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
About the Mount Sinai Health System The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven member hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services—from community-based facilities to tertiary and quaternary care.
The System includes approximately 6,600 primary and specialty care physicians, 12-minority-owned free-standing ambulatory surgery centers, over 45 ambulatory practices throughout the five boroughs of New York City, Westchester, and Long Island, as well as 31 affiliated community health centers. Physicians are affiliated with the Icahn School of Medicine at Mount Sinai, which is ranked among the top 20 medical schools both in National Institutes of Health funding and by U.S. News & World Report.