Defining cardiac adaptations and safety of endurance training in patients with m.3243A>G-related mitochondrial disease☆☆,☆☆☆

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Abstract

Background

Cardiac hypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Endurance exercise training improves symptoms and skeletal muscle function, yet cardiac adaptations are unknown.

Methods and results

Before and after 16-weeks of training, exercise capacity, cardiac magnetic resonance imaging and phosphorus-31 spectroscopy, disease burden, fatigue, quality of life, heart rate variability (HRV) and blood pressure variability (BPV) were assessed in 10 adult patients with m.3243A>G-related mitochondrial disease, and compared to age- and gender-matched sedentary control subjects. At baseline, patients had increased left ventricular mass index (LVMI, p < 0.05) and LV mass to end-diastolic volume ratio, and decreased longitudinal shortening and myocardial phosphocreatine/adenosine triphosphate ratio (all p < 0.01). Peak arterial–venous oxygen difference (p < 0.05), oxygen uptake (VO2) and power were decreased in patients (both p < 0.01) with no significant difference in cardiac power output. All patients remained stable and completed ≥ 80% sessions. With training, there were similar proportional increases in peak VO2, anaerobic threshold and work capacity in patients and controls. LVMI increased in both groups (p < 0.01), with no significant effect on myocardial function or bioenergetics. Pre- and post-exercise training, HRV and BPV demonstrated increased low frequency and decreased high frequency components in patients compared to controls (all p < 0.05).

Conclusion

Patients with mitochondrial disease and controls achieved similar proportional benefits of exercise training, without evidence of disease progression, or deleterious effects on cardiac function. Reduced exercise capacity is largely mediated through skeletal muscle dysfunction at baseline and sympathetic over-activation may be important in pathogenesis.

Keywords

Mitochondrial DNA
Endurance exercise
Autonomic function
Cardio-pulmonary exercise testing
Cardiac magnetic resonance imaging
Cardiac magnetic resonance spectroscopy

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Funding: This work was supported by the Wellcome Trust [BH092142 to MGDB, 096919Z/11/Z and 074454/Z/04/Z to DMT and RWT]; the Medical Research Council [G1100160 to KGH, G0601943 to DMT and G0800674 to DMT and RWT]; the UK National Institute for Health Research Biomedical Research Centre for Ageing and Age-related Diseases award to Newcastle upon Tyne Hospitals NHS Foundation Trust [for DMT, GSG and cardiac tagging software]; the British Heart Foundation [CH/07/001 to BDK]; and the UK NHS Specialized Services and Newcastle upon Tyne Hospitals NHS Foundation Trust that support the ‘Rare Mitochondrial Disorders of Adults and Children’ Diagnostic Service [http://www.mitochondrialncg.nhs.uk].

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All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

1

These authors contributed equally to this work.