Antioxidant defense and protection against cardiac arrhythmias: lessons from a mammalian hibernator (the woodchuck)

Abstract

Hibernating animals show resistance to hypothermia-induced cardiac arrhythmias. However, it is not clear whether and how mammalian hibernators are resistant to ischemia-induced arrhythmias. The goal of this investigation was to determine the susceptibility of woodchucks ( Marmota monax) to arrhythmias and their mechanisms after coronary artery occlusion at the same room temperature in both winter, the time for hibernation, and summer, when they do not hibernate. By monitoring telemetric electrocardiograms, we found significantly higher arrhythmia scores, calculated as the severity of arrhythmias, with incidence of ventricular tachycardia, ventricular fibrillation, and thus sudden cardiac death (SCD) in woodchucks in summer than they had in winter. The level of catalase expression in woodchuck hearts was significantly higher, whereas the level of oxidized Ca/calmodulin-dependent protein kinase II (CaMKII) was lower in winter than it was in summer. Ventricular myocytes isolated from woodchucks in winter were more resistant to HO-induced early afterdepolarizations (EADs) compared with myocytes isolated from woodchucks in summer. The EADs were eliminated by inhibiting CaMKII (with KN-93), l-type Ca current (with nifedipine), or late Na current (with ranolazine). In woodchucks, in the summer, the arrhythmia score was significantly reduced by overexpression of catalase ( via adenoviral vectors) or the inhibition of CaMKII (with KN-93) in the heart. This study suggests that the heart of the mammalian hibernator is more resistant to ischemia-induced arrhythmias and SCD in winter. Increased antioxidative capacity and reduced CaMKII activity may confer resistance in woodchuck hearts against EADs and arrhythmias during winter. The profound protection conferred by catalase overexpression or CaMKII inhibition in this novel natural animal model may provide insights into clinical directions for therapy of arrhythmias.-Zhao, Z., Kudej, R. K., Wen, H., Fefelova, N., Yan, L., Vatner, D. E., Vatner, S. F., Xie, L.-H. Antioxidant defense and protection against cardiac arrhythmias: lessons from a mammalian hibernator (the woodchuck).

Molecular interactions underpinning the phenotype of hibernation in mammals

“…To study the function of individual genes in hibernating mammals, tissue-specific overexpression of cloned sequences has been accomplished using adenoviral vectors in the liver of ground squirrels (Nelson et al, 2013), and more recently in the heart of marmots (Zhao et al, 2018). In the -omics era, multiple screening methods have been used to monitor the expression of large sets of genes to better understand the cumulative effect of differential gene expression on hibernation.…”

Potential Arrhythmogenic Role of TRPC Channels and Store-Operated Calcium Entry Mechanism in Mouse Ventricular Myocytes

“…Each of these 3 sets of stimulation were repeated 3 times. Arrhythmias will be categorized into 5 groups and assigned the following points: 0 points, no arrhythmia; 1 point, 1–3 premature ventricular complexes (PVCs); 2 points, non-sustained VT (4–10 consecutive PVCs, including bigeminal/trigeminal PVCs); 3 points, sustained VT (>10 consecutive PVCs); and 4 points, VF/SCD (Zhao et al, 2018).…”

Calcium and Heart Failure: How Did We Get Here and Where Are We Going?

“…Therefore, CaMKII has been considered as a target for the treatment of arrhythmias and heart failure [ 213 , 214 ]. Beneficial effects of CaMKII inhibition have been observed in experiments using animal models and cardiac myocytes from heart failure patients [ 214 , 215 , 216 , 217 ]. However, a recent report on the first clinical trial (Phase II) with the CaMKII inhibitor (NP202) revealed no prevention of post-MI heart failure [ 218 ].…”