Editor’s Note: This story, first published in 2004, has been updated.
Cardiovascular disease, like cancer, is a health problem best treated with prevention and early detection. Physicians successfully identify many at-risk patients by measuring the blood levels of markers like LDL cholesterol. However, for many patients, their first indication of cardiovascular disease is suffering a heart attack or stroke.
“The cornerstone of risk determination is found in the parameters that have been measured and validated through prospective epidemiological studies,” says Douglas Vaughan, M.D., chair of Medicine at Northwestern University Feinberg School of Medicine and former chief of Cardiovascular Medicine at Vanderbilt University Medical Center. “Those (studies) have really defined the power of factors such as high HDL, low LDL, hypertension and smoking as authentic determinants of risk over time.”
Yet an increasing number of patients develop cardiovascular disease in the absence of these traditional risk factors. “That has motivated and catalyzed a search for other important markers or determinants of risk,” he says.
One emerging risk factor, insulin resistance, increases cardiovascular disease risk without significantly impacting lipid levels. “Generally, people with insulin resistance don’t have high LDL; they’ve got a low HDL, they’ve got high TG,” Vaughan says. Finding the link between insulin resistance and heart disease, therefore, is critically important.
One possibility: a serum protein involved in clot formation called plasminogen activator inhibitor-1 (PAI-1). “The neat thing about PAI-1 is that it is driven by so many different factors that contribute to cardiovascular disease in the 21st Century,” Vaughan says, including inflammation and insulin resistance. PAI-1 levels track with CRP, making PAI-1 an “integrative marker of multi-factorial inputs that might influence your (heart disease) risk,” he says.
Vaughan’s laboratory has published several papers describing how the PAI-1 gene is regulated. When the PAI-1 gene becomes “switched on,” the result is higher plasma levels of PAI-1 protein. Recent reports from Vaughan’s laboratory have identified ways in which the PAI-1 gene might be switched on by inflammation. Others have reported that drugs designed to combat insulin resistance decrease circulating levels of PAI-1. “If you improve the lipid profile and if you reduce insulin resistance in patients,” he says, “you would predict that their PAI-1 levels are going to come down.”
Meanwhile, new technologies such as cardiac magnetic resonance imaging (MRI) and multi-slice computed tomography (CT), offer the promise of non-invasive, real-time diagnosis of coronary artery disease—at an earlier stage than ever before. Coupled with analysis of circulating markers of heart disease, perhaps even more patients can be spared the pain, expense, and morbidity of a heart attack or stroke.