Rapid track articles are released online early because Circulation editors believe the work has major clinical impact or represents important basic science discoveries.
"Increasing evidence indicates that atherosclerosis is an inflammatory disease," says senior author Frank Ruschitzka, M.D., of the department of cardiology at University Hospital in Zürich, Switzerland. "Thus, anti-inflammatory agents used to treat arthritis, such as COX-2 inhibitors, may not only reduce inflammation in the joints, but could possibly have that same anti-inflammatory benefit in the vessel wall. This study is the first to show that relationship."
COX-2 inhibitors such as celecoxib (trade name Celebrex) are second-generation anti-inflammatory drugs – known as nonsteroidal anti-inflammatory drugs (NSAIDs) – used for arthritis and other inflammatory conditions. These newer painkillers are associated with a lower incidence of stomach irritation than other NSAIDs, such as aspirin and ibuprofen.
Swiss researchers studied 14 male patients, aged 46 to 77, with severe heart disease. They had standard cardiovascular therapy that includes blood-thinning aspirin and lipid-lowering statin drugs. The patients received 200 milligrams of celecoxib or placebo for two weeks. Afterwards, the groups switched treatments.
Researchers assessed endothelial function, C-reactive protein (CRP), oxidized low-density lipoprotein (ox-LDL), and prostaglandins following treatment.
Endothelial function is a measurement of how well the inner lining of the blood vessels (the endothelium) controls expansion and contraction of the vessel. If the endothelium is coated with fatty deposits, it is less able to help the blood vessel expand. Other parts of the blood vessel, such as the muscular wall of the vessel itself, are also involved in expanding and contracting, but different mechanisms control this action so it is independent of endothelial function.
A process called flow-mediated dilation of the brachial artery (in the arm) was used to measure endothelium expansion and blood flow. Celecoxib improved endothelium-dependent vasodilation by 3.3 percent, while those on placebo improved by 2 percent. As a control, the researchers also measured endothelium-independent vasodilation, induced by the drug nitroglycerin.
This measure was about the same between the placebo and treatment groups. CRP is a protein the body releases in reaction to inflammation. Elevated levels are associated with increased risk for cardiovascular disease. CRP levels were 1.3 mg/L after celecoxib, compared with 1.8 mg/L after placebo.
Ox-LDL is a form of LDL (the so-called "bad" cholesterol) that has combined with oxygen and is considered more dangerous than LDL because it promotes clogging of blood vessels. Levels of ox-LDL were 43.6 U/L after celecoxib compared with 47.6 U/L after placebo.
Prostaglandins, which contribute to the proper functioning of the stomach, were the same between the two groups.
"This is the first study to demonstrate that a selective COX-2 inhibitor on top of standard therapy improves endothelial function and reduces markers of inflammation and oxidative stress in patients with coronary artery disease," write the researchers.
Another important finding is that celecoxib improves nitric oxide (NO)–mediated endothelial function. NO is important in maintaining blood vessel tone. Decreased nitric oxide production may indicate heart disease progression.
"The findings of the present study show that celecoxib improves NO-mediated endothelial function, which in turn may help improve blood vessel function."
The researchers further explain the significance of reduced ox-LDL as a major cardiovascular benefit of celecoxib therapy by noting that there is an increasing body of evidence that oxidative stress, such as high levels of ox-LDL, is a major culprit of endothelial dysfunction. They also add "there is evidence that COX-2 may be a source of oxygen radicals itself, and therefore inhibition of the enzyme activity may reduce oxidative stress.
"The results of our study suggest that COX-2 inhibition with celecoxib has potential as an add-on therapy to standard treatment," such as statins and ACE inhibitors, for patients with heart disease, state the authors.
"However, the definitive answer as to the net effect of selective COX-2 inhibition on cardiovascular events can only be provided by well-designed large-scale clinical trials," says Ruschitzka.
Co-authors are Rémy Chenevard, M.D.; David Hürlimann, M.D.; Markus Béchir, M.D.; Frank Enseleit, M.D.; Lukas Spieker, M.D.; Matthias Hermann, M.D.; Walter Riesen, Ph.D.; Steffen Gay, M.D.; Renate Gay, M.D.; Michel Neidhart, Ph.D.; Thomas F. Lüscher, M.D.; and Georg Noll, M.D.
NR03-1001 (Circ/Ruschitzka)
CONTACT: For journal copies only,
please call: 214-706-1396
For other information, call:
Carole Bullock: 214-706-1279
Maggie Francis: 214-706-1397