Chronic myocardial infarction promotes atrial action potential alternans, afterdepolarisations and fibrillation

Aims: Atrial fibrillation (AF) is increased in patients with heart failure resulting from myocardial infarction (MI). We aimed to determine the effects of chronic ventricular MI in rabbits on the susceptibility to AF, and underlying atrial electrophysiological and Ca2+-handling mechanisms. Methods and results: In Langendorff-perfused rabbit hearts, under beta-adrenergic-stimulation with isoproterenol (1 µM; ISO), 8 weeks MI decreased AF threshold, indicating increased AF-susceptibility. This was associated with increased atrial action potential duration-alternans at 90% repolarisation, by 147%, and no significant change in mean APD or atrial global conduction velocity (n=6-13 non-MI hearts, 5-12 MI). In atrial isolated myocytes, also under beta-stimulation, L-type Ca2+ current (ICaL) density and intracellular Ca2+-transient amplitude were decreased by MI, by 35% and 41%, respectively, and the frequency of spontaneous depolarisations (SDs) was substantially increased. MI increased atrial myocyte size and capacity, and markedly decreased transverse-tubule density. In non-MI hearts perfused with ISO, the ICaL-blocker nifedipine, at a concentration (0.02 µM) causing an equivalent ICaL-reduction (35%) to that from the MI, did not affect AF-susceptibility, and decreased APD. Conclusion: chronic MI in rabbits remodels atrial structure, electrophysiology and intracellular Ca2+-handling. Increased susceptibility to AF by MI, under beta-adrenergic-stimulation, may result from associated production of atrial APD-alternans and SDs, since steady-state APD and global conduction velocity were unchanged under these conditions, and may be unrelated to the associated reduction in whole-cell ICaL. Future studies may clarify potential contributions of local conduction changes, and cellular and sub-cellular mechanisms of alternans, to the increased AF-susceptibility

Fructose Modulates Cardiomyocyte Excitation-Contraction Coupling and Ca2+ Handling In Vitro

BACKGROUND: High dietary fructose has structural and metabolic cardiac impact, but the potential for fructose to exert direct myocardial action is uncertain. Cardiomyocyte functional responsiveness to fructose, and capacity to transport fructose has not been previously demonstrated. OBJECTIVE: The aim of the present study was to seek evidence of fructose-induced modulation of cardiomyocyte excitation-contraction coupling in an acute, in vitro setting. METHODS AND RESULTS: The functional effects of fructose on isolated adult rat cardiomyocyte contractility and Ca²⁺ handling were evaluated under physiological conditions (37°C, 2 mM Ca²⁺, HEPES buffer, 4 Hz stimulation) using video edge detection and microfluorimetry (Fura2) methods. Compared with control glucose (11 mM) superfusate, 2-deoxyglucose (2 DG, 11 mM) substitution prolonged both the contraction and relaxation phases of the twitch (by 16 and 36% respectively, p<0.05) and this effect was completely abrogated with fructose supplementation (11 mM). Similarly, fructose prevented the Ca²⁺ transient delay induced by exposure to 2 DG (time to peak Ca²⁺ transient: 2 DG: 29.0±2.1 ms vs. glucose: 23.6±1.1 ms vs. fructose +2 DG: 23.7±1.0 ms; p<0.05). The presence of the fructose transporter, GLUT5 (Slc2a5) was demonstrated in ventricular cardiomyocytes using real time RT-PCR and this was confirmed by conventional RT-PCR. CONCLUSION: This is the first demonstration of an acute influence of fructose on cardiomyocyte excitation-contraction coupling. The findings indicate cardiomyocyte capacity to transport and functionally utilize exogenously supplied fructose. This study provides the impetus for future research directed towards characterizing myocardial fructose metabolism and understanding how long term high fructose intake may contribute to modulating cardiac function

Impact of Sarcoplasmic Reticulum Calcium Release on Calcium Dynamics and Action Potential Morphology in Human Atrial Myocytes: A Computational Study

Electrophysiological studies of the human heart face the fundamental challenge that experimental data can be acquired only from patients with underlying heart disease. Regarding human atria, there exist sizable gaps in the understanding of the functional role of cellular Ca2+ dynamics, which differ crucially from that of ventricular cells, in the modulation of excitation-contraction coupling. Accordingly, the objective of this study was to develop a mathematical model of the human atrial myocyte that, in addition to the sarcolemmal (SL) ion currents, accounts for the heterogeneity of intracellular Ca2+ dynamics emerging from a structurally detailed sarcoplasmic reticulum (SR). Based on the simulation results, our model convincingly reproduces the principal characteristics of Ca2+ dynamics: 1) the biphasic increment during the upstroke of the Ca2+ transient resulting from the delay between the peripheral and central SR Ca2+ release, and 2) the relative contribution of SL Ca2+ current and SR Ca2+ release to the Ca2+ transient. In line with experimental findings, the model also replicates the strong impact of intracellular Ca2+ dynamics on the shape of the action potential. The simulation results suggest that the peripheral SR Ca2+ release sites define the interface between Ca2+ and AP, whereas the central release sites are important for the fire-diffuse-fire propagation of Ca2+ diffusion. Furthermore, our analysis predicts that the modulation of the action potential duration due to increasing heart rate is largely mediated by changes in the intracellular Na+ concentration. Finally, the results indicate that the SR Ca2+ release is a strong modulator of AP duration and, consequently, myocyte refractoriness/excitability. We conclude that the developed model is robust and reproduces many fundamental aspects of the tight coupling between SL ion currents and intracellular Ca2+ signaling. Thus, the model provides a useful framework for future studies of excitation-contraction coupling in human atrial myocytes

Influence of ischemic core muscle fibers on surface depolarization potentials in superfused cardiac tissue preparations: a simulation study

Thin-walled cardiac tissue samples superfused with oxygenated solutions are widely used in experimental studies. However, due to decreased oxygen supply and insufficient wash out of waste products in the inner layers of such preparations, electrophysiological functions could be compromised. Although the cascade of events triggered by cutting off perfusion is well known, it remains unclear as to which degree electrophysiological function in viable surface layers is affected by pathological processes occurring in adjacent tissue. Using a 3D numerical bidomain model, we aim to quantify the impact of superfusion-induced heterogeneities occurring in the depth of the tissue on impulse propagation in superficial layers. Simulations demonstrated that both the pattern of activation as well as the distribution of extracellular potentials close to the surface remain essentially unchanged. This was true also for the electrophysiological properties of cells in the surface layer, where most relevant depolarization parameters varied by less than 5.5 %. The main observed effect on the surface was related to action potential duration that shortened noticeably by 53 % as hypoxia deteriorated. Despite the known limitations of such experimental methods, we conclude that superfusion is adequate for studying impulse propagation and depolarization whereas repolarization studies should consider the influence of pathological processes taking place at the core of tissue sample

Gene Knock-Outs of Inositol 1,4,5-Trisphosphate Receptors Types 1 and 2 Result in Perturbation of Cardiogenesis

Rs in cardiogenesis remain unclear.Rs mimicked the phenotype of the AV valve defect that result from the inhibition of calcineurin, and it could be rescued by constitutively active calcineurin.Rs in cardiogenesis in part through the regulation of calcineurin-NFAT signaling

A follow-up study for left ventricular mass on chromosome 12p11 identifies potential candidate genes

<p>Abstract</p> <p>Background</p> <p>Left ventricular mass (LVM) is an important risk factor for cardiovascular disease. Previously we found evidence for linkage to chromosome 12p11 in Dominican families, with a significant increase in a subset of families with high average waist circumference (WC). In the present study, we use association analysis to further study the genetic effect on LVM.</p> <p>Methods</p> <p>Association analysis with LVM was done in the one LOD critical region of the linkage peak in an independent sample of 897 Caribbean Hispanics. Genotype data were available on 7085 SNPs from 23 to 53 MB on chromosome 12p11. Adjustment was made for vascular risk factors and population substructure using an additive genetic model. Subset analysis by WC was performed to test for a difference in genetic effects between the high and low WC subsets.</p> <p>Results</p> <p>In the overall analysis, the most significant association was found to rs10743465, downstream of the <it>SOX5 </it>gene (p = 1.27E-05). Also, 19 additional SNPs had nominal p < 0.001. In the subset analysis, the most significant difference in genetic effect between those with high and low WC occurred with rs1157480 (p = 1.37E-04 for the difference in β coefficients), located upstream of <it>TMTC1</it>. Twelve additional SNPs in or near 6 genes had p < 0.001.</p> <p>Conclusions</p> <p>The current study supports previously identified evidence by linkage for a genetic effect on LVM on chromosome 12p11 using association analysis in population-based Caribbean Hispanic cohort. <it>SOX5 </it>may play an important role in the regulation of LVM. An interaction of <it>TMTC1 </it>with abdominal obesity may contribute to phenotypic variation of LVM.</p

Endothelin-1-stimulated InsP₃-induced Ca²+ release is a nexus for hypertrophic signaling in cardiac myocytes

Ca(2+) elevations are fundamental to cardiac physiology-stimulating contraction and regulating the gene transcription that underlies hypertrophy. How Ca(2+) specifically controls gene transcription on the background of the rhythmic Ca(2+) increases required for contraction is not fully understood. Here we identify a hypertrophy-signaling module in cardiac myocytes that explains how Ca(2+) discretely regulates myocyte hypertrophy and contraction. We show that endothelin-1 (ET-1) stimulates InsP(3)-induced Ca(2+) release (IICR) from perinuclear InsP(3)Rs, causing an elevation in nuclear Ca(2+). Significantly, we show that IICR, but not global Ca(2+) elevations associated with myocyte contraction, couple to the calcineurin (CnA)/NFAT pathway to induce hypertrophy. Moreover, we found that activation of the CnA/NFAT pathway and hypertrophy by isoproterenol and BayK8644, which enhance global Ca(2+) fluxes, was also dependent on IICR and nuclear Ca(2+) elevations. The activation of IICR by these activity-enhancing mediators was explained by their ability to stimulate secretion of autocrine/paracrine ET-1

Negative inotropy of the gastric proton pump inhibitor pantoprazole in myocardium from humans and rabbits - Evaluation of mechanisms

Background - Proton pump inhibitors are used extensively for acid-related gastrointestinal diseases. Their effect on cardiac contractility has not been assessed directly. Methods and Results - Under physiological conditions (37 degrees C, pH 7.35, 1.25 mmol/L Ca2+), there was a dose-dependent decrease in contractile force in ventricular trabeculae isolated from end-stage failing human hearts superfused with pantoprazole. The concentration leading to 50% maximal response was 17.3 +/- 1.3 mu g/mL. Similar observations were made in trabeculae from human atria, normal rabbit ventricles, and isolated rabbit ventricular myocytes. Real-time polymerase chain reaction demonstrated the expression of gastric H+/K+-adenosine triphosphatase in human and rabbit myocardium. However, measurements with BCECF-loaded rabbit trabeculae did not reveal any significant pantoprazole-dependent changes of pH(i). Ca2+ transients recorded from field-stimulated fluo 3-loaded myocytes (F/F-0) were significantly depressed by 10.4 +/- 2.1% at 40 mu g/mL. Intracellular Ca2+ fluxes were assessed in fura 2-loaded, voltage-clamped rabbit ventricular myocytes. Pantoprazole (40 mu g/mL) caused an increase in diastolic [Ca2+](i) by 33 +/- 12%, but peak systolic [Ca2+](i) was unchanged, resulting in a decreased Ca2+ transient amplitude by 25 +/- 8%. The amplitude of the L type Ca2+ current (I-Ca,I-L) was reduced by 35 +/- 5%, and sarcoplasmic reticulum Ca2+ content was reduced by 18 +/- 6%. Measurements of oxalate-supported sarcoplasmic reticulum Ca2+ uptake in permeabilized cardiomyocytes indicated that pantoprazole decreased Ca2+ sensitivity (K-d) of sarcoplasmic reticulum Ca2+ adenosine triphosphatase: control, K-d = 358 +/- 15 nmol/L; 40 mu g/mL pantoprazole, K-d = 395 +/- 12 nmol L (P &lt; 0.05). Pantoprazole also acted on cardiac myofilaments to reduced Ca2+-activated force. Conclusions - Pantoprazole depresses cardiac contractility in vitro by depression of Ca2+ signaling and myofilament activity. In view of the extensive use of this agent, the effects should be evaluated in vivo