No 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 Ն50%) 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.

No 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.

Background: Coronary microvascular dysfunction (CMD) is associated with heart failure with preserved ejection fraction (HFpEF); however, pathophysiology is not well described. Hypothesis:We hypothesized that CMD in women with suspected ischemia with no obstructive coronary artery disease (INOCA) is associated with cardiomyocyte dysfunction reflected by plasma levels of a cardiomyocyte calcium handling protein, cardiac bridge integrator 1 (cBIN1). Methods: Women with suspected INOCA undergoing coronary function testing were included. Coronary flow reserve, vasodilation to nitroglycerin, change in coronary blood flow (ΔCBF), and vasodilation to acetylcholine (ΔAch) were evaluated. cBIN1 score (CS) levels in these women (n = 39) were compared to women with HFpEF (n = 20), heart failure with reduced ejection fraction (HFrEF) (n = 36), and reference controls (RC) (n = 50). Higher CS indicates cardiomyocyte tubule dysfunction.Results: INOCA, HFpEF, and HFrEF women were older than RC (p < .05). Higher CS was associated with vasoconstriction to acetylcholine (r = À0.43, p = .011) with a trend towards lower ΔCBF (r = 0.30, p = .086). Higher CS was specific for ΔAch and ΔCBF but had limited sensitivity. INOCA women had higher CS than RC, but lower CS than HFpEF/HFrEF groups (p < .001).Conclusions: CS, a plasma biomarker indicating poor cardiomyocyte health, was higher in women with suspected INOCA as compared to RC, but lower than in

Rationale: Pressure overload-induced myocardial hypertrophy can progress to heart failure (HF), along with a decline in myocardial expression of cardiac BIN1 (cardiac isoform of bridging integrator 1, cBin1). T-tubule cBIN1-microdomains are critical in maintaining normal cardiac contractility and electrical stability. Objective: To examine whether cBin1 gene transfer can prevent or postpone HF induced by severe pressure overload in a mouse model with transverse aortic constriction (TAC). Methods and Results: Two sets of experiments were designed. In Set 1, TAC was performed in adult male wild type (WT-TAC) and cardiac specific heterozygous Bin1 deleted mice ( Bin1 HT-TAC). In Set 2, TAC was performed in adult male C57BL/6J mice three weeks after retro-orbital injection of adeno-associated virus 9 transducing cBIN1-V5 or GFP-V5 (cBIN1-TAC or GFP-TAC) and compared to sham controls. The primary endpoint measured was survival at 8 weeks with left ventricular ejection fraction >=35% by echocardiogram. The Bin1 HT-TAC group (less cBIN1) and the cBIN1-TAC group (more cBIN1) had significantly less and more endpoint achievement than their respective set controls, indicating a robust protective effect of cBIN1. Left ventricular (LV) hypertrophy occurred in all TAC groups, yet cBIN1-TAC mice had attenuated LV dilation by echocardiogram, improved contractile reserve by pressure-volume loop, reduced pulmonary edema and less HF development. Exploring myocardial remodeling, exogenous cBIN1 retained t-tubule membrane microdomains with organized L-type calcium channels (LTCC) and ryanodine receptors (RyRs) in cBIN1-TAC mice, which otherwise were significantly disrupted in GFP-TAC mice. However, the total LTCC and RyRs protein levels were not significantly altered among groups by Western blotting. Conclusions: Normalization of cBIN1 level can postpone, if not prevent, the transition from compensated LV hypertrophy to dilated cardiomyopathy following pressure overload. The protective mechanism is linked to cBIN1-mediated preservation of dyads at t-tubule membrane microdomains, limiting pathologic remodeling of the calcium handling apparatus during HF progression.

Background: Neurofilament light chain protein (NfL) and tau are plasma biomarkers of neuronal injury which can be elevated in patients with neurodegenerative diseases. N-terminal pro-brain natriuretic peptide (NT-proBNP) is an established marker of volume status in patients with heart failure (HF) and plasma cBIN1 score (CS) is an emerging biomarker of cardiac muscle health. It is not known if, in HF patients, there is a correlation between cardiac markers and brain injury markers.Methods: We studied ambulatory HF patients with either preserved and reduced ejection fraction (N = 50 with 25 HFrEF and 25 HFpEF) and age and sex matched healthy controls (N = 50). Plasma NT-proBNP and CS were determined using commercial kits. A bead-based ELISA assay was used to quantify femtomolar concentrations of plasma neuronal markers NfL and total tau.Results: Plasma levels of NT-proBNP and CS in heart failure patients were significantly higher than those from healthy controls. In both patients with HFrEF and HFpEF, we found independent and direct correlations between the volume status marker NT-proBNP, but not the cardiomyocyte origin muscle health marker CS, with NfL (r = 0.461, p = 0.0007) and tau (r = 0.333, p = 0.0183).Conclusion: In patients with HF with or without preserved ejection fraction, plasma levels of NfL and tau correlate with volume status rather than muscle health, indicating volume overload-associated neuronal injury.

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