Troponin genes offer new insights to familial heart failure

Mutations in the troponin protein complex may be useful for predicting the course of heart failure due to dilated cardiomyopathy and also for guiding treatment and research, according to a new study in the Nov. 16, 2004 issue of the Journal of the American College of Cardiology.

“Mutations in the troponin genes were not uncommon in dilated cardiomyopathy,” said Jens Mogensen, M.D., Ph.D. “All individuals with mutations had signs and symptoms of disease. Overall, the affected individuals had a severe prognosis. The data suggest that genetic investigations of the troponin genes may help to identify a subset of dilated cardiomyopathy families at high risk of rapid disease development. This may hopefully lead to improved management and prognosis,” Dr. Mogensen said.

Dr. Mogensen performed the research with colleagues at St. George’s Hospital Medical School in London, Harefield Hospital in Middlesex and John Radcliffe Hospital in Oxford, United Kingdom. The work was supported by the British Heart Foundation. Dr. Mogensen is now at Skejby University Hospital in Arhus, Denmark.

This study is the largest of its type examining mutations in the troponin complex. This protein complex, which has three subunits called troponin I (TnI), troponin T (TnT) and troponin C (TnC), plays a crucial role in muscle contraction and relaxation. This study is the first to detect a link between troponin C and dilated cardiomyopathy.

The researchers performed genetic investigations of 235 consecutive patients with dilated cardiomyopathy of unknown causes. Dilated cardiomyopathy ran in the families of 105 of the 235 patients (43 percent). Of the patients in families with dilated cardiomyopathy, 5 percent carried troponin C and T mutations, and all of those who had these specific mutations developed severe disease (full penetrance).

“Functional studies showed impairment of mutated troponin interaction compared to normal protein indicating an altered regulation of heart muscle contractions. The data suggest that mutation analysis of the troponin complex in dilated cardiomyopathy patients may prove valuable in early identification of individuals with adverse prognosis and high risk of premature death. Since current heart failure therapy is very effective and has improved prognosis considerably, early diagnosis of ‘at risk individuals’ may lead to improved management and survival,” Dr. Mogensen said.

“The importance of genetic diagnosis is to identify those individuals in a heart failure family who carry a mutation before they develop signs and symptoms of disease. These individuals are at risk of disease development later in life and should undergo regular follow up to enable early diagnosis and thereby ensure early treatment to improve their prognosis,” he added.

Besides identifying patients who may benefit from early or intensive treatment, the genetic clues suggest areas for basic research into the causes and mechanisms of dilated cardiomyopathy.

“More sophisticated protein interaction studies of the mutations identified are needed to elucidate the mechanisms leading to dilated cardiomyopathy. Once these mechanisms are fully understood, it may be possible to develop specific drugs to try preventing disease development in this category of patients, although it will be difficult. The disease is transmitted with dominant inheritance, which implies that affected individuals are likely to harbor both normal and mutated protein. The mutated protein may have a poisonous effect on cell function and dominate the function of normal protein, which makes development of disease-preventing drugs very complex,” Dr. Mogensen said.

In an editorial authored with R. John Solaro, M.D., Jeffrey A. Towbin, M.D., F.A.C.C., at the Baylor College of Medicine in Houston, wrote that the novelty of this genetic finding and the specific location of the mutation make these results especially interesting. Dr. Towbin noted the poor outcomes of patients with these mutations, as well as the fact that symptoms did not appear before age 16, which may offer clues to how the condition develops.

“Dilated cardiomyopathy runs in families, that is, it is inherited. If someone in a family is diagnosed, other close relatives should be evaluated,” Dr. Towbin said.

But the editorial noted that the findings of this study need to be confirmed.

“Caution, however, should be maintained regarding genotype-phenotype correlation interpretations. Many previous studies on cardiac genetics have suggested ‘benign’ or ‘malignant’ outcomes related to gene mutations, and many of these have later been shown to be inconsistent and nonspecific. Whether these mutations determine the outcome or whether the small number of patients and potential selection bias is responsible for the appearance of a cause and effect relationship remains to be proven,” the authors wrote in their editorial.

Comments by other researchers not connected with this study were mixed.

Akinori Kimura, M.D., Ph.D., at the Tokyo Medical and Dental University in Japan said it was striking that troponin mutations were found in 5 percent of the cases of familial dilated cardiomyopathy and that the mutations were associated with severe clinical courses.

“This is clinically important in that one may find malignant troponin mutations in the preclinical stage of dilated cardiomyopathy in individuals having a family history of dilated cardiomyopathy,” Dr. Kimura said. “These studies suggest that a therapeutic target for cardiac failure may be the troponin complex.”

Meanwhile, Calum A. MacRae, M.D., Ph.D. at Massachusetts General Hospital in Boston praised the methodology of this study. However, he said he is skeptical that these results will be immediately useful in heart disease clinics.

“It’s not a perfect study, but it’s a large and very well-executed study combining patients with dilated cardiomyopathy and their family members, yet it just doesn’t come close to allowing us to make any meaningful predictions from genetics,” Dr. MacRae said. “It really demonstrates just how difficult it is going to be to use genetics to make risk prediction a reality.”

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