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

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.