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From Systemic Inflammation to Myocardial Fibrosis: The Heart Failure With Preserved Ejection Fraction Paradigm
Walter J Paulus1, Michael R Zile2
1Amsterdam University Medical Centers, The Netherlands (W.J.P.).
Circulation Research
|May 13, 2021
Summary
Comorbidities, particularly metabolic ones, drive heart failure with preserved ejection fraction (HFpEF) via inflammation and fibrosis. New evidence supports this, revealing cellular mechanisms and patient subgroups, guiding future HFpEF treatments.
Area of Science:
- Cardiology
- Immunology
- Pathophysiology
Background:
- Comorbidities, especially metabolic ones, are linked to heart failure with preserved ejection fraction (HFpEF) development and severity.
- The comorbidity-inflammation paradigm suggests systemic inflammation and myocardial fibrosis are key drivers.
- Emerging evidence strengthens the inflammatory/profibrotic role in HFpEF.
Purpose of the Study:
- To present novel experimental and clinical evidence supporting the inflammatory/profibrotic paradigm in HFpEF.
- To elucidate the mechanisms linking comorbidities to myocardial changes in HFpEF.
- To identify potential therapeutic targets for HFpEF.
Main Methods:
- Analysis of myocardial infiltration by immunocompetent cells in obesity and hypertension.
- Investigation of inducible nitric oxide synthase expression in cardiomyocytes.
- Application of machine learning to define HFpEF phenogroups.
- Mediation analysis of comorbidities, inflammatory biomarkers, and myocardial structure/function.
Main Results:
- Obesity and hypertension induce myocardial infiltration and inflammation.
- Proinflammatory cytokines lead to inducible nitric oxide synthase expression and protein accumulation.
- Machine learning identified distinct inflammatory/profibrotic HFpEF phenogroups.
- Early preclinical HFpEF shows links between comorbidities, inflammation, and endothelial adhesion molecules.
Conclusions:
- The inflammatory/profibrotic paradigm is strongly supported by new evidence in HFpEF.
- Understanding these mechanisms opens avenues for novel HFpEF treatments.
- Future therapies may target inflammatory cytokines, protein ubiquitylation, titin stiffness, and fibrosis.
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