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Electrophysiological heterogeneities in normal and diseased hearts

Ewa Soltysinska 

Summary

Electrophysiological heterogeneities in normal and diseased hearts: molecular and functional correlates 

Rhythmic contractions of the heart are crucial for its pumping function. Maintenance of rhythmic activity is achieved by generation and propagation of electrical signal in a form of an action potential. The cardiac action potential is a result of a well-regulated interaction of a number of ionic currents that are passed through the specialized groups of proteins such as ion channels, pumps and transporters. Even minor malfunctions of any one of those may result in the disturbance of cardiac rhythm defined as arrhythmia.   

Ventricular arrhythmias are a common cause of mortality in both patients with compensated cardiac hypertrophy and heart failure (HF). An important mechanism of arrhythmogenesis in cardiac patients is disease-associated electrical remodeling referring to the changes in impulse generation, action potential conduction, and ventricular repolarization. Electrical remodeling is mediated by both malfunction of individual ionic currents and complex alterations of intrinsic spatial and temporal electrophysiological heterogeneities. One of the regional heterogeneities believed to play a key role in normal ventricular activation and repolarization is a transmural dispersion of electrical activity across the ventricular wall. An altered distribution pattern of the ionic currents across ventricular wall may create a substrate for tachyarrhythmia. Therefore, I set out to investigate the mRNA and protein expression levels of key cardiac ion channels and transporters in transmural samples of ventricular tissue from end-stage failing human hearts (Study I). The performed quantifications demonstrate an impaired transmural expression pattern for several gene transcripts including KCNJ11 (Kir6.2), KCNE1, ABCC8 (SUR1), SLC8A1 (NCX1) and RyR2 but a preserved gradient of mRNA and protein distribution for KCNIP2 (KChIP2) and SCN5A (Nav1.5) subunits. Additionally, the transcripts encoding CACN1C (Cav1.2), HCN2, KCNJ2 (Kir2.1), KCNE1 and SLC8A1 (NCX1) were noted to be up-regulated in the failing hearts while a down-regulation was observed for KCNIP2 (KChIP2) and ATP2A2 (SERCA2). The revealed changes may be important to unravel the mechanisms contributing to increased arrhythmic susceptibility of failing hearts.   

The importance of transmural heterogeneities for the mechanisms of arrhythmogenesis has been addressed using the Na+ channel as an example. In Study I, I report on greater Na+ channel expression levels at ventricular endocardial than epicardial layers in both failing and non-diseased human hearts. The functional significance of these non-uniformities has been determined using the guinea-pig model showing the same transmural pattern in Na+ channel distribution (Study II). We found that non-uniform Na+ channel distribution translates into important electrophysiological heterogeneities across ventricular wall, as assessed in isolated, perfused guinea-pig heart preparations. In particular, greater expression of Na+ channels at endocardium may account for greater excitability, steeper electrical restitution slopes and faster restitution kinetics, and greater arrhythmic susceptibility, as compared to epicardium.  

The mechanisms contributing to electrical remodeling in cardiac disease are still largely unknown. Clinical studies suggest that sustained sympathetic activation is a hallmark of heart failure, thus raising a possibility that disease-associated electrical derangements may be promoted by adrenergic overstimulation. This issue has been addressed in the Study III using the guinea-pig model of chronic β-adrenoceptor agonist (isoproterenol) administration. Short term elevation in the adrenergic tone (2 weeks isoproterenol administration via subcutaneously implanted osmotic minipumps) was found to produce no myocardial structural and contractile changes, as well as no electrical derangements as assessed at baseline. However, acute challenge with adrenergic agonist revealed blunted left ventricular contractile and electrophysiological responsiveness, which has been ascribed to β-adrenoceptor uncoupling from adenylate cyclase due to reduced stimulatory G-protein (Gsα) myocardial expression levels. These findings demonstrate that at a pre-clinical stage of cardiac disease, although electrical derangements are not present at rest, they may nevertheless develop upon acute adrenergic activation, and potentially contribute to exercise intolerance in cardiac patients. 

Sustained sympathetic activation over longer periods of time (daily isoproterenol injections over 12 weeks) has been found to promote a heart failure phenotype including structural changes (cardiac hypertrophy and dilatation), contractile dysfunction and pulmonary edema. These changes were associated with electrical remodeling as evidenced by prolongation of ventricular repolarization, altered rate-dependent adaptation of action potential, impaired spatial repolarization gradients and epicardial activation-to-repolarization coupling. In contrast to the pre-clinical stage of cardiac disease, the electrical derangements in decompensated heart failure are clearly manifested in the basal state (i.e., in the absence of acute β-adrenoceptor stimulation). Collectively, these findings suggest that electrical remodeling is a process that might evolve throughout the whole course of cardiac disease, although the underlying pathophysiological mechanisms may differ at the preclinical and advanced stage of heart failure electrical derangements as assessed at baseline. However, acute challenge with adrenergic agonist revealed blunted left ventricular contractile and electrophysiological responsiveness, which has been ascribed to β-adrenoceptor uncoupling from adenylate cyclase due to reduced stimulatory G-protein (Gsα) myocardial expression levels. These findings demonstrate that at a pre-clinical stage of cardiac disease, although electrical derangements are not present at rest, they may nevertheless develop upon acute adrenergic activation, and potentially contribute to exercise intolerance in cardiac patients.  Sustained sympathetic activation over longer periods of time (daily isoproterenol injections over 12 weeks) has been found to promote a heart failure phenotype including structural changes (cardiac hypertrophy and dilatation), contractile dysfunction and pulmonary edema. These changes were associated with electrical remodeling as evidenced by prolongation of ventricular repolarization, altered rate-dependent adaptation of action potential, impaired spatial repolarization gradients and epicardial activation-to-repolarization coupling. In contrast to the pre-clinical stage of cardiac disease, the electrical derangements in decompensated heart failure are clearly manifested in the basal state (i.e., in the absence of acute β-adrenoceptor stimulation). Collectively, these findings suggest that electrical remodeling is a process that might evolve throughout the whole course of cardiac disease, although the underlying pathophysiological mechanisms may differ at the preclinical and advanced stage of heart failure.