Four Biomarkers Predict Event Risk in Women


ORLANDO, FLA. — The presence of inflammatory markers, a low hemoglobin level, or both is superior to traditional cardiovascular risk factors for predicting adverse cardiovascular outcomes in women under evaluation for suspected myocardial ischemia, Christopher B. Arant, M.D., said at the annual meeting of the American College of Cardiology.

The standard cardiovascular risk factors appear to considerably underestimate the true risk of cardiovascular events in women presenting with chest pain, added Dr. Arant, a cardiologist at the University of Florida, Gainesville.

He reported on 595 women, mean age 58 years, who underwent coronary angiography as part of an evaluation for suspected myocardial ischemia in the National Heart, Lung, and Blood Institute-sponsored Women and Ischemia Syndrome Evaluation (WISE).

During a mean 3.6 years of follow-up, all-cause mortality among the women was 7%, and the rate of an MI, heart failure, stroke, another vascular event, or death was 20%. Yet their predicted 10-year risk of a cardiovascular event based on their Framingham risk score was just 4.6%. This underestimate emphasizes the need to develop better methods of recognizing women at high risk, which is the mission of WISE.

Inflammation plays a key role in atherosclerosis and its related complications, perhaps even more so in women than in men. Dr. Arant and his coinvestigators previously examined the predictive power of three inflammatory markers—C-reactive protein, interleukin-6, and serum amyloid A—and showed that they were strong predictors of cardiovascular risk in the WISE cohort. They separately established that hemoglobin level was an independent predictor of adverse cardiovascular outcomes.

In their new study, they showed that adding a hemoglobin concentration below 12 g/dL to the three inflammatory markers created a four-biomarker combination that incrementally and independently predicted cardiovascular events in the WISE study women. (See above.)

In a Cox multivariate regression analysis, the only traditional risk factors that predicted cardiovascular events were diabetes, which was associated with a 79% increase in risk, and obstructive coronary artery disease on angiography, which conferred a 65% increased risk.

In contrast, the presence of any one of the four biomarkers was associated with a 90% increased risk of cardiovascular events during follow-up. Two positive biomarkers conferred a 192% increased risk. Women with three had a 368% increased risk, and those with four abnormal biomarkers had a 550% increased risk.

The same graded relationship held true between abnormal biomarkers and all-cause mortality. The risk of death increased 4.5-fold in women with one abnormal biomarker, compared with those with none, and 19.2-fold in subjects with four biomarkers.

The mean hemoglobin in the WISE cohort was 12.9 g/dL. Why a modest reduction to below 12 g/dL was predictive of cardiovascular events in the WISE population remains speculative. Hemoglobin is not an obvious marker of inflammation. Yet physicians have known for some time that low hemoglobin is an independent predictor of cardiovascular events in patients with heart failure, and more recent data suggest that the same applies in acute MI.

One possibility is that mild anemia may reflect bone marrow underproduction of red blood cells due to systemic inflammation. Thus, in that sense, a low hemoglobin may indeed be a surrogate marker for inflammation. However, the observation that adding hemoglobin to the three inflammatory markers yielded an incremental increase in event risk in WISE suggests a low hemoglobin may be acting directly to increase risk, Dr. Arant said.

Studies of sickle cell anemia patients suggest that hemoglobin may be important in the transport of nitric oxide, known to play a key role in endothelial function. Nearly two-thirds of women in WISE did not have obstructive coronary artery disease, instead presumably had what is often described as microvascular disease. Thus inadequate nitric oxide could exacerbate their endothelial dysfunction, which might explain the link between low hemoglobin and increased cardiovascular events, he said.

A clinical pearl from the WISE chest pain registry is that women with cardiac ischemia have a very high prevalence of atypical angina. “We like to say any pain above the waist in women who have risk factors requires a good history and physical exam and really needs to be considered as an anginal equivalent,” he said.

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