Slowing down a killer

With advanced lab research and careful clinical trials working together, doctors are learning new methods in the battle against heart disease.

LSUHSC-Shreveport

Heart attack: two dreaded words that translate into the leading cause of death in American adults. Last year almost half of the 1.1 million Americans who suffered a heart attack died from it. Despite aggressive public education campaigns to warn Americans about heart attack risk factors, many of those victims didn't know they had coronary heart disease until their chest pains announced it.

At Louisiana State University Health Sciences Center in Shreveport (LSUHSC-S), scientists who do heart research in the laboratory, like physiologist David Lefer, Ph.D., are collaborating with physicians, like cardiologist Jalal Ghali, with a common purpose: improving treatments for heart patients.

Developing both new medications and medical devices for heart disease patients is the shared goal of Lefer and Ghali, who are part of a network of basic scientists and clinician researchers conducting heart research at LSUHSC-S. To work more effectively, the group of faculty experts recently joined forces in a new LSUHSC-S initiative, the Institute for Cardiovascular Diseases and Imaging.

A local benefactor's generous bequest dedicated to cardiovascular research is providing resources to support the initiative. Funds are being allocated to underwrite both basic and clinical research in cardiovascular disease. An internal advisory board, a cross-section of faculty with cardiovascular expertise, catalogued the considerable existing institutional strengths in cardiovascular programs and research at LSUHSC-S, then began making investments from the bequest to bolster institutional cardiovascular research.

Among the faculty leaders in the multidisciplinary cardiovascular team are Lefer, professor of molecular and cellular physiology, and Ghali, professor of medicine, section of cardiology.

Both specialize in heart research and share the goal of better treatments for heart disease, but their approaches differ. Lefer conducts bench research-the basic scientific investigations that take place in a laboratory-while Ghali treats patients with heart diseases.

Lefer is looking at animal models to learn more about the altered human physiology that results form heart failure and ischemic heart disease, or heart attack. His research group is working to identify critical genes in the heart and blood vessels that increase or decrease the severity of ischemic heart disease and congestive heart failure. Once important genes are identified, the group will focus on developing novel therapies to inhibit or promote the function of the proteins these genes encode.

The development of mice in which genes are knocked out or over-expressed is a very important component of Lefer's research. Once gene-mutant mice are developed, they can be tested in experimental models of heart attacks or heart failure and the investigators can evaluate the disease severity. At present, Lefer's group is focusing on a number of genes and proteins that modulate coronary artery and cardiac cell function.

The group also focuses on mice with type 2 diabetes mellitus since diabetic patients are at risk for a very severe form of ischemic heart disease and congestive heart failure. It is very important to investigate cardiovascular disease in the setting of diabetes, according to Lefer, since diabetics are two to four times more likely to suffer from heart disease than nondiabetics. Seventy-five percent of all diabetes-related deaths are attributed to heart disease.

Adding impetus to the research is the fact that diabetes has become an epidemic in the United States, where 18.3 million persons, an astonishing 6.3 percent of the total population, are diagnosed with diabetes mellitus. Another estimated 13 million individuals with diabetes have not been diagnosed, according to 2004 American Diabetes Association figures.

The knowledge gained from Lefer's work is already contributing to the development of new drugs aimed at preventing certain genes from damaging the heart.

The next step in moving new medications and medical devices from the laboratory to the hospital or doctor's office is clinical trials-carefully controlled use of the products in humans.

That's where faculty physicians like Ghali play a key role. Ghali's clinical research involves all major aspects of cardiovascular diseases, but he is particularly interested in heart failure.

He has been intimately involved in clinical trials that established the safety and benefit of contemporary medications for the management of chronic heart failure, including angiotensin enzyme inhibitors, angiotensin receptor blockers and beta blockers, and for acute heart failure like natriuretic peptide (Nesiritide). He's been part of the investigation of many medications that aim to improve the squeezing function of the heart muscle, which is impaired in heart failure and results in diminished blood circulation.

Ghali's clinical research has included studies of medications that improve handling of sodium, potassium or calcium in the heart muscle, medications that improve the energy of the weakened heart muscle, procedures that reduce inflammation, and protocols involving gene therapy. In the latter, the investigational drug is directly injected into the coronary arteries to provide more blood supply and improved flow of blood to the heart muscle.

In addition to the medications directly involved with the heart muscle, Ghali has been a leading participant in trials assessing different kinds of medications that help to remove the extra fluid in patients with heart failure without damaging the kidneys.

And not all of Ghali's investigations involve potential medications. He is part of a National Institutes of Health-sponsored trial to determine whether regular exercise three times a week improves survival and decreases hospitalizations of patients with heart failure, and he has been actively involved in device therapy for heart failure, including a major study that recently proved that inserting a biventricular pacer and defibrillator prolongs survival and decreases hospitalization in patients with heart failure.

Overall, Ghali currently is conducting 30 separate clinical trials, primarily on drugs being evaluated for treatment of heart failure, to evaluate the benefit/risk of the product. The federal Food and Drug Administration uses the information from such clinical trials to decide whether to approve the new medicine or whether a medical device should be placed on the market.

At LSUHSC-S, basic research in cardiovascular disease is supported by the National Institutes of Health and the American Diabetes Association. Pharmaceutical companies and manufacturers of medical devices under development also pay academic health sciences centers like LSUHSC-S to perform clinical trials.