Scientists Reveal New Findings for Reversing Early and Late Atherosclerosis
Icahn School of Medicine at Mount Sinai study suggests early-stage atherosclerosis is reversible, and identifies new genetic targets for fighting advanced atherosclerosis.
Research at Icahn School of Medicine at Mount Sinai has led to important new discoveries about the process behind regression of atherosclerosis, the main underlying cause of heart attack and stroke. In the paper published today in PLoS Genetics, scientists from Mount Sinai and the Karolinska Institute in Sweden studied how atherosclerosis is reversed by lowering LDL cholesterol in mice. Remarkably, early-stage atherosclerotic plaques were entirely reversible, while more advanced plaques developed a resistance to low LDL cholesterol therapy.
In addition, the researchers also identified gene networks within atherosclerotic plaques leading to the discovery of new molecular targets that could help improve responsiveness to LDL-cholesterol therapy in advanced atherosclerosis.
Atherosclerosis, the hardening of the arteries due to the buildup of cholesterol-rich plaques in the walls of arteries, is the primary cause of heart attacks and strokes, which together account for more than half of all deaths worldwide. Advanced atherosclerosis is dangerous and underlies most cases of heart attack or stroke. Scientists have been searching for ways to prevent early-stage atherosclerosis from progressing to the more dangerous, advanced stage to improve outcomes for those patients at risk of coronary or carotid artery disease (CAD).
"The vascular process that responds to plasma cholesterol lowering therapy was not previously well understood, so our aim in this study was to establish a clearer picture of this function," said Johan Björkegren, MD, PhD, co-lead study author and Professor of Genetics and Genomic Sciences at Icahn School of Medicine at Mount Sinai. "Our discovery that early-stage atherosclerosis can regress completely, whereas later-stage atherosclerosis is resistant to treatment, suggests that individuals at increased CAD risk would benefit greatly from early prevention using lipid-lowering drugs like statins."
These new study findings add support to the 2013 American Heart Association guidelines proposing that healthy people at increased risk for CAD shall receive statin therapies even if their LDL cholesterol levels are only mildly elevated in that statin therapy to people with early lesions might be more effective to reverse atherosclerosis than administrating these drugs to patients with more advanced forms of arterial plaques.
In the study, scientists also identified gene networks responsible for the effect of LDL-cholesterol lowering on atherosclerosis regression. In mice with early-stage atherosclerosis, a key driver gene in the network known as PPARG was found to be involved in causing the complete regression. In mature and advanced cases, different key driver genes in the network proved to be most influential in controlling the regression of atherosclerosis: MLL5 in mature cases and SRSF10/XRN2 in advanced cases.
The study authors note that these three key genetic drivers may serve as new targets to improve regression of more advanced forms of atherosclerosis.
"It is our hope that the genetic targets we identified in more advanced atherosclerosis will be useful in developing new therapies to reverse dangerous advanced arterial plaque disease," states Dr. Björkegren.
The new study, entitled "Plasma Cholesterol–Induced Lesion Networks Activated before Regression of Early, Mature, and Advanced Atherosclerosis," was published in PLoS Genetics and is available here: http://www.plosgenetics.org/doi/pgen.1004201
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Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, over 400 outpatient practices, nearly 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time — discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture outpatient surgery centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. We are consistently ranked by U.S. News & World Report's Best Hospitals, receiving high "Honor Roll" status, and are highly ranked: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. U.S. News & World Report’s “Best Children’s Hospitals” ranks Mount Sinai Kravis Children's Hospital among the country’s best in 4 out of 10 pediatric specialties. The Icahn School of Medicine at Mount Sinai is one of three medical schools that have earned distinction by multiple indicators: It is consistently ranked in the top 20 by U.S. News & World Report's "Best Medical Schools," aligned with a U.S. News & World Report "Honor Roll" Hospital, and top 20 in the nation for National Institutes of Health funding and top 5 in the nation for numerous basic and clinical research areas. Newsweek’s “The World’s Best Smart Hospitals” ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.