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  • Introduction Classically increased cardiac fibrosis has been


    Introduction Classically, increased cardiac fibrosis has been shown to be associated with altered cardiac conduction, causing conduction slowing, block, and reentry in studies on isolated animal and diseased human cardiac tissues [1–3]. Interestingly, similar findings were also demonstrated in isolated Langendorff-perfused explanted human hearts with dilated cardiomyopathy [4,5]. While alterations of cardiac conduction [6,7] and the resulting reentrant wavefront of excitation [8] are uniformly accepted as arrhythmic consequences of increased cardiac fibrosis, recent experimental and computational studies indicate that fibrosis may also importantly modulate the formation of cardiac afterpotentials, notably early afterdepolarizations (EADs), that lead to triggered activity causing atrial fibrillation (AF) [9] and ventricular fibrillation (VF) [10–12]. Taken together, these findings indicate that increased cardiac fibrosis promotes tachyarrhythmias not only by the mechanism of reentry but also by the mechanism of triggered activity, potentially making cardiac fibrosis a highly effective antiarrhythmic target. In this review, we demonstrate how the interaction of fibrotic ventricles with oxidative or metabolic stress leads to the emergence of EADs, triggered activity, and VF. Specifically, we describe the dynamic scenario starting from cellular EADs that promote triggered activity causing focal ventricular tachycardia (VT), which then degenerates to VF. We also discuss recent experimental and clinical studies that show the potential antiarrhythmic benefits of drug-induced prevention and/or reduction of ventricular fibrosis [13–17].
    Oxidative stress
    Metabolic stress Glycolysis accounts for less than 5% of total cellular ATP production in the beating heart under aerobic conditions. However, studies of isolated cardiac myocytes have shown that cardiac stress induced by selectively inhibiting glycolytic ATP production can lead to electromechanical alternans and triggered action potentials, without affecting mitochondrial ATP production or redox state [30,40]. We have shown that fibrotic aged hearts but not non-fibrotic adult hearts are highly vulnerable to EAD-mediated triggered activity causing VT/VF during GI. With GI, simultaneous shortening of the sigma receptor duration (APD) and slowing of intracellular calcium decline rate results in elevation of during phase 3 repolarization, a condition shown to promote EADs in fibrotic rabbit ventricles [41] and in canine pulmonary veins [42] and atria [43]. Maintained elevation of enhances the forward mode of the Na+/Ca2+ exchanger (NCX), generating a net depolarizing inward current [42,44]. Inhibition of the NCX prevents GI-mediated EADs, which supports this scenario [12].
    Do myocardial cells in the aged heart undergo electrical remodeling? Although disruption of normal cell-to-cell coupling by fibrosis provides a plausible explanation for the increased susceptibility of aged hearts to EADs and EAD-mediated arrhythmias, there remains the possibility that aged ventricular myocytes, unlike adult myocytes, become exquisitely sensitive to stress-mediated EADs and triggered activity. To test whether this happens, we studied aged and adult isolated myocytes under patch-clamp conditions and subjected them to similar degrees of stresses. No difference was found between the aged and adult isolated myocytes in their abilities to generate EADs [45]. This indicates lack of electrical remodeling at the single-cell level, making a strong case for enhanced fibrosis in the genesis of EAD at the whole-heart level.
    The role of anti-fibrotic therapy against VT/VF The link between ventricular fibrosis and the risk of ventricular arrhythmia in the setting of reduced repolarization reserve suggests that targeting both fibrosis and reversal of stress-induced repolarization reserve reduction may be important strategies to prevent VT/VF. We recently have shown that increase in the repolarization reserve by blocking late inward Na+ current with ranolazine suppressed and prevented oxidative stress-induced EADs, triggered activity, and VT/VF in aged fibrotic rat hearts [11]. This pharmacological strategy to suppress EAD-mediated VF appears very promising, as it does not interfere with the normal physiological cardiac ion channel function but instead normalizes the delayed inactivation of the Na current (late INa) while preserving normal excitation–contraction coupling [11]. In addition to increasing the repolarization reserve, new antifibrotic strategies are being developed that hold promise for future effective prevention of sudden cardiac death caused by VF. For example, a recent study found that in patients with hypertrophic cardiomyopathy, myocardial fibrosis as measured by late gadolinium enhancement cardiovascular magnetic resonance (CMR) was an independent predictor of adverse outcome [46]. Interestingly, these investigators found that the extent of myocardial fibrosis was an independent predictor for arrhythmias including sustained VT and VF [46].