It's not only about cholesterol

Then, a funny thing happened in the cardiology business: Researchers began to discover there was more to heart disease than clogs. Deep in the cells lining arteries, they realized, biochemical events unfold that can make a 20-percent blockage more dangerous than an 80-percent one.

And that understanding, in turn, is giving rise to a constellation of new methods that aim to measure heart disease -- tests that would augment the tried-and-true cholesterol screening. The result could be earlier detection of the disease, better strategies for prevention, and fewer lives lost to America's number-one killer.

"A lot of us are working on ways to regenerate the damaged heart but, really, at the end of the day, you would prefer not to have to do that," said Dr. Douglas Losordo, chief of cardiology at Caritas St. Elizabeth's Medical Center. "If we can identify who needs to have cholesterol-lowering drugs in their water and who doesn't, that's going to be attractive to patients, doctors, and the people who pay the bills -- because prevention is going to cost a lot less than dealing with the consequences of the disease."

The field is so hot right now that one Harvard Medical School specialist estimates that, over the past six months, colleagues have asked him to review one new research paper on the topic every week.

"I'm sure every generation sounds this way when it says, `We're finally beginning to understand the science' of a disease," said Dr. Wilson Colucci, chief of cardiovascular medicine at Boston University Medical Center. "But with heart disease, it happens to be true, and the pace of the science is accelerating."

Clear evidence of that emerged in the past three weeks when the nation's two premier medical journals published reports from research teams in Boston and Cleveland detailing potentially crucial advances in understanding how to better detect cardiovascular illness.

Those findings build on a seminal recognition about heart disease that has profoundly reshaped the landscape of cardiology in recent years: The heart and the vessels traveling in and out of it are not rigid and frozen like lead piping.

"Much to everybody's surprise, it's not a static system of pipes and fluids but instead a very dynamic biological system where the blood vessels are very dynamic, the heart's very dynamic, and there are many cell types," Colucci said. "These concepts are beginning to explain the disease we see."

In certain pivotal respects, heart disease has loomed as an enduring mystery to physicians and patients alike. For a couple of decades, specialists have known that high levels of the bad cholesterol -- LDL -- stood as a primary marker of cardiovascular disease. But while 50 percent of patients who have heart attacks and strokes have high cholesterol, the other half don't, said Dr. Frederick A. Spencer, director of the coronary care unit at UMass Memorial Medical Center.

So researchers knew they needed to hunt for other biochemical and genetic factors that could foretell cardiac illness before it turned lethal. And that, in turn, has stoked the quest to discover something called biomarkers -- specifics traits used to identify disease and measure its progression.

"The drivers of those biomarkers for Mrs. Jones may be different than those for Mr. Black, which may then guide us to a panel of medicines that may work best for Mrs. Jones and a slightly different panel that may work better for Mr. Black," said Dr. David Morrow, a cardiologist at Brigham and Women's Hospital.

Two biomarkers and one genetic feature have stimulated particular interest in recent months, with one of them already beginning to be incorporated into routine medical practice.

That biomarker is known as C-reactive protein, and a team of scientists at the Brigham has been instrumental in both advancing understanding of the substance and advocating its use as a means of detecting heart disease.

Everyone has the protein, but patients with heart disease can have dangerously elevated levels. Researchers believe that while cholesterol tests identify patients with excessive deposits of plaque, C-reactive protein readings take that analysis a step further by detecting blockages that are most likely to rupture and produce a potentially fatal clot.

In a finding that rocked the field of cardiology a year ago, the Brigham scientists, led by Dr. Paul Ridker, reported that C-reactive protein was a more reliable way to predict whether a patient would have a heart attack than cholesterol testing.

"We would hope the knowledge that your C-reactive protein is elevated would motivate both the patient and the physician to lead healthier lives," said Ridker, director of the Brigham's Center for Cardiovascular Disease Prevention. "Sometimes the knowledge that you're at higher risk is just what you need to get yourself to finally go to the gym, throw out the cigarettes, and lose some weight."

While simple blood tests for C-reactive protein are already available and in use, two other discoveries are in earlier stages of investigation.

In the Oct. 23 edition of The New England Journal of Medicine, researchers from the Cleveland Clinic described how they tested 604 patients for the presence of an enzyme called myeloperoxidase, a well-known component of the body's disease-fighting army.

"It plays a role in fighting invading parasites and pathogens, and it works by waging chemical warfare, by generating toxic compounds that play a role in killing the bug," said Dr. Stanley Hazen, section head of preventive cardiology at Cleveland Clinic. "They're not smart bombs, they're dumb bombs. They're messy."

Those messy bombs, it turns out, proliferate in the damaged tissue of patients with heart disease. Scientists don't know yet whether the enzyme is culpable in causing heart disease, but their studies suggest powerfully that, like cholesterol and C-reactive protein, detecting its presence could direct treatment.

That same hope drives researchers at Tufts-New England Medical Center, the Massachusetts Institute of Technology, and BU as they study a tiny genetic quirk that could signal a sharply elevated risk of heart attacks and other life-threatening conditions.

Last week, they reported in The Journal of the American Medical Association that a slight variation in the genetic profile of estrogen receptors results in a threefold increase in heart attacks and other major cardiovascular events, including strokes. Estrogen receptors are proteins that alert cells to the presence of estrogen and, in turn, allow the hormone to do its work inside cells.

Still, scientists know the path from laboratory discovery to bedside medical test is pocked more with frustration than triumph.

"While a lot of these research reports are coming out," said Dr. Ernst Schaefer, director of the Lipid and Heart Disease Prevention Clinic at Tufts-New England Medical, "whether they make it to routine clinical practice is an entirely different question."

Researchers at Brigham and Women's Hospital are trying to determine whether drugs called statins can reduce heart disease in patients with normal levels of cholesterol but elevated rates of C-reactive protein. The statin drugs are most widely given to reduce cholesterol, but research has shown they may also prevent heart disease in people with high C-reactive protein readings. Researchers hope to enroll 15,000 participants across North America. More information on participating may be obtained at www.jupiterstudy.com or by calling 1-888-660-8254.