(Circulation. 1995;91:1266-1268.)
© 1995 American Heart Association, Inc.
Articles |
Cardiac Involvement in Mitochondrial Diseases, and Vice Versa
From the University of Texas Southwestern Medical Center, Dallas, Tex.
Correspondence to R. Sanders Williams, MD, Division of Cardiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, NB11.200, Dallas, TX 75235-8573.
Key Words: Editorials • cells • cardiovascular diseases • cardiomyopathy
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In this issue of Circulation, Anan et al1 describe cardiac abnormalities occurring in a small group of patients with well-defined defects in mitochondrial DNA (mtDNA). Abnormal cardiac findings, as assessed by ECG, chest radiograph, echocardiography, and His bundle electrograms, were detected in patients within each of four categories of mitochondrial diseases.
Conduction disturbances were observed uniformly in patients with Kearns-Sayre syndrome, while some patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) exhibited symmetric left ventricular hypertrophy with either normal or abnormal wall motion. Asymmetric septal hypertrophy with a hypokinetic ventricle was present in a majority of patients with MERRF (myoclonus epilepsy with ragged red fibers) and progressed over time to dilated cardiomyopathy in one individual. Cardiac abnormalities were less prevalent in patients with ocular myopathy, but diffuse hypokinesis was noted in 1 of 6 patients. Kearns-Sayre syndrome and ocular myopathy result from accumulation of deleted forms of mtDNA in affected tissues, whereas MERRF and MELAS are caused by single nucleotide substitutions in the mitochondrial tRNALys and tRNALeu genes, respectively.
Cardiac dysfunction occurring in conjuction with neuropathic and skeletal myopathic symptoms in patients with mitochondrial gene defects has been described previously in case and kindred reports, as reviewed by Wallace,2 but this recent work analyzes a somewhat larger set of patients from several diagnostic categories. The authors conclude that mitochondrial gene defects cause specific cardiac abnormalities that are characteristic of the particular molecular pathology. Only a small number of patients within each category of mitochondrial disease were studied, and the clinical assessments were neither comprehensive nor highly detailed. Patients with apparently normal hearts were not subjected to provocative stimuli that may have unmasked more subtle abnormalities. Nevertheless, this fundamental conclusion appears to be justified and parallels the clustering of specific clinical manifestations of encephalomyopathy in patients harboring particular mutations in mitochondrial DNA.
Cardiac involvement in mitochondrial genetic diseases is, therefore, a prominent feature of these disorders. While the well-defined mitochondrial genetic diseases examined by Anan and colleagues1 are relatively rare, increased awareness among clinicians has led to more frequent diagnosis, and scores of studies describing small groups of patients have appeared in the last few years. Phenotypic abnormalities in individuals bearing these genetic defects may be evident at birth or may not be apparent until later ages. The lay press gave prominent attention in 1994 to the diagnosis of mitochondrial myopathy in a former champion of the Tour de France. Mitochondrial gene defects are transmitted in the germ line only from the maternal side, but some kindreds with mitochondrial gene defects, particularly those involving deleted forms of mtDNA, demonstrate a mendelian pattern of inheritance, indicating defects in nuclear genes that control features of mtDNA replication. Some patients also present without affected relatives, representing apparently new mutational events.
Current treatment of patients with mitochondrial gene defects is unsatisfactory, and no animal models are available for testing potential therapeutic strategies. In addition, the recent, spectacular progress in defining the molecular pathology of these diseases currently holds little immediate promise for development of gene therapy, since no clinically relevant techniques for introduction of foreign DNA into mitochondria of mammalian cells have been developed. Innovative strategies are needed to offer these patients any real prospect of effective treatment.
While the importance of cardiac involvement in mitochondrial diseases is now clear, what about the converse issue—the role of mitochondrial gene defects in the general population of patients presenting with cardiac symptoms?
A quantitative deficiency of mtDNA has been observed in HIV-infected patients treated with nucleoside analogues and is proposed to contribute to myopathic symptoms in these individuals.3 4 Mitochondrial gene defects also have been noted in patients with doxorubicin-induced cardiomyopathy and myotonic dystrophy.5 6 Other investigators have detected mtDNA deletions and/or point mutations in hearts from patients with chronic ischemic heart disease, dilated cardiomyopathy, and hypertrophic cardiomyopathy.7 8 9 10 11 12 Even in the absence of clinical heart disease, accumulation of mutated forms of mtDNA occurs in association with advancing age.13 It is unusual to detect mtDNA abnormalities in healthy young individuals, but sensitive PCR-based screening techniques identify mutated forms of mtDNA in tissues from many older persons.14 15 16 17 18 19 20 21
A unifying hypothesis has emerged to account for these clinical observations. Neurons and cardiomyocytes exit from the cell cycle in the early neonatal period, such that nuclear DNA replication virtually ceases in these cells. Replication of mitochondrial DNA, by contrast, continues for the lifetime of the organism, and mutations arise at some finite rate, which may be augmented by disease. Transient ischemia and reperfusion, for example, may stimulate intramitochondrial generation of free radicals that act locally on nucleotide bases within the mitochondrial genome.22 23 24 DNA repair mechanisms are poorly developed or lacking in mitochondria, and abnormal forms of mtDNA are replicated in conjunction with wild-type forms. Certain mutated forms of mtDNA exhibit a replicative advantage,25 and the proportion of mutated versus wild-type forms may increase over time. In long-lived cardiomyocytes, the combination of enhanced replication of mutated genomes and a finite rate of new mutations will increase the relative abundance of abnormal forms of mtDNA. Since cell division has ceased, there is no opportunity for differential segregation of mutant mtDNAs to daughter cells, which otherwise may mitigate the consequences of mtDNA mutations in rapidly dividing cell populations.
This line of reasoning is plausible and consistent with most of the existing data. Controversy arises, however, with respect to the question of whether the accumulation of mutated forms of mtDNA seen in the aged, ischemic, or cardiomyopathic heart is physiologically relevant and contributes to myocardial dysfunction. In theoretical terms, heteroplasmy (the presence of a mixed population of mutated and wild-type mitochondrial genomes within the same cell) should protect the myocardial cell from phenotypic abnormalities resulting from a small proportion of abnormal genomes. As long as a sufficient number of wild-type genomes are present to supply essential mitochondrial gene products, cell viability and function should be preserved, unless the mitochondrial DNA mutation exerts a dominant negative effect.
This concept has been tested experimentally in cultured cells by King and Attardi,26 who used an elegant organelle transfer method. Cells devoid of mtDNA can be generated in culture by long-term growth in the presence of increasing concentrations of ethidium bromide.27 Such cells exhibit defective respiration but can meet energy demands through glycolysis and remain viable if supplemental pyruvate and uridine are provided. Respiratory sufficiency can be restored to such mtDNA- cells by microinjection of mitochondria containing wild-type mtDNA isolated from other cells. If mitochondria are isolated from patients with inherited mitochondrial gene defects, the ability to restore respiratory function with given proportions of mutant to wild-type mtDNA can be assessed. Using this system, Chomyn et al28 concluded that respiratory function was perturbed only when mutant mitochondrial genomes (tRNALys mutant from a patient with MERRF syndrome) represented a majority of the total population. In human skeletal muscles, a similarly large fraction of mutant genomes appears to be required before clinical difficulties ensue.29
Little information is available, however, to determine what burden of mutant mtDNAs can be borne without physiological compromise by contracting cardiomyocytes or specialized cells of the cardiac conduction system. Results generated under artificial conditions of cell culture may not be applicable to the intact, contracting myocardium, with its high demand for oxidative metabolism and distinctive cellular architecture. In senescent human skeletal muscles, individual myocytes with defective respiration are observed,30 suggesting that mtDNA abnormalities may accumulate to levels sufficient to impair mitochondrial function in individual cells. Defective respiration also may occur in cardiomyocytes from patients with inherited hypertrophic cardiomyopathy,31 who demonstrate a higher prevalence of abnormal mitochondrial genomes.11 In the hypertrophic or ischemic myocardium, otherwise mild deficits in respiratory capacity may tip the balance toward functional decompensation. The resolution of this issue remains a major challenge to investigators in this field.
As described in a recent review by Luft in the Proceedings of the National Academy of Sciences,32 "mitochondrial medicine" is an expanding discipline, and a greater awareness of this interesting family of disorders should increase the likelihood that these patients will be appropriately identified and managed. Cardiologists and internists should be aware of the cardiovascular manifestations that may accompany other symptoms in many of these patients. The true prevalence of mitochondrial disease among the general population of patients with myocardial dysfunction remains unknown.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Received December 24, 1994; accepted December 27, 1994.
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References |
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TopIntroductionReferences |
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