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Cellular and molecular pathobiology of heart failure with preserved ejection fraction

A Publisher Correction to this article was published on 21 January 2021

This article has been updated

Abstract

Heart failure with preserved ejection fraction (HFpEF) affects half of all patients with heart failure worldwide, is increasing in prevalence, confers substantial morbidity and mortality, and has very few effective treatments. HFpEF is arguably the greatest unmet medical need in cardiovascular disease. Although HFpEF was initially considered to be a haemodynamic disorder characterized by hypertension, cardiac hypertrophy and diastolic dysfunction, the pandemics of obesity and diabetes mellitus have modified the HFpEF syndrome, which is now recognized to be a multisystem disorder involving the heart, lungs, kidneys, skeletal muscle, adipose tissue, vascular system, and immune and inflammatory signalling. This multiorgan involvement makes HFpEF difficult to model in experimental animals because the condition is not simply cardiac hypertrophy and hypertension with abnormal myocardial relaxation. However, new animal models involving both haemodynamic and metabolic disease, and increasing efforts to examine human pathophysiology, are revealing new signalling pathways and potential therapeutic targets. In this Review, we discuss the cellular and molecular pathobiology of HFpEF, with the major focus being on mechanisms relevant to the heart, because most research has focused on this organ. We also highlight the involvement of other important organ systems, including the lungs, kidneys and skeletal muscle, efforts to characterize patients with the use of systemic biomarkers, and ongoing therapeutic efforts. Our objective is to provide a roadmap of the signalling pathways and mechanisms of HFpEF that are being characterized and which might lead to more patient-specific therapies and improved clinical outcomes.

Key points

  • The historical focus of studies into the pathophysiology of heart failure with preserved ejection fraction (HFpEF) has been on diastolic dysfunction, cardiac hypertrophy and myocardial fibrosis.

  • However, HFpEF actually involves many different components affecting both systolic and diastolic heart function and also other organs and systems, including the lungs, kidneys, vasculature, adipose tissue and skeletal muscle.

  • Preclinical studies, particularly those combining obesity and metabolic defects with haemodynamic and cardiac disease as occurs in the majority of patients with HFpEF, are beginning to reveal novel molecular mechanisms and therapeutic targets.

  • The proposed molecular and cellular abnormalities in HFpEF and those observed in diabetes mellitus and obesity overlap substantially, including metabolic defects in fuel utilization and efficiency, inflammatory responses, lipotoxicity, pathological growth of myocytes and loss of cytoprotective signalling.

  • In addition to exploring novel haemodynamic interventions with drugs and devices, new therapies are targeting pleiotropic signalling cascades to counteract changes in metabolic, inflammatory and pathological stress pathways.

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Fig. 1: Signalling pathways in cardiac hypertrophy.
Fig. 2: Fibrotic–inflammatory remodelling in heart failure with preserved ejection fraction.
Fig. 3: Components of the cGMP–PKG signalling systems and their cellular effectors.
Fig. 4: Dysregulated oxidative and nitrosative stress in HFpEF pathogenesis.
Fig. 5: Metabolic flexibility and HFpEF.

Change history

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Mishra, S., Kass, D.A. Cellular and molecular pathobiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 18, 400–423 (2021). https://doi.org/10.1038/s41569-020-00480-6

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