Cold Exposure Exacerbates Cardiac Dysfunction in a Model of Heart Failure with Preserved Ejection Fraction in Male and Female C57Bl/6J Mice

Background. Standard room temperature housing (~22°C) represents a stress for labora-tory mice, resulting in an increased metabolic rate, calorie consumption, heart rate, and catecholamine levels compared to thermoneutral conditions (29-32°C). Using a recently established two-hit heart failure with preserved ejection fraction (HFpEF) model (Angio-tensin II + High-fat diet for 28 days; MHS), we investigated how housing temperature modulates cardiac remodeling and function in male and female C57Bl/6J mice. Methods. Using the MHS mouse model, we studied cardiac remodeling and function in 8-week-old C57Bl6/J mice of both sexes housed at 10°C, 22°C and 30°C for four weeks. Control mice were analyzed in parallel. Before the MHS, the animals were allowed to ac-climate for a week before the MHS started. Results. Mice housed at 10°C consumed more food and had increased fat mass compared to those at 22°C or 30°C. This was accompanied by increased heart weight, stroke volume, heart rate and cardiac output. Mice housed at 22 °C and 30 °C were similar for these car-diac parameters. Following MHS, mice at 10°C and 22°C developed marked cardiac hy-pertrophy, whereas thermoneutral housing attenuated this response and reduced left atri-al enlargement. Cold-exposed females showed more diastolic dysfunction after MHS (in-creased E’ wave, E/E’, and isovolumetric relaxation time) than those at 22°C or 30°C. Ejec-tion fraction and cardiac output declined significantly at 10°C after MHS but were pre-served at 22°C and 30°C in females. Conclusions. Cold housing exacerbates cardiac dysfunction in mice subjected to HFpEF-inducing stress, with pronounced effects in females. In contrast, thermoneutrality limits the cardiac hypertrophic response.