Inhibition of the voltage-gated potassium channel Kv1.5 by hydrogen sulfide attenuates remodeling through S-nitrosylation-mediated signaling.

The voltage-gated K+ channel plays a key role in atrial excitability, conducting the ultra-rapid rectifier K+ current (IKur) and contributing to the repolarization of the atrial action potential. In this study, we examine its regulation by hydrogen sulfide (H2S) in HL-1 cardiomyocytes and in HEK293 cells expressing human Kv1.5. Pacing induced remodeling resulted in shorting action potential duration, enhanced both Kv1.5 channel and H2S producing enzymes protein expression in HL-1 cardiomyocytes. H2S supplementation reduced these remodeling changes and restored action potential duration through inhibition of Kv1.5 channel. H2S also inhibited recombinant hKv1.5, lead to nitric oxide (NO) mediated S-nitrosylation and activated endothelial nitric oxide synthase (eNOS) by increased phosphorylation of Ser1177, prevention of NO formation precluded these effects. Regulation of Ikur by H2S has important cardiovascular implications and represents a novel and potential therapeutic target.

Imaging, biomarker and invasive assessment of diffuse left ventricular myocardial fibrosis in atrial fibrillation.

BACKGROUND: Using cardiovascular magnetic resonance imaging (CMR), it is possible to detect diffuse fibrosis of the left ventricle (LV) in patients with atrial fibrillation (AF), which may be independently associated with recurrence of AF after ablation. By conducting CMR, clinical, electrophysiology and biomarker assessment we planned to investigate LV myocardial fibrosis in patients undergoing AF ablation. METHODS: LV fibrosis was assessed by T1 mapping in 31 patients undergoing percutaneous ablation for AF. Galectin-3, coronary sinus type I collagen C terminal telopeptide (ICTP), and type III procollagen N terminal peptide were measured with ELISA. Comparison was made between groups above and below the median for LV extracellular volume fraction (ECV), followed by regression analysis. RESULTS: On linear regression analysis LV ECV had significant associations with invasive left atrial pressure (Beta 0.49, P = 0.008) and coronary sinus ICTP (Beta 0.75, P < 0.001), which remained significant on multivariable regression. CONCLUSION: LV fibrosis in patients with AF is associated with left atrial pressure and invasively measured levels of ICTP turnover biomarker.

Intra-cardiac and peripheral levels of biochemical markers of fibrosis in patients undergoing catheter ablation for atrial fibrillation.

AIMS: Measurement of circulating biomarkers of fibrosis may have a role in selecting patients and treatment strategy for catheter ablation. Pro-collagen type III N-terminal pro-peptide (PIIINP), C-telopeptide of type I collagen (ICTP), fibroblast growth factor 23 (FGF-23), and galectin 3 (gal-3) have all been suggested as possible biomarkers for this indication, but studies assessing whether peripheral levels reflect intra-cardiac levels are scarce. METHODS AND RESULTS: We studied 93 patients undergoing ablation for paroxysmal atrial fibrillation (AF) (n = 63) or non-paroxysmal AF (n = 30). Femoral venous, left and right atrial, and coronary sinus blood were analysed using ELISA to determine biomarker levels. Levels were compared with control patients (n = 36) and baseline characteristics, including left atrial voltage mapping data. C-telopeptide of type I collagen levels were higher in AF than in non-AF patients (P = 0.007). Peripheral ICTP levels were higher than all intra-cardiac levels (P < 0.001). Peripheral gal-3 levels were higher than left atrial levels (P = 0.001). Peripheral levels of FGF-23 and PIIINP were not significantly different from intra-cardiac levels. CS levels of ICTP were higher than right and left atrial levels (P < 0.001). gal-3 was higher in women vs. men (P ≤ 0.001) and with higher body mass index (P ≤ 0.001). ICTP levels increased with reducing ejection fraction (P ≤ 0.012). CONCLUSIONS: Atrial fibrillation patients have higher levels of circulating ICTP than matched non-AF controls. In AF ablation patients, intra-cardiac sampling of FGF-23 or PIIINP gives no further information over peripheral sampling. For gal-3 and ICTP, intra-cardiac sampling may be necessary to assess their association with intra-cardiac processes. None of the biomarkers is related to fibrosis assessed by left atrial voltage.

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

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

Effect of regional differences in cardiac cellular electrophysiology on the stability of ventricular arrhythmias: a computational study.

Re-entry is an important mechanism of cardiac arrhythmias. During re-entry a wave of electrical activation repeatedly propagates into recovered tissue, rotating around a rod-like filament. Breakdown of a single re-entrant wave into multiple waves is believed to underlie the transition from ventricular tachycardia to ventricular fibrillation. Several mechanisms of breakup have been identified including the effect of anisotropic conduction in the ventricular wall. Cells in the inner and outer layers of the ventricular wall have different action potential durations (APD), and support re-entrant waves with different periods. The aim of this study was to use a computational approach to study twisting and breakdown in a transmural re-entrant wave spanning these regions, and examine the relative role of this effect and anisotropic conduction. We used a simplified model of action potential conduction in the ventricular wall that we modified so that it supported stable re-entry in an anisotropic model with uniform APD. We first examined the effect of regional differences on breakdown in an isotropic model with transmural differences in APD, and found that twisting of the re-entrant filament resulted in buckling and breakdown during the second cycle of re-entry. We found that breakdown was amplified in the anisotropic model, resulting in complex activation in the region of longest APD. This study shows that regional differences in cardiac electrophysiology are a potentially important mechanism for destabilizing re-entry and may act synergistically with other mechanisms to mediate the transition from ventricular tachycardia to ventricular fibrillation.

Sustained inward current and pacemaker activity of mammalian sinoatrial node.

INTRODUCTION: A novel sustained inward Na+ current i(sv), which sensitive to Ca2+-antagonists and potentiated by beta-adrenergic stimulation, has been described in pacemaker cells of rabbit, guinea pig, and rat sinoatrial node, as well as rabbit AV node. Although i(st) has been suggested to be an important pacemaker current, this has never been tested experimentally because of the lack of a specific blocker. In this study, we address the role of i(st) in the pacemaker activity of the sinoatrial node cell using computer models. METHODS AND RESULTS: The newly developed models of Zhang et al. for peripheral and central rabbit sinoatrial node cells and models of Noble and Noble, Demir et al., Wilders et al., and Dokos et al. for typical rabbit sinoatrial node cells were modified to incorporate equations for i(st). The conductance g(st) was chosen to give a current density-voltage relationship consistent with experimental data. In the models of Zhang et al. (periphery), Noble and Noble, and Dokos et al., in which i(st) was smaller or about the same amplitude as other inward currents, i(st) increased the pacemaking rate by 0.6%, 2.2%, and 0.8%, respectively. In the models of Zhang et al. (center), Demir et al., and Wilders et al., in which i(st) was larger than some other inward ionic currents, i(st) increased the pacemaking rate by 7%, 20%, and 14%, respectively. CONCLUSION: i(st) has the potential to be a regulator of pacemaker activity, although its importance will depend on the amplitude of i(st) relative to the amplitude of other inward currents involved in pacemaker activity.