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.