Etiology-Dependent Impairment of Diastolic Cardiomyocyte Calcium Homeostasis in Heart Failure With Preserved Ejection Fraction

Abstract

Background: Whereas heart failure with reduced ejection fraction (HFrEF) is associated with ventricular dilation and markedly reduced systolic function, heart failure with preserved ejection fraction (HFpEF) patients exhibit concentric hypertrophy and diastolic dysfunction. Impaired cardiomyocyte Ca²⁺ homeostasis in HFrEF has been linked to disruption of membrane invaginations called t-tubules, but it is unknown if such changes occur in HFpEF.

Objectives: This study examined whether distinct cardiomyocyte phenotypes underlie the heart failure entities of HFrEF and HFpEF.

Methods: T-tubule structure was investigated in left ventricular biopsies obtained from HFrEF and HFpEF patients, whereas cardiomyocyte Ca²⁺ homeostasis was studied in rat models of these conditions.

Results: HFpEF patients exhibited increased t-tubule density in comparison with control subjects. Super-resolution imaging revealed that higher t-tubule density resulted from both tubule dilation and proliferation. In contrast, t-tubule density was reduced in patients with HFrEF. Augmented collagen deposition within t-tubules was observed in HFrEF but not HFpEF hearts. A causative link between mechanical stress and t-tubule disruption was supported by markedly elevated ventricular wall stress in HFrEF patients. In HFrEF rats, t-tubule loss was linked to impaired systolic Ca²⁺ homeostasis, although diastolic Ca²⁺ removal was also reduced. In contrast, Ca²⁺ transient magnitude and release kinetics were largely maintained in HFpEF rats. However, diastolic Ca²⁺ impairments, including reduced sarco/endoplasmic reticulum Ca²⁺-ATPase activity, were specifically observed in diabetic HFpEF but not in ischemic or hypertensive models.

Conclusions: Although t-tubule disruption and impaired cardiomyocyte Ca²⁺ release are hallmarks of HFrEF, such changes are not prominent in HFpEF. Impaired diastolic Ca²⁺ homeostasis occurs in both conditions, but in HFpEF, this mechanism for diastolic dysfunction is etiology-dependent.

Keywords: calcium cycling/excitation-contraction coupling; heart failure with preserved ejection fraction; pathophysiology; remodeling; transverse tubules; wall stress.