Etiology-Dependent Impairment of Diastolic Cardiomyocyte Calcium Homeostasis in Heart Failure With Preserved Ejection Fraction
- PMID: 33509397
- PMCID: PMC7840890
- DOI: 10.1016/j.jacc.2020.11.044
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.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Author Disclosures This study was supported by the European Union’s Horizon 2020 Research and Innovation Programme (Consolidator grant to Dr. Louch) under grant agreement No. 647714. Additional support was provided by The South-Eastern Norway Regional Health Authority, Anders Jahre’s Fund for the Promotion of Science, the Research Council of Norway, the Norwegian Institute of Public Health, Oslo University Hospital, the University of Oslo, the K.G. Jebsen Center for Cardiac Research, Norway, the European Union Projects No. FP7-HEALTH-2010.2.4.2-4 (‘‘MEDIA-Metabolic Road to Diastolic Heart Failure’’), and the Marsden Fund administered by the Royal Society of New Zealand (UOO1501). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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Comment in
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HFpEF: Should We Consider Diabetic Patients Separately?: The Cardiomyocytes Say Yes.J Am Coll Cardiol. 2021 Feb 2;77(4):420-422. doi: 10.1016/j.jacc.2020.11.051. J Am Coll Cardiol. 2021. PMID: 33509398 No abstract available.
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