Predictors and prognosis of right ventricular function in pulmonary hypertension due to heart failure with reduced ejection fraction

Abstract

Aims: Failure of right ventricular (RV) function worsens outcome in pulmonary hypertension (PH). The adaptation of RV contractility to afterload, the RV-pulmonary artery (PA) coupling, is defined by the ratio of RV end-systolic to PA elastances (Ees/Ea). Using pressure-volume loop (PV-L) technique we aimed to identify an Ees/Ea cut-off predictive for overall survival and to assess hemodynamic and morphologic conditions for adapted RV function in secondary PH due to heart failure with reduced ejection fraction (HFREF).

Methods and results: This post hoc analysis is based on 112 patients of the prospective Magdeburger Resynchronization Responder Trial. All patients underwent right and left heart echocardiography and a baseline PV-L and RV catheter measurement. A subgroup of patients (n = 50) without a pre-implanted cardiac device underwent magnetic resonance imaging at baseline. The analysis revealed that 0.68 is an optimal Ees/Ea cut-off (area under the curve: 0.697, P < 0.001) predictive for overall survival (median follow up = 4.7 years, Ees/Ea ≥ 0.68 vs. <0.68, log-rank 8.9, P = 0.003). In patients with PH (n = 76, 68%) multivariate Cox regression demonstrated the independent prognostic value of RV-Ees/Ea in PH patients (hazard ratio 0.2, P < 0.038). Patients without PH (n = 36, 32%) and those with PH but RV-Ees/Ea ≥ 0.68 showed comparable RV-Ees/Ea ratios (0.88 vs. 0.9, P = 0.39), RV size/function, and survival. In contrast, secondary PH with RV-PA coupling ratio Ees/Ea < 0.68 corresponded extremely close to cut-off values that define RV dilatation/remodelling (RV end-diastolic volume >160 mL, RV-mass/volume-ratio ≤0.37 g/mL) and dysfunction (right ventricular ejection fraction <38%, tricuspid annular plane systolic excursion <16 mm, fractional area change <42%, and stroke-volume/end-systolic volume ratio <0.59) and is associated with a dramatically increased short and medium-term all-cause mortality. Independent predictors of prognostically unfavourable RV-PA coupling (Ees/Ea < 0.68) in secondary PH were a pre-existent dilated RV [end-diastolic volume >171 mL, odds ratio (OR) 0.96, P = 0.021], high pulsatile load (PA compliance <2.3 mL/mmHg, OR 8.6, P = 0.003), and advanced systolic left heart failure (left ventricular ejection fraction <30%, OR 1.23, P = 0.028).

Conclusions: The RV-PA coupling ratio Ees/Ea predicts overall survival in PH due to HFREF and is mainly affected by pulsatile load, RV remodelling, and left ventricular dysfunction. Prognostically favourable coupling (RV-Ees/Ea ≥ 0.68) in PH was associated with preserved RV size/function and mid-term survival, comparable with HFREF without PH.

Keywords: Arterial elastance; End-systolic elastance; Pressure-volume loops; RVEF, TAPSE, FAC, PA compliance; Right ventricle-pulmonary arterial coupling.

Figure 1

Survival analysis. (A) Kaplan–Meier estimates of time to all‐cause death stratified by pulmonary hypertension (PH) vs. no‐PH in patients with heart failure with reduced ejection fraction (HFREF) [PH is defined by pulmonary artery (PA) mean ≥25 mmHg]. (B) Kaplan–Meier estimates of time to death stratified by HFREF patients without PH (no‐PH) and PH patients stratified by the pressure–volume (PV) loop‐derived Ees/Ea ratio (≥0.68 vs. <0.68). (C) Boxplot analysis of the PV loop‐derived Ees/Ea of HFREF patients without PH (No‐PH) and PH patients stratified according to the Ees/Ea ratio cut‐off of 0.68. PH: (PA mean ≥25 mmHg), No‐PH: HFREF patients with PA mean <25 mmHg. AUC, area under the curve; Ees, RV end‐systolic elastance; Eea, pulmonary arterial end‐systolic elastance.

Figure 2

Box plot analysis of haemodynamically and non‐invasively evaluated RV function and morphology according the stratified patient groups (no‐PH, PH and Ees/Ea ≥ vs. <0.68). (A) Pressure–volume (PV) loop‐derived intrinsic RV contractility Ees vs. afterload Ea: Showing an adaptive Ees increase to increased EA in PH‐Ees/Ea ≥ 0.68 with the resulting similar Ees/Ea values between no‐PH and PH with an Ees/Ea ratio ≥0.68. A significantly higher afterload of Ea in PH‐Ees/Ea < 0.68 compared to PH‐Ees/Ea ≥ 0.68 (P < 0.001) could be observed, accompanied by a non‐adaptive significantly lower Ees (P = 0.001). (B) MRI‐derived RV end‐systolic and ‐diastolic volumes, (C,D) RV mass/BSA and RV mass/volume ratio. (E,F) MRI‐derived RV‐ejection fraction (RV‐EF) in the subgroup of patients without an implanted device and TAPSE in all patients with heart failure with reduced ejection fraction (HFREF). (G,H) PV‐loop derived Tau and Eed. Eed, end‐diastolic elastance; Ees, right ventricular end‐systolic elastance; Ea, pulmonary arterial end‐systolic elastance; MRI, magnetic resonance imaging; PH, pulmonary hypertension (PA mean ≥25 mmHg); no‐PH, HFREF patients without PH; RVESV, right ventricular end‐systolic volume; RVEDV, right ventricular end‐diastolic volume; RV‐EF, RV ejection fraction; TAPSE, tricuspid annular plane systolic excursion; Tau, relaxation time constant.

Figure 3

Relationship of intrinsic RV contractility of Ees to afterload Ea in patients with PH. A: Stratified by the prognostically relevant cut‐off of 0.68 for pressure–volume (PV) loop‐derived Ees/Ea. The straight lines denote the regression lines for both differently coupled groups. Patients with a PH‐Ees/Ea ≥ 0.68 demonstrated the tighter correlation between Es and Ea and a steeper regression line than PH patients with an Ees/Ea < 0.68. (B) PA compliance is an independent predictor of prognostically relevant RV‐PA coupling dichotomized at an Ees/Ea of 0.68. The straight line denotes an Ees/Ea ratio of 0.68. The best cut‐off of PA compliance to discriminate an Ees/Ea of 0.68, determined by receiver operating characteristic (ROC) analysis, was 2.3 mL/mmHg. Patients with a PA compliance ≥2.3 mL/mmHg were marked by an asterisk (*). Hollow circles denote patients with PA compliance <2.3 mL/mmHg. Right: Box plot analysis of the median PA compliance in PH patients according to the Ees/Ea ratio ≥ vs. < 0.68. (C) RVEDV is an independent predictor of prognostically relevant RV‐PA coupling dichotomized at an Ees/Ea of 0.68. The straight line denotes an Ees/Ea ratio of 0.68. The best cut‐off of RVEDV to discriminate an Ees/Ea of 0.68, determined by ROC analysis, was 171 mL. Patients with a RVEDV <171 mL were marked with an asterisk (*) and are more concentrated left of the regression line of Ees/Ea = 0.68. Hollow circles denote patients with RVEDV ≥171 mL. Right: Box plot analysis of the median RVEDV in PH patients according the Ees/Ea ratio ≥ vs. < 0.68. (D) LV‐EF is an independent predictor of prognostically relevant RV‐PA coupling dichotomized at an Ees/Ea of 0.68. The straight line denotes an Ees/Ea ratio of 0.68. The best cut‐off of LV‐EF to discriminate an Ees/Ea of 0.68, determined by ROC analysis, was 30%. Patients with an EF ≥ 30% were marked with an asterisk (*) and are more concentrated left of the regression line of Ees/Ea = 0.68. Hollow circles denote patients with LV‐EF < 30%. Right: Box plot analysis of the median LV‐EF in PH patients according to the Ees/Ea ratio ≥0.68 vs. <0.68. Eea, pulmonary arterial end‐systolic elastance; Ees, RV end‐systolic elastance; LV, left ventricle; EF, ejection fraction; PH, pulmonary hypertension; PA, pulmonary artery; RV, right ventricle; RVEDV, RV end‐diastolic volume.

Figure 4

Linear regression analysis of the relationship between the pressure–volume (PV) loop‐derived Ees/Ea ratio and RV size/function, and the SV/ESV ratio as potential non‐invasive surrogates for haemodynamic coupling ratio Ees/Ea. The magnetic resonance imaging analysis within the subgroup of patients without an implanted device. Eea, pulmonary arterial end‐systolic elastance; Ees, RV end‐systolic elastance; RVEDV, RV end‐diastolic volume; RVESV, RV end‐systolic volume; RV‐EF, RV‐ejection fraction; SV, stroke volume.