RAGE May Influence Diabetic Plaque Rupture
RAGE—the receptor for advanced glycation end products—may enhance the inflammatory reaction and expression of cyclooxygenase-2 and prostaglandin E (PGE) synthase-1 (COX-2/mPGES-1) in patients with diabetes, thus advancing the cascade of events that can lead to plaque rupture within human arteries, said Italian and US researchers in this week’s issue of the journal Circulation (Circulation. 2003;108:1070–1077OpenUrl).
The researchers, led by Francesco Cipollone, MD, of the University of Chieti “G D’Annunzio” School of Medicine, had already provided evidence that COX-2/mPGES-1 was associated with metalloproteinase-induced plaque rupture. In an attempt to identify the transmembrane signaling pathways influencing the expression of COX-2/mPGES-1, they sought to characterize RAGE expression in human plaque. Plaques from the carotid arteries of 60 patients who had undergone endarterectomy were divided into diabetic and nondiabetic categories. The plaques were then analyzed to determine RAGE, nuclear factor (NF)-B, COX-2/mPGES-1, matrix metalloproteinase (MMP)-2 and MMP-9, lipid, and oxidized low-density lipoprotein content. Collagen content was determined by immunohistochemistry and Western blot. Immunohistochemistry was also used to identify CD68+ macrophages, CD3+ T lymphocytes, smooth muscle cells, and HLA-DR+ inflammatory cells.
They found that diabetic plaques had more macrophages, T lymphocytes, and HLA-DR+ cells than did nondiabetic plaques. They were more immunoreactive for RAGE, activated NF-B, COX-2/ mPGES-1, and MMPs.
They concluded that in humans, “RAGE overexpression is associated with enhanced inflammatory reaction and COX-2/mPGES-1 expression in diabetic plaque macrophages, and this effect may contribute to plaque destabilization by inducing culprit metalloproteinase expression.”
Vitamins C and E May Slow Atherosclerosis Progression in Hyperlipidemic Children
Fifteen children with familial hypercholesterolemia who received 500 mg per day of vitamin C and 400 international units daily of vitamin E for 6 weeks and who remained on the National Cholesterol Education Program Step II diet for 6 months appeared to experience improved flow-mediated dilation of the brachial artery. The vitamins did not have an effect on biomarkers for oxidative stress or levels of asymmetric dimethylarginine, which inhibits nitric oxide.
The researchers, led by Marguerite M. Engler, PhD, of the University of California at San Francisco, noted in this week’s issue of the journal Circulation (Circulation. 2003;108:1059–1063) that endothelial dysfunction is considered an early event in atherosclerosis and a risk predictor of future coronary artery disease. The scientists concluded that the antioxidant therapy with vitamins C and E did restore endothelial function in the children.
“Early detection and treatment of endothelial dysfunction in high-risk children may retard the progression of atherosclerosis,” they wrote.
Depression Doubles Chance of Death After Bypass Surgery
Patients who suffer from depression after coronary artery bypass graft surgery face a mortality risk that is double that of their nondepressed counterparts, said researchers in the August 23, 2003, issue of The Lancet (Lancet. 2003;362:604–609OpenUrl). The researchers said their results indicate that patients need to be screened for depression before surgery.
In their study, the researchers analyzed the medical records of more than 800 bypass patients. They found that patients with moderate to severe depression at the time of surgery or those who had mild depression before the procedure and whose depression continued for 6 months afterwards were more than twice as likely to die after undergoing the operation. The follow-up lasted as long as 12 years and averaged 5.2 years per patient.
In a released statement, James Blumenthal, PhD, said, “Despite our advances in surgical and medical management of patients after coronary artery bypass surgery, depression is an important independent predictor of death after surgery and should be carefully monitored and treated if necessary. We believe that psychological assessment before and after surgery could be a low-cost and relatively easy way of potentially saving lives.”
The researchers said that the strength of the association between depression and death was surprising. “The key for us now is to determine whether or not treating the depression—whether by medications, psychological approaches or exercise—can positively affect outcomes,” said Mark Newman, MD, Chairman of Anesthesiology at Duke.
Everolimus May Alleviate Vasculopathy in Heart Transplantation Patients
Everolimus was more effective in suppressing vasculopathy in heart transplantation patients than azathioprine, said researchers led by Howard J. Eisen, MD, of Temple University, in the August 28, 2003, issue of The New England Journal of Medicine (N Engl J Med. 2003;349:847–858OpenUrlCrossRefPubMed).
Everolimus both inhibits proliferation and suppresses the immune system. Azathioprine is considered an immunosuppressive drug. In the study, researchers randomly assigned 634 patients to 1.5 or 3 mg per day of everolimus or to 1 to 3 mg of azathioprine per kilogram of body weight per day. Patients also received cyclosporine, corticosteroids, and statins.
Patients were followed up until they had died, suffered loss of the graft, undergone retransplantation, had proved grade 3A rejection, or had rejection with compromise of blood flow. Patients in the group that received 3 mg or 1.5 mg daily of everolimus were significantly less likely to have reached one of the end points than those who received azathioprine. In fact, 27% of the 3-mg-everolimus group and 36.4% of the 1.5-mg-everolimus group had reached one of the end points, compared with 46.7% of the azathioprine group.
When patients underwent intravascular ultrasonography, those who received everolimus had a smaller average increase in maximal intimal thickness 12 months after transplantation than did those who took azathioprine. Although the rate of cytomegalovirus infection was less in the everolimus groups, rates of bacterial infection were higher in the 3-mg-everolimus group than in the azathioprine group. In addition, serum creatinine levels were significantly higher in the 2 everolimus groups. Despite this, the researchers concluded that everolimus was more effective than azathioprine in reducing heart transplantation–associated vasculopathy.