintaining sinus rhythm, while dronedarone was associated with fewer adverse effects resulting in early termination of the drug. Dronedarone is the first antiarrhythmic drug for the treatment of atrial fibrillation and atrial flutter shown to reduce cardiovascular hospitalizations. In patients with structural heart disease who have an ejection fraction >35% and no recent decompensated heart failure, dronedarone should be considered earlier than amiodarone in the treatment algorithm. PMID:20730068

  9. Modeling beta-adrenergic control of cardiac myocyte contractility in silico

    NASA Technical Reports Server (NTRS)

    Saucerman, Jeffrey J.; Brunton, Laurence L.; Michailova, Anushka P.; McCulloch, Andrew D.; McCullough, A. D. (Principal Investigator)

    2003-01-01

    The beta-adrenergic signaling pathway regulates cardiac myocyte contractility through a combination of feedforward and feedback mechanisms. We used systems analysis to investigate how the components and topology of this signaling network permit neurohormonal control of excitation-contraction coupling in the rat ventricular myocyte. A kinetic model integrating beta-adrenergic signaling with excitation-contraction coupling was formulated, and each subsystem was validated with independent biochemical and physiological measurements. Model analysis was used to investigate quantitatively the effects of specific molecular perturbations. 3-Fold overexpression of adenylyl cyclase in the model allowed an 85% higher rate of cyclic AMP synthesis than an equivalent overexpression of beta 1-adrenergic receptor, and manipulating the affinity of Gs alpha for adenylyl cyclase was a more potent regulator of cyclic AMP production. The model predicted that less than 40% of adenylyl cyclase molecules may be stimulated under maximal receptor activation, and an experimental protocol is suggested for validating this prediction. The model also predicted that the endogenous heat-stable protein kinase inhibitor may enhance basal cyclic AMP buffering by 68% and increasing the apparent Hill coefficient of protein kinase A activation from 1.0 to 2.0. Finally, phosphorylation of the L-type calcium channel and phospholamban were found sufficient to predict the dominant changes in myocyte contractility, including a 2.6x increase in systolic calcium (inotropy) and a 28% decrease in calcium half-relaxation time (lusitropy). By performing systems analysis, the consequences of molecular perturbations in the beta-adrenergic signaling network may be understood within the context of integrative cellular physiology.

  10. Ca2+ paradox injury mediated through TRPC channels in mouse ventricular myocytes.

    PubMed

    Kojima, Akiko; Kitagawa, Hirotoshi; Omatsu-Kanbe, Mariko; Matsuura, Hiroshi; Nosaka, Shuichi

    2010-12-01

    BACKGROUND AND PURPOSE The Ca(2+) paradox is an important phenomenon associated with Ca(2+) overload-mediated cellular injury in myocardium. The present study was undertaken to elucidate molecular and cellular mechanisms for the development of the Ca(2+) paradox. EXPERIMENTAL APPROACH Fluorescence imaging was performed on fluo-3 loaded quiescent mouse ventricular myocytes using confocal laser scanning microscope. KEY RESULTS The Ca(2+) paradox was readily evoked by restoration of the extracellular Ca(2+) following 10-20 min of nominally Ca(2+)-free superfusion. The Ca(2+) paradox was significantly reduced by blockers of transient receptor potential canonical (TRPC) channels (2-aminoethoxydiphenyl borate, Gd(3+), La(3+)) and anti-TRPC1 antibody. The sarcoplasmic reticulum (SR) Ca(2+) content, assessed by caffeine application, gradually declined during Ca(2+)-free superfusion, which was further accelerated by metabolic inhibition. Block of SR Ca(2+) leak by tetracaine prevented Ca(2+) paradox. The Na(+) /Ca(2+) exchange (NCX) blocker KB-R7943 significantly inhibited Ca(2+) paradox when applied throughout superfusion period, but had little effect when added for a period of 3 min before and during Ca(2+) restoration. The SR Ca(2+) content was better preserved during Ca(2+) depletion by KB-R7943. Immunocytochemistry confirmed the expression of TRPC1, in addition to TRPC3 and TRPC4, in mouse ventricular myocytes. CONCLUSIONS AND IMPLICATIONS These results provide evidence that (i) the Ca(2+) paradox is primarily mediated by Ca(2+) entry through TRPC (probably TRPC1) channels that are presumably activated by SR Ca(2+) depletion; and (ii) reverse mode NCX contributes little to the Ca(2+) paradox, whereas inhibition of NCX during Ca(2+) depletion improves SR Ca(2+) loading, and is associated with reduced incidence of Ca(2+) paradox in mouse ventricular myocytes.

  11. LabHEART: an interactive computer model of rabbit ventricular myocyte ion channels and Ca transport

    NASA Technical Reports Server (NTRS)

    Puglisi, J. L.; Bers, D. M.

    2001-01-01

    An interactive computer program, LabHEART, was developed to simulate the action potential (AP), ionic currents, and Ca handling mechanisms in a rabbit ventricular myocyte. User-oriented, its design allows switching between voltage and current clamp and easy on-line manipulation of key parameters to change the original formulation. The model reproduces normal rabbit ventricular myocyte currents, Ca transients, and APs. We also changed parameters to simulate data from heart failure (HF) myocytes, including reduced transient outward (I(to)) and inward rectifying K currents (I(K1)), enhanced Na/Ca exchange expression, and reduced sarcoplasmic reticulum Ca-ATPase function, but unaltered Ca current density. These changes caused reduced Ca transient amplitude and increased AP duration (especially at lower frequency) as observed experimentally. The model shows that the increased Na/Ca exchange current (I(NaCa)) in HF lowers the intracellular [Ca] threshold for a triggered AP from 800 to 540 nM. Similarly, the decrease in I(K1) reduces the threshold to 600 nM. Changes in I(to) have no effect. Combining enhanced Na/Ca exchange with reduced I(K1) (as in HF) lowers the threshold to trigger an AP to 380 nM. These changes reproduce experimental results in HF, where the contributions of different factors are not readily distinguishable. We conclude that the triggered APs that contribute to nonreentrant ventricular tachycardia in HF are due approximately equally (and nearly additively) to alterations in I(NaCa) and I(K1). A free copy of this software can be obtained at http://www.meddean.luc.edu/lumen/DeptWebs/physio/bers.html.

  12. Some growth factors stimulate cultured adult rabbit ventricular myocyte hypertrophy in the absence of mechanical loading

    NASA Technical Reports Server (NTRS)

    Decker, R. S.; Cook, M. G.; Behnke-Barclay, M.; Decker, M. L.

    1995-01-01

    Cultured adult rabbit cardiac myocytes treated with recombinant growth factors display enhanced rates of protein accumulation (ie, growth) in response to insulin and insulin-like growth factors (IGFs), but epidermal growth factor, acidic or basic fibroblast growth factor, and platelet-derived growth factor failed to increase contractile protein synthesis or growth of the heart cells. Insulin and IGF-1 increased growth rates by stimulating anabolic while simultaneously inhibiting catabolic pathways, whereas IGF-2 elevated growth modestly by apparently inhibiting lysosomal proteolysis. Neutralizing antibodies directed against either IGF-1 or IGF-2 or IGF binding protein 3 blocked protein accumulation. A monoclonal antibody directed against the IGF-1 receptor also inhibited changes in protein turnover provoked by recombinant human IGF-1 but not IGF-2. Of the other growth factors tested, only transforming growth factor-beta 1 increased the fractional rate of myosin heavy chain (MHC) synthesis, with beta-MHC synthesis being elevated and alpha-MHC synthesis being suppressed. However, the other growth factors were able to modestly stimulate the rate of DNA synthesis in this preparation. Bromodeoxyuridine labeling revealed that these growth factors increased DNA synthesis in myocytes and nonmyocytes alike, but the heart cells displayed neither karyokinesis or cytokinesis. In contrast, cocultures of cardiac myocytes and nonmyocytes and nonmyocyte-conditioned culture medium failed to enhance the rate of cardiac MHC synthesis or its accumulation, implying that quiescent heart cells do not respond to "conditioning" by cardiac nonmyocytes. These findings demonstrated that insulin and the IGFs promote passively loaded cultured adult rabbit heart cells to hypertrophy but suggest that other growth factors tested may be limited in this regard.

  13. Inorganic polyphosphate in cardiac myocytes: from bioenergetics to the permeability transition pore and cell survival.

    PubMed

    Dedkova, Elena N

    2016-02-01

    Inorganic polyphosphate (polyP) is a linear polymer of Pi residues linked together by high-energy phosphoanhydride bonds as in ATP. PolyP is present in all living organisms ranging from bacteria to human and possibly even predating life of this planet. The length of polyP chain can vary from just a few phosphates to several thousand phosphate units long, depending on the organism and the tissue in which it is synthesized. PolyP was extensively studied in prokaryotes and unicellular eukaryotes by Kulaev's group in the Russian Academy of Sciences and by the Nobel Prize Laureate Arthur Kornberg at Stanford University. Recently, we reported that mitochondria of cardiac ventricular myocytes contain significant amounts (280±60 pmol/mg of protein) of polyP with an average length of 25 Pi and that polyP is involved in Ca(2+)-dependent activation of the mitochondrial permeability transition pore (mPTP). Enzymatic polyP depletion prevented Ca(2+)-induced mPTP opening during ischaemia; however, it did not affect reactive oxygen species (ROS)-mediated mPTP opening during reperfusion and even enhanced cell death in cardiac myocytes. We found that ROS generation was actually enhanced in polyP-depleted cells demonstrating that polyP protects cardiac myocytes against enhanced ROS formation. Furthermore, polyP concentration was dynamically changed during activation of the mitochondrial respiratory chain and stress conditions such as ischaemia/reperfusion (I/R) and heart failure (HF) indicating that polyP is required for the normal heart metabolism. This review discusses the current literature on the roles of polyP in cardiovascular health and disease. PMID:26862184

  14. An integrative model of the cardiac ventricular myocyte incorporating local control of Ca2+ release.

    PubMed Central

    Greenstein, Joseph L; Winslow, Raimond L

    2002-01-01

    The local control theory of excitation-contraction (EC) coupling in cardiac muscle asserts that L-type Ca(2+) current tightly controls Ca(2+) release from the sarcoplasmic reticulum (SR) via local interaction of closely apposed L-type Ca(2+) channels (LCCs) and ryanodine receptors (RyRs). These local interactions give rise to smoothly graded Ca(2+)-induced Ca(2+) release (CICR), which exhibits high gain. In this study we present a biophysically detailed model of the normal canine ventricular myocyte that conforms to local control theory. The model formulation incorporates details of microscopic EC coupling properties in the form of Ca(2+) release units (CaRUs) in which individual sarcolemmal LCCs interact in a stochastic manner with nearby RyRs in localized regions where junctional SR membrane and transverse-tubular membrane are in close proximity. The CaRUs are embedded within and interact with the global systems of the myocyte describing ionic and membrane pump/exchanger currents, SR Ca(2+) uptake, and time-varying cytosolic ion concentrations to form a model of the cardiac action potential (AP). The model can reproduce both the detailed properties of EC coupling, such as variable gain and graded SR Ca(2+) release, and whole-cell phenomena, such as modulation of AP duration by SR Ca(2+) release. Simulations indicate that the local control paradigm predicts stable APs when the L-type Ca(2+) current is adjusted in accord with the balance between voltage- and Ca(2+)-dependent inactivation processes as measured experimentally, a scenario where common pool models become unstable. The local control myocyte model provides a means for studying the interrelationship between microscopic and macroscopic behaviors in a manner that would not be possible in experiments. PMID:12496068

  15. Dynamics of Muscle Microcirculatory and Blood-myocyte O2 Flux During Contractions

    PubMed Central

    Poole, David C.; Copp, Steven W.; Hirai, Daniel M.; Musch, Timothy I.

    2011-01-01

    The O2 requirements of contracting skeletal muscle may increase 100-fold above rest. In 1919 August Krogh’s brilliant insights recognized the capillary as the principal site for this increased blood-myocyte O2 flux. Based on the premise that most capillaries did not sustain RBC flux at rest Krogh proposed that capillary recruitment (i.e., initiation of red blood cell (RBC) flux in previously non-flowing capillaries) increased the capillary surface area available for O2 flux and reduced mean capillary-to-mitochondrial diffusion distances. More modern experimental approaches reveal that most muscle capillaries may support RBC flux at rest. Thus, rather than contraction-induced capillary recruitment per se, increased RBC flux and hematocrit within already-flowing capillaries likely elevate perfusive and diffusive O2 conductances and hence blood-myocyte O2 flux. Additional surface area for O2 exchange is recruited but, crucially, this may occur along the length of already-flowing capillaries (i.e. longitudinal recruitment). Today, the capillary is still considered the principal site for O2 and substrate delivery to contracting skeletal muscle. Indeed, the presence of very low intramyocyte O2 partial pressures (PO2’s) and the absence of PO2 gradients, whilst refuting the relevance of diffusion distances, place an even greater importance on capillary hemodynamics. This emergent picture calls for a paradigm-shift in our understanding of the function of capillaries by de-emphasizing de novo ‘capillary recruitment.’ Diseases such as heart failure impair blood-myocyte O2 flux, in part, by decreasing the proportion of RBC-flowing capillaries. Knowledge of capillary function in healthy muscle is requisite for identification of pathology and efficient design of therapeutic treatments. PMID:21199399

  16. Silent Atrial Fibrillation: Definition, Clarification, and Unanswered Issues.

    PubMed

    Kennedy, Harold L

    2015-11-01

    Silent or subclinical asymptomatic atrial fibrillation has currently gained wide interest in the epidemiologic, neurologic and cardiovascular communities. The association of brief episodes of paroxysmal atrial fibrillation or surrogate atrial arrhythmias which predict future clinical adverse events have been established. Nevertheless there exists a confounding array of definitions to indicate its presence without discrete indication of which populations should be examined. Moreover the term "atrial fibrillation burden" (AFB) has emerged from such studies with a plethora of descriptions to prognosticate both arrhythmic and clinical adverse events. This presentation suggests clarification of diagnostic definitions associated with silent atrial fibrillation, and a more precise description of AFB. It examines the populations across the current disease and cardiovascular invasive therapeutic spectrum that lead to both silent atrial fibrillation and AFB. It describes the diagnostic methods of arrhythmia detection utilizing the surface ECG, subcutaneous ECG or intra-cardiac devices and their relationship in seeking meaningful arrhythmic markers of silent atrial fibrillation. Whereas a wide range of clinical risk factors of silent atrial fibrillation have been validated in the literature, there is an ongoing search for those arrhythmic risk factors that precisely identify and prognosticate outcome events in diverse populations at risk of atrial fibrillation and its complications. This presentation identifies this chaos, and focuses attention on the issues to be addressed to facilitate descriptive and comparative scientific studies in the future. It is a call to action specifically to the medical arrhythmic community and its specialty societies (i.e., ISHNE, HRS, EHRA) to begin a quest to unravel the arrhythmic quagmire associated with "silent atrial fibrillation."

  17. Native American medicine.

    PubMed

    Cohen, K

    1998-11-01

    This article summarizes common principles, practices, and ethics of Native American healing, the traditional medicine of North America. Native American healing, spirituality, culture, and, in modern times, political, social, and economic concerns are closely intertwined. Intuition and spiritual awareness are a healer's most essential diagnostic tools. Therapeutic methods include prayer, music, ritual purification, herbalism, massage, ceremony, and personal innovations of individual healers. A community of friends, family, and helpers often participate in the healing intervention and help to alleviate the alienation caused by disease. A healthy patient has a healthy relationship with his or her community and, ultimately, with the greater community of nature known as "All Relations." The goal of Native American healing is to find wholeness, balance, harmony, beauty, and meaning. "Healing," making whole, is as important as curing disease; at times they are identical.

  18. Disrupted calcium release as a mechanism for atrial alternans associated with human atrial fibrillation.

    PubMed

    Chang, Kelly C; Bayer, Jason D; Trayanova, Natalia A

    2014-12-01

    Atrial fibrillation (AF) is the most common cardiac arrhythmia, but our knowledge of the arrhythmogenic substrate is incomplete. Alternans, the beat-to-beat alternation in the shape of cardiac electrical signals, typically occurs at fast heart rates and leads to arrhythmia. However, atrial alternans have been observed at slower pacing rates in AF patients than in controls, suggesting that increased vulnerability to arrhythmia in AF patients may be due to the proarrythmic influence of alternans at these slower rates. As such, alternans may present a useful therapeutic target for the treatment and prevention of AF, but the mechanism underlying alternans occurrence in AF patients at heart rates near rest is unknown. The goal of this study was to determine how cellular changes that occur in human AF affect the appearance of alternans at heart rates near rest. To achieve this, we developed a computational model of human atrial tissue incorporating electrophysiological remodeling associated with chronic AF (cAF) and performed parameter sensitivity analysis of ionic model parameters to determine which cellular changes led to alternans. Of the 20 parameters tested, only decreasing the ryanodine receptor (RyR) inactivation rate constant (kiCa) produced action potential duration (APD) alternans seen clinically at slower pacing rates. Using single-cell clamps of voltage, fluxes, and state variables, we determined that alternans onset was Ca2+-driven rather than voltage-driven and occurred as a result of decreased RyR inactivation which led to increased steepness of the sarcoplasmic reticulum (SR) Ca2+ release slope. Iterated map analysis revealed that because SR Ca2+ uptake efficiency was much higher in control atrial cells than in cAF cells, drastic reductions in kiCa were required to produce alternans at comparable pacing rates in control atrial cells. These findings suggest that RyR kinetics may play a critical role in altered Ca2+ homeostasis which drives proarrhythmic

  19. Genetic Loci Associated With Atrial Fibrillation: Relation to Left Atrial Structure in the Framingham Heart Study

    PubMed Central

    Magnani, Jared W.; Yin, Xiaoyan; McManus, David D.; Chuang, Michael L.; Cheng, Susan; Lubitz, Steven A.; Arora, Garima; Manning, Warren J.; Ellinor, Patrick T.; Benjamin, Emelia J.

    2014-01-01

    Background Atrial fibrillation (AF) results in significant morbidity and mortality. Genome‐wide association studies (GWAS) have identified genetic variants associated with AF. Whether genetic variants associated with AF are also associated with atrial structure, an intermediate phenotype for AF, has had limited investigation. We sought to investigate associations between single nucleotide polymorphisms (SNPs) and atrial structure obtained by cardiovascular imaging in the Framingham Heart Study. Methods and Results We selected 11 SNPs that have been associated with AF in GWAS. We examined the SNPs' relations to cross‐sectional left atrial (LA) dimensions (determined by transthoracic echocardiography) and LA volume (determined by cardiovascular magnetic resonance [CMR]) employing linear regression. The total sample included 1555 participants with CMR LA volume (age 60±9 years, 53% women) and 6861 participants with echocardiographic LA diameter (age 48±13 years, 52% women) measured. We employed a significance threshold of P<0.0023 to account for multiple testing of the 11 SNPs and 2 LA measures. In a primary analysis, no SNPs were significantly related to the LA measures. Likewise, in secondary analyses excluding individuals with prevalent AF (n=77, CMR sample; n=105, echocardiography sample) no SNPs were related to LA volume or diameter. Conclusion In a community‐based cohort, we did not identify a statistically significant association between selected SNPs associated with AF and measures of LA anatomy. Further investigations with larger longitudinally assessed samples and a broader array of SNPs may be necessary to determine the relation between genetic loci associated with AF and atrial structure. PMID:24695651

  20. Predictors of atrial fibrillation termination and clinical success of catheter ablation of persistent atrial fibrillation.

    PubMed

    Heist, E Kevin; Chalhoub, Fadi; Barrett, Conor; Danik, Stephan; Ruskin, Jeremy N; Mansour, Moussa

    2012-08-15

    The termination of persistent atrial fibrillation (AF) during catheter ablation has been associated in some, but not all, studies with reduced arrhythmia during clinical follow-up. We sought to determine the rate of persistent AF termination achievable with a stepwise ablation strategy, the predictors of AF termination, and the clinical outcomes associated with termination and nontermination. A total of 143 consecutive patients (age 62 ± 9 years, AF duration 5.7 ± 5.2 years) with persistent and longstanding persistent AF resistant to antiarrhythmic medication who presented in AF for catheter ablation were studied. Ablation was done with a stepwise approach, including pulmonary vein isolation, followed by complex fractionated atrial electrogram ablation and ablation of resultant atrial tachycardias. Clinical follow-up was then performed after a 2-month blanking period to assess arrhythmia recurrence, defined as AF or atrial tachycardia lasting ≥ 30 seconds. AF termination by ablation was achieved in 95 (66%) of the 143 patients. Multivariate predictors of AF termination included longer baseline AF cycle length (p <0.001) and smaller left atrial size (p = 0.002). AF termination by ablation was associated with both a lower incidence of arrhythmia recurrence after a single procedure without antiarrhythmic drugs (p = 0.01) and overall clinical success (single or multiple procedures, with or without antiarrhythmic drugs; p = 0.005). On multivariate analysis, the predictors of overall clinical success included AF termination by ablation (p = 0.001), a shorter ablation duration (p = 0.002), younger age (p = 0.02), male gender (p = 0.03), and the presence of hypertension (p = 0.03). In conclusion, among patients with persistent AF, termination of AF by ablation can be achieved in most patients and is associated with reduced recurrence of arrhythmia. PMID:22591670

  1. Prevalence of left atrial abnormalities in atrial fibrillation versus normal sinus patients

    PubMed Central

    Ketai, Loren H; Teague, Shawn D; Rissing, Stacy M

    2016-01-01

    Background Atrial fibrillation (AF) may be the cause or sequela of left atrial abnormalities and variants. Purpose To determine the prevalence of left atrial (LA) abnormalities in AF patients compared to normal sinus rhythm (NSR) patients. Material and Methods We retrospectively reviewed 281 cardiac CT examinations from 2010 to 2012, excluding patients with prior pulmonary vein ablation, known coronary artery disease, prior coronary stent placement, or coronary artery bypass grafts. The first group consisted of 159 AF patients undergoing cardiac CT prior to pulmonary vein ablation and the second group consisted of 122 NSR patients evaluated with coronary CT angiography. Demographic data were collected. LA abnormalities were analyzed. Left atrial diameter was measured on an axial view. Results A total of 281 patients were included. The male gender has significantly higher prevalence of AF than female gender, P value <0.001. Patients with AF were significantly older (mean age, 57.4 years; standard deviation [SD], 11.8 years) than NSR patients (mean age, 53.4 years; SD, 13.6 years), P value, 0.01. The left atrial diameter was greater in the AF patients (mean diameter, 4.3 cm; SD, 0.82 cm) versus the NSR patients (3.4 cm; SD, 0.58 cm), P value, <0.0001. LA diverticulum was the most prevalent variant, occurring in 28.4% of the entire patient population followed by LA pouch, occurring in 24%. There was no significant between group differences in the prevalence of these or the remainder of the LA variants. Conclusion AF patients differed significantly from NSR patients in LA size, gender, and mean age. There was no statistical significance between the two groups with regard to the LA morphologic abnormalities other than size. PMID:27358747

  2. Cardiac Myocyte Alternans in Intact Heart: Influence of Cell-Cell Coupling and β-Adrenergic Stimulation

    PubMed Central

    Hammer, Karin P.; Ljubojevic, Senka; Ripplinger, Crystal M.; Pieske, Burkert M.; Bers, Donald M.

    2015-01-01

    Background Cardiac alternans are proarrhythmic and mechanistically link cardiac mechanical dysfunction and sudden cardiac death. Beat-to-beat alternans occur when beats with large Ca2+ transients and long action potential duration (APD) alternate with the converse. APD alternans are typically driven by Ca2+ alternans and sarcoplasmic reticulum (SR) Ca2+ release alternans. But the effect of intercellular communication via gap junctions (GJ) on alternans in intact heart remains unknown. Objective We assessed the effects of cell-to-cell coupling on local alternans in intact Langen-dorff-perfused mouse hearts, measuring single myocyte [Ca2+] alternans synchronization among neighboring cells, and effects of β-adrenergic receptor (β-AR) activation and reduced GJ coupling. Methods and Results Mouse hearts (C57BL/6) were retrogradely perfused and loaded with Fluo-8 AM to record cardiac myocyte [Ca2+] in situ with confocal microscopy. Single cell resolution allowed analysis of alternans within the intact organ during alternans induction. Carbenoxolone (25 μM), a GJ inhibitor, significantly increased the occurrence and amplitude of alternans in single cells within the intact heart. Alternans were concordant between neighboring cells throughout the field of view, except transiently during onset. β-AR stimulation only reduced Ca2+ alternans in tissue that had reduced GJ coupling, matching effects seen in isolated myocytes. Conclusions Ca2+ alternans among neighboring myocytes is predominantly concordant, likely because of electrical coupling between cells. Consistent with this, partial GJ uncoupling increased propensity and amplitude of Ca2+ alternans, and made them more sensitive to reversal by β-AR activation, as in isolated myocytes. Electrical coupling between myocytes may thus limit the alternans initiation, but also allow alternans to be more stable once established. PMID:25828762

  3. Distinct effects of Abelson kinase mutations on myocytes and neurons in dissociated Drosophila embryonic cultures: mimicking of high temperature.

    PubMed

    Liu, Lijuan; Wu, Chun-Fang

    2014-01-01

    Abelson tyrosine kinase (Abl) is known to regulate axon guidance, muscle development, and cell-cell interaction in vivo. The Drosophila primary culture system offers advantages in exploring the cellular mechanisms mediated by Abl with utilizing various experimental manipulations. Here we demonstrate that single-embryo cultures exhibit stage-dependent characteristics of cellular differentiation and developmental progression in neurons and myocytes, as well as nerve-muscle contacts. In particular, muscle development critically depends on the stage of dissociated embryos. In wild-type (WT) cultures derived from embryos before stage 12, muscle cells remained within cell clusters and were rarely detected. Interestingly, abundant myocytes were spotted in Abl mutant cultures, exhibiting enhanced myocyte movement and fusion, as well as neuron-muscle contacts even in cultures dissociated from younger, stage 10 embryos. Notably, Abl myocytes frequently displayed well-expanded lamellipodia. Conversely, Abl neurons were characterized with fewer large veil-like lamellipodia, but instead had increased numbers of filopodia and darker nodes along neurites. These distinct phenotypes were equally evident in both homo- and hetero-zygous cultures (Abl/Abl vs. Abl/+) of different alleles (Abl(1) and Abl(4) ) indicating dominant mutational effects. Strikingly, in WT cultures derived from stage 10 embryos, high temperature (HT) incubation promoted muscle migration and fusion, partially mimicking the advanced muscle development typical of Abl cultures. However, HT enhanced neuronal growth with increased numbers of enlarged lamellipodia, distinct from the characteristic Abl neuronal morphology. Intriguingly, HT incubation also promoted Abl lamellipodia expansion, with a much greater effect on nerve cells than muscle. Our results suggest that Abl is an essential regulator for myocyte and neuron development and that high-temperature incubation partially mimics the faster muscle development

  4. Long-term hypothermic preservation of cardiac myocytes isolated from the neonatal rat ventricle: a comparison of various crystalloid solutions.

    PubMed

    Orita, H; Fukasawa, M; Uchino, H; Uchida, T; Shiono, S; Washio, M

    1995-01-01

    In this study, the functional and biochemical effects of crystalloid solutions on immature cardiac myocytes incubated under hypothermic conditions were evaluated. Cardiac myocytes were isolated from neonatal rat ventricles and cultured for 4 days, following which 12.5 x 10(5) myocytes per flask were incubated at 4 degrees C for 3, 6, 12, and 18 h in five types of crystalloid solutions: lactated Ringer's (LR), St. Thomas' Hospital (ST), University of Wisconsin (UW), 5% glucose-based potassium (GK), and normal saline (NS). The levels of creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) in the solutions were measured after each hypothermic incubation, following which the myocytes were cultured for an additional 24 h at 37 degrees C to evaluate the recovery of the myocyte beating rate. In the LR, UW, and NS groups, the recovery ratios of the myocyte beating rate were over 95% of the control (the beating rate prior to hypothermic incubation) at 3 h, but decreased to 20.3, 15.1, and 0%, respectively, at 18 h. The ST and GK groups had significantly lower recovery ratios than the other three groups (72.9% and 63.4%, respectively) at 3 h. The release of CPK and LDH in the LR, UW, and NS groups was significantly suppressed compared to the ST and GK groups, with the greatest suppression observed in the LR group. Moreover, the ST and GK groups had the highest CPK and LDH levels, respectively. Thus, LR solution had the least cytotoxic effects, indicating that it could be the most suitable basic solution of the various cardioplegic or preservation solutions during the neonatal period. PMID:7640455

  5. Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability.

    PubMed

    Campbell, Matthew D; Witcher, Marc; Gopal, Anoop; Michele, Daniel E

    2016-05-01

    Delta-sarcoglycan is a component of the sarcoglycan subcomplex within the dystrophin-glycoprotein complex located at the plasma membrane of muscle cells. While recessive mutations in δ-sarcoglycan cause limb girdle muscular dystrophy 2F, dominant mutations in δ-sarcoglycan have been linked to inherited dilated cardiomyopathy (DCM). The purpose of this study was to investigate functional cellular defects present in adult cardiac myocytes expressing mutant δ-sarcoglycans harboring the dominant inherited DCM mutations R71T or R97Q. This study demonstrates that DCM mutant δ-sarcoglycans can be stably expressed in adult rat cardiac myocytes and traffic similarly to wild-type δ-sarcoglycan to the plasma membrane, without perturbing assembly of the dystrophin-glycoprotein complex. However, expression of DCM mutant δ-sarcoglycan in adult rat cardiac myocytes is sufficient to alter cardiac myocyte plasma membrane stability in the presence of mechanical strain. Upon cyclical cell stretching, cardiac myocytes expressing mutant δ-sarcoglycan R97Q or R71T have increased cell-impermeant dye uptake and undergo contractures at greater frequencies than myocytes expressing normal δ-sarcoglycan. Additionally, the R71T mutation creates an ectopic N-linked glycosylation site that results in aberrant glycosylation of the extracellular domain of δ-sarcoglycan. Therefore, appropriate glycosylation of δ-sarcoglycan may also be necessary for proper δ-sarcoglycan function and overall dystrophin-glycoprotein complex function. These studies demonstrate that DCM mutations in δ-sarcoglycan can exert a dominant negative effect on dystrophin-glycoprotein complex function leading to myocardial mechanical instability that may underlie the pathogenesis of δ-sarcoglycan-associated DCM.

  6. Heart failure after transvenous closure of atrial septal defect associated with atrial standstill and thiamine-responsive megaloblastic anemia.

    PubMed

    Doğan, Vehbi; Senocak, Filiz; Orün, Utku Arman; Ceylan, Ozben

    2013-10-01

    Despite advances in device closure for atrial septal defect, post-closure heart failure remains a clinical problem in adult patients but is seen only rarely in children. An eight-year-old boy, who had been followed by a local pediatrician with the diagnosis of diabetes mellitus and congenital heart disease, was consulted to us for cardiac re-evaluation. Electrocardiography demonstrated absent P waves, and echocardiography revealed enlargement of the right ventricle and both atria and secundum atrial septal defect. With the diagnosis of atrial standstill, secundum atrial septal defect and thiamine-responsive megaloblastic anemia, acute heart failure developed after transvenous closure of the atrial septal defect, which improved dramatically with thiamine and supportive treatment. PMID:24164997

  7. Electrogram Morphology Recurrence Patterns during Atrial Fibrillation

    PubMed Central

    Ng, Jason; Gordon, David; Passman, Rod S.; Knight, Bradley P.; Arora, Rishi; Goldberger, Jeffrey J.

    2014-01-01

    Background Traditional mapping of atrial fibrillation (AF) is limited by changing electrogram morphologies and variable cycle lengths. Objective We tested the hypothesis that morphology recurrence plot analysis would identify sites of stable and repeatable electrogram morphology patterns. Methods AF electrograms recorded from left atrial (LA) and right atrial (RA) sites in 19 patients (10 male, 59±10 years old) prior to AF ablation were analyzed. Morphology recurrence plots for each electrogram recording were created by cross-correlation of each automatically detected activation with every other activation in the recording. A recurrence percentage, the percentage of the most common morphology, and the mean cycle length of activations with the most common morphology (CLR) were computed. Results The morphology recurrence plots commonly showed checkerboard patterns of alternating high and low cross correlation values indicating periodic recurrences in morphologies. The mean recurrence percentage for all sites and all patients was 38±25%. The highest recurrence percentage per patient averaged 83±17%. The highest recurrence percentage was located in the RA in 5 patients and in the LA in 14 patients. Patients with sites of shortest CLR in the LA and RA had ablation failure rates of 25% and 100%, respectively (HR=4.95; p=0.05). Conclusions A new technique to characterize electrogram morphology recurrence demonstrated that there is a distribution of sites with high and low repeatability of electrogram morphologies. Sites with rapid activation of highly repetitive morphology patterns may be critical to sustaining AF. Further testing of this approach to map and ablate AF sources is warranted. PMID:25101485

  8. Atrial fibrillation: mechanisms, therapeutics, and future directions.

    PubMed

    Pellman, Jason; Sheikh, Farah

    2015-04-01

    Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, affecting 1% to 2% of the general population. It is characterized by rapid and disorganized atrial activation leading to impaired atrial function, which can be diagnosed on an EKG by lack of a P-wave and irregular QRS complexes. AF is associated with increased morbidity and mortality and is a risk factor for embolic stroke and worsening heart failure. Current research on AF support and explore the hypothesis that initiation and maintenance of AF require pathophysiological remodeling of the atria, either specifically as in lone AF or secondary to other heart disease as in heart failure-associated AF. Remodeling in AF can be grouped into three categories that include: (i) electrical remodeling, which includes modulation of L-type Ca(2+) current, various K(+) currents and gap junction function; (ii) structural remodeling, which includes changes in tissues properties, size, and ultrastructure; and (iii) autonomic remodeling, including altered sympathovagal activity and hyperinnervation. Electrical, structural, and autonomic remodeling all contribute to creating an AF-prone substrate which is able to produce AF-associated electrical phenomena including a rapidly firing focus, complex multiple reentrant circuit or rotors. Although various remodeling events occur in AF, current AF therapies focus on ventricular rate and rhythm control strategies using pharmacotherapy and surgical interventions. Recent progress in the field has started to focus on the underlying substrate that drives and maintains AF (termed upstream therapies); however, much work is needed in this area. Here, we review current knowledge of AF mechanisms, therapies, and new areas of investigation. PMID:25880508

  9. Atrial overexpression of angiotensin-converting enzyme 2 improves the canine rapid atrial pacing-induced structural and electrical remodeling. Fan, ACE2 improves atrial substrate remodeling.

    PubMed

    Fan, Jinqi; Zou, Lili; Cui, Kun; Woo, Kamsang; Du, Huaan; Chen, Shaojie; Ling, Zhiyu; Zhang, Quanjun; Zhang, Bo; Lan, Xianbin; Su, Li; Zrenner, Bernhard; Yin, Yuehui

    2015-01-01

    The purpose of this study was to investigate whether atrial overexpression of angiotensin-converting enzyme 2 (ACE2) by homogeneous transmural atrial gene transfer can reverse atrial remodeling and its mechanisms in a canine atrial-pacing model. Twenty-eight mongrel dogs were randomly divided into four groups: Sham-operated, AF-control, gene therapy with adenovirus-enhanced green fluorescent protein (Ad-EGFP) and gene therapy with Ad-ACE2 (Ad-ACE2) (n = 7 per subgroup). AF was induced in all dogs except the Sham-operated group by rapid atrial pacing at 450 beats/min for 2 weeks. Ad-EGFP and Ad-ACE2 group then received epicardial gene painting. Three weeks after gene transfer, all animals except the Sham group underwent rapid atrial pacing for another 3 weeks and then invasive electrophysiological, histological and molecular studies. The Ad-ACE2 group showed an increased ACE2 and Angiotensin-(1-7) expression, and decreased Angiotensin II expression in comparison with Ad-EGFP and AF-control group. ACE2 overexpression attenuated rapid atrial pacing-induced increase in activated extracellular signal-regulated kinases and mitogen-activated protein kinases (MAPKs) levels, and decrease in MAPK phosphatase 1(MKP-1) level, resulting in attenuation of atrial fibrosis collagen protein markers and transforming growth factor-β1. Additionally, ACE2 overexpression also modulated the tachypacing-induced up-regulation of connexin 40, down-regulation of connexin 43 and Kv4.2, and significantly decreased the inducibility and duration of AF. ACE2 overexpression could shift the renin-angiotensin system balance towards the protective axis, attenuate cardiac fibrosis remodeling associated with up-regulation of MKP-1 and reduction of MAPKs activities, modulate tachypacing-induced ion channels and connexin remodeling, and subsequently reduce the inducibility and duration of AF.

  10. Prediction of sinus rhythm maintenance following DC-cardioversion of persistent atrial fibrillation – the role of atrial cycle length

    PubMed Central

    Meurling, Carl J; Roijer, Anders; Waktare, Johan EP; Holmqvist, Fredrik; Lindholm, Carl J; Ingemansson, Max P; Carlson, Jonas; Stridh, Martin; Sörnmo, Leif; Olsson, S Bertil

    2006-01-01

    Background Atrial electrical remodeling has been shown to influence the outcome the outcome following cardioversion of atrial fibrillation (AF) in experimental studies. The aim of the present study was to find out whether a non-invasively measured atrial fibrillatory cycle length, alone or in combination with other non-invasive parameters, could predict sinus rhythm maintenance after cardioversion of AF. Methods Dominant atrial cycle length (DACL), a previously validated non-invasive index of atrial refractoriness, was measured from lead V1 and a unipolar oesophageal lead prior to cardioversion in 37 patients with persistent AF undergoing their first cardioversion. Results 32 patients were successfully cardioverted to sinus rhythm. The mean DACL in the 22 patients who suffered recurrence of AF within 6 weeks was 152 ± 15 ms (V1) and 147 ± 14 ms (oesophagus) compared to 155 ± 17 ms (V1) and 151 ± 18 ms (oesophagus) in those maintaining sinus rhythm (NS). Left atrial diameter was 48 ± 4 mm and 44 ± 7 mm respectively (NS). The optimal parameter predicting maintenance of sinus rhythm after 6 weeks appeared to be the ratio of the lowest dominant atrial cycle length (oesophageal lead or V1) to left atrial diameter. This ratio was significantly higher in patients remaining in sinus rhythm (3.4 ± 0.6 vs. 3.1 ± 0.4 ms/mm respectively, p = 0.04). Conclusion In this study neither an index of atrial refractory period nor left atrial diameter alone were predictors of AF recurrence within the 6 weeks of follow-up. The ratio of the two (combining electrophysiological and anatomical measurements) only slightly improve the identification of patients at high risk of recurrence of persistent AF. Consequently, other ways to asses electrical remodeling and / or other variables besides electrical remodeling are involved in determining the outcome following cardioversion. PMID:16533393

  11. NASA's First Atrial Fibrillation Case - Deke Slayton

    NASA Technical Reports Server (NTRS)

    Tarver, William J.

    2010-01-01

    Concerns about heart dysrhythmia have been present since the earliest days of the US manned space program. While information about an astronaut's health is general kept private, one of the original seven American astronaut's health status was played out in a very public forum. Donald "Deke" Slayton was removed from the second manned space flight when it was discovered he had idiopathic atrial fibrillation. Referencing the original medical documents, details of how this was discovered and managed from the medical perspective will be reviewed. This is NASA's first heart dysrhythmia case in an astronaut and it proves quite interesting when placed in historic perspective.

  12. The polyuria of paroxysmal atrial tachycardia

    NASA Technical Reports Server (NTRS)

    Kinney, M. J.; Stein, R. M.; Discala, V. A.

    1974-01-01

    Two patients with paroxysmal atrial fibrillation and an associated polyuria were studied to delineate the mechanism of the increase in urine flow. A striking saluresis was noted in both patients. The increased sodium excretion was probably due to decreased sodium reabsorption, perhaps at proximal tubular nephron sites. This inhibition of sodium reabsorption could explain both the saluresis and some part or all of the polyuria. Re-evaluation of earlier case reports reveals patterns of concomitant salt and water excretion consistent with this mechanism. The saluresis cannot be explained by the previously favored hypothesis of antidiuretic hormone inhibition.

  13. Science Linking Pulmonary Veins and Atrial Fibrillation

    PubMed Central

    Mahida, Saagar; Sacher, Frederic; Derval, Nicolas; Berte, Benjamin; Yamashita, Seigo; Hooks, Darren; Denis, Arnaud; Amraoui, Sana; Hocini, Meleze; Haissaguerre, Michel; Jais, Pierre

    2015-01-01

    Over the past few decades, significant progress has been made in understanding the mechanistic basis of atrial fibrillation (AF). One of the most important discoveries in this context has been that pulmonary veins (PV) play a prominent role in the pathogenesis of AF. PV isolation has since become the most widely used technique for treatment of paroxysmal AF. Multiple studies have demonstrated that the electrophysiological and anatomical characteristics of PVs create a proarrhythmogenic substrate. The following review discusses the mechanistic links between PVs and AF. PMID:26835098

  14. Minimally Invasive Atrial Fibrillation Surgery: Hybrid Approach

    PubMed Central

    Beller, Jared P.; Downs, Emily A.; Ailawadi, Gorav

    2016-01-01

    Atrial fibrillation is a challenging pathologic process. There continues to be a great need for the development of a reproducible, durable cure when medical management has failed. An effective, minimally invasive, sternal-sparing intervention without the need for cardiopulmonary bypass is a promising treatment approach. In this article, we describe a hybrid technique being refined at our center that combines a thoracoscopic epicardial surgical approach with an endocardial catheter-based procedure. We also discuss our results and review the literature describing this unique treatment approach. PMID:27127561

  15. Atrial natriuretic factor and body water distribution.

    PubMed

    Vidal, N A; Arranz, C T; Mones Sias, M C; Herrmann, A P; Martinez Seeber, A

    1987-11-01

    In the rat, the effects of an atrial natriuretic factor (ANF) (Rat, 8-33 Peninsula Lab) on body water distribution have been evaluated. The ANF administration to nephrectomized animals produced a decrease in plasma volume and a slight increase in haematocrit and in plasma albumin concentration. No modifications were observed in total and intracellular water. The fluid efflux from the capillaries appeared to be located in the interstitial space. These results suggest that ANF could regulate plasma volume and systemic blood pressure, concurrently with its other known effects.

  16. Cardiometabolic risk factors and atrial fibrillation.

    PubMed

    Menezes, Arthur R; Lavie, Carl J; Dinicolantonio, James J; O'Keefe, James; Morin, Daniel P; Khatib, Sammy; Abi-Samra, Freddy M; Messerli, Franz H; Milani, Richard V

    2013-01-01

    Atrial fibrillation (AF) is the most common arrhythmia worldwide; it is a significant risk factor for stroke and embolization, and has an impact on cardiac function. Despite its impact on morbidity and mortality, our understanding of the etiology and pathophysiology of this disease process is still incomplete. Over the past several decades, there has been evidence to suggest that AF has a significant correlation with metabolic syndrome (MetS). Furthermore, AF appears to be more closely related to specific components of MetS compared with others. This article provides an overview of the various components of MetS and their impact on AF. PMID:24448257

  17. The Epidemiology of Atrial Fibrillation and Stroke.

    PubMed

    Pistoia, Francesca; Sacco, Simona; Tiseo, Cindy; Degan, Diana; Ornello, Raffaele; Carolei, Antonio

    2016-05-01

    The burden of stroke is increasing due to aging population and unhealthy lifestyle habits. The considerable rise in atrial fibrillation (AF) is due to greater diffusion of risk factors and screening programs. The link between AF and ischemic stroke is strong. The subtype most commonly associated with AF is cardioembolic stroke, which is particularly severe and shows the highest rates of mortality and permanent disability. A trend toward a higher prevalence of cardioembolic stroke in high-income countries is probably due to the greater diffusion of AF and the control of atherosclerotic of risk factors. PMID:27150174

  18. Native plant diversity increases herbivory to non-natives.

    PubMed

    Pearse, Ian S; Hipp, Andrew L

    2014-11-01

    There is often an inverse relationship between the diversity of a plant community and the invasibility of that community by non-native plants. Native herbivores that colonize novel plants may contribute to diversity-invasibility relationships by limiting the relative success of non-native plants. Here, we show that, in large collections of non-native oak trees at sites across the USA, non-native oaks introduced to regions with greater oak species richness accumulated greater leaf damage than in regions with low oak richness. Underlying this trend was the ability of herbivores to exploit non-native plants that were close relatives to their native host. In diverse oak communities, non-native trees were on average more closely related to native trees and received greater leaf damage than those in depauperate oak communities. Because insect herbivores colonize non-native plants that are similar to their native hosts, in communities with greater native plant diversity, non-natives experience greater herbivory.

  19. Native American Resource Book.

    ERIC Educational Resources Information Center

    Spears, Carl D., Comp.; And Others

    Focusing on the Southeastern American Indian cultures, this Native American resource guide is designed for use in the elementary and secondary schools of the East Baton Rouge Parish and is a product of a 1975 Indian Advisory Committee composed of Indian parents, teachers, and staff members. Objectives of these materials require the Indian student,…

  20. The Native American Speaks.

    ERIC Educational Resources Information Center

    Bromberg, Walter; And Others

    This publication is the product of several workshops and is aimed at multi-ethnic integration of teacher attitudes, curriculum content, and teaching techniques. The 7 articles and 3 bibliographies, contributed by Native American consultants, emphasize recognition and alteration of bias in teacher attitudes, curriculum content, and teaching…

  1. Native Americans: Subject Guide.

    ERIC Educational Resources Information Center

    Bonanni, Mimmo; Etter, Patricia A.

    This annotated subject guide lists reference material that deals with Native Americans and is available in the Arizona State University Libraries. Entries were published 1933-98, but mostly in the 1980s-90s. The guide is not comprehensive, but rather a selective list of resources useful for researching a topic in a variety of fields. The guide…

  2. Rebuilding Native American Communities

    ERIC Educational Resources Information Center

    Coyhis, Don; Simonelli, Richard

    2005-01-01

    The Wellbriety Movement in Native American communities draws on the wisdom and participation of traditional elders. Beginning with a basic community teaching called the Four Laws of Change and the Healing Forest Model, the Wellbriety Movement blends Medicine Wheel knowledge with the 12 Steps of Alcoholics Anonymous to provide culture-specific…

  3. Native American Literature.

    ERIC Educational Resources Information Center

    Porter, C. Fayne; And Others

    Designed to accommodate a semester course in Native American Literature for secondary students, this teacher's guide includes a general introduction, a statement of the philosophy and goals upon which it is predicated, a nine-week block on post-Columbian literature, a nine-week block on oral literature, separate appendices for each block, a…

  4. Native American Cultural Groups.

    ERIC Educational Resources Information Center

    Roy, Loriene, Comp.

    Part of a larger report on the Four Directions Project, an American Indian technology innovation project, this section includes 13 "pathfinders" to locating information on Native American and other indigenous cultural groups. The pathfinders were designed by students in the Graduate School of Library and Information Science at the University of…

  5. Exploring Native American Symbolism.

    ERIC Educational Resources Information Center

    Dufrene, Phoebe

    This paper described the events and results of a workshop on Native American symbolism presented to educators and held in Kansas City, Missouri. The presenter maintained that some of the most crucial problems facing U.S. educators and students are caused by racial misunderstandings, and that the universality of artistic expression can be a vehicle…

  6. High frequency stimulation of cardiac myocytes: a theoretical and computational study.

    PubMed

    Weinberg, Seth H

    2014-12-01

    High-frequency stimulation (HFS) has recently been identified as a novel approach for terminating life-threatening cardiac arrhythmias. HFS elevates myocyte membrane potential and blocks electrical conduction for the duration of the stimulus. However, low amplitude HFS can induce rapidly firing action potentials, which may reinitiate an arrhythmia. The cellular level mechanisms underlying HFS-induced electrical activity are not well understood. Using a multiscale method, we show that a minimal myocyte model qualitatively reproduces the influence of HFS on cardiac electrical activity. Theoretical analysis and simulations suggest that persistent activation and de-inactivation of ionic currents, in particular a fast inward window current, underlie HFS-induced action potentials and membrane potential elevation, providing hypotheses for future experiments. We derive analytical expressions to describe how HFS modifies ionic current amplitude and gating dynamics. We show how fast inward current parameters influence the parameter regimes for HFS-induced electrical activity, demonstrating how the efficacy of HFS as a therapy for terminating arrhythmias may depend on the presence of pathological conditions or pharmacological treatments. Finally, we demonstrate that HFS terminates cardiac arrhythmias in a one-dimensional ring of cardiac tissue. In this study, we demonstrate a novel approach to characterize the influence of HFS on ionic current gating dynamics, provide new insight into HFS of the myocardium, and suggest mechanisms underlying HFS-induced electrical activity.

  7. Sarcolemmal ATP-sensitive potassium channel protects cardiac myocytes against lipopolysaccharide-induced apoptosis.

    PubMed

    Zhang, Xiaohui; Zhang, Xiaohua; Xiong, Yiqun; Xu, Chaoying; Liu, Xinliang; Lin, Jian; Mu, Guiping; Xu, Shaogang; Liu, Wenhe

    2016-09-01

    The sarcolemmal ATP-sensitive K+ (sarcKATP) channel plays a cardioprotective role during stress. However, the role of the sarcKATP channel in the apoptosis of cardiomyocytes and association with mitochondrial calcium remains unclear. For this purpose, we developed a model of LPS-induced sepsis in neonatal rat cardiomyocytes (NRCs). The TUNEL assay was performed in order to detect the apoptosis of cardiac myocytes and the MTT assay was performed to determine cellular viability. Exposure to LPS significantly decreased the viability of the NRCs as well as the expression of Bcl-2, whereas it enhanced the activity and expression of the apoptosis-related proteins caspase-3 and Bax, respectively. The sarcKATP channel blocker, HMR-1098, increased the apoptosis of NRCs, whereas the specific sarcKATP channel opener, P-1075, reduced the apoptosis of NRCs. The mitochondrial calcium uniporter inhibitor ruthenium red (RR) partially inhibited the pro-apoptotic effect of HMR-1098. In order to confirm the role of the sarcKATP channel, we constructed a recombinant adenovirus vector carrying the sarcKATP channel mutant subunit Kir6.2AAA to inhibit the channel activity. Kir6.2AAA adenovirus infection in NRCs significantly aggravated the apoptosis of myocytes induced by LPS. Elucidating the regulatory mechanisms of the sarcKATP channel in apoptosis may facilitate the development of novel therapeutic targets and strategies for the management of sepsis and cardiac dysfunction. PMID:27430376

  8. Transforming growth factor-{beta}2 enhances differentiation of cardiac myocytes from embryonic stem cells

    SciTech Connect

    Kumar, Dinender . E-mail: Dinender.Kumar@uvm.edu; Sun, Baiming

    2005-06-24

    Stem cell therapy holds great promise for the treatment of injured myocardium, but is challenged by a limited supply of appropriate cells. Three different isoforms of transforming growth factor-{beta} (TGF-{beta}) -{beta}1, -{beta}2, and -{beta}3 exhibit distinct regulatory effects on cell growth, differentiation, and migration during embryonic development. We compared the effects of these three different isoforms on cardiomyocyte differentiation from embryonic stem (ES) cells. In contrast to TGF-{beta}1, or -{beta}3, treatment of mouse ES cells with TGF-{beta}2 isoform significantly increased embryoid body (EB) proliferation as well as the extent of the EB outgrowth that beat rhythmically. At 17 days, 49% of the EBs treated with TGF-{beta}2 exhibited spontaneous beating compared with 15% in controls. Cardiac myocyte specific protein markers sarcomeric myosin and {alpha}-actin were demonstrated in beating EBs and cells isolated from EBs. In conclusion, TGF-{beta}2 but not TGF-{beta}1, or -{beta}3 promotes cardiac myocyte differentiation from ES cells.

  9. Irregularly Appearing Early Afterdepolarizations in Cardiac Myocytes: Random Fluctuations or Dynamical Chaos?

    PubMed Central

    Sato, Daisuke; Xie, Lai-Hua; Nguyen, Thao P.; Weiss, James N.; Qu, Zhilin

    2010-01-01

    Irregularly occurring early afterdepolarizations (EADs) in cardiac myocytes are traditionally hypothesized to be caused by random ion channel fluctuations. In this study, we combined 1), patch-clamp experiments in which action potentials were recorded at different pacing cycle lengths from isolated rabbit ventricular myocytes under several experimental conditions inducing EADs, including oxidative stress with hydrogen peroxide, calcium overload with BayK8644, and ionic stress with hypokalemia; 2), computer simulations using a physiologically detailed rabbit ventricular action potential model, in which repolarization reserve was reduced to generate EADs and random ion channel or path cycle length fluctuations were implemented; and 3), iterated maps with or without noise. By comparing experimental, modeling, and bifurcation analyses, we present evidence that noise-induced transitions between bistable states (i.e., between an action potential with and without an EAD) is not sufficient to account for the large variation in action potential duration fluctuations observed in experimental studies. We conclude that the irregular dynamics of EADs is intrinsically chaotic, with random fluctuations playing a nonessential, auxiliary role potentiating the complex dynamics. PMID:20682253

  10. A comparative assessment of fluo Ca2+ indicators in rat ventricular myocytes

    PubMed Central

    Hagen, Brian M.; Boyman, Liron; Kao, Joseph P.Y.; Lederer, W. Jonathan

    2012-01-01

    Summary The fluo family of indicators is frequently used in studying Ca2+ physiology; however, choosing which fluo indicator to use is not obvious. Indicator properties are typically determined in well-defined aqueous solutions. Inside cells, however, the properties can change markedly. We have characterized each of three fluo variants (fluo-2MA, fluo-3 and fluo-4) in two forms—the acetoxymethyl (AM) ester and the K+ salt. We loaded indicators into rat ventricular myocytes and used confocal microscopy to monitor depolarization-induced fluorescence changes and fractional shortening. Myocytes loaded with the indicator AM esters showed significantly different Ca2+ transients and fractional shortening kinetics. Loading the K+ salts via whole-cell patch-pipette eliminated differences between fluo-3 and fluo-4, but not fluo-2. Cells loaded with different indicator AM esters showed different staining patterns—suggesting differential loading into organelles. Ca2+ dissociation constants (Kd,Ca), measured in protein-rich buffers mimicking the cytosol were significantly higher than values determined in simple buffers. This increase in Kd,Ca (decrease in Ca2+ affinity) was greatest for fluo-3 and fluo-4, and least for fluo-2. We conclude that the structurally-similar fluo variants differ with respect to cellular loading, subcellular compartmentalization, and intracellular Ca2+ affinity. Therefore, judicious choice of fluo indicator and loading procedure is advisable when designing experiments. PMID:22721780

  11. Sarcolemmal ATP-sensitive potassium channel protects cardiac myocytes against lipopolysaccharide-induced apoptosis

    PubMed Central

    Zhang, Xiaohui; Zhang, Xiaohua; Xiong, Yiqun; Xu, Chaoying; Liu, Xinliang; Lin, Jian; Mu, Guiping; Xu, Shaogang; Liu, Wenhe

    2016-01-01

    The sarcolemmal ATP-sensitive K+ (sarcKATP) channel plays a cardioprotective role during stress. However, the role of the sarcKATP channel in the apoptosis of cardiomyocytes and association with mitochondrial calcium remains unclear. For this purpose, we developed a model of LPS-induced sepsis in neonatal rat cardiomyocytes (NRCs). The TUNEL assay was performed in order to detect the apoptosis of cardiac myocytes and the MTT assay was performed to determine cellular viability. Exposure to LPS significantly decreased the viability of the NRCs as well as the expression of Bcl-2, whereas it enhanced the activity and expression of the apoptosis-related proteins caspase-3 and Bax, respectively. The sarcKATP channel blocker, HMR-1098, increased the apoptosis of NRCs, whereas the specific sarcKATP channel opener, P-1075, reduced the apoptosis of NRCs. The mitochondrial calcium uniporter inhibitor ruthenium red (RR) partially inhibited the pro-apoptotic effect of HMR-1098. In order to confirm the role of the sarcKATP channel, we constructed a recombinant adenovirus vector carrying the sarcKATP channel mutant subunit Kir6.2AAA to inhibit the channel activity. Kir6.2AAA adenovirus infection in NRCs significantly aggravated the apoptosis of myocytes induced by LPS. Elucidating the regulatory mechanisms of the sarcKATP channel in apoptosis may facilitate the development of novel therapeutic targets and strategies for the management of sepsis and cardiac dysfunction. PMID:27430376

  12. Na+ Transport in Cardiac Myocytes; Implications for Excitation-Contraction Coupling

    PubMed Central

    Bers, Donald M.; Despa, Sanda

    2009-01-01

    Intracellular Na+ concentration ([Na+]i) is very important in modulating the contractile and electrical activity of the heart. Upon electrical excitation of the myocardium, voltage-dependent Na+ channels open, triggering the upstroke of the action potential (AP). During the AP, Ca2+ enters the myocytes via L-type Ca2+ channels. This triggers Ca2+ release from the sarcoplasmic reticulum (SR) and thus activates contraction. Relaxation occurs when cytosolic Ca2+ declines, mainly due to re-uptake into the SR via SR Ca2+-ATPase and extrusion from the cell via the Na+/Ca2+ exchanger (NCX). NCX extrudes one Ca2+ ion in exchange for three Na+ ions and its activity is critically regulated by [Na+]i. Thus, via NCX, [Na+]i is centrally involved in the regulation of intracellular [Ca2+] and contractility. Na+ brought in by Na+ channels, NCX and other Na+ entry pathways is extruded by the Na+/K+ pump (NKA) to keep [Na+]i low. NKA is regulated by phospholemman, a small sarcolemmal protein that associates with NKA. Unphosphorylated phospholemman inhibits NKA by decreasing the pump affinity for internal Na+ and this inhibition is relieved upon phosphorylation. Here we discuss the main characteristics of the Na+ transport pathways in cardiac myocytes and their physiological and pathophysiological relevance. PMID:19243007

  13. Cardiac fibroblasts are predisposed to convert into myocyte phenotype: Specific effect of transforming growth factor. beta

    SciTech Connect

    Eghbali, M.; Tomek, R.; Woods, C.; Bhambi, B. )

    1991-02-01

    Cardiac fibroblasts are mainly responsible for the synthesis of major extracellular matrix proteins in the heart, including fibrillar collagen types I and III and fibronectin. In this report we show that these cells, when stimulated by transforming growth factor {beta}{sub 1} (TGF-{beta}{sub 1}), acquire certain myocyte-specific properties. Cultured cardiac fibroblasts from adult rabbit heart were treated with TGF-{beta}{sub 1}, (10-15 ng/ml) for different periods of time. Northern hybridization analysis of total RNA showed that cells treated with TGF-{beta}{sub 1} became stained with a monoclonal antibody to muscle-specific actin. After treatment of quiescent cells with TGF-{beta}{sub 1}, cell proliferation (as measured by ({sup 3}H)thymidine incorporation) was moderately increased. Cultured cardiac fibroblasts at the subconfluent stage, when exposed to TGF-{beta}{sub 1} in the presence of 10% fetal bovine serum, gave rise to a second generation of slowly growing cells that expressed muscle-specific actin filaments. The findings demonstrate that cardiac fibroblasts can be made to differentiate into cells that display many characteristics of cardiac myocytes. TGF-{beta}{sub 1} seems to be a specific inducer of such conversion.

  14. Patterns of evolution of myocyte damage after human heart transplantation detected by indium-111 monoclonal antimyosin

    SciTech Connect

    Ballester-Rodes, M.; Carrio-Gasset, I.; Abadal-Berini, L.; Obrador-Mayol, D.; Berna-Roqueta, L.; Caralps-Riera, J.M.

    1988-09-15

    The indium-111 labeled Fab fragment of antimyosin monoclonal antibody was used to study cardiac rejection and the time course of myocyte damage after transplantation. Fifty-three studies were performed in 21 patients, 17 men and 4 women, aged 19 to 54 years (mean 37 +/- 8), from 7 to 40 months after transplantation. Repeat studies were available in 8, and 10 were studied after the first year of transplantation. A heart-to-lung ratio was used for quantitation of uptake (normal 1.46 +/- 0.04). Differences between absent (1.69 +/- 0.29) and moderate (1.90 +/- 0.36) rejection were significant (p less than 0.03). Antimyosin ratio at 1 to 3 months (1.89 +/- 0.35) differed from that at greater than 12 months (1.65 +/- 0.2) (p less than 0.01). Repeat studies revealed a decrease in antimyosin ratio in 5 patients with uneventful clinical course; 2 had persistent activity after transplantation and suffered heart failure from rejection. After 1 year of transplantation uptake was within normal limits in 7 of 10 patients, and high uptake was associated with vascular rejection in 1. Because they can define evolving patterns of myocardial lesion activity, antimyosin studies could be useful both in patient management and in concentrating resources for those patients who most require them. The heart-to-lung ratio is suggested to monitor sequentially the degree of myocyte damage after transplantation.

  15. X-ray microanalysis of single cardiac myocytes frozen under voltage-clamp conditions

    SciTech Connect

    Wendt-Gallitelli, M.F.; Isenberg, G.

    1989-02-01

    By means of a patch pipette, an isolated ventricular myocyte was transferred into the taper of a silver holder covered by pioloform film. Once the cell was on the film, the cell was voltage clamped (pulses from -45 to +5 mV at 0.5 Hz). The amount of Ca entry was estimated from the Ca current. When contractility (cell shortening) was potentiated with either five pulses of 0.2 s or four pulses of 1 s, shock freezing was timed 116 or 816 ms after start of the clamp pulse. Electron micrographs from freeze-substituted cells revealed the good preservation of the intracellular compartments. The myocytes were cut at -150 degrees C, and the cryosections were freeze dried. In representative examples, the amount of Ca entry is compared with the subcellular Ca distribution as it is analyzed with energy dispersive X-ray microprobe analysis in cytoplasm, junctional sarcoplasmic reticulum (SR), mitochondria, and the subsarcolemmal space (sarcolemma, peripheral SR, fringe of cytosol).

  16. High frequency stimulation of cardiac myocytes: A theoretical and computational study

    NASA Astrophysics Data System (ADS)

    Weinberg, Seth H.

    2014-12-01

    High-frequency stimulation (HFS) has recently been identified as a novel approach for terminating life-threatening cardiac arrhythmias. HFS elevates myocyte membrane potential and blocks electrical conduction for the duration of the stimulus. However, low amplitude HFS can induce rapidly firing action potentials, which may reinitiate an arrhythmia. The cellular level mechanisms underlying HFS-induced electrical activity are not well understood. Using a multiscale method, we show that a minimal myocyte model qualitatively reproduces the influence of HFS on cardiac electrical activity. Theoretical analysis and simulations suggest that persistent activation and de-inactivation of ionic currents, in particular a fast inward window current, underlie HFS-induced action potentials and membrane potential elevation, providing hypotheses for future experiments. We derive analytical expressions to describe how HFS modifies ionic current amplitude and gating dynamics. We show how fast inward current parameters influence the parameter regimes for HFS-induced electrical activity, demonstrating how the efficacy of HFS as a therapy for terminating arrhythmias may depend on the presence of pathological conditions or pharmacological treatments. Finally, we demonstrate that HFS terminates cardiac arrhythmias in a one-dimensional ring of cardiac tissue. In this study, we demonstrate a novel approach to characterize the influence of HFS on ionic current gating dynamics, provide new insight into HFS of the myocardium, and suggest mechanisms underlying HFS-induced electrical activity.

  17. Restoration of β -Adrenergic Signaling in Failing Cardiac Ventricular Myocytes via Adenoviral-Mediated Gene Transfer

    NASA Astrophysics Data System (ADS)

    Akhter, Shahab A.; Skaer, Christine A.; Kypson, Alan P.; McDonald, Patricia H.; Peppel, Karsten C.; Glower, Donald D.; Lefkowitz, Robert J.; Koch, Walter J.

    1997-10-01

    Cardiovascular gene therapy is a novel approach to the treatment of diseases such as congestive heart failure (CHF). Gene transfer to the heart would allow for the replacement of defective or missing cellular proteins that may improve cardiac performance. Our laboratory has been focusing on the feasibility of restoring β -adrenergic signaling deficiencies that are a characteristic of chronic CHF. We have now studied isolated ventricular myocytes from rabbits that have been chronically paced to produce hemodynamic failure. We document molecular β -adrenergic signaling defects including down-regulation of myocardial β -adrenergic receptors (β -ARs), functional β -AR uncoupling, and an upregulation of the β -AR kinase (β ARK1). Adenoviral-mediated gene transfer of the human β 2-AR or an inhibitor of β ARK1 to these failing myocytes led to the restoration of β -AR signaling. These results demonstrate that defects present in this critical myocardial signaling pathway can be corrected in vitro using genetic modification and raise the possibility of novel inotropic therapies for CHF including the inhibition of β ARK1 activity in the heart.

  18. Gaining myocytes or losing fibroblasts: Challenges in cardiac fibroblast reprogramming for infarct repair.

    PubMed

    Nagalingam, Raghu S; Safi, Hamza A; Czubryt, Michael P

    2016-04-01

    Unlike most somatic tissues, the heart possesses a very limited inherent ability to repair itself following damage. Attempts to therapeutically salvage the myocardium after infarction, either by sparing surviving myocytes or by injection of exogenous cells of varied provenance, have met with limited success. Cardiac fibroblasts are numerous, resistant to hypoxia, and amenable to phenotype reprogramming to cardiomyocytes - a potential panacea to an intractable problem. However, the long-term effects of mass conversion of fibroblasts are as-yet unknown. Since fibroblasts play key roles in normal cardiac function, treating these cells as a ready source of replacements for myocytes may have the effect of swapping one problem for another. This review briefly examines the roles of cardiac fibroblasts, recaps the strides made so far in their reprogramming to cardiomyocytes both in vitro and in vivo, and discusses the potential ramifications of large-scale cellular identity swapping. While such therapy offers great promise, the potential repercussions require consideration and careful study. PMID:26640115

  19. Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog.

    PubMed

    LeGrice, I J; Smaill, B H; Chai, L Z; Edgar, S G; Gavin, J B; Hunter, P J

    1995-08-01

    We have studied the three-dimensional arrangement of ventricular muscle cells and the associated extracellular connective tissue matrix in dog hearts. Four hearts were potassium-arrested, excised, and perfusion-fixed at zero transmural pressure. Full-thickness segments were cut from the right and left ventricular walls at a series of precisely located sites. Morphology was visualized macroscopically and with scanning electron microscopy in 1) transmural planes of section and 2) planes tangential to the epicardial surface. The appearance of all specimens was consistent with an ordered laminar arrangement of myocytes with extensive cleavage planes between muscle layers. These planes ran radially from endocardium toward epicardium in transmural section and coincided with the local muscle fiber orientation in tangential section. Stereological techniques were used to quantify aspects of this organization. There was no consistent variation in the cellular organization of muscle layers (48.4 +/- 20.4 microns thick and 4 +/- 2 myocytes across) transmurally or in different ventricular regions (23 sites in 6 segments), but there was significant transmural variation in the coupling between adjacent layers. The number of branches between layers decreased twofold from subepicardium to midwall, whereas the length distribution of perimysial collagen fibers connecting muscle layers was greatest in the midwall. We conclude that ventricular myocardium is not a uniformly branching continuum but a laminar hierarchy in which it is possible to identify three axes of material symmetry at any point.

  20. Pertussis toxin treatment attenuates some effects of insulin in BC3H-1 murine myocytes

    SciTech Connect

    Luttrell, L.M.; Hewlett, E.L.; Romero, G.; Rogol, A.D.

    1988-05-05

    The effects of pertussis toxin (PT) treatment on insulin-stimulated myristoyl-diacylglycerol (DAG) generation, hexose transport, and thymidine incorporation were studied in differentiated BC3H-1 mycocytes. Insulin treatment caused a biphasic increase in myristoyl-DAG production which was abolished in myocytes treated with PT. There was no effect of PT treatment on basal (nonstimulated) myristoyl-DAG production. Insulin-stimulated hydrolysis of a membrane phosphatidylinositol glycan was blocked by PT treatment. ADP-ribosylation of BC3H-1 plasma membranes with (/sup 32/P)NAD revealed a 40-kDa protein as the major PT substrate in vivo and in vitro. The time course and dose dependence of the effects of PT on diacylglycerol generation correlated with the in vivo ADP-ribosylation of the 40-kDa substrate. Pertussis toxin treatment resulted in a 71% attenuation of insulin-stimulated hexose uptake without effect on either basal or phorbol ester-stimulated uptake. The stimulatory effects of insulin and fetal calf serum on (/sup 3/H)thymidine incorporation into quiescent myocytes were attenuated by 61 and 59%, respectively, when PT was added coincidently with the growth factors. Nonstimulated and EGF-stimulated (/sup 3/H)thymidine incorporation was unaffected by PT treatment. These data suggest that a PT-sensitive G protein is involved in the cellular signaling mechanisms of insulin.

  1. Important role of energy-dependent mitochondrial pathways in cultured rat cardiac myocyte apoptosis.

    PubMed

    Shiraishi, J; Tatsumi, T; Keira, N; Akashi, K; Mano, A; Yamanaka, S; Matoba, S; Asayama, J; Yaoi, T; Fushiki, S; Fliss, H; Nakagawa, M

    2001-10-01

    Recent studies have suggested that apoptosis and necrosis share common features in their signaling pathway and that apoptosis requires intracellular ATP for its mitochondrial/apoptotic protease-activating factor-1 suicide cascade. The present study was, therefore, designed to examine the role of intracellular energy levels in determining the form of cell death in cardiac myocytes. Neonatal rat cardiac myocytes were first incubated for 1 h in glucose-free medium containing oligomycin to achieve metabolic inhibition. The cells were then incubated for another 4 h in similar medium containing staurosporine and graded concentrations of glucose to manipulate intracellular ATP levels. Under ATP-depleting conditions, the cell death caused by staurosporine was primarily necrotic, as determined by creatine kinase release and nuclear staining with ethidium homodimer-1. However, under ATP-replenishing conditions, staurosporine increased the percentage of apoptotic cells, as determined by nuclear morphology and DNA fragmentation. Caspase-3 activation by staurosporine was also ATP dependent. However, loss of mitochondrial transmembrane potential (DeltaPsi(m)), Bax translocation, and cytochrome c release were observed in both apoptotic and necrotic cells. Moreover, cyclosporin A, an inhibitor of mitochondrial permeability transition, attenuated staurosporine-induced apoptosis and necrosis through the inhibition of DeltaPsi(m) reduction, cytochrome c release, and caspase-3 activation. Our data therefore suggest that staurosporine induces cell demise through a mitochondrial death signaling pathway and that the presence of intracellular ATP favors a shift from necrosis to apoptosis through caspase activation. PMID:11557554

  2. Glucose deprivation causes oxidative stress and stimulates aggresome formation and autophagy in cultured cardiac myocytes.

    PubMed

    Marambio, Paola; Toro, Barbra; Sanhueza, Carlos; Troncoso, Rodrigo; Parra, Valentina; Verdejo, Hugo; García, Lorena; Quiroga, Clara; Munafo, Daniela; Díaz-Elizondo, Jessica; Bravo, Roberto; González, María-Julieta; Diaz-Araya, Guilermo; Pedrozo, Zully; Chiong, Mario; Colombo, María Isabel; Lavandero, Sergio

    2010-06-01

    Aggresomes are dynamic structures formed when the ubiquitin-proteasome system is overwhelmed with aggregation-prone proteins. In this process, small protein aggregates are actively transported towards the microtubule-organizing center. A functional role for autophagy in the clearance of aggresomes has also been proposed. In the present work we investigated the molecular mechanisms involved on aggresome formation in cultured rat cardiac myocytes exposed to glucose deprivation. Confocal microscopy showed that small aggregates of polyubiquitinated proteins were formed in cells exposed to glucose deprivation for 6 h. However, at longer times (18 h), aggregates formed large perinuclear inclusions (aggresomes) which colocalized with gamma-tubulin (a microtubule-organizing center marker) and Hsp70. The microtubule disrupting agent vinblastine prevented the formation of these inclusions. Both small aggregates and aggresomes colocalized with autophagy markers such as GFP-LC3 and Rab24. Glucose deprivation stimulates reactive oxygen species (ROS) production and decreases intracellular glutathione levels. ROS inhibition by N-acetylcysteine or by the adenoviral overexpression of catalase or superoxide dismutase disrupted aggresome formation and autophagy induced by glucose deprivation. In conclusion, glucose deprivation induces oxidative stress which is associated with aggresome formation and activation of autophagy in cultured cardiac myocytes. PMID:20176105

  3. Executioner Caspase-3 and 7 Deficiency Reduces Myocyte Number in the Developing Mouse Heart

    PubMed Central

    Cardona, Maria; López, Juan Antonio; Serafín, Anna; Rongvaux, Anthony; Inserte, Javier; García-Dorado, David; Flavell, Richard; Llovera, Marta; Cañas, Xavier; Vázquez, Jesús; Sanchis, Daniel

    2015-01-01

    Executioner caspase-3 and -7 are proteases promoting cell death but non-apoptotic roles are being discovered. The heart expresses caspases only during development, suggesting they contribute to the organ maturation process. Therefore, we aimed at identifying novel functions of caspases in heart development. We induced simultaneous deletion of executioner caspase-3 and -7 in the mouse myocardium and studied its effects. Caspase knockout hearts are hypoplastic at birth, reaching normal weight progressively through myocyte hypertrophy. To identify the molecular pathways involved in these effects, we used microarray-based transcriptomics and multiplexed quantitative proteomics to compare wild type and executioner caspase-deficient myocardium at different developmental stages. Transcriptomics showed reduced expression of genes promoting DNA replication and cell cycle progression in the neonatal caspase-deficient heart suggesting reduced myocyte proliferation, and expression of non-cardiac isoforms of structural proteins in the adult null myocardium. Proteomics showed reduced abundance of proteins involved in oxidative phosphorylation accompanied by increased abundance of glycolytic enzymes underscoring retarded metabolic maturation of the caspase-null myocardium. Correlation between mRNA expression and protein abundance of relevant genes was confirmed, but transcriptomics and proteomics indentified complementary molecular pathways influenced by caspases in the developing heart. Forced expression of wild type or proteolytically inactive caspases in cultured cardiomyocytes induced expression of genes promoting cell division. The results reveal that executioner caspases can modulate heart’s cellularity and maturation during development, contributing novel information about caspase biology and heart development. PMID:26121671

  4. Idiopathic atrial fibrillation in a champion Standardbred racehorse.

    PubMed

    Stewart, G A; Fulton, L J; McKellar, C D

    1990-05-01

    Atrial fibrillation is described in a champion pacer which earlier had been named Australian Harness Horse of the Year as a 3-year-old in 1986-87. Prior to conversion atrial fibrillation had been present for at least 6 weeks, during which the horse had not raced. Successful treatment was achieved with two 10g doses of quinidine sulphate per oesophageal tube, after slow digitalisation with intravenous digoxin over 4d. Four hours after commencement of quinidine therapy the arrhythmia had regressed to atrial flutter and converted to sinus rhythm 10 min later. Considering his age, standard of racing and high reputation the horse's overall performance as a 5-year-old after conversion from atrial fibrillation appeared comparable to his previous performance as a 4-year-old before the disorder occurred. In one of the wins since his return to sinus rhythm, the horse recorded his fastest winning speed and created a new track record at the major Melbourne racetrack. The absence of abnormalities of atrial and atrio-ventricular conduction after the cessation of the arrhythmia, together with the horse's return to successful racing, indicate that this was case of atrial fibrillation occurring as a functional disorder without persistent atrial pathology. PMID:2378602

  5. Atrial Arrhythmias in Astronauts - Summary of a NASA Summit

    NASA Technical Reports Server (NTRS)

    Barr, Yael R.; Watkins, Sharmila D.; Polk, J. D.

    2010-01-01

    Background and Problem Definition: To evaluate NASA s current standards and practices related to atrial arrhythmias in astronauts, Space Medicine s Advanced Projects Section at the Johnson Space Center was tasked with organizing a summit to discuss the approach to atrial arrhythmias in the astronaut cohort. Since 1959, 11 cases of atrial fibrillation, atrial flutter, or supraventricular tachycardia have been recorded among active corps crewmembers. Most of the cases were paroxysmal, although a few were sustained. While most of the affected crewmembers were asymptomatic, those slated for long-duration space flight underwent radiofrequency ablation treatment to prevent further episodes of the arrhythmia. The summit was convened to solicit expert opinion on screening, diagnosis, and treatment options, to identify gaps in knowledge, and to propose relevant research initiatives. Summit Meeting Objectives: The Atrial Arrhythmia Summit brought together a panel of six cardiologists, including nationally and internationally renowned leaders in cardiac electrophysiology, exercise physiology, and space flight cardiovascular physiology. The primary objectives of the summit discussions were to evaluate cases of atrial arrhythmia in the astronaut population, to understand the factors that may predispose an individual to this condition, to understand NASA s current capabilities for screening, diagnosis, and treatment, to discuss the risks associated with treatment of crewmembers assigned to long-duration missions or extravehicular activities, and to discuss recommendations for prevention or management of future cases. Summary of Recommendations: The summit panel s recommendations were grouped into seven categories: Epidemiology, Screening, Standards and Selection, Treatment of Atrial Fibrillation Manifesting Preflight, Atrial Fibrillation during Flight, Prevention of Atrial Fibrillation, and Future Research

  6. Cost effectiveness of therapies for atrial fibrillation. A review.

    PubMed

    Teng, M P; Catherwood, L E; Melby, D P

    2000-10-01

    Atrial fibrillation is the most common supraventricular tachyarrhythmia encountered in clinical practice, affecting over 5% of persons over the age of 65 years. A common pathophysiological mechanism for arrhythmia development is atrial distention and fibrosis induced by hypertension, coronary artery disease or ventricular dysfunction. Less frequently, atrial fibrillation is caused by mitral stenosis or other provocative factors such as thyrotoxicosis, pericarditis or alcohol intoxication. Depending on the extent of associated cardiovascular disease, atrial fibrillation may produce haemodynamic compromise, or symptoms such as palpitations, fatigue, chest pain or dyspnoea. Arrhythmia-induced atrial stasis can precipitate clot formation and the potential for subsequent thromboembolism. Comprehensive management of atrial fibrillation requires a multifaceted approach directed at controlling symptoms, protecting the patient from ischaemic stroke or peripheral embolism and possible conversion to or maintenance of sinus rhythm. Numerous randomised trials have demonstrated the efficacy of warfarin--and less so aspirin (acetylsalicylic acid)--in reducing the risk of embolic events. Furthermore, therapeutic strategies exist that can favourably modify symptoms by restoring and maintaining sinus rhythm with cardioversion and antiarrhythmic prophylaxis. However, the risks and benefits of various treatments is highly dependent on patient-specific features, emphasising the need for an individualised approach. This article reviews the findings of cost-effectiveness studies published over the past decade that have evaluated different components of treatment strategies for atrial fibrillation. These studies demonstrate the economic attractiveness of acute management options, long term warfarin prophylaxis, telemetry-guided initiation of antiarrhythmic therapy, approaches to restore and maintain sinus rhythm, and the potential role of transoesophageal echocardiographic screening for

  7. Recurrent syncope after left atrial appendage occlusion.

    PubMed

    Cruz-Gonzalez, Ignacio; Perez-Rivera, Jose-Angel; Bethencourt, Armando

    2015-02-01

    We present the case of a 72-year-old woman with permanent atrial fibrillation and contraindication to long-term oral anticoagulant therapy who underwent left atrial appendage (LAA) occlusion. A 24-mm Amplatzer Cardiac Plug (St Jude Medical) device was deployed. The inferior part of the external disc of the device appeared to be over the posterior leaflet of the mitral valve but no significant mitral stenosis or mitral regurgitation was detected before deployment. After the procedure the patient suffered several syncopes when she tried to stand up. A transesophageal echocardiography (TEE) was performed and no significant differences on the device position were detected, it was not possible to perform the TEE in a stand-up position due to the patient symptoms (hypotension, tachycardia, dizziness, and loss of consciousness). After discussion with the surgical team, surgical removal of the device and surgical exclusion of LAA was performed. The symptoms disappeared and the patient was discharged. In the best of our knowledge, this is the first time that recurrent syncope has been described as a complication of LAA occlusion. PMID:25044597

  8. Relation of porphyria to atrial fibrillation.

    PubMed

    Dhoble, Abhijeet; Patel, Mehul B; Abdelmoneim, Sahar S; Puttarajappa, Chethan; Abela, George S; Bhatt, Deepak L; Thakur, Ranjan K

    2009-08-01

    Porphyrias are a group of inherited disorders affecting enzymes in the heme biosynthesis pathway, leading to overproduction and/or accumulation of porphyrin or its precursors. Porphyrias have been associated with autonomic dysfunction, which in turn can develop atrial fibrillation (AF). The purpose of this study was to characterize the prevalence of AF and atrial flutter (AFl) in patients with porphyrias. A single-center retrospective cohort study was designed using data from chart reviews of patients who were admitted to the hospital from January 2000 to June 2008. Fifty-six distinct cases were found with a discharge diagnosis of porphyria including all its subtypes. From the same database, age- and gender-matched controls were identified using computer-generated random numbers. We selected 1 age- and gender-matched control for each case. Electrocardiograms and echocardiograms were reviewed by 2 independent reviewers. Only patients with available 12-lead electrocardiograms that showed AF/AFl were labeled with that diagnosis. All patients with a diagnosis of porphyria were included in the study irrespective of their age. Seven of 56 patients with porphyria met inclusion criteria, yielding a prevalence of AF/AFl of 12.5%. This association was significant (p = 0.028, relative risk 7.45, 95% confidence interval 1.01 to 66.14) compared with the age- and gender-matched control group (2%). In conclusion, our observations suggest that porphyria may be significantly associated with AF/AFl.

  9. Current hot potatoes in atrial fibrillation ablation.

    PubMed

    Roten, Laurent; Derval, Nicolas; Pascale, Patrizio; Scherr, Daniel; Komatsu, Yuki; Shah, Ashok; Ramoul, Khaled; Denis, Arnaud; Sacher, Frédéric; Hocini, Mélèze; Haïssaguerre, Michel; Jaïs, Pierre

    2012-11-01

    Atrial fibrillation (AF) ablation has evolved to the treatment of choice for patients with drug-resistant and symptomatic AF. Pulmonary vein isolation at the ostial or antral level usually is sufficient for treatment of true paroxysmal AF. For persistent AF ablation, drivers and perpetuators outside of the pulmonary veins are responsible for AF maintenance and have to be targeted to achieve satisfying arrhythmia-free success rate. Both complex fractionated atrial electrogram (CFAE) ablation and linear ablation are added to pulmonary vein isolation for persistent AF ablation. Nevertheless, ablation failure and necessity of repeat ablations are still frequent, especially after persistent AF ablation. Pulmonary vein reconduction is the main reason for arrhythmia recurrence after paroxysmal and to a lesser extent after persistent AF ablation. Failure of persistent AF ablation mostly is a consequence of inadequate trigger ablation, substrate modification or incompletely ablated or reconducting linear lesions. In this review we will discuss these points responsible for AF recurrence after ablation and review current possibilities on how to overcome these limitations. PMID:22920482

  10. Atrial Fibrillation and SCN5A Variants

    PubMed Central

    Savio-Galimberti, Eleonora; Darbar, Dawood

    2014-01-01

    Although atrial fibrillation (AF) is clinically and genetically a highly heterogeneous disease, recent studies suggest that the arrhythmia may arise because of interactions between genetic and acquired risk factors – the so called “double-hit” hypothesis. Genome-wide association studies have identified common AF susceptibility loci, and linkage analysis and candidate gene approaches have identified mutations in genes that encode for cardiac ion channels and signaling proteins; however, most of the heritability of AF still remains unexplained. The voltage-dependent cardiac sodium channel, encoded by SCN5A, conducts the main cardiac inward sodium current (INa) and is responsible for the upstroke of the atrial action potential. Mutations in SCN5A, which encodes the α-subunit of the NaV1.5 channel, have been linked with increased susceptibility to not only AF but also ventricular arrhythmias (long QT syndrome, Brugada syndrome), progressive cardiac conduction disease, and overlap syndromes with mixed arrhythmia phenotypes. Over the last decade, functional characterization of SCN5A mutations by expressing the channel in heterologous expression systems and applying cellular electrophysiological techniques has not only advanced our understanding of molecular mechanisms of AF but also potentially identified a mechanism-based approach to treating this common and morbid condition. PMID:25484998

  11. [The natural course of atrial septal defects].

    PubMed

    Strube, G; Holtz, H; Dittrich, P; Assmann, I; Dück, K D; Rothe, R

    1981-09-15

    61 patients at the age of 18 to 70 years with untreated atrial septum defect were examined 7.5 to 21 (on the average 10.5) years after the first recognition. Subjective symptomatology, clinical picture, size of the heart, mean pressure of the pulmonary artery and shunt volume at the beginning and at the end of the period of observation were analysed. The results reveal an above all favourable prognosis of the congenital malformation. In a course without complications an age can be reached adequate to the average life-expectance. After the 40th year of age, however, in 75% of the patients complaints appeared or their number increased. With growing age the size of the heart and the frequency of disturbances of the cardiac rhythm increased. In the small left-to right-shunt (less than 30% of the pulmonary flow) in the majority of the cases (85%) the prognosis proved to be good. Even in shunt volumes of more than 60% in half of the patients no essential deterioration developed in the period of observation. No clear relations were found between the mean pressure of the pulmonary artery and the clinical degree of severity. The indication to the operative correction of the atrial septum defect diagnosed only at the adult age demands a critical individual judgement, in which case apart from the haemodynamic parameters anamnesis and clinical findings within a cardiological observation of the course are of particular importance.

  12. P-wave Variability and Atrial Fibrillation

    PubMed Central

    Censi, Federica; Corazza, Ivan; Reggiani, Elisa; Calcagnini, Giovanni; Mattei, Eugenio; Triventi, Michele; Boriani, Giuseppe

    2016-01-01

    The analysis of P-wave template has been widely used to extract indices of Atrial Fibrillation (AF) risk stratification. The aim of this paper was to assess the potential of the analysis of the P-wave variability over time in patients suffering from atrial fibrillation. P-wave features extracted from P-wave template together with novel indices of P-wave variability have been estimated in a population of patients suffering from persistent AF and compared to those extracted from control subjects. We quantify the P-wave variability over time using three algorithms and we extracted three novel indices: one based on the cross-correlation coefficients among the P-waves (Cross-Correlation Index, CCI), one associated to variation in amplitude of the P-waves (Amplitude Dispersion Index, ADI), one sensible to the phase shift among P-waves (Warping Index, WI). The control group resulted to be characterized by shorter P-wave duration and by a less amount of fragmentation and variability, respect to AF patients. The parameter CCI shows the highest sensitivity (97.3%) and a good specificity (95%). PMID:27225709

  13. P-wave Variability and Atrial Fibrillation.

    PubMed

    Censi, Federica; Corazza, Ivan; Reggiani, Elisa; Calcagnini, Giovanni; Mattei, Eugenio; Triventi, Michele; Boriani, Giuseppe

    2016-01-01

    The analysis of P-wave template has been widely used to extract indices of Atrial Fibrillation (AF) risk stratification. The aim of this paper was to assess the potential of the analysis of the P-wave variability over time in patients suffering from atrial fibrillation. P-wave features extracted from P-wave template together with novel indices of P-wave variability have been estimated in a population of patients suffering from persistent AF and compared to those extracted from control subjects. We quantify the P-wave variability over time using three algorithms and we extracted three novel indices: one based on the cross-correlation coefficients among the P-waves (Cross-Correlation Index, CCI), one associated to variation in amplitude of the P-waves (Amplitude Dispersion Index, ADI), one sensible to the phase shift among P-waves (Warping Index, WI). The control group resulted to be characterized by shorter P-wave duration and by a less amount of fragmentation and variability, respect to AF patients. The parameter CCI shows the highest sensitivity (97.3%) and a good specificity (95%). PMID:27225709

  14. Studying Native America: Problems and Prospects.

    ERIC Educational Resources Information Center

    Thornton, Russell, Ed.

    Based on a conference, this volume examines the past, present, and future of Native American studies. Native American studies seeks to understand Native Americans, America, and the world from a Native American indigenous perspective, and thereby broaden the education of both Native and non-Native Americans. Part 1 asks who Native Americans are…

  15. Native Peoples-Native Homelands Climate Change Workshop: Lessons Learned

    NASA Technical Reports Server (NTRS)

    Maynard, Nancy G.

    2003-01-01

    The Native Peoples-Native Homelands Climate Change Workshop was held on October 28 through November 01,1998, as part of a series of workshops being held around the U.S. to improve the understanding of the potential consequences of climate variability and change for the Nation. This workshop was specifically designed by Native Peoples to examine the impacts of climate change and extreme weather variability on Native Peoples and Native Homelands from an indigenous cultural and spiritual perspective and to develop recommendations as well as identify potential response actions. The workshop brought together interested Native Peoples, representatives of Tribal governments, traditional elders, Tribal leaders, natural resource managers, Tribal College faculty and students, and climate scientists fiom government agencies and universities. It is clear that Tribal colleges and universities play a unique and critical role in the success of these emerging partnerships for decision-making in addition to the important education function for both Native and non-Native communities such as serving as a culturally-appropriate vehicle for access, analysis, control, and protection of indigenous cultural and intellectual property. During the discussions between scientists and policy-makers from both Native and non-Native communities, a number of important lessons emerged which are key to building more effective partnerships between Native and non-Native communities for collaboration and decision-making for a more sustainable future. This talk summarizes the key issues, recommendations, and lessons learned during this workshop.

  16. Transseptal fine needle aspiration of a large left atrial tumour.

    PubMed

    Wong, Chi Wing; Ruygrok, Peter; Sutton, Timothy; Ding, Patricia; van Vliet, Chris; Occleshaw, Christopher; Smith, Warren

    2010-07-01

    The diagnosis of cardiac tumours is often based on images without tissue diagnosis or tissue obtained at surgery. Percutaneous myocardial biopsy via a transvenous approach has been described in literatures but this technique is not feasible with left atrial tumours. We report a patient presenting with heart failure and left atrial tumour. The diagnosis of spindle cell neoplasm was established pre-operatively via successful transseptal fine needle aspiration of cells from a left atrial tumour. We believe this technique worth consideration to aid pre-surgery diagnosis.

  17. Atrial Septal Aneurysm Presenting as Clubbing without Clinically Apparent Cyanosis.

    PubMed

    Goyal, Laxmi Kant; Banerjee, S; Yadav, R N; Singh, Gajraj; Ganguli, Sujata; Isran, Rohit

    2015-09-01

    Atrial septal aneurysm (ASA) is a localised "saccular" deformity which protrudes to the right or the left atrium or on both sides. It is a rare, but well recognised cardiac abnormality. It is usually an incidental finding or may presents as atrial arrhythmias or arterial embolism. Though it is an acyanotic congenital heart disease but it may result in significant right to left shunt and cyanosis. We describe a patient of ASA with atrial septal defect who presented with clubbing and right to left shunt without clinically apparent cyanosis. PMID:27608873

  18. Native Americans' Interest in Horticulture.

    ERIC Educational Resources Information Center

    Meyer, Mary Hockenberry

    1999-01-01

    Focus groups arranged by local Native American Master Gardeners on two Minnesota reservations determined community interest in extension-horticulture programs. Topics of interest included food preservation and historical Native-American uses of plants. (SK)

  19. 76 FR 22413 - Alaska Native Claims Selection

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-21

    ...) to Afognak Native Corporation, Successor in Interest to Port Lions Native Corporation. The decision... surface estate is conveyed to Afognak Native Corporation, Successor in Interest to Port Lions...

  20. Four-and-a-half LIM domains proteins are novel regulators of the protein kinase D pathway in cardiac myocytes.

    PubMed

    Stathopoulou, Konstantina; Cuello, Friederike; Candasamy, Alexandra J; Kemp, Elizabeth M; Ehler, Elisabeth; Haworth, Robert S; Avkiran, Metin

    2014-02-01

    PKD (protein kinase D) is a serine/threonine kinase implicated in multiple cardiac roles, including the phosphorylation of the class II HDAC5 (histone deacetylase isoform 5) and thereby de-repression of MEF2 (myocyte enhancer factor 2) transcription factor activity. In the present study we identify FHL1 (four-and-a-half LIM domains protein 1) and FHL2 as novel binding partners for PKD in cardiac myocytes. This was confirmed by pull-down assays using recombinant GST-fused proteins and heterologously or endogenously expressed PKD in adult rat ventricular myocytes or NRVMs (neonatal rat ventricular myocytes) respectively, and by co-immunoprecipitation of FHL1 and FHL2 with GFP-PKD1 fusion protein expressed in NRVMs. In vitro kinase assays showed that neither FHL1 nor FHL2 is a PKD1 substrate. Selective knockdown of FHL1 expression in NRVMs significantly inhibited PKD activation and HDAC5 phosphorylation in response to endothelin 1, but not to the α₁-adrenoceptor agonist phenylephrine. In contrast, selective knockdown of FHL2 expression caused a significant reduction in PKD activation and HDAC5 phosphorylation in response to both stimuli. Interestingly, neither intervention affected MEF2 activation by endothelin 1 or phenylephrine. We conclude that FHL1 and FHL2 are novel cardiac PKD partners, which differentially facilitate PKD activation and HDAC5 phosphorylation by distinct neurohormonal stimuli, but are unlikely to regulate MEF2-driven transcriptional reprogramming.

  1. Development of a transgenic goat model wih cardiac-specific overexpression of transforming growth factor - {beta} 1 to study the relationship between atrial fibrosis and atrial fibrillation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Studies on patients, large animal models and transgenic mouse models have shown a strong association of atrial fibrosis with atrial fibrillation (AF). However, it is unclear whether there is a causal relationship between atrial fibrosis and AF or whether these events appear as a result of independen...

  2. Digital Natives or Digital Tribes?

    ERIC Educational Resources Information Center

    Watson, Ian Robert

    2013-01-01

    This research builds upon the discourse surrounding digital natives. A literature review into the digital native phenomena was undertaken and found that researchers are beginning to identify the digital native as not one cohesive group but of individuals influenced by other factors. Primary research by means of questionnaire survey of technologies…

  3. The lack of target specificity of small molecule anticancer kinase inhibitors is correlated with their ability to damage myocytes in vitro

    SciTech Connect

    Hasinoff, Brian B. Patel, Daywin

    2010-12-01

    Many new targeted small molecule anticancer kinase inhibitors are actively being developed. However, the clinical use of some kinase inhibitors has been shown to result in cardiotoxicity. In most cases the mechanisms by which they exert their cardiotoxicity are not well understood. We have used large scale profiling data on 8 FDA-approved tyrosine kinase inhibitors and 10 other kinase inhibitors to a panel of 317 kinases in order to correlate binding constants and kinase inhibitor binding selectivity scores with kinase inhibitor-induced damage to neonatal rat cardiac myocytes. The 18 kinase inhibitors that were the subject of this study were: canertinib, dasatinib, dovitinib, erlotinib, flavopiridol, gefitinib, imatinib, lapatinib, midostaurin, motesanib, pazopanib, sorafenib, staurosporine, sunitinib, tandutinib, tozasertib, vandetanib and vatalanib. The combined tyrosine kinase and serine-threonine kinase selectivity scores were highly correlated with the myocyte-damaging effects of the kinase inhibitors. This result suggests that myocyte damage was due to a lack of target selectivity to binding of both tyrosine kinases and serine-threonine kinases, and was not due to binding to either group specifically. Finally, the strength of kinase inhibitor binding for 290 kinases was examined for correlations with myocyte damage. Kinase inhibitor binding was significantly correlated with myocyte damage for 12 kinases. Thus, myocyte damage may be multifactorial in nature with the inhibition of a number of kinases involved in producing kinase inhibitor-induced myocyte damage.

  4. The lack of target specificity of small molecule anticancer kinase inhibitors is correlated with their ability to damage myocytes in vitro.

    PubMed

    Hasinoff, Brian B; Patel, Daywin

    2010-12-01

    Many new targeted small molecule anticancer kinase inhibitors are actively being developed. However, the clinical use of some kinase inhibitors has been shown to result in cardiotoxicity. In most cases the mechanisms by which they exert their cardiotoxicity are not well understood. We have used large scale profiling data on 8 FDA-approved tyrosine kinase inhibitors and 10 other kinase inhibitors to a panel of 317 kinases in order to correlate binding constants and kinase inhibitor binding selectivity scores with kinase inhibitor-induced damage to neonatal rat cardiac myocytes. The 18 kinase inhibitors that were the subject of this study were: canertinib, dasatinib, dovitinib, erlotinib, flavopiridol, gefitinib, imatinib, lapatinib, midostaurin, motesanib, pazopanib, sorafenib, staurosporine, sunitinib, tandutinib, tozasertib, vandetanib and vatalanib. The combined tyrosine kinase and serine-threonine kinase selectivity scores were highly correlated with the myocyte-damaging effects of the kinase inhibitors. This result suggests that myocyte damage was due to a lack of target selectivity to binding of both tyrosine kinases and serine-threonine kinases, and was not due to binding to either group specifically. Finally, the strength of kinase inhibitor binding for 290 kinases was examined for correlations with myocyte damage. Kinase inhibitor binding was significantly correlated with myocyte damage for 12 kinases. Thus, myocyte damage may be multifactorial in nature with the inhibition of a number of kinases involved in producing kinase inhibitor-induced myocyte damage. PMID:20832415

  5. CaMKII Negatively Regulates Calcineurin-NFAT Signaling in Cardiac Myocytes

    PubMed Central

    MacDonnell, Scott M.; Weisser-Thomas, Jutta; Kubo, Hajime; Hanscome, Marie; Liu, Qinghang; Jaleel, Naser; Berretta, Remus; Chen, Xiongwen; Brown, Joan H.; Sabri, Abdel-Karim; Molkentin, Jeffery D.; Houser, Steven R.

    2009-01-01

    Rationale Pathologic cardiac myocyte hypertrophy is thought to be induced by the persistent increases in intracellular Ca2+ needed to maintain cardiac function when systolic wall stress is increased. Hypertrophic Ca2+ binds to calmodulin (CaM) and activates the phosphatase calcineurin (Cn) and CaM kinase (CaMKII). Cn dephosphorylates cytoplasmic nuclear factor of activated T-cells (NFAT), inducing its translocation to the nucleus where it activates anti-apoptotic and hypertrophic target genes. Cytoplasmic CaMKII regulates Ca2+ handling proteins but whether or not it is directly involved in hypertrophic and survival signaling is not known. Objective This study explored the hypothesis that cytoplasmic CaMKII reduces NFAT nuclear translocation by inhibiting the phosphatase activity of Cn. Methods and Results GFP-tagged NFATc3 was used to determine the cellular location of NFAT in cultured neonatal rat ventricular myocytes (NRVM) and adult feline ventricular myocytes. Constitutively active (CaMKII-CA) or dominant negative (CaMKII-DN) mutants of cytoplasmic targeted CaMKIIδc were used to activate and inhibit cytoplasmic CaMKII activity. In NRVM CaMKII-DN (48.5±3%, P<0.01 vs control) increased while CaMKII-CA decreased (5.9±1%, P<0.01 vs control) NFAT nuclear translocation (Control: 12.3±1%). Cn inhibitors were used to show that these effects were caused by modulation of Cn activity. Increasing Ca2+ increased Cn-dependent NFAT translocation (to 71.7±7%, p<0.01) and CaMKII-CA reduced this effect (to 17.6±4%). CaMKII-CA increased TUNEL and caspase-3 activity (P<0.05). CaMKII directly phosphorylated Cn at Ser197 in CaMKII-CA infected NRVM and in hypertrophied feline hearts. Conclusion These data show that activation of cytoplasmic CaMKII inhibits NFAT nuclear translocation by phosphorylation and subsequent inhibition of Cn. PMID:19608982

  6. NFAT transcription factor regulation by urocortin II in cardiac myocytes and heart failure.

    PubMed

    Walther, Stefanie; Awad, Sawsan; Lonchyna, Vassyl A; Blatter, Lothar A

    2014-03-01

    Urocortin II (UcnII), a cardioactive peptide with beneficial effects in normal and failing hearts, is also arrhythmogenic and prohypertrophic. We demonstrated that cardiac effects are mediated by a phosphatidylinositol-3 kinase (PI3K)/Akt kinase (Akt)/endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling pathways. Nuclear factor of activated T-cells (NFAT) transcription factors play a key role in the regulation of gene expression in cardiac development, maintenance of an adult differentiated cardiac phenotype, and remodeling processes in cardiac hypertrophy and heart failure (HF). We tested the hypothesis that UcnII differentially regulates NFAT activity in cardiac myocytes from both normal and failing hearts through the PI3K/Akt/eNOS/NO pathway. Isoforms NFATc1 and NFATc3 revealed different basal subcellular distribution in normal and HF rabbit ventricular myocytes with a nuclear NFATc1 and a cytosolic localization of NFATc3. However, in HF, the nuclear localization of NFATc1 was less pronounced, whereas the nuclear occupancy of NFATc3 was increased. In normal myocytes, UcnII induced nuclear export of NFATc1 and attenuated NFAT-dependent transcriptional activity but did not affect the distribution of NFATc3. In HF UcnII facilitated nuclear export of both isoforms and reduced transcriptional activity. NFAT regulation was mediated by a PI3K/Akt/eNOS/NO signaling cascade that converged on the activation of several kinases, including glycogen synthase kinase-3β (GSK3β), c-Jun NH2-terminal kinase (JNK), p38 mitogen-activated kinase (p38), and PKG, resulting in phosphorylation, deactivation, and nuclear export of NFAT. In conclusion, while NFATc1 and NFATc3 reveal distinct subcellular distribution patterns, both are regulated by the UcnII-PI3K/Akt/eNOS/NO pathway that converges on the activation of NFAT kinases and NFAT inactivation. The data reconcile cardioprotective and prohypertrophic UcnII effects mediated by different NFAT isoforms.

  7. [Esophageal echocardiography in patients with cerebrovascular stroke and atrial fibrillation].

    PubMed

    Chlumský, J; Bojar, M; Sváb, P; Holá, D

    1997-04-01

    Atrial fibrillation is an important risk factor of embolization into the CNS. Thus affected patients should receive permanent anticoagulant therapy. Oesophageal echocardiography (TEE) can help our decision in patients with relative contraindications of anticoagulant therapy. TEE was performed in 52 patients with atrial fibrillation and cerebrovascular attack (CMP) with an ischaemic aetiology. Transthoracic echocardiography did not reveal the source of embolization. In 10% patients a thrombus was found in the appendage of the left atrium, in another 9% patients a spontaneous echocontrast was found in the left atrium (prethrombotic condition) and in 5% patients an open foramen ovale. The results indicate the highly probable etiology of embolization in patients with cerebrovascular attacks and atrial fibrillation. This supports the recommendation of absolute indication of anticoagulant treatment in patients with cerebrovascular attacks and atrial fibrillation.

  8. Genetics Home Reference: chronic atrial and intestinal dysrhythmia

    MedlinePlus

    ... Registry (1 link) Chronic atrial and intestinal dysrhythmia Scientific ... Brooker AS, Berkowitz KM. The roles of cohesins in mitosis, meiosis, and human health and disease. Methods Mol Biol. 2014;1170:229-66. doi: 10. ...

  9. Atrial Natriuretic Peptide Inhibits Spontaneous Contractile Activity of Lymph Nodes.

    PubMed

    Lobov, G I; Pan'kova, M N

    2016-06-01

    Atrial natriuretic peptide dose-dependently inhibited spontaneous phase and tonic activity of smooth muscle strips from the capsule of isolated bovine mesenteric lymph nodes. Pretreatment with L-NAME, diclofenac, and methylene blue had practically no effect on the peptide-induced relaxation responses. In contrast, glibenclamide significantly reduced the inhibitory effect of atrial natriuretic peptide. We suppose that the NO-dependent and cyclooxygenase signaling pathways are not involved in implementation of the inhibitory effects of atrial natriuretic peptide. ATP-sensitive K(+)-channels of the smooth muscle cell membrane are the last component in the signaling pathway leading to relaxation of smooth muscles of the lymph node capsule caused by atrial natriuretic peptide; activation of these channels leads to membrane hyperpolarization and smooth muscle relaxation. PMID:27383173

  10. Apixaban for the prevention of stroke in atrial fibrillation.

    PubMed

    Littrell, Rachel; Flaker, Greg

    2012-02-01

    Until recently, pharmaceutical options for stroke prevention in atrial fibrillation were restricted to aspirin or vitamin K antagonist therapy. In recent years development has been underway for alternatives. Apixaban, a direct Factor Xa inhibitor, is orally dosed, target selective and has few known drug or food interactions. As such, it is a member of a new generation of anticoagulants expected to revolutionize the way we approach anticoagulation for stroke prevention in atrial fibrillation. Apixaban has been studied in Phase II and Phase III trials for a variety of indications. The AVERROES trial established apixaban as superior to aspirin for stroke reduction in patients with atrial fibrillation for whom vitamin K antagonist therapy is unsuitable. The recent ARISTOTLE trial found apixaban to be superior to warfarin for stroke prevention in a wide range of patients with atrial fibrillation, with significantly lower bleeding risk, and lower risk of all-cause mortality. PMID:22292869

  11. R-CEPIA1er as a new tool to directly measure sarcoplasmic reticulum [Ca] in ventricular myocytes.

    PubMed

    Bovo, Elisa; Martin, Jody L; Tyryfter, Jollyn; de Tombe, Pieter P; Zima, Aleksey V

    2016-07-01

    In cardiomyocytes, [Ca] within the sarcoplasmic reticulum (SR; [Ca]SR) partially determines the amplitude of cytosolic Ca transient that, in turn, governs myocardial contraction. Therefore, it is critical to understand the molecular mechanisms that regulate [Ca]SR handling. Until recently, the best approach available to directly measure [Ca]SR was to use low-affinity Ca indicators (e.g., Fluo-5N). However, this approach presents several limitations, including nonspecific cellular localization, dye extrusion, and species limitation. Recently a new genetically encoded family of Ca indicators has been generated, named Ca-measuring organelle-entrapped protein indicators (CEPIA). Here, we tested the red fluorescence SR-targeted Ca sensor (R-CEPIA1er) as a tool to directly measure [Ca]SR dynamics in ventricular myocytes. Infection of rabbit and rat ventricular myocytes with an adenovirus expressing the R-CEPIA1er gene displayed prominent localization in the SR and nuclear envelope. Calibration of R-CEPIA1er in myocytes resulted in a Kd of 609 μM, suggesting that this sensor is sensitive in the whole physiological range of [Ca]SR [Ca]SR dynamics measured with R-CEPIA1er were compared with [Ca]SR measured with Fluo5-N. We found that both the time course of the [Ca]SR depletion and fractional SR Ca release induced by an action potential were similar between these two Ca sensors. R-CEPIA1er fluorescence did not decline during experiments, indicating lack of dye extrusion or photobleaching. Furthermore, measurement of [Ca]SR with R-CEPIA1er can be combined with cytosolic [Ca] measurements (with Fluo-4) to obtain more detailed information regarding Ca handling in cardiac myocytes. In conclusion, R-CEPIA1er is a promising tool that can be used to measure [Ca]SR dynamics in myocytes from different animal species. PMID:27233762

  12. Inherited Structural Heart Diseases With Potential Atrial Fibrillation Occurrence.

    PubMed

    Manuguerra, Roberta; Callegari, Sergio; Corradi, Domenico

    2016-02-01

    Inherited cardiac diseases inducing structural remodeling of the myocardium sometimes develop arrhythmias of various kinds. Among these rhythm disturbances, atrial fibrillation is well known to frequently worsen the prognosis of the primary disorder by increasing morbidity and mortality, especially because of a higher rate of heart failure. In this manuscript, we have reviewed the literature on the most important inherited structural cardiac diseases in whose clinical history atrial fibrillation may occur fairly often.

  13. Termination of acute wide QRS complex atrial fibrillation with ibutilide.

    PubMed

    Sobel, R M; Dhruva, N N

    2000-07-01

    Ibutilide is a Vaughan-Williams class III antiarrhythmic agent approved for chemical cardioversion of acute onset atrial fibrillation/flutter. Emergency physicians rarely use ibutilide despite its proven clinical value. We report a case of successful chemical cardioversion using ibutilide in a patient with atrial fibrillation and delayed ventricular depolarization (wide QRS complex). We recommend that ibutilide be considered for wider use in the emergency department and that further studies be conducted.

  14. Renal Denervation Suppresses the Inducibility of Atrial Fibrillation in a Rabbit Model for Atrial Fibrosis.

    PubMed

    Wei, Yong; Xu, Juan; Zhou, Genqing; Chen, Songwen; Ouyang, Ping; Liu, Shaowen

    2016-01-01

    Renal denervation (RD) was reported to reduce the susceptibility of atrial fibrillation (AF), but the underlying mechanism has not been well understood. This study was performed to investigate the effect of RD on the inducibility of AF in a rabbit model for atrial fibrosis and to explore the potential mechanisms. Thirty-five rabbits were randomly assigned into sham-operated group (n = 12), abdominal aortic constriction (AAC) group (n = 12) and AAC with RD (AAC-RD) group (n = 11). The incidence of AF induced by burst pacing in atriums was determined. Blood was collected to measure the levels of rennin, angiotensin II and aldosterone. Atrial samples were preserved to evaluate protein and gene expression of collagen, connective tissue growth factor (CTGF) and transforming growth factor-β1 (TGF-β1). Our data suggested cardiac structure remodeling and atrial fibrosis were successfully induced by AAC. Compared with the AAC group, the AAC-RD rabbits had smaller ascending aortic diameter and left ventricular end-systolic diameter. For burst pacing at the left atrium (LA), AF was induced in two of the 12 rabbits in the sham-operated group, 10 of the 12 rabbits in the AAC group, and 2 of the 11 rabbits in the AAC-RD group, with great difference among the three groups (P = 0.001). The percentage of LA burst stimulations with induced AF achieved 47.2% in the AAC group, which was higher than those in both the AAC-RD (12.1%) and the Sham-operated (5.6%) groups. Significantly increasing intercellular space in the AAC group (P<0.001) compared with the sham-operated rabbits. RD clearly decreased the volume fraction of collagen in LA and right atrium compared with that of the AAC group (P< 0.01). AAC-induced elevation of collagen I, CTGF and TGF-β1 was suppressed by RD. In conclusion, RD suppressed the inducibility of AF in a rabbit model for pressure associated atrial fibrosis, potentially by modulating renin-angiotensin-aldosterone system and decreasing pro-fibrotic factors

  15. Renal Denervation Suppresses the Inducibility of Atrial Fibrillation in a Rabbit Model for Atrial Fibrosis

    PubMed Central

    Zhou, Genqing; Chen, Songwen; Ouyang, Ping; Liu, Shaowen

    2016-01-01

    Renal denervation (RD) was reported to reduce the susceptibility of atrial fibrillation (AF), but the underlying mechanism has not been well understood. This study was performed to investigate the effect of RD on the inducibility of AF in a rabbit model for atrial fibrosis and to explore the potential mechanisms. Thirty-five rabbits were randomly assigned into sham-operated group (n = 12), abdominal aortic constriction (AAC) group (n = 12) and AAC with RD (AAC-RD) group (n = 11). The incidence of AF induced by burst pacing in atriums was determined. Blood was collected to measure the levels of rennin, angiotensin II and aldosterone. Atrial samples were preserved to evaluate protein and gene expression of collagen, connective tissue growth factor (CTGF) and transforming growth factor-β1 (TGF-β1). Our data suggested cardiac structure remodeling and atrial fibrosis were successfully induced by AAC. Compared with the AAC group, the AAC-RD rabbits had smaller ascending aortic diameter and left ventricular end-systolic diameter. For burst pacing at the left atrium (LA), AF was induced in two of the 12 rabbits in the sham-operated group, 10 of the 12 rabbits in the AAC group, and 2 of the 11 rabbits in the AAC-RD group, with great difference among the three groups (P = 0.001). The percentage of LA burst stimulations with induced AF achieved 47.2% in the AAC group, which was higher than those in both the AAC-RD (12.1%) and the Sham-operated (5.6%) groups. Significantly increasing intercellular space in the AAC group (P<0.001) compared with the sham-operated rabbits. RD clearly decreased the volume fraction of collagen in LA and right atrium compared with that of the AAC group (P< 0.01). AAC-induced elevation of collagen I, CTGF and TGF-β1 was suppressed by RD. In conclusion, RD suppressed the inducibility of AF in a rabbit model for pressure associated atrial fibrosis, potentially by modulating renin-angiotensin-aldosterone system and decreasing pro-fibrotic factors

  16. Atrial Fibrillation, Cognitive Decline And Dementia

    PubMed Central

    Alonso, Alvaro; Arenas de Larriva, Antonio P.

    2016-01-01

    Atrial fibrillation (AF) is a common cardiac arrhythmia. Growing evidence supports a role for AF as a risk factor for cognitive decline and dementia. In this review, we summarize epidemiologic observations linking AF with cognitive outcomes, describe potential mechanisms, and explore the impact of AF treatments on cognitive decline and dementia. Community-based, observational studies show a consistent higher rate of cognitive decline and risk of dementia in persons with AF. These associations are partly due to the increased risk of clinical stroke in AF, but other mechanisms, including incidence of silent cerebral infarcts, microbleeds, and cerebral hypoperfusion, are likely additional contributors. Adequate oral anticoagulation and improved management of the overall cardiovascular risk profile in persons with AF offer the promise of reducing the impact of AF on cognitive decline and dementia. PMID:27547248

  17. Bridging the gender gap in atrial fibrillation.

    PubMed

    Oza, Nishaki Mehta; Baveja, Swati; Tedrow, Usha

    2015-03-01

    Women have a similar lifetime prevalence of non-valvular atrial fibrillation (NVAF) compared with that of men. Given the significant morbidity and potential mortality associated with NVAF, it is crucial to understand gender differences with NVAF. Women can be more symptomatic than men. Despite a higher baseline stroke risk, they are less likely to be on anticoagulation. Women have a greater risk of thromboembolism and a similar rate of bleeding risk compared with men on anticoagulation. Initial experience suggests that novel oral anticoagulants have similar safety and efficacy profile in men and women. Although women can have more adverse reactions from antiarrhythmic therapies, they are often referred later than men for ablation. As a group, a mitigating factor in ablation referral is that women also have a higher incidence of procedural complications from catheter ablation. This review summarizes the available literature highlighting significant gender-based differences and also highlights areas for research to improve NVAF outcomes in women. PMID:25586881

  18. Individualising Anticoagulant Therapy in Atrial Fibrillation Patients.

    PubMed

    Alings, Marco

    2016-08-01

    Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have emerged as alternatives to VKAs for the prevention of stroke in patients with non-valvular atrial fibrillation. Four NOACS: dabigatran, apixaban, rivaroxaban and edoxaban, have received regulatory approval in Europe from the European Medicines Agency. Numerous factors can influence the decision to prescribe a NOAC, the most important of which are assessment of stroke and bleeding risks. Given the variation in design of the pivotal phase III clinical trials investigating the efficacy and safety of NOACs, and in the absence of head-to-head comparative data, it is impossible to recommend one NOAC over the other. However, NOACS offer the opportunity for individualised therapy based on factors such as renal function, age or patient/doctor preference for once- or twice-daily dosing regimens. Dose reduction of some NOACS should be considered in at-risk patient populations. PMID:27617088

  19. Familial recurrent atrial myxoma: Carney's complex.

    PubMed

    Shetty Roy, A Nagesh; Radin, Michael; Sarabi, Dennis; Shaoulian, Emanuel

    2011-02-01

    We report on a family of 4 members, all of whom have had multifocal, recurrent atrial myxomas associated with skin pigmentation, melanotic schwannomas, mucocutaneous myxomas, and tumors of the ovary and pituitary, adrenal, and thyroid glands. Immunochemistry of the myxoma cells is positive for calretinin, confirming their neuroendocrine origin. Genetic studies confirmed mutations in the gene coding protein kinase A, regulatory subunit 1-α (PRKAR1α). This is Carney's complex, characterized by multiple, mucocutaneous myxomas; pigmented lesions over the lips, conjunctiva, and genitalia; adenomas of the breast and thyroid; schwannomas; and endocrinal abnormalities including C