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

<b>Background</b>: Standard room temperature housing (~22 °C) represents a stress for laboratory 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 model of heart failure with preserved ejection fraction (HFpEF) (Angiotensin II + High-fat diet for 28 days; MHS), we investigated how housing temperature modulates cardiac remodelling and function in male and female C57Bl/6J mice. <b>Methods</b>: Using the MHS mouse model, we investigated cardiac remodelling and function in 8-week-old C57BL/6J 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 acclimate for a week before the MHS started. <b>Results</b>: 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 cardiac parameters. Following MHS, mice at 10 °C and 22 °C developed marked cardiac hypertrophy, whereas thermoneutral housing attenuated this response and reduced left atrial enlargement. Cold-exposed females showed more diastolic dysfunction after MHS (increased E' wave, E/E', and isovolumetric relaxation time) than those at 22 °C or 30 °C. Ejection fraction and cardiac output declined significantly at 10 °C after MHS but were preserved at 22 °C and 30 °C in females. <b>Conclusions</b>: 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.