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Cardiac manifestations of mitochondrial disorders.

This letter was referred to Dr. Deborah E. Meyers and colleagues, who reply in this manner: 
 
We appreciate the thoughtful response of Finsterer and Zarrouk-Mahjoub to our article on cardiac manifestations of mitochondrial disorders.1 Their letter emphasizes the increasingly recognized role that mitochondrial dysregulation probably plays in a broad range of cardiovascular and age-related disorders. Finsterer and Zarrouk-Mahjoub point out that pulmonary artery hypertension (PAH) should have been included in our Table I, which lists common clinical manifestations of mitochondrial disorders. They cite 2 reports of rare syndromes to support this view. The first syndrome, HUPRA (hyperuricemia, PAH, renal failure in infancy, alkalosis), has been observed in infants and is associated with a mutation in the SARS2 gene, which encodes mitochondrial seryl-tRNA synthetase.2,3 The 2nd rare syndrome cited is microphthalmia with linear skin lesions (MLS); it has been associated with both holocytochrome c-type synthase (HCCS), which encodes a crucial participant in the respiratory chain, and COX7B mutations.4 A panoply of congenital cardiac abnormalities is observed in MLS; PAH has been described in several cases only. The most notable aspect of these 2 reports is not the association with PAH, but the fact that both HUPRA and MLS represent true developmental phenotypes associated with mitochondrial genetic abnormalities. This is entirely distinct from the manner in which classical mitochondrial disorders are usually characterized: as a progressive postnatal organ-failure syndrome that manifests itself in multiple organs and systems. 
 
We concur with Finsterer and Zarrouk-Mahjoub that nonsyndromic PAH can be considered broadly in terms of mitochondrial dysregulation. A recent review of metabolism and bioenergetics in the right ventricle and pulmonary vasculature cited evidence that mitochondrial-metabolic abnormalities have been identified in PAH.5 Notable abnormalities in pyruvate-dehydrogenase-kinase–mediated inhibition of pyruvate dehydrogenase resulted in a “glycolytic shift” that could be detected early in the clinical course of PAH. This shift reduced contractility in the right ventricle, and the pulmonary vasculature cells became hyperproliferative and apoptosis-resistant. In our article, we attempted to stress that energy deficiency is both a cause and an effect of disease. There is always the lurking question of whether an identified mitochondrial abnormality is the cause or effect of common disease processes. 
 
Finsterer and Zarrouk-Mahjoub note that hypertension, which is a highly polygenic condition influenced by the environment, is occasionally associated with mitochondrial disorders. They cite a report by Sobenin and colleagues,6 who observed altered heteroplasmy levels of G15059G>A in patients with hypertension compared with normotensive control subjects. Confounding this observation is the demonstration of similarly altered levels of heteroplasmy (the ratio of wild-type to mutant mtDNA) in older patients (in whom hypertension is common) and in patients with hypertriglyceridemia. Further weakening the association is that heteroplasmy levels are known to be altered in a range of chronic diseases including atherosclerosis, Alzheimer's disease, and diabetes mellitus. Again, the question arises: is demonstrating an association by itself adequate to implicate a mitochondrial abnormality as causative? 
 
We agree that abnormalities of bioenergetics are increasingly recognized as major culprits in cardiomyopathy in both inherited and acquired cardiac disease. In our article,1 we made the specific point that “mitochondria are a crucial platform for energy transduction, cell signaling, and cell-death pathways even in the absence of underlying mitochondrial disease.” We also mentioned transplantation as a potential therapy for selected patients who have mitochondrial cardiomyopathies, although international experience with this approach is limited. Care would need to be paid to the “mitochondrial stress management” strategies in the peri-transplant period that we outlined. Transplantation would constitute a substantial physiologic stress for a mitochondrial-disorder patient. 
 
Although no large, multicenter, randomized, controlled trials have established mortality benefits in treating mitochondrial disorders, there seems to be a benefit from using coenzyme Q, L-carnitine, creatine phosphate, thiamine, and riboflavin in combination as part of a “mitochondrial cocktail” during crisis.7 The data are limited, but it will be interesting to see whether such medications in combination can have a synergistic effect on respiratory chain function during crisis, because most studies have involved individual drugs and stable patients with mitochondrial disorders. No well-defined dosage has been established, and individual responses to such medications can differ because of genetic differences in mitochondrial metabolism. We hope that by delineating what is known, what is not known, and what is controversial regarding available clinical management strategies, we can promote increasing recognition of mitochondrial disorders and thoughtful management, based on current knowledge. 
 
 
Deborah E. Meyers, MD, FACC 
 
Texas Heart Institute, Houston, Texas 
 
 
 
Haseeb Ilias Basha, MD 
 
Michigan State University, Flint, Michigan 
 
 
 
Mary Kay Koenig, MD 
 
The University of Texas Medical School at Houston, Houston, Texas