Key result
High fat/sugar diet increases diastolic dysfunction ~35% and worsens cardiomyocyte stiffness in mice.
Why the study?
There are no specific treatments for diastolic dysfunction, making the understanding of its cardiomyocyte origins an important priority to identify new therapeutics.
Does a high fat/sugar diet induce intrinsic cardiomyocyte stiffness and in vivo diastolic dysfunction in a murine model?
Does a high fat/sugar diet induce intrinsic cardiomyocyte stiffness and in vivo diastolic dysfunction in a murine model?
Effect estimate: elevated by 35%
Absolute Event Rate: 22.3% vs 16.7%
p-value: p=0.005
Under mechanical load, isolated cardiomyocytes from mice with diet-induced cardiometabolic disease exhibit intrinsic stiffness that directly correlates with in vivo diastolic dysfunction, highlighting altered myofilament-Ca2+ interactions as a potential therapeutic target.
May implicate cardiomyocyte stiffness in diet-related diastolic dysfunction; hypothesis-generating in mice and leaves open human translation.
Cardiometabolic 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 define in vitro stiffness properties of isolated cardiomyocytes derived from rodent hearts exhibiting diastolic dysfunction in vivo in response to dietary induction of cardiometabolic disease. Male mice fed a high fat/sugar diet (HFSD vs . control) exhibited diastolic dysfunction (echo E / e ′ Doppler ratio). Intact paced cardiomyocytes were functionally investigated in three conditions: non‐loaded, loaded and stretched. Mean stiffness of HFSD cardiomyocytes was 70% higher than control. E / e ′ for the HFSD hearts was elevated by 35%. A significant relationship was identified between in vitro cardiomyocyte stiffness and in vivo dysfunction severity. With conversion from the non‐loaded to loaded condition, the decrement in maximal sarcomere lengthening rate was more accentuated in HFSD cardiomyocytes ( vs . control). With stretch, the Ca 2+ transient decay time course was prolonged. With increased pacing, cardiomyocyte stiffness was elevated, yet diastolic Ca 2+ elevation was attenuated. Our findings show unequivocally that cardiomyocyte mechanical dysfunction cannot be detected by analysis of non‐loaded shortening. Collectively, these findings demonstrate that a component of cardiac diastolic dysfunction in cardiometabolic disease is derived from cardiomyocyte stiffness. Differential responses to load, stretch and pacing suggest that a previously undescribed alteration in myofilament–Ca 2+ interaction contributes to intrinsic cardiomyocyte stiffness in cardiometabolic disease. image Key points Understanding 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 measured in vivo (echocardiography) for mice fed a high‐fat/sugar diet (HFSD, ≥25 weeks). Performance of intact isolated cardiomyocytes derived from the same hearts was measured during pacing under non‐loaded, loaded and stretched conditions in vitro . Calibrated cardiomyocyte stretches demonstrated that stiffness (stress/strain) was elevated in HFSD cardiomyocytes in vitro and correlated with diastolic dysfunction ( E / e ′) in vivo . HFSD cardiomyocyte Ca 2+ transient decay was prolonged in response to stretch. Stiffness was accentuated with pacing increase while the elevation in diastolic Ca 2+ was attenuated. Data show unequivocally that cardiomyocyte mechanical dysfunction cannot be detected by analysis of non‐loaded shortening. These findings suggest that stretch‐dependent augmentation of the myofilament–Ca 2+ response during diastole partially underlies elevated cardiomyocyte stiffness and diastolic dysfunction of hearts of animals with cardiometabolic disease.
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Janssens et al. (2024) studied Cardiometabolic disease and diastolic dysfunction. High fat/sugar diet (HFSD) vs. Control reference diet (16% kcal from fat, 100 g/kg sucrose) was evaluated on In vivo diastolic dysfunction (E/e' ratio) (elevated by 35%, p=0.005). High fat/sugar diet feeding in male mice increased in vivo diastolic dysfunction (E/e' ratio) by 35% and intrinsic in vitro cardiomyocyte stiffness by 70% compared to a control diet.
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