Mechanical loading reveals an intrinsic cardiomyocyte stiffness contribution to diastolic dysfunction in murine cardiometabolic disease

Abstract

ABSTRACTCardiometabolic syndromes including diabetes and obesity are associated with occurrence of heart failure with diastolic dysfunction. There are no specific treatments for diastolic dysfunction and therapies to manage symptoms have limited efficacy. Understanding of the cardiomyocyte origins of diastolic dysfunction is an important priority to identify new therapeutics. The investigative goal was to experimentally definein vitrostiffness (stress/strain) properties of isolated cardiomyocytes derived from rodent hearts exhibiting diastolic dysfunctionin vivoin response to dietary induction of cardiometabolic disease.Mice fed a High Fat/Sugar Diet (HFSD vs control) for at least 25 weeks exhibited glucose intolerance, obesity and diastolic dysfunction (echo E/e’). Intact paced cardiomyocytes were functionally investigated in three conditions: non-loaded, loaded and stretched.Mean stiffness of HFSD cardiomyocytes was 70% higher than control. The E/e’ doppler ratio for the origin hearts was elevated by 35%. A significant relationship was identified betweenin vitrocardiomyocyte stiffness andin vivodysfunction severity. With conversion from non-loaded to loaded condition, the decrement in maximal sarcomere lengthening rate was more accentuated in HFSD cardiomyocytes (vs control). With stretch, the Ca2+transient decay time course was prolonged. With transition from 2-4Hz pacing, HFSD cardiomyocyte stiffness was further increased, yet diastolic Ca2+rise was 50% less than control.Collectively, these findings demonstrate that a component of cardiac diastolic dysfunction in cardiometabolic disease is derived from intrinsic cardiomyocyte mechanical abnormality. Differential responses to load, stretch and pacing suggest that a previously undescribed alteration in myofilament-Ca2+interaction contributes to cardiomyocyte stiffness in cardiometabolic disease.KEY POINTSUnderstanding cardiomyocyte stiffness components is an important priority for identifying new therapeutics for diastolic dysfunction, a key feature of cardiometabolic disease.In this study cardiac function was measuredin vivo(echocardiography) for mice fed a high-fat/sugar diet (HFSD, ≥25weeks) and performance of intact isolated cardiomyocytes derived from the same hearts was measured during pacing under non-loaded, loaded and stretched conditionsin vitro.Using a calibrated cardiomyocyte stretch protocol, stiffness (stress/strain) was elevated in HFSD cardiomyocytesin vitroand correlated with diastolic dysfunction (E/e’)in vivo.The HFSD cardiomyocyte Ca2+transient decay was prolonged in response to stretch, and stiffness was accentuated in response to pacing increase while the rise in diastolic Ca2+was attenuated.These findings suggest that stretch-dependent augmentation of the myofilament-Ca2+response during diastole partially underlies elevated cardiomyocyte stiffness and diastolic dysfunction of hearts of animals with cardiometabolic disease.