Researchers Probe Aortic Stenosis

Chicago—An age-old problem may not be an old-age phenomenon as conventional wisdom has believed.

The cardiology community has long assumed that aortic stenosis is a wear-and-tear, degenerative process caused, in part, by a heart beating for many decades. But research over the past few years suggests a different, more active, cause—lipoprotein deposits and inflammation of the aortic valve, with resulting calcification and ossification.

And if it is an active process, then medical therapy, such as statins or angiotensin-converting enzyme (ACE) inhibitors, may delay or possibly prevent clinical aortic valvular disease, even allowing patients to avoid valve replacement surgery, said Kevin D. O'Brien, MD, at the American College of Cardiology annual Scientific Session, held here on March 30-April 2.

"Over the past few years we've changed the evidence and then raised the possibility that if the process is atherogenic, then maybe targeting this would slow the rates of calcium formation," said O'Brien, who is an associate professor of medicine in the division of cardiology at the University of Washington in Seattle.

Preliminary research has supported this hypothesis. Researchers from the Mayo Clinic in Rochester, Minn, found that among 38 patients treated with statins, the odds ratio of aortic stenosis progression was 0.46 compared with 118 untreated patients (J Am Coll Cardiol. 2002;40:1723-1730). O'Brien and colleagues conducted a retrospective analysis of 65 patients. Twenty-eight patients received statins and the therapy was associated with about a 63% lower rate of aortic valve calcium accumulation (Lancet. 2002;359:1125-1126). And a retrospective study by researchers from the Cleveland Clinic in Cleveland, Ohio, found that 57 patients who received statins had an annualized mean decrease in aortic valve area of 0.06 cm² compared with a decrease of 0.11 cm² in 117 patients who were not taking statins—demonstrating a significant reduction in aortic stenosis progression in the treated group (Circulation. 2001;104:2205-2209).

An analysis of 21 human aortic valves by O'Brien and colleagues found that ACE was not detected in normal valves, but was present in all valves with lesions, suggesting a possible role for ACE inhibitors in the treatment of aortic stenosis (Circulation. 2002;106:2224-2230). The researchers said ACE was found in association with low-density lipoprotein (LDL) cholesterol, which raises the possibility that LDL carries the ACE into lesions, where the enzyme then contributes to aortic stenosis.

The relatively slow shift among researchers to perceiving aortic stenosis as an active process is due to three barriers, O'Brien said. First, the model of aortic stenosis as a degenerative process was a widely accepted concept. Second, appropriate animal models to develop clinical tests were lacking. Third, researchers had no method to identify and monitor early disease in humans.

Studies by researchers from Northwestern University in Chicago and the Mayo Clinic are helping to overcome the first barrier. Using a hypercholesterolemic rabbit model, these investigators showed evidence of a proliferative, atherosclerosislike process in the aortic valve, with increased numbers of macrophages and proliferation cell nuclear antigen levels and bone matrix proteins (Circulation. 2002;105:2660-2665).

"Aortic stenosis has not really been studied for a long time," said Nalini M. Rajamannan, MD, an associate professor in the division of cardiology at Northwestern's Feinberg School of Medicine. "But we found these valves are developing atheroscleroticlike lesions."

While Rajamannan's rabbit model provides insight into the origins of aortic stenosis, it does not quite surmount the second barrier. In other words, it is not a perfect model of the human disease and does not allow full understanding of the disease process, according to O'Brien.

"Rajamannan is feeding rabbits large amounts of cholesterol and getting inflammation but not calcification," O'Brien said. "So you're getting atherosclerosis, and there's an analogy of people with high LDL cholesterol levels also getting valve disease, but it's different histologically."

As for the third barrier, O'Brien said that until recently, imaging technology was unable to detect aortic sclerosis, which is thought to be the asymptomatic precursor of hemodynamically significant aortic stenosis. But that has changed with advent of electron beam tomography (EBT). Now clinicians have a tool to monitor aortic valve pathology in vivo and perhaps offer treatment prior to onset of aortic stenosis.

(In this issue, researchers present results from a study evaluating the use of coronary artery calcification screening by EBT to motivate patients to reduce coronary heart disease risk factors. See page 2215 and an accompanying editorial on page 2270.)

"Echocardiography can monitor progression in the late stage of the disease," O'Brien said. "But what about the three decades prior when it's growing in a patient? This may be a good time to target the disease with therapy. But you have to measure it, and now we can."

So while O'Brien's second barrier has yet to be breached, many researchers are now calling for large randomized therapeutic trials to determine the correct approach to treating aortic sclerosis and stenosis.

"The time is right for clinical trials," said Robert O. Bonow, MD, president of the American Heart Association. "But these trials will be difficult to conduct because the risk factors for aortic valve calcification appear to be the same for atherosclerosis, so your subject population may already be on an ACE inhibitor or statin."

For these reasons, Rajamannan said a placebo-controlled trial would be inappropriate.

"We're hoping for a prospective trial where we randomize perhaps to low and high dose of statin therapy to see what is needed to reduce this progression," Rajamannan said.

Another question centers around the uniqueness of the potential patient populations who may benefit from statin or ACE inhibitor therapy. After all, a large percentage of patients at various stages of risk for cardiovascular disease will already be receiving medical therapy—the same treatment proposed for aortic stenosis.

O'Brien said he is not convinced the populations will be the same.

"If you define atherosclerosis as having obstruction to blood flow in the arteries, then there's not a great relationship between that and aortic stenosis," O'Brien said. "So it's not a perfect correlation that everyone with calcific aortic valve disease also has cardiovascular disease."

For Rajamannan, even if the two populations are shown to benefit from the same medical therapies, prospective trials are needed to fine-tune such treatment.

"These populations need to be defined, and we need guidelines for treatment of aortic sclerosis," Rajamannan said.