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NEJM
Arnold Strauss, M.D., and James E. Lock, M.D. Improvements in the treatment of congenital heart disease are among the most impressive medical achievements of the second half of the 20th century. In 1950, patent ductus arteriosus and aortic coarctation were the only correctable lesions, and the likelihood that an infant who received a diagnosis of heart disease in the 1960s would survive the first year of life was only 60 percent, whether treated medically or surgically.1 Between 1979 and 1997, infant mortality from heart disease declined by 39 percent,2 and survival rates continue to improve. In many centers, one-year survival rates for infants undergoing heart surgery now exceed 95 percent. Despite these striking advances in treatment, the genetic causes of structural heart disease have only begun to be identified in the past 10 years.3 The results of the treatment of cardiomyopathies in children stand in stark contrast to the successes with the treatment of congenital heart disease. The availability of sophisticated medical management has not yet altered the death rate or the need for transplantation in these children.4 Almost 40 percent of children with symptoms of cardiomyopathy ultimately die of the condition or require cardiac transplantation, and this percentage has remained unaltered by decades of medical research.5,6 In the face of this lack of therapeutic progress, in this issue of the Journal, Nugent et al.7 and Lipshultz et al.8 approach the problem of pediatric cardiomyopathies from an epidemiologic point of view, defining the scope of the problem and providing important insights that may well guide future therapies. There are several major findings of these two elegant studies. First, they used different ascertainment procedures to document an annual incidence of pediatric cardiomyopathy between 1.13 and 1.24 cases per 100,000 children in regions as geographically diverse as the American Southwest, the American Northeast, and the Australian continent. These rates are higher than those reported in prior series.9 Second, both studies prove that the highest incidence of pediatric cardiomyopathy is in the first year of life, with almost half of all cases ascertained by this age, an incidence that is 8 to 12 times as high as that at older ages. Awareness of this result should prompt early diagnostic evaluation in infants with signs and symptoms of congestive heart failure (dilated cardiomyopathy) and a family history of cardiomyopathy. A second peak occurs in adolescence. Third, both reports demonstrate racial and ethnic differences in incidence, with higher incidences among black and Hispanic children than among white children in the United States and a higher incidence among indigenous children than nonindigenous children in Australia. These differences suggest that genetic or environmental factors, such as susceptibility to viral infections or exposure to toxins, can alter the incidence. Fourth, both studies found a significant difference in the incidence according to sex. The reason for this difference is that mutations in the dystrophin gene (in the case of Duchenne's and Becker's muscular dystrophies) and the tafazzin or G4.5 gene (in the case of the Barth syndrome), which are located on the X chromosome, are relatively common causes of cardiomyopathy in boys. Fifth, both reports emphasize the large familial component of cardiomyopathy, which represents 9 percent (42 of 467 cases)9 to 20 percent8 of cases. These must be minimal estimates, because there was no consistent evaluation of family members. These results and similar findings in many other studies10,11 emphasize the major role that genetic causes have in the pathogenesis of cardiomyopathy, in both adults and children. On the basis of these results, we would recommend that first-degree relatives of children with cardiomyopathies undergo clinical, echocardiographic, and laboratory evaluation. These studies have some important limitations. A minority of specific causes are reported; 57 to 68 percent of cases are described as idiopathic or unclassified. Among the remaining cases, the American study reports a specific diagnosis in only 17.5 percent, including 2 percent with documented myocarditis and 3 percent with probable myocarditis. The Australian group reports an overall incidence of confirmed or probable myocarditis of 24 percent. This discrepancy is distressing, considering that both groups used the Dallas criteria to make this pathological diagnosis. As was the case in many previous studies, the diagnosis of myocarditis may be subjective, depending on who examines the sample. Alternatively, the difference may be explained by differences in susceptibility to viral infection. Neither group reports specific viral causes of myocarditis. The diagnosis of viral myocarditis relies on serologic, culture, polymerase-chain-reaction (PCR), and pathological criteria. We recommend that a careful search for viral infection, with the use of cardiac biopsy and PCR analysis, be considered in all patients with dilated cardiomyopathy. A second limitation is that the authors rely on the World Health Organization's functional categorization of dilated, hypertrophic, and restrictive cardiomyopathy. Although this classification is helpful in the assessment of possible causes, the clinical course, and treatment, further studies to determine the underlying causes are clearly necessary. Finally, minimal outcome data are reported: the U.S. group reported a two-year survival rate of 83 percent overall, with an additional 7 percent of patients undergoing transplantation, and the Australian group reported that 3.5 percent of cases were diagnosed initially at autopsy. Clearly, longer follow-up of these nearly 800 children is necessary to help us understand the risks and outcomes over time and to tease out differences in outcome according to functional and etiologic classifications. These and other recent studies prompt two questions: Why have the childhood cardiomyopathies been so resistant to advances in biomedical understanding and treatments, and how can we materially improve this outcome? In our view, the key to an understanding of these disorders is the realization that many cases have underlying genetic causes. Environmental toxins such as cardiotoxic drugs, nutritional and trace-element deficiencies, maternal diabetes, and infectious agents are known causes, but these account for a minority of cases of cardiomyopathy. Nonetheless, these causes of cardiomyopathy are treatable, and the underlying dysfunction is usually reversible. Much of cardiomyopathy is familial,8,9 suggesting that there are multiple genetic causes. Over the past 20 years, mutations in more than 30 specific genes have been implicated, including sarcomeric proteins such as the myosin heavy chain, myosin-binding proteins, and troponins in hypertrophic cardiomyopathy and cytoskeletal proteins such as dystrophin, desmin, taffazin, lamin, titin, and actin in dilated cardiomyopathy. Mutations in calcium-metabolizing genes12 and cell-signaling molecules such as adenosine monophosphate�activated protein kinase also cause cardiomyopathy.13 In addition, mutations in enzymes and transporters essential for myocardial energy production in mitochondria, such as the fatty-acid�oxidation enzymes, the carnitine transporter, and components of the respiratory-chain oxidative phosphorylation pathway, have been documented to cause cardiomyopathy. In a few instances, such as those involving deficiencies of the carnitine transporter and fatty-acid�oxidation enzymes, specific treatments reverse the cardiomyopathy.14,15 This outcome proves that an understanding of the specific genetic cause of cardiomyopathy can result in specific curative treatments, a potential paradigm for the future. In the current era of genomics and proteomics, discovering the genetic causes of pediatric and adult cardiomyopathy is becoming increasingly simple and rapid, providing hope that directed therapies can be developed. The current treatment for cardiomyopathy is usually transplantation. Although the rates of long-term survival with the use of immunosuppression are impressive, cardiac transplantation is unlikely to result in a normal life expectancy in children with cardiomyopathy. Recent findings suggest that novel therapies may be on the horizon. For example, several studies show that stem cells can be isolated, amplified in culture, and manipulated to differentiate into cardiomyocytes. After injection or implantation, small numbers of such cells are incorporated into functioning myocardium, raising the tantalizing possibility that stem-cell therapy may someday be used to reverse myocardial dysfunction. In addition, a recent report indicates that zebrafish myocardium16 can regenerate. As we come to understand the mechanisms that allow the regulation of regeneration in myocardium, treatment through the induction of regeneration may prove feasible, especially in patients with postinfectious and toxic cardiomyopathy.
From the Department of Pediatrics, Vanderbilt University School of Medicine, Nashville (A.S.); and the Department of Cardiology, Children's Hospital, Harvard Medical School, Boston (J.E.L.). References
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