Prognostic Importance of Impaired Systolic Function in Heart Failure With Preserved Ejection Fraction and the Impact of Spironolactone

Abstract

Background: Impairment in left ventricular systolic function has been described in heart failure (HF) with preserved ejection fraction (HFpEF), but its prognostic relevance is not known. We determined whether left ventricular longitudinal strain (LS) is predictive of cardiovascular outcomes in HFpEF beyond clinical and conventional echocardiographic measures.

Methods and results: LS was assessed by 2-dimensional speckle-tracking echocardiography at baseline in 447 patients with HFpEF enrolled in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. At a median follow-up of 2.6 years (interquartile range, 1.5-3.9 years), 115 patients experienced the primary composite outcome of cardiovascular death, HF hospitalization, or aborted cardiac arrest. Impaired LS, defined as an absolute LS <15.8%, was present in 52% of patients and was predictive of the composite outcome (adjusted hazard ratio, 2.14; 95% confidence interval, 1.26-3.66; P=0.005), cardiovascular death alone (adjusted hazard ratio, 3.20; 95% confidence interval, 1.44-7.12; P=0.004), and HF hospitalization alone (adjusted hazard ratio, 2.23; 95% confidence interval, 1.16-4.28; P=0.016) after adjustment for clinical and conventional echocardiographic variables. LS was the strongest echocardiographic predictor of the composite outcome. Exploratory analysis in a subset of 131 patients with follow-up LS assessed after 12 to 18 months demonstrated a trend toward improvement in LS associated with spironolactone in patients enrolled in the Americas but not in Russia or Georgia.

Conclusions: Impaired left ventricular systolic function is a powerful predictor of HF hospitalization, cardiovascular death, or aborted cardiac arrest in HFpEF independent of clinical predictors. Impaired LS represents a novel imaging biomarker to identify patients with HFpEF at particularly high risk for cardiovascular morbidity and mortality.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

Keywords: clinical trial; heart failure; heart ventricles; preserved left ventricular function; spironolactone; strain.

Figure 1

Consort diagram of the study population. *Unacceptable image quality was defined as missing view, lack of a full cardiac cycle, more than 2 segment dropout, or significant foreshortening of the left ventricle.

Figure 2

Distribution of LV LS in the TOPCAT Echo study.

Figure 3

Comparison of LS (panel A), e’ (panel B), E/e’ (panel C), and LV mass index (panel D) between elderly TOPCAT patients with HFpEF (aged 65–91) and age-, gender-, and race-matched community dwelling persons without HF from the ARIC study.

Figure 4

(A) Restricted cubic spline analysis demonstrating the unadjusted hazard ratio (black line) and 95% confidence limits (grey lines) for the primary composite endpoint of HF hospitalization, aborted cardiac arrest, or CV death (n=447; reference value: −20%). (B) Forest plot demonstrating the hazard ratio for the primary outcome, per standard deviation change in echocardiographic risk factors in HFpEF in multivariable adjusted models in the TOPCAT echocardiography study. Caption: For panel A, hazard ratios (HR) are per 1% absolute increase in LS. Histograms demonstrate the distribution of LS in the study population. Fully adjusted analysis (Model 2) is adjusted for age, gender, race, randomization strata (prior HF hospitalization or biomarker criteria), region of enrollment (Americas versus Russia or Georgia), randomized treatment assignment, core lab LVEF, history of atrial fibrillation, heart rate, New York Heart Association class, history of stroke, creatinine, hematocrit, LV mass, LVESVi, and E/E’ ratio. Values presented are a linear approximation. For panel B, risk associated with negative LVEF and e’ are shown. Covariates in multivariable model are the same as in panel (A) with the exception of LV mass, LVESVi, and E/E’ ratio. See text for further details.

Figure 4

(A) Restricted cubic spline analysis demonstrating the unadjusted hazard ratio (black line) and 95% confidence limits (grey lines) for the primary composite endpoint of HF hospitalization, aborted cardiac arrest, or CV death (n=447; reference value: −20%). (B) Forest plot demonstrating the hazard ratio for the primary outcome, per standard deviation change in echocardiographic risk factors in HFpEF in multivariable adjusted models in the TOPCAT echocardiography study. Caption: For panel A, hazard ratios (HR) are per 1% absolute increase in LS. Histograms demonstrate the distribution of LS in the study population. Fully adjusted analysis (Model 2) is adjusted for age, gender, race, randomization strata (prior HF hospitalization or biomarker criteria), region of enrollment (Americas versus Russia or Georgia), randomized treatment assignment, core lab LVEF, history of atrial fibrillation, heart rate, New York Heart Association class, history of stroke, creatinine, hematocrit, LV mass, LVESVi, and E/E’ ratio. Values presented are a linear approximation. For panel B, risk associated with negative LVEF and e’ are shown. Covariates in multivariable model are the same as in panel (A) with the exception of LV mass, LVESVi, and E/E’ ratio. See text for further details.

Figure 5

Venn diagram demonstrating the overlap between abnormal LS, LVH, and elevated E/E’ patients among patients will all 3 measures available (n=330). Panel (B) shows the event rates (per 100 person-years) among the 330 participants with all three measures of the primary composite endpoint (CV death, HF hospitalization, aborted cardiac arrest; 87 total events), CV death alone (32 total events), and of HF hospitalization alone (47 total events) based on the number of abnormal echo findings (abnormal LS, LVH, and elevated E/E’).

Figure 5

Venn diagram demonstrating the overlap between abnormal LS, LVH, and elevated E/E’ patients among patients will all 3 measures available (n=330). Panel (B) shows the event rates (per 100 person-years) among the 330 participants with all three measures of the primary composite endpoint (CV death, HF hospitalization, aborted cardiac arrest; 87 total events), CV death alone (32 total events), and of HF hospitalization alone (47 total events) based on the number of abnormal echo findings (abnormal LS, LVH, and elevated E/E’).

Figure 6

Change in LS value from randomization to follow-up (12–18 months) by treatment arm (spironolactone versus placebo) among patients enrolled in (A) the Americas and (B) Russia and Georgia. P for interaction between randomized treatment assignment and change in LS by region=0.09. Baseline-adjusted analysis is based on an ANCOVA. Fully adjusted analysis adjusted for baseline characteristics that differed significantly between treatment arms by region. In the Americas, the multivariable model adjusted for randomization strata (prior hospitalization or natriuretic peptide level), age, race, heart rate, and LVEDVi. In Russia and Georgia, the multivariable model adjusted for randomization strata, history of hypertension, and the presence of significant valvular disease.