Ventricular stiffening and chamber contracture in heart failure with higher ejection fraction

Abstract

Aims: Ancillary analyses from clinical trials have suggested reduced efficacy for neurohormonal antagonists among patients with heart failure and preserved ejection fraction (HFpEF) and higher ranges of ejection fraction (EF).

Methods and results: A total of 621 patients with HFpEF were grouped into those with low-normal left ventricular EF (LVEF) (HFpEF_<65% , n = 319, 50% ≤ LVEF <65%) or HFpEF_≥65% (n = 302, LVEF ≥65%), and compared with 149 age-matched controls undergoing comprehensive echocardiography and invasive cardiopulmonary exercise testing. A sensitivity analysis was performed in a second non-invasive community-based cohort of patients with HFpEF (n = 244) and healthy controls without cardiovascular disease (n = 617). Patients with HFpEF_≥65% had smaller left ventricular (LV) end-diastolic volume than HFpEF_<65% , but LV systolic function assessed by preload recruitable stroke work and stroke work/end-diastolic volume was similarly impaired. Patients with HFpEF_≥65% displayed an end-diastolic pressure-volume relationship (EDPVR) that was shifted leftward, with increased LV diastolic stiffness constant β, in both invasive and community-based cohorts. Cardiac filling pressures and pulmonary artery pressures at rest and during exercise were similarly abnormal in all EF subgroups. While patients HFpEF_≥57% displayed leftward shifted EDPVR, those with HFpEF_<57% had a rightward shifted EDPVR more typical of heart failure with reduced EF.

Conclusion: Most pathophysiologic differences in patients with HFpEF and higher EF are related to smaller heart size, increased LV diastolic stiffness, and leftward shift in the EDPVR. These findings may help to explain the absence of efficacy for neurohormonal antagonists in this group and raise a new hypothesis, that interventions to stimulate eccentric LV remodelling and enhance diastolic capacitance may be beneficial for patients with HFpEF and EF in the higher range.

Keywords: Cardiac remodelling; Haemodynamics; Heart failure; Heart failure with preserved ejection fraction; Ventricular function.

Figure 1:

Mean end diastolic pressure volume relationships (EDPVR) for patients with HFsnEF (blue triangles), HFlnEF (red circles), and controls (black squares). The dashed lines denote mean resting left ventricular filling pressures measured at cardiac catheterization in the two HFpEF groups (upper horizontal line, 17 mmHg) and in the control patients (bottom horizontal line, 9 mmHg). LVEDV, left ventricular end diastolic volume; LVEDP, left ventricular end diastolic pressure.

Figure 2:

Mean end diastolic pressure volume relationships (EDPVR) for patients with for patients with HFpEF separated into those with lower EF (≤57%, red circles), middle EF (58–69%, blue triangles), and the highest EF (≥70%, pink triangles) as compared to controls (black squares). Abbreviations as in Figure 1.

Figure 3:

Left ventricular structure and function in the community-based cohort. Patients with HFpEF_≥65% displayed lower left ventricular (LV) end diastolic volume index (LVEDVI) compared with HFpEF_<65% and healthy controls. Estimated LV volume indexed to body surface area at an EDP of 15 mmHg (V₁₅ index) was lower in HFpEF_<65% than controls, and lower in HFpEF_≥65% than both HFpEF_<65% and controls. LV end systolic elastance (Ees) increased from controls to HFpEF_≥65% and HFpEF_≥65%, but LV myocardial contractility assessed by stress-corrected midwall fractional shortening (Sc-MFS) was lower in both HFpEF groups than controls.