Cardiac manifestations of mitochondrial disease

Abstract

Due to critical dependence of the heart on oxidative metabolism, cardiac involvement in mitochondrial disease is common and may occur as the principal clinical manifestation or part of multisystem disease. The basic features of cardiac mitochondrial disease expression remain uncertain and no effective treatment exists. Previous research has suggested that cardiac involvement in mitochondrial disease is an important cause of morbidity and early mortality in paediatric populations. In this thesis, a retrospective study confirms the frequent occurrence of cardiac involvement in adults, and demonstrates a significant impact on survival; the importance of specific mt-tRNA mutations and age of symptom onset as predictors of cardiac involvement is also highlighted. Conversely, in children with end-stage cardiomyopathy of unknown aetiology, a prospective study identifies respiratory chain disease as an important cause of disease, altering patient management in a high-risk population in whom mitochondrial disease was not suspected. Using histochemical and immunohistochemical analysis of cardiac tissue, profound complex I deficiency is demonstrated in all cardiomyocytes displaying any evidence of COX-deficiency but also in cells without COX deficiency, supporting the primacy of this factor in patients with well-characterised mt-tRNA mutations. Differences in cardiac complex I expression between patients harbouring m.3243A>G and m.8344A>G mutations may impact on cardiac phenotype; chamber-specific respiratory chain abnormalities are noted and, while tissue segregation may play a role in frequency and severity of cardiac involvement, skeletal muscle mitochondrial DNA mutation load is not a consistent marker of risk. Advanced imaging techniques are used to demonstrate early concentric hypertrophic remodelling, and specific changes in intramyocardial strains and torsion, in patients harbouring the m.3243A>G or m.8344A>G mutations without clinical evidence of cardiac involvement. However, an endurance exercise interventional study shows that patients experience comparable cardiac hypertrophic and haemodynamic adaptations to sedentary controls and confirms the safety and efficacy of 16 weeks’ training.