Strain-Specific Patterns of Cardiac Rhythm, Autonomic Nervous System Activity, and Susceptibility to Heart Failure in Mice

Background. Transgenic mice are widely used to study cardiac function but strain-dependent differences in autonomic nervous system activity (ANSA) have not been explored. To test the hypothesis that the homeostatic state of ANSA is strain-specific, we compared 1) short-term pharmacological responses of cardiac rhythm in FVB versus C57Black6/SV129 wild-type mice, and 2) long-term physiological dynamics of cardiac rhythm in TNF- α transgenic mice with heart failure on an FVB background (TNF-α mice). Methods and results. Ambulatory telemetry ECG recordings were examined in 10 FVB, 9 C57Black6/SV129, and 13 TNF- α mice. Baseline heart rate (HR) was higher in FVB mice than in C57Black6/SV129 or TNF- α mice. Changes in HR and HR variability have been examined after injection of saline, isoproterenol, propranolol, metoxamine, prazosin, carbocholine, and atropine. In FVB mice, HR did not change after injection of isoproterenol or atropine, but decreased after propranolol. In C57Black6/SV129 mice, HR did not change after propranolol but increased after injection of isoproterenol and atropine. Mean HR, but not the indices of HR variability, was an excellent predictor of response to autonomic agents. The proportion of surviving animals was higher in TNF- α mice with heart failure on an FVB background than in TNF- α mice on a mixed FVB/ C57Black6 background. Conclusions. The homeostatic states of ANSA are strain-specific, which can explain the inter-strain differences in mean HR, pharmacological responses, and survival of animals with congestive heart failure. The lack of increased HR during the development of heart failure in TNF- α mice on an FVB background may depend in part on the baseline high sympathetic activity in this strain. Strain-specific differences should be considered in selecting the strains of mice used for transgenic and gene-targeting experiments. The time course of changes in RR-intervals during pharmacological tests was analyzed in 37.5-sec intervals and averaged for each consecutive 7.5 min-interval. To estimate the pharmacological effects, four consecutive 7.5-min windows before and four consecutive 7.5 min-windows after the injection were included in the nonparametric ANOVA. The mean values represent averages over 30 min before and after the injections. Strain-dependent survival. Male TNF- α mice (x-linked transgene) were mated with FVB or C57Black6 females. Survival of female TNF- α transgene offspring was compared on the FVB versus 50% FVB/50% C57Black6 background using the Kaplan-Meier cumulative survival curve and Gehan’s Wilcoxon test. Statistical analysis . Comparisons between strains were performed using nonparametric Mann-Whitney U-test. Changes in the variables during pharmacological tests were estimated using nonparametric Friedman ANOVA for repeated measurements. Nonparametric Spearman correlations were used to assess the relationship between mean heart rate and its reaction to pharmacological tests. Results are presented as mean ± standard deviation unless otherwise indicated. Statistical significance was accepted at the level of P<0.05. The strain-differences in blood pressure and in the intrinsic HR after combined blockage of beta-adrenergic and muscarinic receptors have not been examined in this study. These experiments, although not crucially important for the goal of this investigation, could provide additional information about homeostatic states of autonomic nervous system activity in each strain. The data regarding HR and pharmacological responses in TNF- α mice on an FVB/ C57Black6 background was unavailable at the time of this study, precluding direct comparison of ANSA in TNF- α mice on an FVB/ C57Black6 and on a pure FVB background.