Ability of Statins to Improve Heart Failure is Focus of Research

BUFFALO, N.Y. -- Cardiac researchers at the University at Buffalo have received a four-year, $512,000 grant from the U.S. Department of Veterans Affairs to investigate how a common cholesterol-lowering drug increases cardiac-muscle cells and helps to stem the progress of heart failure.

The research group, headed by John M. Canty, Jr., M.D., Albert and Elizabeth Rekate Professor and chief of the Division of Cardiovascular Medicine in the School of Medicine and Biomedical Sciences, demonstrated in earlier research that pravastatin, used widely to lower blood cholesterol, increases the concentration of endogenous stem cells from bone marrow that participate in cardiac repair.

The goal of this new work is to develop pharmacological and cell-based approaches to treat ischemic cardiomyopathy in patients before advanced heart failure develops. Heart failure is a condition in which the heart can not pump enough blood to the body's organs. It is classified into four stages, from mild, with no symptoms, to severe, characterized by the inability to carry out any physical activity without discomfort.

The research is being conducted in UB's Center for Research in Cardiovascular Medicine, which Canty heads. Gen Suzuki, M.D., Ph.D., research assistant professor of medicine who conducted the previous stem cell studies, is co-investigator. Vijay Iyer, M.D., Ph.D., and Thomas Ciamato, M.D., Ph.D., both research assistant professors of medicine, also are involved in the study.

Earlier research conducted elsewhere had shown that HMG-CoA reductase inhibitors (statins) increase the number of circulating bone-marrow-derived, or hematopoietic, stem cells in blood, but most of that work had focused on statins' effects in improving blood flow. Localization of the statin-induced stem cells in the heart or the ability of statins to increase cardiac-muscle-cell numbers had not been studied until the UB work.

The UB study employs the cardiovascular research center's unique swine model of hibernating myocardium, a condition in which cardiac muscle cells, or myocytes, reduce their contraction yet remain

viable in areas that have received reduced blood flow over an extended period of time due to narrowed arteries.

In preliminary studies, researchers treated normal pigs and pigs with hibernating myocardium with pravastatin for four weeks and compared the results. Results showed that high doses of pravastatin increased the number of stem cells that localized in hibernating muscle.

In addition, many newly formed myocytes were detected. While increased stem cells also were seen in normal hearts after pravastatin, they resulted in myocyte growth and development only in diseased hearts.

To carry out their new studies, the researchers will develop a swine model of ischemic heart failure by artificially narrowing two of three coronary arteries.

They hypothesize that using high doses of statins can prevent the progression of heart failure in this model by recruiting stem cells to strengthen the heart muscle, resulting in improved function of the left ventricle, the primary pumping chamber.

"Statins have been widely employed to reduce coronary events and improve prognosis in patients with established coronary artery disease, as well as for primary prevention in patients with high cholesterol that have other coronary risk factors," said Canty.

"The mechanisms responsible for their beneficial actions have focused largely on the favorable effects of cholesterol lowering on atherosclerotic plaques, as well as on the endothelium or inner lining of the blood vessel wall," Canty said. "Stabilization of atherosclerotic plaques and improvement in endothelial-mediated blood vessel relaxation have been thought to be the major explanations for their beneficial actions.

"The ability of this class of drugs to induce endogenous repair of the heart may have been under-appreciated," he said. "People taking statins may have been enhancing endogenous stem cell repair for years without us realizing it.

"Importantly, it is possible that the beneficial effect on stem cells is related to an effect of statins independent of cholesterol lowering. When patients are taken off statins, they might lose these beneficial effects, as well as the benefits of cholesterol lowering. Thus, how cholesterol is lowered and with which drug class may be important in determining all of the beneficial effects of treatment."

Canty, head of the Cardiovascular Disease Group at UB's New York State Center of Excellence in Bioinformatics and Life Sciences, noted that when the mechanisms underlying the induction of new cardiac stem cells are fully understood, there may be other drugs that will produce results better than statins for treating heart failure.

The University at Buffalo is a premier research-intensive public university, a flagship institution in the State University of New York system and its largest and most comprehensive campus. UB's more

than 28,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs. The School of Medicine and Biomedical Sciences, School of Dental Medicine, School of Nursing, School of Pharmacy and Pharmaceutical Sciences and School of Public Health and Health Professions are the five schools that constitute UB's Academic Health Center. Founded in 1846, the University at Buffalo is a member of the Association of American Universities.

The University at Buffalo is in full compliance with mandates of state and federal regulatory agencies pertaining to the humane use and care of research animals.