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

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

Jerremy Weerts  1 , Blanche L M Schroen  2 , Arantxa Barandiarán Aizpurua  2 , Tos T J M Berendschot  3 , Lloyd Brandts  4 , Carroll A B Webers  3 , Sami O Simons  5 , Steven J R Meex  6 , Ronald Henry  7 , Carla J H van der Kallen  7 , Hans-Peter Brunner-La Rocca  2 , Christian Knackstedt  2 , Stephane R B Heymans  2 , Rudolf A de Boer  8 , Vanessa P M van Empel #  2 , Alfons J H M Houben #  7
Affiliations

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

Jerremy Weerts et al. Cardiovasc Diabetol. .

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 (pint=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 (pint=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 (pint=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.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: All subjects provided written informed consent. The study was conducted following the Declaration of Helsinki and approved by an independent ethics committee (academic hospital Maastricht/Maastricht University: METC19-005). It was also pre-registered at the Netherlands Trial Register (NTR NL7655). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

None
Figure created in BioRender (i88u523).
Fig. 1
Fig. 1
Microvascular retinal differences between patients with HFpEF and control individuals. Panel A shows the retinal dilation in response to flicker-light by arterioles and venules. Values for controls are based on the intercept for each respective linear regression model. Values for HFpEF patients represent the mean difference compared to control individuals. Each blunt head represents the standard error of measurement. Conclusions are made based on the corrected results of model 4 (adjustment for age, sex, systolic blood pressure, body mass index, diabetes mellitus status, haemoglobin, and smoking status) and are displayed here as Corrected. Differences in arteriolar and venular retinal diameters (CRAE and CRVE, respectively) are shown in panel B. Sex-specific CRVE differences are shown in panel C.
Fig. 2
Fig. 2
Microvascular skin and renal differences between patients with HFpEF and control individuals. Results are displayed as in Fig. 2, and interpretation should focus on differences from confounder-corrected analyses. Panel A shows the endothelial power based on flowmotion signals without adjustment and with full adjustment (Corrected). Because of an interaction with diabetes mellitus, panel B shows endothelial power differences between patients with HFpEF and control individuals stratified for diabetes mellitus status. Group differences in respiratory power based on flowmotion signals are depicted in panel C. Panel D displays the differences in heat-induced skin hyperemia in patients with HFpEF and control individuals. Panel E shows the difference in UACR between groups without adjustment and with full adjustments (Corrected). Panel F shows the fully adjusted UACR group differences stratified by sex
See this image and copyright information in PMC

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