Heart Failure With Preserved Ejection Fraction: Heterogeneous Syndrome, Diverse Preclinical Models

Circulation Research, Journal Year: 2022, Volume and Issue: 130(12), P. 1906 - 1925

Published: June 9, 2022

Heart failure with preserved ejection fraction (HFpEF) represents one of the greatest challenges facing cardiovascular medicine today. Despite being most common form heart worldwide, there has been limited success in developing therapeutics for this syndrome. This is largely due to our incomplete understanding biology driving its systemic pathophysiology and heterogeneity clinical phenotypes, which are increasingly recognized as distinct HFpEF phenogroups. Development efficacious fundamentally relies on robust preclinical models that not only faithfully recapitulate key features syndrome but also enable rigorous investigation putative mechanisms disease context clinically relevant phenotypes. In review, we propose a research strategy conceptually grounded model diversification aims better align evolving HFpEF. Although often viewed major obstacle research, challenge notion argue embracing it may be demystifying pathobiology. Here, first provide an overarching guideline through stepwise approach comprehensive cardiac extra-cardiac phenotyping. We then present overview currently available models, focused 3 leading phenogroups, primarily based aging, cardiometabolic stress, chronic hypertension. discuss how well these reflect their phenogroup highlight some more recent mechanistic insights they providing into complex underlying

Language: Английский

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Inflammation in Obesity-Related HFpEF

Journal of the American College of Cardiology, Journal Year: 2024, Volume and Issue: 84(17), P. 1646 - 1662

Published: Aug. 30, 2024

Inflammation is thought to be an important mechanism for the development and progression of obesity-related heart failure with preserved ejection fraction (HFpEF). In STEP-HFpEF Program, once-weekly 2.4 mg semaglutide improved failure-related symptoms, physical limitations, exercise function, reduced levels C-reactive protein (CRP), a biomarker inflammation, body weight in participants HFpEF. However, neither prevalence nor clinical characteristics patients who have various magnitudes inflammation context HFpEF been well described. Furthermore, whether beneficial effects on HF efficacy endpoints Program are modified by baseline has not fully established. Finally, relationship between reduction changes CRP across defined.

Language: Английский

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Immune checkpoints in cardiac physiology and pathology: therapeutic targets for heart failure

Nature Reviews Cardiology, Journal Year: 2024, Volume and Issue: 21(7), P. 443 - 462

Published: Jan. 26, 2024

Language: Английский

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Cardiac metabolism in HFpEF: from fuel to signalling

Cardiovascular Research, Journal Year: 2022, Volume and Issue: 118(18), P. 3556 - 3575

Published: Dec. 7, 2022

Heart failure (HF) is marked by distinctive changes in myocardial uptake and utilization of energy substrates. Among the different types HF, HF with preserved ejection fraction (HFpEF) a highly prevalent, complex, heterogeneous condition for which metabolic derangements seem to dictate disease progression. Changes intermediate metabolism cardiometabolic HFpEF-among most prevalent forms HFpEF-have large impact both on provision number signalling pathways heart. This dual, vs. signalling, role played particular long-chain fatty acids (LCFAs) short-chain carbon sources [namely, (SCFAs) ketone bodies (KBs)]. LCFAs are key fuels heart, but their excess can be harmful, as case toxic accumulation lipid by-products (i.e. lipotoxicity). SCFAs KBs have been proposed potential major, alternative source HFpEF. At same time, substrate protein post-translational modifications other direct indirect pivotal importance HFpEF pathogenesis. An in-depth molecular understanding biological functions substrates will instrumental development novel therapeutic approaches Here, we summarize current evidence HFpEF, discuss metabolites through, at least part, fate modifications, highlight clinical translational challenges around therapy

Language: Английский

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Total-Body PET/CT Applications in Cardiovascular Diseases: A Perspective Document of the SNMMI Cardiovascular Council

Journal of Nuclear Medicine, Journal Year: 2024, Volume and Issue: 65(4), P. 607 - 616

Published: Feb. 22, 2024

Digital PET/CT systems with a long axial field of view have become available and are emerging as the current state art. These new camera provide wider anatomic coverage, leading to major increases in system sensitivity. Preliminary results demonstrated improvements image quality quantification, well substantial advantages tracer kinetic modeling from dynamic imaging. also potentially allow for low-dose examinations reductions acquisition time. Thereby, they hold great promise improve PET-based interrogation cardiac physiology biology. Additionally, whole-body coverage enables simultaneous assessment multiple organs large vascular structures body, opening opportunities imaging systemic mechanisms, disorders, or treatments their interactions cardiovascular whole. The aim this perspective document is debate potential applications, challenges, opportunities, remaining challenges applying disease.

Language: Английский

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AdipoRon ameliorates the progression of heart failure with preserved ejection fraction via mitigating lipid accumulation and fibrosis

Journal of Advanced Research, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 1, 2024

Obesity and imbalance in lipid homeostasis contribute greatly to heart failure with preserved ejection fraction (HFpEF), the dominant form of failure. Few effective therapies exist control metabolic alterations homeostasis.

Language: Английский

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Uncovering the Role of Prokineticin Pathway on Epicardial Adipose Tissue (EAT) Development and EAT-Associated Cardiomyopathy

Trends in Cardiovascular Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Immunometabolism at the Heart of Cardiovascular Disease

JACC Basic to Translational Science, Journal Year: 2023, Volume and Issue: 8(7), P. 884 - 904

Published: April 26, 2023

Immune cell function among the myocardium, now more than ever, is appreciated to regulate cardiac and pathophysiology. This case for both innate immunity, which includes neutrophils, monocytes, dendritic cells, macrophages, as well adaptive T cells B cells. fueled by cell-intrinsic shifts in metabolism, such glycolysis oxidative phosphorylation, metabolite availability, originates from surrounding extracellular milieu varies during ischemia metabolic syndrome. crosstalk with parenchymal cardiomyocytes fibroblasts, also regulated complex cellular circuits. Although our understanding of immunometabolism has advanced rapidly over past decade, part through valuable insights made cultured there remains much learn about contributions vivo directly within myocardium. Insight into fundamental molecular mechanisms holds potential inform interventions that shift balance maladaptive cardioprotective potentially even regenerative. Herein, we review current working immunometabolism, specifically settings sterile ischemic injury or cardiometabolic disease, contribute onset heart failure. We discuss gaps knowledge this context therapeutic implications.

Language: Английский

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Single-Cell RNA Sequencing Reveals Metabolic Stress-Dependent Activation of Cardiac Macrophages in a Model of Dyslipidemia-Induced Diastolic Dysfunction

Circulation, Journal Year: 2023, Volume and Issue: 150(19), P. 1517 - 1532

Published: Dec. 21, 2023

BACKGROUND: Metabolic distress is often associated with heart failure preserved ejection fraction (HFpEF) and represents a therapeutic challenge. Metabolism-induced systemic inflammation links comorbidities HFpEF. How metabolic changes affect myocardial in the context of HFpEF not known. METHODS: We found that ApoE knockout mice fed Western diet recapitulate many features Single-cell RNA sequencing was used for expression analysis CD45 + cardiac cells to evaluate involvement diastolic dysfunction. focused bioinformatics on macrophages, obtaining high-resolution identification subsets these heart, enabling us study outcomes macrophage infiltrate identify macrophage-to-cardiomyocyte regulatory axis. To test whether clinically relevant sodium glucose cotransporter-2 inhibitor could ameliorate immune profile our model, were randomized receive dapagliflozin or vehicle 8 weeks. RESULTS: presented reduced function, exercise tolerance, increased pulmonary congestion lipid overload polyunsaturated fatty acids. The main cell types infiltrating included 4 subpopulations resident monocyte-derived determining proinflammatory exclusively knockout-Western mice. Lipid had direct effect inflammatory gene activation mediated through endoplasmic reticulum stress pathways. Investigation axis revealed potential effects cardiomyocytes multiple cytokines secreted by affecting pathways such as hypertrophy, fibrosis, autophagy. Finally, we describe an anti-inflammatory inhibition this model. CONCLUSIONS: Using single-cell model dysfunction driven hyperlipidemia, have determined cells, particular suggest inhibitors agents targeting specific phenotype

Language: Английский

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Impaired T cell IRE1α/XBP1 signaling directs inflammation in experimental heart failure with preserved ejection fraction

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(24)

Published: Oct. 24, 2023

Heart failure with preserved ejection fraction (HFpEF) is a widespread syndrome limited therapeutic options and poorly understood immune pathophysiology. Using 2-hit preclinical model of cardiometabolic HFpEF that induces obesity hypertension, we found cardiac T cell infiltration lymphoid expansion occurred concomitantly pathology diastolic dysfunction, cardiomyocyte hypertrophy, phospholamban phosphorylation were dependent. Heart-infiltrating cells not restricted to antigens uniquely characterized by impaired activation the inositol-requiring enzyme 1α/X-box-binding protein 1 (IRE1α/XBP1) arm unfolded response. Notably, selective ablation XBP1 in enhanced their persistence heart organs mice HFpEF. Furthermore, IRE1α/XBP1 was restored after withdrawal 2 comorbidities inducing HFpEF, resulting partial improvement pathology. Our results demonstrated dysfunction hypertrophy dependent reversible dysregulation axis signature

Language: Английский

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