(This story has been posted on The Wall Street Journal Online's Health Blog at http://blogs.wsj.com/health.) By Jonathan D. Rockoff In 2004, Merck pulled the popular pain medication Vioxx from the market, after a study showed it doubled the risk of heart attack or stroke. Now we know more about what caused these side effects, according to researchers at the University of Pennsylvania's Perelman School of Medicine. Their conclusion: In trying to relieve pain, these drugs also suppress the production of enzymes that play a key role protecting the heart. In the journal Science Translational Medicine today, the researchers published the last of some 20 studies in humans and mice examining the biological underpinnings for the cardiovascular risks from taking Vioxx and related drugs. The label for Pfizer's Celebrex, the only drug in the class still on the market, warns about the risks. These drugs aimed to provide pain relief without causing the bleeding ulcers that could result from taking other painkillers. They'd do that by blocking a single enzyme, called Cox-2, that makes fats that cause pain. Yet one of these fats protects the heart. Blocking Cox-2's production turns out to have a cascade of biological effects that raise the cardiovascular risk even among healthy patients, says Garret FitzGerald, director of Penn's Institute for Translational Medicine and Therapeutics. For instance, blocking Cox-2 suppresses production of molecules that protect the heart by breaking up potential clots and promoting blood flow. Merck said in a email that it hadn't had an opportunity to thoroughly review the mice-study data released today, but that "experience has shown that the results of animal studies do not always translate well into humans." Pfizer said a study in genetically-modified mice isn't sufficient to "draw conclusions" about the benefits and risks of Celebrex, and the company is conducting a clinical trial in patients to assess the drug's long-term cardiovascular risk. "Since 2005 the FDA has required that all prescription NSAIDs, non-selective and COX-2 selective, carry the same warnings for potential cardiovascular risk," the company said in a statement. A study published last month in the Proceedings of the National Academy of Sciences showed how suppressing Cox-2 causes hardening of arteries in mice. That explains why clinical testing of the drugs indicated they can raise the heart risks even among healthy patients who are taking the drugs for more than a year, FitzGerald says. With a theory explaining why drugs like Vioxx can be dangerous, FitzGerald says a consortium of researchers is now exploring ways to identify patients who could benefit from taking one of the drugs without great risk. -For continuously updated news from The Wall Street Journal, see WSJ.com at http://wsj.com.