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bioRxiv · 10.1101/2025.09.10.675427

Slow Calcium Removal Prolongs Ventricular Relaxation in Mice with HFpEF

Zawadzki, T. S.·Usai, D. S.·Jacobsen, J. C. B.·Thomsen, M. B.
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Abstract

BackgroundHeart failure with preserved ejection fraction (HFpEF) accounts for over half of heart failure cases, yet its underlying mechanisms incompletely understood and effective therapies are lacking. Diastolic dysfunction, the hallmark of HFpEF, may arise from impaired active myocardial relaxation, but the contribution of intracellular calcium (Ca2+) handling remains unclear. MethodsWe used a validated "two-hit" murine model of HFpEF, induced by diet-driven obesity and hypertension, to investigate ventricular Ca2+ dynamics. Cardiac function was assessed in vivo by echocardiography, ex vivo in isolated working hearts, and at the cellular level using Fura-2-based Ca2+ imaging of isolated ventricular myocytes. ResultsHFpEF mice developed obesity, diastolic dysfunction, hypertrophy, reduced cardiac index, and exercise intolerance despite preserved ejection fraction. Impaired lusitropy was evident in vivo, ex vivo, and at the cellular level, where ventricular myocytes from HFpEF hearts displayed elevated diastolic [Ca2+]i, increased Ca2+ transient amplitudes, and frequency-dependent slowing of Ca2+ clearance ({tau}), most pronounced at 4 Hz (33% slower vs. controls, p < 0.05). HFpEF myocytes also exhibited an attenuated {beta}-adrenergic response to isoprenaline, further limiting diastolic reserve. ConclusionsHFpEF is characterised by a distinct ventricular myocyte Ca2+ handling phenotype, diverging from heart failure with reduced ejection fraction (HFrEF), with elevated diastolic Ca2+, exaggerated and prolonged Ca2+ transients, and blunted {beta}-adrenergic modulation. These abnormalities converge to impair lusitropy and exercise tolerance, highlighting altered Ca2+ dynamics as a central mechanism in HFpEF. Targeting these specific Ca2+ handling defects may represent a novel therapeutic strategy.

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Zawadzki, T. S., Usai, D. S., Jacobsen, J. C. B., Thomsen, M. B.. 2025-09-16. Slow Calcium Removal Prolongs Ventricular Relaxation in Mice with HFpEF. https://doi.org/10.1101/2025.09.10.675427

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