ACE-Inhibitor Reverses Heart Enlargement, Cuts Cardiovascular Risk

The drug ramipril reversed or prevented left ventricular hypertrophy (LVH) in individuals without hypertension or in those with controlled hypertension. Ramipril, also known by the trade name Altace, is an angiotensin-converting enzyme (ACE) inhibitor.

ACE inhibitors expand blood vessels and decrease resistance to ease blood flow and reduce the heart’s workload. Initially approved in 1991 as an anti-hypertensive, the U.S. Food and Drug Administration later broadened that approval to include prevention of heart attacks and strokes.

This study by James Mathew, M.D., associate professor of medicine at the University of Iowa College of Medicine, Iowa City, and other researchers from the landmark Heart Outcome Prevention Evaluation (HOPE) study by Salim Yusuf, Ph.D. of McMaster University, Canada, and the Canadian Cardiovascular Collaborators, found that ramipril causes regression and prevention of LVH in a broad range of patients with normal or controlled blood pressure with or without coronary artery disease.

In LVH, or enlarged heart, the heart’s main pumping chamber becomes enlarged as a result of an increased workload that may be caused by hypertension or valvular disease. With time, the fibers of the heart muscle thicken and become less able to relax. This reduces the heart’s capacity to meet the output demands of normal circulation.

In this HOPE sub-study, researchers examined the electrocardiograms (ECG) of 8,281 patients at the beginning and end of the 4.5-year study, comparing the prevalence, regression or development of LVH, together with patient outcomes such as heart attacks, stroke and heart failure.

The full HOPE trial compared the effects of ramipril in addition to standard therapy, with placebo and vitamin E in about 9,500 patients at high risk for cardiovascular events.

Results announced in 1999, showed ramipril reduced the risk of cardiovascular deaths by 25 percent and heart attack by 20 percent and stroke by 32 percent, says Mathew.

Here, in the sub-study, researchers found that ramipril either prevented or caused gradual regression of LVH, independent of blood pressure reduction, in 91.9 percent of patients.

The rate of strokes, heart attacks and cardiovascular deaths among those who did not develop LVH or experienced regression was 12.3 percent, while the rate was 15.8 percent among individuals who developed LVH or experienced no regression.

The risk of developing congestive heart failure was 9.3 percent among those with regression or prevention and 15.4 percent in the group with LVH development or persistence.

Since the regression was independent of blood pressure reduction, researchers suspect that ACE inhibitors have a direct effect in causing regression.

By identifying and monitoring changes in LVH status by electrocardiogram (ECG), it is possible to predict outcomes for patients with the condition. ECGs are recommended as a part of routine evaluation of patients with hypertension.

Mathew believes it should now become part of routine evaluation of high-risk patients regardless of blood pressure levels. “What we know so far about left ventricular hypertrophy is that if the condition is confirmed by electrocardiogram or echocardiogram, it predicts a worse prognosis for the heart patient,” says Mathew.

“But until now, no agent has been shown to lower risk by causing a regression of LVH. We think we can now reduce the risk of cardiovascular events and death by regression of LVH using ECG markers. The ECG is easily applied and relatively inexpensive.”

Interestingly, 90 percent of those receiving placebo also experienced prevention or regression. Researchers call this “intriguing,” but say it may be related to other risk factor modifications among those who participated in the clinical trial.

In an accompanying editorial, Gregory Y.H. Lip, M.D., professor of cardiovascular medicine, at the University Department of Medicine, City Hospital, in Birmingham, U.K., praised the study.

“This large, important study represents one of the first that convincingly demonstrates that reversal of LVH results in a clinical benefit, in a population at high risk of heart problems,” he says. “Speculation now arises on the mechanism(s) by which this occurs, as they may lead to a greater understanding of how heart disease develops, especially since the benefits were also seen in patients without hypertension.”

Lip writes that regression among placebo subjects raises the question of how “typical” are individuals enrolled in clinical trials. They are motivated patients; they receive careful follow-up care, education, and lifestyle modification advice. “A placebo-control group may not be truly ‘untreated’ . . .,” he says.

He also notes that it is unclear whether ECGs can provide an accurate diagnosis of LVH, writing that “although the ECG is a useful screening tool for LVH, it has a relatively low specificity and sensitivity.”

Co-authors are Peter Sleight, M.D.; Eva Lonn, M.D.; David Johnstone, M.D.; Janice Pogue, Ph.D.; Qilong Yi, Ph.D.; Jackie Bosch, Bruce Sussex, M.D.; Jeffrey Probstfield, M.D.; and Salim Yusuf, Ph.D.