New heart research path opens

In the largest study of people with an intractable and common form of heart failure, researchers found that adding a blood pressure medicine to the patients' regimen made no difference.

Two doctors from the Medical University of South Carolina say the reason for that is that researchers are looking for answers in the wrong place.

The results of the I-PRESERVE study, which involved more than 4,000 patients in 25 countries, were presented as a late-breaking clinical trial at the November American Heart Association's Scientific Sessions.

Heart failure can happen two ways. Either the heart pumps blood poorly or the heart has difficulty expanding and filling with blood.

The I-PRESERVE trial followed patients whose hearts were growing stiff and unable to fill properly. Irbesartan appeared ideal because the drug reduces the hardening of tissue and showed promising results in heart failure patients whose hearts didn't pump properly.

"There is a tremendous perception that a drug that works for one type of heart failure will work for all types," MUSC's Dr. Francis Spinale said. "(This study) put all that to rest. It can't be denied. Drugs for patients whose hearts don't pump well have absolutely no use for patients whose hearts don't fill well."

Dr. Michael Zile, also from MUSC and an investigator in the I-PRESERVE trial, said, "We need new drugs. We need new diagnostic approaches. We need new therapies."

Spinale and Zile have identified a family of proteins, called matrix metalloprotienases (MMP), that offer another direction for medical science to explore. These proteins play a crucial role in why the supporting tissue surrounding the heart changes in heart failure patients.

"(Spinale and Zile) have been the leaders in understanding the role of these proteins and the changes in the heart that cause heart failure," said Dr. William C. Little, chief of cardiology at Wake Forest University.

The symptoms of both forms of heart failure are indistinguishable — fatigue, shortness of breath and edema, or swelling.

About 30 years ago, the development of ultrasound made it easy for doctors to see hearts not squeezing properly, Little said. This form of failure is called "systolic."

But there were a lot of people whose hearts appeared to pump well but who still suffered from heart failure. It would be about another decade before scientists figured out those patients' hearts weren't filling properly, or had "diastolic" heart failure, Little said.

More than 5 million Americans are living with heart failure, according to the American Heart Association, and 550,000 cases are diagnosed each year.

Zile said that about 50 percent of patients he sees with heart failure have normal systolic function. For them, the diastolic heart failure patients, he said, "We have no established therapy."

The I-PRESERVE study may be the impetus to steer medical research in another direction for treatment. Spinale started looking elsewhere in the early 1990s, when he accidentally walked into a cancer conference and heard an oncologist talking about how when a tumor invades normal tissue, MMPs change the matrix that surrounds the cell. The matrix is a supporting structure for cells.

"We're looking into a space no one's looked at before — between the cells. It's almost like discovering a different universe or galaxy," Spinale said. He began wondering if these MMPs might play a role in major cardiovascular disease.

By examining the diseased hearts of transplant patients, Spinale and other MUSC investigators discovered these MMPs were very active. From these published discoveries, Spinale and Zile developed a blood test to measure these MMPs in bloodstreams of patients for early disease screening.

Dr. William H. Gaasch, senior consultant in cardiology at Lahey Clinic in Burlington, Mass., said MMPs are an exciting place to direct research when it comes to diastolic heart failure, but MMPs are unlikely to be the sole process involved. "That system of balancing or counterbalancing enzymes may very well be involved in diastolic heart failure," he said. "This is a very good idea."

While any new treatments are years away, early detection could lead to more aggressive management of the disease and perhaps gain people years of life.

The set of enzymes the doctors are testing is patented by MUSC and has been licensed to Ortho-Clinical Diagnostics, a subsidiary of Johnson & Johnson, in a $2.1 million agreement. Half of that sum is a grant to identify and study patients with diastolic heart failure.

Their ongoing research also is funded by the National Institutes of Health and the Department of Veterans Affairs.