Prognostic importance of pathophysiologic markers in patients with heart failure and preserved ejection fraction

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome associated with multiple pathophysiologic abnormalities, including left ventricular (LV) diastolic dysfunction, longitudinal LV systolic dysfunction, abnormal ventricular-arterial coupling, pulmonary hypertension, and right ventricular (RV) remodeling/dysfunction. However, the relative prognostic significance of each of these pathophysiologic abnormalities in HFpEF is unknown.

Methods and results: We prospectively studied 419 patients with HFpEF using echocardiography and sphygmomanometry to assess HFpEF pathophysiologic markers. Cox proportional hazards analyses were used to determine the associations between pathophysiologic markers and outcomes. Mean age was 65±12 years; 62% were women; 39% were black; comorbidities were common; and study participants met published criteria for HFpEF. RV abnormalities were frequent: 28% had abnormal tricuspid annular plane systolic excursion, 15% had reduced RV fractional area change, and 34% had RV hypertrophy. During a median follow-up time of 18 months, 102 (24%) were hospitalized for HF and 175 (42%) experienced the composite end point of cardiovascular hospitalization or death. Decreased LV compliance, measured as reduced LV end-diastolic volume at an idealized LV end-diastolic pressure of 20 mm Hg (EDV20), and RV remodeling, as indicated by increased RV wall thickness, were the 2 pathophysiologic markers most predictive of worse outcomes: adjusted hazard ratio per 1 SD decrease in EDV20=1.39 (95% confidence interval [CI], 1.10-1.75; P=0.006), and hazard ratio per 1 SD increase in RV wall thickness=1.37 (95% CI, 1.16-1.61; P<0.001). These associations persisted after additional adjustment for markers of HF severity. By contrast, markers of LV relaxation, longitudinal LV systolic dysfunction, and ventricular-arterial coupling were not significantly associated with adverse outcomes.

Conclusions: In patients with HFpEF, reduced LV compliance and RV remodeling are the strongest pathophysiologic predictors of adverse outcomes.

Keywords: heart failure, diastolic; heart ventricles; ventricular dysfunction, right.

Figure 1

LV end-diastolic pressure–volume relationships stratified by the combined outcome of cardiovascular hospitalization or death. In the group of heart failure with preserved ejection fraction (HFpEF) patients who were not anemic (N=224, 53% of the cohort), lower EDV₂₀ was significantly associated with adverse events, as shown by the end-diastolic pressure–volume relationship (EDPVR) curves. The EDPVR curve was shifted up and to the left, reflecting a stiffer LV, in nonanemic patients who had an adverse event during follow-up. The association between LV stiffness (EDV₂₀) and outcomes was not present in HFpEF patients who were anemic at baseline (N=195, 47% of the cohort). CV indicates cardiovascular; and EDV₂₀, left ventricular (LV) end-diastolic volume at an idealized LV end-diastolic pressure of 20 mm Hg.

Figure 2

Bar graphs comparing RV structural and functional parameters by the presence or absence of the primary (CV hospitalization or death) and secondary outcomes (HF hospitalization). RV wall thickness (A), RV/LV maximal diameter ratio (B), TAPSE (C), RV end-diastolic area index (D), RV end-systolic area index (E), and RVFAC (F). CV indicates cardiovascular; FAC, fractional area change; HF, heart failure; hosp, hospitalization; LV, left ventricular; RV, right ventricular; and TAPSE, tricuspid annular plane systolic excursion.

Figure 3

Kaplan–Meier survival curves for cardiovascular hospitalization or death, stratified by the median values of EDV₂₀ and RV wall thickness. A, Patients with reduced LV compliance (ie, stiffer LV). B, Patients with increased RV wall thickness were more likely to have an adverse outcome (cardiovascular hospitalization or death) during follow-up. EDV₂₀ indicates left ventricular (LV) end-diastolic volume at an idealized LV end-diastolic pressure of 20 mm Hg; and RV, right ventricular.

Figure 4

Kaplan–Meier survival curves for cardiovascular hospitalization or death according to the presence or absence of reduced LV compliance and increased RV wall thickness. Patients with both reduced LV compliance and increased LV wall thickness had worse outcomes, indicating an additive effect of both abnormalities on prognosis. EDV₂₀ indicates left ventricular (LV) end-diastolic volume at an idealized LV end-diastolic pressure of 20 mm Hg; and RV, right ventricular.

Figure 5

Kaplan–Meier survival curves for heart failure hospitalization according to the presence or absence of RV dysfunction and increased RVWT. A, Heart failure hospitalization stratified by median TAPSE showing that patients with heart failure with preserved ejection fraction with lower TAPSE were more likely to be hospitalized for heart failure. B, Patients with low TAPSE and increased RVWT were most likely to be hospitalized for heart failure, showing the additive effect of both RV hypertrophy and dysfunction. RVWT indicates right ventricular wall thickness; and TAPSE, tricuspid annular plane systolic excursion. High/low TAPSE defined by median value (1.95 cm); and high/low RVWT defined by median value (4.8 mm).