The Missing Link Between Infection and Coronary Artery Disease
According to a study in this week’s issue of Circulation (Circulation. 2002;106:184–190), pathogen burden, rather than the type of organism involved, is more likely to be associated with endothelial dysfunction and the severity of coronary artery disease.
Researchers and physicians from the National Heart, Lung, and Blood Institute at the National Institutes of Health, the Cardiovascular Research Institute, and Medstar Research Institute at Washington Hospital Center in Washington, DC, led by Abhiram Prasad, MD, MRCP, assessed the endothelial function of 218 patients undergoing angiography with the use of intracoronary acetylcholine and endothelium independent function with sodium nitroprusside and adenosine. γ-Globulin antibody titers to cytomegalovirus, Chlamydia pneumoniae, Helicobacter pylori, hepatitis A virus, and herpes simplex-1 virus were also measured. Pathogen burden was defined as the number of positive antibodies.
They found that pathogen burden is an independent risk factor for:
the presence of coronary artery disease
the severity of coronary artery disease
coronary vascular endothelial dysfunction
Patients with 4 or 5 previous infections had a 4.1-fold higher risk of coronary artery disease than those patients with ≤1 previous infection.
“There was a progressive decline in the dilator response to ACE (acetylcholine) as pathogen burden increased, providing a mechanistic explanation of how infections might predispose to atherogenesis by causing endothelial dysfunction,” the authors wrote.
“Importantly, we found that the pathogen burden predicted the presence and severity of CAD more strongly than any single pathogen,” they noted in their article. “It is likely that despite major differences in the biologic and clinical consequences that result from human infection with these pathogens, there may be shared pathways by which diverse organisms produce vascular endothelial injury. These are likely to involve the autoimmune and the coagulation pathways, and as demonstrated in this study, also lead to an integrated injury of the vascular endothelium and inflammation.”
In an accompanying editorial (Circulation. 2002;106:164–166), Joseph A. Vita, MD, and Joseph Loscalzo, MD, PhD, of Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, noted: “The study provides further evidence for a relationship between prior infection and extent of atherosclerosis, and offers interesting new information about the potential relation between chronic infection and endothelial dysfunction. The work by Prasad and colleagues suggests that chronic infection may be added to the list of factors that induce endothelial dysfunction and contribute to the development and clinical expression of atherosclerosis. Furthermore, the study results are consistent with the notion that the number and severity of risk factors is particularly important for quantifying risk. The ability of the endothelium to resist the ‘burden’ of risk factors may be determined by genetic, dietary, and other environmental factors, and may itself contribute to overall cardiovascular disease risk.”
Drs Christine E. Seidman and Jonathan G. Seidman Receive 12th Bristol-Myers Squibb Award
Christine E. Seidman, MD, and Jonathan G. Seidman, PhD, received the 12th Annual Bristol-Myers Squibb Award for Distinguished Achievement in Cardiovascular Research at a dinner held in their honor on June 24, 2002, in New York. The husband and wife team received the award for their research into inherited human pathologies, including groundbreaking work to elucidate the cause of hypertrophic cardiomyopathy (HCM). They shared a $50 000 cash prize and each received a commemorative silver medallion.
Dr Christine Seidman is a Professor in the Departments of Medicine and Genetics at Harvard Medical School and a Howard Hughes Medical Institute investigator. She is an attending physician and Director of the Cardiovascular Genetics service at The Brigham and Women’s Hospital in Boston, Mass.
Dr Jonathan Seidman is the Henrietta B. and Frederick H. Bugher Professor of Cardiovascular Genetics at Harvard Medical School and a Howard Hughes Medical Institute investigator as well.
“Through molecular genetics, the Seidmans established the fundamental basis of understanding the causes and clinical implications of hypertrophic cardiomyopathy and other inheritable heart diseases,” said Richard Gregg, MD, Vice-President of Clinical Discovery at Bristol-Myers Squibb Pharmaceutical Research Institute. “Not only have they made enormous contributions to science with their landmark studies, but they have also served as an inspiration to other scientists throughout the world.”
The pair received their undergraduate degrees in biochemistry from Harvard University, he in 1972 and she in 1974. Dr Jonathan Seidman received his doctorate from the University of Wisconsin in Madison in 1975 and did his postdoctoral work in the laboratory of Dr Philip Leder in the Laboratory of Molecular Genetics at the National Institute of Child Health and Human Development, where he later served as a staff fellow and an investigator. He joined the Harvard Department of Genetics in 1981.
Dr Christine Seidman received her medical degree from George Washington University in Washington, DC, in 1978 and did her internship and residency at Johns Hopkins Hospital in 1981. From 1982 until 1986, she was a clinical and research cardiology fellow at Massachusetts General Hospital and a research fellow at Harvard. She joined the faculty at The Brigham and Women’s Hospital in 1986.
The pair began their collaboration in 1985 and by 1987 had initiated a research program to define the molecular genetics of inherited diseases that affect the cardiovascular system. Focusing initially on HCM, they were the first to elucidate its cause as genetic mutations in the proteins of the sarcomere. They localized the mutation to chromosome 14 in 1989 and within 3 months had identified the β-cardiac myosin heavy chain as the locus of the mutation. Since then, they have found 4 other gene mutations associated with HCM: cardiac troponin T on chromosome 1, cardiac myosin binding protein-C on chromosome 11, α-tropomyosin on chromosome 15, and α-cardiac myosin heavy chain, a second disease gene on chromosome 14, which is related to β-cardiac myosin heavy chain but which causes elderly onset HCM. Their work has given scientists new insights into the pathogenesis of hypertrophy and heart failure, as well as providing improved prognostic information to patients and families, including those at risk.
Studies by the Seidmans have also led to an understanding of the molecular genetic basis for dilated cardiomyopathy, the most common cause of heart failure requiring cardiac transplantation.
AHA, ACC, and NHLBI Reaffirm the Safety and Importance of Statins
The 3 major organizations dealing with the health of the heart reaffirmed their belief that statins are safe and effective in lowering cholesterol in an advisory issued June 28, 2002.
Leaders of the American College of Cardiology (ACC), American Heart Association (AHA), and the National Heart, Lung, and Blood Institute (NHLBI) issued the 6-page advisory as information needed by patients and physicians in the wake of the withdrawal of the drug Baycol (Bayer Pharmaceutical Division) from the market nearly a year ago. The organizations noted that the 5 statins still on the market are safe and effective for most patients and in combination with dietary and lifestyle changes, can be important in maintaining a healthy heart.
Claude Lenfant, MD, director of the NHLBI, said statins are still the first choice for many of these patients and their physicians. “Of course, the decision to use drug treatment is a matter for the clinical judgment of the physicians and discussion with the patient,” Dr Lenfant said.
The advisory outlines specific characteristics that may predispose some patients taking a statin to muscle pain and weakness, or myopathy, and stresses that these patients should be monitored more carefully. The advisory also advises physicians to strongly encourage their patients to report unintended side effects, such as muscle soreness, weakness, or brown urine.
The complete clinical advisory is available on the AHA website at www.americanheart.org/presenter.jhtml? identifier=3003472, on the ACC website at www.acc.org/clinical/alerts/statins_june02.pdf, and on the NHLBI website at www.nhlbi.nih.gov/guidelines/cholesterol. The advisory will be published in the August 20, 2002, issue of Circulation.