Characterizing heart failure with preserved and reduced ejection fraction: An imaging and plasma biomarker approach

Abstract

Introduction: The pathophysiology of heart failure with preserved ejection fraction (HFpEF) remains incompletely defined. We aimed to characterize HFpEF compared to heart failure with reduced ejection fraction (HFrEF) and asymptomatic hypertensive or non-hypertensive controls.

Materials and methods: Prospective, observational study of 234 subjects (HFpEF n = 140; HFrEF n = 46, controls n = 48, age 73±8, males 49%) who underwent echocardiography, cardiovascular magnetic resonance imaging (CMR), plasma biomarker analysis (panel of 22) and 6-minute walk testing (6MWT). The primary end-point was the composite of all-cause mortality and/or HF hospitalization.

Results: Compared to controls both HF groups had lower exercise capacity, lower left ventricular (LV) EF, higher LV filling pressures (E/E', B-type natriuretic peptide [BNP], left atrial [LA] volumes), more right ventricular (RV) systolic dysfunction, more focal and diffuse fibrosis and higher levels of all plasma markers. LV remodeling (mass/volume) was different between HFpEF (concentric, 0.68±0.16) and HFrEF (eccentric, 0.47±0.15); p<0.0001. Compared to controls, HFpEF was characterized by (mild) reductions in LVEF, more myocardial fibrosis, LA remodeling/dysfunction and RV dysfunction. HFrEF patients had lower LVEF, increased LV volumes, greater burden of focal and diffuse fibrosis, more RV remodeling, lower LAEF and higher LA volumes compared to HFpEF. Inflammatory/fibrotic/renal dysfunction plasma markers were similarly elevated in both HF groups but markers of cardiomyocyte stretch/damage (BNP, pro-BNP, N-terminal pro-atrial natriuretic peptide and troponin-I) were higher in HFrEF compared to HFpEF; p<0.0001. Focal fibrosis was associated with galectin3, GDF-15, MMP-3, MMP-7, MMP-8, BNP, pro-BNP and NTproANP; p<0.05. Diffuse fibrosis was associated with GDF-15, Tenascin-C, MMP-2, MMP-3, MMP-7, BNP, proBNP and NTproANP; p<0.05. Composite event rates (median 1446 days follow-up) did not differ between HFpEF and HFrEF (Log-Rank p = 0.784).

Conclusions: HFpEF is a distinct pathophysiological entity compared to age- and sex-matched HFrEF and controls. HFpEF and HFrEF are associated with similar adverse outcomes. Inflammation is common in both HF phenotypes but cardiomyocyte stretch/stress is greater in HFrEF.

Fig 1. Study overview.

Consort diagram illustrating recruitment and reasons for exclusion. CMR = cardiovascular magnetic resonance imaging; HCM = hypertrophic cardiomyopathy; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; ILR = implantable loop recorder; PAF = paroxysmal atrial fibrillation; TTE = transthoracic echocardiography.

Fig 2. Summary of directional change of CMR and plasma biomarkers profiles compared to controls.

CMR images at the top of the illustration. Panel A: mid-ventricular end-diastolic cines showing concentric remodeling in HFpEF and eccentric remodeling in HFrEF; Panel B: Late gadolinium enhancement images showing (white arrows) small, sub-endocardial ischemic fibrosis in HFpEF and more extensive ischemic fibrosis involving multiple segments in HFrEF; Panel C: Late gadolinium enhancement images showing (white arrows) non-ischemic fibrosis in HFpEF and HFrEF; Panel D: Post-contrast mid-ventricular extra-cellular volume colour maps showing increased diffuse fibrosis in both HFpEF and HFrEF.

Fig 3. Plasma biomarkers that were different between HFpEF and HFrEF: Natriuretic peptides.

BNP = B-type natriuretic peptide; Pro-BNP = pro-B-type natriuretic peptide; NTpro-ANP = N-terminal pro-atrial natriuretic peptide; p<0.05 for all.