The Heart Foundation supports a large and diverse research program devoted to unraveling the causes of heart disease at a genetic and molecular level, improving methods of early detection, and developing and testing new preventive and therapeutic strategies.
By Prediman K. (P.K.) Shah, MD, FACC, FACP, FCCP
Shapell and Webb Family Endowed Chair in Cardiology
Director, Division of Cardiology & Oppenheimer Atherosclerosis
Research Center at Cedars-Sinai Medical Center
Professor of Medicine, David Geffen School of Medicine at UCLA
Professor, Cedars-Sinai Professorial Series
The Heart Foundation supports specific research programs of the Division of Cardiology’s Oppenheimer Atherosclerosis Research Center under the direction of Dr. PK Shah.
The Cedars-Sinai Division of Cardiology is internationally recognized for outstanding heart care built on decades of innovation and leading-edge research. From cardiac imaging and advanced diagnostics to surgical repair of complex heart problems, the training of future heart specialists, and leading-edge research that deepens medical knowledge and practice, the Cardiology Division is renowned for excellence and innovations.
The Oppenheimer Atherosclerosis Research Center (ARC) was established in 1993 by Dr. PK Shah. A team of 17 researchers work in the ARC under the overall direction of Dr. Shah to unravel the mechanisms leading to plaque build-up and develop new treatments for atherosclerosis, a common and lethal disease responsible for most heart attacks, strokes and sudden deaths.
Brief Update on a Selection of Key Research Projects Supported by The Heart Foundation
Over the past year, Dr. P.K. Shah, Director of the Division of Cardiology and the Oppenheimer Atherosclerosis Research Center (ARC) at Cedars-Sinai Medical Center, and his team have continued on their path to uncover the causes of arterial plaque build-up and to develop new treatments for the resulting condition called atherosclerosis. Fighting against cardiac disease since 1976, Dr. Shah has logged countless hours of study, clinical trials, and even serendipitous discovery to bring him closer to realizing his ultimate goal of eliminating atherosclerosis. Because of his strength in clinical work, as well as his expertise among researchers and talent as a mentor and guide, he is heralded as one of the top cardiologists in the country. His interests in the broader field of medicine—including neurology, neuroscience, and immunology—make him an excellent physician, capable of tackling complex illnesses that require a more holistic and integrated approach.
Oppenheimer Atherosclerosis Research Center at Cedars-Sinai Medical Center: Highlights of Ongoing Research
Work continues on the Vaccine to reduce cholesterol plaque build-up. We have shown that antigens from within the protein part of the bad cholesterol (LDL cholesterol) when injected in a vaccine formulation, reduce artery clogging cholesterol plaque in experimental animals. In the past year , several new findings have shed light on how the Vaccine actually suppresses an autoimmune response to the body’s own bad cholesterol (LDL) thereby reducing inflammation in the artery wall. Furthermore, work in our laboratories have also shown that in experimental models of aortic aneurysm and high blood pressure, the Vaccine also reduces the severity of the aneurysm and risk of its rupture while at the same time reducing elevated blood pressure. These new findings suggest that the Vaccine may have effects in addition to reducing cholesterol plaque deposits. Following discussions with the FDA, we are currently optimizing the formulations of the Vaccine to make it suitable for testing in humans. We are hopeful that after all the due diligence is completed, we will soon enter human trials.
Over the past several years we have conducted numerous studies to show that intravenous injection of a protein called Apo A-I Milano produced from a naturally occurring mutant gene rapidly reduces cholesterol plaque and arterial inflammation in experimental animals. These observations were later confirmed in a small human trial in which 5 weekly intravenous infusions of the protein led to measurable shrinkage of coronary plaque in human subjects. We are now taking another approach to exploit the benefits of this mutant protein. By splicing the mutant gene into the backbone of an innocuous virus (called AAV) , we can now deliver the gene itself by injecting the virus carrying the gene, kind of like a Trojan horse approach. We have shown that once the gene is injected, it instructs the animal’s body to produce the mutant protein which in turn dramatically reduces plaque build-up in the arteries but also shrinks pre-existing plaque thereby reversing arterial blockage. To take it to the next step, we are now working diligently to modify the technique so that in the foreseeable future we can actually test this idea in humans.
We are also testing the idea that the Apo A-I Milano gene could reduce the brain pathology and brain dysfunction in a mouse model of Alzheimer’s disease. The rationale for this study is growing evidence that cholesterol in the brain cell membrane can facilitate the production of Amyloid fibrils that damage the nerve cells in the brain contributing to Alzheimer’s dementia. One of the prominent effects of Apo A-I Milano is to remove excess cholesterol from cell membranes which could help reduce the production of brain toxic Amyloid fibrils. Using a special innocuous virus engineered to deliver the cargo to the brain, we are testing Apo A-I Milano gene transfer in a mouse model of Alzheimer’s disease in collaboration with a group of neuroscientists.
New Experimental Non-Statin Cholesterol Lowering Drugs
Approximately 1 out of 1 million individuals carry a genetic mutation that causes them to have cholesterol levels of 500- over 1000mg/dl causing them to experience heart attacks, strokes and death in their teens and twenties. This genetic defect makes them resistant to statins and many other currently available cholesterol lowering drugs. The only currently available treatment for these unfortunate patients is to undergo LDL-Apheresis (a sort of dialysis to remove the bad cholesterol by filtering their blood and re-infusing filtered blood) for 4 hours at a time once every 1-2 weeks for life. In the past 3 years we have been testing an experimental non-statin oral drug called Lomatipide (Juxtapid) as part of a multicenter trial. This drug significantly reduces bad cholesterol levels (by about 50%) which reduces the frequency of LDL apheresis for these patients. The FDA has recently approved this drug (Juxtapid) for use in such patients based on the results of the multicenter trial.
Help may be on the way for some patients who need significant cholesterol lowering and for whom statins are either only partly effective or are poorly tolerated because of muscle aches and weakness. A new class of drugs that block the actions of a key enzyme called PCSK9 can lower bad cholesterol by 50-70% with once every 2-4 weekly subcutaneous injections. We are participating in two multicenter trials of these PCSK blocking agents which hold considerable promise for effective cholesterol lowering when standard drugs are ineffective or not tolerated.
As with patient care and teaching, biomedical research is a significant part of Dr. Shah’s life’s work. He and his dedicated team examine the underpinnings and biology of plaque build-up and the role of genes and genetic mutations. The pace and promise of such discoveries are likely to yield further medical insights and therapeutic breakthroughs that were unimaginable just one generation ago. Thanks to the efforts of physician researchers like Dr. Shah, this is an incredible period of learning, applying, and reimagining the possibilities of medicine for the benefit of humankind.