Left atrial and ventricular cardiomyocyte remodeling in rodent models of cardiometabolic heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome characterized by the key features exercise intolerance, increased ventricular filling pressures and atrial remodeling. This thesis investigates the influence of adrenergic and nitro-oxidative signaling on left atrial and left ventricular cardiomyocyte active function and its relation to key features of HFpEF in rodent models of HFpEF. METHODS HFpEF was modeled in rats or mice by combining metabolic syndrome and hypertension (cardiometabolic HFpEF). Ventricular function, relaxation, adrenergic output reserve and atrial remodeling were characterized using (stress-)echocardiography and treadmill testing. Atrial and ventricular cardiomyocytes were isolated and sarcomere shortening, calcium handling and NO release were assessed using fluorescent indicators, both with and without adrenergic stimuli and modulators of NO synthases and ROS signaling. Western blotting was performed on left ventricular tissue. RESULTS Both animal models exhibited the typical features of HFpEF. In the mouse model, we found exercise intolerance which was associated with a loss of adrenergic reserve in vivo. This could be attributed to a loss of adrenergic reserve in ventricular cardiomyocytes from HFpEF mice. We found largely preserved beta-1 adrenergic signaling but impaired nitrooxidative signaling as a driving factor. Surprisingly, active ventricular cardiomyocyte relaxation was intact in both animal models. Atrial cardiomyocytes in the rat HFpEF model showed intact contractile properties but increased arrhythmogenicity, which could be reduced by in-vivo treatment with a dual SGLT1/SGLT2 inhibitor. CONCLUSION Impairment of the adrenergic reserve contributes to exercise intolerance in a rodent model of cardiometabolic HFpEF. The underlying alterations in cardiomyocyte function and upstream signaling pathways differ fundamentally from those previously described in heart failure with reduced ejection fraction, potentially explaining the different clinical response to medication. Surprisingly, active relaxation in isolated ventricular cardiomyocytes in both HFpEF animal models was intact, suggesting that changes of preload or afterload, passive myocardial properties or para- or endocrine modulators play a significant role in driving diastolic dysfunction in these models. Atrial cardiomyocytes displayed intact contractility but increased arrhythmogenicity, explaining the close association of HFpEF and atrial fibrillation. SGLT1/2 inhibition constitutes a potential therapeutic target to reduce arrhythmogenicity.