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MELAS syndrome and cardiomyopathy: linking mitochondrial function to heart failure pathogenesis

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Abstract

Heart failure remains an important clinical burden, and mitochondrial dysfunction plays a key role in its pathogenesis. The heart has a high metabolic demand, and mitochondrial function is a key determinant of myocardial performance. In mitochondrial disorders, hypertrophic remodeling is the early pattern of cardiomyopathy with progression to dilated cardiomyopathy, conduction defects and ventricular pre-excitation occurring in a significant proportion of patients. Cardiac dysfunction occurs in approximately a third of patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, a stereotypical example of a mitochondrial disorder leading to a cardiomyopathy. We performed unique comparative ultrastructural and gene expression in a MELAS heart compared with non-failing controls. Our results showed a remarkable increase in mitochondrial inclusions and increased abnormal mitochondria in MELAS cardiomyopathy coupled with variable sarcomere thickening, heterogeneous distribution of affected cardiomyocytes and a greater elevation in the expression of disease markers. Investigation and management of patients with mitochondrial cardiomyopathy should follow the well-described contemporary heart failure clinical practice guidelines and include an important role of medical and device therapies. Directed metabolic therapy is lacking, but current research strategies are dedicated toward improving mitochondrial function in patients with mitochondrial disorders.

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Acknowledgments

We are very grateful to the family of the child affected by MELAS, because the donation of the heart for research during a rapid autopsy allowed us to perform this unique study. We are also very grateful to Mr. Richard Vriend for the processing of the samples for ultrastructural investigation. The authors would like to acknowledge the physicians, surgeons, nurses and other healthcare team members that provided such prodigious care to this patient.

Funding sources

Our research was funded by operating grants from Heart and Stroke Foundation (HSF), Canadian Institutes of Health Research (CIHR) and Alberta Innovates-Health Solutions (AIHS).

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Authors and Affiliations

  1. Department of Laboratory Medicine and Pathology, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada

    Ying-Han R. Hsu & Consolato Sergi

  2. Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440 112 Street NW, Edmonton, AB, T6G 2B7, Canada

    Haran Yogasundaram, Nirmal Parajuli, Lucas Valtuille & Gavin Y. Oudit

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  1. Ying-Han R. Hsu
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Hsu, YH.R., Yogasundaram, H., Parajuli, N. et al. MELAS syndrome and cardiomyopathy: linking mitochondrial function to heart failure pathogenesis. Heart Fail Rev 21, 103–116 (2016). https://doi.org/10.1007/s10741-015-9524-5

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