Cardiac Myosin Binding Protein C is an Ultra-early and Cardiac-specific Biomarker of Myocardial Necrosis

Rationale: We recently demonstrated that proteolytic cleavage fragments of cardiac myo-sin binding protein-C (cMyBP-C) can be detected in the serum after myocardial infarction (MI) in a rat model and in patients with MI. The findings implied that serum cMyBP-C might be useful as cardiac-specific biomarker for MI. The release kinetics of cMyBP-C in the circulation post-MI remains to be elucidated. Objective: Determine the release kinetics of cMyBP-C as an ultra-early and cardiac-specific biomarker of myocardial necrosis. Method and Results: To determine the exact timing of cMyBP-C release in the bloodstream post-acute MI, left anterior descending (LAD) coronary artery was ligated in adult swine (n=6). ECG showed significant ST elevation. Infarct size represented 12.4 ± 1.9% of total ven-tricular mass. Blood samples were collected before and at predetermined time points between 30 min and 14 days after LAD ligation. Plasma cMyBP-C level was quantified using a highly sensitive and rapid sandwich enzyme-linked immunosorbent assay. Compared with baseline, cMyBP-C levels were increased in post-MI serum within 45 min (0.64 ± 0.52 ng/ml) after LAD ligation and declined after 16 hrs to the baseline level (0.01 ± 0.00 ng/ ml). In contrast, cardiac troponin I (cTnI) level peaked after 6 hrs and returned to baseline after 10 days. To validate these findings in humans, serial blood samples were taken from 5 patients with hypertrophic cardiomyopathy undergoing transcoronary ablation of septal hypertrophy (TASH). Similar to the swine model, the level of cMyBP-C increased 30 min after TASH (0.25 ± 0.15 ng/ml) and peaked at 4 hrs (0.56 ± 0.27 ng/ml), confirming that cMyBP-C is a promising ultra-early biomarker of MI. Furthermore, cMyBP-C level was determined in patients with acute coronary syndromes (ACS) from the SYNERGY library population and a healthy control group (n=160 and 61, respectively). Seventy-eight percent (125 out of 160) of patients with ACS had detectable cMyBP-C serum levels (2.9 ± 1.2 ng/ml), implicating serum cMyBP-C as a biomarker for ACS. Conclusion: The rapid appearance of proteolyzed cMyBP-C in the circulation post-acute MI in a swine model and in human patients with ACS and post-TASH identify serum cMyBP-C as an ultra-early biomarker of myocardial necrosis. Purpose: Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric septal hypertrophy, diastolic dysfunction, myocardial disarray and lacks curative treatment. It is often caused by mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C). Most of the mutations alter mRNA splicing and result in aberrant mRNAs and proteins. In …