Genetic background dominates the susceptibility to ventricular arrhythmias in a murine model of β-adrenergic stimulation

Abstract

In cardiovascular research, several mouse strains with differing genetic backgrounds are used to investigate mechanisms leading to and sustaining ventricular arrhythmias. The genetic background has been shown to affect the studied phenotype in other research fields. Surprisingly little is known about potential strain-specific susceptibilities towards ventricular arrhythmias in vivo. Here, we hypothesized that inter-strain differences reported in the responsiveness of the β-adrenergic pathway, which is relevant for the development of arrhythmias, translate into a strain-specific vulnerability. To test this hypothesis, we characterized responses to β-adrenergic blockade (metoprolol) and β-adrenergic stimulation (isoproterenol) in 4 mouse strains commonly employed in cardiovascular research (Balb/c, BS, C57Bl/6 and FVB) using telemetric ECG recordings. We report pronounced differences in the electrical vulnerability following isoproterenol: Balb/c mice developed the highest number and the most complex arrhythmias while BS mice were protected. Balb/c mice, therefore, seem to be the background of choice for experiments requiring the occurrence of arrhythmias while BS mice may give insight into electrical stability. Arrhythmias did not correlate with the basal β-adrenergic tone, with the response to β-adrenergic stimulation or with the absolute heart rates during β-adrenergic stimulation. Thus, genetic factors dominate the susceptibility to ventricular arrhythmias in this model of β-adrenergic stimulation.

Antiarrhythmic Effects of Melatonin and Omega-3 Are Linked with Protection of Myocardial Cx43 Topology and Suppression of Fibrosis in Catecholamine Stressed Normotensive and Hypertensive Rats

“…While, none SHR died due to ISO suggesting that responsiveness to catecholamine overdrive is blunted in this sympathomimetic strain, alike the responses to the excess of thyroid hormones [29]. Strain-related genetic factors have been shown to dominate the susceptibility to ventricular arrhythmias in mice model of β-adrenergic ISO stimulation [48].…”

Genetic background influences expression and function of the cation channel TRPM4 in the mouse heart

“…The studies above as well as our findings emphasize that the analysis of null alleles or disease-related mutations in multiple mouse strains is recommendable. Ultimately, the most adequate species and strain need to be chosen to study distinct physiological or pathophysiological processes [2,13,38,41] and to test potential therapeutic strategies. Obviously, the 129SvJ strain is more suitable to study TRPM4-dependent processes in the heart compared to the C57Bl/6N strain where the homeostatic expression level is comparably low.…”

AAV9-Mediated Overexpression of TRPM4 Increases the Incidence of Stress-Induced Ventricular Arrhythmias in Mice

“…As shown in previous studies, mice are relatively resistant to the development of ventricular tachycardia and ventricular fibrillation (for reviews see London, 2004; Choy et al, 2016). Variation in the susceptibility for complex arrhythmias clearly also depends on the mouse strain (Jelinek et al, 2018). In our study, mice are backcrossed to the C57Bl6/N background, in which complex arrhythmias have been difficult to elicit (Jelinek et al, 2018).…”

“…Variation in the susceptibility for complex arrhythmias clearly also depends on the mouse strain (Jelinek et al, 2018). In our study, mice are backcrossed to the C57Bl6/N background, in which complex arrhythmias have been difficult to elicit (Jelinek et al, 2018). Nevertheless, one mouse, injected with AAV2/9_CMV-TRPM4, developed ventricular fibrillation and idioventricular rhythm in the stress-test.…”