Increased susceptibility of aged hearts to ventricular fibrillation during oxidative stress

Abstract

Oxidative stress with hydrogen peroxide (H(2)O(2)) readily promotes early afterdepolarizations (EADs) and triggered activity (TA) in isolated rat and rabbit ventricular myocytes. Here we examined the effects of H(2)O(2) on arrhythmias in intact Langendorff rat and rabbit hearts using dual-membrane voltage and intracellular calcium optical mapping and glass microelectrode recordings. Young adult rat (3-5 mo, N = 25) and rabbit (3-5 mo, N = 6) hearts exhibited no arrhythmias when perfused with H(2)O(2) (0.1-2 mM) for up to 3 h. However, in 33 out of 35 (94%) aged (24-26 mo) rat hearts, 0.1 mM H(2)O(2) caused EAD-mediated TA, leading to ventricular tachycardia (VT) and fibrillation (VF). Aged rabbits (life span, 8-12 yr) were not available, but 4 of 10 middle-aged rabbits (3-5 yr) developed EADs, TA, VT, and VF. These arrhythmias were suppressed by the reducing agent N-acetylcysteine (2 mM) and CaMKII inhibitor KN-93 (1 microM) but not by its inactive form (KN-92, 1 microM). There were no significant differences between action potential duration (APD) or APD restitution slope before or after H(2)O(2) in aged or young adult rat hearts. In histological sections, however, trichrome staining revealed that aged rat hearts exhibited extensive fibrosis, ranging from 10-90%; middle-aged rabbit hearts had less fibrosis (5-35%), whereas young adult rat and rabbit hearts had <4% fibrosis. In aged rat hearts, EADs and TA arose most frequently (70%) from the left ventricular base where fibrosis was intermediate ( approximately 30%). Computer simulations in two-dimensional tissue incorporating variable degrees of fibrosis showed that intermediate (but not mild or severe) fibrosis promoted EADs and TA. We conclude that in aged ventricles exposed to oxidative stress, fibrosis facilitates the ability of cellular EADs to emerge and generate TA, VT, and VF at the tissue level.

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade

“…These findings are consistent with our previous findings in aged rats and rabbits atria [1,7,20,22] as well as in aged human atria [23]. …”

“…Furthermore, elevation of the H 2 O 2 concentration for up to 2 mM (N=5) in the young/adult hearts still failed to promote EADs and/or atrial ectopic activity consistent with our previous findings [1,7,22] and by Lin CS et al [24]. The discrepancy between the ease of oxidative EAD formation at the single myocyte level isolated from young/adult atria [18,25] and the resistance to EAD formation at the atrial tissue level in young/adult hearts, suggests that atrial tissue factor(s) must have been responsible in the aged tissue to readily promote EAD and EAD-mediated triggered activity.…”

“…Because oxidative stress with H 2 O 2 also promotes VF in aged hearts [1] we determined the mechanism(s) of spontaneous AF initiation of AF only when the AF preceded the VF or when the AF was not associated with VF as shown in figure 2. Under these conditions the AF emerged after a mean of 12 ± 7 min exposure to H 2 O 2 and was often preceded by a transient period of monomorphic atrial tachycardia or flutter (AT/AFl) at a mean cycle length (CL) of 80 ± 46 ms (Figure 2).…”

“…Oxidative stress has been shown to increase the susceptibility of the heart to ventricular and atrial fibrillation (VF and AF respectively) in animal models that manifest increased cardiac fibrosis [1,2]. Increased systemic and atrial myocardial oxidative stress is often observed in post-operative patients with new onset (acute) paroxysmal AF (POAF) [3,4] with an incidence of up to 50% [5].…”

Characteristics of chaotic processes in electrocardiographically identified ventricular arrhythmia

“…The occurrence of serious arrhythmia may be independent from the presence of risk factors, as it is associated with difficult-to-evaluate genetic predisposition and other factors modifying myocardial susceptibility to arrhythmia [14].…”