---
title: "HFpEF: Cardiac–Extracardiac Interactions and Impact of Novel Pharmacotherapies"
id: "pubmed-42764312"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42764312"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42764312/"
doi: "10.1007/s10741-026-10671-x"
published_at: "2026-09-21T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# HFpEF: Cardiac–Extracardiac Interactions and Impact of Novel Pharmacotherapies
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42764312
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42764312/)
- **DOI:** [10.1007/s10741-026-10671-x](https://doi.org/10.1007%2Fs10741-026-10671-x)
- **Published At:** 2026-09-21T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Heart failure with preserved ejection fraction (**HFpEF**) is described as a systemic disease driven by convergence of metabolic comorbidities—**obesity**, **type 2 diabetes (T2D)**, and **chronic kidney disease (CKD)**—that promote systemic inflammation, endothelial dysfunction, and myocardial fibrosis. - **Microvascular dysfunction** is an important mechanistic link between these comorbidities and organ abnormalities within and beyond the heart, although a definitive causal role in HFpEF remains incompletely established. - Impaired microvascular function in the pulmonary and peripheral circulations may contribute to reduced tissue perfusion, **exercise intolerance**, and **dyspnoea**, in addition to myocardial stiffness and diastolic dysfunction. - CKD can amplify HFpEF pathophysiology via volume and neurohormonal mechanisms and by circulating uraemic and inflammatory mediators that worsen endothelial function, supporting a **kidney–microvascular axis**. - Historically, effective therapies for HFpEF were limited; recent pharmacologic advances include **sodium–glucose cotransporter 2 inhibitors (SGLT2i)**, **glucagon‑like peptide‑1 receptor agonists (GLP‑1 RAs)** and **dual incretin (GLP‑1/GIP) therapies**, plus (non‑steroidal) **mineralocorticoid receptor antagonists**, which have reshaped the therapeutic landscape. - These agents have demonstrated improvements in cardiovascular and renal outcomes for patients with HFpEF and exert complementary actions on hemodynamic stress, metabolic dysregulation, inflammation, and fibrosis. - The reviewed therapies may also improve microvascular function across multiple vascular beds, potentially addressing both cardiac and extracardiac contributors to HFpEF. - The article provides an organ‑by‑organ synthesis of interactions among the heart, kidney, systemic microvasculature, pulmonary circulation, and skeletal muscle in cardio‑kidney metabolic syndrome (CKMS)–related HFpEF, and it maps clinical and mechanistic effects of therapies across these systems. - The authors note remaining mechanistic and clinical evidence gaps where further research is needed to clarify causal pathways and treatment mechanisms.
## Clinical Analysis & Structured Key Points
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Heart failure with a preserved ejection fraction: synergy between cardiac and extracardiac mechanisms and effects of novel therapies [Soufiane Nassiri](https://pubmed.ncbi.nlm.nih.gov/?term=Nassiri+S&cauthor_id=42764312)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#full-view-affiliation-1 "Departments of Cardiology, Diabetes Centre, Internal Medicine Amsterdam, Physiology, University Medical Centre, Amsterdam Cardiovascular Sciences, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#full-view-affiliation-2 "Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands."), [M Louis Handoko](https://pubmed.ncbi.nlm.nih.gov/?term=Handoko+ML&cauthor_id=42764312)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#full-view-affiliation-3 "Department of Cardiology, Transplantation Centre, University Medical Centre Utrecht, Utrecht, The Netherlands."), [Arno A van de Bovenkamp](https://pubmed.ncbi.nlm.nih.gov/?term=van+de+Bovenkamp+AA&cauthor_id=42764312)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#full-view-affiliation-1 "Departments of Cardiology, Diabetes Centre, Internal Medicine Amsterdam, Physiology, University Medical Centre, Amsterdam Cardiovascular Sciences, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#full-view-affiliation-2 "Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands."), [Vanessa P M van Empel](https://pubmed.ncbi.nlm.nih.gov/?term=van+Empel+VPM&cauthor_id=42764312)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#full-view-affiliation-4 "Department of Cardiology, Physiology, Cardiovascular Research Institute Maastricht \(CARIM\), Maastricht University, Maastricht, the Netherlands."), [Daniël H van Raalte](https://pubmed.ncbi.nlm.nih.gov/?term=van+Raalte+DH&cauthor_id=42764312)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#full-view-affiliation-1 "Departments of Cardiology, Diabetes Centre, Internal Medicine Amsterdam, Physiology, University Medical Centre, Amsterdam Cardiovascular Sciences, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#full-view-affiliation-2 "Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands."), [Etto C Eringa](https://pubmed.ncbi.nlm.nih.gov/?term=Eringa+EC&cauthor_id=42764312)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#full-view-affiliation-5 "Departments of Cardiology, Diabetes Centre, Internal Medicine Amsterdam, Physiology, University Medical Centre, Amsterdam Cardiovascular Sciences, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands. e.eringa@amsterdamumc.nl.")[ 6 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#full-view-affiliation-6 "Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands. e.eringa@amsterdamumc.nl.")[ 7 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#full-view-affiliation-7 "Department of Cardiology, Physiology, Cardiovascular Research Institute Maastricht \(CARIM\), Maastricht University, Maastricht, the Netherlands. e.eringa@amsterdamumc.nl.") Affiliations Expand ### Affiliations * 1 Departments of Cardiology, Diabetes Centre, Internal Medicine Amsterdam, Physiology, University Medical Centre, Amsterdam Cardiovascular Sciences, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands. * 2 Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands. * 3 Department of Cardiology, Transplantation Centre, University Medical Centre Utrecht, Utrecht, The Netherlands. * 4 Department of Cardiology, Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands. * 5 Departments of Cardiology, Diabetes Centre, Internal Medicine Amsterdam, Physiology, University Medical Centre, Amsterdam Cardiovascular Sciences, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands. e.eringa@amsterdamumc.nl. * 6 Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands. e.eringa@amsterdamumc.nl. * 7 Department of Cardiology, Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands. e.eringa@amsterdamumc.nl. * PMID: **42764312** * DOI: [ 10.1007/s10741-026-10671-x ](https://doi.org/10.1007/s10741-026-10671-x) Item in Clipboard Review # Heart failure with a preserved ejection fraction: synergy between cardiac and extracardiac mechanisms and effects of novel therapies Soufiane Nassiri et al. Heart Fail Rev. 2026. Show details Display options Display options Format Abstract PubMed PMID Heart Fail Rev Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Heart+Fail+Rev%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Heart+Fail+Rev%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42764312/) . 2026 Sep 21;31(1):108. doi: 10.1007/s10741-026-10671-x. ### Authors [Soufiane Nassiri](https://pubmed.ncbi.nlm.nih.gov/?term=Nassiri+S&cauthor_id=42764312)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#short-view-affiliation-1 "Departments of Cardiology, Diabetes Centre, Internal Medicine Amsterdam, Physiology, University Medical Centre, Amsterdam Cardiovascular Sciences, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#short-view-affiliation-2 "Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands."), [M Louis Handoko](https://pubmed.ncbi.nlm.nih.gov/?term=Handoko+ML&cauthor_id=42764312)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#short-view-affiliation-3 "Department of Cardiology, Transplantation Centre, University Medical Centre Utrecht, Utrecht, The Netherlands."), [Arno A van de Bovenkamp](https://pubmed.ncbi.nlm.nih.gov/?term=van+de+Bovenkamp+AA&cauthor_id=42764312)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#short-view-affiliation-1 "Departments of Cardiology, Diabetes Centre, Internal Medicine Amsterdam, Physiology, University Medical Centre, Amsterdam Cardiovascular Sciences, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#short-view-affiliation-2 "Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands."), [Vanessa P M van Empel](https://pubmed.ncbi.nlm.nih.gov/?term=van+Empel+VPM&cauthor_id=42764312)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#short-view-affiliation-4 "Department of Cardiology, Physiology, Cardiovascular Research Institute Maastricht \(CARIM\), Maastricht University, Maastricht, the Netherlands."), [Daniël H van Raalte](https://pubmed.ncbi.nlm.nih.gov/?term=van+Raalte+DH&cauthor_id=42764312)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#short-view-affiliation-1 "Departments of Cardiology, Diabetes Centre, Internal Medicine Amsterdam, Physiology, University Medical Centre, Amsterdam Cardiovascular Sciences, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#short-view-affiliation-2 "Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands."), [Etto C Eringa](https://pubmed.ncbi.nlm.nih.gov/?term=Eringa+EC&cauthor_id=42764312)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#short-view-affiliation-5 "Departments of Cardiology, Diabetes Centre, Internal Medicine Amsterdam, Physiology, University Medical Centre, Amsterdam Cardiovascular Sciences, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands. e.eringa@amsterdamumc.nl.")[ 6 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#short-view-affiliation-6 "Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands. e.eringa@amsterdamumc.nl.")[ 7 ](https://pubmed.ncbi.nlm.nih.gov/42764312/#short-view-affiliation-7 "Department of Cardiology, Physiology, Cardiovascular Research Institute Maastricht \(CARIM\), Maastricht University, Maastricht, the Netherlands. e.eringa@amsterdamumc.nl.") ### Affiliations * 1 Departments of Cardiology, Diabetes Centre, Internal Medicine Amsterdam, Physiology, University Medical Centre, Amsterdam Cardiovascular Sciences, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands. * 2 Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands. * 3 Department of Cardiology, Transplantation Centre, University Medical Centre Utrecht, Utrecht, The Netherlands. * 4 Department of Cardiology, Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands. * 5 Departments of Cardiology, Diabetes Centre, Internal Medicine Amsterdam, Physiology, University Medical Centre, Amsterdam Cardiovascular Sciences, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands. e.eringa@amsterdamumc.nl. * 6 Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands. e.eringa@amsterdamumc.nl. * 7 Department of Cardiology, Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands. e.eringa@amsterdamumc.nl. * PMID: **42764312** * DOI: [ 10.1007/s10741-026-10671-x ](https://doi.org/10.1007/s10741-026-10671-x) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID ## Abstract Heart failure with preserved ejection fraction (HFpEF) is a systemic disease in which metabolic comorbidities obesity, type 2 diabetes (T2D), and chronic kidney disease (CKD) converge to drive systemic inflammation, endothelial dysfunction, and myocardial fibrosis. Microvascular dysfunction represents an important link between these comorbidities and abnormalities within and beyond the heart, although its causal contribution to HFpEF remains incompletely established. In addition to promoting myocardial stiffness and diastolic dysfunction, impaired microvascular function across the pulmonary and peripheral circulations may contribute to reduced tissue perfusion, exercise intolerance, and dyspnoea. CKD may further aggravate this process through volume and neurohormonal pathways as well as circulating uraemic and inflammatory factors that impair endothelial function, through a kidney-microvascular axis. Despite its high prevalence and poor prognosis, therapeutic options for HFpEF have historically been limited. Recent advances, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 (GLP-1) receptor agonists and dual incretin therapies (GLP-1/GIP RAs), and (non-steroidal) mineralocorticoid receptor antagonists, have reshaped the therapeutic landscape by improving cardiovascular and renal outcomes in patients with HFpEF. These agents exert complementary effects on hemodynamic stress, metabolic dysregulation, inflammation, and fibrosis, and may also improve microvascular function across multiple vascular beds. In this narrative review, we provide an organ-by-organ synthesis of the pathophysiological interactions among the heart, kidney, systemic microvasculature, pulmonary circulation, and skeletal muscle in CKMS-related HFpEF. We further map the clinical and mechanistic effects of aforementioned therapies across these interconnected organ systems and highlight areas in which mechanistic and clinical evidence gaps remain. **Keywords:** Cardio-kidney metabolic syndrome; Chronic kidney disease; Glucagon-like peptide-1 receptor agonists; HFpEF; Microvascular dysfunction; Mineralocorticoid receptor antagonists; Obesity; Sodium-glucose cotransporter 2 inhibitors; Type 2 diabetes. © 2026. The Author(s). [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. ## References 1. 1. van Essen BJ, Emmens JE, Tromp J, Ouwerkerk W, Smit MD, Geluk CA et al (2025) Sex-specific risk factors for new-onset heart failure: the PREVEND study at 25 years. Eur Heart J 46(16):1528–1536 - [PubMed](https://pubmed.ncbi.nlm.nih.gov/39786471/) - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/12011521/) 2. 1. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M et al (2023) 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 44(37):3627–3639 - [PubMed](https://pubmed.ncbi.nlm.nih.gov/37622666/) 3. 1. Shah SJ, Kitzman DW, Borlaug BA, van Heerebeek L, Zile MR, Kass DA et al (2016) Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction: A Multiorgan Roadmap. Circulation 134(1):73–90 - [PubMed](https://pubmed.ncbi.nlm.nih.gov/27358439/) - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/4930115/) 4. 1. van Heerebeek L, Hamdani N, Falcão-Pires I, Leite-Moreira AF, Begieneman MP, Bronzwaer JG et al (2012) Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation 126(7):830–839 - [PubMed](https://pubmed.ncbi.nlm.nih.gov/22806632/) 5. 1. Guazzi M, Borlaug BA (2012) Pulmonary Hypertension Due to Left Heart Disease. Circulation 126(8):975–990 - [PubMed](https://pubmed.ncbi.nlm.nih.gov/22908015/) Show all 111 references ## Publication types * Review Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Review%22%5Bpt%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Review) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42764312/) ## MeSH terms * Diabetes Mellitus, Type 2 / complications Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.
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