Dataset Information

Concentric hypertrophic remodelling and subendocardial dysfunction in mitochondrial DNA point mutation carriers.

ABSTRACT:

Aims

Hypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Screening strategies for cardiac disease are unclear. We investigated whether myocardial abnormalities could be identified in mitochondrial DNA mutation carriers without clinical cardiac involvement.

Methods and results

Cardiac magnetic resonance imaging was performed in 22 adult patients with mitochondrial disease due to the m.3243A>G mutation, but no known cardiac involvement, and 22 age- and gender-matched control subjects: (i) Phosphorus-31- magnetic resonance spectroscopy, (ii) cine imaging (iii), cardiac tagging and (iv) late gadolinium enhancement (LGE) imaging. Disease burden was determined using the Newcastle Mitochondrial Disease Adult Scale (NMDAS) and urinary mutation load. Compared with control subjects, patients had an increased left ventricular mass index (LVMI), LV mass to end-diastolic volume (M/V) ratio, wall thicknesses (all P < 0.01), torsion and torsion to endocardial strain ratio (both P < 0.05). Longitudinal shortening was decreased in patients (P < 0.0001) and correlated with an increased LVMI (r = -0.52, P < 0.03), but there were no differences in the diastolic function. Among patients there was no correlation of LVMI or the M/V ratio with diabetic or hypertensive status, but the mutation load and NMDAS correlated with the LVMI (r = 0.71 and r = 0.79, respectively, both P < 0.001). The phosphocreatine/adenosine triphosphate ratio was decreased in patients (P < 0.001) but did not correlate with other parameters. No patients displayed focal LGE.

Conclusion

Concentric remodelling and subendocardial dysfunction occur in patients carrying m.3243A>G mutation without clinical cardiac disease. Patients with higher mutation loads and disease burden may be at increased risk of cardiac involvement.

SUBMITTER: Bates MG

PROVIDER: S-EPMC3681541 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Publications

Concentric hypertrophic remodelling and subendocardial dysfunction in mitochondrial DNA point mutation carriers.

Bates Matthew G D MG Hollingsworth Kieren G KG Newman Jane H JH Jakovljevic Djordje G DG Blamire Andrew M AM MacGowan Guy A GA Keavney Bernard D BD Chinnery Patrick F PF Turnbull Douglass M DM Taylor Robert W RW Trenell Michael I MI Gorman Grainne S GS

European heart journal. Cardiovascular Imaging 20121104 7

<h4>Aims</h4>Hypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Screening strategies for cardiac disease are unclear. We investigated whether myocardial abnormalities could be identified in mitochondrial DNA mutation carriers without clinical cardiac involvement.<h4>Methods and results</h4>Cardiac magnetic resonance imaging was performed in 22 adult patients with mitochondrial disease du ...[more]

PMID: 23129433

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Project description:Background Impaired myocardial blood flow (MBF) in the absence of epicardial coronary disease is a feature of hypertrophic cardiomyopathy (HCM). Although most evident in hypertrophied or scarred segments, reduced MBF can occur in apparently normal segments. We hypothesized that impaired MBF and myocardial perfusion reserve, quantified using perfusion mapping cardiac magnetic resonance, might occur in the absence of overt left ventricular hypertrophy (LVH) and late gadolinium enhancement, in mutation carriers without LVH criteria for HCM (genotype-positive, left ventricular hypertrophy-negative). Methods and Results A single center, case-control study investigated MBF and myocardial perfusion reserve (the ratio of MBF at stress:rest), along with other pre-phenotypic features of HCM. Individuals with genotype-positive, left ventricular hypertrophy-negative (n=50) with likely pathogenic/pathogenic variants and no evidence of LVH, and matched controls (n=28) underwent cardiac magnetic resonance. Cardiac magnetic resonance identified LVH-fulfilling criteria for HCM in 5 patients who were excluded. Individuals with genotype-positive, left ventricular hypertrophy-negative had longer indexed anterior mitral valve leaflet length (12.52±2.1 versus 11.55±1.6 mm/m2, P=0.03), lower left ventricular end-systolic volume (21.0±6.9 versus 26.7±6.2 mm/m2, P≤0.005) and higher left ventricular ejection fraction (71.9±5.5 versus 65.8±4.4%, P≤0.005). Maximum wall thickness was not significantly different (9.03±1.95 versus 8.37±1.2 mm, P=0.075), and no subject had significant late gadolinium enhancement (minor right ventricle‒insertion point late gadolinium enhancement only). Perfusion mapping demonstrated visual perfusion defects in 9 (20%) carriers versus 0 controls (P=0.011). These were almost all septal or near right ventricle insertion points. Globally, myocardial perfusion reserve was lower in carriers (2.77±0.83 versus 3.24±0.63, P=0.009), with a subendocardial:subepicardial myocardial perfusion reserve gradient (2.55±0.75 versus 3.2±0.65, P=<0.005; 3.01±0.96 versus 3.47±0.75, P=0.026) but equivalent MBF (2.75±0.82 versus 2.65±0.69 mL/g per min, P=0.826). Conclusions Regional and global impaired myocardial perfusion can occur in HCM mutation carriers, in the absence of significant hypertrophy or scarring.

Project description:BackgroundHypertrophic 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.MethodsWe performed a comprehensive multiomics 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).ResultsIntegrated 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 creatine kinase and ATP synthesis. Accompanying these metabolic derangements, electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance.ConclusionsOverall, 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.

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

Concentric hypertrophic remodelling and subendocardial dysfunction in mitochondrial DNA point mutation carriers.

Aims

Methods and results

Conclusion

Publications

Concentric hypertrophic remodelling and subendocardial dysfunction in mitochondrial DNA point mutation carriers.

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