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In This Issue:
First of two parts; Next week, BWH Bulletin examines the work behind the landmark JUPITER trial.
On his first day as a student at Harvard Medical School in 1981, Paul Ridker received a call from professor Charles Hennekens, MD, but it had nothing to do with science or medicine. Hennekens, then BWH’s chief of Preventive Medicine now living in Florida, wanted a squash game with Ridker, who had played as an undergrad at Brown University.
Ridker met Hennekens on the courts, later enrolled in his epidemiology class—co-taught by Julie Buring—and worked in his lab that next summer processing blood samples for the Physicians Health Study, the first randomized trial to demonstrate that aspirin reduces heart attack risk. Those 20,000-plus blood samples, which are still stored at a BWH facility, provided the raw material for Ridker’s future research on high-sensitivity C-reactive protein, or hsCRP, a biomarker for inflammation that is now in wide clinical use to detect heart disease risk. Working with more than a dozen other BWH investigators, Ridker would go on to establish not only that hsCRP predicts high risk of heart attack and stroke among apparently healthy men and women, but would eventually demonstrate that statin therapy can cut that risk in half even when cholesterol levels are low.
“Any honest scientist will tell you that serendipity and collaboration are as important as insight and dedication,” said Ridker. “The BWH has provided an enormous amount of both over the past 20 years.”
From the launch of the Physicians Health Study in the early 1980s to the November 2008 release of the JUPITER trial results, an exceptional number of BWH faculty and researchers have contributed to the evolution of the CRP story through studies including the CARE trial, PRINCE, PROVE IT-IT TIMI 22, Women’s Health Study, Nurses Health Study, LANCET and the Women’s Genome Health Study.
“This is a true Brigham story that reflects longstanding commitments of our faculty to the basic and clinical science of inflammation, starting with the Robert Breck Brigham as an arthritis center studying inflammation biology,” Ridker said.
Ridker’s research has had diverse influences, including the basic investigative work of Michael Gimbrone, MD, chair of Pathology, and Peter Libby, MD, chief of Cardiovascular Medicine, as well as clinical collaborations with Eugene Braunwald, MD, former chair of Medicine and principal investigator of BWH’s Thrombolysis in Myocardial Infarction (TIMI) clinical studies group. Gimbrone, Libby and other BWH scientists, including Charles Serhan of Anesthesiology, Perioperative and Pain Medicine, have made major contributions to understanding inflammation and inflammatory processes involved in atherosclerosis and vascular biology, while Braunwald’s TIMI trials have revolutionized treatment for cardiac patients with a wide range of interventions that are now standards of care worldwide.
“BWH has been at the nexus of inflammation research for more than 25 years,” said Ridker, who is the Braunwald Professor of Medicine at HMS and BWH. “The BWH has remarkable core strength in basic vascular biology and inflammation research, access to many large-scale epidemiological studies and an abundance of some of the country’s brightest clinical investigators. Collaborations within this institution have simply been terrific.”
After the initial observations regarding hsCRP and vascular risk were made in men, Ridker was able to work with Julie Buring, ScD, to confirm that hsCRP levels predict heart attack and stroke in women in another large-scale BWH-run trial, the Women’s Health Study. That study required tens of thousands of hsCRP assays to be run, an effort spearheaded by pathologist Nader Rifai, PhD, of Children’s Hospital and HMS, who helped create commercial tests to carefully measure hsCRP in clinical samples.
Working collaboratively with investigators in the Cholesterol and Recurrent Events, or CARE, trial led at BWH by Marc Pfeffer, MD, and Frank Sacks, MD, Ridker and his colleagues then showed that statin therapy could lower CRP independently of lowering lipid levels. The Brigham-run PRINCE trial, led by Michelle Albert, MD, confirmed that statins could lower CRP levels in addition to lowering cholesterol in a reliable, reproducible manner. Meanwhile, other BWH investigators involved in the Women’s Health Study, including Samia Mora, MD, showed correlations between diet and exercise and CRP levels, while Aruna Pradhan, MD, showed that hsCRP levels predict the onset of type 2 diabetes. Ridker’s research group, assisted by BWH investigators Robert Zee, MD, Jackie Suk-Danik, MD, David Kwiatkowski, MD, and Dan Chasman, PhD, then collaborated to discover many of the core genetic determinants of CRP. Pradhan is now the lead investigator of the BWH-run LANCET trial designed to assess whether treatments for diabetes impact inflammation.
A major inflammation break-through came in 2005 from the PROVE IT – TIMI 22 trial led by Braunwald and Chris Cannon, MD, that initially showed that higher dose statins provide better clinical outcomes. Collaborating with these BWH investigators, Ridker used the PROVE IT database to show definitively that the benefits of statin therapy were related as much to CRP reduction as to cholesterol reduction, data that would prove crucial to the JUPITER trial itself. Translating this work to public health, the Reynolds Risk Score was then developed, a formula that more accurately predicts the risk of heart attack and stroke for both men and women. In addition to the traditional risk factors of age, gender, cholesterol, blood pressure and smoking, the Reynolds Risk Score (www.reynoldsriskscore.org) adds hsCRP levels and family history and was based on statistical analyses done by Nancy Cook, ScD, of BWH’s Division of Preventive Medicine.