Plasma cBIN1 Score (CS) Identifies HFrEF and Can Predict Cardiac Hospitalization in Stable Ambulatory Patients
Authors: Xie Yu , Hitzeman Tara C. , Zadikany Ronit H. , Nikolova Andriana P. , Baum Rachel , Xu Bing , Agvanian Sosse , Melmed Gil Y. , McGovern Dermot T. , Geft Dael R. , Chang David H. , Moriguchi Jaime D. , Hage Antoine , Azarbal Babak , Czer Lawrence S. , Kittleson Michelle M. , Patel Jignesh K. , Wu Alan H. B. , Kobashigawa Jon A. , Hamilton Michele , Hong TingTing , Shaw Robin M. 
Published: January 2018

Objective: We determined, in stable ambulatory heart failure with reduced ejection fraction (HFrEF) subjects and matched controls, the capability of a novel blood based cardiac-specific cBIN1 Score (CS), which assesses the health of cardiac muscle, to identify patients with known heart failure (HF) and to prognosticate future hospitalization. Background: Limited clinical tools are available in assessing cardiac muscle health in stable ambulatory patients. Cardiac bridging integrator 1 (cBIN1) is a cardiomyocyte t-tubule membrane scaffolding protein which regulates calcium signaling in cardiomyocytes, decreases in failing muscle, and is present in plasma in levels that correlate with cardiac content. We hypothesize that CS, a normalized index of plasma cBIN1 concentration, can function as a diagnostic and prognostic biomarker of HF. Methods: Plasma cBIN1 concentration is measured by an ELISA test, and CS is calculated as the natural log of the ratio of a constant population mean cBIN1 to measured cBIN1 concentration. We determined CS among 125 clinically stable individuals with HFrEF (LVEF &le; 40%) (mean age 56 &plusmn; 10 years old, 79% men) and 125 age, sex matched volunteers with no known history of HF. We obtained plasma concentrations of NT-proBNP, a marker of volume status, as comparison. Baseline co-morbidities and 18-month longitudinal clinical information were obtained through electronic medical records. Results: CS follows a normal distribution with a median of 0 in the control population and median is significantly increased among HFrEF patients to 1.8 (IQR 1.4 &ndash; 2.1, p &lt; 0.0001). CS diagnosed HFrEF with a receiver operating characteristic (ROC) area under the curve (AUC) of 0.93 (AUC is 0.98 for NT-proBNP, and combined CS and NT-proBNP AUC is 0.99). Unlike NT-proBNP, CS does not correlate with body mass index (BMI) in either the control or HFrEF population (Pearson&rsquo;s r = -0.15, p = 0.12; Pearson&rsquo;s r = 0.003, p = 0.97, respectively). NT-proBNP significantly correlates with renal function (Pearson&rsquo;s r = -0.37, p = 0.001), while CS also has no correlation (Pearson&rsquo;s r = 0.03, p = 0.71). During an 18-month follow-up, a high CS &ge; 1.8 at the initial visit predicted future cardiovascular hospitalizations (38% vs. 21%, p = 0.04, hazard ratio 2.0). NT-proBNP did not predict future cardiovascular hospitalizations. Conclusions: Plasma cBIN1 based CS is insensitive to BMI and renal function and differentiates myocardial health between patients with HFrEF versus matched controls. An abnormally high CS reflected poor intrinsic myocardial health and can predict future 18-month cardiac hospitalization in stable ambulatory patients.