Biomarker profiles of favorable ventricular remodeling in heart failure patients with reduced ejection fraction: Insights from the echocardiographic substudy of the VICTORIA trial

Abstract

Abstract Background Favorable ventricular remodeling, defined as a decrease in left ventricular end-systolic volume indexed (LVESVI) to body surface area or an increase in left ventricular ejection fraction (LVEF), is associated with improved clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Because the underlying biomarker correlates remain unclear, we investigated circulating biomarker profiles and their relationship to ventricular remodeling. Methods We studied 419 high-risk patients with worsening HFrEF from the Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) trial with core-lab assessed echocardiograms and measurements of 92 biomarkers (Olink CVD III panel). Biomarkers were measured in plasma using proximity extension assays and conventional ELISAs. Paired biomarkers (in 306 patients) and echocardiographic measurements (in 419 patients) were available at baseline and 8 months post-randomization. We evaluated the association of biomarkers at baseline and their temporal changes with favorable cardiac remodeling. Favorable remodeling was prespecified as a 5% LVEF absolute increase or 15% LVESVI relative decrease between baseline and 8 months. Reported p-values for protein changes are adjusted for the false discovery rate (FDR) at 0.05 to account for multiple comparisons. Results Of 419 patients (median age 66 [interquartile range 57-74] years, 27.4% women), 206 (49.2%) had favorable remodeling and 213 (50.8%) did not. Patients with favorable remodeling had a lower median body mass index (26.5 vs 28.3 kg/m2, P = 0.010), lower prevalence of diabetes (36.4% vs 47.4%, P = 0.022) and coronary artery disease (39.3% vs 62.0%, P<0.001). After correcting for multiple testing, no baseline biomarker levels differed between patients with and without favorable remodeling. Between baseline and 8 months, however, there was a significant decrease in biomarkers relating to inflammation and cardiac metabolism with favorable remodeling compared with those without (Figure). Particularly NT-proBNP (ratio 0.46, 95%confidence interval [CI] 0.38-0.57), TNF Superfamily Member 13b (ratio 0.85, 95%CI 0.80-0.91), growth differentiation factor-15 (ratio 0.76, 95%CI 0.68-0.84), cathepsin D (ratio 0.88, 95%CI 0.82-0.94), and insulin growth factor binding protein 7 (ratio 0.81, 95%CI 0.74-0.88) showed a significantly larger decrease in those with than those without favorable remodeling (Figure and Table). Conclusion Our results suggest favorable cardiac remodeling occurs in half of high-risk HFrEF with recent worsening. We provide new insights into the clinical phenoype and associated inflammatory and cardiac metabolism changes. These findings may help identify potential treatment targets for future drug discovery.