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Sample records for normal human heart

  1. General anesthesia suppresses normal heart rate variability in humans

    NASA Astrophysics Data System (ADS)

    Matchett, Gerald; Wood, Philip

    2014-06-01

    The human heart normally exhibits robust beat-to-beat heart rate variability (HRV). The loss of this variability is associated with pathology, including disease states such as congestive heart failure (CHF). The effect of general anesthesia on intrinsic HRV is unknown. In this prospective, observational study we enrolled 100 human subjects having elective major surgical procedures under general anesthesia. We recorded continuous heart rate data via continuous electrocardiogram before, during, and after anesthesia, and we assessed HRV of the R-R intervals. We assessed HRV using several common metrics including Detrended Fluctuation Analysis (DFA), Multifractal Analysis, and Multiscale Entropy Analysis. Each of these analyses was done in each of the four clinical phases for each study subject over the course of 24 h: Before anesthesia, during anesthesia, early recovery, and late recovery. On average, we observed a loss of variability on the aforementioned metrics that appeared to correspond to the state of general anesthesia. Following the conclusion of anesthesia, most study subjects appeared to regain their normal HRV, although this did not occur immediately. The resumption of normal HRV was especially delayed on DFA. Qualitatively, the reduction in HRV under anesthesia appears similar to the reduction in HRV observed in CHF. These observations will need to be validated in future studies, and the broader clinical implications of these observations, if any, are unknown.

  2. Integrated Transcriptome Map Highlights Structural and Functional Aspects of the Normal Human Heart.

    PubMed

    Caracausi, Maria; Piovesan, Allison; Vitale, Lorenza; Pelleri, Maria Chiara

    2017-04-01

    A systematic meta-analysis of the available gene expression profiling datasets for the whole normal human heart generated a quantitative transcriptome reference map of this organ. Transcriptome Mapper (TRAM) software integrated 32 gene expression profile datasets from different sources returning a reference value of expression for each of the 43,360 known, mapped transcripts assayed by any of the experimental platforms used in this regard. Main findings include the visualization at the gene and chromosomal levels of the classical description of the basic histology and physiology of the heart, the identification of suitable housekeeping reference genes, the analysis of stoichiometry of gene products, and the focusing on chromosome 21 genes, which are present in one excess copy in Down syndrome subjects, presenting cardiovascular defects in 30-40% of cases. Independent in vitro validation showed an excellent correlation coefficient (r = 0.98) with the in silico data. Remarkably, heart/non-cardiac tissue expression ratio may also be used to anticipate that effects of mutations will most probably affect or not the heart. The quantitative reference global portrait of gene expression in the whole normal human heart illustrates the structural and functional aspects of the whole organ and is a general model to understand the mechanisms underlying heart pathophysiology. J. Cell. Physiol. 232: 759-770, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  3. Increased Heart Rate Variability but Normal Resting Metabolic Rate in Hypocretin/Orexin-Deficient Human Narcolepsy

    PubMed Central

    Fronczek, Rolf; Overeem, Sebastiaan; Reijntjes, Robert; Lammers, Gert Jan; van Dijk, J. Gert; Pijl, Hanno

    2008-01-01

    Study Objectives: We investigated autonomic balance and resting metabolic rate to explore their possible involvement in obesity in hypocretin/orexin-deficient narcoleptic subjects. Methods: Resting metabolic rate (using indirect calorimetry) and variability in heart rate and blood pressure were determined in the fasted resting state. Subjects included 15 untreated, hypocretin-deficient male narcoleptics and 15 male controls matched for age and body mass index. Results: Spectral power analysis revealed greater heart rate and blood pressure variability in hypocretin-deficient male narcoleptic patients (heart rate: p = 0.01; systolic blood pressure: p = 0.02; diastolic: p < 0.01). The low to high frequency ratio of heart rate power did not differ between groups (p = 0.48), nor did resting metabolic rate (controls: 1767 ± 226 kcal/24 h; patients: 1766 ± 227 kcal/24h; p = 0.99). Conclusions: Resting metabolic rate was not reduced in hypocretin-deficient narcoleptic men and therefore does not explain obesity in this group. Whether the increased heart rate and blood pressure variability—suggesting reduced sympathetic tone—is involved in this regard remains to be elucidated. Citation: Fronczek R; Overeem S; Reijntjes R; Lammers GJ; van Dijk JG; Pijl H. Increased heart rate variability but normal resting metabolic rate in hypocretin/orexin-deficient human narcolepsy. J Clin Sleep Med 2008;4(3):248–254. PMID:18595438

  4. Sarcoplasmic reticulum-associated cyclic adenosine 5'-monophosphate phosphodiesterase activity in normal and failing human hearts.

    PubMed Central

    Movsesian, M A; Smith, C J; Krall, J; Bristow, M R; Manganiello, V C

    1991-01-01

    Sarcoplasmic reticulum-associated cAMP phosphodiesterase activity was examined in microsomes prepared from the left ventricular myocardium of eight heart transplant recipients with end-stage idiopathic dilated cardiomyopathy and six unmatched organ donors with normal cardiac function. At cAMP concentrations less than or equal to 1.0 microM, sarcoplasmic reticulum-associated cAMP phosphodiesterase activity was functionally homogeneous. cAMP phosphodiesterase activity was inhibited competitively by cGMP (Ki = 0.031 +/- 0.008 microM) and the cilostamide derivative OPC 3911 (Ki = 0.018 +/- 0.004 microM), but was essentially insensitive to rolipram. Vmax and Km were 781.7 +/- 109.2 nmol/mg per min and 0.188 +/- 0.031 microM, respectively, in microsomes prepared from nonfailing hearts and 793.9 +/- 68.9 nmol/mg per min and 0.150 +/- 0.027 microM in microsomes prepared from failing hearts. Microsomes prepared from nonfailing and failing hearts did not differ with respect to either the ratio of cAMP phosphodiesterase activity to ATP-dependent Ca2+ accumulation activity or the sensitivity of cAMP phosphodiesterase activity to inhibition by OPC 3911. These data suggest that the diminished inotropic efficacy of phosphodiesterase inhibitors in failing human hearts does not result from changes in the level, kinetic properties, or pharmacologic sensitivity of sarcoplasmic reticulum-associated cAMP phosphodiesterase activity. PMID:1647414

  5. Immunocytochemical reaction of sera from chagasic patients against Trypanosoma cruzi, intestine of Triatoma infestans and normal human heart.

    PubMed

    Gutiérrez, L S; Burgos, C; Bianchi, R; Burgos, M H

    1999-01-01

    Chagas disease has been considered by some authors as an autoimmune pathology and denied by others. In this paper we present by means of immunocytochemical reactions with sera of chagasic patients, evidence in favor of the presence of similar antigens in the parasite, vector and non chagasic human heart. The immunocytochemical technique used permits the localization by electron microscopy of the antigens in the peritrophic membrane of the parasite and basement membranes of the vector's midgut and of the myosin band of the normal human heart. These observations support the assumption of an autoimmune response in Chagas disease.

  6. Anatomy of the pig heart: comparisons with normal human cardiac structure

    PubMed Central

    CRICK, SIMON J.; SHEPPARD, MARY N.; HO, SIEW YEN; GEBSTEIN, LIOR; ANDERSON, ROBERT H.

    1998-01-01

    Transgenic technology has potentially solved many of the immunological difficulties of using pig organs to support life in the human recipient. Nevertheless, other problems still remain. Knowledge of cardiac anatomy of the pig (Sus scrofa) is limited despite the general acceptance in the literature that it is similar to that of man. A qualitative analysis of porcine and human cardiac anatomy was achieved by gross examination and dissection of hearts with macrophotography. The porcine organ had a classic ‘Valentine heart’ shape, reflecting its location within the thorax and to the orientation of the pig's body (unguligrade stance). The human heart, in contrast, was trapezoidal in silhouette, reflecting man's orthograde posture. The morphologically right atrium of the pig was characterised by the tubular shape of its appendage (a feature observed on the left in the human heart). The porcine superior and inferior caval veins opened into the atrium at right angles to one another, whereas in man the orifices were directly in line. A prominent left azygous vein (comparable to the much reduced left superior caval or oblique vein in man) entered on the left side of the pig heart and drained via the coronary sinus. The porcine left atrium received only 2 pulmonary veins, whereas 4 orifices were generally observed in man. The sweep between the inlet and outlet components of the porcine right ventricle was less marked than in man, and a prominent muscular moderator band was situated in a much higher position within the porcine right ventricle compared with that of man. The apical components of both porcine ventricles possessed very coarse trabeculations, much broader than those observed in the human ventricles. In general, aortic-mitral fibrous continuity was reduced in the outlet component of the porcine left ventricle, with approximately two-thirds of the aortic valve being supported by left ventricular musculature. Several potentially significant differences exist

  7. Prostacyclins have no direct inotropic effect on isolated atrial strips from the normal and pressure-overloaded human right heart.

    PubMed

    Holmboe, Sarah; Andersen, Asger; Jensen, Rebekka V; Kimose, Hans Henrik; Ilkjær, Lars B; Shen, Lei; Clapp, Lucie H; Nielsen-Kudsk, Jens Erik

    2017-01-01

    Prostacyclins are vasodilatory agents used in the treatment of pulmonary arterial hypertension. The direct effects of prostacyclins on right heart function are still not clarified. The aim of this study was to investigate the possible direct inotropic properties of clinical available prostacyclin mimetics in the normal and the pressure-overloaded human right atrium. Trabeculae from the right atrium were collected during surgery from chronic thromboembolic pulmonary hypertension (CTEPH) patients with pressure-overloaded right hearts, undergoing pulmonary thromboendarterectomy (n = 10) and from patients with normal right hearts operated by valve replacement or coronary bypass surgery (n = 9). The trabeculae were placed in an organ bath, continuously paced at 1 Hz. They were subjected to increasing concentrations of iloprost, treprostinil, epoprostenol, or MRE-269, followed by isoprenaline to elicit a reference inotropic response. The force of contraction was measured continuously. The expression of prostanoid receptors was explored through quantitative polymerase chain reaction (qPCR). Iloprost, treprostinil, epoprostenol, or MRE-269 did not alter force of contraction in any of the trabeculae. Isoprenaline showed a direct inotropic response in both trabeculae from the pressure-overloaded right atrium and from the normal right atrium. Control experiments on ventricular trabeculae from the pig failed to show an inotropic response to the prostacyclin mimetics. qPCR demonstrated varying expression of the different prostanoid receptors in the human atrium. In conclusion, prostacyclin mimetics did not increase the force of contraction of human atrial trabeculae from the normal or the pressure-overloaded right heart. These data suggest that prostacyclin mimetics have no direct inotropic effects in the human right atrium.

  8. Blood pressure and heart rate variability analysis of orthostatic challenge in normal human pregnancies.

    PubMed

    Heiskanen, Nonna; Saarelainen, Heli; Valtonen, Pirjo; Lyyra-Laitinen, Tiina; Laitinen, Tomi; Vanninen, Esko; Heinonen, Seppo

    2008-11-01

    The aim of the present study was to evaluate pregnancy-related changes in autonomic regulatory functions in healthy subjects. We studied cardiovascular autonomic responses to head-up tilt (HUT) in 28 pregnant women during the third trimester of pregnancy and 3 months after parturition. The maternal ECG and non-invasive beat-to-beat blood pressure were recorded in the horizontal position (left-lateral position) and during HUT in the upright position. Stroke volume was assessed from blood pressure signal by using the arterial pulse contour method. Heart rate variability (HRV) was analysed in frequency domain, and baroreflex sensitivity by the cross-spectral and the sequence methods. In the horizontal position, all frequency components of HRV were lower during pregnancy than 3 months after parturition (P < 0.01 to <0.001), while pregnancy had no influence on normalized low frequency and high frequency powers. During pregnancy haemodynamics was well balanced with only minor changes in response to postural change while haemodynamic responses to HUT were more remarkable after parturition. In pregnant women HRV and especially its very low frequency component increased in response to HUT, whereas at 3 months after parturition the direction of these changes was opposite. Parasympathetic deactivation towards term is likely to contribute to increased heart rate and cardiac output at rest, whereas restored sympathetic modulation with modest responses may contribute stable peripheral resistance and sufficient placental blood supply under stimulated conditions. It is important to understand cardiovascular autonomic nervous system and haemodynamic control in normal pregnancy before being able to judge whether they are dysregulated in complicated pregnancies.

  9. Increased heart rate variability but normal resting metabolic rate in hypocretin/orexin-deficient human narcolepsy.

    PubMed

    Fronczek, Rolf; Overeem, Sebastiaan; Reijntjes, Robert; Lammers, Gert Jan; van Dijk, J Gert; Pijl, Hanno

    2008-06-15

    We investigated autonomic balance and resting metabolic rate to explore their possible involvement in obesity in hypocretin/orexin-deficient narcoleptic subjects. Resting metabolic rate (using indirect calorimetry) and variability in heart rate and blood pressure were determined in the fasted resting state. Subjects included 15 untreated, hypocretin-deficient male narcoleptics and 15 male controls matched for age and body mass index. Spectral power analysis revealed greater heart rate and blood pressure variability in hypocretin-deficient male narcoleptic patients (heart rate: p = 0.01; systolic blood pressure: p = 0.02; diastolic: p < 0.01). The low to high frequency ratio of heart rate power did not differ between groups (p = 0.48), nor did resting metabolic rate (controls: 1767 +/- 226 kcal/24 h; patients: 1766 +/- 227 kcal/24h; p = 0.99). Resting metabolic rate was not reduced in hypocretin-deficient narcoleptic men and therefore does not explain obesity in this group. Whether the increased heart rate and blood pressure variability--suggesting reduced sympathetic tone--is involved in this regard remains to be elucidated.

  10. Propagation of vibration caused by electrical excitation in the normal human heart.

    PubMed

    Kanai, Hiroshi

    2009-06-01

    The ability to noninvasively detect regional dynamic myocardial damage related to action potentials and mechanical properties affected by heart disease is of great clinical importance. Though there are invaluable clinical tools for diagnosis of a broad range of cardiac conditions, such myocardial properties cannot be evaluated. We have previously shown that pulsive vibration occurs on the myocardium after electrical stimulation of an isolated heart. In this study, using a novel technique for ultrasonic measurement of the myocardial motion, we detected pulsive vibrations spontaneously caused by electrical excitation and by valve closure. Using a sparse sector scan, the vibrations were measured almost simultaneously at about 10,000 points set in the heart wall at a high temporal resolution. The consecutive spatial distributions of the phase of the vibrations revealed wave propagation along the wall in healthy subjects for the first time in vivo. At around the time of the Q-wave of the electrocardiogram, the propagation started from the interventricular septum and extended to both the base and apical sides of the heart with a speed of 1 m/s, which corresponds to the propagation of electrical excitation from the Purkinje fiber-myocyte junction in the interventricular septum. Other vibrations then propagated from the base at several m/s, although some of them had dispersion properties. These are shear waves caused by the mitral-valve closure, corresponding to the first heart sound. These phenomena have potential for detection of regional myocardial tissue damage related to propagation of the action potentials and regional myocardial viscoelasticity.

  11. Heterogeneity of Fractional Anisotropy and Mean Diffusivity Measurements by In Vivo Diffusion Tensor Imaging in Normal Human Hearts

    PubMed Central

    Ferreira, Pedro F.; Nielles-Vallespin, Sonia; Ismail, Tevfik; Kilner, Philip J.; Gatehouse, Peter D.; de Silva, Ranil; Prasad, Sanjay K.; Giannakidis, Archontis; Firmin, David N.; Pennell, Dudley J.

    2015-01-01

    Background Cardiac diffusion tensor imaging (cDTI) by cardiovascular magnetic resonance has the potential to assess microstructural changes through measures of fractional anisotropy (FA) and mean diffusivity (MD). However, normal variation in regional and transmural FA and MD is not well described. Methods Twenty normal subjects were scanned using an optimised cDTI sequence at 3T in systole. FA and MD were quantified in 3 transmural layers and 4 regional myocardial walls. Results FA was higher in the mesocardium (0.46 ±0.04) than the endocardium (0.40 ±0.04, p≤0.001) and epicardium (0.39 ±0.04, p≤0.001). On regional analysis, the FA in the septum was greater than the lateral wall (0.44 ±0.03 vs 0.40 ±0.05 p = 0.04). There was a transmural gradient in MD increasing towards the endocardium (epicardium 0.87 ±0.07 vs endocardium 0.91 ±0.08×10-3 mm2/s, p = 0.04). With the lateral wall (0.87 ± 0.08×10-3 mm2/s) as the reference, the MD was higher in the anterior wall (0.92 ±0.08×10-3 mm2/s, p = 0.016) and septum (0.92 ±0.07×10-3 mm2/s, p = 0.028). Transmurally the signal to noise ratio (SNR) was greatest in the mesocardium (14.5 ±2.5 vs endocardium 13.1 ±2.2, p<0.001; vs epicardium 12.0 ± 2.4, p<0.001) and regionally in the septum (16.0 ±3.4 vs lateral wall 11.5 ± 1.5, p<0.001). Transmural analysis suggested a relative reduction in the rate of change in helical angle (HA) within the mesocardium. Conclusions In vivo FA and MD measurements in normal human heart are heterogeneous, varying significantly transmurally and regionally. Contributors to this heterogeneity are many, complex and interactive, but include SNR, variations in cardiac microstructure, partial volume effects and strain. These data indicate that the potential clinical use of FA and MD would require measurement standardisation by myocardial region and layer, unless pathological changes substantially exceed the normal variation identified. PMID:26177211

  12. Distribution of normal human left ventricular myofiber stress at end diastole and end systole: a target for in silico design of heart failure treatments

    PubMed Central

    Genet, Martin; Lee, Lik Chuan; Nguyen, Rebecca; Haraldsson, Henrik; Acevedo-Bolton, Gabriel; Zhang, Zhihong; Ge, Liang; Ordovas, Karen; Kozerke, Sebastian

    2014-01-01

    Ventricular wall stress is believed to be responsible for many physical mechanisms taking place in the human heart, including ventricular remodeling, which is frequently associated with heart failure. Therefore, normalization of ventricular wall stress is the cornerstone of many existing and new treatments for heart failure. In this paper, we sought to construct reference maps of normal ventricular wall stress in humans that could be used as a target for in silico optimization studies of existing and potential new treatments for heart failure. To do so, we constructed personalized computational models of the left ventricles of five normal human subjects using magnetic resonance images and the finite-element method. These models were calibrated using left ventricular volume data extracted from magnetic resonance imaging (MRI) and validated through comparison with strain measurements from tagged MRI (950 ± 170 strain comparisons/subject). The calibrated passive material parameter values were C0 = 0.115 ± 0.008 kPa and B0 = 14.4 ± 3.18; the active material parameter value was Tmax = 143 ± 11.1 kPa. These values could serve as a reference for future construction of normal human left ventricular computational models. The differences between the predicted and the measured circumferential and longitudinal strains in each subject were 3.4 ± 6.3 and 0.5 ± 5.9%, respectively. The predicted end-diastolic and end-systolic myofiber stress fields for the five subjects were 2.21 ± 0.58 and 16.54 ± 4.73 kPa, respectively. Thus these stresses could serve as targets for in silico design of heart failure treatments. PMID:24876359

  13. Distribution of normal human left ventricular myofiber stress at end diastole and end systole: a target for in silico design of heart failure treatments.

    PubMed

    Genet, Martin; Lee, Lik Chuan; Nguyen, Rebecca; Haraldsson, Henrik; Acevedo-Bolton, Gabriel; Zhang, Zhihong; Ge, Liang; Ordovas, Karen; Kozerke, Sebastian; Guccione, Julius M

    2014-07-15

    Ventricular wall stress is believed to be responsible for many physical mechanisms taking place in the human heart, including ventricular remodeling, which is frequently associated with heart failure. Therefore, normalization of ventricular wall stress is the cornerstone of many existing and new treatments for heart failure. In this paper, we sought to construct reference maps of normal ventricular wall stress in humans that could be used as a target for in silico optimization studies of existing and potential new treatments for heart failure. To do so, we constructed personalized computational models of the left ventricles of five normal human subjects using magnetic resonance images and the finite-element method. These models were calibrated using left ventricular volume data extracted from magnetic resonance imaging (MRI) and validated through comparison with strain measurements from tagged MRI (950 ± 170 strain comparisons/subject). The calibrated passive material parameter values were C0 = 0.115 ± 0.008 kPa and B0 = 14.4 ± 3.18; the active material parameter value was Tmax = 143 ± 11.1 kPa. These values could serve as a reference for future construction of normal human left ventricular computational models. The differences between the predicted and the measured circumferential and longitudinal strains in each subject were 3.4 ± 6.3 and 0.5 ± 5.9%, respectively. The predicted end-diastolic and end-systolic myofiber stress fields for the five subjects were 2.21 ± 0.58 and 16.54 ± 4.73 kPa, respectively. Thus these stresses could serve as targets for in silico design of heart failure treatments.

  14. Cardiac fibroblast-derived extracellular matrix (biomatrix) as a model for the studies of cardiac primitive cell biological properties in normal and pathological adult human heart.

    PubMed

    Castaldo, Clotilde; Di Meglio, Franca; Miraglia, Rita; Sacco, Anna Maria; Romano, Veronica; Bancone, Ciro; Della Corte, Alessandro; Montagnani, Stefania; Nurzynska, Daria

    2013-01-01

    Cardiac tissue regeneration is guided by stem cells and their microenvironment. It has been recently described that both cardiac stem/primitive cells and extracellular matrix (ECM) change in pathological conditions. This study describes the method for the production of ECM typical of adult human heart in the normal and pathological conditions (ischemic heart disease) and highlights the potential use of cardiac fibroblast-derived ECM for in vitro studies of the interactions between ECM components and cardiac primitive cells responsible for tissue regeneration. Fibroblasts isolated from adult human normal and pathological heart with ischemic cardiomyopathy were cultured to obtain extracellular matrix (biomatrix), composed of typical extracellular matrix proteins, such as collagen and fibronectin, and matricellular proteins, laminin, and tenascin. After decellularization, this substrate was used to assess biological properties of cardiac primitive cells: proliferation and migration were stimulated by biomatrix from normal heart, while both types of biomatrix protected cardiac primitive cells from apoptosis. Our model can be used for studies of cell-matrix interactions and help to determine the biochemical cues that regulate cardiac primitive cell biological properties and guide cardiac tissue regeneration.

  15. Reconstruction and Visualization of Fiber and Laminar Structure inthe Normal Human Heart from Ex Vivo DTMRI Data

    SciTech Connect

    Rohmer, Damien; Sitek, Arkadiusz; Gullberg, Grant T.

    2006-12-18

    Background - The human heart is composed of a helicalnetwork of muscle fibers. These fibers are organized to form sheets thatare separated by cleavage surfaces. This complex structure of fibers andsheets is responsible for the orthotropic mechanical properties ofcardiac muscle. The understanding of the configuration of the 3D fiberand sheet structure is important for modeling the mechanical andelectrical properties of the heart and changes in this configuration maybe of significant importance to understand the remodeling aftermyocardial infarction.Methods - Anisotropic least square filteringfollowed by fiber and sheet tracking techniques were applied to DiffusionTensor Magnetic Resonance Imaging (DTMRI) data of the excised humanheart. The fiber configuration was visualized by using thin tubes toincrease 3-dimensional visual perception of the complex structure. Thesheet structures were reconstructed from the DTMRI data, obtainingsurfaces that span the wall from the endo- to the epicardium. Allvisualizations were performed using the high-quality ray-tracing softwarePOV-Ray. Results - The fibers are shown to lie in sheets that haveconcave or convex transmural structure which correspond to histologicalstudies published in the literature. The fiber angles varied depending onthe position between the epi- and endocardium. The sheets had a complexstructure that depended on the location within the myocardium. In theapex region the sheets had more curvature. Conclusions - A high-qualityvisualization algorithm applied to demonstrated high quality DTMRI datais able to elicit the comprehension of the complex 3 dimensionalstructure of the fibers and sheets in the heart.

  16. Gene expression profiling of human hibernating myocardium: increased expression of B-type natriuretic peptide and proenkephalin in hypocontractile vs normally-contracting regions of the heart.

    PubMed

    Prasad, Sanjay K; Clerk, Angela; Cullingford, Timothy E; Chen, Alexander W Y; Kemp, Timothy J; Cannell, Timothy M; Cowie, Martin R; Petrou, Mario

    2008-12-01

    A greater understanding of the molecular basis of hibernating myocardium may assist in identifying those patients who would most benefit from revascularization. Paired heart biopsies were taken from hypocontractile and normally-contracting myocardium (identified by cardiovascular magnetic resonance) from 6 patients with chronic stable angina scheduled for bypass grafting. Gene expression profiles of hypocontractile and normally-contracting samples were compared using Affymetrix microarrays. The data for patients with confirmed hibernating myocardium were analysed separately and a different, though overlapping, set (up to 380) of genes was identified which may constitute a molecular fingerprint for hibernating myocardium. The expression of B-type natriuretic peptide (BNP) was increased in hypocontractile relative to normally-contracting myocardium. The expression of BNP correlated most closely with the expression of proenkephalin and follistatin 3, which may constitute additional heart failure markers. Our data illustrate differential gene expression in hypocontractile and/hibernating myocardium relative to normally-contracting myocardium within individual human hearts. Changes in expression of these genes, including increased relative expression of natriuretic and other factors, may constitute a molecular signature for hypocontractile and/or hibernating myocardium.

  17. Effect of mental challenge induced by movie clips on action potential duration in normal human subjects independent of heart rate.

    PubMed

    Child, Nicholas; Hanson, Ben; Bishop, Martin; Rinaldi, Christopher A; Bostock, Julian; Western, David; Cooklin, Michael; O'Neil, Mark; Wright, Matthew; Razavi, Reza; Gill, Jaswinder; Taggart, Peter

    2014-06-01

    Mental stress and emotion have long been associated with ventricular arrhythmias and sudden death in animal models and humans. The effect of mental challenge on ventricular action potential duration (APD) in conscious healthy humans has not been reported. Activation recovery intervals measured from unipolar electrograms as a surrogate for APD (n=19) were recorded from right and left ventricular endocardium during steady-state pacing, whilst subjects watched an emotionally charged film clip. To assess the possible modulating role of altered respiration on APD, the subjects then repeated the same breathing pattern they had during the stress, but without the movie clip. Hemodynamic parameters (mean, systolic, and diastolic blood pressure, and rate of pressure increase) and respiration rate increased during the stressful part of the film clip (P=0.001). APD decreased during the stressful parts of the film clip, for example, for global right ventricular activation recovery interval at end of film clip 193.8 ms (SD, 14) versus 198.0 ms (SD, 13) during the matched breathing control (end film left ventricle 199.8 ms [SD, 16] versus control 201.6 ms [SD, 15]; P=0.004). Respiration rate increased during the stressful part of the film clip (by 2 breaths per minute) and was well matched in the respective control period without any hemodynamic or activation recovery interval changes. Our results document for the first time direct recordings of the effect of a mental challenge protocol on ventricular APD in conscious humans. The effect of mental challenge on APD was not secondary to emotionally induced altered respiration or heart rate. © 2014 American Heart Association, Inc.

  18. Suppression of slow delayed rectifier current by a truncated isoform of KvLQT1 cloned from normal human heart.

    PubMed

    Jiang, M; Tseng-Crank, J; Tseng, G N

    1997-09-26

    It has been suggested that the cardiac slow delayed rectifier channel is formed by the association of two subunits: IsK (also called minK) and KvLQT1. N-terminal splice variants of the human KvLQT1 gene have been identified, but the functional roles of different KvLQT1 isoforms are not clear. Using the nested 5'-rapid amplification of cDNA ends technique, we obtained a truncated isoform of KvLQT1 (termed tKvLQT1) that lacks the N-terminal cytoplasmic domain and the initial one-third of the first transmembrane domain. The function of tKvLQT1 was tested by oocyte expression, alone or together with the full-length KvLQT1 or a human IsK clone (hIsK). tKvLQT1 alone did not generate functional channels. However, it suppressed the KvLQT1 current when coexpressed with the full-length isoform. It also suppressed the slow delayed rectifier current induced by hIsK, probably by competing with the KvLQT1 subunit endogenous to Xenopus oocytes in coassembly with the hIsK subunit. On the other hand, tKvLQT1 did not suppress the expression of Kv1.4, Kv4.3, or hERG. Using the reverse transcription-polymerase chain reaction technique, we further show that the truncated and full-length isoforms are coexpressed in different regions of human heart. Therefore, tKvLQT1 may modulate the function of IKs in human cardiac myocytes.

  19. Effect of mental challenge induced by movie clips on action potential duration in normal human subjects independent of heart rate

    PubMed Central

    Child, Nicholas; Hanson, Ben; Bishop, Martin; Rinaldi, Christopher A; Bostock, Julian; Western, David; Cooklin, Michael; O’Neil, Mark; Wright, Matthew; Razavi, Reza; Gill, Jaswinder; Taggart, Peter

    2014-01-01

    Background Mental stress and emotion have long been associated with ventricular arrhythmias and sudden death in animal models and humans. The effect of mental challenge on ventricular action potential duration (APD) in conscious healthy humans has not been reported. Methods and Results Activation recovery intervals (ARI) measured from unipolar electrograms as a surrogate for APD (n=19) were recorded from right and left ventricular endocardium during steady state pacing while subjects watched an emotionally charged film clip. To assess the possible modulating role of altered respiration on APD, the subjects then repeated the same breathing pattern they had during the stress, but without the movie clip. Haemodynamic parameters (mean, systolic, and diastolic blood pressure, and rate of pressure increase) and respiration rate increased during the stressful part of the film clip (p=0.001). APD decreased during the stressful parts of the film clip, eg for global RV ARI at end of film clip 193.8ms (SD 14) vs 198.0ms (SD13) during the matched breathing control (end film LV 199.8ms (SD16) vs control 201.6ms (SD15), p=0.004. Respiration rate increased during the stressful part of the film clip (by 2 breaths/minute), and was well matched in the respective control period without any haemodynamic or ARI changes. Conclusions Our results document for the first time direct recordings of the effect of a mental challenge protocol on ventricular action potential duration in conscious humans. The effect of mental challenge on APD was not secondary to emotionally-induced altered respiration or heart rate. PMID:24833641

  20. The Battle of "The Normal Heart."

    ERIC Educational Resources Information Center

    Rottman, Larry

    1990-01-01

    The history of the controversy over Southwest Missouri State University's production of "The Normal Heart," a play about acquired immune deficiency syndrome, is chronicled and concern is expressed about the resurgence of bitterness and hatred in the debate over academic freedom, even within the academic community. (MSE)

  1. Human heart by art.

    PubMed

    Tamir, Abraham

    2012-11-01

    Heart is of great importance in maintaining the life of the body. Enough to stop working for a few minutes to cause death, and hence the great importance in physiology, medicine, and research. This fact was already emphasized in the Bible in the Book of Proverbs, chapter 4 verse 23: "Keep your heart with all diligence, for out of it is the wellspring of life." Art was able to demonstrate the heart from various aspects; realistically, as done by Leonardo de Vinci who demonstrated the halves of the heart and its blood vessels. Symbolically, as a source of life, the heart was demonstrated by the artist Mrs. Erlondeiel, as a caricature by Salvador Dali, as an open heart by Sawaya, etc. Finally, it should be emphasized that different demonstrations of the human heart by many artworks make this most important organ of our body (that cannot be seen from outside) more familiar and clearer to us. And this is the purpose of this article-to demonstrate the heart through a large number of artworks of different kinds.

  2. Exercises in anatomy: the normal heart.

    PubMed

    Anderson, Robert H; Sarwark, Anne; Spicer, Diane E; Backer, Carl L

    2014-01-01

    In the first of our exercises in anatomy, created for the Multimedia Manual of the European Association of Cardiothoracic Surgery, we emphasized that thorough knowledge of intracardiac anatomy was an essential part of the training for all budding cardiac surgeons, explaining how we had used the archive of congenitally malformed hearts maintained at Lurie Children's Hospital in Chicago to prepare a series of videoclips, demonstrating the salient features of tetralogy of Fallot. In this series of videoclips, we extend our analysis of the normal heart, since for our initial exercise we had concentrated exclusively on the structure of the right ventricular outflow tract. We begin our overview of normal anatomy by emphasizing the need, in the current era, to describe the heart in attitudinally appropriate fashion. Increasingly, clinicians are demonstrating the features of the heart as it is located within the body. It is no longer satisfactory, therefore, to describe these components in a 'Valentine' fashion, as continues to be the case in most textbooks of normal or cardiac anatomy. We then emphasize the importance of the so-called morphological method, which states that structures within the heart should be defined on the basis of their own intrinsic morphology, and not according to other parts, which are themselves variable. We continue by using this concept to show how it is the appendages that serve to distinguish between the atrial chambers, while the apical trabecular components provide the features to distinguish the ventricles. We then return to the cardiac chambers, emphasizing features of surgical significance, in particular the locations of the cardiac conduction tissues. We proceed by examining the cardiac valves, and conclude by providing a detailed analysis of the septal structures. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

  3. Is the normal heart rate ``chaotic'' due to respiration?

    NASA Astrophysics Data System (ADS)

    Wessel, Niels; Riedl, Maik; Kurths, Jürgen

    2009-06-01

    The incidence of cardiovascular diseases increases with the growth of the human population and an aging society, leading to very high expenses in the public health system. Therefore, it is challenging to develop sophisticated methods in order to improve medical diagnostics. The question whether the normal heart rate is chaotic or not is an attempt to elucidate the underlying mechanisms of cardiovascular dynamics and therefore a highly controversial topical challenge. In this contribution we demonstrate that linear and nonlinear parameters allow us to separate completely the data sets of the three groups provided for this controversial topic in nonlinear dynamics. The question whether these time series are chaotic or not cannot be answered satisfactorily without investigating the underlying mechanisms leading to them. We give an example of the dominant influence of respiration on heart beat dynamics, which shows that observed fluctuations can be mostly explained by respiratory modulations of heart rate and blood pressure (coefficient of determination: 96%). Therefore, we recommend reformulating the following initial question: "Is the normal heart rate chaotic?" We rather ask the following: "Is the normal heart rate `chaotic' due to respiration?"

  4. Is the normal heart rate "chaotic" due to respiration?

    PubMed

    Wessel, Niels; Riedl, Maik; Kurths, Jürgen

    2009-06-01

    The incidence of cardiovascular diseases increases with the growth of the human population and an aging society, leading to very high expenses in the public health system. Therefore, it is challenging to develop sophisticated methods in order to improve medical diagnostics. The question whether the normal heart rate is chaotic or not is an attempt to elucidate the underlying mechanisms of cardiovascular dynamics and therefore a highly controversial topical challenge. In this contribution we demonstrate that linear and nonlinear parameters allow us to separate completely the data sets of the three groups provided for this controversial topic in nonlinear dynamics. The question whether these time series are chaotic or not cannot be answered satisfactorily without investigating the underlying mechanisms leading to them. We give an example of the dominant influence of respiration on heart beat dynamics, which shows that observed fluctuations can be mostly explained by respiratory modulations of heart rate and blood pressure (coefficient of determination: 96%). Therefore, we recommend reformulating the following initial question: "Is the normal heart rate chaotic?" We rather ask the following: "Is the normal heart rate 'chaotic' due to respiration?"

  5. Correcting human heart 31P NMR spectra for partial saturation. Evidence that saturation factors for PCr/ATP are homogeneous in normal and disease states

    NASA Astrophysics Data System (ADS)

    Bottomley, Paul A.; Hardy, Christopher J.; Weiss, Robert G.

    Heart PCr/ATP ratios measured from spatially localized 31P NMR spectra can be corrected for partial saturation effects using saturation factors derived from unlocalized chest surface-coil spectra acquired at the heart rate and approximate Ernst angle for phosphor creatine (PCr) and again under fully relaxed conditions during each 31P exam. To validate this approach in studies of normal and disease states where the possibility of heterogeneity in metabolite T1 values between both chest muscle and heart and normal and disease states exists, the properties of saturation factors for metabolite ratios were investigated theoretically under conditions applicable in typical cardiac spectroscopy exams and empirically using data from 82 cardiac 31P exams in six study groups comprising normal controls ( n = 19) and patients with dilated ( n = 20) and hypertrophic ( n = 5) cardiomyopathy, coronary artery disease ( n = 16), heart transplants ( n = 19), and valvular heart disease ( n = 3). When TR ≪ T1,(PCr), with T1(PCr) ⩾ T1(ATP), the saturation factor for PCr/ATP lies in the range 1.5 ± 0.5, regardless of the T1 values. The precise value depends on the ratio of metabolite T1 values rather than their absolute values and is insensitive to modest changes in TR. Published data suggest that the metabolite T1 ratio is the same in heart and muscle. Our empirical data reveal that the saturation factors do not vary significantly with disease state, nor with the relative fractions of muscle and heart contributing to the chest surface-coil spectra. Also, the corrected myocardial PCr/ATP ratios in each normal or disease state bear no correlation with the corresponding saturation factors nor the fraction of muscle in the unlocalized chest spectra. However, application of the saturation correction (mean value, 1.36 ± 0.03 SE) significantly reduced scatter in myocardial PCr/ATP data by 14 ± 11% (SD) ( p ⩽ 0.05). The findings suggest that the relative T1 values of PCr and ATP are

  6. Quantification of leucocytes, T-lymphocytes and macrophages in autoptical endomyocardial tissue from 56 normal human hearts during the first year of life.

    PubMed

    Grasmeyer, Sarah; Oswald, Sylvia; Madea, Burkhard

    2016-05-01

    This study evaluated the normal number of inflammatory cells in the heart in the first year of life using two methods to compare their ability to quantitate physiological myocardial infiltration. Eight endomyocardial samples from both ventricles were obtained at autopsy from 56 structurally normal hearts during the first year of life. In each sample the numbers of leucocytes, T-lymphocytes and macrophages were counted once in 20 randomly chosen high-power fields (400×) as well as in a 10mm(2) area of randomly chosen myocardial tissue (100×) by two independent investigators. Compared to the literature a greater representative proportion of myocardial tissue was analyzed. The results of the enumeration in mm(2) were converted into high-power-fields to compare both methods. The mean numbers and standard deviations for leucocytes, T-lymphocytes and macrophages were calculated. Both counting methods showed similar results with low inflammatory cell counts per single heart and staining. A greater understanding of the physiological myocardial infiltration by leucocytes, T-lymphocytes and macrophages is important for postmortem forensic cases, and for the interpretation of endomyocardial biopsies in infants.

  7. Thoracic ectopia cordis with anatomically normal heart.

    PubMed

    Gonçalves, Flávio Donizete; Novaes, Fernando Rotatori; Maia, Marcelo Alves; Barros, Francisco de Assis

    2007-01-01

    Ectopia cordis is a rare congenital malformation, which is commonly associated with other intracardiac defects. At two-day-old full-term baby girl was admitted to Santa Casade Misericórdia Hospital Montes Claros, NG, Brazil, with thoracic ectopia cordis. A transthoracic echocardiographic study did not identify any associated congenital heart diseases. The infant underwent surgical treatment using a rib graft to create a neo-sternum. She was discharged after presenting a good outcome on the 20th postoperative day.

  8. Pulsed-wave Doppler tissue imaging velocities in normal geriatric cats and geriatric cats with primary or systemic diseases linked to specific cardiomyopathies in humans, and the influence of age and heart rate upon these velocities.

    PubMed

    Simpson, Kerry E; Gunn-Moore, Danièlle A; Shaw, Darren J; French, Anne T; Dukes-McEwan, Joanna; Moran, Carmel M; Corcoran, Brendan M

    2009-04-01

    Pulsed-wave Doppler tissue imaging (pw-DTI) techniques allow the non-invasive assessment of myocardial dynamics. pw-DTI has demonstrated regional and global diastolic impairment in various forms of human and feline cardiomyopathy. We hypothesise that in geriatric cats with systemic diseases that have been linked to specific cardiomyopathies in human beings, the myocardial velocity profile will be altered when compared to either normal or hypertrophic cardiomyopathy (HCM) cats; and that both age and heart rate have a significant affect upon pw-DTI velocities. The aims of this study were to determine whether the feline M-mode or myocardial velocity profile is altered in geriatric cats with disease states that have been linked to specific cardiomyopathies in humans when compared to normal geriatric cats or geriatric cats with HCM and to determine whether age or heart rate has a significant effect upon pw-DTI velocities within these groups of cats. Sixty-six cats aged 8 years or above were included in the study, and were divided as follows: Unaffected (n=8), basilar septal bulge (BSB) (17), HCM (14), hyperthyroid (HiT(4)) (12) and chronic renal failure (CRF) (15). Systolic blood pressure was normal in all the cats. pw-DTI systolic (S'), early (E') and late diastolic (A') velocities were assessed from standardised sites within the myocardium, and the relationships between these and disease group, age and heart rate were then assessed. In cats with HCM, the E' velocity was decreased at various sites. Conversely, the HiT(4) cats demonstrated increased S' velocities. The only site at which the age of the cat was significantly related to myocardial velocities was the S' velocity from the apical mid-septum. There were also significant positive relationships between heart rate and the magnitude of myocardial S', E' and A' velocities of radial motion and S' and A' velocities of longitudinal motion. pw-DTI detected diastolic dysfunction in untreated cats with HCM and increased

  9. Screening for Heart Murmurs. What's Normal and What's Not.

    ERIC Educational Resources Information Center

    Pflieger, Kurt L.; Strong, William B.

    1992-01-01

    A step-by-step guide to auscultating young athletes helps physicians identify normal heart murmurs as well as sounds that might signify underlying cardiac pathology. Rapid, thorough preparticipation screening can help differentiate athletes who may require treatment or activity restriction from those with normal murmurs who can remain active. (SM)

  10. Normalization in human somatosensory cortex.

    PubMed

    Brouwer, Gijs Joost; Arnedo, Vanessa; Offen, Shani; Heeger, David J; Grant, Arthur C

    2015-11-01

    Functional magnetic resonance imaging (fMRI) was used to measure activity in human somatosensory cortex and to test for cross-digit suppression. Subjects received stimulation (vibration of varying amplitudes) to the right thumb (target) with or without concurrent stimulation of the right middle finger (mask). Subjects were less sensitive to target stimulation (psychophysical detection thresholds were higher) when target and mask digits were stimulated concurrently compared with when the target was stimulated in isolation. fMRI voxels in a region of the left postcentral gyrus each responded when either digit was stimulated. A regression model (called a forward model) was used to separate the fMRI measurements from these voxels into two hypothetical channels, each of which responded selectively to only one of the two digits. For the channel tuned to the target digit, responses in the left postcentral gyrus increased with target stimulus amplitude but were suppressed by concurrent stimulation to the mask digit, evident as a shift in the gain of the response functions. For the channel tuned to the mask digit, a constant baseline response was evoked for all target amplitudes when the mask was absent and responses decreased with increasing target amplitude when the mask was concurrently presented. A computational model based on divisive normalization provided a good fit to the measurements for both mask-absent and target + mask stimulation. We conclude that the normalization model can explain cross-digit suppression in human somatosensory cortex, supporting the hypothesis that normalization is a canonical neural computation.

  11. Introduction to Controversial Topics in Nonlinear Science: Is the Normal Heart Rate Chaotic?

    NASA Astrophysics Data System (ADS)

    Glass, Leon

    2009-06-01

    In June 2008, the editors of Chaos decided to institute a new section to appear from time to time that addresses timely and controversial topics related to nonlinear science. The first of these deals with the dynamical characterization of human heart rate variability. We asked authors to respond to the following questions: Is the normal heart rate chaotic? If the normal heart rate is not chaotic, is there some more appropriate term to characterize the fluctuations (e.g., scaling, fractal, multifractal)? How does the analysis of heart rate variability elucidate the underlying mechanisms controlling the heart rate? Do any analyses of heart rate variability provide clinical information that can be useful in medical assessment (e.g., in helping to assess the risk of sudden cardiac death)? If so, please indicate what additional clinical studies would be useful for measures of heart rate variability to be more broadly accepted by the medical community. In addition, as a challenge for analysis methods, PhysioNet [A. L. Goldberger et al., "PhysioBank, PhysioToolkit, and PhysioNet: Components of a new research resource for complex physiologic signals," Circulation 101, e215-e220 (2000)] provided data sets from 15 patients of whom five were normal, five had heart failure, and five had atrial fibrillation (http://www.physionet.org/challenge/chaos/). This introductory essay summarizes the main issues and introduces the essays that respond to these questions.

  12. Anatomy of the Heart

    MedlinePlus

    ... picture of the outside of a normal, healthy, human heart. Heart Exterior Figure A shows the location of ... picture of the inside of a normal, healthy, human heart. Heart Interior Figure A shows the location of ...

  13. Biventricular pacing in paced patients with normal hearts.

    PubMed

    Simantirakis, Emmanuel N; Arkolaki, Eva G; Chrysostomakis, Stavros I; Vardas, Panos E

    2009-11-01

    Right ventricular apical (RVA) stimulation, although beneficial in the treatment of symptomatic bradycardia, has proven detrimental in a substantial percentage of pacemaker recipients, leading to iatrogenic deterioration of left ventricular structure and function. Alternative right ventricular pacing sites appeared advantageous but their superiority has not been proven. Biventricular stimulation is effective in reducing ventricular dyssynchrony in subgroups of heart failure patients, improving their functional capacity, morbidity, and mortality. Therefore, it seems logical that this pacing strategy, by eliminating ventricular dyssynchrony, could play an important role in preventing the deleterious effects of chronic RVA stimulation in patients with normal hearts who undergo cardiac pacing for bradycardia indications. Preliminary investigations have yielded encouraging results, but further studies with harder endpoints such as quality of life, morbidity, and mortality are necessary to clarify the potentially advantageous effect of biventricular stimulation in paced patients with normal hearts.

  14. A novel distributed model of the heart under normal and congestive heart failure conditions.

    PubMed

    Ravanshadi, Samin; Jahed, Mehran

    2013-04-01

    Conventional models of cardiovascular system frequently lack required detail and focus primarily on the overall relationship between pressure, flow and volume. This study proposes a localized and regional model of the cardiovascular system. It utilizes noninvasive blood flow and pressure seed data and temporal cardiac muscle regional activity to predict the operation of the heart under normal and congestive heart failure conditions. The analysis considers specific regions of the heart, namely, base, mid and apex of left ventricle. The proposed method of parameter estimation for hydraulic electric analogy model is recursive least squares algorithm. Based on simulation results and comparison to clinical data, effect of congestive heart failure in the heart is quantified. Accumulated results for simulated ejection fraction percentage of the apex, mid and base regions of the left ventricle in congestive heart failure condition were 39 ± 6, 36 ± 9 and 38 ± 8, respectively. These results are shown to satisfactorily match those found through clinical measurements. The proposed analytical method can in effect be utilized as a preclinical and predictive tool for high-risk heart patients and candidates for heart transplant, assistive device and total artificial heart.

  15. Universal structures of normal and pathological heart rate variability.

    PubMed

    Gañán-Calvo, Alfonso M; Fajardo-López, Juan

    2016-02-25

    The circulatory system of living organisms is an autonomous mechanical system softly tuned with the respiratory system, and both developed by evolution as a response to the complex oxygen demand patterns associated with motion. Circulatory health is rooted in adaptability, which entails an inherent variability. Here, we show that a generalized N-dimensional normalized graph representing heart rate variability reveals two universal arrhythmic patterns as specific signatures of health one reflects cardiac adaptability, and the other the cardiac-respiratory rate tuning. In addition, we identify at least three universal arrhythmic profiles whose presences raise in proportional detriment of the two healthy ones in pathological conditions (myocardial infarction; heart failure; and recovery from sudden death). The presence of the identified universal arrhythmic structures together with the position of the centre of mass of the heart rate variability graph provide a unique quantitative assessment of the health-pathology gradient.

  16. Universal structures of normal and pathological heart rate variability

    PubMed Central

    Gañán-Calvo, Alfonso M.; Fajardo-López, Juan

    2016-01-01

    The circulatory system of living organisms is an autonomous mechanical system softly tuned with the respiratory system, and both developed by evolution as a response to the complex oxygen demand patterns associated with motion. Circulatory health is rooted in adaptability, which entails an inherent variability. Here, we show that a generalized N-dimensional normalized graph representing heart rate variability reveals two universal arrhythmic patterns as specific signatures of health one reflects cardiac adaptability, and the other the cardiac-respiratory rate tuning. In addition, we identify at least three universal arrhythmic profiles whose presences raise in proportional detriment of the two healthy ones in pathological conditions (myocardial infarction; heart failure; and recovery from sudden death). The presence of the identified universal arrhythmic structures together with the position of the centre of mass of the heart rate variability graph provide a unique quantitative assessment of the health-pathology gradient. PMID:26912108

  17. Elevated vascular endothelial cell growth factor affects mesocardial morphogenesis and inhibits normal heart bending.

    PubMed

    Drake, Christopher J; Wessels, Andy; Trusk, Tom; Little, Charles D

    2006-01-01

    Signaling by means of vascular endothelial cell growth factor (VEGF) and its receptors (VEGFRs) is required for cardiovascular development. To examine how VEGF/VEGFR receptor signaling affects early endocardial cell behavior, embryonic quail hearts were subjected to elevated VEGF165 levels (five- to nine-somite stage). Primitive embryonic hearts microinjected with recombinant human (rh)VEGF165 exhibit several distinct malformations compared with hearts in untreated embryos: the endocardial tube is malformed with tortuous cords and folds surrounded by a diminished cardiac jelly space, and the lumens of affected hearts are conspicuously reduced. Furthermore, the embryonic heart fails to loop properly. Inhibition of bending is accompanied by an apparent failure of the dorsal mesocardium to atrophy--an event thought to be necessary for heart bending. Instead of atrophy, VEGF-treated mesocardia exhibit a marked increased in the number of resident endothelial cells. Collectively, the data suggest that the abnormally robust mesocardia in VEGF-treated hearts impede the mechanical deformation required for normal heart bending. We conclude that the excessive VEGF signaling culminates in a physical or biomechanical mechanism that acts over a wide, tissue-level, length scale to cause a severe developmental defect--failure of heart bending. 2005 Wiley-Liss, Inc.

  18. Systems Biology Applied to Heart Failure With Normal Ejection Fraction

    PubMed Central

    Mesquita, Evandro Tinoco; Jorge, Antonio Jose Lagoeiro; de Souza, Celso Vale; Cassino, João Paulo Pedroza

    2014-01-01

    Heart failure with normal ejection fraction (HFNEF) is currently the most prevalent clinical phenotype of heart failure. However, the treatments available have shown no reduction in mortality so far. Advances in the omics sciences and techniques of high data processing used in molecular biology have enabled the development of an integrating approach to HFNEF based on systems biology. This study aimed at presenting a systems-biology-based HFNEF model using the bottom-up and top-down approaches. A literature search was conducted for studies published between 1991 and 2013 regarding HFNEF pathophysiology, its biomarkers and systems biology. A conceptual model was developed using bottom-up and top-down approaches of systems biology. The use of systems-biology approaches for HFNEF, a complex clinical syndrome, can be useful to better understand its pathophysiology and to discover new therapeutic targets. PMID:24918915

  19. Determinants for Heart Rate Variability in a Normal Korean Population

    PubMed Central

    Kim, Gyung-Mee

    2011-01-01

    This study examined the normal ranges and the determinants for various parameters of the short-term heart rate variability (HRV) measurements in a large Korean sample of healthy people. HRV measurements were obtained in 2,748 healthy men and 735 healthy women 18-65 yr of age. The mean total power (TP), low frequency (LF), high frequency (HF), and LF/HF ratio were 1,358.9 ± 1,840.8 ms2, 417.3 ± 807.6 ms2, 254.1 ± 414.1 ms2, and 2.4 ± 20.9 ms2 in the frequency-domain spectral analysis. The mean standard deviation of the normal-to-normal (NN) interval (SDNN) and the square root of the mean squared differences of successive NN intervals (RMSSD) were 39.6 ± 22.1 ms and 29.7 ± 18.1 ms in the time-domain analysis. The female subjects had significantly higher SDNN, RMSSD, and HF values than the male subjects. After controlling for age, there was no statistically significant difference in the SDNN. Quantile regression analysis showed that age and mean heart rate had a significant impact on short-term HRV measurement. Given that both clinicians and researchers are increasingly relying on short-term HRV assessment in measuring stress, our work suggests that age and gender should be considered as independent determinants for HRV. PMID:22022180

  20. The Scaling Exponent Distinguishes the Injured Sick Hearts Against Normal Healthy Hearts

    NASA Astrophysics Data System (ADS)

    Yazawa, Toru; Tanaka, Katsunori

    2009-05-01

    We analyzed heartbeat-intervals with our own program of detrended fluctuation analysis (DFA) to quantify the irregularity of the heartbeat. The present analysis revealed that normal healthy subjects have the scaling exponent of 1.0, and ischemic heart disease pushes the scaling exponent up to 1.2-1.5. We conclude that the scaling exponent, calculated by the DFA, reflects a risk for the "failing" heart. The scaling exponents could determine whether the subjects are under sick or in healthy conditions on the basis of cardiac physiology.

  1. Predictability of normal heart rhythms and deterministic chaos

    NASA Astrophysics Data System (ADS)

    Lefebvre, J. H.; Goodings, D. A.; Kamath, M. V.; Fallen, E. L.

    1993-04-01

    The evidence for deterministic chaos in normal heart rhythms is examined. Electrocardiograms were recorded of 29 subjects falling into four groups—a young healthy group, an older healthy group, and two groups of patients who had recently suffered an acute myocardial infarction. From the measured R-R intervals, a time series of 1000 first differences was constructed for each subject. The correlation integral of Grassberger and Procaccia was calculated for several subjects using these relatively short time series. No evidence was found for the existence of an attractor having a dimension less than about 4. However, a prediction method recently proposed by Sugihara and May and an autoregressive linear predictor both show that there is a measure of short-term predictability in the differenced R-R intervals. Further analysis revealed that the short-term predictability calculated by the Sugihara-May method is not consistent with the null hypothesis of a Gaussian random process. The evidence for a small amount of nonlinear dynamical behavior together with the short-term predictability suggest that there is an element of deterministic chaos in normal heart rhythms, although it is not strong or persistent. Finally, two useful parameters of the predictability curves are identified, namely, the `first step predictability' and the `predictability decay rate,' neither of which appears to be significantly correlated with the standard deviation of the R-R intervals.

  2. miRNA Expression in Pediatric Failing Human Heart

    PubMed Central

    Stauffer, Brian L.; Russell, Gloria; Nunley, Karin; Miyamoto, Shelley D.; Sucharov, Carmen C.

    2013-01-01

    miRNAs are short regulatory RNAs that can regulate gene expression through interacting with the 3'UTR of target mRNAs. Although the role of miRNAs has been extensively studied in adult human and animal models of heart disease, nothing is known about their expression in pediatric heart failure patients. Different than adults with heart failure, pediatric patients respond well to phosphodiesterase inhibitor (PDEi) treatment, which is safe in the outpatient setting, results in fewer heart failure emergency department visits, fewer cardiac hospital admissions and improved NYHA classification. We have recently shown that the pediatric heart failure patients display a unique molecular profile that is different from adults with heart failure. In this study we show for the first time that pediatric heart failure patients display a unique miRNA profile, and that expression of some miRNAs correlate with response to PDEi treatment. Moreover, we show that expression of Smad4, a potential target for PDEi-regulated miRNAs, is normalized in PDEi-treated patients. Since miRNAs may be used as therapy for human heart failure, our results underscore the importance of defining the molecular characteristics of pediatric heart failure patients, so age-appropriate therapy can be designed for this population. PMID:23333438

  3. Characterization of the human heart mitochondrial proteome.

    PubMed

    Taylor, Steven W; Fahy, Eoin; Zhang, Bing; Glenn, Gary M; Warnock, Dale E; Wiley, Sandra; Murphy, Anne N; Gaucher, Sara P; Capaldi, Roderick A; Gibson, Bradford W; Ghosh, Soumitra S

    2003-03-01

    To gain a better understanding of the critical role of mitochondria in cell function, we have compiled an extensive catalogue of the mitochondrial proteome using highly purified mitochondria from normal human heart tissue. Sucrose gradient centrifugation was employed to partially resolve protein complexes whose individual protein components were separated by one-dimensional PAGE. Total in-gel processing and subsequent detection by mass spectrometry and rigorous bioinformatic analysis yielded a total of 615 distinct protein identifications. All protein pI values, molecular weight ranges, and hydrophobicities were represented. The coverage of the known subunits of the oxidative phosphorylation machinery within the inner mitochondrial membrane was >90%. A significant proportion of identified proteins are involved in signaling, RNA, DNA, and protein synthesis, ion transport, and lipid metabolism. The biochemical roles of 19% of the identified proteins have not been defined. This database of proteins provides a comprehensive resource for the discovery of novel mitochondrial functions and pathways.

  4. Computer Simulation of the Beating Human Heart

    NASA Astrophysics Data System (ADS)

    Peskin, Charles S.; McQueen, David M.

    2001-06-01

    The mechanical function of the human heart couples together the fluid mechanics of blood and the soft tissue mechanics of the muscular heart walls and flexible heart valve leaflets. We discuss a unified mathematical formulation of this problem in which the soft tissue looks like a specialized part of the fluid in which additional forces are applied. This leads to a computational scheme known as the Immersed Boundary (IB) method for solving the coupled equations of motion of the whole system. The IB method is used to construct a three-dimensional Virtual Heart, including representations of all four chambers of the heart and all four valves, in addition to the large arteries and veins that connect the heart to the rest of the circulation. The chambers, valves, and vessels are all modeled as collections of elastic (and where appropriate, actively contractile) fibers immersed in viscous incompressible fluid. Results are shown as a computer-generated video animation of the beating heart.

  5. On the nature of heart rate variability in a breathing normal subject: a stochastic process analysis.

    PubMed

    Buchner, Teodor; Petelczyc, Monika; Zebrowski, Jan J; Prejbisz, Aleksander; Kabat, Marek; Januszewicz, Andrzej; Piotrowska, Anna Justyna; Szelenberger, Waldemar

    2009-06-01

    Human heart rate is moderated by the autonomous nervous system acting predominantly through the sinus node (the main cardiac physiological pacemaker). One of the dominant factors that determine the heart rate in physiological conditions is its coupling with the respiratory rhythm. Using the language of stochastic processes, we analyzed both rhythms simultaneously taking the data from polysomnographic recordings of two healthy individuals. Each rhythm was treated as a sum of a deterministic drift term and a diffusion term (Kramers-Moyal expansion). We found that normal heart rate variability may be considered as the result of a bidirectional coupling of two nonlinear oscillators: the heart itself and the respiratory system. On average, the diffusion (noise) component measured is comparable in magnitude to the oscillatory (deterministic) term for both signals investigated. The application of the Kramers-Moyal expansion may be useful for medical diagnostics providing information on the relation between respiration and heart rate variability. This interaction is mediated by the autonomous nervous system, including the baroreflex, and results in a commonly observed phenomenon--respiratory sinus arrhythmia which is typical for normal subjects and often impaired by pathology.

  6. Data from acellular human heart matrix.

    PubMed

    Sánchez, Pedro L; Fernández-Santos, M Eugenia; Espinosa, M Angeles; González-Nicolas, M Angeles; Acebes, Judith R; Costanza, Salvatore; Moscoso, Isabel; Rodríguez, Hugo; García, Julio; Romero, Jesús; Kren, Stefan M; Bermejo, Javier; Yotti, Raquel; Del Villar, Candelas Pérez; Sanz-Ruiz, Ricardo; Elizaga, Jaime; Taylor, Doris A; Fernández-Avilés, Francisco

    2016-09-01

    Perfusion decellularization of cadaveric hearts removes cells and generates a cell-free extracellular matrix scaffold containing acellular vascular conduits, which are theoretically sufficient to perfuse and support tissue-engineered heart constructs. This article contains additional data of our experience decellularizing and testing structural integrity and composition of a large series of human hearts, "Acellular human heart matrix: a critical step toward whole heat grafts" (Sanchez et al., 2015) [1]. Here we provide the information about the heart decellularization technique, the valve competence evaluation of the decellularized scaffolds, the integrity evaluation of epicardial and myocardial coronary circulation, the pressure volume measurements, the primers used to assess cardiac muscle gene expression and, the characteristics of donors, donor hearts, scaffolds and perfusion decellularization process.

  7. Cardiac troponin T is necessary for normal development in the embryonic chick heart.

    PubMed

    England, Jennifer; Pang, Kar Lai; Parnall, Matthew; Haig, Maria Isabel; Loughna, Siobhan

    2016-09-01

    The heart is the first functioning organ to develop during embryogenesis. The formation of the heart is a tightly regulated and complex process, and alterations to its development can result in congenital heart defects. Mutations in sarcomeric proteins, such as alpha myosin heavy chain and cardiac alpha actin, have now been associated with congenital heart defects in humans, often with atrial septal defects. However, cardiac troponin T (cTNT encoded by gene TNNT2) has not. Using gene-specific antisense oligonucleotides, we have investigated the role of cTNT in chick cardiogenesis. TNNT2 is expressed throughout heart development and in the postnatal heart. TNNT2-morpholino treatment resulted in abnormal atrial septal growth and a reduction in the number of trabeculae in the developing primitive ventricular chamber. External analysis revealed the development of diverticula from the ventricular myocardial wall which showed no evidence of fibrosis and still retained a myocardial phenotype. Sarcomeric assembly appeared normal in these treated hearts. In humans, congenital ventricular diverticulum is a rare condition, which has not yet been genetically associated. However, abnormal haemodynamics is known to cause structural defects in the heart. Further, structural defects, including atrial septal defects and congenital diverticula, have previously been associated with conduction anomalies. Therefore, to provide mechanistic insights into the effect that cTNT knockdown has on the developing heart, quantitative PCR was performed to determine the expression of the shear stress responsive gene NOS3 and the conduction gene TBX3. Both genes were differentially expressed compared to controls. Therefore, a reduction in cTNT in the developing heart results in abnormal atrial septal formation and aberrant ventricular morphogenesis. We hypothesize that alterations to the haemodynamics, indicated by differential NOS3 expression, causes these abnormalities in growth in cTNT knockdown

  8. Mitochondrial Fission and Autophagy in the Normal and Diseased Heart

    PubMed Central

    Iglewski, Myriam; Hill, Joseph A.; Lavandero, Sergio; Rothermel, Beverly A.

    2011-01-01

    Sustained hypertension promotes structural, functional and metabolic remodeling of cardiomyocyte mitochondria. As long-lived, postmitotic cells, cardiomyocytes turn over mitochondria continuously to compensate for changes in energy demands and to remove damaged organelles. This process involves fusion and fission of existing mitochondria to generate new organelles and separate old ones for degradation via autophagy. Autophagy is a lysosome-dependent proteolytic pathway capable of processing cellular components, including organelles and protein aggregates. Autophagy can be either nonselective or selective and contributes to remodeling of the myocardium under stress. Fission of mitochondria, loss of membrane potential, and ubiquitination are emerging as critical steps that direct selective autophagic degradation of mitochondria. This review discusses the molecular mechanisms controlling mitochondrial dynamics, including fission, fusion, transport, and degradation. Furthermore, it examines recent studies revealing the importance of these processes in normal and diseased heart. PMID:20865352

  9. [Sudden cardiac death in individuals with normal hearts: an update].

    PubMed

    González-Melchor, Laila; Villarreal-Molina, Teresa; Iturralde-Torres, Pedro; Medeiros-Domingo, Argelia

    2014-01-01

    Sudden death (SD) is a tragic event and a world-wide health problem. Every year, near 4-5 million people experience SD. SD is defined as the death occurred in 1h after the onset of symptoms in a person without previous signs of fatality. It can be named "recovered SD" when the case received medical attention, cardiac reanimation effective defibrillation or both, surviving the fatal arrhythmia. Cardiac channelopathies are a group of diseases characterized by abnormal ion channel function due to genetic mutations in ion channel genes, providing increased susceptibility to develop cardiac arrhythmias and SD. Usually the death occurs before 40 years of age and in the autopsy the heart is normal. In this review we discuss the main cardiac channelopathies involved in sudden cardiac death along with current management of cases and family members that have experienced such tragic event.

  10. Development of the human heart.

    PubMed

    Sylva, Marc; van den Hoff, Maurice J B; Moorman, Antoon F M

    2014-06-01

    Molecular and genetic studies around the turn of this century have revolutionized the field of cardiac development. We now know that the primary heart tube, as seen in the early embryo contains little more than the precursors for the left ventricle, whereas the precursor cells for the remainder of the cardiac components are continuously added, to both the venous and arterial pole of the heart tube, from a single center of growth outside the heart. While the primary heart tube is growing by addition of cells, it does not show significant cell proliferation, until chamber differentiation and expansion starts locally in the tube, by which the chambers balloon from the primary heart tube. The transcriptional repressors Tbx2 and Tbx3 locally repress the chamber-specific program of gene expression, by which these regions are allowed to differentiate into the distinct components of the conduction system. Molecular genetic lineage analyses have been extremely valuable to assess the distinct developmental origin of the various component parts of the heart, which currently can be unambiguously identified by their unique molecular phenotype. Despite the enormous advances in our knowledge on cardiac development, even the most common congenital cardiac malformations are only poorly understood. The challenge of the newly developed molecular genetic techniques is to unveil the basic gene regulatory networks underlying cardiac morphogenesis.

  11. Metabolic gene profile in early human fetal heart development.

    PubMed

    Iruretagoyena, J I; Davis, W; Bird, C; Olsen, J; Radue, R; Teo Broman, A; Kendziorski, C; Splinter BonDurant, S; Golos, T; Bird, I; Shah, D

    2014-07-01

    The primitive cardiac tube starts beating 6-8 weeks post fertilization in the developing embryo. In order to describe normal cardiac development during late first and early second trimester in human fetuses this study used microarray and pathways analysis and created a corresponding 'normal' database. Fourteen fetal hearts from human fetuses between 10 and 18 weeks of gestational age (GA) were prospectively collected at the time of elective termination of pregnancy. RNA from recovered tissues was used for transcriptome analysis with Affymetrix 1.0 ST microarray chip. From the amassed data we investigated differences in cardiac development within the 10-18 GA period dividing the sample by GA in three groups: 10-12 (H1), 13-15 (H2) and 16-18 (H3) weeks. A fold change of 2 or above adjusted for a false discovery rate of 5% was used as initial cutoff to determine differential gene expression for individual genes. Test for enrichment to identify functional groups was carried out using the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Array analysis correctly identified the cardiac specific genes, and transcripts reported to be differentially expressed were confirmed by qRT-PCR. Single transcript and Ontology analysis showed first trimester heart expression of myosin-related genes to be up-regulated >5-fold compared with second trimester heart. In contrast the second trimester hearts showed further gestation-related increases in many genes involved in energy production and cardiac remodeling. In conclusion, fetal heart development during the first trimester was dominated by heart-specific genes coding for myocardial development and differentiation. During the second trimester, transcripts related to energy generation and cardiomyocyte communication for contractile coordination/proliferation were more dominant. Transcripts related to fatty acid metabolism can be seen as early as 10 weeks and clearly increase as the heart matures. Retinol

  12. The human heart: application of the golden ratio and angle.

    PubMed

    Henein, Michael Y; Zhao, Ying; Nicoll, Rachel; Sun, Lin; Khir, Ashraf W; Franklin, Karl; Lindqvist, Per

    2011-08-04

    The golden ratio, or golden mean, of 1.618 is a proportion known since antiquity to be the most aesthetically pleasing and has been used repeatedly in art and architecture. Both the golden ratio and the allied golden angle of 137.5° have been found within the proportions and angles of the human body and plants. In the human heart we found many applications of the golden ratio and angle, in addition to those previously described. In healthy hearts, vertical and transverse dimensions accord with the golden ratio, irrespective of different absolute dimensions due to ethnicity. In mild heart failure, the ratio of 1.618 was maintained but in end-stage heart failure the ratio significantly reduced. Similarly, in healthy ventricles mitral annulus dimensions accorded with the golden ratio, while in dilated cardiomyopathy and mitral regurgitation patients the ratio had significantly reduced. In healthy patients, both the angles between the mid-luminal axes of the pulmonary trunk and the ascending aorta continuation and between the outflow tract axis and continuation of the inflow tract axis of the right ventricle approximate to the golden angle, although in severe pulmonary hypertension, the angle is significantly increased. Hence the overall cardiac and ventricular dimensions in a normal heart are consistent with the golden ratio and angle, representing optimum pump structure and function efficiency, whereas there is significant deviation in the disease state. These findings could have anatomical, functional and prognostic value as markers of early deviation from normality.

  13. Tissue microarray profiling in human heart failure.

    PubMed

    Lal, Sean; Nguyen, Lisa; Tezone, Rhenan; Ponten, Fredrik; Odeberg, Jacob; Li, Amy; Dos Remedios, Cristobal

    2016-09-01

    Tissue MicroArrays (TMAs) are a versatile tool for high-throughput protein screening, allowing qualitative analysis of a large number of samples on a single slide. We have developed a customizable TMA system that uniquely utilizes cryopreserved human cardiac samples from both heart failure and donor patients to produce formalin-fixed paraffin-embedded sections. Confirmatory upstream or downstream molecular studies can then be performed on the same (biobanked) cryopreserved tissue. In a pilot study, we applied our TMAs to screen for the expression of four-and-a-half LIM-domain 2 (FHL2), a member of the four-and-a-half LIM family. This protein has been implicated in the pathogenesis of heart failure in a variety of animal models. While FHL2 is abundant in the heart, not much is known about its expression in human heart failure. For this purpose, we generated an affinity-purified rabbit polyclonal anti-human FHL2 antibody. Our TMAs allowed high-throughput profiling of FHL2 protein using qualitative and semiquantitative immunohistochemistry that proved complementary to Western blot analysis. We demonstrated a significant relative reduction in FHL2 protein expression across different forms of human heart failure. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Pancreastatin molecular forms in normal human plasma.

    PubMed

    Kitayama, N; Tateishi, K; Funakoshi, A; Miyasaka, K; Shimazoe, T; Kono, A; Iwamoto, N; Matsuoka, Y

    1994-01-01

    Circulating molecular forms with pancreastatin (PST)-like immunoreactivity in plasma from normal subjects were examined. An immunoreactive form corresponding to a human PST-like sequence [human chromogranin-A-(250-301)] (hPST-52) and a larger form (mol wt 15-21 kDa) were detected by gel filtration of plasma from normal subjects. On high performance liquid chromatography, predominant immunoreactive forms coeluted with the three larger forms which were purified from the xenograft of human pancreatic islet cell carcinoma cell line QGP-1N cells and with synthetic hPST-52. The fraction containing larger forms purified from xenograft of QGP-1N cells had biological activity equivalent to that of hPST-52 on the inhibition of pancreatic exocrine secretion. These results suggest that the larger molecular forms as well as hPST-52 may be physiologically important circulating forms of PST in human.

  15. Morphology and biomechanics of human heart

    NASA Astrophysics Data System (ADS)

    Chelnokova, Natalia O.; Golyadkina, Anastasiya A.; Kirillova, Irina V.; Polienko, Asel V.; Ivanov, Dmitry V.

    2016-03-01

    Object of study: A study of the biomechanical characteristics of the human heart ventricles was performed. 80 hearts were extracted during autopsy of 80 corpses of adults (40 women and 40 men) aged 31-70 years. The samples were investigated in compliance with the recommendations of the ethics committee. Methods: Tension and compression tests were performed with help of the uniaxial testing machine Instron 5944. Cardiometry was also performed. Results: In this work, techniques for human heart ventricle wall biomechanical properties estimation were developed. Regularities of age and gender variability in deformative and strength properties of the right and left ventricle walls were found. These properties were characterized by a smooth growth of myocardial tissue stiffness and resistivity at a relatively low strain against reduction in their strength and elasticity from 31-40 to 61-70 years. It was found that tissue of the left ventricle at 61-70 years had a lower stretchability and strength compared with tissues of the right ventricle and septum. These data expands understanding of the morphological organization of the heart ventricles, which is very important for the development of personalized medicine. Taking into account individual, age and gender differences of the heart ventricle tissue biomechanical characteristics allows to rationally choosing the type of patching materials during reconstructive operations on heart.

  16. Heart rate variability in normal and pathological sleep

    PubMed Central

    Tobaldini, Eleonora; Nobili, Lino; Strada, Silvia; Casali, Karina R.; Braghiroli, Alberto; Montano, Nicola

    2013-01-01

    Sleep is a physiological process involving different biological systems, from molecular to organ level; its integrity is essential for maintaining health and homeostasis in human beings. Although in the past sleep has been considered a state of quiet, experimental and clinical evidences suggest a noteworthy activation of different biological systems during sleep. A key role is played by the autonomic nervous system (ANS), whose modulation regulates cardiovascular functions during sleep onset and different sleep stages. Therefore, an interest on the evaluation of autonomic cardiovascular control in health and disease is growing by means of linear and non-linear heart rate variability (HRV) analyses. The application of classical tools for ANS analysis, such as HRV during physiological sleep, showed that the rapid eye movement (REM) stage is characterized by a likely sympathetic predominance associated with a vagal withdrawal, while the opposite trend is observed during non-REM sleep. More recently, the use of non-linear tools, such as entropy-derived indices, have provided new insight on the cardiac autonomic regulation, revealing for instance changes in the cardiovascular complexity during REM sleep, supporting the hypothesis of a reduced capability of the cardiovascular system to deal with stress challenges. Interestingly, different HRV tools have been applied to characterize autonomic cardiac control in different pathological conditions, from neurological sleep disorders to sleep disordered breathing (SDB). In summary, linear and non-linear analysis of HRV are reliable approaches to assess changes of autonomic cardiac modulation during sleep both in health and diseases. The use of these tools could provide important information of clinical and prognostic relevance. PMID:24137133

  17. Programming and reprogramming a human heart cell.

    PubMed

    Sahara, Makoto; Santoro, Federica; Chien, Kenneth R

    2015-03-12

    The latest discoveries and advanced knowledge in the fields of stem cell biology and developmental cardiology hold great promise for cardiac regenerative medicine, enabling researchers to design novel therapeutic tools and approaches to regenerate cardiac muscle for diseased hearts. However, progress in this arena has been hampered by a lack of reproducible and convincing evidence, which at best has yielded modest outcomes and is still far from clinical practice. To address current controversies and move cardiac regenerative therapeutics forward, it is crucial to gain a deeper understanding of the key cellular and molecular programs involved in human cardiogenesis and cardiac regeneration. In this review, we consider the fundamental principles that govern the "programming" and "reprogramming" of a human heart cell and discuss updated therapeutic strategies to regenerate a damaged heart.

  18. NORMAL HUMAN VARIATION: REFOCUSSING THE ENHANCEMENT DEBATE

    PubMed Central

    Kahane, Guy; Savulescu, Julian

    2015-01-01

    This article draws attention to several common mistakes in thinking about biomedical enhancement, mistakes that are made even by some supporters of enhancement. We illustrate these mistakes by examining objections that John Harris has recently raised against the use of pharmacological interventions to directly modulate moral decision-making. We then apply these lessons to other influential figures in the debate about enhancement. One upshot of our argument is that many considerations presented as powerful objections to enhancement are really strong considerations in favour of biomedical enhancement, just in a different direction. Another upshot is that it is unfortunate that much of the current debate focuses on interventions that will radically transform normal human capacities. Such interventions are unlikely to be available in the near future, and may not even be feasible. But our argument shows that the enhancement project can still have a radical impact on human life even if biomedical enhancement operated entirely within the normal human range. PMID:23906367

  19. Normal human variation: refocussing the enhancement debate.

    PubMed

    Kahane, Guy; Savulescu, Julian

    2015-02-01

    This article draws attention to several common mistakes in thinking about biomedical enhancement, mistakes that are made even by some supporters of enhancement. We illustrate these mistakes by examining objections that John Harris has recently raised against the use of pharmacological interventions to directly modulate moral decision-making. We then apply these lessons to other influential figures in the debate about enhancement. One upshot of our argument is that many considerations presented as powerful objections to enhancement are really strong considerations in favour of biomedical enhancement, just in a different direction. Another upshot is that it is unfortunate that much of the current debate focuses on interventions that will radically transform normal human capacities. Such interventions are unlikely to be available in the near future, and may not even be feasible. But our argument shows that the enhancement project can still have a radical impact on human life even if biomedical enhancement operated entirely within the normal human range.

  20. Mechano-regulation of the beating heart at the cellular level--mechanosensitive channels in normal and diseased heart.

    PubMed

    Friedrich, Oliver; Wagner, Soeren; Battle, Andrew R; Schürmann, Sebastian; Martinac, Boris

    2012-01-01

    The heart as a contractile hollow organ finely tunes mechanical parameters such as stroke volume, stroke pressure and cardiac output according to filling volumes, filling pressures via intrinsic and neuronal routes. At the cellular level, cardiomyocytes in beating hearts are exposed to large mechanical stress during successive heart beats. Although the mechanisms of excitation-contraction coupling are well established in mammalian heart cells, the putative contribution of mechanosensitive channels to Ca²⁺ homeostasis, Ca²⁺ signaling and force generation has been primarily investigated in relation to heart disease states. For instance, transient receptor potential channels (TRPs) are up-regulated in animal models of congestive heart failure or hypertension models and seem to play a vital role in pathological Ca²⁺ overload to cardiomyocytes, thus aggravating the pathology of disease at the cellular level. Apart from that, the contribution of mechanosensitive channels (MsC) in the normal beating heart to the downstream force activation cascade has not been addressed. We present an overview of the current literature and concepts of mechanosensitive channel involvement in failing hearts and cardiomyopathies and novel data showing a likely contribution of Ca²⁺ influx via mechanosensitive channels in beating normal cardiomyocytes during systolic shortening.

  1. [Humanization and nursing assistance to normal childbirth].

    PubMed

    Moura, Fernanda Maria de Jesus S Pires; Crizostomo, Cilene Delgado; Nery, Inez Sampaio; Mendonça, Rita de Cássia Magalhães; de Araújo, Olívia Dias; da Rocha, Silvana Santiago

    2007-01-01

    Bibliographical study that sought to identify the scientific production about humanization and nursing assistance to normal childbirth. The sources were scientific articles from SCIELO-Brasil's database, from 2000 to 2007. We obtained 13 articles as result from the search, which were grouped in the following categories: childbirth medicalization, humanization of assistance to childbirth, companion during childbirth and performance of the obstetric nurse. The analysis pointed out that the current paradigm is centralized on childbirth intervention, despite of humanization movements defending the natural and physiological childbirth made by the nurse. We concluded that qualified and humanized assistance to childbirth and birth privileges women's respect, dignity and autonomy, regarding women's active role in the birth process.

  2. Dynamic mapping of normal human hippocampal development.

    PubMed

    Gogtay, Nitin; Nugent, Tom F; Herman, David H; Ordonez, Anna; Greenstein, Deanna; Hayashi, Kiralee M; Clasen, Liv; Toga, Arthur W; Giedd, Jay N; Rapoport, Judith L; Thompson, Paul M

    2006-01-01

    The hippocampus, which plays an important role in memory functions and emotional responses, has distinct subregions subserving different functions. Because the volume and shape of the hippocampus are altered in many neuropsychiatric disorders, it is important to understand the trajectory of normal hippocampal development. We present the first dynamic maps to reveal the anatomical sequence of normal human hippocampal development. A novel hippocampal mapping technique was applied to a database of prospectively obtained brain magnetic resonance imaging (MRI) scans (100 scans in 31 children and adolescents), scanned every 2 yr for 6-10 yr between ages 4 and 25. Our results establish that the structural development of the human hippocampus is remarkably heterogeneous, with significant differences between posterior (increase over time) and anterior (loss over time) subregions. These distinct developmental trajectories of hippocampal subregions may parallel differences in their functional development.

  3. Moxifloxacin Increases Heart Rate in Humans

    PubMed Central

    Mason, Jay W.; Moon, Thomas E.

    2017-01-01

    (1) Background: We assessed the effect of moxifloxacin on heart rate, and reviewed the heart rate effects of other antibiotics; (2) Methods: A total of 335 normal volunteers had 12-lead electrocardiograms recorded at multiple time points before and during treatment with moxifloxacin and with placebo in seven consecutive, thorough QT studies of crossover design; (3) Results: The average baseline heart rate across the seven studies was 61.5 bpm. The heart rate after moxifloxacin dosing was analyzed at five time points shared by all seven studies (hours 1, 2, 3, 12 and 24). The maximum mean heart rate (HR) increase for the seven studies combined was 2.4 bpm (95% CI 1.6, 3.3) at hour 2. The range of mean maximum increases among the seven studies was 2.1 to 4.3 bpm. For the seven studies combined, the increase was statistically significant at all but the 24 h time point. The maximum observed individual increase in HR was 36 bpm and the mean maximum increase was 30 ± 4.1 bpm by time point and 8 ± 6.9 bpm by subject. Many antibiotics increase HR, some several-fold more than moxifloxacin. However, clinicians and clinical investigators give little attention to this potential adverse effect in the medical literature; (4) Conclusions: The observed moxifloxacin-induced increase in HR is large enough to be clinically relevant, and it is a potentially important confounder in thorough QT studies using moxifloxacin as an active control. More attention to heart rate effects of antibiotics is warranted. PMID:28165431

  4. Heart research advances using database search engines, Human Protein Atlas and the Sydney Heart Bank.

    PubMed

    Li, Amy; Estigoy, Colleen; Raftery, Mark; Cameron, Darryl; Odeberg, Jacob; Pontén, Fredrik; Lal, Sean; Dos Remedios, Cristobal G

    2013-10-01

    This Methodological Review is intended as a guide for research students who may have just discovered a human "novel" cardiac protein, but it may also help hard-pressed reviewers of journal submissions on a "novel" protein reported in an animal model of human heart failure. Whether you are an expert or not, you may know little or nothing about this particular protein of interest. In this review we provide a strategic guide on how to proceed. We ask: How do you discover what has been published (even in an abstract or research report) about this protein? Everyone knows how to undertake literature searches using PubMed and Medline but these are usually encyclopaedic, often producing long lists of papers, most of which are either irrelevant or only vaguely relevant to your query. Relatively few will be aware of more advanced search engines such as Google Scholar and even fewer will know about Quertle. Next, we provide a strategy for discovering if your "novel" protein is expressed in the normal, healthy human heart, and if it is, we show you how to investigate its subcellular location. This can usually be achieved by visiting the website "Human Protein Atlas" without doing a single experiment. Finally, we provide a pathway to discovering if your protein of interest changes its expression level with heart failure/disease or with ageing.

  5. Virtual histology of the human heart using optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Ambrosi, Christina M.; Moazami, Nader; Rollins, Andrew M.; Efimov, Igor R.

    2009-09-01

    Optical coherence tomography (OCT) allows for the visualization of micron-scale structures within nontransparent biological tissues. For the first time, we demonstrate the use of OCT in identifying components of the cardiac conduction system and other structures in the explanted human heart. Reconstructions of cardiac structures up to 2 mm below the tissue surface were achieved and validated with Masson Trichrome histology in atrial, ventricular, sinoatrial nodal, and atrioventricular nodal preparations. The high spatial resolution of OCT provides visualization of cardiac fibers within the myocardium, as well as elements of the cardiac conduction system; however, a limiting factor remains its depth penetration, demonstrated to be ~2 mm in cardiac tissues. Despite its currently limited imaging depth, the use of OCT to identify the structural determinants of both normal and abnormal function in the intact human heart is critical in its development as a potential aid to intracardiac arrhythmia diagnosis and therapy.

  6. Fatty acid uptake in normal human myocardium

    SciTech Connect

    Vyska, K.; Meyer, W.; Stremmel, W.; Notohamiprodjo, G.; Minami, K.; Machulla, H.J.; Gleichmann, U.; Meyer, H.; Koerfer, R. )

    1991-09-01

    Fatty acid binding protein has been found in rat aortic endothelial cell membrane. It has been identified to be a 40-kDa protein that corresponds to a 40-kDa fatty acid binding protein with high affinity for a variety of long chain fatty acids isolated from rat heart myocytes. It is proposed that this endothelial membrane fatty acid binding protein might mediate the myocardial uptake of fatty acids. For evaluation of this hypothesis in vivo, influx kinetics of tracer-labeled fatty acids was examined in 15 normal subjects by scintigraphic techniques. Variation of the plasma fatty acid concentration and plasma perfusion rate has been achieved by modulation of nutrition state and exercise conditions. The clinical results suggest that the myocardial fatty acid influx rate is saturable by increasing fatty acid plasma concentration as well as by increasing plasma flow. For analysis of these data, functional relations describing fatty acid transport from plasma into myocardial tissue in the presence and absence of an unstirred layer were developed. The fitting of these relations to experimental data indicate that the free fatty acid influx into myocardial tissue reveals the criteria of a reaction on a capillary surface in the vicinity of flowing plasma but not of a reaction in extravascular space or in an unstirred layer and that the fatty acid influx into normal myocardium is a saturable process that is characterized by the quantity corresponding to the Michaelis-Menten constant, Km, and the maximal velocity, Vmax, 0.24 {plus minus} 0.024 mumol/g and 0.37 {plus minus} 0.013 mumol/g(g.min), respectively. These data are compatible with a nondiffusional uptake process mediated by the initial interaction of fatty acids with the 40-kDa membrane fatty acid binding protein of cardiac endothelial cells.

  7. Pharmacology and inotropic potential of forskolin in the human heart.

    PubMed Central

    Bristow, M R; Ginsburg, R; Strosberg, A; Montgomery, W; Minobe, W

    1984-01-01

    We evaluated the effects of the diterpene compound forskolin in human myocardial adenylate cyclase preparations, isolated trabeculae and papillary muscles derived from failing human hearts, and acutely instrumented dogs. Forskolin was a potent, powerful activator of human myocardial adenylate cyclase and produced maximal effects that were 4.82 (normally functioning left ventricle) and 6.13 (failing left ventricle) fold greater than isoproterenol. In contrast to isoproterenol, forskolin retained full activity in membrane preparations derived from failing hearts. In cyclase preparations, forskolin demonstrated unique substrate and Mg2+ kinetic properties that could be distinguished from hormone receptor-coupled agonists or fluoride ion. The adenylate cyclase stimulatory effect of forskolin was synergistic with isoproterenol, apparently due to the location of forskolin activation being beyond the level of hormone receptor-agonist in the receptor-cyclase complex. Forskolin was a potent positive inotrope in failing human myocardium, producing a stimulation of contraction that was similar to isoproterenol. Finally, in open chest dogs forskolin was a positive inotropic agent that reduced preload and afterload. We conclude that forskolin belongs to a class of agents that may have therapeutic potential in the treatment of congestive heart failure. Images PMID:6330174

  8. Normal limits for heart rate as established using 24-hour ambulatory electrocardiography in children and adolescents.

    PubMed

    Salameh, Aida; Gebauer, Roman A; Grollmuss, Oswin; Vít, Pavel; Reich, Oleg; Janousek, Jan

    2008-10-01

    To the best of our knowledge, normal limits of heart rate with respect to gender, and as established using 24-hour ambulatory Holter electrocardiography, have yet to be published for the entire age range of children and adolescents. To establish the normal limits for heart rate in newborns, infants, children, and adolescents of both genders. We obtained 24-hour Holter recordings from 616 healthy subjects aged from birth to 20 years with structurally normal hearts. The subjects were not receiving medication, and had not been submitted to prior cardiac intervention. Off-line analysis was performed with Mars 8000 scanners, analysing 5 consecutive RR intervals by the software available for automatic calculation of heart rate. All subjects were in sinus rhythm. Best-fit non-linear regressions were applied to correlate age and gender with minimum and mean heart rate, as well as with maximal RR-interval, and to calculate the 5th, 25th, 75th and 95th percentiles. We observed significant gender-dependent differences in heart rate for persons aged 10 years and older, with the males exhibiting lower minimal and mean heart rates, and higher RR-intervals, than the females. Correlation of heart rate with age and gender could be established with sufficient accuracy using non-linear regression (p less than 0.0001): Minimum heart rate (male: R(2)=0.778, female: R(2) = 0.664) and mean heart rate (male: R(2) = 0.820, female: R(2) = 0.736) decreased with age, while the maximal RR-interval prolonged (male: R(2) = 0.562, female: R(2) = 0.486). Age and gender-related graphs of centiles were constructed. Heart rate, as documented using Holter recodings, can be correlated with age and gender, permitting establishments of normal gender-specific limits for children and adolescents.

  9. Fractal character of the electrocardiogram: distinguishing heart-failure and normal patients.

    PubMed

    Turcott, R G; Teich, M C

    1996-01-01

    Statistical analysis of the sequence of heartbeats can provide information about the state of health of the heart. We used a variety of statistical measures to identify the form of the point process that describes the human heartbeat. These measures are based on both interevent intervals and counts, and include the interevent-interval histogram, interval-based periodogram, rescaled range analysis, the event-number histogram, Fano-factor, Allan Factor, and generalized-rate-based periodogram. All of these measures have been applied to data from both normal and heart-failure patients, and various surrogate versions thereof. The results show that almost all of the interevent-interval and the long-term counting statistics differ in statistically significant ways for the two classes of data. Several measures reveal 1/f-type fluctuations (long-duration power-law correlation). The analysis that we have conducted suggests the use of a conveniently calculated, quantitative index, based on the Allan factor, that indicates whether a particular patient does or does not suffer from heart failure. The Allan factor turns out to be particularly useful because it is easily calculated and is jointly responsive to both short-term and long-term characteristics of the heartbeat time series. A phase-space reconstruction based on the generalized heart rate is used to obtain a putative attractor's capacity dimension. Though the dependence of this dimension on the embedding dimension is consistent with that of a low-dimensional dynamical system (with a larger apparent dimension for normal subjects), surrogate-data analysis shows that identical behavior emerges from temporal correlation in a stochastic process. We present simulated results for a purely stochastic integrate-and-fire model, comprising a fractal-Gaussian-noise kernel, in which the sequence of heartbeats is determined by level crossings of fractional Brownian motion. This model characterizes the statistical behavior of the human

  10. Effects of increased heart work on glycolysis and adenine nucleotides in the perfused heart of normal and diabetic rats

    PubMed Central

    Opie, L. H.; Mansford, K. R. L.; Owen, Patricia

    1971-01-01

    1. In the isolated perfused rat heart, the contractile activity and the oxygen uptake were varied by altering the aortic perfusion pressure, or by the atrial perfusion technique (`working heart'). 2. The maximum increase in the contractile activity brought about an eightfold increase in the oxygen uptake. The rate of glycolytic flux rose, while tissue contents of hexose monophosphates, citrate, ATP and creatine phosphate decreased, and contents of ADP and AMP rose. 3. The changes in tissue contents of adenine nucleotides during increased heart work were time-dependent. The ATP content fell temporarily (30s and 2min) after the start of left-atrial perfusion; at 5 and 10min values were normal; and at 30 and 60min values were decreased. ADP and AMP values were increased in the first 15min, but were at control values 30 or 60min after the onset of increased heart work. 4. During increased heart work changes in the tissue contents of adenine nucleotide and of citrate appeared to play a role in altered regulation of glycolysis at the level of phosphofructokinase activity. 5. In recirculation experiments increased heart work for 30min was associated with increased entry of [14C]glucose (11.1mm) and glycogen into glycolysis and a comparable increase in formation of products of glycolysis (lactate, pyruvate and 14CO2). There was no major accumulation of intermediates. Glycogen was not a major fuel for respiration. 6. Increased glycolytic flux in Langendorff perfused and working hearts was obtained by the addition of insulin to the perfusion medium. The concomitant increases in the tissue values of hexose phosphates and of citrate contrasted with the decreased values of hexose monophosphates and of citrate during increased glycolytic flux obtained by increased heart work. 7. Decreased glycolytic flux in Langendorff perfused hearts was obtained by using acute alloxan-diabetic and chronic streptozotocin-diabetic rats; in the latter condition there were decreased tissue

  11. Cardiac Extracellular Vesicles in Normal and Infarcted Heart

    PubMed Central

    Chistiakov, Dimitry A.; Orekhov, Alexander N.; Bobryshev, Yuri V.

    2016-01-01

    Heart is a complex assembly of many cell types constituting myocardium, endocardium and epicardium that intensively communicate to each other in order to maintain the proper cardiac function. There are many types of intercellular intracardiac signals, with a prominent role of extracellular vesicles (EVs), such as exosomes and microvesicles, for long-distant delivering of complex messages. Cardiomyocytes release EVs, whose content could significantly vary depending on the stimulus. In stress, such as hypoxia, inflammation or injury, cardiomyocytes increase secretion of EVs. In hypoxic conditions, cardiac EVs are enriched with angiogenic and prosurvival factors. In acute myocardial infarction (AMI), damaged cardiac muscle cells produce EVs with increased content of angiogenic, anti-apoptotic, mitogenic and growth factors in order to induce repair and healing of the infarcted myocardium. Exosomal microRNAs play a central role in cardiac regeneration. In AMI, circulating cardiac EVs abundantly contain cardiac-specific miRNAs that serve as indicators of cardiac damage and have a big diagnostic potential as AMI biomarkers. Cardioprotective and regenerative properties of exosomes derived from cardiac and non-cardiac stem/progenitor cells are very helpful to be used in cell-free cardiotherapy and regeneration of post-infarct myocardium. PMID:26742038

  12. Prospective Association of Physical Activity and Heart Failure Hospitalizations Among Black Adults With Normal Ejection Fraction: The Jackson Heart Study.

    PubMed

    Koo, Patrick; Gjelsvik, Annie; Choudhary, Gaurav; Wu, Wen-Chih; Wang, Wei; McCool, F Dennis; Eaton, Charles B

    2017-09-07

    Given high rates of obesity, hypertension, and diabetes mellitus, black persons are at risk to develop heart failure. The association of moderate to vigorous physical activity (MVPA) and heart failure in black adults is underresearched. The purpose of this study was to explore whether greater MVPA was associated with lower risk of heart failure hospitalizations (HFHs) among black adults with normal ejection fractions. We performed a prospective analysis of 4066 black adults who participated in the Jackson Heart Study and who had physical activity measured, had normal ejection fraction on 2-dimensional echocardiograms, and were followed for 7 years for incident HFH. We used Cox proportional regression analyses adjusted for age, sex, body mass index, smoking status, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, coronary heart disease, atrial fibrillation, and chronic kidney disease and examined effect modification by sex and body mass index. Of the eligible population, 1925 participants, according to the duration of MVPA, had poor health (0 minutes/week), 1332 had intermediate health (1-149 minutes/week), and 809 had ideal health (≥150 minutes/week). There were 168 incident HFHs. MVPA for intermediate and ideal health was associated with decreasing risk of incident HFH (hazard ratio: 0.70 [95% confidence interval, 49-1.00] and 0.35 [95% confidence interval, 0.19-0.64], respectively; Ptrend=0.003). The full model revealed hazard ratios of 0.74 [95% confidence interval, 0.52-1.07] and 0.41 [95% confidence interval, 0.22-0.74], respectively. There was no effect modification between MVPA and body mass index or sex on incident HFH. A dose-response relationship between increasing levels of MVPA and protection from incident HFH was found in black men and women with normal ejection fractions. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  13. The variability problem of normal human walking.

    PubMed

    Simonsen, Erik B; Alkjær, Tine

    2012-03-01

    Previous investigations have suggested considerable inter-individual variability in the time course pattern of net joint moments during normal human walking, although the limited sample sizes precluded statistical analyses. The purpose of the present study was to obtain joint moment patterns from a group of normal subjects and to test whether or not the expected differences would prove to be statistically significant. Fifteen healthy male subjects were recorded on video while they walked across two force platforms. Ten kinematic and kinetic parameters were selected and input to a statistical cluster analysis to determine whether or not the 15 subjects could be divided into different 'families' (clusters) of walking strategy. The net joint moments showed a variability corroborating earlier reports. The cluster analysis showed that the 15 subjects could be grouped into two clusters of 5 and 10 subjects, respectively. Five parameters differed significantly, so the group of 5 subjects was characterized by (1) a higher peak knee joint extensor moment, (2) more flexed knee joint angle at heel strike, (3) during the whole stance phase, (4) lower peak knee joint flexor moment and (5) lower ankle joint angle at flat foot position. Calculation of bone-on-bone forces in the knee joint showed a value of 64 N/kg body weight in the K+ group and 55 N/kg in the K- group (p<0.05). It is unknown if differences of similar magnitude contribute to early joint degeneration in some individuals while not in others.

  14. Large-scale discovery of enhancers from human heart tissue.

    PubMed

    May, Dalit; Blow, Matthew J; Kaplan, Tommy; McCulley, David J; Jensen, Brian C; Akiyama, Jennifer A; Holt, Amy; Plajzer-Frick, Ingrid; Shoukry, Malak; Wright, Crystal; Afzal, Veena; Simpson, Paul C; Rubin, Edward M; Black, Brian L; Bristow, James; Pennacchio, Len A; Visel, Axel

    2011-12-04

    Development and function of the human heart depend on the dynamic control of tissue-specific gene expression by distant-acting transcriptional enhancers. To generate an accurate genome-wide map of human heart enhancers, we used an epigenomic enhancer discovery approach and identified ∼6,200 candidate enhancer sequences directly from fetal and adult human heart tissue. Consistent with their predicted function, these elements were markedly enriched near genes implicated in heart development, function and disease. To further validate their in vivo enhancer activity, we tested 65 of these human sequences in a transgenic mouse enhancer assay and observed that 43 (66%) drove reproducible reporter gene expression in the heart. These results support the discovery of a genome-wide set of noncoding sequences highly enriched in human heart enhancers that is likely to facilitate downstream studies of the role of enhancers in development and pathological conditions of the heart.

  15. Disposition of human fibrinopeptide A in normal and nephrectomized rabbits

    SciTech Connect

    Harenberg, J.; Stehle, G.; Waibel, S.; Hermann, H.J.; Eisenhut, M.; Zimmermann, R.

    1983-10-01

    The distribution, elimination, and metabolism of human fibrinopeptide A (FPA) were studied in normal and nephrectomized rabbits. The activity of /sup 125/I-labeled desamino-tyrosyl human FPA (DAT-FPA) was followed over 4 hours after i.v. administration. Results show that in normal rabbits (n . 10) DAT-FPA is eliminated from plasma in four phases with half-lives of 30 sec, 3.5 min, 15 min, and 90 min. The distribution of /sup 123/I-labeled DAT-FPA in plasma was determined in 15 control rabbits with scintigraphy over 2 hours. DAT-FPA was distributed primarily in the cardiovascular system, liver, and kidneys. In some animals minimal radioactivity was detected over the gall bladder. Radioactivity accumulated rapidly in the urinary bladder, approximately 50% being recorded after 15 min and 90% after 120 min. In the heart area radioactivity decreased with half-lives of 25 sec, 7.5 min, 25 min, and 180 min. Nephrectomized rabbits had similar initial fast distribution of DAT-FPA after administration of /sup 125/I-labeled (n . 10) and /sup 123/I-labeled peptide (n . 10). The estimated half-life of the slow component was in the order of several hours. The results of the scintigraphic and gel chromatographic studies show that FPA is primarily excreted in the urine. Previously reported half-lives of FPA reflect distribution rather than steady state conditions.

  16. Sodium MRI in human heart: a review.

    PubMed

    Bottomley, Paul A

    2016-02-01

    This paper offers a critical review of the properties, methods and potential clinical application of sodium ((23)Na) MRI in human heart. Because the tissue sodium concentration (TSC) in heart is about ~40 µmol/g wet weight, and the (23)Na gyromagnetic ratio and sensitivity are respectively about one-quarter and one-11th of that of hydrogen ((1)H), the signal-to-noise ratio of (23)Na MRI in the heart is about one-6000th of that of conventional cardiac (1)H MRI. In addition, as a quadrupolar nucleus, (23)Na exhibits ultra-short and multi-component relaxation behavior (T1 ~ 30 ms; T2 ~ 0.5-4 ms and 12-20 ms), which requires fast, specialized, ultra-short echo-time MRI sequences, especially for quantifying TSC. Cardiac (23)Na MRI studies from 1.5 to 7 T measure a volume-weighted sum of intra- and extra-cellular components present at cytosolic concentrations of 10-15 mM and 135-150 mM in healthy tissue, respectively, at a spatial resolution of about 0.1-1 ml in 10 min or so. Currently, intra- and extra-cellular sodium cannot be unambiguously resolved without the use of potentially toxic shift reagents. Nevertheless, increases in TSC attributable to an influx of intra-cellular sodium and/or increased extra-cellular volume have been demonstrated in human myocardial infarction consistent with prior animal studies, and arguably might also be seen in future studies of ischemia and cardiomyopathies--especially those involving defects in sodium transport. While technical implementation remains a hurdle, a central question for clinical use is whether cardiac (23)Na MRI can deliver useful information unobtainable by other more convenient methods, including (1)H MRI.

  17. Relaxographic studies of aging normal human lenses.

    PubMed

    Bettelheim, Frederick A; Lizak, Martin J; Zigler, J Samuel

    2002-12-01

    Ten excised normal human lenses of various ages were studied. Seven sections of each lens, from anterior outer cortex to posterior outer cortex were imaged and the T(1) (spin-lattice) and T(2) (spin-spin) relaxation data on each section were collected. T(1) and T(2) relaxation were analysed by fitting pixel intensity to one term exponential expressions. Both T(1) and T(2) relaxation times showed minimal values in the nuclear region and maxima at the two outer cortexes. The pre-exponential terms of the fittings of both T(1) and T(2) relaxation,M(1) and M(2), were normalized in order to eliminate instrumental variations over a 2 year period. M(2) had a maximum in the nucleus and minima in the two cortexes. M(1) exhibited minimal value in the nucleus and maxima at the two cortexes. The positional dependence of T(2) relaxation times as well as that of M(2) indicated that they represent the behavior of the bound water in the lens. The positional dependence of M(1) suggests that this relaxation represents the total water that has a minimal value in the nucleus. The T(2) relaxation time decreases with increase in the age of the lens at each location. The slope of the change in T(2) relaxation time with age is greatest in the outer cortexes and diminishes as one proceeds to the nucleus. T(1) relaxation times and M(1) do not show significant change with age. This and the age dependence of the other relaxographic parameters imply that the aging of the lens involves major changes in its hydration properties that are more accentuated in the cortexes. The interpretation of these changes is in agreement with the syneretic theory of lens aging.

  18. Cardiovascular cast model fabrication and casting effectiveness evaluation in fetus with severe congenital heart disease or normal heart.

    PubMed

    Wang, Yu; Cao, Hai-yan; Xie, Ming-xing; He, Lin; Han, Wei; Hong, Liu; Peng, Yuan; Hu, Yun-fei; Song, Ben-cai; Wang, Jing; Wang, Bin; Deng, Cheng

    2016-04-01

    To investigate the application and effectiveness of vascular corrosion technique in preparing fetal cardiovascular cast models, 10 normal fetal heart specimens with other congenital disease (control group) and 18 specimens with severe congenital heart disease (case group) from induced abortions were enrolled in this study from March 2013 to June 2015 in our hospital. Cast models were prepared by injecting casting material into vascular lumen to demonstrate real geometries of fetal cardiovascular system. Casting effectiveness was analyzed in terms of local anatomic structures and different anatomical levels (including overall level, atrioventricular and great vascular system, left-sided and right-sided heart), as well as different trimesters of pregnancy. In our study, all specimens were successfully casted. Casting effectiveness analysis of local anatomic structures showed a mean score from 1.90±1.45 to 3.60±0.52, without significant differences between case and control groups in most local anatomic structures except left ventricle, which had a higher score in control group (P=0.027). Inter-group comparison of casting effectiveness in different anatomical levels showed no significant differences between the two groups. Intra-group comparison also revealed undifferentiated casting effectiveness between atrioventricular and great vascular system, or left-sided and right-sided heart in corresponding group. Third-trimester group had a significantly higher perfusion score in great vascular system than second-trimester group (P=0.046), while the other anatomical levels displayed no such difference. Vascular corrosion technique can be successfully used in fabrication of fetal cardiovascular cast model. It is also a reliable method to demonstrate three-dimensional anatomy of severe congenital heart disease and normal heart in fetus.

  19. The large septal arteries in normal hearts, in aortic valve disease, and in tetralogy of Fallot.

    PubMed

    Melo, J Q; Abecasis, M E; Neves, J S; Bruges, L O; Ramos, S B; Martins, A P

    1995-12-01

    Several surgical techniques such as the Ross operation or total correction of tetralogy of Fallot require incisions of the upper ventricular septum. Very few reports on the anatomy of the septal arteries of the pathologic heart can be found in the literature. To get a more precise knowledge of the large septal arteries in pathologic hearts, we have compared the anatomy of normal hearts with that of hearts with aortic valve disease and of tetralogy of Fallot. Twenty-six normal heart specimens (group A), 11 with aortic valve disease (group B), and 4 with tetralogy of Fallot (group C) were dissected. In groups B and C a single large septal artery was always found. The large septal artery had the orientation previously described for normal hearts. Still, its course in the lower border of the anterior extension of the septomarginal trabecula was deeper. The anterior extension of the septomarginal trabecula was 4 +/- 3 mm deep in group A, 6 +/- 2 mm in group B, and 3 mm in group C. The interventricular septum was much thicker in groups B and C than in group A. The position of the large septal artery can be predicted from coronary angiography and from the morphology of the anterior extension of the septomarginal trabecula. Knowledge of its position can improve the safety of operations performed on the outflow of the interventricular septum.

  20. The Relationships between Body Mass Index and Left Ventricular Diastolic Function in a Structurally Normal Heart with Normal Ejection Fraction

    PubMed Central

    Jin, Han-Young; Jang, Jae-Sik; Yang, Tae-Hyun; Kim, Dae-Kyeong; Kim, Dong-Soo

    2017-01-01

    Background We conducted research to determine the effect of the weight on left ventricular (LV) diastolic function in Asians, who are at greater risk of cardiovascular events compared to individuals from Western countries with similar body mass indices (BMIs). Methods We studied 543 participants with structurally normal hearts and normal ejection fractions. Participants were classified as normal-weight (BMI < 23.0 kg/m2), overweight (BMI 23.0–27.4 kg/m2), or obese (BMI ≥ 27.5 kg/m2). Peak E velocity, peak A velocity, and E′ velocity were measured and E/E′ was calculated. Results Overweight participants had lower E than normal-weight participants (p = 0.001). E′ velocities in overweight and obese participants were less than those in normal weight participants (both p < 0.001). The E/E′ ratio in obese participants was higher compared to the value in normal-weight participants (p < 0.001) and overweight participants (p = 0.025). BMI was associated with E (R = −0.108), A (R = 0.123), E′ (R = −0.229), and E/E′ ratio (R = 0.138) (all p < 0.05). In multivariate analyses, BMI was independently associated with higher A, lower E′, and higher E/E′. The risk of diastolic dysfunction was significantly higher among overweight [adjusted odds ratio: 2.088; 95% confidence interval (CI): 1.348–3.235; p = 0.001] and obese participants (adjusted odds ratio: 5.910; 95% CI: 2.871–12.162; p < 0.001) compared to normal-weight participants. Conclusion Obesity and overweight independently predicted diastolic dysfunction. An optimal body weight lower than the universal cut-off is reasonable for preventing LV heart failure in Asians. PMID:28400930

  1. Antibodies to endogenous tear protein in normal human tears.

    PubMed

    Remington, Susann G; Crow, Jean M; Nelson, J Daniel

    2009-10-01

    To identify endogenous tear proteins immunoselected by antibodies from normal human ocular tears. Proteins were immunoselected from normal human tear samples without the addition of primary antibodies. Captured proteins were electrophoresed in polyacrylamide gels and silver stained. Human tears were also used as primary antibodies on immunoblots of tear proteins. Lysozyme, lipocalin-1, and lactoferrin were immunoselected from normal human tear samples without the addition of primary antibodies. Antibodies from normal tears recognized lysozyme on immunoblots of tear proteins. Normal human ocular tears contain antibodies to endogenous tear protein.

  2. [Successful radiofrequency catheter ablation of the symptomatic ventricular tachycardia in structurally normal heart. Case report].

    PubMed

    Maciag, Aleksander; Sterliński, Maciej; Pytkowski, Mariusz; Jankowska, Agnieszka; Szwed, Hanna

    2003-12-01

    Radiofrequency catheter ablation (RFA) in structurally normal heart ventricular arrhythmias has been found to be promising direction of develop. Authors presented the case of successful RFA of symptomatic ventricular tachycardia originating from right ventricle outflow tract (RVOT). Arrhythmogenic locus was localised basing on ECG pattern, analyze of endocardial potentials and pace mapping method. In two-year follow up she was free of symptoms and ventricular arrhythmia, no medication needed. RFA is an effective and safe therapy in ventricular tachycardia in structurally normal heart.

  3. Zebrafish heart as a model for human cardiac electrophysiology.

    PubMed

    Vornanen, Matti; Hassinen, Minna

    2016-01-01

    The zebrafish (Danio rerio) has become a popular model for human cardiac diseases and pharmacology including cardiac arrhythmias and its electrophysiological basis. Notably, the phenotype of zebrafish cardiac action potential is similar to the human cardiac action potential in that both have a long plateau phase. Also the major inward and outward current systems are qualitatively similar in zebrafish and human hearts. However, there are also significant differences in ionic current composition between human and zebrafish hearts, and the molecular basis and pharmacological properties of human and zebrafish cardiac ionic currents differ in several ways. Cardiac ionic currents may be produced by non-orthologous genes in zebrafish and humans, and paralogous gene products of some ion channels are expressed in the zebrafish heart. More research on molecular basis of cardiac ion channels, and regulation and drug sensitivity of the cardiac ionic currents are needed to enable rational use of the zebrafish heart as an electrophysiological model for the human heart.

  4. Echocardiographic image of an active human heart

    NASA Technical Reports Server (NTRS)

    2003-01-01

    Echocardiographic images provide quick, safe images of the heart as it beats. While a state-of-the art echocardiograph unit is part of the Human Research Facility on International Space Station, quick transmission of images and data to Earth is a challenge. NASA is developing techniques to improve the echocardiography available to diagnose sick astronauts as well as study the long-term effects of space travel on their health. Echocardiography uses ultrasound, generated in a sensor head placed against the patient's chest, to produce images of the structure of the heart walls and valves. However, ultrasonic imaging creates an enormous volume of data, up to 220 million bits per second. This can challenge ISS communications as well as Earth-based providers. Compressing data for rapid transmission back to Earth can degrade the quality of the images. Researchers at the Cleveland Clinic Foundation are working with NASA to develop compression techniques that meet imaging standards now used on the Internet and by the medical community, and that ensure that physicians receive quality diagnostic images.

  5. Human heart conjugate cooling simulation: unsteady thermo-fluid-stress analysis.

    PubMed

    Abdoli, Abas; Dulikravich, George S; Bajaj, Chandrajit; Stowe, David F; Jahania, M Salik

    2014-11-01

    The main objective of this work was to demonstrate computationally that realistic human hearts can be cooled much faster by performing conjugate heat transfer consisting of pumping a cold liquid through the cardiac chambers and major veins while keeping the heart submerged in cold gelatin filling a cooling container. The human heart geometry used for simulations was obtained from three-dimensional, high resolution CT-angio scans. Two fluid flow domains for the right (pulmonic) and left (systemic) heart circulations, and two solid domains for the heart tissue and gelatin solution were defined for multi-domain numerical simulation. Detailed unsteady temperature fields within the heart tissue were calculated during the conjugate cooling process. A linear thermoelasticity analysis was performed to assess the stresses applied on the heart due to the coolant fluid shear and normal forces and to examine the thermal stress caused by temperature variation inside the heart. It was demonstrated that a conjugate cooling effort with coolant temperature at +4°C is capable of reducing the average heart temperature from +37°C to +8°C in 25 minutes for cases in which the coolant was steadily pumped only through major heart inlet veins and cavities. Copyright © 2014 John Wiley & Sons, Ltd.

  6. Human heart conjugate cooling simulation: Unsteady thermo-fluid-stress analysis

    PubMed Central

    Abdoli, Abas; Dulikravich, George S.; Bajaj, Chandrajit; Stowe, David F.; Jahania, M. Salik

    2015-01-01

    The main objective of this work was to demonstrate computationally that realistic human hearts can be cooled much faster by performing conjugate heat transfer consisting of pumping a cold liquid through the cardiac chambers and major veins while keeping the heart submerged in cold gelatin filling a cooling container. The human heart geometry used for simulations was obtained from three-dimensional, high resolution MRI scans. Two fluid flow domains for the right (pulmonic) and left (systemic) heart circulations, and two solid domains for the heart tissue and gelatin solution were defined for multi-domain numerical simulation. Detailed unsteady temperature fields within the heart tissue were calculated during the conjugate cooling process. A linear thermoelasticity analysis was performed to assess the stresses applied on the heart due to the coolant fluid shear and normal forces and to examine the thermal stress caused by temperature variation inside the heart. It was demonstrated that a conjugate cooling effort with coolant temperature at +4°C is capable of reducing the average heart temperature from +37°C to +8°C in 25 minutes for cases in which the coolant was steadily pumped only through major heart inlet veins and cavities. PMID:25045006

  7. Arrhythmogenic and metabolic remodelling of failing human heart

    PubMed Central

    Gloschat, C. R.; Koppel, A. C.; Aras, K. K.; Brennan, J. A.; Holzem, K. M.

    2016-01-01

    Abstract Heart failure (HF) is a major cause of morbidity and mortality worldwide. The global burden of HF continues to rise, with prevalence rates estimated at 1–2% and incidence approaching 5–10 per 1000 persons annually. The complex pathophysiology of HF impacts virtually all aspects of normal cardiac function – from structure and mechanics to metabolism and electrophysiology – leading to impaired mechanical contraction and sudden cardiac death. Pharmacotherapy and device therapy are the primary methods of treating HF, but neither is able to stop or reverse disease progression. Thus, there is an acute need to translate basic research into improved HF therapy. Animal model investigations are a critical component of HF research. However, the translation from cellular and animal models to the bedside is hampered by significant differences between species and among physiological scales. Our studies over the last 8 years show that hypotheses generated in animal models need to be validated in human in vitro models. Importantly, however, human heart investigations can establish translational platforms for safety and efficacy studies before embarking on costly and risky clinical trials. This review summarizes recent developments in human HF investigations of electrophysiology remodelling, metabolic remodelling, and β‐adrenergic remodelling and discusses promising new technologies for HF research. PMID:27019074

  8. Differential expression of the cardiac ryanodine receptor in normal and arrhythmogenic right ventricular cardiomyopathy canine hearts.

    PubMed

    Meurs, Kathryn M; Lacombe, Veronique A; Dryburgh, Keith; Fox, Philip R; Reiser, Peter R; Kittleson, Mark D

    2006-08-01

    Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a form of cardiomyopathy characterized by ventricular tachyarrhythmias and a fibrofatty infiltrate that is believed to preferentially affect the right ventricle. Mutations in the cardiac ryanodine receptor (RyR2) gene have been identified in some human families with a unique form of ARVC, ARVC2. Although the RyR2 has significant importance in excitation-contraction coupling across the ventricles, mutations in the gene encoding for it appear to have the greatest impact on the right ventricle in ARVC2. Using a canine model (boxer), the RyR2 protein and message RNA in the right ventricle, left ventricle and interventricular septum from normal dogs and dogs with ARVC were investigated by immunoblotting and real time PCR. The cardiac RyR2 message and protein expression were differentially expressed across the cardiac walls in the normal heart, with the lowest concentration expressed in the right ventricle (P < 0.05). The message and protein expression of the RyR2 were reduced in all chambers in the canine model of ARVC. We propose that the increased susceptibility of the right ventricle to ARVC may be associated with the lower baseline protein concentration of RyR2 in the normal right ventricle compared to the left ventricle and interventricular septum and that all three areas are equally affected in this canine model of ARVC. Using this naturally occurring model of canine ARVC, we may have provided new insights into the pathogenesis of this cardiomyopathy.

  9. Energy metabolism in the normal and failing heart: potential for therapeutic interventions.

    PubMed

    Stanley, William C; Chandler, Margaret P

    2002-04-01

    The chronically failing heart has been shown to be metabolically abnormal, in both animal models and in patients. Little data are available on the rate of myocardial glucose, lactate and fatty acid metabolism and oxidation in heart failure patients, thus at present, it is not possible to draw definitive conclusions about cardiac substrate preference in the various stages and manifestations of the disease. Normal cardiac function is dependent on a constant resynthesis of ATP by oxidative phosphorylation in the mitochondria. The healthy heart gets 60-90% of its energy for oxidative phosphorylation from fatty acid oxidation, with the balance from lactate and glucose. There is some indication that compensated NYHA Class III heart failure patients have a significantly greater rate of lipid oxidation, and decreased glucose uptake and carbohydrate oxidation compared to healthy age-matched individuals, and that therapies that acutely switch the substrate of the heart away from fatty acids result in improvement in left ventricular function. Clinical studies using long-term therapy with beta-adrenergic receptor antagonists show improved left ventricular function that corresponds with a switch away from fatty acid oxidation towards more carbohydrate oxidation by the heart. These findings suggest that chronic manipulation of myocardial substrate oxidation toward greater carbohydrate oxidation and less fatty acid oxidation may improve ventricular performance and slow the progression of left ventricular dysfunction in heart failure patients. At present, this intriguing hypothesis requires further evaluation.

  10. Teaching Recognition of Normal and Abnormal Heart Sounds Using Computer-Assisted Instruction

    ERIC Educational Resources Information Center

    Musselman, Eugene E.; Grimes, George M.

    1976-01-01

    The computer is being used in an innovative manner to teach the recognition of normal and abnormal canine heart sounds at the University of Chicago. Experience thus far indicates that the PLATO program resources allow the maximum development of the student's proficiency in auscultation. (Editor/LBH)

  11. Teaching Recognition of Normal and Abnormal Heart Sounds Using Computer-Assisted Instruction

    ERIC Educational Resources Information Center

    Musselman, Eugene E.; Grimes, George M.

    1976-01-01

    The computer is being used in an innovative manner to teach the recognition of normal and abnormal canine heart sounds at the University of Chicago. Experience thus far indicates that the PLATO program resources allow the maximum development of the student's proficiency in auscultation. (Editor/LBH)

  12. [Application of spatio-temporal image correlation in normal fetal heart ultrasonography].

    PubMed

    Wu, Ying; Liu, Tao; Xiong, Yi; Zang, Ling

    2008-02-01

    To explore the clinical application of real-time three-dimensional ultrasonography in the routine scanning of normal fetal heart. A total of 110 volume datasets of normal fetal hearts in the second trimester were acquired by spatio-temporal image correlation (STIC). An off-line analysis of acquired volume datasets was performed to examine each segment of fetal heart with tomographic ultrasound imaging (TUI) and dynamic multi-planar mode (MP). The re-slice images of four-chamber view, ventricular outflow tract views, and the three vessels plane were viewed with TUI. The quality of images obtained from TUI was compared with the conventional 2D imaging mode. The volume datasets were displayed interactively with MP as a series of three-orthogonal planes. The dynamic loops of one cardiac cycle were preformed by navigating the pivot point and rotational axis and shifting each re-slice image plane inside the volume datasets. Satisfactory gray-scale volume acquisitions were accomplished in 110 cases. The average STIC scanning time of fetal heart was (55 +/- 15) s. An offline analysis showed that four standard planes of 2D routine screening for fetal hearts were easily obtained by TUI. The quality of the images derived from volume datasets were comparable to that directly obtained from 2D echocardiography. The visualization rate had no significant difference between TUI and routine 2D screening (P > 0.05). In MP mode, 39 cases with the starting plan of apical four-chamber view were obtained. Each segment of fetal heart was almost visualized off line, both in a frozen state and with heart in motion to fulfill sequential segmental analysis in fetal cardiac anatomy. The 72% - 100% main features of atria, ventricles, aorta, and the junction segments were viewed with MP by adjusting the three dimensional volume datasets, whose quality and contents met the expectations of off-line segmental analysis of normal fetal heart. A sagittal section of ventricular septum was obtained in

  13. Multivariate Normal Tissue Complication Probability Modeling of Heart Valve Dysfunction in Hodgkin Lymphoma Survivors

    SciTech Connect

    Cella, Laura; Liuzzi, Raffaele; Conson, Manuel; D’Avino, Vittoria; Salvatore, Marco; Pacelli, Roberto

    2013-10-01

    Purpose: To establish a multivariate normal tissue complication probability (NTCP) model for radiation-induced asymptomatic heart valvular defects (RVD). Methods and Materials: Fifty-six patients treated with sequential chemoradiation therapy for Hodgkin lymphoma (HL) were retrospectively reviewed for RVD events. Clinical information along with whole heart, cardiac chambers, and lung dose distribution parameters was collected, and the correlations to RVD were analyzed by means of Spearman's rank correlation coefficient (Rs). For the selection of the model order and parameters for NTCP modeling, a multivariate logistic regression method using resampling techniques (bootstrapping) was applied. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC). Results: When we analyzed the whole heart, a 3-variable NTCP model including the maximum dose, whole heart volume, and lung volume was shown to be the optimal predictive model for RVD (Rs = 0.573, P<.001, AUC = 0.83). When we analyzed the cardiac chambers individually, for the left atrium and for the left ventricle, an NTCP model based on 3 variables including the percentage volume exceeding 30 Gy (V30), cardiac chamber volume, and lung volume was selected as the most predictive model (Rs = 0.539, P<.001, AUC = 0.83; and Rs = 0.557, P<.001, AUC = 0.82, respectively). The NTCP values increase as heart maximum dose or cardiac chambers V30 increase. They also increase with larger volumes of the heart or cardiac chambers and decrease when lung volume is larger. Conclusions: We propose logistic NTCP models for RVD considering not only heart irradiation dose but also the combined effects of lung and heart volumes. Our study establishes the statistical evidence of the indirect effect of lung size on radio-induced heart toxicity.

  14. On the conscious control of the human heart.

    PubMed

    Pokrovskii, Vladimir M; Polischuk, Lily V

    2012-06-01

    This study describes methods of volitional management of heart rhythms and proves that it is possible by means of management of its operations, subject to arbitrary control, which also has a strong functional connection to the center of the heart rhythm formation in the brain. Experiments demonstrate that it is possible for arbitrary changes in the heart rhythm to be made through conscious control of the breathing rhythm, and even a short-term cardiac arrest by means of contracting abdominal muscles. We postulate that the management of human heart rhythm is indirectly regulated through arbitrary controlled operations. The present article describes and analyzes ways that enable a human to consciously and purposefully manage the frequency of heart contractions. Common principles of arbitrary management of the heart rhythm in humans are uncovered through analysis.

  15. Measures of brain morphology and infarction in the framingham heart study: establishing what is normal.

    PubMed

    DeCarli, Charles; Massaro, Joseph; Harvey, Danielle; Hald, John; Tullberg, Mats; Au, Rhoda; Beiser, Alexa; D'Agostino, Ralph; Wolf, Philip A

    2005-04-01

    Numerous anatomical and brain imaging studies find substantial differences in brain structure between men and women across the span of human aging. The ability to extend the results of many of these studies to the general population is limited, however, due to the generally small sample size and restrictive health criteria of these studies. Moreover, little attention has been paid to the possible impact of brain infarction on age-related differences in regional brain volumes. Given the current lack of normative data on gender and aging related differences in regional brain morphology, particularly with regard to the impact of brain infarctions, we chose to quantify brain MRIs from more than 2200 male and female participants of the Framingham Heart Study who ranged in age from 34 to 97 years. We believe that MRI analysis of the Framingham Heart Study more closely represents the general population enabling more accurate estimates of regional brain changes that occur as the consequence of normal aging. As predicted, men had significantly larger brain volumes than women, but these differences were generally not significant after correcting for gender related differences in head size. Age explained approximately 50% of total cerebral brain volume differences, but age-related differences were generally small prior to age 50, declining substantially thereafter. Frontal lobe volumes showed the greatest decline with age (approximately 12%), whereas smaller differences were found for the temporal lobes (approximately 9%). Age-related differences in occipital and parietal lobe were modest. Age-related gender differences were generally small, except for the frontal lobe where men had significantly smaller lobar brain volumes throughout the age range studied. The prevalence of MRI infarction was common after age 50, increased linearly with age and was associated with significantly larger white matter hyperintensity (WMH) volumes beyond that associated with age

  16. Normal Values for Heart Electrophysiology Parameters of Healthy Swine Determined on Electrophysiology Study.

    PubMed

    Noszczyk-Nowak, Agnieszka; Cepiel, Alicja; Janiszewski, Adrian; Pasławski, Robert; Gajek, Jacek; Pasławska, Urszula; Nicpoń, Józef

    2016-01-01

    Swine are a well-recognized animal model for human cardiovascular diseases. Despite the widespread use of porcine model in experimental electrophysiology, still no reference values for intracardiac electrical activity and conduction parameters determined during an invasive electrophysiology study (EPS) have been developed in this species thus far. The aim of the study was to develop a set of normal values for intracardiac electrical activity and conduction parameters determined during an invasive EPS of swine. The study included 36 healthy domestic swine (24-40 kg body weight). EPS was performed under a general anesthesia with midazolam, propofol and isoflurane. The reference values for intracardiac electrical activity and conduction parameters were calculated as arithmetic means ± 2 standard deviations. The reference values were determined for AH, HV and PA intervals, interatrial conduction time at its own and imposed rhythm, sinus node recovery time (SNRT), corrected sinus node recovery time (CSNRT), anterograde and retrograde Wenckebach points, atrial, atrioventricular node and ventricular refractory periods. No significant correlations were found between body weight and heart rate of the examined pigs and their electrophysiological parameters. The hereby presented reference values can be helpful in comparing the results of various studies, as well as in more accurately estimating the values of electrophysiological parameters that can be expected in a given experiment.

  17. Cardiac resynchronisation therapy in patients with heart failure and a normal QRS duration: the RESPOND study.

    PubMed

    Foley, Paul W X; Patel, Kiran; Irwin, Nick; Sanderson, John E; Frenneaux, Michael P; Smith, Russell E A; Stegemann, Berthold; Leyva, Francisco

    2011-07-01

    To evaluate the clinical response to cardiac resynchronisation therapy (CRT) in patients with heart failure and a normal QRS duration (<120 ms). Single centre. 60 patients with heart failure and a normal QRS duration receiving optimal pharmacological treatment (OPT). Patients were randomly assigned to CRT (n=29) or to a control group (OPT, n=31). Cardiovascular magnetic resonance was used in order to avoid scar at the site of left ventricular (LV) lead deployment. The primary end point was a change in 6 min walking distance (6-MWD). Other measures included a change in quality of life scores (Minnesota Living with Heart Failure questionnaire) and New York Heart Association class. In 93% of implantations, the LV lead was deployed over non-scarred myocardium. At 6 months, the 6-MWD increased with CRT compared with OPT (p<0.0001), with more patients reaching a ≥25% increase (51.7% vs 12.9%, p=0.0019). Compared with OPT, CRT led to an improvement in quality-of-life scores (p=0.0265) and a reduction in NYHA class (p<0.0001). The composite clinical score (survival for 6 months free of heart failure hospitalisations plus improvement by one or more NYHA class or by ≥25% in 6-MWD) was better in CRT than in OPT (83% vs 23%, respectively; p<0.0001). Although no differences in total or cardiovascular mortality emerged between OPT and CRT, patients receiving OPT had a higher risk of death from pump failure than patients assigned to CRT (HR=8.41, p=0.0447) after a median follow-up of 677.5 days. CRT leads to an improvement in symptoms, exercise capacity and quality of life in patients with heart failure and a normal QRS duration. (ClinicalTrials.gov number, NCT00480051.).

  18. Protein tyrosine phosphatase activity in the neural crest is essential for normal heart and skull development

    PubMed Central

    Nakamura, Tomoki; Gulick, James; Colbert, Melissa C.; Robbins, Jeffrey

    2009-01-01

    Mutations within the protein tyrosine phosphatase, SHP2, which is encoded by PTPN11, cause a significant proportion of Noonan syndrome (NS) cases, typically presenting with both cardiac disease and craniofacial abnormalities. Neural crest cells (NCCs) participate in both heart and skull formation, but the role of SHP2 signaling in NCC has not yet been determined. To gain insight into the role of SHP2 in NCC function, we ablated PTPN11 specifically in premigratory NCCs. SHP2-deficient NCCs initially exhibited normal migratory and proliferative patterns, but in the developing heart failed to migrate into the developing outflow tract. The embryos displayed persistent truncus arteriosus and abnormalities of the great vessels. The craniofacial deficits were even more pronounced, with large portions of the face and cranium affected, including the mandible and frontal and nasal bones. The data show that SHP2 activity in the NCC is essential for normal migration and differentiation into the diverse lineages found in the heart and skull and demonstrate the importance of NCC-based normal SHP2 activity in both heart and skull development, providing insight into the syndromic presentation characteristic of NS. PMID:19541608

  19. Pulmonary veins in the normal lung and pulmonary hypertension due to left heart disease.

    PubMed

    Hunt, James M; Bethea, Brian; Liu, Xiang; Gandjeva, Aneta; Mammen, Pradeep P A; Stacher, Elvira; Gandjeva, Marina R; Parish, Elisabeth; Perez, Mario; Smith, Lynelle; Graham, Brian B; Kuebler, Wolfgang M; Tuder, Rubin M

    2013-11-15

    Despite the importance of pulmonary veins in normal lung physiology and the pathobiology of pulmonary hypertension with left heart disease (PH-LHD), pulmonary veins remain largely understudied. Difficult to identify histologically, lung venous endothelium or smooth muscle cells display no unique characteristic functional and structural markers that distinguish them from pulmonary arteries. To address these challenges, we undertook a search for unique molecular markers in pulmonary veins. In addition, we addressed the expression pattern of a candidate molecular marker and analyzed the structural pattern of vascular remodeling of pulmonary veins in a rodent model of PH-LHD and in lung tissue of patients with PH-LHD obtained at time of placement on a left ventricular assist device. We detected urokinase plasminogen activator receptor (uPAR) expression preferentially in normal pulmonary veins of mice, rats, and human lungs. Expression of uPAR remained elevated in pulmonary veins of rats with PH-LHD; however, we also detected induction of uPAR expression in remodeled pulmonary arteries. These findings were validated in lungs of patients with PH-LHD. In selected patients with sequential lung biopsy at the time of removal of the left ventricular assist device, we present early data suggesting improvement in pulmonary hemodynamics and venous remodeling, indicating potential regression of venous remodeling in response to assist device treatment. Our data indicate that remodeling of pulmonary veins is an integral part of PH-LHD and that pulmonary veins share some key features present in remodeled yet not normotensive pulmonary arteries.

  20. Critical Scale Invariance in a Healthy Human Heart Rate

    NASA Astrophysics Data System (ADS)

    Kiyono, Ken; Struzik, Zbigniew R.; Aoyagi, Naoko; Sakata, Seiichiro; Hayano, Junichiro; Yamamoto, Yoshiharu

    2004-10-01

    We demonstrate the robust scale-invariance in the probability density function (PDF) of detrended healthy human heart rate increments, which is preserved not only in a quiescent condition, but also in a dynamic state where the mean level of the heart rate is dramatically changing. This scale-independent and fractal structure is markedly different from the scale-dependent PDF evolution observed in a turbulentlike, cascade heart rate model. These results strongly support the view that a healthy human heart rate is controlled to converge continually to a critical state.

  1. Breathing rates and heart rate spectrograms regarding body position in normal subjects.

    PubMed

    Avbelj, Viktor; Kalisnik, Jurij-Matija; Trobec, Roman; Gersak, Borut

    2003-05-01

    The right lateral body position has been proposed as an effective vagal enhancer. However, the possibility of breathing affecting heart rate power spectra in different body positions has not been assessed. The level of vagal modulation in various body positions in normal subjects was estimated by calculating heart rate power spectra. The results suggest that the levels of vagal modulation do not necessarily reflect a change due to assuming different body position, but might be the consequence of changed breathing patterns. Before adopting the right lateral body position as vagal enhancing, the contribution of varying breathing pattern should be eliminated.

  2. Right ventricular wall abscess in structurally normal heart after leg osteomyelitis: First case.

    PubMed

    Ahmad, Tanveer; Pasarad, Ashwini Kumar; Kishore, Kolkebaile Sadanand; Maheshwarappa, Nandakumar Neralakere

    2016-09-01

    A 3-year-old girl presented with fever and acute dyspnea for 4 days. She had suffered an injury to the left lower leg 3 weeks earlier, with abscess formation. Magnetic resonance imaging showed osteomyelitis of the lower tibia. Echocardiography showed a mass in the right ventricular wall. She underwent concomitant heart surgery for removal of the right ventricular mass and limb arthrotomy. We believe this is a first reported case in which a ventricular wall abscess developed in a structurally normal heart following leg osteomyelitis.

  3. Normal and abnormal human vestibular ocular function

    NASA Technical Reports Server (NTRS)

    Peterka, R. J.; Black, F. O.

    1986-01-01

    The major motivation of this research is to understand the role the vestibular system plays in sensorimotor interactions which result in spatial disorientation and motion sickness. A second goal was to explore the range of abnormality as it is reflected in quantitative measures of vestibular reflex responses. The results of a study of vestibular reflex measurements in normal subjects and preliminary results in abnormal subjects are presented in this report. Statistical methods were used to define the range of normal responses, and determine age related changes in function.

  4. 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

  5. Study of the normal heart size in Northwest part of Iranian population: a cadaveric study

    PubMed Central

    Mohammadi, Shabnam; Hedjazi, Arya; Sajjadian, Maryam; Ghoroubi, Naser; Mohammadi, Maryam; Erfani, Saeed

    2016-01-01

    Introduction: The heart is in a muscular organ in the middle mediastinum. According to our knowledge, there is no standard data about the anthropologic parameters of normal Iranian hearts. Hence, the aim of the present study was to investigate the normal heart size in Iranian cadavers. Methods: In a cross-sectional study, 550 cadavers (104 female/446 male) from June 2014 to July 2015 in the Razavi Khorasan province of Iran were included in the study. After approval of the Ethical Committee, cadavers were divided into 10 groups based on age groups. Length, width, weight, chordae tendineae, papillary muscles, and heart valves were measured using vernier caliper. Finally, data were analyzed using SPSS software. Results: The mean values of the demographic data were as follows: age= 42.12 ± 21.34 years; weight = 60.38 ± 15.32 kg; height = 158.14 ± 23.77 cm; and BMI = 24.66 ± 17.60 kg/m2. The mean values of the heart length, width, chordae tendineae, pupillary muscles, weight, and index of the heart were 11.41 ± 2.15 cm, 8.21 ± 4.38 cm, 19.41 ± 6.70, 5.74 ± 1.96, 247.78 ± 62.27 grams, and 5.74 ± 1.96, respectively. In addition, the circumference of the tricuspid valve, circumference of the mitral valves, and tricuspid and mitral areas were 8.80 ± 1.11 cm, 9.43 ± 1.44 cm, 4.11 ± 0.71 cm2, and 4.50 ± 0.90 cm2, respectively. Conclusion: Mean values of the heart’s length and width was similar to previous reports from western population. The circumference of the tricuspid valve was less than the textbook’s data, while circumference of the mitral valves was more than it. The study findings provide valuable information about standard data of the heart in the Iranian population, which is useful for surgeons as well as anthropologists. However, multi-center studies with a larger sample size are required to complete data about anatomical characteristics of normal hearts. PMID:27777697

  6. Evolutionary anticipation of the human heart.

    PubMed

    Victor, S; Nayak, V M

    2000-09-01

    We have studied the comparative anatomy of hearts from fish, frog, turtle, snake, crocodile, birds (duck, chicken, quail), mammals (elephant, dolphin, sheep, goat, ox, baboon, wallaby, mouse, rabbit, possum, echidna) and man. The findings were analysed with respect to the mechanism of evolution of the heart.

  7. Polymorphic Ventricular Tachycardia/Ventricular Fibrillation and Sudden Cardiac Death in the Normal Heart.

    PubMed

    Shah, Ashok J; Hocini, Meleze; Denis, Arnaud; Derval, Nicolas; Sacher, Frederic; Jais, Pierre; Haissaguerre, Michel

    2016-09-01

    Primary electrical diseases manifest with polymorphic ventricular tachycardia (PMVT) and ventricular fibrillation (VF) and along with idiopathic VF contribute to about 10% of sudden cardiac deaths (SCDs) overall. These disorders include long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, and early repolarization syndrome. This article reviews the clinical electrophysiological management of PMVT/VF in a structurally normal heart affected with these disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Power flow in normal human voice production

    NASA Astrophysics Data System (ADS)

    Krane, Michael

    2016-11-01

    The principal mechanisms of energy utilization in voicing are quantified using a simplified model, in order to better define voice efficiency. A control volume analysis of energy utilization in phonation is presented to identify the energy transfer mechanisms in terms of their function. Conversion of subglottal airstream potential energy into useful work done (vocal fold vibration, flow work, sound radiation), and into heat (sound radiation absorbed by the lungs, glottal jet dissipation) are described. An approximate numerical model is used to compute the contributions of each of these mechanisms, as a function of subglottal pressure, for normal phonation. Acknowledge support of NIH Grant 2R01DC005642-10A1.

  9. Modeling heart rate variability in healthy humans: a turbulence analogy.

    PubMed

    Lin, D C; Hughson, R L

    2001-02-19

    Many complex systems share similar statistical characteristics. In this Letter, a turbulence analogy is proposed for the long-term heart rate variability of healthy humans. Based on such an analogy, the equivalence of an inertial range is found and a cascade model, which captures the statistical properties of the heart rate data, is given.

  10. Modeling Heart Rate Variability in Healthy Humans: A Turbulence Analogy

    NASA Astrophysics Data System (ADS)

    Lin, D. C.; Hughson, R. L.

    2001-02-01

    Many complex systems share similar statistical characteristics. In this Letter, a turbulence analogy is proposed for the long-term heart rate variability of healthy humans. Based on such an analogy, the equivalence of an inertial range is found and a cascade model, which captures the statistical properties of the heart rate data, is given.

  11. Changes in oxygen saturation and heart frequency during sleep in young normal subjects.

    PubMed Central

    Gimeno, F; Peset, R

    1984-01-01

    Changes in oxygen saturation and heart frequency were measured during sleep in a group of 21 normal subjects (9 women and 12 men) aged 19-25. At the time of the investigation all were non-smokers, they had no respiratory complaints, and indices of lung function (lung volumes, volume-pressure diagram, and diffusing capacity for carbon monoxide) were within normal limits. In contrast to published data, there were no major changes in oxygen saturation and no differences between men and women. PMID:6474401

  12. Adult human heart slices are a multicellular system suitable for electrophysiological and pharmacological studies.

    PubMed

    Camelliti, Patrizia; Al-Saud, Sara Abou; Smolenski, Ryszard T; Al-Ayoubi, Samha; Bussek, Alexandra; Wettwer, Erich; Banner, Nicholas R; Bowles, Christopher T; Yacoub, Magdi H; Terracciano, Cesare M

    2011-09-01

    Electrophysiological and pharmacological data from the human heart are limited due to the absence of simple but representative experimental model systems of human myocardium. The aim of this study was to establish and characterise adult human myocardial slices from small patients' heart biopsies as a simple, reproducible and relevant preparation suitable for the study of human cardiac tissue at the multicellular level. Vibratome-cut myocardial slices were prepared from left ventricular biopsies obtained from end-stage heart failure patients undergoing heart transplant or ventricular assist device implantation, and from hearts of normal dogs. Multiple slices were prepared from each biopsy. Regular contractility was observed at a range of stimulation frequencies (0.1-2 Hz), and stable electrical activity, monitored using multi-electrode arrays (MEA), was maintained for at least 8 h from slice preparation. ATP/ADP and phosphocreatine/creatine ratios were comparable to intact organ values, and morphology and gap junction distribution were representative of native myocardium. MEA recordings showed that field potential duration (FPD) and conduction velocity (CV) in human and dog slices were similar to the values previously reported for papillary muscles, ventricular wedges and whole hearts. Longitudinal CV was significantly faster than transversal CV, with an anisotropic ratio of 3:1 for human and 2.3:1 for dog slices. Importantly, slices responded to the application of E-4031, chromanol and 4-aminopyridine, three potassium channel blockers known to affect action potential duration, with an increase in FPD. We conclude that viable myocardial slices with preserved structural, biochemical and electrophysiological properties can be prepared from adult human and canine heart biopsies and offer a novel preparation suitable for the study of heart failure and drug screening.

  13. As normal a life as possible: mothers and their daughters with congenital heart disease.

    PubMed

    Gantt, Laura

    2002-01-01

    In this study, I used a qualitative descriptive methodology to examine the effect of chronic illness on the mother-daughter relationship. Many studies have examined the effects of the child's illness on the mother-child relationship when the child is very young, but few have looked at the ongoing problems that chronic illness may cause. Eleven mothers and 11 daughters were interviewed. Normalizing in the face of chronic illness was the overriding theme of the study. Two subthemes related to normalizing arose from the data. "It's no big deal" was found to best describe how most mothers and their daughters with heart disease viewed their lives and relationships. One other subtheme, "Sometimes it's a very big deal," was described by those mothers and daughters who could not, due to ongoing health problems, normalize their lives. Relationships with family as well as age, severity of illness, and developmental stage, were seen as mediators of normalizing in the lives of the participants.

  14. PPARdelta activation normalizes cardiac substrate metabolism and reduces right ventricular hypertrophy in congestive heart failure.

    PubMed

    Jucker, Beat M; Doe, Christopher P; Schnackenberg, Christine G; Olzinski, Alan R; Maniscalco, Kristeen; Williams, Carolyn; Hu, Tom C-C; Lenhard, Stephen C; Costell, Melissa; Bernard, Roberta; Sarov-Blat, Lea; Steplewski, Klaudia; Willette, Robert N

    2007-07-01

    Previously, it was shown that selective deletion of peroxisome proliferator activated receptor delta (PPARdelta) in the heart resulted in a cardiac lipotoxicity, hypertrophy, and heart failure. The aim of the present study was to determine the effects of chronic and selective pharmacological activation of PPARdelta in a model of congestive heart failure. PPARdelta-specific agonist treatment (GW610742X at 30 and 100 mg/kg/day for 6-9 weeks) was initiated immediately postmyocardial infarction (MI) in Sprague-Dawley rats. Magnetic resonance imaging/spectroscopy was used to assess cardiac function and energetics. A 1-(13)C glucose clamp was performed to assess relative cardiac carbohydrate versus fat oxidation. Additionally, cardiac hemodynamics and reverse-transcription polymerase chain reaction gene expression analysis was performed. MI rats had significantly reduced left ventricle (LV) ejection fractions and whole heart phosphocreatine/adenosine triphosphate ratio compared with Sham animals (reduction of 43% and 14%, respectively). However, GW610742X treatment had no effect on either parameter. In contrast, the decrease in relative fat oxidation rate observed in both LV and right ventricle (RV) following MI (decrease of 58% and 54%, respectively) was normalized in a dose-dependent manner following treatment with GW610742X. These metabolic changes were associated with an increase in lipid transport/metabolism target gene expression (eg, CD36, CPT1, UCP3). Although there was no difference between groups in LV weight or infarct size measured upon necropsy, there was a dramatic reduction in RV hypertrophy and lung congestion (decrease of 22-48%, P<0.01) with treatment which was associated with a >7-fold decrease (P<0.05) in aterial natriuretic peptide gene expression in RV. Diuretic effects were not observed with GW610742X. In conclusion, chronic treatment with a selective PPARdelta agonist normalizes cardiac substrate metabolism and reduces RV hypertrophy and pulmonary

  15. Autophagy in term normal human placentas.

    PubMed

    Signorelli, P; Avagliano, L; Virgili, E; Gagliostro, V; Doi, P; Braidotti, P; Bulfamante, G P; Ghidoni, R; Marconi, A M

    2011-06-01

    Autophagy is an inducible catabolic process that responds to environment and is essential for cell survival during stress, starvation and hypoxia. Its function in the human placenta it is not yet understood. We collected 14 placentas: 7 at vaginal delivery and 7 at elective caesarean section after uneventful term pregnancies. The presence of autophagy was assessed in different placental areas by immunoblotting, immunohistochemistry and electron microscopy. We found that autophagy is significantly higher in placentas obtained from cesarean section than in those from vaginal delivery. Moreover there is a significant inverse relationship between autophagy and umbilical arterial glucose concentration.

  16. Embryonic even skipped-Dependent Muscle and Heart Cell Fates Are Required for Normal Adult Activity, Heart Function, and Lifespan

    PubMed Central

    Fujioka, Miki; Wessells, Robert J.; Han, Zhe; Liu, Jiandong; Fitzgerald, Kerry; Yusibova, Galina L.; Zamora, Monica; Ruiz-Lozano, Pilar; Bodmer, Rolf; Jaynes, James B.

    2009-01-01

    The Drosophila pair-rule gene even skipped (eve) is required for embryonic segmentation and later in specific cell lineages in both the nervous system and the mesoderm. We previously generated eve mesoderm-specific mutants by combining an eve null mutant with a rescuing transgene that includes the entire locus, but with the mesodermal enhancer removed. This allowed us to analyze in detail the defects that result from a precisely targeted elimination of mesodermal eve expression in the context of an otherwise normal embryo. Absence of mesodermal eve causes a highly selective loss of the entire eve-expressing lineage in this germ layer, including those progeny that do not continue to express eve, suggesting that mesodermal eve precursor specification is not implemented. Despite the resulting absence of a subset of muscles and pericardial cells, mesoderm-specific eve mutants survive to fertile adulthood, providing an opportunity to examine the effects of these developmental abnormalities on adult fitness and heart function. We find that in these mutants, flying ability, myocardial performance under normal and stressed conditions, and lifespan are severely reduced. These data imply a nonautonomous role of the affected pericardial cells and body wall muscles in developing and/or maintaining cardiac performance and possibly other functions contributing to normal lifespan. Given the similarities of molecular-genetic control between Drosophila and vertebrates, these findings suggest that peri/epicardial influences may well be important for proper myocardial function. PMID:16239588

  17. Prevalence and predictors of ventriculo-atrial conduction in structurally normal hearts.

    PubMed

    Patil, Ganesh; Phadke, Milind; Lokhandwala, Yash; Shaikh, Zohaib; Nathani, Pratap; Mahajan, Ajay

    The prevalence of ventriculo-atrial (VA) conduction varies from 20% to 90%, depending on the population studied (Militianu et al., 1997; Inoue et al., 1985; Kazmierczak et al., 1993; Ciemniewski et al., 1990; Hayes and Furman, 1983; Westveer et al., 1984). This wide range is mostly based on studies done in patients with implanted devices or impaired atrioventricular conduction. However, the prevalence of VA conduction in structurally normal heart has not been well documented till date. To study the prevalence and identify predictors of retrograde conduction via the His-Purkinje system and AV node in structurally normal hearts. We included 54 consecutive adults without structural heart disease who underwent electrophysiological (EP) study for various tachycardias. The basic parameters including PR, AH and HV intervals, atrioventricular Wenckebach point (AVWP) and anterograde effective refractory period (ERP) of atrioventricular node (AVNERP), were measured after ablation. The VA conduction was assessed basally and if absent, after isoprenaline. The VA Wenckebach point (VAWP) and retrograde ERP(VAERP) were recorded in patients showing VA conduction. The mean age was 37.1±12.6years. Twenty five (46%) of the patients were men. VA conduction was present in 30 (55%) patients at baseline. Of the remaining 24 patients, 18 (34%) showed VA conduction after isoprenaline. Only 6 (11%) patients failed to reveal VA conduction even after adequate response to isoprenaline. Amongst all clinical and EP variables analysed, only the HV interval was shorter (p<0.01) in patients with VA conduction. In structurally normal hearts, VA conduction was present at baseline in 55% of patients. Isoprenaline unmasked VA conduction in an additional 34% of the subjects. The HV interval was longer in patients without VA conduction. Copyright © 2016. Published by Elsevier B.V.

  18. Normalization of the heart rate response to exercise 6 months after cardiac transplantation.

    PubMed

    Buendía Fuentes, F; Martínez-Dolz, L; Almenar Bonet, L; Sánchez-Lázaro, I; Navarro Manchón, J; Sánchez-Gómez, J M; Raso Raso, R; Agüero-Ramón-Llin, J; Sancho-Tello de Carranza, M J; Salvador Sanz, A

    2010-10-01

    Heart transplant recipients show an abnormal heart rate (HR) response to exercise due to complete cardiac denervation after surgery. They present elevated resting HR, minimal increase in HR during exercise, with maximal HR reached during the recovery period. The objective of this study was to study the frequency of normalization of the abnormal HR in the first 6 months after transplantation. We prospectively studied 27 heart transplant recipients who underwent treadmill exercise tests at 2 and 6 months after heart transplantation (HT). HR responses to exercise were classified as normal or abnormal, depending on achieving all of the following criteria: (1) increased HR for each minute of exercise, (2) highest HR at the peak exercise intensity, and (3) decreased HR for each minute of the recovery period. The HR response at 2 months was compared with the results at 6 months post-HT. At 2 months post-HT, 96.3% of the patients showed abnormal HR responses to exercise. Four months later, 11 patients (40.7%) had normalized HR responses (P<.001), which also involved a significant decrease in the time to achieve the highest HR after exercise (124.4±63.8 seconds in the first test and 55.6±44.6 seconds in the second). A significant improvement in exercise capacity and chronotropic competence was also shown in tests performed at 6 months after surgery. We observed important improvements in HR responses to exercise at 6 months after HT, which may represent early functional cardiac reinnervation. Copyright © 2010 Elsevier Inc. All rights reserved.

  19. The effect of exercise training on transverse tubules in normal, remodeled, and reverse remodeled hearts.

    PubMed

    Kemi, Ole J; Hoydal, Morten A; Macquaide, Niall; Haram, Per M; Koch, Lauren G; Britton, Steven L; Ellingsen, Oyvind; Smith, Godfrey L; Wisloff, Ulrik

    2011-09-01

    The response of transverse (T)-tubules to exercise training in health and disease remains unclear. Therefore, we studied the effect of exercise training on the density and spacing of left ventricle cardiomyocyte T-tubules in normal and remodeled hearts that associate with detubulation, by confocal laser scanning microscopy. First, exercise training in normal rats increased cardiomyocyte volume by 16% (P < 0.01), with preserved T-tubule density. Thus, the T-tubules adapted to the physiologic hypertrophy. Next, we studied T-tubules in a rat model of metabolic syndrome with pressure overload-induced concentric left ventricle hypertrophy, evidenced by 15% (P < 0.01) increased cardiomyocyte size. These rats had only 85% (P < 0.01) of the T-tubule density of control rats. Exercise training further increased cardiomyocyte volume by 8% (P < 0.01); half to that in control rats, but the T-tubule density remained unchanged. Finally, post-myocardial infarction heart failure induced severe cardiac pathology, with a 70% (P < 0.01) increased cardiomyocyte volume that included both eccentric and concentric hypertrophy and 55% (P < 0.01) reduced T-tubule density. Exercise training reversed 50% (P < 0.01) of the pathologic hypertrophy, whereas the T-tubule density increased by 40% (P < 0.05) compared to sedentary heart failure, but remained at 60% of normal hearts (P < 0.01). Physiologic hypertrophy associated with conserved T-tubule spacing (~1.8-1.9 µm), whereas in pathologic hypertrophy, T-tubules appeared disorganized without regular spacing. In conclusion, cardiomyocytes maintain the relative T-tubule density during physiologic hypertrophy and after mild concentric pathologic hypertrophy, whereas after severe pathologic remodeling with a substantial loss of T-tubules; exercise training reverses the remodeling and partly corrects the T-tubule density.

  20. The effect of exercise training on transverse tubules in normal, remodeled, and reverse remodeled hearts

    PubMed Central

    Kemi, Ole J; Hoydal, Morten A; MacQuaide, Niall; Haram, Per M; Koch, Lauren G; Britton, Steven L; Ellingsen, Oyvind; Smith, Godfrey L; Wisloff, Ulrik

    2011-01-01

    The response of transverse (T)-tubules to exercise training in health and disease remains unclear. Therefore, we studied the effect of exercise training on the density and spacing of left ventricle cardiomyocyte T-tubules in normal and remodeled hearts that associate with detubulation, by confocal laser scanning microscopy. First, exercise training in normal rats increased cardiomyocyte volume by 16% (p<0.01), with preserved T-tubule density. Thus, the T-tubules adapted to the physiologic hypertrophy. Next, we studied T-tubules in a rat model of metabolic syndrome with pressure overload-induced concentric left ventricle hypertrophy, evidenced by 15% (p<0.01) increased cardiomyocyte size. These rats had only 85% (p<0.01) of the T-tubule density of control rats. Exercise training further increased cardiomyocyte volume by 8% (p<0.01); half to that in control rats, but the T-tubule density remained unchanged. Finally, post-myocardial infarction heart failure induced severe cardiac pathology, with a 70% (p<0.01) increased cardiomyocyte volume that included both eccentric and concentric hypertrophy and 55% (p<0.01) reduced T-tubule density. Exercise training reversed 50% (p<0.01) of the pathologic hypertrophy, whereas the T-tubule density increased by 40% (p<0.05) compared to sedentary heart failure, but remained at 60% of normal hearts (p<0.01). Physiologic hypertrophy associated with conserved T-tubule spacing (~1.8–1.9 μm), whereas in pathologic hypertrophy, T-tubules appeared disorganized without regular spacing. In conclusion, cardiomyocytes maintain the relative T-tubule density during physiologic hypertrophy and after mild concentric pathologic hypertrophy, whereas after severe pathologic remodeling with a substantial loss of T-tubules; exercise training reverses the remodeling and partly corrects the T-tubule density. PMID:21660947

  1. The effects of baseline heart rate recovery normality and exercise training protocol on heart rate recovery in patients with heart failure.

    PubMed

    Yaylalı, Yalın Tolga; Fındıkoğlu, Gülin; Yurtdaş, Mustafa; Konukçu, Sibel; Şenol, Hande

    2015-09-01

    It is unclear which exercise training protocol yields superior heart rate recovery (HRR) improvement in heart failure (HF) patients. Whether baseline HRR normality plays a role in the improvement is unknown. We hypothesized that an exercise training protocol and baseline HRR normality would be factors in altering HRR in HF patients. In this prospective, randomized, controlled and 3 group parallel study, 41 stable HF patients were randomly assigned to 3-times-weekly training sessions for 12 weeks, consisting of i) 30 minutes of interval training (IT) (n=17, 63.7±8.8 years old) versus ii) 30 minutes of continuous training (CT) (n=13, 59.6±6.8 years old) versus iii) no training (CON) (n=11, 60.6±9.9 years old). Each patient had cardiopulmonary exercise testing before and after the training program. Maximum heart rates attained during the test and heart rates at 1 and 2 min (HRR1 and HRR2) during the recovery phase were recorded. Paired samples t-test or Wilcoxon signed-rank test was used for comparisons before and after training. One-way ANOVA or Kruskal-Wallis variance analysis was used for comparisons among groups. HRR1 was unchanged after training. HRR2 improved in the IT group after training, and post-training HRR2 values were significantly faster in the IT group than in controls. Both HRR1 and HRR2 was significantly faster, irrespective of exercise protocol in patients with abnormal baseline values after training. HRR1 did not improve after training. HRR2 improved only in the IT group. Both HRRs in patients with abnormal baseline values improved after both exercise protocols. IT might be superior to CT in improving HRR2. Baseline HRR might play a role in its response to exercise.

  2. Phase Transition in a Healthy Human Heart Rate

    NASA Astrophysics Data System (ADS)

    Kiyono, Ken; Struzik, Zbigniew R.; Aoyagi, Naoko; Togo, Fumiharu; Yamamoto, Yoshiharu

    2005-07-01

    A healthy human heart rate displays complex fluctuations which share characteristics of physical systems in a critical state. We demonstrate that the human heart rate in healthy individuals undergoes a dramatic breakdown of criticality characteristics, reminiscent of continuous second order phase transitions. By studying the germane determinants, we show that the hallmark of criticality—highly correlated fluctuations—is observed only during usual daily activity, and a breakdown of these characteristics occurs in prolonged, strenuous exercise and sleep. This finding is the first reported discovery of the dynamical phase transition phenomenon in a biological control system and will be a key to understanding the heart rate control system in health and disease.

  3. 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.

  4. Right Heart 4DMRI Flow Visualization in Normal and Hypertensive subjects

    NASA Astrophysics Data System (ADS)

    Hertzberg, Jean; Browning, James; Fenster, Brett; Schroeder, Joyce

    2015-11-01

    Recent advances in time-resolved 3D cardiac magnetic resonance imaging (4DMRI) have allowed for the 3-dimensional characterization of blood flow in the right ventricle (RV) and right atrium (RA). In this talk, an overview of a large, ongoing, multi-disciplinary investigation of 4D right heart hemodynamics in normal and pathologic patients is given, as well as lessons learned from 4DMRI cardiac research. Time-resolved visualization techniques for understanding and communicating complex right heart flow structures throughout the cardiac cycle are presented. Finally, a qualitative visual comparison of 3D flow structures in the vena cava, RA, and RV between healthy subjects and pulmonary hypertensive patients is presented.

  5. Reproducibility of heart rate variability from short-term recordings during five manoeuvres in normal subjects.

    PubMed

    Carrasco, S; González, R; Gaitán, M J; Yáñez, O

    2003-01-01

    Due to limited and contradictory information available, the reproducibility of temporal and spectral measurements of heart rate variability from short-term recordings was evaluated in normal subjects during supine, controlled breathing, standing, exercise and recovery conditions. Five-minute tachograms from 11 individuals were obtained during the specified manoeuvres, and repeated three times in a five day period. Besides temporal and spectral indexes, the central frequencies were also computed. The ANOVA presented non-significant differences among the repetitions for any of the parameters studied. Most intra-class correlation coefficients were over 0.68. The central frequency of the low component diminished during the manoeuvres. In healthy individuals, the temporal and spectral measurements of the heart rate variability from short-term records are stable in a five day period for the manoeuvres studied. Central frequencies of the spectral components might be used as indexes of the autonomic activity.

  6. Mapping Molecular Agents Distributions in Whole Mice Hearts Using Born-Normalized Optical Projection Tomography

    PubMed Central

    Razansky, Daniel; Gorbatov, Rostic; Ntziachristos, Vasilis; Sbarbati, Andrea; Nahrendorf, Matthias; Weissleder, Ralph

    2012-01-01

    To date there is a lack of tools to map the spatio-temporal dynamics of diverse cells in experimental heart models. Conventional histology is labor intensive with limited coverage, whereas many imaging techniques do not have sufficiently high enough spatial resolution to map cell distributions. We have designed and built a high resolution, dual channel Born-normalized near-infrared fluorescence optical projection tomography system to quantitatively and spatially resolve molecular agents distribution within whole murine heart. We validated the use of the system in a mouse model of monocytes/macrophages recruitment during myocardial infarction. While acquired, data were processed and reconstructed in real time. Tomographic analysis and visualization of the key inflammatory components were obtained via a mathematical formalism based on left ventricular modeling. We observed extensive monocyte recruitment within and around the infarcted areas and discovered that monocytes were also extensively recruited into non-ischemic myocardium, beyond that of injured tissue, such as the septum. PMID:22509302

  7. Zebrafish heart as a model for human cardiac electrophysiology

    PubMed Central

    Vornanen, Matti; Hassinen, Minna

    2016-01-01

    ABSTRACT The zebrafish (Danio rerio) has become a popular model for human cardiac diseases and pharmacology including cardiac arrhythmias and its electrophysiological basis. Notably, the phenotype of zebrafish cardiac action potential is similar to the human cardiac action potential in that both have a long plateau phase. Also the major inward and outward current systems are qualitatively similar in zebrafish and human hearts. However, there are also significant differences in ionic current composition between human and zebrafish hearts, and the molecular basis and pharmacological properties of human and zebrafish cardiac ionic currents differ in several ways. Cardiac ionic currents may be produced by non-orthologous genes in zebrafish and humans, and paralogous gene products of some ion channels are expressed in the zebrafish heart. More research on molecular basis of cardiac ion channels, and regulation and drug sensitivity of the cardiac ionic currents are needed to enable rational use of the zebrafish heart as an electrophysiological model for the human heart. PMID:26671745

  8. Analysis of right ventricular function during bypass of the left side of the heart by afterload alterations in both normal and failing hearts.

    PubMed

    Park, C H; Nishimura, K; Kitano, M; Matsuda, K; Okamoto, Y; Ban, T

    1996-05-01

    This study investigated the mechanism of right ventricular failure during bypass of the left side of the heart by precisely assessing right ventricular function with use of a conductance catheter. Bypass of the left side of the heart was established with a centrifugal pump in 10 mongrel dogs weighing 11 to 19 kg. Right ventricular function during left heart bypass was evaluated by two parameters that were both derived from measurement of relative change in right ventricular volume by the conductance catheter technique. One parameter was the right ventricular end-systolic pressure-volume relationship as a load-independent index, and the other was the peak right ventricular pressure-right ventricular stroke volume relationship as a "force-velocity relationship." These parameters were measured in both normal and failing hearts while afterload was increased by bilateral intrapulmonary balloon inflation. Moreover, changes in these relationships were observed by varying assist ratios of left heart bypass from 0% to 100%. Failing heart models were induced by normothermic aortic clamping for 20 minutes. The right ventricular end-systolic pressure-volume relationship in normal hearts did not change, irrespective of the assist ratio of left heart bypass, whereas that in failing hearts decreased from 4.25 +/- 1.41 mm Hg/ml without bypass of the left side of the heart to 3.53 +/- 1.30 mm Hg/ml after 100% assist of left heart bypass (p < 0.05). In the peak right ventricular pressure-right ventricular stroke volume relationship, right ventricular stroke volume was almost constant in normal hearts when afterload was increased regardless of the assist ratio of left heart bypass. Moreover, right ventricular stroke volume was maintained at a higher level during bypass of the left side of the heart compared with that without left heart bypass. However, that slope of the relationship in failing hearts was inversely linear and became significantly steeper after 100% assist of bypass of

  9. Influence of peak exercise heart rate on normal thallium-201 myocardial clearance

    SciTech Connect

    Kaul, S.; Chesler, D.A.; Pohost, G.M.; Strauss, H.W.; Okada, R.D.; Boucher, C.A.

    1986-01-01

    Measurement of myocardial clearance rates between initial and delayed images is a major justification for adding computer quantification to the interpretation of exercise /sup 201/TI images. To clarify the range of normal thallium clearance and its relationship to the level of exercise achieved, exercise thallium images in 89 normal subjects were analyzed: 45 asymptomatic subjects with less than 1% probability of coronary artery disease (CAD) (Group I), and 44 patients with chest pain found to have no significant CAD on angiography (Group II). Mean initial regional thallium uptake was similar in the two groups, but myocardial thallium clearance (mean +/- 1 s.d.) was slower in Group II, expressed as a longer half-life in the myocardium (8.2 +/- 7.6 hr compared with 3.4 +/- 0.7 hr p less than 0.001). Analysis of variance using ten clinical and exercise variables as covariates showed that the slower clearance in Group II was related to a lower peak exercise heart rate (HR) (154 +/- 27 compared with 183 +/- 11, respectively, p less than 0.001). By linear regression analysis, a decrease in peak HR of 1 beat/min was associated with a slower thallium clearance (longer half-life) of 0.05 hr. Using this formula, the clearance value in each patient was then corrected for peak exercise heart rate by decreasing measured clearance by 0.05 hr multiplied by the amount peak exercise heart rate which was below 183 (the mean value in Group I). There were no differences in the corrected clearance between the two groups. We conclude that thallium myocardial clearance after exercise is related in part to factors other than the presence of CAD, being slower when peak exercise HR is lower. Therefore, thallium clearance rates alone uncorrected for peak exercise heart rate should be used with caution when diagnosing CAD.

  10. Upregulation of autophagy genes and the unfolded protein response in human heart failure.

    PubMed

    Jensen, Brian C; Bultman, Scott J; Holley, Darcy; Tang, Wei; de Ridder, Gustaaf; Pizzo, Salvatore; Bowles, Dawn; Willis, Monte S

    2017-01-01

    The cellular environment of the mammalian heart constantly is challenged with environmental and intrinsic pathological insults, which affect the proper folding of proteins in heart failure. The effects of damaged or misfolded proteins on the cell can be profound and result in a process termed "proteotoxicity". While proteotoxicity is best known for its role in mediating the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, its role in human heart failure also has been recognized. The UPR involves three branches, including PERK, ATF6, and IRE1. In the presence of a misfolded protein, the GRP78 molecular chaperone that normally interacts with the receptors PERK, ATF6, and IRE-1 in the endoplasmic reticulum detaches to attempt to stabilize the protein. Mouse models of cardiac hypertrophy, ischemia, and heart failure demonstrate increases in activity of all three branches after removing GRP78 from these internal receptors. Recent studies have linked elevated PERK and CHOP in vitro with regulation of ion channels linked with human systolic heart failure. With this in mind, we specifically investigated ventricular myocardium from 10 patients with a history of conduction system defects or arrhythmias for expression of UPR and autophagy genes compared to myocardium from non-failing controls. We identified elevated Chop, Atf3, and Grp78 mRNA, along with XBP-1-regulated Cebpa mRNA, indicative of activation of the UPR in human heart failure with arrhythmias.

  11. [Coronary blood outflow along parasinoidal pathways in the left heart (possible pathogenesis of angina attacks with normal coronary circulation)].

    PubMed

    Kositskiĭ, G I; D'iakonova, I N; Tverskaia, M S

    1984-04-01

    Acute experiments on isolated cat hearts were made to study the involvement of the parasinus pathways of the left heart in the blood outflow from the myocardium. The magnitude of the blood outflow to the left heart via the parasinus pathways may vary within a wide range, depending on heart function conditions. During heart work normalization, the specific values of the outflow to the left heart are minimal, amounting on an average to 10%, those under heart perfusion with venous blood to 39%, reaching 64% after 30 minutes of ischemia. The data obtained indicate that the assessment of myocardial supply by the blood inflow to the coronary arteries cannot be regarded as adequate and that angina pectoris attacks may occur because of the shunt drainage of the coronary blood, by-passing the myocardial capillaries.

  12. Spectrum of Ventricular Arrhythmias Arising from Papillary Muscle in the Structurally Normal Heart.

    PubMed

    Naksuk, Niyada; Kapa, Suraj; Asirvatham, Samuel J

    2016-09-01

    Papillary muscle is an endocavitary structure that can give rise to ventricular arrhythmias in a structurally normal heart. Its manifestation is generally benign. The papillary muscle's complex anatomy and the presence of intermixed Purkinje fibers can create a substrate for idiopathic ventricular fibrillation. Although differentiating ventricular arrhythmias originating from the papillary muscle and the fascicles is challenging and not always possible, the distinction may be helpful for planning ablation. The propensity for difficulty with ablation of papillary arrhythmias results in a variable success rate. Improvement in techniques to stabilize the catheter, use of imaging, and methods of energy delivery are required to improve ablation outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Prostaglandin modulation of venoconstriction to physiological stress in normals and heart failure patients.

    PubMed

    Dzeka, T Nancy; Arnold, J Malcolm O

    2003-03-01

    Prostaglandins released from blood vessels modulate vascular tone, and inhibition of their production during exogenous infusions of catecholamines causes increased venoconstriction. To determine the influence of prostaglandin production on venoconstriction during physiological stimuli known to cause sympathetic activation, and to assess its importance in chronic heart failure (CHF), we studied 11 normal subjects (62 +/- 4 yr) and 14 patients with CHF (64 +/- 2 yr, left ventricular ejection fraction 23 +/- 1%, New York Heart Association classes II and III) (means +/- SE). Dorsal hand vein distension was measured during mental arithmetic (MA), cold pressor test (CPT), and lower body negative pressure (LBNP; -10 and -40 mmHg), with saline infusion in one hand and local indomethacin (cyclooxygenase inhibitor) infusion (3 microg/min) in the other. Acetylcholine (0.01-1 nmol/min) dilated veins preconstricted with PGF(2alpha) in normals but, consistent with endothelial dysfunction, barely did so in CHF patients (P = 0.001). Nonendothelial venodilation to sodium nitroprusside (0.3-10 nmol/min) was not different between normals and CHF patients. Resting venous norepinephrine levels were higher in CHF patients (2,812 +/- 420 pmol/l) than normals (1,418 +/- 145 pmol/l, P = 0.007). In normals, indomethacin caused increased venoconstriction to MA (from 4.9 +/- 1.5 to 19.2 +/- 4.5%, P = 0.022) and CPT (from 2.9 +/- 3.8 to 17.6 +/- 4.2%, P = 0.007). In CHF, indomethacin caused increased venoconstriction to MA (from 6.6 +/- 3.9% to 19.0 +/- 4.5%, P = 0.014), CPT (from 9.6 +/- 2.1% to 20.1 +/- 3.7%, P = 0.001), and -40 mmHg LBNP (from 10.7 +/- 3.0% to 23.2 +/- 3.8%, P = 0.041). Control responses for all tests were not different between normals and CHF patients. The effects of indomethacin on venoconstriction to MA and CPT were not different between normals and CHF patients, but venoconstriction to -40 mmHg LBNP was accentuated in CHF patients (P = 0.036). Inhibition of

  14. Best Practice BioBanking of Human Heart Tissue

    PubMed Central

    Lal, Sean; Li, Amy; Allen, David; Allen, Paul D; Bannon, Paul; Cartmill, Tim; Cooke, Roger; Farnsworth, Alan; Keogh, Anne; dos Remedios, Cristobal

    2015-01-01

    This review provides a guide to researchers who wish to establish a biobank. It also gives practical advice to investigators seeking access to samples of healthy or diseased human hearts. We begin with a brief history of the Sydney Heart Bank (SHB) from when it began in 1989, including the pivotal role played by the late Victor Chang. We discuss our standard operating procedures for tissue collection which include cryopreservation and the quality assurance needed to maintain the long-term molecular and cellular integrity of the samples. The SHB now contains about 16,000 heart samples derived from over 450 patients who underwent isotopic heart transplant procedures and from over 100 healthy organ donors. These enable us to provide samples from a wide range of categories of heart failure. So far, we have delivered heart samples to more than 50 laboratories over two decades, and we answer their most frequently asked questions. Other SHB services include the development of tissue microarrays (TMA). These enable end users to perform preliminary examinations of the expression and localisation of target molecules in diseased or aging donor hearts, all in a single section of the TMA. Finally, the processes involved in managing tissue requests from external users and logistics considerations for the shipment of human tissue are discussed in detail. PMID:26998172

  15. Best Practice BioBanking of Human Heart Tissue.

    PubMed

    Lal, Sean; Li, Amy; Allen, David; Allen, Paul D; Bannon, Paul; Cartmill, Tim; Cooke, Roger; Farnsworth, Alan; Keogh, Anne; Dos Remedios, Cristobal

    2015-12-01

    This review provides a guide to researchers who wish to establish a biobank. It also gives practical advice to investigators seeking access to samples of healthy or diseased human hearts. We begin with a brief history of the Sydney Heart Bank (SHB) from when it began in 1989, including the pivotal role played by the late Victor Chang. We discuss our standard operating procedures for tissue collection which include cryopreservation and the quality assurance needed to maintain the long-term molecular and cellular integrity of the samples. The SHB now contains about 16,000 heart samples derived from over 450 patients who underwent isotopic heart transplant procedures and from over 100 healthy organ donors. These enable us to provide samples from a wide range of categories of heart failure. So far, we have delivered heart samples to more than 50 laboratories over two decades, and we answer their most frequently asked questions. Other SHB services include the development of tissue microarrays (TMA). These enable end users to perform preliminary examinations of the expression and localisation of target molecules in diseased or aging donor hearts, all in a single section of the TMA. Finally, the processes involved in managing tissue requests from external users and logistics considerations for the shipment of human tissue are discussed in detail.

  16. Clinical iron deficiency disturbs normal human responses to hypoxia.

    PubMed

    Frise, Matthew C; Cheng, Hung-Yuan; Nickol, Annabel H; Curtis, M Kate; Pollard, Karen A; Roberts, David J; Ratcliffe, Peter J; Dorrington, Keith L; Robbins, Peter A

    2016-06-01

    Iron bioavailability has been identified as a factor that influences cellular hypoxia sensing, putatively via an action on the hypoxia-inducible factor (HIF) pathway. We therefore hypothesized that clinical iron deficiency would disturb integrated human responses to hypoxia. We performed a prospective, controlled, observational study of the effects of iron status on hypoxic pulmonary hypertension. Individuals with absolute iron deficiency (ID) and an iron-replete (IR) control group were exposed to two 6-hour periods of isocapnic hypoxia. The second hypoxic exposure was preceded by i.v. infusion of iron. Pulmonary artery systolic pressure (PASP) was serially assessed with Doppler echocardiography. Thirteen ID individuals completed the study and were age- and sex-matched with controls. PASP did not differ by group or study day before each hypoxic exposure. During the first 6-hour hypoxic exposure, the rise in PASP was 6.2 mmHg greater in the ID group (absolute rises 16.1 and 10.7 mmHg, respectively; 95% CI for difference, 2.7-9.7 mmHg, P = 0.001). Intravenous iron attenuated the PASP rise in both groups; however, the effect was greater in ID participants than in controls (absolute reductions 11.1 and 6.8 mmHg, respectively; 95% CI for difference in change, -8.3 to -0.3 mmHg, P = 0.035). Serum erythropoietin responses to hypoxia also differed between groups. Clinical iron deficiency disturbs normal responses to hypoxia, as evidenced by exaggerated hypoxic pulmonary hypertension that is reversed by subsequent iron administration. Disturbed hypoxia sensing and signaling provides a mechanism through which iron deficiency may be detrimental to human health. ClinicalTrials.gov (NCT01847352). M.C. Frise is the recipient of a British Heart Foundation Clinical Research Training Fellowship (FS/14/48/30828). K.L. Dorrington is supported by the Dunhill Medical Trust (R178/1110). D.J. Roberts was supported by R&D funding from National Health Service (NHS) Blood and Transplant and

  17. Clinical iron deficiency disturbs normal human responses to hypoxia

    PubMed Central

    Frise, Matthew C.; Cheng, Hung-Yuan; Nickol, Annabel H.; Curtis, M. Kate; Pollard, Karen A.; Roberts, David J.; Ratcliffe, Peter J.; Dorrington, Keith L.; Robbins, Peter A.

    2016-01-01

    BACKGROUND. Iron bioavailability has been identified as a factor that influences cellular hypoxia sensing, putatively via an action on the hypoxia-inducible factor (HIF) pathway. We therefore hypothesized that clinical iron deficiency would disturb integrated human responses to hypoxia. METHODS. We performed a prospective, controlled, observational study of the effects of iron status on hypoxic pulmonary hypertension. Individuals with absolute iron deficiency (ID) and an iron-replete (IR) control group were exposed to two 6-hour periods of isocapnic hypoxia. The second hypoxic exposure was preceded by i.v. infusion of iron. Pulmonary artery systolic pressure (PASP) was serially assessed with Doppler echocardiography. RESULTS. Thirteen ID individuals completed the study and were age- and sex-matched with controls. PASP did not differ by group or study day before each hypoxic exposure. During the first 6-hour hypoxic exposure, the rise in PASP was 6.2 mmHg greater in the ID group (absolute rises 16.1 and 10.7 mmHg, respectively; 95% CI for difference, 2.7–9.7 mmHg, P = 0.001). Intravenous iron attenuated the PASP rise in both groups; however, the effect was greater in ID participants than in controls (absolute reductions 11.1 and 6.8 mmHg, respectively; 95% CI for difference in change, –8.3 to –0.3 mmHg, P = 0.035). Serum erythropoietin responses to hypoxia also differed between groups. CONCLUSION. Clinical iron deficiency disturbs normal responses to hypoxia, as evidenced by exaggerated hypoxic pulmonary hypertension that is reversed by subsequent iron administration. Disturbed hypoxia sensing and signaling provides a mechanism through which iron deficiency may be detrimental to human health. TRIAL REGISTRATION. ClinicalTrials.gov (NCT01847352). FUNDING. M.C. Frise is the recipient of a British Heart Foundation Clinical Research Training Fellowship (FS/14/48/30828). K.L. Dorrington is supported by the Dunhill Medical Trust (R178/1110). D.J. Roberts was

  18. Evidence for differential sympathetic and parasympathetic reinnervation after heart transplantation in humans.

    PubMed

    Tio, R A; Reyners, A K; van Veldhuisen, D J; van den Berg, M P; Brouwer, R M; Haaksma, J; Smit, A J; Crijns, H J

    1997-12-11

    During heart transplantation (HTX) all neural connections are severed. In humans, signs of autonomic reinnervation have been found. In this study non-invasive tests were used to compare signs of sympathetic and parasympathetic reinnervation. Non-invasive autonomic function tests and heart rate variability parameters (HRV; 24 h electrocardiographic registration) were used to investigate signs of reinnervation. 16 HTX patients (14 males) were compared with age-and sex-matched controls. Parasympathetic heart rate changes in HTX compared to controls were attenuated during the diving test, deep breathing, the Valsalva maneuver and standing up but not during carotid sinus massage. Sympathetic heart rate increases were lower during the cold pressor test and mental stress. The blood pressure responses were comparable to the control group, but not during active standing and tilting. This finding suggests an obligatory 'blood pressure' role for the innervated heart in these two tests. All HRV parameters were lower in HTX. One or more normal parasympathetic responses were found in 13 out of 16 patients versus 4 out of 16 with normal sympathetic responses (p < 0.05). Heart rate variations were less in case of a higher donor age, and higher in case of a longer time after HTX. Parasympathetic signs of reinnervation are more common than sympathetic signs of reinnervation. A higher donor age reduces signs of reinnervation. If the sympatho-vagal balance is a prognostic factor in HTX patients as it is in other cardiac diseases these findings are clinically relevant.

  19. DNA amplification is rare in normal human cells

    SciTech Connect

    Wright, J.A.; Watt, F.M.; Hudson, D.L.; Stark, G.R. ); Smith, H.S.; Hancock, M.C. )

    1990-03-01

    Three types of normal human cells were selected in tissue culture with three drugs without observing a single amplification event from a total of 5 x 10{sup 8} cells. No drug-resistant colonies were observed when normal foreskin keratinocytes were selected with N-(phosphonacetyl)-L-aspartate or with hydroxyurea or when normal mammary epithelial cells were selected with methotrexate. Some slightly resistant colonies with limited potential for growth were obtained when normal diploid fibroblast cells derived from fetal lung were selected with methotrexate or hydroxyurea but careful copy-number analysis of the dihydrofolate reductase and ribonucleotide reductase genes revealed no evidence of amplification. The rarity of DNA amplification in normal human cells contrasts strongly with the situation in tumors and in established cell lines, where amplification of onogenes and of genes mediating drug resistance is frequent. The results suggest that tumors and cell lines have acquired the abnormal ability to amplify DNA with high frequency.

  20. Scaling Behaviour and Memory in Heart Rate of Healthy Human

    NASA Astrophysics Data System (ADS)

    Cai, Shi-Min; Peng, Hu; Yang, Hui-Jie; Zhou, Tao; Zhou, Pei-Ling; Wang, Bing-Hong

    2007-10-01

    We investigate a set of complex heart rate time series from healthy human in different behaviour states with the detrended fluctuation analysis and diffusion entropy (DE) method. It is proposed that the scaling properties are influenced by behaviour states. The memory detected by DE exhibits an approximately same pattern after a detrending procedure. Both of them demonstrate the long-range strong correlations in heart rate. These findings may be helpful to understand the underlying dynamical evolution process in the heart rate control system, as well as to model the cardiac dynamic process.

  1. Acellular human heart matrix: A critical step toward whole heart grafts.

    PubMed

    Sánchez, Pedro L; Fernández-Santos, M Eugenia; Costanza, Salvatore; Climent, Andreu M; Moscoso, Isabel; Gonzalez-Nicolas, M Angeles; Sanz-Ruiz, Ricardo; Rodríguez, Hugo; Kren, Stefan M; Garrido, Gregorio; Escalante, Jose L; Bermejo, Javier; Elizaga, Jaime; Menarguez, Javier; Yotti, Raquel; Pérez del Villar, Candelas; Espinosa, M Angeles; Guillem, María S; Willerson, James T; Bernad, Antonio; Matesanz, Rafael; Taylor, Doris A; Fernández-Avilés, Francisco

    2015-08-01

    The best definitive treatment option for end-stage heart failure currently is transplantation, which is limited by donor availability and immunorejection. Generating an autologous bioartificial heart could overcome these limitations. Here, we have decellularized a human heart, preserving its 3-dimensional architecture and vascularity, and recellularized the decellularized extracellular matrix (dECM). We decellularized 39 human hearts with sodium-dodecyl-sulfate for 4-8 days. Cell removal and architectural integrity were determined anatomically, functionally, and histologically. To assess cytocompatibility, we cultured human cardiac-progenitor cells (hCPC), bone-marrow mesenchymal cells (hMSCs), human endothelial cells (HUVECs), and H9c1 and HL-1 cardiomyocytes in vitro on dECM ventricles up to 21 days. Cell survival, gene expression, organization and/or electrical coupling were analyzed and compared to conventional 2-dimensional cultures. Decellularization removed cells but preserved the 3-dimensional cardiac macro and microstructure and the native vascular network in a perfusable state. Cell survival was observed on dECM for 21 days. hCPCs and hMSCs expressed cardiocyte genes but did not adopt cardiocyte morphology or organization; HUVECs formed a lining of endocardium and vasculature; differentiated cardiomyocytes organized into nascent muscle bundles and displayed mature calcium dynamics and electrical coupling in recellularized dECM. In summary, decellularization of human hearts provides a biocompatible scaffold that retains 3-dimensional architecture and vascularity and that can be recellularized with parenchymal and vascular cells. dECM promotes cardiocyte gene expression in stem cells and organizes existing cardiomyocytes into nascent muscle showing electrical coupling. These findings represent a first step toward manufacturing human heart grafts or matrix components for treating cardiovascular disease.

  2. Electrocardiographic evaluation in athletes: 'Normal' changes in the athlete's heart and benefits and disadvantages of screening.

    PubMed

    Machado Leite, Sérgio; Freitas, João; Campelo, Manuel; Maciel, M Júlia

    2016-03-01

    Young athletes are considered the healthiest group in society. Although rare, there are still reports of sudden death or cardiac arrest on the playing fields. Clinical evaluation is of paramount importance for the identification of possible pathological states that confer increased risk of these events. Interpretation of the electrocardiogram of young athletes can help identify changes associated with heart disease that might preclude the participation in sports. In this context, it is essential to recognize the electrocardiographic patterns that represent the structural and electrical remodeling resulting from continued adaptation to exercise, and which thus do not increase the risk of adverse events during exercise. The European Society of Cardiology (ESC) and the American Heart Association (AHA) have issued consensus documents summarizing which electrocardiographic abnormalities should be considered 'physiological', resulting from adaptation to exercise ('athlete's heart'), and which should be considered pathological and thus require further study. However, the two societies have different approaches with respect to the electrocardiographic screening of athletes. This paper provides a brief review of current evidence regarding the electrocardiographic findings considered normal and abnormal in athletes, and presents the arguments of the ESC and AHA for electrocardiographic screening in this population. Copyright © 2016 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

  3. Illness, normality and identity: the experience of heart transplant as a young adult.

    PubMed

    Waldron, Rebecca; Malpus, Zoey; Shearing, Vanessa; Sanchez, Melissa; Murray, Craig D

    2017-09-01

    End stage heart failure and transplant present great opportunities and challenges for patients of all ages. However, young adulthood may present additional specific challenges associated with the development of identity, career and romantic relationships. Despite recognition of greater mortality rates in young adults, consideration of the experience of transplant during this life stage has been largely overlooked in the literature. The aim of this study was to explore the experience of heart transplant in young adults. Interviews were conducted with nine participants across three transplant services in the United Kingdom and the data subject to interpretative phenomenological analysis. Analysis identified three themes. "Separating from illness" and "working toward normality" involved limiting the influence of illness on identity, as well as reengaging with typical functioning in young adulthood. "Integrating transplant into identity" involved acknowledging the influence of living with a shortened life expectancy. The need for support that recognizes specific challenges of transplant as a young adult is discussed (e.g. the development of age specific end of life pathways, improved communication between transplant recipients, their families and teams), including consideration of the impact of societal discourses (e.g. gift of life) which provided additional challenges for patients. IMPLICATIONS FOR REHABILITATION Heart transplant presents specific challenges according to the recipient's life stage. The needs of young adult recipients should be considered. Transplant professionals should consider providing opportunities for peer support and addressing the identities and values of young adult transplant recipients during rehabilitation.

  4. How Live Performance Moves the Human Heart.

    PubMed

    Shoda, Haruka; Adachi, Mayumi; Umeda, Tomohiro

    2016-01-01

    We investigated how the audience member's physiological reactions differ as a function of listening context (i.e., live versus recorded music contexts). Thirty-seven audience members were assigned to one of seven pianists' performances and listened to his/her live performances of six pieces (fast and slow pieces by Bach, Schumann, and Debussy). Approximately 10 weeks after the live performance, each of the audience members returned to the same room and listened to the recorded performances of the same pianists' via speakers. We recorded the audience members' electrocardiograms in listening to the performances in both conditions, and analyzed their heart rates and the spectral features of the heart-rate variability (i.e., HF/TF, LF/HF). Results showed that the audience's heart rate was higher for the faster than the slower piece only in the live condition. As compared with the recorded condition, the audience's sympathovagal balance (LF/HF) was less while their vagal nervous system (HF/TF) was activated more in the live condition, which appears to suggest that sharing the ongoing musical moments with the pianist reduces the audience's physiological stress. The results are discussed in terms of the audience's superior attention and temporal entrainment to live performance.

  5. How Live Performance Moves the Human Heart

    PubMed Central

    Shoda, Haruka; Adachi, Mayumi; Umeda, Tomohiro

    2016-01-01

    We investigated how the audience member’s physiological reactions differ as a function of listening context (i.e., live versus recorded music contexts). Thirty-seven audience members were assigned to one of seven pianists’ performances and listened to his/her live performances of six pieces (fast and slow pieces by Bach, Schumann, and Debussy). Approximately 10 weeks after the live performance, each of the audience members returned to the same room and listened to the recorded performances of the same pianists’ via speakers. We recorded the audience members’ electrocardiograms in listening to the performances in both conditions, and analyzed their heart rates and the spectral features of the heart-rate variability (i.e., HF/TF, LF/HF). Results showed that the audience’s heart rate was higher for the faster than the slower piece only in the live condition. As compared with the recorded condition, the audience’s sympathovagal balance (LF/HF) was less while their vagal nervous system (HF/TF) was activated more in the live condition, which appears to suggest that sharing the ongoing musical moments with the pianist reduces the audience’s physiological stress. The results are discussed in terms of the audience’s superior attention and temporal entrainment to live performance. PMID:27104377

  6. High Quality Catalog of Proteotypic Peptides from Human Heart

    PubMed Central

    Kline, Kelli G.; Frewen, Barbara; Bristow, Michael R.; MacCoss, Michael J.; Wu, Christine C.

    2009-01-01

    Proteomics research is beginning to expand beyond the more traditional shotgun analysis of protein mixtures to include targeted analyses of specific proteins using mass spectrometry. Integral to the development of a robust assay based on targeted mass spectrometry is prior knowledge of which peptides provide an accurate and sensitive proxy of the originating gene product (i.e., proteotypic peptides). To develop a catalog of “proteotypic peptides” in human heart, TRIzol extracts of left-ventricular tissue from nonfailing and failing human heart explants were optimized for shotgun proteomic analysis using Multidimensional Protein Identification Technology (MudPIT). Ten replicate MudPIT analyses were performed on each tissue sample and resulted in the identification of 30 605 unique peptides with a q-value ≤ 0.01, corresponding to 7138 unique human heart proteins. Experimental observation frequencies were assessed and used to select over 4476 proteotypic peptides for 2558 heart proteins. This human cardiac data set can serve as a public reference to guide the selection of proteotypic peptides for future targeted mass spectrometry experiments monitoring potential protein biomarkers of human heart diseases. PMID:18803417

  7. High quality catalog of proteotypic peptides from human heart.

    PubMed

    Kline, Kelli G; Frewen, Barbara; Bristow, Michael R; Maccoss, Michael J; Wu, Christine C

    2008-11-01

    Proteomics research is beginning to expand beyond the more traditional shotgun analysis of protein mixtures to include targeted analyses of specific proteins using mass spectrometry. Integral to the development of a robust assay based on targeted mass spectrometry is prior knowledge of which peptides provide an accurate and sensitive proxy of the originating gene product (i.e., proteotypic peptides). To develop a catalog of "proteotypic peptides" in human heart, TRIzol extracts of left-ventricular tissue from nonfailing and failing human heart explants were optimized for shotgun proteomic analysis using Multidimensional Protein Identification Technology (MudPIT). Ten replicate MudPIT analyses were performed on each tissue sample and resulted in the identification of 30 605 unique peptides with a q-value < or = 0.01, corresponding to 7138 unique human heart proteins. Experimental observation frequencies were assessed and used to select over 4476 proteotypic peptides for 2558 heart proteins. This human cardiac data set can serve as a public reference to guide the selection of proteotypic peptides for future targeted mass spectrometry experiments monitoring potential protein biomarkers of human heart diseases.

  8. Renal dysfunction and anemia in patients with heart failure with reduced versus normal ejection fraction.

    PubMed

    Villacorta, Humberto; Saenz-Tello, Bolivar F; Santos, Eduarda Barcellos dos; Steffen, Ricardo; Wiefels, Christiane; Lima, Luiz Costa; Sales, Ana Luíza F; Soares, Pedro; Mesquita, Evandro Tinoco

    2010-03-01

    The presence of anemia and renal dysfunction grants a bad prognosis for patients with heart failure and reduced ejection fraction (HFREF). The impact on patients with heart failure and normal ejection fraction (HFNEF) is not widely studied. To study the prevalence and the prognosis of anemia and renal dysfunction (RD) in patients with heart failure according to the type of ventricular dysfunction. A total of 209 patients with chronic and stable heart failure were prospectively studied. Individuals with ejection fraction <50% were considered as HFREF patients. Anemia was defined, based on WHO criteria, as hemoglobin <13 g/dl for men and <12 g/dl for women. Renal function was calculated by means of the Simplified Modified Diet Renal Disease (sMDRD) formula. Hospitalizations, emergency admittances and obit by cardiac causes were considered as cardiac events. Ninety patients had HFREF and 119 had HFNEF. The glomerular filtration rate (GFR) was smaller in HFREF group (57.6 +/- 66.2 versus 94.8 +/- 36.6 ml/min/1.73m(2); p=0.01). There was no difference in the prevalence of anemia between groups (23.3% versus 18.5%; p=0.34). Moderate to severe RD prevalence was higher in HFREF group (32.2% versus 16.8%; p=0.01). RD was the only factor associated with anemia that was independently associated with cardiac events (HR 2.52; 95%CI=1.27-5.2; p=0.01). RD was less prevalent in HFNEF, while the prevalence of anemia did not differ between groups. RD was predictor of cardiac events independently on ejection fraction.

  9. Genomics, proteomics and bioinformatics of human heart failure

    PubMed Central

    DOS REMEDIOS, C.G.; LIEW, C.C.; ALLEN, P.D.; WINSLOW, R.L.; VAN EYK, J.E.; DUNN, M.J.

    2005-01-01

    Unraveling the molecular complexities of human heart failure, particularly end-stage failure, can be achieved by combining multiple investigative approaches. There are several parts to the problem. Each patient is the product of a complex set of genetic variations, different degrees of influence of diets and lifestyles, and usually heart transplantation patients are treated with multiple drugs. The genomic status of the myocardium of any one transplant patient can be analysed using gene arrays (cDNA- or oligonucleotide-based) each with its own strengths and weaknesses. The proteins expressed by these failing hearts (myocardial proteomics) were first investigated over a decade ago using two-dimensional polyacrylamide gel electrophoresis (2DGE) which promised to resolve several thousand proteins in a single sample of failing heart. However, while 2DGE is very successful for the abundant and moderately expressed proteins, it struggles to identify proteins expressed at low levels. Highly focused first dimension separations combined with recent advances in mass spectrometry now provide new hope for solving this difficulty. Protein arrays are a more recent form of proteomics that hold great promise but, like the above methods, they have their own drawbacks. Our approach to solving the problems inherent in the genomics and proteomics of heart failure is to provide experts in each analytical method with a sample from the same human failing heart. This requires a sufficiently large number of samples from a sufficiently large pool of heart transplant patients as well as a large pool of non-diseased, non-failing human hearts. We have collected more than 200 hearts from patients undergoing heart transplantations and a further 50 non-failing hearts. By combining our expertise we expect to reduce and possibly eliminate the inherent difficulties of each analytical approach. Finally, we recognise the need for bioinformatics to make sense of the large quantities of data that will

  10. The Living Heart Project: A robust and integrative simulator for human heart function

    PubMed Central

    Baillargeon, Brian; Rebelo, Nuno; Fox, David D.; Taylor, Robert L.; Kuhl, Ellen

    2014-01-01

    The heart is not only our most vital, but also our most complex organ: Precisely controlled by the interplay of electrical and mechanical fields, it consists of four chambers and four valves, which act in concert to regulate its filling, ejection, and overall pump function. While numerous computational models exist to study either the electrical or the mechanical response of its individual chambers, the integrative electro-mechanical response of the whole heart remains poorly understood. Here we present a proof-of-concept simulator for a four-chamber human heart model created from computer topography and magnetic resonance images. We illustrate the governing equations of excitation-contraction coupling and discretize them using a single, unified finite element environment. To illustrate the basic features of our model, we visualize the electrical potential and the mechanical deformation across the human heart throughout its cardiac cycle. To compare our simulation against common metrics of cardiac function, we extract the pressure-volume relationship and show that it agrees well with clinical observations. Our prototype model allows us to explore and understand the key features, physics, and technologies to create an integrative, predictive model of the living human heart. Ultimately, our simulator will open opportunities to probe landscapes of clinical parameters, and guide device design and treatment planning in cardiac diseases such as stenosis, regurgitation, or prolapse of the aortic, pulmonary, tricuspid, or mitral valve. PMID:25267880

  11. The Living Heart Project: A robust and integrative simulator for human heart function.

    PubMed

    Baillargeon, Brian; Rebelo, Nuno; Fox, David D; Taylor, Robert L; Kuhl, Ellen

    2014-11-01

    The heart is not only our most vital, but also our most complex organ: Precisely controlled by the interplay of electrical and mechanical fields, it consists of four chambers and four valves, which act in concert to regulate its filling, ejection, and overall pump function. While numerous computational models exist to study either the electrical or the mechanical response of its individual chambers, the integrative electro-mechanical response of the whole heart remains poorly understood. Here we present a proof-of-concept simulator for a four-chamber human heart model created from computer topography and magnetic resonance images. We illustrate the governing equations of excitation-contraction coupling and discretize them using a single, unified finite element environment. To illustrate the basic features of our model, we visualize the electrical potential and the mechanical deformation across the human heart throughout its cardiac cycle. To compare our simulation against common metrics of cardiac function, we extract the pressure-volume relationship and show that it agrees well with clinical observations. Our prototype model allows us to explore and understand the key features, physics, and technologies to create an integrative, predictive model of the living human heart. Ultimately, our simulator will open opportunities to probe landscapes of clinical parameters, and guide device design and treatment planning in cardiac diseases such as stenosis, regurgitation, or prolapse of the aortic, pulmonary, tricuspid, or mitral valve.

  12. Immunohistochemical characterization of FHIT expression in normal human tissues

    PubMed Central

    Kujan, Omar; Abuderman, Abdulwahab; Al-Shawaf, Ahmad Zahi

    2016-01-01

    Background Fragile histidine triad (FHIT) is a tumor suppressor gene that is commonly inactivated in human tumors. Interestingly, the normal pattern of FHIT expression is largely unknown. Aim This study is aimed to characterize the expression of FHIT protein in normal human tissues. Materials and methods A total of 119 normal human tissue specimens were analyzed for the FHIT expression using immunohistochemistry technique. The inclusion criteria included: normal/inflammatory tissue with no evidence of cellular atypia. Results All studied specimens were stained positively with FHIT and showed either nuclear or cytoplasmic expression. Interestingly, the pattern of FHIT staining was similar among different specimens from each organ. FHIT is located predominantly in the nucleus, although cytoplasmic staining is also present in some cell types. Oral squamous epithelium, breast ductal epithelium, squamous and tubal metaplastic epithelium of the uterine cervix, esophageal squamous epithelium, salivary glands, and bronchial epithelia all strongly expressed the nuclear protein. In connective tissue, FHIT has shown strong cytoplasmic expression in histocytes including macrophages and dendritic cells, fibroblasts, and myofibroblasts. Conclusion Documentation of the pattern of FHIT expression in normal tissues will contribute to our understanding of the normal function of this protein and to interpretation of potentially altered FHIT expression in human tumors. PMID:28250975

  13. Normal Heart Rate Variability in Colchicine-Resistant Familial Mediterranean Fever Patients.

    PubMed

    Nussinovitch, Naomi; Esev, Konstantin; Lidar, Merav; Nussinovitch, Udi; Livneh, Avi

    2015-05-01

    The relationship between autonomic nervous system (ANS) dysfunction and familial Mediterranean fever (FMF) is controversial. We recently reported normal heart rate variability (HRV), suggestive of normal ANS, in patients with uncomplicated FMF. To evaluate ANS function in colchicine non-responders by using the HRV tool. The study group comprised 24 FMF patients suffering from recurrent FMF attacks despite treatment with a maximal colchicine dose. Electrocardiogram was measured under strict conditions and HRV parameters were calculated. Results were compared with age- and gender-matched unaffected controls. No statistically significant difference was found between the groups in any of the HRV parameters: maximal RR, minimal RR and average RR intervals, standard deviation of RR interval, square root of the mean squared differences of successive RR intervals, HRV triangular index, NN50, pNN50, and power spectral analysis parameters. Although a small difference in HRV parameters in the current study cannot be entirely excluded, FMF patients in whom colchicine did not provide adequate symptomatic relief and who did not develop amyloidosis appear to have normal HRV parameters suggestive of normal ANS function, compared with healthy adults.

  14. Differences in heart rate variability of female nurses between and within normal and extended work shifts.

    PubMed

    Järvelin-Pasanen, Susanna; Ropponen, Annina; Tarvainen, Mika P; Karjalainen, Pasi A; Louhevaara, Veikko

    2013-01-01

    The aim of this study was to investigate differences in heart rate variability (HRV) reflecting the function of autonomic nervous system (ANS) and psycho-physiological strain associated with normal and extended work shifts in nursing work. Complete data were available from 51 female nurses with a mean age of 40 yr, and based on two comparable 36-h HRV measurements supplemented with a questionnaire. Time-domain (meanRR, SDNN, RMSSD) and frequency-domain (LF power, HF power) parameters represented the HRV data, and were analyzed by linear mixed models. The differences between the compared work shifts were minor, revealing mainly increased sympathetic activity at the beginning of the normal work shift. The HRV parameters detected significant differences between work and leisure-time during the normal and extended work shifts in female nurses. During work shifts, an increase in sympathetic and a decrease in parasympathetic control of HRV was observed when compared to the leisure-time situation. Older subjects had overall lower HRV than younger subjects indicating increased sympathetic activation of ANS, especially during work. HRV parameters revealed significant differences between work, leisure-time and sleep of female nurses, but there were few differences between normal and extended work shifts in HRV parameters. This lack of differences between work shifts may be a consequence of the adaptation of nurses to the extended shifts or the more flexible organization of work duties possible during extended work shifts.

  15. Cardiomyocyte proliferation contributes to heart growth in young humans

    PubMed Central

    Mollova, Mariya; Bersell, Kevin; Walsh, Stuart; Savla, Jainy; Das, Lala Tanmoy; Park, Shin-Young; Silberstein, Leslie E.; dos Remedios, Cristobal G.; Graham, Dionne; Colan, Steven; Kühn, Bernhard

    2013-01-01

    The human heart is believed to grow by enlargement but not proliferation of cardiomyocytes (heart muscle cells) during postnatal development. However, recent studies have shown that cardiomyocyte proliferation is a mechanism of cardiac growth and regeneration in animals. Combined with evidence for cardiomyocyte turnover in adult humans, this suggests that cardiomyocyte proliferation may play an unrecognized role during the period of developmental heart growth between birth and adolescence. We tested this hypothesis by examining the cellular growth mechanisms of the left ventricle on a set of healthy hearts from humans aged 0–59 y (n = 36). The percentages of cardiomyocytes in mitosis and cytokinesis were highest in infants, decreasing to low levels by 20 y. Although cardiomyocyte mitosis was detectable throughout life, cardiomyocyte cytokinesis was not evident after 20 y. Between the first year and 20 y of life, the number of cardiomyocytes in the left ventricle increased 3.4-fold, which was consistent with our predictions based on measured cardiomyocyte cell cycle activity. Our findings show that cardiomyocyte proliferation contributes to developmental heart growth in young humans. This suggests that children and adolescents may be able to regenerate myocardium, that abnormal cardiomyocyte proliferation may be involved in myocardial diseases that affect this population, and that these diseases might be treatable through stimulation of cardiomyocyte proliferation. PMID:23302686

  16. Retinoic acid suppresses interleukin 6 production in normal human osteoblasts.

    PubMed

    Ahmed, N; Sammons, J; Khokher, M A; Hassan, H T

    2000-03-01

    Systemic long-term retinoid therapy for chronic skin diseases significantly reduced bone turnover markers within days and led to bone abnormalities. Retinoic acid (RA) plays a key role in the regulation of mouse bone cell proliferation, differentiation and functions. Meanwhile, there is little information of RA effect on human osteoblast and osteoclast cell development and function. Interleukin 6 (IL-6) is a pleiotropic cytokine with profound effects on bone metabolism. Thus, the present study examined the RA effect on cell differentiation, alkaline phosphatase and osteocalcin production as well as IL-6 production in normal human osteoblasts. The number of large differentiated osteoblast cells decreased in RA-treated cultures P<0.05. The production of bone specific markers, alkaline phosphatase and osteocalcin, was also reduced in RA-treated cultures. Normal human osteoblasts produced 31.0+/-4.8 pg IL-6 per ml in control cultures. Within 24 h, RA at all four concentrations reduced Il-6 production from normal human osteoblasts. The pharmacological concentration of 10(-5) M RA suppressed 90% of IL-6 production. The present study shows for the first time that RA profoundly inhibits IL-6 production in normal human osteoblasts within 24 h and in a dose-dependent manner. RA was shown previously to inhibit IL-6 production in several other normal and malignant human cell types. The associated decrease in osteoblast cell differentiation, alkaline phosphatase and osteocalcin production could result from the rapid RA-inhibition of IL-6 production. Thus, RA inhibition of IL-6 production in normal human osteoblasts may contribute to the bone abnormalities seen after systemic long-term retinoid therapy in some patients. Copyright 2000 Academic Press.

  17. Characteristic parameters of electromagnetic signals from a human heart system

    NASA Astrophysics Data System (ADS)

    Liu, Xin-Yuan; Pei, Liu-Qing; Wang, Yin; Zhang, Su-Ming; Gao, Hong-Lei; Dai, Yuan-Dong

    2011-04-01

    The electromagnetic field of a human heart system is a bioelectromagnetic field. Electrocardiography (ECG) and magnetocardiography (MCG) are both carriers of electromagnetic information about the cardiac system, and they are nonstationary signals. In this study, ECG and MCG data from healthy subjects are acquired; the MCG data are captured using a high-Tc radio frequency superconducting quantum interference device (HTc rf SQUIDs) and the QRS complexes in these data are analysed by the evolutionary spectrum analysis method. The results show that the quality factor Q and the central frequency fz of the QRS complex evolutionary spectrum are the characteristic parameters (CHPs) of ECG and MCG in the time—frequency domain. The confidence intervals of the mean values of the CHPs are estimated by the Student t distribution method in mathematical statistics. We believe that there are threshold ranges of the mean values of Q and fz for healthy subjects. We have postulated the following criterion: if the mean values of CHPs are in the proper ranges, the cardiac system is in a normal condition and it possesses the capability of homeostasis. In contrast, if the mean values of the CHPs do not lie in the proper ranges, the homeostasis of the cardiac system is lacking and some cardiac disease may follow. The results and procedure of MCG CHPs in the study afford a technological route for the application of HTc rf SQUIDs in cardiology.

  18. Right ventricular long noncoding RNA expression in human heart failure

    PubMed Central

    Guo, Yan; Su, Yan Ru; Clark, Travis; Brittain, Evan; Absi, Tarek; Maltais, Simon; Hemnes, Anna

    2015-01-01

    Abstract The expression of long noncoding RNAs (lncRNAs) in human heart failure (HF) has not been widely studied. Using RNA sequencing (RNA-Seq), we compared lncRNA expression in 22 explanted human HF hearts with lncRNA expression in 5 unused donor human hearts. We used Cufflinks to identify isoforms and DESeq to identify differentially expressed genes. We identified the noncoding RNAs by cross-reference to Ensembl release 73 (Genome Reference Consortium human genome build 37) and explored possible functional roles using a variety of online tools. In HF hearts, RNA-Seq identified 84,793 total messenger RNA coding and noncoding different transcripts, including 13,019 protein-coding genes, 2,085 total lncRNA genes, and 1,064 pseudogenes. By Ensembl noncoding RNA categories, there were 48 lncRNAs, 27 pseudogenes, and 30 antisense RNAs for a total of 105 differentially expressed lncRNAs in HF hearts. Compared with donor hearts, HF hearts exhibited differential expression of 7.7% of protein-coding genes, 3.7% of lncRNAs (including pseudogenes), and 2.5% of pseudogenes. There were not consistent correlations between antisense lncRNAs and parent genes and between pseudogenes and parent genes, implying differential regulation of expression. Exploratory in silico functional analyses using online tools suggested a variety of possible lncRNA regulatory roles. By providing a comprehensive profile of right ventricular polyadenylated messenger RNA transcriptome in HF, RNA-Seq provides an inventory of differentially expressed lncRNAs, including antisense transcripts and pseudogenes, for future mechanistic study. PMID:25992278

  19. Human heart failure: determinants of ventricular dysfunction.

    PubMed

    Alpert, N R; Mulieri, L A

    1997-01-01

    Thin muscle strips were obtained from non-failing (NF) and failing (dilated cardiomyopathy (DCM)) hearts, using a new harvesting and dissection technique. The strips were used to carry out a myothermal and mechanical analysis so that contractile and excitation coupling phenomena in the NF and failing (DCM-F) preparations can be compared. Peak isometric force and rate of relaxation in DCM-F were reduced 46% (p < 0.02) while time to peak tension was increased 14% (p < 0.03). Initial, tension dependent, tension independent and the rate of tension independent heat liberation were reduced 62-70% in DCM-F (p < 0.03). The crossbridge force-time integral (FTIXBr) was calculated from these measurements and was shown to increase 40% while the amount and rate of calcium cycled per beat was reduced 70%. As a result of these changes in the contractile and excitation-contraction coupling systems in DCM-F, the force-frequency relationship was significantly blunted while the power output was markedly reduced. These fundamental alterations account for the substantial ventricular dysfunction found in the dilated cardiomyopathic failing heart.

  20. Computational modelling of electrocardiograms: repolarisation and T-wave polarity in the human heart.

    PubMed

    Hurtado, Daniel E; Kuhl, Ellen

    2014-01-01

    For more than a century, electrophysiologists, cardiologists and engineers have studied the electrical activity of the human heart to better understand rhythm disorders and possible treatment options. Although the depolarisation sequence of the heart is relatively well characterised, the repolarisation sequence remains a subject of great controversy. Here, we study regional and temporal variations in both depolarisation and repolarisation using a finite element approach. We discretise the governing equations in time using an unconditionally stable implicit Euler backward scheme and in space using a consistently linearised Newton-Raphson-based finite element solver. Through systematic parameter-sensitivity studies, we establish a direct relation between a normal positive T-wave and the non-uniform distribution of the controlling parameter, which we have termed refractoriness. To establish a healthy baseline model, we calibrate the refractoriness using clinically measured action potential durations at different locations in the human heart. We demonstrate the potential of our model by comparing the computationally predicted and clinically measured depolarisation and repolarisation profiles across the left ventricle. The proposed framework allows us to explore how local action potential durations on the microscopic scale translate into global repolarisation sequences on the macroscopic scale. We anticipate that our calibrated human heart model can be widely used to explore cardiac excitation in health and disease. For example, our model can serve to identify optimal pacing sites in patients with heart failure and to localise optimal ablation sites in patients with cardiac fibrillation.

  1. Computational modeling of electrocardiograms: Repolarization and T-wave polarity in the human heart

    PubMed Central

    Hurtado, Daniel E.; Kuhl, Ellen

    2012-01-01

    For more than a century, electrophysiologists, cardiologists, and engineers have studied the electrical activity of the human heart to better understand rhythm disorders and possible treatment options. While the depolarization sequence of the heart is relatively well characterized, the repolarization sequence remains a subject of great controversy. Here we study regional and temporal variations in both depolarization and repolarization using a finite element approach. We discretize the governing equations in time using an unconditionally stable implicit Euler backward scheme and in space using a consistently linearized Newton-Raphson-based finite element solver. Through systematic parameter-sensitivity studies, we establish a direct relation between a normal positive T-wave and the non-uniform distribution of the controlling parameter, which we have termed refractoriness. To establish a healthy baseline model, we calibrate the refractoriness using clinically measured action potential durations at different locations in the human heart. We demonstrate the potential of our model by comparing the computationally predicted and clinically measured depolarization and repolarization profiles across the left ventricle. The proposed framework allows us to explore how local action potential durations on the microscopic scale translate into global repolarization sequences on the macroscopic scale. We anticipate that our calibrated human heart model can be widely used to explore cardiac excitation in health and disease. For example, our model can serve to identify optimal pacing sites in patients with heart failure and to localize optimal ablation sites in patients with cardiac fibrillation. PMID:23113842

  2. Oral triiodothyronine normalizes triiodothyronine levels after surgery for pediatric congenital heart disease*.

    PubMed

    Marwali, Eva M; Boom, Cindy E; Sakidjan, Indriwanto; Santoso, Anwar; Fakhri, Dicky; Kartini, Ay; Kekalih, Aria; Schwartz, Steven M; Haas, Nikolaus A

    2013-09-01

    This study was conducted to determine if oral triiodothyronine supplementation could prevent the decrease of serum triiodothyronine levels that commonly occurs after cardiopulmonary bypass for pediatric congenital heart surgery. Secondary objectives included identifying any significant adverse effects of oral triiodothyronine supplementation, including any effects on the thyroid/pituitary axis. Randomized, placebo-controlled, doubleblind clinical trial Operating room and ICU. Infants and children younger than 2 years of age undergoing congenital heart surgery using cardiopulmonary bypass (n = 43). Subjects were assigned to placebo (n = 15, group A) or one of two treatment groups: a low-dose group (group B, n = 14, 0.5 mcg/kg triiodothyronine orally every 24 hr for 3 d) or a high-dose group (group C, n = 14, 0.5 mcg/kg triiodothyronine orally every 12 hr for 3 d). Thyroid hormone, including total and free triiodothyronine levels at predetermined time points, potential side effects indicating hyperthyroidism, indicators of the thyroid-pituitary axis, and clinical endpoints. Oral triiodothyronine supplementation twice-daily maintained serum triiodothyronine levels within normal limits in group C, whereas serum levels progressively declined in groups A and B. A statistically significant difference in triiodothyronine levels between the treatment groups occurred between 18 and 36 hours post cross-clamp release, with the largest difference in serum levels between group C and group A noted at 36 hours post cross-clamp release (total triiodothyronine, 0.71 ± 0.15 [0.34-1.08] ng/mL [p < 0.01]; free triiodothyronine, 2.56 ± 0.49 [1.33-3.79] pg/mL [p < 0.01]). There was no evidence of hyperthyroidism or suppression of the pituitary-thyroid axis in either treatment group Oral triiodothyronine supplementation at a dose of 0.5 mcg/kg every 12 hours for 3 days can maintain total and free triiodothyronine levels within normal limits after open-heart surgery using cardiopulmonary

  3. Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo

    SciTech Connect

    Herrmann, Julia E.; Heale, Jason; Bieraugel, Mike; Ramos, Meg; Fisher, Robyn L.; Vickers, Alison E.M.

    2014-01-15

    Human response to isoproterenol induced cardiac injury was evaluated by gene and protein pathway changes in human heart slices, and compared to rat heart slices and rat heart in vivo. Isoproterenol (10 and 100 μM) altered human and rat heart slice markers of oxidative stress (ATP and GSH) at 24 h. In this in vivo rat study (0.5 mg/kg), serum troponin concentrations increased with lesion severity, minimal to mild necrosis at 24 and 48 h. In the rat and the human heart, isoproterenol altered pathways for apoptosis/necrosis, stress/energy, inflammation, and remodeling/fibrosis. The rat and human heart slices were in an apoptotic phase, while the in vivo rat heart exhibited necrosis histologically and further progression of tissue remodeling. In human heart slices genes for several heat shock 70 kD members were altered, indicative of stress to mitigate apoptosis. The stress response included alterations in energy utilization, fatty acid processing, and the up-regulation of inducible nitric oxide synthase, a marker of increased oxidative stress in both species. Inflammation markers linked with remodeling included IL-1α, Il-1β, IL-6 and TNFα in both species. Tissue remodeling changes in both species included increases in the TIMP proteins, inhibitors of matrix degradation, the gene/protein of IL-4 linked with cardiac fibrosis, and the gene Ccl7 a chemokine that induces collagen synthesis, and Reg3b a growth factor for cardiac repair. This study demonstrates that the initial human heart slice response to isoproterenol cardiac injury results in apoptosis, stress/energy status, inflammation and tissue remodeling at concentrations similar to that in rat heart slices. - Highlights: • Human response to isoproterenol induced cardiac injury evaluated in heart slices. • Isoproterenol altered apoptosis, energy, inflammation and remodeling pathways. • Human model verified by comparison to rat heart slices and rat heart in vivo. • Human and rat respond to isoproterenol

  4. Increased angiotensin-I converting enzyme gene expression in the failing human heart. Quantification by competitive RNA polymerase chain reaction.

    PubMed Central

    Studer, R; Reinecke, H; Müller, B; Holtz, J; Just, H; Drexler, H

    1994-01-01

    Local activation of the components of the renin angiotensin system in the heart is regarded as an important modulator of cardiac phenotype and function; however, little is known about their presence, regulation, and potential activation in the human heart. To investigate the gene expression of major angiotensin-II-forming enzymes in left ventricles of normal (n = 9) and failing human hearts (n = 20), we established a competitive RNA-polymerase chain reaction (PCR) for mRNA quantification of angiotensin-I converting enzyme (ACE) and human heart chymase. For each gene, competitor RNA targets with small internal deletions were used as internal standards to quantify the original number of transcripts and to control reverse transcription and PCR. In PCR, each target and the corresponding competitor were amplified by competing for the same primer oligonucleotides. The variability of ACE RNA-PCR was 11% indicating a high reproducibility of this method. In addition, ACE mRNA levels obtained by competitive RNA-PCR correlated favorably with traditional slot blot hybridization (r = 0.69, n = 10; P < 0.05). Compared with nonfailing hearts, the number of ACE transcripts referred to 100 ng of total RNA was increased threefold in patients with chronic heart failure (4.2 +/- 2.5 vs. 12.8 +/- 6 x 10(5); P < 0.0005). In contrast, no significant difference was found in chymase gene expression between normal and failing hearts. Thus, the expression of the cardiac ACE but not of human heart chymase is upregulated in failing human heart indicating an activation of the cardiac renin-angiotensin system in patients with advanced heart failure. Images PMID:8040271

  5. Increased expression of thyroid hormone receptor isoforms in end-stage human congestive heart failure.

    PubMed

    d'Amati, G; di Gioia, C R; Mentuccia, D; Pistilli, D; Proietti-Pannunzi, L; Miraldi, F; Gallo, P; Celi, F S

    2001-05-01

    Thyroid hormone plays an important role on myocardial development and function. The local effects of thyroid hormone are mediated by the receptor isoforms ultimately driving the expression of cardiac-specific genes. Although overt and subclinical thyroid dysfunction causes well-known changes in the cardiovascular system, little is known about local thyroid hormone action in normal and failing human myocardium. With a newly developed multiplex competitive RT-PCR method, we evaluated the expression of thyroid hormone receptor (TR) isoforms alpha-1, alpha-2, and beta-1 in normal human hearts and in end-stage congestive heart failure. A statistically significant difference in the expression of all three TR isoforms was observed among samples from normal subjects, ischemic heart disease (IHD), and dilated cardiomyopathy (DCM). In DCM, compared with normal, the studied TR isoforms were significantly increased. In IHD, the increased expression was found significant only for alpha-1 and alpha-2 isoforms. No differences were observed between the pathologic groups. In conclusion, a coordinated increment in the expression of the TR isoforms was observed in both DCM and IHD by multiplex competitive RT-PCR. The observed changes could represent a compensatory mechanism to myocardial failure or to locally altered thyroid hormone action.

  6. Reorganized PKA-AKAP associations in the failing human heart.

    PubMed

    Aye, Thin-Thin; Soni, Siddarth; van Veen, Toon A B; van der Heyden, Marcel A G; Cappadona, Salvatore; Varro, Andras; de Weger, Roel A; de Jonge, Nicolaas; Vos, Marc A; Heck, Albert J R; Scholten, Arjen

    2012-02-01

    Here we reveal that the characterization of large-scale re-arrangements of signaling scaffolds induced by heart failure can serve as a novel concept to identify more specific therapeutic targets. In the mammalian heart, the cAMP pathway, with the cAMP-dependent protein kinase (PKA) in a central role, acts directly downstream of adrenergic receptors to mediate cardiac contractility and rhythm. Heart failure, characterized by severe alterations in adrenergic stimulation is, amongst other interventions, often treated with β-blockers. Contrasting results, however, have shown both beneficial and detrimental effects of decreased cAMP levels in failing hearts. We hypothesize that the origin of this behavior lies in the complex spatiotemporal organization of the regulatory subunit of PKA (PKA-R), which associates tightly with various A-kinase anchoring proteins (AKAPs) to specifically localize PKA's activity. Using chemical proteomics directly applied to human patient and control heart tissue we demonstrate that the association profile of PKA-R with several AKAPs is severely altered in the failing heart, for instance effecting the interaction between PKA and the novel AKAP SPHKAP was 6-fold upregulated upon failing heart conditions. Also a significant increase in captured cGMP-dependent protein kinase (PKG) and phosphodiesterase 2 (PDE2) was observed. The observed altered profiles can already explain many aspects of the aberrant cAMP-response in the failing human heart, validating that this dataset may provide a resource for several novel, more specific, treatment options. This article is part of a Special Issue entitled "Local Signaling in Myocytes".

  7. Quantification of pulmonary thallium-201 activity after upright exercise in normal persons: importance of peak heart rate and propranolol usage in defining normal values

    SciTech Connect

    Brown, K.A.; Boucher, C.A.; Okada, R.D.; Strauss, H.W.; Pohost, G.M.

    1984-06-01

    Fifty-nine normal patients (34 angiographically normal and 25 clinically normal by Bayesian analysis) underwent thallium-201 imaging after maximal upright exercise. Lung activity was quantitated relative to myocardial activity and a lung/myocardial activity ratio was determined for each patient. Stepwise regression analysis was then used to examine the influence of patient clinical characteristics and exercise variables on the lung/myocardium ratio. Peak heart rate during exercise and propranolol usage both showed significant negative regression coefficients (p less than 0.001). No other patient data showed a significant relation. Using the regression equation and the estimated variance, a 95% confidence level upper limit of normal could be determined for a give peak heart rate and propranolol status. Sixty-one other patients were studied to validate the predicted upper limits of normal based on this model. None of the 27 patients without coronary artery disease had an elevated lung/myocardial ratio, compared with 1 of 8 with 1-vessel disease (difference not significant), 6 of 14 with 2-vessel disease (p less than 0.005), and 6 of 12 with 3-vessel disease (p less than 0.0001). Thus, lung activity on upright exercise thallium-201 studies can be quantitated relative to myocardial activity, and is inversely related to peak heart rate and propranolol use. Use of a regression analysis allows determination of a 95% confidence upper limit of normal to be anticipated in an individual patient.

  8. Decorin and biglycan of normal and pathologic human corneas

    NASA Technical Reports Server (NTRS)

    Funderburgh, J. L.; Hevelone, N. D.; Roth, M. R.; Funderburgh, M. L.; Rodrigues, M. R.; Nirankari, V. S.; Conrad, G. W.

    1998-01-01

    PURPOSE: Corneas with scars and certain chronic pathologic conditions contain highly sulfated dermatan sulfate, but little is known of the core proteins that carry these atypical glycosaminoglycans. In this study the proteoglycan proteins attached to dermatan sulfate in normal and pathologic human corneas were examined to identify primary genes involved in the pathobiology of corneal scarring. METHODS: Proteoglycans from human corneas with chronic edema, bullous keratopathy, and keratoconus and from normal corneas were analyzed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), quantitative immunoblotting, and immunohistology with peptide antibodies to decorin and biglycan. RESULTS: Proteoglycans from pathologic corneas exhibit increased size heterogeneity and binding of the cationic dye alcian blue compared with those in normal corneas. Decorin and biglycan extracted from normal and diseased corneas exhibited similar molecular size distribution patterns. In approximately half of the pathologic corneas, the level of biglycan was elevated an average of seven times above normal, and decorin was elevated approximately three times above normal. The increases were associated with highly charged molecular forms of decorin and biglycan, indicating modification of the proteins with dermatan sulfate chains of increased sulfation. Immunostaining of corneal sections showed an abnormal stromal localization of biglycan in pathologic corneas. CONCLUSIONS: The increased dermatan sulfate associated with chronic corneal pathologic conditions results from stromal accumulation of decorin and particularly of biglycan in the affected corneas. These proteins bear dermatan sulfate chains with increased sulfation compared with normal stromal proteoglycans.

  9. Decorin and biglycan of normal and pathologic human corneas

    NASA Technical Reports Server (NTRS)

    Funderburgh, J. L.; Hevelone, N. D.; Roth, M. R.; Funderburgh, M. L.; Rodrigues, M. R.; Nirankari, V. S.; Conrad, G. W.

    1998-01-01

    PURPOSE: Corneas with scars and certain chronic pathologic conditions contain highly sulfated dermatan sulfate, but little is known of the core proteins that carry these atypical glycosaminoglycans. In this study the proteoglycan proteins attached to dermatan sulfate in normal and pathologic human corneas were examined to identify primary genes involved in the pathobiology of corneal scarring. METHODS: Proteoglycans from human corneas with chronic edema, bullous keratopathy, and keratoconus and from normal corneas were analyzed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), quantitative immunoblotting, and immunohistology with peptide antibodies to decorin and biglycan. RESULTS: Proteoglycans from pathologic corneas exhibit increased size heterogeneity and binding of the cationic dye alcian blue compared with those in normal corneas. Decorin and biglycan extracted from normal and diseased corneas exhibited similar molecular size distribution patterns. In approximately half of the pathologic corneas, the level of biglycan was elevated an average of seven times above normal, and decorin was elevated approximately three times above normal. The increases were associated with highly charged molecular forms of decorin and biglycan, indicating modification of the proteins with dermatan sulfate chains of increased sulfation. Immunostaining of corneal sections showed an abnormal stromal localization of biglycan in pathologic corneas. CONCLUSIONS: The increased dermatan sulfate associated with chronic corneal pathologic conditions results from stromal accumulation of decorin and particularly of biglycan in the affected corneas. These proteins bear dermatan sulfate chains with increased sulfation compared with normal stromal proteoglycans.

  10. Captopril Normalizes Insulin Signaling and Insulin-Regulated Substrate Metabolism in Obese (ob/ob) Mouse Hearts

    PubMed Central

    Tabbi-Anneni, Imene; Buchanan, Jonathan; Cooksey, Robert C.; Abel, E. Dale

    2008-01-01

    The goal of this study was to determine whether inhibiting the renin-angiotensin system would restore insulin signaling and normalize substrate use in hearts from obese ob/ob mice. Mice were treated for 4 wk with Captopril (4 mg/kg·d). Circulating levels of free fatty acids, triglycerides, and insulin were measured and glucose tolerance tests performed. Rates of palmitate oxidation and glycolysis, oxygen consumption, and cardiac power were determined in isolated working hearts in the presence and absence of insulin, along with levels of phosphorylation of Akt and AMP-activated protein kinase (AMPK). Captopril treatment did not correct the hyperinsulinemia or impaired glucose tolerance in ob/ob mice. Rates of fatty acid oxidation were increased and glycolysis decreased in ob/ob hearts, and insulin did not modulate substrate use in hearts of ob/ob mice and did not increase Akt phosphorylation. Captopril restored the ability of insulin to regulate fatty acid oxidation and glycolysis in hearts of ob/ob mice, possibly by increasing Akt phosphorylation. Moreover, AMPK phosphorylation, which was increased in hearts of ob/ob mice, was normalized by Captopril treatment, suggesting that in addition to restoring insulin sensitivity, Captopril treatment improved myocardial energetics. Thus, angiotensin-converting enzyme inhibitors restore the responsiveness of ob/ob mouse hearts to insulin and normalizes AMPK activity independently of effects on systemic metabolic homeostasis. PMID:18450963

  11. FISH CONSUMPTION, METHYLMERCURY, AND HUMAN HEART DISEASE.

    SciTech Connect

    LIPFERT, F.W.; SULLIVAN, T.M.

    2005-09-21

    Environmental mercury continues to be of concern to public health advocates, both in the U.S. and abroad, and new research continues to be published. A recent analysis of potential health benefits of reduced mercury emissions has opened a new area of public health concern: adverse effects on the cardiovascular system, which could account for the bulk of the potential economic benefits. The authors were careful to include caveats about the uncertainties of such impacts, but they cited only a fraction of the applicable health effects literature. That literature includes studies of the potentially harmful ingredient (methylmercury, MeHg) in fish, as well as of a beneficial ingredient, omega-3 fatty acids or ''fish oils''. The U.S. Food and Drug Administration (FDA) recently certified that some of these fat compounds that are primarily found in fish ''may be beneficial in reducing coronary heart disease''. This paper briefly summarizes and categorizes the extensive literature on both adverse and beneficial links between fish consumption and cardiovascular health, which are typically based on studies of selected groups of individuals (cohorts). Such studies tend to comprise the ''gold standard'' of epidemiology, but cohorts tend to exhibit a great deal of variability, in part because of the limited numbers of individuals involved and in part because of interactions with other dietary and lifestyle considerations. Note that eating fish will involve exposure to both the beneficial effects of fatty acids and the potentially harmful effects of contaminants like Hg or PCBs, all of which depend on the type of fish but tend to be correlated within a population. As a group, the cohort studies show that eating fish tends to reduce mortality, especially due to heart disease, for consumption rates up to about twice weekly, above which the benefits tend to level off. A Finnish cohort study showed increased mortality risks in the highest fish-consuming group ({approx}3 times

  12. Direct observation of homoclinic orbits in human heart rate variability

    NASA Astrophysics Data System (ADS)

    Żebrowski, J. J.; Baranowski, R.

    2003-05-01

    Homoclinic trajectories of the interbeat intervals between contractions of ventricles of the human heart are identified. The interbeat intervals are extracted from 24-h Holter ECG recordings. Three such recordings are discussed in detail. Mappings of the measured consecutive interbeat intervals are constructed. In the second and in some cases in the fourth iterate of the map of interbeat intervals homoclinic trajectories associated with a hyperbolic saddle are found. The homoclinic trajectories are often persistent for many interbeat intervals, sometimes spanning many thousands of heartbeats. Several features typical for homoclinic trajectories found in other systems were identified, including a signature of the gluing bifurcation. The homoclinic trajectories are present both in recordings of heart rate variability obtained from patients with an increased number of arrhythmias and in cases in which the sinus rhythm is dominant. The results presented are a strong indication of the importance of deterministic nonlinear instabilities in human heart rate variability.

  13. Programming and reprogramming a human heart cell

    PubMed Central

    Sahara, Makoto; Santoro, Federica; Chien, Kenneth R

    2015-01-01

    The latest discoveries and advanced knowledge in the fields of stem cell biology and developmental cardiology hold great promise for cardiac regenerative medicine, enabling researchers to design novel therapeutic tools and approaches to regenerate cardiac muscle for diseased hearts. However, progress in this arena has been hampered by a lack of reproducible and convincing evidence, which at best has yielded modest outcomes and is still far from clinical practice. To address current controversies and move cardiac regenerative therapeutics forward, it is crucial to gain a deeper understanding of the key cellular and molecular programs involved in human cardiogenesis and cardiac regeneration. In this review, we consider the fundamental principles that govern the “programming” and “reprogramming” of a human heart cell and discuss updated therapeutic strategies to regenerate a damaged heart. PMID:25712211

  14. Systolic Strain Abnormalities to Predict Hospital Readmission in Patients With Heart Failure and Normal Ejection Fraction

    PubMed Central

    Borer, Steven M.; Kokkirala, Aravind; O'Sullivan, David M.; Silverman, David I.

    2011-01-01

    Background Despite intensive investigation, the pathogenesis of heart failure with normal ejection fraction (HFNEF) remains unclear. We hypothesized that subtle abnormalities of systolic function might play a role, and that abnormal systolic strain and strain rate would provide a marker for adverse outcomes. Methods Patients of new CHF and left ventricular ejection fraction > 50% were included. Exclusion criteria were recent myocardial infarction, severe valvular heart disease, severe left ventricular hypertrophy (septum >1.8 cm), or a technically insufficient echocardiogram. Average peak systolic strain and strain rate were measured using an off-line grey scale imaging technique. Systolic strain and strain rate for readmitted patients were compared with those who remained readmission-free. Results One hundred consecutive patients with a 1st admission for HFNEF from January 1, 2004 through December 31, 2007, inclusive, were analyzed. Fifty two patients were readmitted with a primary diagnosis of heart failure. Systolic strain and strain rates were reduced in both study groups compared to controls. However, systolic strain did not differ significantly between the two groups (-11.7% for those readmitted compared with -12.9% for those free from readmission, P = 0.198) and systolic strain rates also were similar (-1.05 s-1 versus -1.09 s-1, P = 0.545). E/e’ was significantly higher in readmitted patients compared with those who remained free from readmission (14.5 versus 11.0, P = 0.013). E/e’ (OR 1.189, 95% CI 1.026-1.378; P = 0.021) was found to be an independent predictor for HFNEF readmission. Conclusions Among patients with new onset HFNEF, SS and SR rates are reduced compared with patients free of HFNEF, but do not predict hospital readmission. Elevated E/e’ is a predictor of readmission in these patients.

  15. The role of PPAR in myocardial response to ischemia in normal and diseased heart.

    PubMed

    Ravingerova, Tana; Adameova, Adriana; Carnicka, Slavka; Nemcekova, Martina; Kelly, Tara; Matejikova, Jana; Galatou, Eleftheria; Barlaka, Eleftheria; Lazou, Antigone

    2011-12-01

    Peroxisome proliferator-activated receptors (PPAR), ligand-activated transcription factors, belong to the nuclear hormone receptor superfamily regulating expression of genes involved in different aspects of lipid metabolism, inflammation and cardiac energy production. Activation of PPAR-α isoform by its natural ligands, fatty acids (FA) and eicosanoids, promotes mitochondrial FA oxidation as the primary ATP-generating pathway. On the other hand, PPAR-γ regulates lipid anabolism or storage, while, until recently, the function of PPAR-β/δ has been less explored. Under conditions associated with acute or chronic oxygen deprivation, PPAR-α modulates expression of genes that determine substrate switch (FA vs. glucose) aimed at maintenance of basic cardiac function. Although PPAR-α and PPAR-γ synthetic agonists, hypolipidemic and antidiabetic drugs, have been reported to protect the heart against ischemia/reperfusion injury, it is still a matter of debate whether PPAR activation plays a beneficial or detrimental role in myocardial response to ischemia, in particular, in pathological conditions. This article reviews some findings demonstrating the impact of PPAR activation on cardiac resistance to ischemia in normal and pathologically altered heart. Specifically, it addresses the issue of susceptibility to ischemia in the diabetic myocardium, with particular regards to the role of PPAR. Finally, involvement of PPAR in the mechanisms of lipid-independent cardioprotective effects of some hypolipidemic drugs is also discussed.

  16. Semaphorin III is needed for normal patterning and growth of nerves, bones and heart.

    PubMed

    Behar, O; Golden, J A; Mashimo, H; Schoen, F J; Fishman, M C

    1996-10-10

    The expression patterns of the recently discovered family of semaphorin genes suggests that they have widespread roles in embryonic development. Some seem to guide neuronal growth cones, but otherwise their functions are unknown. Semaphorin III is a membrane-associated secreted protein with a developmentally dynamic pattern of expression, including particular domains of the nervous system, the borders of developing bones, and the heart. In vitro, semaphorin III causes growth-cone collapse, and repels cutaneous sensory axons from the ventral spinal cord. Mutants in the Drosophila gene semaII, which encodes a related semaphorin, die after eclosion, but no responsible abnormality is evident. We have generated mice mutant in the semaIII gene by homologous recombination. Here we show that in the mutants, some sensory axons project into inappropriate regions of the spinal cord where semaIII is normally expressed. The cerebral cortex of homozygous mutant mice shows a paucity of neuropil and abnormally oriented neuronal processes, especially of the large pyramidal neurons. Certain embryonic bones and cartilaginous structures develop abnormally, with vertebral fusions and partial rib duplications. The few mice that survive more than a few days postnatally manifest pronounced and selective hypertrophy of the right ventricle of the heart and dilation of the right atrium. Thus, semaphorin III might serve as a signal that restrains growth in several developing organs.

  17. Total lymphatic irradiation and bone marrow in human heart transplantation

    SciTech Connect

    Kahn, D.R.; Hong, R.; Greenberg, A.J.; Gilbert, E.F.; Dacumos, G.C.; Dufek, J.H.

    1984-08-01

    Six patients, aged 36 to 59 years, had heart transplants for terminal myocardial disease using total lymphatic irradiation (TLI) and donor bone marrow in addition to conventional therapy. All patients were poor candidates for transplantation because of marked pulmonary hypertension, unacceptable tissue matching, or age. Two patients are living and well more than four years after the transplants. Two patients died of infection at six and seven weeks with normal hearts. One patient, whose preoperative pulmonary hypertension was too great for an orthotopic heart transplant, died at 10 days after such a procedure. The other patient died of chronic rejection seven months postoperatively. Donor-specific tolerance developed in 2 patients. TLI and donor bone marrow can produce specific tolerance to donor antigens and allow easy control of rejection, but infection is still a major problem. We describe a new technique of administering TLI with early reduction of prednisone that may help this problem.

  18. Oxygen consumption of human heart cells in monolayer culture.

    PubMed

    Sekine, Kaori; Kagawa, Yuki; Maeyama, Erina; Ota, Hiroki; Haraguchi, Yuji; Matsuura, Katsuhisa; Shimizu, Tatsuya

    2014-09-26

    Tissue engineering in cardiovascular regenerative therapy requires the development of an efficient oxygen supply system for cell cultures. However, there are few studies which have examined human cardiomyocytes in terms of oxygen consumption and metabolism in culture. We developed an oxygen measurement system equipped with an oxygen microelectrode sensor and estimated the oxygen consumption rates (OCRs) by using the oxygen concentration profiles in culture medium. The heart is largely made up of cardiomyocytes, cardiac fibroblasts, and cardiac endothelial cells. Therefore, we measured the oxygen consumption of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs), cardiac fibroblasts, human cardiac microvascular endothelial cell and aortic smooth muscle cells. Then we made correlations with their metabolisms. In hiPSC-CMs, the value of the OCR was 0.71±0.38pmol/h/cell, whereas the glucose consumption rate and lactate production rate were 0.77±0.32pmol/h/cell and 1.61±0.70pmol/h/cell, respectively. These values differed significantly from those of the other cells in human heart. The metabolism of the cells that constitute human heart showed the molar ratio of lactate production to glucose consumption (L/G ratio) that ranged between 1.97 and 2.2. Although the energy metabolism in adult heart in vivo is reported to be aerobic, our data demonstrated a dominance of anaerobic glycolysis in an in vitro environment. With our measuring system, we clearly showed the differences in the metabolism of cells between in vivo and in vitro monolayer culture. Our results regarding cell OCRs and metabolism may be useful for future tissue engineering of human heart.

  19. From zebrafish heart jogging genes to mouse and human orthologs: using Gene Ontology to investigate mammalian heart development.

    PubMed

    Khodiyar, Varsha K; Howe, Doug; Talmud, Philippa J; Breckenridge, Ross; Lovering, Ruth C

    2013-01-01

    For the majority of organs in developing vertebrate embryos, left-right asymmetry is controlled by a ciliated region; the left-right organizer node in the mouse and human, and the Kuppfer's vesicle in the zebrafish. In the zebrafish, laterality cues from the Kuppfer's vesicle determine asymmetry in the developing heart, the direction of 'heart jogging' and the direction of 'heart looping'.  'Heart jogging' is the term given to the process by which the symmetrical zebrafish heart tube is displaced relative to the dorsal midline, with a leftward 'jog'. Heart jogging is not considered to occur in mammals, although a leftward shift of the developing mouse caudal heart does occur prior to looping, which may be analogous to zebrafish heart jogging. Previous studies have characterized 30 genes involved in zebrafish heart jogging, the majority of which have well defined orthologs in mouse and human and many of these orthologs have been associated with early mammalian heart development.    We undertook manual curation of a specific set of genes associated with heart development and we describe the use of Gene Ontology term enrichment analyses to examine the cellular processes associated with heart jogging.  We found that the human, mouse and zebrafish 'heart jogging orthologs' are involved in similar organ developmental processes across the three species, such as heart, kidney and nervous system development, as well as more specific cellular processes such as cilium development and function. The results of these analyses are consistent with a role for cilia in the determination of left-right asymmetry of many internal organs, in addition to their known role in zebrafish heart jogging.    This study highlights the importance of model organisms in the study of human heart development, and emphasises both the conservation and divergence of developmental processes across vertebrates, as well as the limitations of this approach.

  20. From zebrafish heart jogging genes to mouse and human orthologs: using Gene Ontology to investigate mammalian heart development.

    PubMed Central

    Lovering, Ruth C

    2014-01-01

    For the majority of organs in developing vertebrate embryos, left-right asymmetry is controlled by a ciliated region; the left-right organizer node in the mouse and human, and the Kuppfer’s vesicle in the zebrafish. In the zebrafish, laterality cues from the Kuppfer’s vesicle determine asymmetry in the developing heart, the direction of ‘heart jogging’ and the direction of ‘heart looping’.  ‘Heart jogging’ is the term given to the process by which the symmetrical zebrafish heart tube is displaced relative to the dorsal midline, with a leftward ‘jog’. Heart jogging is not considered to occur in mammals, although a leftward shift of the developing mouse caudal heart does occur prior to looping, which may be analogous to zebrafish heart jogging. Previous studies have characterized 30 genes involved in zebrafish heart jogging, the majority of which have well defined orthologs in mouse and human and many of these orthologs have been associated with early mammalian heart development.    We undertook manual curation of a specific set of genes associated with heart development and we describe the use of Gene Ontology term enrichment analyses to examine the cellular processes associated with heart jogging.  We found that the human, mouse and zebrafish ‘heart jogging orthologs’ are involved in similar organ developmental processes across the three species, such as heart, kidney and nervous system development, as well as more specific cellular processes such as cilium development and function. The results of these analyses are consistent with a role for cilia in the determination of left-right asymmetry of many internal organs, in addition to their known role in zebrafish heart jogging.    This study highlights the importance of model organisms in the study of human heart development, and emphasises both the conservation and divergence of developmental processes across vertebrates, as well as the limitations of this approach. PMID:24627794

  1. Immunohistochemical distribution of desmin in the human fetal heart.

    PubMed

    Yamamoto, Masahito; Abe, Shin-ichi; Rodríguez-Vázquez, José Francisco; Fujimiya, Mineko; Murakami, Gen; Ide, Yoshinobu

    2011-08-01

    Desmin is a member of the intermediate filaments, which play crucial roles in the maturation, maintenance and recovery of muscle fibers. Its expression has been examined in human cardiac muscle, rat and chicken, but its spatial distribution in the human fetal heart has not been described. The present study investigated desmin expression in the human fetal heart and associated great vessels in 14 mid-term fetuses from 9 to 18 weeks of gestation. Immunoreactivity for myosin heavy chain (MHC) and alpha smooth muscle actin (α-SMA), as well as neuron-specific enolase (NSE), was also examined. Increased expression of desmin from 9 to 18 weeks was clearly localized in the atrial wall, the proximal portions of the pulmonary vein and vena cava, and around the atrioventricular node. Desmin-positive structures were also positive for MHC. Meanwhile, the great vessels were also positive for α-SMA. The distribution of desmin exhibited a pattern quite different from that described in previous studies of rat and chicken. Thus, desmin in the human fetal heart does not seem to play a general role in myocardial differentiation but rather a specific role closely related to the maturation of the α-isozyme of MHC. Desmin expression in the developing fetal heart also appeared to be induced by mechanical stress due to the involvement of venous walls against the atrium.

  2. Hierarchical structure in healthy and diseased human heart rate variability

    NASA Astrophysics Data System (ADS)

    Ching, Emily S.; Lin, D. C.; Zhang, C.

    2004-05-01

    It is shown that the healthy and diseased human heart rate variability (HRV) possesses a hierarchical structure of the She-Leveque (SL) form. This structure, first found in measurements in turbulent fluid flows, implies further details in the HRV multifractal scaling. The potential of diagnosis is also discussed based on the characteristics derived from the SL hierarchy.

  3. Trends in cardiovascular engineering: organizing the human heart.

    PubMed

    Tulloch, Nathaniel L; Murry, Charles E

    2013-11-01

    The regulation of heart growth through the interaction of cell types, matrix molecules, and mechanical cues is poorly understood, yet is necessary for the heart to reach its proper size and function. Using mechanical load and vascular cell co-culture in combination with a tissue engineering approach, we have recently been able to generate organized human myocardium in vitro and to modulate cardiomyocyte alignment, proliferation, and hypertrophy within the engineered tissue construct; further, we measured contractile function and the force-length dependence of the engineered tissue as a whole. The goal of these studies has been to characterize in vitro models of human cardiac development and to work towards human therapeutics using organized, vascularized, contractile human cardiac tissue. This review will touch on the current state of knowledge in this field, give an overview of the results of our own recent findings, and present areas of active investigation and new directions for future research. © 2013 Elsevier Inc. All rights reserved.

  4. Hear the beat: decellularized mouse heart regenerated with human induced pluripotent stem cells.

    PubMed

    Lin, Bo; Lu, Tung-Ying; Yang, Lei

    2014-02-01

    Heart tissue engineering holds a great potential for human heart disease therapy. Regeneration of whole biofunctional human heart is the ultimate goal of tissue engineering. Recent advances take the first step towards whole heart regeneration. However, a substantial amount of challenges have to be overcome.

  5. Loss of Brain Aerobic Glycolysis in Normal Human Aging.

    PubMed

    Goyal, Manu S; Vlassenko, Andrei G; Blazey, Tyler M; Su, Yi; Couture, Lars E; Durbin, Tony J; Bateman, Randall J; Benzinger, Tammie L-S; Morris, John C; Raichle, Marcus E

    2017-08-01

    The normal aging human brain experiences global decreases in metabolism, but whether this affects the topography of brain metabolism is unknown. Here we describe PET-based measurements of brain glucose uptake, oxygen utilization, and blood flow in cognitively normal adults from 20 to 82 years of age. Age-related decreases in brain glucose uptake exceed that of oxygen use, resulting in loss of brain aerobic glycolysis (AG). Whereas the topographies of total brain glucose uptake, oxygen utilization, and blood flow remain largely stable with age, brain AG topography changes significantly. Brain regions with high AG in young adults show the greatest change, as do regions with prolonged developmental transcriptional features (i.e., neoteny). The normal aging human brain thus undergoes characteristic metabolic changes, largely driven by global loss and topographic changes in brain AG. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Normalized spectral power of fetal heart rate variability is associated with fetal scalp blood pH.

    PubMed

    van Laar, J O E H; Peters, C H L; Houterman, S; Wijn, P F F; Kwee, A; Oei, S G

    2011-04-01

    Spectral power of fetal heart rate variability is related to fetal condition. Previous studies found an increased normalized low frequency power in case of severe fetal acidosis. To analyze whether absolute or normalized low or high frequency power of fetal heart rate variability is associated with fetal scalp blood pH. Prospective cohort study, performed in an obstetric unit of a tertiary care teaching hospital. Consecutive singleton term fetuses in cephalic presentation that underwent one or more scalp blood samples, monitored during labour using ST-analysis of the fetal electrocardiogram. Ten-minute continuous beat-to-beat fetal heart rate segments, preceding the scalp blood measurement were used. Absolute and normalized spectral power in the low frequency band (0.04-0.15 Hz) and in the high frequency band (0.4-1.5 Hz). In total 39 fetal blood samples from 30 patients were studied. We found that normalized low frequency and normalized high frequency power of fetal heart rate variability is associated with fetal scalp blood pH. The estimated ß of normalized low frequency power was -0.37 (95% confidence interval -0.68 to -0.06) and the relative risk was 0.69 (95% confidence interval 0.51-0.94). The estimated ß of normalized high frequency power was 0.33 (95% confidence interval 0.01-0.65) and the relative risk was 1.39 (95% confidence interval 1.01-1.92). Normalized low and normalized high frequency power of fetal heart rate variability is associated with fetal scalp blood pH. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. Mechanical Unloading Promotes Myocardial Energy Recovery in Human Heart Failure

    PubMed Central

    Gupte, Anisha A.; Hamilton, Dale J.; Cordero-Reyes, Andrea M.; Youker, Keith A.; Yin, Zheng; Estep, Jerry D.; Stevens, Robert D.; Wenner, Brett; Ilkayeva, Olga; Loebe, Matthias; Peterson, Leif E.; Lyon, Christopher J.; Wong, Stephen T.C.; Newgard, Christopher B.; Torre-Amione, Guillermo; Taegtmeyer, Heinrich; Hsueh, Willa A.

    2015-01-01

    Background Impaired bioenergetics is a prominent feature of the failing heart, but the underlying metabolic perturbations are poorly understood. Methods and Results We compared metabolomic, gene transcript, and protein data from six paired failing human left ventricular (LV) tissue samples obtained during left ventricular assist device (LVAD) insertion (heart failure (HF) samples) and at heart transplant (post-LVAD samples). Non-failing left ventricular (NFLV) wall samples procured from explanted hearts of patients with right HF served as novel comparison samples. Metabolomic analyses uncovered a distinct pattern in HF tissue: 2.6 fold increased pyruvate concentrations coupled with reduced Krebs cycle intermediates and short-chain acylcarnitines, suggesting a global reduction in substrate oxidation. These findings were associated with decreased transcript levels for enzymes that catalyze fatty acid oxidation and pyruvate metabolism and for key transcriptional regulators of mitochondrial metabolism and biogenesis, peroxisome proliferator-activated receptor gamma co-activator1α (PGC1A, 1.3 fold) and estrogen-related receptor α (ERRA, 1.2 fold) and γ (ERRG, 2.2 fold). Thus, parallel decreases in key transcription factors and their target metabolic enzyme genes can explain the decreases in associated metabolic intermediates. Mechanical support with LVAD improved all of these metabolic and transcriptional defects. Conclusions These observations underscore an important pathophysiologic role for severely defective metabolism in HF, while the reversibility of these defects by LVAD suggests metabolic resilience of the human heart. PMID:24825877

  8. Linear and nonlinear analysis of normal and CAD-affected heart rate signals.

    PubMed

    Acharya, U Rajendra; Faust, Oliver; Sree, Vinitha; Swapna, G; Martis, Roshan Joy; Kadri, Nahrizul Adib; Suri, Jasjit S

    2014-01-01

    Coronary artery disease (CAD) is one of the dangerous cardiac disease, often may lead to sudden cardiac death. It is difficult to diagnose CAD by manual inspection of electrocardiogram (ECG) signals. To automate this detection task, in this study, we extracted the heart rate (HR) from the ECG signals and used them as base signal for further analysis. We then analyzed the HR signals of both normal and CAD subjects using (i) time domain, (ii) frequency domain and (iii) nonlinear techniques. The following are the nonlinear methods that were used in this work: Poincare plots, Recurrence Quantification Analysis (RQA) parameters, Shannon entropy, Approximate Entropy (ApEn), Sample Entropy (SampEn), Higher Order Spectra (HOS) methods, Detrended Fluctuation Analysis (DFA), Empirical Mode Decomposition (EMD), Cumulants, and Correlation Dimension. As a result of the analysis, we present unique recurrence, Poincare and HOS plots for normal and CAD subjects. We have also observed significant variations in the range of these features with respect to normal and CAD classes, and have presented the same in this paper. We found that the RQA parameters were higher for CAD subjects indicating more rhythm. Since the activity of CAD subjects is less, similar signal patterns repeat more frequently compared to the normal subjects. The entropy based parameters, ApEn and SampEn, are lower for CAD subjects indicating lower entropy (less activity due to impairment) for CAD. Almost all HOS parameters showed higher values for the CAD group, indicating the presence of higher frequency content in the CAD signals. Thus, our study provides a deep insight into how such nonlinear features could be exploited to effectively and reliably detect the presence of CAD. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  9. Influence of heart failure on nucleolar organization and protein expression in human hearts

    SciTech Connect

    Rosello-Lleti, Esther; Rivera, Miguel; Cortes, Raquel; Azorin, Inmaculada; Sirera, Rafael; Martinez-Dolz, Luis; Hove, Leif; Cinca, Juan; Lago, Francisca; Gonzalez-Juanatey, Jose R.; Salvador, Antonio; Portoles, Manuel

    2012-02-10

    Highlights: Black-Right-Pointing-Pointer Heart failure alters nucleolar morphology and organization. Black-Right-Pointing-Pointer Nucleolin expression is significant increased in ischemic and dilated cardiomyopathy. Black-Right-Pointing-Pointer Ventricular function of heart failure patients was related with nucleolin levels. -- Abstract: We investigate for the first time the influence of heart failure (HF) on nucleolar organization and proteins in patients with ischemic (ICM) or dilated cardiomyopathy (DCM). A total of 71 human hearts from ICM (n = 38) and DCM (n = 27) patients, undergoing heart transplantation and control donors (n = 6), were analysed by western-blotting, RT-PCR and cell biology methods. When we compared protein levels according to HF etiology, nucleolin was increased in both ICM (117%, p < 0.05) and DCM (141%, p < 0.01). Moreover, mRNA expression were also upregulated in ICM (1.46-fold, p < 0.05) and DCM (1.70-fold, p < 0.05. Immunofluorescence studies showed that the highest intensity of nucleolin was into nucleolus (p < 0.0001), and it was increased in pathological hearts (p < 0.0001). Ultrastructure analysis by electron microscopy showed an increase in the nucleus and nucleolus size in ICM (17%, p < 0.05 and 131%, p < 0.001) and DCM (56%, p < 0.01 and 69%, p < 0.01). Nucleolar organization was influenced by HF irrespective of etiology, increasing fibrillar centers (p < 0.001), perinucleolar chromatin (p < 0.01) and dense fibrillar components (p < 0.01). Finally, left ventricular function parameters were related with nucleolin levels in ischemic hearts (p < 0.0001). The present study demonstrates that HF influences on morphology and organization of nucleolar components, revealing changes in the expression and in the levels of nucleolin protein.

  10. Partial LVAD restores ventricular outputs and normalizes LV but not RV stress distributions in the acutely failing heart in silico

    PubMed Central

    Sack, Kevin L.; Baillargeon, Brian; Acevedo-Bolton, Gabriel; Genet, Martin; Rebelo, Nuno; Kuhl, Ellen; Klein, Liviu; Weiselthaler, Georg M.; Burkhoff, Daniel; Franz, Thomas; Guccione, Julius M.

    2016-01-01

    Purpose Heart failure is a worldwide epidemic that is unlikely to change as the population ages and life expectancy increases. We sought to detail significant recent improvements to the Dassault Systèmes Living Heart Model (LHM) and use the LHM to compute left ventricular (LV) and right ventricular (RV) myofiber stress distributions under the following 4 conditions: (1) normal cardiac function; (2) acute left heart failure (ALHF); (3) ALHF treated using an LV assist device (LVAD) flow rate of 2 L/min; and (4) ALHF treated using an LVAD flow rate of 4.5 L/min. Methods and Results Incorporating improved systolic myocardial material properties in the LHM resulted in its ability to simulate the Frank-Starling law of the heart. We decreased myocardial contractility in the LV myocardium so that LV ejection fraction decreased from 56% to 28%. This caused mean LV end diastolic (ED) stress to increase to 508% of normal, mean LV end systolic (ES) stress to increase to 113% of normal, mean RV ED stress to decrease to 94% of normal and RV ES to increase to 570% of normal. When ALHF in the model was treated with an LVAD flow rate of 4.5 L/min, most stress results normalized. Mean LV ED stress became 85% of normal, mean LV ES stress became 109% of normal and mean RV ED stress became 95% of normal. However, mean RV ES stress improved less dramatically (to 342% of normal values). Conclusions These simulations strongly suggest that an LVAD is effective in normalizing LV stresses but not RV stresses that become elevated as a result of ALHF. PMID:27646633

  11. Collagen polymorphism in normal and cirrhotic human liver.

    PubMed Central

    Seyer, J M; Hutcheson, E T; Kang, A H

    1977-01-01

    Collagens in normal human liver and in alcoholic cirrhotic liver were investigated. Collagens were solubilized by limited proteolysis with pepsin under nondenaturing conditions, and after purification, were fractionated into types I and III by selective precipitation with NaCl. After carboxymethyl cellulose and agarose chromatography, the resulting alpha-chains from each of the collagen types were analyzed with respect to their amino acid and carbohydrate compositions. A comparison of the results obtained from normal liver with those from the diseases organ revealed no significant differences. The isolated human liver alpha1(I) and alpha1(III) chains were digested with CNBr and the generated peptides were separated and purified by a combination of ion-exchange and molecular sieve chromatography. The molecular weight and the amino acid and the carbohydrate compositions of each of the peptides were identical to those of the corresponding human skin peptides except for the slightly higher content of hydroxylysine in some of the peptides. The relative content of type III in relation to type I collagen in both normal anc cirrhotic liver was determined by digesting washed liver homogenates directly with CNBr and quantitating the resultant alpha1(I) and alpha 1(III) peptides after chromatographic separation. The relative quantities of these peptides indicated that normal human liver contained an average of 47% type III, with the remainder being type I. Cirrhotic liver, on the other hand, contained a significantly smaller proportion of type III, ranging from 18 to 34% in different samples, with a corresponding increase in type I. These findings indicate that although the amino acid and carbohydrate compositions of collagens deposited in cirrhotic liver are normal, the fibrotic process of alcoholic liver disease in humans is accompanied by an alteration in tissue collagen polymorphism, and suggest that the observed alterations may have pathogenetic implications. PMID:833273

  12. Noninvasive recovery of epicardial potentials in a realistic heart-torso geometry. Normal sinus rhythm.

    PubMed

    Messinger-Rapport, B J; Rudy, Y

    1990-04-01

    The inverse problem in electrocardiography implies the reconstruction of electrical events within the heart from information measured noninvasively on the body surface. Deduction of these electrical events is possible from measured epicardial potentials, and, thus, a noninvasive method of recovering epicardial potentials from body surface data is useful in experimental and clinical studies. In the present study, an inverse method that uses Tikhonov regularization was shown to reconstruct, with good accuracy, important events in cardiac excitation. The inverse procedure was employed on data obtained from a human-torso tank in which a beating canine heart was placed in the correct anatomical position. Comparison with the actual, measured epicardial potentials indicates that positions and shapes of potential features (maxima, minima, zero potential line, saddles, etc.) are recovered with good accuracy throughout the QRS. An error in position of up to 1 cm is typical, while amplitudes are slightly diminished. In addition, application was extended from the above setting, in which the geometry was precisely known and potentials at a large number of leads were measured accurately, to a situation that is more representative of clinical and experimental settings. Effects of inaccuracy in location of the position of the heart were examined. A stylized torso that approximates the actual geometry was designed, and its performance in the inverse computations was evaluated. A systematic method of reduction of the number of leads on the body surface was proposed, and the resulting lead configurations were evaluated in terms of the accuracy of inverse solutions. The results indicate that the inverse problem can be stabilized with respect to different types of uncertainties in measured data and offer promise in the use of the inverse procedure in clinical and experimental situations.

  13. Morphogenetic aspects of the septomarginal trabecula in the human heart

    PubMed Central

    Kosiński, Adam; Nowiński, Janusz; Lewicka, Ewa; Dąbrowska-Kugacka, Alicja; Raczak, Grzegorz; Grzybiak, Marek

    2010-01-01

    Introduction The septomarginal trabecula is a constant element of the anatomy of the human heart, which connects the interventricular septum and the anterior wall of the right ventricle. Considering the diversity of opinions about the structure and numerous studies suggesting its important role in haemodynamics and conduction of electrical impulses in the heart, we decided to study this element in detail. Material and methods The research was conducted on 220 human hearts. Attention was mainly paid to the structure and topography of the trabecula. Its relation to the anterior papillary muscle was also a part of the study. Results The presence of this morphologically diverse element was confirmed in each of the studied hearts. In most cases the trabecula originated from the upper part of the interventricular septum, separating at an angle increasing proportionally to the number of branches of the crista supraventricularis as well as the number of secondary trabeculae. The criteria established for the study, which included the course of the trabecula in the lumen of the right ventricle and its relation to the anterior papillary muscle, let us distinguish 4 types of septomarginal trabecula (I, II, III, IV). The most common was type III, the undivided trabecula, tightly connecting with the anterior papillary muscle. Conclusions Based on the results of the following study we propose a hypothesis on the genesis of respective parts of the septomarginal trabecula and a plausible sequence of changes they undergo during human ontogenesis and phylogenesis of the primates. PMID:22419933

  14. Comparative decellularization and recellularization of normal versus emphysematous human lungs.

    PubMed

    Wagner, Darcy E; Bonenfant, Nicholas R; Parsons, Charles S; Sokocevic, Dino; Brooks, Elice M; Borg, Zachary D; Lathrop, Melissa J; Wallis, John D; Daly, Amanda B; Lam, Ying Wai; Deng, Bin; DeSarno, Michael J; Ashikaga, Takamaru; Loi, Roberto; Weiss, Daniel J

    2014-03-01

    Acellular whole human lung scaffolds represent a unique opportunity for ex vivo tissue engineering. However, it remains unclear whether lungs from individuals with chronic lung diseases such as chronic obstructive pulmonary disease (COPD) can be appropriately decellularized and recellularized. To assess this, cadaveric human lungs from normal (non-smoking) patients and from patients with COPD (smoking history) were decellularized and found by histochemical and immunohistochemical staining, electron microscopy, and mass spectrometry to retain characteristic histological architecture and extracellular matrix components (ECM) reflecting either normal or COPD, particularly emphysematous, origin. Inoculation of human bronchial epithelial cells, endothelial progenitor cells, bone marrow-derived mesenchymal stem cells, and lung fibroblasts via airway or vascular routes into small, excised segments of the decellularized lungs demonstrated that normal lung scaffolds robustly supported initial engraftment and growth of each cell type for up to one month. In contrast, despite initial binding, all cell types inoculated into decellularized emphysematous lungs did not survive beyond one week. However, cell attachment and proliferation on solubilized ECM homogenates of decellularized normal and emphysematous lungs coated onto tissue culture plates was comparable and not impaired, suggesting that the 3-dimensional decellularized emphysematous scaffolds may lack the necessary ECM architecture to support sustained cell growth. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Comparative Decellularization and Recellularization of Normal versus Emphysematous Human Lungs

    PubMed Central

    Wagner, Darcy. E.; Bonenfant, Nicholas. R.; Parsons, Charles; Sokocevic, Dino; Brooks, Elice. M.; Borg, Zachary. D.; Lathrop, Melissa. J.; Wallis, John. D.; Daly, Amanda. B.; Lam, Ying Wai; Deng, Bin; DeSarno, Michael. J.; Ashikaga, Takamaru; Loi, Roberto; Weiss, Daniel. J.

    2014-01-01

    Acellular whole human lung scaffolds represent a unique opportunity for ex vivo tissue engineering. However, it remains unclear whether lungs from individuals with chronic lung diseases such as chronic obstructive pulmonary disease (COPD) can be appropriately decellularized and recellularized. To assess this, cadaveric human lungs from normal (non-smoking) patients and from patients with COPD (smoking history) were decellularized and found by histochemical and immunohistochemical staining, electron microscopy, and mass spectrometry to retain characteristic histological architecture and extracellular matrix components (ECM) reflecting either normal or COPD, particularly emphysematous, origin. Inoculation of human bronchial epithelial cells, endothelial progenitor cells, bone marrow-derived mesenchymal stem cells, and lung fibroblasts via airway or vascular routes into small, excised segments of the decellularized lungs demonstrated that normal lung scaffolds robustly supported initial engraftment and growth of each cell type for up to one month. In contrast, despite initial binding, all cell types inoculated into decellularized emphysematous lungs did not survive beyond one week. However, cell attachment and proliferation on solubilized ECM homogenates of decellularized normal and emphysematous lungs coated onto tissue culture plates was comparable and not impaired, suggesting that the 3-dimensional decellularized emphysematous scaffolds may lack the necessary ECM architecture to support sustained cell growth. PMID:24461327

  16. Dynamics of Cell Generation and Turnover in the Human Heart.

    PubMed

    Bergmann, Olaf; Zdunek, Sofia; Felker, Anastasia; Salehpour, Mehran; Alkass, Kanar; Bernard, Samuel; Sjostrom, Staffan L; Szewczykowska, Mirosława; Jackowska, Teresa; Dos Remedios, Cris; Malm, Torsten; Andrä, Michaela; Jashari, Ramadan; Nyengaard, Jens R; Possnert, Göran; Jovinge, Stefan; Druid, Henrik; Frisén, Jonas

    2015-06-18

    The contribution of cell generation to physiological heart growth and maintenance in humans has been difficult to establish and has remained controversial. We report that the full complement of cardiomyocytes is established perinataly and remains stable over the human lifespan, whereas the numbers of both endothelial and mesenchymal cells increase substantially from birth to early adulthood. Analysis of the integration of nuclear bomb test-derived (14)C revealed a high turnover rate of endothelial cells throughout life (>15% per year) and more limited renewal of mesenchymal cells (<4% per year in adulthood). Cardiomyocyte exchange is highest in early childhood and decreases gradually throughout life to <1% per year in adulthood, with similar turnover rates in the major subdivisions of the myocardium. We provide an integrated model of cell generation and turnover in the human heart.

  17. Detection of human cytomegalovirus in normal and neoplastic breast epithelium

    PubMed Central

    2010-01-01

    Introduction Human cytomegalovirus (HCMV) establishes a persistent life-long infection, and can cause severe pathology in the fetus and the immunocompromised host[1]. Breast milk is the primary route of transmission in humans worldwide, and breast epithelium is thus a likely site of persistent infection and/or reactivation, though this phenomenon has not previously been demonstrated. Increasing evidence indicates HCMV infection can modulate signaling pathways associated with oncogenesis. We hypothesized that persistent HCMV infection occurs in normal adult breast epithelium and that persistent viral expression might be associated with normal and neoplastic ductal epithelium. Methods Surgical biopsy specimens of normal breast (n = 38) breast carcinoma (n = 39) and paired normal breast from breast cancer patients (n = 21) were obtained. Specimens were evaluated by immunohistochemistry, in situ hybridization, PCR and DNA sequencing for evidence of HCMV antigens and nucleic acids. Results We detected HCMV expression specifically in glandular epithelium in 17/27 (63%) of normal adult breast cases evaluated. In contrast, HCMV expression was evident in the neoplastic epithelium of 31/32 (97%) patients with ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDC) cases evaluated (p = 0.0009). Conclusions These findings are the first to demonstrate that persistent HCMV infection occurs in breast epithelium in a significant percentage of normal adult females. HCMV expression was also evident in neoplastic breast epithelium in a high percentage of normal and neoplastic breast tissues obtained from breast cancer patients, raising the possibility that viral infection may be involved in the neoplastic process. PMID:21429243

  18. In vivo epicardial force and strain characterisation in normal and MLP-knockout murine hearts.

    PubMed

    Michaelides, M; Georgiadou, S; Constantinides, C

    2015-07-01

    The study's objective is to quantify in vivo epicardial force and strain in the normal and transgenic myocardium using microsensors.Male mice (n = 39), including C57BL/6 (n = 26), 129/Sv (n = 5), wild-type (WT) C57  ×  129Sv (n = 5), and muscle LIM protein (MLP) knock-out (n = 3), were studied under 1.5% isoflurane anaesthesia. Microsurgery allowed the placement of two piezoelectric crystals at longitudinal epicardial loci at the basal, middle, and apical LV regions, and the independent (and/or concurrent) placement of a cantilever force sensor. The findings demonstrate longitudinal contractile and relaxation strains that ranged between 4.8-9.3% in the basal, middle, and apical regions of C57BL/6 mice, and in the mid-ventricular regions of 129/Sv, WT, and MLP mice. Measured forces ranged between 3.1-8.9 mN. The technique's feasibility is also demonstrated in normal mice following afterload, occlusion-reperfusion challenges.Furthermore, the total mid-ventricular forces developed in MLP mice were significantly reduced compared to the WT controls (5.9  ±  0.4 versus 8.9  ±  0.2 mN, p < 0.0001), possibly owing to the fibrotic and stiffer myocardium. No significant strain differences were noted between WT and MLP mice.The possibility of quantifying in vivo force and strain from the normal murine heart is demonstrated with a potential usefulness in the characterisation of transgenic and diseased mice, where regional myocardial function may be significantly altered.

  19. Myocardial muscarinic receptor upregulation and normal response to isoproterenol in denervated hearts by familial amyloid polyneuropathy.

    PubMed

    Delahaye, N; Le Guludec, D; Dinanian, S; Delforge, J; Slama, M S; Sarda, L; Dollé, F; Mzabi, H; Samuel, D; Adams, D; Syrota, A; Merlet, P

    2001-12-11

    Patients with familial amyloid polyneuropathy, a rare hereditary form of amyloidosis, have progressive autonomic neuropathy. The disease usually does not induce heart failure but is associated with sudden death, conduction disturbances, and an increased risk of complications during anesthesia. Although cardiac sympathetic denervation has been clearly demonstrated, the postsynaptic status of the cardiac autonomic nervous system remains unelucidated. Twenty-one patients were studied (age, 39+/-11 years; normal coronary arteries; left ventricular ejection fraction 68+/-9%). To evaluate the density and affinity constants of myocardial muscarinic receptors, PET with (11)C-MQNB (methylquinuclidinyl benzilate), a specific hydrophilic antagonist, was used. Cardiac beta-receptor functional efficiency was studied by the heart rate (HR) response to intravenous infusion of isoproterenol (5 minutes after 2 mg of atropine, 5, 10, and 15 ng/kg per minute during 5 minutes per step). The mean muscarinic receptor density was higher in patients than in control subjects (B'(max), 35.5+/-8.9 versus 26.1+/-6.7 pmol/mL, P=0.003), without change in receptor affinity. The increase in HR after injection of atropine as well as of MQNB was lower in patients compared with control subjects despite a similar basal HR (DeltaHR after atropine, 11+/-21% versus 62+/-17%; P<0.001), consistent with parasympathetic denervation. Incremental infusion of isoproterenol induced a similar increase in HR in patients and control subjects. Cardiac autonomic denervation in familial amyloid polyneuropathy results in an upregulation of myocardial muscarinic receptors but without change in cardiac beta-receptor responsiveness to catecholamines.

  20. Phosphate metabolite concentrations and ATP hydrolysis potential in normal and ischaemic hearts

    PubMed Central

    Wu, Fan; Zhang, Eric Y; Zhang, Jianyi; Bache, Robert J; Beard, Daniel A

    2008-01-01

    To understand how cardiac ATP and CrP remain stable with changes in work rate – a phenomenon that has eluded mechanistic explanation for decades – data from 31phosphate-magnetic resonance spectroscopy (31P-MRS) are analysed to estimate cytoplasmic and mitochondrial phosphate metabolite concentrations in the normal state, during high cardiac workstates, during acute ischaemia and reactive hyperaemic recovery. Analysis is based on simulating distributed heterogeneous oxygen transport in the myocardium integrated with a detailed model of cardiac energy metabolism. The model predicts that baseline myocardial free inorganic phosphate (Pi) concentration in the canine myocyte cytoplasm – a variable not accessible to direct non-invasive measurement – is approximately 0.29 mm and increases to 2.3 mm near maximal cardiac oxygen consumption. During acute ischaemia (from ligation of the left anterior descending artery) Pi increases to approximately 3.1 mm and ATP consumption in the ischaemic tissue is reduced quickly to less than half its baseline value before the creatine phosphate (CrP) pool is 18% depleted. It is determined from these experiments that the maximal rate of oxygen consumption of the heart is an emergent property and is limited not simply by the maximal rate of ATP synthesis, but by the maximal rate at which ATP can be synthesized at a potential at which it can be utilized. The critical free energy of ATP hydrolysis for cardiac contraction that is consistent with these findings is approximately −63.5 kJ mol−1. Based on theoretical findings, we hypothesize that inorganic phosphate is both the primary feedback signal for stimulating oxidative phosphorylation in vivo and also the most significant product of ATP hydrolysis in limiting the capacity of the heart to hydrolyse ATP in vivo. Due to the lack of precise quantification of Piin vivo, these hypotheses and associated model predictions remain to be carefully tested experimentally. PMID:18617566

  1. Effect of Nebivolol on MIBG Parameters and Exercise in Heart Failure with Normal Ejection Fraction.

    PubMed

    Messias, Leandro Rocha; Ferreira, Aryanne Guimarães; Miranda, Sandra Marina Ribeiro de; Teixeira, José Antônio Caldas; Azevedo, Jader Cunha de; Messias, Ana Carolina Nader Vasconcelos; Maróstica, Elisabeth; Mesquita, Claudio Tinoco

    2016-05-01

    More than 50% of the patients with heart failure have normal ejection fraction (HFNEF). Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and cardiopulmonary exercise test (CPET) are prognostic markers in HFNEF. Nebivolol is a beta-blocker with vasodilating properties. To evaluate the impact of nebivolol therapy on CPET and123I-MIBG scintigraphic parameters in patients with HFNEF. Twenty-five patients underwent 123I-MIBG scintigraphy to determine the washout rate and early and late heart-to-mediastinum ratios. During the CPET, we analyzed the systolic blood pressure (SBP) response, heart rate (HR) during effort and recovery (HRR), and oxygen uptake (VO2). After the initial evaluation, we divided our cohort into control and intervention groups. We then started nebivolol and repeated the tests after 3 months. After treatment, the intervention group showed improvement in rest SBP (149 mmHg [143.5-171 mmHg] versus 135 mmHg [125-151 mmHg, p = 0.016]), rest HR (78 bpm [65.5-84 bpm] versus 64.5 bpm [57.5-75.5 bpm, p = 0.028]), peak SBP (235 mmHg [216.5-249 mmHg] versus 198 mmHg [191-220.5 mmHg], p = 0.001), peak HR (124.5 bpm [115-142 bpm] versus 115 bpm [103.7-124 bpm], p= 0.043), HRR on the 1st minute (6.5 bpm [4.75-12.75 bpm] versus 14.5 bpm [6.7-22 bpm], p = 0.025) and HRR on the 2nd minute (15.5 bpm [13-21.75 bpm] versus 23.5 bpm [16-31.7 bpm], p = 0.005), but no change in peak VO2 and 123I-MIBG scintigraphic parameters. Despite a better control in SBP, HR during rest and exercise, and improvement in HRR, nebivolol failed to show a positive effect on peak VO2 and 123I-MIBG scintigraphic parameters. The lack of effect on adrenergic activity may be the cause of the lack of effect on functional capacity.

  2. Autophagy in Normal and Abnormal Early Human Pregnancies.

    PubMed

    Avagliano, Laura; Terraneo, Laura; Virgili, Eleonora; Martinelli, Carla; Doi, Patrizia; Samaja, Michele; Bulfamante, Gaetano Pietro; Marconi, Anna Maria

    2015-07-01

    Autophagy is an inducible catabolic process by which cells degrade and recycle materials to survive stress, starvation, and hypoxia. The aim of this study was to evaluate autophagy at the fetal-maternal interface, to assess autophagy involvement during the early phase of human gestation, and to explore autophagic modification in case of early abnormal pregnancy outcome. Specimens were collected from first-trimester normal gestations undergoing legal termination of pregnancy and first-trimester sporadic spontaneous miscarriages. Autophagy was studied in villous and decidual samples by transmission electron microscopy, immunohistochemistry, immunofluorescence, and Western blotting. Autophagy markers were found in cytotrophoblast, syncytiotrophoblast, extravillous trophoblast, and decidual stromal cells. Autophagy is physiologically involved in early normal gestation. Compared with normal pregnancy, spontaneous miscarriage presents an increase in autophagy expression in villous specimens due to an increment in concentration of autophagic vacuole in syncytiotrophoblast, suggesting a cytoprotective mechanism of the cells to respond to microenvironmental challenge. © The Author(s) 2014.

  3. Raman spectroscopic identification of normal and malignant human stomach cells

    NASA Astrophysics Data System (ADS)

    Yang, Jipeng; Guo, Jianyu; Wu, Liangping; Sun, Zhenrong; Cai, Weiying; Wang, Zugeng

    2005-12-01

    Micro-Raman spectroscopy is employed to identify the normal and malignant human stomach cells. For the cancer cell, the reduced intensity of the Raman peak at 1250 cm^(-1) indicates that the protein secondary structure transforms from ?-sheet or disordered structures to ?-helical, while the increased intensity of the symmetric PO2 stretching vibration mode at 1094 cm^(-1) shows the increased DNA content. The ratio of the intensity at 1315 cm^(-1) to that at 1340 cm^(-1) reduces from 1.8 for the normal cell to 1.1 for the cancer cell in the course of canceration, and the ratio of the intensity at 1655 cm^(-1) to that at 1450 cm^(-1) increases from 1.00 for the cancer cell to 1.26 for the normal cell which indicates that the canceration of stomach cell may induce saturation of the lipid chain.

  4. The human renal lymphatics under normal and pathological conditions

    PubMed Central

    Ishikawa, Y; Akasaka, Y; Kiguchi, H; Akishima-Fukasawa, Y; Hasegawa, T; Ito, K; Kimura-Matsumoto, M; Ishiguro, S; Morita, H; Sato, S; Soh, S; Ishii, T

    2006-01-01

    Ishikawa Y, Akasaka Y, Kiguchi H, Akishima-Fukasawa Y, Hasegawa T, Ito K, Kimura-Matsumoto M, Ishiguro S, Morita H, Sato S, Soh S & Ishii T (2006) Histopathology 49, 265–273 The human renal lymphatics under normal and pathological conditions Aims The renal lymphatics have not been fully documented in humans. The aim of this study was to clarify the morphology of the human renal lymphatic system under normal and pathological conditions by immunohistochemistry using anti-D2-40 antibody. Methods and results Normal and pathological renal tissues obtained at autopsy as well as nephrectomy specimens with renal cell carcinoma (RCC) were used. Thin sections were immunostained with antibodies against D2-40 and CD31. In normal kidney, D2-40+ lymphatics were abundant in the interstitium around the interlobar and arcuate arteries/veins but sporadic in those around the glomeruli or between the tubules in the cortex. A few lymphatics contained erythrocytes in their lumina. Lymphatics were seldom present in the medulla. In RCC cases, lymphatics were evident at the tumour margin, whereas CD31+ capillaries were abundant throughout the tumour and lymphatics were increased in the fibrous interstitium around the tumour. Lymphatic invasion by RCC cells was also detectable. D2-40+ lymphatics were evident in other pathological conditions and end-stage kidney had a denser lymphatic distribution than normal kidney. Conclusions Lymphatics are abundant around the arteries/veins and are also present in the renal cortex and medulla. D2-40 immunostaining is helpful for investigating the pathophysiological role of renal lymphatics. PMID:16918973

  5. The human renal lymphatics under normal and pathological conditions.

    PubMed

    Ishikawa, Y; Akasaka, Y; Kiguchi, H; Akishima-Fukasawa, Y; Hasegawa, T; Ito, K; Kimura-Matsumoto, M; Ishiguro, S; Morita, H; Sato, S; Soh, S; Ishii, T

    2006-09-01

    The renal lymphatics have not been fully documented in humans. The aim of this study was to clarify the morphology of the human renal lymphatic system under normal and pathological conditions by immunohistochemistry using anti-D2-40 antibody. Normal and pathological renal tissues obtained at autopsy as well as nephrectomy specimens with renal cell carcinoma (RCC) were used. Thin sections were immunostained with antibodies against D2-40 and CD31. In normal kidney, D2-40+ lymphatics were abundant in the interstitium around the interlobar and arcuate arteries/veins but sporadic in those around the glomeruli or between the tubules in the cortex. A few lymphatics contained erythrocytes in their lumina. Lymphatics were seldom present in the medulla. In RCC cases, lymphatics were evident at the tumour margin, whereas CD31+ capillaries were abundant throughout the tumour and lymphatics were increased in the fibrous interstitium around the tumour. Lymphatic invasion by RCC cells was also detectable. D2-40+ lymphatics were evident in other pathological conditions and end-stage kidney had a denser lymphatic distribution than normal kidney. Lymphatics are abundant around the arteries/veins and are also present in the renal cortex and medulla. D2-40 immunostaining is helpful for investigating the pathophysiological role of renal lymphatics.

  6. Performance of Junctional Tourniquets in Normal Human Volunteers

    DTIC Science & Technology

    2014-12-01

    PERFORMANCE OF JUNCTIONAL TOURNIQUETS IN NORMAL HUMAN VOLUNTEERS John F. Kragh, Jr., MD, Russ S. Kotwal, MD, MPH, Andrew P. Cap, MD, PhD, James K...Cancio, MD ABSTRACT Background. Inguinal bleeding is a common and pre- ventable cause of death on the battlefield. Four FDA-cleared junctional ...tourniquets (Combat Ready Clamp [CRoC], Ab- dominal Aortic and Junctional Tourniquet [AAJT], Junc- tional Emergency Treatment Tool [JETT], and SAM Junc- tional

  7. Second heart field and the development of the outflow tract in human embryonic heart.

    PubMed

    Yang, Yan-Ping; Li, Hai-Rong; Cao, Xi-Mei; Wang, Qin-Xue; Qiao, Cong-Jin; Ya, Jing

    2013-04-01

    The second heart field (SHF) is indicated to contribute to the embryonic heart development. However, less knowledge is available about SHF development of human embryo due to the difficulty of collecting embryos. In this study, serial sections of human embryos from Carnegie stage 10 (CS10) to CS16 were stained with antibodies against Islet-1 (Isl-1), Nkx2.5, GATA4, myosin heavy chain (MHC) and α-smooth muscle actin (α-SMA) to observe spatiotemporal distribution of SHF and its contribution to the development of the arterial pole of cardiac tube. Our findings suggest that during CS10 to CS12, SHF of the human embryo is composed of the bilateral pharyngeal mesenchyme, the central mesenchyme of the branchial arch and splanchnic mesoderm of the pericardial cavity dorsal wall. With development, SHF translocates and consists of ventral pharyngeal mesenchyme and dorsal wall of the pericardial cavity. Hence, the SHF of human embryo shows a dynamic spatiotemporal distribution pattern. The formation of the Isl-1 positive condense cell prongs provides an explanation for the saddle structure formation at the distal pole of the outflow tract. In human embryo, the Isl-1 positive cells of SHF may contribute to the formation of myocardial outflow tract (OFT) and the septum during different development stages.

  8. Parallel computing simulation of electrical excitation and conduction in the 3D human heart.

    PubMed

    Di Yu; Dongping Du; Hui Yang; Yicheng Tu

    2014-01-01

    A correctly beating heart is important to ensure adequate circulation of blood throughout the body. Normal heart rhythm is produced by the orchestrated conduction of electrical signals throughout the heart. Cardiac electrical activity is the resulted function of a series of complex biochemical-mechanical reactions, which involves transportation and bio-distribution of ionic flows through a variety of biological ion channels. Cardiac arrhythmias are caused by the direct alteration of ion channel activity that results in changes in the AP waveform. In this work, we developed a whole-heart simulation model with the use of massive parallel computing with GPGPU and OpenGL. The simulation algorithm was implemented under several different versions for the purpose of comparisons, including one conventional CPU version and two GPU versions based on Nvidia CUDA platform. OpenGL was utilized for the visualization / interaction platform because it is open source, light weight and universally supported by various operating systems. The experimental results show that the GPU-based simulation outperforms the conventional CPU-based approach and significantly improves the speed of simulation. By adopting modern computer architecture, this present investigation enables real-time simulation and visualization of electrical excitation and conduction in the large and complicated 3D geometry of a real-world human heart.

  9. gamma. sub 2 -MSH immunoreactivity in the human heart

    SciTech Connect

    Ekman, R.; Bjartell, A.; Lisander, J.; Edvinsson, L. )

    1989-01-01

    In patients undergoing aorto-coronary by-pass surgery, we found a 26% arterial-venous difference of immunoreactive {gamma}{sub 2}-melanocytostimulating hormone (MSH), a proopiomelanocortin (POMC) derived peptide known to possess profound hemodynamic effects. These results prompted an investigation of the presence of {gamma}{sub 2}-MSH in the human heart. Using a two-step extraction procedure, regions of human hearts were examined by sensitive and specific radioimmunoassays to determine their {gamma}{sub 2}-MSH content. Mean ({plus minus} SEM) concentrations of 0.14 {plus minus} 0.023 pmol/g and 0.12 {plus minus} 0.017 were found in right atrium and right ventricle, respectively. High performance liquid chromatography indicated that 80-90 % of the total immunoreactivity eluted in a single sharp peak in a position identical to that of synthetic {gamma}{sub 2}-MSH.

  10. Normalization of cardiac substrate utilization and left ventricular hypertrophy precede functional recovery in heart failure regression.

    PubMed

    Byrne, Nikole J; Levasseur, Jody; Sung, Miranda M; Masson, Grant; Boisvenue, Jamie; Young, Martin E; Dyck, Jason R B

    2016-05-15

    Impaired cardiac substrate metabolism plays an important role in heart failure (HF) pathogenesis. Since many of these metabolic changes occur at the transcriptional level of metabolic enzymes, it is possible that this loss of metabolic flexibility is permanent and thus contributes to worsening cardiac function and/or prevents the full regression of HF upon treatment. However, despite the importance of cardiac energetics in HF, it remains unclear whether these metabolic changes can be normalized. In the current study, we investigated whether a reversal of an elevated aortic afterload in mice with severe HF would result in the recovery of cardiac function, substrate metabolism, and transcriptional reprogramming as well as determined the temporal relationship of these changes. Male C57Bl/6 mice were subjected to either Sham or transverse aortic constriction (TAC) surgery to induce HF. After HF development, mice with severe HF (% ejection fraction < 30) underwent a second surgery to remove the aortic constriction (debanding, DB). Three weeks following DB, there was a near complete recovery of systolic and diastolic function, and gene expression of several markers for hypertrophy/HF were returned to values observed in healthy controls. Interestingly, pressure-overload-induced left ventricular hypertrophy (LVH) and cardiac substrate metabolism were restored at 1-week post-DB, which preceded functional recovery. The regression of severe HF is associated with early and dramatic improvements in cardiac energy metabolism and LVH normalization that precede restored cardiac function, suggesting that metabolic and structural improvements may be critical determinants for functional recovery. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

  11. The relationship between resting heart rate variability and erectile tumescence among men with normal erectile function

    PubMed Central

    Harte, Christopher B.

    2013-01-01

    Introduction Individuals with erectile dysfunction have been shown to display lower heart rate variability (HRV), suggesting dysregulation of cardiac autonomic function. No studies have explored whether HRV is predictive of erectile response among men with clinically normal erectile function. Aim To examine associations between resting HRV and objective measures of genital response (i.e., resting penile circumference; erectile tumescence) and self-reported sexual function. Methods The sample comprised 59 male community volunteers (mean age = 20.15 years; SD = 2.52) selected from the control conditions of two previously published studies. Participants reported erectile function in the normal range (scoring ≥ 26 on the International Index of Erectile Function [IIEF]) and had no history of cardiovascular disease or myocardial infarct. During a laboratory visit, self-report, anthropometric, cardiovascular, and electrocardiographic data were assessed, as well as resting penile circumference and erectile tumescence in response to viewing an erotic film. Main Outcome Measures Resting penile responses, erectile tumescence (circumferential change via penile plethysmography), self-reported sexual function per the IIEF, and both time-domain (standard deviation of beat-to-beat [NN] intervals [SDNN], square root of the mean squared difference of successive NN intervals [RMSSD], and percent of NN intervals for which successive heartbeat intervals differed by at least 50 msec [pNN50]) and frequency-domain (low frequency [LF], high frequency [HF], LF/HF ratio) parameters of HRV were assessed. Results Higher resting HF power and lower resting LF/HF ratio were associated with greater erectile tumescence. There were marginally significant positive associations between mean NN interval and pNN50 and penile tumescence. HRV was not associated with self-reported sexual function or with resting penile circumference. Conclusions Results suggested that, among men without erectile

  12. A Public University's Defense of Free Expression: The Issues and Events in the Staging of "The Normal Heart."

    ERIC Educational Resources Information Center

    Smith, Ralph R.; Moore, Dale

    In 1989, some Springfield, Missouri residents demanded cancellation of the Southwest Missouri State University (SMSU) theater department's production of Larry Kramer's play, "The Normal Heart," which they alleged to be obscene. Opponents purchased newspaper advertisements which charged that the publicly funded production promoted a…

  13. The Sydney Heart Bank: improving translational research while eliminating or reducing the use of animal models of human heart disease.

    PubMed

    Dos Remedios, C G; Lal, S P; Li, A; McNamara, J; Keogh, A; Macdonald, P S; Cooke, R; Ehler, E; Knöll, R; Marston, S B; Stelzer, J; Granzier, H; Bezzina, C; van Dijk, S; De Man, F; Stienen, G J M; Odeberg, J; Pontén, F; Linke, W; van der Velden, J

    2017-08-14

    The Sydney Heart Bank (SHB) is one of the largest human heart tissue banks in existence. Its mission is to provide high-quality human heart tissue for research into the molecular basis of human heart failure by working collaboratively with experts in this field. We argue that, by comparing tissues from failing human hearts with age-matched non-failing healthy donor hearts, the results will be more relevant than research using animal models, particularly if their physiology is very different from humans. Tissue from heart surgery must generally be used soon after collection or it significantly deteriorates. Freezing is an option but it raises concerns that freezing causes substantial damage at the cellular and molecular level. The SHB contains failing samples from heart transplant patients and others who provided informed consent for the use of their tissue for research. All samples are cryopreserved in liquid nitrogen within 40 min of their removal from the patient, and in less than 5-10 min in the case of coronary arteries and left ventricle samples. To date, the SHB has collected tissue from about 450 failing hearts (>15,000 samples) from patients with a wide range of etiologies as well as increasing numbers of cardiomyectomy samples from patients with hypertrophic cardiomyopathy. The Bank also has hearts from over 120 healthy organ donors whose hearts, for a variety of reasons (mainly tissue-type incompatibility with waiting heart transplant recipients), could not be used for transplantation. Donor hearts were collected by the St Vincent's Hospital Heart and Lung transplantation team from local hospitals or within a 4-h jet flight from Sydney. They were flushed with chilled cardioplegic solution and transported to Sydney where they were quickly cryopreserved in small samples. Failing and/or donor samples have been used by more than 60 research teams around the world, and have resulted in more than 100 research papers. The tissues most commonly requested are

  14. Daily pattern of %VO2max and heart rates in normal and undernourished school children.

    PubMed

    Spurr, G B; Reina, J C

    1990-10-01

    The pattern of usage of the VO2max, expressed as %VO2max during ordinary school days, with minute-by-minute heart rate recording, was studied in 106 boys and 83 girls, 6-16 yr of age divided into three age groups (6-8, 10-12, and 14-16 yr), living under economically deprived conditions in Colombia and classified as nutritionally normal or marginally malnourished. In a 12-h period, the 12 groups of children spent, on the average, 7-10 h at less than 30% VO2max, 1.5-4 h at 30-50% VO2max, and an accumulated time of 20-60 min above 50% VO2max. The latter occurred in short bursts rather than during sustained periods. There was a statistically significant but small decrease (approximately -3%) in the average 12 h %VO2max with age but no effects of sex or nutritional status. The overall average was about 25% VO2max in all groups. The data may suggest the existence of the regulation of physical activity to some level easily sustainable for long periods. Expressing the data as 30 min averages during 5 h of school and 5 h of free-time activity allows for the possibility of seeing group differences during shorter periods of time. This may prove useful in exercise training programs and studies of effort in the workplace.

  15. Successful Orthotopic Heart Transplantation and Immunosuppressive Management in 2 Human Immunodeficiency Virus-Seropositive Patients.

    PubMed

    Conte, Antonio Hernandez; Kittleson, Michelle M; Dilibero, Deanna; Hardy, W David; Kobashigawa, Jon A; Esmailian, Fardad

    2016-02-01

    Few orthotopic heart transplantations have been performed in patients infected with the human immunodeficiency virus since the first such case was reported in 2001. Since that time, advances in highly active antiretroviral therapy have resulted in potent and durable suppression of the causative human immunodeficiency virus-accompanied by robust immune reconstitution, reversal of previous immunodeficiency, a marked decrease in opportunistic and other infections, and near-normal long-term survival. Although human immunodeficiency virus infection is not an absolute contraindication, few centers in the United States and Canada have performed heart transplantations in this patient population; these patients have been de facto excluded from this procedure in North America. Re-evaluation of the reasons for excluding these patients from cardiac transplantation is warranted in light of such significant advances in antiretroviral therapy. This case report documents successful orthotopic heart transplantation in 2 patients infected with human immunodeficiency virus, and we describe their antiretroviral therapy and immunosuppressive management challenges. Both patients were doing well without sequelae 43 and 38 months after transplantation.

  16. Successful Orthotopic Heart Transplantation and Immunosuppressive Management in 2 Human Immunodeficiency Virus–Seropositive Patients

    PubMed Central

    Kittleson, Michelle M.; Dilibero, Deanna; Hardy, W. David; Kobashigawa, Jon A.; Esmailian, Fardad

    2016-01-01

    Few orthotopic heart transplantations have been performed in patients infected with the human immunodeficiency virus since the first such case was reported in 2001. Since that time, advances in highly active antiretroviral therapy have resulted in potent and durable suppression of the causative human immunodeficiency virus—accompanied by robust immune reconstitution, reversal of previous immunodeficiency, a marked decrease in opportunistic and other infections, and near-normal long-term survival. Although human immunodeficiency virus infection is not an absolute contraindication, few centers in the United States and Canada have performed heart transplantations in this patient population; these patients have been de facto excluded from this procedure in North America. Re-evaluation of the reasons for excluding these patients from cardiac transplantation is warranted in light of such significant advances in antiretroviral therapy. This case report documents successful orthotopic heart transplantation in 2 patients infected with human immunodeficiency virus, and we describe their antiretroviral therapy and immunosuppressive management challenges. Both patients were doing well without sequelae 43 and 38 months after transplantation. PMID:27047290

  17. Noninvasive evaluation of sympathetic nervous system in human heart by positron emission tomography

    SciTech Connect

    Schwaiger, M.; Kalff, V.; Rosenspire, K.; Haka, M.S.; Molina, E.; Hutchins, G.D.; Deeb, M.; Wolfe, E. Jr.; Wieland, D.M. )

    1990-08-01

    The noninvasive functional characterization of the cardiac sympathetic nervous system by imaging techniques may provide important pathophysiological information in various cardiac disease states. Hydroxyephedrine labeled with carbon 11 has been developed as a new catecholamine analogue to be used in the in vivo evaluation of presynaptic adrenergic nerve terminals by positron emission tomography (PET). To determine the feasibility of this imaging approach in the human heart, six normal volunteers and five patients with recent cardiac transplants underwent dynamic PET imaging after intravenous injection of 20 mCi (11C)hydroxyephedrine. Blood and myocardial tracer kinetics were assessed using a regions-of-interest approach. In normal volunteers, blood 11C activity cleared rapidly, whereas myocardium retained 11C activity with a long tissue half-life. Relative tracer retention in the myocardium averaged 79 +/- 31% of peak activity at 60 minutes after tracer injection. The heart-to-blood 11C activity ratio exceeded 6:1 as soon as 30 minutes after tracer injection, yielding excellent image quality. Little regional variation of tracer retention was observed, indicating homogeneous sympathetic innervation throughout the left ventricle. In the transplant recipients, myocardial (11C)hydroxyephedrine retention at 60 minutes was significantly less (-82%) than that of normal volunteers, indicating only little non-neuronal binding of the tracer in the denervated human heart. Thus, (11C)hydroxyephedrine, in combination with dynamic PET imaging, allows the noninvasive delineation of myocardial adrenergic nerve terminals. Tracer kinetic modeling may permit quantitative assessment of myocardial catecholamine uptake, which will in turn provide insights into the effects of various disease processes on the neuronal integrity of the heart.

  18. Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo.

    PubMed

    Herrmann, Julia E; Heale, Jason; Bieraugel, Mike; Ramos, Meg; Fisher, Robyn L; Vickers, Alison E M

    2014-01-15

    Human response to isoproterenol induced cardiac injury was evaluated by gene and protein pathway changes in human heart slices, and compared to rat heart slices and rat heart in vivo. Isoproterenol (10 and 100μM) altered human and rat heart slice markers of oxidative stress (ATP and GSH) at 24h. In this in vivo rat study (0.5mg/kg), serum troponin concentrations increased with lesion severity, minimal to mild necrosis at 24 and 48h. In the rat and the human heart, isoproterenol altered pathways for apoptosis/necrosis, stress/energy, inflammation, and remodeling/fibrosis. The rat and human heart slices were in an apoptotic phase, while the in vivo rat heart exhibited necrosis histologically and further progression of tissue remodeling. In human heart slices genes for several heat shock 70kD members were altered, indicative of stress to mitigate apoptosis. The stress response included alterations in energy utilization, fatty acid processing, and the up-regulation of inducible nitric oxide synthase, a marker of increased oxidative stress in both species. Inflammation markers linked with remodeling included IL-1α, Il-1β, IL-6 and TNFα in both species. Tissue remodeling changes in both species included increases in the TIMP proteins, inhibitors of matrix degradation, the gene/protein of IL-4 linked with cardiac fibrosis, and the gene Ccl7 a chemokine that induces collagen synthesis, and Reg3b a growth factor for cardiac repair. This study demonstrates that the initial human heart slice response to isoproterenol cardiac injury results in apoptosis, stress/energy status, inflammation and tissue remodeling at concentrations similar to that in rat heart slices.

  19. Super Normal Vector for Human Activity Recognition with Depth Cameras.

    PubMed

    Yang, Xiaodong; Tian, YingLi

    2017-05-01

    The advent of cost-effectiveness and easy-operation depth cameras has facilitated a variety of visual recognition tasks including human activity recognition. This paper presents a novel framework for recognizing human activities from video sequences captured by depth cameras. We extend the surface normal to polynormal by assembling local neighboring hypersurface normals from a depth sequence to jointly characterize local motion and shape information. We then propose a general scheme of super normal vector (SNV) to aggregate the low-level polynormals into a discriminative representation, which can be viewed as a simplified version of the Fisher kernel representation. In order to globally capture the spatial layout and temporal order, an adaptive spatio-temporal pyramid is introduced to subdivide a depth video into a set of space-time cells. In the extensive experiments, the proposed approach achieves superior performance to the state-of-the-art methods on the four public benchmark datasets, i.e., MSRAction3D, MSRDailyActivity3D, MSRGesture3D, and MSRActionPairs3D.

  20. Human peripheral nerve macrophages in normal and pathological conditions.

    PubMed

    Bonetti, B; Monaco, S; Giannini, C; Ferrari, S; Zanusso, G; Rizzuto, N

    1993-09-01

    We investigated, by immunocytochemistry and immune electron microscopy, the immunophenotype, morphology and functional properties of human peripheral nervous system (PNS) macrophages (M phi) under normal and pathological conditions. Endoneurial M phi disclosed an elongated, ramified morphology, with the main processes oriented along the major axis of nerve fibers; they shared several lineage-related and functional markers with monocyte/macrophages and central nervous system (CNS) microglia, including CD4, CR3, CR4 and FcRIII. In addition, basal expression of HLA-DR antigens was exclusively confined to M phi in normal PNS. In the course of unrelated pathological conditions, resident M phi underwent activation with transformation to hypertrophic cells or foamy phagocytes and up-regulation of the markers expressed in normal conditions; new expression of a macrophagic antigen was detected on activated M phi. In different neuropathies, HLA-DR expression was also detected on non-myelin forming Schwann cells with ultrastructural features indicative of denervation. The present results demonstrate that the human PNS is provided with an intrinsic population of immunocompetent and potentially phagocytic M phi, which represent the peripheral counterpart of CNS microglia.

  1. Human factors of flight-deck checklists: The normal checklist

    NASA Technical Reports Server (NTRS)

    Degani, Asaf; Wiener, Earl L.

    1991-01-01

    Although the aircraft checklist has long been regarded as the foundation of pilot standardization and cockpit safety, it has escaped the scrutiny of the human factors profession. The improper use, or the non-use, of the normal checklist by flight crews is often cited as the probable cause or at least a contributing factor to aircraft accidents. An attempt is made to analyze the normal checklist, its functions, format, design, length, usage, and the limitations of the humans who must interact with it. The development of the checklist from the certification of a new model to its delivery and use by the customer are discussed. The influence of the government, particularly the FAA Principle Operations Inspector, the manufacturer's philosophy, the airline's culture, and the end user, the pilot, influence the ultimate design and usage of this device. The effects of airline mergers and acquisitions on checklist usage and design are noted. In addition, the interaction between production pressures and checklist usage and checklist management are addressed. Finally, a list of design guidelines for normal checklists is provided.

  2. Gene profile identifies zinc transporters differentially expressed in normal human organs and human pancreatic cancer.

    PubMed

    Yang, J; Zhang, Y; Cui, X; Yao, W; Yu, X; Cen, P; Hodges, S E; Fisher, W E; Brunicardi, F C; Chen, C; Yao, Q; Li, M

    2013-03-01

    Deregulated expression of zinc transporters was linked to several cancers. However, the detailed expression profile of all human zinc transporters in normal human organs and in human cancer, especially in pancreatic cancer is not available. The objectives of this study are to investigate the complete expression patterns of 14 ZIP and 10 ZnT transporters in a large number of normal human organs and in human pancreatic cancer tissues and cell lines. We examined the expression patterns of ZIP and ZnT transporters in 22 different human organs and tissues, 11 pairs of clinical human pancreatic cancer specimens and surrounding normal/benign tissues, as well as 10 established human pancreatic cancer cell lines plus normal human pancreatic ductal epithelium (HPDE) cells, using real time RT-PCR and immunohistochemistry. The results indicate that human zinc transporters have tissue specific expression patterns, and may play different roles in different organs or tissues. Almost all the ZIPs except for ZIP4, and most ZnTs were down-regulated in human pancreatic cancer tissues compared to the surrounding benign tissues. The expression patterns of individual ZIPs and ZnTs are similar among different pancreatic cancer lines. Those results and our previous studies suggest that ZIP4 is the only zinc transporter that is significantly up-regulated in human pancreatic cancer and might be the major zinc transporter that plays an important role in pancreatic cancer growth. ZIP4 might serve as a novel molecular target for pancreatic cancer diagnosis and therapy.

  3. High Contrast Ultrafast Imaging of the Human Heart

    PubMed Central

    Papadacci, Clement; Pernot, Mathieu; Couade, Mathieu; Fink, Mathias; Tanter, Mickael

    2014-01-01

    Non-invasive ultrafast imaging for human cardiac applications is a big challenge to image intrinsic waves such as electromechanical waves or remotely induced shear waves in elastography imaging techniques. In this paper we propose to perform ultrafast imaging of the heart with adapted sector size by using diverging waves emitted from a classical transthoracic cardiac phased array probe. As in ultrafast imaging with plane wave coherent compounding, diverging waves can be summed coherently to obtain high-quality images of the entire heart at high frame rate in a full field-of-view. To image shear waves propagation at high SNR, the field-of-view can be adapted by changing the angular aperture of the transmitted wave. Backscattered echoes from successive circular wave acquisitions are coherently summed at every location in the image to improve the image quality while maintaining very high frame rates. The transmitted diverging waves, angular apertures and subapertures size are tested in simulation and ultrafast coherent compounding is implemented on a commercial scanner. The improvement of the imaging quality is quantified in phantom and in vivo on human heart. Imaging shear wave propagation at 2500 frame/s using 5 diverging waves provides a strong increase of the Signal to noise ratio of the tissue velocity estimates while maintaining a high frame rate. Finally, ultrafast imaging with a 1 to 5 diverging waves is used to image the human heart at a frame rate of 900 frames/s over an entire cardiac cycle. Thanks to spatial coherent compounding, a strong improvement of imaging quality is obtained with a small number of transmitted diverging waves and a high frame rate, which allows imaging the propagation of electromechanical and shear waves with good image quality. PMID:24474135

  4. Lysyl oxidase activity in human normal skins and postburn scars.

    PubMed

    Hayakawa, T; Hino, N; Fuyamada, H; Nagatsu, T; Aoyama, H

    1976-09-06

    Lysyl oxidase activity of human normal skins derived from the frontal thighs of 33 subjects showed large variations and the mean value was 11 455 +/- 7 172 (S.D.) cpm/g of wet weight tissue. The age of lesion affected the lysyl oxidase activity in postburn scars. Granulation tissues showed a fairly low activity; however, the activity increased sharply within 2--3 months, and reached a significantly higher value than that of normal skin. The high level of activity continued for up to 2--3 years, then gradually decreased to normal range after 5 years or so. Lysyl oxidase activity was detected only after 4 M urea treatment of tissues. Benzylamine oxidase activity also showed large variations in both normal skins and postburn scars, with mean values of: 0.128 +/- 0.077 (S.D.) and 0.145 +/- 0.090 (S.D.) mmol/g of wet weight/h, respectively. No correlation was observed between lysyl oxidase and benzylamine oxidase activities. The granulation tissues showed significantly high values of benzylamine oxidase activity in contrast to the low values of lysyl oxidase activity.

  5. Characterization of integrin receptors in normal and neoplastic human brain.

    PubMed Central

    Paulus, W.; Baur, I.; Schuppan, D.; Roggendorf, W.

    1993-01-01

    We studied the immunohistochemical expression of integrin alpha and beta chains in the normal and neoplastic human brain. Normal astrocytes expressed alpha 2, alpha 3, alpha 6, beta 1, and beta 4 chains in some areas facing major interstitial tissues, but they were consistently negative for the other integrins examined (alpha 4, alpha 5, alpha V, alpha L, alpha M, alpha X, beta 2, beta 3). Neoplastic astrocytes in vivo and in vitro showed increased expression of alpha 3 and beta 1, and some also of alpha 5, alpha V, beta 3, and beta 4. Neoexpression of alpha 4 and reduced levels of beta 4 were detected in glioblastoma vascular proliferations compared with normal endothelial cells. Oligodendroglioma, ependymoma, choroid plexus papilloma, pituitary adenoma, and meningioma cells showed the same integrin pattern as their normal counterparts. Adhesion assays using the astrocytoma cell lines U-138 MG and U-373 MG revealed strong attachment to collagen types I to VI and undulin, which was inhibited by antibodies to beta 1, but not by those to alpha 2, alpha 3, alpha 6, and alpha V. We conclude that astrocytomas show increased levels or neoexpression of various integrins and strong attachment to various extracellular matrix components, which appears to be almost exclusively mediated by beta 1-integrins. Images Figure 1 PMID:8317546

  6. Comparison of Immune Profiles in Fetal Hearts with Idiopathic Dilated Cardiomyopathy, Maternal Autoimmune-Associated Dilated Cardiomyopathy and the Normal Fetus.

    PubMed

    Nield, Lynne E; von Both, Ingo; Popel, Najla; Strachan, Kate; Manlhiot, Cedric; Shannon, Patrick; McCrindle, Brian W; Atkinson, Adelle; Miner, Steven E S; Jaeggi, Edgar T; Taylor, Glenn P

    2016-02-01

    The etiology of idiopathic dilated cardiomyopathy (iDCM) remains unknown. Immune therapies have improved outcome in fetuses with DCM born to mothers with autoimmune disease (aDCM). The purpose of this retrospective study was to compare the myocardial B and T cell profiles in fetuses and neonates with idiopathic DCM (iDCM) versus autoimmune-mediated DCM (aDCM) and to describe the normal cell maturation within the human fetal myocardium. Of 60 fetal autopsy cases identified from institutional databases, 10 had aDCM (18-38 weeks), 12 iDCM (19-37 weeks) and 38 had normal hearts (11-40 weeks). Paraffin-embedded myocardium sections were stained for all lymphocyte (CD45), B cells (CD20, CD79a), T cells (CD3, CD4, CD7, CD8) and monocyte (CD68) surface markers. Two independent, blinded cell counts were performed. Normal hearts expressed all B and T cell markers in a bimodal fashion, with peaks at 22 and 37 weeks of gestation. The aDCM cohort was most distinct from normal hearts, with less overall T cell markers [EST -9.1 (2.6) cells/mm(2), p = 0.001], CD4 [EST -2.0 (0.6), p = 0.001], CD3 [EST -3.9 (1.0), p < 0.001], CD7 [EST -3.0 (1.1), p = 0.01] overall B cell markers [EST -4.9 (1.8), p = 0.01] and CD79a counts [EST -2.3 (0.9), p = 0.01]. The iDCM group had less overall B cell markers [EST -4.0 (1.8), p = 0.03] and CD79a [EST -1.7 (0.9), p = 0.05], but no difference in T cell markers. Autoimmune-mediated DCM fetuses have less B and T cell markers, whereas iDCM fetuses have less B cell markers compared with normal fetal hearts. The fetal immune system may play a role in the normal development of the heart and evolution of dilated cardiomyopathy.

  7. The patterns and expression of KDR in normal tissues of human internal organs.

    PubMed

    Huang, Jianfei; Zhu, Huijun; Wang, Xudong; Tang, Qi; Huang, Hua; Wu, Kerong; Zhu, Jin; Feng, Zhenqing; Shi, Gongshen

    2011-12-01

    KDR has been implicated for playing an important role in the formation of new blood vessels and in solid tumor growth. It was considered as one of the most important regulators of angiogenesis and a key target in anticancer treatment. In the present study, we characterized KDR mRNA and protein expression in normal tissues of perinatal and adult tissues using One-step Real-Time RT-PCR and immunohistochemistry with a self-made anti-KDR antibody. The expression of KDR mRNA and protein in perinatal internal organs were all higher than in adult organs including brain, kidney, liver, lung and heart, respectively. KDR protein was presented in the cell plasma membrane of human internal tissues. The expression of KDR protein was raised in macrophage of spleen, and decreased in neurons of brain, myocardium, bronchial epithelial cells and alveolar epithelial cell, proximal and distal tubules cells, and hepatic cells with the maturity process of human organs. Notably, the order of KDR protein expression from highest to lowest is as follows: brain, liver, heart, kidney, and lung in adult tissues with statistically significant. It follows that how to balance the potential therapeutic side effect with human internal organs in targeted therapy of over-expressing KDR tumor.

  8. Influence of the heart rate on mean circumferential shortening velocity: echocardiographic study of 183 normal subjects.

    PubMed

    Mangiarotti, R; Martinotti, R; Monzani, V; Sardella, F; Pierini, A; Pastori, M; Randazzo, A

    1986-01-01

    Echocardiography was used to explore the influence of independent variables (age, body surface area and heart rate) on the mean circumferential shortening velocity (MVCF) in 183 healthy subjects. Multiple stepwise regression analysis shows that heart rate is the only variable of the three just mentioned that influences MVCF. A regression equation is evolved and proposed as an index of MVCF correction for varying heart rates.

  9. The cardio-renal-anemia syndrome in elderly subjects with heart failure and a normal ejection fraction: a comparison with heart failure and low ejection fraction.

    PubMed

    Cohen, Rose S; Mubashir, Asyia; Wajahat, Raja; Mani, Susan; Hummel, Scott; Maurer, Mathew S

    2006-01-01

    The prevalence and severity of anemia and renal dysfunction in heart failure patients with a normal ejection fraction (HFNEF) is uncharacterized. Two hundred eighty-five consecutive patients admitted to a community hospital with heart failure were stratified by the presence or absence of anemia and a normal or reduced ejection fraction. Comparisons of clinical variables were performed. In this sample, 62% of subjects were anemic, with no difference between those with a normal and a reduced ejection fraction (63% vs. 61%). Anemic HFNEF subjects had a lower glomerular filtration rate (37 +/- 21 mL/min vs. 52 +/- 35 mL/min; p < 0.05) and more severe self-reported symptom scores than nonanemic HFNEF subjects. Multivariate analysis confirmed the association of renal dysfunction and anemia. The authors conclude that the degree and magnitude of anemia in elderly inpatients with heart failure does not differ by ejection fraction. Worse symptoms and more severe renal dysfunction were seen in HFNEF subjects with anemia than in HFNEF subjects without anemia.

  10. Effects of ozone in normal human epidermal keratinocytes.

    PubMed

    McCarthy, James T; Pelle, Edward; Dong, Kelly; Brahmbhatt, Krupa; Yarosh, Dan; Pernodet, Nadine

    2013-05-01

    Ozone is a tropospheric pollutant that can form at ground level as a result of an interaction between sunlight and hydrocarbon engine emissions. As ozone is an extremely oxidative reaction product, epidermal cells are in the outer layer of defense against ozone. We exposed normal human epidermal keratinocytes (NHEK) to concentrations of ozone that have been measured in cities and assayed for its effects. Hydrogen peroxide and IL-1α levels both increased while ATP levels decreased. We found a decrease in the NAD-dependent histone deacetylase, sirtuin 3. Lastly, we found that ozone increased DNA damage as evaluated by Comet assay. Taken together, our results show increased damage to NHEK that will ultimately impair normal cellular function as a result of an environmentally relevant ozone exposure. © 2013 John Wiley & Sons A/S.

  11. Effects of water immersion on plasma catecholamines in normal humans

    NASA Technical Reports Server (NTRS)

    Epstein, M.; Johnson, G.; Denunzio, A. G.

    1983-01-01

    An investigation was conducted in order to determine whether water immersion to the neck (NI) alters plasma catecholamines in normal humans. Eight normal subjects were studied during a seated control study (C) and during 4 hr of NI, and the levels of norepinephrine (NE) and epinephrine (E) as determined by radioenzymatic assay were measured hourly. Results show that despite the induction of a marked natriuresis and diuresis indicating significant central hypervolemia, NI failed to alter plasma NE or E levels compared with those of either C or the corresponding prestudy 1.5 hr. In addition, the diuresis and natriuresis was found to vary independently of NE. These results indicate that the response of the sympathetic nervous system to acute volume alteration may differ from the reported response to chronic volume expansion.

  12. Optical Properties of Human Cancer and Normal Cells

    NASA Astrophysics Data System (ADS)

    Sander, Christopher; Sun, Nan; Johnson, Jeffrey; Stack, Sharon; Tanner, Carol; Ruggiero, Steven

    2014-03-01

    We have investigated the optical properties of human oral and ovarian cancer and normal cells. Specifically, we have measured the absolute optical extinction for both whole cells and intra-cellular material in aqueous suspension. Measurements were conducted over a wavelength range of 250 to 1000nm with 1 nm resolution using Light Transmission Spectroscopy (LTS). This provides both the absolute extinction of materials under study and, with Mie inversion, the absolute number of particles of a given diameter as a function of diameter in the range of 1 to 3000 nm. Our preliminary studies show significant differences in both the extinction and particle size distributions associated with cancer versus normal cells, which appear to be correlated with differences in the particle size distribution in the range of ~ 50 to 250 nm.

  13. Immortalization of human normal and NF1 neurofibroma Schwann cells.

    PubMed

    Li, Hua; Chang, Lung-Ji; Neubauer, Debbie R; Muir, David F; Wallace, Margaret R

    2016-10-01

    Neurofibromas, which are benign Schwann cell tumors, are the hallmark feature in the autosomal dominant condition neurofibromatosis 1 (NF1) and are associated with biallelic loss of NF1 gene function. There is a need for effective therapies for neurofibromas, particularly the larger, plexiform neurofibromas. Tissue culture is an important tool for research. However, it is difficult to derive enriched human Schwann cell cultures, and most enter replicative senescence after 6-10 passages, impeding cell-based research in NF1. Through exogenous expression of human telomerase reverse transcriptase and murine cyclin-dependent kinase (mCdk4), normal (NF1 wild-type), neurofibroma-derived Schwann cells heterozygous for NF1 mutation, and neurofibroma-derived Schwann cells homozygous for NF1 mutation were immortalized, including some matched samples from the same NF1 patient. Initial experiments employed retroviral vectors, while subsequent work utilized lentiviral vectors carrying these genes because of improved efficiency. Expression of both transgenes was required for immortalization. Molecular and immunohistochemical analysis indicated that these cell lines are of Schwann cell lineage and have a range of phenotypes, many of which are consistent with their primary cultures. This is the first report of immortalization and detailed characterization of multiple human NF1 normal nerve and neurofibroma-derived Schwann cell lines, which will be highly useful research tools to study NF1 and other Schwann tumor biology and conditions.

  14. Doublecortin expression in the normal and epileptic adult human brain.

    PubMed

    Liu, Y W J; Curtis, M A; Gibbons, H M; Mee, E W; Bergin, P S; Teoh, H H; Connor, B; Dragunow, M; Faull, R L M

    2008-12-01

    Mesial temporal lobe epilepsy (MTLE) is a neurological disorder associated with spontaneous recurrent complex partial seizures and hippocampal sclerosis. Although increased hippocampal neurogenesis has been reported in animal models of MTLE, increased neurogenesis has not been reported in the hippocampus of adult human MTLE cases. Here we showed that cells expressing doublecortin (Dcx), a microtubule-associated protein expressed in migrating neuroblasts, were present in the hippocampus and temporal cortex of the normal and MTLE adult human brain. In particular, increased numbers of Dcx-positive cells were observed in the epileptic compared with the normal temporal cortex. Importantly, 56% of Dcx-expressing cells in the epileptic temporal cortex coexpressed both the proliferative cell marker, proliferating cell nuclear antigen and early neuronal marker, TuJ1, suggesting that they may be newly generated neurons. A subpopulation of Dcx-positive cells in the epileptic temporal cortex also coexpressed the mature neuronal marker, NeuN, suggesting that epilepsy may promote the generation of new neurons in the temporal cortex. This study has identified, for the first time, a novel population of Dcx-positive cells in the adult human temporal cortex that can be upregulated by epilepsy and thus, raises the possibility that these cells may have functional significance in the pathophysiology of epilepsy.

  15. Hemodynamic aspects of normal human feto-placental (umbilical) circulation.

    PubMed

    Acharya, Ganesh; Sonesson, Sven-Erik; Flo, Kari; Räsänen, Juha; Odibo, Anthony

    2016-06-01

    Understanding the changes in normal circulatory dynamics that occur during the course of pregnancy is essential for improving our knowledge of pathophysiological mechanisms associated with feto-placental diseases. The umbilical circulation is the lifeline of the fetus, and it is accessible for noninvasive assessment. However, not all hemodynamic parameters can be reliably measured in utero using currently available technology. Experimental animal studies have been crucial in validating major concepts related to feto-placental circulatory physiology, but caution is required in directly translating the findings of such studies into humans due to species differences. Furthermore, it is important to establish normal reference ranges and take into account gestational age associated changes while interpreting the results of clinical investigation. Therefore, it is necessary to critically evaluate, synthesize and summarize the knowledge available from the studies performed on human pregnancies to be able to appropriately apply them in clinical practice. This narrative review is an attempt to present contemporary concepts on hemodynamics of feto-placental circulation based on human studies. © 2016 Nordic Federation of Societies of Obstetrics and Gynecology.

  16. A quantitative transcriptome reference map of the normal human brain.

    PubMed

    Caracausi, Maria; Vitale, Lorenza; Pelleri, Maria Chiara; Piovesan, Allison; Bruno, Samantha; Strippoli, Pierluigi

    2014-10-01

    We performed an innovative systematic meta-analysis of 60 gene expression profiles of whole normal human brain, to provide a quantitative transcriptome reference map of it, i.e. a reference typical value of expression for each of the 39,250 known, mapped and 26,026 uncharacterized (unmapped) transcripts. To this aim, we used the software named Transcriptome Mapper (TRAM), which is able to generate transcriptome maps based on gene expression data from multiple sources. We also analyzed differential expression by comparing the brain transcriptome with those derived from human foetal brain gene expression, from a pool of human tissues (except the brain) and from the two normal human brain regions cerebellum and cerebral cortex, which are two of the main regions severely affected when cognitive impairment occurs, as happens in the case of trisomy 21. Data were downloaded from microarray databases, processed and analyzed using TRAM software and validated in vitro by assaying gene expression through several magnitude orders by 'real-time' reverse transcription polymerase chain reaction (RT-PCR). The excellent agreement between in silico and experimental data suggested that our transcriptome maps may be a useful quantitative reference benchmark for gene expression studies related to the human brain. Furthermore, our analysis yielded biological insights about those genes which have an intrinsic over-/under-expression in the brain, in addition offering a basis for the regional analysis of gene expression. This could be useful for the study of chromosomal alterations associated to cognitive impairment, such as trisomy 21, the most common genetic cause of intellectual disability.

  17. Regulation of p53 during senescence in normal human keratinocytes

    PubMed Central

    Kim, Reuben H; Kang, Mo K; Kim, Terresa; Yang, Paul; Bae, Susan; Williams, Drake W; Phung, Samantha; Shin, Ki-Hyuk; Hong, Christine; Park, No-Hee

    2015-01-01

    p53, the guardian of the genome, is a tumor suppressor protein and critical for the genomic integrity of the cells. Many studies have shown that intracellular level of p53 is enhanced during replicative senescence in normal fibroblasts, and the enhanced level of p53 is viewed as the cause of senescence. Here, we report that, unlike in normal fibroblasts, the level of intracellular p53 reduces during replicative senescence and oncogene-induced senescence (OIS) in normal human keratinocytes (NHKs). We found that the intracellular p53 level was also decreased in age-dependent manner in normal human epithelial tissues. Senescent NHKs exhibited an enhanced level of p16INK4A, induced G2 cell cycle arrest, and lowered the p53 expression and transactivation activity. We found that low level of p53 in senescent NHKs was due to reduced transcription of p53. The methylation status at the p53 promoter was not altered during senescence, but senescent NHKs exhibited notably lower level of acetylated histone 3 (H3) at the p53 promoter in comparison with rapidly proliferating cells. Moreover, p53 knockdown in rapidly proliferating NHKs resulted in the disruption of fidelity in repaired DNA. Taken together, our study demonstrates that p53 level is diminished during replicative senescence and OIS and that such diminution is associated with H3 deacetylation at the p53 promoter. The reduced intracellular p53 level in keratinocytes of the elderly could be a contributing factor for more frequent development of epithelial cancer in the elderly because of the loss of genomic integrity of cells. PMID:26138448

  18. An image-based model of the whole human heart with detailed anatomical structure and fiber orientation.

    PubMed

    Deng, Dongdong; Jiao, Peifeng; Ye, Xuesong; Xia, Ling

    2012-01-01

    Many heart anatomy models have been developed to study the electrophysiological properties of the human heart. However, none of them includes the geometry of the whole human heart. In this study, an anatomically detailed mathematical model of the human heart was firstly reconstructed from the computed tomography images. In the reconstructed model, the atria consisted of atrial muscles, sinoatrial node, crista terminalis, pectinate muscles, Bachmann's bundle, intercaval bundles, and limbus of the fossa ovalis. The atrioventricular junction included the atrioventricular node and atrioventricular ring, and the ventricles had ventricular muscles, His bundle, bundle branches, and Purkinje network. The epicardial and endocardial myofiber orientations of the ventricles and one layer of atrial myofiber orientation were then measured. They were calculated using linear interpolation technique and minimum distance algorithm, respectively. To the best of our knowledge, this is the first anatomically-detailed human heart model with corresponding experimentally measured fibers orientation. In addition, the whole heart excitation propagation was simulated using a monodomain model. The simulated normal activation sequence agreed well with the published experimental findings.

  19. Growth of the great vessels in the normal human fetus and in the fetus with cardiac defects.

    PubMed

    Ursell, P C; Byrne, J M; Fears, T R; Strobino, B A; Gersony, W M

    1991-11-01

    There is a paucity of quantitative anatomic data regarding human great vessel development that could be useful as a reference for fetal echocardiographers who must distinguish abnormal from normal cardiac development at early stages. To determine normal growth patterns, we plotted the diameters of the aortic and pulmonary valves, ductus arteriosus, aortic isthmus, and descending aorta in 274 autopsy specimens from nonselected spontaneous abortuses of normal karyotype. There was a linear increase in the diameters of these structures within the developmental period studied (10-26 weeks). A relative narrowing of the aorta at the isthmus compared with the aortic valve and descending aorta probably indicates that the majority of fetal left heart output goes to the developing heart and brain. In contrast to previous studies of late gestation and neonatal animals, however, we found that the diameter of the aortic isthmus was larger than that of the ductus arteriosus, suggesting substantial isthmic blood flow in these midtrimester fetuses. Among nineteen other hearts with diverse defects, both of two hearts with a narrow isthmus had an enlarged ductus arteriosus and one heart with pulmonary atresia/intact septum had a narrow ductus and increased aortic valve diameter. During midgestation, the normal heart may have substantial aortic isthmic blood flow that diminishes due to rerouting in late gestation when increased requirements of the fetal brain and other organs prevail. Although fetal shunts may explain some vessel abnormalities, the majority of cardiac defects in this study were not associated with abnormal growth of the great vessels within this developmental age range.

  20. Vulnerability of Normal Human Mammary Epithelial Cells to Oncogenic Transformation

    DTIC Science & Technology

    2012-04-01

    algorithm for CpG-island detection. BMC Bioinformatics 7: 446. 17. Gardiner-Garden M, Frommer M (1987) CpG islands in vertebrate genomes. J Mol Biol...it does not have a CpG island according to the original criteria (Gardiner-Garden and Frommer 1987). H3K4me3 and H3Ac are present in miR-205...culture of normal human mammary epithelial cells. Cancer Res 69: 7557–7568. Gardiner-GardenM, Frommer M. 1987. CpG islands in vertebrate genomes. J Mol

  1. Multiphoton microscopic imaging of human normal and cancerous oesophagus tissue.

    PubMed

    Chen, W S; Wang, Y; Liu, N R; Zhang, J X; Chen, R

    2014-01-01

    In this paper, microstructures of human oesophageal submucosa are evaluated using multiphoton microscopy, based on two-photon excited fluorescence and second harmonic generation. The content and distribution of collagen, elastic fibers and cancer cells in normal and cancerous submucosa layer have been distinctly obtained and briefly discussed. The variation of these components is very relevant to the pathology in oesophagus, especially in early oesophageal cancer. Our results further indicate that the multiphoton microscopy technique has the potential application in vivo in clinical diagnosis and monitoring of early oesophageal cancer. © 2013 The Authors Journal of Microscopy © 2013 Royal Microscopical Society.

  2. Regional pulmonary perfusion following human heart-lung transplantation

    SciTech Connect

    Lisbona, R.; Hakim, T.S.; Dean, G.W.; Langleben, D.; Guerraty, A.; Levy, R.D. )

    1989-08-01

    Ventilation and perfusion scans were obtained in six subjects who had undergone heart-lung transplantation with consequent denervation of the cardiopulmonary axis. Two of the subjects had developed obliterative bronchiolitis, which is believed to be a form of chronic rejection. Their pulmonary function tests demonstrated airflow obstruction and their scintigraphic studies were abnormal. In the remaining four subjects without obstructive airways disease, ventilation and planar perfusion scans were normal. Single photon emission computed tomography imaging of pulmonary perfusion in these patients revealed a layered distribution of blood flow indistinguishable from that of normal individuals. It is concluded that neurogenic mechanisms have little influence on the pattern of local pulmonary blood flow at rest.

  3. Human Mesenchymal Stem Cells Reendothelialize Porcine Heart Valve Scaffolds: Novel Perspectives in Heart Valve Tissue Engineering

    PubMed Central

    Lanuti, Paola; Serafini, Francesco; Pierdomenico, Laura; Simeone, Pasquale; Bologna, Giuseppina; Ercolino, Eva; Di Silvestre, Sara; Guarnieri, Simone; Canosa, Carlo; Impicciatore, Gianna Gabriella; Chiarini, Stella; Magnacca, Francesco; Mariggiò, Maria Addolorata; Pandolfi, Assunta; Marchisio, Marco; Di Giammarco, Gabriele; Miscia, Sebastiano

    2015-01-01

    Abstract Heart valve diseases are usually treated by surgical intervention addressed for the replacement of the damaged valve with a biosynthetic or mechanical prosthesis. Although this approach guarantees a good quality of life for patients, it is not free from drawbacks (structural deterioration, nonstructural dysfunction, and reintervention). To overcome these limitations, the heart valve tissue engineering (HVTE) is developing new strategies to synthesize novel types of valve substitutes, by identifying efficient sources of both ideal scaffolds and cells. In particular, a natural matrix, able to interact with cellular components, appears to be a suitable solution. On the other hand, the well-known Wharton's jelly mesenchymal stem cells (WJ-MSCs) plasticity, regenerative abilities, and their immunomodulatory capacities make them highly promising for HVTE applications. In the present study, we investigated the possibility to use porcine valve matrix to regenerate in vitro the valve endothelium by WJ-MSCs differentiated along the endothelial lineage, paralleled with human umbilical vein endothelial cells (HUVECs), used as positive control. Here, we were able to successfully decellularize porcine heart valves, which were then recellularized with both differentiated-WJ-MSCs and HUVECs. Data demonstrated that both cell types were able to reconstitute a cellular monolayer. Cells were able to positively interact with the natural matrix and demonstrated the surface expression of typical endothelial markers. Altogether, these data suggest that the interaction between a biological scaffold and WJ-MSCs allows the regeneration of a morphologically well-structured endothelium, opening new perspectives in the field of HVTE. PMID:26309804

  4. Three-dimensional interface geometry of the human heart with the artificial heart.

    PubMed

    Uyama, C; Akutsu, T

    1991-01-01

    The interface geometry of human and artificial hearts was defined. It included: 1) the approximate mitral orifice and mitral orifice planes; 2) the approximate tricuspid orifice and tricuspid orifice planes; 3) the long and short diameters of the aorta; 4) the long and short diameters of the pulmonary artery; and 5) the angles between the mitral orifice and tricuspid orifice planes, as well as the axes of the aorta and pulmonary artery. The orifice plane was defined as a plane such that the sum of the squared distances between the plane and points on the orifice contour was minimized. A standard coordinate system was also defined, whose origin was the centroid of the approximate mitral orifice. Its X-Y plane was the approximate mitral orifice plane. One set of interface parameters was determined using magnetic resonance images of a volunteer's heart. The angle between the approximate mitral orifice plane and tricuspid plane was found to be 19.9 degrees. The areas of the approximate mitral and tricuspid orifices were 1020 and 1655 mm2, respectively. The approximate mitral orifice was covered by a 44 x 40 mm rectangle and the approximate tricuspid orifice was covered by a 59 x 41 mm rectangle. This interface geometry is important, not only in the manufacture of artificial hearts of precise dimensions, but also in avoiding complications due to their long-term use.

  5. Timing of left heart base descent in dogs with dilated cardiomyopathy and normal dogs.

    PubMed

    Simpson, Kerry E; Devine, Bryan C; Woolley, Richard; Corcoran, Brendan M; French, Anne T

    2008-01-01

    The identification and assessment of myocardial failure in canine idiopathic dilated cardiomyopathy (DCM) is achieved using a variety of two-dimensional and Doppler echocardiographic techniques. More recently, the availability of tissue Doppler imaging (TDI) has raised the potential for development of new ways of more accurately identifying a disease phenotype. Nevertheless, TDI has not been universally adapted to veterinary clinical cardiology primarily because of the lack of information on its utility in diagnosis. We assessed the application of timing of left heart base descent using TDI in the identification of differences between DCM and normal dogs. The times from the onset of the QRS complex on a simultaneously recorded electrocardiograph to the onset (Q--S'), peak (Q--peak S'), and end (Q--end S') of the systolic velocity peak were measured in the interventricular septum (IVS) and the left ventricular free wall. The duration of S' was also calculated. The Q--S' (FW), Q--end S' (FW), and duration S' (FW) were correlated with ejection fraction in the diseased group (P < 0.05). In addition, Q--S', Q--peak S', Q--end S', and the peak S' velocity were prolonged in the diseased dogs at both the free wall and in the IVS (P < 0.01). The duration of S' was unaffected by disease status. These findings provide insight into the electromechanical uncoupling that occurs in canine DCM and identifies new TDI parameters that can be added to the range of Doppler and echocardiographic parameters used for detecting myocardial failure in the dog.

  6. Cationic channels in normal and dystrophic human myotubes.

    PubMed

    Vandebrouck, C; Duport, G; Cognard, C; Raymond, G

    2001-01-01

    Human skeletal muscle cells obtained from normal and Duchenne muscular dystrophy patients were cocultured with explants of rat dorsal root ganglions. Single-channel recordings were performed with the cell-attached configuration of the patch-clamp technique and negative pressure was applied via the patch-pipette in order to mechanically stimulate the membrane patch. Inward elementary current activity was recorded under control or negative pressure conditions. Its occurrence and mean open probability were higher in Duchenne muscular dystrophy. Amplitude histograms reveal that these channels have a small unitary conductance of around 10 pS in 110 mM Ca2+ and could be inhibited in a dose-dependent manner by gadolinium. Results show that the membrane stress favoured calcium permeation through these channels. Taken together these data provide arguments for the involvement of such channels in calcium overload previously observed in cocultured dystrophic human (Duchenne muscular dystrophy) muscle cells.

  7. Radiofrequency ablation of left atrial flutter mediated with double potentials in a seemingly normally structured heart.

    PubMed

    Peng, Hui; Sun, Zhijun; Zhang, Heping; Wu, Yongquan

    2014-08-20

    Left atrial flutter (left AFL) is common in patients who undergo atrial fibrillation ablation and cardiac surgery; however, few reports describe left AFL in detail in a seemingly normally structured heart, and the mechanisms of the occurrence of such arrhythmia are still not clear. We describe left AFL in patients without prior cardiac surgery or catheter ablation and discuss the electrophysiological characteristics that may explain the preferential generation and perpetuation of such tachycardia. Eleven patients with left AFL, who had no history of cardiac surgery or interventions, underwent electrophysiological studies and 3-dimensional electroanatomic mapping studies. Echocardiography revealed a relatively mild dilation of the left atrium, mild to moderate mitral regurgitation, and a normal left ventricular ejection fraction. The electroanatomic mapping during tachycardia showed a "reentrant" activation pattern in all patients. The mean tachycardia cycle length was 266 ± 17 ms. A single-loop reentrant circuit was identified in 7 patients. A counterclockwise left atrial flutter evolved around the mitral valve annulus in 6 patients. The tachycardia rotated around the left atrial anterior wall in 1 patient. Four patients exhibited a double-loop reentrant circuit with a "figure of 8" pattern reentry. Double potentials as the critical isthmus of the circuit were identified in the left atrial anterior wall near the mitral annulus which displayed a low-voltage area matched with the left atrium-aorta contiguity. The conduction velocity was significantly slower in the double-potential recording area than in the lateral mitral annulus (0.36 ± 0.03 m/s vs 0.74 ± 0.12 m/s; P<0.05). Successful ablation around the double-potential recording site caused an interruption of the tachycardia, and remained free of recurrence during a 12-month follow-up in all patients. Left AFL in patients without a history of surgery or ablation is rarely observed in clinical practice. The

  8. Cardiomyocyte clusters derived from human embryonic stem cells share similarities with human heart tissue.

    PubMed

    Asp, Julia; Steel, Daniella; Jonsson, Marianne; Améen, Caroline; Dahlenborg, Kerstin; Jeppsson, Anders; Lindahl, Anders; Sartipy, Peter

    2010-10-01

    Cardiotoxicity testing is a key activity in the pharmaceutical industry in order to detect detrimental effects of new drugs. A reliable human in vitro model would both be beneficial in selection of lead compounds and be important for reducing animal experimentation. However, the human heart is a complex organ composed of many distinct types of cardiomyocytes, but cardiomyocyte clusters (CMCs) derived from human embryonic stem cells could be an option for a cellular model. Data on functional properties of CMCs demonstrate similarities to their in vivo analogues in human. However, development of an in vitro model requires a more thorough comparison of CMCs to human heart tissue. Therefore, we directly compared individually isolated CMCs to human fetal, neonatal, adult atrial and ventricular heart tissues. Real-time qPCR analysis of mRNA levels and protein staining of ion channels and cardiac markers showed in general a similar expression pattern in CMCs and human heart. Moreover, a significant decrease in beat frequency was noted after addition of Zatebradine, a blocker to I(f) involved in regulation of spontaneous contraction in CMCs. The results underscore the similarities of CMCs to human cardiac tissue, and further support establishment of novel cardiotoxicity assays based on the CMCs in drug discovery.

  9. Divergent viral presentation among human tumors and adjacent normal tissues

    PubMed Central

    Cao, Song; Wendl, Michael C.; Wyczalkowski, Matthew A.; Wylie, Kristine; Ye, Kai; Jayasinghe, Reyka; Xie, Mingchao; Wu, Song; Niu, Beifang; Grubb, Robert; Johnson, Kimberly J.; Gay, Hiram; Chen, Ken; Rader, Janet S.; Dipersio, John F.; Chen, Feng; Ding, Li

    2016-01-01

    We applied a newly developed bioinformatics system called VirusScan to investigate the viral basis of 6,813 human tumors and 559 adjacent normal samples across 23 cancer types and identified 505 virus positive samples with distinctive, organ system- and cancer type-specific distributions. We found that herpes viruses (e.g., subtypes HHV4, HHV5, and HHV6) that are highly prevalent across cancers of the digestive tract showed significantly higher abundances in tumor versus adjacent normal samples, supporting their association with these cancers. We also found three HPV16-positive samples in brain lower grade glioma (LGG). Further, recurrent HBV integration at the KMT2B locus is present in three liver tumors, but absent in their matched adjacent normal samples, indicating that viral integration induced host driver genetic alterations are required on top of viral oncogene expression for initiation and progression of liver hepatocellular carcinoma. Notably, viral integrations were found in many genes, including novel recurrent HPV integrations at PTPN13 in cervical cancer. Finally, we observed a set of HHV4 and HBV variants strongly associated with ethnic groups, likely due to viral sequence evolution under environmental influences. These findings provide important new insights into viral roles of tumor initiation and progression and potential new therapeutic targets. PMID:27339696

  10. Terahertz spectroscopic investigation of human gastric normal and tumor tissues

    NASA Astrophysics Data System (ADS)

    Hou, Dibo; Li, Xian; Cai, Jinhui; Ma, Yehao; Kang, Xusheng; Huang, Pingjie; Zhang, Guangxin

    2014-09-01

    Human dehydrated normal and cancerous gastric tissues were measured using transmission time-domain terahertz spectroscopy. Based on the obtained terahertz absorption spectra, the contrasts between the two kinds of tissue were investigated and techniques for automatic identification of cancerous tissue were studied. Distinctive differences were demonstrated in both the shape and amplitude of the absorption spectra between normal and tumor tissue. Additionally, some spectral features in the range of 0.2~0.5 THz and 1~1.5 THz were revealed for all cancerous gastric tissues. To systematically achieve the identification of gastric cancer, principal component analysis combined with t-test was used to extract valuable information indicating the best distinction between the two types. Two clustering approaches, K-means and support vector machine (SVM), were then performed to classify the processed terahertz data into normal and cancerous groups. SVM presented a satisfactory result with less false classification cases. The results of this study implicate the potential of the terahertz technique to detect gastric cancer. The applied data analysis methodology provides a suggestion for automatic discrimination of terahertz spectra in other applications.

  11. Ketogenic diet: electrophysiological effects on the normal human cortex.

    PubMed

    Cantello, Roberto; Varrasi, Claudia; Tarletti, Roberto; Cecchin, Michela; D'Andrea, Federico; Veggiotti, Pierangelo; Bellomo, Giorgio; Monaco, Francesco

    2007-09-01

    To explore the cortical electrophysiology of the ketogenic diet (KD) in the normal human. KD is effective against refractory epilepsy, but its precise mechanism is obscure. At the transmitter level, an enhancement of GABA inhibition has often been proposed. We studied eight healthy volunteers undergoing a "classic" KD for 2 weeks. We measured several biochemical variables at baseline (T0), after 1 week (T1) and 2 weeks (T2) of KD, then 3 months after the KD conclusion (T3). Ketosis was quantified as 24-h ketonuria. At the same time, we studied the motor cortical excitability by means of transcranial magnetic stimulation (TMS). We also quantitatively evaluated the EEG signal in search of frequency shifts over the rolandic areas. Significant (p < 0.05) neurophysiological changes appeared at T2. These consisted of a strengthening of short-latency cortical inhibition (SICI), a TMS index which is thought to reflect GABA-A inhibition in the cortex. Then, there was an enhancement of the beta EEG band over the perirolandic region, similar to that following administration of GABA-A agonists. All changes disappeared at T3. A standard, short-term KD affected the cortical physiology of the normal human. The main changes were an augmented SICI and an increased perirolandic beta EEG activity, which are compatible with a lower level of neural excitation within the cortex.

  12. Arrhythmogenic remodelling of activation and repolarization in the failing human heart.

    PubMed

    Holzem, Katherine M; Efimov, Igor R

    2012-11-01

    Heart failure is a major cause of disability and death worldwide, and approximately half of heart failure-related deaths are sudden and presumably due to ventricular arrhythmias. Patients with heart failure have been shown to be at 6- to 9-fold increased risk of sudden cardiac death compared to the general population. (AHA. Heart Disease and Stroke Statistics-2003 Update. Heart and Stroke Facts. Dallas, TX: American Heart Association; 2002) Thus, electrophysiological remodelling associated with heart failure is a leading cause of disease mortality and has been a major investigational focus examined using many animal models of heart failure. While these studies have provided an important foundation for understanding the arrhythmogenic pathophysiology of heart failure, the need for corroborating studies conducted on human heart tissue has been increasingly recognized. Many human heart studies of conduction and repolarization remodelling have now been published and shed some light on important, potentially arrhythmogenic, changes in human heart failure. These studies are being conducted at multiple experimental scales from isolated cells to whole-tissue preparations and have provided insight into regulatory mechanisms such as decreased protein expression, alternative mRNA splicing of ion channel genes, and defective cellular trafficking. Further investigations of heart failure in the human myocardium will be essential for determining possible therapeutic targets to prevent arrhythmia in heart failure and for facilitating the translation of basic research findings to the clinical realm.

  13. Transcription abnormalities potentiate apoptosis of normal human fibroblasts.

    PubMed Central

    Andera, L.; Wasylyk, B.

    1997-01-01

    BACKGROUND: Apoptosis is a natural process by which damaged and potentially tumorigenic cells are removed. Induction of apoptosis is important in chemotherapy aimed at eliminating cancer cells. We address the mechanisms by which this process can be triggered in cells that are recalcitrant to cell death induced by DNA-damaging agents. MATERIALS AND METHODS: Normal human fibroblasts and lymphoblasts, and fibroblasts with defined genetic changes, were treated with DNA-damaging agents and inhibitors of transcription. Western blotting was used to study the expression of some of the key factors involved in the response to DNA damage and the induction of apoptosis, namely, p53, p21WAFI,Cip1, Mdm2, Bax, and CD95 (Fas/APO1). Apoptosis was followed by various criteria, including DNA fragmentation, specific proteolysis, cell morphology, viability, and FACS scan for sub-G1 cells. RESULTS: Normal human fibroblasts were more resistant than lymphoblasts to DNA damage-induced apoptosis. The DNA-damaging agents mitomycin C and cisplatin induced rapid apoptosis of fibroblasts with defects in the repair of transcribed DNA, compared with wild-type cells or those with defects in overall genome repair. Short-term treatment with inhibitors of RNA polymerase II transcription, actinomycin D, and alpha-amanitin induced rapid cell death of normal fibroblasts. These results show that there is a link between defective transcription and apoptosis. Treatments and genetic backgrounds that favored apoptosis were associated with efficient and prolonged induction of p53 and often altered or imbalanced expression of its downstream effectors p21WAFI,Cip1 and Mdm2, whereas there were no changes in Bax or CD95 (Fas/APO1). CONCLUSION: Transcription inhibitors increase p53 levels and are better inducers of apoptosis than DNA-damaging agents in some cell types. Apoptosis might be triggered by blocked polymerases and/or faulty expression of downstream effectors. Images FIG. 1 FIG. 2 FIG. 3 FIG. 4 PMID

  14. p120 GAP requirement in normal and malignant human hematopoiesis

    PubMed Central

    1993-01-01

    There is evidence to suggest that the p120 GAP (GAP), originally described as an inhibitor of p21ras, may also serve as a downstream effector of ras-regulated signal transduction. To determine whether GAP expression is required for the growth of human normal and leukemic hematopoietic cells, we used GAP antisense oligodeoxynucleotides to inhibit it and analyzed the effects of this inhibition on the colony- forming ability of nonadherent, T lymphocyte-depleted mononuclear cells and of highly purified progenitors (CD34+ MNC) obtained from the bone marrow and peripheral blood of healthy volunteers or chronic myeloid leukemia (CML, bcr-abl-positive) patients. The acute myelogenous leukemia cell line MO7, the Philadelphia BV173 cell line, and the acute promyelocytic leukemia NB4 and HL-60 cell lines were similarly examined. GAP antisense treatment inhibited colony formation from normal myelo-, erythro-, and megakaryopoietic progenitor cells as well as from CML progenitor cells. Proliferation of MO7 (growth factor- dependent) and BV173 (bcr-abl-dependent) cells, but not that of NB4 and HL-60 (growth factor-independent) cells, was also inhibited, even though a specific downregulation of GAP was observed in each cell line, as analyzed by either or both mRNA and protein expression. Stimulation of MO7 cells with hematopoietic growth factors increased the expression of GAP as well as the levels of active GTP-bound p21ras. Stimulation of GAP expression was inhibited upon GAP antisense treatment. These data indicate that p120 GAP is involved in human normal and leukemic hemopoiesis and strongly suggest that GAP is not only a p21ras inhibitor (signal terminator), but also a positive signal transducer. PMID:8245773

  15. Improvement of Heart Failure by Human Amniotic Mesenchymal Stromal Cell Transplantation in Rats

    PubMed Central

    Razavi Tousi, Seyed Mohammad Taghi; Faghihi, Mahdieh; Nobakht, Maliheh; Molazem, Mohammad; Kalantari, Elham; Darbandi Azar, Amir; Aboutaleb, Nahid

    2016-01-01

    Background: Recently, stem cells have been considered for the treatment of heart diseases, but no marked improvement has been recorded. This is the first study to examine the functional and histological effects of the transplantation of human amniotic mesenchymal stromal cells (hAMSCs) in rats with heart failure (HF). Methods: This study was conducted in the years 2014 and 2015. 35 male Wistar rats were randomly assigned into 5 equal experimental groups (7 rats each) as 1- Control 2- Heart Failure (HF) 3- Sham 4- Culture media 5- Stem Cell Transplantation (SCT). Heart failure was induced using 170 mg/kg/d of isoproterenol subcutaneously injection in 4 consecutive days. The failure confirmed by the rat cardiac echocardiography on day 28. In SCT group, 3×106 cells in 150 µl of culture media were transplanted to the myocardium. At the end, echocardiographic and hemodynamic parameters together with histological evaluation were done. Results: Echocardiography results showed that cardiac ejection fraction in HF group increased from 58/73 ± 9% to 81/25 ± 6/05% in SCT group (p value < 0.001). Fraction shortening in HF group was increased from 27/53 ± 8/58% into 45/55 ± 6/91% in SCT group (p value < 0.001). Furthermore, hAMSCs therapy significantly improved mean diastolic blood pressure, mean arterial pressure, left ventricular systolic pressure, rate pressure product, and left ventricular end-diastolic pressure compared to those in the HF group, with the values reaching the normal levels in the control group. A marked reduction in fibrosis tissue was also found in the SCT group (p value < 0.001) compared with the animals in the HF group. Conclusion: The transplantation of hAMSCs in rats with heart failure not only decreased the level of fibrosis but also conferred significant improvement in heart performance in terms of echocardiographic and hemodynamic parameters. PMID:27956912

  16. Cold pressor stimulus temperature and resting masseter muscle haemodynamics in normal humans.

    PubMed

    Maekawa, K; Kuboki, T; Clark, G T; Shinoda, M; Yamashita, A

    1998-11-01

    Cold pressor stimulation reportedly increases sympathetic nerve activity in human skeletal muscles. This study examined the effect of cold pressor stimulation on the resting haemodynamics of the right masseter muscle in normal individuals, using near-infrared spectroscopy. Nine healthy non-smoking males with no history of chronic muscle pain or vascular headaches participated. Their right hand was immersed in a water bath (4, 10, 15 degrees C) for exactly 1 min. Each trial lasted 7 min (1 min before, 1 min during, 5 min after stimulation) and a strictly random order was utilized for the three test temperatures and the mock trial. Masseter muscle haemoglobin concentration and oxygen saturation, as well as heart rate and blood pressure, were continuously recorded in each trial. After completing the four trials, each participant produced and sustained a 30-s maximum voluntary clench in the intercuspal position. Data across the four trials were baseline-corrected and then magnitude-normalized to the individual's highest absolute haemoglobin and oxygen signal during the 30-s maximal clenching effort. Haemoglobin and oxygen saturation increased progressively during cold pressor stimulation as the water temperature decreased (Hb, p < 0.0001; O2, p = 0.0327); very little effect was seen during the mock trial. Heart rate and blood pressure also increased progressively during the stimulation as the temperature decreased (heart rate, p = 0.0013; systolic blood pressure, p = 0.0042; diastolic blood pressure, p = 0.0156). These data suggest that cold pressor, stimulation induces a strong increase in intramuscular blood volume which appears to be due to both a local vasodilative response and increased cardiac output.

  17. Global Bi-ventricular endocardial distribution of activation rate during long duration ventricular fibrillation in normal and heart failure canines.

    PubMed

    Luo, Qingzhi; Jin, Qi; Zhang, Ning; Han, Yanxin; Wang, Yilong; Huang, Shangwei; Lin, Changjian; Ling, Tianyou; Chen, Kang; Pan, Wenqi; Wu, Liqun

    2017-04-13

    The objective of this study was to detect differences in the distribution of the left and right ventricle (LV & RV) activation rate (AR) during short-duration ventricular fibrillation (SDVF, <1 min) and long-duration ventricular fibrillation VF (LDVF, >1 min) in normal and heart failure (HF) canine hearts. Ventricular fibrillation (VF) was electrically induced in six healthy dogs (control group) and six dogs with right ventricular pacing-induced congestive HF (HF group). Two 64-electrode basket catheters deployed in the LV and RV were used for global endocardium electrical mapping. The AR of VF was estimated by fast Fourier transform analysis from each electrode. In the control group, the LV was activated faster than the RV in the first 20 s, after which there was no detectable difference in the AR between them. When analyzing the distribution of the AR within the bi-ventricles at 3 min of LDVF, the posterior LV was activated fastest, while the anterior was slowest. In the HF group, a detectable AR gradient existed between the two ventricles within 3 min of VF, with the LV activating more quickly than the RV. When analyzing the distribution of the AR within the bi-ventricles at 3 min of LDVF, the septum of the LV was activated fastest, while the anterior was activated slowest. A global bi-ventricular endocardial AR gradient existed within the first 20 s of VF but disappeared in the LDVF in healthy hearts. However, the AR gradient was always observed in both SDVF and LDVF in HF hearts. The findings of this study suggest that LDVF in HF hearts can be maintained differently from normal hearts, which accordingly should lead to the development of different management strategies for LDVF resuscitation.

  18. THERP and HEART integrated methodology for human error assessment

    NASA Astrophysics Data System (ADS)

    Castiglia, Francesco; Giardina, Mariarosa; Tomarchio, Elio

    2015-11-01

    THERP and HEART integrated methodology is proposed to investigate accident scenarios that involve operator errors during high-dose-rate (HDR) treatments. The new approach has been modified on the basis of fuzzy set concept with the aim of prioritizing an exhaustive list of erroneous tasks that can lead to patient radiological overexposures. The results allow for the identification of human errors that are necessary to achieve a better understanding of health hazards in the radiotherapy treatment process, so that it can be properly monitored and appropriately managed.

  19. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts.

    PubMed

    Chong, James J H; Yang, Xiulan; Don, Creighton W; Minami, Elina; Liu, Yen-Wen; Weyers, Jill J; Mahoney, William M; Van Biber, Benjamin; Cook, Savannah M; Palpant, Nathan J; Gantz, Jay A; Fugate, James A; Muskheli, Veronica; Gough, G Michael; Vogel, Keith W; Astley, Cliff A; Hotchkiss, Charlotte E; Baldessari, Audrey; Pabon, Lil; Reinecke, Hans; Gill, Edward A; Nelson, Veronica; Kiem, Hans-Peter; Laflamme, Michael A; Murry, Charles E

    2014-06-12

    Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by providing human cardiomyocytes to support heart regeneration. Studies of human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small-animal models have shown favourable effects of this treatment. However, it remains unknown whether clinical-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that cryopreservation and intra-myocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a 3-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small-animal models, non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome.

  20. Human cancers overexpress genes that are specific to a variety of normal human tissues

    PubMed Central

    Lotem, Joseph; Netanely, Dvir; Domany, Eytan; Sachs, Leo

    2005-01-01

    We have analyzed gene expression data from three different kinds of samples: normal human tissues, human cancer cell lines, and leukemic cells from lymphoid and myeloid leukemia pediatric patients. We have searched for genes that are overexpressed in human cancer and also show specific patterns of tissue-dependent expression in normal tissues. Using the expression data of the normal tissues, we identified 4,346 genes with a high variability of expression and clustered these genes according to their relative expression level. Of 91 stable clusters obtained, 24 clusters included genes preferentially expressed either only in hematopoietic tissues or in hematopoietic and one to two other tissues; 28 clusters included genes preferentially expressed in various nonhematopoietic tissues such as neuronal, testis, liver, kidney, muscle, lung, pancreas, and placenta. Analysis of the expression levels of these two groups of genes in the human cancer cell lines and leukemias identified genes that were highly expressed in cancer cells but not in their normal counterparts and, thus, were overexpressed in the cancers. The different cancer cell lines and leukemias varied in the number and identity of these overexpressed genes. The results indicate that many genes that are overexpressed in human cancer cells are specific to a variety of normal tissues, including normal tissues other than those from which the cancer originated. It is suggested that this general property of cancer cells plays a major role in determining the behavior of the cancers, including their metastatic potential. PMID:16339305

  1. hnRNP U protein is required for normal pre-mRNA splicing and postnatal heart development and function

    PubMed Central

    Ye, Junqiang; Beetz, Nadine; O’Keeffe, Sean; Tapia, Juan Carlos; Macpherson, Lindsey; Chen, Weisheng V.; Bassel-Duby, Rhonda; Olson, Eric N.; Maniatis, Tom

    2015-01-01

    We report that mice lacking the heterogeneous nuclear ribonucleoprotein U (hnRNP U) in the heart develop lethal dilated cardiomyopathy and display numerous defects in cardiac pre-mRNA splicing. Mutant hearts have disorganized cardiomyocytes, impaired contractility, and abnormal excitation–contraction coupling activities. RNA-seq analyses of Hnrnpu mutant hearts revealed extensive defects in alternative splicing of pre-mRNAs encoding proteins known to be critical for normal heart development and function, including Titin and calcium/calmodulin-dependent protein kinase II delta (Camk2d). Loss of hnRNP U expression in cardiomyocytes also leads to aberrant splicing of the pre-mRNA encoding the excitation–contraction coupling component Junctin. We found that the protein product of an alternatively spliced Junctin isoform is N-glycosylated at a specific asparagine site that is required for interactions with specific protein partners. Our findings provide conclusive evidence for the essential role of hnRNP U in heart development and function and in the regulation of alternative splicing. PMID:26039991

  2. hnRNP U protein is required for normal pre-mRNA splicing and postnatal heart development and function.

    PubMed

    Ye, Junqiang; Beetz, Nadine; O'Keeffe, Sean; Tapia, Juan Carlos; Macpherson, Lindsey; Chen, Weisheng V; Bassel-Duby, Rhonda; Olson, Eric N; Maniatis, Tom

    2015-06-09

    We report that mice lacking the heterogeneous nuclear ribonucleoprotein U (hnRNP U) in the heart develop lethal dilated cardiomyopathy and display numerous defects in cardiac pre-mRNA splicing. Mutant hearts have disorganized cardiomyocytes, impaired contractility, and abnormal excitation-contraction coupling activities. RNA-seq analyses of Hnrnpu mutant hearts revealed extensive defects in alternative splicing of pre-mRNAs encoding proteins known to be critical for normal heart development and function, including Titin and calcium/calmodulin-dependent protein kinase II delta (Camk2d). Loss of hnRNP U expression in cardiomyocytes also leads to aberrant splicing of the pre-mRNA encoding the excitation-contraction coupling component Junctin. We found that the protein product of an alternatively spliced Junctin isoform is N-glycosylated at a specific asparagine site that is required for interactions with specific protein partners. Our findings provide conclusive evidence for the essential role of hnRNP U in heart development and function and in the regulation of alternative splicing.

  3. Myocardial commitment from human pluripotent stem cells: Rapid production of human heart grafts.

    PubMed

    Garreta, Elena; de Oñate, Lorena; Fernández-Santos, M Eugenia; Oria, Roger; Tarantino, Carolina; Climent, Andreu M; Marco, Andrés; Samitier, Mireia; Martínez, Elena; Valls-Margarit, Maria; Matesanz, Rafael; Taylor, Doris A; Fernández-Avilés, Francisco; Izpisua Belmonte, Juan Carlos; Montserrat, Nuria

    2016-08-01

    Genome editing on human pluripotent stem cells (hPSCs) together with the development of protocols for organ decellularization opens the door to the generation of autologous bioartificial hearts. Here we sought to generate for the first time a fluorescent reporter human embryonic stem cell (hESC) line by means of Transcription activator-like effector nucleases (TALENs) to efficiently produce cardiomyocyte-like cells (CLCs) from hPSCs and repopulate decellularized human heart ventricles for heart engineering. In our hands, targeting myosin heavy chain locus (MYH6) with mCherry fluorescent reporter by TALEN technology in hESCs did not alter major pluripotent-related features, and allowed for the definition of a robust protocol for CLCs production also from human induced pluripotent stem cells (hiPSCs) in 14 days. hPSCs-derived CLCs (hPSCs-CLCs) were next used to recellularize acellular cardiac scaffolds. Electrophysiological responses encountered when hPSCs-CLCs were cultured on ventricular decellularized extracellular matrix (vdECM) correlated with significant increases in the levels of expression of different ion channels determinant for calcium homeostasis and heart contractile function. Overall, the approach described here allows for the rapid generation of human cardiac grafts from hPSCs, in a total of 24 days, providing a suitable platform for cardiac engineering and disease modeling in the human setting.

  4. Age- and gender-specific changes of tricuspid annular motion velocities in normal hearts.

    PubMed

    Hayashi, Shuji; Yamada, Hirotsugu; Nishio, Susumu; Hotchi, Junko; Bando, Mika; Takagawa, Yuriko; Saijo, Yoshihito; Hirata, Yukina; Sata, Masataka

    2015-05-01

    Mitral annular motion (MAM) and tricuspid annular motion (TAM) velocities obtained by pulsed tissue Doppler echocardiography have been used to evaluate left ventricular (LV) and right ventricular (RV) functions. Although TAM velocity has been clinically applied for evaluating various cardiac diseases, the effects of age and gender remain unclear. Therefore, we aimed to determine the effects of age and gender on TAM velocity in normal hearts. We randomly selected 265 subjects (mean age, 59 years; range, 20-89 years) without abnormal clinical, electrocardiographic, and echocardiographic findings from a pool of subjects who had undergone transthoracic echocardiography. They were classified into four age groups: 20-39, 40-59, 60-79, and >80 years. Pulsed wave Doppler was applied to obtain MAM velocity of the lateral side and TAM velocity of the RV free wall side. The peak systolic (s'), early diastolic (e'), and atrial systolic (a') velocities of MAM and TAM were measured in all subjects. While MAM-s' (r=-0.267, p<0.001) correlated with age, TAM-s' did not (p=0.755). TAM-s' in any age groups had no significant gender differences. TAM-e' (r=-0.447, p<0.001) and MAM-e' (r=-0.724, p<0.001) correlated with age, respectively. In those aged 40-59 years, both TAM-e' (p=0.002) and MAM-e' (p=0.048) in females were significantly higher than those in males. The gender differences diminished in the ≥60 years age groups. There was no age-associated decline in TAM-s', while TAM-e' varied with age and gender as did MAM-e'. Although the same criteria for the TAM-s' can be used for identifying abnormal RV systolic function regardless of age and gender, age and gender differences must be considered when one utilizes the TAM-e' for the diagnosis or management of cardiovascular disease. Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

  5. Standardized echocardiographic assessment of cardiac function in normal adult zebrafish and heart disease models.

    PubMed

    Wang, Louis W; Huttner, Inken G; Santiago, Celine F; Kesteven, Scott H; Yu, Ze-Yan; Feneley, Michael P; Fatkin, Diane

    2017-01-01

    The zebrafish (Danio rerio) is an increasingly popular model organism in cardiovascular research. Major insights into cardiac developmental processes have been gained by studies of embryonic zebrafish. However, the utility of zebrafish for modeling adult-onset heart disease has been limited by a lack of robust methods for in vivo evaluation of cardiac function. We established a physiological protocol for underwater zebrafish echocardiography using high frequency ultrasound, and evaluated its reliability in detecting altered cardiac function in two disease models. Serial assessment of cardiac function was performed in wild-type zebrafish aged 3 to 12 months and the effects of anesthetic agents, age, sex and background strain were evaluated. There was a varying extent of bradycardia and ventricular contractile impairment with different anesthetic drugs and doses, with tricaine 0.75 mmol l(-1) having a relatively more favorable profile. When compared with males, female fish were larger and had more measurement variability. Although age-related increments in ventricular chamber size were greater in females than males, there were no sex differences when data were normalized to body size. Systolic ventricular function was similar in both sexes at all time points, but differences in diastolic function were evident from 6 months onwards. Wild-type fish of both sexes showed a reliance on atrial contraction for ventricular diastolic filling. Echocardiographic evaluation of adult zebrafish with diphtheria toxin-induced myocarditis or anemia-induced volume overload accurately identified ventricular dilation and altered contraction, with suites of B-mode, ventricular strain, pulsed-wave Doppler and tissue Doppler indices showing concordant changes indicative of myocardial hypocontractility or hypercontractility, respectively. Repeatability, intra-observer and inter-observer correlations for echocardiographic measurements were high. We demonstrate that high frequency

  6. Standardized echocardiographic assessment of cardiac function in normal adult zebrafish and heart disease models

    PubMed Central

    Wang, Louis W.; Huttner, Inken G.; Santiago, Celine F.; Kesteven, Scott H.; Yu, Ze-Yan; Feneley, Michael P.

    2017-01-01

    ABSTRACT The zebrafish (Danio rerio) is an increasingly popular model organism in cardiovascular research. Major insights into cardiac developmental processes have been gained by studies of embryonic zebrafish. However, the utility of zebrafish for modeling adult-onset heart disease has been limited by a lack of robust methods for in vivo evaluation of cardiac function. We established a physiological protocol for underwater zebrafish echocardiography using high frequency ultrasound, and evaluated its reliability in detecting altered cardiac function in two disease models. Serial assessment of cardiac function was performed in wild-type zebrafish aged 3 to 12 months and the effects of anesthetic agents, age, sex and background strain were evaluated. There was a varying extent of bradycardia and ventricular contractile impairment with different anesthetic drugs and doses, with tricaine 0.75 mmol l−1 having a relatively more favorable profile. When compared with males, female fish were larger and had more measurement variability. Although age-related increments in ventricular chamber size were greater in females than males, there were no sex differences when data were normalized to body size. Systolic ventricular function was similar in both sexes at all time points, but differences in diastolic function were evident from 6 months onwards. Wild-type fish of both sexes showed a reliance on atrial contraction for ventricular diastolic filling. Echocardiographic evaluation of adult zebrafish with diphtheria toxin-induced myocarditis or anemia-induced volume overload accurately identified ventricular dilation and altered contraction, with suites of B-mode, ventricular strain, pulsed-wave Doppler and tissue Doppler indices showing concordant changes indicative of myocardial hypocontractility or hypercontractility, respectively. Repeatability, intra-observer and inter-observer correlations for echocardiographic measurements were high. We demonstrate that high

  7. Antenatal architecture and activity of the human heart

    PubMed Central

    Pervolaraki, Eleftheria; Anderson, Richard A.; Benson, Alan P.; Hayes-Gill, Barrie; Holden, Arun V.; Moore, Benjamin J. R.; Paley, Martyn N.; Zhang, Henggui

    2013-01-01

    We construct the components for a family of computational models of the electrophysiology of the human foetal heart from 60 days gestational age (DGA) to full term. This requires both cell excitation models that reconstruct the myocyte action potentials, and datasets of cardiac geometry and architecture. Fast low-angle shot and diffusion tensor magnetic resonance imaging (DT-MRI) of foetal hearts provides cardiac geometry with voxel resolution of approximately 100 µm. DT-MRI measures the relative diffusion of protons and provides a measure of the average intravoxel myocyte orientation, and the orientation of any higher order orthotropic organization of the tissue. Such orthotropic organization in the adult mammalian heart has been identified with myocardial sheets and cleavage planes between them. During gestation, the architecture of the human ventricular wall changes from being irregular and isotropic at 100 DGA to an anisotropic and orthotropic architecture by 140 DGA, when it has the smooth, approximately 120° transmural change in myocyte orientation that is characteristic of the adult mammalian ventricle. The DT obtained from DT-MRI provides the conductivity tensor that determines the spread of potential within computational models of cardiac tissue electrophysiology. The foetal electrocardiogram (fECG) can be recorded from approximately 60 DGA, and RR, PR and QT intervals between the P, R, Q and T waves of the fECG can be extracted by averaging from approximately 90 DGA. The RR intervals provide a measure of the pacemaker rate, the QT intervals an index of ventricular action potential duration, and its rate-dependence, and so these intervals constrain and inform models of cell electrophysiology. The parameters of models of adult human sinostrial node and ventricular cells that are based on adult cell electrophysiology and tissue molecular mapping have been modified to construct preliminary models of foetal cell electrophysiology, which reproduce these

  8. Human penile erection and organic impotence: normal histology and histopathology.

    PubMed

    Conti, G; Virag, R

    1989-01-01

    A very large amount of human material (7 embryos, 12 stillborns, 12 penes of males aged between 2 and 86 years, as well as bioptical material from 80 subjects affected by impotence problems) has been examined so as to study the penis arterial and venous walls, the blood flow regulation mechanisms and the intracavernal trabecular morphology. The amount of muscle tissue and of collagenous connective tissue has been numerically quantified by computer-assisted methods. This study enables the authors to underline three fundamental facts: (a) it confirms the normal penile erection mechanism, and the consequent theory, (b) it confirms that vascular sclerosis is a systemic phenomenon correlated to age, and that the penis is not exempt, and (c) in the case of impotence problems, the same sclerosis phenomenon may appear at an earlier age, and therefore induce pathological impotence.

  9. The cardiac glycoside-receptor system in the human heart.

    PubMed

    Erdmann, E; Brown, L

    1983-01-01

    Specific binding sites have been demonstrated to exist in the heart for several drugs and hormones such as beta-blocking agents, cardiac glycosides, catecholamines, insulin, glucagon and acetylcholine. The specific binding sites for cardiac glycosides in the human heart have certain properties which make it likely that they are the pharmacological receptors for the therapeutic and toxic actions of digitalis glycosides: they are located in the cell membrane and bind cardioactive steroids reversibly with high affinity: half-maximal receptor binding occurs at approximately 2 nM (approximately 1.5 ng/ml) for digoxin; potassium decreases receptor affinity, calcium increases it; specific binding of ouabain, digoxin or digitoxin is related to inhibition of (Na+ + K+)-ATPase activity--which is supposed to be the receptor enzyme for cardiac glycosides. Human left ventricle contains approximately 1.5 x 10(14) binding sites/g wet weight, right ventricle approximately 0.9 x 10(14). In disease the number of receptors may decrease (hypothyroid states, myocardial infarction) or increase (hyperthyroidism, chronic hypokalaemia). Certain drugs (such as phenytoin) or different temperatures or pH changes cause a change in digitalis-receptor affinity. Thus, the number of receptors and possibly their properties are subject to regulation in clinically relevant situations. Further investigations will probably reveal those pathophysiological states, which allow the explanation of toxicity or digitalis refractoriness.

  10. Telocytes and putative stem cells in ageing human heart.

    PubMed

    Popescu, Laurentiu M; Curici, Antoanela; Wang, Enshi; Zhang, Hao; Hu, Shengshou; Gherghiceanu, Mihaela

    2015-01-01

    Tradition considers that mammalian heart consists of about 70% non-myocytes (interstitial cells) and 30% cardiomyocytes (CMs). Anyway, the presence of telocytes (TCs) has been overlooked, since they were described in 2010 (visit www.telocytes.com). Also, the number of cardiac stem cells (CSCs) has not accurately estimated in humans during ageing. We used electron microscopy to identify and estimate the number of cells in human atrial myocardium (appendages). Three age-related groups were studied: newborns (17 days-1 year), children (6-17 years) and adults (34-60 years). Morphometry was performed on low-magnification electron microscope images using computer-assisted technology. We found that interstitial area gradually increases with age from 31.3 ± 4.9% in newborns to 41 ± 5.2% in adults. Also, the number of blood capillaries (per mm(2) ) increased with several hundreds in children and adults versus newborns. CMs are the most numerous cells, representing 76% in newborns, 88% in children and 86% in adults. Images of CMs mitoses were seen in the 17-day newborns. Interestingly, no lipofuscin granules were found in CMs of human newborns and children. The percentage of cells that occupy interstitium were (depending on age): endothelial cells 52-62%; vascular smooth muscle cells and pericytes 22-28%, Schwann cells with nerve endings 6-7%, fibroblasts 3-10%, macrophages 1-8%, TCs about 1% and stem cells less than 1%. We cannot confirm the popular belief that cardiac fibroblasts are the most prevalent cell type in the heart and account for about 20% of myocardial volume. Numerically, TCs represent a small fraction of human cardiac interstitial cells, but because of their extensive telopodes, they achieve a 3D network that, for instance, supports CSCs. The myocardial (very) low capability to regenerate may be explained by the number of CSCs, which decreases fivefold by age (from 0.5% to 0.1% in newborns versus adults).

  11. Differential Intracochlear Sound Pressure Measurements in Normal Human Temporal Bones

    NASA Astrophysics Data System (ADS)

    Nakajima, Hideko Heidi; Dong, Wei; Olson, Elizabeth S.; Merchant, Saumil N.; Ravicz, Michael E.; Rosowski, John J.

    2009-02-01

    We present the first simultaneous sound pressure measurements in scala vestibuli and scala tympani of the cochlea in human cadaveric temporal bones. Micro-scale fiberoptic pressure sensors enabled the study of differential sound pressure at the cochlear base. This differential pressure is the input to the cochlear partition, driving cochlear waves and auditory transduction. Results showed that: pressure of scala vestibuli was much greater than scala tympani except at low and high frequencies where scala tympani pressure affects the input to the cochlea; the differential pressure proved to be an excellent measure of normal ossicular transduction of sound (shown to decrease 30-50 dB with ossicular disarticulation, whereas the individual scala pressures were significantly affected by non-ossicular conduction of sound at high frequencies); the middle-ear gain and differential pressure were generally bandpass in frequency dependence; and the middle-ear delay in the human was over twice that of the gerbil. Concurrent stapes velocity measurements allowed determination of the differential impedance across the partition and round-window impedance. The differential impedance was generally resistive, while the round-window impedance was consistent with a compliance in conjunction with distributed inertia and damping. Our techniques can be used to study inner-ear conductive pathologies (e.g., semicircular dehiscence), as well as non-ossicular cochlear stimulation (e.g., round-window stimulation) - situations that cannot be completely quantified by measurements of stapes velocity or scala-vestibuli pressure by themselves.

  12. Complement Interaction with Trypanosomatid Promastigotes in Normal Human Serum

    PubMed Central

    Domínguez, Mercedes; Moreno, Inmaculada; López-Trascasa, Margarita; Toraño, Alfredo

    2002-01-01

    In normal human serum (NHS), axenic promastigotes of Crithidia, Phytomonas, and Leishmania trigger complement activation, and from 1.2 to 1.8 × 105 C3 molecules are deposited per promastigote within 2.5 min. In Leishmania, promastigote C3 binding capacity remains constant during in vitro metacyclogenesis. C3 deposition on promastigotes activated through the classical complement pathway reaches a 50% maximum after ∼50 s, and represents >85% of total C3 bound. In C1q- and C2-deficient human sera, promastigotes cannot activate the classical pathway (CP) unless purified C1q or C2 factors, respectively, are supplemented, demonstrating a requirement for CP factor in promastigote C3 opsonization. NHS depleted of natural anti-Leishmania antibodies cannot trigger promastigote CP activation, but IgM addition restores C3 binding. Furthermore, Leishmania binds natural antibodies in ethylenediaminetetracetic acid (EDTA)-treated NHS; after EDTA removal, promastigote-bound IgM triggers C3 deposition in natural antibody-depleted NHS. Serum collectins and pentraxins thus do not participate significantly in NHS promastigote C3 opsonization. Real-time kinetic analysis of promastigote CP-mediated lysis indicates that between 85–95% of parasites are killed within 2.5 min of serum contact. These data indicate that successful Leishmania infection in man must immediately follow promastigote transmission, and that Leishmania evasion strategies are shaped by the selective pressure exerted by complement. PMID:11854358

  13. Altered Human Memory Modification in the Presence of Normal Consolidation.

    PubMed

    Censor, Nitzan; Buch, Ethan R; Nader, Karim; Cohen, Leonardo G

    2016-09-01

    Following initial learning, the memory is stabilized by consolidation mechanisms, and subsequent modification of memory strength occurs via reconsolidation. Yet, it is not clear whether consolidation and memory modification are the same or different systems-level processes. Here, we report disrupted memory modification in the presence of normal consolidation of human motor memories, which relate to differences in lesioned brain structure after stroke. Furthermore, this behavioral dissociation was associated with macrostructural network architecture revealed by a graph-theoretical approach, and with white-matter microstructural integrity measured by diffusion-weighted MRI. Altered macrostructural network architecture and microstructural integrity of white-matter underlying critical nodes of the related network predicted disrupted memory modification. To the best of our knowledge, this provides the first evidence of mechanistic differences between consolidation, and subsequent memory modification through reconsolidation, in human procedural learning. These findings enable better understanding of these memory processes, which may guide interventional strategies to enhance brain function and resulting behavior. Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  14. Heart transplant - slideshow

    MedlinePlus

    ... ency/presentations/100086.htm Heart transplant - series—Normal anatomy To use the sharing features on this page, ... Bethesda, MD 20894 U.S. Department of Health and Human Services National Institutes of Health Page last updated: ...

  15. Selective inhibition of the late sodium current has no adverse effect on electrophysiological or contractile function of the normal heart.

    PubMed

    Fernandes, Sarah; Hoyer, Kirsten; Liu, Gongxin; Wang, Wei-Qun; Dhalla, Arvinder K; Belardinelli, Luiz; Rajamani, Sridharan

    2014-06-01

    Inhibition of cardiac late Na(+) current (I(Na,L)) decreases sodium-dependent calcium overload in diseased hearts. Because INa,L is small in the absence of disease, its inhibition is not expected to significantly alter function of the normal heart. To test this hypothesis, we determined the effects of GS-458967 (GS967), a novel selective inhibitor of I(Na,L) (IC(50) = 0.13 μM), on cardiac function and hemodynamics. The bradycardic agent ivabradine and the Na(+) channel blocker flecainide were used for comparison. A single per os administration of GS967 (5 mg/kg) had no effect on blood pressure or heart rate (HR) in unanesthetized rats. In anesthetized rats, GS967 (0.6 ± 0.1 μM plasma concentration) had no significant effect on HR, PR or QRS electrocardiogram intervals, or contraction. Flecainide (8 mg/kg) slowed HR by 23% ± 3% (P < 0.001), prolonged the PR and QRS intervals by 42% ± 8% and 64% ± 12% (P < 0.001), and had a significant negative inotropic effect. Ivabradine (3 mg/kg) slowed HR by 36% ± 6% (P < 0.001). In rat and rabbit isolated perfused hearts, GS967 (0.1-3 μM) had no significant effects on HR, QRS interval, or contractile function. The results show that selective inhibition of cardiac I(Na,L) is not associated with chronotropic, dromotropic, inotropic, or hemodynamic changes.

  16. Hierarchical Structure of Heart Rate Variability in Humans

    NASA Astrophysics Data System (ADS)

    Gao, X. Z.; Ching, E. S. C.; Lin, D. C.

    2004-03-01

    We show a hierarchical structure (HS) of the She-Leveque form in the beat-to-beat RR intervals of heart rate variability (HRV) in humans. This structure, first found as an empirical law in turbulent fluid flows, implies further details in the HRV multifractal scaling. We tested HS using daytime RRi data from healthy subjects and heart diseased patients with congestive heart failure and found a universal law C(b) where b characterizes the multifractality of HRV and C is related to a co-dimension parameter of the most violent events in the fluctuation. The potential of diagnosis is discussed based on the characteristics of this finding. To model the HRV phenomenology, we propose a local-feedback-global-cascade (LFGC) model based on the She-Waymire (SW) cascade solution to the HS in fluid turbulence. This model extends from the previous work in that it integrates additive law multiplicatively into the cascade structure. It is an attempt to relate to the cardiovascular physiology which consists of numerous feedback controls that function primarily on the principle of additive law. In particular, the model is based on the same philosophy as the SW cascade that its multifractal dynamics consists of a singular and a modulating component. In the LFGC model, we introduce local feedback to model the dynamics of the modulating effect. The novelty of our model is to incorporate the cascade structure in the scheduling for the feedback control. This model also represents an alternative solution to the HS. We will present the simulation results by the LFGC model and discuss its implication in physiology terms.

  17. Epigenomic Landscape of Human Fetal Brain, Heart, and Liver.

    PubMed

    Yan, Liying; Guo, Hongshan; Hu, Boqiang; Li, Rong; Yong, Jun; Zhao, Yangyu; Zhi, Xu; Fan, Xiaoying; Guo, Fan; Wang, Xiaoye; Wang, Wei; Wei, Yuan; Wang, Yan; Wen, Lu; Qiao, Jie; Tang, Fuchou

    2016-02-26

    The epigenetic regulation of spatiotemporal gene expression is crucial for human development. Here, we present whole-genome chromatin immunoprecipitation followed by high throughput DNA sequencing (ChIP-seq) analyses of a wide variety of histone markers in the brain, heart, and liver of early human embryos shortly after their formation. We identified 40,181 active enhancers, with a large portion showing tissue-specific and developmental stage-specific patterns, pointing to their roles in controlling the ordered spatiotemporal expression of the developmental genes in early human embryos. Moreover, using sequential ChIP-seq, we showed that all three organs have hundreds to thousands of bivalent domains that are marked by both H3K4me3 and H3K27me3, probably to keep the progenitor cells in these organs ready for immediate differentiation into diverse cell types during subsequent developmental processes. Our work illustrates the potentially critical roles of tissue-specific and developmental stage-specific epigenomes in regulating the spatiotemporal expression of developmental genes during early human embryonic development. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Epigenomic Landscape of Human Fetal Brain, Heart, and Liver*

    PubMed Central

    Yan, Liying; Guo, Hongshan; Hu, Boqiang; Li, Rong; Yong, Jun; Zhao, Yangyu; Zhi, Xu; Fan, Xiaoying; Guo, Fan; Wang, Xiaoye; Wang, Wei; Wei, Yuan; Wang, Yan; Wen, Lu; Qiao, Jie; Tang, Fuchou

    2016-01-01

    The epigenetic regulation of spatiotemporal gene expression is crucial for human development. Here, we present whole-genome chromatin immunoprecipitation followed by high throughput DNA sequencing (ChIP-seq) analyses of a wide variety of histone markers in the brain, heart, and liver of early human embryos shortly after their formation. We identified 40,181 active enhancers, with a large portion showing tissue-specific and developmental stage-specific patterns, pointing to their roles in controlling the ordered spatiotemporal expression of the developmental genes in early human embryos. Moreover, using sequential ChIP-seq, we showed that all three organs have hundreds to thousands of bivalent domains that are marked by both H3K4me3 and H3K27me3, probably to keep the progenitor cells in these organs ready for immediate differentiation into diverse cell types during subsequent developmental processes. Our work illustrates the potentially critical roles of tissue-specific and developmental stage-specific epigenomes in regulating the spatiotemporal expression of developmental genes during early human embryonic development. PMID:26719341

  19. Long-Term Outcome of Non-Sustained Ventricular Tachycardia in Structurally Normal Hearts.

    PubMed

    Lin, Chin-Yu; Chang, Shih-Lin; Chung, Fa-Po; Chen, Yun-Yu; Lin, Yenn-Jiang; Lo, Li-Wei; Hu, Yu-Feng; Tuan, Ta-Chuan; Chao, Tze-Fan; Liao, Jo-Nan; Chang, Yao-Ting; Lin, Chung-Hsing; Allamsetty, Suresh; Walia, Rohit; Te, Abigail Louise D; Yamada, Shinya; Chiang, Shuo-Ju; Tsao, Hsuan-Ming; Chen, Shih-Ann

    2016-01-01

    The impact of non-sustained ventricular tachycardia (NSVT) on the risk of thromboembolic event and clinical outcomes in patients without structural heart disease remains undetermined. This study aimed to evaluate the association between NSVT and clinical outcomes. The study population of 5903 patients was culled from the "Registry of 24-hour ECG monitoring at Taipei Veterans General Hospital" (REMOTE database) between January 1, 2002 and December 31, 2004. Of that total, we enrolled 3767 patients without sustained ventricular tachycardia, structural heart disease, and permanent pacemaker. For purposes of this study, NSVT was defined as 3 or more consecutive beats arising below the atrioventricular node with an RR interval of <600 ms (>100 beats/min) and lasting < 30 seconds. There were 776 deaths, 2042 hospitalizations for any reason, 638 cardiovascular (CV)-related hospitalizations, 350 ischemic strokes, 409 transient ischemic accident (TIA), 368 new-onset heart failure (HF), and 260 new-onset atrial fibrillation (AF) with a mean follow-up duration of 10 ± 1 years. In multivariate analysis, the presence of NSVT was independently associated with death (hazard ratio [HR]: 1.362, 95% confidence interval [CI]: 1.071-1.731), CV hospitalization (HR: 1.527, 95% CI: 1.171-1.992), ischemic stroke (HR: 1.436, 95% CI: 1.014-2.032), TIA (HR 1.483, 95% CI: 1.069-2.057), and new-onset HF (HR: 1.716, 95% CI: 1.243-2.368). There was no significant association between the presence of NSVT and all-cause hospitalization or new-onset AF. In patients without structural heart disease, presence of NSVT on 24-hour monitoring was independently associated with death, CV hospitalization, ischemic stroke, TIA, and new onset heart failure.

  20. Failure of "effective" treatment for heart failure to improve normal customary activity.

    PubMed Central

    Walsh, J. T.; Andrews, R.; Evans, A.; Cowley, A. J.

    1995-01-01

    OBJECTIVES--To examine the effects of drug treatment on laboratory exercise tests in relation to measures of daily activity in patients with chronic heart failure. SETTING--University teaching hospital. SUBJECTS--18 patients with mild to moderate chronic heart failure (New York Heart Association functional class II-III) and 10 age matched healthy controls. METHODS--Assessments were made before and after 12 weeks of vasodilator drug treatment. Exercise capacity was measured during two different types of treadmill exercise, one using a ramp protocol and the other a fixed work load. Corridor walk tests at three self selected speeds were also undertaken and measures of customary activity assessed from pedometer scores. RESULTS--Exercise times were significantly increased from baseline (P < 0.01) with both treadmill protocols after 12 weeks of drug treatment, with a positive correlation between the duration of treadmill exercise for both protocols (r = 0.69, P < 0.01). Corridor walk tests of 100 m at a self selected slow speed also improved (P < 0.02) but these did not correlate with the changes in treadmill exercise time. The pedometer scores of the patients with heart failure were greatly reduced compared with those of the controls (258 (45) x 10(2) v 619 (67) x 10(2) steps/week, P < 0.001) and after 12 weeks of treatment were unchanged (261 (42) x 10(2) steps/week). CONCLUSIONS--These data confirm the need to use different exercise protocols when assessing the benefits of drug treatment in patients with chronic heart failure. Treatments that seem effective with conventional laboratory based exercise tests may not improve daily activities. This may reflect a failure of apparently successful treatment and should be considered when interpreting clinical trials. PMID:7488449

  1. Long-Term Outcome of Non-Sustained Ventricular Tachycardia in Structurally Normal Hearts

    PubMed Central

    Lin, Chin-Yu; Chang, Shih-Lin; Chung, Fa-Po; Chen, Yun-Yu; Lin, Yenn-Jiang; Lo, Li-Wei; Hu, Yu-Feng; Tuan, Ta-Chuan; Chao, Tze-Fan; Liao, Jo-Nan; Chang, Yao-Ting; Lin, Chung-Hsing; Allamsetty, Suresh; Walia, Rohit; Te, Abigail Louise D.; Yamada, Shinya; Chiang, Shuo-Ju; Tsao, Hsuan-Ming; Chen, Shih-Ann

    2016-01-01

    Background The impact of non-sustained ventricular tachycardia (NSVT) on the risk of thromboembolic event and clinical outcomes in patients without structural heart disease remains undetermined. This study aimed to evaluate the association between NSVT and clinical outcomes. Methods The study population of 5903 patients was culled from the “Registry of 24-hour ECG monitoring at Taipei Veterans General Hospital” (REMOTE database) between January 1, 2002 and December 31, 2004. Of that total, we enrolled 3767 patients without sustained ventricular tachycardia, structural heart disease, and permanent pacemaker. For purposes of this study, NSVT was defined as 3 or more consecutive beats arising below the atrioventricular node with an RR interval of <600 ms (>100 beats/min) and lasting < 30 seconds. Result There were 776 deaths, 2042 hospitalizations for any reason, 638 cardiovascular (CV)-related hospitalizations, 350 ischemic strokes, 409 transient ischemic accident (TIA), 368 new-onset heart failure (HF), and 260 new-onset atrial fibrillation (AF) with a mean follow-up duration of 10 ± 1 years. In multivariate analysis, the presence of NSVT was independently associated with death (hazard ratio [HR]: 1.362, 95% confidence interval [CI]: 1.071–1.731), CV hospitalization (HR: 1.527, 95% CI: 1.171–1.992), ischemic stroke (HR: 1.436, 95% CI: 1.014–2.032), TIA (HR 1.483, 95% CI: 1.069–2.057), and new-onset HF (HR: 1.716, 95% CI: 1.243–2.368). There was no significant association between the presence of NSVT and all-cause hospitalization or new-onset AF. Conclusion In patients without structural heart disease, presence of NSVT on 24-hour monitoring was independently associated with death, CV hospitalization, ischemic stroke, TIA, and new onset heart failure. PMID:27548469

  2. Human heart rate variability relation is unchanged during motion sickness

    NASA Technical Reports Server (NTRS)

    Mullen, T. J.; Berger, R. D.; Oman, C. M.; Cohen, R. J.

    1998-01-01

    In a study of 18 human subjects, we applied a new technique, estimation of the transfer function between instantaneous lung volume (ILV) and instantaneous heart rate (HR), to assess autonomic activity during motion sickness. Two control recordings of ILV and electrocardiogram (ECG) were made prior to the development of motion sickness. During the first, subjects were seated motionless, and during the second they were seated rotating sinusoidally about an earth vertical axis. Subjects then wore prism goggles that reverse the left-right visual field and performed manual tasks until they developed moderate motion sickness. Finally, ILV and ECG were recorded while subjects maintained a relatively constant level of sickness by intermittent eye closure during rotation with the goggles. Based on analyses of ILV to HR transfer functions from the three conditions, we were unable to demonstrate a change in autonomic control of heart rate due to rotation alone or due to motion sickness. These findings do not support the notion that moderate motion sickness is manifested as a generalized autonomic response.

  3. Human heart rate variability relation is unchanged during motion sickness

    NASA Technical Reports Server (NTRS)

    Mullen, T. J.; Berger, R. D.; Oman, C. M.; Cohen, R. J.

    1998-01-01

    In a study of 18 human subjects, we applied a new technique, estimation of the transfer function between instantaneous lung volume (ILV) and instantaneous heart rate (HR), to assess autonomic activity during motion sickness. Two control recordings of ILV and electrocardiogram (ECG) were made prior to the development of motion sickness. During the first, subjects were seated motionless, and during the second they were seated rotating sinusoidally about an earth vertical axis. Subjects then wore prism goggles that reverse the left-right visual field and performed manual tasks until they developed moderate motion sickness. Finally, ILV and ECG were recorded while subjects maintained a relatively constant level of sickness by intermittent eye closure during rotation with the goggles. Based on analyses of ILV to HR transfer functions from the three conditions, we were unable to demonstrate a change in autonomic control of heart rate due to rotation alone or due to motion sickness. These findings do not support the notion that moderate motion sickness is manifested as a generalized autonomic response.

  4. Statistical Properties of the Interbeat Interval Cascade in Human Hearts

    NASA Astrophysics Data System (ADS)

    Ghasemi, Fatemeh; Peinke, J.; Reza Rahimi Tabar, M.; Sahimi, Muhammad

    Statistical properties of interbeat intervals cascade in human hearts are evaluated by considering the joint probability distribution P (Δx2, τ2 Δx1, τ1) for two interbeat increments Δx1 and Δx2 of different time scales τ1 and τ2. We present evidence that the conditional probability distribution P (Δx2, τ2 | Δx1, τ1) may be described by a Chapman-Kolmogorov equation. The corresponding Kramers-Moyal (KM) coefficients are evaluated. The analysis indicates that while the first and second KM coefficients take on well-defined and significant values, the higher-order coefficients in the KM expansion are small. As a result, the joint probability distributions of the increments in the interbeat intervals are described by a Fokker-Planck equation, with the first two KM coefficients acting as the drift and diffusion coefficients. The method provides a novel technique for distinguishing two classes of subjects, namely, healthy ones and those with congestive heart failure, in terms of the drift and diffusion coefficients which behave differently for two classes of the subjects.

  5. A quantitative transcriptome reference map of the normal human hippocampus.

    PubMed

    Caracausi, Maria; Rigon, Vania; Piovesan, Allison; Strippoli, Pierluigi; Vitale, Lorenza; Pelleri, Maria Chiara

    2016-01-01

    We performed an innovative systematic meta-analysis of 41 gene expression profiles of normal human hippocampus to provide a quantitative transcriptome reference map of it, i.e. a reference typical value of expression for each of the 30,739 known mapped and the 16,258 uncharacterized (unmapped) transcripts. For this aim, we used the software called TRAM (Transcriptome Mapper), which is able to generate transcriptome maps based on gene expression data from multiple sources. We also analyzed differential expression by comparing the hippocampus with the whole brain transcriptome map to identify a typical expression pattern of this subregion compared with the whole organ. Finally, due to the fact that the hippocampus is one of the main brain region to be severely affected in trisomy 21 (the best known genetic cause of intellectual disability), a particular attention was paid to the expression of chromosome 21 (chr21) genes. Data were downloaded from microarray databases, processed, and analyzed using TRAM software. Among the main findings, the most over-expressed loci in the hippocampus are the expressed sequence tag cluster Hs.732685 and the member of the calmodulin gene family CALM2. The tubulin folding cofactor B (TBCB) gene is the best gene at behaving like a housekeeping gene. The hippocampus vs. the whole brain differential transcriptome map shows the over-expression of LINC00114, a long non-coding RNA mapped on chr21. The hippocampus transcriptome map was validated in vitro by assaying gene expression through several magnitude orders by "Real-Time" reverse transcription polymerase chain reaction (RT-PCR). The highly significant agreement between in silico and experimental data suggested that our transcriptome map may be a useful quantitative reference benchmark for gene expression studies related to human hippocampus. Furthermore, our analysis yielded biological insights about those genes that have an intrinsic over-/under-expression in the hippocampus.

  6. Characterizing the normal proteome of human ciliary body

    PubMed Central

    2013-01-01

    Background The ciliary body is the circumferential muscular tissue located just behind the iris in the anterior chamber of the eye. It plays a pivotal role in the production of aqueous humor, maintenance of the lens zonules and accommodation by changing the shape of the crystalline lens. The ciliary body is the major target of drugs against glaucoma as its inhibition leads to a drop in intraocular pressure. A molecular study of the ciliary body could provide a better understanding about the pathophysiological processes that occur in glaucoma. Thus far, no large-scale proteomic investigation has been reported for the human ciliary body. Results In this study, we have carried out an in-depth LC-MS/MS-based proteomic analysis of normal human ciliary body and have identified 2,815 proteins. We identified a number of proteins that were previously not described in the ciliary body including importin 5 (IPO5), atlastin-2 (ATL2), B-cell receptor associated protein 29 (BCAP29), basigin (BSG), calpain-1 (CAPN1), copine 6 (CPNE6), fibulin 1 (FBLN1) and galectin 1 (LGALS1). We compared the plasma proteome with the ciliary body proteome and found that the large majority of proteins in the ciliary body were also detectable in the plasma while 896 proteins were unique to the ciliary body. We also classified proteins using pathway enrichment analysis and found most of proteins associated with ubiquitin pathway, EIF2 signaling, glycolysis and gluconeogenesis. Conclusions More than 95% of the identified proteins have not been previously described in the ciliary body proteome. This is the largest catalogue of proteins reported thus far in the ciliary body that should provide new insights into our understanding of the factors involved in maintaining the secretion of aqueous humor. The identification of these proteins will aid in understanding various eye diseases of the anterior segment such as glaucoma and presbyopia. PMID:23914977

  7. Impact of gemifloxacin on the normal human intestinal microflora.

    PubMed

    Barker, P J; Sheehan, R; Teillol-Foo, M; Palmgren, A C; Nord, C E

    2001-02-01

    Gemifloxacin is a new fluoroquinolone that has been shown to possess a broad spectrum of antimicrobial activity against gram-positive and gram-negative microorganisms including methicillin-susceptible and methicillin-resistant staphylococci, Streptococcus pneumoniae, Haemophilus influenzae and most members of the family Enterobacteriaceae. The aim of the present study was to investigate the effect of gemifloxacin on the human intestinal microflora. Gemifloxacin was given in oral doses of 320 mg for 7 days to 10 healthy subjects and 5 subjects received a once-daily dose of matched placebo for 7 days. Faecal samples were collected prior to administration (days -8 and -6), during the administration period (days 2 and 4) and after withdrawal of administration (days 8, 11, 21, 28 and 56). In the aerobic intestinal microflora the numbers of enterobacteria were suppressed during the gemifloxacin administration and the numbers of enterococci and streptococci were also decreased. No other aerobic microorganisms were affected. In the anaerobic microflora the numbers of anaerobic cocci and lactobacilli were suppressed during the gemifloxacin administration while no other changes occurred. The microflora was normalized 49 days after the administration of gemifloxacin had stopped. No selection or overgrowth of resistant bacterial strains or yeasts occurred. The ecological impact of gemifloxacin was shown to be selective and similar to that of ciprofloxacin, levofloxacin and ofloxacin.

  8. Accelerated aging syndromes, are they relevant to normal human aging?

    PubMed

    Dreesen, Oliver; Stewart, Colin L

    2011-09-01

    Hutchinson-Gilford Progeria (HGPS) and Werner syndromes are diseases that clinically resemble some aspects of accelerated aging. HGPS is caused by mutations in theLMNA gene resulting in post-translational processing defects that trigger Progeria in children. Werner syndrome, arising from mutations in the WRN helicase gene, causes premature aging in young adults. What are the molecular mechanism(s) underlying these disorders and what aspects of the diseases resemble physiological human aging? Much of what we know stems from the study of patient derived fibroblasts with both mutations resulting in increased DNA damage, primarily at telomeres. However, in vivo patients with Werner's develop arteriosclerosis, among other pathologies. In HGPS patients, including iPS derived cells from HGPS patients, as well as some mouse models for Progeria, vascular smooth muscle (VSM) appears to be among the most severely affected tissues. Defective Lamin processing, associated with DNA damage, is present in VSM from old individuals, indicating processing defects may be a factor in normal aging. Whether persistent DNA damage, particularly at telomeres, is the root cause for these pathologies remains to be established, since not all progeroid Lmna mutations result in DNA damage and genome instability.

  9. Neuropeptides of human thymus in normal and pathological conditions.

    PubMed

    Mignini, F; Sabbatini, M; D'Andrea, V; Cavallotti, C

    2011-05-01

    Human thymus of healthy subjects and patients affected by thymoma-associated Myastenia Gravis were studied in order to visualize and compare the morphological distributive pattern of four neuropeptides: vasoactive intestinal peptide, substance P, neuropeptide Y, and neurotensin. Based on our observations, we formulated hypotheses on their relations in neuro-immunomodulation under physiological and pathophysiological conditions. Immuno-histochemical staining for neuropeptides was performed and morphological and morphometrical analyses were conducted on healthy and diseased thymus. In normal thymus, a specific distributive pattern was observed for the several neuropeptide-positive nerves in different thymus lobular zones. In particular substance P-positive fibers were observed in subcapsular zone, specifically located into parenchyma, where they represent the almost total amount of fibers; neurotensin-positive fibers were observed primarily located in parenchyma than perivascular site of several thymus lobular zones, and more abundant the cortico-medullary and medullary zones. Instead VIP- and NPY-positive fibers were widely distributed in perivascular and parenchymal sites of several thymus lobular zones. In thymoma, the distribution of neuropeptide-positive fibers was quantitatively reduced, while cells immunopositive to VIP and substance P were quantitatively increased and dispersed. Observation of the perivascular and parenchymal distribution of the analyzed neuropeptides suggests evidence that a regulatory function is performed by nerves and cells that secrete neuropeptide into the thymus. The alteration of neuropeptide patterns in thymoma suggests that these neurotransmitters play a role in autoimmune diseases such as Myastenia Gravis.

  10. 7Li NMR study of normal human erythrocytes

    NASA Astrophysics Data System (ADS)

    Pettegrew, J. W.; Post, J. F. M.; Panchalingam, K.; Withers, G.; Woessner, D. E.

    The biological action of lithium is of great interest because of the therapeutic efficacy of the cation in manic-depressive illness. To investigate possible molecular interactions of lithium, 7Li NMR studies were conducted on normal human erythrocytes which had been incubated with lithium chloride. The uptake of lithium ions was followed by 7Li NMR, using a dysprosium, tripolyphosphate shift reagent. Lithium uptake followed single-exponential kinetics with a time constant of 14.7 h. The intracellular lithium relaxation times were T 1 ⋍ 5 s and T 2 ⋍ 0.15 s, which implies a lengthening of the lithium correlation time. It was found that lithium does not interact significantly with hemoglobin, the erythrocyte membrane, or artificial phospholipid membranes. Based on measurements of lithium T1 and T2 in concentrated agar gels, the large difference between T1 and T2 for intracellular lithium ions may be due to diffusion of the hydrated lithium ion through heterogeneous electrostatic field gradients created by the erythrocyte membrane-associated cytoskeletal network. Lithium binding to the membrane-associated cytoskeleton, however, cannot be ruled out. Because of the large differences between T1 and T2 of intracellular lithium ions, 1Li NMR may be a sensitive and promising noninvasive method to probe the intracellular environment.

  11. Heart rate variability of human in hypoxic oxygen-argon environment

    NASA Astrophysics Data System (ADS)

    Khayrullina, Rezeda; Smoleevskiy, Alexandr; Bubeev, Yuri

    Human adaptive capacity, reliability and stability in extreme environments depend primarily on the individual resistance to stresses, includes both innate and acquired components. We have conducted studies in six healthy subjects - men aged between 24 to 42 years who psychophysiological indicators acterizing the severity of stress reactions studied directly during an emergency situation, before and after it. The subjects were in a hypoxic oxygen-argon atmosphere 10 days. Cardiovascular system is one of the first to respond to stressful reaction. The method of heart rate variability (HRV) allows us to estimate balance of sympathetic and parasympathetic parts of vegetative nervous system. In the course of the baseline study it was found that resting heart rate (HR) in the examined individuals is within normal limits. During the experiment in all subjects there was a trend towards more frequent heartbeat. Each subject at one stage or another stay in a hypoxic oxygen-argon environment heart rate go beyond the group norm, but the extent and duration of these abnormalities were significantly different. Marked increase in middle heart rate during of subjects experiment, fluctuating within a wide range (from 2.3% to 29.1%). Marked increase in middle heart rate during of subjects experiment, fluctuating within a wide range (from 2.3% to 29.1%). This suggests that the ability to adapt to living in the investigated gas environment have marked individual differences. SDNN (mean square deviation of all R-R intervals) is the integral indicator of the total effect of the sinus node to the sympathetic and parasympathetic parts of vegetative nervous system, as well as indicating the higher functional reserves of the cardiovascular systems. Increase in heart rate in the majority of subject was accompanied by an increase in individual SDNN. This suggests that the parasympathetic system is able to balance the increase in activity of the sympathetic system, and functional reserves are

  12. Syneretic response of aging normal human lens to pressure.

    PubMed

    Bettelheim, Frederick A; Lizak, Martin J; Zigler, J Samuel

    2003-01-01

    The study was designed to observe whether a reversible syneretic response to pressure is operative in normal human lenses and whether such a response demonstrates a uniform age dependence. Seven sections (from the anterior outer cortex to the posterior outer cortex) of 10 human lenses were imaged at 2 atmospheres (atm) pressure and the T(1) (spin-lattice) and T(2) (spin-spin) relaxation data on each section were collected. The pressure was then released and NMR relaxographic data were collected under 1 atm. Both T(1) and T(2) relaxation times were at their minimum in the nuclear region and at their maximum at the two outer cortexes. With increasing pressure, T(2) relaxation times decreased. The pressure-dependent change in T(2) relaxation times decreased with age. Changes in T(1) relaxation times showed no consistent pressure or age dependence. The population index of T(2) relaxation, M(2), had a maximum in the nucleus and a minimum in the two cortexes. The population index of T(1) relaxation, M(1,) was minimal in the nucleus and maximal at the two cortexes. M(2) increased with increasing pressure, whereas M(1) did not show consistent pressure dependence. The percentage of change in M(2) (DeltaM(2)) showed a statistically significant increase with increasing age, whereas the %DeltaM(1) showed no significant age-dependent trend. The positional dependence of relaxation times and the population indexes indicated that spin-spin relaxation represents the behavior of the bound water and the spin-lattice relaxation that of total water. As pressure increases, the strength of hydrogen bonding as well as the amount of bound water increases. The pressure-induced change in the total water is minimal. Thus, the free water-to-bound water ratio decreases with increasing pressure, demonstrating a significant syneretic response. The extent of reversible syneretic response decreases with age and is actually reversed in older lenses. The implication is that the ability of the human

  13. Human Error Assessment and Reduction Technique (HEART) and Human Factor Analysis and Classification System (HFACS)

    NASA Technical Reports Server (NTRS)

    Alexander, Tiffaney Miller

    2017-01-01

    Research results have shown that more than half of aviation, aerospace and aeronautics mishaps incidents are attributed to human error. As a part of Quality within space exploration ground processing operations, the identification and or classification of underlying contributors and causes of human error must be identified, in order to manage human error.This presentation will provide a framework and methodology using the Human Error Assessment and Reduction Technique (HEART) and Human Factor Analysis and Classification System (HFACS), as an analysis tool to identify contributing factors, their impact on human error events, and predict the Human Error probabilities (HEPs) of future occurrences. This research methodology was applied (retrospectively) to six (6) NASA ground processing operations scenarios and thirty (30) years of Launch Vehicle related mishap data. This modifiable framework can be used and followed by other space and similar complex operations.

  14. Is "treat your child normally" helpful advice for parents of survivors of treatment of hypoplastic left heart syndrome?

    PubMed

    Rempel, Gwen R; Harrison, Margaret J; Williamson, Deanna L

    2009-04-01

    Developing technology affords children with complex congenitally malformed hearts a chance for survival. Parents gratefully pursue life-saving options on behalf of their children, despite the risks to the life of their child, and uncertainty about outcomes. Little is known about how mothers and fathers experience parenting a child whose new state as a survivor may include less than optimal developmental sequels. Our study involved multiple interactive interviews with 9 mothers and 7 fathers of infants and preschool children with hypoplastic left heart syndrome who had survived the Norwood surgical approach. Qualitative methodology included grounded theory methods of simultaneous collection and analysis of data, and we used open and selective coding of transcribed interviews. Parents used normalization in the context of uncertainty regarding the ongoing survival of their child. Parents described their underweight children as being on their own growth curve, and viewed their developmental progress, however delayed, as reason for celebration, as they had been prepared for their child to die. There is growing evidence that children with congenitally malformed hearts who require surgical intervention during the first year of life may experience developmental delay. The use of normalization by their parents may be effective in decreasing their worry regarding the uncertain future faced by their child, but may negatively affect the developmental progress of the child if they do not seek resources to assist development. Advice from paediatric specialists for parents to view their children as normal needs to be balanced with assistance for parents to access services to support optimal growth and development of their child.

  15. Target heart rate to determine the normal value of coronary flow reserve during dobutamine stress echocardiography

    PubMed Central

    2011-01-01

    Background The determination of coronary flow reserve (CFR) is an essential concept at the moment of decision-making in ischemic heart disease. There are several direct and indirect tests to evaluate this parameter. In this sense, dobutamine stress echocardiography is one of the pharmacological method most commonly used worldwide. It has been previously demonstrated that CFR can be determined by this technique. Despite our wide experience with dobutamine stress echocardiography, we ignored the necessary heart rate to consider sufficient the test for the analysis of CFR. For this reason, our main goal was to determine the velocity of coronary flow in each stage of dobutamine stress echocardiography and the heart rate value necessary to double the baseline values of coronary flow velocity in the territory of the left anterior descending (LAD) coronary artery. Methods A total of 33 consecutive patients were analyzed. The patients included had low risk for coronary artery disease. All the participants underwent dobutamine stress echocardiography and coronary artery flow velocity was evaluated in the distal segment of LAD coronary artery using transthoracic color-Doppler echocardiography. Results The feasibility of determining CFR in the territory of the LAD during dobutamine stress echocardiography was high: 31/33 patients (94%). Mean CFR was 2.67 at de end of dobutamine test. There was an excellent concordance between delta HR (difference between baseline HR and maximum HR) and the increase in the CFR (correlation coefficient 0.84). In this sense, we found that when HR increased by 50 beats, CFR was ≥ 2 (CI 93-99.2%). In addition, 96.4% of patients reached a CFR ≥ 2 (IC 91.1 - 99%) at 75% of their predicted maximum heart rate. Conclusions We found that the feasibility of dobutamine stress echocardiography to determine CFR in the territory of the LAD coronary artery was high. In this study, it was necessary to achieve a difference of 50 bpm from baseline HR or at

  16. Target heart rate to determine the normal value of coronary flow reserve during dobutamine stress echocardiography.

    PubMed

    Forte, Ezequiel H; Rousse, Maria G; Lowenstein, Jorge A

    2011-04-04

    The determination of coronary flow reserve (CFR) is an essential concept at the moment of decision-making in ischemic heart disease. There are several direct and indirect tests to evaluate this parameter. In this sense, dobutamine stress echocardiography is one of the pharmacological method most commonly used worldwide. It has been previously demonstrated that CFR can be determined by this technique. Despite our wide experience with dobutamine stress echocardiography, we ignored the necessary heart rate to consider sufficient the test for the analysis of CFR. For this reason, our main goal was to determine the velocity of coronary flow in each stage of dobutamine stress echocardiography and the heart rate value necessary to double the baseline values of coronary flow velocity in the territory of the left anterior descending (LAD) coronary artery. A total of 33 consecutive patients were analyzed. The patients included had low risk for coronary artery disease. All the participants underwent dobutamine stress echocardiography and coronary artery flow velocity was evaluated in the distal segment of LAD coronary artery using transthoracic color-Doppler echocardiography. The feasibility of determining CFR in the territory of the LAD during dobutamine stress echocardiography was high: 31/33 patients (94%). Mean CFR was 2.67 at de end of dobutamine test.There was an excellent concordance between delta HR (difference between baseline HR and maximum HR) and the increase in the CFR (correlation coefficient 0.84). In this sense, we found that when HR increased by 50 beats, CFR was ≥ 2 (CI 93-99.2%). In addition, 96.4% of patients reached a CFR ≥ 2 (IC 91.1 - 99%) at 75% of their predicted maximum heart rate. We found that the feasibility of dobutamine stress echocardiography to determine CFR in the territory of the LAD coronary artery was high. In this study, it was necessary to achieve a difference of 50 bpm from baseline HR or at least 75% of the maximum predicted heart

  17. Telocytes and putative stem cells in ageing human heart

    PubMed Central

    Popescu, Laurentiu M; Curici, Antoanela; Wang, Enshi; Zhang, Hao; Hu, Shengshou; Gherghiceanu, Mihaela

    2015-01-01

    Tradition considers that mammalian heart consists of about 70% non-myocytes (interstitial cells) and 30% cardiomyocytes (CMs). Anyway, the presence of telocytes (TCs) has been overlooked, since they were described in 2010 (visit http://www.telocytes.com). Also, the number of cardiac stem cells (CSCs) has not accurately estimated in humans during ageing. We used electron microscopy to identify and estimate the number of cells in human atrial myocardium (appendages). Three age-related groups were studied: newborns (17 days–1 year), children (6–17 years) and adults (34–60 years). Morphometry was performed on low-magnification electron microscope images using computer-assisted technology. We found that interstitial area gradually increases with age from 31.3 ± 4.9% in newborns to 41 ± 5.2% in adults. Also, the number of blood capillaries (per mm2) increased with several hundreds in children and adults versus newborns. CMs are the most numerous cells, representing 76% in newborns, 88% in children and 86% in adults. Images of CMs mitoses were seen in the 17-day newborns. Interestingly, no lipofuscin granules were found in CMs of human newborns and children. The percentage of cells that occupy interstitium were (depending on age): endothelial cells 52–62%; vascular smooth muscle cells and pericytes 22–28%, Schwann cells with nerve endings 6–7%, fibroblasts 3–10%, macrophages 1–8%, TCs about 1% and stem cells less than 1%. We cannot confirm the popular belief that cardiac fibroblasts are the most prevalent cell type in the heart and account for about 20% of myocardial volume. Numerically, TCs represent a small fraction of human cardiac interstitial cells, but because of their extensive telopodes, they achieve a 3D network that, for instance, supports CSCs. The myocardial (very) low capability to regenerate may be explained by the number of CSCs, which decreases fivefold by age (from 0.5% to 0.1% in newborns versus adults). PMID:25545142

  18. A Simple Dissection Method for the Conduction System of the Human Heart

    ERIC Educational Resources Information Center

    Yanagawa, Nariaki; Nakajima, Yuji

    2009-01-01

    A simple dissection guide for the conduction system of the human heart is shown. The atrioventricular (AV) node, AV bundle, and right bundle branch were identified in a formaldehyde-fixed human heart. The sinu-atrial (SA) node could not be found, but the region in which SA node was contained was identified using the SA nodal artery. Gross…

  19. A Simple Dissection Method for the Conduction System of the Human Heart

    ERIC Educational Resources Information Center

    Yanagawa, Nariaki; Nakajima, Yuji

    2009-01-01

    A simple dissection guide for the conduction system of the human heart is shown. The atrioventricular (AV) node, AV bundle, and right bundle branch were identified in a formaldehyde-fixed human heart. The sinu-atrial (SA) node could not be found, but the region in which SA node was contained was identified using the SA nodal artery. Gross…

  20. Rodent heart failure models do not reflect the human circulating microRNA signature in heart failure.

    PubMed

    Vegter, Eline L; Ovchinnikova, Ekaterina S; Silljé, Herman H W; Meems, Laura M G; van der Pol, Atze; van der Velde, A Rogier; Berezikov, Eugene; Voors, Adriaan A; de Boer, Rudolf A; van der Meer, Peter

    2017-01-01

    We recently identified a set of plasma microRNAs (miRNAs) that are downregulated in patients with heart failure in comparison with control subjects. To better understand their meaning and function, we sought to validate these circulating miRNAs in 3 different well-established rat and mouse heart failure models, and correlated the miRNAs to parameters of cardiac function. The previously identified let-7i-5p, miR-16-5p, miR-18a-5p, miR-26b-5p, miR-27a-3p, miR-30e-5p, miR-199a-3p, miR-223-3p, miR-423-3p, miR-423-5p and miR-652-3p were measured by means of quantitative real time polymerase chain reaction (qRT-PCR) in plasma samples of 8 homozygous TGR(mREN2)27 (Ren2) transgenic rats and 8 (control) Sprague-Dawley rats, 6 mice with angiotensin II-induced heart failure (AngII) and 6 control mice, and 8 mice with ischemic heart failure and 6 controls. Circulating miRNA levels were compared between the heart failure animals and healthy controls. Ren2 rats, AngII mice and mice with ischemic heart failure showed clear signs of heart failure, exemplified by increased left ventricular and lung weights, elevated end-diastolic left ventricular pressures, increased expression of cardiac stress markers and reduced left ventricular ejection fraction. All miRNAs were detectable in plasma from rats and mice. No significant differences were observed between the circulating miRNAs in heart failure animals when compared to the healthy controls (all P>0.05) and no robust associations with cardiac function could be found. The previous observation that miRNAs circulate in lower levels in human patients with heart failure could not be validated in well-established rat and mouse heart failure models. These results question the translation of data on human circulating miRNA levels to experimental models, and vice versa the validity of experimental miRNA data for human heart failure.

  1. RNA expression profile of calcified bicuspid, tricuspid, and normal human aortic valves by RNA sequencing.

    PubMed

    Guauque-Olarte, Sandra; Droit, Arnaud; Tremblay-Marchand, Joël; Gaudreault, Nathalie; Kalavrouziotis, Dimitri; Dagenais, Francois; Seidman, Jonathan G; Body, Simon C; Pibarot, Philippe; Mathieu, Patrick; Bossé, Yohan

    2016-10-01

    The molecular mechanisms leading to premature development of aortic valve stenosis (AS) in individuals with a bicuspid aortic valve are unknown. The objective of this study was to identify genes differentially expressed between calcified bicuspid aortic valves (BAVc) and tricuspid valves with (TAVc) and without (TAVn) AS using RNA sequencing (RNA-Seq). We collected 10 human BAVc and nine TAVc from men who underwent primary aortic valve replacement. Eight TAVn were obtained from men who underwent heart transplantation. mRNA levels were measured by RNA-Seq and compared between valve groups. Two genes were upregulated, and none were downregulated in BAVc compared with TAVc, suggesting a similar gene expression response to AS in individuals with bicuspid and tricuspid valves. There were 462 genes upregulated and 282 downregulated in BAVc compared with TAVn. In TAVc compared with TAVn, 329 genes were up- and 170 were downregulated. A total of 273 upregulated and 147 downregulated genes were concordantly altered between BAVc vs. TAVn and TAVc vs. TAVn, which represent 56 and 84% of significant genes in the first and second comparisons, respectively. This indicates that extra genes and pathways were altered in BAVc. Shared pathways between calcified (BAVc and TAVc) and normal (TAVn) aortic valves were also more extensively altered in BAVc. The top pathway enriched for genes differentially expressed in calcified compared with normal valves was fibrosis, which support the remodeling process as a therapeutic target. These findings are relevant to understand the molecular basis of AS in patients with bicuspid and tricuspid valves.

  2. Developing a novel comprehensive framework for the investigation of cellular and whole heart electrophysiology in the in situ human heart: historical perspectives, current progress and future prospects.

    PubMed

    Taggart, Peter; Orini, Michele; Hanson, Ben; Hayward, Martin; Clayton, Richard; Dobrzynski, Halina; Yanni, Joseph; Boyett, Mark; Lambiase, Pier D

    2014-08-01

    Understanding the mechanisms of fatal ventricular arrhythmias is of great importance. In view of the many electrophysiological differences that exist between animal species and humans, the acquisition of basic electrophysiological data in the intact human heart is essential to drive and complement experimental work in animal and in-silico models. Over the years techniques have been developed to obtain basic electrophysiological signals directly from the patients by incorporating these measurements into routine clinical procedures which access the heart such as cardiac catheterisation and cardiac surgery. Early recordings with monophasic action potentials provided valuable information including normal values for the in vivo human heart, cycle length dependent properties, the effect of ischaemia, autonomic nervous system activity, and mechano-electric interaction. Transmural recordings addressed the controversial issue of the mid myocardial "M" cell. More recently, the technique of multielectrode mapping (256 electrodes) developed in animal models has been extended to humans, enabling mapping of activation and repolarisation on the entire left and right ventricular epicardium in patients during cardiac surgery. Studies have examined the issue of whether ventricular fibrillation was driven by a "mother" rotor with inhomogeneous and fragmented conduction as in some animal models, or by multiple wavelets as in other animal studies; results showed that both mechanisms are operative in humans. The simpler spatial organisation of human VF has important implications for treatment and prevention. To link in-vivo human electrophysiological mapping with cellular biophysics, multielectrode mapping is now being combined with myocardial biopsies. This technique enables region-specific electrophysiology changes to be related to underlying cellular biology, for example: APD alternans, which is a precursor of VF and sudden death. The mechanism is incompletely understood but related

  3. Fragmentation of DNA in morphologically normal human spermatozoa.

    PubMed

    Avendaño, Conrado; Franchi, Anahí; Taylor, Steven; Morshedi, Mahmood; Bocca, Silvina; Oehninger, Sergio

    2009-04-01

    To evaluate DNA fragmentation in spermatozoa with normal morphological appearance. Prospective study. Academic tertiary center. Fertile, subfertile, and infertile men were studied. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-fluorescein nick-end labeling assay and morphology assessment by phase contrast in the swim-up fractions. Simultaneous assessment of the percentage of normally shaped sperm and DNA fragmentation. No DNA fragmentation was found in spermatozoa with normal morphology in any of the samples from the fertile group. In only one sample from the subfertile group did we observed normally shaped sperm cells exhibiting DNA fragmentation. However, in all the samples from the infertile group, we observed normal spermatozoa with DNA fragmentation. Spermatozoa from this late group exhibited a high proportion of DNA damage. In infertile men with moderate and severe teratozoospermia, the spermatozoa with apparently normal morphology present in the motile fractions after swim-up may have DNA fragmentation.

  4. Alloantigen presenting function of normal human CD34+ hematopoietic cells.

    PubMed

    Rondelli, D; Andrews, R G; Hansen, J A; Ryncarz, R; Faerber, M A; Anasetti, C

    1996-10-01

    The identification of the CD34 molecule, expressed almost exclusively on human hematopoietic stem cells and committed progenitors, and the development of CD34-specific monoclonal antibodies have made procurement of relatively pure populations of CD34+ marrow cells for autologous transplantation feasible. Characterization of the immunogenicity of CD34+ marrow cells may facilitate the design of successful strategies to use these cells for allogeneic transplantation. CD34+ marrow cells from normal volunteers were enriched to greater than 98% purity by immunoaffinity chromatography on column followed by fluorescence-activated cell sorting. Purified CD34+ cells were tested for expression of HLA-DR and other accessory molecules, and function in hematopoietic colony growth and mixed leukocyte culture (MLC) assays. Greater than 95% CD34+ cells were positive for HLA-DR and 74% +/- 10% were highly positive for CD18, the common beta-chain of a leukointegrin family. CD34+/CD18- cells were small, agranular lymphocytes which contained the majority of precursors for colony-forming cells detected in long-term cultures. They produced almost no stimulation of purified T cells from HLA-DR-incompatible individuals in bulk MLC or in limiting dilution assay. In contrast, CD34+/CD18+ cells were large, were enriched for cells forming mixed colonies in short- but not long-term assays, and were capable of stimulating allogeneic T cells. CD86, a natural ligand for the T-cell activation molecule CD28, was coexpressed with CD18 in 6% +/- 3% of CD34+ cells. CD34+/CD86+ cells, but not CD34+/CD86- cells, exhibited strong alloantigen presenting function. Thus, pluripotent hematopoietic activity and alloantigen presenting function are attributes of distinct subsets of CD34+ marrow cells. CD34+/CD18- or CD34+/CD86- cells may be more effective than either the whole CD34+ population or unseparated marrow in engrafting allogeneic recipients and may also facilitate induction of tolerance.

  5. Effects of formaldehyde on normal xenotransplanted human tracheobronchial epithelium.

    PubMed Central

    Ura, H.; Nowak, P.; Litwin, S.; Watts, P.; Bonfil, R. D.; Klein-Szanto, A. J.

    1989-01-01

    Epithelial cells obtained from autopsies of full-term fetuses or infants less than 1 year old were isolated, amplified in primary cultures and inoculated in deepithelialized rat tracheas. These tracheas were then sealed and transplanted subcutaneously into irradiated athymic nude mice. Four weeks after transplantation the tracheal lumen was completely covered by epithelium, most of which was of mucociliary respiratory type. At this stage, tracheal transplants containing tracheobronchial epithelium from 20 different donors were exposed to silastic devices containing 0, 0.5, 1 and 2 mg paraformaldehyde. The tracheal transplants were examined histologically at 2, 4, 8, and 16 weeks after transplantation. Before sacrifice, all animals were injected with a single pulse of tritiated thymidine. Important epithelial alterations could be seen in the formaldehyde treated transplants with a maximum effect visible at 2 weeks after exposure. The highest dose of 2 mg produced, in most cases, numerous areas of epithelial erosion and inflammation whereas this effect was not as evident with the lower doses. All doses produced areas of hyperplastic epithelium alternating with areas of pleomorphic-atrophic epithelium. Although the differences in predominance of different types of epithelium was not clearly dose-dependent, the labeling index (LI) showed dose dependence between 2 and 4 weeks after initiation of exposure. The maximum mean LI was three to four times higher than normal, although in some focal hyperplastic-metaplastic lesions the LI was increased up to 20 times. These studies show that formaldehyde, although toxic at higher doses, is able to elicit at lower doses a proliferative response of the human respiratory epithelium that is not preceded by a massive toxic effect. This response is similar, although less intense than that of the rat respiratory epithelium in which formaldehyde proved to be a carcinogen. Images Figure 2 Figure 5 PMID:2913828

  6. Color Vision Sensitivity in Normally Dichromatic Species and Humans

    DTIC Science & Technology

    2007-11-02

    postre - ceptoral color processing. To test this, we determined color discrimination thresholds in normally occurring dichromats, including the chipmunk, the 13-lined ground squirrel, and the tree shrew.

  7. Masked diastolic dysfunction caused by exercise testing in hypertensive heart failure patients with normal ejection fraction and normal or mildly increased LV mass.

    PubMed

    Plehn, Gunnar; Vormbrock, Julia; Christ, Martin; Prull, Magnus; Lefringhausen, Lutz; Trappe, Hans-Joachim; Meissner, Axel

    2009-10-01

    It is not clear whether in patients with the clinical suspicion of heart failure with normal ejection fraction (HFNEF) exercise assessment of diastolic function may help to unmask abnormalities not detected by resting measurements. A combined radionuclide angiographic and haemodynamic exercise study was performed to confirm definite diastolic dysfunction in hypertensive patients with exertional dyspnoea and no other detectable cause of their symptoms. Only patients with normal baseline left ventricular (LV) systolic and diastolic function parameters as evaluated by routine cardiac catheterization and transmitral Doppler echocardiography were accepted (n = 38). All parameters were compared to a control group (n = 10). Twenty-eight patients showed an abnormal elevation in pulmonary capillary wedge pressure with exercise. As a consequence of a reduced exercise stroke volume (58 +/- 13 vs. 70 +/- 12 ml/m2; P = 0.01) peak cardiac output was reduced in HFNEF (9.3 +/- 1.7 vs. 7.6 +/- 2.0 l/min/m2; P = 0.02). These changes were equally demonstrable in patients with and without ventricular hypertrophy. LV end-systolic wall stress (ESWS) was increased at rest and during exercise in HFNEF patients without hypertrophy. However, a positive relationship between ESWS and the corresponding exercise stroke volume (r = 0.57; P = 0.002) was observed in the entire HFNEF group. Detection of diastolic dysfunction in suspected HFNEF is not only a question of the diagnostic methods used, but of the conditions under which the patients are investigated.

  8. Role of Genetic Testing in Patients with Ventricular Arrhythmias in Apparently Normal Hearts.

    PubMed

    Hofman, Nynke; Wilde, Arthur A M

    2016-09-01

    Ventricular arrhythmias without structural heart disease are responsible for ∼35% of patients who have sudden cardiac death before the age of 40 years. Molecular autopsy and/or cardiological investigation of nearby family members often reveals the diagnosis and genetic testing can be helpful in family screening and risk stratification in disease carriers. Extended gene panels can be screened in a short period of time at low cost. A multidisciplinary team of (genetically) specialized clinicians is necessary to judge all the available details and to decide on the significance of the variant and further strategies.

  9. A fast method to measure the 3D surface of the human heart

    NASA Astrophysics Data System (ADS)

    Cao, Yiping; Su, Xianyu; Xiang, Liqun; Chen, Wenjing; Zhang, Qican

    2003-12-01

    Three-dimensional (3-D) automatic measurement of an object is widely used in many fields. In Biology and Medicine society, it can be applicable for surgery, orthopedics, viscera disease analysis and diagnosis etc. Here a new fast method to measure the 3D surface of human heart is proposed which can provide doctors a lot of information, such as the size of heart profile, the sizes of the left or right heart ventricle, and the curvature center and radius of heart ventricle, to fully analyze and diagnose pathobiology of human heart. The new fast method is optically and noncontacted and based upon the Phase Measurement Profilometry (PMP), which has higher measuring precision. A human heart specimen experiment has verified our method.

  10. The restoration of chronotropic competence in heart failure patients with normal ejection fraction (RESET) study: rationale and design.

    PubMed

    Kass, David A; Kitzman, Dalane W; Alvarez, Guy E

    2010-01-01

    Heart failure with preserved ejection fraction (HFpEF) is the predominant form of heart failure among the elderly and in women. However, there are few if any evidence-based therapeutic options for HFpEF. The chief complaint of HFpEF is reduced tolerance to physical exertion. Recent data revealed that 1 potential mechanism of exertional intolerance in HFpEF patients is inadequate chronotropic response. Although there is considerable evidence demonstrating the benefits of rate-adaptive pacing (RAP) provided from implantable cardiac devices in patients with an impaired chronotropic response, the effect of RAP in HFpEF is unknown. The Restoration of Chronotropic CompEtence in Heart Failure PatientS with Normal Ejection FracTion (RESET) study is a prospective, multicenter, double-blind, randomized with stratification, study assessing the effect of RAP on peak oxygen consumption and quality of life. RAP therapy will be evaluated in a crossover paired fashion for each patient within each study stratum. Study strata are based on patient beta-blocker usage at time of enrollment. The study is powered to assess the impact of pacing independently in both strata. The RESET study seeks to evaluate the potential benefit of RAP in patients with symptomatic mild to moderate HFpEF and chronotropic impairment. Study enrollment began in July 2008.

  11. The effect of Ginkgo biloba extract on mitochondrial oxidative phosphorylation in the normal and ischemic rat heart.

    PubMed

    Bernatoniene, Jurga; Majiene, Daiva; Peciura, Rimantas; Laukeviciene, Ale; Bernatoniene, Ruta; Mekas, Tauras; Kasauskas, Arturas; Kopustinskiene, Dalia

    2011-07-01

    Free radical-induced myocardial damage and impairment of vascular endothelium-dependent relaxation are amongst the most important mechanisms responsible for ischemic heart injury. Ginkgo biloba leaf extract (GE) has been reported to improve blood circulation in the brain and have a beneficial impact on the cardiovascular system but its cardioprotective effects have not been elucidated yet. Therefore, this study investigated the influence of GE in 70% ethanol (1:5) administered orally to rats on the functions of isolated heart mitochondria under normal and ischemic conditions. Wistar rats were given GE or ethanol (solvent control) at a dosage of 0.32 mL/kg in drinking water for 10 and 18 days, while the control animals received untreated drinking water. Mitochondrial respiration rates were determined oxygraphically. Pyruvate and malate, succinate or palmitoyl-L-carnitine and malate were used as substrates. The GE treatment partially uncoupled mitochondrial oxidation from phosphorylation, reduced the generation of free radicals in the mitochondria, diminished the ischemia-induced V₃ decrease and the degree of respiration stimulation by exogenous cytochrome c. Thus, these results indicate that GE exerts cardioprotective effects reducing ischemia-caused impairment of the functions of heart mitochondria.

  12. Incidence and characteristics of left ventricular false tendons and trabeculations in the normal and pathologic heart by second harmonic echocardiography.

    PubMed

    Tamborini, Gloria; Pepi, Mauro; Celeste, Fabrizio; Muratori, Manuela; Susini, Francesca; Maltagliati, Anna; Veglia, Fabrizio

    2004-04-01

    We sought to review echocardiographic incidence of anomalous images (AI) as false tendons and trabeculations of the left ventricle (LV) in light of recent advancements in echocardiographic evaluation of heart anatomy. In 1580 patients the presence of false tendons, trabeculations, or thrombi was evaluated with transthoracic echocardiography and correlated to clinical characteristics and echocardiographic parameters. Incidence of AI was 46.7% (75% false tendons, 23% trabeculations, 2% thrombi), slightly higher in pathologic (48.9%) than in normal hearts (40.8%). AI were more frequent in male patients (52%) than in female patients (39.7%) and associated with LV dilatation, hypertrophy, and systolic dysfunction. False tendons and trabeculations were not related to age. Male sex was the most significant independent predictor of AI. In 2 patients, isolated LV noncompaction of myocardium was diagnosed and confirmed by magnetic resonance imaging. This study shows a high prevalence of AI for patients with and without pathologic hearts suggesting the need of updating LV echocardiographic anatomy. It also emphasizes the necessity for an awareness of these anatomic variants when evaluating patients for mural thrombi and cardiomyopathies.

  13. Heart disease is common in humans and chimpanzees, but is caused by different pathological processes.

    PubMed

    Varki, Nissi; Anderson, Dan; Herndon, James G; Pham, Tho; Gregg, Christopher J; Cheriyan, Monica; Murphy, James; Strobert, Elizabeth; Fritz, Jo; Else, James G; Varki, Ajit

    2009-02-01

    Heart disease is common in both humans and chimpanzees, manifesting typically as sudden cardiac arrest or progressive heart failure. Surprisingly, although chimpanzees are our closest evolutionary relatives, the major cause of heart disease is different in the two species. Histopathology data of affected chimpanzee hearts from two primate centers, and analysis of literature indicate that sudden death in chimpanzees (and in gorillas and orangutans) is commonly associated with diffuse interstitial myocardial fibrosis of unknown cause. In contrast, most human heart disease results from coronary artery atherosclerosis, which occludes myocardial blood supply, causing ischemic damage. The typical myocardial infarction of humans due to coronary artery thrombosis is rare in these apes, despite their human-like coronary-risk-prone blood lipid profiles. Instead, chimpanzee 'heart attacks' are likely due to arrythmias triggered by myocardial fibrosis. Why do humans not often suffer from the fibrotic heart disease so common in our closest evolutionary cousins? Conversely, why do chimpanzees not have the kind of heart disease so common in humans? The answers could be of value to medical care, as well as to understanding human evolution. A preliminary attempt is made to explore possibilities at the histological level, with a focus on glycosylation changes.

  14. Genome-wide analysis of alternative splicing during human heart development

    NASA Astrophysics Data System (ADS)

    Wang, He; Chen, Yanmei; Li, Xinzhong; Chen, Guojun; Zhong, Lintao; Chen, Gangbing; Liao, Yulin; Liao, Wangjun; Bin, Jianping

    2016-10-01

    Alternative splicing (AS) drives determinative changes during mouse heart development. Recent high-throughput technological advancements have facilitated genome-wide AS, while its analysis in human foetal heart transition to the adult stage has not been reported. Here, we present a high-resolution global analysis of AS transitions between human foetal and adult hearts. RNA-sequencing data showed extensive AS transitions occurred between human foetal and adult hearts, and AS events occurred more frequently in protein-coding genes than in long non-coding RNA (lncRNA). A significant difference of AS patterns was found between foetal and adult hearts. The predicted difference in AS events was further confirmed using quantitative reverse transcription-polymerase chain reaction analysis of human heart samples. Functional foetal-specific AS event analysis showed enrichment associated with cell proliferation-related pathways including cell cycle, whereas adult-specific AS events were associated with protein synthesis. Furthermore, 42.6% of foetal-specific AS events showed significant changes in gene expression levels between foetal and adult hearts. Genes exhibiting both foetal-specific AS and differential expression were highly enriched in cell cycle-associated functions. In conclusion, we provided a genome-wide profiling of AS transitions between foetal and adult hearts and proposed that AS transitions and deferential gene expression may play determinative roles in human heart development.

  15. Three-dimensional heart dose reconstruction to estimate normal tissue complication probability after breast irradiation using portal dosimetry

    SciTech Connect

    Louwe, R. J. W.; Wendling, M.; Herk, M. B. van; Mijnheer, B. J.

    2007-04-15

    Irradiation of the heart is one of the major concerns during radiotherapy of breast cancer. Three-dimensional (3D) treatment planning would therefore be useful but cannot always be performed for left-sided breast treatments, because CT data may not be available. However, even if 3D dose calculations are available and an estimate of the normal tissue damage can be made, uncertainties in patient positioning may significantly influence the heart dose during treatment. Therefore, 3D reconstruction of the actual heart dose during breast cancer treatment using electronic imaging portal device (EPID) dosimetry has been investigated. A previously described method to reconstruct the dose in the patient from treatment portal images at the radiological midsurface was used in combination with a simple geometrical model of the irradiated heart volume to enable calculation of dose-volume histograms (DVHs), to independently verify this aspect of the treatment without using 3D data from a planning CT scan. To investigate the accuracy of our method, the DVHs obtained with full 3D treatment planning system (TPS) calculations and those obtained after resampling the TPS dose in the radiological midsurface were compared for fifteen breast cancer patients for whom CT data were available. In addition, EPID dosimetry as well as 3D dose calculations using our TPS, film dosimetry, and ionization chamber measurements were performed in an anthropomorphic phantom. It was found that the dose reconstructed using EPID dosimetry and the dose calculated with the TPS agreed within 1.5% in the lung/heart region. The dose-volume histograms obtained with EPID dosimetry were used to estimate the normal tissue complication probability (NTCP) for late excess cardiac mortality. Although the accuracy of these NTCP calculations might be limited due to the uncertainty in the NTCP model, in combination with our portal dosimetry approach it allows incorporation of the actual heart dose. For the anthropomorphic

  16. Heart rate recovery normality data recorded in response to a maximal exercise test in physically active men.

    PubMed

    Vicente-Campos, Davinia; Martín López, Aurora; Nuñez, María Jesús; López Chicharro, Jose

    2014-06-01

    Despite a growing clinical interest in determining the heart rate recovery (HRR) response to exercise, the limits of a normal HRR have not yet been well established. This study was designed to examine HRR following a controlled maximal exercise test in healthy, physically active adult men. The subjects recruited (n = 789) performed a maximal stress test on a treadmill. HRR indices were calculated by subtracting the first and third minute heart rates (HRs) during recovery from the maximal HR obtained during stress testing and designated these as HRR-1 and HRR-3, respectively. The relative change in HRR was determined as the decrease in HR produced at the time points 1 and 3 min after exercise as a percentage of the peak HR (%HRR-1/HR(peak) and %HRR-3/HR(peak), respectively). Percentile values of HRR-1 and HRR-3 were generated for the study population. Mean HHR-1 and HHR-3 were 15.24 ± 8.36 and 64.58 ± 12.17 bpm, respectively, and %HRR-1/HR(peak) and %HRR-3/HR(peak) were 8.60 ± 4.70 and 36.35 ± 6.79%, respectively. Significant correlation was detected between Peak VO2 and HRR-3 (r = 0.36; p < 0.001) or %HRR-3/HR(peak) (r = 0.23; p < 0.001). Our study provides normality data for HRR following a maximal Ergometry test obtained in a large population of physically active men.

  17. Cardioprotective stress response in the human fetal heart

    PubMed Central

    Coles, John G.; Boscarino, Cathy; Takahashi, Mark; Grant, Diane; Chang, Astra; Ritter, Julia; Dai, Xiaojing; Du, Changqing; Musso, Gabriel; Yamabi, Hideaki; Goncalves, Jason; Kumar, Ashu Sunny; Woodgett, James; Lu, Huanzhang; Hannigan, Gregory

    2016-01-01

    Objective We propose that the fetal heart is highly resilient to hypoxic stress. Our objective was to elucidate the human fetal gene expression profile in response to simulated ischemia and reperfusion to identify molecular targets that account for the innate cardioprotection exhibited by the fetal phenotype. Methods Primary cultures of human fetal cardiac myocytes (gestational age, 15–20 weeks) were exposed to simulated ischemia and reperfusion in vitro by using a simulated ischemic buffer under anoxic conditions. Total RNA from treated and baseline cells were isolated, reverse transcribed, and labeled with Cy3 or Cy5 and hybridized to a human cDNA microarray for expression analysis. This analysis revealed a highly significant (false discovery rate, <3%) suppression of interleukin 6 transcript levels during the reperfusion phase confirmed by means of quantitative polymerase chain reaction (0.25 ± 0.11-fold). Interleukin 6 signaling during ischemia and reperfusion was assessed at the protein expression level by means of Western measurements of interleukin 6 receptor, the signaling subunit of the interleukin 6 receptor complex (gp130), and signal transducer of activated transcription 3. Posttranslational changes in the protein kinase B signaling pathway were determined on the basis of the phosphorylation status of protein kinase B, mitogen-activated protein kinase, and glycogen synthase kinase 3β. The effect of suppression of a prohypertrophic kinase, integrin-linked kinase, with short-interfering RNA was determined in an ischemia and reperfusion–stressed neonatal rat cardiac myocyte model. Endogenous secretion of interleukin 6 protein in culture supernatants was measured by enzyme-linked immunosorbent assay. Results Human fetal cardiac myocytes exhibited a significantly lower rate of apoptosis induction during ischemia and reperfusion and after exposure to staurosporine and recombinant interleukin 6 compared with that observed in neonatal rat cardiac myocytes

  18. Structure and function relationship of human heart from DENSE MRI

    NASA Astrophysics Data System (ADS)

    Moghaddam, Abbas N.; Gharib, Morteza

    2007-03-01

    The study here, suggests a macroscopic structure for the Left Ventricle (LV), based on the heart kinematics which is obtained through imaging. The measurement of the heart muscle deformation using the Displacement ENcoding with Stimulated Echoes (DENSE) MRI, which describes the heart kinematics in the Lagrangian frame work, is used to determine the high resolution patterns of true myocardial strain. Subsequently, the tangential Shortening Index (SI) and the thickening of the LV wall are calculated for each data point. Considering the heart as a positive-displacement pump, the contribution of each segment of LV in the heart function, can be determined by the SI and thickening of the wall in the same portion. Hence the SI isosurfaces show the extent and spatial distribution of the heart activity and reveals its macro structure. The structure and function of the heart are, therefore, related which in turn results in a macroscopic model for the LV. In particular, it was observed that the heart functionality is not uniformly distributed in the LV, and the regions with greater effect on the pumping process, form a band which wraps around the heart. These results, which are supported by the established histological evidence, may be considered as a landmark in connecting the structure and function of the heart through imaging. Furthermore, the compatibility of this model with microscopic observations about the fiber direction is investigated. This method may be used for planning as well as post evaluation of the ventriculoplasty.

  19. Proteome-wide protein concentrations in the human heart.

    PubMed

    Aye, Thin Thin; Scholten, Arjen; Taouatas, Nadia; Varro, Andras; Van Veen, Toon A B; Vos, Marc A; Heck, Albert J R

    2010-10-01

    The largest component of the human heart, the left ventricle (LV), plays a major role in delivering blood throughout the body. Therefore, an in-depth detailed quantitative proteome analysis of the human LV is a valuable resource. For this purpose, a multifaceted proteomics approach combining differential sample fractionations (gel, strong cation exchange (SCX)), enzymatic digestions (trypsin, chymotrypsin, LysN), and peptide fragmentation techniques (CID and ETcaD) was used to enhance protein sequence coverage, identification confidence and quantitative abundance determination. Using stringent criteria, 3584 distinct proteins could be identified from the latest well-annotated Swissprot database (23,000 entries). Commutatively, the over 130,000 identified MS/MS spectra were used to assess concentrations of each identified LV protein through a combination of spectral counting methods. Among the most concentrated proteins, many currently used biomarkers for detection of myocardial infarction reside. These cardiac leakage markers have a good diagnostic power, but their prognostic potential seems limited. Discovery of markers that represent etiological determinants of cardiac disease require a shift of focus towards the signaling proteome. Therefore, a protein-class centered quantitative analysis of kinases, phosphatases and GTPases was adopted. These comparative analyses revealed many cardiac involved kinases (PKA, CaMKII, ERK) to reside among the most abundant signaling proteins, and also to mediate many observed in vivo phosphorylation sites. The abundance chart of signaling proteins may assist in identifying novel functional pathways, for instance through the abundant, but relatively little known, kinases STK38L and OXSR1. The obtained quantitative protein library of the human left ventricle is a valuable resource to isolate signaling based, putative biomarkers with concentrations likely to be detectable in plasma.

  20. Inhibitors of human heart chymase based on a peptide library.

    PubMed Central

    Bastos, M; Maeji, N J; Abeles, R H

    1995-01-01

    We have synthesized two sets of noncleavable peptide-inhibitor libraries to map the S and S' subsites of human heart chymase. Human heart chymase is a chymotrypsin-like enzyme that converts angiotensin I to angiotensin II. The first library consists of peptides with 3-fluorobenzylpyruvamides in the P1 position. (Amino acid residues of substrates numbered P1, P2, etc., are toward the N-terminal direction, and P'1, P'2, etc., are toward the C-terminal direction from the scissile bond.) The P'1 and P'2 positions were varied to contain each one of the 20 naturally occurring amino acids and P'3 was kept constant as an arginine. The second library consists of peptides with phenylalanine keto-amides at P1, glycine in P'1, and benzyloxycarbonyl (Z)-isoleucine in P4. The P2 and P3 positions were varied to contain each of the naturally occurring amino acids, except for cysteine and methionine. The peptides of both libraries are attached to a solid support (pins). The peptides are evaluated by immersing the pins in a solution of the target enzyme and evaluating the amount of enzyme absorbed. The pins with the best inhibitors will absorb most enzyme. The libraries select the best and worst inhibitors within each group of peptides and provide an approximate ranking of the remaining peptides according to Ki. Through this library, we determined that Z-Ile-Glu-Pro-Phe-CO2Me and (F)-Phe-CO-Glu-Asp-ArgOMe should be the best inhibitors of chymase in this collection of peptide inhibitors. We synthesized the peptides and found Ki values were 1 nM and 1 microM, respectively. The corresponding Ki values for chymotrypsin were 10 nM and 100 microM. The use of libraries of inhibitors has advantages over the classical method of synthesis of potential inhibitors in solution: the libraries are reusable, the same libraries can be used with a variety of different serine proteases, and the method allows the screening of hundreds of compounds in short periods of time. Images Fig. 1 PMID:7624313

  1. Inhibitors of human heart chymase based on a peptide library.

    PubMed

    Bastos, M; Maeji, N J; Abeles, R H

    1995-07-18

    We have synthesized two sets of noncleavable peptide-inhibitor libraries to map the S and S' subsites of human heart chymase. Human heart chymase is a chymotrypsin-like enzyme that converts angiotensin I to angiotensin II. The first library consists of peptides with 3-fluorobenzylpyruvamides in the P1 position. (Amino acid residues of substrates numbered P1, P2, etc., are toward the N-terminal direction, and P'1, P'2, etc., are toward the C-terminal direction from the scissile bond.) The P'1 and P'2 positions were varied to contain each one of the 20 naturally occurring amino acids and P'3 was kept constant as an arginine. The second library consists of peptides with phenylalanine keto-amides at P1, glycine in P'1, and benzyloxycarbonyl (Z)-isoleucine in P4. The P2 and P3 positions were varied to contain each of the naturally occurring amino acids, except for cysteine and methionine. The peptides of both libraries are attached to a solid support (pins). The peptides are evaluated by immersing the pins in a solution of the target enzyme and evaluating the amount of enzyme absorbed. The pins with the best inhibitors will absorb most enzyme. The libraries select the best and worst inhibitors within each group of peptides and provide an approximate ranking of the remaining peptides according to Ki. Through this library, we determined that Z-Ile-Glu-Pro-Phe-CO2Me and (F)-Phe-CO-Glu-Asp-ArgOMe should be the best inhibitors of chymase in this collection of peptide inhibitors. We synthesized the peptides and found Ki values were 1 nM and 1 microM, respectively. The corresponding Ki values for chymotrypsin were 10 nM and 100 microM. The use of libraries of inhibitors has advantages over the classical method of synthesis of potential inhibitors in solution: the libraries are reusable, the same libraries can be used with a variety of different serine proteases, and the method allows the screening of hundreds of compounds in short periods of time.

  2. Muscarinic M3 receptor subtype gene expression in the human heart.

    PubMed

    Hellgren, I; Mustafa, A; Riazi, M; Suliman, I; Sylvén, C; Adem, A

    2000-01-20

    The heart is an important target organ for cholinergic function. In this study, muscarinic receptor subtype(s) in the human heart were determined using reverse transcription-polymerase chain reaction. Our results demonstrated muscarinic receptor M2 and M3 subtype RNA in left/right atria/ventricles of donor hearts. Receptor autoradiography analysis using selective muscarinic ligands indicated an absence of M1 receptor subtype in the human heart. The level of muscarinic receptor binding in atria was two to three times greater than in ventricles. Our results suggest that muscarinic receptors in the human heart are of the M2 and M3 subtypes. This is the first report of M3 receptors in the human myocardium.

  3. Increased phase synchronization of spontaneous calcium oscillations in epileptic human versus normal rat astrocyte cultures

    NASA Astrophysics Data System (ADS)

    Balázsi, Gábor; Cornell-Bell, Ann H.; Moss, Frank

    2003-06-01

    Stochastic synchronization analysis is applied to intracellular calcium oscillations in astrocyte cultures prepared from epileptic human temporal lobe. The same methods are applied to astrocyte cultures prepared from normal rat hippocampus. Our results indicate that phase-repulsive coupling in epileptic human astrocyte cultures is stronger, leading to an increased synchronization in epileptic human compared to normal rat astrocyte cultures.

  4. A Multiscale Model of Cardiovascular System Including an Immersed Whole Heart in the Cases of Normal and Ventricular Septal Defect (VSD).

    PubMed

    Lee, Wanho; Jung, Eunok

    2015-07-01

    A mathematical and computational model combining the heart and circulatory system has been developed to understand the hemodynamics of circulation under normal conditions and ventricular septal defect (VSD). The immersed boundary method has been introduced to describe the interaction between the moving two-dimensional heart and intracardiac blood flow. The whole-heart model is governed by the Navier-Stokes system; this system is combined with a multi-compartment model of circulation using pressure-flow relations and the linearity of the discretized Navier-Stokes system. We investigate the velocity field, flowmeters, and pressure-volume loop in both normal and VSD cases. Simulation results show qualitatively good agreements with others found in the literature. This model, combining the heart and circulation, is useful for understanding the complex, hemodynamic mechanisms involved in normal circulation and cardiac diseases.

  5. [Can the child with congenital heart disease have a normal life-style?].

    PubMed

    Mătăsaru, Silvia; Felea, Doina; Cosmescu, Adriana; Barbacariu, Liliana; Petroaie, Antoneta; Momanu, Otilia; Slănină, Ana Maria

    2005-01-01

    Is it possible for the child with Congenital Heart Disease to have an adequate life-style? The life-style of the child mainly depends on the life-style of his/her family. Consecutively, the parents themselves must adopt a healthy life-style to be a good example for their children; on the other side, certain restrictions (hyponatremic regimen, the limitation of the physical activity) must be shared among entire family, the education of the parents being essential. To accomplish this, there must be an interdisciplinary team, including the GP, the cardiologist, the psychotherapist and the physiotherapist. This article discusses the factors influencing the life-style, their dependence on the family social status, on the diagnosis, on the child's age. The psychotherapeutic approach becomes very important at puberty. There is also essential the transition to the adult life, so these children will benefit of maximum of choices in life.

  6. Atrioventricular and ventriculoatrial branches of the coronary arteries in human hearts.

    PubMed

    Tose, D; DiDio, L J; Baptista, C A; Miglino, M A

    1991-01-01

    Atrioventricular (AV) and ventriculoatrial (VA) branches of the coronary arteries are vessels which supply simultaneously atrial and ventricular walls by means of recurrent rami. The terminology indicates the name of the main vessel followed by the name of the recurrent vessel both combined in an adjective. These branches establish a vascular 'suture' across the coronary sulcus in front (superficially to) or behind (deeply to) the trunks of the right coronary artery and of the left coronary artery (circumflex artery). The AV and VA branches, found in 95% of 40 human hearts, should be considered a normal characteristic of the coronary circulation and an important anatomical factor for the clinical interpretation of pathological cardiac phenomena.

  7. Renal denervation in heart failure with normal left ventricular ejection fraction. Rationale and design of the DIASTOLE (DenervatIon of the renAl Sympathetic nerves in hearT failure with nOrmal Lv Ejection fraction) trial.

    PubMed

    Verloop, Willemien L; Beeftink, Martine M A; Nap, Alex; Bots, Michiel L; Velthuis, Birgitta K; Appelman, Yolande E; Cramer, Maarten-Jan; Agema, Willem R P; Scholtens, Asbjorn M; Doevendans, Pieter A; Allaart, Cor P; Voskuil, Michiel

    2013-12-01

    Aim Increasing evidence suggests an important role for hyperactivation of the sympathetic nervous system (SNS) in the clinical phenomena of heart failure with normal LVEF (HFNEF) and hypertension. Moreover, the level of renal sympathetic activation is directly related to the severity of heart failure. Since percutaneous renal denervation (pRDN) has been shown to be effective in modulating elevated SNS activity in patients with hypertension, it can be hypothesized that pRDN has a positive effect on HFNEF. The DIASTOLE trial will investigate whether renal sympathetic denervation influences parameters of HFNEF. Methods DIASTOLE is a multicentre, randomized controlled trial. Sixty patients, diagnosed with HFNEF and treated for hypertension, will be randomly allocated in a 1:1 ratio to undergo renal denervation on top of medical treatment (n = 30) or to maintain medical treatment alone (n = 30). The primary objective is to investigate the efficacy of pRDN by means of pulsed wave Doppler echocardiographic parameters. Secondary objectives include safety of pRDN and a comparison of changes in the following parameters after pRDN: LV mass, LV volume, LVEF, and left atrial volume as determined by magnetic resonance imaging. Also, MIBG (metaiodobenzylguanidine) uptake and washout, BNP levels, blood pressure, heart rate variability, exercise capacity, and quality of life will be assessed. Perspective DIASTOLE is a randomized controlled trial evaluating renal denervation as a treatment option for HFNEF. The results of the current trial will provide important information regarding the treatment of HFNEF, and therefore may have major impact on future therapeutic strategies. Trail registration NCT01583881.

  8. Neuregulin-1β induces proliferation, survival and paracrine signaling in normal human cardiac ventricular fibroblasts.

    PubMed

    Kirabo, Annet; Ryzhov, Sergey; Gupte, Manisha; Sengsayadeth, Seng; Gumina, Richard J; Sawyer, Douglas B; Galindo, Cristi L

    2017-04-01

    Neuregulin-1β (NRG-1β) is critical for cardiac development and repair, and recombinant forms are currently being assessed as possible therapeutics for systolic heart failure. We previously demonstrated that recombinant NRG-1β reduces cardiac fibrosis in an animal model of cardiac remodeling and heart failure, suggesting that there may be direct effects on cardiac fibroblasts. Here we show that NRG-1β receptors (ErbB2, ErbB3, and ErbB4) are expressed in normal human cardiac ventricular (NHCV) fibroblast cell lines. Treatment of NHCV fibroblasts with recombinant NRG-1β induced activation of the AKT pathway, which was phosphoinositide 3-kinase (PI3K)-dependent. Moreover, the NRG-1β-induced PI3K/AKT signaling in these cells required phosphorylation of both ErbB2 and ErbB3 receptors at tyrosine (Tyr)1248 and Tyr1289 respectively. RNASeq analysis of NRG-1β-treated cardiac fibroblasts obtained from three different individuals revealed a global gene expression signature consistent with cell growth and survival. We confirmed enhanced cellular proliferation and viability in NHCV fibroblasts in response to NRG-1β, which was abrogated by PI3K, ErbB2, and ErbB3 inhibitors. NRG-1β also induced production and secretion of cytokines (interleukin-1α and interferon-γ) and pro-reparative factors (angiopoietin-2, brain-derived neurotrophic factor, and crypto-1), suggesting a role in cardiac repair through the activation of paracrine signaling. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Restoration of normal sympathetic neural function in heart failure following baroreflex activation therapy: final 43-month study report.

    PubMed

    Dell'Oro, Raffaella; Gronda, Edoardo; Seravalle, Gino; Costantino, Giuseppe; Alberti, Luca; Baronio, Barbara; Staine, Tiziana; Vanoli, Emilio; Mancia, Giuseppe; Grassi, Guido

    2017-08-14

    Baroreflex activation therapy (BAT) exerts in severe heart failure sympathoinhibitory effects, improving clinical variables and reducing hospitalization rate. The current follow-up study was aimed at determining the long-term effects of BAT, assessing whether BAT in heart failure allows to restore physiological levels of sympathetic function. Seven patients out of the 11 heart failure patients aged 66.5 ± 3 years (mean ± SEM) in New York Heart Association Class III with left ventricular ejection fraction 40% or less and impaired functional capacity recruited in the study survived at the final follow-up (43.5 ± 2.1 months). Measurements included muscle sympathetic nerve activity (MSNA, microneurography) and spontaneous baroreflex-MSNA sensitivity together with hospitalization rate, echocardiography, Minnesota score, New York Heart Association class and standard clinical data. Measurements were collected before and at 6, 21 and 43 months following BAT. Data were compared with those collected in 17 age-matched healthy controls. All assessments were made with the heart failure patient on optimal active therapy. In the seven patients, BAT maintained its beneficial effects over 43.5 ± 2.1 months of follow-up. MSNA values underwent a progressive significant reduction from baseline to 21 and 43 months follow-up following BAT (from 46.2 ± 2.4 to 31.3 ± 3.0 e 26.6 ± 2.0 bursts/min, P < 0.05 at least), becoming almost superimposable to the ones seen in healthy controls (25.5 ± 0.8 bursts/min). Baroreflex-MSNA sensitivity improved, without achieving, however, a full normalization. Blood pressure and heart rate did not change. Left ventricular ejection fraction improved significantly from 32.3 ± 2 to 36.7 ± 3% (P < 0.05). Hospitalization rate decreased substantially when measured as days/year/patients it decreased from 10.3 ± 2.5 preimplant to 1.01 ± 1.4 at the 43.5th month follow-up (P < 0.02). No side

  10. Time-lapse imaging of human heart motion with switched array UWB radar.

    PubMed

    Brovoll, Sverre; Berger, Tor; Paichard, Yoann; Aardal, Øyvind; Lande, Tor Sverre; Hamran, Svein-Erik

    2014-10-01

    Radar systems for detection of human heartbeats have mostly been single-channel systems with limited spatial resolution. In this paper, a radar system for ultra-wideband (UWB) imaging of the human heart is presented. To make the radar waves penetrate the human tissue the antenna is placed very close to the body. The antenna is an array with eight elements, and an antenna switch system connects the radar to the individual elements in sequence to form an image. Successive images are used to build up time-lapse movies of the beating heart. Measurements on a human test subject are presented and the heart motion is estimated at different locations inside the body. The movies show rhythmic motion consistent with the beating heart, and the location and shape of the reflections correspond well with the expected response form the heart wall. The spatial dependent heart motion is compared to ECG recordings, and it is confirmed that heartbeat modulations are seen in the radar data. This work shows that radar imaging of the human heart may provide valuable information on the mechanical movement of the heart.

  11. Effect of digoxin on the heart in normal subjects: influence of isometric exercise and autonomic blockade: a noninvasive study.

    PubMed

    Partanen, J; Heikkilä, J; Pellinen, T; Nieminen, M S

    1988-03-01

    1. Eight healthy subjects were studied before digoxin and after successive therapy periods of 1 week 0.125, 0.25 and 0.50 mg of digoxin. The mean serum concentrations (+/- s. d.) were 0.4 +/- 0.2, 0.6 +/- 0.3 and 1.4 +/- 0.5 nmol l-1, respectively. The effects of digitalis were studied by echocardiography and systolic time intervals at rest and after 3 min handgrip exercise. Effects of simultaneous autonomic blockade induced by atropine and propranolol were also examined. 2. Digoxin in increasing doses slowed the heart rate at rest; with the daily dose of 0.50 mg from 63 +/- 10 to 53 +/- 6 beats min-1, and fractional shortening rose from 28 +/- 6 to 33 +/- 3% (P less than 0.05 for both). Preload, afterload and cardiac output did not change. The electromechanic systolic time index (QS2I) decreased (P less than 0.001) and the observed alteration of QS2I was dose-related. 3. The influence of digoxin was similar during isometric exercise, except for unchanged fractional shortening. 4. During autonomic blockade digoxin slowed the intrinsic heart rate from 93 +/- 6 to 86 +/- 6 beats min-1 (0.25 mg) and to 83 +/- 6 beats min-1 (0.50 mg) (P less than 0.01 for both). QS2I was shortened (P less than 0.01). Echocardiographically determined ejection phase indices remained unchanged. 5. When handgrip stress was induced during autonomic blockade, digoxin evoked a clearcut increase in contractile function, resembling the effects of digoxin alone at rest. Thus, fractional shortening increased by 14% and QS2I decreased by 16 ms (P less than 0.01 for both). 6. We conclude that digoxin increases the contractility in normal heart without changes in loading conditions. The rise in inotropy at rest is obvious from both fractional shortening by echo and systolic time intervals. The same takes place during handgrip with autonomic blockade, when the heart lacks sympathetic support. The influence of long-term digoxin on heart rate is partly direct without autonomic mediation. The effect of

  12. Effect of digoxin on the heart in normal subjects: influence of isometric exercise and autonomic blockade: a noninvasive study.

    PubMed Central

    Partanen, J; Heikkilä, J; Pellinen, T; Nieminen, M S

    1988-01-01

    1. Eight healthy subjects were studied before digoxin and after successive therapy periods of 1 week 0.125, 0.25 and 0.50 mg of digoxin. The mean serum concentrations (+/- s. d.) were 0.4 +/- 0.2, 0.6 +/- 0.3 and 1.4 +/- 0.5 nmol l-1, respectively. The effects of digitalis were studied by echocardiography and systolic time intervals at rest and after 3 min handgrip exercise. Effects of simultaneous autonomic blockade induced by atropine and propranolol were also examined. 2. Digoxin in increasing doses slowed the heart rate at rest; with the daily dose of 0.50 mg from 63 +/- 10 to 53 +/- 6 beats min-1, and fractional shortening rose from 28 +/- 6 to 33 +/- 3% (P less than 0.05 for both). Preload, afterload and cardiac output did not change. The electromechanic systolic time index (QS2I) decreased (P less than 0.001) and the observed alteration of QS2I was dose-related. 3. The influence of digoxin was similar during isometric exercise, except for unchanged fractional shortening. 4. During autonomic blockade digoxin slowed the intrinsic heart rate from 93 +/- 6 to 86 +/- 6 beats min-1 (0.25 mg) and to 83 +/- 6 beats min-1 (0.50 mg) (P less than 0.01 for both). QS2I was shortened (P less than 0.01). Echocardiographically determined ejection phase indices remained unchanged. 5. When handgrip stress was induced during autonomic blockade, digoxin evoked a clearcut increase in contractile function, resembling the effects of digoxin alone at rest. Thus, fractional shortening increased by 14% and QS2I decreased by 16 ms (P less than 0.01 for both). 6. We conclude that digoxin increases the contractility in normal heart without changes in loading conditions. The rise in inotropy at rest is obvious from both fractional shortening by echo and systolic time intervals. The same takes place during handgrip with autonomic blockade, when the heart lacks sympathetic support. The influence of long-term digoxin on heart rate is partly direct without autonomic mediation. The effect of

  13. Mechanisms that initiate ventricular tachycardia in the infarcted human heart

    PubMed Central

    Segal, Oliver R.; Chow, Anthony W.C.; Peters, Nicholas S.; Davies, D. Wyn

    2010-01-01

    Background Precise mechanisms that initiate ventricular tachycardia (VT) in the intact infarcted human heart have not been defined. Objective The purpose of this study was to investigate the mechanisms that underlie human postinfarct VT initiation. Methods Noncontact mapping of the left ventricle was performed in 9 patients (age 67.1 ± 7.8 years, ejection fraction 34.4% ± 5%) with previous myocardial infarction and sustained monomorphic VT. Results Circuits in which ≥30% of the diastolic pathway (DP) could be defined were identified in 12 VTs (cycle length 357 ± 60 ms). Eighteen VT episodes were initiated with pacing, and one occurred spontaneously. Ten complete and two partial circuits were mapped (89% ± 25% of the DP). In all complete circuits, pacing led to the development of unidirectional conduction block at the location of the subsequent VT exit site and the formation of functional block creating a border(s) for subsequent DP. Wavefront velocity in the DP region slowed from 1.22 ± 0.2 m/s during sinus rhythm to 0.59 ± 0.14 m/s during VT (P <.005). In 11 initiation episodes, lines of functional block and areas of slow conduction developed progressively over one to six reentrant cycles before a stable DP was established and sustained monomorphic VT ensued. The formation of unidirectional or functional lines of block was not identified during identical pacing protocols that failed to initiate VT (n = 14). Conclusion Initiation of sustained monomorphic VT requires the development of unidirectional block and formation of lines of functional block creating borders for a DP in areas of slow conduction. A transitional stage often exists during the initiation process before a stable VT circuit is established. PMID:20129286

  14. ProBNP1-108 Processing and Degradation in Human Heart Failure

    PubMed Central

    Huntley, Brenda K.; Sandberg, Sharon M.; Heublein, Denise M.; Sangaralingham, S. Jeson; Burnett, John C.; Ichiki, Tomoko

    2014-01-01

    Background We have reported that proBNP1-108 circulates and is processed to mature BNP1-32 in human blood. Building on these findings, we sought to determine whether proBNP1-108 processed forms in normal circulation are biologically active and stimulate cGMP, and whether proBNP1-108 processing and activity are altered in human heart failure (HF) compared to normal. Since BNP1-32 is deficient while proBNP1-108 is abundant in HF, we hypothesize that proBNP1-108 processing and degradation are impaired in HF patients ex vivo. Methods and Results We measured circulating molecular forms including BNP1-32, proBNP1-108, and NT-proBNP and all were significantly higher in HF patients compared to normals. Fresh serum samples from normals or HF patients were incubated with or without exogenous non-glycosylated proBNP1-108 tagged with 6 C-terminal Histidines to facilitate peptide isolation. His-tag ProBNP1-108 was efficiently processed into BNP1-32/3-32 at 5 min in normal serum, persisted for 15 min, then disappeared. Delayed processing of proBNP1-108 was observed in HF samples and the degradation pattern differed depending on LV function. The 5 min processed forms from both normal and HF serums were active and generated cGMP via GC-A receptors, however the 180 min samples were not active. The proBNP1-108 processing enzyme corin and BNP degrading enzyme DPPIV were reduced in HF versus normal, perhaps contributing to differential BNP metabolism in HF. Conclusions Exogenous proBNP1-108 is processed into active BNP1-32 and ultimately degraded in normal circulation. The processing and degradation of BNP molecular forms was altered but complete in HF which may contribute the pathophysiology of HF. PMID:25339504

  15. Resonance of about-weekly human heart rate rhythm with solar activity change.

    PubMed

    Cornelissen, G; Halberg, F; Wendt, H W; Bingham, C; Sothern, R B; Haus, E; Kleitman, E; Kleitman, N; Revilla, M A; Revilla, M; Breus, T K; Pimenov, K; Grigoriev, A E; Mitish, M D; Yatsyk, G V; Syutkina, E V

    1996-12-01

    In several human adults, certain solar activity rhythms may influence an about 7-day rhythm in heart rate. When no about-weekly feature was found in the rate of change in sunspot area, a measure of solar activity, the double amplitude of a circadian heart rate rhythm, approximated by the fit of a 7-day cosine curve, was lower, as was heart rate corresponds to about-weekly features in solar activity and/or relates to a sunspot cycle.

  16. Transmural Heterogeneity and Remodeling of Ventricular Excitation-Contraction Coupling in Human Heart Failure

    PubMed Central

    Lou, Qing; Fedorov, Vadim V.; Glukhov, Alexey V.; Moazami, Nader; Fast, Vladimir G.; Efimov, Igor R.

    2011-01-01

    Background Excitation-contraction (EC) coupling is altered in the end-stage heart failure (HF). However, spatial heterogeneity of this remodeling has not been established at the tissue level in failing human heart. The objective is to study functional remodeling of EC coupling and calcium handling in failing and nonfailing human hearts. Methods and Results We simultaneously optically mapped action potentials (AP) and calcium transients (CaT) in coronary-perfused left ventricular wedge preparations from nonfailing (n = 6) and failing (n = 5) human hearts. Our major findings are: (1) CaT duration minus AP duration was longer at sub-endocardium in failing compared to nonfailing hearts during bradycardia (40 beats/min). (2) The transmural gradient of CaT duration was significantly smaller in failing hearts compared with nonfailing hearts at fast pacing rates (100 beats/min). (3) CaT in failing hearts had a flattened plateau at the midmyocardium; and exhibited a “two-component” slow rise at sub-endocardium in three failing hearts. (4) CaT relaxation was slower at sub-endocardium than that at sub-epicardium in both groups. Protein expression of sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) was lower at sub-endocardium than that at sub-epicardium in both nonfailing and failing hearts. SERCA2a protein expression at sub-endocardium was lower in hearts with ischemic cardiomyopathy compared with nonischemic cardiomyopathy. Conclusions For the first time, we present direct experimental evidence of transmural heterogeneity of EC coupling and calcium handling in human hearts. End-stage HF is associated with the heterogeneous remodeling of EC coupling and calcium handling. PMID:21502574

  17. Automated identification of normal and diabetes heart rate signals using nonlinear measures.

    PubMed

    Rajendra Acharya, U; Faust, Oliver; Adib Kadri, Nahrizul; Suri, Jasjit S; Yu, Wenwei

    2013-10-01

    Diabetes mellitus (DM) affects considerable number of people in the world and the number of cases is increasing every year. Due to a strong link to the genetic basis of the disease, it is extremely difficult to cure. However, it can be controlled to prevent severe consequences, such as organ damage. Therefore, diabetes diagnosis and monitoring of its treatment is very important. In this paper, we have proposed a non-invasive diagnosis support system for DM. The system determines whether or not diabetes is present by determining the cardiac health of a patient using heart rate variability (HRV) analysis. This analysis was based on nine nonlinear features namely: Approximate Entropy (ApEn), largest Lyapunov exponet (LLE), detrended fluctuation analysis (DFA) and recurrence quantification analysis (RQA). Clinically significant measures were used as input to classification algorithms, namely AdaBoost, decision tree (DT), fuzzy Sugeno classifier (FSC), k-nearest neighbor algorithm (k-NN), probabilistic neural network (PNN) and support vector machine (SVM). Ten-fold stratified cross-validation was used to select the best classifier. AdaBoost, with least squares (LS) as weak learner, performed better than the other classifiers, yielding an average accuracy of 90%, sensitivity of 92.5% and specificity of 88.7%. © 2013 Elsevier Ltd. All rights reserved.

  18. Cardiac Function at Rest and During Exercise in Normals and in Patients with Coronary Heart Disease: Evaluation by Radionuclide Angiocardiography

    PubMed Central

    Rerych, Stephen K.; Scholz, Peter M.; Newman, Glenn E.; Sabiston, David C.; Jones, Robert H.

    1978-01-01

    This study demonstrates that radionuclide angiocardiography provides a simple and noninvasive approach for evaluation of myocardial function. Previous work concerning myocardial performance has been generally conducted with the patient in the supine position. Radionuclide angiocardiograms were performed in the present study at rest and during exercise in 30 normal subjects and in 30 patients with ischemic coronary artery disease. There were 30 normal controls (Group I), ten with single coronary artery disease (Group II), and 20 patients with multiple vessel coronary disease (Group III). All subjects were studied in the erect posture on a bicycle ergometer. In the normal controls, the mean heart rate doubled and the cardiac output tripled during exercise. Intensive training can lead to extraordinary levels of cardiac performance as shown in a world-class athlete who during peak exercise attained a heart rate of 210, an ejection fraction of 97%, and a cardiac output of 56 litres per minute. In the patients with coronary artery disease, both groups, were able to increase cardiac output to approximately twice the resting value. The magnitude of increase in blood pressure during exercise was not significantly different in the three groups. However, definite changes were present in the end-diastolic volume at rest was 116 and rose to 128 ml in Group I, 93 rising to 132 ml in Group II, and 138 increasing to 216 ml in Group III. The stroke volume increased comparably in all three groups, but the ejection fraction from rest to exercise showed a marked contrast in the controls compared to those with multivessel coronary disease. The ejection fraction rose in Group I from 66 to 80% during exercise, while in Group II it fell from 69 to 67%, and in Group III from 60 to 46%. These findings indicate that patients with ischemic myocardial disease respond to the stress of exercise by cardiac dilatation to maintain of increase stroke volume at increased heart rates. Moreover, the

  19. Echocardiography of the normal camel (Camelus dromedaries) heart: technique and cardiac dimensions

    PubMed Central

    2012-01-01

    Background Echocardiography and intra-cardiac dimensions have not previously been reported in adult camels despite its potential application for medical purpose. The aim of this study was to describe the results of a prospective study, aiming to report normal cardiac appearance and normal chamber dimensions in adult camels (Camelus dromedarius). Results On the right side, when the probe was placed in the 5th or 4th intercostal space (ICS), the caudal long-axis four-chamber view of the ventricles, atria, and the interventricular septum was obtained. Placing the probe slightly more cranially in the 4th ICS, the caudal long-axis four-chamber view and the caudal long-axis view of the left ventricular outflow tract (LVOT) were imaged. In 7 camels, a hybrid view between a “four-chamber” and “LVOT view” was imaged from the same position. The short-axis view of the ventricles was obtained in the 4th ICS where the transducer was rotated between 0° and 25°. Placement of the transducer in the 3rd ICS allowed visualisation of the right ventricular outflow tract (RVOT). On the left side, when the probe was placed in the 5th or 4th ICS, a four-chamber view was obtained. The LVOT is imaged in the 4th ICS and the RVOT was seen from the 3rd ICS. Conclusions This study showed that it is possible to obtain good-quality echocardiograms in adult camels and provide normal cardiac dimensions. This study could be used as a reference for further studies concerning camels with cardiac diseases. PMID:22862855

  20. Echocardiography of the normal camel (Camelus dromedaries) heart: technique and cardiac dimensions.

    PubMed

    Tharwat, Mohamed; Al-Sobayil, Fahd; Ali, Ahmed; Buczinski, Sébastien

    2012-08-03

    Echocardiography and intra-cardiac dimensions have not previously been reported in adult camels despite its potential application for medical purpose. The aim of this study was to describe the results of a prospective study, aiming to report normal cardiac appearance and normal chamber dimensions in adult camels (Camelus dromedarius). On the right side, when the probe was placed in the 5th or 4th intercostal space (ICS), the caudal long-axis four-chamber view of the ventricles, atria, and the interventricular septum was obtained. Placing the probe slightly more cranially in the 4th ICS, the caudal long-axis four-chamber view and the caudal long-axis view of the left ventricular outflow tract (LVOT) were imaged. In 7 camels, a hybrid view between a "four-chamber" and "LVOT view" was imaged from the same position. The short-axis view of the ventricles was obtained in the 4th ICS where the transducer was rotated between 0° and 25°. Placement of the transducer in the 3rd ICS allowed visualisation of the right ventricular outflow tract (RVOT). On the left side, when the probe was placed in the 5th or 4th ICS, a four-chamber view was obtained. The LVOT is imaged in the 4th ICS and the RVOT was seen from the 3rd ICS. This study showed that it is possible to obtain good-quality echocardiograms in adult camels and provide normal cardiac dimensions. This study could be used as a reference for further studies concerning camels with cardiac diseases.

  1. Comparison at Necropsy of Heart Weight in Women Aged 20 to 29 Years With Fatal Trauma or Chemical Intoxication Versus Fatal Natural Cause (A Search for the Normal Adult Heart Weight).

    PubMed

    Blackbourne, Brian D; Vasudevan, Anupama; Roberts, William C

    2017-03-01

    The present obesity epidemic makes determining the normal heart weight in adults difficult. This study examines the heart weight at autopsy in 104 women aged 20 to 29 years who died in 1978 to 1980 before the overweight epidemic ensued. Of the 104 cases, the hearts weighed ≤300 g in 86 (83%) and >300 g in 18 (17%). Of the 67 cases dying from an unnatural cause (trauma or chemical intoxication), only 3 (4%) had hearts weighing >300 g; of the 37 patients dying from a variety of natural causes, 15 (41%) had hearts weighing >300 g (p <0.001). The body mass index (BMI) was ≤25 kg/m(2) in 82 cases (79%) and the hearts in them ranged from 120 to 400 g (mean 262 ± 51; median 257 g); of the 22 cases (21%) in whom the BMI was >25 kg/m(2), the hearts ranged from 230 to 850 g (mean 351 ± 142; median 300 g). In conclusion, the cases dying from an unnatural cause had smaller mean heart weights than those women dying from a natural cause and those with a normal BMI (≤25 kg/m(2)) had smaller mean heart weights than those with a BMI >25 kg/m(2). The normal heart weight in young women dying from an unnatural cause with few exceptions is <300 g. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Effects of GUASHA on Heart Rate Variability in Healthy Male Volunteers under Normal Condition and Weightlifters after Weightlifting Training Sessions

    PubMed Central

    Chatchawan, Uraiwan; Nakmareong, Saowanee; Silsirivanit, Atit; Wang, Yingying; Xie, Dongbei; Yang, Jinsheng; Eungpinichpong, Wichai

    2015-01-01

    Objectives. This paper aims at exploring the effects of GUASHA on heart rate variability between healthy volunteers under normal condition and weightlifters after training sessions. Methods. Ten healthy male volunteers under normal condition and 15 male weightlifters after weightlifting training sessions were recruited into two groups. Electrocardiography was recorded before and immediately after 20-minute GUASHA. HRV was calculated in both the time domain and the frequency domain. Results. Stress index was reduced, while standard deviation of N-N intervals (SDNN), proportion derived by dividing the number of interval differences of successive N-N intervals greater than 50 ms, and root mean square of successive differences (RMSSD) were enhanced after GUASHA therapy in the two groups. The changes in SDNN and RMSSD were higher in the healthy men group than in the weightlifters group. In addition, low frequency was decreased whereas high frequency was significantly increased in healthy men after the GUASHA session. Conclusions. GUASHA therapy facilitates the parasympathetic nervous activity and modulates the balance between parasympathetic and sympathetic activities in both healthy men under normal condition and weightlifters after training sessions as indicated. Although the changes of the HRV parameters were similar in both groups, the responsiveness was more pronounced in healthy men than in male weightlifters. PMID:26120346

  3. Muscle pump-dependent self-perfusion mechanism in legs in normal subjects and patients with heart failure.

    PubMed

    Shiotani, Issei; Sato, Hideyuki; Sato, Hiroshi; Yokoyama, Hiroshi; Ohnishi, Yozo; Hishida, Eiji; Kinjo, Kunihiro; Nakatani, Daisaku; Kuzuya, Tsunehiko; Hori, Masatsugu

    2002-04-01

    Leg venous pressure markedly falls during upright exercise via a muscle pump effect, creating de novo perfusion pressure. We examined physiological roles of this mechanism in increasing femoral artery blood flow (FABF) and its alterations in chronic heart failure (CHF). In 10 normal subjects and 10 patients with CHF, standard hemodynamic variables, mean ankle vein pressure (MAVP), and FABF with Doppler techniques were obtained during graded upright bicycle exercise. To evaluate a nonspecific blood flow response, normal subjects also performed supine exercise. In normal subjects, MAVP rapidly declined by 45 mmHg and FABF correspondingly increased 5.3-fold without a systemic pressor response during 10 s of light upright exercise at 5 W. Approximately 67% of the blood flow response was attributed to the venous pressure drop-dependent mechanism. In CHF patients, MAVP declined by only 36 mmHg and FABF increased only 1.7-fold during the same upright exercise. The muscle venous pump has an ability to increase FABF at least threefold via the venous pressure drop-dependent mechanism. This mechanism is impaired in CHF patients.

  4. Decreased central venous oxygen saturation despite normalization of heart rate and blood pressure post shock resuscitation in sick dogs.

    PubMed

    Young, Brian C; Prittie, Jennifer E; Fox, Philip; Barton, Linda J

    2014-01-01

    To evaluate traditional and global perfusion parameters in clinical canine shock patients, and to evaluate for occult hypoperfusion as evidenced by low central venous oxygen saturation or high plasma lactate concentrations in clinical patients resuscitated to traditional endpoints. Clinical observational trial designed with a 1-year data entry period and patient follow-up of 28 days posthospital presentation. Large, private urban teaching hospital, and emergency and critical care center. Adult canine patients presenting to the emergency department with untreated shock. None. Patients received fluid resuscitation to normalize perfusion parameters based on physical examination and arterial blood pressure (BP). Monitoring of central venous pressure (CVP) and central venous oxygen saturation (ScvO2 ) was feasible with current standard of care interventions in critically ill, client-owned dogs. Decreased ScvO2 was observed in 37.8% of patients resuscitated to normal traditional perfusion parameters. Hyperlactatemia was commonly recorded. Decreased ScvO2 exists in a significant proportion of critically ill dogs following standard fluid resuscitation for shock, providing a relevant target population for implementation of a more standardized early goal-directed therapy bundle in veterinary patients. Normalization of heart rate, blood pressure, mentation, and perfusion parameters directed by physical examination may be attained despite the persistence of significant tissue hypoperfusion and oxygen debt. © Veterinary Emergency and Critical Care Society 2014.

  5. Usefulness of verapamil for congestive heart failure associated with abnormal left ventricular diastolic filling and normal left ventricular systolic performance

    SciTech Connect

    Setaro, J.F.; Zaret, B.L.; Schulman, D.S.; Black, H.R.; Soufer, R. )

    1990-10-15

    Normal left ventricular systolic performance with impaired left ventricular diastolic filling may be present in a substantial number of patients with congestive heart failure (CHF). To evaluate the effect of oral verapamil in this subset, 20 men (mean age 68 +/- 5 years) with CHF, intact left ventricular function (ejection fraction greater than 45%) and abnormal diastolic filling (peak filling rate less than 2.5 end-diastolic volumes per second (edv/s)) were studied in a placebo-controlled, double-blind 5-week crossover trial. All patients underwent echocardiography to rule out significant valvular disease, and thallium-201 stress scintigraphy to exclude major active ischemia. Compared to baseline values, verapamil significantly improved exercise capacity by 33% (13.9 +/- 4.3 vs 10.7 +/- 3.4 minutes at baseline) and peak filling rate by 30% (2.29 +/- 0.54 vs 1.85 +/- 0.45 edv/s at baseline) (all p less than 0.05). Placebo values were 12.3 +/- 4.0 minutes and 2.16 +/- 0.48 edv/s, respectively (difference not significant for both). Improvement from baseline in an objective clinico-radiographic heart failure score (scale 0 to 13) was significantly greater with verapamil compared to placebo (median improvement in score: 3 vs 1, p less than 0.01). Mean ejection fraction and systolic blood pressure were unchanged from baseline; diastolic blood pressure and heart rate decreased to a small degree. Verapamil may have therapeutic efficacy in patients with CHF, preserved systolic function and impaired diastolic filling.

  6. The Visible Heart® project and free-access website 'Atlas of Human Cardiac Anatomy'.

    PubMed

    Iaizzo, Paul A

    2016-12-01

    Pre- and post-evaluations of implantable cardiac devices require innovative and critical testing in all phases of the design process. The Visible Heart(®) Project was successfully launched in 1997 and 3 years later the Atlas of Human Cardiac Anatomy website was online. The Visible Heart(®) methodologies and Atlas website can be used to better understand human cardiac anatomy, disease states and/or to improve cardiac device design throughout the development process. To date, Visible(®) Heart methodologies have been used to reanimate 75 human hearts, all considered non-viable for transplantation. The Atlas is a unique free-access website featuring novel images of functional and fixed human cardiac anatomies from >400 human heart specimens. Furthermore, this website includes education tutorials on anatomy, physiology, congenital heart disease and various imaging modalities. For instance, the Device Tutorial provides examples of commonly deployed devices that were present at the time of in vitro reanimation or were subsequently delivered, including: leads, catheters, valves, annuloplasty rings, leadless pacemakers and stents. Another section of the website displays 3D models of vasculature, blood volumes, and/or tissue volumes reconstructed from computed tomography (CT) and magnetic resonance images (MRI) of various heart specimens. A new section allows the user to interact with various heart models. Visible Heart(®) methodologies have enabled our laboratory to reanimate 75 human hearts and visualize functional cardiac anatomies and device/tissue interfaces. The website freely shares all images, video clips and CT/MRI DICOM files in honour of the generous gifts received from donors and their families. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For Permissions, please email: journals.permissions@oup.com.

  7. Mutations in NTRK3 suggest a novel signaling pathway in human congenital heart disease

    PubMed Central

    Werner, Petra; Paluru, Prasuna; Simpson, Anisha M.; Latney, Brande; Iyer, Radhika; Brodeur, Garrett M.; Goldmuntz, Elizabeth

    2014-01-01

    Congenital heart defects (CHDs) are the most common major birth defects and the leading cause of death from congenital malformations. The etiology remains largely unknown, though genetic variants clearly contribute. In a previous study, we identified a large copy number variant (CNV) that deleted 46 genes in a patient with a malalignment type ventricular septal defect (VSD). The CNV included the gene NTRK3 encoding neurotrophic tyrosine kinase receptor C (TrkC), which is essential for normal cardiogenesis in animal models. To evaluate the role of NTRK3 in human CHDs, we studied 467 patients with related heart defects for NTRK3 mutations. We identified four missense mutations in four patients with VSDs that were not found in ethnically matched controls and were predicted to be functionally deleterious. Functional analysis using neuroblastoma cell lines expressing mutant TrkC demonstrated that one of the mutations (c.278C>T, p.T93M) significantly reduced autophosphorylation of TrkC in response to ligand binding, subsequently decreasing phosphorylation of downstream target proteins. In addition compared to WT, three of the four cell lines expressing mutant TrkC showed altered cell growth in low-serum conditions without supplemental NT-3. These findings suggest a novel pathophysiological mechanism involving NTRK3 in the development of VSDs. PMID:25196463

  8. Evaluation of shear stress accumulation on blood components in normal and dysfunctional bileaflet mechanical heart valves using smoothed particle hydrodynamics.

    PubMed

    Shahriari, S; Maleki, H; Hassan, I; Kadem, L

    2012-10-11

    Evaluating shear induced hemodynamic complications is one of the major concerns in design of the mechanical heart valves (MHVs). The monitoring of these events relies on both numerical simulations and experimental measurements. Currently, numerical approaches are mainly based on a combined Eulerian-Lagrangian approach. A more straightforward evaluation can be based on the Lagrangian analysis of the whole blood. As a consequence, Lagrangian meshfree methods are more adapted to such evaluation. In this study, smoothed particle hydrodynamics (SPH), a fully meshfree particle method originated to simulate compressible astrophysical flows, is applied to study the flow through a normal and a dysfunctional bileaflet mechanical heart valves (BMHVs). The SPH results are compared with the reference data. The accumulation of shear stress patterns on blood components illustrates the important role played by non-physiological flow patterns and mainly vortical structures in this issue. The statistical distribution of particles with respect to shear stress loading history provides important information regarding the relative number of blood components that can be damaged. This can be used as a measure of the response of blood components to the presence of the valve implant or any implantable medical device. This work presents the first attempt to simulate pulsatile flow through BMHVs using SPH method.

  9. Fetal Heart Rate Analysis for Automatic Detection of Perinatal Hypoxia Using Normalized Compression Distance and Machine Learning

    PubMed Central

    Barquero-Pérez, Óscar; Santiago-Mozos, Ricardo; Lillo-Castellano, José M.; García-Viruete, Beatriz; Goya-Esteban, Rebeca; Caamaño, Antonio J.; Rojo-Álvarez, José L.; Martín-Caballero, Carlos

    2017-01-01

    Accurate identification of Perinatal Hypoxia from visual inspection of Fetal Heart Rate (FHR) has been shown to have limitations. An automated signal processing method for this purpose needs to deal with time series of different lengths, recording interruptions, and poor quality signal conditions. We propose a new method, robust to those issues, for automated detection of perinatal hypoxia by analyzing the FHR during labor. Our system consists of several stages: (a) time series segmentation; (b) feature extraction from FHR signals, including raw time series, moments, and usual heart rate variability indices; (c) similarity calculation with Normalized Compression Distance, which is the key element for dealing with FHR time series; and (d) a simple classification algorithm for providing the hypoxia detection. We analyzed the proposed system using a database with 32 fetal records (15 controls). Time and frequency domain and moment features had similar performance identifying fetuses with hypoxia. The final system, using the third central moment of the FHR, yielded 92% sensitivity and 85% specificity at 3 h before delivery. Best predictions were obtained in time intervals more distant from delivery, i.e., 4–3 h and 3–2 h. PMID:28293198

  10. Longitudinal Evaluation of Fatty Acid Metabolism in Normal and Spontaneously Hypertensive Rat Hearts with Dynamic MicroSPECT Imaging

    DOE PAGES

    Reutter, Bryan W.; Huesman, Ronald H.; Brennan, Kathleen M.; ...

    2011-01-01

    The goal of this project is to develop radionuclide molecular imaging technologies using a clinical pinhole SPECT/CT scanner to quantify changes in cardiac metabolism using the spontaneously hypertensive rat (SHR) as a model of hypertensive-related pathophysiology. This paper quantitatively compares fatty acid metabolism in hearts of SHR and Wistar-Kyoto normal rats as a function of age and thereby tracks physiological changes associated with the onset and progression of heart failure in the SHR model. The fatty acid analog, 123 I-labeled BMIPP, was used in longitudinal metabolic pinhole SPECT imaging studies performed every seven months for 21 months. The uniquenessmore » of this project is the development of techniques for estimating the blood input function from projection data acquired by a slowly rotating camera that is imaging fast circulation and the quantification of the kinetics of 123 I-BMIPP by fitting compartmental models to the blood and tissue time-activity curves.« less

  11. Prospective isolation of human embryonic stem cell-derived cardiovascular progenitors that integrate into human fetal heart tissue.

    PubMed

    Ardehali, Reza; Ali, Shah R; Inlay, Matthew A; Abilez, Oscar J; Chen, Michael Q; Blauwkamp, Timothy A; Yazawa, Masayuki; Gong, Yongquan; Nusse, Roeland; Drukker, Micha; Weissman, Irving L

    2013-02-26

    A goal of regenerative medicine is to identify cardiovascular progenitors from human ES cells (hESCs) that can functionally integrate into the human heart. Previous studies to evaluate the developmental potential of candidate hESC-derived progenitors have delivered these cells into murine and porcine cardiac tissue, with inconclusive evidence regarding the capacity of these human cells to physiologically engraft in xenotransplantation assays. Further, the potential of hESC-derived cardiovascular lineage cells to functionally couple to human myocardium remains untested and unknown. Here, we have prospectively identified a population of hESC-derived ROR2(+)/CD13(+)/KDR(+)/PDGFRα(+) cells that give rise to cardiomyocytes, endothelial cells, and vascular smooth muscle cells in vitro at a clonal level. We observed rare clusters of ROR2(+) cells and diffuse expression of KDR and PDGFRα in first-trimester human fetal hearts. We then developed an in vivo transplantation model by transplanting second-trimester human fetal heart tissues s.c. into the ear pinna of a SCID mouse. ROR2(+)/CD13(+)/KDR(+)/PDGFRα(+) cells were delivered into these functioning fetal heart tissues: in contrast to traditional murine heart models for cell transplantation, we show structural and functional integration of hESC-derived cardiovascular progenitors into human heart.

  12. Left ventricular stiffness estimated by diastolic wall strain is associated with paroxysmal atrial fibrillation in structurally normal hearts.

    PubMed

    Uetake, Shunsuke; Maruyama, Mitsunori; Yamamoto, Teppei; Kato, Katsuhito; Miyauchi, Yasushi; Seino, Yoshihiko; Shimizu, Wataru

    2016-12-01

    Left ventricular (LV) diastolic dysfunction depends on an impaired relaxation and stiffness. Abnormal LV relaxation contributes to the development of atrial fibrillation (AF), but the role of LV stiffness in AF remains unclear. Diastolic wall strain (DWS), a load-independent, noninvasive direct measure of LV stiffness, correlates with prevalent AF. This study included 328 consecutive subjects with structurally normal hearts: 164 paroxysmal AF patients and 164 age- and sex-matched (1:1) controls. We calculated the DWS from the M-mode echocardiographic measurements of the LV posterior wall thickness at end-systole and end-diastole during sinus rhythm. The DWS was lower in the AF patients (0.35 ± 0.07) than in the controls (0.41 ± 0.06; P < 0.001). After adjusting for the risk factors of AF using a conditional logistic regression analysis, a history of hypertension, plasma brain-type natriuretic peptide level, and DWS were independently associated with AF prevalence, whereas body mass index, LV mass index, left atrial volume, and any conventional indices of the diastolic function were not. A low DWS (<0.380) was the strongest indicator of AF (odds ratio: 6.22, 95% confidence interval: 3.08-14.2, P < 0.001). Increased LV stiffness estimated by DWS was a strong determinant of the prevalence of AF. LV stiffness may play a role in the pathogenesis of paroxysmal AF in structurally normal hearts. © 2016 Wiley Periodicals, Inc.

  13. Classification of caesarean section and normal vaginal deliveries using foetal heart rate signals and advanced machine learning algorithms.

    PubMed

    Fergus, Paul; Hussain, Abir; Al-Jumeily, Dhiya; Huang, De-Shuang; Bouguila, Nizar

    2017-07-06

    Visual inspection of cardiotocography traces by obstetricians and midwives is the gold standard for monitoring the wellbeing of the foetus during antenatal care. However, inter- and intra-observer variability is high with only a 30% positive predictive value for the classification of pathological outcomes. This has a significant negative impact on the perinatal foetus and often results in cardio-pulmonary arrest, brain and vital organ damage, cerebral palsy, hearing, visual and cognitive defects and in severe cases, death. This paper shows that using machine learning and foetal heart rate signals provides direct information about the foetal state and helps to filter the subjective opinions of medical practitioners when used as a decision support tool. The primary aim is to provide a proof-of-concept that demonstrates how machine learning can be used to objectively determine when medical intervention, such as caesarean section, is required and help avoid preventable perinatal deaths. This is evidenced using an open dataset that comprises 506 controls (normal virginal deliveries) and 46 cases (caesarean due to pH ≤ 7.20-acidosis, n = 18; pH > 7.20 and pH < 7.25-foetal deterioration, n = 4; or clinical decision without evidence of pathological outcome measures, n = 24). Several machine-learning algorithms are trained, and validated, using binary classifier performance measures. The findings show that deep learning classification achieves sensitivity = 94%, specificity = 91%, Area under the curve = 99%, F-score = 100%, and mean square error = 1%. The results demonstrate that machine learning significantly improves the efficiency for the detection of caesarean section and normal vaginal deliveries using foetal heart rate signals compared with obstetrician and midwife predictions and systems reported in previous studies.

  14. Tomographic ultrasound imaging of the fetal heart: a new technique for identifying normal and abnormal cardiac anatomy.

    PubMed

    Devore, Greggory R; Polanko, Bardo

    2005-12-01

    In 2003 and 2004, the American College of Radiology, the American Institute of Ultrasound in Medicine, and the American College of Obstetricians and Gynecologists published guidelines for the standard ultrasound examination of the fetus. Each group recommended that the outflow tracts of the fetal heart be examined if technically feasible. One method to accomplish this task is to perform a free-hand sweep of the transducer beam directed in a transverse plane from the 4-chamber view to the fetal neck. One problem with this approach is that the examiner may not direct the beam transversely and, therefore, may not accurately identify the outflow tract anatomy. A new technology, tomographic ultrasound imaging (TUI), allows the examiner to obtain a volume data set that simultaneously displays multiple images at specific distances from the 4-chamber view. This study examined TUI technology for identifying normal and abnormal fetal cardiac anatomy with the use of either static or spatiotemporal image correlation volume data sets. The 4 views used in the screening examination of the outflow tracts of the fetal heart (4-chamber, 5-chamber, 3-vessel, and tracheal views) could be identified with the use of TUI technology in fetuses between 13 and 40 weeks' gestation. Examples of fetuses with abnormal cardiac anatomy of the outflow tracts (tetralogy of Fallot, transposition of the great vessels, and pulmonary stenosis) all showed abnormal anatomy on TUI. Tomographic ultrasound imaging technology enables the fetal examiner to evaluate the 4-chamber view and the outflow tracts in a systematic manner to identify normal and abnormal cardiac anatomy.

  15. Ventricular tachycardia and exercise related syncope in children with structurally normal hearts: emphasis on repolarisation abnormality.

    PubMed Central

    Noh, C. I.; Song, J. Y.; Kim, H. S.; Choi, J. Y.; Yun, Y. S.

    1995-01-01

    OBJECTIVE--To emphasize the importance of ventricular tachycardia associated with repolarisation abnormality in syncope associated with exercise. DESIGN--Retrospective analysis of data on children presenting with syncope between 1985 and 1993. PATIENTS--5 apparently normal children with recurrent exercise related syncope associated with electrocardiographically abnormal TU complexes. RESULTS--3 children were diagnosed as having an intermediate form of the long QT syndrome and catecholamine sensitive ventricular tachycardia because the abnormal TU complexes were associated with polymorphic ventricular tachycardia that was not typical of torsades de pointes. Tachycardia was induced by exercise in all patients and by isoprenaline in the one patient who was tested. One patient also had sinus node dysfunction. One child had incessant salvos of polymorphic ventricular arrhythmias and intermittent abnormal TU complexes suggestive of repolarisation abnormalities. The other had typical congenital long QT syndrome. Treatment was effective in three patients; two patients took a beta blocker alone and one took a beta blocker and low doses of amiodarone. One patient died suddenly, death being associated with sinus node dysfunction. In one patient with incessant ventricular arrhythmias treatment with a beta blocker, amiodarone, or Ic drugs was ineffective and always associated with proarrhythmia or syncope. He was not given further treatment and was asymptomatic despite having mild cardiomegaly. CONCLUSIONS--Ventricular tachycardia associated with repolarisation abnormality was an important cause of exercise related syncope in apparently normal children. TU complex abnormalities can be identified by repeated electrocardiography. beta Blockers are effective in preventing recurrent episodes. The role of amiodarone in this type of ventricular tachycardia needs further evaluation. PMID:7626354

  16. A high-resolution atlas and statistical model of the human heart from multislice CT.

    PubMed

    Hoogendoorn, Corné; Duchateau, Nicolas; Sánchez-Quintana, Damián; Whitmarsh, Tristan; Sukno, Federico M; De Craene, Mathieu; Lekadir, Karim; Frangi, Alejandro F

    2013-01-01

    Atlases and statistical models play important roles in the personalization and simulation of cardiac physiology. For the study of the heart, however, the construction of comprehensive atlases and spatio-temporal models is faced with a number of challenges, in particular the need to handle large and highly variable image datasets, the multi-region nature of the heart, and the presence of complex as well as small cardiovascular structures. In this paper, we present a detailed atlas and spatio-temporal statistical model of the human heart based on a large population of 3D+time multi-slice computed tomography sequences, and the framework for its construction. It uses spatial normalization based on nonrigid image registration to synthesize a population mean image and establish the spatial relationships between the mean and the subjects in the population. Temporal image registration is then applied to resolve each subject-specific cardiac motion and the resulting transformations are used to warp a surface mesh representation of the atlas to fit the images of the remaining cardiac phases in each subject. Subsequently, we demonstrate the construction of a spatio-temporal statistical model of shape such that the inter-subject and dynamic sources of variation are suitably separated. The framework is applied to a 3D+time data set of 138 subjects. The data is drawn from a variety of pathologies, which benefits its generalization to new subjects and physiological studies. The obtained level of detail and the extendability of the atlas present an advantage over most cardiac models published previously.

  17. Lack of effect of prior training on subsequent ischaemic and infarcting myocardium and collateral development in dogs with normal hearts.

    PubMed

    Cohen, M V; Steingart, R M

    1987-04-01

    To determine whether exercise training in animals with normal coronary arteries has a salutary effect on ischaemic myocardium, 24 dogs were randomly assigned to be either trained or confined to cages for three months. All dogs then underwent left thoracotomy for placement of indwelling right and left atrial and aortic catheters and a loose snare ligature around the proximal left circumflex coronary artery. Three days after operation control scintigrams were recorded after injection of thallous chloride-201 in animals running on a treadmill to achieve exercise heart rates of 220 beats.min-1. Four days later the snares were pulled to occlude the left circumflex artery and infarct size determined by measuring venous activity of creatine phosphokinase. Three days after infarction the first post-ligation scintigram was performed after thallium-201 injection in exercising animals. Exercise scans were repeated at 10 days and 2, 4, and 6 weeks after coronary ligation. During the final exercise study collateral blood flow was measured with radioactive microspheres. There was no difference in mean creatine phosphokinase appearance time, peak creatine phosphokinase activity, or measured infarct size between the trained and sedentary dogs. The ratio of thallium-201 activity in left circumflex artery or ischaemic area to left anterior descending artery or normally perfused myocardium fell from 100% before occlusion to 86.6% in the sedentary animals and 80.6% in the trained dogs three days after coronary ligation. Although these falls were significant (p less than 0.025 and p less than 0.005 respectively), there was no difference between groups. Over the next five and a half weeks the scintigraphic defect shrank as the thallium-201 ratio gradually increased, but changes were again similar in both groups. At six weeks there was little difference in exercise collateral flow to left circumflex artery myocardium and flow to normal myocardial tissue in cage confined and trained dogs

  18. Twelve-hour reanimation of a human heart following donation after circulatory death.

    PubMed

    Rosenfeldt, Franklin; Ou, Ruchong; Woodard, John; Esmore, Donald; Marasco, Silvana

    2014-01-01

    Despite increasing use of donation after cardiac death (DCD) and encouraging results for non-cardiac transplants, DCD cardiac transplantation has not been widely adopted because, (1) the DCD heart sustains warm ischaemic injury during the death process and (2) conventional static cold storage significantly adds to the ischaemic injury. We have developed a simple system for perfusion of the DCD heart with cold crystalloid solution using gravity-feed that can reduce ischaemic injury and potentially render the heart suitable for transplantation. This report describes the first application of this technique to a human DCD heart with good functional metabolic recovery over 12h on an ex vivo rig.

  19. Thyroid Function Within the Normal Range and Risk of Coronary Heart Disease

    PubMed Central

    Åsvold, Bjørn O.; Vatten, Lars J.; Bjøro, Trine; Bauer, Douglas C.; Bremner, Alexandra; Cappola, Anne R.; Ceresini, Graziano; den Elzen, Wendy P. J.; Ferrucci, Luigi; Franco, Oscar H.; Franklyn, Jayne A.; Gussekloo, Jacobijn; Iervasi, Giorgio; Imaizumi, Misa; Kearney, Patricia M.; Khaw, Kay-Tee; Maciel, Rui M. B.; Newman, Anne. B.; Peeters, Robin P.; Psaty, Bruce M.; Razvi, Salman; Sgarbi, José A.; Stott, David J.; Trompet, Stella; Vanderpump, Mark P. J.; Völzke, Henry; Walsh, John P.; Westendorp, Rudi G. J.; Rodondi, Nicolas

    2016-01-01

    Importance Some experts suggest that serum thyrotropin levels in the upper part of the current reference range should be considered abnormal, an approach that would reclassify many individuals as having mild hypothyroidism. Health hazards associated with such thyrotropin levels are poorly documented, but conflicting evidence suggests that thyrotropin levels in the upper part of the reference range may be associated with an increased risk of coronary heart disease (CHD). Objective To assess the association between differences in thyroid function within the reference range and CHD risk. Design, Setting, and Participants Individual participant data analysis of 14 cohorts with baseline examinations between July 1972 and April 2002 and with median follow-up ranging from 3.3 to 20.0 years. Participants included 55 412 individuals with serum thyrotropin levels of 0.45 to 4.49 mIU/L and no previously known thyroid or cardiovascular disease at baseline. Exposures Thyroid function as expressed by serum thyrotropin levels at baseline. Mainoutcomes and Measures Hazard ratios (HRs) of CHD mortality and CHD events according to thyrotropin levels after adjustment for age, sex, and smoking status. Results Among 55 412 individuals, 1813 people (3.3%) died of CHD during 643 183 person-years of follow-up. In 10 cohorts with information on both nonfatal and fatal CHD events, 4666 of 48 875 individuals (9.5%) experienced a first-time CHD event during 533 408 person-years of follow-up. For each 1-mIU/L higher thyrotropin level, the HR was 0.97 (95% CI, 0.90-1.04) for CHD mortality and 1.00 (95% CI, 0.97-1.03) for a first-time CHD event. Similarly, in analyses by categories of thyrotropin, the HRs of CHD mortality (0.94 [95% CI, 0.74-1.20]) and CHD events (0.97 [95% CI, 0.83-1.13]) were similar among participants with the highest (3.50-4.49 mIU/L) compared with the lowest (0.45-1.49 mIU/L) thyrotropin levels. Subgroup analyses by sex and age group yielded similar results. Conclusions and

  20. Prognostic Significance of Discharge Hyponatremia in Heart Failure Patients With Normal Admission Sodium (from the ESCAPE Trial).

    PubMed

    Omar, Hesham R; Charnigo, Richard; Guglin, Maya

    2017-08-15

    Hyponatremia in acute decompensated heart failure (HF) is indicative of a poor prognosis and predicts morbidity and mortality. We explored the predictive utility of hyponatremia at the time of hospital discharge among HF patients with normal admission sodium (Na). Characteristics and outcomes of HF patients enrolled in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial, who had normal Na on admission, were compared between those who were hyponatremic (Na <135 meq/L) or normonatremic on discharge. Three hundred six patients with normal admission Na had either hyponatremia (n = 86) or normal Na (n = 220) on discharge. Compared with patients with normal Na on discharge, hyponatremic patients were younger (p = 0.004), with lower discharge systolic (p <0.001) and diastolic (p = 0.004) blood pressure, higher discharge blood urea nitrogen (p = 0.011) despite similar creatinine (p = 0.566), lower ejection fraction (p = 0.007), and higher left ventricular end-diastolic (p = 0.028) and end-systolic (p = 0.007) dimensions. Despite comparable congestion on hospital admission, patients with discharge hyponatremia had a higher degree of decongestion throughout hospitalization evident in the significantly greater admission to discharge weight loss (p = 0.044) and admission to discharge reduction in inferior vena cava diameter (p = 0.014). Despite longer initial hospitalization (p = 0.004), total duration in hospital at 30 days (p = 0.004) and 6 months (p = 0.045), there were no significant differences between patients with discharge hyponatremia versus normal Na on discharge regarding rehospitalization (p = 0.386), all-cause mortality (p = 0.440), and composite of death, cardiac rehospitalization, and cardiac transplant (p = 0.799), all up to 6-month following randomization. Restricted cubic spline analysis also showed no significant relationships between discharge Na and the aforementioned 3 outcomes. Cox

  1. Theoretical analysis of the magnetocardiographic pattern for reentry wave propagation in a three-dimensional human heart model.

    PubMed

    Im, Uk Bin; Kwon, Soon Sung; Kim, Kiwoong; Lee, Yong Ho; Park, Yong Ki; Youn, Chan Hyun; Shim, Eun Bo

    2008-01-01

    We present a computational study of reentry wave propagation using electrophysiological models of human cardiac cells and the associated magnetic field map of a human heart. We examined the details of magnetic field variation and related physiological parameters for reentry waves in two-dimensional (2-D) human atrial tissue and a three-dimensional (3-D) human ventricle model. A 3-D mesh system representing the human ventricle was reconstructed from the surface geometry of a human heart. We used existing human cardiac cell models to simulate action potential (AP) propagation in atrial tissue and 3-D ventricular geometry, and a finite element method and the Galerkin approximation to discretize the 3-D domain spatially. The reentry wave was generated using an S1-S2 protocol. The calculations of the magnetic field pattern assumed a horizontally layered conductor for reentry wave propagation in the 3-D ventricle. We also compared the AP and magnetocardiograph (MCG) magnitudes during reentry wave propagation to those during normal wave propagation. The temporal changes in the reentry wave motion and magnetic field map patterns were also analyzed using two well-known MCG parameters: the current dipole direction and strength. The current vector in a reentry wave forms a rotating spiral. We delineated the magnetic field using the changes in the vector angle during a reentry wave, demonstrating that the MCG pattern can be helpful for theoretical analysis of reentry waves.

  2. Human gene copy number spectra analysis in congenital heart malformations

    PubMed Central

    Mahnke, Donna K.; Struble, Craig A.; Tuffnell, Maureen E.; Stamm, Karl D.; Hidestrand, Mats; Harris, Susan E.; Goetsch, Mary A.; Simpson, Pippa M.; Bick, David P.; Broeckel, Ulrich; Pelech, Andrew N.; Tweddell, James S.; Mitchell, Michael E.

    2012-01-01

    The clinical significance of copy number variants (CNVs) in congenital heart disease (CHD) continues to be a challenge. Although CNVs including genes can confer disease risk, relationships between gene dosage and phenotype are still being defined. Our goal was to perform a quantitative analysis of CNVs involving 100 well-defined CHD risk genes identified through previously published human association studies in subjects with anatomically defined cardiac malformations. A novel analytical approach permitting CNV gene frequency “spectra” to be computed over prespecified regions to determine phenotype-gene dosage relationships was employed. CNVs in subjects with CHD (n = 945), subphenotyped into 40 groups and verified in accordance with the European Paediatric Cardiac Code, were compared with two control groups, a disease-free cohort (n = 2,026) and a population with coronary artery disease (n = 880). Gains (≥200 kb) and losses (≥100 kb) were determined over 100 CHD risk genes and compared using a Barnard exact test. Six subphenotypes showed significant enrichment (P ≤ 0.05), including aortic stenosis (valvar), atrioventricular canal (partial), atrioventricular septal defect with tetralogy of Fallot, subaortic stenosis, tetralogy of Fallot, and truncus arteriosus. Furthermore, CNV gene frequency spectra were enriched (P ≤ 0.05) for losses at: FKBP6, ELN, GTF2IRD1, GATA4, CRKL, TBX1, ATRX, GPC3, BCOR, ZIC3, FLNA and MID1; and gains at: PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, HRAS, GATA6 and RUNX1. Of CHD subjects, 14% had causal chromosomal abnormalities, and 4.3% had likely causal (significantly enriched), large, rare CNVs. CNV frequency spectra combined with precision phenotyping may lead to increased molecular understanding of etiologic pathways. PMID:22318994

  3. Transcriptome of human foetal heart compared with cardiomyocytes from pluripotent stem cells.

    PubMed

    van den Berg, Cathelijne W; Okawa, Satoshi; Chuva de Sousa Lopes, Susana M; van Iperen, Liesbeth; Passier, Robert; Braam, Stefan R; Tertoolen, Leon G; del Sol, Antonio; Davis, Richard P; Mummery, Christine L

    2015-09-15

    Differentiated derivatives of human pluripotent stem cells (hPSCs) are often considered immature because they resemble foetal cells more than adult, with hPSC-derived cardiomyocytes (hPSC-CMs) being no exception. Many functional features of these cardiomyocytes, such as their cell morphology, electrophysiological characteristics, sarcomere organization and contraction force, are underdeveloped compared with adult cardiomyocytes. However, relatively little is known about how their gene expression profiles compare with the human foetal heart, in part because of the paucity of data on the human foetal heart at different stages of development. Here, we collected samples of matched ventricles and atria from human foetuses during the first and second trimester of development. This presented a rare opportunity to perform gene expression analysis on the individual chambers of the heart at various stages of development, allowing us to identify not only genes involved in the formation of the heart, but also specific genes upregulated in each of the four chambers and at different stages of development. The data showed that hPSC-CMs had a gene expression profile similar to first trimester foetal heart, but after culture in conditions shown previously to induce maturation, they cluster closer to the second trimester foetal heart samples. In summary, we demonstrate how the gene expression profiles of human foetal heart samples can be used for benchmarking hPSC-CMs and also contribute to determining their equivalent stage of development.

  4. The human subject: an integrative animal model for 21(st) century heart failure research.

    PubMed

    Chandrasekera, P Charukeshi; Pippin, John J

    2015-01-01

    Heart failure remains a leading cause of death and it is a major cause of morbidity and mortality affecting tens of millions of people worldwide. Despite decades of extensive research conducted at enormous expense, only a handful of interventions have significantly impacted survival in heart failure. Even the most widely prescribed treatments act primarily to slow disease progression, do not provide sustained survival advantage, and have adverse side effects. Since mortality remains about 50% within five years of diagnosis, the need to increase our understanding of heart failure disease mechanisms and development of preventive and reparative therapies remains critical. Currently, the vast majority of basic science heart failure research is conducted using animal models ranging from fruit flies to primates; however, insights gleaned from decades of animal-based research efforts have not been proportional to research success in terms of deciphering human heart failure and developing effective therapeutics for human patients. Here we discuss the reasons for this translational discrepancy which can be equally attributed to the use of erroneous animal models and the lack of widespread use of human-based research methodologies and address why and how we must position our own species at center stage as the quintessential animal model for 21(st) century heart failure research. If the ultimate goal of the scientific community is to tackle the epidemic status of heart failure, the best way to achieve that goal is through prioritizing human-based, human-relevant research.

  5. The human subject: an integrative animal model for 21st century heart failure research

    PubMed Central

    Chandrasekera, P Charukeshi; Pippin, John J

    2015-01-01

    Heart failure remains a leading cause of death and it is a major cause of morbidity and mortality affecting tens of millions of people worldwide. Despite decades of extensive research conducted at enormous expense, only a handful of interventions have significantly impacted survival in heart failure. Even the most widely prescribed treatments act primarily to slow disease progression, do not provide sustained survival advantage, and have adverse side effects. Since mortality remains about 50% within five years of diagnosis, the need to increase our understanding of heart failure disease mechanisms and development of preventive and reparative therapies remains critical. Currently, the vast majority of basic science heart failure research is conducted using animal models ranging from fruit flies to primates; however, insights gleaned from decades of animal-based research efforts have not been proportional to research success in terms of deciphering human heart failure and developing effective therapeutics for human patients. Here we discuss the reasons for this translational discrepancy which can be equally attributed to the use of erroneous animal models and the lack of widespread use of human-based research methodologies and address why and how we must position our own species at center stage as the quintessential animal model for 21st century heart failure research. If the ultimate goal of the scientific community is to tackle the epidemic status of heart failure, the best way to achieve that goal is through prioritizing human-based, human-relevant research. PMID:26550463

  6. Systems approach to understanding electromechanical activity in the human heart: a national heart, lung, and blood institute workshop summary.

    PubMed

    Rudy, Yoram; Ackerman, Michael J; Bers, Donald M; Clancy, Colleen E; Houser, Steven R; London, Barry; McCulloch, Andrew D; Przywara, Dennis A; Rasmusson, Randall L; Solaro, R John; Trayanova, Natalia A; Van Wagoner, David R; Varró, András; Weiss, James N; Lathrop, David A

    2008-09-09

    The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of cardiologists, cardiac electrophysiologists, cell biophysicists, and computational modelers on August 20 and 21, 2007, in Washington, DC, to advise the NHLBI on new research directions needed to develop integrative approaches to elucidate human cardiac function. The workshop strove to identify limitations in the use of data from nonhuman animal species for elucidation of human electromechanical function/activity and to identify what specific information on ion channel kinetics, calcium handling, and dynamic changes in the intracellular/extracellular milieu is needed from human cardiac tissues to develop more robust computational models of human cardiac electromechanical activity. This article summarizes the workshop discussions and recommendations on the following topics: (1) limitations of animal models and differences from human electrophysiology, (2) modeling ion channel structure/function in the context of whole-cell electrophysiology, (3) excitation-contraction coupling and regulatory pathways, (4) whole-heart simulations of human electromechanical activity, and (5) what human data are currently needed and how to obtain them. The recommendations can be found on the NHLBI Web site at http://www.nhlbi.nih.gov/meetings/workshops/electro.htm.

  7. Normal and shear strains of the left ventricle in healthy human subjects measured by two-dimensional speckle tracking echocardiography

    PubMed Central

    2014-01-01

    Background Animal studies have shown that shear deformation of myocardial sheets in transmural planes of left ventricular (LV) wall is an important mechanism for systolic wall thickening, and normal and shear strains of the LV free wall differ from those of the interventricular septum (IVS). We sought to test whether these also hold for human hearts. Methods Thirty healthy volunteers (male 23 and female 7, aged 34 ± 6 years) from Outpatient Department of the University of Tokyo Hospital were included. Echocardiographic images were obtained in the left decubitus position using a commercially available system (Aloka SSD-6500, Japan) equipped with a 3.5-MHz transducer. The ECG was recorded simultaneously. The peak systolic radial normal strain (length change), shear strain (angle change) and time to peak systolic radial normal strain were obtained non-invasively by two-dimensional speckle tracking echocardiography. Results The peak systolic radial normal strain in both IVS and LV posterior wall (LVPW) showed a trend to increase progressively from the apical level to the basal level, especially at short axis views, and the peak systolic radial normal strain of LVPW was significantly greater than that of IVS at all three levels. The time to peak systolic radial normal strain was the shortest at the basal IVS, and increased progressively from the base to the apical IVS. It gradually increased from the apical to the basal LVPW in sequence, especially at short axis views. The peak of radial normal strain of LVPW occurred much later than the peak of IVS at all three levels. For IVS, the shear deformation was clockwise at basal level, and counterclockwise at mid and apical levels in LV long-axis view. For LVPW, the shear deformations were all counterclockwise in LV long-axis view and increased slightly from base to the apex. LVPW showed larger shear strains than IVS at all three levels. Bland-Altman analysis shows very good agreement between measurements taken by the

  8. Is Heart Period Variability Associated with the Administration of Lifesaving Interventions in Individual Prehospital Trauma Patients with Normal Standard Vital Signs?

    DTIC Science & Technology

    2010-08-01

    an underlying traumatic injury and associated pain but also due to other stimuli potentially associated with the trauma setting, such as anxiety...Electronic evaluation of the fetal heart rate VIII. Patterns preceding fetal death, further observations. Am J Obstet Gy- necol 1963; 87:814–826 3...Haddad GG: Heart rate control in normal and aborted -SIDS in- fants. Am J Physiol 1993; 264:R638–R646 38. Peng CK, Havlin S, Stanley HE, et al: Quan

  9. In vitro suppression of normal human bone marrow progenitor cells by human immunodeficiency virus.

    PubMed Central

    Steinberg, H N; Crumpacker, C S; Chatis, P A

    1991-01-01

    Incubation of normal human nonadherent and T-cell-depleted bone marrow cells with HIVIIIB at multiplicities of infection (MOI) ranging from 0.0001:1 to 1:1 reverse transcriptase (RT) units resulted in the dose-dependent suppression of the in vitro growth of erythroid burst-forming unit (BFU-E), granulocyte-macrophage (CFU-GM), and T-lymphocyte (CFU-TL) colonies of progenitor cells. Maximum inhibition of colony formation was observed at a 1:1 ratio of virus to bone marrow cells. At this MOI, BFU-E and CFU-GM colonies were inhibited by 60 to 80%, while CFU-TL colonies were totally suppressed. Inhibition of colony formation was also observed at an MOI of 0.1:1 but not with further log dilutions of the virus. Incubation of the virus with antibody to gp160 resulted in the complete reversal of stem cell suppression and the normalization of colony growth in vitro. For BFU-E and CFU-GM colonies, this reversal was observed with dilutions of antibody up to 1:100 and was no longer observed at titers greater than 1:500. The CFU-TL colony number normalized at titers between 1:10 and 1:50. Human immunodeficiency virus (HIV) also suppressed by 50% the growth of colonies derived from CD34+ stem cell fractions. Infection of CD34+ cells and T-cell-depleted, nonadherent cell fractions was demonstrated by detection with HIV-specific DNA probe following amplification by polymerase chain reaction. The results suggest that HIV can directly infect human bone marrow progenitor cells and affect their ability to proliferate and give rise to colonies in vitro. The results indicate a direct role for the virus in bone marrow suppression and a possible mechanism for the cytopenias observed in patients with AIDS. Images PMID:2002542

  10. Altered protein levels in the isolated extracellular matrix of failing human hearts with dilated cardiomyopathy.

    PubMed

    DeAguero, Joshua L; McKown, Elizabeth N; Zhang, Liwen; Keirsey, Jeremy; Fischer, Edgar G; Samedi, Von G; Canan, Benjamin D; Kilic, Ahmet; Janssen, Paul M L; Delfín, Dawn A

    Dilated cardiomyopathy (DCM) is associated with extensive pathological cardiac remodeling and involves numerous changes in the protein expression profile of the extracellular matrix of the heart. We obtained seven human, end-stage, failing hearts with DCM (DCM-failing) and nine human, nonfailing donor hearts and compared their extracellular matrix protein profiles. We first showed that the DCM-failing hearts had indeed undergone extensive remodeling of the left ventricle myocardium relative to nonfailing hearts. We then isolated the extracellular matrix from a subset of these hearts and performed a proteomic analysis on the isolated matrices. We found that the levels of 26 structural proteins were altered in the DCM-failing isolated cardiac extracellular matrix compared to nonfailing isolated cardiac extracellular matrix. Overall, most of the extracellular matrix proteins showed reduced levels in the DCM-failing hearts, while all of the contractile proteins showed increased levels. There was a mixture of increased and decreased levels of cytoskeletal and nuclear transport proteins. Using immunoprobing, we verified that collagen IV (α2 and α6 isoforms), zyxin, and myomesin protein levels were reduced in the DCM-failing hearts. We expect that these data will add to the understanding of the pathology associated with heart failure with DCM.

  11. Invasive 3-Dimensional Organotypic Neoplasia from Multiple Normal Human Epithelia

    PubMed Central

    Ridky, Todd W.; Chow, Jennifer M.; Wong, David J.; Khavari, Paul A.

    2013-01-01

    Refined cancer models are required to assess the burgeoning number of potential targets for cancer therapeutics within a rapid and clinically relevant context. Here we utilize tumor-associated genetic pathways to transform primary human epithelial cells from epidermis, oropharynx, esophagus, and cervix into genetically defined tumors within a human 3-dimensional (3-D) tissue environment incorporating cell-populated stroma and intact basement membrane. These engineered organotypic tissues recapitulated natural features of tumor progression, including epithelial invasion through basement membrane, a complex process critically required for biologic malignancy in 90% of human cancers. Invasion was rapid, and potentiated by stromal cells. Oncogenic signals in 3-D tissue, but not 2-D culture, resembled gene expression profiles from spontaneous human cancers. Screening well-characterized signaling pathway inhibitors in 3-D organotypic neoplasia helped distil a clinically faithful cancer gene signature. Multi-tissue 3-D human tissue cancer models may provide an efficient and relevant complement to current approaches to characterize cancer progression. PMID:21102459

  12. In situ expression of cytokines in human heart allografts.

    PubMed

    Van Hoffen, E; Van Wichen, D; Stuij, I; De Jonge, N; Klöpping, C; Lahpor, J; Van Den Tweel, J; Gmelig-Meyling, F; De Weger, R

    1996-12-01

    Although allograft rejection, the major complication of human organ transplantation, has been extensively studied, little is known about the exact cellular localization of the cytokine expression inside the graft during rejection. Therefore, we used in situ hybridization and immunohistochemistry to study local cytokine mRNA and protein expression in human heart allografts, in relation to the phenotypical characteristics of the cellular infiltrate. Clear expression of mRNA for interleukin (IL)-6, IL-8, IL-9, and IL-10 and weak expression for IL-2, IL-4, IL-5, and tumor necrosis factor (TNF)-alpha was detected in biopsies exhibiting high rejection grades (grade 3A/B). Also at lower grades of rejection, mRNA for IL-6 and IL-9 was present. Some mRNA for IL-1 beta, TNF-beta, and interferon (IFN)-gamma was detected in only a few biopsies. Using immunohistochemistry, IL-2, IL-3, and IL-10 protein was detected in biopsies with high rejection grades, whereas few cells expressed IL-6, IL-8, and IFN-gamma. In biopsies with lower grades of rejection, a weaker expression of these cytokines was observed. IL-4 was hardly detected in any of the biopsies. The level of IL-12 expression was equal in all biopsies. Although mRNA expression of several cytokines was expressed at a low level compared with the protein level of those cytokines, there was a good correlation between localization of cytokine mRNA and protein. Expression of IL-2, IL-4, IL-5, TNF-alpha, and IFN-gamma was mainly detected in lymphocytes. IL-3, IL-6, IL-10, and IL-12 were not detected or not only detected in lymphocytes but also in other stromal elements (eg, macrophages). Macrophage production of IL-3 and IL-12 was confirmed by immunofluorescent double labeling with CD68. We conclude that cardiac allograft rejection is not simply regulated by T helper cell cytokine production, but other intragraft elements contribute considerably to this process.

  13. Sequential changes of left ventricular function after cineangiography in normal heart and coronary artery disease.

    PubMed

    Kaku, K; Hirota, Y; Shimizu, G; Furubayashi, K; Kawamura, K

    1984-06-01

    To evaluate the effect of contrast material on left ventricular (LV) function, LV pressure and its first derivative were continuously monitored during and after LV cineangiography with Mikro-tip angiocatheters in 15 normal subjects (Group 1) and patients with coronary artery disease (CAD) without LV asynergy (Group 2, n = 10), with mild asynergy (Group 3, n = 12) and severe asynergy (Group 4, n = 13). In all 4 groups, systolic hypotension, decrease of negative dP/dt, and prolonged time constant of LV pressure fall (T) were observed in 30 seconds after dye injection, and all these parameters returned to the control value in 2 minutes. LV end-diastolic pressure (EDP) began to elevate at one minute, reached its peak at 2 minutes, and stayed elevated for 7 minutes. Although significant decrease in LV systolic pressure was seen, indexes of LV contractility, peak positive dP/dt and (dP/dt)/DP40, showed increase in all groups. No different directional changes of these parameters were observed among 4 groups. The degree of LVEDP elevation was parallel to the diastolic elastic stiffness constant (K) in Group 1 (r = 0.64, (p less than 0.05). It is concluded that systolic hypotension and prolonged relaxation are only transient, and elevation of LVEDP after the contrast material injection seems to be the effect of only acute volume overload.

  14. Ventricular stimulus site influences dynamic dispersion of repolarization in the intact human heart

    PubMed Central

    Orini, Michele; Simon, Ron B.; Providência, Rui; Khan, Fakhar Z.; Segal, Oliver R.; Babu, Girish G.; Bradley, Richard; Rowland, Edward; Ahsan, Syed; Chow, Anthony W.; Lowe, Martin D.; Taggart, Peter

    2016-01-01

    The spatial variation in restitution properties in relation to varying stimulus site is poorly defined. This study aimed to investigate the effect of varying stimulus site on apicobasal and transmural activation time (AT), action potential duration (APD) and repolarization time (RT) during restitution studies in the intact human heart. Ten patients with structurally normal hearts, undergoing clinical electrophysiology studies, were enrolled. Decapolar catheters were placed apex to base in the endocardial right ventricle (RVendo) and left ventricle (LVendo), and an LV branch of the coronary sinus (LVepi) for transmural recording. S1–S2 restitution protocols were performed pacing RVendo apex, LVendo base, and LVepi base. Overall, 725 restitution curves were analyzed, 74% of slopes had a maximum slope of activation recovery interval (ARI) restitution (Smax) > 1 (P < 0.001); mean Smax = 1.76. APD was shorter in the LVepi compared with LVendo, regardless of pacing site (30-ms difference during RVendo pacing, 25-ms during LVendo, and 48-ms during LVepi; 50th quantile, P < 0.01). Basal LVepi pacing resulted in a significant transmural gradient of RT (77 ms, 50th quantile: P < 0.01), due to loss of negative transmural AT-APD coupling (mean slope 0.63 ± 0.3). No significant transmural gradient in RT was demonstrated during endocardial RV or LV pacing, with preserved negative transmural AT-APD coupling (mean slope −1.36 ± 1.9 and −0.71 ± 0.4, respectively). Steep ARI restitution slopes predominate in the normal ventricle and dynamic ARI; RT gradients exist that are modulated by the site of activation. Epicardial stimulation to initiate ventricular activation promotes significant transmural gradients of repolarization that could be proarrhythmic. PMID:27371682

  15. National prevalence of coronary heart disease and its relationship with human development index: A systematic review.

    PubMed

    Zhu, Ke-Fu; Wang, Yu-Ming; Zhu, Jin-Zhou; Zhou, Qin-Yi; Wang, Ning-Fu

    2016-03-01

    Coronary heart disease has become a major health concern over the past several decades. Several reviews have assessed the effects of socioeconomic status on the coronary heart disease epidemic in communities and countries, but only a few reviews have been performed at a global level. This study was to explore the relationship between the prevalence of coronary heart disease and socioeconomic development worldwide using the Human Development Index. Systematic review. The data in this study were collected from the MEDLINE database. Cross-sectional studies reporting the prevalence of coronary heart disease until November 2014 were collected. The Human Development Index was sourced from the United Nations Development Programme Database and was used to measure the socioeconomic achievements of countries. Each country was classified as a developing or developed country based on its level of development according to the Human Development Index value. Based on the data analysis on the global level, coronary heart disease prevalence had no association with the national Human Development Index (rho = 0.07). However, there was a positive association between coronary heart disease prevalence and the national Human Development Index in developing countries, although a negative association existed in developed countries (rho = 0.47 and -0.34, respectively). In addition, the past decades have witnessed a growing coronary heart disease epidemic in developing countries, with reverse trends observed in developed countries (P = 0.021 and 0.002, respectively). With the development of socioeconomic status, as measured by the Human Development Index, the prevalence of coronary heart disease is growing in developing countries, while declining in developed countries. Future research needs to pay more attention to the reasonable allocation of medical resources and control of coronary heart disease risk factors. © The European Society of Cardiology 2015.

  16. Myocardial bridges of the coronary arteries in the human fetal heart.

    PubMed

    Cakmak, Yusuf Ozgür; Cavdar, Safiye; Yalin, Aymelek; Yener, Nuran; Ozdogmus, Omer

    2010-09-01

    During the last century, many investigators reported on myocardial bridges in the adult human heart. In the present study, 39 human fetal hearts (the mean gestastional age was 30 weeks) were studied for myocardial bridging, and the results were correlated with adult data. Among the 39 (27 male and 12 female) fetal hearts studied, 26 bridges were observed on 18 fetal hearts (46.2%). Ten of the bridges had one myocardial bridge, whereas double myocardial bridges were observed in eight fetal hearts. The most frequent myocardial bridges were observed on the left anterior descending artery (LAD), which had 13 bridges (50%). Eight (30.7%) myocardial bridges were on the diagonal artery, and on the posterior descending artery there were five (19.3%). Myocardial bridges were not observed on the circumflex artery. The data presented in this study may provide potentially useful information for the preoperative evaluation of the newborn and may have a clinical implication for sudden fetal death.

  17. Normal human synovial fluid: osmolality and exercise-induced changes.

    PubMed

    Baumgarten, M; Bloebaum, R D; Ross, S D; Campbell, P; Sarmiento, A

    1985-12-01

    We measured the osmolality of human synovial fluid in the knees of healthy young adults following minimum activity and exercise. These results were compared with each subject's blood-serum osmolality. The synovial fluid was hyperosmolal with minimum activity, decreasing to blood-serum levels after exercise.

  18. Distribution of beta-endorphin immunoreactivity in normal human pituitary.

    PubMed Central

    Mendelsohn, G; D'Agostino, R; Eggleston, J C; Baylin, S B

    1979-01-01

    Recent immunohistochemical demonstration of calcitonin in rat pituitary has suggested that calcitonin, in addition to ACTH, endorphins, lipotropins, and melanocyte-stimulating hormones might be derived from a 31,000-dalton glycoprotein percursor molecule. This immunoperoxidase study demonstrates a similar distribution for beta-endorphin and ACTH immunoreactivity in human pituitary; however, the two peptides are not necessarily present in the same cells at all times. Calcitonin could not be demonstrated in human pituitary under conditions suitable for demonstration of the peptide in thyroid C cells. Weakly positive immunostaining could be obtained only with much increase in antiserum concentration and length of incubation, and higher concentrations of calcitonin were needed to abolish staining in preabsorption studies. It thus appears that the immunoreactive calcitonin in human pituitary differs from that in thyroid C cells. Likewise, we could not demonstrate immunoreactive endorphin in any developmental stage of medullary thyroid carcinoma. Our study suggests that caution should be applied in considering a physiologic role for calcitonin in the pituitary and in postulating a common peptide origin for endorphin and calcitonin in humans. Images PMID:221539

  19. Heart rate variability and QT dispersion study in brain death patients and comatose patients with normal brainstem function.

    PubMed

    Vakilian, Ali Reza; Iranmanesh, Farhad; Nadimi, Ali Esmaeili; Kahnali, Jafar Ahmadi

    2011-03-01

    To compare heart rate variability (HRV) and QT dispersion in comatose patients with normal brainstem function and with brain death. Cross-sectional comparative study. The Intensive Care Unit of Ali-Ebn-Abitaleleb Hopital, Rafsanjan Medical University from September 2007 to June 2009. Fourteen brain death patients with clinical signs of imminent brain death and 15 comatose patients were examined by neurologist in intensive care unit. HRV, RR interval and QT dispersion on ECG were assessed for 24 hours in both groups. Independent t-test and chi-square test were used for statistical analysis to determine significance which was set at p < 0.05. According to Holter findings, mean of standard deviation of RR-interval in the comatose and brain death groups was 48.33 and 35 respectively (p = 0.045). Mean of covariance coefficient of RR-interval was 0.065 in the comatose group and 0.043 in the brain deaths (p = 0.006). QT dispersion was not significant difference in two groups. HRV and RR-interval analysis appeared as an early finding for the diagnosis of brainstem death in comparison to comatose patients with normal brainstem function. QT dispersion had not significant in this regard.

  20. Visualization of Fiber Structurein the Left and Right Ventricleof a Human Heart

    SciTech Connect

    Rohmer, Damien; Sitek, Arkadiusz; Gullberg, Grant T.

    2006-07-12

    The human heart is composed of a helical network of musclefibers. Anisotropic least squares filtering followed by fiber trackingtechniques were applied to Diffusion Tensor Magnetic Resonance Imaging(DTMRI) data of the excised human heart. The fiber configuration wasvisualized by using thin tubes to increase 3-dimensional visualperception of the complex structure. All visualizations were performedusing the high-quality ray-tracing software POV-Ray. The fibers are shownwithin the left and right ventricles. Both ventricles exhibit similarfiber architecture and some bundles of fibers are shown linking right andleft ventricles on the posterior region of the heart.

  1. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans.

    PubMed Central

    Anderson, E A; Hoffman, R P; Balon, T W; Sinkey, C A; Mark, A L

    1991-01-01

    Hyperinsulinemia may contribute to hypertension by increasing sympathetic activity and vascular resistance. We sought to determine if insulin increases central sympathetic neural outflow and vascular resistance in humans. We recorded muscle sympathetic nerve activity (MSNA; microneurography, peroneal nerve), forearm blood flow (plethysmography), heart rate, and blood pressure in 14 normotensive males during 1-h infusions of low (38 mU/m2/min) and high (76 mU/m2/min) doses of insulin while holding blood glucose constant. Plasma insulin rose from 8 +/- 1 microU/ml during control, to 72 +/- 8 and 144 +/- 13 microU/ml during the low and high insulin doses, respectively, and fell to 15 +/- 6 microU/ml 1 h after insulin infusion was stopped. MSNA, which averaged 21.5 +/- 1.5 bursts/min in control, increased significantly (P less than 0.001) during both the low and high doses of insulin (+/- 5.4 and +/- 9.3 bursts/min, respectively) and further increased during 1-h recovery (+15.2 bursts/min). Plasma norepinephrine levels (119 +/- 19 pg/ml during control) rose during both low (258 +/- 25; P less than 0.02) and high (285 +/- 95; P less than 0.01) doses of insulin and recovery (316 +/- 23; P less than 0.01). Plasma epinephrine levels did not change during insulin infusion. Despite the increased MSNA and plasma norepinephrine, there were significant (P less than 0.001) increases in forearm blood flow and decreases in forearm vascular resistance during both doses of insulin. Systolic pressure did not change significantly during infusion of insulin and diastolic pressure fell approximately 4-5 mmHg (P less than 0.01). This study suggests that acute increases in plasma insulin within the physiological range elevate sympathetic neural outflow but produce forearm vasodilation and do not elevate arterial pressure in normal humans. PMID:2040704

  2. Minimal changes in heart rate of incubating American Oystercatchers (Haematopus palliatus) in response to human activity

    USGS Publications Warehouse

    Borneman, Tracy E.; Rose, Eli T.; Simons, Theodore R.

    2014-01-01

    An organism's heart rate is commonly used as an indicator of physiological stress due to environmental stimuli. We used heart rate to monitor the physiological response of American Oystercatchers (Haematopus palliatus) to human activity in their nesting environment. We placed artificial eggs with embedded microphones in 42 oystercatcher nests to record the heart rate of incubating oystercatchers continuously for up to 27 days. We used continuous video and audio recordings collected simultaneously at the nests to relate physiological response of birds (heart rate) to various types of human activity. We observed military and civilian aircraft, off-road vehicles, and pedestrians around nests. With the exception of high-speed, low-altitude military overflights, we found little evidence that oystercatcher heart rates were influenced by most types of human activity. The low-altitude flights were the only human activity to significantly increase average heart rates of incubating oystercatchers (12% above baseline). Although statistically significant, we do not consider the increase in heart rate during high-speed, low-altitude military overflights to be of biological significance. This noninvasive technique may be appropriate for other studies of stress in nesting birds.

  3. Human papilloma virus DNAs immortalize normal human mammary epithelial cells and reduce their growth factor requirements

    SciTech Connect

    Band, V.; Zajchowski, D.; Kulesa, V.; Sager, R. )

    1990-01-01

    Human papilloma virus (HPV) types 16 and 18 are most commonly associated with cervical carcinoma in patients and induce immortalization of human keratinocytes in culture. HPV has not been associated with breast cancer. This report describes the immortalization of normal human mammary epithelial cells (76N) by plasmid pHPV18 or pHPV16, each containing the linearized viral genome. Transfectants were grown continuously for more than 60 passages, whereas 76N cells senesce after 18-20 passages. The transfectants also differ from 76N cells in cloning in a completely defined medium called D2 and growing a minimally supplemented defined medium (D3) containing epidermal growth factor. All transfectant tested contain integrated HPV DNA, express HPV RNA, and produce HPV E7 protein. HPV transfectants do not form tumors in a nude mouse assay. It is concluded that products of the HPV genome induce immortalization of human breast epithelial cells and reduce their growth factor requirements. This result raises the possibility that HPV might be involved in breast cancer. Furthermore, other tissue-specific primary epithelial cells that are presently difficult to grown and investigate may also be immortalized by HPV.

  4. Effects of Moxa (Folium Artemisiae argyi) Smoke Exposure on Heart Rate and Heart Rate Variability in Healthy Young Adults: A Randomized, Controlled Human Study

    PubMed Central

    Cui, Yingxue; Zhao, Baixiao; Huang, Yuhai; Chen, Zhanghuang; Liu, Ping; Huang, Jian; Lao, Lixing

    2013-01-01

    Objective. To determine the effects of the moxa smoke on human heart rate (HR) and heart rate variability (HRV). Methods. Fifty-five healthy young adults were randomly divided into experimental (n = 28) and control (n = 27) groups. Experimental subjects were exposed to moxa smoke (2.5 ± 0.5 mg/m3) twice for 25 minutes in one week. ECG monitoring was performed before, during, and after exposure. Control subjects were exposed to normal indoor air in a similar environment and similarly monitored. Followup was performed the following week. Short-term (5 min) HRV parameters were analyzed with HRV analysis software. SPSS software was used for statistical analysis. Results. During and after the first exposure, comparison of percentage changes or changes in all parameters between groups showed no significant differences. During the second exposure, percentage decrease in HR, percentage increases in lnTP, lnHF, lnLF, and RMSSD, and increase in PNN50 were significantly greater in the experimental group than in control. Conclusion. No significant adverse HRV effects were associated with this clinically routine 25-minute exposure to moxa smoke, and the data suggests that short-term exposure to moxa smoke might have positive regulating effects on human autonomic function. Further studies are warranted to confirm these findings. PMID:23762143

  5. Formaldehyde solutions in simulated sweat increase human melanoma but not normal human keratinocyte cells proliferation.

    PubMed

    Rizzi, M; Cravello, B; Tonello, S; Renò, F

    2016-12-01

    Our skin is in close contact with clothes most of the time thus risking potentially noxious chemicals contact. One of the potentially harmful manufacturing by-products that can be released by textiles when sweating is formaldehyde, used as an anti-crease treatment. As it is known to be carcinogenic to humans and a potent skin sensitizer, the aim of this study was to investigate its effects on both normal human keratinocytes (HaCaT cells) and on a highly invasive malignant melanoma cell line (SK-MEL-28) in order to contribute to the definition of safety cut-off to be applied to the production processes. Formaldehyde concentrations below the commonly accepted limits (10-50μM) were obtained by diluting formaldehyde in simulated sweat (UNI EN ISO 105-E04). The effects on cell proliferation were evaluated by cell counting, while ERK pathway activation was evaluated by western blot. Low concentrations of formaldehyde (10μM) in both acidic and alkaline simulated sweat were able to increase malignant melanoma cell proliferation, while not affecting normal keratinocytes. Melanoma proliferation increase was greater in acidic (pH=5.5) than in alkaline (pH=8) conditions. Moreover, formaldehyde stimulation was able to induce ERK pathway activation. The data obtained suggest the need for an even increasing attention to the potentially harmful effects of textile manufacturing by-products. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Specific binding of beta-endorphin to normal human erythrocytes

    SciTech Connect

    Chenet, B.; Hollis, V. Jr.; Kang, Y.; Simpkins, C.

    1986-03-05

    Beta-endorphin (BE) exhibits peripheral functions which may not be mediated by interactions with receptors in the brain. Recent studies have demonstrated binding of BE to both opioid and non-opioid receptors on lymphocytes and monocytes. Abood has reported specific binding of /sup 3/H-dihydromorphine in erythrocytes. Using 5 x 10/sup -11/M /sup 125/I-beta-endorphin and 10/sup -5/M unlabeled BE, they have detected 50% specific binding to human erythrocytes. This finding is supported by results from immunoelectron microscopy using rabbit anti-BE antibody and biotinylated secondary antibody with avidin-biotin complexes horseradish peroxidase. Binding is clearly observed and is confined to only one side of the cells. Conclusions: (1) BE binding to human erythrocytes was demonstrated by radioreceptor assay and immunoelectron microscopy, and (2) BE binding sites exist on only one side of the cells.

  7. Amino acid immunoreactivity in normal human retina and after brachytherapy.

    PubMed

    de Souza, Clairton F; Acosta, Monica L; Polkinghorne, Philip J; McGhee, Charles N J; Kalloniatis, Michael

    2013-09-01

    We localised amino acids in the mid-peripheral aged human retina and a retina that had undergone radiation treatment 10 years earlier. The distribution pattern of glutamate, γ-amino butyric acid (GABA), glycine, glutamine and taurine, reflected patterns established in the primate retina. The retina that had undergone radiation exposure displayed both anatomical and neurochemical remodelling. The proximal retina comprised around 40 to 45 per cent of the total retina and neuronal kinesis and aberrant neuronal projections were also present. Amino acid neurochemistry was strikingly different with Müller cells displaying GABA loading, glycinergic neurons displaced and displaying a very high level of glycine labelling. We conclude that radiation exposure triggered these changes in the human retina and likely reflects general remodelling of structure and function following ischaemic damage to endothelial cells.

  8. Neurophysiological model of the normal and abnormal human pupil

    NASA Technical Reports Server (NTRS)

    Krenz, W.; Robin, M.; Barez, S.; Stark, L.

    1985-01-01

    Anatomical, experimental, and computer simulation studies were used to determine the structure of the neurophysiological model of the pupil size control system. The computer simulation of this model demonstrates the role played by each of the elements in the neurological pathways influencing the size of the pupil. Simulations of the effect of drugs and common abnormalities in the system help to illustrate the workings of the pathways and processes involved. The simulation program allows the user to select pupil condition (normal or an abnormality), specific site along the neurological pathway (retina, hypothalamus, etc.) drug class input (barbiturate, narcotic, etc.), stimulus/response mode, display mode, stimulus type and input waveform, stimulus or background intensity and frequency, the input and output conditions, and the response at the neuroanatomical site. The model can be used as a teaching aid or as a tool for testing hypotheses regarding the system.

  9. Neurophysiological model of the normal and abnormal human pupil

    NASA Technical Reports Server (NTRS)

    Krenz, W.; Robin, M.; Barez, S.; Stark, L.

    1985-01-01

    Anatomical, experimental, and computer simulation studies were used to determine the structure of the neurophysiological model of the pupil size control system. The computer simulation of this model demonstrates the role played by each of the elements in the neurological pathways influencing the size of the pupil. Simulations of the effect of drugs and common abnormalities in the system help to illustrate the workings of the pathways and processes involved. The simulation program allows the user to select pupil condition (normal or an abnormality), specific site along the neurological pathway (retina, hypothalamus, etc.) drug class input (barbiturate, narcotic, etc.), stimulus/response mode, display mode, stimulus type and input waveform, stimulus or background intensity and frequency, the input and output conditions, and the response at the neuroanatomical site. The model can be used as a teaching aid or as a tool for testing hypotheses regarding the system.

  10. The anatomic basis for ventricular arrhythmia in the normal heart: what the student of anatomy needs to know.

    PubMed

    Hai, Jo Jo; Lachman, Nirusha; Syed, Faisal F; Desimone, Christopher V; Asirvatham, Samuel J

    2014-09-01

    The traditional route for teaching cardiac anatomy involves didactic instruction, cadaver dissections, and familiarization with the main structure and relationships of the cardiac chambers, valves, and vasculature. In contemporary cardiac electrophysiology, however, a very different view of anatomy is required including details rarely appreciated with a general overview. In this review, we discuss the critical advances in cardiac electrophysiology that were possible only because of understanding detailed anatomic relationships. While we briefly discuss the clinical relevance, we explain in depth the necessary structural information for the student of clinical anatomy. Interspersed through the text are boxes that highlight and summarize the critical pieces of knowledge to be borne in mind while studying the fascinating structural anatomy of the human heart. © 2014 Wiley Periodicals, Inc.

  11. Mineral density volume gradients in normal and diseased human tissues

    SciTech Connect

    Djomehri, Sabra I.; Candell, Susan; Case, Thomas; Browning, Alyssa; Marshall, Grayson W.; Yun, Wenbing; Lau, S. H.; Webb, Samuel; Ho, Sunita P.; Aikawa, Elena

    2015-04-09

    Clinical computed tomography provides a single mineral density (MD) value for heterogeneous calcified tissues containing early and late stage pathologic formations. The novel aspect of this study is that, it extends current quantitative methods of mapping mineral density gradients to three dimensions, discretizes early and late mineralized stages, identifies elemental distribution in discretized volumes, and correlates measured MD with respective calcium (Ca) to phosphorus (P) and Ca to zinc (Zn) elemental ratios. To accomplish this, MD variations identified using polychromatic radiation from a high resolution micro-computed tomography (micro-CT) benchtop unit were correlated with elemental mapping obtained from a microprobe X-ray fluorescence (XRF) using synchrotron monochromatic radiation. Digital segmentation of tomograms from normal and diseased tissues (N=5 per group; 40-60 year old males) contained significant mineral density variations (enamel: 2820-3095mg/cc, bone: 570-1415mg/cc, cementum: 1240-1340mg/cc, dentin: 1480-1590mg/cc, cementum affected by periodontitis: 1100-1220mg/cc, hypomineralized carious dentin: 345-1450mg/cc, hypermineralized carious dentin: 1815-2740mg/cc, and dental calculus: 1290-1770mg/cc). A plausible linear correlation between segmented MD volumes and elemental ratios within these volumes was established, and Ca/P ratios for dentin (1.49), hypomineralized dentin (0.32-0.46), cementum (1.51), and bone (1.68) were observed. Furthermore, varying Ca/Zn ratios were distinguished in adapted compared to normal tissues, such as in bone (855-2765) and in cementum (595-990), highlighting Zn as an influential element in prompting observed adaptive properties. Hence, results provide insights on mineral density gradients with elemental concentrations and elemental footprints that in turn could aid in elucidating mechanistic processes for pathologic formations.

  12. Mineral density volume gradients in normal and diseased human tissues

    DOE PAGES

    Djomehri, Sabra I.; Candell, Susan; Case, Thomas; ...

    2015-04-09

    Clinical computed tomography provides a single mineral density (MD) value for heterogeneous calcified tissues containing early and late stage pathologic formations. The novel aspect of this study is that, it extends current quantitative methods of mapping mineral density gradients to three dimensions, discretizes early and late mineralized stages, identifies elemental distribution in discretized volumes, and correlates measured MD with respective calcium (Ca) to phosphorus (P) and Ca to zinc (Zn) elemental ratios. To accomplish this, MD variations identified using polychromatic radiation from a high resolution micro-computed tomography (micro-CT) benchtop unit were correlated with elemental mapping obtained from a microprobe X-raymore » fluorescence (XRF) using synchrotron monochromatic radiation. Digital segmentation of tomograms from normal and diseased tissues (N=5 per group; 40-60 year old males) contained significant mineral density variations (enamel: 2820-3095mg/cc, bone: 570-1415mg/cc, cementum: 1240-1340mg/cc, dentin: 1480-1590mg/cc, cementum affected by periodontitis: 1100-1220mg/cc, hypomineralized carious dentin: 345-1450mg/cc, hypermineralized carious dentin: 1815-2740mg/cc, and dental calculus: 1290-1770mg/cc). A plausible linear correlation between segmented MD volumes and elemental ratios within these volumes was established, and Ca/P ratios for dentin (1.49), hypomineralized dentin (0.32-0.46), cementum (1.51), and bone (1.68) were observed. Furthermore, varying Ca/Zn ratios were distinguished in adapted compared to normal tissues, such as in bone (855-2765) and in cementum (595-990), highlighting Zn as an influential element in prompting observed adaptive properties. Hence, results provide insights on mineral density gradients with elemental concentrations and elemental footprints that in turn could aid in elucidating mechanistic processes for pathologic formations.« less

  13. Mineral Density Volume Gradients in Normal and Diseased Human Tissues

    PubMed Central

    Djomehri, Sabra I.; Candell, Susan; Case, Thomas; Browning, Alyssa; Marshall, Grayson W.; Yun, Wenbing; Lau, S. H.; Webb, Samuel; Ho, Sunita P.

    2015-01-01

    Clinical computed tomography provides a single mineral density (MD) value for heterogeneous calcified tissues containing early and late stage pathologic formations. The novel aspect of this study is that, it extends current quantitative methods of mapping mineral density gradients to three dimensions, discretizes early and late mineralized stages, identifies elemental distribution in discretized volumes, and correlates measured MD with respective calcium (Ca) to phosphorus (P) and Ca to zinc (Zn) elemental ratios. To accomplish this, MD variations identified using polychromatic radiation from a high resolution micro-computed tomography (micro-CT) benchtop unit were correlated with elemental mapping obtained from a microprobe X-ray fluorescence (XRF) using synchrotron monochromatic radiation. Digital segmentation of tomograms from normal and diseased tissues (N=5 per group; 40-60 year old males) contained significant mineral density variations (enamel: 2820-3095mg/cc, bone: 570-1415mg/cc, cementum: 1240-1340mg/cc, dentin: 1480-1590mg/cc, cementum affected by periodontitis: 1100-1220mg/cc, hypomineralized carious dentin: 345-1450mg/cc, hypermineralized carious dentin: 1815-2740mg/cc, and dental calculus: 1290-1770mg/cc). A plausible linear correlation between segmented MD volumes and elemental ratios within these volumes was established, and Ca/P ratios for dentin (1.49), hypomineralized dentin (0.32-0.46), cementum (1.51), and bone (1.68) were observed. Furthermore, varying Ca/Zn ratios were distinguished in adapted compared to normal tissues, such as in bone (855-2765) and in cementum (595-990), highlighting Zn as an influential element in prompting observed adaptive properties. Hence, results provide insights on mineral density gradients with elemental concentrations and elemental footprints that in turn could aid in elucidating mechanistic processes for pathologic formations. PMID:25856386

  14. [Heart rhythm indices during human solving of arithmetic tasks].

    PubMed

    Danilova, N N; Korshunova, S G; Sokolov, E N

    1994-01-01

    Heart rate and respiration were recorded in a group of 90 subjects (25 males and 65 females) aged 17-19 during rest and under informational load (arithmetical tasks) lasting 3 min each. Off-line spectral analysis was performed for all the subjects. Anxiety according to Spilberger and strength of excitation-inhibition according to Strelau were also tested. It was shown that heart rate increased significantly in the group as a whole, however, variability of RR-intervals remained unchanged. Then two subgroups of subjects who responded to information load by a decrease and increase of RR-interval variability were distinguished. These subgroups were characterized respectively by the high and low levels of personal anxiety. The decrease of RR-interval variability in the high-anxiety subgroup was associated with a decrease of power in all frequency bands of the rate spectrum. The increase of RR-interval variability in the low-anxiety subground was due to an increase of heart rate modulation in a low-frequency band of the heart rate spectrum. Fatigue is regarded as a cause of such heart rate modulation.

  15. Quantitation of small intestinal permeability during normal human drug absorption

    PubMed Central

    2013-01-01

    Background Understanding the quantitative relationship between a drug’s physical chemical properties and its rate of intestinal absorption (QSAR) is critical for selecting candidate drugs. Because of limited experimental human small intestinal permeability data, approximate surrogates such as the fraction absorbed or Caco-2 permeability are used, both of which have limitations. Methods Given the blood concentration following an oral and intravenous dose, the time course of intestinal absorption in humans was determined by deconvolution and related to the intestinal permeability by the use of a new 3 parameter model function (“Averaged Model” (AM)). The theoretical validity of this AM model was evaluated by comparing it to the standard diffusion-convection model (DC). This analysis was applied to 90 drugs using previously published data. Only drugs that were administered in oral solution form to fasting subjects were considered so that the rate of gastric emptying was approximately known. All the calculations are carried out using the freely available routine PKQuest Java (http://www.pkquest.com) which has an easy to use, simple interface. Results Theoretically, the AM permeability provides an accurate estimate of the intestinal DC permeability for solutes whose absorption ranges from 1% to 99%. The experimental human AM permeabilities determined by deconvolution are similar to those determined by direct human jejunal perfusion. The small intestinal pH varies with position and the results are interpreted in terms of the pH dependent octanol partition. The permeability versus partition relations are presented separately for the uncharged, basic, acidic and charged solutes. The small uncharged solutes caffeine, acetaminophen and antipyrine have very high permeabilities (about 20 x 10-4 cm/sec) corresponding to an unstirred layer of only 45 μm. The weak acid aspirin also has a large AM permeability despite its low octanol partition at pH 7.4, suggesting

  16. Morphological variations of papillary muscles in the mitral valve complex in human cadaveric hearts.

    PubMed

    Gunnal, Sandhya Arvind; Wabale, Rajendra Namdeo; Farooqui, Mujeebuddin Samsamuddin

    2013-01-01

    Papillary muscle rupture and dysfunction can lead to complications of prolapsed mitral valve and mitral regurgitation. Multiple operative procedures of the papillary muscles, such as resection, repositioning and realignment, are carried out to restore normal physiological function. Therefore, it is important to know both the variations and the normal anatomy of papillary muscles. This study was carried out on 116 human cadaveric hearts. The left ventricles were opened along the left border in order to view the papillary muscles. The number, shape, position and pattern of the papillary muscles were observed. In this series, the papillary muscles were mostly found in groups instead of in twos, as is described in standard textbooks. Four different shapes of papillary muscles were identified - conical, broad-apexed, pyramidal and fan-shaped. We also discovered various patterns of papillary muscles. No two mitral valve complexes have the same architectural arrangement. Each case seems to be unique. Therefore, it is important for scientists worldwide to study the variations in the mitral valve complex in order to ascertain the reason behind each specific architectural arrangement. This will enable cardiothoracic surgeons to tailor the surgical procedures according to the individual papillary muscle pattern.

  17. 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.

  18. 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.

  19. Human interstitial cellular model in therapeutics of heart valve calcification.

    PubMed

    He, Caimei; Tang, Hai; Mei, Zijian; Li, Nichujie; Zeng, Zhi; Darko, Kwame Oteng; Yin, Yulong; Hu, Chien-An Andy; Yang, Xiaoping

    2017-05-23

    Calcific aortic valve disease is a common, severe heart condition that is currently with no proven, effective drug treatment and requires a surgical valve replacement or an entire heart explanation. Thus, developing novel, targeted therapeutic approaches becomes a major goal for cardiovascular disease research. To achieve this goal, isolated heart valve interstitial cells could be an advanced model to explore molecular mechanisms and measure drug efficacy. Based on this progress, molecular mechanisms that harbor components of  inflammation and fibrosis coupled with proteins, for example, BMP-2, TLRs, RANKL, Osteoprotegerin, have been proposed. Small molecules or antibodies targeting these proteins have shown promising efficacy for either reversing or slowing down calcification development in vitro. In this review, we summarize these potential therapeutics with some highlights of interstitial cellular models.

  20. Sodium tungstate administration ameliorated diabetes-induced electrical and contractile remodeling of rat heart without normalization of hyperglycemia.

    PubMed

    Aydemir, Mustafa; Ozturk, Nihal; Dogan, Serdar; Aslan, Mutay; Olgar, Yusuf; Ozdemir, Semir

    2012-08-01

    Recently, sodium tungstate was suggested to improve cardiac performance of diabetic rats in perfused hearts based on its insulinomimetic activity. In this study, we aimed to investigate the cellular and molecular mechanisms underlying this beneficial effect of sodium tungstate. Tungstate was administered (100 mg/kg/day) to diabetic and control rats intragastrically for 6 weeks. Blood glucose levels increased, whereas body weight, heart weight and plasma insulin levels decreased significantly in diabetic animals. Interestingly, none of these parameters was changed by tungstate treatment. On the other hand, fractional shortening and accompanying intracellular Ca(2+) [Ca(2+)](i) transients of isolated ventricular myocytes were measured, and sodium tungstate was found to improve the peak shortening and the amplitude of [Ca(2+)](i) transients in diabetic cardiomyocytes. Potassium and L-type Ca(2+) currents were also recorded in isolated ventricular cells. Significant restoration of suppressed I (to) and I (ss) was achieved by tungstate administration. Nevertheless, L-type calcium currents did not change either in untreated or treated diabetic rats. Tissue biochemical parameters including TBARS, protein carbonyl content, xanthine oxidase (XO) and xanthine dehydogenase (XDH) were also determined, and diabetes revealed a marked increase in TBARS and carbonyl content which were decreased significantly by tungstate treatment. Conversely, although XO and XDH activities didn't change in untreated diabetic rats, a remarkable but insignificant decrease was detected in treated animals. In conclusion, tungstate treatment improved diabetes-induced contractile abnormalities via restoration of dysregulated [Ca(2+)](i) and altered ionic currents. This beneficial effect is due to antioxidant property of sodium tungstate rather than normalization of hyperglycemia.

  1. Normal accidents: human error and medical equipment design.

    PubMed

    Dain, Steven

    2002-01-01

    High-risk systems, which are typical of our technologically complex era, include not just nuclear power plants but also hospitals, anesthesia systems, and the practice of medicine and perfusion. In high-risk systems, no matter how effective safety devices are, some types of accidents are inevitable because the system's complexity leads to multiple and unexpected interactions. It is important for healthcare providers to apply a risk assessment and management process to decisions involving new equipment and procedures or staffing matters in order to minimize the residual risks of latent errors, which are amenable to correction because of the large window of opportunity for their detection. This article provides an introduction to basic risk management and error theory principles and examines ways in which they can be applied to reduce and mitigate the inevitable human errors that accompany high-risk systems. The article also discusses "human factor engineering" (HFE), the process which is used to design equipment/ human interfaces in order to mitigate design errors. The HFE process involves interaction between designers and endusers to produce a series of continuous refinements that are incorporated into the final product. The article also examines common design problems encountered in the operating room that may predispose operators to commit errors resulting in harm to the patient. While recognizing that errors and accidents are unavoidable, organizations that function within a high-risk system must adopt a "safety culture" that anticipates problems and acts aggressively through an anonymous, "blameless" reporting mechanism to resolve them. We must continuously examine and improve the design of equipment and procedures, personnel, supplies and materials, and the environment in which we work to reduce error and minimize its effects. Healthcare providers must take a leading role in the day-to-day management of the "Perioperative System" and be a role model in

  2. Intact Imaging of Human Heart Structure Using X-ray Phase-Contrast Tomography.

    PubMed

    Kaneko, Yukihiro; Shinohara, Gen; Hoshino, Masato; Morishita, Hiroyuki; Morita, Kiyozo; Oshima, Yoshihiro; Takahashi, Masashi; Yagi, Naoto; Okita, Yutaka; Tsukube, Takuro

    2017-02-01

    Structural examination of human heart specimens at the microscopic level is a prerequisite for understanding congenital heart diseases. It is desirable not to destroy or alter the properties of such specimens because of their scarcity. However, many of the currently available imaging techniques either destroy the specimen through sectioning or alter the chemical and mechanical properties of the specimen through staining and contrast agent injection. As a result, subsequent studies may not be possible. X-ray phase-contrast tomography is an imaging modality for biological soft tissues that does not destroy or alter the properties of the specimen. The feasibility of X-ray phase-contrast tomography for the structural examination of heart specimens was tested using infantile and fetal heart specimens without congenital diseases. X-ray phase-contrast tomography was carried out at the SPring-8 synchrotron radiation facility using the Talbot grating interferometer at the bending magnet beamline BL20B2 to visualize the structure of five non-pretreated whole heart specimens obtained by autopsy. High-resolution, three-dimensional images were obtained for all specimens. The images clearly showed the myocardial structure, coronary vessels, and conduction bundle. X-ray phase-contrast tomography allows high-resolution, three-dimensional imaging of human heart specimens. Intact imaging using X-ray phase-contrast tomography can contribute to further structural investigation of heart specimens with congenital heart diseases.

  3. Reconstruction of normal and pathological human epidermis on polycarbonate filter.

    PubMed

    De Vuyst, Evelyne; Charlier, Céline; Giltaire, Séverine; De Glas, Valérie; de Rouvroit, Catherine Lambert; Poumay, Yves

    2014-01-01

    This chapter provides methods suitable for the culture of primary human keratinocytes in serum-free culture conditions, starting from very small skin biopsies. It also explains procedures required for reconstruction of a stratified epidermis on polycarbonate filter, starting from keratinocytes cultured in serum-free conditions. Tissues reconstructed according to this method have been proven suitable for characterization of epidermal morphogenesis and for in vitro studies of the epidermal barrier. Utilization of the same method for successful isolation of keratinocytes from a patient suffering from Darier's disease and the reconstruction of a pathological epidermis which displays the same histological features as in vivo are also presented.

  4. Glucose homeostasis during spontaneous labor in normal human pregnancy.

    PubMed

    Maheux, P C; Bonin, B; Dizazo, A; Guimond, P; Monier, D; Bourque, J; Chiasson, J L

    1996-01-01

    Using stable isotope, glucose turnover was measured in six normal pregnant women during the various stages of labor; during the latent (A1) and active (A2) phases of cervical dilatation, during fetal expulsion (B), and during placental expulsion (C). These data were compared to measurements made in five postpartum women. Pancreatic hormones and cortisol were also measured. In four other normal women undergoing spontaneous labor, catecholamines and free fatty acids were measured. Plasma glucose increased throughout labor from 4.0 +/- 0.2 (A1) to 5.5 +/- 0.5 mmol/L (C) (P < 0.01), compared to 4.7 +/- 0.1 in the postpartum women. Glucose utilization and production were increased throughout labor at 33.4 +/- 3.1 and 32.8 +/- 3.1 mumol/kg min, respectively, compared to 8.2 +/- 0.9 in postpartum women. Glucose metabolic clearance was also increased to 7.5 +/- 0.8 mL/kg.min compared to that in nonpregnant women (1.8 +/- 0.3). Plasma insulin remained at 59 +/- 5 pmol/L during stages A1, A2, and B, but increased to 115 +/- 15 pmol/L during stage C. Plasma glucagon was increased throughout labor at 127 +/- 7 pg/mL, compared to 90 +/- 4 pg/mL in control postpartum women. Plasma cortisol increased during labor from 921 +/- 136 to 2018 +/- 160 nmol/L, compared to 645 +/- 355 during the postpartum period. Epinephrine and norepinephrine also increased during labor from 218 +/- 132 pmol/L and 1.09 +/- 0.16 nmol/L to 1119 +/- 158 and 3.61 +/- 1.04, respectively. It is concluded that labor is associated with a marked increase in glucose utilization and production. These findings suggest that muscle contraction (uterus and skeletal) independent of insulin is a major regulator of glucose utilization during labor. Furthermore, the increase in hepatic glucose production could be favored by an increase in glucagon, catecholamines, and cortisol.

  5. Right ventricular arrhythmogenesis in failing human heart: the role of conduction and repolarization remodeling

    PubMed Central

    Lou, Qing; Janks, Deborah L.; Holzem, Katherine M.; Lang, Di; Onal, Birce; Ambrosi, Christina M.; Fedorov, Vadim V.; Wang, I-Wen

    2012-01-01

    Increased dispersion of repolarization has been suggested to underlie increased arrhythmogenesis in human heart failure (HF). However, no detailed repolarization mapping data were available to support the presence of increased dispersion of repolarization in failing human heart. In the present study, we aimed to determine the existence of enhanced repolarization dispersion in the right ventricular (RV) endocardium from failing human heart and examine its association with arrhythmia inducibility. RV free wall preparations were dissected from five failing and five nonfailing human hearts, cannulated and coronary perfused. RV endocardium was optically mapped from an ∼6.3 × 6.3 cm2 field of view. Action potential duration (APD), dispersion of APD, and conduction velocity (CV) were quantified for basic cycle lengths (BCL) ranging from 2,000 ms to the functional refractory period. We found that RV APD was significantly prolonged within the failing group compared with the nonfailing group (560 ± 44 vs. 448 ± 39 ms, at BCL = 2,000 ms, P < 0.05). Dispersion of APD was increased in three failing hearts (161 ± 5 vs. 86 ± 19 ms, at BCL = 2,000 ms). APD alternans were induced by rapid pacing in these same three failing hearts. CV was significantly reduced in the failing group compared with the nonfailing group (81 ± 11 vs. 98 ± 8 cm/s, at BCL = 2,000 ms). Arrhythmias could be induced in two failing hearts exhibiting an abnormally steep CV restitution and increased dispersion of repolarization due to APD alternans. Dispersion of repolarization is enhanced across the RV endocardium in the failing human heart. This dispersion, together with APD alternans and abnormal CV restitution, could be responsible for the arrhythmia susceptibility in human HF. PMID:23042951

  6. Right ventricular arrhythmogenesis in failing human heart: the role of conduction and repolarization remodeling.

    PubMed

    Lou, Qing; Janks, Deborah L; Holzem, Katherine M; Lang, Di; Onal, Birce; Ambrosi, Christina M; Fedorov, Vadim V; Wang, I-Wen; Efimov, Igor R

    2012-12-15

    Increased dispersion of repolarization has been suggested to underlie increased arrhythmogenesis in human heart failure (HF). However, no detailed repolarization mapping data were available to support the presence of increased dispersion of repolarization in failing human heart. In the present study, we aimed to determine the existence of enhanced repolarization dispersion in the right ventricular (RV) endocardium from failing human heart and examine its association with arrhythmia inducibility. RV free wall preparations were dissected from five failing and five nonfailing human hearts, cannulated and coronary perfused. RV endocardium was optically mapped from an ∼6.3 × 6.3 cm(2) field of view. Action potential duration (APD), dispersion of APD, and conduction velocity (CV) were quantified for basic cycle lengths (BCL) ranging from 2,000 ms to the functional refractory period. We found that RV APD was significantly prolonged within the failing group compared with the nonfailing group (560 ± 44 vs. 448 ± 39 ms, at BCL = 2,000 ms, P < 0.05). Dispersion of APD was increased in three failing hearts (161 ± 5 vs. 86 ± 19 ms, at BCL = 2,000 ms). APD alternans were induced by rapid pacing in these same three failing hearts. CV was significantly reduced in the failing group compared with the nonfailing group (81 ± 11 vs. 98 ± 8 cm/s, at BCL = 2,000 ms). Arrhythmias could be induced in two failing hearts exhibiting an abnormally steep CV restitution and increased dispersion of repolarization due to APD alternans. Dispersion of repolarization is enhanced across the RV endocardium in the failing human heart. This dispersion, together with APD alternans and abnormal CV restitution, could be responsible for the arrhythmia susceptibility in human HF.

  7. Maintenance of the normal flora of human skin grafts transplanted to mice.

    PubMed

    Kearney, J N; Gowland, G; Holland, K T; Cunliffe, W J

    1982-10-01

    Full-thickness human cadaver skin was maintained on the dorso-lateral thoracic region of hairless mice whose immune rejection mechanism was suppressed using anti-mouse-thymocyte globulin. The bacterial profile of the pregrafted skin did not differ significantly from the normal human microflora. In contrast, the murine skin exhibited quantitative and qualitative differences from the human flora, in particular by the complete absence of Propionibacterium acnes, the dominant bacterium on sebum-rich areas of human skin. The normal microbial profile of the human grafts was maintained throughout the experimental period despite the novel environmental milieu. There was little contamination of the grafts from the normal murine flora. It was concluded that the grafted human skin would provide a realistic model for studying the ecology of human cutaneous micro-organisms.

  8. A deep sequencing approach to uncover the miRNOME in the human heart.

    PubMed

    Leptidis, Stefanos; El Azzouzi, Hamid; Lok, Sjoukje I; de Weger, Roel; Olieslagers, Servé; Olieslagers, Serv; Kisters, Natasja; Silva, Gustavo J; Heymans, Stephane; Cuppen, Edwin; Berezikov, Eugene; De Windt, Leon J; da Costa Martins, Paula

    2013-01-01

    MicroRNAs (miRNAs) are a class of non-coding RNAs of ∼22 nucleotides in length, and constitute a novel class of gene regulators by imperfect base-pairing to the 3'UTR of protein encoding messenger RNAs. Growing evidence indicates that miRNAs are implicated in several pathological processes in myocardial disease. The past years, we have witnessed several profiling attempts using high-density oligonucleotide array-based approaches to identify the complete miRNA content (miRNOME) in the healthy and diseased mammalian heart. These efforts have demonstrated that the failing heart displays differential expression of several dozens of miRNAs. While the total number of experimentally validated human miRNAs is roughly two thousand, the number of expressed miRNAs in the human myocardium remains elusive. Our objective was to perform an unbiased assay to identify the miRNOME of the human heart, both under physiological and pathophysiological conditions. We used deep sequencing and bioinformatics to annotate and quantify microRNA expression in healthy and diseased human heart (heart failure secondary to hypertrophic or dilated cardiomyopathy). Our results indicate that the human heart expresses >800 miRNAs, the majority of which not being annotated nor described so far and some of which being unique to primate species. Furthermore, >250 miRNAs show differential and etiology-dependent expression in human dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM). The human cardiac miRNOME still possesses a large number of miRNAs that remain virtually unexplored. The current study provides a starting point for a more comprehensive understanding of the role of miRNAs in regulating human heart disease.

  9. Alterations in apoptotic signaling in human idiopathic cardiomyopathic hearts in failure.

    PubMed

    Steenbergen, Charles; Afshari, Cynthia A; Petranka, John G; Collins, Jennifer; Martin, Karla; Bennett, Lee; Haugen, Astrid; Bushel, Pierre; Murphy, Elizabeth

    2003-01-01

    Dilated cardiomyopathy, a disease of unknown etiology and pathogenesis, is associated with heart failure and compensatory hypertrophy. Although cell and animal models suggest a role for altered gene expression in the transition to heart failure, there is a paucity of data derived from the study of human heart tissue. In this study, we used DNA microarray profiling to investigate changes in the expression of genes involved in apoptosis that occur in human idiopathic dilated cardiomyopathic hearts that had progressed to heart failure. We observed altered gene expression consistent with a proapoptotic shift in the TNF-alpha signaling pathway. Specifically, we found decreased expression of TNF-alpha- and NF-kappaB-induced antiapoptotic genes such as growth arrest and DNA damage-inducible (GADD)45beta, Flice inhibitory protein (FLIP), and TNF-induced protein 3 (A20). Consistent with a role for apoptosis in heart failure, we also observed a significant decrease in phosphorylation of BAD at Ser-112. This study identifies several pathways that are altered in human heart failure and provides new targets for therapy.

  10. Effects of Load on Normal Human Osteoblast Function

    NASA Astrophysics Data System (ADS)

    Reseland, J. E.; Devakottai, Sundar; Sundaresan, A.

    2013-02-01

    The effects of load on the secretion and expression of bone markers were tested at different stages of differentiation of primary human osteoblasts. NHOs were both seeded with and without cytodex 3 beads (Sigma),transferred to a NASA rotating wall vessel (modeled microgravity) and harvested at day 7 and day 14. Differentiated and undifferentiated NHOs were loaded at 6-50G for 30 min and compared to cells incubated at 1G after 1 day and 3 days. Collectively the results demonstrate that load has a differential effect on osteoblast differentiation as seen in modeled microgravity and shows specificity in expression of bone cell markers vs. expression of secreted paracrine signaling markers.

  11. Nonlinear time series analysis of normal and pathological human walking

    NASA Astrophysics Data System (ADS)

    Dingwell, Jonathan B.; Cusumano, Joseph P.

    2000-12-01

    Characterizing locomotor dynamics is essential for understanding the neuromuscular control of locomotion. In particular, quantifying dynamic stability during walking is important for assessing people who have a greater risk of falling. However, traditional biomechanical methods of defining stability have not quantified the resistance of the neuromuscular system to perturbations, suggesting that more precise definitions are required. For the present study, average maximum finite-time Lyapunov exponents were estimated to quantify the local dynamic stability of human walking kinematics. Local scaling exponents, defined as the local slopes of the correlation sum curves, were also calculated to quantify the local scaling structure of each embedded time series. Comparisons were made between overground and motorized treadmill walking in young healthy subjects and between diabetic neuropathic (NP) patients and healthy controls (CO) during overground walking. A modification of the method of surrogate data was developed to examine the stochastic nature of the fluctuations overlying the nominally periodic patterns in these data sets. Results demonstrated that having subjects walk on a motorized treadmill artificially stabilized their natural locomotor kinematics by small but statistically significant amounts. Furthermore, a paradox previously present in the biomechanical literature that resulted from mistakenly equating variability with dynamic stability was resolved. By slowing their self-selected walking speeds, NP patients adopted more locally stable gait patterns, even though they simultaneously exhibited greater kinematic variability than CO subjects. Additionally, the loss of peripheral sensation in NP patients was associated with statistically significant differences in the local scaling structure of their walking kinematics at those length scales where it was anticipated that sensory feedback would play the greatest role. Lastly, stride-to-stride fluctuations in the

  12. [Thyroid stimulating immunoglobulin bioassay using cultured normal human thyroid cells].

    PubMed

    Ando, M; Yamauchi, K; Tanaka, H; Mori, Y; Takatsuki, K; Yamamoto, M; Matsui, N; Tomita, A

    1985-08-20

    It is currently believed that the thyroid stimulating immunoglobulin (TSI) of Graves' disease is involved in the pathogenesis of hyperthyroidism through the stimulation of the adenylate cyclase-cyclic AMP system. To evaluate this mechanism, TSI in the serum of patients with Graves' disease was determined by its ability to generate cyclic AMP (cAMP) in monolayer cells prepared from a normal thyroid gland. The thyroid tissue was digested with collagenase, and the liberated follicles were collected from the supernatant and cultured for 7 days. One gram of thyroid tissue yielded more than 1 X 10(7) monolayer cells which were stored in aliquots at -80C. Cells (1 approximately 2 X 10(4)/0.28 cm2 microtiter well) were incubated for 4 hours in 0.2 ml Hanks solution poor in NaCl, with various amounts of bovine TSH (bTSH) or 1.5 mg/ml Graves' serum IgG extracted by polyethylene glycol. cAMP accumulated in medium and cells was measured by RIA. Total cAMP (both medium and cells) was about 4 times higher when NaCl was deleted from Hanks solution. Moreover, as more than 90% of the cAMP was released into the medium, it was possible to omit the measurement of cellular cAMP, which requires extraction. The increase in medium cAMP concentration was dependent upon the number of cells, incubation time, and dose of bTSH. Time course and dose response curves in medium cAMP stimulated by IgG from 3 Graves' patients paralleled those of bTSH equivalent units. Accordingly, TSI activity could be expressed in bTSH equivalent units (bTSH microUeq). The assay could detect 1.0 or 3.3 microU/ml of bTSH and was highly reproducible. TSI activity in all of 16 IgGs from normal subjects was under 3.3 bTSH microUeq/ml, while it was greater than 3.3 bTSH microUeq/ml in IgGs from 33 of 37 (89%) untreated patients with Graves disease. Of the 13 patients followed for 2 to 7 months while on antithyroid drugs, 12 had greater than 3.3 bTSH microUeq/ml and, with the exception of one, all showed a decrease in

  13. Infrequency of cytomegalovirus genome in coronary arteriopathy of human heart allografts.

    PubMed Central

    Gulizia, J. M.; Kandolf, R.; Kendall, T. J.; Thieszen, S. L.; Wilson, J. E.; Radio, S. J.; Costanzo, M. R.; Winters, G. L.; Miller, L. L.; McManus, B. M.

    1995-01-01

    In heart transplantation, long-term engraftment success is severely limited by the rapid development of obliterative disease of the coronary arteries. Data from various groups have been suggestive of a pathogenetic role of herpesviruses, particularly human cytomegalovirus, in accelerated allograft coronary artery disease; however, results are not yet conclusive. This study examines the hypothesis that human cytomegalovirus infection of allograft tissues is related pathogenetically and directly to accelerated coronary artery disease. Using in situ DNA hybridization and polymerase chain reaction, we examined particular coronary artery segments from 41 human heart allografts (ranging from 4 days to greater than 4 years after transplantation; mean, 457 days) and 22 donor age- and gender-comparable, coronary site-matched trauma victims for presence of human cytomegalovirus DNA. Human cytomegalovirus genome was detected in 8 of 41 (19.5%) allografts and in 1 of 22 (4.5%) control hearts. This difference in positivity was not statistically significant (P = 0.10). In the human cytomegalovirus-positive hearts, viral genome was localized to perivascular myocardium or coronary artery media or adventitia. Human cytomegalovirus genome was not detected in arterial intima of any allograft or control heart, although human cytomegalovirus genome was readily identified within intima of small pulmonary arteries from lung tissue with human cytomegalovirus pneumonitis. By statistical analyses, the presence of human cytomegalovirus genome was not associated with the nature or digitized extent of transplant arteriopathy, evidence of rejection, allograft recipient or donor serological data suggestive of human cytomegalovirus infection, duration of allograft implantation, or causes of death or retransplantation. Thus, our data indicate a low frequency of detectable human cytomegalovirus genome in accelerated coronary artery disease and do not support a direct role for human cytomegalovirus

  14. Encounters with the Human Heart: An Interview with John Stone.

    ERIC Educational Resources Information Center

    Flynn, Dale Bachman

    1995-01-01

    Interviews Dale Bachman Flynn, professor of cardiology and dean of admissions and student affairs at Emory University School of Medicine, about his "In the Country of Hearts," a collection of stories about his medical practice. Discusses Flynn's personal life; his life-long practice of writing; and his interest in the intersections among medicine,…

  15. Encounters with the Human Heart: An Interview with John Stone.

    ERIC Educational Resources Information Center

    Flynn, Dale Bachman

    1995-01-01

    Interviews Dale Bachman Flynn, professor of cardiology and dean of admissions and student affairs at Emory University School of Medicine, about his "In the Country of Hearts," a collection of stories about his medical practice. Discusses Flynn's personal life; his life-long practice of writing; and his interest in the intersections among medicine,…

  16. Heart Rate and Heart Rate Variability in Dairy Cows with Different Temperament and Behavioural Reactivity to Humans

    PubMed Central

    Tőzsér, János; Szenci, Ottó; Póti, Péter; Pajor, Ferenc

    2015-01-01

    From the 1990s, extensive research was started on the physiological aspects of individual traits in animals. Previous research has established two extreme (proactive and reactive) coping styles in several animal species, but the means of reactivity with the autonomic nervous system (ANS) activity has not yet been investigated in cattle. The aim of this study was the characterization of cardiac autonomic activity under different conditions in cows with different individual characteristics. For this purpose, we investigated heart rate and ANS-related heart rate variability (HRV) parameters of dairy cows (N = 282) on smaller- and larger-scale farms grouped by (1) temperament and (2) behavioural reactivity to humans (BRH). Animals with high BRH scores were defined as impulsive, while animals with low BRH scores were defined as reserved. Cardiac parameters were calculated for undisturbed lying (baseline) and for milking bouts, the latter with the presence of an unfamiliar person (stressful situation). Sympathetic tone was higher, while vagal activity was lower in temperamental cows than in calm animals during rest both on smaller- and larger-scale farms. During milking, HRV parameters were indicative of a higher sympathetic and a lower vagal activity of temperamental cows as compared to calm ones in farms of both sizes. Basal heart rate did not differ between BRH groups either on smaller- or larger-scale farms. Differences between basal ANS activity of impulsive and reserved cows reflected a higher resting vagal and lower sympathetic activity of reserved animals compared to impulsive ones both on smaller- and larger-scale farms. There was no difference either in heart rate or in HRV parameters between groups during milking neither in smaller- nor in larger-scale farms. These two groupings allowed to draw possible parallels between personality and cardiac autonomic activity during both rest and milking in dairy cows. Heart rate and HRV seem to be useful for

  17. Heart Rate and Heart Rate Variability in Dairy Cows with Different Temperament and Behavioural Reactivity to Humans.

    PubMed

    Kovács, Levente; Kézér, Fruzsina Luca; Tőzsér, János; Szenci, Ottó; Póti, Péter; Pajor, Ferenc

    2015-01-01

    From the 1990s, extensive research was started on the physiological aspects of individual traits in animals. Previous research has established two extreme (proactive and reactive) coping styles in several animal species, but the means of reactivity with the autonomic nervous system (ANS) activity has not yet been investigated in cattle. The aim of this study was the characterization of cardiac autonomic activity under different conditions in cows with different individual characteristics. For this purpose, we investigated heart rate and ANS-related heart rate variability (HRV) parameters of dairy cows (N = 282) on smaller- and larger-scale farms grouped by (1) temperament and (2) behavioural reactivity to humans (BRH). Animals with high BRH scores were defined as impulsive, while animals with low BRH scores were defined as reserved. Cardiac parameters were calculated for undisturbed lying (baseline) and for milking bouts, the latter with the presence of an unfamiliar person (stressful situation). Sympathetic tone was higher, while vagal activity was lower in temperamental cows than in calm animals during rest both on smaller- and larger-scale farms. During milking, HRV parameters were indicative of a higher sympathetic and a lower vagal activity of temperamental cows as compared to calm ones in farms of both sizes. Basal heart rate did not differ between BRH groups either on smaller- or larger-scale farms. Differences between basal ANS activity of impulsive and reserved cows reflected a higher resting vagal and lower sympathetic activity of reserved animals compared to impulsive ones both on smaller- and larger-scale farms. There was no difference either in heart rate or in HRV parameters between groups during milking neither in smaller- nor in larger-scale farms. These two groupings allowed to draw possible parallels between personality and cardiac autonomic activity during both rest and milking in dairy cows. Heart rate and HRV seem to be useful for

  18. Beta adrenoreceptor subtype cross regulation in the human heart.

    PubMed

    Hall, J A; Ferro, A; Dickerson, J E; Brown, M J

    1993-04-01

    To find out in a prospective study whether beta 1 blocker treatment causes selective beta 2 adrenoreceptor sensitisation, and to find whether such sensitisation is confined to the heart. A placebo controlled cross over study of two weeks of selective beta 1 blocker treatment with 10 mg of bisoprolol daily. Six healthy volunteers. Three days after stopping the 10 mg of bisoprolol or placebo, subjects underwent treadmill exercise (to measure cardiac beta 1 receptor responsiveness) and were given salbutamol injections (to measure cardiac beta 2 receptor responsiveness). Secondary end points were the responses of serum potassium, glucose, and insulin to beta 2 stimulation. There was no difference in exercise induced increases in heart rate, but after treatment with bisoprolol the dose of salbutamol required to increase heart rate by 40 beats/min was 1.9 micrograms/kg compared with 2.9 micrograms/kg after placebo (p < 0.005). The fall in diastolic blood pressure was not significantly different on the two occasions. Hypokalaemia induced by salbutamol, but not hyperglycaemia or hyperinsulinaemia, was enhanced after bisoprolol. This study shows that treatment with a beta 1 blocker in vivo leads to sensitisation of cardiac beta 2 adrenoreceptors but not cardiac beta 1 adrenoreceptors or vascular beta 2 receptors. This previously unrecognised form of receptor cross sensitisation in the heart may noticeably diminish the efficacy of selective beta 1 blockade in preventing arrhythmias in patients with ischaemic heart disease. These findings reopen the question of which type of beta blocker is more appropriate for such patients.

  19. Angiotensin II formation in the intact human heart. Predominance of the angiotensin-converting enzyme pathway.

    PubMed Central

    Zisman, L S; Abraham, W T; Meixell, G E; Vamvakias, B N; Quaife, R A; Lowes, B D; Roden, R L; Peacock, S J; Groves, B M; Raynolds, M V

    1995-01-01

    It has been proposed that the contribution of myocardial tissue angiotensin converting enzyme (ACE) to angiotensin II (Ang II) formation in the human heart is low compared with non-ACE pathways. However, little is known about the actual in vivo contribution of these pathways to Ang II formation in the human heart. To examine angiotensin II formation in the intact human heart, we administered intracoronary 123I-labeled angiotensin I (Ang I) with and without intracoronary enalaprilat to orthotopic heart transplant recipients. The fractional conversion of Ang I to Ang II, calculated after separation of angiotensin peptides by HPLC, was 0.415 +/- 0.104 (n = 5, mean +/- SD). Enalaprilat reduced fractional conversion by 89%, to a value of 0.044 +/- 0.053 (n = 4, P = 0.002). In a separate study of explanted hearts, a newly developed in vitro Ang II-forming assay was used to examine cardiac tissue ACE activity independent of circulating components. ACE activity in solubilized left ventricular membrane preparations from failing hearts was 49.6 +/- 5.3 fmol 125I-Ang II formed per minute per milligram of protein (n = 8, +/- SE), and 35.9 +/- 4.8 fmol/min/mg from nonfailing human hearts (n = 7, P = 0.08). In the presence of 1 microM enalaprilat, ACE activity was reduced by 85%, to 7.3 +/- 1.4 fmol/min/mg in the failing group and to 4.6 +/- 1.3 fmol/min/mg in the nonfailing group (P < 0.001). We conclude that the predominant pathway for angiotensin II formation in the human heart is through ACE. Images PMID:7657820

  20. Disposition of soy isoflavones in normal human breast tissue.

    PubMed

    Bolca, Selin; Urpi-Sarda, Mireia; Blondeel, Phillip; Roche, Nathalie; Vanhaecke, Lynn; Possemiers, Sam; Al-Maharik, Nawaf; Botting, Nigel; De Keukeleire, Denis; Bracke, Marc; Heyerick, Arne; Manach, Claudine; Depypere, Herman

    2010-04-01

    Despite decades of research on the relation between soy and breast cancer, questions regarding the absorption, metabolism, and distribution of isoflavones in breast tissue largely remain unanswered. We evaluated the potential health effects of isoflavone consumption on normal breast tissue; isoflavone concentrations, metabolites, and biodistribution were investigated and compared with 17beta-estradiol exposure. In this dietary intervention study, healthy women were randomly allocated to a soy milk (n = 11; 16.98-mg genistein and 5.40-mg daidzein aglycone equivalents per dose), soy supplement (n = 10; 5.27-mg genistein and 17.56-mg daidzein aglycone equivalents per dose), or control (n = 10) group. After a run-in period > or = 4 d, 3 doses of soy milk or soy supplements were taken daily for 5 d before an esthetic breast reduction. Blood and breast biopsies were collected during surgery and analyzed with liquid chromatography-tandem mass spectrometry. After soy administration, genistein and total daidzein concentrations, which were expressed as aglycone equivalents, ranged from 135.1 to 2831 nmol/L and 105.1 to 1397 nmol/L, respectively, in hydrolyzed serum and from 92.33 to 493.8 pmol/g and 22.15 to 770.8 pmol/g, respectively, in hydrolyzed breast tissue. The major metabolites identified in nonhydrolyzed samples were genistein-7-O-glucuronide and daidzein-7-O-glucuronide, with an overall glucuronidation of 98%. Total isoflavones showed a breast adipose/glandular tissue distribution of 40:60, and their mean (+/-SEM) derived 17beta-estradiol equivalents toward estrogen receptor beta were 21 +/- 4-fold and 40 +/- 10-fold higher than the 17beta-estradiol concentrations in adipose (0.283 +/- 0.089 pmol/g, P < 0.001) and glandular (0.246 +/- 0.091 pmol/g, P = 0.001) fractions, respectively. After intake of soy milk and soy supplements, isoflavones reach exposure levels in breast tissue at which potential health effects may occur.

  1. Proteomic analysis of membrane microdomains derived from both failing and non-failing human hearts.

    PubMed

    Banfi, Cristina; Brioschi, Maura; Wait, Robin; Begum, Shajna; Gianazza, Elisabetta; Fratto, Pasquale; Polvani, Gianluca; Vitali, Ettore; Parolari, Alessandro; Mussoni, Luciana; Tremoli, Elena

    2006-03-01

    Eukaryotic cells plasma membranes are organized into microdomains of specialized function such as lipid rafts and caveolae, with a specific lipid composition highly enriched in cholesterol and glycosphingolipids. In addition to their role in regulating signal transduction, multiple functions have been proposed, such as anchorage of receptors, trafficking of cholesterol, and regulation of permeability. However, an extensive understanding of their protein composition in human heart, both in failing and non-failing conditions, is not yet available. Membrane microdomains were isolated from left ventricular tissue of both failing (n = 15) and non-failing (n = 15) human hearts. Protein composition and differential protein expression was explored by comparing series of 2-D maps and subsequent identification by LC-MS/MS analysis. Data indicated that heart membrane microdomains are enriched in chaperones, cytoskeletal-associated proteins, enzymes and protein involved in signal transduction pathway. In addition, differential protein expression profile revealed that 30 proteins were specifically up- or down-regulated in human heart failure membrane microdomains. This study resulted in the identification of human heart membrane microdomain protein composition, which was not previously available. Moreover, it allowed the identification of multiple proteins whose expression is altered in heart failure, thus opening new perspectives to determine which role they may play in this disease.

  2. Analysis of in vivo somatic mutations in normal human cells

    SciTech Connect

    Gupta, P.K.; Sahota, A.; Boyadjiev, S.A.

    1994-09-01

    We have used the APRT locus located at 16q24.3 to study the nature of loss of heterozygosity (LOH) in human T lymphocytes in vivo. T lymphocytes were isolated from blood from APRT (+/{minus}) obligated heterozygotes with known germline mutations. The cells were immediatley placed in culture medium containing 100 {mu}M 2,6-diaminopurine (DAP) to select for drug-resistant clones ({minus}/{minus}) already present. These clones were first examined using polymorphic CA microsatellite repeat markers D16S303 and D16S305 that are distal and proximal to APRT, respectively. The retention of heterozygosity of these markers is suggestive of minor changes in the APRT gene, the exact nature of which were determined by DNA sequencing. Nineteen out of 70 DAP-resistant clones from one heterozygote showed APRT sequence changes. The loss of heterozygosity of markers D16S303 and D16S305 in the remaining clones suggests LOH involving multilocus chromosomal events. These clones were then sequentially typed using additional CA repeat markers proximal and distal to APRT. The extent of LOH in these clones was found to vary from <5 cM to almost the entire 16q arm. Preliminary results suggest that there are multiple sites along the chromosome from which LOH proceeds distally in these clones. Cytogenetic analysis of 10 clones suggested mitotic recombination in 9 and deletion in one. Studies are in progress to further characterize the molecular mechanisms of LOH.

  3. The physiology of the normal human breast: an exploratory study.

    PubMed

    Mills, Dixie; Gordon, Eva J; Casano, Ashley; Lahti, Sarah Michelle; Nguyen, Tinh; Preston, Alex; Tondre, Julie; Wu, Kuan; Yanase, Tiffany; Chan, Henry; Chia, David; Esfandiari, Mahtash; Himmel, Tiffany; Love, Susan M

    2011-12-01

    The physiology of the nonlactating human breast likely plays a key role in factors that contribute to the etiology of breast cancer and other breast conditions. Although there has been extensive research into the physiology of lactation, few reports explore the physiology of the resting mammary gland, including mechanisms by which compounds such as hormones, drugs, and potential carcinogens enter the breast ducts. The purpose of this study was to explore transport of exogenous drugs into ductal fluid in nonlactating women and determine if their concentrations in the fluid are similar to those observed in the breast milk of lactating women. We selected two compounds that have been well characterized during lactation, caffeine and cimetidine. Caffeine passively diffuses into breast milk, but cimetidine is actively transported and concentrated in breast milk. After ingestion of caffeine and cimetidine, 14 nonlactating subjects had blood drawn and underwent ductal lavage at five time points over 12 h to measure drug levels in the fluid and blood. The concentrations of both caffeine and cimetidine in lavage fluid were substantially less than those observed in breast milk. Our results support recent evidence that the cimetidine transporter is not expressed in the nonlactating mammary gland, and highlight intriguing differences in the physiology and molecular transport of the lactating and nonlactating breast. The findings of this exploratory study warrant further exploration into the physiology of the nonlactating mammary gland to elucidate factors involved in disease initiation and progression.

  4. A quantitative systematic review of normal values for short-term heart rate variability in healthy adults.

    PubMed

    Nunan, David; Sandercock, Gavin R H; Brodie, David A

    2010-11-01

    Heart rate variability (HRV) is a known risk factor for mortality in both healthy and patient populations. There are currently no normative data for short-term measures of HRV. A thorough review of short-term HRV data published since 1996 was therefore performed. Data from studies published after the 1996 Task Force report (i.e., between January 1997 and September 2008) and reporting short-term measures of HRV obtained in normally healthy individuals were collated and factors underlying discrepant values were identified. Forty-four studies met the pre-set inclusion criteria involving 21,438 participants. Values for short-term HRV measures from the literature were lower than Task Force norms. A degree of homogeneity for common measures of HRV in healthy adults was shown across studies. A number of studies demonstrate large interindividual variations (up to 260,000%), particularly for spectral measures. A number of methodological discrepancies underlined disparate values. These include a systematic failure within the literature (a) to recognize the importance of RR data recognition/editing procedures and (b) to question disparate HRV values observed in normally healthy individuals. A need for large-scale population studies and a review of the Task Force recommendations for short-term HRV that covers the full-age spectrum were identified. Data presented should be used to quantify reference ranges for short-term measures of HRV in healthy adult populations but should be undertaken with reference to methodological factors underlying disparate values. Recommendations for the measurement of HRV require updating to include current technologies.

  5. Effects of hydrophilic and lipophilic beta-blockers on heart rate variability and baroreflex sensitivity in normal subjects.

    PubMed

    Pitzalis, M V; Mastropasqua, F; Massari, F; Forleo, C; Passantino, A; Colombo, R; Totaro, P; Rizzon, P

    1998-03-01

    To evaluate the effect of a hydrophilic and a lipophilic beta-blocker on the autonomic nervous system, 20 normal subjects were studied under baseline conditions and 7 days after being randomly assigned to metoprolol (200 mg/day), nadolol (80 mg/day), and placebo. Under each condition, the time-domain parameters were analyzed by means of 24-hour ECG monitoring and the frequency-domain parameters by means of the autoregressive method using 10-minute ECGs during rest, controlled respiration, and after a head-up tilt test. The alpha index (the gain in the relationship between the RR period and systolic arterial pressure variability) was also calculated. Both nadolol and metoprolol significantly increased all of the time-domain parameters except the standard deviation of the RH intervals; they also modified the frequency-domain parameters. Both blunted the significant reduction in the high frequency (HF) component and alpha index during tilt. In normal subjects, hydrophilic and lipophilic beta-blockers similarly modify the time- and frequency-domain parameters that are particularly evident when high sympathetic tone is present (during daytime and tilt). The value of the alpha index was increased by both beta-blockers in the HF, but not in the low frequency band; this difference might be due to the fact that the former is a measure of the vagal component of the baroreflex control and the latter a measure of the sympathetic component. The effects of hydrophilic and lipophilic beta-blockers on the time- and frequency-domain parameters of heart rate variability are similar.

  6. Nε-lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 in normal and dystrophic heart

    PubMed Central

    Colussi, Claudia; Rosati, Jessica; Straino, Stefania; Spallotta, Francesco; Berni, Roberta; Stilli, Donatella; Rossi, Stefano; Musso, Ezio; Macchi, Emilio; Mai, Antonello; Sbardella, Gianluca; Castellano, Sabrina; Chimenti, Cristina; Frustaci, Andrea; Nebbioso, Angela; Altucci, Lucia; Capogrossi, Maurizio C.; Gaetano, Carlo

    2011-01-01

    Wanting to explore the epigenetic basis of Duchenne cardiomyopathy, we found that global histone acetylase activity was abnormally elevated and the acetylase P300/CBP-associated factor (PCAF) coimmunoprecipitated with connexin 43 (Cx43), which was Nε-lysine acetylated and lateralized in mdx heart. This observation was paralleled by Cx43 dissociation from N-cadherin and zonula occludens 1, whereas pp60-c-Src association was unaltered. In vivo treatment of mdx with the pan-histone acetylase inhibitor anacardic acid significantly reduced Cx43 Nε-lysine acetylation and restored its association to GAP junctions (GJs) at intercalated discs. Noteworthy, in normal as well as mdx mice, the class IIa histone deacetylases 4 and 5 constitutively colocalized with Cx43 either at GJs or in the lateralized compartments. The class I histone deacetylase 3 was also part of the complex. Treatment of normal controls with the histone deacetylase pan-inhibitor suberoylanilide hydroxamic acid (MC1568) or the class IIa-selective inhibitor 3-{4-[3-(3-fluorophenyl)-3-oxo-1-propen-1-yl]-1-methyl-1H-pyrrol-2-yl}-N-hydroxy-2-propenamide (MC1568) determined Cx43 hyperacetylation, dissociation from GJs, and distribution along the long axis of ventricular cardiomyocytes. Consistently, the histone acetylase activator pentadecylidenemalonate 1b (SPV106) hyperacetylated cardiac proteins, including Cx43, which assumed a lateralized position that partly reproduced the dystrophic phenotype. In the presence of suberoylanilide hydroxamic acid, cell to cell permeability was significantly diminished, which is in agreement with a Cx43 close conformation in the consequence of hyperacetylation. Additional experiments, performed with Cx43 acetylation mutants, revealed, for the acetylated form of the molecule, a significant reduction in plasma membrane localization and a tendency to nuclear accumulation. These results suggest that Cx43 Nε-lysine acetylation may have physiopathological consequences for cell to

  7. Identification of normal neurohormonal activity in mild congestive heart failure and stimulating effect of upright posture and diuretics.

    PubMed

    Kubo, S H; Clark, M; Laragh, J H; Borer, J S; Cody, R J

    1987-12-01

    To characterize further the pathophysiology of the neurohormonal vasoconstrictor pathways in congestive heart failure (CHF), plasma renin activity, plasma norepinephrine, blood pressure, blood volume and renal hemodynamics were measured in 12 patients with mild to moderate CHF. In addition, the response to the gravitational stress of head-up tilt and the influence of 3 weeks of furosemide treatment as stimuli of neurohormonal activity were assessed. Supine plasma renin activity before diuretics was relatively normal at 1.94 +/- 1.6 ng/ml/hr and was significantly increased to 3.9 +/- 2.7 ng/ml/hr after diuretics. During tilt, there was a significant reflex increase in plasma renin activity both before and after diuretics. Plasma norepinephrine was also relatively normal before diuretics (325 +/- 211 pg/ml), did not increase after diuretics, but showed significant increases during tilt both before and after diuretics. Diuretic administration led to decreases in both systolic and diastolic blood pressures, but there was no change in body weight or total blood volume. In addition, diuretic administration did not result in any significant changes of renal blood flow (546 +/- 119 to 634 +/- 204 ml/min/1.73m2), glomerular filtration rate (81 +/- 22 to 90 +/- 27 ml/min/1.73m2) or filtration fraction (0.26 to 0.25). The present study demonstrates that the renin-angiotensin system and the sympathetic nervous system were not activated in the early symptomatic stages of CHF and that baroreceptor stimulation of these pathways during head-up tilt was relatively preserved. Renin secretion increased during diuretic administration, suggesting that the macula densa signal for renin release was also preserved in patients with relatively mild CHF.

  8. Effect of Ceftaroline on Normal Human Intestinal Microflora▿

    PubMed Central

    Panagiotidis, Georgios; Bäckström, Tobias; Asker-Hagelberg, Charlotte; Jandourek, Alena; Weintraub, Andrej; Nord, Carl Erik

    2010-01-01

    Ceftaroline is a new broad-spectrum cephalosporin being developed for the treatment of serious bacterial infections, including those caused by aerobic Gram-positive and Gram-negative bacteria. The purpose of the present study was to investigate the effect of administration of ceftaroline on the intestinal flora of healthy subjects. Twelve healthy subjects (6 males and 6 females), 20 to 41 years of age, received ceftaroline (600 mg) by intravenous infusion every 12 h (q12h) for 7 days. Plasma and feces were collected for determination of ceftaroline concentration and analysis of fecal flora. Fecal specimens were cultured on nonselective and selective media. Different colony types were counted, isolated in pure culture, and identified to the genus level. All new strains of colonizing bacteria were tested for susceptibility to ceftaroline. The concentrations of ceftaroline in plasma were as follows: on day 2, 17.5 to 34.8 mg/liter; on day 5, 19.7 to 33.2 mg/liter; and on day 7, 18.0 to 29.8 mg/liter. No ceftaroline concentrations were found on day −1, 9, 14, or 21. No measurable concentrations in feces were found on day −1, 2, 5, 7, 9, 14, or 21. There was a minor impact on the numbers of Escherichia coli strains, while the numbers of enterococci and Candida albicans strains were not affected. There were moderate decreases in the numbers of bifidobacteria and lactobacilli during the first 7 days, while the numbers of clostridia increased during the same period. No impact on the numbers of Bacteroides bacteria was noticed. No new colonizing aerobic or anaerobic bacteria resistant to ceftaroline (MIC ≥ 4 mg/liter) were found. Ceftaroline had no significant ecological impact on the human intestinal microflora. PMID:20231399

  9. Ecological impact of MCB3837 on the normal human microbiota.

    PubMed

    Rashid, Mamun-Ur; Dalhoff, Axel; Bäckström, Tobias; Björkhem-Bergman, Linda; Panagiotidis, Georgios; Weintraub, Andrej; Nord, Carl Erik

    2014-08-01

    MCB3837 is a novel, water-soluble, injectable prodrug that is rapidly converted to the active substance MCB3681 in vivo following intravenous (i.v.) administration. Both MCB3837 and MCB3681 are oxazolidinone-quinolone hybrid molecules. The purpose of the present study was to investigate the effect of MCB3681 on the human skin, nose, oropharyngeal and intestinal microbiota following administration of MCB3837. Twelve healthy male subjects received i.v. MCB3837 (6 mg/kg body weight) once daily for 5 days. Skin, nose, saliva and faecal samples were collected on Day -1 (pre dose), during administration on Days 2 and 5, and post dose on Days 8, 12 and 19. Micro-organisms were identified to genus level. No measurable concentrations of MCB3681 were found in any saliva samples or in the faecal samples on Day -1. On Day 2, 10 volunteers had faecal MCB3681 concentrations between 16.5 mg/kg faeces and 275.1mg/kg faeces; no MCB3681 in faeces could be detected in two of the volunteers. On Day 5, all volunteers had faecal concentrations of MCB3681 ranging from 98.9 to 226.3 mg/kg. MCB3681 caused no ecological changes in the skin, nasal and oropharyngeal microbiota. The numbers of enterococci, bifidobacteria, lactobacilli and clostridia decreased in the intestinal microbiota during administration of the drug. Numbers of Escherichia coli, other enterobacteria and Candida were not affected during the study. There was no impact on the number of Bacteroides. The faecal microbiota was normalised on Day 19. No new colonising aerobic or anaerobic Gram-positive bacteria with MCB3681 minimum inhibitory concentrations of ≥4 mg/L were found. Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  10. Interferon-γ induces senescence in normal human melanocytes.

    PubMed

    Wang, Suiquan; Zhou, Miaoni; Lin, Fuquan; Liu, Dongyin; Hong, Weisong; Lu, Liangjun; Zhu, Yiping; Xu, Aie

    2014-01-01

    Interferon-γ (IFN-γ) plays an important role in the proceedings of vitiligo through recruiting lymphocytes to the lesional skin. However, the potential effects of IFN-γ on skin melanocytes and the subsequent contribution to the vitiligo pathogenesis are still unclear. To investigate the effects of IFN-γ on viability and cellular functions of melanocytes. Primary human melanocytes were treated with IFN-γ. Cell viability, apoptosis, cell cycle melanin content and intracellular reactive oxygen species (ROS) level were measured. mRNA expression was examined by real-time PCR. The release of interleukin 6 (IL-6) and heat shock protein 70 (HSP-70) was monitored by ELISA. β-galactosidase staining was utilized to evaluate melanocyte senescence. Persistent IFN-γ treatment induced viability loss, apoptosis, cell cycle arrest and senescence in melanocytes. Melanocyte senescence was characterized as the changes in pigmentation and morphology, as well as the increase of β-galactosidase activity. Increase of p21Cip1/Waf1 protein was evident in melanocytes after IFN-γ treatment. IFN-γ induction of senescence was attenuated by siRNAs against p21, Janus kinase 2 (JAK2) or signal transducer and activator of transcription 1 (STAT1), but not by JAK1 siRNA nor by p53 inhibitor pifithrin-α. IFN-γ treatment increased the accumulation of intracellular ROS in melanocytes, while ROS scavenger N-acetyl cysteine (NAC) effectively inhibited IFN-γ induced p21 expression and melanocyte senescence. IL-6 and HSP-70 release was significantly induced by IFN-γ treatment, which was largely inhibited by NAC. The increase of IL-6 and HSP-70 release could also be observed in senescent melanocytes. IFN-γ can induce senescence in melanocytes and consequently enhance their immuno-competency, leading to a vitiligo-prone milieu.

  11. Interferon-γ Induces Senescence in Normal Human Melanocytes

    PubMed Central

    Wang, Suiquan; Zhou, Miaoni; Lin, Fuquan; Liu, Dongyin; Hong, Weisong; Lu, Liangjun; Zhu, Yiping; Xu, Aie

    2014-01-01

    Background Interferon-γ (IFN-γ) plays an important role in the proceedings of vitiligo through recruiting lymphocytes to the lesional skin. However, the potential effects of IFN-γ on skin melanocytes and the subsequent contribution to the vitiligo pathogenesis are still unclear. Objective To investigate the effects of IFN-γ on viability and cellular functions of melanocytes. Methods Primary human melanocytes were treated with IFN-γ. Cell viability, apoptosis, cell cycle melanin content and intracellular reactive oxygen species (ROS) level were measured. mRNA expression was examined by real-time PCR. The release of interleukin 6 (IL-6) and heat shock protein 70 (HSP-70) was monitored by ELISA. β-galactosidase staining was utilized to evaluate melanocyte senescence. Results Persistent IFN-γ treatment induced viability loss, apoptosis, cell cycle arrest and senescence in melanocytes. Melanocyte senescence was characterized as the changes in pigmentation and morphology, as well as the increase of β-galactosidase activity. Increase of p21Cip1/Waf1 protein was evident in melanocytes after IFN-γ treatment. IFN-γ induction of senescence was attenuated by siRNAs against p21, Janus kinase 2 (JAK2) or signal transducer and activator of transcription 1 (STAT1), but not by JAK1 siRNA nor by p53 inhibitor pifithrin-α. IFN-γ treatment increased the accumulation of intracellular ROS in melanocytes, while ROS scavenger N-acetyl cysteine (NAC) effectively inhibited IFN-γ induced p21 expression and melanocyte senescence. IL-6 and HSP-70 release was significantly induced by IFN-γ treatment, which was largely inhibited by NAC. The increase of IL-6 and HSP-70 release could also be observed in senescent melanocytes. Conclusion IFN-γ can induce senescence in melanocytes and consequently enhance their immuno-competency, leading to a vitiligo-prone milieu. PMID:24681574

  12. Average acceleration and deceleration capacity of fetal heart rate in normal pregnancy and in pregnancies complicated by fetal growth restriction.

    PubMed

    Graatsma, E M; Mulder, E J H; Vasak, B; Lobmaier, S M; Pildner von Steinburg, S; Schneider, K T M; Schmidt, G; Visser, G H A

    2012-12-01

    To study fetal heart rate (FHR), its short term variability (STV), average acceleration capacity (AAC), and average deceleration capacity (ADC) throughout uncomplicated gestation, and to perform a preliminary comparison of these FHR parameters between small-for dates (SFD) and control fetuses. Prospective observational study of 7 h FHR-recordings obtained with a fetal-ECG monitor in the second half of uncomplicated pregnancies (n = 90) and pregnancies complicated by fetal SFD (n = 30). FHR and STV were calculated according to established analysis. True beat-to-beat FHR, recorded at 1 ms accuracy, was used to calculate AAC and ADC using Phase Rectified Signal Averaging (PRSA). Mean values of FHR, STV, AAC, and ADC derived from recordings in SFD fetuses were compared with the reference curves. Compared with the control group the mean z-scores for STV, AAC, and ADC in SFD fetuses were lower by 1.0 SD, 1.5 SD, and 1.7 SD, respectively (p < 0.0001 for all comparisons). In SFD fetuses, both the AAC and ADC z-scores were lower than the STV z-scores (p < 0.02 and p < 0.002, respectively). Analysis of the AAC and ADC as recorded with a high resolution fECG recorder may differentiate better between normal and SFD fetuses than STV.

  13. Increased Left Ventricular Stiffness Impairs Exercise Capacity in Patients with Heart Failure Symptoms Despite Normal Left Ventricular Ejection Fraction

    PubMed Central

    Sinning, David; Kasner, Mario; Westermann, Dirk; Schulze, Karsten; Schultheiss, Heinz-Peter; Tschöpe, Carsten

    2011-01-01

    Aims. Several mechanisms can be involved in the development of exercise intolerance in patients with heart failure despite normal left ventricular ejection fraction (HFNEF) and may include impairment of left ventricular (LV) stiffness. We therefore investigated the influence of LV stiffness, determined by pressure-volume loop analysis obtained by conductance catheterization, on exercise capacity in HFNEF. Methods and Results. 27 HFNEF patients who showed LV diastolic dysfunction in pressure-volume (PV) loop analysis performed symptom-limited cardiopulmonary exercise testing (CPET) and were compared with 12 patients who did not show diastolic dysfunction in PV loop analysis. HFNEF patients revealed a lower peak performance (P = .046), breathing reserve (P = .006), and ventilation equivalent for carbon dioxide production at rest (P = .002). LV stiffness correlated with peak oxygen uptake (r = −0.636, P < .001), peak oxygen uptake at ventilatory threshold (r = −0.500, P = .009), and ventilation equivalent for carbon dioxide production at ventilatory threshold (r = 0.529, P = .005). Conclusions. CPET parameters such as peak oxygen uptake, peak oxygen uptake at ventilatory threshold, and ventilation equivalent for carbon dioxide production at ventilatory threshold correlate with LV stiffness. Increased LV stiffness impairs exercise capacity in HFNEF. PMID:21403885

  14. Severe pneumonia after heart transplantation as a result of human parvovirus B19.

    PubMed

    Janne