Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF

Abstract

Aims: To date, clinical evidence of microvascular dysfunction in patients with heart failure (HF) with preserved ejection fraction (HFpEF) has been limited. We aimed to investigate the prevalence of coronary microvascular dysfunction (CMD) and its association with systemic endothelial dysfunction, HF severity, and myocardial dysfunction in a well defined, multi-centre HFpEF population.

Methods and results: This prospective multinational multi-centre observational study enrolled patients fulfilling strict criteria for HFpEF according to current guidelines. Those with known unrevascularized macrovascular coronary artery disease (CAD) were excluded. Coronary flow reserve (CFR) was measured with adenosine stress transthoracic Doppler echocardiography. Systemic endothelial function [reactive hyperaemia index (RHI)] was measured by peripheral arterial tonometry. Among 202 patients with HFpEF, 151 [75% (95% confidence interval 69-81%)] had CMD (defined as CFR <2.5). Patients with CMD had a higher prevalence of current or prior smoking (70% vs. 43%; P = 0.0006) and atrial fibrillation (58% vs. 25%; P = 0.004) compared with those without CMD. Worse CFR was associated with higher urinary albumin-to-creatinine ratio (UACR) and NTproBNP, and lower RHI, tricuspid annular plane systolic excursion, and right ventricular (RV) free wall strain after adjustment for age, sex, body mass index, atrial fibrillation, diabetes, revascularized CAD, smoking, left ventricular mass, and study site (P < 0.05 for all associations).

Conclusions: PROMIS-HFpEF is the first prospective multi-centre, multinational study to demonstrate a high prevalence of CMD in HFpEF in the absence of unrevascularized macrovascular CAD, and to show its association with systemic endothelial dysfunction (RHI, UACR) as well as markers of HF severity (NTproBNP and RV dysfunction). Microvascular dysfunction may be a promising therapeutic target in HFpEF.

Figure 1

Patient flow diagram.

Figure 2

Box-and-whisker plots showing coronary flow reserve stratified by presence or absence of atrial fibrillation (left panel) and current or prior smoking (right panel). AF, atrial fibrillation.

Figure 3

Correlations between coronary flow reserve and biomarkers, systemic endothelial function, and echocardiographic parameters. CFR, coronary flow reserve; GLS, left ventricular global longitudinal strain; LA, left atrial; NTproBNP, N-terminal pro-B-type natriuretic peptide; RHI, reactive hyperaemia index, a marker of systemic endothelial function; TAPSE, tricuspid annular plane systolic excursion; UACR, urinary albumin-to-creatinine ratio.

Figure 4

Examples of coronary Doppler tracings at rest and with adenosine, tricuspid annular plane systolic excursion, and right ventricular free wall strain curves in a study patient without coronary microvascular dysfunction (left panel) vs. a study patient with coronary microvascular dysfunction (right panel). The patient without coronary microvascular dysfunction had a normal coronary flow reserve (2.88), whereas the patient with coronary microvascular dysfunction had a reduced coronary flow reserve (1.63). The lower coronary flow reserve in the patient with coronary microvascular dysfunction was associated with lower tricuspid annular plane systolic excursion and worse right ventricular free wall strain (as shown in the figure), as well as lower reactive hyperaemia index (1.65 vs. 2.05), worse left ventricular global longitudinal strain (7.8% vs. 13.2%), and worse left atrial reservoir strain (6.7% vs. 15.8%). CFR, coronary flow reserve; CMD, coronary microvascular dysfunction; LV, left ventricular; RHI, reactive hyperaemia index; RV, right ventricular; RVFW, right ventricular free wall; TAPSE, tricuspid annular plane systolic excursion.

Take home figure

Heart failure with preserved ejection fraction—systemic endothelial dysfunction, coronary microvascular dysfunction, and longitudinal myocardial dysfunction. Heart failure with preserved ejection fraction is associated with a high prevalence of longitudinal fibre (subendocardial) myocardial dysfunction, coronary microvascular dysfunction, and systemic endothelial dysfunction.