cBIN1 Score (CS) Identifies Ambulatory HFrEF Patients and Predicts Cardiovascular Events

Tara C Hitzeman, Yu Xie, Ronit H Zadikany, Andriana P Nikolova, Rachel Baum, Ana-Maria Caldaruse, Sosse Agvanian, Gil Y Melmed, Dermot P B McGovern, Dael R Geft, David H Chang, Jaime D Moriguchi, Antoine Hage, Babak Azarbal, Lawrence S Czer, Michelle M Kittleson, Jignesh K Patel, Alan H B Wu, Jon A Kobashigawa, Michele Hamilton, TingTing Hong, Robin M Shaw, Tara C Hitzeman, Yu Xie, Ronit H Zadikany, Andriana P Nikolova, Rachel Baum, Ana-Maria Caldaruse, Sosse Agvanian, Gil Y Melmed, Dermot P B McGovern, Dael R Geft, David H Chang, Jaime D Moriguchi, Antoine Hage, Babak Azarbal, Lawrence S Czer, Michelle M Kittleson, Jignesh K Patel, Alan H B Wu, Jon A Kobashigawa, Michele Hamilton, TingTing Hong, Robin M Shaw

Abstract

Background: Cardiac Bridging Integrator 1 (cBIN1) is a membrane deformation protein that generates calcium microdomains at cardiomyocyte t-tubules, whose transcription is reduced in heart failure, and is released into blood. cBIN1 score (CS), an inverse index of plasma cBIN1, measures cellular myocardial remodeling. In patients with heart failure with preserved ejection fraction (HFpEF), CS diagnoses ambulatory heart failure and prognosticates hospitalization. The performance of CS has not been tested in patients with heart failure with reduced ejection fraction (HFrEF).

Methods and results: CS was determined from plasma of patients recruited in a prospective study. Two comparative cohorts consisted of 158 ambulatory HFrEF patients (left ventricular ejection fraction (LVEF) ≤ 40%, 57 ± 10 years, 80% men) and 115 age and sex matched volunteers with no known history of HF. N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations were also analyzed for comparison. CS follows a normal distribution with a median of 0 in the controls, which increases to a median of 1.9 (p < 0.0001) in HFrEF patients. CS correlates with clinically assessed New York Heart Association Class (p = 0.007). During 1-year follow-up, a high CS (≥ 1.9) in patients predicts increased cardiovascular events (43% vs. 26%, p = 0.01, hazard ratio 1.9). Compared to a model with demographics, clinical risk factors, and NT-proBNP, adding CS to the model improved the overall continuous net reclassification improvement (NRI 0.64; 95% CI 0.18-1.10; p = 0.006). Although performance for diagnosis and prognosis was similar to CS, NT-proBNP did not prognosticate between patients whose NT-proBNP values were > 400 pg/ml.

Conclusion: CS, which is mechanistically distinct from NT-proBNP, successfully differentiates myocardial health between patients with HFrEF and matched controls. A high CS reflects advanced NYHA stage, pathologic cardiac muscle remodeling, and predicts 1-year risk of cardiovascular events in ambulatory HFrEF patients. CS is a marker of myocardial remodeling in HFrEF patients, independent of volume status.

Keywords: cBIN1 score; calcium handling; cardiac muscle remodeling; heart failure; ion channels.

Copyright © 2020 Hitzeman, Xie, Zadikany, Nikolova, Baum, Caldaruse, Agvanian, Melmed, McGovern, Geft, Chang, Moriguchi, Hage, Azarbal, Czer, Kittleson, Patel, Wu, Kobashigawa, Hamilton, Hong and Shaw.

Figures

FIGURE 1
FIGURE 1
Distribution of CS among HFrEF and matched controls. The vertical axis is the cBIN1 score (CS), and the width of each violin graph depicts the density plot at each measured value. The HFrEF cohort median CS is elevated relative to the controls, 1.9 (IQR 1.4–2.4) compared to 0 (IQR -0.5–0.7), respectively (p < 0.0001).
FIGURE 2
FIGURE 2
Receiver operating characteristic (ROC) curves. ROC curve containing the various sensitivities and specificities of CS (AUC = 0.973, red), NT-proBNP (AUC = 0.967, blue), and combined NT-proBNP and CS (AUC = 0.995, green) to diagnose disease in our control and HFrEF cohorts.
FIGURE 3
FIGURE 3
Cardiovascular event free survival of HFrEF patients during 12-month follow-up. (A) Kaplain-Meier survival curve is shown here for all HFrEF patients. The red line demonstrates patients with CS < 1.9 and the blue line demonstrate patients with CS ≥ 1.9. Event free survival is defined as patients who did not have a cardiovascular (CV) event (HF-related hospitalization, cardiac hospitalization, LVAD, OHT, or death) during 12-months follow-up. A low CS (<1.9) predicted a higher event-free survival among all HFrEF patients (p = 0.01). (B) Scatterplot of 12-month event-free survival vs. CS for all CS ≥ 1.9 indicates a negative correlation (Pearsons’s correlation coefficient −0.91, p < 0.0001).

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