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

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.