Microvascular dysfunction across organs in heart failure with preserved ejection fraction: the PROSE-HFpEF case-control study

Jerremy Weerts; Blanche L M Schroen; Arantxa Barandiarán Aizpurua; Tos T J M Berendschot; Lloyd Brandts; Carroll A B Webers; Sami O Simons; Steven J R Meex; Ronald Henry; Carla J H van der Kallen; Hans-Peter Brunner-La Rocca; Christian Knackstedt; Stephane R B Heymans; Rudolf A de Boer; Vanessa P M van Empel; Alfons J H M Houben

doi:10.1186/s12933-025-02850-1

Microvascular dysfunction across organs in heart failure with preserved ejection fraction: the PROSE-HFpEF case-control study

Cardiovasc Diabetol. 2025 Jul 30;24(1):310. doi: 10.1186/s12933-025-02850-1.

Authors

Jerremy Weerts¹, Blanche L M Schroen², Arantxa Barandiarán Aizpurua², Tos T J M Berendschot³, Lloyd Brandts⁴, Carroll A B Webers³, Sami O Simons⁵, Steven J R Meex⁶, Ronald Henry⁷, Carla J H van der Kallen⁷, Hans-Peter Brunner-La Rocca², Christian Knackstedt², Stephane R B Heymans², Rudolf A de Boer⁸, Vanessa P M van Empel^#², Alfons J H M Houben^#⁷

Affiliations

¹ Department of Cardiology, CARIM Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre (MUMC+), PO Box 616, 6200 MD, Maastricht, The Netherlands. jerremy.weerts@mumc.nl.
² Department of Cardiology, CARIM Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre (MUMC+), PO Box 616, 6200 MD, Maastricht, The Netherlands.
³ University Eye Clinic Maastricht, Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands.
⁴ Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands.
⁵ Department of Respiratory Medicine, NUTRIM Research Institute of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands.
⁶ Department of Clinical Chemistry, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands.
⁷ Department of Internal Medicine, CARIM Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands.
⁸ Department of Cardiology, Thorax Center, Cardiovascular Institute, Erasmus MC, Rotterdam, the Netherlands.

^# Contributed equally.

Abstract

Background: Systemic microvascular dysfunction is proposed as a key pathophysiological process in heart failure with preserved ejection fraction (HFpEF). This study compared microvasculature across vascular beds in HFpEF patients and controls.

Methods: This prospective, case-control study included subjects ≥ 60years. HFpEF patients were diagnosed in an expert centre. Controls without HF were selected from the Maastricht Study, a population cohort enriched with diabetes mellitus. Microvascular assessments included central retinal venular/arteriolar calibres (CRVE/CRAE), flicker-light-induced retinal dilation, skin microvascular flowmotion and heat-induced hyperemia, and urinary albumin-to-creatinine ratio (UACR). Group differences were evaluated with confounder-adjustments (age, sex, blood pressure, body mass index, diabetes, haemoglobin, smoking). Interactions with sex and diabetes mellitus were tested, and stratified analyses were performed when significant interactions were present.

Results: Microvascular assessments were performed in 138 HFpEF patients and 2140 controls. Microvascular differences were present between groups in all vascular beds. However, confounder-adjusted analyses attenuated differences. Confounder-adjusted analyses indicated that HFpEF patients versus controls still had retinal differences: narrower CRVE (- 8.1 μm, p = 0.008) and narrower CRAE trend (- 3.5 μm, p = 0.073), but similar flicker-light-induced retinal venular/arteriolar dilation (- 0.23%, p = 0.392; - 0.18%, p = 0.593, respectively). Confounder-adjusted analyses showed similar skin flowmotion measures (i.e. endothelial power - 0.09log(PU²), p = 0.181), and heat-induced hyperemia (0.02log(%), p = 0.605) between groups. UACR remained higher in HFpEF after confounder adjustments (0.56log(g/mol), p = < 0.001). Interaction analyses revealed that female patients had narrower CRVE versus controls (p_int=0.023; females - 13.8 μm, p < 0.001; males 1.2 μm, p = 0.812). Patients had lower skin endothelial flowmotion power only when diabetes was co-occurring (p_int=0.048; - 0.36 log(PU² ), p = 0.014). UACR was higher in male and female patients versus controls, but was more pronounced in males (p_int=0.002).

Conclusions: HFpEF patients showed microvascular differences versus controls across all vascular beds studied. However, confounder-adjusted differences remained significant in eyes and kidneys. The findings across multiple organs support that MVD is likely a more systemic process than only local MVD in HFpEF, and possible sex-specific underlying pathophysiology.

Registration: URL: https://onderzoekmetmensen.nl ; Unique identifier: NL7655.

Keywords: Diastolic heart failure; HFpEF; Heart failure with preserved ejection fraction; Microcirculation; Microvascular dysfunction; Pathophysiology; Sex differences.

MeSH terms

Aged
Aged, 80 and over
Albuminuria / physiopathology
Case-Control Studies
Female
Heart Failure* / diagnosis
Heart Failure* / physiopathology
Humans
Male
Microcirculation*
Microvessels* / physiopathology
Middle Aged
Netherlands / epidemiology
Prospective Studies
Retinal Vessels* / physiopathology
Risk Factors
Skin* / blood supply
Stroke Volume*
Vasodilation
Ventricular Function, Left*

Grants and funding

CVON2017-21-SHE PREDICTS HF/Hartstichting