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NEW ORLEANS -- Women with metabolic syndrome have an increased risk of developing symptomatic peripheral arterial disease, mediated mainly by the syndrome's associated inflammation and endothelial activation.

"The bottom line is if you account for the inflammation associated with the metabolic syndrome, there is no residual risk associated with the syndrome itself," Dr. Aruna D. Pradhan said at the annual scientific sessions of the American Heart Association.

She reported on 27,111 middle-aged female health professionals free of known cardiovascular disease when they enrolled in the Women's Health Study. At entry, one-quarter met criteria for the metabolic syndrome. At that time 28% of those with metabolic syndrome had diabetes, as did 1.8% of the others.

During a median 13.3 years of prospective follow-up, 114 women developed symptomatic peripheral artery disease (PAD). In an unadjusted first-pass analysis, women with metabolic syndrome at baseline were 62% more likely to go on to develop PAD. And for each additional metabolic syndrome-defining risk factor present beyond the requisite minimum three out of five, the risk of PAD increased by 26%.

However, women with metabolic syndrome also were slightly older, less likely to exercise, more likely to smoke, and had a higher body mass index in addition to their much greater prevalence of diabetes. Upon adjustment for these factors in a Cox multivariate proportional hazards analysis, the presence of the metabolic syndrome remained a significant risk factor for PAD. Indeed, women with metabolic syndrome had an adjusted 48% greater likelihood of PAD, and this risk climbed by another 21% for each additional metabolic syndrome-defining trait present, according to Dr. Pradhan of Brigham and Women's Hospital, Boston.

But the nearly 7,000 women with metabolic syndrome also differed from the more than 20,000 others in another important way: They had markedly higher levels of biomarkers of systemic inflammation.

The median plasma level of high-sensitivity C-reactive protein (hsCRP) among participants with metabolic syndrome at baseline was 3.98 mg/L, compared with 1.53 mg/L in women without metabolic syndrome. Levels of soluble intercellular adhesion molecule-1 (ICAM-1) averaged 374 ng/mL in the metabolic syndrome group and 333 ng/mL in the comparison arm. As the number of metabolic syndrome elements present increased from zero to five, median CRP increased from 1.0 to 5.9 mg/L and median ICAM-1 rose from 321 to 413 ng/mL.

When hsCRP and ICAM-1 levels were folded into the multivariate adjustment model, metabolic syndrome was no longer associated with a significantly increased risk of PAD, suggesting that systemic inflammation is the driving force in the development of PAD, not the high triglycerides, low HDL, or other components of the metabolic syndrome.

Session cochair Dr. William R. Hiatt said it's speculative as to whether these study findings apply to men, or to the development of asymptomatic PAD, which is far more prevalent than symptomatic disease. Men have a higher incidence of symptomatic PAD than women, at least in clinical trials, noted Dr. Hiatt, professor of medicine at the University of Colorado, Denver.

When asked to comment on this study, Dr. Spence Taylor, professor of vascular surgery, the University of South Carolina, Columbia, stated: "In this current report, Dr. Pradhan has suggested that the plasma markers of CRP and ICAM-1 are perhaps the most important predictors of PAD. Indeed, they appear to be statistically more important than the metabolic syndrome or the individual components comprising the metabolic syndrome itself.

"Are these serum markers part of the pathologic process or are they "innocent bystanders" of systemic inflammation associated with PAD? While they appear to be of prognostic importance, do they play a role in patient outcomes, or, for that matter, pathophysiology? To that end, our group has extensively studied outcomes after intervention for PAD. We have come to realize there are patient populations we simply do not help. While outcomes appear to be dependent upon intrinsic patient comorbidities at presentation, we have yet to find one comorbidity or a series of comorbidities which universally predict failure after revascularization. Perhaps CRP and/or ICAM-1 are part of the equation. Are these markers elevated in patients who experience adverse outcome after intervention? Would manipulating levels by controlling risk factors alter outcome after intervention? Are these serum markers the "silver bullet" for enhancing outcomes after treatment of PAD?

"I am reminded of studies from the 1980s where elevated levels of prostaglandins and leukotrienes were found to be associated with Multisystem Organ Failure. While many postulated that inhibiting or blocking these inflammatory mediators might be of benefit, pharmacologic blockade, unfortunately, has not been shown to alter the course of Multisystem Organ Failure for most patients. I suspect this will be the case with CRP and ICAM-1 as it relates to the progression of PAD as well. Time will tell. In the meantime, Dr. Pradhan and associates have provided us hope and perhaps a neat new tool for the assessment and treatment of PAD.