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Review
. 2025 Jul 3;24(1):265.
doi: 10.1186/s12933-025-02774-w.

Cardiometabolic heart failure with preserved ejection fraction: from molecular signatures to personalized treatment

Era Gorica  1   2 , Martin A Geiger  3 , Ludovica Di Venanzio  3 , Natalia Atzemian  3 , Jan Alphard Kleeberger  3   4 , Dominique Grigorian  3 , Alessia Mongelli  3 , Besa Emini Veseli  3 , Shafeeq A Mohammed  3 , Frank Ruschitzka  3   4 , Andreas J Flammer  3   4 , David Niederseer  3   5   6 , Sarah Costantino  3   4 , Francesco Paneni  7   8
Affiliations
Review

Cardiometabolic heart failure with preserved ejection fraction: from molecular signatures to personalized treatment

Era Gorica et al. Cardiovasc Diabetol. .

Abstract

Heart failure with preserved ejection fraction (HFpEF) represents nearly half of all heart failure cases globally. The increased prevalence of cardiometabolic disease, driven by unhealthy lifestyles, has led to a growing population of people developing the so called "cardiometabolic HFpEF (cmHFpEF)" phenotype. This condition represents an end stage cardiometabolic phenotype which results from the clustering of metabolic stress (obesity), hemodynamic stress (hypertension), immune activation, and systemic inflammation. This form of HFpEF is preceded by a "metabolic cardiomyopathy" phenotype, characterized by myocardial metabolic remodeling, rewiring of lipid metabolism, and inflammation eventually fostering left ventricular hypertrophy, diastolic dysfunction and atrial dilatation. Recent work over the last years has unveiled the molecular cues underpinning cmHFpEF pathogenesis thus contributing to the identification of novel therapeutic approaches to treat this complex syndrome. The present review provides an overview of recent advances in cmHFpEF biology and pathophysiology with particular emphasis on the following aspects: (i) metabolic alterations associated with cmHFpEF; (ii) changes of the immune landscape; (iii) microvascular dysfunction; (iv) inflammation; (v) chromatin remodeling. Additionally, we will discuss potential mechanisms-based therapeutic strategies to tackle this growing health concern.

Keywords: Epigenetics; HFpEF; Inflammation; Metabolism; Obesity.

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Conflict of interest statement

Declarations. Competing interest: Francesco Paneni and Era Gorica manage the collection “Cardiometabolic HFpEF with focus on type 2 diabetes mellitus” and the co-author Francesco Paneni is also an Associate Editor of the journal. They haven't been involved in the peer review of this article. Prof. Ruschitzka has not received personal payments by pharmaceutical companies or device manufacturers in the last 3 years (remuneration for the time spent in activities, such as participation as steering committee member of clinical trials and member of the Pfizer Research Award selection committee in Switzerland, were made directly to the University of Zurich). The Department of Cardiology (University Hospital of Zurich/University of Zurich) reports research-, educational- and/or travel grants from Abbott, Abiomed, Alnylam, Amarin, Amgen, Astra Zeneca, At the Limits Ltd., Bayer, Biotronik, BMS, Boehringer Ingelheim, Boston Scientific, Bracco, CM Microport, Concept Medical, CTI, Daiichi Sankyo, Davos Congress, Edwards Lifesciences, FomF GmbH, Hamilton Health Sciences, Holcim, IHF, Innosuisse, IumiraDX, Kantar, LabPoint, MedAlliance, Medcon International, Medical Education Global Solutions, Medtronic, MicroPort, Monocle, Novartis, Novo Nordisk, OM Pharma, Pfizer, Quintiles Switzerland Sarl, RecorMedical, Roche Diagnostics, Roche Pharma, Sahajanand IN, Sanofi, Sarstedt AG, Servier, Sorin SRM SAS, SSS Int., Terumo Deutschland, Trama Solutions, V- Wave, Vifor, ZOLL. These grants do not impact on Prof. Ruschitzka`s personal remuneration. AJF declares fees from Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Pfizer, Roche, Vifor, and Zoll, as well as grant support by Novartis, AstraZeneca and Berlin Heart unrelated to this article. DN disclosures honoraria, consultant fees and/or travel expenses from Abbott, Amgen, Astra Zeneca, Bristol Myers Squibb SA, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Dr. Willmar Schwabe GmbH & Co. KG, Emilwood Service Limited, Gerson Lehman Group (GLG) Consulting, Novartis, Novo Nordisk, Pfizer, walk and feel, and Zoll. FP reports receiving fees for serving on advisory boards from Novo Nordisk.

Figures

Fig. 1
Fig. 1
Risk factors clustering in patients with cmHFpEF
Fig. 2
Fig. 2
Schematic showing altered biological processes in the cmHFpEF myocardium
Fig. 3
Fig. 3
Molecular hallmarks of cmHFpEF. cmHFpEF is characterized by endothelial dysfunction and impaired nitric oxide (NO) signaling, fibrosis and extracellular matrix (ECM) remodeling, impaired autophagy, mitochondrial dysfunction accompanied by increased oxidative stress and energy deficiency, and chronic inflammation with increased cytokine production. These interconnected mechanisms contribute to myocardial dysfunction and HFpEF disease progression
Fig. 4
Fig. 4
Epigenetic dysregulation in cmHFpEF. DNA methylation, histone modifications, and microRNA dysregulation impact pathogenesis of HFpEF. Epigenetic changes regulate key genes involved in metabolic dysfunction, inflammation, fibrosis, endothelial dysfunction, contributing to cardiac hypertrophy and diastolic dysfunction
See this image and copyright information in PMC

References

    1. Tan YT, Wenzelburger F, Lee E, Heatlie G, Leyva F, Patel K, et al. The pathophysiology of heart failure with normal ejection fraction: exercise echocardiography reveals complex abnormalities of both systolic and diastolic ventricular function involving torsion, untwist, and longitudinal motion. J Am Coll Cardiol. 2009;54(1):36–46. - DOI - PubMed
    1. Rosch S, Kresoja KP, Besler C, Fengler K, Schöber AR, von Roeder M, et al. Characteristics of heart failure with preserved ejection fraction across the range of left ventricular ejection fraction. Circulation. 2022;146(7):506–18. - DOI - PubMed
    1. Pecchia B, Samuel R, Shah V, Newman E, Gibson GT. Mechanisms ofexercise intolerance in heart failure with preserved ejection fraction (HFpEF). Heart Fail Rev. 2025. 10.1007/s10741-025-10504-3. - DOI - PMC - PubMed
    1. Miranda JJ, Barrientos-Gutiérrez T, Corvalan C, Hyder AA, Lazo-Porras M, Oni T, et al. Understanding the rise of cardiometabolic diseases in low- and middle-income countries. Nat Med. 2019;25(11):1667–79. - DOI - PubMed
    1. Shahim B, Kapelios CJ, Savarese G, Lund LH. Global public health burden of heart failure: an updated review. Card Fail Rev. 2023;9: e11. - DOI - PMC - PubMed

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