“In a relatively short-term study, we’ve shown that this drug has a significant effect on the stiffness of the most central of blood vessels—the aorta—which is the biggest artery in your body,” says lead author Gary F. Mitchell, M.D., a cardiologist and president of Cardiovascular Engineering, Inc., of Holliston, Mass. The aorta carries blood from the heart’s left ventricle, down the center of the body and out to all the organs.
Vessel stiffness causes an increase in systolic blood pressure. Systolic pressure is the upper number in the blood pressure reading and indicates the blood pressure when the heart is contracting. Diastolic pressure, the bottom number, reflects the pressure when heart is resting.
“Up to 50 million people in the United States have high blood pressure and over 90 percent of those people have elevated systolic pressures, which is predominantly due to increased stiffness of the larger arteries. Furthermore, only 25 percent of all patients have their blood pressure controlled with currently available medication,” says Mitchell.
“Up to this time, we’ve only had limited understanding of how various blood pressure lowering drugs affect arterial stiffness,” he adds. “Large artery stiffening was thought to be a natural irreversible part of aging. This study clearly demonstrates that the stiffness in large arteries can be reduced and that the reduction in stiffness is beyond what would be seen using drugs that lower blood pressure by other mechanisms.”
Researchers studied 167 patients with moderate high blood pressure in a 12-week double-blind trial called Conduit Hemodynamics of Omapatrilat International Research Study (CHOIRS). Participants were randomly assigned to treatment with the well-known angiotensin converting enzyme (ACE) inhibitor enalapril or the investigational drug omapatrilat, one of a new class of compounds called vasopeptidase inhibitors.
Like an ACE inhibitor, the single-molecule omapatrilat blocks production of the potent vasoconstrictor hormone, angiotensin II. It also blocks the breakdown of a family of hormones that cause vessels—especially large arteries—to dilate and become less stiff, Mitchell explains. The researchers used pulse pressure (the difference between the upper and lower numbers in a blood pressure reading) to compare the two treatments. Elevated pulse pressure is one indication of stiffening of the body’s large central vessels, Mitchell says, adding that studies by his group and others have shown that increased pulse pressure strongly predicts heart attacks, congestive heart failure, stroke and cardiovascular mortality. As a reference, normal blood pressure, which is 120/80 millimeters of mercury (mm Hg), translates to a pulse pressure of 40 mm Hg.
First, the researchers measured blood pressure in the arm, the standard way blood pressure is taken at most physicians’ offices. Omapatrilat reduced such peripheral pulse pressures by 8.2 mm Hg, while the ACE inhibitor reduced pressures by 4 mm Hg.
They also measured pulse pressure in the large aorta, closer to the heart. Omapatrilat was even more effective at reducing the central pulse pressure: a drop of 10.2 mm Hg versus a 3.2 mm Hg reduction for the ACE inhibitor. Finally, they measured the stiffness of the central aorta and demonstrated that the reductions in pulse pressure were attributable to a reduction in central aortic stiffness.
“Omapatrilat reduced central pulse pressure pretty remarkably,” says Mitchell. The two compounds had similar side effect rates, the researchers report.
Blood pressure represents a balance between the body’s natural vasoconstricting and vasodilating systems, Mitchell explains. “There are a couple of approaches to reducing blood pressure: either reduce levels of vasoconstrictors at work in the body or increase levels of vasodilators. ACE inhibitors reduce levels of vasoconstrictors. A vasopeptidase inhibitor reduces vasoconstrictors and increases vasodilators.
“We thought this was going to be a magic combination in terms of vessel stiffness and it is exactly as we had hypothesized,” Mitchell says.
“Because the effects of omapatrilat on vessel function were in excess of those achieved by the ACE inhibitor, the mechanism of action of omapatrilat may be responsible for these results,” says Marc A. Pfeffer, M.D., Ph.D., professor of medicine, Harvard Medical School and director of the clinical coordinating center for CHOIRS. “The impact of these unique properties on large vessels needs to be further studied to determine if they will translate into improved clinical outcomes.”
Co-authors include: Joseph L. Izzo, Jr., M.D.; Yves Lacourcière, M.D.; Jean-Pascal Ouellet, M.D.; Joel Neutel, M.D.; Chunlin Qian, Ph.D.; Linda J. Kerwin, M.S.; Alan J. Block, Ph.D.; and Marc A. Pfeffer, M.D., Ph.D.
Drs. Mitchell, Izzo, Lacourcière, Ouellet and Neutel have received research grants from Bristol-Myers Squibb. Dr. Pfeffer has received research grants and honoraria from the company. Drs. Qian and Block and L. Kerwin are employees of Bristol-Myers Squibb. This study was funded by a grant from Bristol-Myers Squibb Pharmaceutical Research Institute.
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