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Sample records for native atrial myocytes

  1. Benchmarking electrophysiological models of human atrial myocytes

    PubMed Central

    Wilhelms, Mathias; Hettmann, Hanne; Maleckar, Mary M.; Koivumäki, Jussi T.; Dössel, Olaf; Seemann, Gunnar

    2013-01-01

    Mathematical modeling of cardiac electrophysiology is an insightful method to investigate the underlying mechanisms responsible for arrhythmias such as atrial fibrillation (AF). In past years, five models of human atrial electrophysiology with different formulations of ionic currents, and consequently diverging properties, have been published. The aim of this work is to give an overview of strengths and weaknesses of these models depending on the purpose and the general requirements of simulations. Therefore, these models were systematically benchmarked with respect to general mathematical properties and their ability to reproduce certain electrophysiological phenomena, such as action potential (AP) alternans. To assess the models' ability to replicate modified properties of human myocytes and tissue in cardiac disease, electrical remodeling in chronic atrial fibrillation (cAF) was chosen as test case. The healthy and remodeled model variants were compared with experimental results in single-cell, 1D and 2D tissue simulations to investigate AP and restitution properties, as well as the initiation of reentrant circuits. PMID:23316167

  2. Mechanism for Triggered Waves in Atrial Myocytes.

    PubMed

    Shiferaw, Yohannes; Aistrup, Gary L; Wasserstrom, J Andrew

    2017-08-08

    Excitation-contraction coupling in atrial cells is mediated by calcium (Ca) signaling between L-type Ca channels and Ryanodine receptors that occurs mainly at the cell boundary. This unique architecture dictates essential aspects of Ca signaling under both normal and diseased conditions. In this study we apply laser scanning confocal microscopy, along with an experimentally based computational model, to understand the Ca cycling dynamics of an atrial cell subjected to rapid pacing. Our main finding is that when an atrial cell is paced under Ca overload conditions, Ca waves can then nucleate on the cell boundary and propagate to the cell interior. These propagating Ca waves are referred to as "triggered waves" because they are initiated by L-type Ca channel openings during the action potential. These excitations are distinct from spontaneous Ca waves originating from random fluctuations of Ryanodine receptor channels, and which occur after much longer waiting times. Furthermore, we argue that the onset of these triggered waves is a highly nonlinear function of the sarcoplasmic reticulum Ca load. This strong nonlinearity leads to aperiodic response of Ca at rapid pacing rates that is caused by the complex interplay between paced Ca release and triggered waves. We argue further that this feature of atrial cells leads to dynamic instabilities that may underlie atrial arrhythmias. These studies will serve as a starting point to explore the nonlinear dynamics of atrial cells and will yield insights into the trigger and maintenance of atrial fibrillation. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  3. Ultrarapid delayed rectifier current inactivation in human atrial myocytes: properties and consequences.

    PubMed

    Feng, J; Xu, D; Wang, Z; Nattel, S

    1998-11-01

    The ultrarapid delayed rectifier current (IK,ur) plays a significant role in human atrial repolarization and is generally believed to show little rate dependence because of slow and partial inactivation. This study was designed to evaluate in detail the properties and consequences of IK,ur inactivation in isolated human atrial myocytes. IK,ur inactivated with a biexponential time course and a half-inactivation voltage of -7.5 +/- 0.6 mV (mean +/- SE), with complete inactivation during 50-s pulses to voltages positive to +10 mV (37 degreesC). Recovery from inactivation proceeded slowly, with time constants of 0.42 +/- 0.06 and 7.9 +/- 0.9 s at -80 mV (37 degreesC). Substantial frequency dependence was observed at 37 degreesC over a clinically relevant range of frequencies. Inactivation was faster and occurred at more positive voltages at 37 degreesC compared with room temperature. The voltage and time dependencies of Kv1.5 inactivation were studied in Xenopus oocytes to avoid overlapping currents and strongly resembled those of IK,ur in native myocytes. We conclude that, while IK,ur inactivation is slow, it is extensive, and slow recovery from inactivation confers important frequency dependence with significant consequences for understanding the role of IK,ur in human atrial repolarization.

  4. Enhanced expression of ROCK in left atrial myocytes of mitral regurgitation: a potential mechanism of myolysis.

    PubMed

    Chen, Huang-Chung; Chang, Jen-Ping; Chang, Tzu-Hao; Lin, Yu-Sheng; Huang, Yao-Kuang; Pan, Kuo-Li; Fang, Chih-Yuan; Chen, Chien-Jen; Ho, Wan-Chun; Chen, Mien-Cheng

    2015-05-09

    Severe mitral regurgitation (MR) may cause myolysis in the left atrial myocytes. Myolysis may contribute to atrial enlargement. However, the relationship between Rho-associated kinase (ROCK) and myolysis in the left atrial myocytes of MR patients remain unclear. This study comprised 22 patients with severe MR [12 with atrial fibrillation (AF) and ten in sinus rhythm]. Left atrial appendage tissues were obtained during surgery. Normal left atrial tissues were purchased. Immunofluorescence histochemical and immunoblotting studies were performed. The expression of ROCK2 in the myolytic left atrial myocytes of MR AF patients (p = 0.009) and MR sinus patients (p = 0.011) were significantly higher than that of the normal subjects. Similarly, the expression of ROCK1 in the myolytic left atrial myocytes of MR AF patients was significantly higher than that of the normal subjects (p = 0.010), and the expression of ROCK1 in the myolytic left atrial myocytes of MR sinus patients was higher than that of the normal subjects (p = 0.091). Immunofluorescence study revealed significant co-localization and juxtaposition of ROCK2 and cleaved caspase-3 in the left atrial myocytes both in the MR AF group (Pearson's coefficient = 0.74 ± 0.03) and the MR sinus group (Pearson's coefficient = 0.73 ± 0.02). Similarly, immunofluorescence study revealed significant co-localization and juxtaposition of ROCK1 and cleaved caspase-3 in the left atrial myocytes both in the MR AF group (Pearson's coefficient = 0.65 ± 0.03) and the MR sinus group (Pearson's coefficient = 0.65 ± 0.03). Correlation analysis demonstrated that there was a significant direct relationship between the expression of ROCK2 in the myolytic left atrial myocytes and left atrial diameter in the MR patients (p = 0.041; r = 0.440). Moreover, the ratio of phosphorylated myosin-binding subunit of myosin light chain phosphatase (pMBS)/total MBS of left atrial tissues was significantly higher in the MR AF group (p < 0.04) and the

  5. Differences between outward currents of human atrial and subepicardial ventricular myocytes.

    PubMed Central

    Amos, G J; Wettwer, E; Metzger, F; Li, Q; Himmel, H M; Ravens, U

    1996-01-01

    1. Outward currents were studied in myocytes isolated from human atrial and subepicardial ventricular myocardium using the whole-cell voltage clamp technique at 22 degrees C. The Na+ current was inactivated with prepulses to -40 mV and the Ca2+ current was eliminated by both reducing extracellular [Ca2+] to 0.5 mM and addition of 100 microM CdCl2 to the bath solution. 2. In human myocytes, three different outward currents were observed. A slowly inactivating sustained outward current, I(so), was found in atrial but not ventricular myocytes. A rapidly inactivating outward current, I(to), of similar current density was observed in cells from the two tissues. An additional uncharacterized non-inactivating background current of similar size was observed in atrial and in ventricular myocytes. 3. I(to) and I(so) could be differentiated in atrial myocytes by their different kinetics and potential dependence of inactivation, and their different sensitivities to block by 4-amino-pyridine, suggesting that two individual channel types were involved. 4. In atrial cells, inactivation of I(to) was more rapid and steady-state inactivation occurred at more negative membrane potentials than in ventricular cells. Furthermore, the recovery of I(to) from inactivation was slower and without overshoot in atrial myocytes. In addition, 4-aminopyridine-induced block of I(to) was more efficient in atrial than in ventricular cells. These observations suggest that the channels responsible for atrial and ventricular I(to) were not identical. 5. We conclude that the differences in outward currents substantially contribute to the particular shapes of human atrial and ventricular action potentials. The existence of I(so) in atrial cells only provides a clinically interesting target for anti-arrhythmic drug action, since blockers of I(so) would selectively prolong the atrial refractory period, leaving ventricular refractoriness unaltered. PMID:9011620

  6. Heat stress responses modulate calcium regulations and electrophysiological characteristics in atrial myocytes.

    PubMed

    Chen, Yao-Chang; Kao, Yu-Hsun; Huang, Chun-Feng; Cheng, Chen-Chuan; Chen, Yi-Jen; Chen, Shih-Ann

    2010-04-01

    Heat stress-induced responses change the ionic currents and calcium homeostasis. However, the molecular insights into the heat stress responses on calcium homeostasis remain unclear. The purposes of this study were to examine the mechanisms of heat stress responses on calcium handling and electrophysiological characteristics in atrial myocytes. We used indo-1 fluorimetric ratio technique and whole-cell patch clamp to investigate the intracellular calcium, action potentials, and ionic currents in isolated rabbit single atrial cardiomyocytes with or without (control) exposure to heat stress (43 degrees C, 15 min) 5+/-1 h before experiments. The expressions of sarcoplasmic reticulum ATPase (SERCA2a), and Na(+)-Ca(2+) exchanger (NCX) in the control and heat stress-treated atrial myocytes were evaluated by Western blot and real-time PCR. As compared with control myocytes, the heat stress-treated myocytes had larger sarcoplasmic reticulum calcium content and larger intracellular calcium transient with a shorter decay portion. Heat stress-treated myocytes also had larger L-type calcium currents, transient outward potassium currents, but smaller NCX currents. Heat stress responses increased the protein expressions, SERCA2a, NCX, and heat shock protein. However, heat stress responses did not change the RNA expression of SERCA2a and NCX. In conclusion, heat stress responses change calcium handling through protein but not RNA regulation.

  7. Cyclical stretch induces structural changes in atrial myocytes.

    PubMed

    De Jong, Anne Margreet; Maass, Alexander H; Oberdorf-Maass, Silke U; De Boer, Rudolf A; Van Gilst, Wiek H; Van Gelder, Isabelle C

    2013-06-01

    Atrial fibrillation (AF) often occurs in the presence of an underlying disease. These underlying diseases cause atrial remodelling, which make the atria more susceptible to AF. Stretch is an important mediator in the remodelling process. The aim of this study was to develop an atrial cell culture model mimicking remodelling due to atrial pressure overload. Neonatal rat atrial cardiomyocytes (NRAM) were cultured and subjected to cyclical stretch on elastic membranes. Stretching with 1 Hz and 15% elongation for 30 min. resulted in increased expression of immediate early genes and phosphorylation of Erk and p38. A 24-hr stretch period resulted in hypertrophy-related changes including increased cell diameter, reinduction of the foetal gene program and cell death. No evidence of apoptosis was observed. Expression of atrial natriuretic peptide, brain natriuretic peptide and growth differentiation factor-15 was increased, and calcineurin signalling was activated. Expression of several potassium channels was decreased, suggesting electrical remodelling. Atrial stretch-induced change in skeletal α-actin expression was inhibited by pravastatin, but not by eplerenone or losartan. Stretch of NRAM results in elevation of stress markers, changes related to hypertrophy and dedifferentiation, electrical remodelling and cell death. This model can contribute to investigating the mechanisms involved in the remodelling process caused by stretch and to the testing of pharmaceutical agents.

  8. Effects of NIP-141 on K currents in human atrial myocytes.

    PubMed

    Seki, Akiko; Hagiwara, Nobuhisa; Kasanuki, Hiroshi

    2002-01-01

    A novel benzopyran derivative, NIP-141, effectively terminates experimental atrial fibrillation in canine hearts by prolonging atrial refractoriness. However, the effects of this drug on human atrial myocytes are unknown. This experiment evaluated the effects of NIP-141 on K currents in isolated human atrial myocytes using a whole-cell voltage-clamp method. NIP-141 inhibited the transient outward current (I(to)) and the ultra-rapid delayed rectifier K current (I(Kur)), each in a dose-dependent manner, with half-maximal inhibition concentrations of 16.3 microM and 5.3 microM, respectively (n = 5). NIP-141 inhibited both K currents in a voltage- and use-independent fashion, and it preferentially blocked them in the open state and dissociated rapidly from the channel. Because both K currents contribute significantly to the repolarization of the atrial action potential, these findings suggest that NIP-141 may terminate atrial fibrillation by prolonging action potential duration.

  9. Excavatolide B Modulates the Electrophysiological Characteristics and Calcium Homeostasis of Atrial Myocytes

    PubMed Central

    Hwang, Hwong-Ru; Tai, Buh-Yuan; Cheng, Pao-Yun; Chen, Ping-Nan; Sung, Ping-Jyun; Wen, Zhi-Hong; Hsu, Chih-Hsueng

    2017-01-01

    Severe bacterial infections caused by sepsis always result in profound physiological changes, including fever, hypotension, arrhythmia, necrosis of tissue, systemic multi-organ dysfunction, and finally death. The lipopolysaccharide (LPS) provokes an inflammatory response under sepsis, which may increase propensity to arrhythmogenesis. Excavatolide B (EXCB) possesses potent anti-inflammatory effects. However, it is not clear whether EXCB could modulate the electrophysiological characteristics and calcium homeostasis of atrial myocytes. This study investigated the effects of EXCB on the atrial myocytes exposed to lipopolysaccharide. A whole-cell patch clamp and indo-1 fluorimetric ratio technique was employed to record the action potential (AP), ionic currents, and intracellular calcium ([Ca2+]i) in single, isolated rabbit left atrial (LA) cardiomyocytes, with and without LPS (1 μg/mL) and LPS + EXCB administration (10 μM) for 6 ± 1 h, in order to investigate the role of EXCB on atrial electrophysiology. In the presence of LPS, EXCB-treated LA myocytes (n = 13) had a longer AP duration at 20% (29 ± 2 vs. 20 ± 2 ms, p < 0.05), 50% (52 ± 4 vs. 40 ± 3 ms, p < 0.05), and 90% (85 ± 5 vs. 68 ± 3 ms, p < 0.05), compared to the LPS-treated cells (n = 12). LPS-treated LA myocytes showed a higher late sodium current, Na+/Ca2+ exchanger current, transient outward current, and delayed rectifier potassium current, but a lower l-type Ca2+ current, than the control LA myocytes. Treatment with EXCB reversed the LPS-induced alterations of the ionic currents. LPS-treated, EXCB-treated, and control LA myocytes exhibited similar Na+ currents. In addition, the LPS-treated LA myocytes exhibited a lower [Ca2+]i content and higher sarcoplasmic reticulum calcium content, than the controls. EXCB reversed the LPS-induced calcium alterations. In conclusion, EXCB modulates LPS-induced LA electrophysiological characteristics and calcium homeostasis, which may contribute to attenuating

  10. Effects of Acetylcholine and Noradrenalin on Action Potentials of Isolated Rabbit Sinoatrial and Atrial Myocytes

    PubMed Central

    Verkerk, Arie O.; Geuzebroek, Guillaume S. C.; Veldkamp, Marieke W.; Wilders, Ronald

    2012-01-01

    The autonomic nervous system controls heart rate and contractility through sympathetic and parasympathetic inputs to the cardiac tissue, with acetylcholine (ACh) and noradrenalin (NA) as the chemical transmitters. In recent years, it has become clear that specific Regulators of G protein Signaling proteins (RGS proteins) suppress muscarinic sensitivity and parasympathetic tone, identifying RGS proteins as intriguing potential therapeutic targets. In the present study, we have identified the effects of 1 μM ACh and 1 μM NA on the intrinsic action potentials of sinoatrial (SA) nodal and atrial myocytes. Single cells were enzymatically isolated from the SA node or from the left atrium of rabbit hearts. Action potentials were recorded using the amphotericin-perforated patch-clamp technique in the absence and presence of ACh, NA, or a combination of both. In SA nodal myocytes, ACh increased cycle length and decreased diastolic depolarization rate, whereas NA decreased cycle length and increased diastolic depolarization rate. Both ACh and NA increased maximum upstroke velocity. Furthermore, ACh hyperpolarized the maximum diastolic potential. In atrial myocytes stimulated at 2 Hz, both ACh and NA hyperpolarized the maximum diastolic potential, increased the action potential amplitude, and increased the maximum upstroke velocity. Action potential duration at 50 and 90% repolarization was decreased by ACh, but increased by NA. The effects of both ACh and NA on action potential duration showed a dose dependence in the range of 1–1000 nM, while a clear-cut frequency dependence in the range of 1–4 Hz was absent. Intermediate results were obtained in the combined presence of ACh and NA in both SA nodal and atrial myocytes. Our data uncover the extent to which SA nodal and atrial action potentials are intrinsically dependent on ACh, NA, or a combination of both and may thus guide further experiments with RGS proteins. PMID:22754533

  11. Mathematical Models of Atrial and Ventricular Myocytes from the Rabbit Heart

    NASA Astrophysics Data System (ADS)

    Murphey, Carey Richard

    Mathematical models of rabbit atrial and ventricular myocytes that are based on quantitative voltage clamp data from emzymatically isolated cardiac myocytes have been developed. These models are capable of accurately simulating the transmembrane ionic currents recorded in response to a step change in membrane potential (whole-cell voltage clamp response), the nonpropagated membrane action potential (MAP), and the frequency-dependent action potential waveshape changes occurring in response to variations in rate of stimulation. Rectangular pulse, ramp and action potential voltage -clamp measurements of the transmembrane ionic currents have allowed us to model a number of processes thought to be important during repolarization. These computations provide important biophysical insights into the electrophysiological activity of atrial and ventricular cells and their associated intra- and extracellular ionic concentration changes. The present model also has useful predictive capabilities. We have used the model to: (1) estimate the intracellular Ca^{2+} transient in these myocytes and to compare the relative occupancy of the Ca^{2+} binding sites in the contractile proteins with known cellular mechanical activity, and (2) predict the response of the atrial cell to potassium current blockade via BaCl_2 to the bathing medium.

  12. Selective activation of heteromeric SK channels contributes to action potential repolarization in mouse atrial myocytes.

    PubMed

    Hancock, Jane M; Weatherall, Kate L; Choisy, Stéphanie C; James, Andrew F; Hancox, Jules C; Marrion, Neil V

    2015-05-01

    Activation of small conductance calcium-activated potassium (SK) channels is proposed to contribute to repolarization of the action potential in atrial myocytes. This role is controversial, as these cardiac SK channels appear to exhibit an uncharacteristic pharmacology. The objectives of this study were to resolve whether activation of SK channels contributes to atrial action potential repolarization and to determine the likely subunit composition of the channel. The effect of 2 SK channel inhibitors was assessed on outward current evoked in voltage clamp and on action potential duration in perforated patch and whole-cell current clamp recording from acutely isolated mouse atrial myocytes. The presence of SK channel subunits was assessed using immunocytochemistry. A significant component of outward current was reduced by the SK channel blockers apamin and UCL1684. Block by apamin displayed a sensitivity indicating that this current was carried by homomeric SK2 channels. Action potential duration was significantly prolonged by UCL1684, but not by apamin. This effect was accompanied by an increase in beat-to-beat variability and action potential triangulation. This pharmacology was matched by that of expressed heteromeric SK2-SK3 channels in HEK293 cells. Immunocytochemistry showed that atrial myocytes express both SK2 and SK3 channels with an overlapping expression pattern. Only proposed heteromeric SK2-SK3 channels are physiologically activated to contribute to action potential repolarization, which is indicated by the difference in pharmacology of evoked outward current and prolongation of atrial action potential duration. The effect of blocking this channel on the action potential suggests that SK channel inhibition during cardiac function has the potential to be proarrhythmic. Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

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

    PubMed Central

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

    2011-01-01

    Transverse (t) tubules are surface membrane invaginations that are present in all mammalian cardiac ventricular cells. The apposition of L-type Ca2+ 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 Ca2+. T tubules are virtually absent in the atria of small mammals, and therefore Ca2+ 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, Ca2+ 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 Ca2+ transient and how this is perturbed in disease. PMID:21841013

  14. Swelling-induced Cl- current in guinea-pig atrial myocytes: inhibition by glibenclamide.

    PubMed Central

    Sakaguchi, M; Matsuura, H; Ehara, T

    1997-01-01

    1. Whole-cell currents were recorded from guinea-pig atrial myocytes using the patch-clamp technique under conditions designed to block K+ channels, Ca2+ channels and electrogenic transporters. 2. Exposure of atrial myocytes to the hyposmotic external solution (Na+ reduction to about 70% of control) resulted in hyposmotic cell swelling which was associated with activation of an outwardly rectifying Cl- current (ICl,swell). 3. Whereas the activation of ICl,swell was not significantly affected by replacement of ATP in the pipette solution with the non-hydrolysable ATP analogue 5'-adenylyl-imidodiphosphate (AMP-PNP), its activation was greatly reduced in cells dialysed with an ATP-free pipette solution, thus indicating that the activation process of ICl,swell requires the presence of intracellular ATP, but not its hydrolysis. 4. Bath application of glibenclamide produced a concentration-dependent block of ICl,swell with a half-maximal inhibitory concentration (IC50) of 60.0 microM and a Hill coefficient of 2.1. The maximal effect (100% inhibition) was obtained with 500 microM glibenclamide. The steady-state inhibition showed little voltage dependence, while glibenclamide at concentrations of more than 100 microM inhibited the outward ICl,swell more rapidly than the inward ICl,swell. The glibenclamide inhibition was fully reversible after removal of the drug, even when a maximal effect (full inhibition) was achieved at a high drug concentration (500 microM). 5. These results show that (i) glibenclamide is one of the most potent inhibitors of guinea-pig atrial ICl,swell, and (ii) atrial ICl,swell and the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- currents are almost equally sensitive to inhibition by glibenclamide. Images Figure 1 PMID:9409470

  15. Adrenergic control of the ultrarapid delayed rectifier current in canine atrial myocytes.

    PubMed

    Yue, L; Feng, J; Wang, Z; Nattel, S

    1999-04-15

    1. The effects of adrenergic stimulation on the ultrarapid delayed rectifier K+ current (IKur,d) of dog atrial myocytes was studied with patch-clamp methods. 2. Isoproterenol (isoprenaline) increased IKur,d in a concentration-dependent fashion with an EC50 of 7.3 +/- 0.8 nM. The effect of isoproterenol was blocked by propranolol, mimicked by forskolin and 8-bromo-cAMP, and prevented by inhibition of protein kinase A. 3. Phenylephrine (in the presence of propranolol) increased IKur,d with an EC50 of 0.49 +/- 0.06 microM. The effect of phenylephrine was blocked by prazosin, prevented by inhibition of protein kinase C, and mimicked by activation of protein kinase C with phorbol ester. 4. Phenylephrine significantly abbreviated canine atrial action potential duration in the absence of tetraethylammonium (TEA). When TEA was present under both control conditions and in the presence of phenylephrine, phenylephrine failed to alter canine atrial repolarization. 5. We conclude that beta- and alpha-adrenergic stimulation increase IKur,d via protein kinase A and C, respectively, and that the induced changes in IKur,d may play a role in adrenergic control of canine atrial repolarization.

  16. Aerobic interval training partly reverse contractile dysfunction and impaired Ca2+ handling in atrial myocytes from rats with post infarction heart failure.

    PubMed

    Johnsen, Anne Berit; Høydal, Morten; Røsbjørgen, Ragnhild; Stølen, Tomas; Wisløff, Ulrik

    2013-01-01

    There is limited knowledge about atrial myocyte Ca(2+) handling in the failing hearts. The aim of this study was to examine atrial myocyte contractile function and Ca(2+) handling in rats with post-infarction heart failure (HF) and to examine whether aerobic interval training could reverse a potential dysfunction. Post-infarction HF was induced in Sprague Dawley rats by ligation of the left descending coronary artery. Atrial myocyte shortening was depressed (p<0.01) and time to relaxation was prolonged (p<0.01) in sedentary HF-rats compared to healthy controls. This was associated with decreased Ca(2+) amplitude, decreased SR Ca(2+) content, and slower Ca(2+) transient decay. Atrial myocytes from HF-rats had reduced sarcoplasmic reticulum Ca(2+) ATPase activity, increased Na(+)/Ca(2+)-exchanger activity and increased diastolic Ca(2+) leak through ryanodine receptors. High intensity aerobic interval training in HF-rats restored atrial myocyte contractile function and reversed changes in atrial Ca(2+) handling in HF. Post infarction HF in rats causes profound impairment in atrial myocyte contractile function and Ca(2+) handling. The observed dysfunction in atrial myocytes was partly reversed after aerobic interval training.

  17. Aerobic Interval Training Partly Reverse Contractile Dysfunction and Impaired Ca2+ Handling in Atrial Myocytes from Rats with Post Infarction Heart Failure

    PubMed Central

    Johnsen, Anne Berit; Høydal, Morten; Røsbjørgen, Ragnhild; Stølen, Tomas; Wisløff, Ulrik

    2013-01-01

    Background There is limited knowledge about atrial myocyte Ca2+ handling in the failing hearts. The aim of this study was to examine atrial myocyte contractile function and Ca2+ handling in rats with post-infarction heart failure (HF) and to examine whether aerobic interval training could reverse a potential dysfunction. Methods and results Post-infarction HF was induced in Sprague Dawley rats by ligation of the left descending coronary artery. Atrial myocyte shortening was depressed (p<0.01) and time to relaxation was prolonged (p<0.01) in sedentary HF-rats compared to healthy controls. This was associated with decreased Ca2+ amplitude, decreased SR Ca2+ content, and slower Ca2+ transient decay. Atrial myocytes from HF-rats had reduced sarcoplasmic reticulum Ca2+ ATPase activity, increased Na+/Ca2+-exchanger activity and increased diastolic Ca2+ leak through ryanodine receptors. High intensity aerobic interval training in HF-rats restored atrial myocyte contractile function and reversed changes in atrial Ca2+ handling in HF. Conclusion Post infarction HF in rats causes profound impairment in atrial myocyte contractile function and Ca2+ handling. The observed dysfunction in atrial myocytes was partly reversed after aerobic interval training. PMID:23799089

  18. miR-208b upregulation interferes with calcium handling in HL-1 atrial myocytes: Implications in human chronic atrial fibrillation.

    PubMed

    Cañón, Susana; Caballero, Ricardo; Herraiz-Martínez, Adela; Pérez-Hernández, Marta; López, Begoña; Atienza, Felipe; Jalife, José; Hove-Madsen, Leif; Delpón, Eva; Bernad, Antonio

    2016-10-01

    MicroRNAs (miR) have considerable potential as therapeutic tools in cardiac diseases. Alterations in atrial miR are involved in the development of atrial fibrillation (AF), but the molecular mechanism underlying their contribution to atrial remodeling in chronic atrial fibrillation (CAF) is only partially understood. Here we used miR array to analyze the miR profile of atrial biopsies from sinus rhythm (SR) and CAF patients. qRT-PCR identified a distinctive CAF-miR signature and described conserved miR-208b upregulation in human and ovine AF atrial tissue. We used bioinformatics analysis to predict genes and signaling pathways as putative miR-208b targets, which highlighted genes from the cardiac muscle gene program and from canonical WNT, gap-junction and Ca(2+) signaling networks. Results from analysis of miR-208b-overexpressing HL-1 atrial myocytes and from myocytes isolated from CAF patients showed that aberrant miR-208b levels reduced the expression and function of L-type Ca(2+) channel subunits (CACNA1C and CACNB2) as well as the sarcoplasmic reticulum-Ca(2+) pump SERCA2. These findings clearly pointed to CAF-specific upregulated miR-208b as an important mediator in Ca(2+) handling impairment during atrial remodeling. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Interactions between endothelin-1 and atrial natriuretic peptide influence cultured chick cardiac myocyte contractility.

    PubMed

    Bézie, Y; Mesnard, L; Longrois, D; Samson, F; Perret, C; Mercadier, J J; Laurent, S

    1996-09-12

    We have previously shown that rat atrial natriuretic peptide (ANP) reduces the contractility of cultured, spontaneously beating chick embryo ventricular cells, an effect opposite to that of endothelin-1. Endothelin-1 has been described as a secretagogue for natriuretic peptides in vitro and in vivo. Natriuretic peptides can inhibit endothelin-1 secretion from cultured endothelial cells, suggesting a negative feedback mechanism between endothelial cells and cardiomyocytes. The aim of this study was to determine whether ANP attenuated the endothelin-1-induced increase in myocyte contractility. Using a video-microscopy system we studied the contractility of isolated cultured chick ventricular myocytes in response to endothelin-1, chicken natriuretic peptide (ChNP), and both. We also used Northern blot analysis to study the time course of ChNP expression in response to endothelin-1. Endothelin-1 (10(-8) M) increased chick cardiomyocyte contractility by 20-25% between 5 and 15 min (P < 0.05). Although ChNP (3 x 10(-7) M) did not significantly change the amplitude of contraction in basal conditions, it prevented the endothelin-1-induced increase in contractility (P < 0.05) when perfused prior to endothelin-1, and reversed it when perfused 5 min after endothelin-1 exposure (P < 0.05). Endothelin-1 significantly increased the accumulation of ChNP mRNA in chick ventricular myocytes as early as the 30 min after exposure (P < 0.05), with a maximal effect after 2 h of stimulation (P < 0.01); no effect was observed after 4 h. These data support an interaction between endothelin-1 and natriuretic peptides as autocrine/paracrine factors regulating the contractile function of chick cardiac myocytes, as well as their antagonistic effects on cardiac cell contractility. The early and transient expression of ChNP mRNA in response to endothelin-1 may be involved in this interaction.

  20. Increased Ca buffering underpins remodelling of Ca(2+) handling in old sheep atrial myocytes.

    PubMed

    Clarke, Jessica D; Caldwell, Jessica L; Pearman, Charles M; Eisner, David A; Trafford, Andrew W; Dibb, Katharine M

    2017-07-28

    Ageing is associated with an increased risk of cardiovascular disease and arrhythmias, with the most common arrhythmia being found in the atria of the heart. Little is known about how the normal atria of the heart remodel with age and thus why dysfunction might occur. We report alterations to the atrial systolic Ca(2+) transient that have implications for the function of the atrial in the elderly. We describe a novel mechanism by which increased Ca buffering can account for changes to systolic Ca(2+) in the old atria. The present study helps us to understand how the processes regulating atrial contraction are remodelled during ageing and provides a basis for future work aiming to understand why dysfunction develops. Many cardiovascular diseases, including those affecting the atria, are associated with advancing age. Arrhythmias, including those in the atria, can arise as a result of electrical remodelling or alterations in Ca(2+) homeostasis. In the atria, age-associated changes in the action potential have been documented. However, little is known about remodelling of intracellular Ca(2+) homeostasis in the healthy aged atria. Using single atrial myocytes from young and old Welsh Mountain sheep, we show the free Ca(2+) transient amplitude and rate of decay of systolic Ca(2+) decrease with age, whereas sarcoplasmic reticulum (SR) Ca content increases. An increase in intracellular Ca buffering explains both the decrease in Ca(2+) transient amplitude and decay kinetics in the absence of any change in sarcoendoplasmic reticulum calcium transport ATPase function. Ageing maintained the integrated Ca(2+) influx via ICa-L but decreased peak ICa-L . Decreased peak ICa-L was found to be responsible for the age-associated increase in SR Ca content but not the decrease in Ca(2+) transient amplitude. Instead, decreased peak ICa-L offsets increased SR load such that Ca(2+) release from the SR was maintained during ageing. The results of the present study highlight a novel

  1. Differential A1 adenosine receptor reserve for two actions of adenosine on guinea pig atrial myocytes.

    PubMed

    Srinivas, M; Shryock, J C; Dennis, D M; Baker, S P; Belardinelli, L

    1997-10-01

    Adenosine activates adenosine-induced inwardly rectifying K+ current (IKAdo) and inhibits isoproterenol (100 nM)-stimulated L-type Ca2+ current (beta-ICa,L) of guinea pig atrial myocytes with EC50 values of 2.17 and 0.20 microM, respectively. We determined whether this 11-fold difference in potency of adenosine is due to the existence of a greater A1 adenosine receptor reserve for the inhibition of beta-ICa,L than for the activation of IKAdo. Atrial myocytes were pretreated with vehicle (control) or the irreversible A1 adenosine receptor antagonist 8-cyclopentyl-3-[3-[[4-(fluorosulfonyl)benzoyl]oxy]propyl]-1-propylxa nthine (FSCPX) (10 and 50 nM) for 30 min, and after a 60-min washout period, concentration-response curves were determined for the adenosine-induced activation of IKAdo and inhibition of beta-ICa,L. Pretreatment of atrial myocytes with 10 nM FSCPX reduced the maximal activation of IKAdo by 60% (7.9 +/- 0.2 to 3.2 +/- 0.1 pA/pF). In contrast, a higher concentration of FSCPX (50 nM) was required to reduce the maximal inhibition of beta-ICa,L by 39% (95 +/- 4% to 58. 7 +/- 5.6%) and caused a 15-fold increase in the EC50 value of adenosine. Values of the equilibrium dissociation constant (KA) for adenosine to activate IKAdo and inhibit beta-ICa,L, estimated according to the method of Furchgott, were 2.7 and 5.6 microM, respectively. These values were used to determine the relationship between adenosine receptor occupancy and response. Half-maximal and maximal activations of IKAdo required occupancies of 40% and 98% of A1 adenosine receptors, respectively. In contrast, occupancies of only 4% and 70%, respectively, of A1 adenosine receptors were sufficient to cause half-maximal and maximal inhibitions of beta-ICa, L. Consistent with this result, a partial agonist of the A1 adenosine receptor SHA040 inhibited beta-ICa,L by 60 +/- 3.5% but activated IKAdo by only 18.1 +/- 2.5%. The results indicate that the A1 adenosine receptor is coupled more efficiently to

  2. Local calcium gradients during excitation–contraction coupling and alternans in atrial myocytes

    PubMed Central

    Blatter, Lothar A; Kockskämper, Jens; Sheehan, Katherine A; Zima, Aleksey V; Hüser, Jörg; Lipsius, Stephen L

    2003-01-01

    Subcellular Ca2+ signalling during normal excitation-contraction (E-C) coupling and during Ca2+ alternans was studied in atrial myocytes using fast confocal microscopy and measurement of Ca2+ currents (ICa). Ca2+ alternans, a beat-to-beat alternation in the amplitude of the [Ca2+]i transient, causes electromechanical alternans, which has been implicated in the generation of cardiac fibrillation and sudden cardiac death. Cat atrial myocytes lack transverse tubules and contain sarcoplasmic reticulum (SR) of the junctional (j-SR) and non-junctional (nj-SR) types, both of which have ryanodine-receptor calcium release channels. During E-C coupling, Ca2+ entering through voltage-gated membrane Ca2+ channels (ICa) triggers Ca2+ release at discrete peripheral j-SR release sites. The discrete Ca2+ spark-like increases of [Ca2+]i then fuse into a peripheral ‘ring’ of elevated [Ca2+]i, followed by propagation (via calcium-induced Ca2+ release, CICR) to the cell centre, resulting in contraction. Interrupting ICa instantaneously terminates j-SR Ca2+ release, whereas nj-SR Ca2+ release continues. Increasing the stimulation frequency or inhibition of glycolysis elicits Ca2+ alternans. The spatiotemporal [Ca2+]i pattern during alternans shows marked subcellular heterogeneities including longitudinal and transverse gradients of [Ca2+]i and neighbouring subcellular regions alternating out of phase. Moreover, focal inhibition of glycolysis causes spatially restricted Ca2+ alternans, further emphasising the local character of this phenomenon. When two adjacent regions within a myocyte alternate out of phase, delayed propagating Ca2+ waves develop at their border. In conclusion, the results demonstrate that (1) during normal E-C coupling the atrial [Ca2+]i transient is the result of the spatiotemporal summation of Ca2+ release from individual release sites of the peripheral j-SR and the central nj-SR, activated in a centripetal fashion by CICR via ICa and Ca2+ release from j

  3. Voltage and Calcium Dual Channel Optical Mapping of Cultured HL-1 Atrial Myocyte Monolayer

    PubMed Central

    Zhao, Weiwei; Fast, Vladimir G.; Ye, Tong; Ai, Xun

    2015-01-01

    Optical mapping has proven to be a valuable technique to detect cardiac electrical activity on both intact ex vivo hearts and in cultured myocyte monolayers. HL-1 cells have been widely used as a 2-Dimensional cellular model for studying diverse aspects of cardiac physiology. However, it has been a great challenge to optically map calcium (Ca) transients and action potentials simultaneously from the same field of view in a cultured HL-1 atrial cell monolayer. This is because special handling and care is required to prepare healthy cells that can be electrically captured and optically mapped. Therefore, we have developed an optimal working protocol for dual channel optical mapping. In this manuscript, we have described in detail how to perform the dual channel optical mapping experiment. This protocol is a useful tool to enhance the understanding of action potential propagation and Ca kinetics in arrhythmia development. PMID:25867896

  4. Identification of a T-type Ca(2+) channel isoform in murine atrial myocytes (AT-1 cells)

    PubMed

    Satin, J; Cribbs, L L

    2000-03-31

    Calcium channels are important targets for therapeutics, but their molecular diversity complicates characterization of these channels in native heart cells. In this study, we identify a new splice variant of a low-voltage activated, or T-type Ca(2+), channel in murine atrial myocytes. To date, alpha1G and alpha1H are the only 2 T-type Ca(2+) channel isoforms found in cardiovascular tissue. We compared alpha1G and alpha1H channel current heterologously expressed in HEK 293 cells with T-type current from the murine atrial tumor cell, AT-1. AT-1 cell T-type current (I(T)) has the same voltage dependence of activation and inactivation as alpha1G and alpha1H. The cloned T-type channels and AT-1 T-type current share similar kinetics of macroscopic inactivation and deactivation. The kinetics of recovery from inactivation of T-type currents serves as an electrophysiological signature for T-channel isoform. alpha1G and AT-1 I(T) have a similar recovery from inactivation time course that is faster than that for alpha1H. In all cases, T-type current recovers with a biexponential time course, and the relative amplitude of fast and slow time courses explains the slower alpha1H recovery kinetics, rather than differences in the time constants of the individual transitions. Thus, the T-type channels may be an important contributor to automaticity in heart cells, and molecular diversity is reflected in the pathway of recovery from inactivation.

  5. Unifying principles of calcium wave propagation - Insights from a three-dimensional model for atrial myocytes.

    PubMed

    Thul, R; Rietdorf, K; Bootman, M D; Coombes, S

    2015-09-01

    Atrial myocytes in a number of species lack transverse tubules. As a consequence the intracellular calcium signals occurring during each heartbeat exhibit complex spatio-temporal dynamics. These calcium patterns arise from saltatory calcium waves that propagate via successive rounds of diffusion and calcium-induced calcium release. The many parameters that impinge on calcium-induced calcium release and calcium signal propagation make it difficult to know a priori whether calcium waves will successfully travel, or be extinguished. In this study, we describe in detail a mathematical model of calcium signalling that allows the effect of such parameters to be independently assessed. A key aspect of the model is to follow the triggering and evolution of calcium signals within a realistic three-dimensional cellular volume of an atrial myocyte, but with low computational costs. This is achieved by solving the linear transport equation for calcium analytically between calcium release events and by expressing the onset of calcium liberation as a threshold process. The model makes non-intuitive predictions about calcium signal propagation. For example, our modelling illustrates that the boundary of a cell produces a wave-guiding effect that enables calcium ions to propagate further and for longer, and can subtly alter the pattern of calcium wave movement. The high spatial resolution of the modelling framework allows the study of any arrangement of calcium release sites. We demonstrate that even small variations in randomly positioned release sites cause highly heterogeneous cellular responses. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.

  6. Choline chloride activates time-dependent and time-independent K+ currents in dog atrial myocytes.

    PubMed

    Fermini, B; Nattel, S

    1994-01-01

    Using the whole cell configuration of the patch-clamp technique, we studied the effect of isotonic replacement of bath sodium chloride (NaCl) by choline chloride (ChCl) in dog atrial myocytes. Our results show that ChCl triggered 1) activation of a time-independent background current, characterized by a shift of the holding current in the outward direction at potentials positive to the K+ equilibrium potential (EK), and 2) activation of a time- and voltage-dependent outward current, following depolarizing voltage steps positive to EK. Because the choline-induced current obtained by depolarizing steps exhibited properties similar to the delayed rectifier K+ current (IK), we named it IKCh. The amplitude of IKCh was determined by extracellular ChCl concentration, and this current was generally undetectable in the absence of ChCl. IKCh was not activated by acetylcholine (0.001-1.0 mM) or carbachol (10 microM) and could not be recorded in the absence of ChCl or when external NaCl was replaced by sucrose or tetramethylammonium chloride. IKCh was inhibited by atropine (0.01-1.0 microM) but not by the M1 antagonist pirenzepine (up to 10 microM). This current was carried mainly by K+ and was inhibited by CsCl (120 mM, in the pipette) or barium (1 mM, in the bath). We conclude that in dog atrial myocytes, ChCl activates a background conductance comparable to ACh-dependent K+ current, together with a time-dependent K+ current showing properties similar to IK.

  7. Activation and propagation of Ca(2+) release during excitation-contraction coupling in atrial myocytes.

    PubMed

    Kockskämper, J; Sheehan, K A; Bare, D J; Lipsius, S L; Mignery, G A; Blatter, L A

    2001-11-01

    Fast two-dimensional confocal microscopy and the Ca(2+) indicator fluo-4 were used to study excitation-contraction (E-C) coupling in cat atrial myocytes which lack transverse tubules and contain both subsarcolemmal junctional (j-SR) and central nonjunctional (nj-SR) sarcoplasmic reticulum. Action potentials elicited by field stimulation induced transient increases of intracellular Ca(2+) concentration ([Ca(2+)](i)) that were highly inhomogeneous. Increases started at distinct subsarcolemmal release sites spaced approximately 2 microm apart. The amplitude and the latency of Ca(2+) release from these sites varied from beat to beat. Subsarcolemmal release fused to build a peripheral ring of elevated [Ca(2+)](i), which actively propagated to the center of the cells via Ca(2+)-induced Ca(2+) release. Resting myocytes exhibited spontaneous Ca(2+) release events, including Ca(2+) sparks and local (microscopic) or global (macroscopic) [Ca(2+)](i) waves. The microscopic [Ca(2+)](i) waves propagated in a saltatory fashion along the sarcolemma ("coupled" Ca(2+) sparks) revealing the sequential activation of Ca(2+) release sites of the j-SR. Moreover, during global [Ca(2+)](i) waves, Ca(2+) release was evident from individual nj-SR sites. Ca(2+) release sites were arranged in a regular three-dimensional grid as deduced from the functional data and shown by immunostaining of ryanodine receptor Ca(2+) release channels. The longitudinal and transverse distances between individual Ca(2+) release sites were both approximately 2 microm. Furthermore, electron microscopy revealed a continuous sarcotubular network and one peripheral coupling of j-SR with the sarcolemma per sarcomere. The results demonstrate directly that, in cat atrial myocytes, the action potential-induced whole-cell [Ca(2+)](i) transient is the spatio-temporal summation of Ca(2+) release from subsarcolemmal and central sites. First, j-SR sites are activated in a stochastic fashion by the opening of voltage

  8. Nitric oxide regulates the calcium current in isolated human atrial myocytes.

    PubMed Central

    Kirstein, M; Rivet-Bastide, M; Hatem, S; Bénardeau, A; Mercadier, J J; Fischmeister, R

    1995-01-01

    Cardiac Ca2+ current (ICa) was shown to be regulated by cGMP in a number of different species. Recently, we found that the NO-donor SIN-1 (3-morpholino-sydnonimine) exerts a dual regulation of ICa in frog ventricular myocytes via an accumulation of cGMP. To examine whether NO also regulates Ca2+ channels in human heart, we investigated the effects of SIN-1 on ICa in isolated human atrial myocytes. An extracellular application of SIN-1 produced a profound stimulatory effect on basal ICa at concentrations > 1 pM. Indeed, 10 pM SIN-1 induced a approximately 35% increase in ICa. The stimulatory effect of SIN-1 was maximal at 1 nM (approximately 2-fold increase in ICa) and was comparable with the effect of a saturating concentration (1 microM) of isoprenaline, a beta-adrenergic agonist. Increasing the concentration of SIN-1 to 1-100 microM reduced the stimulatory effect in two thirds of the cells. The stimulatory effect of SIN-1 was not mimicked by SIN-1C, the cleavage product of SIN-1 produced after liberation of NO. This suggests that NO mediates the effects of SIN-1 on ICa. Because, in frog heart, the stimulatory effect of SIN-1 on ICa was found to be due to cGMP-induced inhibition of cGMP-inhibited phosphodiesterase (cGI-PDE), we compared the effects of SIN-1 and milrinone, a cGI-PDE selective inhibitor, on ICa in human. Milrinone (10 microM) induced a strong stimulation of ICa (approximately 150%), demonstrating that cGI-PDE controls the amplitude of basal ICa in this tissue. In the presence of milrinone, SIN-1 (0.1-1 nM) had no stimulatory effect on ICa, suggesting that the effects of SIN-1 and MIL were not additive. We conclude that NO may stimulate ICa in human atrial myocytes via inhibition of the cGI-PDE. Images PMID:7860763

  9. 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

  10. Effects of potassium channel openers on Na+ and K+ currents in rabbit sinus node and atrial myocytes.

    PubMed

    Tromba, C; Cohen, I S

    1995-05-12

    The effects of the potassium channel openers (KCOs) Cromakalim and Lemakalim on rabbit sinoatrial and atrial myocytes were examined by means of the whole-cell patch-clamp technique. Lemakalin (up to 100 microM) had no effect on potassium current in sinoatrial cells. Both Lemakalim and Cromakalim (100 microM) displayed a two-fold action on atrial myocytes: (1) they increased an outwardly rectifying conductance at potentials positive to EK and, (2) they markedly decreased a TTX-sensitive Na+ current active in the voltage range -50/-30 mV. This novel action on TTX-sensitive currents is of particular interest since these two benzopyrans have been thought to specifically target potassium channels.

  11. Intracellular mechanisms for alpha 1-adrenergic regulation of the transient outward current in rabbit atrial myocytes.

    PubMed Central

    Braun, A P; Fedida, D; Clark, R B; Giles, W R

    1990-01-01

    1. The intracellular mechanism(s) underlying the decrease of a transient outward K+ current (It) induced by alpha 1-adrenergic agonists was studied in isolated adult rabbit atrial myocytes using whole-cell voltage clamp and cell-attached patch clamp techniques. Experiments were carried out at 22-23 degrees C. 2. Application of the specific alpha 1-adrenergic agonist, methoxamine, produced a decrease in It which was irreversible after the non-hydrolysable GTP analogues, GTP gamma S and Gpp(NH)p, had been introduced into cells via the recording micropipette. 3. Pre-treatment of cells with 0.1-0.15 microgram/ml pertussis toxin (PT) for 8-9 h at 30-34 degrees C did not prevent the alpha 1-induced decrease in It. Yet, this protocol, as measured by the PT-catalysed incorporation of [32P]ADP-ribose in membrane-associated 40 and 41 kDa proteins, effectively caused the ADP-ribosylation of approximately 70% of the PT-sensitive GTP-binding proteins (i.e. Gi) in these treated cells. After taking into account the proportion of non-viable cells (20-30%), the effectiveness of this treatment probably approaches 100% in the viable myocytes from which electrophysiological recordings were made. 4. Cell-attached patch recordings showed that bath application of methoxamine altered the single-channel events underlying It by decreasing their opening probability. Averaged currents from ensemble single-channel openings recorded in the presence of 0.2 mM-methoxamine outside the patch reproduced the features of alpha 1-adrenergic modulation of the macroscopic It observed during whole-cell voltage clamp measurements. This observation provides evidence for the involvement of a diffusible intracellular second messenger in the alpha 1-adrenergic modulation of It. 5. The protein kinase C (PKC) activators, 4 beta-phorbol 12-myristate 13-acetate (PMA) and 1-oleoyl-2-acetylglycerol (OAG) increased It, when included in the bath perfusate, whereas the inactive analogues, 4 alpha-phorbol and 4 alpha

  12. Two distinct types of inwardly rectifying K+ channels in bull-frog atrial myocytes.

    PubMed Central

    Clark, R B; Nakajima, T; Giles, W; Kanai, K; Momose, Y; Szabo, G

    1990-01-01

    1. Single atrial myocytes were enzymatically isolated from the bull-frog as previously described (Hume & Giles, 1981), and patch-clamp techniques were used in an attempt to identify and separate two inwardly rectifying K+ channels in this tissue. 2. Single-channel measurements consistently demonstrated the existence of two different resting K+ channels, which both exhibited strong inward rectification. The unitary conductances of these K+ channels were 34 +/- 4 and 22 +/- 3 pS (mean +/- S.D., at 22-24 degrees C) when measured with 110 mM-K+ in the pipette solution, and their mean open times were 0.87 +/- 0.33 and 129.9 +/- 49.4 ms, respectively. 3. In the absence of acetylcholine (ACh) in the pipette, openings of the larger channels with the shorter open times occurred at a very low frequency. When ACh was present in the patch pipette, the activity of this channel increased significantly, although the single-channel conductance and gating behaviour were very similar either with or without ACh in the pipette. 4. The zero-current voltage (extrapolated from the inward currents through these types of channels) depended on the extracellular K+ concentration. [K+]o, in the fashion expected for a predominantly K(+)-selective channel: it shifted by 58 mV for a tenfold change in [K+]o. Very similar results were obtained from whole-cell voltage-clamp measurements (53 mV for a tenfold change in [K+]o). 5. The conductance of both types of K+ channels depended on [K+]o. The single-channel conductances were 25 +/- 3 and 13 +/- 2 pS with 50 mM [K+]o, and 19 +/- 4 and 9 +/- 2 pS with 20 mM [K+]o, respectively. 6. These results demonstrate that two types of resting inwardly rectifying K+ channels can be identified in single atrial myocytes. One of these is an inwardly rectifying K+ channel (IK1) previously identified in whole-cell voltage-clamp experiments (Hume & Giles, 1983). The second channel is the muscarinic receptor-regulated K+ channel (IK(ACh) which was first described in

  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.

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

    PubMed Central

    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

  15. Activation of muscarinic K+ current in guinea-pig atrial myocytes by a serum factor.

    PubMed Central

    Banach, K; Hüser, J; Lipp, P; Wellner, M C; Pott, L

    1993-01-01

    1. Atrial myocytes obtained by enzymatic perfusion of hearts from adult guinea-pigs and cultured for 0-14 days were studied using the whole-cell voltage-clamp technique. 2. Superfusion of the myocytes with diluted sera (1:100 to 1:10,000) from different species (human, horse, guinea-pig) evoked an inward rectifying K+ current. The voltage-dependent properties of this current were identical to those of the K+ current activated by acetylcholine (IK(ACh)). Current density in the presence of horse serum (1:100) approximately corresponded to the non-desensitizing fraction of IK(ACh) during superfusion with 1-2 x 10(-6) M ACh. 3. During a maximal serum-evoked current, application of ACh (10(-6) M) failed to evoke additional K+ current. After switching superfusion from serum-containing to serum-free solution, the K+ current decayed 1-2 orders of magnitude slower than ACh-activated IK(ACh). During the decay of the serum-evoked current, a proportional increase in responsiveness to ACh was recorded. During submaximal activation of K+ current by serum, a saturating concentration of ACh resulted in a total current that was identical to the current evoked by ACh alone minus the desensitizing component. Thus, activation of K+ current by serum caused desensitization of IK(ACh). From these results it is concluded that sera contain a factor that activates the same population of K+ channels as ACh. 4. Irreversible activation of IK(ACh) by ACh in myocytes dialysed with the GTP-analogue GTP-gamma-S abolished sensitivity to serum and vice versa. 5. The effect of serum was not modified by atropine (10(-6) M) which completely blocked the response to 2 x 10(-6) M ACh. Furthermore, theophylline (1 mM), which completely inhibited IK(ACh) activation by adenosine (100 microM), failed to inhibit the effect of serum. Thus, neither muscarinic nor purinergic (A1) receptors are involved. 6. The peptide somatostatin (10(-6) M) and the alpha 1-agonist phenylephrine (1 microM) which previously have

  16. If blocking potency of ivabradine is preserved under elevated endotoxin levels in human atrial myocytes

    PubMed Central

    Scheruebel, Susanne; Koyani, Chintan N.; Hallström, Seth; Lang, Petra; Platzer, Dieter; Mächler, Heinrich; Lohner, Karl; Malle, Ernst; Zorn-Pauly, Klaus; Pelzmann, Brigitte

    2014-01-01

    Lower heart rate is associated with better survival in patients with multiple organ dysfunction syndrome (MODS), a disease mostly caused by sepsis. The benefits of heart rate reduction by ivabradine during MODS are currently being investigated in the MODIfY clinical trial. Ivabradine is a selective inhibitor of the pacemaker current If and since If is impaired by lipopolysaccharide (LPS, endotoxin), a trigger of sepsis, we aimed to explore If blocking potency of ivabradine under elevated endotoxin levels in human atrial cardiomyocytes. Treatment of myocytes with S-LPS (containing the lipid A moiety, a core oligosaccharide and an O-polysaccharide chain) but not R595 (an O-chain lacking LPS-form) caused If inhibition under acute and chronic septic conditions. The specific interaction of S-LPS but not R595 to pacemaker channels HCN2 and HCN4 proves the necessity of O-chain for S-LPS–HCN interaction. The efficacy of ivabradine to block If was reduced under septic conditions, an observation that correlated with lower intracellular ivabradine concentrations in S-LPS- but not R595-treated cardiomyocytes. Computational analysis using a sinoatrial pacemaker cell model revealed that despite a reduction of If under septic conditions, ivabradine further decelerated pacemaking activity. This novel finding, i.e. If inhibition by ivabradine under elevated endotoxin levels in vitro, may provide a molecular understanding for the efficacy of this drug on heart rate reduction under septic conditions in vivo, e.g. the MODIfY clinical trial. PMID:24583250

  17. The MAPK pathway is involved in the regulation of rapid pacing-induced ionic channel remodeling in rat atrial myocytes.

    PubMed

    Cheng, Wei; Zhu, Yun; Wang, Haidong

    2016-03-01

    Alterations to the expression L‑type calcium channels (LTCCs) and Kv4.3 potassium channels form the possible basis of atrial electrical remodeling during rapid pacing. The mitogen‑activated protein kinase (MAPK) pathway is affected by increases in cytoplasmic Ca2+, and therefore represents an attractive candidate for the regulation and mediation of Ca2+‑induced ion channel remodeling. The present study aimed to investigate alterations to the ion channel‑MAPK axis, and to determine its influence on ion channel remodeling during atrial fibrillation. Rat atrial myocytes were isolated, cultured, and in vitro rapid pacing was established. Intracellular Ca2+ signals were monitored using the Fluo‑3/AM Ca2+ indicator. Verapamil, PD98058 and SB203580 were added to the culture medium of various groups at specific time‑points. The mRNA expression levels of LTCC‑α1c and Kv4.3 potassium channels were detected by reverse transcription‑polymerase chain reaction. Western blotting was performed to determine the expression levels of channel and signaling proteins. The results demonstrated that fast pacing significantly increased the intracellular Ca2+ concentration in atrial myocytes, whereas treatment with verapamil markedly inhibited this increase. In addition, verapamil significantly antagonized the rapid pacing‑induced activation of extracellular signal‑regulated kinase (ERK) and p38MAPK. These results indicated that the MAPK pathway may have an important role in the opening of LTCCs, and alterations to MAPK molecule expression could affect the expression and remodeling of ion channels.

  18. 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

  19. Subcellular Ca2+ alternans represents a novel mechanism for the generation of arrhythmogenic Ca2+ waves in cat atrial myocytes

    PubMed Central

    Kockskämper, Jens; Blatter, Lothar A

    2002-01-01

    Ca2+ alternans is a potentially arrhythmogenic beat-to-beat alternation of the amplitude of the action potential-induced [Ca2+]i transient in cardiac myocytes. Despite its pathophysiological significance the cellular mechanisms underlying Ca2+ alternans are poorly understood. Recent evidence, however, points to the modulation of Ca2+-induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR) by localized alterations in energy metabolism as an important determinant of Ca2+ alternans. We therefore studied the subcellular properties of Ca2+ alternans in field-stimulated cat atrial myocytes employing fast two-dimensional fluorescence confocal microscopy. Ca2+ alternans was elicited by an increase in stimulation frequency or by metabolic interventions targeting glycolysis. Marked subcellular variations in the time of onset, the magnitude, and the phase of alternans were observed. Longitudinal and transverse gradients of Ca2+ alternans were found as well as neighbouring subcellular regions alternating out-of-phase. Moreover, focal inhibition of glycolysis resulted in spatially restricted Ca2+ alternans. When two adjacent regions within a myocyte alternated out-of-phase, steep [Ca2+]i gradients developed at their border giving rise to delayed propagating Ca2+ waves. The results demonstrate that Ca2+ alternans is a subcellular phenomenon caused by modulation of SR Ca2+ release, which is mediated, at least in part, by local inhibition of energy metabolism. The generation of arrhythmogenic Ca2+ waves by subcellular variations in the phase of Ca2+ alternans represents a novel mechanism for the development of atrial disrhythmias. PMID:12433950

  20. Calcium‐activated chloride current determines action potential morphology during calcium alternans in atrial myocytes

    PubMed Central

    Kanaporis, Giedrius

    2016-01-01

    Key points Cardiac alternans – periodic beat‐to‐beat alternations in contraction, action potential (AP) morphology or cytosolic calcium transient (CaT) amplitude – is a high risk indicator for cardiac arrhythmias and sudden cardiac death. However, it remains an unresolved issue whether beat‐to‐beat alternations in intracellular Ca2+ ([Ca2+]i) or AP morphology are the primary cause of pro‐arrhythmic alternans.Here we show that in atria AP alternans occurs secondary to CaT alternans.CaT alternans leads to complex beat‐to‐beat changes in Ca2+‐regulated ion currents that determine alternans of AP morphology.We report the novel finding that alternans of AP morphology is largely sustained by the activity of Ca2+‐activated Cl− channels (CaCCs). Suppression of the CaCCs significantly reduces AP alternans, while CaT alternans remains unaffected.The demonstration of a major role of CaCCs in the development of AP alternans opens new possibilities for atrial alternans and arrhythmia prevention. Abstract Cardiac alternans, described as periodic beat‐to‐beat alternations in contraction, action potential (AP) morphology or cytosolic Ca transient (CaT) amplitude, is a high risk indicator for cardiac arrhythmias and sudden cardiac death. We investigated mechanisms of cardiac alternans in single rabbit atrial myocytes. CaTs were monitored simultaneously with membrane currents or APs recorded with the patch clamp technique. Beat‐to‐beat alternations of AP morphology and CaT amplitude revealed a strong quantitative correlation. Application of voltage clamp protocols in the form of pre‐recorded APs (AP‐clamp) during pacing‐induced CaT alternans revealed a Ca2+‐dependent current consisting of a large outward component (4.78 ± 0.58 pA pF–1 in amplitude) coinciding with AP phases 1 and 2 that was followed by an inward current (−0.42 ± 0.03 pA pF–1; n = 21) during AP repolarization. Approximately 90% of the initial outward current

  1. Calcium-activated chloride current determines action potential morphology during calcium alternans in atrial myocytes.

    PubMed

    Kanaporis, Giedrius; Blatter, Lothar A

    2016-02-01

    Cardiac alternans--periodic beat-to-beat alternations in contraction, action potential (AP) morphology or cytosolic calcium transient (CaT) amplitude--is a high risk indicator for cardiac arrhythmias and sudden cardiac death. However, it remains an unresolved issue whether beat-to-beat alternations in intracellular Ca(2+) ([Ca(2+)]i ) or AP morphology are the primary cause of pro-arrhythmic alternans. Here we show that in atria AP alternans occurs secondary to CaT alternans. CaT alternans leads to complex beat-to-beat changes in Ca(2+)-regulated ion currents that determine alternans of AP morphology. We report the novel finding that alternans of AP morphology is largely sustained by the activity of Ca(2+)-activated Cl(-) channels (CaCCs). Suppression of the CaCCs significantly reduces AP alternans, while CaT alternans remains unaffected. The demonstration of a major role of CaCCs in the development of AP alternans opens new possibilities for atrial alternans and arrhythmia prevention. Cardiac alternans, described as periodic beat-to-beat alternations in contraction, action potential (AP) morphology or cytosolic Ca transient (CaT) amplitude, is a high risk indicator for cardiac arrhythmias and sudden cardiac death. We investigated mechanisms of cardiac alternans in single rabbit atrial myocytes. CaTs were monitored simultaneously with membrane currents or APs recorded with the patch clamp technique. Beat-to-beat alternations of AP morphology and CaT amplitude revealed a strong quantitative correlation. Application of voltage clamp protocols in the form of pre-recorded APs (AP-clamp) during pacing-induced CaT alternans revealed a Ca(2+)-dependent current consisting of a large outward component (4.78 ± 0.58 pA pF(-1) in amplitude) coinciding with AP phases 1 and 2 that was followed by an inward current (-0.42 ± 0.03 pA pF(-1); n = 21) during AP repolarization. Approximately 90% of the initial outward current was blocked by substitution of Cl(-) ions or application

  2. Clarithromycin reduces Isus and Ito currents in human atrial myocytes with minor repercussions on action potential duration.

    PubMed

    Gluais, Pascale; Bastide, Michèle; Grandmougin, Daniel; Fayad, Georges; Adamantidis, Monique

    2003-12-01

    The macrolide antibacterial agent clarithromycin has been shown to cause QT interval prolongation on the electrocardiogram. In rabbit heart preparations clarithromycin (concentration dependently) lengthened the action potential duration and blocked the delayed rectifier current. The aim of the present study was to investigate the clarithromycin effects: (i) on the Ca2+ L-type and the main K+ repolarizing currents on human atrial myocytes, using whole-cell patch clamp recordings and (ii) on action potentials recorded from human atrial and ventricular myocardium using conventional microelectrodes. It has been found that (i) 10-30 microM clarithromycin reduced the sustained current Isus significantly and that a 100 microM concentration was needed to cause a significant reduction in the transient outward current Ito, whereas clarithomycin did not affect the calcium current and (ii) clarithromycin (10-100 microM) prolonged the action potential duration in atrial preparations but did not alter the different parameters of the ventricular action potential. It is concluded that clarithromycin exerts direct cardiac electrophysiological effects that may contribute to pro-arrythmic potential.

  3. Antisense oligonucleotides against rat brain α1E DNA and its atrial homologue decrease T-type calcium current in atrial myocytes

    PubMed Central

    Piedras-Rentería, Erika S.; Chen, Chien-Chang; Best, Philip M.

    1997-01-01

    Low voltage-activated, or T-type, calcium currents are important regulators of neuronal and muscle excitability, secretion, and possibly cell growth and differentiation. The gene (or genes) coding for the pore-forming subunit of low voltage-activated channel proteins has not been unequivocally identified. We have used reverse transcription–PCR to identify partial clones from rat atrial myocytes that share high homology with a member of the E class of calcium channel genes. Antisense oligonucleotides targeting one of these partial clones (raE1) specifically block the increase in T-current density that normally results when atrial myocytes are treated with insulin-like growth factor 1 (IGF-1). Antisense oligonucleotides targeting portions of the neuronal rat α1E sequence, which are not part of the clones detected in atrial tissue, also block the IGF-1-induced increase in T-current, suggesting that the high homology to α1E seen in the partial clone may be present in the complete atrial sequence. The basal T-current expressed in these cells is also blocked by antisense oligonucleotides, which is consistent with the notion that IGF-1 up-regulates the same gene that encodes the basal current. These results support the hypothesis that a member of the E class of calcium channel genes encodes a low voltage-activated calcium channel in atrial myocytes. PMID:9405717

  4. Comparative effects of clarithromycin on action potential and ionic currents from rabbit isolated atrial and ventricular myocytes.

    PubMed

    Gluais, Pascale; Bastide, Michìle; Caron, Jacques; Adamantidis, Monique

    2003-04-01

    Prolongation of QT interval by several antibacterial drugs is an unwanted side effect that may be associated with development of ventricular arrhythmias. The macrolide antibacterial agent clarithromycin has been shown to cause QT prolongation. To determine the electrophysiologic basis for this arrhythmogenic potential, we investigated clarithromycin effects on (i). action potentials recorded from rabbit Purkinje fibers and atrial and ventricular myocardium using conventional microelectrodes and (ii). potassium and calcium currents recorded from rabbit atrial and ventricular isolated myocytes using whole-cell patch clamp recordings. We found that (i). clarithromycin (3-100 microM) exerted concentration-dependent lengthening effects on action potential duration in all tissues, with higher efficacy and reverse frequency-dependence in Purkinje fibers. However, clarithromycin did not cause development of early afterdepolarizations, and the parameters other than action potential duration were almost unaffected; (ii). clarithromycin (10-100 microM) reduced the delayed rectifier current. Significant blockade (approximately 30%) was found at the concentration of 30 microM. At 100 microM, it decreased significantly the maximum peak of the calcium current amplitude but failed to alter the transient outward and inwardly rectifier currents. It was concluded that these effects might be an explanation for the QT prolongation observed in some patients treated with clarithromycin.

  5. 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.

  6. Persistence of Pro-Arrhythmic Spatio-Temporal Calcium Patterns in Atrial Myocytes: A Computational Study of Ping Waves

    PubMed Central

    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. PMID:22934033

  7. An outwardly rectifying anionic background current in atrial myocytes from the human heart.

    PubMed

    Li, H; Zhang, H; Hancox, J C; Kozlowski, R Z

    2007-08-03

    This report describes a hitherto unreported anionic background current from human atrial cardiomyocytes. Under whole-cell patch-clamp with anion-selective conditions, an outwardly rectifying anion current (I(ANION)) was observed, which was larger with iodide than nitrate, and with nitrate than chloride as charge carrier. In contrast with a previously identified background anionic current from small mammal cardiomyocytes, I(ANION) was not augmented by the pyrethroid tefluthrin (10 microM); neither was it inhibited by hyperosmolar external solution nor by DIDS (200 microM); thus I(ANION) was not due to basal activity of volume-sensitive anion channels. I(ANION) was partially inhibited by the Cl(-) channel blockers NPPB (50 microM) and Gly H-101 (30 microM). Incorporation of I(ANION) into a human atrial action potential (AP) simulation led to depression of the AP plateau, accompanied by alterations to plateau inward calcium current, and to AP shortening at 50% but not 90% of complete repolarization, demonstrating that I(ANION) can influence the human atrial AP profile.

  8. Exploring Regulatory Mechanisms of Atrial Myocyte Hypertrophy of Mitral Regurgitation through Gene Expression Profiling Analysis: Role of NFAT in Cardiac Hypertrophy

    PubMed Central

    Chang, Tzu-Hao; Chen, Mien-Cheng; Chang, Jen-Ping; Huang, Hsien-Da; Ho, Wan-Chun; Lin, Yu-Sheng; Pan, Kuo-Li; Huang, Yao-Kuang; Liu, Wen-Hao; Wu, Chia-Chen

    2016-01-01

    Background Left atrial enlargement in mitral regurgitation (MR) predicts a poor prognosis. The regulatory mechanisms of atrial myocyte hypertrophy of MR patients remain unknown. Methods and Results This study comprised 14 patients with MR, 7 patients with aortic valve disease (AVD), and 6 purchased samples from normal subjects (NC). We used microarrays, enrichment analysis and quantitative RT-PCR to study the gene expression profiles in the left atria. Microarray results showed that 112 genes were differentially up-regulated and 132 genes were differentially down-regulated in the left atria between MR patients and NC. Enrichment analysis of differentially expressed genes demonstrated that “NFAT in cardiac hypertrophy” pathway was not only one of the significant associated canonical pathways, but also the only one predicted with a non-zero score of 1.34 (i.e. activated) through Ingenuity Pathway Analysis molecule activity predictor. Ingenuity Pathway Analysis Global Molecular Network analysis exhibited that the highest score network also showed high association with cardiac related pathways and functions. Therefore, 5 NFAT associated genes (PPP3R1, PPP3CB, CAMK1, MEF2C, PLCE1) were studies for validation. The mRNA expressions of PPP3CB and MEF2C were significantly up-regulated, and CAMK1 and PPP3R1 were significantly down-regulated in MR patients compared to NC. Moreover, MR patients had significantly increased mRNA levels of PPP3CB, MEF2C and PLCE1 compared to AVD patients. The atrial myocyte size of MR patients significantly exceeded that of the AVD patients and NC. Conclusions Differentially expressed genes in the “NFAT in cardiac hypertrophy” pathway may play a critical role in the atrial myocyte hypertrophy of MR patients. PMID:27907007

  9. 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.

  10. Shear stress induces a longitudinal Ca(2+) wave via autocrine activation of P2Y1 purinergic signalling in rat atrial myocytes.

    PubMed

    Kim, Joon-Chul; Woo, Sun-Hee

    2015-12-01

    Atrial myocytes are exposed to shear stress during the cardiac cycle and haemodynamic disturbance. In response, they generate a longitudinally propagating global Ca(2+) wave. Here, we investigated the cellular mechanisms underlying the shear stress-mediated Ca(2+) wave, using two-dimensional confocal Ca(2+) imaging combined with a pressurized microflow system in single rat atrial myocytes. Shear stress of ∼16 dyn cm(-2) for 8 s induced ∼1.2 aperiodic longitudinal Ca(2+) waves (∼79 μm s(-1)) with a delay of 0.2-3 s. Pharmacological blockade of ryanodine receptors (RyRs) or inositol 1,4,5-trisphosphate receptors (IP3 Rs) abolished shear stress-induced Ca(2+) wave generation. Furthermore, in atrial myocytes from type 2 IP3R (IP3R2) knock-out mice, shear stress failed to induce longitudinal Ca(2+) waves. The phospholipase C (PLC) inhibitor U73122, but not its inactive analogue U73343, abolished the shear-induced longitudinal Ca(2+) wave. However, pretreating atrial cells with blockers for stretch-activated channels, Na(+)-Ca(2+) exchanger, transient receptor potential melastatin subfamily 4, or nicotinamide adenine dinucleotide phosphate oxidase did not suppress wave generation under shear stress. The P2 purinoceptor inhibitor suramin, and the potent P2Y1 receptor antagonist MRS 2179, both suppressed the Ca(2+) wave, whereas the P2X receptor antagonist, iso-PPADS, did not alter it. Suppression of gap junction hemichannels permeable to ATP or extracellular application of ATP-metabolizing apyrase inhibited the wave. Removal of external Ca(2+) to enhance hemichannel opening facilitated the wave generation. Our data suggest that longitudinally propagating, regenerative Ca(2+) release through RyRs is triggered by P2Y1-PLC-IP3R2 signalling that is activated by gap junction hemichannel-mediated ATP release in atrial myocytes under shear stress. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  11. Ionic currents during sustained pacemaker activity in rabbit sino-atrial myocytes.

    PubMed Central

    Zaza, A; Micheletti, M; Brioschi, A; Rocchetti, M

    1997-01-01

    1. The contribution of various ionic currents to diastolic depolarization (DD) in rabbit sinoatrial myocytes was evaluated by the action potential clamp technique. Individual currents were identified, during sustained pacemaking activity reproduced under voltage clamp conditions, according to their sensitivity to specific channel blockers. 2. The current sensitive to dihydropyridines (DHPs), blockers of L-type Ca2+ current (ICa,L), was small and outward during most of DD. Diastolic DHP-sensitive current was affected by changes in the driving force for K+, but it was insensitive to E-4031, which blocks the current termed IK,r; it was abolished by cell dialysis with a Ca2+ chelator. 3. The current sensitive to 2 mM Cs+ (ICs), a blocker of hyperpolarization-activated current (I(f)), was inward during the whole DD and it was substantially larger than the net inward current flowing during this phase. However, diastolic IK,r, identified in the same cells as the current sensitive to the blocker E-4031, exceeded ICs 2-fold. 4. These findings suggest that: (a) Ca2+ influx during the pacemaker cycle increases a K+ conductance, thus inverting the direction of the net current generated by L-type Ca2+ channel activity during DD; (b) the magnitude of I(f) would be adequate to account fully for DD; however, the coexistence of a larger IK,r suggests that other channels besides I(f) contribute inward current during this phase. PMID:9457645

  12. [Application of recording SK2 current in human atrial myocytes by perforated patch clamp techniques with the mix of beta-escin and amphotericin B].

    PubMed

    Wang, Hua; Li, Tao; Lei, Ming; Li, Miao-ling; Ding, Yin-yuan; Yang, Yan; Zeng, Xiao-rong

    2012-05-01

    To establish a perforated patch-clamp technology with amphotericin B and beta-escin and to research the regulation of small conductance calcium-activated potassium channel SK2 currents by calcium ions. Single human atrial myocytes were enzymatically isolated from the right atrial appendage. Amphotericin B and / or beta-escin were used by perforated electrode liquid. The regulation of SK2 current by calcium ions in human atrial myocytes was performed with the perforated patch-clamp technique. The intracellular calcium changes were measured by the intracellular calcium test system. Mixed perforated electrode liquid compared with 150 microg/ml amphotericin B or 6.88 microg/ml beta-escin alone, it was easy to seal cells and activate SK2 current by the former method. Moreover, the ration of F340/380 was consistent with the change of intracellular free calcium ion concentration increase after the formation of perforation. The ration of F340/380 was measured by intracellular calcium test system. The appropriate concentration of amphotericin B mixed with beta-escin can form a stable whole-cell patch recording technology that is appropriate for the research of SK2 current regulation by intracellular calcium.

  13. I(f) blocking potency of ivabradine is preserved under elevated endotoxin levels in human atrial myocytes.

    PubMed

    Scheruebel, Susanne; Koyani, Chintan N; Hallström, Seth; Lang, Petra; Platzer, Dieter; Mächler, Heinrich; Lohner, Karl; Malle, Ernst; Zorn-Pauly, Klaus; Pelzmann, Brigitte

    2014-07-01

    Lower heart rate is associated with better survival in patients with multiple organ dysfunction syndrome (MODS), a disease mostly caused by sepsis. The benefits of heart rate reduction by ivabradine during MODS are currently being investigated in the MODIfY clinical trial. Ivabradine is a selective inhibitor of the pacemaker current If and since If is impaired by lipopolysaccharide (LPS, endotoxin), a trigger of sepsis, we aimed to explore If blocking potency of ivabradine under elevated endotoxin levels in human atrial cardiomyocytes. Treatment of myocytes with S-LPS (containing the lipid A moiety, a core oligosaccharide and an O-polysaccharide chain) but not R595 (an O-chain lacking LPS-form) caused If inhibition under acute and chronic septic conditions. The specific interaction of S-LPS but not R595 to pacemaker channels HCN2 and HCN4 proves the necessity of O-chain for S-LPS-HCN interaction. The efficacy of ivabradine to block If was reduced under septic conditions, an observation that correlated with lower intracellular ivabradine concentrations in S-LPS- but not R595-treated cardiomyocytes. Computational analysis using a sinoatrial pacemaker cell model revealed that despite a reduction of If under septic conditions, ivabradine further decelerated pacemaking activity. This novel finding, i.e. If inhibition by ivabradine under elevated endotoxin levels in vitro, may provide a molecular understanding for the efficacy of this drug on heart rate reduction under septic conditions in vivo, e.g. the MODIfY clinical trial. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  14. 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

  15. Inositol-1,4,5-trisphosphate induced Ca2+ release and excitation–contraction coupling in atrial myocytes from normal and failing hearts

    PubMed Central

    Hohendanner, Felix; Walther, Stefanie; Maxwell, Joshua T; Kettlewell, Sarah; Awad, Sawsan; Smith, Godfrey L; Lonchyna, Vassyl A; Blatter, Lothar A

    2015-01-01

    We studied excitation–contraction coupling (ECC) and inositol-1,4,5-triphosphate (IP3)-dependent Ca2+ release in normal and heart failure (HF) rabbit atrial cells. Left ventricular HF was induced by combined volume and pressure overload. In HF atrial myocytes diastolic [Ca2+]i was increased, action potential (AP)-induced Ca2+ transients (CaTs) were larger in amplitude, primarily due to enhanced Ca2+ release from central non-junctional sarcoplasmic reticulum (SR) and centripetal propagation of activation was accelerated, whereas HF ventricular CaTs were depressed. The larger CaTs were due to enhanced IP3 receptor-induced Ca2+ release (IICR) and reduced mitochondrial Ca2+ buffering, consistent with a reduced mitochondrial density and Ca2+ uptake capacity in HF. Elementary IP3 receptor-mediated Ca2+ release events (Ca2+ puffs) were more frequent in HF atrial myoctes and were detected more often in central regions of the non-junctional SR compared to normal cells. HF cells had an overall higher frequency of spontaneous Ca2+ waves and a larger fraction of waves (termed arrhythmogenic Ca2+ waves) triggered APs and global CaTs. The higher propensity of arrhythmogenic Ca2+ waves resulted from the combined action of enhanced IICR and increased activity of sarcolemmal Na+–Ca2+ exchange depolarizing the cell membrane. In conclusion, the data support the hypothesis that in atrial myocytes from hearts with left ventricular failure, enhanced CaTs during ECC exert positive inotropic effects on atrial contractility which facilitates ventricular filling and contributes to maintaining cardiac output. However, HF atrial cells were also more susceptible to developing arrhythmogenic Ca2+ waves which might form the substrate for atrial rhythm disorders frequently encountered in HF. Key points Impaired calcium (Ca2+) signalling is the main contributor to depressed ventricular contractile function and occurrence of arrhythmia in heart failure (HF). Here we report that in atrial cells

  16. 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.

  17. The contribution of the 'pacemaker' current (if) to generation of spontaneous activity in rabbit sino-atrial node myocytes.

    PubMed Central

    DiFrancesco, D

    1991-01-01

    1. The contribution to the diastolic depolarization of the hyperpolarization-activated current, if, relative to other components was investigated in isolated rabbit sino-atrial (SA) node myocytes. 2. During the diastolic phase the membrane potential depolarized by 0.1096 +/- 0.014 V/s, which requires only about 3 pA of inward current in a cell with an average capacity of 30 pF. The problem of which ionic component is responsible for initiating the diastolic depolarization was investigated by analysing the composition and the properties of the net inward current in the diastolic range of voltages. 3. The measured instantaneous 'background' current activated during voltage clamp steps from a holding potential of -35 mV was outward positive to approximately -61 mV, and had a region of negative slope conductance from -45 to -35 mV. 4. The instantaneous component lost its rectifying behaviour in the presence of Ni2+ (100 microM) and nitrendipine (10 microM). These blockers of Ca(2+)-dependent currents modified the instantaneous I-V relation at voltages positive to -45 to -50 mV, thus implying that Ca2+ currents become important at less negative potentials than -50 mV, towards the very end of diastolic depolarization. 5. Possible errors introduced by voltage clamp analysis with the whole-cell method on the instantaneous current and on if measurement were evaluated. Leakage through the seal resistance caused the instantaneous I-V relation to be displaced in the inward direction at negative voltages. Correction for the seal leakage moved the reversal potential for the instantaneous current toward the negative direction from -61 to approximately -66 mV. Thus, no depolarization can be driven by the background current beyond -66 mV. 6. During voltage clamp analysis, lack of series-resistance compensation led to lack of intracellular voltage control, as was apparent using a second pipette on the same cell. This slowed activation of if and led to a 1.5- to 2-fold reduction of

  18. Inhibition of cAMP-Dependent PKA Activates β2-Adrenergic Receptor Stimulation of Cytosolic Phospholipase A2 via Raf-1/MEK/ERK and IP3-Dependent Ca2+ Signaling in Atrial Myocytes

    PubMed Central

    Ji, X.; Maxwell, J. T.; Mignery, G. A.; Samarel, A. M.; Lipsius, S. L.

    2016-01-01

    We previously reported in atrial myocytes that inhibition of cAMP-dependent protein kinase (PKA) by laminin (LMN)-integrin signaling activates β2-adrenergic receptor (β2-AR) stimulation of cytosolic phospholipase A2 (cPLA2). The present study sought to determine the signaling mechanisms by which inhibition of PKA activates β2-AR stimulation of cPLA2. We therefore determined the effects of zinterol (0.1 μM; zint-β2-AR) to stimulate ICa,L in atrial myocytes in the absence (+PKA) and presence (-PKA) of the PKA inhibitor (1 μM) KT5720 and compared these results with atrial myocytes attached to laminin (+LMN). Inhibition of Raf-1 (10 μM GW5074), phospholipase C (PLC; 0.5 μM edelfosine), PKC (4 μM chelerythrine) or IP3 receptor (IP3R) signaling (2 μM 2-APB) significantly inhibited zint-β2-AR stimulation of ICa,L in–PKA but not +PKA myocytes. Western blots showed that zint-β2-AR stimulation increased ERK1/2 phosphorylation in–PKA compared to +PKA myocytes. Adenoviral (Adv) expression of dominant negative (dn) -PKCα, dn-Raf-1 or an IP3 affinity trap, each inhibited zint-β2-AR stimulation of ICa,L in + LMN myocytes compared to control +LMN myocytes infected with Adv-βgal. In +LMN myocytes, zint-β2-AR stimulation of ICa,L was enhanced by adenoviral overexpression of wild-type cPLA2 and inhibited by double dn-cPLA2S505A/S515A mutant compared to control +LMN myocytes infected with Adv-βgal. In–PKA myocytes depletion of intracellular Ca2+ stores by 5 μM thapsigargin failed to inhibit zint-β2-AR stimulation of ICa,L via cPLA2. However, disruption of caveolae formation by 10 mM methyl-β-cyclodextrin inhibited zint-β2-AR stimulation of ICa,L in–PKA myocytes significantly more than in +PKA myocytes. We conclude that inhibition of PKA removes inhibition of Raf-1 and thereby allows β2-AR stimulation to act via PKCα/Raf-1/MEK/ERK1/2 and IP3-mediated Ca2+ signaling to stimulate cPLA2 signaling within caveolae. These findings may be relevant to the

  19. Direct Evidence for Microdomain-Specific Localization and Remodeling of Functional L-Type Calcium Channels in Rat and Human Atrial Myocytes

    PubMed Central

    Glukhov, Alexey V.; Balycheva, Marina; Sanchez-Alonso, Jose L.; Ilkan, Zeki; Alvarez-Laviada, Anita; Bhogal, Navneet; Diakonov, Ivan; Schobesberger, Sophie; Sikkel, Markus B.; Bhargava, Anamika; Faggian, Giuseppe; Punjabi, Prakash P.; Houser, Steven R.

    2015-01-01

    Background— Distinct subpopulations of L-type calcium channels (LTCCs) with different functional properties exist in cardiomyocytes. Disruption of cellular structure may affect LTCC in a microdomain-specific manner and contribute to the pathophysiology of cardiac diseases, especially in cells lacking organized transverse tubules (T-tubules) such as atrial myocytes (AMs). Methods and Results— Isolated rat and human AMs were characterized by scanning ion conductance, confocal, and electron microscopy. Half of AMs possessed T-tubules and structured topography, proportional to cell width. A bigger proportion of myocytes in the left atrium had organized T-tubules and topography than in the right atrium. Super-resolution scanning patch clamp showed that LTCCs distribute equally in T-tubules and crest areas of the sarcolemma, whereas, in ventricular myocytes, LTCCs primarily cluster in T-tubules. Rat, but not human, T-tubule LTCCs had open probability similar to crest LTCCs, but exhibited ≈40% greater current. Optical mapping of Ca2+ transients revealed that rat AMs presented ≈3-fold as many spontaneous Ca2+ release events as ventricular myocytes. Occurrence of crest LTCCs and spontaneous Ca2+ transients were eliminated by either a caveolae-targeted LTCC antagonist or disrupting caveolae with methyl-β-cyclodextrin, with an associated ≈30% whole-cell ICa,L reduction. Heart failure (16 weeks post–myocardial infarction) in rats resulted in a T-tubule degradation (by ≈40%) and significant elevation of spontaneous Ca2+ release events. Although heart failure did not affect LTCC occurrence, it led to ≈25% decrease in T-tubule LTCC amplitude. Conclusions— We provide the first direct evidence for the existence of 2 distinct subpopulations of functional LTCCs in rat and human AMs, with their biophysical properties modulated in heart failure in a microdomain-specific manner. PMID:26450916

  20. High-resolution measurement and calibration of Ca(2+)-transients using Indo-1 in guinea-pig atrial myocytes under voltage clamp.

    PubMed

    Callewaert, G; Lipp, P; Pott, L; Carmeliet, E

    1991-04-01

    Spherical atrial myocytes obtained by enzymatic dispersion of hearts from adult guinea-pigs were loaded with the fluorescent Ca(2+)-indicator Indo-1 via patch-clamp pipettes. The dialysing solution additionally contained citrate (60 mM) as low-affinity ('linear') Ca(2+)-chelating compound in order to slow intracellular Ca(2+)-transients. Changes in Indo-1 fluorescence under voltage-clamp due to Ca(2+)-entry and/or release from the SR were calibrated using an in vivo procedure to determine the limiting fluorescence ratios. Sample recordings will be presented to demonstrate that components of a [Ca2+]i-transient due to entry via L-type Ca(2+)-channels and due to Ca(2+)-release from the SR can be directly visualized.

  1. 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

  2. Inhibitory effects of hesperetin on Nav1.5 channels stably expressed in HEK 293 cells and on the voltage-gated cardiac sodium current in human atrial myocytes

    PubMed Central

    Wang, Huan; Wang, Hong-fei; Zhang, Hao; Wang, Chen; Chen, Yu-fang; Ma, Rong; Xiang, Ji-zhou; Du, Xin-ling; Tang, Qiang

    2016-01-01

    Aim: Voltage-gated sodium channels composed of a pore-forming α subunit and auxiliary β subunits are responsible for the upstroke of the action potential in cardiac myocytes. The pore-forming subunit of the cardiac sodium channel Nav1.5, which is encoded by SCN5A, is the main ion channel that conducts the voltage-gated cardiac sodium current (INa) in cardiac cells. The current study sought to investigate the inhibitory effects of hesperetin on human cardiac Nav1.5 channels stably expressed in human embryonic kidney 293 (HEK 293) cells and on the voltage-gated cardiac sodium current (INa) in human atrial myocytes. Methods: The effects of hesperetin on human cardiac Nav1.5 channels expressed in HEK 293 cells and on cardiac Na+ currents in human atrial myocytes were examined through whole-cell patch-clamp techniques. Results: Nav1.5 currents were potently and reversibly suppressed in a concentration- and voltage-dependent manner by hesperetin, which exhibited an IC50 of 62.99 μmol/L. Hesperetin significantly and negatively shifted the voltage-dependent activation and inactivation curves. Hesperetin also markedly decelerated Nav1.5 current inactivation and slowed the recovery from Nav1.5 channel inactivation. The hesperetin-dependent blockage of Nav1.5 currents was frequency-dependent. Hesperetin also potently and reversibly inhibited Na+ current (INa) in human atrial myocytes, consistently with its effects on Nav1.5 currents in HEK 293 cells. Conclusion: Hesperetin is a potent inhibitor of INa in human atrial myocytes and Nav1.5 channels expressed in human embryonic kidney 293 cells. Hesperetin probably functions by blocking the open state and the inactivated state of these channels. PMID:27694909

  3. Shear stress activates monovalent cation channel transient receptor potential melastatin subfamily 4 in rat atrial myocytes via type 2 inositol 1,4,5-trisphosphate receptors and Ca(2+) release.

    PubMed

    Son, Min-Jeong; Kim, Joon-Chul; Kim, Sung Woo; Chidipi, Bojjibabu; Muniyandi, Jeyaraj; Singh, Thoudam Debraj; So, Insuk; Subedi, Krishna P; Woo, Sun-Hee

    2016-06-01

    During each contraction and haemodynamic disturbance, cardiac myocytes are subjected to fluid shear stress as a result of blood flow and the relative movement of sheets of myocytes. The present study aimed to characterize the shear stress-sensitive membrane current in atrial myocytes using the whole-cell patch clamp technique, combined with pressurized fluid flow, as well as pharmacological and genetic interventions of specific proteins. The data obtained suggest that shear stress indirectly activates the monovalent cation current carried by transient receptor potential melastatin subfamily 4 channels via type 2 inositol 1,4,5-trisphosphate receptor-mediated Ca(2+) release in subsarcolemmal domains of atrial myocytes. Ca(2+) -mediated interactions between these two proteins under shear stress may be an important mechanism by which atrial cells measure mechanical stress and translate it to alter their excitability. Atrial myocytes are subjected to shear stress during the cardiac cycle under physiological or pathological conditions. The ionic currents regulated by shear stress remain poorly understood. We report the characteristics, molecular identity and activation mechanism of the shear stress-sensitive current (Ishear ) in rat atrial myocytes. A shear stress of ∼16 dyn cm(-2) was applied to single myocytes using a pressurized microflow system, and the current was measured by whole-cell patch clamp. In symmetrical CsCl solutions with minimal concentrations of internal EGTA, Ishear showed an outwardly rectifying current-voltage relationship (reversal at -2 mV). The current was conducted primarily (∼80%) by monovalent cations but not Ca(2+) . It was suppressed by intracellular Ca(2+) buffering at a fixed physiological level, inhibitors of transient receptor potential melastatin subfamily 4 (TRPM4), intracellular introduction of TRPM4 antibodies or knockdown of TRPM4 expression, suggesting that TRPM4 carries most of this current. A notable reduction in Ishear

  4. Endocytosis and uptake of lucifer yellow by cultured atrial myocytes and isolated intact atria from adult rats. Regulation and subcellular localization.

    PubMed

    Page, E; Goings, G E; Upshaw-Earley, J; Hanck, D A

    1994-08-01

    The time course of endocytic uptake of Lucifer yellow (LY) was followed by fluorescence and electron microscopy after exposure of primary cultures of atrial myocytes from adult rats to LY under conditions that prevented transplasmalemmal LY entry via channels or carriers. After a 2-minute exposure to LY at 37 degrees C, electron microscopy revealed classic clathrin-coated vesicles fused to endosomes, which were absent in LY-free medium or at 2 degrees C, suggesting that LY turns on endocytosis or accelerates a slow constitutive endocytosis. Fluorescence microscopy, which detected no LY entry at 2 minutes in LY, showed punctate cytoplasmic fluorescent densities after 10 minutes, which were readily distinguishable from intrinsic perinuclear fluorescence. Fluorescence microscopy after immunostaining with antibodies against clathrin, vacuolar H(+)-ATPase, atrial peptide, or a marker for acidified compartments suggested LY sorting into an acidified prelysosomal pathway. Using absence of punctate fluorescence after 10 minutes in LY as a criterion for inhibition of endocytosis, we showed that endocytosis was inhibited by inhibitors of protein phosphatases 1 and 2A or inhibitors of cAMP-dependent protein kinases 1 and 2, by effects of caffeine on sarcoplasmic reticulum Ca2+ release, and by temperatures below 18 degrees C, but not by staurosporine, phorbol esters, pertussis toxin, thapsigargin, preventing contractions with nifedipine, ryanodine and low [Ca2+]o, or raising cytosolic cAMP concentrations. Both phosphatase inhibitors and caffeine also inhibited a fraction of LY uptake by intact rat atria. We conclude that endocytic uptake of LY is an energy-dependent, specifically regulated process, whose understanding and control are potentially important for the medically relevant problem of introducing drugs and macromolecules into atrial heart muscle cells.

  5. 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).

  6. Atrial natriuretic peptide behaviour and myocyte hypertrophic profile in combined pressure and volume-induced cardiac hypertrophy.

    PubMed

    Cavallero, Susana; González, Germán E; Puyó, Ana M; Rosón, María I; Pérez, Susana; Morales, Celina; Hertig, Cecilia M; Gelpi, Ricardo J; Fernández, Belisario E

    2007-09-01

    To investigate cardiomyocyte hypertrophy and hormonal profile in cardiac hypertrophy resulting from sequentially applied overloads. We studied Sprague-Dawley rats with renovascular hypertension (RV), where pressure overload predominates, or deoxycorticosterone acetate (DOCA)-salt (DS), where volume overload predominates, at 2 and 4 weeks of treatment, and the combination of both models in inverse sequence: RV 2 weeks/DS 2 weeks (RV2/DS2) and DS 2 weeks/RV 2 weeks (DS2/RV2), and their sham controls (Sh). Blood pressure and cardiomyocyte diameter increased to a similar extent in RV and DS at 2 and 4 weeks and in combined models. Cardiomyocyte length increased remarkably in the DS4 group. Circulating atrial natriuretic peptide (ANP) was elevated in all hypertensive groups after 2 and 4 weeks. The RV2/DS2 group showed similar plasma ANP levels to RV4, but DS2/RV2 exhibited a three-fold increase in ANP levels (P<0.001 versus Sh4, DS2 and DS4). Atrial ANP mRNA remained unchanged in all groups. DS treatment alone or in combination with RV increased left ventricular ANP mRNA, meanwhile only RV treatment increased left ventricular B-type natriuretic peptide (BNP) mRNA. Ventricular ANP expression levels, but not circulating ANP, correlated with both cardiomyocyte diameter (r=0.859, P<0.01) and length (r=0.848, P<0.01). Renal expression of natriuretic peptide receptor C (NPR-C) was unchanged in RV4 but decreased to a similar extent in the DS4 group and both combined treatments. Morphometric patterns seem to be more related to the paracrine function of the heart than to the secretion of ANP and the endocrine function. Plasma ANP in the DS2/RV2 group could indicate a different evolution of the remodelling process. ANP expression seems to be a more sensitive marker for volume than for pressure overload.

  7. The pacemaker current If in single human atrial myocytes and the effect of β-adrenoceptor and A1-adenosine receptor stimulation

    PubMed Central

    Porciatti, Francesco; Pelzmann, Brigitte; Cerbai, Elisabetta; Schaffer, Peter; Pino, Roberto; Bernhart, Eva; Koidl, Bernd; Mugelli, Alessandro

    1997-01-01

    We used single human atrial myocytes to study If occurrence, properties and pharmacological modulation. Cells were obtained by chunk enzymatic digestion from samples of right atrial appendages of patients undergoing corrective cardiac surgery. Patch-clamped cells in the whole-cell configuration were superfused with a modified Tyrode solution to reduce contamination by interfering currents and to amplify If. The average cell membrane capacitance was 85.06±2.41 pF (n=531). Data were consistent with the geometrical dimensions of the cells (length 94.2±1.89 μm, width 17.9±0.42 μm, n=126). When hyperpolarizing to −120 mV from a holding potential of −40 mV, 252 of 306 tested cells (82%) expressed a hyperpolarization-activated inward current (If density =3.77±0.25 pA pF−1); the current was considered to be present in a given cell if its density at −120 mV was larger than 0.5 pA pF−1. Current activation was sigmoidal and fitted a Boltzmann model; the average activation curve (n=25) showed a maximum current amplitude of 205.97±19.94 pA, corresponding to 3.87±0.63 pA pF−1, voltage of half-maximal activation (V1/2) at −86.68±2.19 mV and a slope of −11.39±0.69 mV. The reversal potential of If measured by tail-current analysis was −13.07±1.92 mV (n=6). The addition of CsCl (5 mM) fully and reversibly blocked the current. In the presence of the β-adrenoceptor agonist isoprenaline (Iso, 1 μM), V1/2 was significantly shifted toward less negative potentials by 6.06±1.96 mV (n=16, P=0.0039). The selective A1-adenosine receptor agonist cyclopentyladenosine (CPA, 1 μM) caused a statistically significant shift of V1/2 toward more negative potentials with respect to the control curve, both in the absence (−7.37±1.83 mV, P=0.0005, n=11) and in the presence of 1 μM Iso (−4.97±1.78, P=0.031, n=6). These results demonstrate that a current with the properties of If described in cardiac primary and secondary

  8. Mechanisms of action of antiarrhythmic agent bertosamil on hKv1.5 channels and outward potassium current in human atrial myocytes.

    PubMed

    Godreau, David; Vranckx, Roger; Hatem, Stéphane N

    2002-02-01

    We analyzed the mechanism of action of the antiarrhythmic agent bertosamil on hKv1.5 channels expressed in Chinese hamster ovary cells (I(hKv1.5)) and on the outward current (I(o)) of human atrial myocytes (HAMs) by using the whole cell patch-clamp technique to record current. External application of 10 microM bertosamil inhibited I(hKv1.5), accelerated its time-dependent decay, and slowed its deactivation. When bertosamil was applied at rest or intracellularly (50 microM), it accelerated the rate of I(hKv1.5) inactivation without change of the peak amplitude. At the steady-state effect of intracellular bertosamil, external drug application only inhibited I(hKv1.5). When cesium was the charge carrier, bertosamil inhibited I(hKv1.5) but had no effect on its time course. Intracellular tetraethylammonium inhibited I(hKv1.5), suppressed its inactivation, and prevented bertosamil effects. Bertosamil-treated I(hKv1.5) became highly sensitive to the rate of membrane stimulation and to cumulative inactivation phenomenon. In HAMs, bertosamil also increased the rate and extent of I(o) inactivation and slowed its recovery from inactivation, whereas after drug application I(o) became highly sensitive to cumulative inactivation phenomenon. In conclusion, bertosamil 1) causes a use-dependent inhibition of the current upon external drug application, and 2) accelerates the rate of current inactivation when applied at rest or intracellularly. These effects result from both an open-channel block and acceleration of the rate of channel inactivation and contribute to the modulation by bertosamil of I(o) in HAM.

  9. 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.

  10. 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. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Activation of native TRPC1/C5/C6 channels by endothelin-1 is mediated by both PIP3 and PIP2 in rabbit coronary artery myocytes.

    PubMed

    Saleh, Sohag N; Albert, Anthony P; Large, William A

    2009-11-15

    We investigate activation mechanisms of native TRPC1/C5/C6 channels (termed TRPC1 channels) by stimulation of endothelin-1 (ET-1) receptor subtypes in freshly dispersed rabbit coronary artery myocytes using single channel recording and immunoprecipitation techniques. ET-1 evoked non-selective cation channel currents with a unitary conductance of 2.6 pS which were not inhibited by either ET(A) or ET(B) receptor antagonists, respectively BQ-123 and BQ788, when administered separately. However, in the presence of both antagonists, ET-1-evoked channel activity was abolished indicating that both ET(A) and ET(B) receptor stimulation activate this conductance. Stimulation of both ET(A) and ET(B) receptors evoked channel activity which was inhibited by the protein kinase C (PKC) inhibitor chelerythrine and by anti-TRPC1 antibodies indicating that activation of both receptor subtypes causes TRPC1 channel activation by a PKC-dependent mechanism. ET(A) receptor-mediated TRPC1 channel activity was selectively inhibited by phosphoinositol-3-kinase (PI-3-kinase) inhibitors wortmannin (50 nM) and PI-828 and by antibodies raised against phosphoinositol-3,4,5-trisphosphate (PIP(3)), the product of PI-3-kinase-mediated phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP(2)). Moreover, exogenous application of diC8-PIP(3) stimulated PKC-dependent TRPC1 channel activity. These results indicate that stimulation of ET(A) receptors evokes PKC-dependent TRPC1 channel activity through activation of PI-3-kinase and generation of PIP(3). In contrast, ET(B) receptor-mediated TRPC1 channel activity was inhibited by the PI-phospholipase C (PI-PLC) inhibitor U73122. 1-Oleoyl-2-acetyl-sn-glycerol (OAG), an analogue of diacylglycerol (DAG), which is a product of PI-PLC, also activated PKC-dependent TRPC1 channel activity. OAG-induced TRPC1 channel activity was inhibited by anti-phosphoinositol-4,5-bisphosphate (PIP(2)) antibodies and high concentrations of wortmannin (20 microM) which

  12. Amino acid sequence of homologous rat atrial peptides: natriuretic activity of native and synthetic forms.

    PubMed Central

    Seidah, N G; Lazure, C; Chrétien, M; Thibault, G; Garcia, R; Cantin, M; Genest, J; Nutt, R F; Brady, S F; Lyle, T A

    1984-01-01

    A substance called atrial natriuretic factor (ANF), localized in secretory granules of atrial cardiocytes, was isolated as four homologous natriuretic peptides from homogenates of rat atria. The complete sequence of the longest form showed that it is composed of 33 amino acids. The three other shorter forms (2-33, 3-33, and 8-33) represent amino-terminally truncated versions of the 33 amino acid parent molecule as shown by analysis of sequence, amino acid composition, or both. The proposed primary structure agrees entirely with the amino acid composition and reveals no significant sequence homology with any known protein or segment of protein. The short form ANF-(8-33) was synthesized by a multi-fragment condensation approach and the synthetic product was shown to exhibit specific activity comparable to that of the natural ANF-(3-33). PMID:6232612

  13. 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

  14. Triggering of sarcoplasmic reticulum Ca2+ release and contraction by reverse mode Na+/Ca2+ exchange in trout atrial myocytes.

    PubMed

    Hove-Madsen, Leif; Llach, Anna; Tibbits, Glen F; Tort, Lluis

    2003-05-01

    Whole cell patch clamp and intracellular Ca(2+) transients in trout atrial cardiomyocytes were used to quantify calcium release from the sarcoplasmic reticulum (SR) and examine its dependency on the Ca(2+) trigger source. Short depolarization pulses (2-20 ms) elicited large caffeine-sensitive tail currents. The Ca(2+) carried by the caffeine-sensitive tail current after a 2-ms depolarization was 0.56 amol Ca(2+)/pF, giving an SR Ca(2+) release rate of 279 amol Ca(2+). pF(-1). s(-1) or 4.3 mM/s. Depolarizing cells for 10 ms to different membrane potentials resulted in a local maximum of SR Ca(2+) release, intracellular Ca(2+) transient, and cell shortening at 10 mV. Although 100 microM CdCl(2) abolished this local maximum, it had no effect on SR Ca(2+) release elicited by a depolarization to 110 or 150 mV, and the SR Ca(2+) release was proportional to the membrane potential in the range -50 to 150 mV with 100 microM CdCl(2). Increasing the intracellular Na(+) concentration ([Na(+)]) from 10 to 16 mM enhanced SR Ca(2+) release but reduced cell shortening at all membrane potentials examined. In the absence of TTX, SR Ca(2+) release was potentiated with 16 mM but not 10 mM pipette [Na(+)]. Comparison of the total sarcolemmal Ca(2+) entry and the Ca(2+) released from the SR gave a gain factor of 18.6 +/- 7.7. Nifedipine (Nif) at 10 microM inhibited L-type Ca(2+) current (I(Ca)) and reduced the time integral of the tail current by 61%. The gain of the Nif-sensitive SR Ca(2+) release was 16.0 +/- 4.7. A 2-ms depolarization still elicited a contraction in the presence of Nif that was abolished by addition of 10 mM NiCl(2). The gain of the Nif-insensitive but NiCl(2)-sensitive SR Ca(2+) release was 14.8 +/- 7.1. Thus both reverse-mode Na(+)/Ca(2+) exchange (NCX) and I(Ca) can elicit Ca(2+) release from the SR, but I(Ca) is more efficient than reverse-mode NCX in activating contraction. This difference may be due to extrusion of a larger fraction of the Ca(2+) released from

  15. Intramyocardial Fibroblast - Myocyte Communication

    PubMed Central

    Kakkar, Rahul; Lee, Richard T.

    2009-01-01

    Cardiac fibroblasts are emerging as key components of normal cardiac function as well as the response to stressors and injury. These most numerous cells of the heart interact with myocytes via paracrine mechanisms, alterations in extracellular matrix homeostasis, and direct cell-cell interactions. It is possible that they are a contributor to the inability of adult myocytes to proliferate, and may influence cardiac progenitor biology. Furthering our understanding of how cardiac fibroblast and myocytes interact may provide an avenue to novel treatments for heart failure prevention. This review discusses the most recent concepts in cardiac fibroblast-myocyte communication and areas of potential future research. PMID:20056945

  16. Effects of Na+ Current and Mechanogated Channels in Myofibroblasts on Myocyte Excitability and Repolarization

    PubMed Central

    Zhang, Jingtao; Lin, Jialun; Han, Guilai

    2016-01-01

    Fibrotic remodeling, characterized by fibroblast phenotype switching, is often associated with atrial fibrillation and heart failure. This study aimed to investigate the effects on electrotonic myofibroblast-myocyte (Mfb-M) coupling on cardiac myocytes excitability and repolarization of the voltage-gated sodium channels (VGSCs) and single mechanogated channels (MGCs) in human atrial Mfbs. Mathematical modeling was developed from a combination of (1) models of the human atrial myocyte (including the stretch activated ion channel current, ISAC) and Mfb and (2) our formulation of currents through VGSCs (INa_Mfb) and MGCs (IMGC_Mfb) based upon experimental findings. The effects of changes in the intercellular coupling conductance, the number of coupled Mfbs, and the basic cycle length on the myocyte action potential were simulated. The results demonstrated that the integration of ISAC, INa_Mfb, and IMGC_Mfb reduced the amplitude of the myocyte membrane potential (Vmax) and the action potential duration (APD), increased the depolarization of the resting myocyte membrane potential (Vrest), and made it easy to trigger spontaneous excitement in myocytes. For Mfbs, significant electrotonic depolarizations were exhibited with the addition of INa_Mfb and IMGC_Mfb. Our results indicated that ISAC, INa_Mfb, and IMGC_Mfb significantly influenced myocytes and Mfbs properties and should be considered in future cardiac pathological mathematical modeling. PMID:27980607

  17. Left ventricular native T1 time and the risk of atrial fibrillation recurrence after pulmonary vein isolation in patients with paroxysmal atrial fibrillation.

    PubMed

    Kato, Shingo; Foppa, Murilo; Roujol, Sébastien; Basha, Tamer; Berg, Sophie; Kissinger, Kraig V; Goddu, Beth; Manning, Warren J; Nezafat, Reza

    2016-01-15

    Native T1 mapping has emerged as a noninvasive non-contrast magnetic resonance imaging (MRI) method to assess for diffuse myocardial fibrosis. However, LV native T1 time in AF patients and its clinical relevance are unclear. Fifty paroxysmal AF patients referred for PVI (60 ± 8 years, 37 male) and 11 healthy control subjects (57 ± 8 years, 10 male) were studied. All patients were in sinus rhythm during the MRI scan. Native T1 mapping images were acquired using a Modified Look-Locker imaging (MOLLI) sequence in 3 short-axis planes (basal, mid and apical slices) using an electrocardiogram triggered single-shot acquisition with a balanced steady-state free precession readout. Late gadolinium enhanced (LGE) MRI was acquired to evaluate for LV myocardial scar. LV ejection fraction was similar between groups (AF: 61 ± 6%; controls: 60 ± 6%, p=0.75). No LV myocardial scar was observed in any patient on LGE. Myocardial native T1 time was greater in AF patients (1099 ± 52 vs 1042 ± 20 msec, p<0.001). During a median follow-up period of 326 days, 18 of 50 (36%) patients experienced recurrence of AF. Multivariate Cox proportional hazard analysis identified elevated native T1 time as an independent predictor of recurrence of AF (HR: 6.53, 95% CI: 1.25-34.3, p=0.026). There are differences in the native LV myocardial T1 time between AF patients with preserved LV function referred for PVI and normal controls. Native T1 time is an independent predictor of recurrence of AF after PVI in patients with paroxysmal AF. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  18. Atrial-ventricular differences in rabbit cardiac voltage-gated Na(+) currents: Basis for atrial-selective block by ranolazine.

    PubMed

    Caves, Rachel E; Cheng, Hongwei; Choisy, Stéphanie C; Gadeberg, Hanne C; Bryant, Simon M; Hancox, Jules C; James, Andrew F

    2017-06-10

    Class 1 antiarrhythmic drugs are highly effective in restoring and maintaining sinus rhythm in atrial fibrillation patients but carry a risk of ventricular tachyarrhythmia. The antianginal agent ranolazine is a prototypic atrial-selective voltage-gated Na(+) channel blocker but the mechanisms underlying its atrial-selective action remain unclear. The present study examined the mechanisms underlying the atrial-selective action of ranolazine. Whole-cell voltage-gated Na(+) currents (INa) were recorded at room temperature (∼22°C) from rabbit isolated left atrial and right ventricular myocytes. INa conductance density was ∼1.8-fold greater in atrial than in ventricular cells. Atrial INa was activated at command potentials ∼7 mV more negative and inactivated at conditioning potentials ∼11 mV more negative than ventricular INa. The onset of inactivation of INa was faster in atrial cells than in ventricular myocytes. Ranolazine (30 μM) inhibited INa in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated/inactivated state block. Ranolazine caused a significantly greater negative shift in voltage of half-maximal inactivation in atrial cells than in ventricular cells, the recovery from inactivation of INa was slowed by ranolazine to a greater extent in atrial myocytes than in ventricular cells, and ranolazine produced an instantaneous block that showed marked voltage dependence in atrial cells. Differences exist between rabbit atrial and ventricular myocytes in the biophysical properties of INa. The more negative voltage dependence of INa activation and inactivation, together with trapping of the drug in the inactivated channel, underlies an atrial-selective action of ranolazine. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Ablation of sarcolipin results in atrial remodeling

    PubMed Central

    Xie, Lai-Hua; Shanmugam, Mayilvahanan; Park, Ji Yeon; Zhao, Zhenghang; Wen, Hairuo; Tian, Bin; Periasamy, Muthu

    2012-01-01

    Sarcolipin (SLN) is a key regulator of sarco(endo)plasmic reticulum (SR) Ca2+-ATPase (SERCA), and its expression is altered in diseased atrial myocardium. To determine the precise role of SLN in atrial Ca2+ homeostasis, we developed a SLN knockout (sln−/−) mouse model and demonstrated that ablation of SLN enhances atrial SERCA pump activity. The present study is designed to determine the long-term effects of enhanced SERCA activity on atrial remodeling in the sln−/− mice. Calcium transient measurements show an increase in atrial SR Ca2+ load and twitch Ca2+ transients. Patch-clamping experiments demonstrate activation of the forward mode of sodium/calcium exchanger, increased L-type Ca2+ channel activity, and prolongation of action potential duration at 90% repolarization in the atrial myocytes of sln−/− mice. Spontaneous Ca2+ waves, delayed afterdepolarization, and triggered activities are frequent in the atrial myocytes of sln−/− mice. Furthermore, loss of SLN in atria is associated with increased interstitial fibrosis and altered expression of genes encoding collagen and other extracellular matrix proteins. Our results also show that the sln−/− mice are susceptible to atrial arrhythmias upon aging. Together, these findings indicate that ablation of SLN results in increased SERCA activity and SR Ca2+ load, which, in turn, could cause abnormal intracellular Ca2+ handling and atrial remodeling. PMID:22496245

  20. Quality Metrics for Stem Cell-Derived Cardiac Myocytes

    PubMed Central

    Sheehy, Sean P.; Pasqualini, Francesco; Grosberg, Anna; Park, Sung Jin; Aratyn-Schaus, Yvonne; Parker, Kevin Kit

    2014-01-01

    Summary Advances in stem cell manufacturing methods have made it possible to produce stem cell-derived cardiac myocytes at industrial scales for in vitro muscle physiology research purposes. Although FDA-mandated quality assurance metrics address safety issues in the manufacture of stem cell-based products, no standardized guidelines currently exist for the evaluation of stem cell-derived myocyte functionality. As a result, it is unclear whether the various stem cell-derived myocyte cell lines on the market perform similarly, or whether any of them accurately recapitulate the characteristics of native cardiac myocytes. We propose a multiparametric quality assessment rubric in which genetic, structural, electrophysiological, and contractile measurements are coupled with comparison against values for these measurements that are representative of the ventricular myocyte phenotype. We demonstrated this procedure using commercially available, mass-produced murine embryonic stem cell- and induced pluripotent stem cell-derived myocytes compared with a neonatal mouse ventricular myocyte target phenotype in coupled in vitro assays. PMID:24672752

  1. Differential responses of rabbit ventricular and atrial transient outward current (Ito) to the Ito modulator NS5806.

    PubMed

    Cheng, Hongwei; Cannell, Mark B; Hancox, Jules C

    2017-03-01

    Transient outward potassium current (Ito) in the heart underlies phase 1 repolarization of cardiac action potentials and thereby affects excitation-contraction coupling. Small molecule activators of Ito may therefore offer novel treatments for cardiac dysfunction, including heart failure and atrial fibrillation. NS5806 has been identified as a prototypic activator of canine Ito This study investigated, for the first time, actions of NS5806 on rabbit atrial and ventricular Ito Whole cell patch-clamp recordings of Ito and action potentials were made at physiological temperature from rabbit ventricular and atrial myocytes. 10 μmol/L NS5806 increased ventricular Ito with a leftward shift in Ito activation and accelerated restitution. At higher concentrations, stimulation of Ito was followed by inhibition. The EC50 for stimulation was 1.6 μmol/L and inhibition had an IC50 of 40.7 μmol/L. NS5806 only inhibited atrial Ito (IC50 of 18 μmol/L) and produced a modest leftward shifts in Ito activation and inactivation, without an effect on restitution. 10 μmol/L NS5806 shortened ventricular action potential duration (APD) at APD20-APD90 but prolonged atrial APD NS5806 also reduced atrial AP upstroke and amplitude, consistent with an additional atrio-selective effect on Na(+) channels. In contrast to NS5806, flecainide, which discriminates between Kv1.4 and 4.x channels, produced similar levels of inhibition of ventricular and atrial Ito NS5806 discriminates between rabbit ventricular and atrial Ito, with mixed activator and inhibitor actions on the former and inhibitor actions against the later. NS5806 may be of significant value for pharmacological interrogation of regional differences in native cardiac Ito. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

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

    PubMed

    Cao, Hong; Huang, Congxin; Wang, Xin

    2016-05-01

    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.

  3. 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

  4. Rescue of Injured Myocytes

    DTIC Science & Technology

    1989-01-01

    model of chemical hypoxia, we decreased extracellular pH (pH ) as we added the metabolic inhibitors , KCN and iodoacetate, to hepaocyte suspensions...that an acidic extracellular pH protected against loss of viability during ATP deple- tion in a model of ’ chemical hypoxia’ with metabolic inhibitors ...functional re- covery of myocytes after various periods of chemical hypoxia, a model of ATP depletion using inhibitors of oxidative phosphorylation and gly

  5. 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.

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

    PubMed Central

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

    2015-01-01

    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. PMID:26400986

  7. [Atrial fibrillation].

    PubMed

    Cárdenas, Manuel

    2007-01-01

    Atrial fibrillation is an arrhythmia characterized by no-coordinated atrial contraction that results in an inefficient atrial systole. The clinical classification of atrial fibrillation includes: ocassional, paroxysmal, persistent, and permanent. Multiple mechanisms have been described and accounts for a single ECG manifestation. Treatment should be individualized and has to considered several aspects including age, associated heart disease, and symptoms. Treatment strategies are: rhythm control, rate control, and thromboprophylaxis.

  8. Phospholemman Overexpression Inhibits Na+-K+-ATPase in Adult Rat Cardiac Myocytes: Relevance to Decreased Na+ pump Activity in Post-Infarction Myocytes

    PubMed Central

    Zhang, Xue-Qian; Moorman, J. Randall; Ahlers, Belinda A.; Carl, Lois L.; Lake, Douglas E.; Song, Jianliang; Mounsey, J. Paul; Tucker, Amy L.; Chan, Yiu-mo; Rothblum, Lawrence I.; Stahl, Richard C.; Carey, David J.; Cheung, Joseph Y.

    2005-01-01

    Messenger RNA levels of phospholemman (PLM), a member of the FXYD family of small single-span membrane proteins with putative ion-transport regulatory properties, were increased in postinfarction (MI) rat myocytes. We tested the hypothesis that the previously observed reduction in Na+-K+-ATPase activity in MI rat myocytes was due to PLM overexpression. In rat hearts harvested 3 and 7 days post-MI, PLM protein expression was increased by 2- and 4-fold, respectively. To simulate increased PLM expression post-MI, PLM was overexpressed in normal adult rat myocytes by adenovirus-mediated gene transfer. PLM overexpression did not affect the relative level of phosphorylation on serine68 of PLM. Na+-K+-ATPase activity was measured as ouabain-sensitive Na+-K+ pump current (Ip). Compared to control myocytes overexpressing green fluorescent protein alone, Ip measured in myocytes overexpressing PLM was significantly (P<0.0001) lower at similar membrane voltages, pipette Na+ ([Na+]pip) and extracellular K+ concentrations ([K+]o). From −70 to +60 mV, neither [Na+]pip nor [K+]o required to attain half-maximal Ip was significantly different between control and PLM myocytes. This phenotype of decreased Vmax without appreciable changes in Km for Na+ and K+ in PLM overexpressed myocytes was similar to that observed in MI rat myocytes. Inhibition of Ip by PLM overexpression was not due to decreased Na+-K+-ATPase expression since there were no changes in either protein or messenger RNA levels of either α1 or α2 isoforms of Na+-K+-ATPase. In native rat cardiac myocytes, PLM co-immunoprecipitated with α-subunits of Na+-K+-ATPase. Inhibition of Na+-K+-ATPase by PLM overexpression, in addition to previously reported decrease in Na+-K+-ATPase expression, may explain altered Vmax but not Km of Na+-K+-ATPase in postinfarction rat myocytes. PMID:16195392

  9. Atrial metabolism and tissue perfusion as determinants of electrical and structural remodelling in atrial fibrillation.

    PubMed

    Opacic, Dragan; van Bragt, Kelly A; Nasrallah, Hussein M; Schotten, Ulrich; Verheule, Sander

    2016-04-01

    Atrial fibrillation (AF) is the most common tachyarrhythmia in clinical practice. Over decades of research, a vast amount of knowledge has been gathered about the causes and consequences of AF related to cellular electrophysiology and features of the tissue structure that influence the propagation of fibrillation waves. Far less is known about the role of myocyte metabolism and tissue perfusion in the pathogenesis of AF. However, the rapid rates of electrical activity and contraction during AF must present an enormous challenge to the energy balance of atrial myocytes. This challenge can be met by scaling back energy demand and by increasing energy supply, and there are several indications that both phenomena occur as a result of AF. Still, there is ample evidence that these adaptations fall short of redressing this imbalance, which may represent a driving force for atrial electrical as well as structural remodelling. In addition, several 'metabolic diseases' such as diabetes, obesity, and abnormal thyroid function precipitate some well-known 'culprits' of the AF substrate such as myocyte hypertrophy and fibrosis, while some other AF risk factors, such as heart failure, affect atrial metabolism. This review provides an overview of metabolic and vascular alterations in AF and their involvement in its pathogenesis.

  10. 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.

  11. 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.

  12. 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

  13. 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

  14. Systematic reduction of a detailed atrial myocyte model

    NASA Astrophysics Data System (ADS)

    Lombardo, Daniel M.; Rappel, Wouter-Jan

    2017-09-01

    Cardiac arrhythmias are a major health concern and often involve poorly understood mechanisms. Mathematical modeling is able to provide insights into these mechanisms which might result in better treatment options. A key element of this modeling is a description of the electrophysiological properties of cardiac cells. A number of electrophysiological models have been developed, ranging from highly detailed and complex models, containing numerous parameters and variables, to simplified models in which variables and parameters no longer directly correspond to electrophysiological quantities. In this study, we present a systematic reduction of the complexity of the detailed model of Koivumaki et al. using the recently developed manifold boundary approximation method. We reduce the original model, containing 42 variables and 37 parameters, to a model with only 11 variables and 5 parameters and show that this reduced model can accurately reproduce the action potential shape and restitution curve of the original model. The reduced model contains only five currents and all variables and parameters can be directly linked to electrophysiological quantities. Due to its reduction in complexity, simulation times of our model are decreased more than three-fold. Furthermore, fitting the reduced model to clinical data is much more efficient, a potentially important step towards patient-specific modeling.

  15. Fibroblast growth factor-21 is positively associated with atrial fibrosis in atrial fibrillation patients with rheumatic heart disease.

    PubMed

    Wang, Rui; Yi, Xin; Li, Xiaoyan; Jiang, Xuejun

    2015-01-01

    Fibroblast growth factor-21 (FGF-21) has been discovered as a strong hormone, plays an important role in lipid metabolism, glucose metabolism, associated with several diseases such as obesity, metabolic syndrome, diabetes mellitus, and cardiovascular events; however, no evidence is available concerning the relationship of FGF-21 and atrial fibrosis in patients with atrial fibrillation (AF) and rheumatic heart disease (RHD). Twenty-four rheumatic heart disease patients were divided into two groups, 12 cases with AF and 12 cases with sinus rhythm (SR). Clinical characteristics and blood samples were collected before surgery; right atrial appendage samples were taken in the surgery of valve replacement. HE staining was performed to determine cross-sectional area of atrial myocytes; Masson stained sections and mRNA levels of cardiac fibrosis biomarkers were used to evaluate the degree of cardiac fibrosis; the level of FGF-21 was evaluated via enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and real-time polymerase chain reaction (PCR). Compared with SR group, cross-sectional area of atrial myocytes and collagen volume fraction were significantly increased in the atrial tissue of AF group. The distribution of FGF-21 in the AF group was remarkably higher than SR group. In addition, plasma and mRNA levels of FGF-21 in atrial tissue of AF showed the same trend as the result of immunohistochemistry. Using linear correlation analysis, the expression level of FGF-21 was found to be positively related to the degree of atrial fibrosis. FGF-21 might involve in the development and maintenance of atrial fibrosis in atrial fibrillation with rheumatic heart disease, and FGF-21 could be used as a novel biomarker to evaluate myocardial fibrosis in the future.

  16. Atrial Fibrillation

    MedlinePlus

    ... information about the heart's electrical system and detailed animations, go to the Diseases and Conditions Index How ... can't restore a normal heart rhythm. The animation below shows atrial fibrillation. Click the "start" button ...

  17. Left Ventricular Native T1 time and the Risk of Arial fibrillation Recurrence after Pulmonary Vein Isolation in Patients with Paroxysmal Atrial Fibrillation

    PubMed Central

    Kato, Shingo; Foppa, Murilo; Roujol, Sébastien; Basha, Tamer; Berg, Sophie; Kissinger, Kraig V.; Goddu, Beth; Manning, Warren J; Nezafat, Reza

    2016-01-01

    Background Native T1 mapping has emerged as a noninvasive non-contrast magnetic resonance imaging (MRI) method to assess for diffuse myocardial fibrosis. However, LV native T1 time in AF patients and its clinical relevance are unclear. Methods Fifty paroxysmal AF patients referred for PVI (60±8 years, 37 male) and 11 healthy control subjects (57±8 years, 10 male) were studied. All patients were in sinus rhythm during the MRI scan. Native T1 mapping images were acquired using a Modified Look-Locker imaging (MOLLI) sequence in 3 short-axis planes (basal, mid and apical slices) using an electrocardiogram triggered single-shot acquisition with a balanced steady-state free precession readout. Late gadolinium enhanced (LGE) MRI was acquired to evaluate for LV myocardial scar. Results LV ejection fraction was similar between groups (AF: 61±6%; controls: 60±6%, p=0.75). No LV myocardial scar was observed in any patient on LGE. Myocardial native T1 time was greater in AF patients (1099±52 vs 1042±20 msec, p<0.001). During a median follow-up period of 326 days, 18 of 50 (36%) patients experienced recurrence of AF. Multivariate Cox proportional hazard analysis identified elevated native T1 time as an independent predictor of recurrence of AF (HR: 6.53, 95% CI: 1.25–34.3, p=0.026). Conclusions There are differences in the native LV myocardial T1 time between AF patients with preserved LV function referred for PVI and normal controls. Native T1 time is an independent predictor of recurrence of AF after PVI in patients with paroxysmal AF. PMID:26599750

  18. Localization of atrial natriuretic peptide mRNA and immunoreactivity in the rat heart and human atrial appendage

    SciTech Connect

    Hamid, Q.; Wharton, J.; Terenghi, G.; Hassall, C.J.S.; Aimi, J.; Taylor, K.M.; Nakazato, H.; Dixon, J.E.; Burnstock, G.; Polak, J.M.

    1987-10-01

    The localization of mRNA encoding preproatrial natriuretic peptide was investigated in tissue sections and cultures of rat heart and in sections of human right atrial appendage using the technique of in situ hybridization with /sup 32/P- and /sup 35/S-labeled RNA probes. Rat atrial natriuretic peptide (ANP) transcripts were demonstrated in numerous atrial myocytes and, to a lesser extent, in ventricular myocytes in both tissue sections and newborn rat heart cultures. These findings are consistent with those obtained by RNA blot analysis of rat heart total RNA, indicating that a single prepro-ANP transcript of approx. 900 nucleotides was present in the ventricles as well as the atria. Using a /sup 35/S-labeled RNA probe for human ANP mRNA, ANP transcripts were also localized to the majority of myocytes in the human right atrial appendage. Only background levels of autoradiographic labeling were obtained when RNA probes identical to the coding sequence of rat or human ANP mRNA were used. A close correlation was found between the distribution of ANP immunoreactivity and prepro-ANP mRNA in these preparations. These results provide unequivocal evidence for the expression of the ANP gene in the rat ventricles, as well as the atria, because myocytes in these tissues have been established as the sites of both ANP localization and precursor biosynthesis. The combined use of cardiac cultures and in situ hybridization may be of value in future studies investigating the regulation of ANP synthesis in cardiac myocytes.

  19. Modulation of excitability, membrane currents and survival of cardiac myocytes by N-acylethanolamines.

    PubMed

    Voitychuk, Oleg I; Asmolkova, Valentyna S; Gula, Nadiya M; Sotkis, Ganna V; Galadari, Sehamuddin; Howarth, Frank C; Oz, Murat; Shuba, Yaroslav M

    2012-09-01

    N-acylethanolamines (NAE) are endogenously produced lipids playing important roles in a diverse range of physiological and pathological conditions. In the present study, using whole-cell patch clamp technique, we have for the first time investigated the effects of the most abundantly produced NAEs, N-stearoylethanolamine (SEA) and N-oleoylethanolamine (OEA), on electric excitability and membrane currents in cardiomyocytes isolated from endocardial, epicardial, and atrial regions of neonatal rat heart. SEA and OEA (1-10μM) attenuated electrical activity of the myocytes from all regions of the cardiac muscle by hyperpolarizing resting potential, reducing amplitude, and shortening the duration of the action potential. However, the magnitudes of these effects varied significantly depending on the type of cardiac myocyte (i.e., endocardial, epicardial, atrial) with OEA being generally more potent. OEA and to a lesser extent SEA suppressed in a concentration-dependent manner currents through voltage-gated Na(+) (VGSC) and L-type Ca(2+) (VGCC) channels, but induced variable cardiac myocyte type-dependent effects on background K(+) and Cl(-) conductance. The mechanisms of inhibitory action of OEA on cardiac VGSCs and VGCCs involved influence on channels' activation/inactivation gating and partial blockade of ion permeation. OEA also enhanced the viability of cardiac myocytes by reducing necrosis without a significant effect on apoptosis. We conclude that SEA and OEA attenuate the excitability of cardiac myocytes mainly through inhibition of VGSCs and VGCC-mediated Ca(2+) entry. Since NAEs are known to increase during tissue ischemia and infarction, these effects of NAEs may mediate some of their cardioprotective actions during these pathological conditions. Copyright © 2012 Elsevier B.V. All rights reserved.

  20. Association of left atrial endothelin-1 with atrial rhythm, size, and fibrosis in patients with structural heart disease.

    PubMed

    Mayyas, Fadia; Niebauer, Mark; Zurick, Andrew; Barnard, John; Gillinov, A Marc; Chung, Mina K; Van Wagoner, David R

    2010-08-01

    Atrial fibrillation (AF) promotes atrial remodeling and can develop secondary to heart failure or mitral valve disease. Cardiac endothelin-1 (ET-1) expression responds to wall stress and can promote myocyte hypertrophy and interstitial fibrosis. We tested the hypothesis that atrial ET-1 is elevated in AF and is associated with AF persistence. Left atrial appendage tissue was studied from coronary artery bypass graft, valve repair, and/or Maze procedure in patients in sinus rhythm with no history of AF (SR, n=21), with history of AF but in SR at surgery (AF/SR, n=23), and in AF at surgery (AF/AF, n=32). The correlation of LA size with atrial protein and mRNA expression of ET-1 and ET-1 receptors (ETAR and ETBR) was evaluated. LA appendage ET-1 content was higher in AF/AF than in SR, but receptor levels were similar. Immunostaining revealed that ET-1 and its receptors were present both in atrial myocytes and in fibroblasts. ET-1 content was positively correlated with LA size, heart failure, AF persistence, and severity of mitral regurgitation. Multivariate analysis confirmed associations of ET-1 with AF, hypertension, and LA size. LA size was associated with ET-1 and MR severity. ET-1 mRNA levels were correlated with genes involved in cardiac dilatation, hypertrophy, and fibrosis. Elevated atrial ET-1 content is associated with increased LA size, AF rhythm, hypertension, and heart failure. ET-1 is associated with atrial dilatation, fibrosis, and hypertrophy and probably contributes to AF persistence. Interventions that reduce atrial ET-1 expression and/or block its receptors may slow AF progression.

  1. 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.

  2. Analysis of Tubular Membrane Networks in Cardiac Myocytes from Atria and Ventricles

    PubMed Central

    Kohl, Tobias; Lehnart, Stephan E.

    2014-01-01

    In cardiac myocytes a complex network of membrane tubules - the transverse-axial tubule system (TATS) - controls deep intracellular signaling functions. While the outer surface membrane and associated TATS membrane components appear to be continuous, there are substantial differences in lipid and protein content. In ventricular myocytes (VMs), certain TATS components are highly abundant contributing to rectilinear tubule networks and regular branching 3D architectures. It is thought that peripheral TATS components propagate action potentials from the cell surface to thousands of remote intracellular sarcoendoplasmic reticulum (SER) membrane contact domains, thereby activating intracellular Ca2+ release units (CRUs). In contrast to VMs, the organization and functional role of TATS membranes in atrial myocytes (AMs) is significantly different and much less understood. Taken together, quantitative structural characterization of TATS membrane networks in healthy and diseased myocytes is an essential prerequisite towards better understanding of functional plasticity and pathophysiological reorganization. Here, we present a strategic combination of protocols for direct quantitative analysis of TATS membrane networks in living VMs and AMs. For this, we accompany primary cell isolations of mouse VMs and/or AMs with critical quality control steps and direct membrane staining protocols for fluorescence imaging of TATS membranes. Using an optimized workflow for confocal or superresolution TATS image processing, binarized and skeletonized data are generated for quantitative analysis of the TATS network and its components. Unlike previously published indirect regional aggregate image analysis strategies, our protocols enable direct characterization of specific components and derive complex physiological properties of TATS membrane networks in living myocytes with high throughput and open access software tools. In summary, the combined protocol strategy can be readily applied

  3. Muscarinic cholinergic regulation of cardiac myocyte ICa-L is absent in mice with targeted disruption of endothelial nitric oxide synthase

    PubMed Central

    Han, Xinqiang; Kubota, Isao; Feron, Olivier; Opel, Douglas J.; Arstall, Margaret A.; Zhao, You-Yang; Huang, Paul; Fishman, Mark C.; Michel, Thomas; Kelly, Ralph A.

    1998-01-01

    Cardiac myocytes have been shown to express constitutively endothelial nitric oxide synthase (eNOS) (nitric oxide synthase 3), the activation of which has been implicated in the regulation of myocyte L-type voltage-sensitive calcium channel current (ICa-L) and myocyte contractile responsiveness to parasympathetic nervous system signaling, although this implication remains controversial. Therefore, we examined the effect of the muscarinic cholinergic agonist carbachol (CCh) on ICa-L and contractile amplitude in isoproterenol (ISO)-prestimulated ventricular myocytes isolated from adult mice, designated eNOSnull mice, with targeted disruption of the eNOS gene. Although both eNOSnull and wild-type (WT) ventricular myocytes exhibited similar increases in ICa-L in response to ISO, there was no measurable suppression of ICa-L by CCh in cells from eNOSnull mice, in contrast to cells from WT mice. These results were reflected in the absence of an effect of CCh on the positive inotropic effect of ISO in eNOSnull myocytes. Also, unlike myocytes from WT animals, eNOSnull myocytes failed to exhibit an increase in cGMP content in response to CCh. Nevertheless, the pharmacologic nitric oxide donors 3-morpholino-sydnonimine and S-nitroso-acetyl-cystein increased cGMP generation and suppressed ISO-augmented ICa-L in eNOSnull cells, suggesting that the signal transduction pathway(s) downstream of eNOS remained intact. Of importance, activation of the acetylcholine-activated K+ channel by CCh was unaffected in atrial and ventricular eNOSnull myocytes. These results confirm the obligatory role of eNOS in coupling muscarinic receptor activation to cGMP-dependent control of ICa-L in cardiac myocytes. PMID:9600997

  4. Microstructured Cocultures of Cardiac Myocytes and Fibroblasts: A Two-Dimensional In Vitro Model of Cardiac Tissue

    NASA Astrophysics Data System (ADS)

    Camelliti, Patrizia; McCulloch, Andrew D.; Kohl, Peter

    2005-06-01

    Cardiac myocytes and fibroblasts are essential elements of myocardial tissue structure and function. In vivo, myocytes constitute the majority of cardiac tissue volume, whereas fibroblasts dominate in numbers. In vitro, cardiac cell cultures are usually designed to exclude fibroblasts, which, because of their maintained proliferative potential, tend to overgrow the myocytes. Recent advances in microstructuring of cultures and cell growth on elastic membranes have greatly enhanced in vitro preservation of tissue properties and offer a novel platform technology for producing more in vivo-like models of myocardium. We used microfluidic techniques to grow two-dimensional structured cardiac tissue models, containing both myocytes and fibroblasts, and characterized cell morphology, distribution, and coupling using immunohistochemical techniques. In vitro findings were compared with in vivo ventricular cyto-architecture. Cardiac myocytes and fibroblasts, cultured on intersecting 30-[mu]m-wide collagen tracks, acquire an in vivo-like phenotype. Their spatial arrangement closely resembles that observed in native tissue: Strands of highly aligned myocytes are surrounded by parallel threads of fibroblasts. In this in vitro system, fibroblasts form contacts with other fibroblasts and myocytes, which can support homogeneous and heterogeneous gap junctional coupling, as observed in vivo. We conclude that structured cocultures of cardiomyocytes and fibroblasts mimic in vivo ventricular tissue organization and provide a novel tool for in vitro research into cardiac electromechanical function.

  5. Phosphoproteomic profiling of the myocyte.

    PubMed

    Edwards, Alistair V G; Cordwell, Stuart J; White, Melanie Y

    2011-10-01

    Protein phosphorylation underpins major cellular processes including energy metabolism, signal transduction, excitation-contraction coupling, apoptosis, and cell survival mechanisms and is thus critical to the myocyte. Targeted approaches, whereby a handful of phosphoproteins are investigated, can suffer from a relatively narrow view of cellular phosphorylation. In contrast, recent technical advances have allowed for the comprehensive documentation of phosphorylation events in complex biological environments, providing a deeper view of the "phosphoproteome." A global, high-throughput characterization of the myocardial phosphoproteome, however, has not yet been achieved. Efficient analysis of phosphorylated proteins and their roles in a dynamic cellular environment requires high-resolution strategies that can identify, localize, and quantify many thousands of phosphorylation sites in a single experiment. Such an approach requires specific enrichment and purification techniques, developed to align with high-end instrumentation for analysis. Cutting-edge phosphoproteomics is no longer restricted to gel-based technology, instead focusing on affinity enrichment prior to liquid chromatography and mass spectrometry. We will describe the best current methods and how they can be applied, as well as the challenges associated with them. We also present current phosphoproteomic investigations in the myocyte and its subcompartments. Although the techniques and instrumentation required to achieve the goal of a myocardial phosphoprotein catalog in physiological and diseased states are highly specialized, the potential biological insight provided by such an approach makes phosphoproteomics an important new avenue of investigation for the cardiovascular researcher.

  6. Atrial Fibrillation: Complications

    MedlinePlus

    ... this page please turn JavaScript on. Feature: Atrial Fibrillation Atrial Fibrillation: Complications Past Issues / Winter 2015 Table of Contents ... two major complications—stroke and heart failure. Atrial Fibrillation and Stroke Click to enlarge image This illustration ...

  7. Atrial Fibrillation: Treatment

    MedlinePlus

    ... this page please turn JavaScript on. Feature: Atrial Fibrillation Atrial Fibrillation: Treatment Past Issues / Winter 2015 Table of Contents Treatment for atrial fibrillation depends on how often you have symptoms, how ...

  8. Extra-atrial expression of the gene for atrial natriuretic factor.

    PubMed Central

    Gardner, D G; Deschepper, C F; Ganong, W F; Hane, S; Fiddes, J; Baxter, J D; Lewicki, J

    1986-01-01

    Atrial natriuretic factor (ANF) is a group of peptides, originally isolated from the cardiac atria, that have a number of important effects on blood pressure, renal function, and salt balance. In the current study, expression of the ANF gene in certain extra-atrial tissues of the rat has been examined by radioimmunoassay of extracted ANF protein and by blot-hybridization, nuclease S1 analysis, and primer-extension analysis of the ANF mRNA. ANF peptides and mRNA were detected in cardiac ventricles, lung, and pituitary gland at levels generally less than or equal to 1% those of cardiac atria. The ANF transcripts in extra-atrial tissue appear to be very similar to those synthesized in the atria. They are polyadenylylated, are equivalent in overall length (950-1050 nucleotides), and have identical 5' termini. A secondary transcription start site mapping approximately 80 base pairs upstream from the primary start site is employed in atria and to a lesser extent in other tissues. The ANF transcript is present throughout the cardiac ventricles from apex to base and in the septum as well as the ventricular free walls. The transcript is more prevalent in the left ventricle and interventricular septum than in the right ventricle. Immunocytochemistry using various anti-rat ANF antibodies localized ANF immunoreactivity to the atrial myocytes; the ventricular myocytes, particularly along the endothelial surface of the ventricular chamber; perialveolar cells in the lung; and the gonadotropin-producing cells of the pituitary. The data indicate that the capacity for ANF gene expression extends beyond atrial tissue, albeit at much reduced levels, and may suggest alternative, perhaps paraendocrine, functions for the peptide in these tissues. Images PMID:2428040

  9. Imaging atrial arrhythmic intracellular calcium in intact heart

    PubMed Central

    Xie, Wenjun; Santulli, Gaetano; Guo, Xiaoxiao; Gao, Melanie; Chen, Bi-Xing; Marks, Andrew R.

    2014-01-01

    Abnormalities in intracellular Ca2+ signaling have been proposed to play an essential role in the pathophysiology of atrial arrhythmias. However, a direct observation of intracellular Ca2+ in atrial myocytes during atrial arrhythmias is lacking. Here, we have developed an ex vivo model of simultaneous Ca2+ imaging and electrocardiographic recording in cardiac atria. Using this system we were able to record atrial arrhythmic intracellular Ca2+ activities. Our results indicate that atrial arrhythmias can be tightly linked to intracellular Ca2+ waves and Ca2+ alternans. Moreover, we applied this strategy to analyze Ca2+ signals in the hearts of WT and knock-in mice harboring a ‘leaky’ type 2 ryanodine receptor (RyR2-R2474S). We showed that sarcoplasmic reticulum (SR) Ca2+ leak increases the susceptibility to Ca2+ alternans and Ca2+ waves increasing the incidence of atrial arrhythmias. Reduction of SR Ca2+ leak via RyR2 by acute treatment with S107 reduced both Ca2+ alternans and Ca2+ waves, and prevented atrial arrhythmias. PMID:24041536

  10. Imaging atrial arrhythmic intracellular calcium in intact heart.

    PubMed

    Xie, Wenjun; Santulli, Gaetano; Guo, Xiaoxiao; Gao, Melanie; Chen, Bi-Xing; Marks, Andrew R

    2013-11-01

    Abnormalities in intracellular Ca(2+) signaling have been proposed to play an essential role in the pathophysiology of atrial arrhythmias. However, a direct observation of intracellular Ca(2+) in atrial myocytes during atrial arrhythmias is lacking. Here, we have developed an ex vivo model of simultaneous Ca(2+) imaging and electrocardiographic recording in cardiac atria. Using this system we were able to record atrial arrhythmic intracellular Ca(2+) activities. Our results indicate that atrial arrhythmias can be tightly linked to intracellular Ca(2+) waves and Ca(2+) alternans. Moreover, we applied this strategy to analyze Ca(2+) signals in the hearts of WT and knock-in mice harboring a 'leaky' type 2 ryanodine receptor (RyR2-R2474S). We showed that sarcoplasmic reticulum (SR) Ca(2+) leak increases the susceptibility to Ca(2+) alternans and Ca(2+) waves increasing the incidence of atrial arrhythmias. Reduction of SR Ca(2+) leak via RyR2 by acute treatment with S107 reduced both Ca(2+) alternans and Ca(2+) waves, and prevented atrial arrhythmias.

  11. Energetic metabolism during acute stretch-related atrial fibrillation Shortened title: atrial fibrillation and metabolism

    PubMed Central

    Kalifa, J; Maixent, JM; Chalvidan, T; Dalmasso, C; Colin, D; Cozma, D; Laurent, P; Deharo, JC; Djiane, P; Cozzone, P; Bernard, M

    2010-01-01

    Background and methods Perturbations in energetic metabolism and impaired atrial contractility may play an important role in the pathogenesis of atrial fibrillation (AF). Besides, atrial stretch is commonly associated with AF. However, the atrial energetics of stretch-related AF are poorly understood. Here, we measured indicators of energy metabolism during acute-stretch related AF. PCr, adenine nucleotides and derivatives concentrations as well as the activity of the F0F1-ATPase and Na,K-ATPase were obtained after one hour of stretch and/or AF in isolated rabbit hearts and compared to control hearts without stretch and AF. Results After one hour of stretch-related AF, the total adenine nucleotides pool was significantly lower (42.2±2.6 versus 63.7±8.3 µmol/g protein in control group, p<0.05) and the PCr/ATP ratio significantly higher (2.3±0.3 vs 1.1± 0.1 in control group p<0.05), because of ATP, ADP and AMP decrease and PCr increase. The sum of high energy phosphate compounds did not change. There were no significant differences in F0F1-ATPase nor Na,K-ATPase activity between the groups. Conclusions Results show that in this experimental model, acute-stretch related AF induces specific modifications of atrial myocytes energetics that may play a pivotal role in the perpetuation of the arrhythmia. PMID:18553177

  12. Atrial Fibrillation.

    PubMed

    Zimetbaum, Peter

    2017-03-07

    This issue provides a clinical overview of atrial fibrillation, focusing on diagnosis, treatment, and practice improvement. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of additional science writers and physician writers.

  13. 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.

  14. Ca(2+) release events in cardiac myocytes up close: insights from fast confocal imaging.

    PubMed

    Shkryl, Vyacheslav M; Blatter, Lothar A

    2013-01-01

    The spatio-temporal properties of Ca(2+) transients during excitation-contraction coupling and elementary Ca(2+) release events (Ca(2+) 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. Ca(2+) 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. Ca(2+) sparks in atrial cells originating from non-junctional SR and in ventricular myocytes were symmetrical. Ca(2+) spark recording in line scan mode at 40,000 lines/s uncovered step-like increases of [Ca(2+)]i. 2-D imaging of Ca(2+) transients revealed an asynchronous activation of release sites and allowed the sequential recording of Ca(2+) entry through surface membrane Ca(2+) channels and subsequent activation of Ca(2+)-induced Ca(2+) release. With a latency of 2.5 ms after application of an electrical stimulus, Ca(2+) entry could be detected that was followed by SR Ca(2+) release after an additional 3 ms delay. Maximum Ca(2+) release was observed 4 ms after the beginning of release. The timing of Ca(2+) entry and release was confirmed by simultaneous [Ca(2+)]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 Ca(2+) release events that fused into a peripheral ring of elevated [Ca(2+)]i that subsequently propagated in a wave-like fashion towards the center of the cell. In ventricular myocytes asynchronous Ca(2+) release signals from discrete sites with no preferential subcellular location preceded the whole-cell Ca(2+) transient. In summary, ultra-fast confocal imaging allows investigation of Ca(2+) signals with a time resolution similar to patch clamp technique, however in a less invasive fashion.

  15. Effects of tanshinone VI on the hypertrophy of cardiac myocytes and fibrosis of cardiac fibroblasts of neonatal rats.

    PubMed

    Maki, Toshiyuki; Kawahara, Yuji; Tanonaka, Kouichi; Yagi, Akira; Takeo, Satoshi

    2002-12-01

    The possible effects of tanshinone VI (tsh), a diterpene from the root of Tan-Shen (Salvia miltiorrhiza, Bunge (Labiatae)) on hypertrophy and fibrosis in cultured neonatal rat cardiac myocytes and fibroblasts were examined. Tsh had no significant effect on protein synthesis, which was evaluated by [3H]-leucine incorporation into the acid insoluble fraction in the cells, in the absence of stimulatory factors in cardiac myocytes. The amount of protein produced in cardiac myocytes was increased by 10(-8) M endothelin-1 (ET-1), 10(-6) M phenylephrine (PE), or 10(-8) M insulin-like growth factor-1 (IGF-1), suggesting that hypertrophy of cardiac myocytes in vitro was induced by these factors. The ET-1-, PE-, or IGF-1-induced increase in protein synthesis was attenuated by treatment with 10(-5) M tsh. Treatment with 10(-5) M tsh significantly decreased the synthesis of collagen by cardiac fibroblasts, which was evaluated by [3H]-proline incorpolation into acid-insoluble fraction of the fiblobrasts, in the absence of stimulatory factors for the production. Fetal bovine serum (FBS) or IGF-1 increased collagen synthesis in a concentration-dependent manner. The increase at 5% FBS or 10(-8) M IGF-1 was inhibited by 10(-5) M tsh. Fibroblast-conditioned medium (FB-CM) increased protein synthesis in cardiac myocytes in a concentration-dependent manner (10; - 100 %). Tsh attenuated the FB-CM-induced increase in protein synthesis by cardiac myocytes. These results show that tsh may attenuate the humoral factor-induced hypertrophy of cardiac myocytes and fibrosis of cardiac fibroblasts. The findings suggest that tsh may improve the development of cardiac remodeling under pathophysiological conditions. Abbreviations. ANP:atrial natriuretic peptide DMEM:Dulbecco-modified Eagle's medium ET-1:endothelin-1 FB-CM:fibroblast-conditioned medium FBS:fetal bovine serum IGF-1:insulin-like growth factor-1 PE:phenylephrine tsh:tanshinone VI

  16. 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

  17. Matrix metalloproteinase inhibition attenuates atrial remodeling and vulnerability to atrial fibrillation in a canine model of heart failure.

    PubMed

    Moe, Gordon W; Laurent, Gabriel; Doumanovskaia, Liia; Konig, Andrea; Hu, Xudong; Dorian, Paul

    2008-11-01

    Atrial structural remodeling occurs in evolving heart failure (HF) and is an important substrate for the development of atrial fibrillation (AF). The matrix metalloproteinases (MMPs) play a role in extracellular remodeling, and recent studies have demonstrated increased atrial MMP activity in HF. Whether increased MMP activity directly contributes to atrial remodeling and AF in the setting of HF remains unclear. The current study examined the effects of MMP inhibition on atrial structural remodeling and AF vulnerability during HF progression. Three groups of dogs (n = 5 each)--control normal dogs (controls) and 10 dogs subjected to simultaneous atrioventricular pacing (SAVP) for 2 weeks to induce HF and randomly assigned to treatment with placebo (SAVP-placebo) or a MMP inhibitor PGE-7113313, a MMP-1-sparing MMP inhibitor, 6 mg/kg orally twice daily (SAVP-MMPi)--were studied. SAVP-MMPi dogs had less AF inducibility (percent of burst attempts leading to AF episodes: 1.7 +/- 2.9 seconds vs. 23+/-19 seconds, mean +/- SD, P < .05) and maintenance (AF duration: 253 [105 to 326] vs. 1932 [1296 to 2724] seconds, median [25th-75th quartile], P < .05) than SAVP-placebo dogs. The SAVP-MMPi dogs had significantly smaller increases in atrial myocyte cross sectional area, collagen area fraction, and MMP-9 activity relative to controls than SAVP-placebo. There were, however, no significant differences in the changes in chamber dimension and function in the left atrium. This unique finding of an attenuation of the vulnerability to AF in conjunction with reduced myocyte hypertrophy and fibrosis after MMP inhibition suggests that heightened MMP activity in the atria contributes to atrial structural remodeling and AF promotion during evolving HF.

  18. 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

  19. 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

  20. Evolution of ventricular myocyte electrophysiology.

    PubMed

    Rosati, Barbara; Dong, Min; Cheng, Lan; Liou, Shian-Ren; Yan, Qinghong; Park, Ji Young; Shiang, Elaine; Sanguinetti, Michael; Wang, Hong-Sheng; McKinnon, David

    2008-11-12

    The relative importance of regulatory versus structural evolution for the evolution of different biological systems is a subject of controversy. The primacy of regulatory evolution in the diversification of morphological traits has been promoted by many evolutionary developmental biologists. For physiological traits, however, the role of regulatory evolution has received less attention or has been considered to be relatively unimportant. To address this issue for electrophysiological systems, we examined the importance of regulatory and structural evolution in the evolution of the electrophysiological function of cardiac myocytes in mammals. In particular, two related phenomena were studied: the change in action potential morphology in small mammals and the scaling of action potential duration across mammalian phylogeny. In general, the functional properties of the ion channels involved in ventricular action potential repolarization were found to be relatively invariant. In contrast, there were large changes in the expression levels of multiple ion channel and transporter genes. For the Kv2.1 and Kv4.2 potassium channel genes, which are primary determinants of the action potential morphology in small mammals, the functional properties of the proximal promoter regions were found to vary in concordance with species-dependent differences in mRNA expression, suggesting that evolution of cis-regulatory elements is the primary determinant of this trait. Scaling of action potential duration was found to be a complex phenomenon, involving changes in the expression of a large number of channels and transporters. In this case, it is concluded that regulatory evolution is the predominant mechanism by which the scaling is achieved.

  1. Changes in extracellular K+ concentration modulate contractility of rat and rabbit cardiac myocytes via the inward rectifier K+ current IK1

    PubMed Central

    Bouchard, Ron; Clark, Robert B; Juhasz, Alexander E; Giles, Wayne R

    2004-01-01

    The mechanisms underlying the inotropic effect of reductions in [K+]o were studied using recordings of membrane potential, membrane current, cell shortening and [Ca2+]i in single, isolated cardiac myocytes. Three types of mammalian myocytes were chosen, based on differences in the current density and intrinsic voltage dependence of the inwardly rectifying background K+ current IK1 in each cell type. Rabbit ventricular myocytes had a relatively large IK1 with a prominent negative slope conductance whereas rabbit atrial cells expressed much smaller IK1, with little or no negative slope conductance. IK1 in rat ventricle was intermediate in both current density and slope conductance. Action potential duration is relatively short in both rabbit atrial and rat ventricular myocytes, and consequently both cell types spend much of the duty cycle at or near the resting membrane potential. Rapid increases or decreases of [K+]o elicited significantly different inotropic effects in rat and rabbit atrial and ventricular myocytes. Voltage-clamp and current-clamp experiments showed that the effects on cell shortening and [Ca2+]i following changes in [K+]o were primarily the result of the effects of alterations in IK1, which changed resting membrane potential and action potential waveform. This in turn differentially altered the balance of Ca2+ efflux via the sarcolemmal Na+–Ca2+ exchanger, Ca2+ influx via voltage-dependant Ca2+ channels and sarcoplasmic reticulum (SR) Ca2+ release in each cell type. These results support the hypothesis that the inotropic effect of alterations of [K+]o in the heart is due to significant non-linear changes in the current–voltage relation for IK1 and the resulting modulation of the resting membrane potential and action potential waveform. PMID:14990678

  2. Modeling Hypertrophic IP3 Transients in the Cardiac Myocyte

    PubMed Central

    Cooling, Michael; Hunter, Peter; Crampin, Edmund J.

    2007-01-01

    Cardiac hypertrophy is a known risk factor for heart disease, and at the cellular level is caused by a complex interaction of signal transduction pathways. The IP3-calcineurin pathway plays an important role in stimulating the transcription factor NFAT which binds to DNA cooperatively with other hypertrophic transcription factors. Using available kinetic data, we construct a mathematical model of the IP3 signal production system after stimulation by a hypertrophic α-adrenergic agonist (endothelin-1) in the mouse atrial cardiac myocyte. We use a global sensitivity analysis to identify key controlling parameters with respect to the resultant IP3 transient, including the phosphorylation of cell-membrane receptors, the ligand strength and binding kinetics to precoupled (with GαGDP) receptor, and the kinetics associated with precoupling the receptors. We show that the kinetics associated with the receptor system contribute to the behavior of the system to a great extent, with precoupled receptors driving the response to extracellular ligand. Finally, by reparameterizing for a second hypertrophic α-adrenergic agonist, angiotensin-II, we show that differences in key receptor kinetic and membrane density parameters are sufficient to explain different observed IP3 transients in essentially the same pathway. PMID:17693463

  3. 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

  4. What Is Atrial Fibrillation?

    MedlinePlus

    ANSWERS by heart Cardiovascular Conditions What Is Atrial Fibrillation? Your heart has a natural pacemaker, called the “ ... if the electric signals are normal. In atrial fibrillation (AFib), the heart’s two small upper chambers (atria) ...

  5. Atrial fibrillation or flutter

    MedlinePlus

    ... atrial fibrillation include: Alcohol use (especially binge drinking) Coronary artery disease Heart attack or heart bypass surgery Heart failure ... low. An ECG (a test that records the electrical activity of the heart) may show atrial fibrillation ...

  6. Angiotensin II activates signal transducers and activators of transcription 3 via Rac1 in the atrial tissue in permanent atrial fibrillation patients with rheumatic heart disease.

    PubMed

    Xue, Xiao-Dong; Huang, Jian-Hua; Wang, Hui-Shan

    2015-01-01

    Patients with rheumatic heart disease (RHD) often experience persistent atrial fibrillation (AF) associated with adverse atrial structural remodeling (ASR) manifested by atrial fibrosis and left atrial enlargement. The aim of this study was to explore the potential molecular signaling mechanisms for atrial fibrosis and ASR. Twenty RHD patients with persistent AF and 10 RHD patients with sinus rhythm (Group A) were recruited in our study, which all underwent transthoracic echocardiography. Right atrial appendage (RAA) tissue samples were obtained from these patients during mitral/aortic valve replacement operation. The AF patients were further divided into two groups according to left atrial diameter (LAD): Group B with LAD ranging 50-65 mm and Group C with LAD >65 mm. Histological examinations were performed with hematoxylin-eosin staining and Masson's trichrome staining. Atrial angiotensin II (AngII) content was measured by ELISA. Rac1 and STAT3 protein levels were determined by Western blot analysis. Hematoxylin-eosin staining demonstrated highly organized arrangement of atrial muscles in control Group A and significant derangement in both Group B and C AF patients with reduced cell density and increased cell size. Moreover, Masson's trichrome staining showed that atrial myocytes were surrounded by large trunks of collagen fibers in both Group B and C, but not in Group A. There was a positive correlation between atrial tissue fibrosis and LAD. AngII content was markedly higher in Group C than in Group B than in Group A, which was positively correlated with LAD. Similarly, Rac1 and STAT3 protein levels were found considerably higher in Group C and B than in Group A with excellent correlation to LAD. Our study unraveled for the first time the AngII/Rac1/STAT3 signaling as a mechanism for ASR thereby AF in a particular clinical setting-RHD patients with persistent AF and indicated inhibition of this pathway may help ameliorating adverse ASR.

  7. [Atrial fibrillation].

    PubMed

    Colín Lizalde, L J

    2001-01-01

    Atrial fibrillation (AF) is the most common sustained arrhythmia. AF has now been exhaustively studied: more is known about its mechanism and research is moving towards new forms of treatment. For chronic AF, basically the control of ventricular rate and the brain protection are the main issues. It is well known that with the identification of high risk group for embolism, oral anticoagulation should be administered. Ventricular rate control can be achieved by using betablockers or calcium channel blockers, unless these are contraindicated for the elderly. Oral anticoagulation prevents the stroke. The main mechanism of AF is the re-entry of multiple wavelets, but now it is more frequently found on patients with focal AF. Therapies are employed to bring the patient to a sinusal rhythm as soon as possible with antiarryhthmics or electric cardioversion externally or internally. The internal procedure includes 1 to 15 J and the success rate is of 91% vs 67% in relation to the external one. The introduction of the catheter ablation has opened new frontiers for the treatment of AF, first as the ablate-and-pace technique and now trying to mimic the maze procedure or with the ablation of the focal tachycardia. The stimulation for prevention of AF under research, as well as the implantable dysfibrillation for selected patients. On going studies will show the possible benefit of this type of benefits.

  8. 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

  9. 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

  10. Management of atrial fibrillation.

    PubMed

    Moukabary, Talal; Gonzalez, Mario D

    2015-07-01

    Atrial fibrillation is a very common clinical problem with a high prevalence that is expected to rise over time because of increasing risk factors (eg, age, obesity, hypertension). This high prevalence is also associated with high cost, because atrial fibrillation represents about 1% of overall health care spending. The management of atrial fibrillation involves multiple facets: (1) management of underlying disease if present and the management of atrial fibrillation risk factors, (2) prevention of thromboembolism, (3) control of the ventricular rate during atrial fibrillation, and (4) restoration and maintenance of normal sinus rhythm.

  11. Effect of berberine on acetylcholine-induced atrial fibrillation in rabbit

    PubMed Central

    Zhou, Zhi-Wen; Zheng, Hong-Chao; Zhao, Li-Fang; Li, Wei; Hou, Jian-Wen; Yu, Yi; Miao, Pi-Zhi; Zhu, Jian-Ming

    2015-01-01

    The purpose of this study was to test the efficacy of Berberine (Ber) on atrial fibrillation (AF) induced by acetylcholine (ACh) and explore its underlying mechanisms of action. In vivo electrophysiology experiments were performed in adult anesthetized rabbits. Single atrial myocytes were isolated from rabbit hearts and action potentials recorded using patch clamp techniques. AF was induced by rapid atrial burst pacing during intravenous (IV) ACh infusion alone or with IV Ber. Compared to the Baseline, IV Ber (2 mg/kg) prolonged the RR interval and effective refractory period (195 ± 10 vs. 215 ± 11 msec; 80 ± 4 vs. 85 ± 5 msec, respectively; both P<0.05). The induced rate of sustained 1 min AF was lower during ACh infusion with Ber than during ACh infusion alone (4/10 vs. 30/35, P<0.01). The termination rate of ACh-induced AF was higher with IV Ber (1 mg/kg) than with IV saline (sustained 1 min AF: 6/8 vs. 6/20, sustained 10 min AF: 8/10 vs. 1/6, both P<0.05). ACh perfusion significantly shortened the action potential duration (APD) of isolated atrial myocytes (APD50: 152 ± 13 vs. 81 ± 10 msec; APD90: 256 ± 19 vs. 132 ± 13 msec, both P<0.01). Application of Ber reversed the APD shortening induced by ACh (APD50: 81 ± 10 vs. 134 ± 15 msec; APD90: 132 ± 13 vs: 213 ± 17 msec, both P<0.01). We conclude that Ber suppresses ACh-induced AF in the rabbit by increasing atrial effective refractory period and prolonging the APD of atrial myocytes. PMID:26396675

  12. 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.

  13. 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.

  14. Mechano-chemo-transduction in cardiac myocytes.

    PubMed

    Chen-Izu, Ye; Izu, Leighton T

    2017-06-15

    The heart has the ability to adjust to changing mechanical loads. The Frank-Starling law and the Anrep effect describe exquisite intrinsic mechanisms the heart has for autoregulating the force of contraction to maintain cardiac output under changes of preload and afterload. Although these mechanisms have been known for more than a century, their cellular and molecular underpinnings are still debated. How does the cardiac myocyte sense changes in preload or afterload? How does the myocyte adjust its response to compensate for such changes? In cardiac myocytes Ca(2+) is a crucial regulator of contractile force and in this review we compare and contrast recent studies from different labs that address these two important questions. The 'dimensionality' of the mechanical milieu under which experiments are carried out provide important clues to the location of the mechanosensors and the kinds of mechanical forces they can sense and respond to. As a first approximation, sensors inside the myocyte appear to modulate reactive oxygen species while sensors on the cell surface appear to also modulate nitric oxide signalling; both signalling pathways affect Ca(2+) handling. Undoubtedly, further studies will add layers to this simplified picture. Clarifying the intimate links from cellular mechanics to reactive oxygen species and nitric oxide signalling and to Ca(2+) handling will deepen our understanding of the Frank-Starling law and the Anrep effect, and also provide a unified view on how arrhythmias may arise in seemingly disparate diseases that have in common altered myocyte mechanics. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

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

    NASA Astrophysics Data System (ADS)

    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.

  16. How Is Atrial Fibrillation Treated?

    MedlinePlus

    ... from the NHLBI on Twitter. How Is Atrial Fibrillation Treated? Treatment for atrial fibrillation (AF) depends on ... much thyroid hormone). Who Needs Treatment for Atrial Fibrillation? People who have AF but don't have ...

  17. Deglutition induced atrial tachycardia and atrial fibrillation.

    PubMed

    Kanjwal, Yousuf; Imran, Naser; Grubb, Blair

    2007-12-01

    Deglutition induced supraventricular tachycardia is an uncommon condition postulated to be a vagally mediated phenomenon due to mechanical stimulation. Patients usually present with mild symptoms or may have severe debilitating symptoms. Treatment with Class I agents, beta blockers, calcium channel blockers, amiodarone and radiofrquency catheter ablation has shown to be successful in the majority of reported cases. We report the case of a 46-year-old healthy woman presenting with palpitations on swallowing that was documented to be transient atrial tachycardia with aberrant ventricular conduction as well as transient atrial fibrillation. She was successfully treated with propafenone with no induction of swallowing-induced tachycardia after treatment. This is also the first case to show swallowing-induced atrial tachycardia and atrial fibrillation in the same patient.

  18. AZD1305 Exerts Atrial-Predominant Electrophysiological Actions and Is Effective in Suppressing Atrial Fibrillation and Preventing Its Re-induction in the Dog

    PubMed Central

    Burashnikov, Alexander; Zygmunt, Andrew C.; Diego, Jose M. Di; Linhardt, Gunilla; Carlsson, Leif; Antzelevitch, Charles

    2010-01-01

    Recent development of drugs for the treatment of atrial fibrillation (AF) has focused on atrial-selective agents. We examined the atrioventricular differences in sodium channel block of the antiarrhythmic agent AZD1305 in atria and ventricles of anesthetized dogs in vivo, in canine isolated arterially-perfused preparations in vitro and in isolated myocytes using whole-cell patch-clamp techniques. AZD1305 did not change heart rate or blood pressure in vivo but prolonged action potential duration and increased effective refractory period, diastolic threshold of excitation, and conduction time preferentially in atria both in vitro and in vivo. AZD1305 reduced the maximum rate of rise of the action potential (AP) upstroke (Vmax) predominantly in atria (-51±10% in atria vs. -31±23% in ventricles; 3 μM; cycle length =500 ms). Fast sodium current (INa) was blocked by AZD1305 to a greater degree in atrial vs. ventricular myocytes (particularly tonic inhibition). In coronary-perfused right atria, AZD1305 very effectively prevented induction of persistent acetylcholine-mediated AF and, in a different set of atria, terminated persistent AF (in 5/5 and 7/8 atria, respectively). In conclusion, AZD1305 exerts atrial-predominant sodium channel-blocking effects in vitro and in vivo, and effectively suppresses AF. PMID:20386458

  19. 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

  20. Atrial fibrillation - discharge

    MedlinePlus

    Auricular fibrillation - discharge; A-fib - discharge; AF - discharge; Afib - discharge ... been in the hospital because you have atrial fibrillation . This condition occurs when your heart beats faster ...

  1. Downregulated protein expression of transcriptional activator ELK-1 in atrial myocardium of chronic AF patients.

    PubMed

    Zeng, Xiangjun; Xiao, Xuejun; Wu, Yueheng; Huang, Huanlei

    2015-01-01

    The structural alterations in atrial myocytes appear to be an adaptive response of dedifferentiation during chronic atrial fibrillation (AF). Transcriptional activator ELK-1, one of the members of ETS family, has been shown to play an important role in regulating cell differentiation, It is reasonable to presume that ELK-1 participate in the molecular and structural remodeling by which AF is sustained. To prove this hypothesis, the expression of ELK-1 protein in chronically fibrillating atria compared to that in normal rhythmic atria was detected. Right atrial myocardium were obtained from twenty-four patients undergoing valve replacement surgery, twelve patients were in chronic AF (>6 months), whereas the others were in sinus rhythm (SR). The protein expression level of ELK-1 was quantified by Western blot analysis, and the cellular localization and expression pattern of ELK-1 was examined by immunohistochemical staining and indirect immunofluorescence. Western blot analysis showed that the protein expression of ELK-1 was significantly reduced in the atrial tissue of chronic AF patients compared to that in the controls. Immunohistochemistry showed that ELK-1 immunostaining occurred in both cytosolic and nuclear compartments of atrial myocardium. Indirect immunofluorescence showed that the nuclei of normal rhythmic atrial cells were densely labeled, whereas the nuclei in chronically fibrillating atrial cells were very faintly labeled. Our results suggest that the downregulated expression of transcriptional activator ELK-1 may play an important role in the pathogenesis of AF.

  2. Risperidone prolongs cardiac action potential through reduction of K+ currents in rabbit myocytes.

    PubMed

    Gluais, Pascale; Bastide, Michèle; Caron, Jacques; Adamantidis, Monique

    2002-05-31

    Prolongation of QT interval by antipsychotic drugs is an unwanted side effect that may lead to ventricular arrhythmias. The antipsychotic agent risperidone has been shown to cause QT prolongation, especially in case of overdosage. We investigated risperidone effects on action potentials recorded from rabbit Purkinje fibers and ventricular myocardium and on potassium currents recorded from atrial and ventricular rabbit isolated myocytes. The results showed that (1) risperidone (0.1-3 microM) exerted potent lengthening effects on action potential duration in both tissues with higher potency in Purkinje fibers and caused the development of early afterdepolarizations at low stimulation rate; (2) risperidone (0.03-0.3 microM) reduced significantly the current density of the delayed rectifier current and at 30 microM decreased the transient outward and the inward rectifier currents. This study might explain QT prolongation observed in some patients treated with risperidone and gives enlightenment on the risk of cardiac adverse events.

  3. Computational Approaches to Understanding the Role of Fibroblast-Myocyte Interactions in Cardiac Arrhythmogenesis

    PubMed Central

    Brown, Tashalee R.; Krogh-Madsen, Trine; Christini, David J.

    2015-01-01

    The adult heart is composed of a dense network of cardiomyocytes surrounded by nonmyocytes, the most abundant of which are cardiac fibroblasts. Several cardiac diseases, such as myocardial infarction or dilated cardiomyopathy, are associated with an increased density of fibroblasts, that is, fibrosis. Fibroblasts play a significant role in the development of electrical and mechanical dysfunction of the heart; however the underlying mechanisms are only partially understood. One widely studied mechanism suggests that fibroblasts produce excess extracellular matrix, resulting in collagenous septa. These collagenous septa slow propagation, cause zig-zag conduction paths, and decouple cardiomyocytes resulting in a substrate for arrhythmia. Another emerging mechanism suggests that fibroblasts promote arrhythmogenesis through direct electrical interactions with cardiomyocytes via gap junctions. Due to the challenges of investigating fibroblast-myocyte coupling in native cardiac tissue, computational modeling and in vitro experiments have facilitated the investigation into the mechanisms underlying fibroblast-mediated changes in cardiomyocyte action potential morphology, conduction velocity, spontaneous excitability, and vulnerability to reentry. In this paper, we summarize the major findings of the existing computational studies investigating the implications of fibroblast-myocyte interactions in the normal and diseased heart. We then present investigations from our group into the potential role of voltage-dependent gap junctions in fibroblast-myocyte interactions. PMID:26601107

  4. Mechanisms Underlying Atrial-Selective Block of Sodium Channels by Wenxin Keli: Experimental and Theoretical Analysis

    PubMed Central

    Hu, Dan; Barajas-Martínez, Hector; Burashnikov, Alexander; Panama, Brian K.; Cordeiro, Jonathan M.; Antzelevitch, Charles

    2016-01-01

    Introduction Atrial-selective inhibition of cardiac sodium channel current (INa) and INa-dependent parameters has been shown to contribute to the safe and effective management of atrial fibrillation. The present study was designed to examine the basis for the atrial-selective actions of Wenxin Keli. Methods Whole cell INa was recorded at rroom temperature in canine atrial and ventricular myocytes. Trains of 40 pulses were elicited over a range of pulse durations and interpulse intervals to determine tonic and use-dependent block. A Markovian model for INa that incorporates interaction of Wenxin Keli with different states of the channel was developed to examine the basis for atrial selectivity of the drug. Results Our data indicate that Wenxin Keli does not bind significantly to either closed or open states of the sodium channel, but binds very rapidly to the inactivated state of the channel and dissociates rapidly from the closed state. Action potentials recorded from atrial and ventricular preparations in the presence of 5g/L Wenxin Keli were introduced into the computer model in current clamp mode to simulate the effects on maximum upstroke velocity (Vmax). The model predicted much greater inhibition of Vmax in atrial vs. ventricular cells at rapid stimulation rates. Conclusion Our findings suggest that atrial selectivity of Wenxin Keli to block INa is due to more negative steady-state inactivation, less negative resting membrane potential, and shorter diastolic intervals in atrial vs. ventricular cells at rapid activation rates. These actions of Wenxin Keli account for its relatively safe and effective suppression of atrial fibrillation. PMID:26820362

  5. 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. Copyright © 2015 the American Physiological Society.

  6. A comparison of transient outward currents in canine cardiac Purkinje cells and ventricular myocytes.

    PubMed

    Han, W; Wang, Z; Nattel, S

    2000-08-01

    Although abnormalities in Purkinje cell (PC) repolarization are important causes of cardiac arrhythmias, the detailed properties of repolarizing currents in PCs are incompletely understood. We compared transient outward K(+) current (I(to)) in single PCs from canine false tendons with midmyocardial ventricular myocytes (VMs). I(to) reactivation was biexponential, with a similar rapid-phase time constant (30 +/- 5 and 35 +/- 4 ms for VM and PC, respectively) but a large, slow component in PCs with a much greater time constant than VM (1,427 +/- 70 vs. 181 +/- 24 ms, P < 0.001). Tetraethylammonium had no effect on VM I(to) but reversibly inhibited PC I(to) (IC(50) = 2.4 +/- 0.4 mM). PC I(to) was also more sensitive to 4-aminopyridine (IC(50) = 50 +/- 7 vs. 526 +/- 49 microM in VM, P < 0.0001). H(2)O(2) slowed I(to) inactivation in PCs but did not affect VM I(to). We conclude that PC I(to) shows significant differences from VM I(to), with some features, such as tetraethylammonium sensitivity, that have been reported in neither cardiac I(to) of atrial or ventricular myocytes nor cloned K(+) channel subunits (Kv1.4, Kv4.2, or Kv4.3) known to participate in cardiac I(to).

  7. Mitogenic cardiomyopathy: a lethal neonatal familial dilated cardiomyopathy characterized by myocyte hyperplasia and proliferation.

    PubMed

    Chang, Kenneth T E; Taylor, Glenn P; Meschino, Wendy S; Kantor, Paul F; Cutz, Ernest

    2010-07-01

    Pediatric cardiomyopathies are a heterogenous group of conditions of which dilated cardiomyopathies are the most common clinicomorphologic subtype. However, the etiology and pathogenesis of many cases of dilated cardiomyopathies remain unknown. We describe a series of 5 cases of a rare but clinically and histologically distinctive dilated cardiomyopathy that was uniformly lethal in early infancy. The 5 cases include 2 pairs of siblings. There was parental consanguinity in 1 of the 2 pairs of siblings. Death occurred in early infancy (range, 22-67 days; mean, 42 days) after a short history of general lethargy, decreased feeding, respiratory distress, or cyanosis. There was no specific birth or early neonatal problems. Autopsy revealed congestive cardiac failure and enlarged, dilated hearts with ventricular dilatation more pronounced than atrial dilatation, and endocardial fibroelastosis. Histology showed prominent hypertrophic nuclear changes of cardiac myofibers and markedly increased myocyte mitotic activity including occasional atypical mitoses. Immunohistochemical staining for Mib1 showed a markedly increased proliferative index of 10% to 20%. Ancillary investigations, including molecular studies, did not reveal a primary cause for the cardiomyopathies. This distinctive dilated cardiomyopathy characterized by unusual histologic features of myocyte nuclear hypertrophy and marked mitotic activity is lethal in early infancy. Its occurrence in 2 pairs of siblings suggests familial inheritance. Although the underlying molecular pathogenesis remains to be elucidated, it is important to recognize this distinctive entity for purposes of genetic counseling.

  8. Slow Conduction in the Border Zones of Patchy Fibrosis Stabilizes the Drivers for Atrial Fibrillation: Insights from Multi-Scale Human Atrial Modeling

    PubMed Central

    Morgan, Ross; Colman, Michael A.; Chubb, Henry; Seemann, Gunnar; Aslanidi, Oleg V.

    2016-01-01

    Introduction: The genesis of atrial fibrillation (AF) and success of AF ablation therapy have been strongly linked with atrial fibrosis. Increasing evidence suggests that patient-specific distributions of fibrosis may determine the locations of electrical drivers (rotors) sustaining AF, but the underlying mechanisms are incompletely understood. This study aims to elucidate a missing mechanistic link between patient-specific fibrosis distributions and AF drivers. Methods: 3D atrial models integrated human atrial geometry, rule-based fiber orientation, region-specific electrophysiology, and AF-induced ionic remodeling. A novel detailed model for an atrial fibroblast was developed, and effects of myocyte-fibroblast (M-F) coupling were explored at single-cell, 1D tissue and 3D atria levels. Left atrial LGE MRI datasets from 3 chronic AF patients were segmented to provide the patient-specific distributions of fibrosis. The data was non-linearly registered and mapped to the 3D atria model. Six distinctive fibrosis levels (0–healthy tissue, 5–dense fibrosis) were identified based on LGE MRI intensity and modeled as progressively increasing M-F coupling and decreasing atrial tissue coupling. Uniform 3D atrial model with diffuse (level 2) fibrosis was considered for comparison. Results: In single cells and tissue, the largest effect of atrial M-F coupling was on the myocyte resting membrane potential, leading to partial inactivation of sodium current and reduction of conduction velocity (CV). In the 3D atria, further to the M-F coupling, effects of fibrosis on tissue coupling greatly reduce atrial CV. AF was initiated by fast pacing in each 3D model with either uniform or patient-specific fibrosis. High variation in fibrosis distributions between the models resulted in varying complexity of AF, with several drivers emerging. In the diffuse fibrosis models, waves randomly meandered through the atria, whereas in each the patient-specific models, rotors stabilized in

  9. Relaxation abnormalities in single cardiac myocytes from renovascular hypertensive rats.

    PubMed

    Yelamarty, R V; Moore, R L; Yu, F T; Elensky, M; Semanchick, A M; Cheung, J Y

    1992-04-01

    In myocardial hypertrophy secondary to renovascular hypertension, the rate of intracellular Ca2+ concentration decline during relaxation in paced left ventricular (LV) myocytes isolated from hypertensive (Hyp) rats is much slower compared with that from normotensive (Sham) rats. By use of a novel liquid-crystal television-based optical-digital processor capable of performing on-line real-time Fourier transformation and the striated pattern (similar to 1-dimensional diffraction grating) of cardiac muscle cells, sarcomere shortening and relaxation velocities were measured in single Hyp and Sham myocytes 18 h after isolation. There were no differences in resting sarcomere length, percent of maximal shortening, time to peak shortening, and average sarcomere shortening velocity between Sham and Hyp cardiac cells. In contrast, average sarcomere relaxation velocity and half-relaxation time were significantly prolonged in Hyp myocytes. Contractile differences between Sham and Hyp myocytes detected by the optical-digital processor are confirmed by an independent method of video tracking of whole cell length changes during excitation-contraction. Despite the fact that freshly isolated myocytes contract more rigorously than 18-h-old myocytes, the relaxation abnormality was still observed in freshly isolated Hyp myocytes, suggesting impaired relaxation is an intrinsic property of Hyp myocytes rather than changes brought about by short-term culture. We postulate that reduced sarcomere relaxation velocity is a direct consequence of impaired Ca2+ sequestration-extrusion during relaxation in Hyp myocytes and may be responsible for diastolic dysfunction in hypertensive hypertrophic myocardium at the cellular level.

  10. Progesterone Protects Against BPA-induced Arrhythmias in Female Rat Cardiac Myocytes via Rapid Signaling.

    PubMed

    Ma, Jianyong; Hong, Kui; Wang, Hong-Sheng

    2017-01-25

    Bisphenol A (BPA) is an estrogenic endocrine disrupting chemical (EDC) that has a range of potential adverse health effects. Previously we showed that acute exposure to BPA promoted arrhythmias in female rat hearts through estrogen receptor rapid signaling. Progesterone (P4) and estrogen have antagonistic or complementary actions in a number of tissues and systems. In the current study, we examined the influence, and possible protective effect, of P4 on the rapid cardiac actions of BPA in female rat cardiac myocytes. Preincubation with physiological concentration (1 nM) of P4 abolished BPA-induced triggered activities in female cardiac myocytes. Further, P4 abrogated BPA-induced alterations in Ca2+ handling including elevated sarcoplasmic reticulum Ca2+ leak and Ca2+ load. Key to the inhibitory effect of P4 is its blockade of BPA-induced increase in the phosphorylation of phospholamban. At myocyte and protein levels, these inhibitory actions of P4 were blocked by pretreatment with the nuclear P4 receptor (nPR) antagonist RU486. Analysis using membrane impermeable BSA-conjugated P4 suggested that the actions of P4 were mediated by membrane-initiated signaling. The inhibitory G (Gi) protein and phophoinositide-3 kinase (PI3K), but not tyrosine protein kinase activation, were involved in the observed effects of P4. In conclusion, P4 exerts an acute protective effect against BPA-induced arrhythmogenesis in female cardiac myocytes, through nPR and the Gi/PI3K signaling pathway. Our findings highlight the importance of considering the impact of EDCs in the context of native hormonals, and may provide potential therapeutic strategies for the protection against the cardiac toxicities associated with BPA exposure.

  11. Atrial Model Development and Prototype Simulations: CRADA Final Report on Tasks 3 and 4

    SciTech Connect

    O'Hara, T.; Zhang, X.; Villongco, C.; Lightstone, F.; Richards, D.

    2016-10-28

    The goal of this CRADA was to develop essential tools needed to simulate human atrial electrophysiology in 3-dimensions using an anatomical image-based anatomy and physiologically detailed human cellular model. The atria were modeled as anisotropic, representing the preferentially longitudinal electrical coupling between myocytes. Across the entire anatomy, cellular electrophysiology was heterogeneous, with left and right atrial myocytes defined differently. Left and right cell types for the “control” case of sinus rhythm (SR) was compared with remodeled electrophysiology and calcium cycling characteristics of chronic atrial fibrillation (cAF). The effects of Isoproterenol (ISO), a beta-adrenergic agonist that represents the functional consequences of PKA phosphorylation of various ion channels and transporters, was also simulated in SR and cAF to represent atrial activity under physical or emotional stress. Results and findings from Tasks 3 & 4 are described. Tasks 3 and 4 are, respectively: Input parameters prepared for a Cardioid simulation; Report including recommendations for additional scenario development and post-processing analytic strategy.

  12. Inhibition of potassium currents is involved in antiarrhythmic effect of moderate ethanol on atrial fibrillation.

    PubMed

    Yang, Baode; Li, Chenxing; Sun, Junyi; Wang, Xinghui; Liu, Xinling; Yang, Chun; Chen, Lina; Zhou, Jun; Hu, Hao

    2017-03-08

    Excessive consumption of alcohol is a well-established risk factor of atrial fibrillation (AF). However, the effects of moderate alcohol drinking remain to be elucidated. This study was designed to determine the effects of moderate ethanol ingestion on atrial fibrillation and the electrophysiological mechanisms. In acetylcholine-induced canine and mouse AF models, the moderate ethanol prevented the generation and persistence of AF through prolonging the latent period of AF and shortening the duration of AF. The action potential duration (APD) was remarkably prolonged under the concentration range of 12.5-50.0mM ethanol in guinea pig atrial myocytes. Ultra-rapid delayed rectified potassium currents (IKv1.5) were markedly inhibited by 12.5-50.0mM ethanol in a concentration-dependent manner. Ethanol with 50.0mM could inhibit rapid delayed rectifier potassium currents (IhERG). Ethanol under 6.25-50.0mM did not affect on inward rectifier potassium currents (IKir2.1). Collectively, the present study provided an evidence that moderate ethanol intake can prolong the APD of atrial myocytes by inhibition of IKv1.5 and IhERG, which contributed to preventing the development and duration of AF.

  13. Mechanistic Inquiry into the Role of Tissue Remodeling in Fibrotic Lesions in Human Atrial Fibrillation

    PubMed Central

    McDowell, Kathleen S.; Vadakkumpadan, Fijoy; Blake, Robert; Blauer, Joshua; Plank, Gernot; MacLeod, Rob S.; Trayanova, Natalia A.

    2013-01-01

    Atrial fibrillation (AF), the most common arrhythmia in humans, is initiated when triggered activity from the pulmonary veins propagates into atrial tissue and degrades into reentrant activity. Although experimental and clinical findings show a correlation between atrial fibrosis and AF, the causal relationship between the two remains elusive. This study used an array of 3D computational models with different representations of fibrosis based on a patient-specific atrial geometry with accurate fibrotic distribution to determine the mechanisms by which fibrosis underlies the degradation of a pulmonary vein ectopic beat into AF. Fibrotic lesions in models were represented with combinations of: gap junction remodeling; collagen deposition; and myofibroblast proliferation with electrotonic or paracrine effects on neighboring myocytes. The study found that the occurrence of gap junction remodeling and the subsequent conduction slowing in the fibrotic lesions was a necessary but not sufficient condition for AF development, whereas myofibroblast proliferation and the subsequent electrophysiological effect on neighboring myocytes within the fibrotic lesions was the sufficient condition necessary for reentry formation. Collagen did not alter the arrhythmogenic outcome resulting from the other fibrosis components. Reentrant circuits formed throughout the noncontiguous fibrotic lesions, without anchoring to a specific fibrotic lesion. PMID:23790385

  14. Atrial Tachycardias Following Atrial Fibrillation Ablation

    PubMed Central

    Sághy, László; Tutuianu, Cristina; Szilágyi, Judith

    2015-01-01

    One of the most important proarrhythmic complications after left atrial (LA) ablation is regular atrial tachycardia (AT) or flutter. Those tachycardias that occur after atrial fibrillation (AF) ablation can cause even more severe symptoms than those from the original arrhythmia prior to the index ablation procedure since they are often incessant and associated with rapid ventricular response. Depending on the method and extent of LA ablation and on the electrophysiological properties of underlying LA substrate, the reported incidence of late ATs is variable. To establish the exact mechanism of these tachycardias can be difficult and controversial but correlates with the ablation technique and in the vast majority of cases the mechanism is reentry related to gaps in prior ablation lines. When tachycardias occur, conservative therapy usually is not effective, radiofrequency ablation procedure is mostly successful, but can be challenging, and requires a complex approach. PMID:25308808

  15. 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

  16. Free Fatty Acid Effects on the Atrial Myocardium: Membrane Ionic Currents Are Remodeled by the Disruption of T-Tubular Architecture

    PubMed Central

    O’Connell, Ryan P.; Musa, Hassan; Gomez, Mario San Martin; Avula, Uma Mahesh; Herron, Todd J.; Kalifa, Jerome; Anumonwo, Justus M. B.

    2015-01-01

    Background Epicardial adiposity and plasma levels of free fatty acids (FFAs) are elevated in atrial fibrillation, heart failure and obesity, with potentially detrimental effects on myocardial function. As major components of epicardial fat, FFAs may be abnormally regulated, with a potential to detrimentally modulate electro-mechanical function. The cellular mechanisms underlying such effects of FFAs are unknown. Objective To determine the mechanisms underlying electrophysiological effects of palmitic (PA), stearic (SA) and oleic (OA) FFAs on sheep atrial myocytes. Methods We used electrophysiological techniques, numerical simulations, biochemistry and optical imaging to examine the effects of acutely (≤ 15 min), short-term (4–6 hour) or 24-hour application of individual FFAs (10 μM) on isolated ovine left atrial myocytes (LAMs). Results Acute and short-term incubation in FFAs resulted in no differences in passive or active properties of isolated left atrial myocytes (LAMs). 24-hour application had differential effects depending on the FFA. PA did not affect cellular passive properties but shortened (p<0.05) action potential duration at 30% repolarization (APD30). APD50 and APD80 were unchanged. SA had no effect on resting membrane potential but reduced membrane capacitance by 15% (p<0.05), and abbreviated APD at all values measured (p≤0.001). OA did not significantly affect passive or active properties of LAMs. Measurement of the major voltage-gated ion channels in SA treated LAMs showed a ~60% reduction (p<0.01) of the L-type calcium current (ICa-L) and ~30% reduction (p<0.05) in the transient outward potassium current (ITO). A human atrial cell model recapitulated SA effects on APD. Optical imaging showed that SA incubated for 24 hours altered t-tubular structure in isolated cells (p<0.0001). Conclusions SA disrupts t-tubular architecture and remodels properties of membrane ionic currents in sheep atrial myocytes, with potential implications in

  17. Left Atrial Appendage Exclusion for Atrial Fibrillation

    PubMed Central

    Syed, Faisal F.; DeSimone, Christopher V.; Friedman, Paul A.; Asirvatham, Samuel J.

    2015-01-01

    SYNOPSIS Percutaneous left atrial appendage (LAA) closure is increasingly being used as a treatment strategy to prevent stroke in patients with atrial fibrillation (AF) who have contraindications to anticoagulants. A number of approaches and devices have been developed in the last few years, each with their own unique set of advantages and disadvantages. We review the published studies on surgical and percutaneous approaches to LAA closure; focusing on stroke mechanisms in AF, LAA structure and function relevant to stroke prevention, practical differences in procedural approach, and clinical considerations surrounding management. PMID:25443240

  18. Chloride Channels are Involved in the Development of Atrial Fibrillation - A Transcriptomic and proteomic Study.

    PubMed

    Jiang, Yi-Yao; Hou, Hai-Tao; Yang, Qin; Liu, Xiao-Cheng; He, Guo-Wei

    2017-08-31

    Electrical and structural remodeling processes are contributors to the self-perpetuating nature of atrial fibrillation (AF). However, their correlation has not been clarified. In this study, human atrial tissues from the patients with rheumatic mitral valve disease in either sinus rhythm or persistent AF were analyzed using a combined transcriptomic and proteomic approach. An up-regulation in chloride intracellular channel (CLIC) 1, 4, 5 and a rise in type IV collagen were revealed. Combined with the results from immunohistochemistry and electron microscope analysis, the distribution of type IV collagen and effects of fibrosis on myocyte membrane indicated the possible interaction between CLIC and type IV collagen, confirmed by protein structure prediction and co-immunoprecipitation. These results indicate that CLICs play an important role in the development of atrial fibrillation and that CLICs and structural type IV collagen may interact on each other to promote the development of AF in rheumatic mitral valve disease.

  19. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation.

    PubMed

    Yue, L; Feng, J; Gaspo, R; Li, G R; Wang, Z; Nattel, S

    1997-10-01

    Rapid electrical activation, as occurs during atrial fibrillation (AF), is known to cause reductions in atrial refractoriness and in adaptation to heart rate of the atrial refractory period, which promote the maintenance of AF, but the underlying ionic mechanisms are unknown. In order to determine the cellular and ionic changes caused by chronic atrial tachycardia, we studied right atrial myocytes from dogs subjected to 1, 7, or 42 days of atrial pacing at 400/min and compared them with myocytes from sham-operated dogs (pacemaker inserted but not activated). Rapid pacing led to progressive increases in the duration of AF induced by bursts of 10-Hz stimuli (from 3 +/- 2 seconds in sham-operated dogs to 3060 +/- 707 seconds in dogs after 42 days of pacing, P < .001) and reduced atrial refractoriness and adaptation to rate of the atrial refractory period. Voltage-clamp studies showed that chronic rapid pacing did not alter inward rectifier K+ current, rapid or slow components of the delayed rectifier current, the ultrarapid delayed rectifier current, T-type Ca2+ current, or Ca(2+)-dependent Cl- current. In contrast, the densities of transient outward current (Ito) and L-type Ca2+ current (ICa) were progressively reduced as the duration of rapid pacing increased, without concomitant changes in kinetics or voltage dependence. In keeping with in vivo changes in refractoriness, action potential duration (APD) and APD adaptation to rate were decreased by rapid pacing. The response of the action potential and ionic currents flowing during the action potential (as exposed by action-potential voltage clamp) to nifedipine in normal canine cells and in cells from rapidly paced dogs suggested that the APD changes in paced dogs were largely due to reductions in ICa. We conclude that sustained atrial tachycardia reduces Ito and ICa, that the reduced ICa decreases APD and APD adaptation to rate, and that these cellular changes likely account for the alterations in atrial

  20. 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

    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

    2014-12-14

    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. 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. 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. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.

  1. 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

  2. Surgery for Atrial Fibrillation.

    PubMed

    Lawrance, Christopher P; Henn, Matthew C; Damiano, Ralph J

    2016-04-01

    Atrial fibrillation is the most common cardiac arrhythmia, and its treatment options include drug therapy or catheter-based or surgical interventions. The surgical treatment of atrial fibrillation has undergone multiple evolutions over the last several decades. The Cox-Maze procedure went on to become the gold standard for the surgical treatment of atrial fibrillation and is currently in its fourth iteration (Cox-Maze IV). This article reviews the indications and preoperative planning for performing a Cox-Maze IV procedure. This article also reviews the literature describing the surgical results for both approaches including comparisons of the Cox-Maze IV to the previous cut-and-sew method.

  3. Surgery for atrial fibrillation.

    PubMed

    Lawrance, Christopher P; Henn, Matthew C; Damiano, Ralph J

    2014-11-01

    Atrial fibrillation is the most common cardiac arrhythmia, and its treatment options include drug therapy or catheter-based or surgical interventions. The surgical treatment of atrial fibrillation has undergone multiple evolutions over the last several decades. The Cox-Maze procedure went on to become the gold standard for the surgical treatment of atrial fibrillation and is currently in its fourth iteration (Cox-Maze IV). This article reviews the indications and preoperative planning for performing a Cox-Maze IV procedure. This article also reviews the literature describing the surgical results for both approaches including comparisons of the Cox-Maze IV to the previous cut-and-sew method.

  4. Signaling Pathways in Cardiac Myocyte Apoptosis

    PubMed Central

    Xia, Peng; Liu, Yuening

    2016-01-01

    Cardiovascular diseases, the number 1 cause of death worldwide, are frequently associated with apoptotic death of cardiac myocytes. Since cardiomyocyte apoptosis is a highly regulated process, pharmacological intervention of apoptosis pathways may represent a promising therapeutic strategy for a number of cardiovascular diseases and disorders including myocardial infarction, ischemia/reperfusion injury, chemotherapy cardiotoxicity, and end-stage heart failure. Despite rapid growth of our knowledge in apoptosis signaling pathways, a clinically applicable treatment targeting this cellular process is currently unavailable. To help identify potential innovative directions for future research, it is necessary to have a full understanding of the apoptotic pathways currently known to be functional in cardiac myocytes. Here, we summarize recent progress in the regulation of cardiomyocyte apoptosis by multiple signaling molecules and pathways, with a focus on the involvement of these pathways in the pathogenesis of heart disease. In addition, we provide an update regarding bench to bedside translation of this knowledge and discuss unanswered questions that need further investigation. PMID:28101515

  5. 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

  6. Gremlin 2 promotes differentiation of embryonic stem cells to atrial fate by activation of the JNK signaling pathway

    PubMed Central

    Tanwar, Vineeta; Bylund, Jeffery B.; Hu, Jianyong; Yan, Jingbo; Walthall, Joel M.; Mukherjee, Amrita; Heaton, William H.; Wang, Wen-Der; Potet, Franck; Rai, Meena; Kupershmidt, Sabina; Knapik, Ela W.; Hatzopoulos, Antonis K.

    2014-01-01

    The Bone Morphogenetic Protein antagonist Gremlin 2 (Grem2) is required for atrial differentiation and establishment of cardiac rhythm during embryonic development. A human Grem2 variant has been associated with familial atrial fibrillation, suggesting that abnormal Grem2 activity causes arrhythmias. However, it is not known how Grem2 integrates into signaling pathways to direct atrial cardiomyocyte differentiation. Here, we demonstrate that Grem2 expression is induced concurrently with the emergence of cardiovascular progenitor cells during differentiation of mouse embryonic (ES) stem cells. Grem2 exposure enhances the cardiogenic potential of ES cells by ~20–120 fold, preferentially inducing genes expressed in atrial myocytes such as Myl7, Nppa and Sarcolipin. We show that Grem2 acts upstream to upregulate pro-atrial transcriptional factors CoupTFII and Hey1 and downregulate atrial fate repressors Irx4 and Hey2. The molecular phenotype of Grem2-induced atrial cardiomyocytes was further supported by induction of ion channels encoded by Kcnj3, Kcnj5, and Cacna1D genes and establishment of atrial-like action potentials shown by electrophysiological recordings. We show that promotion of atrial-like cardiomyocyte is specific to the Gremlin subfamily of BMP antagonists. Grem2 pro-atrial differentiation activity is conveyed by non-canonical BMP signaling through phosphorylation of JNK and can be reversed by specific JNK inhibitors, but not by dorsomorphin, an inhibitor of canonical BMP signaling. Taken together, our data provide novel mechanistic insights into atrial cardiomyocyte differentiation from pluripotent stem cells and will assist the development of future approaches to study and treat arrhythmias. PMID:24648383

  7. Left Atrial Ablation for Atrial Fibrillation

    PubMed Central

    Sternik, Leonid; Schaff, Hartzel V.; Luria, David; Glikson, Michael; Kogan, Alexander; Malachy, Ateret; First, Maya; Raanani, Ehud

    2011-01-01

    The maze procedure is the gold standard for the ablation of atrial fibrillation, and the “box lesion” around the pulmonary veins is the most important part of this procedure. We have created this lesion with a bipolar radiofrequency ablator, abandoning the usual use of this device (to achieve bilateral epicardial isolation of the pulmonary veins). From March 2004 through the end of May 2010, we performed surgical ablation of atrial fibrillation in 240 patients. Of this number, 205 underwent operation by a hybrid maze technique and the remaining 35 (our study cohort) underwent the creation of a box lesion around the pulmonary veins by means of a bipolar radiofrequency device. Ablation lines were created by connecting the left atriotomy to the amputated left atrial appendage, with 2 ablation lines made with a bipolar radiofrequency device above and below the pulmonary veins. Lesions were made along the transverse and oblique sinuses by epicardial and endocardial application of a bipolar device. The left atrial isthmus was ablated by bipolar radiofrequency and cryoprobe. No complications were associated with the box lesion: 90% and 89% of patients were in sinus rhythm at 3 and 6 months of follow-up, respectively. By creating a box lesion around the pulmonary veins, we expect to improve transmurality by means of epicardial and endocardial ablation of 1 rather than 2 layers of atrial wall, as in epicardial pulmonary vein isolation. Isolation of the entire posterior wall of the left atrium is better electrophysiologically and renders dissection around the pulmonary veins unnecessary. PMID:21494518

  8. Impact of atrial remodeling on heart rhythm after radiofrequency ablation and mitral valve operations.

    PubMed

    Olasinska-Wisniewska, Anna; Mularek-Kubzdela, Tatiana; Grajek, Stefan; Marszalek, Andrzej; Sarnowski, Wojciech; Jemielity, Marek; Seniuk, Wojciech; Lesiak, Maciej; Prech, Marek; Podzerek, Tomasz

    2012-05-01

    This study was conducted to determine the effect of left atrial structural remodeling on heart rhythm after radiofrequency ablation concomitant to mitral valve operation. Sixty-six consecutive patients with of atrial fibrillation (AF) and mitral valve disease underwent radiofrequency ablation and mitral valve operation. Heart rhythm was evaluated before and at 3, 6, and 12 months postoperatively. Biopsy specimens of the posterior wall of the left atrium were evaluated for the extent of fibrosis, myocyte diameter, intensity of inflammatory infiltrates, degree of myocytolysis, and capillary density. Ten patients died and 1 patient was lost to follow-up. Heart rhythm at 12 months was used to divide the remaining 55 patients into two groups: group I, 34 with sinus rhythm; group II, 21 with AF. Paroxysmal AF preoperatively was more frequent among group I patients, and persistent/long-standing persistent AF in group II (p=0.0006). Groups I and II differed significantly in myocyte diameter (17.9±3.5 vs 20.3±4.6 μm, p=0.04), fibrosis percentage (38.7%±11.2% vs 47.6%±12.3%, p=0.009), inflammatory infiltrates (p=0.02), and preoperative left atrial diameter (5.03±0.7 vs 5.5±0.8 cm, p=0.04). No differences were found in capillary density (797.9±500.6 vs 946.0±373.7/mm2, p=0.3) and myocytolysis (p=0.4). Multivariate analysis showed myocyte diameter (p=0.047) and fibrosis (p=0.014) were independent predictors for an AF persistence at 12 months. Left atrial structural remodeling strongly affects heart rhythm after concomitant radiofrequency ablation and mitral valve operation. Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  9. Atrial Fibrillation in Children

    MedlinePlus

    ... attribute childhood AF to congenital heart abnormalities or post-surgical complications. Learn more about children and arrhythmia. This content was last reviewed July 2016. Atrial Fibrillation • Introduction • What is ...

  10. 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 ...

  11. Atrial Fibrillation - Multiple Languages

    MedlinePlus

    ... Supplements Videos & Tools You Are Here: Home → Multiple Languages → All Health Topics → Atrial Fibrillation URL of this page: https://medlineplus.gov/languages/atrialfibrillation.html Other topics A-Z Expand Section ...

  12. 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.

  13. Network Reconstruction and Systems Analysis of Cardiac Myocyte Hypertrophy Signaling*

    PubMed Central

    Ryall, Karen A.; Holland, David O.; Delaney, Kyle A.; Kraeutler, Matthew J.; Parker, Audrey J.; Saucerman, Jeffrey J.

    2012-01-01

    Cardiac hypertrophy is managed by a dense web of signaling pathways with many pathways influencing myocyte growth. A quantitative understanding of the contributions of individual pathways and their interactions is needed to better understand hypertrophy signaling and to develop more effective therapies for heart failure. We developed a computational model of the cardiac myocyte hypertrophy signaling network to determine how the components and network topology lead to differential regulation of transcription factors, gene expression, and myocyte size. Our computational model of the hypertrophy signaling network contains 106 species and 193 reactions, integrating 14 established pathways regulating cardiac myocyte growth. 109 of 114 model predictions were validated using published experimental data testing the effects of receptor activation on transcription factors and myocyte phenotypic outputs. Network motif analysis revealed an enrichment of bifan and biparallel cross-talk motifs. Sensitivity analysis was used to inform clustering of the network into modules and to identify species with the greatest effects on cell growth. Many species influenced hypertrophy, but only a few nodes had large positive or negative influences. Ras, a network hub, had the greatest effect on cell area and influenced more species than any other protein in the network. We validated this model prediction in cultured cardiac myocytes. With this integrative computational model, we identified the most influential species in the cardiac hypertrophy signaling network and demonstrate how different levels of network organization affect myocyte size, transcription factors, and gene expression. PMID:23091058

  14. Electrical remodeling of cardiac myocytes from mice with heart failure due to the overexpression of tumor necrosis factor-alpha.

    PubMed

    Petkova-Kirova, Polina S; Gursoy, Erdal; Mehdi, Haider; McTiernan, Charles F; London, Barry; Salama, Guy

    2006-05-01

    Mice that overexpress the inflammatory cytokine tumor necrosis factor-alpha in the heart (TNF mice) develop heart failure characterized by atrial and ventricular dilatation, decreased ejection fraction, atrial and ventricular arrhythmias, and increased mortality (males > females). Abnormalities in Ca2+ handling, prolonged action potential duration (APD), calcium alternans, and reentrant atrial and ventricular arrhythmias were previously observed with the use of optical mapping of perfused hearts from TNF mice. We therefore tested whether altered voltage-gated outward K+ and/or inward Ca2+ currents contribute to the altered action potential characteristics and the increased vulnerability to arrhythmias. Whole cell voltage-clamp recordings of K+ currents from left ventricular myocytes of TNF mice revealed an approximately 50% decrease in the rapidly activating, rapidly inactivating transient outward K+ current Ito and in the rapidly activating, slowly inactivating delayed rectifier current IK,slow1, an approximately 25% decrease in the rapidly activating, slowly inactivating delayed rectifier current IK,slow2, and no significant change in the steady-state current Iss compared with controls. Peak amplitudes and inactivation kinetics of the L-type Ca2+ current ICa,L were not altered. Western blot analyses revealed a reduction in the proteins underlying Kv4.2, Kv4.3, and Kv1.5. Thus decreased K+ channel expression is largely responsible for the prolonged APD in the TNF mice and may, along with abnormalities in Ca2+ handling, contribute to arrhythmias.

  15. Phenotypic screen quantifying differential regulation of cardiac myocyte hypertrophy identifies CITED4 regulation of myocyte elongation

    PubMed Central

    Ryall, Karen A.; Bezzerides, Vassilios J.; Rosenzweig, Anthony; Saucerman, Jeffrey J.

    2014-01-01

    Cardiac hypertrophy is controlled by a highly connected signaling network with many effectors of cardiac myocyte size. Quantification of the contribution of individual pathways to specific changes in shape and transcript abundance is needed to better understand hypertrophy signaling and to improve heart failure therapies. We stimulated cardiac myocytes with 15 hypertrophic agonists and quantitatively characterized differential regulation of 5 shape features using high-throughput microscopy and transcript levels of 12 genes using qPCR. Transcripts measured were associated with phenotypes including fibrosis, cell death, contractility, proliferation, angiogenesis, inflammation, and the fetal cardiac gene program. While hypertrophy pathways are highly connected, the agonist screen revealed distinct hypertrophy phenotypic signatures for the 15 receptor agonists. We then used k-means clustering of inputs and outputs to identify a network map linking input modules to output modules. Five modules were identified within inputs and outputs with many maladaptive outputs grouping together in one module: Bax, C/EBPβ, Serca2a, TNFα, and CTGF. Subsequently, we identified mechanisms underlying two correlations revealed in the agonist screen: correlation between regulators of fibrosis and cell death signaling (CTGF and Bax mRNA) caused by AngII; and myocyte proliferation (CITED4 mRNA) and elongation caused by Nrg1. Follow-up experiments revealed positive regulation of Bax mRNA level by CTGF and an incoherent feedforward loop linking Nrg1, CITED4 and elongation. With this agonist screen, we identified the most influential inputs in the cardiac hypertrophy signaling network for a variety of features related to pathological and protective hypertrophy signaling and shared regulation among cardiac myocyte phenotypes. PMID:24613264

  16. H2S inhibits angiotensin II-induced atrial Kv1.5 upregulation by attenuating Nox4-mediated ROS generation during atrial fibrillation.

    PubMed

    Lu, Guihua; Xu, Chenggui; Tang, Kaiyu; Zhang, Juhong; Li, Qinglang; Peng, Longyun; Wang, Yesong; Huang, Zhibin; Gao, Xiuren

    2017-01-29

    Our previous study demonstrated that angiotensin II (Ang II) upregulates the expression of Kv1.5, a promising target for atrial fibrillation (AF) therapy, by activating ROS-dependent P-Smad2/3 and P-ERK 1/2. A recent study showed that hydrogen sulfide (H2S) may modulate the effects of angiotensin II (Ang II) by inhibiting the NADPH oxidase 4 (Nox4)-ROS signaling in the heart. The present study aimed to determine whether H2S is involved in the regulation of atrial Kv1.5 via ROS-related mechanisms in AF. Cultured neonatal rat atrial myocytes and a beagle model of AF were used for this study. In the neonatal rat atrial myocytes, quantitative PCR and enzyme immunoassays revealed that the mRNA expression levels of angiotensinogen, angiotensin-converting enzyme, and Ang II type I receptor (AT1R) and the Ang II supernatant concentration were significantly increased by hydrogen peroxide (H2O2) incubation, and these H2O2-induced alterations were reversed by diphenyleneiodonium, apocynin and H2S supplementation. Flow cytometry and Western blotting revealed that blockade of H2S biosynthesis using dl-propargylglycine increased ROS production and the expression of Ang II and Kv1.5. Sodium hydrosulfide (an exogenous H2S donor) and Nox4 siRNA inhibited Ang II-induced ROS production and Ang II-induced expression of Kv1.5, P-Smad2/3, P-ERK 1/2. Sodium hydrosulfide suppressed the Ang II-induced upregulation of Nox4. In our beagle AF model, 24 h of rapid atrial pacing (RAP) increased the atrial Ang II concentration, ROS production and the protein expression of Nox4, Kv1.5, P-Smad2/3 and P-ERK 1/2. These RAP-induced changes were inhibited by H2S supplementation and losartan (an AT1R blocker) pretreatment. In conclusion, our study indicates that H2S downregulates Ang II-induced atrial Kv1.5 expression by attenuating Nox4-related ROS-triggered P-Smad2/3 and P-ERK 1/2 activation during AF. H2S supplementation would be beneficial for AF treatment via the suppression of atrial Kv1

  17. Effects of seasonal acclimatization on action potentials and sarcolemmal K(+) currents in roach (Rutilus rutilus) cardiac myocytes.

    PubMed

    Badr, Ahmed; Hassinen, Minna; El-Sayed, Mohamed F; Vornanen, Matti

    2017-03-01

    Temperature sensitivity of electrical excitability is a potential limiting factor for high temperature tolerance of ectotherms. The present study examines whether heat resistance of electrical excitability of cardiac myocytes is modified by seasonal thermal acclimatization in roach (Rutilus rutilus), a eurythermal teleost species. To this end, temperature dependencies of ventricular action potentials (APs), and atrial and ventricular K(+) currents were measured from winter-acclimatized (WiR) and summer-acclimatized (SuR) roach. Under patch-clamp recording conditions, ventricular APs could be triggered over a wide range of temperatures (4-43°C) with prominent changes in resting membrane potential (RMP), AP duration and amplitude. In general, APs of SuR were slightly more tolerant to high temperatures than those of WiR, e.g. the break point temperature (TBP) of RMP was 37.6±0.4°C in WiR and 41±1°C in SuR (p<0.05). Of the two major cardiac K(+) currents, the inward rectifier K(+) current (IK1) was particularly heat resistant in both SuR (TBP 39.4±0.4°C) and WiR (TBP 40.0±0.4°C) ventricular myocytes. The delayed rectifier K(+) current (IKr) was not as heat resistant as IK1. Surprisingly, IKr of WiR tolerated heat better (TBP 31.9±0.8°C) than IKr of SuR (TBP 24.1±0.5°C) (p<0.05). IKr (Erg2) channel transcripts of both atrial and ventricular myocytes were up-regulated in WiR. IK1 (Kir2) channel transcripts were not affected by seasonal acclimatization, although ventricular IK1 current was up-regulated in summer. Collectively, these findings show that thermal tolerance limits of K(+) currents in isolated myocytes between seasonally acclimatized roach are much less pronounced than the heat sensitivity of ECG variables in intact fish.

  18. Atrial fibrillation (acute onset)

    PubMed Central

    2014-01-01

    Introduction Acute atrial fibrillation is rapid, irregular, and chaotic atrial activity of recent onset. Various definitions of acute atrial fibrillation have been used in the literature, but for the purposes of this review we have included studies where atrial fibrillation may have occurred up to 7 days previously. Risk factors for acute atrial fibrillation include increasing age, cardiovascular disease, alcohol, diabetes, and lung disease. Acute atrial fibrillation increases the risk of stroke and heart failure. The condition resolves spontaneously within 24 to 48 hours in more than 50% of people; however, many people will require interventions to control heart rate or restore sinus rhythm. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent embolism, for conversion to sinus rhythm, and to control heart rate in people with recent-onset atrial fibrillation (within 7 days) who are haemodynamically stable? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 26 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review, we present information relating to the effectiveness and safety of the following interventions: amiodarone, antithrombotic treatment before cardioversion, atenolol, bisoprolol, carvedilol, digoxin, diltiazem, direct current cardioversion, flecainide, metoprolol, nebivolol, propafenone, sotalol, timolol, and verapamil. PMID:25430048

  19. Can Atrial Fibrillation Be Prevented?

    MedlinePlus

    ... from the NHLBI on Twitter. How Can Atrial Fibrillation Be Prevented? Following a healthy lifestyle and taking ... for heart disease may help you prevent atrial fibrillation (AF). These steps include: Following a heart healthy ...

  20. Calsequestrin 2 deletion causes sinoatrial node dysfunction and atrial arrhythmias associated with altered sarcoplasmic reticulum calcium cycling and degenerative fibrosis within the mouse atrial pacemaker complex1

    PubMed Central

    Glukhov, Alexey V.; Kalyanasundaram, Anuradha; Lou, Qing; Hage, Lori T.; Hansen, Brian J.; Belevych, Andriy E.; Mohler, Peter J.; Knollmann, Björn C.; Periasamy, Muthu; Györke, Sandor; Fedorov, Vadim V.

    2015-01-01

    Aims Loss-of-function mutations in Calsequestrin 2 (CASQ2) are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT patients also exhibit bradycardia and atrial arrhythmias for which the underlying mechanism remains unknown. We aimed to study the sinoatrial node (SAN) dysfunction due to loss of CASQ2. Methods and results In vivo electrocardiogram (ECG) monitoring, in vitro high-resolution optical mapping, confocal imaging of intracellular Ca2+ cycling, and 3D atrial immunohistology were performed in wild-type (WT) and Casq2 null (Casq2−/−) mice. Casq2−/− mice exhibited bradycardia, SAN conduction abnormalities, and beat-to-beat heart rate variability due to enhanced atrial ectopic activity both at baseline and with autonomic stimulation. Loss of CASQ2 increased fibrosis within the pacemaker complex, depressed primary SAN activity, and conduction, but enhanced atrial ectopic activity and atrial fibrillation (AF) associated with macro- and micro-reentry during autonomic stimulation. In SAN myocytes, CASQ2 deficiency induced perturbations in intracellular Ca2+ cycling, including abnormal Ca2+ release, periods of significantly elevated diastolic Ca2+ levels leading to pauses and unstable pacemaker rate. Importantly, Ca2+ cycling dysfunction occurred not only at the SAN cellular level but was also globally manifested as an increased delay between action potential (AP) and Ca2+ transient upstrokes throughout the atrial pacemaker complex. Conclusions Loss of CASQ2 causes abnormal sarcoplasmic reticulum Ca2+ release and selective interstitial fibrosis in the atrial pacemaker complex, which disrupt SAN pacemaking but enhance latent pacemaker activity, create conduction abnormalities and increase susceptibility to AF. These functional and extensive structural alterations could contribute to SAN dysfunction as well as AF in CPVT patients. PMID:24216388

  1. Remodeling of atrial ATP-sensitive K+ channels in a model of salt-induced elevated blood pressure

    PubMed Central

    Lader, Joshua M.; Vasquez, Carolina; Bao, Li; Maass, Karen; Qu, Jiaxiang; Kefalogianni, Eirini; Fishman, Glenn I.; Coetzee, William A.

    2011-01-01

    Hypertension is associated with the development of atrial fibrillation; however, the electrophysiological consequences of this condition remain poorly understood. ATP-sensitive K+ (KATP) channels, which contribute to ventricular arrhythmias, are also expressed in the atria. We hypothesized that salt-induced elevated blood pressure (BP) leads to atrial KATP channel activation and increased arrhythmia inducibility. Elevated BP was induced in mice with a high-salt diet (HS) for 4 wk. High-resolution optical mapping was used to measure atrial arrhythmia inducibility, effective refractory period (ERP), and action potential duration at 90% repolarization (APD90). Excised patch clamping was performed to quantify KATP channel properties and density. KATP channel protein expression was also evaluated. Atrial arrhythmia inducibility was 22% higher in HS hearts compared with control hearts. ERP and APD90 were significantly shorter in the right atrial appendage and left atrial appendage of HS hearts compared with control hearts. Perfusion with 1 μM glibenclamide or 300 μM tolbutamide significantly decreased arrhythmia inducibility and prolonged APD90 in HS hearts compared with untreated HS hearts. KATP channel density was 156% higher in myocytes isolated from HS animals compared with control animals. Sulfonylurea receptor 1 protein expression was increased in the left atrial appendage and right atrial appendage of HS animals (415% and 372% of NS animals, respectively). In conclusion, KATP channel activation provides a mechanistic link between salt-induced elevated BP and increased atrial arrhythmia inducibility. The findings of this study have important implications for the treatment and prevention of atrial arrhythmias in the setting of hypertensive heart disease and may lead to new therapeutic approaches. PMID:21724863

  2. 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

  3. Atrial selectivity of antiarrhythmic drugs

    PubMed Central

    Ravens, Ursula; Poulet, Claire; Wettwer, Erich; Knaut, Michael

    2013-01-01

    New antiarrhythmic drugs for treatment of atrial fibrillation should ideally be atrial selective in order to avoid pro-arrhythmic effects in the ventricles. Currently recognized atrial selective targets include atrial Nav1.5 channels, Kv1.5 channels and constitutively active Kir3.1/3.4 channels, each of which confers atrial selectivity by different mechanisms. Na+ channel blockers with potential- and frequency-dependent action preferentially suppress atrial fibrillation because of the high excitation rate and less negative atrial resting potential, which promote drug binding in atria. Kv1.5 channels are truly atrial selective because they do not conduct repolarizing current IKur in ventricles. Constitutively active IK,ACh is predominantly observed in remodelled atria from patients in permanent atrial fibrillation (AF). A lot of effort has been invested to detect compounds which will selectively block Kir3.1/Kir3.4 in their remodelled constitutively active form. Novel drugs which have been and are being developed aim at atrial-selective targets. Vernakalant and ranolazine which mainly block atrial Na+ channels are clinically effective. Newly designed selective IKur blockers and IK,ACh blockers are effective in animal models; however, clinical benefit in converting AF into sinus rhythm (SR) or reducing AF burden remains to be demonstrated. In conclusion, atrial-selective antiarrhythmic agents have a lot of potential, but a long way to go. PMID:23732646

  4. Na+ current expression in human atrial myofibroblasts: identity and functional roles

    PubMed Central

    Koivumäki, Jussi T.; Clark, Robert B.; Belke, Darrell; Kondo, Colleen; Fedak, Paul W. M.; Maleckar, Mary M. C.; Giles, Wayne R.

    2014-01-01

    In the mammalian heart fibroblasts have important functional roles in both healthy conditions and diseased states. During pathophysiological challenges, a closely related myofibroblast cell population emerges, and can have distinct, significant roles. Recently, it has been reported that human atrial myofibroblasts can express a Na+ current, INa. Some of the biophysical properties and molecular features suggest that this INa is due to expression of Nav 1.5, the same Na+ channel α subunit that generates the predominant INa in myocytes from adult mammalian heart. In principle, expression of Nav 1.5 could give rise to regenerative action potentials in the fibroblasts/myofibroblasts. This would suggest an active as opposed to passive role for fibroblasts/myofibroblasts in both the “trigger” and the “substrate” components of cardiac rhythm disturbances. Our goals in this preliminary study were: (i) to confirm and extend the electrophysiological characterization of INa in a human atrial fibroblast/myofibroblast cell population maintained in conventional 2-D tissue culture; (ii) to identify key molecular properties of the α and β subunits of these Na+ channel(s); (iii) to define the biophysical and pharmacological properties of this INa; (iv) to integrate the available multi-disciplinary data, and attempt to illustrate its functional consequences, using a mathematical model in which the human atrial myocyte is coupled via connexins to fixed numbers of fibroblasts/myofibroblasts in a syncytial arrangement. Our experimental findings confirm that a significant fraction (approximately 40–50%) of these human atrial myofibroblasts can express INa. However, our data suggest that INa may be generated by a combination of Nav 1.9, Nav 1.2, and Nav 1.5. Our results, when complemented with mathematical modeling, provide a background for re-evaluating pharmacological management of supraventricular rhythm disorders, e.g., persistent atrial fibrillation. PMID:25147525

  5. Na(+) current expression in human atrial myofibroblasts: identity and functional roles.

    PubMed

    Koivumäki, Jussi T; Clark, Robert B; Belke, Darrell; Kondo, Colleen; Fedak, Paul W M; Maleckar, Mary M C; Giles, Wayne R

    2014-01-01

    In the mammalian heart fibroblasts have important functional roles in both healthy conditions and diseased states. During pathophysiological challenges, a closely related myofibroblast cell population emerges, and can have distinct, significant roles. Recently, it has been reported that human atrial myofibroblasts can express a Na(+) current, INa. Some of the biophysical properties and molecular features suggest that this INa is due to expression of Nav 1.5, the same Na(+) channel α subunit that generates the predominant INa in myocytes from adult mammalian heart. In principle, expression of Nav 1.5 could give rise to regenerative action potentials in the fibroblasts/myofibroblasts. This would suggest an active as opposed to passive role for fibroblasts/myofibroblasts in both the "trigger" and the "substrate" components of cardiac rhythm disturbances. Our goals in this preliminary study were: (i) to confirm and extend the electrophysiological characterization of INa in a human atrial fibroblast/myofibroblast cell population maintained in conventional 2-D tissue culture; (ii) to identify key molecular properties of the α and β subunits of these Na(+) channel(s); (iii) to define the biophysical and pharmacological properties of this INa; (iv) to integrate the available multi-disciplinary data, and attempt to illustrate its functional consequences, using a mathematical model in which the human atrial myocyte is coupled via connexins to fixed numbers of fibroblasts/myofibroblasts in a syncytial arrangement. Our experimental findings confirm that a significant fraction (approximately 40-50%) of these human atrial myofibroblasts can express INa. However, our data suggest that INa may be generated by a combination of Nav 1.9, Nav 1.2, and Nav 1.5. Our results, when complemented with mathematical modeling, provide a background for re-evaluating pharmacological management of supraventricular rhythm disorders, e.g., persistent atrial fibrillation.

  6. 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. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. [Ultrastructural features of femoral artery myocytes during experimental leg lengthening].

    PubMed

    Ir'ianov, Iu M; Migalkin, N S; Kniazeva, L M

    1984-11-01

    Femoral arteries in mature dogs have been studied electron microscopically at various stages of the shin lengthening performed after G. A. Ilizarov method. Certain ultrastructural signs demonstrating biosynthetic and secretory activation of myocytes directed to intensification of elastogenetic processes have been revealed. Immature elastic fibers are forming around myocytes as aggregations of microfibrils, later accumulations of amorphous material appear in them. On the 28th, 42d days of distraction, hyperproduction of intra- and extracellular vesicles is noted, as well as that of intracellular matrix. Cytoplasmic islets of myocytes and intercellular connections increase in number. In the subintimal layer, of the tunica media and at its border with adventitium, longitudinally situating fasciculi of smooth muscle cells are forming. The myocytic ultrastructural peculiarities noted, the new formations of elastic elements depend, at early stages of the experiment, on changes of regional hemodynamics, and at advanced stages - also on the effect of longitudinally acting tension stress.

  8. Reduced density and altered regulation of rat atrial L-type Ca2+ current in heart failure

    PubMed Central

    Bond, Richard C.; Bryant, Simon M.; Watson, Judy J.; Hancox, Jules C.; Orchard, Clive H.

    2017-01-01

    Constitutive regulation by PKA has recently been shown to contribute to L-type Ca2+ current (ICaL) at the ventricular t-tubule in heart failure. Conversely, reduction in constitutive regulation by PKA has been proposed to underlie the downregulation of atrial ICaL in heart failure. The hypothesis that downregulation of atrial ICaL in heart failure involves reduced channel phosphorylation was examined. Anesthetized adult male Wistar rats underwent surgical coronary artery ligation (CAL, N=10) or equivalent sham-operation (Sham, N=12). Left atrial myocytes were isolated ~18 wk postsurgery and whole cell currents recorded (holding potential=-80 mV). ICaL activated by depolarizing pulses to voltages from -40 to +50 mV were normalized to cell capacitance and current density-voltage relations plotted. CAL cell capacitances were ~1.67-fold greater than Sham (P ≤ 0.0001). Maximal ICaL conductance (Gmax) was downregulated more than 2-fold in CAL vs. Sham myocytes (P < 0.0001). Norepinephrine (1 μmol/l) increased Gmax >50% more effectively in CAL than in Sham so that differences in ICaL density were abolished. Differences between CAL and Sham Gmax were not abolished by calyculin A (100 nmol/l), suggesting that increased protein dephosphorylation did not account for ICaL downregulation. Treatment with either H-89 (10 μmol/l) or AIP (5 μmol/l) had no effect on basal currents in Sham or CAL myocytes, indicating that, in contrast to ventricular myocytes, neither PKA nor CaMKII regulated basal ICaL. Expression of the L-type α1C-subunit, protein phosphatases 1 and 2A, and inhibitor-1 proteins was unchanged. In conclusion, reduction in PKA-dependent regulation did not contribute to downregulation of atrial ICaL in heart failure. NEW & NOTEWORTHY Whole cell recording of L-type Ca2+ currents in atrial myocytes from rat hearts subjected to coronary artery ligation compared with those from sham-operated controls reveals marked reduction in current density in heart failure without

  9. Reduced density and altered regulation of rat atrial L-type Ca(2+) current in heart failure.

    PubMed

    Bond, Richard C; Bryant, Simon M; Watson, Judy J; Hancox, Jules C; Orchard, Clive H; James, Andrew F

    2017-03-01

    Constitutive regulation by PKA has recently been shown to contribute to L-type Ca(2+) current (ICaL) at the ventricular t-tubule in heart failure. Conversely, reduction in constitutive regulation by PKA has been proposed to underlie the downregulation of atrial ICaL in heart failure. The hypothesis that downregulation of atrial ICaL in heart failure involves reduced channel phosphorylation was examined. Anesthetized adult male Wistar rats underwent surgical coronary artery ligation (CAL, N=10) or equivalent sham-operation (Sham, N=12). Left atrial myocytes were isolated ~18 wk postsurgery and whole cell currents recorded (holding potential=-80 mV). ICaL activated by depolarizing pulses to voltages from -40 to +50 mV were normalized to cell capacitance and current density-voltage relations plotted. CAL cell capacitances were ~1.67-fold greater than Sham (P ≤ 0.0001). Maximal ICaL conductance (Gmax ) was downregulated more than 2-fold in CAL vs. Sham myocytes (P < 0.0001). Norepinephrine (1 μmol/l) increased Gmax >50% more effectively in CAL than in Sham so that differences in ICaL density were abolished. Differences between CAL and Sham Gmax were not abolished by calyculin A (100 nmol/l), suggesting that increased protein dephosphorylation did not account for ICaL downregulation. Treatment with either H-89 (10 μmol/l) or AIP (5 μmol/l) had no effect on basal currents in Sham or CAL myocytes, indicating that, in contrast to ventricular myocytes, neither PKA nor CaMKII regulated basal ICaL Expression of the L-type α1C-subunit, protein phosphatases 1 and 2A, and inhibitor-1 proteins was unchanged. In conclusion, reduction in PKA-dependent regulation did not contribute to downregulation of atrial ICaL in heart failure.NEW & NOTEWORTHY Whole cell recording of L-type Ca(2+) currents in atrial myocytes from rat hearts subjected to coronary artery ligation compared with those from sham-operated controls reveals marked reduction in current density in heart failure

  10. Bioengineering Human Myocardium on Native Extracellular Matrix

    PubMed Central

    Guyette, Jacques P.; Charest, Jonathan M; Mills, Robert W; Jank, Bernhard J.; Moser, Philipp T.; Gilpin, Sarah E.; Gershlak, Joshua R.; Okamoto, Tatsuya; Gonzalez, Gabriel; Milan, David J.; Gaudette, Glenn R.; Ott, Harald C.

    2015-01-01

    Rationale More than 25 million individuals suffer from heart failure worldwide, with nearly 4,000 patients currently awaiting heart transplantation in the United States. Donor organ shortage and allograft rejection remain major limitations with only about 2,500 hearts transplanted each year. As a theoretical alternative to allotransplantation, patient-derived bioartificial myocardium could provide functional support and ultimately impact the treatment of heart failure. Objective The objective of this study is to translate previous work to human scale and clinically relevant cells, for the bioengineering of functional myocardial tissue based on the combination of human cardiac matrix and human iPS-derived cardiac myocytes. Methods and Results To provide a clinically relevant tissue scaffold, we translated perfusion-decellularization to human scale and obtained biocompatible human acellular cardiac scaffolds with preserved extracellular matrix composition, architecture, and perfusable coronary vasculature. We then repopulated this native human cardiac matrix with cardiac myocytes derived from non-transgenic human induced pluripotent stem cells (iPSCs) and generated tissues of increasing three-dimensional complexity. We maintained such cardiac tissue constructs in culture for 120 days to demonstrate definitive sarcomeric structure, cell and matrix deformation, contractile force, and electrical conduction. To show that functional myocardial tissue of human scale can be built on this platform, we then partially recellularized human whole heart scaffolds with human iPSC-derived cardiac myocytes. Under biomimetic culture, the seeded constructs developed force-generating human myocardial tissue, showed electrical conductivity, left ventricular pressure development, and metabolic function. Conclusions Native cardiac extracellular matrix scaffolds maintain matrix components and structure to support the seeding and engraftment of human iPS-derived cardiac myocytes, and enable

  11. The contribution of pathways initiated via the Gq\\11 G-protein family to atrial fibrillation.

    PubMed

    Tinker, Andrew; Finlay, Malcom; Nobles, Muriel; Opel, Aaisha

    2016-03-01

    Atrial fibrillation is the commonest cardiac arrhythmia and leads to significant clinical morbidity and mortality. It has a complex pathophysiology but is often initiated by atrial ectopic beats and because of atrial remodelling once it occurs it can become established. Thus therapeutic interventions designed to prevent the initial occurrence of the arrhythmia are particularly needed. At the cellular level, these ectopic beats arise because of abnormal calcium release events from the sarcoplasmic reticulum leading to an inward current mediated by the sodium-calcium exchanger. There has been considerable interest in this over the last few years largely focused on the ryanodine receptor and related signalling pathways. However, atrial myocytes also possess a well-developed inositol trisphosphate (IP3) dependent calcium release system and this has been less studied. In this review we focus on pathways and molecules that couple via the Gq\\11 family of G-proteins including regulators of G-protein signalling that may influence IP3 mediated calcium release and atrial fibrillation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model.

    PubMed

    Courtemanche, M; Ramirez, R J; Nattel, S

    1998-07-01

    The mechanisms underlying many important properties of the human atrial action potential (AP) are poorly understood. Using specific formulations of the K+, Na+, and Ca2+ currents based on data recorded from human atrial myocytes, along with representations of pump, exchange, and background currents, we developed a mathematical model of the AP. The model AP resembles APs recorded from human atrial samples and responds to rate changes, L-type Ca2+ current blockade, Na+/Ca2+ exchanger inhibition, and variations in transient outward current amplitude in a fashion similar to experimental recordings. Rate-dependent adaptation of AP duration, an important determinant of susceptibility to atrial fibrillation, was attributable to incomplete L-type Ca2+ current recovery from inactivation and incomplete delayed rectifier current deactivation at rapid rates. Experimental observations of variable AP morphology could be accounted for by changes in transient outward current density, as suggested experimentally. We conclude that this mathematical model of the human atrial AP reproduces a variety of observed AP behaviors and provides insights into the mechanisms of clinically important AP properties.

  13. Distribution of phenotypically disparate myocyte subpopulations in airway smooth muscle.

    PubMed

    Halayko, Andrew J; Stelmack, Gerald L; Yamasaki, Akira; McNeill, Karol; Unruh, Helmut; Rector, Edward

    2005-01-01

    Phenotype and functional heterogeneity of airway smooth muscle (ASM) cells in vitro is well known, but there is limited understanding of these features in vivo. We tested whether ASM is composed of myocyte subsets differing in contractile phenotype marker expression. We used flow cytometry to compare smooth muscle myosin heavy chain (smMHC) and smooth muscle-alpha-actin (sm-alpha-actin) abundance in myocytes dispersed from canine trachealis. Based on immunofluorescent intensity and light scatter characteristics (forward and 90 degrees side scatter), 2 subgroups were identified and isolated. Immunoblotting confirmed smMHC and sm-alpha-actin were 10- and 5-fold greater, respectively, in large, elongate myocytes that comprised approximately 60% of total cells. Immunohistochemistry revealed similar phenotype heterogeneity in human bronchial smooth muscle. Canine tracheal myocyte subpopulations isolated by flow cytometry were used to seed primary subcultures. Proliferation of subcultures established with myocytes exhibiting low levels of smMHC and sm-alpha-actin was approximately 2 x faster than subcultures established with ASM cells with a high marker protein content. These studies demonstrate broad phenotypic heterogeneity of myocytes in normal ASM tissue that is maintained in cell culture, as demonstrated by divergent proliferative capacity. The distinct roles of these subgroups could be a key determinant of normal and pathological lung development and biology.

  14. [Chromogranin A: immunocytochemical localization in secretory granules of frog atrial cardiomyocytes].

    PubMed

    Krylova, M I

    2007-01-01

    Chromogranin A (CgA) is a member of the granin family of acidic proteins that present in the secretory granules (SGs) of many endocrine, neuroendocrine and neuronal cells. Atrial natriuretic peptide (ANP)-storing SGs in atrial cardiomyocytes of rat heart also contain CgA. Cardiosuppressive effect of CgA-derived peptides (vasostatins) on in vitro isolated and perfused working frog and rat hearts has been shown under both basal conditions and beta-adrenergic stimulation. More recently it has been revealed that rat heart produces and processes CgA-derived vasostatin-containing peptides. Until now nothing has been known about the presence of CgA in an amphibian heart. We have investigated the subcellular localization of CgA in atrial myocytes of adult frog Rana temporaria heart using ultraimmunocytochemical method. Immunocytochemical staining of the frog atrial tissue for CgA and ANP has shown that out of three morphologically different types (A, B and D) of specific cytoplasmic granules (SCGs) present in myocytes only two (A and B)--large (120-200 nm in diameter) granules with more and with less electron dense core--exhibit immunoreactivity (IR) to these two antigens. The third type (D) of granules (80-100 nm in diameter) are small membrane bound granules characterized by highly electron dense core surrounded with a thin halo. These granules revealed negative reaction on immunostaining for both CgA and ANP. The presence of CgA- and ANP-IR in the same SCGs in frog atrial myocytes is consistent with the endocrine nature of these granules. Taking into account our and literature data we propose that CgA present in frog atrial cardiomyocite SCGs might be a precursor of vasostatin-containing peptides, as it takes place in rat heart. It is possible that these CgA-derived peptides together with ANP exert their regulatory function through the autocrine and/or paracrine mechanisms and play important cardioprotective role in frog heart under stress condition.

  15. Rivaroxaban in atrial fibrillation

    PubMed Central

    Giorgi, Mariano A; Miguel, Lucas San

    2012-01-01

    Warfarin is the traditional therapeutic option available to manage thromboembolic risk in atrial fibrillation. The hemorrhagic risk with warfarin depends mainly on the international normalized ratio (INR). Data from randomized controlled trials show that patients have a therapeutic INR (2.00–3.00) only 61%–68% of the time while taking warfarin, and this target is sometimes hard to establish. Many compounds have been developed in order to optimize the profile of oral anticoagulants. We focus on one of them, rivaroxaban, comparing it with novel alternatives, ie, dabigatran and apixaban. The indication for rivaroxaban in nonvalvular atrial fibrillation was evaluated in ROCKET-AF (Rivaroxaban-once daily, Oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation). In this trial, rivaroxaban was associated with a 12% reduction in the incidence of the primary endpoint compared with warfarin (hazard ratio 0.88; 95% confidence interval [CI] 0.74–1.03; P < 0.001 for noninferiority and P = 0.12 for superiority). However, patients remained in the therapeutic range for INR only 55% of the time, which is less than that in RE-LY (the Randomized Evaluation of Long-Term Anticoagulation Therapy, 64%) and in the ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation, 66%). This shorter time spent in the therapeutic range has been one of the main criticisms of the ROCKET-AF trial, but could actually reflect what happens in real life. In addition, rivaroxaban exhibits good pharmacokinetic and pharmacoeconomic properties. Novel anticoagulants are a viable and commercially available alternative to vitamin K antagonists nowadays for the prevention of thromboembolic complications in atrial fibrillation. Rivaroxaban is an attractive alternative, but the true picture of this novel compound in atrial fibrillation will only become available with more widespread

  16. Regulatory volume increase and regulatory volume decrease responses in HL-1 atrial myocytes.

    PubMed

    Cacace, Veronica I; Finkelsteyn, Andres G; Tasso, Laura M; Kusnier, Carlos F; Gomez, Karina A; Fischbarg, Jorge

    2014-01-01

    we have investigated whether cultured cardiomyocytes of the cell line HL-1 have the ability to perform regulatory volume responses both in hypotonic and hypertonic conditions. Furthermore, we characterized those regulatory responses and studied the effects of bumetanide and DIDS in volume regulation of HL-1 cells. we used a light scattering system to measure the transient volume changes of HL-1 cells when subjected to osmotic challenge. We found that HL-1 cells correct for their volume excess by undergoing regulatory volume decrease (RVD), and also respond to hypertonic stress with a regulatory volume increase (RVI). Rate of RVD was 0.08 ± 0.04 intensity/min, and rate of RVI was 0.09 ± 0.01 intensity/min. Volume recovery was 83.68 ± 5.73 % for RVD and 92.3 ± 2.3 % for RVI. Bumetanide 50 µM inhibited volume recovery, from 92.3 ± 2.3 % (control) to 24.6 ± 8.8 % and reduced the rate of RVI from 0.070 ± 0.020 intensity/min (control) to 0.010 ± 0.005 intensity/min. 50 µM DIDS reduced volume recovery to 42.93 ± 7.7 % and rate of RVI, to 0.03 ± 0.01 intensity/min. these results suggest that bumetanide- and DIDS-sensitive mechanisms are involved in the RVI of HL-1 cells, which points to the involvement of the Na(+)/K(+)/2Cl(-) cotransporter and Cl(-)/bicarbonate exchanger in RVI, respectively. © 2014 S. Karger AG, Basel.

  17. Right atrial spleen.

    PubMed Central

    Kuijer, P; Dion, R; van Merrienboer, F

    1985-01-01

    A large cardiac tumour occupying most of the right atrium and the right ventricle and causing inflow obstruction to the right heart was confirmed by cross sectional echocardiography in a 41 year old man. After surgical resection histological examination showed that the atrial tumour had the characteristics of splenic tissue. Possible mechanisms for the development of such a tumour include an origin analogous to that of an accessory spleen or the implantation and subsequent growth of lymphoid tissue in a pre-existing superior vena caval or high right atrial angioma. Images PMID:4041304

  18. Identification of cardiac progenitors that survive in the ischemic human heart after ventricular myocyte death

    PubMed Central

    Omatsu-Kanbe, Mariko; Nozuchi, Nozomi; Nishino, Yuka; Mukaisho, Ken-ichi; Sugihara, Hiroyuki; Matsuura, Hiroshi

    2017-01-01

    Atypically-shaped cardiomyocytes (ACMs) are beating heart cells identified in the cultures of cardiomyocyte-removed fractions obtained from adult mouse hearts. Since ACMs spontaneously develop into beating cells in the absence of hormones or chemicals, these cells are likely to be a type of cardiac progenitors rather than stem cells. “Native ACMs” are found as small interstitial cells among ventricular myocytes that co-express cellular prion protein (PrP) and cardiac troponin T (cTnT) in mouse and human heart tissues. However, the endogenous behavior of human ACMs is unclear. In the present study, we demonstrate that PrP+ cTnT+ cells are present in the human heart tissue with myocardial infarction (MI). These cells were mainly found in the border of necrotic cardiomyocytes caused by infarcts and also in the hibernating myocardium subjected to the chronic ischemia. The ratio of PrP+ cTnT+ cells to the total cells observed in the normal heart tissue section of mouse and human was estimated to range from 0.3–0.8%. Notably, living human PrP+ cTnT+ cells were identified in the cultures obtained at pathological autopsy despite exposure to lethal ischemic conditions for hours after death. These findings suggest that ACMs could survive in the ischemic human heart and develop into a sub-population of cardiac myocytes. PMID:28120944

  19. Control of cardiac-specific transcription by p300 through myocyte enhancer factor-2D.

    PubMed

    Slepak, T I; Webster, K A; Zang, J; Prentice, H; O'Dowd, A; Hicks, M N; Bishopric, N H

    2001-03-09

    The transcriptional integrator p300 regulates gene expression by interaction with sequence-specific DNA-binding proteins and local remodeling of chromatin. p300 is required for cardiac-specific gene transcription, but the molecular basis of this requirement is unknown. Here we report that the MADS (MCM-1, agamous, deficiens, serum response factor) box transcription factor myocyte enhancer factor-2D (MEF-2D) acts as the principal conduit for cardiac transcriptional activation by p300. p300 activation of the native 2130-base pair human skeletal alpha-actin promoter required a single hybrid MEF-2/GATA-4 DNA motif centered at -1256 base pairs. Maximal expression of the promoter in cultured myocytes and in vivo correlated with binding of both MEF-2 and p300, but not GATA-4, to this AT-rich motif. p300 and MEF-2 were coprecipitated from cardiac nuclear extracts by an oligomer containing this element. p300 was found exclusively in a complex with MEF-2D at this and related sites in other cardiac-restricted promoters. MEF-2D, but not other MEFs, significantly potentiated cardiac-specific transcription by p300. No physical or functional interaction was observed between p300 and other factors implicated in skeletal actin transcription, including GATA-4, TEF-1, or SRF. These results show that, in the intact cell, p300 interactions with its protein targets are highly selective and that MEF-2D is the preferred channel for p300-mediated transcriptional control in the heart.

  20. Modulation by chloramine-T of 4-aminopyridine-sensitive transient outward current in rabbit atrial cells.

    PubMed

    Tanaka, H; Habuchi, Y; Nishio, M; Suto, F; Yoshimura, M

    1998-09-25

    The effects of an oxidizing agent, chloramine-T, on the 4-aminopyridine-sensitive transient outward current (ITO) were investigated in rabbit atrial myocytes by using patch-clamp techniques. Extracellular application of chloramine-T at 20 microM irreversibly slowed the time course of inactivation of the whole-cell ITO, and increased the peak by 19.3% (n = 19) at +40 mV. At 100 microM, chloramine-T decreased the peak by 22.5% (n = 9) of the control, and subsequently induced a glibenclamide-sensitive time-independent outward K+ current. Under superfusion with dithiothreitol (3 mM), chloramine-T (100 microM) produced no change in ITO. The chloramine-T-induced slowing of ITO inactivation was partially reversed by subsequent application of 3 mM dithiothreitol. In single-channel recordings with the cell-attached patch configuration, chloramine-T (20 microM) increased the open probability of the ITO channel from 0.15 to 0.46 at a potential 100 mV positive to the resting potential, and the mean open lifetime from 5.1 ms to 7.0 ms (n = 5). The unitary current amplitude was not affected. As a result, chloramine-T increased the ensemble current in amplitude and slowed its decay. These results indicated that: (1) inactivation of the native A-type channels of rabbit heart is susceptible to oxidation; and (2) oxidation of ITO channels may contribute to the genesis of arrhythmias.

  1. Distribution and function of sodium channel subtypes in human atrial myocardium.

    PubMed

    Kaufmann, Susann G; Westenbroek, Ruth E; Maass, Alexander H; Lange, Volkmar; Renner, Andre; Wischmeyer, Erhard; Bonz, Andreas; Muck, Jenny; Ertl, Georg; Catterall, William A; Scheuer, Todd; Maier, Sebastian K G

    2013-08-01

    Voltage-gated sodium channels composed of a pore-forming α subunit and auxiliary β subunits are responsible for the upstroke of the action potential in cardiac muscle. However, their localization and expression patterns in human myocardium have not yet been clearly defined. We used immunohistochemical methods to define the level of expression and the subcellular localization of sodium channel α and β subunits in human atrial myocytes. Nav1.2 channels are located in highest density at intercalated disks where β1 and β3 subunits are also expressed. Nav1.4 and the predominant Nav1.5 channels are located in a striated pattern on the cell surface at the z-lines together with β2 subunits. Nav1.1, Nav1.3, and Nav1.6 channels are located in scattered puncta on the cell surface in a pattern similar to β3 and β4 subunits. Nav1.5 comprised approximately 88% of the total sodium channel staining, as assessed by quantitative immunohistochemistry. Functional studies using whole cell patch-clamp recording and measurements of contractility in human atrial cells and tissue showed that TTX-sensitive (non-Nav1.5) α subunit isoforms account for up to 27% of total sodium current in human atrium and are required for maximal contractility. Overall, our results show that multiple sodium channel α and β subunits are differentially localized in subcellular compartments in human atrial myocytes, suggesting that they play distinct roles in initiation and conduction of the action potential and in excitation-contraction coupling. TTX-sensitive sodium channel isoforms, even though expressed at low levels relative to TTX-sensitive Nav1.5, contribute substantially to total cardiac sodium current and are required for normal contractility. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes". Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Kb-R7943 prevents acute, atrial fibrillation-induced shortening of atrial refractoriness in anesthetized dogs.

    PubMed

    Miyata, Akira; Zipes, Douglas P; Hall, Stephen; Rubart, Michael

    2002-09-10

    To test the hypothesis that Ca2+ influx via Na+/Ca2+ exchange (NCX) underlies atrial fibrillation (AF)-induced shortening of atrial effective refractory period (AERP), we examined the potential of KB-R7943 (KB), a selective inhibitor of Ca2+-influx mode NCX, to attenuate this effect. Studies were performed in 41 isoflurane-anesthetized dogs. In sinus rhythm dogs, peak AERP changes resulting from intravenous KB infusion ranged from (mean+/-SEM) 4.4+/-0.4% (1 mg/kg) to 14.8+/-2.6% (5 mg/kg; ED50=1.9 mg/kg). AERP was maximally prolonged between 5 and 10 minutes after beginning of KB infusion and returned to baseline values within 30 minutes thereafter. Rapid atrial pacing-induced AF reversibly shortened AERP (P<0.001) in 5 dogs, averaging 14.9+/-2.1% after 90 minutes of AF. Both the time course and magnitude of mean AERP changes in 5 AF dogs receiving 5 mg/kg KB were indistinguishable from those in 5 sinus rhythm dogs receiving an equivalent KB dose (P>0.05). We measured cardiac tissue and arterial plasma KB concentrations produced by intravenous infusion (1 mg x kg(-1) x min(-1)) of 5 mg/kg KB. Plasma drug concentration peaked at the end of KB infusions (30.86+/-3.26 nmol/L; n=4 dogs) and declined to 0.56+/-0.19 nmol/L after 100 minutes. The cardiac tissue-to-plasma drug concentration gradient averaged approximately 40 at 100 minutes after start of KB infusion. KB at concentrations achieved in vivo irreversibly blocked NCX-mediated Ca2+ influx in isolated canine right atrial myocytes by approximately 60%, but had no significant effect on NCX-dependent Ca2+ extrusion. NCX-mediated Ca2+ influx plays an important role in acute, AF-induced AERP shortening.

  3. Stem cell stimulation of endogenous myocyte regeneration.

    PubMed

    Weil, Brian R; Canty, John M

    2013-08-01

    Cell-based therapy has emerged as a promising approach to combat the myocyte loss and cardiac remodelling that characterize the progression of left ventricular dysfunction to heart failure. Several clinical trials conducted over the past decade have shown that a variety of autologous bone-marrow- and peripheral-blood-derived stem and progenitor cell populations can be safely administered to patients with ischaemic heart disease and yield modest improvements in cardiac function. Concurrently, rapid progress has been made at the pre-clinical level to identify novel therapeutic cell populations, delineate the mechanisms underlying cell-mediated cardiac repair and optimize cell-based approaches for clinical use. The following review summarizes the progress that has been made in this rapidly evolving field over the past decade and examines how our current understanding of the mechanisms involved in successful cardiac regeneration should direct future investigation in this area. Particular emphasis is placed on discussion of the general hypothesis that the benefits of cell therapy primarily result from stimulation of endogenous cardiac repair processes that have only recently been identified in the adult mammalian heart, rather than direct differentiation of exogenous cells. Continued scientific investigation in this area will guide the optimization of cell-based approaches for myocardial regeneration, with the ultimate goal of clinical implementation and substantial improvement in our ability to restore cardiac function in ischaemic heart disease patients.

  4. Glycolytic oscillations in isolated rabbit ventricular myocytes.

    PubMed

    Yang, Jun-Hai; Yang, Ling; Qu, Zhilin; Weiss, James N

    2008-12-26

    Previous studies have shown that glycolysis can oscillate periodically, driven by feedback loops in regulation of key glycolytic enzymes by free ADP and other metabolites. Here we show both theoretically and experimentally in cardiac myocytes that when the capacity of oxidative phosphorylation and the creatine kinase system to buffer the cellular ATP/ADP ratio is suppressed, glycolysis can cause large scale periodic oscillations in cellular ATP levels (0.02-0.067 Hz), monitored from glibenclamide-sensitive changes in action potential duration or intracellular free Mg2+. Action potential duration oscillations originate primarily from glycolysis, since they 1) occur in the presence of cyanide or rotenone, 2) are suppressed by iodoacetate, 3) are accompanied by at most very small mitochondrial membrane potential oscillations, and 4) exhibit an anti-phase relationship to NADH fluorescence. By uncoupling energy supply-demand balance, glycolytic oscillations may promote injury and electrophysiological heterogeneity during acute metabolic stresses, such as acute myocardial ischemia in which both oxidative phosphorylation and creatine kinase activity are inhibited.

  5. Stem Cell Stimulation of Endogenous Myocyte Regeneration

    PubMed Central

    Weil, Brian R.; Canty, John M.

    2015-01-01

    Cell-based therapy has emerged as a promising approach to combat the myocyte loss and cardiac remodeling that characterize the progression of left ventricular dysfunction to heart failure. Several clinical trials conducted during the past decade have shown that a variety of autologous bone marrow- and peripheral blood-derived stem and progenitor cell populations can be safely administered to patients with ischemic heart disease and yield modest improvements in cardiac function. Concurrently, rapid progress has been made at the preclinical level to identify novel therapeutic cell populations, delineate the mechanisms underlying cell-mediated cardiac repair, and optimize cell-based approaches for clinical use. The following review summarizes the progress that has been made in this rapidly evolving field over the past decade and examines how our current understanding of the mechanisms involved in successful cardiac regeneration should direct future investigation in this area. Particular emphasis is placed on discussion of the general hypothesis that the benefits of cell therapy primarily result from stimulation of endogenous cardiac repair processes that have only recently been identified in the adult mammalian heart, rather than direct differentiation of exogenous cells. Continued scientific investigation in this area will guide the optimization of cell-based approaches for myocardial regeneration, with the ultimate goal of clinical implementation and substantial improvement in our ability to restore cardiac function in ischemic heart disease patients. PMID:23577634

  6. The mechanism of PDT-induced electrical blockade: the measurement of intracellular Ca 2+ concentration changes in cardiac myocytes

    NASA Astrophysics Data System (ADS)

    Ito, A.; Hosokawa, S.; Hakomori, S.; Miyoshi, S.; Soejima, K.; Arai, T.

    2008-02-01

    We propose the application of early state photodynamic therapy (PDT) to treatment of atrial fibrillation, which is a kind of arrhythmia characterized by irregular rapid beating of heart. We had demonstrated that our PDT can block the propagation of electrical excitation in cardiac myocytes. However, the mechanism of the PDT-induced electrical blockade was not clear. In order to clarify this mechanism, changes in intracellular Ca 2+ concentration during the PDT with Talaporfin sodium (water soluble photosensitizer) were measured by fluorescence Ca 2+ indicator, fluo-4 AM. The PDT led to the rapid increase of intracellular Ca 2+ concentration and the changes in cell shapes. These results indicated that extracellular Ca 2+ flowed into the cells mediated by cell membrane. Moreover, we found bubble generation in the cells after the PDT. In conclusion, the PDT-induced electrical blockade in myocytes can be caused by cell death following the bubble generation, which is accompanied by the increase in intracellular Ca 2+ concentration due to the cell membrane malfunction with the PDT.

  7. Crucial role of type 2 inositol 1,4,5-trisphosphate receptors for acetylcholine-induced Ca2+ oscillations in vascular myocytes.

    PubMed

    Morel, Jean-Luc; Fritz, Nicolas; Lavie, Jean-Louis; Mironneau, Jean

    2003-09-01

    The aim of this study was to correlate the expression of InsP3R subtypes in native vascular and visceral myocytes with specific Ca2+-signaling patterns. By Western blot and immunostaining, we showed that rat portal vein expressed InsP3R1 and InsP3R2 but not InsP3R3, whereas rat ureter expressed InsP3R1 and InsP3R3 but not InsP3R2. Acetylcholine induced single Ca2+ responses in all ureteric myocytes but only in 50% of vascular myocytes. In the remaining vascular myocytes, the first transient peak was followed by Ca2+ oscillations. By correlating Ca2+ signals and immunostaining, we revealed that oscillating vascular cells expressed both InsP3R1 and InsP3R2 whereas nonoscillating vascular cells expressed only InsP3R1. Acetylcholine-induced oscillations were not affected by inhibitors of ryanodine receptors, Ca2+-ATPases, Ca2+ influx, and mitochondrial Ca2+ uniporter but were inhibited by intracellular infusion of heparin. Using specific antibodies against InsP3R subtypes, we showed that acetylcholine-induced Ca2+ oscillations were specifically blocked by the anti-InsP3R antibody. These data were supported by antisense oligonucleotides targeting InsP3R2, which selectively inhibited Ca2+ oscillations. Our results suggest that in native smooth muscle cells, a differential expression of InsP3R subtypes encodes specific InsP3-mediated Ca2+ responses and that the presence of the InsP3R2 subtype is required for acetylcholine-induced Ca2+ oscillations in vascular myocytes.

  8. 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.

  9. Structural changes in the progression of atrial fibrillation: potential role of glycogen and fibrosis as perpetuating factors

    PubMed Central

    Zhang, Ling; Huang, Bing; Scherlag, Benjamin J; Ritchey, Jerry W; Embi, Abraham A; Hu, Jialu; Hou, Yuemei; Po, Sunny S

    2015-01-01

    Background: Previous studies of the goat heart subjected to prolonged atrial pacing induced sustained atrial fibrillation (AF). Structural changes included marked accumulation of glycogen in atrial myocytes. Aims: In the present study, we hypothesized that glycogen deposition in canine atrial myocytes promotes paroxysmal forms of AF and is involved in fibrosis development in the later stages of AF. Material & methods: In dogs under pentobarbital anesthesia, tissues were obtained from the right and left atrial appendages (LAA/RAA). Periodic acid Schiff (PAS) and Masson’s trichrome staining of the LAA/RAA from normal dogs, and those subjected to atrial pacing induced AF for 48 h or 8 weeks determined glycogen and collagen concentrations, respectively, using morphometric analysis. Results: At baseline, there was a significant greater concentration of glycogen in the LAA than the RAA (P ≤ 0.05). Compared to the RAA, the LAA glycogen, was dense and locked against the intercalated discs. After pacing induced AF for 48 hours and 8 weeks there was a marked increase in glycogen deposition, significantly greater than in the baseline state (P ≤ 0.05). There was a similar and progressive increase in collagen concentrations in each group (P ≤ 0.05). Conclusions: The differential in glycogen concentration, in conjunction with other factors, neural and electrophysiological, provide a basis for the greater propensity of the left atrium for paroxysmal AF, at baseline and 48 hours of pacing induced AF. The marked increase in collagen at 8 weeks of pacing provides a substrate for sustained AF. Evidence is presented linking glycogen accumulation and fibrosis as factors in the persistent forms of AF. PMID:25973058

  10. Surgery for Atrial Fibrillation

    PubMed Central

    Lawrance, Christopher P.; Henn, Matthew C.; Damiano, Ralph J.

    2015-01-01

    Synopsis Atrial fibrillation is the most common cardiac arrhythmia and its treatment options include drug therapy or, catheter-based or surgical interventions. The surgical treatment of atrial fibrillation has undergone multiple evolutions over the last several decades. The Cox-Maze procedure which was developed by James Cox in 1987 is a procedure where multiple surgical incisions are created along the atria to interrupt the electrical pathways thought to allow atrial fibrillation to persist. This procedure went on to become the gold standard for the surgical treatment of atrial fibrillation and is currently in its 4th iteration called the Cox-Maze IV. The Cox-Maze IV replaced the previous “cut-and-sew” method with a combination of cryoablation and bipolar RF ablation. The adaption of ablation technologies allowed the Cox-Maze IV procedure to be performed through a less invasive right minithoracotomy instead of a traditional sternotomy approach. The aim of this article is to review the indications and preoperative planning for performing a Cox-Maze IV procedure. A description of the operative techniques for both a sternotomy and right mini-thoracotomy approach will be discussed in addition to specific postoperative considerations. Finally, this article will review the literature describing the surgical results for both approaches including comparisons of the Cox-Maze IV to the previous “cut-and-sew” method. PMID:25443237

  11. Posterior left atrial wall hematoma mimicking cystic intracavitary atrial mass.

    PubMed

    Bahnacy, Yasser; Suresh, Cheriyil; Dawoud, Hamed; Zubaid, Mohammad

    2010-10-01

    Atrial myxoma is the most common benign primary tumor of the heart most commonly in the left atrium (LA). Cystic or cavitated intracardiac masses are rare. We report the case of a 43-year-old male patient admitted with chest infection, hemoptysis, and severe respiratory distress, who had to be ventilated. Chest computed tomography showed bilateral lung consolidation with large mass occupying the region of the LA. Transthoracic echocardiography and transesophageal echocardiography showed a large intracavitary left atrial cystic mobile mass. Open-heart surgical exploration did not show any mass inside the LA. A posterior left atrial wall hematoma was found and evacuated. Biopsies confirmed the presence of blood clots. Posterior left atrial wall hematoma may appear as left atrial intracavitary cystic mass and should be included in the differential diagnosis of cystic left atrial mass.

  12. Nuclear morphology and deformation in engineered cardiac myocytes and tissues.

    PubMed

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

    2010-07-01

    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.

  13. 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; Sheehy, 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

  14. 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.

  15. The evolutionary origin of bilaterian smooth and striated myocytes

    PubMed Central

    Brunet, Thibaut; Fischer, Antje HL; Steinmetz, Patrick RH; Lauri, Antonella; Bertucci, Paola; Arendt, Detlev

    2016-01-01

    The dichotomy between smooth and striated myocytes is fundamental for bilaterian musculature, but its evolutionary origin is unsolved. In particular, interrelationships of visceral smooth muscles remain unclear. Absent in fly and nematode, they have not yet been characterized molecularly outside vertebrates. Here, we characterize expression profile, ultrastructure, contractility and innervation of the musculature in the marine annelid Platynereis dumerilii and identify smooth muscles around the midgut, hindgut and heart that resemble their vertebrate counterparts in molecular fingerprint, contraction speed and nervous control. Our data suggest that both visceral smooth and somatic striated myocytes were present in the protostome-deuterostome ancestor and that smooth myocytes later co-opted the striated contractile module repeatedly – for example, in vertebrate heart evolution. During these smooth-to-striated myocyte conversions, the core regulatory complex of transcription factors conveying myocyte identity remained unchanged, reflecting a general principle in cell type evolution. DOI: http://dx.doi.org/10.7554/eLife.19607.001 PMID:27906129

  16. 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.

  17. Oxidative stress decreases microtubule growth and stability in ventricular myocytes.

    PubMed

    Drum, Benjamin M L; Yuan, Can; Li, Lei; Liu, Qinghang; Wordeman, Linda; Santana, L Fernando

    2016-04-01

    Microtubules (MTs) have many roles in ventricular myocytes, including structural stability, morphological integrity, and protein trafficking. However, despite their functional importance, dynamic MTs had never been visualized in living adult myocytes. Using adeno-associated viral vectors expressing the MT-associated protein plus end binding protein 3 (EB3) tagged with EGFP, we were able to perform live imaging and thus capture and quantify MT dynamics in ventricular myocytes in real time under physiological conditions. Super-resolution nanoscopy revealed that EB1 associated in puncta along the length of MTs in ventricular myocytes. The vast (~80%) majority of MTs grew perpendicular to T-tubules at a rate of 0.06μm∗s(-1) and growth was preferentially (82%) confined to a single sarcomere. Microtubule catastrophe rate was lower near the Z-line than M-line. Hydrogen peroxide increased the rate of catastrophe of MTs ~7-fold, suggesting that oxidative stress destabilizes these structures in ventricular myocytes. We also quantified MT dynamics after myocardial infarction (MI), a pathological condition associated with increased production of reactive oxygen species (ROS). Our data indicate that the catastrophe rate of MTs increases following MI. This contributed to decreased transient outward K(+) currents by decreasing the surface expression of Kv4.2 and Kv4.3 channels after MI. On the basis of these data, we conclude that, under physiological conditions, MT growth is directionally biased and that increased ROS production during MI disrupts MT dynamics, decreasing K(+) channel trafficking.

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

    PubMed

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

    2015-11-01

    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. © 2015 by the Society for Experimental Biology and Medicine.

  19. The pacemaker current in cardiac Purkinje myocytes

    PubMed Central

    1995-01-01

    It is generally assumed that in cardiac Purkinje fibers the hyperpolarization activated inward current i(f) underlies the pacemaker potential. Because some findings are at odds with this interpretation, we used the whole cell patch clamp method to study the currents in the voltage range of diastolic depolarization in single canine Purkinje myocytes, a preparation where many confounding limitations can be avoided. In Tyrode solution ([K+]o = 5.4 mM), hyperpolarizing steps from Vh = -50 mV resulted in a time-dependent inwardly increasing current in the voltage range of diastolic depolarization. This time- dependent current (iKdd) appeared around -60 mV and reversed near EK. Small superimposed hyperpolarizing steps (5 mV) applied during the voltage clamp step showed that the slope conductance decreases during the development of this time-dependent current. Decreasing [K+]o from 5.4 to 2.7 mM shifted the reversal potential to a more negative value, near the corresponding EK. Increasing [K+]o to 10.8 mM almost abolished iKdd. Cs+ (2 mM) markedly reduced or blocked the time-dependent current at potentials positive and negative to EK. Ba2+ (4 mM) abolished the time-dependent current in its usual range of potentials and unmasked another time-dependent current (presumably i(f)) with a threshold of approximately -90 mV (> 20 mV negative to that of the time-dependent current in Tyrode solution). During more negative steps, i(f) increased in size and did not reverse. During i(f) the slope conductance measured with small (8-10 mV) superimposed clamp steps increased. High [K+]o (10.8 mM) markedly increased and Cs+ (2 mM) blocked i(f). We conclude that: (a) in the absence of Ba2+, a time-dependent current does reverse near EK and its reversal is unrelated to K+ depletion; (b) the slope conductance of that time-dependent current decreases in the absence of K+ depletion at potentials positive to EK where inactivation of iK1 is unlikely to occur. (c) Ba2+ blocks this time

  20. Genetics Home Reference: familial atrial fibrillation

    MedlinePlus

    ... Home Health Conditions familial atrial fibrillation familial atrial fibrillation Enable Javascript to view the expand/collapse boxes. ... PDF Open All Close All Description Familial atrial fibrillation is an inherited condition that disrupts the heart's ...

  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. Slow [Na+]i dynamics impacts arrhythmogenesis and spiral wave reentry in cardiac myocyte ionic model

    NASA Astrophysics Data System (ADS)

    Krogh-Madsen, Trine; Christini, David J.

    2017-09-01

    Accumulation of intracellular Na+ is gaining recognition as an important regulator of cardiac myocyte electrophysiology. The intracellular Na+ concentration can be an important determinant of the cardiac action potential duration, can modulate the tissue-level conduction of excitation waves, and can alter vulnerability to arrhythmias. Mathematical models of cardiac electrophysiology often incorporate a dynamic intracellular Na+ concentration, which changes much more slowly than the remaining variables. We investigated the dependence of several arrhythmogenesis-related factors on [Na+]i in a mathematical model of the human atrial action potential. In cell simulations, we found that [Na+]i accumulation stabilizes the action potential duration to variations in several conductances and that the slow dynamics of [Na+]i impacts bifurcations to pro-arrhythmic afterdepolarizations, causing intermittency between different rhythms. In long-lasting tissue simulations of spiral wave reentry, [Na+]i becomes spatially heterogeneous with a decreased area around the spiral wave rotation center. This heterogeneous region forms a functional anchor, resulting in diminished meandering of the spiral wave. Our findings suggest that slow, physiological, rate-dependent variations in [Na+]i may play complex roles in cellular and tissue-level cardiac dynamics.

  3. AFos Dissociates Cardiac Myocyte Hypertrophy and Expression of the Pathological Gene Program

    PubMed Central

    Jeong, Mark Y.; Kinugawa, Koichiro; Vinson, Charles; Long, Carlin S.

    2005-01-01

    Background Although induction of activator protein-1 (AP-1) transcription factor activity has been observed in cardiac hypertrophy, a direct role for AP-1 in myocardial growth and gene expression remains obscure. Methods and Results Hypertrophy was induced in cultured neonatal rat cardiomyocytes with phenylephrine or overexpression of a constitutively active MAP3K, MKK6. In both treatment groups, induction of the pathological gene profile was observed, ie, expression of β-myosin heavy chain (βMHC), atrial/brain natriuretic peptides (ANP/BNP), and skeletal α-actin (sACT) was increased, whereas expression for α-myosin heavy chain (αMHC) and the sarcoplasmic reticulum Ca2+-ATPase (SERCA) genes was repressed. The role of AP-1 in the hypertrophic phenotype was evaluated with the use of an adenoviral construct expressing a dominant negative mutant of the c-Fos proto-oncogene (AdAFos). Although AFos did not change the myocyte growth response, it abrogated the gene profile to both agonists, including the upregulation of both αMHC and SERCA expression. Conclusions Although c-Fos/AP-1 is necessary for induction of the pathological/fetal gene program, it does not appear to be critical for cardiomyocyte hypertrophy. PMID:15795322

  4. Slow [Na(+)]i dynamics impacts arrhythmogenesis and spiral wave reentry in cardiac myocyte ionic model.

    PubMed

    Krogh-Madsen, Trine; Christini, David J

    2017-09-01

    Accumulation of intracellular Na(+) is gaining recognition as an important regulator of cardiac myocyte electrophysiology. The intracellular Na(+) concentration can be an important determinant of the cardiac action potential duration, can modulate the tissue-level conduction of excitation waves, and can alter vulnerability to arrhythmias. Mathematical models of cardiac electrophysiology often incorporate a dynamic intracellular Na(+) concentration, which changes much more slowly than the remaining variables. We investigated the dependence of several arrhythmogenesis-related factors on [Na(+)]i in a mathematical model of the human atrial action potential. In cell simulations, we found that [Na(+)]i accumulation stabilizes the action potential duration to variations in several conductances and that the slow dynamics of [Na(+)]i impacts bifurcations to pro-arrhythmic afterdepolarizations, causing intermittency between different rhythms. In long-lasting tissue simulations of spiral wave reentry, [Na(+)]i becomes spatially heterogeneous with a decreased area around the spiral wave rotation center. This heterogeneous region forms a functional anchor, resulting in diminished meandering of the spiral wave. Our findings suggest that slow, physiological, rate-dependent variations in [Na(+)]i may play complex roles in cellular and tissue-level cardiac dynamics.

  5. 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

  6. Myomaker mediates fusion of fast myocytes in zebrafish embryos.

    PubMed

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

    2014-09-05

    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. Atrial fibrillation in the elderly

    PubMed Central

    Franken, Roberto A.; Rosa, Ronaldo F.; Santos, Silvio CM

    2012-01-01

    This review discusses atrial fibrillation according to the guidelines of Brazilian Society of Cardiac Arrhythmias and the Brazilian Cardiogeriatrics Guidelines. We stress the thromboembolic burden of atrial fibrillation and discuss how to prevent it as well as the best way to conduct cases of atrial fibrillatios in the elderly, reverting the arrhythmia to sinus rhythm, or the option of heart rate control. The new methods to treat atrial fibrillation, such as radiofrequency ablation, new oral direct thrombin inhibitors and Xa factor inhibitors, as well as new antiarrhythmic drugs, are depicted. PMID:22916053

  8. Efficacy and safety of bipolar sensing with high atrial sensitivity in dual chamber pacemakers.

    PubMed

    Wiegand, U K; Bode, F; Peters, W; Haase, H; Bonnemeier, H; Katus, H A; Potratz, J

    2000-04-01

    In dual chamber pacemakers, atrial sensing performance is decisive for maintenance of AV synchrony. Particularly, the efficacy of mode switching algorithms during intermittent atrial tachyarrhythmias depends on the sensitive detection of low potential amplitudes. Therefore, a high atrial sensitivity of 0.18 mV, commonly used in single lead VDD pacemakers, was investigated for its efficacy and safety in DDD pacing. Thirty patients received dual chamber pacemakers and bipolar atrial screw-in leads for sinus node syndrome or AV block; 15 patients suffered from intermittent atrial fibrillation. Pace makers were programmed to an atrial sensitivity of 0.18 mV. Two weeks, 3, 9, and 15 months after implantation, P wave sensing threshold and T wave oversensing thresholds for the native and paced T wave were determined. The myopotential oversensing thresholds were evaluated by isometric contraction of the pectoral muscles. Automatic mode switch to DDIR pacing was activated when the mean atrial rate exceeded 180 beats/min. The patients were followed by 24-hour Holter monitoring. Two weeks after implantation, mean atrial sensing threshold was 1.81 +/- 0.85 mV (range 0.25-2.8 mV) without significant differences during further follow-up. Native T wave sensing threshold was < 0.18 mV in all patients. In 13% of patients, paced T waves were perceived in the atrial channel at the highest sensitivity. This T wave sensing could easily be avoided by programming a postventricular atrial refractory period exceeding 300 ms. Myopotential oversensing could not be provoked and Holter records showed no signs of sensing dysfunction. During a 15-month follow-up, 1,191 mode switch events were counted by autodiagnostic pacemaker function. Forty-two of these events occurred during Holter monitoring. Unjustified mode switch was not observed. In DDD pacemakers, bipolar atrial sensing with a very high sensitivity is efficient and safe. Using these sensitivity settings, activation of the mode switch

  9. Racial Differences in Atrial Fibrillation Prevalence and Left Atrial Size

    PubMed Central

    Marcus, Gregory M.; Olgin, Jeffrey E.; Whooley, Mary; Vittinghoff, Eric; Stone, Katie L.; Mehra, Reena; Hulley, Stephen B.; Schiller, Nelson B.

    2010-01-01

    BACKGROUND Previous studies relying on clinical care data have suggested that atrial fibrillation is less common in African Americans than Caucasians, but the mechanism remains unknown. Clinical care may itself vary by race, potentially affecting the accuracy of atrial fibrillation ascertainment in studies relying on clinical data. We sought to examine racial differences in atrial fibrillation prevalence determined by protocol-driven electrocardiograms (ECGs) obtained in prospective cohort studies and to study racial differences in echocardiographic characteristics. METHODS We pooled primary data from 3 cohort studies with atrial fibrillation adjudicated from study protocol ECGs and documentation of potentially important confounders: the Heart and Soul Study (n = 1014), the Heart and Estrogen-Progestin Replacement Study (n = 2673), and The Osteoporotic Fractures in Men Sleep Study (n = 2911). Left atrial anatomic dimensions were compared among races from sinus rhythm echocardiograms in the Heart and Soul Study. RESULTS Of the 6611 participants, 268 (4%) had atrial fibrillation: Caucasians had the highest prevalence (5%), and African Americans had the lowest (1%; P <.001 for each compared with all other races). After adjustment for potential confounders, Caucasians had a 3.8-fold greater odds of having atrial fibrillation than African Americans (95% confidence interval, 1.6–8.8, P = .002). Although ventricular and atrial volumes and function were similar in Caucasians and African Americans, Caucasians had a 2 mm larger anterior-posterior left atrial diameter after adjusting for potential confounders (95% confidence interval, 1–3 mm, P <.001). CONCLUSION ECG confirmed atrial fibrillation is more common in Caucasians than in African Americans, which might be related to the larger left atrial diameter observed in Caucasians. PMID:20227049

  10. Myocyte-specific M-CAT and MEF-1 elements regulate G-protein gamma 3 gene (gamma3) expression in cardiac myocytes.

    PubMed

    McWhinney, Charlene; Robishaw, Janet D

    2008-07-01

    Little is known regarding the mechanisms that control the expression of G-protein alpha, beta, and gamma subtypes. We have previously shown that the G-protein gamma(3) gene is expressed in the heart, brain, lung, spleen, kidney, muscle, and testis in mice. We have also reported that the G-protein gamma(3) subunit is expressed in rat cardiac myocytes, but not in cardiac fibroblasts. Other studies have shown that the gamma(3) subunit couples to the angiotensin A1A receptor in portal vein myocytes, and has been shown to mediate beta-adrenergic desensitization in cardiac myocytes treated with atorvastatin. In the present study, we evaluated G-protein gamma(3) promoter-luciferase reporter constructs in primary myocytes to identify key regulatory promoter regions. We identified two important regions of the promoter (upstream promoter region [UPR] and downstream promoter region [DPR]), which are required for expression in cardiac myocytes. We observed that removal of 48 bp in the UPR diminished gene transcription by 75%, and that the UPR contains consensus elements for myocyte-specific M-CAT and myocyte enhancer factor 1 (MEF-1) elements. The UPR and DPR share transcription factor elements for myocyte-specific M-CAT element. We observed that cardiac myocyte proteins bind to gamma(3) oligonucleotides containing transcription factor elements for myocyte-specific M-CAT and MEF-1. Myocyte-specific M-CAT proteins were supershifted with transcriptional enhancer factor-1 (TEF-1) antibodies binding to the gamma(3) M-CAT element, which is in agreement with reports showing that the M-CAT element binds the TEF-1 family of transcription factors. The 150 bp DPR contains three M-CAT elements, an INR element, an upstream stimulatory factor 1 element, and the transcription start site. We have shown that myocyte gamma(3) gene expression is regulated by myocyte-specific M-CAT and MEF-1 elements.

  11. Photoelectric recording of mechanical responses of cardiac myocytes.

    PubMed

    Meyer, R; Wiemer, J; Dembski, J; Haas, H G

    1987-04-01

    A method to monitor contraction of isolated myocytes by transmicroscopic photometry is illustrated. Two photodiodes are mounted inside an inverse microscope used for visual control of a cell. Illumination of one diode varies in proportion to changes in cell length. The contraction signal is amplified in a comparator circuit. Spatial resolution of the device is in the order of 1 micron which corresponds to about 5% of cell shortening in the fully activated state of contraction. The method was tested on isolated myocytes from guinea-pig ventricle. Optical records of contraction in response to action potentials or during voltage clamp compare well with the contractile behavior of multicellular preparations.

  12. The natriuretic peptides BNP and CNP increase heart rate and electrical conduction by stimulating ionic currents in the sinoatrial node and atrial myocardium following activation of guanylyl cyclase-linked natriuretic peptide receptors.

    PubMed

    Springer, Jeremy; Azer, John; Hua, Rui; Robbins, Courtney; Adamczyk, Andrew; McBoyle, Sarah; Bissell, Mary Beth; Rose, Robert A

    2012-05-01

    Natriuretic peptides (NPs) are best known for their ability to regulate blood vessel tone and kidney function whereas their electrophysiological effects on the heart are less clear. Here, we measured the effects of BNP and CNP on sinoatrial node (SAN) and atrial electrophysiology in isolated hearts as well as isolated SAN and right atrial myocytes from mice. BNP and CNP dose-dependently increased heart rate and conduction through the heart as indicated by reductions in R-R interval, P wave duration and P-R interval on ECGs. In conjunction with these ECG changes BNP and CNP (100 nM) increased spontaneous action potential frequency in isolated SAN myocytes by increasing L-type Ca(2+) current (I(Ca,L)) and the hyperpolarization-activated current (I(f)). BNP had no effect on right atrial myocyte APs in basal conditions; however, in the presence of isoproterenol (10nM), BNP increased atrial AP duration and I(Ca,L). Quantitative gene expression and immunocytochemistry data show that all three NP receptors (NPR-A, NPR-B and NPR-C) are expressed in the SAN and atrium. The effects of BNP and CNP on SAN and right atrial myocytes were maintained in mutant mice lacking functional NPR-C receptors and blocked by the NPR-A antagonist A71915 indicating that BNP and CNP function through their guanylyl cyclase-linked receptors. Our data also show that the effects of BNP and CNP are completely absent in the presence of the phosphodiesterase 3 inhibitor milrinone. Based on these data we conclude that NPs can increase heart rate and electrical conduction by activating the guanylyl cyclase-linked NPR-A and NPR-B receptors and inhibiting PDE3 activity.

  13. Ablation for Atrial Fibrillation

    PubMed Central

    2006-01-01

    Executive Summary Objective To review the effectiveness, safety, and costing of ablation methods to manage atrial fibrillation (AF). The ablation methods reviewed were catheter ablation and surgical ablation. Clinical Need Atrial fibrillation is characterized by an irregular, usually rapid, heart rate that limits the ability of the atria to pump blood effectively to the ventricles. Atrial fibrillation can be a primary diagnosis or it may be associated with other diseases, such as high blood pressure, abnormal heart muscle function, chronic lung diseases, and coronary heart disease. The most common symptom of AF is palpitations. Symptoms caused by decreased blood flow include dizziness, fatigue, and shortness of breath. Some patients with AF do not experience any symptoms. According to United States data, the incidence of AF increases with age, with a prevalence of 1 per 200 people aged between 50 and 60 years, and 1 per 10 people aged over 80 years. In 2004, the Institute for Clinical Evaluative Sciences (ICES) estimated that the rate of hospitalization for AF in Canada was 582.7 per 100,000 population. They also reported that of the patients discharged alive, 2.7% were readmitted within 1 year for stroke. One United States prevalence study of AF indicated that the overall prevalence of AF was 0.95%. When the results of this study were extrapolated to the population of Ontario, the prevalence of AF in Ontario is 98,758 for residents aged over 20 years. Currently, the first-line therapy for AF is medical therapy with antiarrhythmic drugs (AADs). There are several AADs available, because there is no one AAD that is effective for all patients. The AADs have critical adverse effects that can aggravate existing arrhythmias. The drug selection process frequently involves trial and error until the patient’s symptoms subside. The Technology Ablation has been frequently described as a “cure” for AF, compared with drug therapy, which controls AF but does not cure it

  14. The atrial natriuretic factor.

    PubMed Central

    Genest, J

    1986-01-01

    In less than three years since the rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats was reported the factor responsible for the diuretic, natriuretic, and vasodilating activity of the atrial homogenates was isolated, its chemical structure elucidated, and its total synthesis achieved. Also the cDNA and the gene encoding for the atrial natriuretic factor in mice, rats, and man have been cloned and the chromosomal site identified. The major effects of this hormone are vasodilatation, prevention and inhibition of the contraction induced by noradrenaline and angiotensin II, diuresis, and natriuresis associated in most instances with a pronounced increase in glomerular filtration rate and filtration fraction, inhibition of aldosterone secretion, and considerable stimulation of particulate guanylate cyclase activity. High density specific binding sites have been demonstrated in the zona glomerulosa of the adrenal cortex, in the renal glomeruli, and in the collecting ducts, and in the brain areas involved in the regulation of blood pressure and of sodium and water (AV3V region, subfornical organ, nucleus tractus solitarius, area postrema). Images Fig 1 Fig 5 PMID:2945572

  15. Reentry and atrial fibrillation.

    PubMed

    Atienza, Felipe; Jalife, José

    2007-03-01

    The mechanisms of human atrial fibrillation (AF) are poorly understood. Experimental studies have demonstrated that cholinergic AF in the sheep heart is maintained by high-frequency reentrant sources (drivers) that result in a consistent left-to-right frequency gradient. More recently, clinical studies have confirmed the existence of a hierarchical organization in the rate of activation of different regions in the atria of patients with paroxysmal and chronic AF. Although maximal dominant-frequency sites were found to play a crucial role in the maintenance of AF in some patients, whether AF drivers in humans are focal or reentrant and whether changes in driver activity alter spatial frequency gradients are unclear. To test the hypothesis that localized functional reentry maintains AF in humans, we determined the effects of adenosine infusion on local dominant frequency at different sites of both atria. In patients with paroxysmal AF, adenosine infusion increases local dominant frequencies, particularly at the pulmonary vein-left atrial junction region, amplifying a left-to-right frequency gradient. In patients with chronic AF, dominant frequency is significantly higher than in patients with paroxysmal AF in all atrial regions surveyed, with the highest adenosine increase of frequencies outside the pulmonary vein region. Adenosine-induced driver acceleration is strongly suggestive of a reentrant mechanism in both groups of AF patients.

  16. Clinical Applications of Biomarkers in Atrial Fibrillation.

    PubMed

    Chang, Kay-Won; Hsu, Jonathan C; Toomu, Avinash; Fox, Sutton; Maisel, Alan S

    2017-08-16

    While biomarkers have greatly impacted the diagnosis and management of myocardial infarction and heart failure, the use of biomarkers has been slow to permeate management of atrial fibrillation. Guideline recommendations on the use of biomarkers in atrial fibrillation were virtually non-existent until the 2016 European Society of Cardiology guidelines on atrial fibrillation offered a class IIb recommendation to consider using biomarkers such as high sensitivity troponin and natriuretic peptide to further refine stroke and bleeding risk in atrial fibrillation patients. Biomarker levels have been associated with incident atrial fibrillation, post-operative atrial fibrillation, acute atrial fibrillation, diagnosis of myocardial infarction and heart failure in atrial fibrillation, and prognosis in atrial fibrillation. This review will offer an in-depth survey of current evidence on the use of biomarkers in atrial fibrillation and propose clinical algorithms to aid the internist in using biomarkers in atrial fibrillation management. Copyright © 2017. Published by Elsevier Inc.

  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. [Catheter ablation of atrial flutter and paroxysmal atrial fibrillation].

    PubMed

    Márquez, Manlio F

    2003-01-01

    Radiofrequency catheter ablation has emerged as a curative therapy for atrial flutter based on studies demonstrating the role of the cavotricuspid isthmus. With a high rate of success and minimal complications, catheter ablation is the therapy of choice for patients with the common type of atrial flutter. Left atrial flutter, non-cavotricuspid isthmus dependent, and those associated with heart disease have a worst outcome with catheter ablation. Radiofrequency catheter ablation has also emerged as a curative therapy for paroxysmal atrial fibrillation based on studies demonstrating the role of triggering foci in the pulmonary veins for the initiation of atrial fibrillation. Catheter ablation is performed by a transseptal approach using radiofrequency energy at the ostium of each pulmonary vein. Mapping is guided by special catheters. Sequential radiofrequency applications eliminates or dissociates pulmonary vein muscle activity. Although complications exists, this is the only curative method for these patients.

  19. Atrial Septal Defect (For Kids)

    MedlinePlus

    ... Dictionary of Medical Words En Español What Other Kids Are Reading 7 Videos: Kids Talk About Life Video: Am I Normal? (Girls ... Train Your Temper Atrial Septal Defect KidsHealth > For Kids > Atrial Septal Defect Print A A A What's ...

  20. Isorhamnetin protects rat ventricular myocytes from ischemia and reperfusion injury.

    PubMed

    Zhang, Najuan; Pei, Fei; Wei, Huaying; Zhang, Tongtong; Yang, Chao; Ma, Gang; Yang, Chunlei

    2011-01-01

    Ischemia/reperfusion (I/R) has been known to cause damages to ventricular myocytes. Isorhamnetin, one member of flavonoid compounds, has cardioprotective effect, the effect that suggests a possible treatment for I/R damages. In the present investigation, we found that isorhamnetin could significantly promote the viability of neonatal rat ventricular myocytes that were exposed to ischemia/reperfusion (I/R) in vitro. Ventricular myocytes were obtained from neonatal SD rats, and then were divided randomly into three groups, namely I/R-/isor-, I/R+/isor- and I/R+/isor+ group. Before the whole experiment, the most appropriate concentration of isorhamnetin (4 μM) was determined by MTT assay. Our results showed that isorhamnetin could alleviate the damages of I/R to ventricular myocytes through inhibiting lactate dehydrogenase (LDH) activity, and repressing apoptosis. Compared with the counterpart of the I/R+/isor- group, LDH activity in the isorhamnetin-treated group weakened, halving from 24.1 ± 2.3 to 11.4 ± 1.2U/L. Additionally, flow cytometry showed the apparently increased apoptosis rate induced by I/R, the result that was further confirmed by transmission electron microscope. Administration of isorhamnetin, however, assuaged the apoptosis induced by I/R. Corresponding to the reduced apoptosis rate in the I/R+/isor+ group, western blotting assay showed increased amount of Bcl-2 and p53, decreased amount of Bax, and nuclear accumulation of NF-κB/p65.

  1. The Frank-Starling mechanism in vertebrate cardiac myocytes.

    PubMed

    Shiels, Holly A; White, Ed

    2008-07-01

    The Frank-Starling law of the heart applies to all classes of vertebrates. It describes how stretch of cardiac muscle, up to an optimum length, increases contractility thereby linking cardiac ejection to cardiac filling. The cellular mechanisms underlying the Frank-Starling response include an increase in myofilament sensitivity for Ca2+, decreased myofilament lattice spacing and increased thin filament cooperativity. Stretching of mammalian, amphibian and fish cardiac myocytes reveal that the functional peak of the sarcomere length (SL)-tension relationship occurs at longer SL in the non-mammalian classes. These findings correlate with in vivo cardiac function as non-mammalian vertebrates, such as fish, vary stroke volume to a relatively larger extent than mammals. Thus, it seems the length-dependent properties of individual myocytes are modified to accommodate differences in organ function, and the high extensibility of certain hearts is matched by the extensibility of their myocytes. Reasons for the differences between classes are still to be elucidated, however, the structure of mammalian ventricular myocytes, with larger widths and higher levels of passive stiffness than those from other vertebrate classes may be implicated.

  2. Salvianolic acid B inhibits autophagy and protects starving cardiac myocytes

    PubMed Central

    Han, Xiao; Liu, Jian-xun; Li, Xin-zhi

    2011-01-01

    Aim: To investigate the protective or lethal role of autophagy and the effects of Salvianolic acid B (Sal B) on autophagy in starving myocytes. Methods: Cardiac myocytes were incubated under starvation conditions (GD) for 0, 1, 2, 3, and 6 h. Autophagic flux in starving cells was measured via chloroquine (3 μmol/L). After myocytes were treated with Sal B (50 μmol/L) in the presence or absence of chloroquine (3 μmol/L) under GD 3 h, the amount of LC3-II, the abundance of LC3-positive fluorescent dots in cells, cell viability and cellular ATP levels were determined using immunoblotting, immunofluorescence microscopy, MTT assay and luminometer, respectively. Moreover, electron microscopy (EM) and immunofluorescent duel labeling of LC3 and Caspase-8 were used to examine the characteristics of autophagy and apoptosis. Results: Immunoblot analysis showed that the amount of LC3-II in starving cells increased in a time-dependent manner accompanied by increased LC3-positive fluorescence and decreased cell viability and ATP content. Sal B (50 μmol/L) inhibited the increase in LC3-II, reduced the abundance of LC3 immunofluorescence and intensity of Caspase-8 fluorescence, and enhanced cellular viability and ATP levels in myocytes under GD 3 h, regardless of whether chloroquine was present. Conclusion: Autophagy induced by starvation for 3 h led to cell injury. Sal B protected starving cells by blocking the early stage of autophagic flux and inhibiting apoptosis that occurred during autophagy. PMID:21113177

  3. Early morphologic changes following microwave endocardial ablation for treatment of chronic atrial fibrillation during mitral valve surgery.

    PubMed

    Climent, Vicente; Hurlé, Aquilino; Ho, Siew Yen; Sáenz-Santamaría, Javier; Nogales, Agustín G; Sánchez-Quintana, Damián

    2004-11-01

    The aim of this study was to investigate the early qualitative and quantitative structural changes in the left atrial wall after endocardial microwave ablation in patients with chronic atrial fibrillation (AF) undergoing mitral surgery. Seven patients with chronic AF of for at least 6 months underwent surgical microwave energy ablation. Linear isolation of pulmonary veins was performed in all patients by microwave energy applications to the endocardial surface delivered by catheter at 65-W constant power for 45 seconds. Biopsies were obtained from a selected site (below the right lower pulmonary vein) of the left atrial posterior wall before and after the ablation procedure in all patients. Control tissues from the same sites were obtained at autopsy from patients with noncardiac causes of death. Light and electron microscopy was used to examine qualitative and quantitative changes in tissue morphology. Tissues after endocardial ablation procedure showed significantly increased loss of contractile material. Electron microscopy of atrial tissue demonstrated loss of profile of perinuclear and plasma membranes of myocytes, disruption of the endothelial cells of capillary vessels, and presence of macrophages. Lesions created by endocardial microwave energy ablation revealed a transmural effect on the left atrial wall without a significant reduction in thickness but a significant increase in the myolytic areas involving the entire cytosol and occlusion of the small intramyocardial vessels within the ablative lesion.

  4. 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.

  5. A modular instrument for exploring the mechanics of cardiac myocytes.

    PubMed

    Garcia-Webb, M G; Taberner, A J; Hogan, N C; Hunter, I W

    2007-07-01

    The cardiac ventricular myocyte is a key experimental system for exploring the mechanical properties of the diseased and healthy heart. Millions of primary myocytes, which remain viable for 4-6 h, can be readily isolated from animal models. However, currently available instrumentation allows the mechanical properties of only a few physically loaded myocytes to be explored within 4-6 h. Here we describe a modular and inexpensive prototype instrument that could form the basis of an array of devices for probing the mechanical properties of single mammalian myocytes in parallel. This device would greatly increase the throughput of scientific experimentation and could be applied as a high-content screening instrument in the pharmaceutical industry. The instrument module consists of two independently controlled Lorentz force actuators-force transducers in the form of 0.025 x 1 x 5 mm stainless steel cantilevers with 0.5 m/N compliance and 360-Hz resonant frequency. Optical position sensors focused on each cantilever provide position and force resolution of <1 nm/ radicalHz and <2 nN/ radicalHz, respectively. The motor structure can produce peak displacements and forces of +/-200 mum and +/-400 microN, respectively. Custom Visual Basic.Net software provides data acquisition, signal processing, and digital control of cantilever position. The functionality of the instrument was demonstrated by implementation of novel methodologies for loading and attaching healthy mammalian ventricular myocytes to the force sensor and actuator and use of stochastic system identification techniques to measure their passive dynamic stiffness at various sarcomere lengths.

  6. Ryanodine receptor cluster fragmentation and redistribution in persistent atrial fibrillation enhance calcium release

    PubMed Central

    Macquaide, Niall; Tuan, Hoang-Trong Minh; Hotta, Jun-ichi; Sempels, Wouter; Lenaerts, Ilse; Holemans, Patricia; Hofkens, Johan; Jafri, M. Saleet; Willems, Rik; Sipido, Karin R.

    2015-01-01

    Aims In atrial fibrillation (AF), abnormalities in Ca2+ release contribute to arrhythmia generation and contractile dysfunction. We explore whether ryanodine receptor (RyR) cluster ultrastructure is altered and is associated with functional abnormalities in AF. Methods and results Using high-resolution confocal microscopy (STED), we examined RyR cluster morphology in fixed atrial myocytes from sheep with persistent AF (N = 6) and control (Ctrl; N = 6) animals. RyR clusters on average contained 15 contiguous RyRs; this did not differ between AF and Ctrl. However, the distance between clusters was significantly reduced in AF (288 ± 12 vs. 376 ± 17 nm). When RyR clusters were grouped into Ca2+ release units (CRUs), i.e. clusters separated by <150 nm, CRUs in AF had more clusters (3.43 ± 0.10 vs. 2.95 ± 0.02 in Ctrl), which were more dispersed. Furthermore, in AF cells, more RyR clusters were found between Z lines. In parallel experiments, Ca2+ sparks were monitored in live permeabilized myocytes. In AF, myocytes had >50% higher spark frequency with increased spark time to peak (TTP) and duration, and a higher incidence of macrosparks. A computational model of the CRU was used to simulate the morphological alterations observed in AF cells. Increasing cluster fragmentation to the level observed in AF cells caused the observed changes, i.e. higher spark frequency, increased TTP and duration; RyR clusters dispersed between Z-lines increased the occurrence of macrosparks. Conclusion In persistent AF, ultrastructural reorganization of RyR clusters within CRUs is associated with overactive Ca2+ release, increasing the likelihood of propagating Ca2+ release. PMID:26490742

  7. Adolescent feline heart contains a population of small, proliferative ventricular myocytes with immature physiological properties.

    PubMed

    Chen, Xiongwen; Wilson, Rachel M; Kubo, Hajime; Berretta, Remus M; Harris, David M; Zhang, Xiaoying; Jaleel, Naser; MacDonnell, Scott M; Bearzi, Claudia; Tillmanns, Jochen; Trofimova, Irina; Hosoda, Toru; Mosna, Federico; Cribbs, Leanne; Leri, Annarosa; Kajstura, Jan; Anversa, Piero; Houser, Steven R

    2007-03-02

    Recent studies suggest that rather than being terminally differentiated, the adult heart is a self-renewing organ with the capacity to generate new myocytes from cardiac stem/progenitor cells (CS/PCs). This study examined the hypotheses that new myocytes are generated during adolescent growth, to increase myocyte number, and these newly formed myocytes are initially small, mononucleated, proliferation competent, and have immature properties. Ventricular myocytes (VMs) and cKit(+) (stem cell receptor) CS/PCs were isolated from 11- and 22-week feline hearts. Bromodeoxyuridine incorporation (in vivo) and p16(INK4a) immunostaining were measured to assess myocyte cell cycle activity and senescence, respectively. Telomerase activity, contractions, Ca(2+) transients, and electrophysiology were compared in small mononucleated (SMMs) and large binucleated (LBMs) myocytes. Heart mass increased by 101% during adolescent growth, but left ventricular myocyte volume only increased by 77%. Most VMs were binucleated (87% versus 12% mononucleated) and larger than mononucleated myocytes. A greater percentage of SMMs was bromodeoxyuridine positive (SMMs versus LBMs: 3.1% versus 0.8%; P<0.05), and p16(INK4a) negative and small myocytes had greater telomerase activity than large myocytes. Contractions and Ca(2+) transients were prolonged in SMMs versus LBMs and Ca(2+) release was disorganized in SMMs with reduced transient outward current and T-tubule density. The T-type Ca(2+) current, usually seen in fetal/neonatal VMs, was found exclusively in SMMs and in myocytes derived from CS/PC. Myocyte number increases during adolescent cardiac growth. These new myocytes are initially small and functionally immature, with patterns of ion channel expression normally found in the fetal/neonatal period.

  8. 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

  9. Culture and adenoviral infection of sinoatrial node myocytes from adult mice

    PubMed Central

    St. Clair, Joshua R.; Sharpe, Emily J.

    2015-01-01

    Pacemaker myocytes in the sinoatrial node of the heart initiate each heartbeat by firing spontaneous action potentials. However, the molecular processes that underlie pacemaking are incompletely understood, in part because of our limited ability to manipulate protein expression within the native cellular context of sinoatrial node myocytes (SAMs). Here we describe a new method for the culture of fully differentiated SAMs from adult mice, and we demonstrate that robust expression of introduced proteins can be achieved within 24–48 h in vitro via adenoviral gene transfer. Comparison of morphological and electrophysiological characteristics of 48 h-cultured versus acutely isolated SAMs revealed only minor changes in vitro. Specifically, we found that cells tended to flatten in culture but retained an overall normal morphology, with no significant changes in cellular dimensions or membrane capacitance. Cultured cells beat spontaneously and, in patch-clamp recordings, the spontaneous action potential firing rate did not differ between cultured and acutely isolated cells, despite modest changes in a subset of action potential waveform parameters. The biophysical properties of two membrane currents that are critical for pacemaker activity in SAMs, the “funny current” (If) and voltage-gated Ca2+ currents (ICa), were also indistinguishable between cultured and acutely isolated cells. This new method for culture and adenoviral infection of fully-differentiated SAMs from the adult mouse heart expands the range of experimental techniques that can be applied to study the molecular physiology of cardiac pacemaking because it will enable studies in which protein expression levels can be modified or genetically encoded reporter molecules expressed within SAMs. PMID:26001410

  10. SKF-96365 strongly inhibits voltage-gated sodium current in rat ventricular myocytes.

    PubMed

    Chen, Kui-Hao; Liu, Hui; Yang, Lei; Jin, Man-Wen; Li, Gui-Rong

    2015-06-01

    SKF-96365 (1-(beta-[3-(4-methoxy-phenyl) propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride) is a general TRPC channel antagonist commonly used to characterize the potential functions of TRPC channels in cardiovascular system. Recent reports showed that SKF-96365 induced a reduction in cardiac conduction. The present study investigates whether the reduced cardiac conduction caused by SKF-96365 is related to the blockade of voltage-gated sodium current (I Na) in rat ventricular myocytes using the whole-cell patch voltage-clamp technique. It was found that SKF-96365 inhibited I Na in rat ventricular myocytes in a concentration-dependent manner. The compound (1 μM) negatively shifted the potential of I Na availability by 9.5 mV, increased the closed-state inactivation of I Na, and slowed the recovery of I Na from inactivation. The inhibition of cardiac I Na by SKF-96365 was use-dependent and frequency-dependent, and the IC₅₀ was decreased from 1.36 μM at 0.5 Hz to 1.03, 0.81, 0.61, 0.56 μM at 1, 2, 5, 10 Hz, respectively. However, the selective TRPC3 antagonist Pyr3 decreased cardiac I Na by 8.5% at 10 μM with a weak use and frequency dependence. These results demonstrate that the TRPC channel antagonist SKF-96365 strongly blocks cardiac I Na in use-dependent and frequency-dependent manners. Caution should be taken for interpreting the alteration of cardiac electrical activity when SKF-96365 is used in native cells as a TRPC antagonist.

  11. Sustained delivery of MGF peptide from microrods attracts stem cells and reduces apoptosis of myocytes.

    PubMed

    Doroudian, Golnar; Pinney, James; Ayala, Perla; Los, Tamara; Desai, Tejal A; Russell, Brenda

    2014-10-01

    Local release of drugs may have many advantages for tissue repair but also presents major challenges. Bioengineering approaches allow microstructures to be fabricated that contain bioactive peptides for sustained local delivery. Heart tissue damage is associated with local increases in mechano growth factor (MGF), a member of the IGF-1 family. The E domain of MGF peptide is anti-apoptotic and a stem cell homing factor. The objectives of this study were to fabricate a microrod delivery device of poly (ethylene glycol) dimethacrylate (PEGDMA) hydrogel loaded with MGF peptide and to determine the elution profile and bioactivity of MGF. The injectable microrods are 30 kPa stiffness and 15 μm widths by 100 μm lengths, chosen to match heart stiffness and myocyte size. Successful encapsulation of native MGF peptide within microrods was achieved with delivery of MGF for 2 weeks, as measured by HPLC. Migration of human mesenchymal stem cells (hMSCs) increased with MGF microrod treatment (1.72 ± 0.23, p < 0.05). Inhibition of the apoptotic pathway in neonatal rat ventricular myocytes was induced by 8 h of hypoxia (1 % O2). Protection from apoptosis by MGF microrod treatment was shown by the TUNEL assay and increased Bcl-2 expression (2 ± 0.19, p < 0.05). Microrods without MGF regulated the cytoskeleton, adhesion, and proliferation of hMSCs, and MGF had no effect on these properties. Therefore, the combination microdevice provided both the mechanical cues and 2-week MGF bioactivity to reduce apoptosis and recruit stem cells, suggesting potential use of MGF microrods for cardiac regeneration therapy in vivo.

  12. Left Atrial Epicardial Adiposity and Atrial Fibrillation

    PubMed Central

    Batal, Omar; Schoenhagen, Paul; Shao, Mingyuan; Ayyad, Ala Eddin; Van Wagoner, David R.; Halliburton, Sandra S.; Tchou, Patrick J.; Chung, Mina K.

    2010-01-01

    Background Atrial fibrillation (AF) has been linked to inflammatory factors and obesity. Epicardial fat is a source of several inflammatory mediators related to the development of coronary artery disease. We hypothesized that periatrial fat may have a similar role in the development of AF. Methods and Results Left atrium (LA) epicardial fat pad thickness was measured in consecutive cardiac CT angiograms performed for coronary artery disease or AF. Patients were grouped by AF burden: no (n=73), paroxysmal (n=60), or persistent (n=36) AF. In a short-axis view at the mid LA, periatrial epicardial fat thickness was measured at the esophagus (LA-ESO), main pulmonary artery, and thoracic aorta; retrosternal fat was measured in axial view (right coronary ostium level). LA area was determined in the 4-chamber view. LA-ESO fat was thicker in patients with persistent AF versus paroxysmal AF (P=0.011) or no AF (P=0.003). LA area was larger in patients with persistent AF than paroxysmal AF (P=0.004) or without AF (P<0.001). LA-ESO was a significant predictor of AF burden even after adjusting for age, body mass index, and LA area (odds ratio, 5.30; 95% confidence interval, 1.39 to 20.24; P=0.015). A propensity score–adjusted multivariable logistic regression that included age, body mass index, LA area, and comorbidities was also performed and the relationship remained statistically significant (P=0.008). Conclusions Increased posterior LA fat thickness appears to be associated with AF burden independent of age, body mass index, or LA area. Further studies are necessary to examine cause and effect, and if inflammatory, paracrine mediators explain this association. PMID:20504944

  13. Uncontrolled ventricular rate in atrial fibrillation. A manifestation of dissimilar atrial rhythms.

    PubMed Central

    Leier, C V; Johnson, T M; Lewis, R P

    1979-01-01

    A patient with coarse atrial fibrillation and a rapid ventricular response developed periods of high grade atrioventricular block interpersed with periods of rapid ventricular conduction after the administration of digitalis and propranolol. Intracardiac atrial recordings showed similar atrial rhythms of high right atrial flutter and left atrial fibrillation. The low right atrial recordings showed flutter during the periods of fast ventricular rates and fibrillation during periods of slower ventricular rates. Images PMID:475927

  14. 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.

  15. Up-regulation of miR-31 in human atrial fibrillation begets the arrhythmia by depleting dystrophin and neuronal nitric oxide synthase

    PubMed Central

    Carnicer, Ricardo; Recalde, Alice; Muszkiewicz, Anna; Jayaram, Raja; Carena, Maria Cristina; Wijesurendra, Rohan; Stefanini, Matilde; Surdo, Nicoletta C.; Lomas, Oliver; Ratnatunga, Chandana; Sayeed, Rana; Krasopoulos, George; Rajakumar, Timothy; Bueno-Orovio, Alfonso; Verheule, Sander; Fulga, Tudor A.; Rodriguez, Blanca; Schotten, Ulrich

    2016-01-01

    Atrial fibrillation (AF) is a growing public health burden, and its treatment remains a challenge. AF leads to electrical remodeling of the atria, which in turn promotes AF maintenance and resistance to treatment. Although remodeling has long been a therapeutic target in AF, its causes remain poorly understood. We show that atrial-specific up-regulation of microRNA-31 (miR-31) in goat and human AF depletes neuronal nitric oxide synthase (nNOS) by accelerating mRNA decay and alters nNOS subcellular localization by repressing dystrophin translation. By shortening action potential duration and abolishing rate-dependent adaptation of the action potential duration, miR-31 overexpression and/or disruption of nNOS signaling recapitulates features of AF-induced remodeling and significantly increases AF inducibility in mice in vivo. By contrast, silencing miR-31 in atrial myocytes from patients with AF restores dystrophin and nNOS and normalizes action potential duration and its rate dependency. These findings identify atrial-specific up-regulation of miR-31 in human AF as a key mechanism causing atrial dystrophin and nNOS depletion, which in turn contributes to the atrial phenotype begetting this arrhythmia. miR-31 may therefore represent a potential therapeutic target in AF. PMID:27225184

  16. Up-regulation of miR-31 in human atrial fibrillation begets the arrhythmia by depleting dystrophin and neuronal nitric oxide synthase.

    PubMed

    Reilly, Svetlana N; Liu, Xing; Carnicer, Ricardo; Recalde, Alice; Muszkiewicz, Anna; Jayaram, Raja; Carena, Maria Cristina; Wijesurendra, Rohan; Stefanini, Matilde; Surdo, Nicoletta C; Lomas, Oliver; Ratnatunga, Chandana; Sayeed, Rana; Krasopoulos, George; Rajakumar, Timothy; Bueno-Orovio, Alfonso; Verheule, Sander; Fulga, Tudor A; Rodriguez, Blanca; Schotten, Ulrich; Casadei, Barbara

    2016-05-25

    Atrial fibrillation (AF) is a growing public health burden, and its treatment remains a challenge. AF leads to electrical remodeling of the atria, which in turn promotes AF maintenance and resistance to treatment. Although remodeling has long been a therapeutic target in AF, its causes remain poorly understood. We show that atrial-specific up-regulation of microRNA-31 (miR-31) in goat and human AF depletes neuronal nitric oxide synthase (nNOS) by accelerating mRNA decay and alters nNOS subcellular localization by repressing dystrophin translation. By shortening action potential duration and abolishing rate-dependent adaptation of the action potential duration, miR-31 overexpression and/or disruption of nNOS signaling recapitulates features of AF-induced remodeling and significantly increases AF inducibility in mice in vivo. By contrast, silencing miR-31 in atrial myocytes from patients with AF restores dystrophin and nNOS and normalizes action potential duration and its rate dependency. These findings identify atrial-specific up-regulation of miR-31 in human AF as a key mechanism causing atrial dystrophin and nNOS depletion, which in turn contributes to the atrial phenotype begetting this arrhythmia. miR-31 may therefore represent a potential therapeutic target in AF.

  17. [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.

  18. 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.

  19. Distribution and function of sodium channel subtypes in human atrial myocardium

    PubMed Central

    Maass, Alexander H.; Lange, Volkmar; Renner, Andre; Wischmeyer, Erhard; Bonz, Andreas; Muck, Jenny; Ertl, Georg; Catterall, William A.; Scheuer, Todd; Maier, Sebastian K.G.

    2014-01-01

    Voltage-gated sodium channels composed of a pore-forming α subunit and auxiliary β subunits are responsible for the upstroke of the action potential in cardiac muscle. However, their localization and expression patterns in human myocardium have not yet been clearly defined. We used immunohistochemical methods to define the level of expression and the subcellular localization of sodium channel α and β subunits in human atrial myocytes. Nav1.2 channels are located in highest density at intercalated disks where β1 and β3 subunits are also expressed. Nav1.4 and the predominant Nav1.5 channels are located in a striated pattern on the cell surface at the z-lines together with β2 subunits. Nav1.1, Nav1.3, and Nav1.6 channels are located in scattered puncta on the cell surface in a pattern similar to β3 and β4 subunits. Nav1.5 comprised approximately 88% of the total sodium channel staining, as assessed by quantitative immunohistochemistry. Functional studies using whole cell patch-clamp recording and measurements of contractility in human atrial cells and tissue showed that TTX-sensitive (non-Nav1.5) α subunit isoforms account for up to 27% of total sodium current in human atrium and are required for maximal contractility. Overall, our results show that multiple sodium channel α and β subunits are differentially localized in subcellular compartments in human atrial myocytes, suggesting that they play distinct roles in initiation and conduction of the action potential and in excitation–contraction coupling. TTX-sensitive sodium channel isoforms, even though expressed at low levels relative to TTX-sensitive Nav1.5, contribute substantially to total cardiac sodium current and are required for normal contractility. This article is part of a Special Issue entitled “Na+ Regulation in Cardiac Myocytes”. PMID:23702286

  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. 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…

  2. Atrial fibrillation and heart failure: is atrial fibrillation a disease?

    PubMed

    Tilman, V

    2014-09-01

    Atrial fibrillation in heart failure often occur together. The relationship between atrial fibrillation and heart failure has remained a subject of research. The main manifestation of the violation of hydrodynamics in heart failure is the increased end-diastolic pressure, which is transmitted through the intercommunicated system (left ventricle-left atrium-pulmonary veins-alveolar capillaries) causing increased pulmonary wedge pressure with the danger for pulmonary edema. End-diastolic pressure is the sum of left ventricle diastolic pressure and left atrial systolic pressure. Stopping the mechanical systole of the left atrium can reduce the pressure in the system in heart failure. Atrial fibrillation stops the mechanical systole of the left atrium and decreases the intercommunicating pressure and pulmonary wedge pressure. It is possible that atrial fibrillation is a mechanism for protection from increasing end-diastolic pressure and pulmonary wedge pressure, and prevents the danger of pulmonary edema. This hypothesis may explain the relationship between heart failure and atrial fibrillation and their frequent association. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. 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.

  4. N-3 polyunsaturated fatty acid supplementation does not reduce vulnerability to atrial fibrillation in remodeling atria.

    PubMed

    Ramadeen, Andrew; Connelly, Kim A; Leong-Poi, Howard; Hu, Xudong; Fujii, Hiroko; Van Krieken, Richard; Laurent, Gabriel; Holub, Bruce J; Bazinet, Richard P; Dorian, Paul

    2012-07-01

    Prophylactic supplementation with omega-3 polyunsaturated fatty acids (PUFAs) reduce vulnerability to atrial fibrillation (AF). The effect of PUFAs given after cardiac injury has occurred is unknown. To investigate using a model of pacing-induced cardiac injury, the time course of development of injury and whether it was altered by postinjury PUFAs. Sixty-five dogs were randomized to undergo simultaneous atrial and ventricular pacing (SAVP, 220 beats/min) for 0, 2, 7, or 14 days. Twenty-two dogs received PUFAs (850 mg/d) either prophylactically or after some pacing had occurred (postinjury). Electrophysiologic and echocardiographic measurements were taken at baseline and sacrifice. Atrial tissue samples were collected at sacrifice for histologic and molecular analyses. With no PUFAs, the inducibility of AF increased with pacing duration (P < .001). Postinjury PUFAs (started after 7 days of pacing) did not reduce the inducibility of AF after 14 days of pacing (9.3% ± 8.8% no PUFAs vs 9.7% ± 9.9% postinjury PUFAs; P = .91). Atrial myocyte size and fibrosis increased with pacing duration (P < .05). Postinjury PUFAs did not significantly attenuate the cell size increase after 14 days of pacing (no PUFAs 38% ± 30% vs postinjury PUFAs 19% ± 28%; P = .11). Similarly, postinjury PUFAs did not attenuate the increase in fibrosis after 14 days of pacing (no PUFAs 66% ± 51% vs postinjury PUFAs 63% ± 76%; P = .90). PUFA supplementation begun after cardiac injury has already occurred does not reduce atrial structural remodeling or vulnerability to AF. Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  5. 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

  6. Atrial Septal Defect (For Kids)

    MedlinePlus

    ... wall called the septum that normally separates the blue and red blood. In a person with an atrial septal defect, there's an opening in that wall. This hole in the wall lets oxygen-rich blood from ...

  7. Cardiac myocyte exosomes: stability, HSP60, and proteomics.

    PubMed

    Malik, Z A; Kott, K S; Poe, A J; Kuo, T; Chen, L; Ferrara, K W; Knowlton, A A

    2013-04-01

    Exosomes, which are 50- to 100-nm-diameter lipid vesicles, have been implicated in intercellular communication, including transmitting malignancy, and as a way for viral particles to evade detection while spreading to new cells. Previously, we demonstrated that adult cardiac myocytes release heat shock protein (HSP)60 in exosomes. Extracellular HSP60, when not in exosomes, causes cardiac myocyte apoptosis via the activation of Toll-like receptor 4. Thus, release of HSP60 from exosomes would be damaging to the surrounding cardiac myocytes. We hypothesized that 1) pathological changes in the environment, such as fever, change in pH, or ethanol consumption, would increase exosome permeability; 2) different exosome inducers would result in different exosomal protein content; 3) ethanol at "physiological" concentrations would cause exosome release; and 4) ROS production is an underlying mechanism of increased exosome production. We found the following: first, exosomes retained their protein cargo under different physiological/pathological conditions, based on Western blot analyses. Second, mass spectrometry demonstrated that the protein content of cardiac exosomes differed significantly from other types of exosomes in the literature and contained cytosolic, sarcomeric, and mitochondrial proteins. Third, ethanol did not affect exosome stability but greatly increased the production of exosomes by cardiac myocytes. Fourth, ethanol- and hypoxia/reoxygenation-derived exosomes had different protein content. Finally, ROS inhibition reduced exosome production but did not completely inhibit it. In conclusion, exosomal protein content is influenced by the cell source and stimulus for exosome formation. ROS stimulate exosome production. The functions of exosomes remain to be fully elucidated.

  8. 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

  9. 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.

  10. Inhibition of the hyperpolarization-activated current (if) of rabbit SA node myocytes by niflumic acid.

    PubMed

    Accili, E A; DiFrancesco, D

    1996-03-01

    The effects of the amphiphilic substance niflumic acid (NFA) were examined in myocytes isolated from the sino-atrial node of the rabbit heart. NFA (50 and 500 microM), for 30-60 s, produced a reversible negative chronotropic effect by reducing the rate of diastolic depolarization, suggesting an inhibitory effect on the hyperpolarization-activated pacemaker current (if). NFA (from 0.05 to 500 microM) inhibited if by modifying the current kinetics, without alteration of the conductance. This was shown by evidence indicating that: (1) NFA inhibited if during hyperpolarizing pulses to the mid-point of if activation but not at fully activating voltages; (2) the slope and reversal potential of the fully activated current/voltage (I/V) relation were not altered by NFA, indicating no change in slope conductance or ion selectivity; and (3) hyperpolarizing ramp protocols confirmed the lack of action of 50 microM NFA on the fully activated current and a shift of approximately -8 mV. Although similar to inhibition by acetylcholine (ACh), inhibition by NFA was only partly additive with the action of ACh and was not altered by atropine or pertussis toxin, both of which eliminated the action of ACh. The effect of NFA was present after stimulation of adenylate cyclase by forskolin and after inhibition of phosphodiesterase by isobutylmethylxanthine (IBMX). In cell-attached patch measurements, NFA applied externally did not affect if measured in the patch. Finally, application of NFA to the cytoplasmic side of excised patches did not alter the current in the absence or presence of adenosine 3',5'-cyclic monophosphate (cAMP). These results suggest an external, membrane-delimited action of NFA on if.

  11. 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.

  12. Atrial fibrillation and anabolic steroids.

    PubMed

    Sullivan, M L; Martinez, C M; Gallagher, E J

    1999-01-01

    A young male bodybuilder, consuming large doses of anabolic steroids (AS), presented to the Emergency Department (ED) with symptomatic rapid atrial fibrillation (AF). Echocardiogram revealed significant septal hypokinesis, and posterior and septal wall thickness at the upper limit of normal for highly trained athletes. The atrial fibrillation had not recurred at 10 weeks after discontinuation of AS use. Consumption of these agents in athletes has been associated with hypertension, ischemic heart disease, hypertrophic cardiomyopathy, and sudden death.

  13. Neovascularization in Left Atrial Myxoma

    PubMed Central

    Dubey, Laxman; Chaurasia, Amit Kumar

    2012-01-01

    Abstract We report a case with a left atrial mass who underwent coronary angiography to rule out coronary artery disease. Coronary angiography revealed an anomalous tortuous vascular structure originating from the left circumflex coronary artery to the left atrial tumor suggestive of neovascularization. Preoperative coronary angiography is useful for coronary artery evaluation and also provides additional information regarding the feeding vessel supplying the mass. PMID:24757609

  14. [Vectorcardiographic manifestations of atrial enlargements].

    PubMed

    de Micheli, A; Medrano, G A

    1990-01-01

    Rational interpretation of changes of the P loop due to atrial enlargements must to rely on the magnitude and spatial orientation of main resultant vectors of the activation sequence of the atria. Under normal conditions, these vectors give rise to a mean vector oriented to the left downward and discretely forward with respect to their point of origin. In the presence of right atrial enlargement, the manifestation of the first vector of atrial depolarization, oriented downward and forward, is increased. This one moves in the same direction as the mean vector of atrial depolarization, originating an elongated P loop of more than 100 mcv in the three planes. Nevertheless, in the horizontal plane, increase of the P loop voltage predominates when hypertrophy exists, while augmentation of its area predominates when dilatation exists. In left atrial enlargement, the manifestation of the second vector of atrial depolarization, oriented to the left and backward, is augmented, and it moves in the same direction as the mean vector of atrial depolarization. For this, the PF loop acquires a characteristic aspect of a boxing glove, an the PH loop becomes diphasic, with its posterior area more or less prominent, or with a typical figure-eight conformation. If a biatrial enlargement is present, the manifestation of both the main resultant vectors of atrial depolarization is accentuated. Therefore the voltage of the diphasic P loop increases. Moreover the Ps loop has a triangular configuration, with its base of 30 msc or more, located below its point of origin. Generally disturbances of interatrial and intraatrial conduction coexist owing to myocardial damage.

  15. Idiopathic giant right atrial aneurysm

    PubMed Central

    Uppu, Santosh C; Sachdeva, Ritu; Imamura, Michiaki

    2013-01-01

    A 2-year-old boy with an incidental finding of massive cardiomegaly on a chest X-ray was diagnosed with a giant right atrial aneurysm upon further investigation with echocardiography. The patient underwent successful surgical reduction of the right atrium and closure of the patent foramen ovale to prevent thromboembolic complications and to lower the risk of atrial arrhythmias. The resected atrium had paper-thin walls and pathological features of interstitial fibrosis with endocardial thickening. PMID:23626440

  16. Is this atrial fibrillation?

    PubMed

    Jadidi, Amir S; Sunthorn, Henri; Burri, Haran; Gentil-Baron, Pascale; Shah, Dipen

    2009-01-01

    A 19-year-old girl was referred to our cardiology department for catheter ablation (isolation of the pulmonary veins) of paroxysmal atrial fibrillation (AF). The diagnosis was made upon a 12-lead ECG of the arrhythmia documented in the emergency room. The ECG showed an irregular tachycardia without wide QRS complexes. Careful assessment revealed the irregularity of the rhythm was a sweep artifact due to a mechanic failure of the ECG-machine to advance the article smoothly. During EP study a concealed anteroseptal accessory pathway causing an orthodromic AV reentrant tachycardia was eliminated by radio-frequency ablation. This example emphasizes the need for careful assessment of an ECG tracing, including printed legends and technical data.

  17. Comparison of Voltage Gated K(+) Currents in Arterial Myocytes with Heterologously Expressed K v Subunits.

    PubMed

    Cox, Robert H; Fromme, Samantha

    2016-12-01

    We have shown that three components contribute to functional voltage gated K(+) (K v) currents in rat small mesenteric artery myocytes: (1) Kv1.2 plus Kv1.5 with Kvβ1.2 subunits, (2) Kv2.1 probably associated with Kv9.3 subunits, and (3) Kv7.4 subunits. To confirm and address subunit stoichiometry of the first two, we have compared the biophysical properties of K v currents in small mesenteric artery myocytes with those of Kv subunits heterologously expressed in HEK293 cells using whole cell voltage clamp methods. Selective inhibitors of Kv1 (correolide, COR) and Kv2 (stromatoxin, ScTx) channels were used to separate these K v current components. Conductance-voltage and steady state inactivation data along with time constants of activation, inactivation, and deactivation of native K v components were generally well represented by those of Kv1.2-1.5-β1.2 and Kv2.1-9.3 channels. The slope of the steady state inactivation-voltage curve (availability slope) proved to be the most sensitive measure of accessory subunit presence. The availability slope curves exhibited a single peak for both native K v components. Availability slope curves for Kv1.2-1.5-β1.2 and Kv2.1-9.3 channels expressed in human embryonic kidney cells also exhibited a single peak that shifted to more depolarized voltages with increasing accessory to α subunit transfection ratio. Availability slope curves for SxTc-insensitive currents were similar to those of Kv1.2-1.5 expressed with Kvβ1.2 at a 1:5 molar ratio while curves for COR-insensitive currents closely resembled those of Kv2.1 expressed with Kv9.3 at a 1:1 molar ratio. These results support the suggested Kv subunit combinations in small mesenteric artery, and further suggest that Kv1 α and Kvβ1.2 but not Kv2.1 and Kv9.3 subunits are present in a saturated (4:4) stoichiometry.

  18. A unified theory of calcium alternans in ventricular myocytes

    NASA Astrophysics Data System (ADS)

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

    2016-10-01

    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.

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. 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

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

    PubMed Central

    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.

    2015-01-01

    We evaluated whether phospholemman (PLM) regulates L-type Ca2+ current (ICa) in mouse ventricular myocytes. Expression of α1-subunit of L-type Ca2+ 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 (τinact) of ICa was ~39% longer, but deactivation time constant (τdeact) was similar. In the presence of isoproterenol (1 µM), peak ICa was ~48% larger and τinact was ~144% higher in KO myocytes. With Ba2+ as the permeant ion, PLM enhanced voltage-dependent inactivation but had no effect on τdeact. To dissect the molecular determinants by which PLM regulated ICa, we expressed PLM mutants by adenovirus- mediated gene transfer in cultured KO myocytes. After 24 h in culture, KO myocytes expressing green fluorescent protein (GFP) had significantly larger peak ICa and longer τinact 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-phosphorylable 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 Ca2+ 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 Ca2+ influx in cardiac myocytes by reducing maximal ICa and accelerating voltage-dependent inactivation. PMID:25918050

  5. Effects of imipramine on the transient outward current in rabbit atrial single cells.

    PubMed Central

    Delpón, E.; Tamargo, J.; Sánchez-Chapula, J.

    1992-01-01

    1. The effects of imipramine on action potential characteristics and transient outward potassium current (It) of rabbit isolated atrial myocytes were studied using the whole-cell configuration of the patch-clamp technique. 2. Imipramine, 3 microM, decreased action potential amplitude and lengthened the action potential duration measured at 50% of repolarization, whereas it did not modify the final phase of repolarization or the resting membrane potential. These results are similar to those reported in multicellular rabbit atrial preparations. 3. Imipramine, 0.1-100 microM, induced a concentration-dependent inhibition of the peak amplitude of It, a shortening of the time to peak current and an increase in the inactivation rate. The acceleration of the current inactivation is to a major extent responsible for the decrease in the integral of the outward current measured at 50 ms after the start of the pulse. 4. The drug-induced block of It was not associated with changes in the voltage-dependence of the steady-state inactivation curve or in the process of recovery from inactivation of the current. Extrapolation to zero block shows that imipramine did not block It before its activation at the onset of the depolarization. These results suggested that imipramine does not affect the inactivated or the resting state of It channels. 5. It is concluded that in rabbit isolated atrial cells, imipramine inhibits It and that this effect is responsible for the lengthening of the action potential duration produced by this drug. PMID:1382783

  6. Effects of imipramine on the transient outward current in rabbit atrial single cells.

    PubMed

    Delpón, E; Tamargo, J; Sánchez-Chapula, J

    1992-06-01

    1. The effects of imipramine on action potential characteristics and transient outward potassium current (It) of rabbit isolated atrial myocytes were studied using the whole-cell configuration of the patch-clamp technique. 2. Imipramine, 3 microM, decreased action potential amplitude and lengthened the action potential duration measured at 50% of repolarization, whereas it did not modify the final phase of repolarization or the resting membrane potential. These results are similar to those reported in multicellular rabbit atrial preparations. 3. Imipramine, 0.1-100 microM, induced a concentration-dependent inhibition of the peak amplitude of It, a shortening of the time to peak current and an increase in the inactivation rate. The acceleration of the current inactivation is to a major extent responsible for the decrease in the integral of the outward current measured at 50 ms after the start of the pulse. 4. The drug-induced block of It was not associated with changes in the voltage-dependence of the steady-state inactivation curve or in the process of recovery from inactivation of the current. Extrapolation to zero block shows that imipramine did not block It before its activation at the onset of the depolarization. These results suggested that imipramine does not affect the inactivated or the resting state of It channels. 5. It is concluded that in rabbit isolated atrial cells, imipramine inhibits It and that this effect is responsible for the lengthening of the action potential duration produced by this drug.

  7. Non-pharmacological treatment of atrial fibrillation.

    PubMed

    Anfinsen, Ole-Gunnar

    2002-01-01

    In selected patients with atrial fibrillation and severe symptoms, non-pharmacological treatment may be an alternative or supplement to drug therapy. Atrioventricular nodal radiofrequency ablation (requires pacemaker implantation), or atrial pacing for sick sinus syndrome, are established treatment modalities. All other non-pharmacological therapies for atrial fibrillation are still experimental. After the Maze operation, atrial depolarization has to follow one specific path determined by surgical scars in the myocardium. This prevents new episodes of atrial fibrillation, but at a cost of perioperative morbidity and mortality. Catheter-based "Maze-like" radiofrequency ablation is technically difficult, and thrombo-embolic complications may occur. Paroxysmal atrial fibrillation sometimes is initiated by spontaneous depolarizations in a pulmonary vein inlet. Radio frequency ablation against such focal activity has been reported with high therapeutic success, but the results await confirmation from several centres. For ventricular rate control, most electrophysiologists presently prefer ablation to induce a complete atrioventricular conduction block (with pacemaker) rather than trying to modify conduction by incomplete block. Atrial or dual chamber pacing may prevent atrial fibrillation induced by bradycardia. It remains to confirm that biatrial or multisite right atrial pacing prevents atrial fibrillation more efficiently than ordinary right atrial pacing. An atrial defibrillator is able to diagnose and convert atrial fibrillation. The equipment is expensive, and therapy without sedation may be unpleasant beyond tolerability.

  8. Non-pharmacological Treatment of Atrial Fibrillation†

    PubMed Central

    Anfinsen, Ole-Gunnar

    2002-01-01

    In selected patients with atrial fibrillation and severe symptoms, non-pharmacological treatment may be an alternative or supplement to drug therapy. Atrioventricular nodal radiofrequency ablation (requires pacemaker implantation), or atrial pacing for sick sinus syndrome, are established treatment modalities. All other non-pharmacological therapies for atrial fibrillation are still experimental. After the Maze operation, atrial depolarization has to follow one specific path determined by surgical scars in the myocardium. This prevents new episodes of atrial fibrillation, but at a cost of perioperative morbidity and mortality. Catheter-based "Maze-like" radiofrequency ablation is technically difficult, and thrombo-embolic complications may occur. Paroxysmal atrial fibrillation sometimes is initiated by spontaneous depolarizations in a pulmonary vein inlet. Radio frequency ablation against such focal activity has been reported with high therapeutic success, but the results await confirmation from several centres. For ventricular rate control, most electrophysiologists presently prefer ablation to induce a complete atrioventricular conduction block (with pacemaker) rather than trying to modify conduction by incomplete block. Atrial or dual chamber pacing may prevent atrial fibrillation induced by bradycardia. It remains to confirm that biatrial or multisite right atrial pacing prevents atrial fibrillation more efficiently than ordinary right atrial pacing. An atrial defibrillator is able to diagnose and convert atrial fibrillation. The equipment is expensive, and therapy without sedation may be unpleasant beyond tolerability. PMID:17006572

  9. The impact of 6 weeks of atrial fibrillation on left atrial and ventricular structure and function

    PubMed Central

    Kazui, Toshinobu; Henn, Mathew C.; Watanabe, Yoshiyuki; Kovács, Sándor J.; Lawrance, Christopher P.; Greenberg, Jason W.; Moon, Marc; Schuessler, Richard B.; Damiano, Ralph J.

    2015-01-01

    Objective The impact of prolonged episodes of atrial fibrillation on atrial and ventricular function has been incompletely characterized. The purpose of this study was to investigate the influence of atrial fibrillation on left atrial and ventricular function in a rapid paced porcine model of atrial fibrillation. Methods A control group of pigs (group 1, n = 8) underwent left atrial and left ventricular conductance catheter studies and fibrosis analysis. A second group (group 2, n = 8) received a baseline cardiac magnetic resonance imaging to characterize left atrial and left ventricular function. The atria were rapidly paced into atrial fibrillation for 6 weeks followed by cardioversion and cardiac magnetic resonance imaging. Results After 6 weeks of atrial fibrillation, left atrial contractility defined by atrial end-systolic pressure-volume relationship slope was significantly lower in group 2 than in group 1 (1.1 ± 0.5 vs 1.7 ± 1.0; P = .041), whereas compliance from the end-diastolic pressure-volume relationship was unchanged (1.5 ± 0.9 vs 1.6 ± 1.3; P = .733). Compared with baseline, atrial fibrillation resulted in a significantly higher contribution of left atrial reservoir volume to stroke volume (32% vs 17%; P = .005) and lower left atrial booster pump volume contribution to stroke volume (19% vs 28%; P = .029). Atrial fibrillation also significantly increased maximum left atrial volume (206 ± 41 mL vs 90 ± 21 mL; P < .001). Left atrial fibrosis in group 2 was significantly higher than in group 1. Atrial fibrillation decreased left ventricular ejection fraction (29% ± 9% vs 58 ± 8%; P < .001), but left ventricular stroke volume was unchanged. Conclusions In a chronic model of atrial fibrillation, the left atrium demonstrated significant structural remodeling and decreased contractility. These data suggest that early intervention in patients with persistent atrial fibrillation might mitigate against adverse atrial and ventricular structural

  10. 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

  11. Sympathetic neurons are a powerful driver of myocyte function in cardiovascular disease

    PubMed Central

    Larsen, Hege E.; Lefkimmiatis, Konstantinos; Paterson, David J.

    2016-01-01

    Many therapeutic interventions in disease states of heightened cardiac sympathetic activity are targeted to the myocytes. However, emerging clinical data highlights a dominant role in disease progression by the neurons themselves. Here we describe a novel experimental model of the peripheral neuro-cardiac axis to study the neuron’s ability to drive a myocyte cAMP phenotype. We employed a co-culture of neonatal ventricular myocytes and sympathetic stellate neurons from normal (WKY) and pro-hypertensive (SHR) rats that are sympathetically hyper-responsive and measured nicotine evoked cAMP responses in the myocytes using a fourth generation FRET cAMP sensor. We demonstrated the dominant role of neurons in driving the myocyte ß-adrenergic phenotype, where SHR cultures elicited heightened myocyte cAMP responses during neural activation. Moreover, cross-culturing healthy neurons onto diseased myocytes rescued the diseased cAMP response of the myocyte. Conversely, healthy myocytes developed a diseased cAMP response if diseased neurons were introduced. Our results provide evidence for a dominant role played by the neuron in driving the adrenergic phenotype seen in cardiovascular disease. We also highlight the potential of using healthy neurons to turn down the gain of neurotransmission, akin to a smart pre-synaptic ß-blocker. PMID:27966588

  12. Right atrial tunnel to the left atrial appendage: a danger during balloon septostomy.

    PubMed

    Waldman, J D; McFeeley, P; Bornikova, L

    2001-01-01

    Right atrial tunnel to the left atrial appendage is a very rare anomaly not previously described. Per se, it has no physiological significance but is a source of potential disaster during balloon atrial septostomy. The precise anatomy is demonstrated and ways are proposed to avoid tearing the atrial wall during therapeutic cardiac catheterization.

  13. Eleclazine, a new selective cardiac late sodium current inhibitor, confers concurrent protection against autonomically induced atrial premature beats, repolarization alternans and heterogeneity, and atrial fibrillation in an intact porcine model.

    PubMed

    Fuller, Henrique; Justo, Fernanda; Nearing, Bruce D; Kahlig, Kristopher M; Rajamani, Sridharan; Belardinelli, Luiz; Verrier, Richard L

    2016-08-01

    The cardiac late sodium current (INa) has been increasingly implicated in the initiation of atrial fibrillation (AF). Eleclazine (formerly known as GS-6615) is a new selective late INa inhibitor and is undergoing clinical testing for the treatment of cardiac arrhythmias. We tested whether late INa inhibition by eleclazine confers protection against atrial premature beats (APBs) and AF. In closed-chest anesthetized Yorkshire pigs, epinephrine (2.0 µg/kg, intravenous, bolus over 1 minute) was administered alone to induce APBs (n = 6) or in combination with intrapericardial acetylcholine (0.5-4 mL of 12.5 mM solution) to induce spontaneous AF (n = 11). Effects of eleclazine (0.3 and 0.9 mg/kg, intravenous, over 15 minutes) on APBs and AF were determined. Epinephrine-induced APBs were reduced >3-fold (P < .04) after eleclazine (0.9 mg/kg) infusion. The combined administration of epinephrine and acetylcholine resulted in AF in all animals tested, which was invariably preceded by APBs. Eleclazine pretreatment suppressed AF in all 7 animals in at least 1 test episode during the 60- to 150-minute observation period (P = .04). The plasma eleclazine level at 120 minutes was 828 ± 45.8 nM, within exposure range evaluated clinically. Eleclazine shortened ventricular QT and atrial PTa intervals by 7% (P < .001 for both) and reduced atrial repolarization alternans (P = .003) and heterogeneity (P = .021) without attenuation of the inotropic response to catecholamine (P = .56). The drug inhibited the enhanced late INa of single atrial myocytes with a potency of 736 ± 67 nM. Selective cardiac late INa inhibition with eleclazine suppresses autonomically mediated atrial repolarization alternans and heterogeneity, APBs, and AF in an intact porcine model. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  14. Late atypical atrial flutter after ablation of atrial fibrillation.

    PubMed

    Ferreira, Raquel; Primo, João; Adão, Luís; Gonzaga, Anabela; Gonçalves, Helena; Santos, Rui; Fonseca, Paulo; Santos, José; Gama, Vasco

    2016-10-01

    Cardiac surgery for structural heart disease (often involving the left atrium) and radiofrequency catheter ablation of atrial fibrillation have led to an increased incidence of regular atrial tachycardias, often presenting as atypical flutters. This type of flutter is particularly common after pulmonary vein isolation, especially after extensive atrial ablation including linear lesions and/or defragmentation. The authors describe the case of a 51-year-old man, with no relevant medical history, referred for a cardiology consultation in 2009 for paroxysmal atrial fibrillation. After failure of antiarrhythmic therapy, he underwent catheter ablation, with criteria of acute success. Three years later he again suffered palpitations and atypical atrial flutter was documented. The electrophysiology study confirmed the diagnosis of atypical left flutter and reappearance of electrical activity in the right inferior pulmonary vein. This vein was again ablated successfully and there has been no arrhythmia recurrence to date. In an era of frequent catheter ablation it is essential to understand the mechanism of this arrhythmia and to recognize such atypical flutters. Copyright © 2016 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

  15. Adrenergic regulation of a key cardiac potassium channel can contribute to atrial fibrillation: evidence from an IKs transgenic mouse

    PubMed Central

    Sampson, Kevin J; Terrenoire, Cecile; Cervantes, Daniel O; Kaba, Riyaz A; Peters, Nicholas S; Kass, Robert S

    2008-01-01

    Inherited gain-of-function mutations of genes coding for subunits of the heart slow potassium (IKs) channel can cause familial atrial fibrillation (AF). Here we consider a potentially more prevalent mechanism and hypothesize that β-adrenergic receptor (β-AR)-mediated regulation of the IKs channel, a natural gain-of-function pathway, can also lead to AF. Using a transgenic IKs channel mouse model, we studied the role of the channel and its regulation by β-AR stimulation on atrial arrhythmias. In vivo administration of isoprenaline (isoproterenol) predisposes IKs channel transgenic mice but not wild-type (WT) littermates that lack IKs to prolonged atrial arrhythmias. Patch-clamp analysis demonstrated expression and isoprenaline-mediated regulation of IKs in atrial myocytes from transgenic but not WT littermates. Furthermore, computational modelling revealed that β-AR stimulation-dependent accumulation of open IKs channels accounts for the pro-arrhythmic substrate. Our results provide evidence that β-AR-regulated IKs channels can play a role in AF and imply that specific IKs deregulation, perhaps through disruption of the IKs macromolecular complex necessary for β-AR-mediated IKs channel regulation, may be a novel therapeutic strategy for treating this most common arrhythmia. PMID:18006587

  16. Atrial fibrillation in endurance athletes.

    PubMed

    Wilhelm, Matthias

    2014-08-01

    There is a growing population of veteran endurance athletes, regularly participating in training and competition. Although the graded benefit of exercise on cardiovascular health and mortality is well established, recent studies have raised concern that prolonged and strenuous endurance exercise may predispose to atrial and ventricular arrhythmias. Atrial fibrillation (AF) and atrial flutter are facilitated by atrial remodelling, atrial ectopy, and an imbalance of the autonomic nervous system. Endurance sports practice has an impact on all of these factors and may therefore act as a promoter of these arrhythmias. In an animal model, long-term intensive exercise training induced fibrosis in both atria and increased susceptibility to AF. While the prevalence of AF is low in young competitive athletes, it increases substantially in the aging athlete, which is possibly associated with an accumulation of lifetime training hours and participation in competitions. A recent meta-analysis revealed a 5-fold increased risk of AF in middle-aged endurance athletes with a striking male predominance. Beside physical activity, height and absolute left atrial size are independent risk factors for lone AF and the stature of men per se may explain part of their higher risk of AF. Furthermore, for a comparable amount of training volume and performance, male non-elite athletes exhibit a higher blood pressure at rest and peak exercise, a more concentric type of left ventricular remodelling, and an altered diastolic function, possibly contributing to a more pronounced atrial remodelling. The sports cardiologist should be aware of the distinctive features of AF in athletes. Therapeutic recommendations should be given in close cooperation with an electrophysiologist. Reduction of training volume is often not desired and drug therapy not well tolerated. An early ablation strategy may be appropriate for some athletes with an impaired physical performance, especially when continuation of

  17. Surgical Ablation of Atrial Fibrillation.

    PubMed

    Ramlawi, Basel; Abu Saleh, Walid K

    2015-01-01

    The Cox-maze procedure for the restoration of normal sinus rhythm, initially developed by Dr. James Cox, underwent several iterations over the years. The main concept consists of creating a series of transmural lesions in the right and left atria that disrupt re-entrant circuits responsible for propagating the abnormal atrial fibrillation rhythm. The left atrial appendage is excluded as a component of the Maze procedure. For the first three iterations of the Cox- maze procedure, these lesions were performed using a surgical cut-and-sew approach that ensured transmurality. The Cox-Maze IV is the most currently accepted iteration. It achieves the same lesion set of the Cox- maze III but uses alternative energy sources to create the transmural lesions, potentially in a minimally invasive approach on the beating heart. High-frequency ultrasound, microwave, and laser energy have all been used with varying success in the past. Today, bipolar radiofrequency heat or cryotherapy cooling are the most accepted sources for creating linear lesions with consistent safety and transmurality. The robust and reliable nature of these energy delivery methods has yielded a success rate reaching 90% freedom from atrial fibrillation at 12 months. Such approaches offer a significant long-term advantage over catheter-based ablation, especially in patients having longstanding, persistent atrial fibrillation with characteristics such as dilated left atrial dimensions, poor ejection fraction, and failed catheter ablation. Based on these improved results, there currently is significant interest in developing a hybrid ablation strategy that incorporates the superior transmural robust lesions of surgical ablation, the reliable stroke prevention potential of epicardial left atrial appendage exclusion, and sophisticated mapping and confirmatory catheter-based ablation technology. Such a minimally invasive hybrid strategy for ablation may lead to the development of multidisciplinary "Afib teams" to

  18. Who Is at Risk for Atrial Fibrillation?

    MedlinePlus

    ... JavaScript on. Feature: Atrial Fibrillation Who Is at Risk for Atrial Fibrillation? Past Issues / Winter 2015 Table ... than 75. AFib is uncommon in children. Major Risk Factors AFib is more common in people who ...

  19. Isolated Atrial Amyloidosis in Patients with Various Types of Atrial Fibrillation.

    PubMed

    Sukhacheva, T V; Eremeeva, M V; Ibragimova, A G; Vaskovskii, V A; Serov, R A; Revishvili, A Sh

    2016-04-01

    The myocardium of the right and left atrial appendages (auricles) in patients with paroxysmal, persistent, and permanent forms of atrial fibrillation was examined by histological methods and electron microscopy. Isolated atrial amyloidosis was detected in the left (50.0-56.3% patients) and in the right (45.0-55.6% patients) atrial appendages. In all cases, immunohistochemistry revealed atrial natriuretic peptide in fibrillary amyloid deposits. Ultrastructurally, amyloid masses formed clusters of myofibrils 8-10 nm in diameter. They were chaotically located in the extracellular space along the sarcolemma as well as in membrane invaginations, dilated tubules of cardiomyocyte T-tubular system, and vascular walls. Amyloidosis was predominantly observed in women; its degree positively correlated with age of patients and duration of atrial fibrillation but negatively correlated with atrial fibrosis. The study revealed positive (in permanent atrial fibrillation) and negative (in paroxysmal atrial fibrillation) correlation of amyloidosis with myofibril content in atrial cardiomyocytes.

  20. R4496C RyR2 mutation impairs atrial and ventricular contractility

    PubMed Central

    Coppini, Raffaele; Scellini, Beatrice; Ferrara, Claudia; Pioner, Josè Manuel; Mazzoni, Luca; Priori, Silvia; Cerbai, Elisabetta; Tesi, Chiara; Poggesi, Corrado

    2016-01-01

    Ryanodine receptor (RyR2) is the major Ca2+ channel of the cardiac sarcoplasmic reticulum (SR) and plays a crucial role in the generation of myocardial force. Changes in RyR2 gating properties and resulting increases in its open probability (Po) are associated with Ca2+ leakage from the SR and arrhythmias; however, the effects of RyR2 dysfunction on myocardial contractility are unknown. Here, we investigated the possibility that a RyR2 mutation associated with catecholaminergic polymorphic ventricular tachycardia, R4496C, affects the contractile function of atrial and ventricular myocardium. We measured isometric twitch tension in left ventricular and atrial trabeculae from wild-type mice and heterozygous transgenic mice carrying the R4496C RyR2 mutation and found that twitch force was comparable under baseline conditions (30°C, 2 mM [Ca2+]o, 1 Hz). However, the positive inotropic responses to high stimulation frequency, 0.1 µM isoproterenol, and 5 mM [Ca2+]o were decreased in R4496C trabeculae, as was post-rest potentiation. We investigated the mechanisms underlying inotropic insufficiency in R4496C muscles in single ventricular myocytes. Under baseline conditions, the amplitude of the Ca2+ transient was normal, despite the reduced SR Ca2+ content. Under inotropic challenge, however, R4496C myocytes were unable to boost the amplitude of Ca2+ transients because they are incapable of properly increasing the amount of Ca2+ stored in the SR because of a larger SR Ca2+ leakage. Recovery of force in response to premature stimuli was faster in R4496C myocardium, despite the unchanged rates of recovery of L-type Ca2+ channel current (ICa-L) and SR Ca2+ content in single myocytes. A faster recovery from inactivation of the mutant R4496C channels could explain this behavior. In conclusion, changes in RyR2 channel gating associated with the R4496C mutation could be directly responsible for the alterations in both ventricular and atrial contractility. The increased RyR2 Po

  1. Post-Acceleration Chaotic Atrial Rhythm

    DTIC Science & Technology

    1982-04-01

    atrial flutter or two discrete P-wave morphologies with the rate less fibrillation. than 100 bpm). and sinus bradycardia. An occasional The time...mulhilocal paroxysmal atrial tach.- cardia with cclic Wcnckchach phenomenon under observation examinations. The chaotic atrial rhythm in this case ji r 13...CHAOTIC ATRIAL RHYTHM Final Report 1 July 81 - 30 July 81 6. PERFORMING OIG. REPORT NUMBER 7. AUTHOR(s) 8 CONTRACT OR GRANT NUMBERS) r James E

  2. Atrial Myxoma: A Case Presentation and Review

    PubMed Central

    Cohen, Ronny; Singh, Gagandeep; Mena, Derrick; Garcia, Christine A.; Loarte, Pablo; Mirrer, Brooks

    2012-01-01

    Myxomas are the most common primary cardiac tumors, most frequently found in the left atrium. We present a case of an atrial myxoma. An in-depth review of atrial myxoma is presented, examining the important clinical symptoms and diagnostic indicators. The treatment of atrial myxoma is then discussed, with an emphasis on current therapies. An extensive literature review has been performed to present a comprehensive review of the causes, pathophysiology of atrial myxoma.

  3. Increased amount of atrial fibrosis in patients with atrial fibrillation secondary to mitral valve disease.

    PubMed

    Geuzebroek, Guillaume S C; van Amersfoorth, Shirley C M; Hoogendijk, Mark G; Kelder, Johannes C; van Hemel, Norbert M; de Bakker, Jacques M T; Coronel, Ruben

    2012-08-01

    Atrial fibrosis is related to atrial fibrillation but may differ in patients with mitral valve disease or lone atrial fibrillation. Therefore, we studied atrial fibrosis in patients with atrial fibrillation+mitral valve disease or with lone atrial fibrillation and compared it with controls. Left and right atrial appendages amputated during Maze III surgery for lone atrial fibrillation (n=85) or atrial fibrillation+mitral valve disease (n=26) were embedded in paraffin, sectioned, and stained with picrosirius red. Atria from 10 deceased patients without a cardiovascular history served as controls. A total of 1048 images (4-μm sections, 10-fold magnification, 4 images per appendage) were obtained and digitized. The percentage of fibrous tissue was calculated by quantitative morphometry. Irrespective of the presence or absence of atrial fibrillation or mitral valve disease, more fibrous tissue was present in right atrial appendages than in left atrial appendages (12.7%±5.7% vs 8.2%±3.9%; P<.0001). The mean amount of fibrous tissue in the atria was significantly larger in patients with atrial fibrillation+mitral valve disease than in patients with lone AF and controls (13.6%±5.8%, 9.7%±3.2%, and 8.8%±2.4%, respectively; P<.01). No significant differences existed between patients with lone atrial fibrillation and patients without a cardiovascular history (controls). Atria of patients with atrial fibrillation and mitral valve disease have more fibrosis than atria of patients with lone atrial fibrillation. However, patients with lone atrial fibrillation have an equal amount of atrial fibrosis compared with controls. These findings support the notion that fibrosis plays a more important role in the pathogenesis of atrial fibrillation secondary to mitral valve disease than in lone atrial fibrillation and potentially explains the relatively poor success of antiarrhythmic surgery in patients with mitral valve disease. Copyright © 2012 The American Association for

  4. Silent Atrial Fibrillation and Cryptogenic Strokes.

    PubMed

    Dalen, James E; Alpert, Joseph S

    2017-03-01

    A new suspected cause of cryptic strokes is "silent atrial fibrillation." Pacemakers and other implanted devices allow continuous recording of cardiac rhythm for months or years. They have discovered that short periods of atrial fibrillation lasting minutes or hours are frequent and usually are asymptomatic. A meta-analysis of 50 studies involving more than 10,000 patients with a recent stroke found that 7.7% had new atrial fibrillation on their admitting electrocardiogram. In 3 weeks during and after hospitalization, another 16.9% were diagnosed. A total of 23.7% of these stroke patients had silent atrial fibrillation; that is, atrial fibrillation diagnosed after hospital admission. Silent atrial fibrillation is also frequent in patients with pacemakers who do not have a recent stroke. In a pooled analysis of 3 studies involving more than 10,000 patients monitored for 24 months, 43% had at least 1 day with atrial fibrillation lasting more than 5 minutes. Ten percent had atrial fibrillation lasting at least 12 hours. Despite the frequency of silent atrial fibrillation in these patients with multiple risk factors for stroke, the annual incidence of stroke was only 0.23%. When silent atrial fibrillation is detected in patients with recent cryptogenic stroke, anticoagulation is indicated. In patients without stroke, silent atrial fibrillation should lead to further monitoring for clinical atrial fibrillation rather than immediate anticoagulation, as some have advocated.

  5. Rem-GTPase regulates cardiac myocyte L-type calcium current

    PubMed Central

    Magyar, Janos; Kiper, Carmen E.; Sievert, Gail; Cai, Weikang; Shi, Geng-Xian; Crump, Shawn M.; Li, Liren; Niederer, Steven; Smith, Nic; Andres, Douglas A.; Satin, Jonathan

    2012-01-01

    Rationale: The L-type calcium channels (LTCC) are critical for maintaining Ca2+-homeostasis. In heterologous expression studies, the RGK-class of Ras-related G-proteins regulates LTCC function; however, the physiological relevance of RGK–LTCC interactions is untested. Objective: In this report we test the hypothesis that the RGK protein, Rem, modulates native Ca2+ current (ICa,L) via LTCC in murine cardiomyocytes. Methods and Results: Rem knockout mice (Rem−/−) were engineered, and ICa,L and Ca2+-handling properties were assessed. Rem−/− ventricular cardiomyocytes displayed increased ICa,L density. ICa,L activation was shifted positive on the voltage axis, and β-adrenergic stimulation normalized this shift compared with wild-type ICa,L. Current kinetics, steady-state inactivation, and facilitation was unaffected by Rem−/−. Cell shortening was not significantly different. Increased ICa,L density in the absence of frank phenotypic differences motivated us to explore putative compensatory mechanisms. Despite the larger ICa,L density, Rem−/− cardiomyocyte Ca2+ twitch transient amplitude was significantly less than that compared with wild type. Computer simulations and immunoblot analysis suggests that relative dephosphorylation of Rem−/− LTCC can account for the paradoxical decrease of Ca2+ transients. Conclusions: This is the first demonstration that loss of an RGK protein influences ICa,L in vivo in cardiac myocytes. PMID:22854599

  6. Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy.

    PubMed

    Zhou, Jibin; Ahmad, Firdos; Parikh, Shan; Hoffman, Nichole E; Rajan, Sudarsan; Verma, Vipin K; Song, Jianliang; Yuan, Ancai; Shanmughapriya, Santhanam; Guo, Yuanjun; Gao, Erhe; Koch, Walter; Woodgett, James R; Madesh, Muniswamy; Kishore, Raj; Lal, Hind; Force, Thomas

    2016-04-15

    Cardiac myocyte-specific deletion of either glycogen synthase kinase (GSK)-3α and GSK-3β leads to cardiac protection after myocardial infarction, suggesting that deletion of both isoforms may provide synergistic protection. This is an important consideration because of the fact that all GSK-3-targeted drugs, including the drugs already in clinical trial target both isoforms of GSK-3, and none are isoform specific. To identify the consequences of combined deletion of cardiac myocyte GSK-3α and GSK-3β in heart function. We generated tamoxifen-inducible cardiac myocyte-specific mice lacking both GSK-3 isoforms (double knockout). We unexpectedly found that cardiac myocyte GSK-3 is essential for cardiac homeostasis and overall survival. Serial echocardiographic analysis reveals that within 2 weeks of tamoxifen treatment, double-knockout hearts leads to excessive dilatative remodeling and ventricular dysfunction. Further experimentation with isolated adult cardiac myocytes and fibroblasts from double-knockout implicated cardiac myocytes intrinsic factors responsible for observed phenotype. Mechanistically, loss of GSK-3 in adult cardiac myocytes resulted in induction of mitotic catastrophe, a previously unreported event in cardiac myocytes. Double-knockout cardiac myocytes showed cell cycle progression resulting in increased DNA content and multinucleation. However, increased cell cycle activity was rivaled by marked activation of DNA damage, cell cycle checkpoint activation, and mitotic catastrophe-induced apoptotic cell death. Importantly, mitotic catastrophe was also confirmed in isolated adult cardiac myocytes. Together, our findings suggest that cardiac myocyte GSK-3 is required to maintain normal cardiac homeostasis, and its loss is incompatible with life because of cell cycle dysregulation that ultimately results in a severe fatal dilated cardiomyopathy. © 2016 American Heart Association, Inc.

  7. Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy

    PubMed Central

    Zhou, Jibin; Ahmad, Firdos; Parikh, Shan; Hoffman, Nichole E.; Rajan, Sudarsan; Verma, Vipin K.; Song, Jianliang; Yuan, Ancai; Shanmughapriya, Santhanam; Guo, Yuanjun; Gao, Erhe; Koch, Walter; Woodgett, James R.; Muniswamy, Madesh; Kishore, Raj; Lal, Hind; Force, Thomas

    2016-01-01

    Rationale Cardiac myocyte-specific deletion of either Glycogen Synthase Kinase (GSK)3A or GSK3B leads to cardiac protection following myocardial infarction, suggesting that deletion of both isoforms may provide synergistic protection. This is an important consideration due to the fact that all GSK-3–targeted drugs including the drugs already in clinical trial target both isoforms of GSK-3 and none are isoform specific. Objective To identify the consequences of combined deletion of cardiac myocyte GSK3A and GSK3B in heart function. Methods and Results We generated tamoxifen-inducible cardiac myocyte-specific mice lacking both GSK-3 isoforms (double knockout, DKO). We unexpectedly found that cardiac myocyte GSK-3 is essential for cardiac homeostasis and overall survival. Serial echocardiographic analysis reveals that within 2 weeks of tamoxifen treatment, DKO hearts leads to excessive dilatative remodeling and ventricular dysfunction. Further experimentation with isolated adult cardiac myocytes and fibroblasts from DKO implicated cardiac myocytes intrinsic factors responsible for observed phenotype. Mechanistically, loss of GSK-3 in adult cardiac myocytes resulted in induction of mitotic catastrophe, a previously unreported event in cardiac myocytes. DKO cardiac myocytes showed cell cycle progression resulting in increased DNA content and multi-nucleation. However, increased cell cycle activity was rivaled by marked activation of DNA damage, cell cycle checkpoint activation, and mitotic catastrophe induced apoptotic cell death. Importantly, mitotic catastrophe was also confirmed in isolated adult cardiac myocytes. Conclusion Together, our findings suggest that cardiac myocyte GSK-3 is required to maintain normal cardiac homeostasis and its loss is incompatible with life due to cell cycle dysregulation that ultimately results in a severe fatal dilated cardiomyopathy. PMID:26976650

  8. Myomaker is required for the fusion of fast-twitch myocytes in the zebrafish embryo.

    PubMed

    Zhang, Weibin; Roy, Sudipto

    2017-03-01

    During skeletal muscle development, myocytes aggregate and fuse to form multinucleated muscle fibers. Inhibition of myocyte fusion is thought to significantly derail the differentiation of functional muscle fibers. Despite the purported importance of fusion in myogenesis, in vivo studies of this process in vertebrates are rather limited. Myomaker, a multipass transmembrane protein, has been shown to be the first muscle-specific fusion protein essential for myocyte fusion in the mouse. We have generated loss-of-function alleles in zebrafish myomaker, and found that fusion of myocytes into syncytial fast-twitch muscles was significantly compromised. However, mutant myocytes could be recruited to fuse with wild-type myocytes in chimeric embryos, albeit rather inefficiently. Conversely, overexpression of Myomaker was sufficient to induce hyperfusion among fast-twitch myocytes, and it also induced fusion among slow-twitch myocytes that are normally fusion-incompetent. In line with this, Myomaker overexpression also triggered fusion in another myocyte fusion mutant compromised in the function of the junctional cell adhesion molecule, Jam2a. We also provide evidence that Rac, a regulator of actin cytoskeleton, requires Myomaker activity to induce fusion, and that an approximately 3kb of myomaker promoter sequence, with multiple E-box motifs, is sufficient to direct expression within the fast-twitch muscle lineage. Taken together, our findings underscore a conserved role for Myomaker in vertebrate myocyte fusion. Strikingly, and in contrast to the mouse, homozygous myomaker mutants are viable and do not exhibit discernible locomotory defects. Thus, in the zebrafish, myocyte fusion is not an absolute requirement for skeletal muscle morphogenesis and function.

  9. 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.

  10. Transformation of adult rat cardiac myocytes in primary culture.

    PubMed

    Banyasz, Tamas; Lozinskiy, Ilya; Payne, Charles E; Edelmann, Stephanie; Norton, Byron; Chen, Biyi; Chen-Izu, Ye; Izu, Leighton T; Balke, C William

    2008-03-01

    We characterized the morphological, electrical and mechanical alterations of cardiomyocytes in long-term cell culture. Morphometric parameters, sarcomere length, T-tubule density, cell capacitance, L-type calcium current (I(Ca,L)), inward rectifier potassium current (I(K1)), cytosolic calcium transients, action potential and contractile parameters of adult rat ventricular myocytes were determined on each day of 5 days in culture. We also analysed the health of the myocytes using an apoptotic/necrotic viability assay. The data show that myocytes undergo profound morphological and functional changes during culture. We observed a progressive reduction in the cell area (from 2502 +/- 70 microm(2) on day 0 to 1432 +/- 50 microm(2) on day 5), T-tubule density, systolic shortening (from 0.11 +/- 0.02 to 0.05 +/- 0.01 microm) and amplitude of calcium transients (from 1.54 +/- 0.19 to 0.67 +/- 0.19) over 5 days of culture. The negative force-frequency relationship, characteristic of rat myocardium, was maintained during the first 2 days but diminished thereafter. Cell capacitance (from 156 +/- 8 to 105 +/- 11 pF) and membrane currents were also reduced (I(Ca,L), from 3.98 +/- 0.39 to 2.12 +/- 0.37 pA pF; and I(K1), from 34.34p +/- 2.31 to 18.00 +/- 5.97 pA pF(-1)). We observed progressive depolarization of the resting membrane potential during culture (from 77.3 +/- 2.5 to 34.2 +/- 5.9 mV) and, consequently, action potential morphology was profoundly altered as well. The results of the viability assays indicate that these alterations could not be attributed to either apoptosis or necrosis but are rather an adaptation to the culture conditions over time.

  11. 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

  12. [Atrial fibrillation in Graves' disease].

    PubMed

    Kunii, Yo

    2013-01-01

    Heart is easy to be affected by the abnormal thyroid function because cardiac muscle cells have many thyroid hormone receptors. In addition, thyroid hormone goes higher sensitivity to sympathetic nerve as it increases the number of myocardial beta receptor. Therefore, when the thyroid hormone is excessive value, tachycardia and atrial fibrillation may occur regardless of the cause. The atrial fibrillation in Graves' disease can expect spontaneous reversion to sinus rhythm when the hyperthyroidism is controlled. However, cardioversion is indicated for patients who have not returned to sinus rhythm for at least 3 months after the hyperthyroidism is controlled. In this paper, we report the relationship between hyperthyroidism and heart, and the treatment of atrial fibrillation in Graves' disease.

  13. Isolation of cardiac myocytes and fibroblasts from neonatal rat pups.

    PubMed

    Golden, Honey B; Gollapudi, Deepika; Gerilechaogetu, Fnu; Li, Jieli; Cristales, Ricardo J; Peng, Xu; Dostal, David E

    2012-01-01

    Neonatal rat ventricular myocytes (NRVM) and fibroblasts (FBs) serve as in vitro models for studying fundamental mechanisms underlying cardiac pathologies, as well as identifying potential therapeutic targets. Both cell types are relatively easy to culture as monolayers and can be manipulated using molecular and pharmacological tools. Because NRVM cease to proliferate after birth, and FBs undergo phenotypic changes and senescence after a few passages in tissue culture, primary cultures of both cell types are required for experiments. Below we describe methods that provide good cell yield and viability of primary cultures of NRVM and FBs from 0 to 3-day-old neonatal rat pups.

  14. Metabolic coupling of glutathione between mouse and quail cardiac myocytes and its protective role against oxidative stress.

    PubMed

    Nakamura, T Y; Yamamoto, I; Kanno, Y; Shiba, Y; Goshima, K

    1994-05-01

    Cultured quail myocytes were much more resistant to H2O2 toxicity than cultured mouse myocytes. The intracellular concentration of glutathione ([GSH]i) and the activity of gamma-glutamylcysteine synthetase (gamma-GCS) in quail heart cells were about five and three times higher, respectively, than in mouse heart cells, although catalase and glutathione peroxidase (GSHpx) activity was similar in both. Preloading of gamma-glutamylcysteine monoethyl ester (gamma-GCE), a membrane-permeating GSH precursor, increased the H2O2 resistance of cultured mouse myocytes. These observations suggest that the high [GSH]i and the high activity of gamma-GCS in quail myocytes are responsible for their high resistance to H2O2. Both H2O2 sensitivity and [GSH]i of mosaic sheets composed of equal amounts of mouse and quail myocytes approximated those of sheets composed entirely of quail myocytes. From these observations, it is hypothesized that GSH was transferred from quail myocytes to mouse myocytes, probably through gap junctions between them, and that quail myocytes resynthesized GSH by a feedback mechanism, thus maintaining their intracellular GSH levels. When the fluorescent dye lucifer yellow was injected into a beating quail myocyte in a mosaic sheet, it spread to neighboring mouse myocytes but not to neighboring L cells (a cell line derived from mouse connective tissue). These observations indicate that existence of gap junctions in the region of cell contact between mouse and quail myocytes but not between quail myocytes and L cells. When quail myocytes preloaded with [3H]gamma-GCE were cocultured with mouse myocytes and L cells, the radioactivity was transmitted to neighboring mouse myocytes but not L cells. These observations show that GSH and/or its precursors can be transmitted from quail myocytes to mouse myocytes through gap junctions and that this can protect mouse myocytes from H2O2 toxicity. Mouse myocyte sheets composed of 10(4) cells or more showed higher resistance

  15. Abrogation of Nrf2 impairs antioxidant signaling and promotes atrial hypertrophy in response to high-intensity exercise stress.

    PubMed

    Kumar, Radhakrishnan Rajesh; Narasimhan, Madhusudhanan; Shanmugam, Gobinath; Hong, Jennifer; Devarajan, Asokan; Palaniappan, Sethu; Zhang, Jianhua; Halade, Ganesh V; Darley-Usmar, Victor M; Hoidal, John R; Rajasekaran, Namakkal S

    2016-04-05

    Anomalies in myocardial structure involving myocyte growth, hypertrophy, differentiation, apoptosis, necrosis etc. affects its function and render cardiac tissue more vulnerable to the development of heart failure. Although oxidative stress has a well-established role in cardiac remodeling and dysfunction, the mechanisms linking redox state to atrial cardiomyocyte hypertrophic changes are poorly understood. Here, we investigated the role of nuclear erythroid-2 like factor-2 (Nrf2), a central transcriptional mediator, in redox signaling under high intensity exercise stress (HIES) in atria. Age and sex-matched wild-type (WT) and Nrf2(-/-) mice at >20 months of age were subjected to HIES for 6 weeks. Gene markers of hypertrophy and antioxidant enzymes were determined in the atria of WT and Nrf2(-/-) mice by real-time qPCR analyses. Detection and quantification of antioxidants, 4-hydroxy-nonenal (4-HNE), poly-ubiquitination and autophagy proteins in WT and Nrf2(-/-) mice were performed by immunofluorescence analysis. The level of oxidative stress was measured by microscopical examination of di-hydro-ethidium (DHE) fluorescence. Under the sedentary state, Nrf2 abrogation resulted in a moderate down regulation of some of the atrial antioxidant gene expression (Gsr, Gclc, Gstα and Gstµ) despite having a normal redox state. In response to HIES, enlarged atrial myocytes along with significantly increased gene expression of cardiomyocyte hypertrophy markers (Anf, Bnf and β-Mhc) were observed in Nrf2(-/-) when compared to WT mice. Further, the transcript levels of Gclc, Gsr and Gstµ and protein levels of NQO1, catalase, GPX1 were profoundly downregulated along with GSH depletion and increased oxidative stress in Nrf2(-/-) mice when compared to its WT counterparts after HIES. Impaired antioxidant state and profound oxidative stress were associated with enhanced atrial expression of LC3 and ATG7 along with increased ubiquitination of ATG7 in Nrf2(-/-) mice subjected to HIES

  16. Age-related attenuation of isoflurane preconditioning in human atrial cardiomyocytes: roles for mitochondrial respiration and sarcolemmal adenosine triphosphate-sensitive potassium channel activity.

    PubMed

    Mio, Yasushi; Bienengraeber, Martin W; Marinovic, Jasna; Gutterman, David D; Rakic, Mladen; Bosnjak, Zeljko J; Stadnicka, Anna

    2008-04-01

    Clinical trials suggest that anesthetic-induced preconditioning (APC) produces cardioprotection in humans, but the mechanisms of APC and significance of aging for APC in humans are not well understood. Here, the impact of age on the role of two major effectors of APC, mitochondria and sarcolemmal adenosine triphosphate-sensitive potassium (sarcKATP) channels, in preconditioning of the human atrial myocardium were investigated. Right atrial appendages were obtained from adult patients undergoing cardiac surgery and assigned to mid-aged (MA) and old-aged (OA) groups. APC was induced by isoflurane in isolated myocardium and isolated cardiomyocytes. Mitochondrial oxygen consumption measurements, myocyte survival testing, and patch clamp techniques were used to investigate mitochondrial respiratory function and sarcKATP channel activity. After in vitro APC with isoflurane, the respiratory function of isolated mitochondria was better preserved after hypoxia-reoxygenation stress in MA than in OA. In isolated intact myocytes, APC significantly decreased oxidative stress-induced cell death in MA but not in OA, and isoflurane protection from cell death was attenuated by the sarcKATP channel inhibitor HMR-1098. Further, the properties of single sarcKATP channels were similar in MA and OA, and isoflurane sensitivity of pinacidil-activated whole cell KATP current was no different between MA and OA myocytes. Anesthetic-induced preconditioning with isoflurane decreases stress-induced cell death and preserves mitochondrial respiratory function to a greater degree in MA than in OA myocytes; however, sarcKATP channel activity is not differentially affected by isoflurane. Therefore, effectiveness of APC in humans may decrease with advancing age partly because of altered mitochondrial function of myocardial cells.

  17. [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.

  18. [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.

  19. The left atrial "Medusa myxoma".

    PubMed

    Williams, Elbert E; Pratt, Jerry W; Martin, David E

    2014-02-01

    Although myxomas are the most commonly seen primary cardiac tumors, encompassing 30% to 50% of all primary tumors of the heart, they remain a rare finding with an annual reported incidence of 0.5 per million. The presenting symptoms of an atrial myxoma are widely varied as are the clinical consequences. Regardless of presentation, once a diagnosis is made prompt surgical excision is recommended to minimize the potential complications of obstruction or embolization. We present the "Medusa myxoma," an arborizing 4-fingered left atrial myxoma extending from the fossa ovalis across the left atrium.

  20. A review of atrial fibrillation.

    PubMed Central

    Dang, David; Arimie, Raluca; Haywood, L. Julian

    2002-01-01

    Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and accounts for more physician visits and hospital days than any other cardiac rhythm disturbance. Atrial filbrillation is incresing in frequency as the population ages, and therefore, a knowledge of the clinical spectrum and available treatment regimen is essential. Here, we review the pathophysiology, clinical presentation, and current status of management. Experience is being rapidly accumulated in all of the areas discussed in the management of this important clinical entity. Images Figure 1 Figure 2 PMID:12510703

  1. 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

  2. Regulation of cardiac myocyte contractility by phospholemman: Na+/Ca2+ exchange versus Na+ -K+ -ATPase.

    PubMed

    Song, Jianliang; Zhang, Xue-Qian; Wang, JuFang; Cheskis, Ellina; Chan, Tung O; Feldman, Arthur M; Tucker, Amy L; Cheung, Joseph Y

    2008-10-01

    Phospholemman (PLM) regulates cardiac Na(+)/Ca(2+) exchanger (NCX1) and Na(+)-K(+)-ATPase in cardiac myocytes. PLM, when phosphorylated at Ser(68), disinhibits Na(+)-K(+)-ATPase but inhibits NCX1. PLM regulates cardiac contractility by modulating Na(+)-K(+)-ATPase and/or NCX1. In this study, we first demonstrated that adult mouse cardiac myocytes cultured for 48 h had normal surface membrane areas, t-tubules, and NCX1 and sarco(endo)plasmic reticulum Ca(2+)-ATPase levels, and retained near normal contractility, but alpha(1)-subunit of Na(+)-K(+)-ATPase was slightly decreased. Differences in contractility between myocytes isolated from wild-type (WT) and PLM knockout (KO) hearts were preserved after 48 h of culture. Infection with adenovirus expressing green fluorescent protein (GFP) did not affect contractility at 48 h. When WT PLM was overexpressed in PLM KO myocytes, contractility and cytosolic Ca(2+) concentration ([Ca(2+)](i)) transients reverted back to those observed in cultured WT myocytes. Both Na(+)-K(+)-ATPase current (I(pump)) and Na(+)/Ca(2+) exchange current (I(NaCa)) in PLM KO myocytes rescued with WT PLM were depressed compared with PLM KO myocytes. Overexpressing the PLMS68E mutant (phosphomimetic) in PLM KO myocytes resulted in the suppression of I(NaCa) but had no effect on I(pump). Contractility, [Ca(2+)](i) transient amplitudes, and sarcoplasmic reticulum Ca(2+) contents in PLM KO myocytes overexpressing the PLMS68E mutant were depressed compared with PLM KO myocytes overexpressing GFP. Overexpressing the PLMS68A mutant (mimicking unphosphorylated PLM) in PLM KO myocytes had no effect on I(NaCa) but decreased I(pump). Contractility, [Ca(2+)](i) transient amplitudes, and sarcoplasmic reticulum Ca(2+) contents in PLM KO myocytes overexpressing the S68A mutant were similar to PLM KO myocytes overexpressing GFP. We conclude that at the single-myocyte level, PLM affects cardiac contractility and [Ca(2+)](i) homeostasis primarily by its direct

  3. Sarcomere length dependence of rat skinned cardiac myocyte mechanical properties: dependence on myosin heavy chain

    PubMed Central

    Korte, F Steven; McDonald, Kerry S

    2007-01-01

    The effects of sarcomere length (SL) on sarcomeric loaded shortening velocity, power output and rates of force development were examined in rat skinned cardiac myocytes that contained either α-myosin heavy chain (α-MyHC) or β-MyHC at 12 ± 1°C. When SL was decreased from 2.3 μm to 2.0 μm submaximal isometric force decreased ∼40% in both α-MyHC and β-MyHC myocytes while peak absolute power output decreased 55% in α-MyHC myocytes and 70% in β-MyHC myocytes. After normalization for the fall in force, peak power output decreased about twice as much in β-MyHC as in α-MyHC myocytes (41%versus 20%). To determine whether the fall in normalized power was due to the lower force levels, [Ca2+] was increased at short SL to match force at long SL. Surprisingly, this led to a 32% greater peak normalized power output at short SL compared to long SL in α-MyHC myocytes, whereas in β-MyHC myocytes peak normalized power output remained depressed at short SL. The role that interfilament spacing plays in determining SL dependence of power was tested by myocyte compression at short SL. Addition of 2% dextran at short SL decreased myocyte width and increased force to levels obtained at long SL, and increased peak normalized power output to values greater than at long SL in both α-MyHC and β-MyHC myocytes. The rate constant of force development (ktr) was also measured and was not different between long and short SL at the same [Ca2+] in α-MyHC myocytes but was greater at short SL in β-MyHC myocytes. At short SL with matched force by either dextran or [Ca2+], ktr was greater than at long SL in both α-MyHC and β-MyHC myocytes. Overall, these results are consistent with the idea that an intrinsic length component increases loaded crossbridge cycling rates at short SL and β-MyHC myocytes exhibit a greater sarcomere length dependence of power output. PMID:17347271

  4. PGE2-induced hypertrophy of cardiac myocytes involves EP4 receptor-dependent activation of p42/44 MAPK and EGFR transactivation.

    PubMed

    Mendez, Mariela; LaPointe, Margot C

    2005-05-01

    Upon induction of cyclooxygenase-2 (COX-2), neonatal ventricular myocytes (VMs) mainly synthesize prostaglandin E2 (PGE2). The biological effects of PGE2 are mediated through four different G protein-coupled receptor (GPCR) subtypes (EP(1-4)). We have previously shown that PGE2 stimulates cAMP production and induces hypertrophy of VMs. Because the EP4 receptor is coupled to adenylate cyclase and increases in cAMP, we hypothesized that PGE2 induces hypertrophic growth of cardiac myocytes through a signaling cascade that involves EP4-cAMP and activation of protein kinase A (PKA). To test this, we used primary cultures of VMs and measured [3H]leucine incorporation into total protein. An EP4 antagonist was able to partially block PGE2 induction of protein synthesis and prevent PGE2-dependent increases in cell surface area and activity of the atrial natriuretic factor promoter, which are two other indicators of hypertrophic growth. Surprisingly, a PKA inhibitor had no effect. In other cell types, G protein-coupled receptor activation has been shown to transactivate the epidermal growth factor receptor (EGFR) and result in p42/44 mitogen-activated protein kinase (MAPK) activation and cell growth. Immunoprecipitation of myocyte lysates demonstrated that the EGFR was rapidly phosphorylated by PGE2 in VMs, and the EP4 antagonist blocked this. In addition, the selective EGFR inhibitor AG-1478 completely blocked PGE2-induced protein synthesis. We also found that PGE2 rapidly phosphorylated p42/44 MAPK, which was inhibited by the EP4 antagonist and by AG-1478. Finally, the p42/44 MAPK inhibitor PD-98053 (25 micromol/l) blocked PGE2-induced protein synthesis. Altogether, we believe these are the first data to suggest that PGE2 induces protein synthesis in cardiac myocytes in part via activation of the EP4 receptor and subsequent activation of p42/44 MAPK. Activation of p42/44 MAPK is independent of the common cAMP-PKA pathway and involves EP4-dependent transactivation of EGFR.

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

    PubMed

    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

    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 K(v)1.5, and the ionic currents I(KACh) and late I(Na), 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. We made whole-cell patch-clamp recordings of recombinant ion channels, human atrial I(Kur), rat atrial I(KACh), 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. C1 inhibited human peak and late K(v)1.5 currents, frequency-dependently, with IC₅₀ of 0.36 and 0.11 μmol·L(-1) respectively. C1 inhibited I(KACh)(IC₅₀ of 1.9 μmol·L(-1)) and the Na(v)1.5 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. C1 behaved as a promising multifunctional small molecule targeting a number of key pathways involved in AF. © 2013 The British Pharmacological Society.

  7. Differentiation of pre-ablation and post-ablation late gadolinium-enhanced cardiac MRI scans of longstanding persistent atrial fibrillation patients

    NASA Astrophysics Data System (ADS)

    Yang, Guang; Zhuang, Xiahai; Khan, Habib; Haldar, Shouvik; Nyktari, Eva; Li, Lei; Ye, Xujiong; Slabaugh, Greg; Wong, Tom; Mohiaddin, Raad; Keegan, Jennifer; Firmin, David

    2017-03-01

    Late Gadolinium-Enhanced Cardiac MRI (LGE CMRI) is an emerging non-invasive technique to image and quantify preablation native and post-ablation atrial scarring. Previous studies have reported that enhanced image intensities of the atrial scarring in the LGE CMRI inversely correlate with the left atrial endocardial voltage invasively obtained by electro-anatomical mapping. However, the reported reproducibility of using LGE CMRI to identify and quantify atrial scarring is variable. This may be due to two reasons: first, delineation of the left atrium (LA) and pulmonary veins (PVs) anatomy generally relies on manual operation that is highly subjective, and this could substantially affect the subsequent atrial scarring segmentation; second, simple intensity based image features may not be good enough to detect subtle changes in atrial scarring. In this study, we hypothesized that texture analysis can provide reliable image features for the LGE CMRI images subject to accurate and objective delineation of the heart anatomy based on a fully-automated whole heart segmentation (WHS) method. We tested the extracted texture features to differentiate between pre-ablation and post-ablation LGE CMRI studies in longstanding persistent atrial fibrillation patients. These patients often have extensive native scarring and differentiation from post-ablation scarring can be difficult. Quantification results showed that our method is capable of solving this classification task, and we can envisage further deployment of this texture analysis based method for other clinical problems using LGE CMRI.

  8. Active Atrial Function and Atrial Scar Burden After Multiple Catheter Ablations of Persistent Atrial Fibrillation.

    PubMed

    Nührich, Jana M; Geisler, Anne C; Steven, Daniel; Hoffmann, Boris A; Schäffer, Benjamin; Lund, Gunnar; Stehning, Christian; Radunski, Ulf K; Sultan, Arian; Schwarzl, Michael; Adam, Gerhard; Willems, Stephan; Muellerleile, Kai

    2017-02-01

    Extensive and repeated substrate modification (SM) is frequently performed as an ablation strategy in persistent atrial fibrillation (persAF). The effect of these extended ablation strategies on atrial function has not been investigated sufficiently so far. The purpose was to assess atrial function by cardiac magnetic resonance (CMR) and its association with left atrial (LA) scar burden by electroanatomical voltage-mapping after multiple persAF ablation procedures. We included 16 persAF patients who had ≥2 SM procedures and a control group (CG) of 21 persAF patients without prior ablation. CMR was performed in sinus rhythm at least 4 weeks after the last cardioversion. Active left and right (RA) atrial emptying fractions (AEF) as well as peak active left atrial appendage (LAA) emptying velocities were obtained by CMR flow measurements. Furthermore, LA scar burden was quantified on electroanatomical voltage maps by the portion of points with local voltage amplitude <0.2 mV. We found median LA-AEF to be lower (13 [9-22] vs 32 [26-36] %, P < 0.001) and median LA scar burden to be higher (40 [20-68] vs nine [3-18] %, P < 0.05) in the SM group compared with the CG. Furthermore, a significant correlation was found between mean LA voltage and LA-AEF (r(2) = 0.62, P < 0.001). No significant differences were detected with respect to median RA-AEF (41 [28-48] vs 47 [35-50] %, P = 0.43) and median peak LAA emptying velocities (30 [16-40] vs 17 [13-28] cm/s, P = 0.07). Active LA function is preserved but significantly impaired and associated with ablation-related LA scar burden after multiple extensive persAF ablations. ©2016 Wiley Periodicals, Inc.

  9. Myocyte apoptosis occurs early during the development of pressure-overload hypertrophy in infant myocardium.

    PubMed

    Choi, Yeong-Hoon; Cowan, Douglas B; Moran, Adrian M; Colan, Steven D; Stamm, Christof; Takeuchi, Koh; Friehs, Ingeborg; del Nido, Pedro J; McGowan, Francis X

    2009-06-01

    Abnormal hemodynamic loading often accompanies congenital heart disease both before and after surgical repair. Adaptive and maladaptive myocardial responses to increased load are numerous. This study examined the hypothesis that myocyte loss occurs during compensatory hypertrophic growth in the developing infant myocardium subjected to progressive pressure overload. Pressure-overload left ventricular hypertrophy was induced in 7- to 10-day-old rabbits by banding the thoracic aorta. Left ventricular function and mechanics were quantified by serial echocardiography and noninvasive left ventricular wall stress analysis. Left ventricular tissue sections were examined for fibrosis by using Masson's trichrome stain and for myocyte apoptosis by using a myocyte-specific DNA fragmentation assay and caspase-3 activation (specific fluorescent substrate). Significant myocyte apoptosis (198 +/- 37/10(6) myocytes, P < .01 vs control) and caspase-3 activation were present in early hypertrophy when left ventricular contractility was preserved and compensatory hypertrophy had normalized wall stress. By 6 weeks, multiple indices of left ventricular contractility were reduced, and left ventricular wall stress was increased. Myocyte apoptosis was accelerated (361 +/- 56/10(6) myocytes), caspase-3 activity further increased, and the estimated total number of left ventricular myocytes was significantly reduced by 18% +/- 4%. In experimental infant left ventricular hypertrophy, myocyte apoptosis is initiated in the face of normalized wall stress and preserved contractility. The ongoing rate of apoptosis causes a measurable decrease in myocyte number that is coincident with the onset of ventricular dysfunction. It thus appears that pressure overload, even at its earliest stages, is not well tolerated by the developing ventricle.

  10. 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.

  11. Transcriptional reversion of cardiac myocyte fate during mammalian cardiac regeneration.

    PubMed

    O'Meara, Caitlin C; Wamstad, Joseph A; Gladstone, Rachel A; Fomovsky, Gregory M; Butty, Vincent L; Shrikumar, Avanti; Gannon, Joseph B; Boyer, Laurie A; Lee, Richard T

    2015-02-27

    Neonatal mice have the capacity to regenerate their hearts in response to injury, but this potential is lost after the first week of life. The transcriptional changes that underpin mammalian cardiac regeneration have not been fully characterized at the molecular level. The objectives of our study were to determine whether myocytes revert the transcriptional phenotype to a less differentiated state during regeneration and to systematically interrogate the transcriptional data to identify and validate potential regulators of this process. We derived a core transcriptional signature of injury-induced cardiac myocyte (CM) regeneration in mouse by comparing global transcriptional programs in a dynamic model of in vitro and in vivo CM differentiation, in vitro CM explant model, as well as a neonatal heart resection model. The regenerating mouse heart revealed a transcriptional reversion of CM differentiation processes, including reactivation of latent developmental programs similar to those observed during destabilization of a mature CM phenotype in the explant model. We identified potential upstream regulators of the core network, including interleukin 13, which induced CM cell cycle entry and STAT6/STAT3 signaling in vitro. We demonstrate that STAT3/periostin and STAT6 signaling are critical mediators of interleukin 13 signaling in CMs. These downstream signaling molecules are also modulated in the regenerating mouse heart. Our work reveals new insights into the transcriptional regulation of mammalian cardiac regeneration and provides the founding circuitry for identifying potential regulators for stimulating heart regeneration. © 2014 American Heart Association, Inc.

  12. Erythromycin contracts rabbit colon myocytes via occupation of motilin receptors.

    PubMed

    Hasler, W L; Heldsinger, A; Chung, O Y

    1992-01-01

    Erythromycin stimulates gastroduodenal motility via action on motilin receptors. We evaluated erythromycin as a colonic muscle motilin agonist using in vitro rabbit colon studies. Isolated myocytes contracted to erythromycin with a half-maximal effective concentration of 2 pM and peak shortening of 22.4 +/- 2.5% at 1 nM, which was superimposable with the response to motilin. 125I-labeled motilin binding to colon muscle homogenates was saturable and specific with a dissociation constant (Kd) of 0.39 nM and maximal binding (Bmax) of 41 +/- 3 fmol/mg protein. Motilin displaced specifically bound 125I-motilin, with a Kd of 0.31 nM. Erythromycin displaced 125I-motilin but was less potent, with an inhibitory constant of 84.0 nM. Bmax values from displacement studies were similar to the Scatchard data. Motilin receptor protection from alkylation by N-ethylmaleimide preserved contraction to motilin and erythromycin but not acetylcholine or cholecystokinin, whereas protection with erythromycin preserved contraction to motilin but not other agonists. In conclusion, erythromycin binds to colon muscle motilin receptors present in densities similar to reported values for the upper gut. Furthermore, erythromycin contracts colonic myocytes via specific action on motilin receptors. Thus erythromycin may have colonic motor-stimulating properties by action on motilin receptors.

  13. 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.

  14. 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.

  15. Arrhythmia and neuronal/endothelial myocyte uncoupling in hyperhomocysteinemia*

    PubMed Central

    ROSENBERGER, DOROTHEA; MOSHAL, KARNI S.; KARTHA, GANESH K.; TYAGI, NEETU; SEN, UTPAL; LOMINADZE, DAVID; MALDONADO, CLAUDIO; ROBERTS, ANDREW M.; TYAGI, SURESH C.

    2011-01-01

    Elevated levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) are associated with arrhythmogenesis and sudden cardiac death (SCD). Hcy decreases constitutive neuronal and endothelial nitric oxide (NO), and cardiac diastolic relaxation. Hcy increases the iNOS/NO, peroxynitrite, mitochondrial NADPH oxidase, and suppresses superoxide dismutase (SOD) and redoxins. Hcy activates matrix metalloproteinase (MMP), disrupts connexin-43 and increases collagen/elastin ratio. The disruption of connexin-43 and accumulation of collagen (fibrosis) disrupt the normal pattern of cardiac conduction and attenuate NO transport from endothelium to myocyte (E-M) causing E-M uncoupling, leading to a pro-arrhythmic environment. The goal of this review is to elaborate the mechanism of Hcy-mediated iNOS/NO in E-M uncoupling and SCD. It is known that Hcy creates arrhythmogenic substrates (i.e. increase in collagen/elastin ratio and disruption in connexin-43) and exacerbates heart failure during chronic volume overload. Also, Hcy behaves as an agonist to N-methyl-D-aspartate (NMDA, an excitatory neurotransmitter) receptor-1, and blockade of NMDA-R1 reduces the increase in heart rate-evoked by NMDA-analog and reduces SCD. This review suggest that Hcy increases iNOS/NO, superoxide, metalloproteinase activity, and disrupts connexin-43, exacerbates endothelial-myocyte uncoupling and cardiac failure secondary to inducing NMDA-R1. PMID:17178594

  16. Myocyte repolarization modulates myocardial function in aging dogs

    PubMed Central

    Sorrentino, Andrea; Signore, Sergio; 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.

    2016-01-01

    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. PMID:26801307

  17. A cardiac pathway of cyclic GMP-independent signaling of guanylyl cyclase A, the receptor for atrial natriuretic peptide

    PubMed Central

    Klaiber, Michael; Dankworth, Beatrice; Kruse, Martin; Hartmann, Michael; Nikolaev, Viacheslav O.; Yang, Ruey-Bing; Völker, Katharina; Gaßner, Birgit; Oberwinkler, Heike; Feil, Robert; Freichel, Marc; Groschner, Klaus; Skryabin, Boris V.; Frantz, Stefan; Birnbaumer, Lutz; Pongs, Olaf; Kuhn, Michaela

    2011-01-01

    Cardiac atrial natriuretic peptide (ANP) regulates arterial blood pressure, moderates cardiomyocyte growth, and stimulates angiogenesis and metabolism. ANP binds to the transmembrane guanylyl cyclase (GC) receptor, GC-A, to exert its diverse functions. This process involves a cGMP-dependent signaling pathway preventing pathological [Ca2+]i increases in myocytes. In chronic cardiac hypertrophy, however, ANP levels are markedly increased and GC-A/cGMP responses to ANP are blunted due to receptor desensitization. Here we show that, in this situation, ANP binding to GC-A stimulates a unique cGMP-independent signaling pathway in cardiac myocytes, resulting in pathologically elevated intracellular Ca2+ levels. This pathway involves the activation of Ca2+‐permeable transient receptor potential canonical 3/6 (TRPC3/C6) cation channels by GC-A, which forms a stable complex with TRPC3/C6 channels. Our results indicate that the resulting cation influx activates voltage-dependent L-type Ca2+ channels and ultimately increases myocyte Ca2+i levels. These observations reveal a dual role of the ANP/GC-A–signaling pathway in the regulation of cardiac myocyte Ca2+i homeostasis. Under physiological conditions, activation of a cGMP-dependent pathway moderates the Ca2+i-enhancing action of hypertrophic factors such as angiotensin II. By contrast, a cGMP-independent pathway predominates under pathophysiological conditions when GC-A is desensitized by high ANP levels. The concomitant rise in [Ca2+]i might increase the propensity to cardiac hypertrophy and arrhythmias. PMID:22027011

  18. Facts about Atrial Septal Defect

    MedlinePlus

    ... Developmental Disabilities) be credited and notified in any public or private usage of this image. Close × Atrial Septal Defect The images are ... Developmental Disabilities) be credited and notified in any public or private usage of this image. Close Information For... ... Makers Language: English ...

  19. Deglutition-Induced Atrial Fibrillation

    PubMed Central

    Malik, Amyn; Ali, Syed Sohail; Rahmatullah, Amin

    2005-01-01

    We present the case of 38-year-old woman who experienced palpitations on swallowing, which were later found to be atrial fibrillation. Her symptoms improved on treatment with disopyramide and verapamil. Within 9 months, she was weaned from both medications without recurrence of symptoms. PMID:16429915

  20. Glycolytic inhibition: effects on diastolic relaxation and intracellular calcium handling in hypertrophied rat ventricular myocytes.

    PubMed Central

    Kagaya, Y; Weinberg, E O; Ito, N; Mochizuki, T; Barry, W H; Lorell, B H

    1995-01-01

    We tested the hypothesis that glycolytic inhibition by 2-deoxyglucose causes greater impairment of diastolic relaxation and intracellular calcium handling in well-oxygenated hypertrophied adult rat myocytes compared with control myocytes. We simultaneously measured cell motion and intracellular free calcium concentration ([Ca2+]i) with indo-1 in isolated paced myocytes from aortic-banded rats and sham-operated rats. There was no difference in either the end-diastolic or peak-systolic [Ca2+]i between control and hypertrophied myocytes (97 +/- 18 vs. 105 +/- 15 nM, 467 +/- 92 vs. 556 +/- 67 nM, respectively). Myocytes were first superfused with oxygenated Hepes-buffered solution containing 1.2 mM CaCl2, 5.6 mM glucose, and 5 mM acetate, and paced at 3 Hz at 36 degrees C. Exposure to 20 mM 2-deoxyglucose as substitution of glucose for 15 min caused an upward shift of end-diastolic cell position in both control (n = 5) and hypertrophied myocytes (n = 10) (P < 0.001 vs. baseline), indicating an impaired extent of relaxation. Hypertrophied myocytes, however, showed a greater upward shift in end-diastolic cell position and slowing of relaxation compared with control myocytes (delta 144 +/- 28 vs. 55 +/- 15% of baseline diastolic position, P < 0.02). Exposure to 2-deoxyglucose increased end-diastolic [Ca2+]i in both groups (P < 0.001 vs. baseline), but there was no difference between hypertrophied and control myocytes (218 +/- 38 vs. 183 +/- 29 nM, respectively). The effects of 2-deoxyglucose were corroborated in isolated oxygenated perfused hearts in which glycolytic inhibition which caused severe elevation of isovolumic diastolic pressure and prolongation of relaxation in the hypertrophied hearts compared with controls. In summary, the inhibition of the glycolytic pathway impairs diastolic relaxation to a greater extent in hypertrophied myocytes than in control myocytes even in well-oxygenated conditions. The severe impairment of diastolic relaxation induced by 2

  1. Irregular rhythm adversely influences calcium handling in ventricular myocardium: implications for the interaction between heart failure and atrial fibrillation.

    PubMed

    Ling, Liang-han; Khammy, Ouda; Byrne, Melissa; Amirahmadi, Fatemah; Foster, Anna; Li, Gefeng; Zhang, Linda; dos Remedios, Cris; Chen, Chen; Kaye, David M

    2012-11-01

    Despite adequate rate control, the combination of atrial fibrillation with heart failure (HF) has been shown, in a number of studies, to hasten HF progression. In this context, we aimed to test the hypothesis that an irregular ventricular rhythm causes an alteration in ventricular cardiomyocyte excitation-contraction coupling which contributes to the progression of HF. We investigated the effects of electrical field stimulation (average frequency 2 Hz) in an irregular versus regular drive train pattern on the expression of calcium-handling genes and proteins in rat ventricular myocytes. The effect of rhythm on intracellular calcium transients was examined using Fura-2AM fluorescence spectroscopy. In conjunction, calcium-handling protein expression was examined in left ventricular samples obtained from end-stage HF patients, in patients with either persistent atrial fibrillation or sinus rhythm. Compared with regularly paced ventricular cardiomyocytes, in cells paced irregularly for 24 hours, there was a significant reduction in the expression of sarcoplasmic reticulum calcium (Ca(2+)) ATPase together with reduced serine-16 phosphorylation of phospholamban. These findings were accompanied by a 59% reduction (P<0.01) in the peak Ca2+ transient in irregulary paced myocytes compared with those with regular pacing. Consistent with these observations, we observed a 54% (P<0.05) decrease in sarcoplasmic reticulum Ca(2+)ATPase protein expression and an 85% (P<0.01) reduction in the extent of phosphorylation of phospholamban in the left ventricular myocardium of HF patients in atrial fibrillation compared with those in sinus rhythm. Together, these data demonstrate that ventricular rhythmicity contributes significantly to excitation-contraction coupling by altering the expression and activity of key calcium-handling proteins. These data suggest that control of rhythm may be of benefit in patients with HF.

  2. Native Americans with Diabetes

    MedlinePlus

    ... Read the MMWR Science Clips Native Americans with Diabetes Better diabetes care can decrease kidney failure Language: ... between 1996 and 2013. Problem Kidney failure from diabetes was highest among Native Americans. Native Americans are ...

  3. [Atrial fibrillation and cognitive function].

    PubMed

    Duron, Emmanuelle; Hanon, Olivier

    2010-09-01

    Atrial fibrillation (AF), which prevalence increases with age, is a growing public health problem and a well known risk factor for stroke. On the other hand, dementia is one of the most important neurological disorders in the elderly, and with aging of the population in developed countries, the number of demented patients will increase in absence of prevention. In the past decade, several vascular risk factors (hypertension, obesity and metabolic syndrome, hypercholesterolemia) have been found, with various degree of evidence, to be associated with vascular dementia but also, surprisingly, with Alzheimer's disease. This review is devoted to the links between atrial fibrillation, cognitive decline and dementia. Globally, transversal studies showed a significant association between atrial fibrillation, cognitive decline and dementia. However, these studies are particularly sensitive to various biases. In this context, recent longitudinal studies of higher level of evidence have been conducted to assess the link between AF and dementia. One study disclosed a high incidence of dementia among patients suffering from atrial fibrillation during a 4.6 years follow-up. Similarly another study showed that atrial fibrillation was significantly associated with conversion from mild cognitive impairment to dementia during a 3 years follow-up. Nevertheless two other longitudinal studies did not find any significant association between AF and dementia, but this discrepancy should be interpreted taking into account that the comparability of all these studies is moderate because they were using different methodologies (population, cognitive testing, and mean follow-up). Possible explanatory mechanisms for the association between AF and the risk of dementia are proposed, such as thrombo-embolic ischemic damage and cerebral hypo perfusion due to fluctuations in the cardiac output. Thus, there is some evidence that FA could be associated with cognitive decline and dementia but this

  4. Both α1A- and α1B-adrenergic receptor subtypes couple to the transient outward current (ITo) in rat ventricular myocytes

    PubMed Central

    Homma, Nobuo; Hirasawa, Akira; Shibata, Katsushi; Hashimito, Keitaro; Tsujimoto, Gozoh

    2000-01-01

    Regulation of transient outward current (ITo) by α1-adrenergic (α1AR) plays a key role in cardiac repolarization. α1ARs comprise a heterogeneous family; two natively expressed subtypes (α1A and α1B) and three cloned subtypes (α1a, α1b and α1d) can be distinguished. We have examined the electrophysiological role of each α1AR subtype in regulating ITo in isolated rat ventricular myocytes. Reverse transcription-PCR study revealed the presence of three subtype mRNAs (α1a, α1b and α1d) in rat myocytes. Radioligand binding assay using [125I]-HEAT showed that the inhibition curves for α1AAR-selective antagonists (WB4101, 5-methylurapidil, (+)-niguldipine and KMD-3213) in rat ventricles best fit a two-site model, with 30% high and 70% low affinity binding sites. The high affinity sites were resistant to 100 μM chloroethylclonidine (CEC), while the low affinity sites were highly inactivated by CEC. Whole cell voltage clamp study revealed that methoxamine reduced a 4-aminopyridine(4-AP)-sensitive component of ITo in the isolated rat ventricle myocytes. Lower concentrations of KMD-3213 (1 nM) or 5-MU (10 nM) did not affect the methoxamine-induced reduction of ITo. On the other hand, CEC treatment (100 μM) of isolated myocytes reduced the methoxamine-induced reduction of ITo by 46%, and the remaining response was abolished by lower concentrations of KMD-3213 or 5-MU. The results indicate that rat ventricular myocytes express transcripts of the three α1AR subtypes (α1a, α1b and α1d); however, two pharmacologically distinct α1AR subtypes (α1A and α1B) are predominating in receptor populations, with approximately 30% α1AAR and 70% α1BAR. Although both α1A and α1BAR subtypes are coupled to the cardiac ITo, α1BARs predominantly mediate α1AR-induced effect. PMID:10725259

  5. Histopathological characteristics and oxidative injury secondary to atrial fibrillation in the left atrial appendages of patients with different forms of mitral valve disease.

    PubMed

    Yongjun, Qian; Huanzhang, Shao; Wenxia, Zhou; Hong, Tang; Xijun, Xiao

    2013-01-01

    The prevalence of atrial fibrillation (AF) and the frequency cardioversion of AF postoperatively are different in different forms of mitral valve disease. We hypothesized that these differences would relate to different extent of histopathological characteristics and oxidative injury in different forms of mitral valve diseases. Left atrial appendages were obtained from 24 patients of mitral valve disease with or without AF undergoing mitral valve surgery. Control data were obtained from left appendages of 4 persons in normal sinus rhythm (SR) died of traffic accident. Histopathology, immunohistochemistry, Western blotting and enzyme kinetics examination were performed to assess the extent of histopathological characteristics and oxidative injury. The average cross-sectional diameter of atrial myocyte of mitral stenosis (MS)+AF, MS+SR, mitral regurgitation (MR)+AF, MR+SR and control was 25.62±7.56 μm, 20.20±9.34 μm, 21.69±7.00 μm, 13.93±4.32 μm and 9.81±2.34 μm, respectively. Significantly statistical difference was found between each group (P<.05). Increased degree of atrial interstitial fibrosis was seen both in MS and MR with AF patients compared to other groups (P<.05), and the extent of fibrosis was more remarkable in MR patients compared to MS patients (P<.05). The extent of 3-nitrotyrosine (3-NT) immunoreactivity significantly increased in the patients with MS and AF compared to those of MR and AF (P<.05), and the immunoprevalence of 3-NT was significantly increased in patients of MS and SR compared to those of MR and SR (P<.05). Correlation analysis demonstrated a negative correlation between creatine kinase (CK) activity and extent of 3-NT immunoreactivity in atrial tissues (r=-0.382, P<.05). Significant decreases in CK activity were observed in myocardium from all patients of mitral valve disease with or without AF compared to controls (P<.05). Western blotting demonstrating an increased prevalence of 3-NT formation in CK-MM was detected compared

  6. Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization

    PubMed Central

    Voigt, Niels; Garbino, Alejandro; Dixit, Sayali S.; Landstrom, Andrew P.; Li, Na; Wang, Qiongling; Olivotto, Iacopo; Dobrev, Dobromir; Ackerman, Michael J.; Wehrens, Xander H.T.

    2013-01-01

    Objectives To study the role of junctophilin 2 (JPH2) in atrial fibrillation (AF). Background JPH2 is believed to have an important role in sarcoplasmic reticulum (SR) Ca2+ handling and modulation of ryanodine receptor Ca2+ channels (RyR2). Whereas defective RyR2-mediated Ca2+ release contributes to the pathogenesis of AF, nothing is known about the potential role of JPH2 in atrial arrhythmias. Methods Screening 203 unrelated hypertrophic cardiomyopathy patients uncovered a novel JPH2 missense mutation (E169K) in 2 patients with juvenile-onset paroxysmal AF (pAF). Pseudo-knockin (PKI) mouse models were generated to determine the molecular defects underlying the development of AF caused by this JPH2 mutation. Results PKI mice expressing E169K mutant JPH2 exhibited a higher incidence of inducible AF compared with wildtype (WT)-PKI mice, while A399S-PKI mice expressing a HCM-linked JPH2 mutation not associated with atrial arrhythmias were not significantly different from WT-PKI. E169K-PKI but not A399A-PKI atrial cardiomyocytes showed an increased incidence of abnormal SR Ca2+ release events. These changes were attributed to reduced binding of E169KJPH2 to RyR2. Atrial JPH2 levels in WT-JPH2 transgenic, nontransgenic, and JPH2 knockdown mice correlated negatively with the incidence of pacing-induced AF. Ca2+ spark frequency in atrial myocytes and the open probability of single RyR2 channels from JPH2 knockdown mice was significantly reduced by a small JPH2-mimicking oligopeptide. Moreover, patients with pAF had reduced atrial JPH2 levels per RyR2 channel compared to sinus rhythm patients, and an increased frequency of spontaneous Ca2+ release events. Conclusions Our data suggest a novel mechanism by which reduced JPH2-mediated stabilization of RyR2 due to loss-of-function mutation or reduced JPH2:RyR2 ratios can promote SR Ca2+ leak and atrial arrhythmias, representing a potential novel therapeutic target for AF. PMID:23973696

  7. Expression and function of Kv1.1 potassium channels in human atria from patients with atrial fibrillation.

    PubMed

    Glasscock, Edward; Voigt, Niels; McCauley, Mark D; Sun, Qiang; Li, Na; Chiang, David Y; Zhou, Xiao-Bo; Molina, Cristina E; Thomas, Dierk; Schmidt, Constanze; Skapura, Darlene G; Noebels, Jeffrey L; Dobrev, Dobromir; Wehrens, Xander H T

    2015-09-01

    Voltage-gated Kv1.1 channels encoded by the Kcna1 gene are traditionally regarded as being neural-specific with no known expression or intrinsic functional role in the heart. However, recent studies in mice reveal low-level Kv1.1 expression in heart and cardiac abnormalities associated with Kv1.1-deficiency suggesting that the channel may have a previously unrecognized cardiac role. Therefore, this study tests the hypothesis that Kv1.1 channels are associated with arrhythmogenesis and contribute to intrinsic cardiac function. In intra-atrial burst pacing experiments, Kcna1-null mice exhibited increased susceptibility to atrial fibrillation (AF). The atria of Kcna1-null mice showed minimal Kv1 family ion channel remodeling and fibrosis as measured by qRT-PCR and Masson's trichrome histology, respectively. Using RT-PCR, immunocytochemistry, and immunoblotting, KCNA1 mRNA and protein were detected in isolated mouse cardiomyocytes and human atria for the first time. Patients with chronic AF (cAF) showed no changes in KCNA1 mRNA levels relative to controls; however, they exhibited increases in atrial Kv1.1 protein levels, not seen in paroxysmal AF patients. Patch-clamp recordings of isolated human atrial myocytes revealed significant dendrotoxin-K (DTX-K)-sensitive outward current components that were significantly increased in cAF patients, reflecting a contribution by Kv1.1 channels. The concomitant increases in Kv1.1 protein and DTX-K-sensitive currents in atria of cAF patients suggest that the channel contributes to the pathological mechanisms of persistent AF. These findings provide evidence of an intrinsic cardiac role of Kv1.1 channels and indicate that they may contribute to atrial repolarization and AF susceptibility.

  8. Revealing kinetics and state-dependent binding properties of IKur-targeting drugs that maximize atrial fibrillation selectivity

    NASA Astrophysics Data System (ADS)

    Ellinwood, Nicholas; Dobrev, Dobromir; Morotti, Stefano; Grandi, Eleonora

    2017-09-01

    The KV1.5 potassium channel, which underlies the ultra-rapid delayed-rectifier current (IKur) and is predominantly expressed in atria vs. ventricles, has emerged as a promising target to treat atrial fibrillation (AF). However, while numerous KV1.5-selective compounds have been screened, characterized, and tested in various animal models of AF, evidence of antiarrhythmic efficacy in humans is still lacking. Moreover, current guidelines for pre-clinical assessment of candidate drugs heavily rely on steady-state concentration-response curves or IC50 values, which can overlook adverse cardiotoxic effects. We sought to investigate the effects of kinetics and state-dependent binding of IKur-targeting drugs on atrial electrophysiology in silico and reveal the ideal properties of IKur blockers that maximize anti-AF efficacy and minimize pro-arrhythmic risk. To this aim, we developed a new Markov model of IKur that describes KV1.5 gating based on experimental voltage-clamp data in atrial myocytes from patient right-atrial samples in normal sinus rhythm. We extended the IKur formulation to account for state-specificity and kinetics of KV1.5-drug interactions and incorporated it into our human atrial cell model. We simulated 1- and 3-Hz pacing protocols in drug-free conditions and with a [drug] equal to the IC50 value. The effects of binding and unbinding kinetics were determined by examining permutations of the forward (kon) and reverse (koff) binding rates to the closed, open, and inactivated states of the KV1.5 channel. We identified a subset of ideal drugs exhibiting anti-AF electrophysiological parameter changes at fast pacing rates (effective refractory period prolongation), while having little effect on normal sinus rhythm (limited action potential prolongation). Our results highlight that accurately accounting for channel interactions with drugs, including kinetics and state-dependent binding, is critical for developing safer and more effective pharmacological anti

  9. Expression and function of Kv1.1 potassium channels in human atria from patients with atrial fibrillation

    PubMed Central

    Glasscock, Edward; Voigt, Niels; McCauley, Mark D.; Sun, Qiang; Li, Na; Chiang, David Y.; Zhou, Xiao-Bo; Molina, Cristina E.; Thomas, Dierk; Schmidt, Constanze; Skapura, Darlene G.; Noebels, Jeffrey L.; Dobrev, Dobromir; Wehrens, Xander H. T.

    2016-01-01

    Voltage-gated Kv1.1 channels encoded by the Kcna1 gene are traditionally regarded as being neural-specific with no known expression or intrinsic functional role in the heart. However, recent studies in mice reveal low-level Kv1.1 expression in heart and cardiac abnormalities associated with Kv1.1-deficiency suggesting that the channel may have a previously unrecognized cardiac role. Therefore, this study tests the hypothesis that Kv1.1 channels are associated with arrhythmogenesis and contribute to intrinsic cardiac function. In intra-atrial burst pacing experiments, Kcna1-null mice exhibited increased susceptibility to atrial fibrillation (AF). The atria of Kcna1-null mice showed minimal Kv1 family ion channel remodeling and fibrosis as measured by qRT-PCR and Masson’s trichrome histology, respectively. Using RT-PCR, immunocytochemistry, and immunoblotting, KCNA1 mRNA and protein were detected in isolated mouse cardiomyocytes and human atria for the first time. Patients with chronic AF (cAF) showed no changes in KCNA1 mRNA levels relative to controls; however, they exhibited increases in atrial Kv1.1 protein levels, not seen in paroxysmal AF patients. Patch-clamp recordings of isolated human atrial myocytes revealed significant dendrotoxin-K (DTX-K)-sensitive outward current components that were significantly increased in cAF patients, reflecting a contribution by Kv1.1 channels. The concomitant increases in Kv1.1 protein and DTX-K-sensitive currents in atria of cAF patients suggest that the channel contributes to the pathological mechanisms of persistent AF. These findings provide evidence of an intrinsic cardiac role of Kv1.1 channels and indicate that they may contribute to atrial repolarization and AF susceptibility. PMID:26162324

  10. Protein kinase C-alpha-induced hypertrophy of neonatal rat ventricular myocytes.

    PubMed

    Vijayan, Kalpana; Szotek, Erika L; Martin, Jody L; Samarel, Allen M

    2004-12-01

    Protein kinase C (PKC) isoenzymes play a critical role in cardiomyocyte hypertrophy. At least three different phorbol ester-sensitive PKC isoenzymes are expressed in neonatal rat ventricular myocytes (NRVMs): PKC-alpha, -delta, and -epsilon. Using replication-defective adenoviruses (AdVs) that express wild-type (WT) and dominant-negative (DN) PKC-alpha together with phorbol myristate acetate (PMA), which is a hypertrophic agonist and activator of all three PKC isoenzymes, we studied the role of PKC-alpha in signaling-specific aspects of the hypertrophic phenotype. PMA induced nuclear translocation of endogenous and AdV-WT PKC-alpha in NRVMs. WT PKC-alpha overexpression increased protein synthesis and the protein-to-DNA (P/D) ratio but did not affect cell surface area (CSA) or cell shape compared with uninfected or control AdV beta-galactosidase (AdV betagal)-infected cells. PMA-treated uninfected cells displayed increased protein synthesis, P/D ratio, and CSA and elongated morphology. PMA did not further enhance protein synthesis or P/D ratio in AdV-WT PKC-alpha-infected cells. To assess the requirement of PKC-alpha for these PMA-induced changes, AdV-DN PKC-alpha or AdV betagal-infected NRVMs were stimulated with PMA. Without PMA, AdV-DN PKC-alpha had no effects on protein synthesis, P/D ratio, CSA, or shape vs. AdV betagal-infected NRVMs. PMA increased protein synthesis, P/D ratio, and CSA in AdV betagal-infected cells, but these parameters were significantly reduced in PMA-stimulated AdV-DN PKC-alpha-infected NRVMs. Overexpression of DN PKC-alpha enhanced PMA-induced cell elongation. Neither WT PKC-alpha nor DN PKC-alpha affected atrial natriuretic factor gene expression. Insulin-like growth factor-1 also induced nuclear translocation of endogenous PKC-alpha. PMA but not WT PKC-alpha overexpression induced ERK1/2 activation. However, AdV-DN PKC-alpha partially blocked PMA-induced ERK activation. Thus PKC-alpha is necessary for certain aspects of PMA-induced NRVM

  11. Tissue-Specific Cell Cycle Indicator Reveals Unexpected Findings for Cardiac Myocyte Proliferation

    PubMed Central

    Hirai, Maretoshi; Chen, Ju; Evans, Sylvia M.

    2017-01-01

    Rationale Discerning cardiac myocyte cell cycle behavior is challenging owing to commingled cell types with higher proliferative activity. Objective To investigate cardiac myocyte cell cycle activity in development and the early postnatal period. Methods and Results To facilitate studies of cell type–specific proliferation, we have generated tissue-specific cell cycle indicator BAC transgenic mouse lines. Experiments using embryonic fibroblasts from CyclinA2-LacZ-floxed-EGFP, or CyclinA2-EGFP mice, demonstrated that CyclinA2-βgal and CyclinA2-EGFP were expressed from mid-G1 to mid-M phase. Using Troponin T-Cre;CyclinA2-LacZ-EGFP mice, we examined cardiac myocyte cell cycle activity during embryogenesis and in the early postnatal period. Our data demonstrated that right ventricular cardiac myocytes exhibited reduced cell cycle activity relative to left ventricular cardiac myocytes in the immediate perinatal period. Additionally, in contrast to a recent report, we could find no evidence to support a burst of cardiac myocyte cell cycle activity at postnatal day 15. Conclusions Our data highlight advantages of a cardiac myocyte–specific cell cycle reporter for studies of cardiac myocyte cell cycle regulation. PMID:26472817

  12. Managing the Left Atrial Appendage in Atrial Fibrillation: Current State of the Art.

    PubMed

    Khawar, Waqaar; Smith, Nathan; Masroor, Saqib

    2017-08-19

    Patients with atrial fibrillation are at increased risk for thromboembolic stroke originating predominantly in the left atrial appendage. To reduce the risk, the standard of care is anticoagulation. In addition, several devices for exclusion of the left atrial appendage have been developed. PubMed was searched for articles relevant to left atrial appendage management. The resulting articles were reviewed as were relevant articles in their bibliographies. Relevant journals were manually searched for sources. Devices are being used for left atrial appendage exclusion by percutaneous and surgical approaches. Their indications, limitations, and outcomes are reviewed. Excision and exclusion of the left atrial appendage is safe and as effective as medical management of atrial fibrillation for stroke prevention. The choice of treatment should be made based on patients' anatomy, history, and preference informed by an appropriate left atrial appendage management team. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

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

    MedlinePlus

    ... What Are the Signs and Symptoms of Atrial Fibrillation? Atrial fibrillation (AF) usually causes the heart's lower ... pain Dizziness or fainting Fatigue (tiredness) Confusion Atrial Fibrillation Complications AF has two major complications— stroke and ...

  14. 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.

  15. Present treatment options for atrial fibrillation

    PubMed Central

    Lairikyengbam, S; Anderson, M; Davies, A

    2003-01-01

    Atrial fibrillation is the commonest sustained cardiac arrhythmia. It accounts for >35% of all hospital admissions for cardiac arrhythmias in the United States. The presence of atrial fibrillation increases the mortality of a population by up to twofold. The risk of stroke increases from 1.5% in patients with atrial fibrillation from 50–59 years of age to up to 23.5% for such patients aged 80–89 years. Although the diagnosis of atrial fibrillation is usually straightforward, effective treatment is not. This article will discuss how rhythm control of atrial fibrillation can best be achieved, the controversy over the rhythm versus rate control, the maintenance of sinus rhythm with antiarrhythmic drugs after cardioversion, and prevention of thromboembolism. Finally, the recent advances in various non-pharmacological approaches for the treatment of atrial fibrillation will be highlighted. PMID:12612318

  16. Regulation of Myocyte Enhancer Factor-2 Transcription Factors by Neurotoxins

    PubMed Central

    She, Hua; Mao, Zixu

    2011-01-01

    Various isoforms of myocyte enhancer factor-2 (MEF2) constitute a group of nuclear proteins found to play important roles in increasing types of cells. In neurons, MEF2s are required to regulate neuronal development, synaptic plasticity, as well as survival. MEF2s promote the survival of several types of neurons under different conditions. In cellular models, negative regulation of MEF2s by stress and toxic signals contributes to neuronal death. In contrast, enhancing MEF2 activity not only protects cultured primary neurons from death in vitro but also attenuates the loss of dopaminergic neurons in substantia nigra pars compacta in a 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. In this work, the mechanisms of regulation of MEF2 function by several well-known neurotoxins and their implications in various neurodegenerative diseases are reviewed. PMID:21741404

  17. Morphologic features and nuclide composition of infarction-associated cardiac myocyte mineralization in humans.

    PubMed Central

    Lockard, V. G.; Bloom, S.

    1991-01-01

    Low dietary Mg results in Ca loading of cardiac myocytes, which increases the likelihood of myocyte calcification in the event of acute myocardial infarction (AMI), and possibly increases myocyte vulnerability to necrosis. Bloom and Peric-Golia1 previously reported an autopsy study of cases from the Washington, D.C. area (a region with low levels of Mg in the drinking water), demonstrating AMI-associated mineralization in myocytes with histologically normal nuclei and cross striations, as well as in obviously necrotic myocytes. The authors have re-examined mineralized myocytes from the same autopsy material, using electron probe microanalysis, light microscopy, and transmission electron microscopy. Microprobe analysis identified Ca and P as the nuclides composing the inorganic phase of the mineral deposits. Ultrastructurally, all Ca deposits, regardless of size or intracellular location, were composed of aggregates of needlelike hydroxyapatite crystals. The mildest form of intracellular Ca deposition was observed as small Ca deposits limited to some mitochondria of myocytes, which demonstrated intact nuclei and regular sarcomere pattern. More advanced stages of intracellular calcification, in the form of Ca deposits associated with mitochondria, Z-band regions and nuclei, were observed in other myocytes that also retained intact nuclei and sarcomeres. Massive Ca deposits were associated with myocytes which showed morphologic features of advanced necrosis, including loss of nuclei, disruption of sarcomere structure and masses of cellular debris. These observations support the theory originally proposed by Bloom and Peric-Golia1 suggesting that Ca loading of myocytes, possibly related to Mg deficiency in humans, increased vulnerability of the myocytes to subsequent AMI-associated necrosis and dystrophic calcification. In addition, the light microscopic impression of calcification of otherwise normal myocytes is contradicted by the electron microscopic identification

  18. 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.

  19. Pathology-specific effects of the IKur/Ito/IK,ACh blocker AVE0118 on ion channels in human chronic atrial fibrillation

    PubMed Central

    Christ, T; Wettwer, E; Voigt, N; Hála, O; Radicke, S; Matschke, K; Várro, A; Dobrev, D; Ravens, U

    2008-01-01

    Background and purpose This study was designed to establish the pathology-specific inhibitory effects of the IKur/Ito/IK,ACh blocker AVE0118 on atrium-selective channels and its corresponding effects on action potential shape and effective refractory period in patients with chronic AF (cAF). Experimental approach Outward K+-currents of right atrial myocytes and action potentials of atrial trabeculae were measured with whole-cell voltage clamp and microelectrode techniques, respectively. Outward currents were dissected by curve fitting. Key results Four components of outward K+-currents and AF-specific alterations in their properties were identified. Ito was smaller in cAF than in SR, and AVE0118 (10 μM) apparently accelerated its inactivation in both groups without reducing its amplitude. Amplitudes of rapidly and slowly inactivating components of IKur were lower in cAF than in SR. The former was abolished by AVE0118 in both groups, the latter was partially blocked in SR, but not in cAF, even though its inactivation was apparently accelerated in cAF. The large non-inactivating current component was similar in magnitude in both groups, but decreased by AVE0118 only in SR. AVE0118 strongly suppressed AF-related constitutively active IK,ACh and prolonged atrial action potential and effective refractory period exclusively in cAF. Conclusions and implications In atrial myocytes of cAF patients, we detected reduced function of distinct IKur components that possessed decreased component-specific sensitivity to AVE0118 most likely as a consequence of AF-induced electrical remodelling. Inhibition of profibrillatory constitutively active IK,ACh may lead to pathology-specific efficacy of AVE0118 that is likely to contribute to its ability to convert AF into SR. PMID:18536759

  20. 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

  1. [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.

  2. 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

  3. Intracellular calcium handling in ventricular myocytes from mdx mice.

    PubMed

    Williams, Iwan A; Allen, David G

    2007-02-01

    Duchenne muscular dystrophy (DMD) is a lethal degenerative disease of skeletal muscle, characterized by the absence of the cytoskeletal protein dystrophin. Some DMD patients show a dilated cardiomyopathy leading to heart failure. This study explores the possibility that dystrophin is involved in the regulation of a stretch-activated channel (SAC), which in the absence of dystrophin has increased activity and allows greater Ca(2+) into cardiomyocytes. Because cardiac failure only appears late in the progression of DMD, we examined age-related effects in the mdx mouse, an animal model of DMD. Ca(2+) measurements using a fluorescent Ca(2+)-sensitive dye fluo-4 were performed on single ventricular myocytes from mdx and wild-type mice. Immunoblotting and immunohistochemistry were performed on whole hearts to determine expression levels of key proteins involved in excitation-contraction coupling. Old mdx mice had raised resting intracellular Ca(2+) concentration ([Ca(2+)](i)). Isolated ventricular myocytes from young and old mdx mice displayed abnormal Ca(2+) transients, increased protein expression of the ryanodine receptor, and decreased protein expression of serine-16-phosphorylated phospholamban. Caffeine-induced Ca(2+) transients showed that the Na(+)/Ca(2+) exchanger function was increased in old mdx mice. Two SAC inhibitors streptomycin and GsMTx-4 both reduced resting [Ca(2+)](i) in old mdx mice, suggesting that SACs may be involved in the Ca(2+)-handling abnormalities in these animals. This finding was supported by immunoblotting data, which demonstrated that old mdx mice had increased protein expression of canonical transient receptor potential channel 1, a likely candidate protein for SACs. SACs may play a role in the pathogenesis of the heart failure associated with DMD. Early in the disease process and before the onset of clinical symptoms increased, SAC activity may underlie the abnormal Ca(2+) handling in young mdx mice.

  4. Criticality in intracellular calcium signaling in cardiac myocytes.

    PubMed

    Nivala, Michael; Ko, Christopher Y; Nivala, Melissa; Weiss, James N; Qu, Zhilin

    2012-06-06

    Calcium (Ca) is a ubiquitous second messenger that regulates many biological functions. The elementary events of local Ca signaling are Ca sparks, which occur randomly in time and space, and integrate to produce global signaling events such as intra- and intercellular Ca waves and whole-cell Ca oscillations. Despite extensive experimental characterization in many systems, the transition from local random to global synchronous events is still poorly understood. Here we show that criticality, a ubiquitous dynamical phenomenon in nature, is responsible for the transition from local to global Ca signaling. We demonstrate this first in a computational model of Ca signaling in a cardiac myocyte and then experimentally in mouse ventricular myocytes, complemented by a theoretical agent-based model to delineate the underlying dynamics. We show that the interaction between the Ca release units via Ca-induced Ca release causes self-organization of Ca spark clusters. When the coupling between Ca release units is weak, the cluster-size distribution is exponential. As the interactions become strong, the cluster-size distribution changes to a power-law distribution, which is characteristic of criticality in thermodynamic and complex nonlinear systems, and facilitates the formation and propagation of Ca waves and whole-cell Ca oscillations. Our findings illustrate how criticality is harnessed by a biological cell to regulate Ca signaling via self-organization of random subcellular events into cellular-scale oscillations, and provide a general theoretical framework for the transition from local Ca signaling to global Ca signaling in biological cells.

  5. l-Arginine currents in rat cardiac ventricular myocytes

    PubMed Central

    Peluffo, R Daniel

    2007-01-01

    l-Arginine (l-Arg) is a basic amino acid that plays a central role in the biosynthesis of nitric oxide, creatine, agmantine, polyamines, proline and glutamate. Most tissues, including myocardium, must import l-Arg from the circulation to ensure adequate intracellular levels of this amino acid. This study reports novel l-Arg-activated inward currents in whole-cell voltage-clamped rat ventricular cardiomyocytes. Ion-substitution experiments identified extracellular l-Arg as the charge-carrying cationic species responsible for these currents, which, thus, represent l-Arg import into cardiac myocytes. This result was independently confirmed by an increase in myocyte nitric oxide production upon extracellular application of l-Arg. The inward movement of Arg molecules was found to be passive and independent of Na2+, K2+, Ca2+ and Mg2+. The process displayed saturation and membrane potential (Vm)-dependent kinetics, with a K0.5 for l-Arg that increased from 5 mm at hyperpolarizing Vm to 20 mm at +40 mV. l-Lysine and l-ornithine but not d-Arg produced currents with characteristics similar to that activated by l-Arg indicating that the transport process is stereospecific for cationic l-amino acids. l-Arg current was fully blocked after brief incubation with 0.2 mmN-ethylmaleimide. These features suggest that the activity of the low-affinity, high-capacity CAT-2A member of the y2+ family of transporters is responsible for l-Arg currents in acutely isolated cardiomyocytes. Regardless of the mechanism, we hypothesize that a low-affinity arginine transport process in heart, by ensuring substrate availability for sustained NO production, might play a cardio-protective role during catabolic states known to increase Arg plasma levels severalfold. PMID:17303641

  6. 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

  7. Association evidence of CCTTT repeat polymorphism in the iNOS promoter and the risk of atrial fibrillation in Taiwanese

    PubMed Central

    Hsu, Lung-An; Yeh, Yung-Hsin; Chen, Wei-Jan; Kuo, Chi-Tai; Tsai, Feng-Chun; Chan, Yi-Hsin; Wang, Chun-Li; Chang, Chi-Jen; Tsai, Hsin-Yi

    2017-01-01

    Inducible nitric oxide synthase (iNOS) plays an important role in the pathogenesis of atrial fibrillation (AF). The iNOS promoter has a CCTTT-repeat length polymorphism that can determine the level of gene transcription. This study enrolled 200 AF patients and 240 controls. The length of CCTTT-repeat polymorphism in the iNOS promoter region was examined by polymerase chain reactions, with the alleles with ≤11 repeats designated as S and alleles with ≥12 repeats designated as L alleles. AF patients carried significantly higher frequencies of the LL genotype than control subjects (40.0% versus 28.3%, P = 0.010). Multivariate analysis showed that the presence of LL genotype was significantly associated with AF (odds ratio: 1.87, 95% CI = 1.10–3.17, P = 0.021). In vitro, transient transfection assay in HL-1 atrial myocytes showed that the responsiveness of iNOS transcriptional activity to tachypacing was correlated with the length of the CCTTT-repeats. Right atrial tissues from patients with chronic AF were investigated with immunoconfocal microscopy. Patients with LL genotype exhibited greater oxidative stress and substrate remodeling in their atria than those with non-LL genotypes. Our results suggest that the iNOS microsatellite polymorphism may contribute to the genetic background of AF in Chinese-Taiwanese patients. PMID:28205526

  8. Controlled Atrial Fibrillation after Pulmonary Vein Stenting

    PubMed Central

    Park, Young-Ah; Seo, Jiwon

    2017-01-01

    When there is no pulmonary vein reconnection after catheter ablation for atrial fibrillation, patients can experience recurrence of atrial fibrillation without clear evidence of non-pulmonary vein foci. We describe a patient with significant pulmonary vein stenosis and recurrent atrial fibrillation after four ablation procedures. After successful pulmonary vein stenting, the symptoms were resolved, and sinus rhythm was maintained for 2 years without treatment with antiarrhythmic medication. We believe pulmonary vein stenting potentially controlled atrial fibrillation by providing pulmonary vein pressure relief or by compressing the epicardial triggers occurring at the pulmonary vein ostium. PMID:28765746

  9. Ventricular expression of atrial natriuretic polypeptide and its relations with hemodynamics and histology in dilated human hearts. Immunohistochemical study of the endomyocardial biopsy specimens.

    PubMed

    Takemura, G; Fujiwara, H; Horike, K; Mukoyama, M; Saito, Y; Nakao, K; Matsuda, M; Kawamura, A; Ishida, M; Kida, M

    1989-11-01

    To investigate the mechanism of expression of atrial natriuretic polypeptide (ANP) in human ventricles, we conducted an immunohistochemical study of ANP in biventricular endomyocardial biopsy specimens obtained from a total of 49 patients with cardiac dilatation due to dilated cardiomyopathy (21 patients), postmyocarditis (18 patients), or volume overload (five patients) and subjects with no dilatation as controls (five patients). Four-micron thick sections were stained by an indirect immunoperoxidase method using monoclonal antibody to alpha-human ANP as the primary antibody. The frequency of ANP-present myocytes was calculated in each specimen and compared with clinical, echocardiographic, hemodynamic, angiographic, and histologic parameters. ANP-present myocytes were noted in all of the 21 patients with dilated cardiomyopathy, in 11 of the 18 patients with postmyocarditis, in four of the five patients with volume overload, and in zero of the five controls. The mean percentage of ANP-present myocytes was significantly greater in the left-side specimens (35 +/- 37%) than in the right-side ones (2 +/- 4%). The percentage of ANP-present myocytes in the left-side specimens significantly correlated with peak systolic or end-diastolic wall stress (r = 0.67 and 0.58), left ventricular end-systolic or end-diastolic volume index (r = 0.75 and 0.69), or left ventricular end-diastolic pressure (r = 0.42) and inversely correlated with ejection fraction (r = -0.73), systolic left ventricular wall thickness (r = -0.58), or cardiac index (r = -0.30). Expression of ANP was rarely seen in the cases with normal wall stresses, normal ejection fraction, normal volume, or normal myocyte size. However, it was seen frequently even in hearts with normal levels of left ventricular end-diastolic pressure and cardiac index (compensated hearts). The percent of ANP-present myocytes in both sides significantly correlated with size of myocytes (r = 0.48 at right and r = 0.57 at left side) or

  10. 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

  11. 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…

  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…

  13. Regional native plant strategies

    Treesearch

    Wendell G. Hassell

    1999-01-01

    Because of increasing public interest in native plants, regional groups have been cooperating to develop native species. The Federal Native Plants Initiative was formed in 1994 to coordinate and encourage the development and use of native plants. The program they developed includes public involvement, organizational structure, technical work groups, implementation...

  14. Mechanisms of arrhythmogenesis related to calcium-driven alternans in a model of human atrial fibrillation

    PubMed Central

    Chang, Kelly C.; Trayanova, Natalia A.

    2016-01-01

    The occurrence of atrial fibrillation (AF) is associated with progressive changes in the calcium handling system of atrial myocytes. Calcium cycling instability has been implicated as an underlying mechanism of electrical alternans observed in patients who experience AF. However, the extent to which calcium-induced alternation of electrical activity in the atria contributes to arrhythmogenesis is unknown. In this study, we investigated the effects of calcium-driven alternans (CDA) on arrhythmia susceptibility in a biophysically detailed, 3D computer model of the human atria representing electrical and structural remodeling secondary to chronic AF. We found that elevated propensity to CDA rendered the atria vulnerable to ectopy-induced arrhythmia. It also increased the complexity and persistence of arrhythmias induced by fast pacing, with unstable scroll waves meandering and frequently breaking up to produce multiple wavelets. Our results suggest that calcium-induced electrical instability may increase arrhythmia vulnerability and promote increasing disorganization of arrhythmias in the chronic AF-remodeled atria, thus playing an important role in the progression of the disease. PMID:27812021

  15. Mechanisms of arrhythmogenesis related to calcium-driven alternans in a model of human atrial fibrillation

    NASA Astrophysics Data System (ADS)

    Chang, Kelly C.; Trayanova, Natalia A.

    2016-11-01

    The occurrence of atrial fibrillation (AF) is associated with progressive changes in the calcium handling system of atrial myocytes. Calcium cycling instability has been implicated as an underlying mechanism of electrical alternans observed in patients who experience AF. However, the extent to which calcium-induced alternation of electrical activity in the atria contributes to arrhythmogenesis is unknown. In this study, we investigated the effects of calcium-driven alternans (CDA) on arrhythmia susceptibility in a biophysically detailed, 3D computer model of the human atria representing electrical and structural remodeling secondary to chronic AF. We found that elevated propensity to CDA rendered the atria vulnerable to ectopy-induced arrhythmia. It also increased the complexity and persistence of arrhythmias induced by fast pacing, with unstable scroll waves meandering and frequently breaking up to produce multiple wavelets. Our results suggest that calcium-induced electrical instability may increase arrhythmia vulnerability and promote increasing disorganization of arrhythmias in the chronic AF-remodeled atria, thus playing an important role in the progression of the disease.

  16. Cytoplasm resistivity of mammalian atrial myocardium determined by dielectrophoresis and impedance methods.

    PubMed

    Fry, Christopher H; Salvage, Samantha C; Manazza, Alessandra; Dupont, Emmanuel; Labeed, Fatima H; Hughes, Michael P; Jabr, Rita I

    2012-12-05

    Many cardiac arrhythmias are caused by slowed conduction of action potentials, which in turn can be due to an abnormal increase of intracellular myocardial resistance. Intracellular resistivity is a linear sum of that offered by gap junctions between contiguous cells and the cytoplasm of the myocytes themselves. However, the relative contribution of the two components is unclear, especially in atrial myocardium, as there are no precise measurements of cytoplasmic resistivity, R(c). In this study, R(c) was measured in atrial tissue using several methods: a dielectrophoresis technique with isolated cells and impedance measurements with both isolated cells and multicellular preparations. All methods yielded similar values for R(c), with a mean of 138 ± 5 Ω·cm at 23°C, and a Q(10) value of 1.20. This value is about half that of total intracellular resistivity and thus will be a significant determinant of the actual value of action potential conduction velocity. The dielectrophoresis experiments demonstrated the importance of including divalent cations (Ca(2+) and Mg(2+)) in the suspension medium, as their omission reduced cell integrity by lowering membrane resistivity and increasing cytoplasm resistivity. Accurate measurement of R(c) is essential to develop quantitative computational models that determine the key factors contributing to the development of cardiac arrhythmias. Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  17. Cytoplasm Resistivity of Mammalian Atrial Myocardium Determined by Dielectrophoresis and Impedance Methods

    PubMed Central

    Fry, Christopher H.; Salvage, Samantha C.; Manazza, Alessandra; Dupont, Emmanuel; Labeed, Fatima H.; Hughes, Michael P.; Jabr, Rita I.

    2012-01-01

    Many cardiac arrhythmias are caused by slowed conduction of action potentials, which in turn can be due to an abnormal increase of intracellular myocardial resistance. Intracellular resistivity is a linear sum of that offered by gap junctions between contiguous cells and the cytoplasm of the myocytes themselves. However, the relative contribution of the two components is unclear, especially in atrial myocardium, as there are no precise measurements of cytoplasmic resistivity, Rc. In this study, Rc was measured in atrial tissue using several methods: a dielectrophoresis technique with isolated cells and impedance measurements with both isolated cells and multicellular preparations. All methods yielded similar values for Rc, with a mean of 138 ± 5 Ω·cm at 23°C, and a Q10 value of 1.20. This value is about half that of total intracellular resistivity and thus will be a significant determinant of the actual value of action potential conduction velocity. The dielectrophoresis experiments demonstrated the importance of including divalent cations (Ca2+ and Mg2+) in the suspension medium, as their omission reduced cell integrity by lowering membrane resistivity and increasing cytoplasm resistivity. Accurate measurement of Rc is essential to develop quantitative computational models that determine the key factors contributing to the development of cardiac arrhythmias. PMID:23283227

  18. Assessment of atrial electromechanical interval using echocardiography after catheter ablation in patients with persistent atrial fibrillation

    PubMed Central

    Chen, Xiaodong; Chen, Minglong; Wang, Yingying; Yang, Bing; Ju, Weizhu; Zhang, Fengxiang; Cao, Kejiang

    2016-01-01

    Abstract We sought to investigate variation of atrial electromechanical interval after catheter ablation procedure in patients with persistent atrial fibrillation using pulse Doppler (PW) and pulse tissue Doppler imaging (PW-TDI). A total of 25 consecutive in-patients with persistent atrial fibrillation, who restored sinus rhythm after ablation procedure, were recruited in our cardiac center. Echocardiography was performed on each patient at 2 hours, 1 day, 5 days, 1 month and 3 months after the ablation therapy, and atrial electromechanical delay was measured simultaneously by PW and PW-TDI. There was no significant difference between PW and TDI in measuring atrial electromechanical delay. However, at postoperative 2 hours, peak A detection rates were mathematically but nonsignificantly greater by PW-TDI than by PW. Second, there was a significant decreasing trend in atrial electromechanical interval from postoperative 2 hours to 3 months, but only postoperative 2-hour atrial electromechanical interval was significantly greater than atrial electromechanical interval at other time. Lastly, patients without postoperative 2-hour atrial electromechanical interval had a significantly longer duration of atrial fibrillation as compared to those with postoperative 2-hour atrial electromechanical interval, by the PW or by PW-TDI, respectively. In patients with persistent atrial fibrillation, atrial electromechanical interval may decrease significantly within the first 24 hours after ablation but remain consistent later, and was significantly related to patients’ duration of atrial fibrillation. Atrial electromechanical interval, as a potential predicted factor, is recommended to be measured by either PW or TDI after 24 hours, when patients had recovered sinus rhythm by radiofrequency ablation. PMID:27924066

  19. Effect of atrial antitachycardia pacing treatments in patients with an atrial defibrillator: randomised study comparing subthreshold and nominal pacing outputs

    PubMed Central

    Mitchell, A R J; Spurrell, P A R; Cheatle, L; Sulke, N

    2002-01-01

    Objective: To assess the true efficacy of antitachycardia pacing on spontaneous persistent atrial fibrillation in patients with an implanted atrial defibrillator, by comparing the effects of nominal pacing treatment with subthreshold pacing treatment. Design: The effects of antitachycardia pacing and burst 50 Hz atrial pacing on spontaneous atrial arrhythmias were evaluated six months after implantation of a Medtronic Jewel AF® atrial defibrillator. Setting: Cardiology department in a district general hospital. Patients: 15 patients with persistent atrial fibrillation. Interventions: Patients were randomised to either “nominal” output pacing treatment or surface ECG and endocardial electrogram proven subthreshold “sham” pacing treatment for three months, and then crossed over to the alternative treatment for a further three months. Results: During the nominal output phase, 31 episodes of atrial fibrillation were treated with 53 bursts of 50 Hz pacing, 98 sequences of ramp atrial pacing, and 61 sequences of burst atrial pacing. Atrial fibrillation was not pace terminated during any episode. Thirty one episodes of atrial tachycardia were treated with 19 bursts of 50 Hz atrial pacing, 103 sequences of ramp atrial pacing, and 38 sequences of burst atrial pacing. Termination of atrial tachycardia was observed in 17 episodes. During the “sham” pacing period, no episodes were terminated by any pacing treatment. Conclusion: Atrial antitachycardia pacing treatments are ineffective at terminating persistent atrial fibrillation but may be useful in terminating episodes of atrial tachycardia or flutter, thus reducing the burden of arrhythmia. PMID:11997413

  20. De Novo Human Cardiac Myocytes for Medical Research: Promises and Challenges

    PubMed Central

    Hamel, Veronique; Cheng, Kang; Liao, Shudan; Lu, Aizhu; Zheng, Yong; Chen, Yawen; Xie, Yucai

    2017-01-01

    The advent of cellular reprogramming technology has revolutionized biomedical research. De novo human cardiac myocytes can now be obtained from direct reprogramming of somatic cells (such as fibroblasts), from induced pluripotent stem cells (iPSCs, which are reprogrammed from somatic cells), and from human embryonic stem cells (hESCs). Such de novo human cardiac myocytes hold great promise for in vitro disease modeling and drug screening and in vivo cell therapy of heart disease. Here, we review the technique advancements for generating de novo human cardiac myocytes. We also discuss several challenges for the use of such cells in research and regenerative medicine, such as the immature phenotype and heterogeneity of de novo cardiac myocytes obtained with existing protocols. We focus on the recent advancements in addressing such challenges. PMID:28303153

  1. 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.

  2. Characterization of human septic sera induced gene expression modulation in human myocytes

    PubMed Central

    Hussein, Shaimaa; Michael, Paul; Brabant, Danielle; Omri, Abdelwahab; Narain, Ravin; Passi, Kalpdrum; Ramana, Chilakamarti V.; Parrillo, Joseph E.; Kumar, Anand; Parissenti, Amadeo; Kumar, Aseem

    2009-01-01

    To gain a better understanding of the gene expression changes that occurs during sepsis, we have performed a cDNA microarray study utilizing a tissue culture model that mimics human sepsis. This study utilized an in vitro model of cultured human fetal cardiac myocytes treated with 10% sera from septic patients or 10% sera from healthy volunteers. A 1700 cDNA expression microarray was used to compare the transcription profile from human cardiac myocytes treated with septic sera vs normal sera. Septic sera treatment of myocytes resulted in the down-regulation of 178 genes and the up-regulation of 4 genes. Our data indicate that septic sera induced cell cycle, metabolic, transcription factor and apoptotic gene expression changes in human myocytes. Identification and characterization of gene expression changes that occur during sepsis may lead to the development of novel therapeutics and diagnostics. PMID:19684886

  3. Ontogeny of Ca2+-induced Ca2+ release in rabbit ventricular myocytes.

    PubMed

    Huang, Jingbo; Hove-Madsen, Leif; Tibbits, Glen F

    2008-02-01

    It is commonly accepted that L-type Ca(2+) channel-mediated Ca(2+)-induced Ca(2+) release (CICR) is the dominant mode of excitation-contraction (E-C) coupling in the adult mammalian heart and that there is no appreciable CICR in neonates. However, we have observed that cell contraction in the neonatal heart was significantly decreased after sarcoplasmic reticulum (SR) Ca(2+) depletion with caffeine. Therefore, the present study investigated the developmental changes of CICR in rabbit ventricular myocytes at 3, 10, 20, and 56 days of age. We found that the inhibitory effect of the L-type Ca(2+) current (I(Ca)) inhibitor nifedipine (Nif; 15 microM) caused an increasingly larger reduction of Ca(2+) transients on depolarization in older age groups [from approximately 15% in 3-day-old (3d) myocytes to approximately 90% in 56-day-old (56d) myocytes]. The remaining Ca(2+) transient in the presence of Nif in younger age groups was eliminated by the inhibition of Na(+)/Ca(2+) exchanger (NCX) with the subsequent addition of 10 microM KB-R7943 (KB-R). Furthermore, Ca(2+) transients were significantly reduced in magnitude after the depletion of SR Ca(2+) with caffeine in all age groups, although the effect was significantly greater in the older age groups (from approximately 40% in 3d myocytes up to approximately 70% in 56d myocytes). This SR Ca(2+)-sensitive Ca(2+) transient in the earliest developmental stage was insensitive to Nif but was sensitive to the subsequent addition of KB-R, indicating the presence of NCX-mediated CICR that decreased significantly with age (from approximately 37% in 3d myocytes to approximately 0.5% in 56d myocytes). In contrast, the I(Ca)-mediated CICR increased significantly with age (from approximately 10% in 3d myocytes to approximately 70% in 56d myocytes). The CICR gain as estimated by the integral of the CICR Ca(2+) transient divided by the integral of its Ca(2+) transient trigger was smaller when mediated by NCX ( approximately 1.0 for 3d

  4. 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

  5. [Right atrial appendage thrombosis during atrial fibrillation: an element to look for].

    PubMed

    Barbati, Giovanni; De Domenico, Renato; Rossi, Stefania; Vecchiato, Elena; Zeppellini, Roberto

    2017-03-01

    Oral anticoagulant therapy (OAT) is a mainstay of atrial fibrillation (AF) pharmacological treatment. Left atrial appendage closure is a possible treatment, when feasible, in patients with intracerebral hemorrhage during OAT. We report a case of right atrial appendage thrombosis in a patient with chronic AF admitted for syncope due to diuretic-induced orthostatic hypotension. Two years previously, he had undergone left atrial appendage closure with the Amplatzer Cardiac Plug device because of intracerebral hemorrhage during OAT. After neurological consult, OAT was resumed with apixaban 5 mg twice daily, and transesophageal echocardiography performed two months later showed complete resolution of the right atrial appendage thrombosis. This particular case underlines the importance of searching for a possible right atrial appendage thrombosis in patients affected by AF, and suggests that left atrial appendage closure in AF patients not suitable for OAT does not fully eliminate the risk of thromboembolism.

  6. Incidence, Risk Factors, Prognosis, and Electrophysiological Mechanisms of Atrial Arrhythmias after Lung Transplantation

    PubMed Central

    Chaikriangkrai, Kongkiat; Jyothula, Soma; Jhun, Hye Yeon; Chang, Su Min; Graviss, Edward A.; Shuraih, Mossaab; Rami, Tapan G.; Dave, Amish S.; Valderrábano, Miguel

    2015-01-01

    Objective To investigate incidence and timing, risk factors, prognostic significance, and electrophysiological mechanisms of atrial arrhythmia (AA) after lung transplantation. Background Although new-onset AA is common after thoracic surgery and is associated with poorer outcomes, prognostic and mechanistic data is sparse in lung transplant populations. Method A total of 293 consecutive isolated lung transplant recipients without known AA were retrospectively reviewed. Mean follow-up was 28±17 months. Electrophysiology studies (EPS) were performed in 25 patients with AA. Results The highest incidence of new-onset AA after lung transplantation occurred within 30 days postoperative AA, (25 % of all patients). In multivariable analysis, postoperative AA was associated with double lung transplantation (OR 2.79; p=0.005) and lower mean pulmonary artery pressure (OR 0.95; p=0.027). Patients with postoperative AA had longer hospital stays (21 days vs 12 days; p<0.001). Postoperative AA was independently associated with late AA (HR 13.52; p<0.001) but not mortality (HR 1.55; p=0.14). In EPS, there were 14 patients with atrial flutter alone and 11 with atrial flutter and fibrillation. Of all EPS patients, 20 (80%) had multiple AA mechanisms, including peritricuspid flutter (48%), perimitral flutter (36%), right atrial incisional reentry (24%), focal tachycardia from recipient pulmonary vein (PV) antrum (32 %), focal PV fibrillation (24%), and left atrial roof flutter (20%). Left atrial mechanisms were present in 80% (20/25) of EPS patients and originated from the anastomotic PV antrum. Conclusions Postoperative AA was independently associated with longer length of stay and late AA but not mortality. Pleomorphic PV antral arrhythmogenesis from native PV antrum is the main cause of AA after lung transplantation. PMID:26557726

  7. Decreased expression of ryanodine receptors alters calcium-induced calcium release mechanism in mdx duodenal myocytes.

    PubMed

    Morel, Jean-Luc; Rakotoarisoa, Lala; Jeyakumar, Loice H; Fleischer, Sidney; Mironneau, Chantal; Mironneau, Jean

    2004-05-14

    It is generally believed that alterations of calcium homeostasis play a key role in skeletal muscle atrophy and degeneration observed in Duchenne's muscular dystrophy and mdx mice. Mechanical activity is also impaired in gastrointestinal muscles, but the cellular and molecular mechanisms of this pathological state have not yet been investigated. We showed, in mdx duodenal myocytes, that both caffeine- and depolarization-induced calcium responses were inhibited, whereas acetylcholine- and thapsigargin-induced calcium responses were not significantly affected compared with control mice. Calcium-induced calcium release efficiency was impaired in mdx duodenal myocytes depending only on inhibition of ryanodine receptor expression. Duodenal myocytes expressed both type 2 and type 3 ryanodine receptors and were unable to produce calcium sparks. In control and mdx duodenal myocytes, both caffeine- and depolarization-induced calcium responses were dose-dependently and specifically inhibited with the anti-type 2 ryanodine receptor antibody. A strong inhibition of type 2 ryanodine receptor in mdx duodenal myocytes was observed on the mRNA as well as on the protein level. Taken together, our results suggest that inhibition of type 2 ryanodine receptor expression in mdx duodenal myocytes may account for the decreased calcium release from the sarcoplasmic reticulum and reduced mechanical activity.

  8. Dynamics of AV coupling during human atrial fibrillation: role of atrial rate.

    PubMed

    Masè, M; Marini, M; Disertori, M; Ravelli, F

    2015-07-01

    The causal relationship between atrial and ventricular activities during human atrial fibrillation (AF) is poorly understood. This study analyzed the effects of an increase in atrial rate on the link between atrial and ventricular activities during AF. Atrial and ventricular time series were determined in 14 patients during the spontaneous acceleration of the atrial rhythm at AF onset. The dynamic relationship between atrial and ventricular activities was quantified in terms of atrioventricular (AV) coupling by AV synchrogram analysis. The technique identified n:m coupling patterns (n atrial beats in m ventricular cycles), quantifying their percentage, maximal length, and conduction ratio (= m/n). Simulations with a difference-equation AV model were performed to correlate the observed dynamics to specific atrial/nodal properties. The atrial rate increase significantly affected AV coupling and ventricular response during AF. The shortening of atrial intervals from 185 ± 32 to 165 ± 24 ms (P < 0.001) determined transitions toward AV patterns with progressively decreasing m/n ratios (from conduction ratio = 0.34 ± 0.09 to 0.29 ± 0.08, P < 0.01), lower occurrence (from percentage of coupled beats = 27.1 ± 8.0 to 21.8 ± 6.9%, P < 0.05), and higher instability (from maximal length = 3.9 ± 1.5 to 2.8 ± 0.7 s, P < 0.01). Advanced levels of AV block and coupling instability at higher atrial rates were associated with increased ventricular interval variability (from 123 ± 52 to 133 ± 55 ms, P < 0.05). AV pattern transitions and coupling instability in patients were predicted, assuming the filtering of high-rate irregular atrial beats by the slow recovery of nodal excitability. These results support the role of atrial rate in determining AV coupling and ventricular response and may have implications for rate control in AF.

  9. 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.

  10. Giant right atrial thrombi treated with thrombolysis

    PubMed Central

    Ruiz-Bailén, Manuel; López-Caler, Carmen; Castillo-Rivera, Ana; Rucabado-Aguilar, Luis; Cuadra, José Ángel Ramos; Toral, Juan Lara; Cabezas, Cristobal Lozano; Guerrero, Juan Carlos Fernández

    2008-01-01

    The present report describes giant atrial thrombi that were treated with thrombolysis in a community hospital. Two patients with giant atrial thrombi whose treatment involved complications are presented. Both patients developed cardiogenic shock and were treated unsuccessfully with thrombolysis. Because thrombolysis of giant thrombi may be ineffective, patients in this situation may require surgery. PMID:18401474

  11. [Typical atrial flutter: Diagnosis and therapy].

    PubMed

    Thomas, Dierk; Eckardt, Lars; Estner, Heidi L; Kuniss, Malte; Meyer, Christian; Neuberger, Hans-Ruprecht; Sommer, Philipp; Steven, Daniel; Voss, Frederik; Bonnemeier, Hendrik

    2016-03-01

    Typical, cavotricuspid-dependent atrial flutter is the most common atrial macroreentry tachycardia. The incidence of atrial flutter (typical and atypical forms) is age-dependent with 5/100,000 in patients less than 50 years and approximately 600/100,000 in subjects > 80 years of age. Concomitant heart failure or pulmonary disease further increases the risk of typical atrial flutter.Patients with atrial flutter may present with symptoms of palpitations, reduced exercise capacity, chest pain, or dyspnea. The risk of thromboembolism is probably similar to atrial fibrillation; therefore, the same antithrombotic prophylaxis is required in atrial flutter patients. Acutely symptomatic cases may be subjected to cardioversion or pharmacologic rate control to relieve symptoms. Catheter ablation of the cavotricuspid isthmus represents the primary choice in long-term therapy, associated with high procedural success (> 97 %) and low complication rates (0.5 %).This article represents the third part of a manuscript series designed to improve professional education in the field of cardiac electrophysiology. Mechanistic and clinical characteristics as well as management of isthmus-dependent atrial flutter are described in detail. Electrophysiological findings and catheter ablation of the arrhythmia are highlighted.

  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. PMID:27695187

  13. Giant right atrial thrombi treated with thrombolysis.

    PubMed

    Ruiz-Bailén, Manuel; López-Caler, Carmen; Castillo-Rivera, Ana; Rucabado-Aguilar, Luis; Ramos Cuadra, José Angel; Lara Toral, Juan; Lozano Cabezas, Cristobal; Fernández Guerrero, Juan Carlos

    2008-04-01

    The present report describes giant atrial thrombi that were treated with thrombolysis in a community hospital. Two patients with giant atrial thrombi whose treatment involved complications are presented. Both patients developed cardiogenic shock and were treated unsuccessfully with thrombolysis. Because thrombolysis of giant thrombi may be ineffective, patients in this situation may require surgery.

  14. 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.

  15. Is there a synergic effect of propafenone associated with atrial overdrive pacing for atrial arrhythmia prevention? A randomised crossover study

    PubMed Central

    Garrigue, S; Barold, S; Cazeau, S; Hocini, M; Jais, P; Haissaguerre, M; Clementy, J

    2000-01-01

    OBJECTIVE—To assess the effect of adding propafenone to atrial overdrive for the prevention of atrial arrhythmia episodes in patients with DDD pacemakers.
DESIGN—22 patients (8 female, 14 male, mean (SD) age 67 (9) years, range 48 to 77) with DDD pacemakers and frequent paroxysmal atrial arrhythmia episodes were evaluated in a randomised crossover study.
SETTING—University hospital.
METHODS—Atrial overdrive was defined as a paced rate of 10 paced beats/min above the mean ventricular rate stored for the last 24 hours in the pacemaker memory function. The protocol consisted of two phases of one month each. The first phase consisted of atrial overdrive alone, while in the second phase, propafenone (600 mg/day) was added to atrial overdrive (atrial overdrive + propafenone). All 22 patients underwent the two phases in random order.
RESULTS—Mean ventricular rate was 72 (8) beats/min with atrial overdrive v 73 (6) with atrial overdrive + propafenone (NS). With atrial overdrive, 14 patients (64.6%) had no recorded atrial arrhythmia v 15 (68.2%) with atrial overdrive + propafenone (NS). There was no statistical difference between the atrial overdrive and atrial overdrive + propafenone phases with regard to the number of atrial arrhythmia episodes (14 (27) v 13 (28)), their total duration (30 (78) v 29 (63) h), and their maximum duration (41 (72) v 31 (58) min). However, in the brady-tachy subgroup with persistent atrial arrhythmias, atrial overdrive + propafenone produced a shorter mean cumulative duration of atrial arrhythmia than atrial overdrive (104 (115) v 178 (149) h, p = 0.04), with a significant decrease in the number of atrial arrhythmia episodes (134 (98) v 102 (83), p = 0.05). The proportion of asymptomatic atrial arrhythmia episodes increased only in the AV block group during atrial overdrive + propafenone (p = 0.03). Three patients had atrial arrhythmias during atrial overdrive + propafenone but not

  16. β-Adrenergic stimulation increases Cav3.1 activity in cardiac myocytes through protein kinase A.

    PubMed

    Li, Yingxin; Wang, Fang; Zhang, Xiaoying; Qi, Zhao; Tang, Mingxin; Szeto, Christopher; Li, Ying; Zhang, Hongyu; Chen, Xiongwen

    2012-01-01

    The T-type Ca(2+) channel (TTCC) plays important roles in cellular excitability and Ca(2+) regulation. In the heart, TTCC is found in the sinoatrial nodal (SAN) and conduction cells. Cav3.1 encodes one of the three types of TTCCs. To date, there is no report regarding the regulation of Cav3.1 by β-adrenergic agonists, which is the topic of this study. Ventricular myocytes (VMs) from Cav3.1 double transgenic (TG) mice and SAN cells from wild type, Cav3.1 knockout, or Cav3.2 knockout mice were used to study β-adrenergic regulation of overexpressed or native Cav3.1-mediated T-type Ca(2+) current (I(Ca-T(3.1))). I(Ca-T(3.1)) was not found in control VMs but was robust in all examined TG-VMs. A β-adrenergic agonist (isoproterenol, ISO) and a cyclic AMP analog (dibutyryl-cAMP) significantly increased I(Ca-T(3.1)) as well as I(Ca-L) in TG-VMs at both physiological and room temperatures. The ISO effect on I(Ca-L) and I(Ca-T) in TG myocytes was blocked by H89, a PKA inhibitor. I(Ca-T) was detected in control wildtype SAN cells but not in Cav3.1 knockout SAN cells, indicating the identity of I(Ca-T) in normal SAN cells is mediated by Cav3.1. Real-time PCR confirmed the presence of Cav3.1 mRNA but not mRNAs of Cav3.2 and Cav3.3 in the SAN. I(Ca-T) in SAN cells from wild type or Cav3.2 knockout mice was significantly increased by ISO, suggesting native Cav3.1 channels can be upregulated by the β-adrenergic (β-AR) system. In conclusion, β-adrenergic stimulation increases I(Ca-T(3.1)) in cardiomyocytes(,) which is mediated by the cAMP/PKA pathway. The upregulation of I(Ca-T(3.1)) by the β-adrenergic system could play important roles in cellular functions involving Cav3.1.

  17. Modeling CICR in rat ventricular myocytes: voltage clamp studies

    PubMed Central

    2010-01-01

    Background The past thirty-five years have seen an intense search for the molecular mechanisms underlying calcium-induced calcium-release (CICR) in cardiac myocytes, with voltage clamp (VC) studies being the leading tool employed. Several VC protocols including lowering of extracellular calcium to affect Ca2+ loading of the sarcoplasmic reticulum (SR), and administration of blockers caffeine and thapsigargin have been utilized to probe the phenomena surrounding SR Ca2+ release. Here, we develop a deterministic mathematical model of a rat ventricular myocyte under VC conditions, to better understand mechanisms underlying the response of an isolated cell to calcium perturbation. Motivation for the study was to pinpoint key control variables influencing CICR and examine the role of CICR in the context of a physiological control system regulating cytosolic Ca2+ concentration ([Ca2+]myo). Methods The cell model consists of an electrical-equivalent model for the cell membrane and a fluid-compartment model describing the flux of ionic species between the extracellular and several intracellular compartments (cell cytosol, SR and the dyadic coupling unit (DCU), in which resides the mechanistic basis of CICR). The DCU is described as a controller-actuator mechanism, internally stabilized by negative feedback control of the unit's two diametrically-opposed Ca2+ channels (trigger-channel and release-channel). It releases Ca2+ flux into the cyto-plasm and is in turn enclosed within a negative feedback loop involving the SERCA pump, regulating[Ca2+]myo. Results Our model reproduces measured VC data published by several laboratories, and generates graded Ca2+ release at high Ca2+ gain in a homeostatically-controlled environment where [Ca2+]myo is precisely regulated. We elucidate the importance of the DCU elements in this process, particularly the role of the ryanodine receptor in controlling SR Ca2+ release, its activation by trigger Ca2+, and its refractory characteristics

  18. Acute Simvastatin Inhibits KATP Channels of Porcine Coronary Artery Myocytes

    PubMed Central

    Zhang, Qian; Li, Rachel Wai Sum; Kong, Siu Kai; Ngai, Sai Ming; Wan, Song; Ho, Ho Pui; Lee, Simon Ming Yuen; Hoi, Maggie Pui Man; Chan, Shun Wan; Leung, George Pak Heng; Kwan, Yiu Wa

    2013-01-01

    Background Statins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors) consumption provides beneficial effects on cardiovascular systems. However, effects of statins on vascular KATP channel gatings are unknown. Methods Pig left anterior descending coronary artery and human left internal mammary artery were isolated and endothelium-denuded for tension measurements and Western immunoblots. Enzymatically-dissociated/cultured arterial myocytes were used for patch-clamp electrophysiological studies and for [Ca2+]i, [ATP]i and [glucose]o uptake measurements. Results The cromakalim (10 nM to 10 µM)- and pinacidil (10 nM to 10 µM)-induced concentration-dependent relaxation of porcine coronary artery was inhibited by simvastatin (3 and 10 µM). Simvastatin (1, 3 and 10 µM) suppressed (in okadaic acid (10 nM)-sensitive manner) cromakalim (10 µM)- and pinacidil (10 µM)-mediated opening of whole-cell KATP channels of arterial myocytes. Simvastatin (10 µM) and AICAR (1 mM) elicited a time-dependent, compound C (1 µM)-sensitive [3H]-2-deoxy-glucose uptake and an increase in [ATP]i levels. A time (2–30 min)- and concentration (0.1–10 µM)-dependent increase by simvastatin of p-AMPKα-Thr172 and p-PP2A-Tyr307 expression was observed. The enhanced p-AMPKα-Thr172 expression was inhibited by compound C, ryanodine (100 µM) and KN93 (10 µM). Simvastatin-induced p-PP2A-Tyr307 expression was suppressed by okadaic acid, compound C, ryanodine, KN93, phloridzin (1 mM), ouabain (10 µM), and in [glucose]o-free or [Na+]o-free conditions. Conclusions Simvastatin causes ryanodine-sensitive Ca2+ release which is important for AMPKα-Thr172 phosphorylation via Ca2+/CaMK II. AMPKα-Thr172 phosphorylation causes [glucose]o uptake (and an [ATP]i increase), closure of KATP channels, and phosphorylation of AMPKα-Thr172 and PP2A-Tyr307 resulted. Phosphorylation of PP2A-Tyr307 occurs at a site downstream of AMPKα-Thr172 phosphorylation. PMID:23799098

  19. Endothelial actions of atrial and B-type natriuretic peptides

    PubMed Central

    Kuhn, Michaela

    2012-01-01

    The cardiac hormone atrial natriuretic peptide (ANP) is critically involved in the maintenance of arterial blood pressure and intravascular volume homeostasis. Its cGMP-producing GC-A receptor is densely expressed in the microvascular endothelium of the lung and systemic circulation, but the functional relevance is controversial. Some studies reported that ANP stimulates endothelial cell permeability, whereas others described that the peptide attenuates endothelial barrier dysfunction provoked by inflammatory agents such as thrombin or histamine. Many studies in vitro addressed the effects of ANP on endothelial proliferation and migration. Again, both pro- and anti-angiogenic properties were described. To unravel the role of the endothelial actions of ANP in vivo, we inactivated the murine GC-A gene selectively in endothelial cells by homologous loxP/Cre-mediated recombination. Our studies in these mice indicate that ANP, via endothelial GC-A, increases endothelial albumin permeability in the microcirculation of the skin and skeletal muscle. This effect is critically involved in the endocrine hypovolaemic, hypotensive actions of the cardiac hormone. On the other hand the homologous GC-A-activating B-type NP (BNP), which is produced by cardiac myocytes and many other cell types in response to stressors such as hypoxia, possibly exerts more paracrine than endocrine actions. For instance, within the ischaemic skeletal muscle BNP released from activated satellite cells can improve the regeneration of neighbouring endothelia. This review will focus on recent advancements in our understanding of endothelial NP/GC-A signalling in the pulmonary versus systemic circulation. It will discuss possible mechanisms accounting for the discrepant observations made for the endothelial actions of this hormone-receptor system and distinguish between (patho)physiological and pharmacological actions. Lastly it will emphasize the potential therapeutical implications derived from the

  20. Endothelial actions of atrial and B-type natriuretic peptides.

    PubMed

    Kuhn, Michaela

    2012-05-01

    The cardiac hormone atrial natriuretic peptide (ANP) is critically involved in the maintenance of arterial blood pressure and intravascular volume homeostasis. Its cGMP-producing GC-A receptor is densely expressed in the microvascular endothelium of the lung and systemic circulation, but the functional relevance is controversial. Some studies reported that ANP stimulates endothelial cell permeability, whereas others described that the peptide attenuates endothelial barrier dysfunction provoked by inflammatory agents such as thrombin or histamine. Many studies in vitro addressed the effects of ANP on endothelial proliferation and migration. Again, both pro- and anti-angiogenic properties were described. To unravel the role of the endothelial actions of ANP in vivo, we inactivated the murine GC-A gene selectively in endothelial cells by homologous loxP/Cre-mediated recombination. Our studies in these mice indicate that ANP, via endothelial GC-A, increases endothelial albumin permeability in the microcirculation of the skin and skeletal muscle. This effect is critically involved in the endocrine hypovolaemic, hypotensive actions of the cardiac hormone. On the other hand the homologous GC-A-activating B-type NP (BNP), which is produced by cardiac myocytes and many other cell types in response to stressors such as hypoxia, possibly exerts more paracrine than endocrine actions. For instance, within the ischaemic skeletal muscle BNP released from activated satellite cells can improve the regeneration of neighbouring endothelia. This review will focus on recent advancements in our understanding of endothelial NP/GC-A signalling in the pulmonary versus systemic circulation. It will discuss possible mechanisms accounting for the discrepant observations made for the endothelial actions of this hormone-receptor system and distinguish between (patho)physiological and pharmacological actions. Lastly it will emphasize the potential therapeutical implications derived from the

  1. 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

  2. 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.

  3. 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

    2016-01-07

    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.

  4. 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

  5. BAG3 regulates contractility and Ca(2+) homeostasis in adult mouse ventricular myocytes.

    PubMed

    Feldman, Arthur M; Gordon, Jennifer; Wang, JuFang; Song, Jianliang; Zhang, Xue-Qian; Myers, Valerie D; Tilley, Douglas G; Gao, Erhe; Hoffman, Nicholas E; Tomar, Dhanendra; Madesh, Muniswamy; Rabinowitz, Joseph; Koch, Walter J; Su, Feifei; Khalili, Kamel; Cheung, Joseph Y

    2016-03-01

    Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid anti-apoptotic protein that is constitutively expressed in the heart. BAG3 mutations, including mutations leading to loss of protein, are associated with familial cardiomyopathy. Furthermore, BAG3 levels have been found to be reduced in end-stage non-familial failing myocardium. In contrast to neonatal myocytes in which BAG3 is found in the cytoplasm and involved in protein quality control and apoptosis, in adult mouse left ventricular (LV) myocytes BAG3 co-localized with Na(+)-K(+)-ATPase and L-type Ca(2+) channels in the sarcolemma and t-tubules. BAG3 co-immunoprecipitated with β1-adrenergic receptor, L-type Ca(2+) channels and phospholemman. To simulate decreased BAG3 protein levels observed in human heart failure, we targeted BAG3 by shRNA (shBAG3) in adult LV myocytes. Reducing BAG3 by 55% resulted in reduced contraction and [Ca(2+)]i transient amplitudes in LV myocytes stimulated with isoproterenol. L-type Ca(2+) current (ICa) and sarcoplasmic reticulum (SR) Ca(2+) content but not Na(+)/Ca(2+) exchange current (INaCa) or SR Ca(2+) uptake were reduced in isoproterenol-treated shBAG3 myocytes. Forskolin or dibutyryl cAMP restored ICa amplitude in shBAG3 myocytes to that observed in WT myocytes, consistent with BAG3 having effects upstream and at the level of the receptor. Resting membrane potential and action potential amplitude were unaffected but APD50 and APD90 were prolonged in shBAG3 myocytes. Protein levels of Ca(2+) entry molecules and other important excitation-contraction proteins were unchanged in myocytes with lower BAG3. Our findings that BAG3 is localized at the sarcolemma and t-tubules while modulating myocyte contraction and action potential duration through specific interaction with the β1-adrenergic receptor and L-type Ca(2+) channel provide novel insight into the role of BAG3 in cardiomyopathies and increased arrhythmia risks in heart failure.

  6. BAG3 regulates contractility and Ca2+ homeostasis in adult mouse ventricular myocytes

    PubMed Central

    Feldman, Arthur M.; Gordon, Jennifer; Wang, JuFang; Song, Jianliang; Zhang, Xue-Qian; Myers, Valerie D.; Tilley, Douglas G.; Gao, Erhe; Hoffman, Nicholas E.; Tomar, Dhanendra; Madesh, Muniswamy; Rabinowitz, Joseph; Koch, Walter J.; Su, Feifei; Khalili, Kamel; Cheung, Joseph Y.

    2016-01-01

    Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid anti-apoptotic protein that is constitutively expressed in the heart. BAG3 mutations, including mutations leading to loss of protein, are associated with familial cardiomyopathy. Furthermore, BAG3 levels have been found to be reduced in end-stage non-familial failing myocardium. In contrast to neonatal myocytes in which BAG3 is found in the cytoplasm and involved in protein quality control and apoptosis, in adult mouse left ventricular (LV) myocytes BAG3 co-localized with Na+-K+-ATPase and L-type Ca2+ channels in the sarcolemma and t-tubules. BAG3 co-immunoprecipitated with β1-adrenergic receptor, L-type Ca2+ channels and phospholemman. To simulate decreased BAG3 protein levels observed in human heart failure, we targeted BAG3 by shRNA (shBAG3) in adult LV myocytes. Reducing BAG3 by 55% resulted in reduced contraction and [Ca2+]i transient amplitudes in LV myocytes stimulated with isoproterenol. L-type Ca2+ current (ICa) and sarcoplasmic reticulum (SR) Ca2+ content but not Na+/Ca2+ exchange current (INaCa) or SR Ca2+ uptake were reduced in isoproterenol-treated shBAG3 myocytes. Forskolin or dibutyrl cAMP restored ICa amplitude in shBAG3 myocytes to that observed in WT myocytes, consistent with BAG3 having effects upstream and at the level of the receptor. Resting membrane potential and action potential amplitude were unaffected but APD50 and APD90 were prolonged in shBAG3 myocytes. Protein levels of Ca2+ entry molecules and other important excitation-contraction proteins were unchanged in myocytes with lower BAG3. Our findings that BAG3 is localized at the sarcolemma and t-tubules while modulating myocyte contraction and action potential duration through specific interaction with the β1-adrenergic receptor and L-type Ca2+ channel provide novel insight into the role of BAG3 in cardiomyopathies and increased arrhythmia risks in heart failure. PMID:26796036

  7. Regional differences in action potential characteristics and membrane currents of guinea-pig left ventricular myocytes.

    PubMed

    Main, M C; Bryant, S M; Hart, G

    1998-11-01

    Regional differences in action potential characteristics and membrane currents were investigated in subendocardial, midmyocardial and subepicardial myocytes isolated from the left ventricular free wall of guinea-pig hearts. Action potential duration (APD) was dependent on the region of origin of the myocytes (P < 0.01, ANOVA). Mean action potential duration at 90 % repolarization (APD90) was 237 +/- 8 ms in subendocardial (n = 30 myocytes), 251 +/- 7 ms in midmyocardial (n = 30) and 204 +/- 7 ms in subepicardial myocytes (n = 36). L-type calcium current (ICa) density and background potassium current (IK1) density were similar in the three regions studied. Delayed rectifier current (IK) was measured as deactivating tail current, elicited on repolarization back to -45 mV after 2 s step depolarizations to test potentials ranging from -10 to +80 mV. Mean IK density (after a step to +80 mV) was larger in subepicardial myocytes (1.59 +/- 0.16 pA pF-1, n = 16) than in either subendocardial (1.16 +/- 0.12 pA pF-1, n = 17) or midmyocardial (1. 13 +/- 0.11 pA pF-1, n = 21) myocytes (P < 0.05, ANOVA). The La3+-insensitive current (IKs) elicited on repolarization back to -45 mV after a 250 ms step depolarization to +60 mV was similar in the three regions studied. The La3+-sensitive tail current, (IKr) was greater in subepicardial (0.50 +/- 0.04 pA pF-1, n = 11) than in subendocardial (0.25 +/- 0.05 pA pF-1, n = 9) or in midmyocardial myocytes (0.38 +/- 0.05 pA pF-1, n = 11, P < 0.05, ANOVA). The contribution of a Na+ background current to regional differences in APD was assessed by application of 0.1 microM tetrodotoxin (TTX). TTX-induced shortening of APD90 was greater in subendocardial myocytes (35.7 +/- 7.1 %, n = 11) than in midmyocardial (15.7 +/- 3. 8 %, n = 10) and subepicardial (20.2 +/- 4.3 %, n = 11) myocytes (P < 0.05, ANOVA). Regional differences in action potential characteristics between subendocardial, midmyocardial, and subepicardial myocytes isolated from

  8. [Eukaryotic expression vector pcDNA3-HERG transfection inhibits angiotensin II induced neonatal rabbit ventricular myocyte hypertrophy in vitro].

    PubMed

    Zhao, Yong-hui; Cui, Chang-cong; Li, Yu; Huang, Chen

    2009-10-01

    To explore the effects of eukaryotic expression vector pcDNA3-HERG transfection on angiotensin II (Ang II) induced myocyte hypertrophy in cultured neonatal rabbit ventricular myocytes. Neonatal rabbit ventricular myocytes and eukaryotic expression vector pcDNA3-HERG transfected ventricular myocytes were cultured in Dulbecco's-modified Eagle medium (DMEM), containing 1% fetal bovine serum (FBS) for 6 h, then stimulated with Ang II (10(-7) mol/L) for 48 h. Control ventricular myocytes were cultured in Dulbecco's-modified Eagle medium (DMEM), containing 1% fetal bovine serum (FBS) for 54 h. At 6 and 54 h, myocyte hypertrophic parameters including myocyte volume, total protein content and membrane capacitance, action potential duration (APD) and Calcineurin (CaN) activity were measured. Compared to control myocytes, APD at 90% repolarization (APD(90)) was prolonged by 19.8% (P < 0.01), without signs of myocyte hypertrophy at 6 h post Ang II stimulation, APD(90) was prolonged by 22.1% (P < 0.01), myocyte volume, total protein content and membrane capacitance and CaN activity were significantly increased by 40.4%, 40.4%, 38.2% and 114.7% respectively (all P < 0.01) at 48 h after Ang II stimulation. HERG gene transfection upregulated I(HERG) tail current (3.6-fold higher than I(Kr)-rapidly activating delayed rectifier potassium current, P < 0.01). HERG gene transfection also accelerated and repolarization and a shortened APD(90) and inhibited myocyte hypertrophy and CaN activation induced by Ang II. Ang II induced prolongation of APD(90) is directly associated with myocyte hypertrophy by increasing the Ca(2+) influx and resulting in the increment of intracellular Ca(2+) and activation of CaN reaction pathway.

  9. Impact of myocyte strain on cardiac myofilament activation.

    PubMed

    Campbell, Kenneth S

    2011-07-01

    When cardiac myocytes are stretched by a longitudinal strain, they develop proportionally more active force at a given sub-maximal Ca(2+) concentration than they did at the shorter length. This is known as length-dependent activation. It is one of the most important contributors to the Frank-Starling relationship, a critical part of normal cardiovascular function. Despite intense research efforts, the mechanistic basis of the Frank-Starling relationship remains unclear. Potential mechanisms involving myofibrillar lattice spacing, titin-based effects, and cooperative activation have all been proposed. This review summarizes some of these mechanisms and discusses two additional potential theories that reflect the effects of localized strains that occur within and between half-sarcomeres. The main conclusion is that the Frank-Starling relationship is probably the integrated result of many interacting molecular mechanisms. Multiscale computational modeling may therefore provide the best way of determining the key processes that underlie length-dependent activation and their relative strengths.

  10. Contribution of I Ks to ventricular repolarization in canine myocytes.

    PubMed

    Horváth, Balázs; Magyar, János; Szentandrássy, Norbert; Birinyi, Péter; Nánási, Péter P; Bányász, Tamás

    2006-09-01

    The role of the slow delayed rectifier K(+) current (I (Ks)) in cardiac repolarization seems to be largely influenced by the experimental conditions including the species and tissue studied. The aim of this study was to determine the contribution of I (Ks) to repolarization in canine ventricular myocytes by measuring the frequency dependent action potential lengthening effect of 10 microM chromanol 293B using sharp microelectrodes. Pretreatment with isoproterenol (2 nM), E-4031 (1 microM), and injection of inward current pulses were applied to modify action potential configuration. Chromanol alone caused moderate but statistically significant lengthening of action potentials at cycle lengths longer than 500 ms. The lengthening effect of chromanol, which was strongly enhanced in the presence of either isoproterenol or E-4031, was proportional to the amplitude of plateau, whereas poor correlation was found with action potential duration. Similar results were obtained when action potential configuration was modified by injection of depolarizing current pulses. Computer simulations revealed that activation of I (Ks) is a sharp function of the plateau amplitude within the physiological range, while elongation of repolarization may enhance I (Ks) only when it is excessive. It was concluded that the effect of I (Ks) on ventricular repolarization critically depends on the level of action potential plateau; however, other factors, like action potential duration, cycle length, or suppression of other K(+) currents can also influence its contribution.

  11. 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.

  12. Myocyte renewal and therapeutic myocardial regeneration using various progenitor cells.

    PubMed

    Hayashi, Emiko; Hosoda, Toru

    2014-11-01

    Whereas the demand on effective treatment options for chronic heart failure is dramatically increasing, the recent recognition of physiological and pathological myocyte turnover in the adult human heart provided a fundamental basis for the therapeutic regeneration. Divergent modalities were experimentally introduced to this field, and selected ones have been applied clinically; the history began with skeletal myoblasts and bone-marrow-derived cells, and lately mesenchymal stem/stromal cells and resident cardiac cells joined the repertoire. Among them, autologous transplantation of c-kit-positive cardiac stem cells in patients with chronic ventricular dysfunction resulted in an outstanding outcome with long-lasting effects without increasing major adverse events. To further optimize currently available approaches, we have to consider multiple factors, such as the targeting disease, the cell population and number to be administered, and the timing and the route of cell delivery. Exploration of the consequence of the previous clinical trials would allow us to envision an ideal cellular therapy for various cardiovascular disorders.

  13. 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.

  14. Calcium Movements Inside the Sarcoplasmic Reticulum of Cardiac Myocytes

    PubMed Central

    Bers, Donald M.; Shannon, Thomas R.

    2013-01-01

    Sarcoplasmic reticulum (SR) Ca content ([Ca]SRT) is critical to both normal cardiac function and electrophysiology, and changes associated with pathology contribute to systolic and diastolic dysfunction and arrhythmias. The intra-SR free [Ca] ([Ca]SR) dictates the [Ca]SRT, the driving force for Ca release and regulates release channel gating. We discuss measurement of [Ca]SR and [Ca]SRT, how [Ca]SR regulates activation and termination of release, and how Ca diffuses within the SR and influences SR Ca release during excitation-contraction coupling, Ca sparks and Ca waves. The entire SR network is connected and its lumen is also continuous with the nuclear envelope. Rapid Ca diffusion within the SR could stabilize and balance local [Ca]SR within the myocyte, but restrictions to diffusion can create spatial inhomogeneities. Experimental measurements and mathematical models of [Ca]SR to date have greatly enriched our understanding of these [Ca]SR dynamics, but controversies exist and may stimulate new measurements and analysis. PMID:23321551

  15. A mathematical model of spontaneous calcium release in cardiac myocytes

    PubMed Central

    Chen, Wei; Aistrup, Gary; Wasserstrom, J. Andrew

    2011-01-01

    In cardiac myocytes, calcium (Ca) can be released from the sarcoplasmic reticulum independently of Ca influx from voltage-dependent membrane channels. This efflux of Ca, referred to as spontaneous Ca release (SCR), is due to Ryanodine receptor fluctuations, which can induce spontaneous Ca sparks, which propagate to form Ca waves. This release of Ca can then induce delayed after-depolarizations (DADs), which can lead to arrhythmogenic-triggered activity in the heart. However, despite its importance, to date there is no mathematical model of SCR that accounts for experimentally observed features of subcellular Ca. In this article, we present an experimentally based model of SCR that reproduces the timing distribution of spontaneous Ca sparks and key features of the propagation of Ca waves emanating from these spontaneous sparks. We have coupled this model to an ionic model for the rabbit ventricular action potential to simulate SCR within several thousand cells in cardiac tissue. We implement this model to study the formation of an ectopic beat on a cable of cells that exhibit SCR-induced DADs. PMID:21357507

  16. Robotic atrial septal defect closure.

    PubMed

    Senay, Sahin; Gullu, Ahmet Umit; Kocyigit, Muharrem; Degirmencioglu, Aleks; Karabulut, Hasan; Alhan, Cem

    2014-01-01

    Atrial septal defect (ASD) is one of the most common congenital cardiac diseases. This pathology can be treated with percutaneous devices. However, some of the ASDs are not suitable for device closure. Also, there may be device-related late complications of transcatheter ASD closure. Currently, robotic surgical techniques allow surgeons to close ASDs in a totally endoscopic fashion with a high success rate and a low complication rate. This study demonstrates the basic concepts and technique of robotic ASD closure. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

  17. Atrial fibrillation cardioversion following acupuncture.

    PubMed

    Dilber, Dario; Čerkez-Habek, Jasna; Barić, Hrvoje; Gradišer, Marina

    2015-11-01

    Atrial fibrillation (AF) is the most common arrhythmia and it is an independent risk for serious events. Acupuncture has been growing in popularity in the West, and there are reports of its benefits in treating AF. We report a 57-year-old man who was admitted after having an allergic reaction to amiodarone administered to treat paroxysmal AF with fast ventricular response. Cardioversion with intravenous propafenone was uneventful. Before an attempt of electric cardioversion, he was treated with acupuncture as additional therapy to peroral propafenone. After acupuncture treatment consisting of 10 treatments during 30 days period, both immediate cardioversion to sinus rhythm and no paroxysmal AF during 30 days period were recorded.

  18. Analysis of Cardiac Myocyte Maturation Using CASAAV, A Platform for Rapid Dissection of Cardiac Myocyte Gene Function In Vivo.

    PubMed

    Guo, Yuxuan; VanDusen, Nathan J; Zhang, Lina; Gu, Weiliang; Sethi, Isha; Guatimosim, Silvia; Ma, Qing; Jardin, Blake D; Ai, Yulan; Zhang, Donghui; Chen, Biyi; Guo, Ang; Yuan, Guo-Cheng; Song, Long-Sheng; Pu, William T

    2017-03-29

    Rationale: Loss-of-function studies in cardiac myocytes (CMs) are currently limited by the need for appropriate conditional knockout alleles. The factors that regulate CM maturation are poorly understood. Prior studies on CM maturation have been confounded by heart dysfunction caused by whole organ gene inactivation. Objective: To develop a new technical platform to rapidly characterize cell-autonomous gene function in postnatal murine CMs and apply it to identify genes that regulate T-tubules, a hallmark of mature cardiac myocytes. Methods and Results: We developed CASAAV (CRISPR/Cas9-AAV9-based somatic mutagenesis), a platform in which AAV9 delivers tandem guide RNAs targeting a gene of interest and cardiac troponin T promoter (cTNT)-driven Cre to Rosa(Cas9GFP/Cas9GFP) neonatal mice. When directed against junctophilin-2 (Jph2), a gene previously implicated in T-tubule maturation, we achieved efficient, rapid, and CM-specific JPH2 depletion. High-dose AAV9 ablated JPH2 in 64% CMs and caused lethal heart failure, whereas low-dose AAV9 ablated JPH2 in 22% CMs and preserved normal heart function. In the context of preserved heart function, CMs lacking JPH2 developed T-tubules that were nearly morphologically normal, indicating that JPH2 does not have a major, cell-autonomous role in T-tubule maturation. However, in hearts with severe dysfunction, both AAV-transduced and non-transduced CMs exhibited T-tubule disruption, which was more severe in the transduced subset. These data indicate that cardiac dysfunction disrupts T-tubule structure, and that JPH2 protects T-tubules in this context. We then used CASAAV to screen 8 additional genes for required, cell-autonomous roles in T-tubule formation. We identified ryanodine receptor 2 (RYR2) as a novel, cell-autonomously required T-tubule maturation factor. Conclusions: CASAAV is a powerful tool to study cell-autonomous gene functions. Genetic mosaics are invaluable to accurately define cell-autonomous gene function. JPH2

  19. Mechanisms With Clinical Implications for Atrial Fibrillation–Associated Remodeling: Cathepsin K Expression, Regulation, and Therapeutic Target and Biomarker

    PubMed Central

    Fujita, Masaya; Cheng, Xian Wu; Inden, Yasuya; Shimano, Masayuki; Yoshida, Naoki; Inoue, Aiko; Yamamoto, Toshihiko; Takeshita, Kyosuke; Kyo, Seifuku; Taguchi, Noriko; Shi, Guo‐Ping; Kuzuya, Masafumi; Okumura, Kenji; Murohara, Toyoaki

    2013-01-01

    Background The cysteine protease cathepsin K (CatK) has been implicated in the pathogenesis of cardiovascular disease. We sought to determine the link between atrial fibrillation (AF) and plasma CatK levels and to investigate the expression of and therapeutic target for CatK in vivo and in vitro. Methods and Results Plasma CatK and extracellular matrix protein peptides (intact procollagen type I of N‐terminal propeptide; carboxyl‐terminal telopeptide of type I collagen [ICTP]) were measured in 209 consecutive patients with AF (paroxysmal AF, 146; persistent AF, 63) and 112 control subjects. In addition, the regulation of CatK expression was investigated in vivo and vitro. Patients with AF had higher plasma CatK and ICTP levels than did control subjects. Patients with persistent AF had higher levels of plasma CatK and ICTP than did patients with paroxysmal AF. CatK was correlated with ICTP concentration and left atrial diameter in all subjects. In rabbits, superoxide production, CatK activity, fibrosis, and the levels of atrial tissue angiotensin II, angiotensin type 1 receptor, gp91phox, phospho‐p38 mitogen‐activated protein kinase, and CatK were greater in those with tachypacing‐induced AF than in controls, and these changes were reversed with angiotensin type 1 receptor antagonist. Olmesartan and mitogen‐activated protein kinase inhibitor decreased the CatK expression induced by angiotensin II in rat neonatal myocytes. Conclusions These data indicated that increased plasma CatK levels are linked with the presence of AF. Angiotensin type 1 receptor antagonist appears to be effective in alleviating atrial fibrosis in a rabbit AF model, partly reducing angiotensin type 1 receptor‐p38mitogen‐activated protein kinase‐dependent and ‐independent CatK activation, thus preventing AF. PMID:24342995

  20. Prolonged Action Potential and After depolarizations Are Not due to Changes in Potassium Currents in NOS3 Knockout Ventricular Myocytes.

    PubMed

    Wang, Honglan; Bonilla, Ingrid M; Huang, Xin; He, Quanhua; Kohr, Mark J; Carnes, Cynthia A; Ziolo, Mark T

    2012-01-01

    Ventricular myocytes deficient in endothelial nitric oxide synthase (NOS3(-/-)) exhibit prolonged action potential (AP) duration and enhanced spontaneous activity (early and delayed afterdepolarizations) during β-adrenergic (β-AR) stimulation. Studies have shown that nitric oxide is able to regulate various K(+) channels. Our objective was to examine if NOS3(-/-) myocytes had altered K(+) currents. APs, transient outward (I(to)), sustained (I(Ksus)), and inward rectifier (I(K1)) K(+) currents were measured in NOS3(-/-) and wild-type (WT) myocytes. During β-AR stimulation, AP duration (measured as 90% repolarization-APD(90)) was prolonged in NOS3(-/-) compared to WT myocytes. Nevertheless, we did not observe differences in I(to), I(Ksus), or I(K1) between WT and NOS3(-/-) myocytes. Our previous work showed that NOS3(-/-) myocytes had a greater Ca(2+) influx via L-type Ca(2+) channels with β-AR stimulation. Thus, we measured β-AR-stimulated SR Ca(2+) load and found a greater increase in NOS3(-/-) versus WT myocytes. Hence, our data suggest that the prolonged AP in NOS3(-/-) myocytes is not due to changes in I(to), I(Ksus), or I(K1). Furthermore, the increase in spontaneous activity in NOS3(-/-) myocytes may be due to a greater increase in SR Ca(2+) load. This may have important implications for heart failure patients, where arrhythmias are increased and NOS3 expression is decreased.

  1. 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.

  2. Resveratrol protects rabbit ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca2+ overload

    PubMed Central

    Li, Wei; Wang, Yue-peng; Gao, Ling; Zhang, Peng-pai; Zhou, Qing; Xu, Quan-fu; Zhou, Zhi-wen; Guo, Kai; Chen, Ren-hua; Yang, Huang-tian; Li, Yi-gang

    2013-01-01

    Aim: To investigate whether resveratrol suppressed oxidative stress-induced arrhythmogenic activity and Ca2+ overload in ventricular myocytes and to explore the underlying mechanisms. Methods: Hydrogen peroxide (H2O2, 200 μmol/L)) was used to induce oxidative stress in rabbit ventricular myocytes. Cell shortening and calcium transients were simultaneously recorded to detect arrhythmogenic activity and to measure intracellular Ca2+ ([Ca2+]i). Ca2+/calmodulin-dependent protein kinases II (CaMKII) activity was measured using a CaMKII kit or Western blotting analysis. Voltage-activated Na+ and Ca2+ currents were examined using whole-cell recording in myocytes. Results: H2O2 markedly prolonged Ca2+ transient duration (CaTD), and induced early afterdepolarization (EAD)-like and delayed afterdepolarization (DAD)-like arrhythmogenic activity in myocytes paced at 0.16 Hz or 0.5 Hz. Application of resveratrol (30 or 50 μmol/L) dose-dependently suppressed H2O2-induced EAD-like arrhythmogenic activity and attenuated CaTD prolongation. Co-treatment with resveratrol (50 μmol/L) effectively prevented both EAD-like and DAD-like arrhythmogenic activity induced by H2O2. In addition, resveratrol markedly blunted H2O2-induced diastolic [Ca2+]i accumulation and prevented the myocytes from developing hypercontracture. In whole-cell recording studies, H2O2 significantly enhanced the late Na+ current (INa,L) and L-type Ca2+ current (ICa,L) in myocytes, which were dramatically suppressed or prevented by resveratrol. Furthermore, H2O2-induced ROS production and CaMKII activation were significantly prevented by resveratrol. Conclusion: Resveratrol protects ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca2+ overload through inhibition of INa,L/ICa,L, reduction of ROS generation, and prevention of CaMKII activation. PMID:23912472

  3. Resveratrol protects rabbit ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca2+ overload.

    PubMed

    Li, Wei; Wang, Yue-peng; Gao, Ling; Zhang, Peng-pai; Zhou, Qing; Xu, Quan-fu; Zhou, Zhi-wen; Guo, Kai; Chen, Ren-hua; Yang, Huang-tian; Li, Yi-gang

    2013-09-01

    To investigate whether resveratrol suppressed oxidative stress-induced arrhythmogenic activity and Ca(2+) overload in ventricular myocytes and to explore the underlying mechanisms. Hydrogen peroxide (H2O2, 200 μmol/L)) was used to induce oxidative stress in rabbit ventricular myocytes. Cell shortening and calcium transients were simultaneously recorded to detect arrhythmogenic activity and to measure intracellular Ca(2+) ([Ca(2+)]i). Ca(2+)/calmodulin-dependent protein kinases II (CaMKII) activity was measured using a CaMKII kit or Western blotting analysis. Voltage-activated Na(+) and Ca(2+) currents were examined using whole-cell recording in myocytes. H2O2 markedly prolonged Ca(2+) transient duration (CaTD), and induced early afterdepolarization (EAD)-like and delayed afterdepolarization (DAD)-like arrhythmogenic activity in myocytes paced at 0.16 Hz or 0.5 Hz. Application of resveratrol (30 or 50 μmol/L) dose-dependently suppressed H2O2-induced EAD-like arrhythmogenic activity and attenuated CaTD prolongation. Co-treatment with resveratrol (50 μmol/L) effectively prevented both EAD-like and DAD-like arrhythmogenic activity induced by H2O2. In addition, resveratrol markedly blunted H2O2-induced diastolic [Ca(2+)]i accumulation and prevented the myocytes from developing hypercontracture. In whole-cell recording studies, H2O2 significantly enhanced the late Na(+) current (I(Na,L)) and L-type Ca(2+) current (I(Ca,L)) in myocytes, which were dramatically suppressed or prevented by resveratrol. Furthermore, H2O2-induced ROS production and CaMKII activation were significantly prevented by resveratrol. Resveratrol protects ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca(2+) overload through inhibition of I(Na,L)/I(Ca,L), reduction of ROS generation, and prevention of CaMKII activation.

  4. Inhibition of fibroblast proliferation in cardiac myocyte cultures by surface microtopography.

    PubMed

    Boateng, Samuel Y; Hartman, Thomas J; Ahluwalia, Neil; Vidula, Himabindu; Desai, Tejal A; Russell, Brenda

    2003-07-01

    Cardiac myocyte cultures usually require pharmacological intervention to prevent overproliferation of contaminating nonmyocytes. Our aim is to prevent excessive fibroblast cell proliferation without the use of cytostatins. We have produced a silicone surface with 10-microm vertical projections that we term "pegs," to which over 80% of rat neonatal cardiac fibroblasts attach within 48 h after plating. There was a 50% decrease in cell proliferation by 5 days of culture compared with flat membranes (P < 0.001) and a concomitant 60% decrease (P < 0.01) in cyclin D1 protein levels, suggesting a G1/S1 cell cycle arrest due to microtopography. Inhibition of Rho kinase with 5 or 20 microM Y-27632 reduced attachment of fibroblasts to the pegs by over 50% (P < 0.001), suggesting that this signaling pathway plays an important role in the process. Using mobile and immobile 10-microm polystyrene spheres, we show that reactive forces are important for inhibiting fibroblast cell proliferation, because mobile spheres failed to reduce cell proliferation. In primary myocyte cultures, pegs also inhibit fibroblast proliferation in the absence of cytostatins. The ratio of aminopropeptide of collagen protein from fibroblasts to myosin from myocytes was significantly reduced in cultures from pegged surfaces (P < 0.01), suggesting an increase in the proportion of myocytes on the pegged surfaces. Connexin43 protein expression was also increased, suggesting improved myocyte-myocyte interaction in the presence of pegs. We conclude that this microtextured culture system is useful for preventing proliferation of fibroblasts in myocyte cultures and may ultimately be useful for tissue engineering applications in vivo.

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

    PubMed

    Leo, M Dennis; Bulley, Simon; Bannister, John P; Kuruvilla, Korah P; Narayanan, Damodaran; Jaggar, Jonathan H

    2015-09-15

    Arterial smooth muscle cells (myocytes) express large-conductance Ca(2+)-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. Copyright © 2015 the American Physiological Society.

  6. 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.

  7. 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…

  8. 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…

  9. 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…

  10. Native American Homeschooling Association.

    ERIC Educational Resources Information Center

    Rozon, Gina

    2000-01-01

    The Native American Home School Association helps Native parents to provide a good education free from the assimilationist tendencies of public school and to transmit Native values and culture. Discusses various home schooling styles, the effectiveness of home schooling in terms of academic achievement and socialization, and the effectiveness of…

  11. Association of left atrial function with incident atypical atrial flutter after atrial fibrillation ablation.

    PubMed

    Gucuk Ipek, Esra; Marine, Joseph E; Habibi, Mohammadali; Chrispin, Jonathan; Lima, Joao; Rickard, Jack; Spragg, David; Zimmerman, Stefan L; Zipunnikov, Vadim; Berger, Ronald; Calkins, Hugh; Nazarian, Saman

    2016-02-01

    Symptomatic left atrial (LA) flutter (LAFL) is common after atrial fibrillation (AF) ablation. The purpose of this study was to examine the association of baseline LA function with incident LAFL after AF ablation. The source cohort included 216 patients with cardiac magnetic resonance (CMR) before initial AF ablation between 2010 and 2013. Patients who underwent cryoballoon or laser ablation, patients with AF during CMR, and those with suboptimal CMR, or missing follow-up data were excluded. Baseline LA volume and function were assessed by feature-tracking CMR analysis. The final cohort included 119 patients (mean age 58.9 ± 11 years; 76.5% men; 70.6% patients with paroxysmal AF). During a median follow-up of 421 days (interquartile range 235-751 days), 22 patients (18.5%) had incident LAFL. Baseline LA volume was similar between the 2 groups. In contrast, baseline reservoir, conduit, and contractile function of the LA were significantly impaired in patients with incident LAFL. Baseline global peak longitudinal atrial strain (PLAS) <22.65% predicted incident LAFL with 86% sensitivity and 68% specificity (C statistic 0.76). In a multivariable model adjusting for age, heart failure, and LA volume, PLAS (hazard ratio 0.9 per % increase in PLAS; P = .003) and LA linear lesions (hazard ratio 2.94; P = .020) were independently associated with incident LAFL. The coexistence of PLAS <22.65% and linear lesions was associated with 9-fold increased hazard of incident LAFL. Baseline LA function and linear lesions were independently associated with incident LAFL after AF ablation. Linear lesions should be limited to selected cases, especially in patients with impaired LA function. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  12. Incidence and clinical predictors of subsequent atrial fibrillation requiring additional ablation after cavotricuspid isthmus ablation for typical atrial flutter.

    PubMed

    De Bortoli, Alessandro; Shi, Li-Bin; Ohm, Ole-Jørgen; Hoff, Per Ivar; Schuster, Peter; Solheim, Eivind; Chen, Jian

    2017-06-01

    We sought to investigate the incidence of atrial fibrillation after catheter ablation for typical atrial flutter and to determine the predictors for symptomatic atrial fibrillation that required a further additional dedicated ablation procedure. 127 patients underwent elective cavotricuspid isthmus ablation with the indication of symptomatic, typical atrial flutter. The occurrence of atrial flutter, atrial fibrillation, cerebrovascular events and the need for additional ablation procedures for symptomatic atrial fibrillation was assessed during long-term follow-up. The majority of patients (70%) manifested atrial fibrillation during a follow-up period of 68 ± 24 months, and a significant proportion (42%) underwent one or multiple atrial fibrillation ablation procedures after an average of 26 months from the index procedure. Recurrence of typical atrial flutter was rare. Ten patients (8%) suffered cerebrovascular events. Earlier documentation of atrial fibrillation (OR 3.53), previous use of flecainide (OR 3.33) and left atrial diameter (OR 2.96) independently predicted occurrence of atrial fibrillation during the follow-up. A combination of pre- and intra-procedural documentation of atrial fibrillation (OR 3.81) and previous use of flecainide (OR 2.43) independently predicted additional atrial fibrillation ablation. Atrial fibrillation occurred in the majority of patients after ablation for typical atrial flutter and 42% of them required an additional dedicated ablation procedure. Pre- and intraprocedural documentation of atrial fibrillation together with previous use of flecainide independently predicted atrial fibrillation occurrence and a need for additional ablation. Anticoagulation treatment should be continued in high-risk patients in spite of clinical disappearance of atrial flutter.

  13. Procollagen propeptides: serum markers for atrial fibrosis?

    PubMed

    Neuberger, Hans-Ruprecht; Cacciatore, Angela; Reil, Jan-Christian; Gräber, Stefan; Schäfers, Hans-Joachim; Ukena, Christian; Böhm, Michael; Mewis, Christian

    2012-08-01

    Atrial fibrosis and its spatial heterogeneity are regarded as a substrate for the perpetuation of atrial arrhythmias. During collagen synthesis and degradation, collagen propeptides and telopeptides are released into the blood. This study tested the hypothesis that serum markers of collagen turnover correlate with atrial fibrosis. We prospectively included 28 patients in sinus rhythm undergoing cardiac surgery. Plasma concentrations of the carboxy- and amino-terminal propeptide of procollagen type-I (PICP and PINP) and type-III (PIIINP), and the C-terminal telopeptide of type-I collagen (ICTP) were determined. Interstitial fibrosis of left (n = 10) and right atrial appendages (n = 28) was analyzed histologically. We found a correlation between left and right atrial fibrosis (r (s) = 0.79, p < 0.01). Interestingly, the higher the interstitial collagen content, the higher was the spatial heterogeneity of fibrosis (r (s) = 0.90, p < 0.001). However, PICP, PIIINP, and ICTP were not correlated to left or right atrial collagen content, or to the spatial heterogeneity of atrial fibrosis. There was a weak and even negative correlation between the serum PINP concentration and the degree of fibrosis in both the left and the right atrium (r (s) = -0.65 (p = 0.04) and r (s) = -0.42 (p = 0.03), respectively). A high degree of interstitial atrial fibrosis indicates a high degree of spatial heterogeneity of interstitial collagen. Although serum PICP is known to be correlated with ventricular fibrosis, this and other serum markers of collagen turnover (PINP, PIIINP, and ICTP) do not directly reflect atrial fibrosis in patients with severe cardiac disease.

  14. Response of atrial flutter to overdrive atrial pacing and intravenous disopyramide phosphate, singly and in combination.

    PubMed Central

    Camm, J; Ward, D; Spurrell, R

    1980-01-01

    Ten patients who suffered spontaneous paroxysms of atrial flutter were investigated by electrophysiological techniques. Two had overt Wolff-Parkinson-White syndrome; three Lown-Ganong-Levine syndrome; and one a concealed accessory atrioventricular connection. Atrial flutter was initiated, at study, by right atrial pacing and electrograms from the right atrium and coronary sinus were observed for at least five minutes to ensure stable flutter in both atria. Atrial flutter was terminated by 2.5 s or 5 s bursts of atrial pacing at rates 10, 50, or 100 beats/min faster than the intrinsic flutter rate in only two patients. Atrial flutter, which was reinitiated in two patients, was then treated with intravenous disopyramide phosphate, 2 mg/kg body weight, infused over five minutes. In all 10 patients the atrial rate slowed from a mean of 310 +/- 39 beats/min to 217 +/- 27 beats/min and atrial flutter terminated in one case. Though the mean ventricular rate fell from 161 +/- 52 beats/min to 156 +/- 45 beats/min the atrioventricular conduction ratio fell from 2.17 +/- 0.86 to 1.55 +/- 0.59 and four patients were left with symptomatically significant increases of ventricular rate. In seven of nine patients overdrive atrial pacing, repeated after disopryamide, resulted in the conversion of atrial flutter to sinus rhythm. In this study, overdrive atrial pacing and intravenous disopyramide, singly and in combination, terminated atrial flutter in nine of the 10 patients and it is suggested that this method may provide an effective alternative to direct current cardioversion. PMID:7426181

  15. Cholinergic modulation of the basal L-type calcium current in ferret right ventricular myocytes

    PubMed Central

    Bett, Glenna C L; Dai, Shuiping; Campbell, Donald L

    2002-01-01

    The effects of the cholinergic muscarinic agonist carbachol (CCh) on the basal L-type calcium current, ICa,L, in ferret right ventricular (RV) myocytes were studied using whole cell patch clamp. CCh produced two major effects: (i) in all myocytes, extracellular application of CCh inhibited ICa,L in a reversible concentration-dependent manner; and (ii) in many (but not all) myocytes, upon washout CCh produced a significant transient stimulation of ICa,L (‘rebound stimulation’). Inhibitory effects could be observed at 1 × 10−10m CCh. The mean steady-state inhibitory concentration-response relationship was shallow and could be described with a single Hill equation (maximum inhibition = 34.5 %, IC50 = 4 × 10−8m, Hill coefficient n = 0.60). Steady-state inhibition (1 or 10 μM CCh) had no significant effect on ICa,L selectivity or macroscopic (i) activation characteristics, (ii) inactivation kinetics, (iii) steady-state inactivation or (iv) kinetics of recovery from inactivation. Maximal inhibition of nitric oxide synthase (NOS) activity (preincubation of myocytes in 1 mm l-NMMA (NG-monomethyl-l-arginine) + 1 mm l-NNA (NG-nitro-l-arginine) for 2–3 h plus inclusion of 1 mm l-NMMA + 1 mm l-NNA in the patch pipette solution) produced no significant attenuation of the CCh-mediated inhibition of ICa,L. Protocols involving (i) the nitric oxide (NO) scavenger PTIO (2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide; 200 μM), (ii) imposition of a ‘cGMP clamp’ (100 μM 8-Bromo-cGMP), and (iii) inhibition of soluble guanylyl cyclase (ODQ (1H-[1,2,4,]oxadiazolo(4,3,-a)quinoxalin-1-one), 50 μM) all failed to attenuate CCh-mediated inhibition of Ica,L. While CCh consistently inhibited basal ICa,L in all RV myocytes studied, not all myocytes displayed rebound stimulation upon CCh washout. However, there was no difference between CCh-mediated inhibition of ICa,L between these two RV myocyte types, and in myocytes displaying rebound stimulation neither ODQ nor 8

  16. Cyclic GMP protein kinase activity is reduced in thyroxine-induced hypertrophic cardiac myocytes.

    PubMed

    Yan, Lin; Zhang, Qihang; Scholz, Peter M; Weiss, Harvey R

    2003-12-01

    1. We tested the hypothesis that the cGMP-dependent protein kinase has major negative functional effects in cardiac myocytes and that the importance of this pathway is reduced in thyroxine (T4; 0.5 mg/kg per day for 16 days) hypertrophic myocytes. 2. Using isolated ventricular myocytes from control (n = 7) and T4-treated (n = 9) rabbit hypertrophic hearts, myocyte shortening was studied with a video edge detector. Oxygen consumption was measured using O2 electrodes. Protein phosphorylation was measured autoradiographically. 3. Data were collected following treatment with: (i) 8-(4-chlorophenylthio)guanosine-3',5'-monophosphate (PCPT; 10-7 or 10-5 mol/L); (ii) 8-bromo-cAMP (10-5 mol/L) followed by PCPT; (iii) beta-phenyl-1,N2-etheno-8-bromoguanosine-3',5'-monophosphorothioate, SP-isomer (SP; 10-7 or 10-5 mol/L); or (iv) 8-bromo-cAMP (10-5 mol/L) followed by SP. 4. There were no significant differences between groups in baseline percentage shortening (Pcs; 4.9 +/- 0.2 vs 5.6 +/- 0.4% for control and T4 groups, respectively) and maximal rate of shortening (Rs; 64.8 +/- 5.9 vs 79.9 +/- 7.1 micro m/ s for control and T4 groups, respectively). Both SP and PCPT decreased Pcs (-43 vs-21% for control and T4 groups, respectively) and Rs (-36 vs-22% for control and T4 groups, respectively), but the effect was significantly reduced in T4 myocytes. 8-Bromo-cAMP similarly increased Pcs (28 vs 23% for control and T4 groups, respectively) and Rs (20 vs 19% for control and T4 groups, respectively). After 8-bromo-cAMP, SP and PCPT decreased Pcs (-34%) and Rs (-29%) less in the control group. However, the effects of these drugs were not altered in T4 myocytes (Pcs -24%; Rs -22%). Both PCPT and cAMP phosphorylated the same five protein bands. In T4 myocytes, these five bands were enhanced less. 5. We conclude that, in control ventricular myocytes, the cGMP-dependent protein kinase exerted major negative functional effects but, in T4-induced hypertrophic myocytes, the importance of

  17. Metabolites of MDMA induce oxidative stress and contractile dysfunction in adult rat left ventricular myocytes.

    PubMed

    Shenouda, Sylvia K; Varner, Kurt J; Carvalho, Felix; Lucchesi, Pamela A

    2009-03-01

    Repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy) produces eccentric left ventricular (LV) dilation and diastolic dysfunction. While the mechanism(s) underlying this toxicity are unknown, oxidative stress plays an important role. MDMA is metabolized into redox cycling metabolites that produce superoxide. In this study, we demonstrated that metabolites of MDMA induce oxidative stress and contractile dysfunction in adult rat left ventricular myocytes. Metabolites of MDMA used in this study included alpha-methyl dopamine, N-methyl alpha-methyl dopamine and 2,5-bis(glutathion-S-yl)-alpha-MeDA. Dihydroethidium was used to detect drug-induced increases in reactive oxygen species (ROS) production in ventricular myocytes. Contractile function and changes in intracellular calcium transients were measured in paced (1 Hz), Fura-2 AM loaded, myocytes using the IonOptix system. Production of ROS in ventricular myocytes treated with MDMA was not different from control. In contrast, all three metabolites of MDMA exhibited time- and concentration-dependent increases in ROS that were prevented by N-acetyl-cysteine (NAC). The metabolites of MDMA, but not MDMA alone, significantly decreased contractility and impaired relaxation in myocytes stimulated at 1 Hz. These effects were prevented by NAC. Together, these data suggest that MDMA-induced oxidative stress in the left ventricle can be due, at least in part, to the metabolism of MDMA to redox active metabolites.

  18. Three-dimensional alignment of the aggregated myocytes in the normal and hypertrophic murine heart.

    PubMed

    Schmitt, Boris; Fedarava, Katsiaryna; Falkenberg, Jan; Rothaus, Kai; Bodhey, Narendra K; Reischauer, Carolin; Kozerke, Sebastian; Schnackenburg, Bernhard; Westermann, Dirk; Lunkenheimer, Paul P; Anderson, Robert H; Berger, Felix; Kuehne, Titus

    2009-09-01

    Several observations suggest that the transmission of myocardial forces is influenced in part by the spatial arrangement of the myocytes aggregated together within ventricular mass. Our aim was to assess, using diffusion tensor magnetic resonance imaging (DT-MRI), any differences in the three-dimensional arrangement of these myocytes in the normal heart compared with the hypertrophic murine myocardium. We induced ventricular hypertrophy in seven mice by infusion of angiotensin II through a subcutaneous pump, with seven other mice serving as controls. DT-MRI of explanted hearts was performed at 3.0 Tesla. We used the primary eigenvector in each voxel to determine the three-dimensional orientation of aggregated myocytes in respect to their helical angles and their transmural courses (intruding angles). Compared with controls, the hypertrophic hearts showed significant increases in myocardial mass and the outer radius of the left ventricular chamber (P < 0.05). In both groups, a significant change was noted from positive intruding angles at the base to negative angles at the ventricular apex (P < 0.01). Compared with controls, the hypertrophied hearts had significantly larger intruding angles of the aggregated myocytes, notably in the apical and basal slices (P < 0.001). In both groups, the helical angles were greatest in midventricular sections, albeit with significantly smaller angles in the mice with hypertrophied myocardium (P < 0.01). The use of DT-MRI revealed significant differences in helix and intruding angles of the myocytes in the mice with hypertrophied myocardium.

  19. Simultaneous orientation and cellular force measurements in adult cardiac myocytes using three-dimensional polymeric microstructures.

    PubMed

    Zhao, Yi; Lim, Chee Chew; Sawyer, Douglas Brian; Liao, Ronglih; Zhang, Xin

    2007-09-01

    A number of techniques have been developed to monitor contractile function in isolated cardiac myocytes. While invaluable observations have been gained from these methodologies in understanding the contractile processes of the heart, they are invariably limited by their in vitro conditions. The present challenge is to develop innovative assays to mimic the in vivo milieu so as to allow a more physiological assessment of cardiac myocyte contractile forces. Here we demonstrate the use of a silicone elastomer, poly(dimethylsiloxane) (PDMS), to simultaneously orient adult cardiac myocytes in primary culture and measure the cellular forces in a three-dimensional substrate. The realignment of adult cardiac myocytes in long-term culture (7 days) was achieved due to directional reassembly of the myofibrils along the parallel polymeric sidewalls. The cellular mechanical forces were recorded in situ by observing the deformation of the micropillars embedded in the substrate. By coupling the cellular mechanical force measurements with on-chip cell orientation, this novel assa