Brake Job

"A larger-than-normal heart is a serious medical condition, known as 'hypertrophy,' and is a common feature of heart failure that can be fatal," says study senior author and cardiologist David Kass, M.D., a professor at the Johns Hopkins University School of Medicine and its Heart Institute. Kass is also the Abraham and Virginia Weiss Professor of Cardiology at Hopkins.

Kass chose sildenafil for his research because it was known to block an enzyme that breaks down an important molecule that serves as a "natural brake" to overgrowth in the heart.

"We thought we could more strongly apply the brake on hypertrophy in the heart if we used sildenafil to prevent the breakdown of [the key molecule] cyclic GMP," he says. The enzyme, PDE5A (phosphodiesterase-5A), also is involved preventing the relaxation of blood vessels in the penis to maintain erections.

Human Trials Planned

The Johns Hopkins findings, to be published in the journal Nature Medicine online January 23, are the first to show that sildenafil is an effective treatment for a chronic heart condition. It is also the first study to reveal that the enzyme pathway blocked by sildenafil (PDE5A), never before known to play a significant role in the heart, is active when the heart is exposed to pressure stress and hypertrophied.

The results provide some of the strongest evidence to date that blocking the heart's adaptive response to hypertrophy does not harm its function but, in fact, may improve it, Kass says. Already, plans are under way by the Hopkins researchers for a multicenter trial to test if sildenafil has the same effects on hypertrophy in humans.

Prizer, the manufacturer of Viagra, had no involvement in the design or support of the research.

Promising Results in Mice

In the first of several experiments, each involving groups of 10 to 40 male mice, the Hopkins team stimulated hypertrophy for up to nine weeks, but only by half as much in those that had also consumed sildenafil in their food at 100 milligrams per kilogram per day. In mice, this dose produces blood levels similar to those achieved in humans given standard clinical doses.

The mice fed sildenafil also showed 67 percent less muscle fibrosis, a complication that often occurs with hypertrophy, as compared to mice that were not fed the drug. The treated mice also had smaller hearts and improved heart function, whereas the untreated hearts were dilated with weakened function. For all mice with hypertrophy, the condition was surgically produced by constricting the main artery carrying blood from the heart to create pressure stress.

In a second experiment, the researchers used the same dose of sildenafil and examined its effects on reversing hypertrophy that had already occurred. Initially, these mice were exposed to pressure stress for seven to 10 days, with hearts developing fibrosis and muscle growth by nearly 65 percent. After two weeks of therapy, fibrosis and muscle growth almost completely disappeared. In mice that did not have therapy, hearts continued to get bigger.

Already Safe and Effective

In a surprising result, the researchers found that heart function, as measured by pressure-volume analysis of the muscle's ability to contract and pump blood, actually improved after hypertrophy had been stopped and treated. While researchers previously thought that hypertrophy was an adaptive response to pressure stress, the functional gains lasted despite the heart's continued exposure to high blood pressure.

Improvements were seen in more than 10 measures of heart function, including heart relaxation, cardiac output and heart contractility, which increased by nearly 40 percent. These improvements were seen even when therapy was deferred and started two weeks after hypertrophy had already developed.

"This study shows that sildenafil can make hypertrophy go away," says Kass. "Its effects can be both stopped in their tracks and reversed. Overall, the results provide a better understanding of the biological pathways involved in hypertrophy and heart dilation, leading contributors to heart failure. They suggest possible therapies in the future, including sildenafil, which has the added benefit of already being studied as safe and effective for another medical condition."

"It also suggests that less but, perhaps, the right kind of hypertrophy can be good for the heart. However, more study is required before we fully understand the benefits of sildenafil on the heart."