Diastolic Cardiomyocyte Calcium Homeostasis in HFrEF, HFpEF

Abnormalities prominent in heart failure with reduced ejection fraction (HFrEF), including disruption of cardiomyocyte t-tubules and impaired Ca²⁺ release, may not be common in heart failure with preserved ejection fraction (HFpEF), according to a study published in the Journal of the American College of Cardiology.

In this study, T-tubule structure was examined in left ventricular biopsies from patients with HFrEF (n=11) and HFpEF (n=20). Biopsies from regionally matched nonfailing control patients treated with coronary bypass surgery (n=6) were compared with those with HFpEF, and left ventricular free wall biopsies from patients with healthy hearts (n=4) were compared with biopsies from patients with HFrEF. The researchers also studied cardiomyocyte Ca²⁺ homeostasis in HFrEF and HFpEF rat models.

Patients with HFpEF had increased t-tubule density, lower E/A ratios and e’ values, and increased E/e’ measurements compared with control patients. According to super-resolution imaging, higher t-tubule density was a result of tubule dilation and proliferation. In patients with vs without HFrEF, T-tubule density was reduced, and marked systolic and diastolic dysfunction were observed.

Greater collagen deposition within t-tubules were observed in biopsies from patients with HFrEF but not in HFpEF. Elevated ventricular wall stress was found to underlie the causal relationship between mechanical stress and t-tubule disruption in patients with HFrEF.

In rats with HFrEF, an association between t-tubule loss and impaired systolic Ca²⁺ homeostasis was established, despite a reduction in diastolic Ca²⁺ removal. In HFpEF rat models, Ca²⁺ transient magnitude and release kinetics were mostly maintained, but diastolic Ca²⁺ (particularly, sarco/endoplasmic reticulum Ca²⁺-ATPase activity) was impaired in rat models of HFpEF and diabetes, but not HFpEF with ischemia or hypertension.

A limitation of this study is the sole inclusion of frozen samples as well as the small number of biopsies in the final analysis.

“These findings support the notion that HFpEF includes a nonhomogenous group of patients with dissimilar pathophysiologies, requiring tailored treatment strategies,” concluded the researchers.

Reference

Frisk M, Le C, Shen X, et al. Etiology-dependent impairment of diastolic cardiomyocyte calcium homeostasis in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2021;77(4):405-419. doi:10.1016/j.jacc.2020.11.044