Cardiac myosin-binding protein C is a novel marker of myocardial injury and fibrosis in aortic stenosis

Atul Anand, Calvin Chin, Anoop S V Shah, Jacek Kwiecinski, Alex Vesey, Joanna Cowell, Ekkehard Weber, Thomas Kaier, David E Newby, Marc Dweck, Michael S Marber, Nicholas L Mills, Atul Anand, Calvin Chin, Anoop S V Shah, Jacek Kwiecinski, Alex Vesey, Joanna Cowell, Ekkehard Weber, Thomas Kaier, David E Newby, Marc Dweck, Michael S Marber, Nicholas L Mills

Abstract

Objective: Cardiac myosin-binding protein C (cMyC) is an abundant sarcomeric protein and novel highly specific marker of myocardial injury. Myocyte death characterises the transition from hypertrophy to replacement myocardial fibrosis in advanced aortic stenosis. We hypothesised that serum cMyC concentrations would be associated with cardiac structure and outcomes in patients with aortic stenosis.

Methods: cMyC was measured in two cohorts in which serum had previously been prospectively collected: a mechanism cohort of patients with aortic stenosis (n=161) and healthy controls (n=46) who underwent cardiac MRI, and an outcome cohort with aortic stenosis (n=104) followed for a median of 11.3 years.

Results: In the mechanism cohort, cMyC concentration correlated with left ventricular mass (adjusted β=11.0 g/m2 per log unit increase in cMyC, P<0.001), fibrosis volume (adjusted β=8.0 g, P<0.001) and extracellular volume (adjusted β=1.3%, P=0.01) in patients with aortic stenosis but not in controls. In those with late gadolinium enhancement (LGE) indicative of myocardial fibrosis, cMyC concentrations were higher (32 (21-56) ng/L vs 17 (12-24) ng/L without LGE, P<0.001). cMyC was unrelated to coronary calcium scores. Unadjusted Cox proportional hazards analysis in the outcome cohort showed greater all-cause mortality (HR 1.49 per unit increase in log cMyC, 95% CI 1.11 to 2.01, P=0.009).

Conclusions: Serum cMyC concentration is associated with myocardial hypertrophy, fibrosis and an increased risk of mortality in aortic stenosis. The quantification of serum sarcomeric protein concentrations provides objective measures of disease severity and their clinical utility to monitor the progression of aortic stenosis merits further study.

Clinical trial registration: NCT1755936; Post-results.

Trial registration: ClinicalTrials.gov NCT01755936.

Keywords: aortic stenosis; cardiac magnetic resonance (CMR) imaging.

Conflict of interest statement

Competing interests: AA has received speaker fees from Abbott Laboratories. ASVS has acted as a consultant for Abbott Laboratories. NLM has acted as a consultant for Abbott Laboratories, Beckman-Coulter, Roche and Singulex. Singulex was contracted to undertake the analyses of cMyC on a fee-for-service basis and holds no commercial interest. MSM is named as an inventor on a patent held by King’s College London for the detection of cardiac myosin-binding protein C as a biomarker of myocardial injury. All other authors have no conflicts of interest to declare.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1
Figure 1
Relationships between cMyC and markers of disease severity in the mechanism cohort. β values (95% CI) represent change in the progression variable for each log unit change in cMyC concentration after adjustment in multivariate modelling. Markers of disease severity are: (A) indexed LV mass (g/m2) determined by MRI; (B) fibrosis volume (g) by MRI; (C) AVmax (m/s) determined by echocardiography; (D) diastolic function from echocardiographic measures of E/e′ ratio. *Adjusted for age, sex, glomerular filtration rate, AVmax, cardiac troponin, history of ischaemic heart disease, diabetes and hypertension. +As above plus body surface area. ‡As above excluding AVmax. AV, aortic valve; cMyC, cardiac myosin-binding protein C; LV, left ventricle.
Figure 2
Figure 2
cMyC and late gadolinium enhancement. (A) Receiver operating characteristic (ROC) curve analysis for outcome of LGE. Addition of cMyC improves the prediction of age and gender for LGE, P=0.002 (DeLong’s method with bootstrapping). (B) Logistic regression modelling for the predicted probability of LGE with serum cMyC concentration (adjusted for age and sex). Shaded area represents 95% CI. AUC, area under the curve; cMyC, cardiac myosin-binding protein C; LGE, late gadolinium enhancement.
Figure 3
Figure 3
Patterns of myocyte death in patients with aortic stenosis. Images showing differing patterns of oncosis and autophagy visualised using a 3,3′-diaminobenzidine-based detection kit in individuals with aortic stenosis. (A) Oncosis and (B) autophagy in a patient with a low (9.4 ng/L) cMyC concentration. (C) Oncosis and (D) autophagy in a patient with a high (87.2 ng/L) cMyC concentration. There is a marked difference in staining intensity by cMyC concentration for both oncosis and autophagy. cMyC, cardiac myosin-binding protein C.
Figure 4
Figure 4
Survival by tertiles of cMyC in the outcome cohort. cMyC, cardiac myosin-binding protein C.

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