Coats, CJ;
Heywood, WE;
Virasami, A;
Ashrafi, N;
Syrris, P;
dos Remedios, C;
Treibel, TA;
... Elliott, PM; + view all
(2018)
Proteomic Analysis of the Myocardium in Hypertrophic Obstructive Cardiomyopathy.
Circulation: Genomic and Precision Medicine
, 11
(12)
, Article e001974. 10.1161/CIRCGEN.117.001974.
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Abstract
Background: Hypertrophic cardiomyopathy (HCM) is characterized by a complex phenotype that is only partly explained by the biological effects of individual genetic variants. The aim of this study was to use proteomic analysis of myocardial tissue to explore the post genomic phenotype. Methods: Label-free proteomic analysis was used initially to compare protein profiles in myocardial samples from eleven patients with HCM undergoing surgical myectomy with control samples from six healthy unused donor hearts. Differentially expressed proteins of interest were validated in myocardial samples from 65 unrelated individuals [HCM (n=51), controls (n=7) and aortic stenosis (n=7)] by the development and use of targeted multiple reaction monitoring (MRM) based triple quadrupole mass spectrometry. Results: In this exploratory study, 1586 proteins were identified with 151 proteins differentially expressed in HCM samples compared to controls (p<0.05). Protein expression profiling showed that many proteins identified in the initial discovery study were associated with metabolism, muscle contraction, calcium regulation and oxidative stress. Proteins down-regulated in HCM versus controls included creatine kinase M-type, Fructose-bisphosphate aldolase A and phosphoglycerate mutase (p<0.001). Proteins up-regulated in HCM included lumican, carbonic anhydrase 3, desmin, alpha actin skeletal and four and half LIM domain protein 1 (p<0.01). Myocardial lumican concentration correlated with left atrial area (rho 0.34, p=0.015), late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (P=0.03) and the presence of a pathogenic sarcomere mutation (p=0.04). Conclusion: The myocardial proteome of HCM provides supporting evidence for dysregulation of metabolic and structural proteins. The finding that lumican is raised in HCM hearts provides insight into the myocardial fibrosis that characterizes this disease.
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