Stanford Report Online

Stanford Report, May 9, 2001
Study links Syndrome X to increased risk of developing coronary artery disease


Heart transplant recipients are more likely to develop and die from coronary artery disease if they have a metabolic disorder called Syndrome X, according to a study by Stanford University Medical Center researchers. Ironically, medications that patients take to avoid rejecting their new hearts can cause the disorder, also known as dysmetabolic syndrome. But it's not just heart transplant recipients who should be concerned about the syndrome.

"This is an issue even outside of transplantation," said Hannah Valantine, MD, professor of cardiovascular medicine. "The number of people receiving heart transplants is not that great, but the number with dysmetabolic syndrome is extremely high, and these patients are at very high risk for cardiovascular disease."

Nearly half of all heart transplant patients develop transplant coronary artery disease, or TxCAD, within five years after transplant. In TxCAD the arteries of the new heart become narrowed and clogged by plaque. Severe cases can lead to retransplantation or death.

Valantine, lead author of the study published in the May 1 issue of Circulation, previously showed that abnormally high triglyceride levels are correlated with an increased chance of developing TxCAD. Triglycerides are a type of fat manufactured by the liver from carbohydrates. Because an elevated triglyceride level is one symptom of dysmetabolic syndrome, Valantine wondered if other symptoms of the syndrome would also increase the risk of TxCAD for these patients.

The researchers studied 66 patients who received heart transplants between two and four years earlier. Once a year the researchers used specialized ultrasound technology to measure the thickness of the interior lining of the patients' coronary arteries. They also tested them for telltale symptoms of dysmetabolic syndrome: elevated triglyceride levels; decreased levels of high density lipoproteins (HDLs); and higher-than-normal levels of glucose and insulin after a meal. Then they followed the patients for eight years to see which, if any, developed or died from TxCAD.

The researchers found that the artery linings of patients with dysmetabolic syndrome were more likely than those of patients without the syndrome to thicken dangerously to more than 0.3 millimeters in the years following transplantation -- a key marker of coronary artery disease. The artery linings of people without coronary artery disease are usually less than 0.28 millimeters, and the interior of the artery is about 3-5 millimeters in diameter, approximately the size of a large peppercorn.

In the study, only 46 percent of the patients with thick arterial linings were likely to make it through the subsequent five years without other symptoms of coronary artery disease, compared with 82 percent of the patients without significant thickening.

Even more alarmingly, patients with dysmetabolic syndrome were significantly less likely to survive the eight-year follow-up period.

Unfortunately, the drugs that patients must take to avoid rejecting their new hearts interfere with the way fats are metabolized in the body and can actually cause patients to develop the syndrome.

"Many studies have shown that the arteries of heart transplant patients have very high levels of triglycerides," said Valantine. "This probably reflects the fact that the corticosteroids we use for immunosuppression can cause patients to have high levels of triglycerides over long periods of time."

Dysmetabolic syndrome was recognized and defined in 1988 by Stanford researcher Gerald Reaven, MD, who initially named it "Syndrome X." The panel of cardiovascular risk factors that define the syndrome are all associated with the development of insulin resistance. In a normal, healthy person the pancreas releases insulin after a meal in response to rising levels of glucose in the blood, and the insulin stimulates the body's cells to absorb the sugar and store it for later use. Patients whose cells are resistant to the effects of insulin need to churn out more insulin to deal with the same amount of sugar. As the insulin becomes less effective, the cells absorb less of the sugar and blood-glucose levels remain high.

This dysfunctional cascade also affects fat metabolism and leads to the high triglyceride and low HDL levels that are also markers of the disorder.

Insulin resistance is a hallmark of type-II diabetes, and patients who are insulin-resistant often eventually become diabetic. But unlike diabetics, patients in the early stages of insulin resistance have normal blood-sugar levels when fasting.

Although patients taking immunosuppressive drugs are at greater risk of developing the syndrome than the majority of the population, the study emphasizes that everyone should be concerned about the role dysmetabolic disorder plays in heart disease, said Valantine.

"You can draw a parallel; high triglyceride and low HDL levels have been recognized as a risk factor for cardiovascular disease in native hearts. It's as if we've gotten to the same point by approaching it in a different way -- in this case we've induced it with our nasty immunosuppressive drugs," Valantine said.

The fact that heart transplant recipients with dysmetabolic syndrome have a significantly higher risk of developing and dying from TxCAD should be a wake-up call for all physicians caring for transplant patients, she added.

"We should definitely start paying more attention to the post-prandial glucose and insulin levels of these heart transplant patients," said Valantine. "If they are elevated, we should try to get them down with changes in diet and drug treatment. We should also be cautious and try to use lower doses of the immunosuppressive drugs such as corticosteroids that cause these problems."