Temporal Patterns of 14 Blood Biomarker candidates of Cardiac Remodeling in Relation to Prognosis of Patients With Chronic Heart Failure-The Bio- SH i FT Study

Abstract

Background Remodeling biomarkers carry high potential for predicting adverse events in chronic heart failure ( CHF ) patients. However, temporal patterns during the course of CHF , and especially the trajectory before an adverse event, are unknown. We studied the prognostic value of temporal patterns of 14 cardiac remodeling biomarker candidates in stable patients with CHF from the Bio-SHiFT (Serial Biomarker Measurements and New Echocardiographic Techniques in Chronic Heart Failure Patients Result in Tailored Prediction of Prognosis) study. Methods and Results In 263 CHF patients, we performed trimonthly blood sampling during a median follow-up of 2.2 years. For the analysis, we selected all baseline samples, the 2 samples closest to the primary end point ( PE ), or the last sample available for end point-free patients. Thus, in 567 samples, we measured suppression of tumorigenicity-2, galectin-3, galectin-4, growth differentiation factor-15, matrix metalloproteinase-2, 3, and 9, tissue inhibitor metalloproteinase-4, perlecan, aminopeptidase-N, caspase-3, cathepsin-D, cathepsin-Z, and cystatin-B. The PE was a composite of cardiovascular mortality, heart transplantation, left ventricular assist device implantation, and HF hospitalization. Associations between repeatedly measured biomarker candidates and the PE were investigated by joint modeling. Median age was 68 (interquartile range: 59-76) years with 72% men; 70 patients reached the PE . Repeatedly measured suppression of tumorigenicity-2, galectin-3, galectin-4, growth differentiation factor-15, matrix metalloproteinase-2 and 9, tissue inhibitor metalloproteinase-4, perlecan, cathepsin-D, and cystatin-B levels were significantly associated with the PE , and increased as the PE approached. The slopes of biomarker trajectories were also predictors of clinical outcome, independent of their absolute level. Associations persisted after adjustment for clinical characteristics and pharmacological treatment. Suppression of tumorigenicity-2 was the strongest predictor (hazard ratio: 7.55 per SD difference, 95% CI : 5.53-10.30), followed by growth differentiation factor-15 (4.06, 2.98-5.54) and matrix metalloproteinase-2 (3.59, 2.55-5.05). Conclusions Temporal patterns of remodeling biomarker candidates predict adverse clinical outcomes in CHF . Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01851538.

Trial registration: ClinicalTrials.gov NCT01851538.

Keywords: biomarkers; cardiac remodeling; heart failure; prognosis; repeated measurements.

Figures

Figure 1

Average temporal patterns of cardiac remodeling biomarker candidates during follow‐up. X‐axis: time remaining to the primary end point (for patients who experienced incident adverse events) or time remaining to last sample moment (for patients who remained event free). Of note is that “time zero” is defined as the occurrence of the end point and is depicted on the right side of the x‐axis, so that the average marker trajectory can be visualized as the end point approaches (inherently to this representation, baseline sampling occurred before “time zero”). Y‐axis: biomarker levels in arbitrary, relative units (normalized protein expression, NPX on linear scale). Solid red line: Average temporal pattern of biomarker candidate level in patients who reached the primary end point during follow‐up. Solid blue line: Average temporal pattern of biomarker candidate level in patients who remained end point free (solid blue line). Dashed lines: 95% CI. AP‐N indicates aminopeptidase‐N; CASP3, caspase‐3; CSTB, cystatin‐B; CTSD, cathepsin D; CTSZ, cathepsin Z; Gal‐3, galectin‐3; Gal‐4, galectin‐4; GDF‐15, growth differentiation factor 15; MMP‐2, 3, and 9, matrix metalloproteinase 2, 3, and 9; NPX, normalized protein expression; NT‐proBNP, N‐terminal pro–B‐type natriuretic peptide; PLC, perlecan; ST2, suppression of tumorigenicity‐2; TIMP‐4, tissue inhibitor metalloproteinase 4.