Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction

Abstract

Background: Characterization of myocardial structural changes in heart failure with preserved ejection fraction (HFpEF) has been hindered by the limited availability of human cardiac tissue. Cardiac hypertrophy, coronary artery disease (CAD), coronary microvascular rarefaction, and myocardial fibrosis may contribute to HFpEF pathophysiology.

Methods and results: We identified HFpEF patients (n=124) and age-appropriate control subjects (noncardiac death, no heart failure diagnosis; n=104) who underwent autopsy. Heart weight and CAD severity were obtained from the autopsy reports. With the use of whole-field digital microscopy and automated analysis algorithms in full-thickness left ventricular sections, microvascular density (MVD), myocardial fibrosis, and their relationship were quantified. Subjects with HFpEF had heavier hearts (median, 538 g; 169% of age-, sex-, and body size-expected heart weight versus 335 g; 112% in controls), more severe CAD (65% with ≥1 vessel with >50% diameter stenosis in HFpEF versus 13% in controls), more left ventricular fibrosis (median % area fibrosis, 9.6 versus 7.1) and lower MVD (median 961 versus 1316 vessels/mm(2)) than control (P<0.0001 for all). Myocardial fibrosis increased with decreasing MVD in controls (r=-0.28, P=0.004) and HFpEF (r=-0.26, P=0.004). Adjusting for MVD attenuated the group differences in fibrosis. Heart weight, fibrosis, and MVD were similar in HFpEF patients with CAD versus without CAD.

Conclusions: In this study, patients with HFpEF had more cardiac hypertrophy, epicardial CAD, coronary microvascular rarefaction, and myocardial fibrosis than controls. Each of these findings may contribute to the left ventricular diastolic dysfunction and cardiac reserve function impairment characteristic of HFpEF.

Keywords: autopsy; endothelium; fibrosis; heart failure, diastolic; hypertrophy; microvessels; pathology.

Figure 1

Cardiac hypertrophy and CAD in HFpEF and control. Frequency distributions indicate higher absolute heart weight (A) and percent expected (for age, sex and body size) heart weight (B), higher coronary artery disease (CAD) score (C) and more frequent multi-vessel coronary disease (D) in HFpEF than control.

Figure 2

Coronary microvascular density (MVD) in HFpEF and control. The frequency distribution for total MVD (A) is shifted downward in HFpEF. Tukey box plots (box: median, 75^th, and 25^th percentiles; whiskers: highest value within 75^th percentile plus 1.5*IQR and lowest value within the 25^th percentile minus 1.5*IQR, symbols show outliers if present) of regional MVD (B) demonstrate similar reduction in MVD across the sub-epicardial (Epi), mid-myocardial (Midwall), sub-endocardial (Endo) and papillary muscle (Pap) in HFpEF. Representative examples of anti-CD 31 stained left ventricular sections with algorithm-defined capillaries (yellow), pre-capillary arterioles (orange) and larger intra-myocardial arteries (red) illustrate the lower MVD in HFpEF (C) as compared to control (D) subjects.

Figure 3

Cardiac fibrosis in HFpEF and control. The frequency distribution for percent area fibrosis (A) is shifted upward in HFpEF. In B, log-transformed percent area fibrosis increases similarly with decreasing MVD in HFpEF and controls but remains higher in HFpEF than control at any level of MVD. In C–F, representative examples of SAB stained left ventricular sections with algorithm-defined fibrosis (red), myocardium (yellow) and space (white) from HFpEF patients with 3% (C), 7% (D), 10% (E) and 21 % (F) fibrosis.

Figure 4

Coronary microvascular density (MVD) and fibrosis in HFpEF and HFrEF. Microvascular Density (MVD, A) and percent fibrosis (B) are compared among controls (n=104), HFpEF (n=124) and HFrEF (n=27) patients. Data are displayed as Tukey box plots. In C, log-transformed % fibrosis increases with decreasing MVD but remains higher in HFrEF than control. In HF patients, adjusting for MVD, fibrosis is similar in HFpEF and HFpEF.