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 Î²=11.0 g/m2 per log unit increase in cMyC, P<0.001), fibrosis volume (adjusted Î²=8.0 g, P<0.001) and extracellular volume (adjusted Î²=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 (21â€“56) ng/L vs 17 (12â€“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.
- aortic stenosis
- cardiac magnetic resonance (CMR) imaging
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Contributors AA conducted the analysis presented and drafted the submission. CC conducted the study for the mechanism cohort. ASVS contributed to analysis of data. JK performed the histological analysis. JC conducted the study for the outcomes cohort. MD, DEN, NLM and MSM contributed to the planning, conduct and reporting of the studies included in the manuscript. The above named authors and all other authors named provided further critical review of the manuscript and further input on revisions.
Funding This research is supported by research fellowships from Chest Heart and Stroke Scotland (15/A163) and the British Heart Foundation (FS/10/024/28266 and FS/15/13/31320). The development of the cMyC biomarker is supported by grants from the MRC UK (G1000737), Guy’s and St Thomas’ Charity (R060701, R100404), British Heart Foundation (TG/15/1/31518) and the UK Department of Health through the National Institute for Health Research Biomedical Research Centre award to Guy’s and St Thomas’ National Health Service Foundation Trust. DEN is supported by the British Heart Foundation (CH/9/002) and the Wellcome Trust (WT103782AIA).
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.
Ethics approval The studies were approved by the South East Scotland Research Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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