Association of a Novel Diagnostic Biomarker, the Plasma Cardiac Bridging Integrator 1 Score, With Heart Failure With Preserved Ejection Fraction and Cardiovascular Hospitalization

Abstract

Importance: Transverse tubule remodeling is a hallmark of heart failure. Cardiac bridging integrator 1 (cBIN1) is a circulating membrane scaffolding protein that is essential for transverse tubule health, and its plasma level declines with disease.

Objective: To determine if a cBIN1-derived score can serve as a diagnostic biomarker of heart failure with preserved ejection fraction (HFpEF).

Design, setting, and participants: In this cohort study, the cBIN1 score (CS) was determined from enzyme-linked immunoabsorbent assay-measured plasma cBIN1 concentrations from study participants in an ambulatory heart failure clinic at Cedars-Sinai Medical Center. Consecutive patients with a confirmed diagnosis of heart failure with preserved ejection fraction (HFpEF; defined by a left ventricular ejection fraction ≥50%) were recruited from July 2014 to November 2015 and compared with age-matched and sex-matched healthy volunteers with no known cardiovascular diagnoses and participants with risk factors for heart failure but no known HFpEF. Baseline characteristics and 1-year longitudinal clinical information were obtained through electronic medical records. Data analysis occurred from November 2016 to November 2017.

Main outcomes and measures: The analysis examined the ability of the CS and N-terminal pro-B-type natriuretic peptide (NT-proBNP) results to differentiate among patients with HFpEF, healthy control participants, and control participants with risk factors for heart failure. We further explored the association of the CS with future cardiovascular hospitalizations.

Results: A total of 52 consecutive patients with a confirmed diagnosis of HFpEF were enrolled (mean [SD] age, 57 [15] years; 33 [63%] male). The CS values are significantly higher in the patients with HFpEF (median [interquartile range (IQR)], 1.85 [1.51-2.28]) than in the 2 control cohorts (healthy control participants: median [IQR], -0.03 [-0.48 to 0.41]; control participants with risk factors only: median [IQR], -0.08 [-0.75 to 0.42]; P < .001). For patients with HFpEF, the CS outperforms NT-proBNP when the comparator group was either healthy control participants (CS: area under curve [AUC], 0.98 [95% CI, 0.96-1.00]; NT-proBNP level: AUC, 0.93 [95% CI, 0.88-0.99]; P < .001) or those with risk factors (CS: AUC, 0.98 [95% CI, 0.97-1.00]; NT-proBNP: AUC, 0.93 [95% CI, 0.88-0.99]; P < .001). Kaplan-Meier analysis of 1-year cardiovascular hospitalizations adjusted for age, sex, body mass index, and NT-proBNP levels reveals that patients with HFpEF with CS greater than or equal to 1.80 have a hazard ratio of 3.8 (95% CI, 1.3-11.2; P = .02) for hospitalizations compared with those with scores less than 1.80.

Conclusions and relevance: If further validated, the plasma CS, a marker of transverse tubule dysfunction, may serve as a biomarker of cardiomyocyte remodeling that has the potential to aide in the diagnosis of HFpEF.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Chang reports holding stock from Abbott and Abvvie and serving as a principal investigator for studies funded by Mesoblast and Amgen. Drs Hong and Shaw both report grants from the National Heart, Lung, and Blood Institute, the Department of Defense, and the American Heart Association during the conduct of the study, and they both hold patents WO 2010/124240 and WO 2012/054764, which are licensed to Sarcotein Diagnostics. Dr Patel reports grants from Pfizer and Alnylam. No other disclosures were reported.

Figures

Figure 1.. Violin Plots of Cardiac Bridging Integrator 1 (cBIN1) Scores and ln N-terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) in the Study Cohorts

A, Distribution of cBIN1 score values in the matched healthy control group (median [IQR], −0.03 [−0.48 to 0.41]), the risk-factor control group (median [IQR], −0.08 [−0.75 to 0.42) and the group with heart failure with preserved ejection fraction (HFpEF) (median [IQR], 1.85 [1.51-2.28]; P < .001). B, Distribution of ln NT-proBNP values in the matched healthy control cohort (median [IQR], 3.58 [2.94-4.28]), the risk-factor control cohort (median [IQR], 3.04 [2.56-3.76]) and patients with HFpEF (median [IQR], 5.62 [4.60-7.14]; P < .001).

Figure 2.. Receiver Operating Characteristic Curves for N-terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) Levels, Cardiac Bridging Integrator 1 (cBIN1) Scores, and Both Assays

A, The cBIN1 scores yielded an area under the curve (AUC) of 0.98 (95% CI, 0.96-1.00), while the AUC for NT-proBNP is 0.93 (95% CI, 0.88-0.99), and the AUC for the 2 tests combined is 0.99 (95% CI, 0.98-1.00). B, The AUC for cBIN1 scores is 0.98 (95% CI, 0.97-1.00), the AUC for NT-proBNP is 0.93 (95% CI, 0.88-0.99), and the AUC for the 2 tests combined is 0.99 (95% CI, 0.99-1.00).