Comparative Analysis of Housing Temperature Impact on Heart Failure with Preserved Ejection Fraction in J vs N Strain C57BL/6 Mice

Abstract

IntroductionHeart failure studies are conducted in preclinical animal models with different genotypic strains, 7-times higher metabolic rate, 5 to 6 times higher heart rate, and are housed in a cold-stressed environment of 23{degrees}C, unlike humans. These differences severely affect how animals respond to interventions, particularly those that lead to the development of metabolic syndrome, such as the two-hit model of diet-induced obesity (DIO) and N-nitro-L-arginine methyl ester (L-NAME) administration. A two-hit model of diet-induced obesity (DIO) and L-NAME administration has been proposed to induce heart failure with preserved ejection fraction (HFpEF) and mimic the hallmarks of metabolic syndrome and inflammation-induced heart failure in humans [1]. However, studies have reported conflicting results using this model. In this study, we examined the influence of mouse strain and environmental temperature on the development of metabolic syndrome and HFpEF using a two-hit model. MethodsEight-week-old, C57BL/6 mice (n=30) from the J and N strains were randomized to receive a high-fat diet (HFD) plus L-NAME versus a regular chow diet; and were randomized to be housed at a regular temperature of 23 {degrees}C versus a thermoneutral temperature of 30 {degrees}C. Glucose tolerance test (GTT, 2g/kg body weight), blood pressure via tail cuff, and echocardiography were conducted at baseline and, then at 5 and 15 weeks. Metabolic phenotyping was conducted at week 15 by using the Promethion Sable System. ResultsOur study revealed the significant effects of housing temperature and strain on the development of metabolic syndrome and HFpEF following the initiation of HFD +L-NAME over 5 and 15 weeks. At 5 weeks, both strains showed thermoneutral housing-induced attenuation of the effects of HFD + L-NAME on blood pressure and glucose tolerance, with the J strain exhibiting reduced diastolic dysfunction. By week 15, thermoneutral housing decreased energy expenditure (EE) and fat oxidation in both strains, while specifically reducing the respiratory exchange ratio (RER)_and glucose oxidation in J strain. Ejection fraction increased in both strains compared with the Chow group, except for J strain at 23 {degrees}C. Notably, physical activity levels remained constant across the groups, suggesting that the observed metabolic changes were not activity related. These findings highlight the complex physiological adaptations of these strains to different housing temperatures. ConclusionsThermoneutral housing conditions elicited strain-specific metabolic and cardiac effects in mice, with the J strain showing more pronounced responses. These findings highlight the critical influence of ambient temperature on experimental outcomes in rodent models, emphasizing the need to consider housing conditions when interpreting the results of metabolic and cardiovascular research.