Mutant Gene Predicts Heart Disease
Heart failure is the only major cardiovascular disease that continues to increase in incidence, with 400,000 new cases diagnosed in the U.S. each year. Heart failure is now the most common cause of death among patients 65 years of age and older. Moreover, the prognosis for heart failure patients remains poor, with a 50% mortality rate within five years of diagnosis. Japanese researchers have recently identified a mutant gene that is associated with an increased risk for high blood pressure and enlargement of the left ventricle, both risk factors for heart failure.
High blood pressure is a major factor contributing to heart failure. In patients with heart failure, the heart cannot adequately continue pumping all the blood that circulates through it, resulting in a back-up of blood into the veins and fluid accumulation in the body. In response to an elevated blood pressure, the heart works harder and harder, eventually leading to compensatory enlargement of the left ventricle.
This enlargement or hypertrophy of the left ventricle is strongly associated with cardiovascular morbidity and mortality. In addition to high blood pressure, obesity, insulin sensitivity, and family history are all factors which have been linked to the development of left ventricular hypertrophy.
The gene the Japanese researchers identified encodes for angiotensin converting enzyme (ACE), which also appears to be an independent risk factor for left ventricular hypertrophy. Researchers at Shiga University studied 268 individuals chosen at random from an outpatient clinic, using ultrasound to measure the size of the patients' left ventricles. They also performed polymerase chain reaction evaluations of genomic DNA (from peripheral leukocytes) to determine the patient's ACE genotype. The study revealed that variations of the gene with two key deletions called the "DD genotype" were significant predictors of left ventricular hypertrophy..
The researchers believe that the DD genotype may stimulate increased ACE activity in heart and blood vessels. This would lead to formation of angiotensin II, a powerful hormone that constricts blood vessels and raises blood pressure. The increased blood pressure eventually leads to ventricular hypertrophy.
The current findings contribute to other experimental and clinical studies suggesting a role for the cardiac-renin-angiotensin system in the development of left ventricular hypertrophy. In particular, the data suggest intracardiac formation of angiotensin II independent of the circulating renin-angiotensin system.
ACE has long been recognized to play a role in the development of high blood pressure. Indeed, a whole class of drugs, the ACE-inhibitors, has become one of the most effective treatments for high blood pressure. However, large clinical studies have shown that treatment with ACE-inhibitors can also reduce left ventricular enlargement in those with a propensity for developing it. However, different drugs in the same class produce varying degrees of benefit. The current findings may help explain these differences.
The Japanese study complements other recent studies indicating an increased risk of heart attack and stroke in patients with the DD genotype. The findings should help in the study of the causes of heart failure in general and could lead to diagnostic tests to identify high risk patients.
For more information see: Iwai et al., Circulation, 12/94.
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