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Might also lead to earlier diagnoses and improved therapies for cardiovascular disease
Shown is a cross-section of a peripheral artery from the leg of a patient with chronic limb ischemia, a condition in which excessive plaque buildup causes the arteries to narrow. A new study from the Washington University School of Medicine in St. Louis has identified an important protein in the blood that could be measured to identify such patients earlier in the disease process, so that they can be treated more quickly and severe forms of the disease avoided.
“data-medium-file =” https://medicine.wustl.edu/wp-content/uploads/TibialArteryPlaque_Zayed-300×200.jpg “data-large-file =” https://medicine.wustl.edu/wp-content /uploads/TibialArteryPlaque_Zayed-700×467.jpg “/>Zayed Research Laboratory
To track cardiovascular health, doctors measure blood pressure, cholesterol levels, and blood sugar, along with a number of other risk factors for cardiovascular disease. Such measures can help predict whether a person is at risk of heart attack or stroke. But there is no blood test that can accurately assess how much a person’s arteries can narrow or clog.
Now, researchers at Washington University School of Medicine in St. Louis have shown that high levels of a certain protein circulating in the blood pinpoint a severe type of peripheral arterial disease that narrows the arteries in the legs and can increase the risk of heart attack and stroke . The protein called circulating fatty acid synthase (cFAS) is an enzyme that makes saturated fat. Until recently it was believed that fatty acid synthase was only found within cells. The new study suggests that fatty acid synthase also circulates in the bloodstream and could play an important role in the plaque formation characteristic of cardiovascular disease.
The study appears online in the journal Scientific Reports.
Approximately 12 million people in the US have some form of peripheral arterial disease, a narrowing of the arteries in the legs, and approximately 1 million of these patients develop a severe form called chronic limb threatening ischemia. These patients often undergo vascular surgery to open their peripheral arteries to improve blood flow to the legs. In severe cases, the diseased leg may need to be amputated.
“These patients are at risk of losing their legs, which is devastating to their quality of life,” said senior author Mohamed A. Zayed, MD, PhD, associate professor of surgery and radiology. “They lose their ability to walk and about half of them die within the next two years. We need to identify these patients earlier so that we can aggressively treat them much earlier in the disease process. Our data suggest that blood cFAS levels may be an accurate predictor of which patients are at high risk for the severe forms of the disease. “
Zayed and colleagues collected blood samples from 87 patients before undergoing vascular surgery to treat chronic limb ischemia. The researchers found that blood cFAS levels were independently linked to the disease. A diagnosis of type 2 diabetes and smoking status also correlated strongly and independently with chronic limb ischemia. When all three factors were taken together, they were able to predict the presence of the disease with an accuracy of 83%.
The researchers also found that levels of cFAS in the blood were linked to fatty acid synthase levels in plaques from the femoral artery, the main vessel that supplies blood to the legs. In addition, the researchers found that cFAS circulated through the bloodstream while it was attached to LDL, the so-called “bad” LDL cholesterol, which begs an interesting question.
“I often visit patients in my office with high LDL but otherwise healthy people – they have no signs of disease in their arteries,” said Zayed, who is also a vascular surgeon at Barnes-Jewish Hospital. “We scratched our heads about it. Are we putting these patients on cholesterol-lowering drugs? Are you still at high risk for cardiovascular disease? Our guidelines tell us to be aggressive when treating these patients. But my suspicion is that the problem isn’t just LDL. Rather, the problem is enzymes bound to LDL that cause the cardiovascular disease that we see, especially in the peripheral arteries, as well as the coronary arteries that supply blood to the heart and the carotid arteries that supply blood to the brain . ”
The researchers found that LDL is more abundant in the blood than cFAS, so the key metric may not be the LDL itself, but how much of the LDL cFAS carries with it.
In previous work, Zayed and his colleagues showed that blood cFAS levels are also elevated in patients with plaque build-up in the carotid arteries that supply blood to the brain. This work also showed that the cFAS circulating in the blood originated in the liver. The evidence suggests that LDL acts as a delivery vehicle for cFAS, which then contributes to the formation of plaque in key arteries throughout the body.
Zayed and colleagues are also investigating cFAS as a potential target for new drug therapies that could slow plaque build-up and treat or prevent cardiovascular disease.
“There are drugs that inhibit fatty acid synthase and we are working on evaluating new ones that are more targeted,” said Zayed. “Neither of them are ready for human clinical trials for this purpose, but we’re using these drugs to test animal models of the disease to see if they actually reduce plaque build-up in the arteries. It would be wonderful to be able to practice precise vascular medicine – to tailor therapy to high-risk patients, to reduce their risk of developing serious complications from cardiovascular disease. “
Meanwhile, Zayed is working with Washington University’s Office of Technology Management to develop a test kit to measure cFAS in blood so that high-risk patients can be identified earlier.
This work was supported by the National Institutes of Health (NIH) Grant Numbers NIH / NIDDK P30 DK020589, NIH / NIDDK R01 DK101392, NIH / NHLBI K08 HL132060, and NIH / NHLBI R01 HL153262; the Wylie Scholar Award from the Vascular Cures Foundation; the American Surgical Association Research Fellowship Award; the Research Investigator Award from the Society for Vascular Surgery Foundation; and the Washington University School of Medicine Diabetes Research Center.
Tay S, De Silva GS, Engel CM, Harroun N, Penrose AS, Desai KA, Yan Y, Semenkovich CF, Zayed MA. Prevalence of increased serum fatty acid synthase in chronic, limb-threatening ischemia. Scientific reports. September 29, 2021.
The 1,700 faculty physicians at Washington University School of Medicine are also the medical staff for the Barnes-Jewish and St. Louis Children’s Hospitals. The School of Medicine is a leader in medical research, teaching, and patient care and consistently ranks among the best medical schools in the country according to the US News & World Report. The School of Medicine is affiliated with BJC HealthCare through its affiliation with Barnes-Jewish and St. Louis Children’s Hospital.