Dataset Information

A Proteomic Analysis of the Myocardium in Hypertrophic Obstructive Cardiomyopathy

ABSTRACT: Hypertrophic cardiomyopathy (HCM) is characterised 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 thepostgenomic phenotype.

INSTRUMENT(S): Q-Tof Premier

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Caroline Coats

LAB HEAD: Dr Kevin Mills

PROVIDER: PXD011994 | Pride | 2019-08-14

REPOSITORIES: Pride

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Publications

Proteomic Analysis of the Myocardium in Hypertrophic Obstructive Cardiomyopathy.

Coats Caroline J CJ Heywood Wendy E WE Virasami Alex A Ashrafi Nadia N Syrris Petros P Dos Remedios Cris C Treibel Thomas A TA Moon James C JC Lopes Luis R LR McGregor Christopher G A CGA Ashworth Michael M Sebire Neil J NJ McKenna William J WJ Mills Kevin K Elliott Perry M PM

Circulation. Genomic and precision medicine 20181201 12

<h4>Background</h4>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 postgenomic phenotype.<h4>Methods</h4>Label-free proteomic analysis was used initially to compare protein profiles in myocardial samples from 11 patients with HCM undergoing surgical myectomy with control samples from 6 healthy unu ...[more]

PMID: 30562113

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Project description:Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure-function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM. We performed a comprehensive multi-omics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts). Integrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, and phosphocreatine) and a reduction in mitochondrial genes involved in the creatine kinase and ATP synthesis. Accompanying these metabolic derangements, quantitative electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase (CS) activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species (ROS) and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance. Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.

Dataset Information

A Proteomic Analysis of the Myocardium in Hypertrophic Obstructive Cardiomyopathy

Publications

Proteomic Analysis of the Myocardium in Hypertrophic Obstructive Cardiomyopathy.

Similar Datasets

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