Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder, meaning that it takes just one parent to be a carrier of the disease to pass the defect to the child. HCM is the most common cause of sudden cardiac death in the young and affects one in every 500 individuals, including professional athletes. It is characterized by enlargement of the left ventricle, the heart's main pumping chamber.
More than 140 disease-causing mutations for HCM have been identified in up to 10 genes. The most common is a mutation in the gene for the beta-myosin heavy chain - a major component in heart muscle. Myosin is one of the proteins responsible for contraction of heart muscle.
"However, many individuals with the most common mutation do not manifest hypertrophy until later in life; therefore, it is very challenging to identify the disease in time to help people," says Scott Solomon, M.D., director of noninvasive cardiology at Brigham and Women's Hospital, Cardiovascular Division and Harvard Medical School in Boston.
"Thickened hearts indicate hypertrophic cardiomyopathy, but not all individuals will develop this thickening. We wanted to find a way to diagnose the disorder earlier in the disease process," says Solomon.
Solomon and researchers led by Carolyn Y. Ho, M.D., used a relatively new imaging technique called Doppler tissue imaging (DTI), which is a real-time noninvasive ultrasound procedure that shows how fast the heart muscle moves during contraction and relaxation.
Researchers found that individuals who had HCM tended to have lower velocities during the relaxation phase of the cardiac cycle.
Three groups of individuals were studied: Eighteen individuals with left ventricular hypertrophy and a genetic defect in the beta-myosin gene for cardiomyopathy, 18 who had the genetic defect but did not have hypertrophy, and 36 healthy individuals. Their ages ranged from 24 to 36.
Researchers found that the left ventricular ejection fraction was significantly higher and early diastolic velocities were significantly lower in those with the beta-myosin gene mutation, regardless of whether they had left ventricular hypertrophy.
Researchers determined a cut-off velocity of 13.5 centimeters per second (cm/sec) as being about 86 percent accurate in identifying individuals with the genetic defect. The combination of ejection fraction of greater than 68 percent and early diastolic myocardial velocity of less than 15 cm/sec was 100 percent specific and 44 percent sensitive in predicting affected genotype.
"Although velocity alone was not sufficiently sensitive as a sole diagnostic criterion, the combination of early diastolic myocardial velocity and ejection fraction was highly predictive of the gene mutation in individuals without overt manifestations of the disease," he says.
According to Robert Roberts, M.D., Don W. Chapman Professor of Medicine, Baylor College of Medicine, who wrote an accompanying editorial: "Familial hypertrophic cardiomyopathy is a most unusual and puzzling disease. The heart is supernormal and thus not infrequently seen in the most elite of athletes. It is treacherous since sudden death is often the first manifestation, yet elegantly clothed in deception since the defect is present from conception."
Roberts further notes that knowledge of genetics has advanced rapidly with at least ten genes for cardiomyopathy identified and over 150 mutations for the disease. However, there are several barriers to the clinical application of this knowledge.
"Multiple genes make screening individuals formidable in terms of cost and time, thus there is a need to develop a rapid and accurate method. This new technique may be one answer," says Roberts.
Hypertrophy seldom develops prior to puberty. The new tissue Doppler imaging offers some promise for diagnosis in younger individuals, says Roberts. He says it also demonstrates that diastolic abnormalities may be an early sign and potential trigger leading to hypertrophy.
"Advances like this one may make a difference with this disease as well as help us understand and prevent sudden death in our population, particularly in young athletes," says Roberts.
Solomon's co-authors are Nancy K. Sweitzer, M.D., Ph.D.; Barbara McDonough; Barry J. Maron, M.D.; Susan A. Casey; J.G. Seidman, Ph.D.; and Christine E. Seidman, M.D.
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