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Myocardial Metabolic Reprogramming in HFpEF

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Abstract

Heart failure (HF) caused by structural or functional cardiac abnormalities is a significant cause of morbidity and mortality worldwide. While HF with reduced ejection fraction (HErEF) is well understood, more than half of patients have HF with preserved ejection fraction (HFpEF). Currently, the treatment for HFpEF primarily focuses on symptom alleviation, lacking specific drugs. The stressed heart undergoes metabolic switches in substrate preference, which is a compensatory process involved in cardiac pathological remodeling. Although metabolic reprogramming in HF has gained attention in recent years, its role in HFpEF still requires further elucidation. In this review, we present a summary of cardiac mitochondrial dysfunction and cardiac metabolic reprogramming in HFpEF. Additionally, we emphasize potential therapeutic approaches that target metabolic reprogramming for the treatment of HFpEF.

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Data Availability

All data used are available from the corresponding author on reasonable request.

Abbreviations

AMPK:

Adenosine monophosphate-activated protein kinase

BCAA:

Branched chain amino acids

cGMP:

Cyclic GMP

EAT:

Epicardial adipose tissue

ECs:

Endothelial cells

EF:

Ejection fraction

ETC:

Electron transport chain

FA:

Fatty acids

FAP:

Fibroblast activation protein

FXI:

Factor XI

HErEF:

HF with reduced EF

HF:

Heart failure

HFpEF:

HF with preserved EF

iNOS:

Inducible nitric oxide synthase

IRE1α:

Inositol-requiring protein 1α

LDLR:

Low-density lipoprotein receptor

NAD+:

Nicotinamide adenine dinucleotide

NAM:

Nicotinamide

NO:

Nitric oxide

OXPHOS:

Oxidative phosphorylation

PCSK9:

Proprotein convertase subtilisin/kexin type 9

PH-HFpEF:

Pulmonary hypertension associated with HFpEF

PKG:

Protein kinase G

ROS:

Reactive oxygen species

SAUNA:

Salty drinking water/unilateral nephrectomy/aldosterone

sGC:

Soluble guanylate cyclase

SGLT2:

Sodium-dependent glucose transporters 2

SIRT3:

Sirtuin 3

T2D:

Type 2 diabetes

XBP1:

X-box binding protein 1

ZSF1:

Zucker/fatty spontaneously hypertensive F1 hybrid

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Funding

This research was supported by funding from the National Natural Science Foundation of China (82070261, 82170251, 82100312), the National Key Research and Development Program of China (No.2021YFA1100501), the China Postdoctoral Science Foundation (No.2021M692640), the Youth Innovation Team of Shaanxi Universities, the Innovation Foundation for Doctor Dissertation of Northwestern Polytechnical University (CX2022068), and the Training Program of Practice and Innovation for Postgraduates of Northwestern Polytechnical University (PF2023032).

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  1. Zihui Zhang and Mingchu Sun contributed equally to this work.

Authors and Affiliations

  1. Xi’an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi’an, Shaanxi, 710072, People’s Republic of China

    Zihui Zhang, Mingchu Sun, Wenhua Jiang, Chan Zhang & Heng Ma

  2. Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, People’s Republic of China

    Lu Yu

  3. Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, 710032, People’s Republic of China

    Heng Ma

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  1. Zihui Zhang
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Associate Editor Yihua Bei oversaw the review of this article

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Clinical Relevance

Metabolic reprogramming is a crucial alteration in the pathophysiology of HFpEF, and this study aims to review its molecular basis as a potential therapeutic target. The findings suggest that targeting metabolic reprogramming could be an essential strategy for the treatment of HFpEF.

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Zhang, Z., Sun, M., Jiang, W. et al. Myocardial Metabolic Reprogramming in HFpEF. J. of Cardiovasc. Trans. Res. 17, 121–132 (2024). https://doi.org/10.1007/s12265-023-10433-2

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