Abstract
Abstract
Heart failure with preserved ejection fraction (HFpEF) accounts for over half of heart failure cases, yet its underlying mechanisms remain incompletely understood and effective therapies are lacking. Diastolic dysfunction, a hallmark of HFpEF, may arise from impaired active myocardial relaxation, but the contribution of intracellular calcium (Ca
2+
) handling remains unclear. This study aimed to document impaired lusitropy and diastolic dysfunction in HFpEF, and to determine the contribution of altered ventricular Ca
2+
handling to slowed myocardial relaxation. HFpEF was induced by diet‐driven obesity and hypertension. Cardiac function was assessed
in vivo
by echocardiography,
ex vivo
in preload‐controlled isolated hearts and at the cellular level by Ca
2+
imaging of isolated ventricular myocytes. HFpEF mice developed diastolic dysfunction, hypertrophy, reduced cardiac output and exercise intolerance, yet ejection fraction was preserved. Impaired lusitropy was evident
in vivo
,
ex vivo
and at the cellular level, where basal cytosolic Ca
2+
handling was preserved, but the β‐adrenergic‐recruitable acceleration of Ca
2+
clearance was impaired. This attenuated lusitropic response to β‐adrenergic stimulation in HFpEF myocytes was mirrored
in vivo
during echocardiography. Slowed myocardial relaxation is a consistent feature of HFpEF, evident at the organ, tissue and cellular levels. β‐Adrenergic stimulation normally enhances lusitropy, but this response is blunted in HFpEF hearts both
in vivo
and in isolated cardiomyocytes. Impaired β‐adrenergic amplification of Ca
2+
removal is associated with slowed ventricular relaxation, reduced cardiac output and exercise intolerance in HFpEF, identifying defective lusitropic reserve as a potential therapeutic target.
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Key points
Heart failure with preserved ejection fraction (HFpEF) lacks effective therapies, in part because the disease mechanisms remain incompletely defined.
Using a mouse model combining obesity and hypertension, we demonstrate diastolic dysfunction, reduced cardiac output and exercise intolerance despite preserved ejection fraction. Ventricular relaxation was impaired in HFpEF mice
in vivo
and
ex vivo
.
β‐Adrenergic lusitropic reserve was reduced in HFpEF mice during ultrasound echocardiography, which was mirrored by a blunted β‐adrenergic acceleration of cytosolic Ca
2+
removal in disaggregated cells from HFpEF hearts.
These findings identify defective myocyte Ca
2+
handling as a distinct mechanistic contributor to HFpEF pathophysiology and suggest that therapeutic strategies aimed at restoring Ca
2+
removal and lusitropic reserve may improve diastolic performance and functional capacity in HFpEF patients.