Pressure-volume loop derived left ventricular hypercontractility is associated with reduced long-term survival in heart failure with preserved ejection fraction

AIMS: Supported by the observation of different responses to pharmacotherapy patients with highest left ventricular (LV) ejection fraction (EF) in heart failure with preserved EF (HFpEF), two different hemodynamic phenotypes have been identified in pressure-volume loop (PVL) analysis. Patients with low-normal EF performing a rightward shift in response to exercise and patients with high-normal EF characterized by LV hypercontractility and severe diastolic stiffness to answer exercise-induced afterload excess. This study aimed to investigate whether LV hypercontractility is associated with long-term survival in HFpEF patients.

METHODS: HFpEF patients underwent cardiac magnetic resonance imaging (CMR) prior to invasive evaluation. PVL analysis was performed at rest and preload reduction via transient occlusion of the inferior caval vein. Characterizing load-independent systolic LV function, LV contractility was derived as end-systolic elastance (Ees). Diastolic LV function was assessed as the end-diastolic pressure to indexed end-diastolic volume ratio (EDP/EDVi) and load-independently as the β constant of the end-diastolic PV relation. While hypercontractile HFpEF was defined as the highest tertile of Ees, the lowest and middle tertile were considered normocontractile HFpEF (Figure 1 A+B). The association to long-term survival was analyzed using log-rank test.

RESULTS: A total of 58 HFpEF patients were included, with a median follow-up time of 1766 days (IQR 1253–3285). Baseline characteristics (age, sex, medical history, and NYHA class) did not differ between both HFpEF groups. In PVL analysis, hypercontractile HFpEF patients showed smaller EDVi (p=0.03) and end-systolic volumes (p=0.02) with higher EF (p=0.04). While EDP did not differ between cohorts (p=0.24) end-systolic pressure (ESP) was significantly higher in hypercontractile HFpEF (161 mmHg [IQR 145–178] vs. 146 mmHg [IQR 123–160], p=0.02). As expected, Ees was elevated in hypercontractile patients (2.71 mmHg/ml [IQR 2.12–3.51] vs. 1.51 mmHg/ml [IQR 1.20–1.74], p<0.01), with a concomitant increase in LV afterload (arterial elastance, Ea: 2.01 mmHg/ml [IQR 1.71–2.54] vs. 1.72 mmHg/ml [IQR 1.47–1.90], p=0.01). Consequently, the coupling ratio (Ees/Ea) was balanced in normocontractile HFpEF but favored LV systolic function in hypercontractile HFpEF (0.83 [IQR 0.72–1.02] vs. 1.42 [IQR 1.12–1.70], p<0.01).
Interestingly, hypercontractile HFpEF patients also had higher diastolic stiffness with higher EDP/EDVi ratio (0.30 [IQR 0.23–0.32] vs. 0.23 [0.18–0.30], p=0.03) and elevated β constant (0.04 [IQR 0.03–0.05] vs. 0.02 [IQR 0.01–0.03], p<0.01).
Although no significant association was found between coupling ratio and survival (log-rank p=0.29), hypercontractility was significantly associated with reduced long-term survival (p=0.01), Figure 1C.

CONCLUSION: This is the first study to demonstrate reduced long-term survival in hypercontractile HFpEF patients assessed by state-of-the-art PVL analysis. Elevation of the coupling ratio without association to survival characterized a pseudobalanced state maintaining cardiac output at the cost of hypercontractility. Hypercontractile HFpEF is characterized by smaller LVs and might cause incomplete relaxation with worsening LV diastolic function. Given the lack of benefit of current HFpEF therapies in patients with the highest EF, these findings highlight the unmet need for treatments targeting afterload and hypercontractility in HFpEF.