The search for an early biomarker to fight atherosclerosis

The Journal of the American Heart Association recently published the conclusive results from a study directed by Dr. Éric Thorin of the Montreal Heart Institute (MHI), which suggests for the first time that a blood protein contributes to the early development of atherosclerosis.

Dr. Thorin, his team and his collaborators discovered that the blood levels of angiopoietin-like protein 2 (angptl2) are six times higher in subjects with coronary heart disease than in healthy subjects of the same age. Their basic research study also revealed that angptl2, which is undetectable in young mice, increases with age in healthy subjects and increases prematurely in subjects who have high cholesterol and pre-atherosclerotic lesions. Entitled “Angiopoietin-like 2 promotes atherogenesis in mice,” this study was conducted using an animal model consisting of three to twelve-month-old mice.

These results represent a major advance in the prevention and treatment of atherosclerosis. “Although much work remains to be done to broaden our knowledge of this protein’s mechanisms of action, angiopoietin-like protein 2 may represent an early biomarker not only to prevent vascular damage but also to predict atherosclerotic disease,” explained Dr. Thorin. Preventing cardiovascular disease is an important goal both to increase healthy life expectancy and decrease pressure on our health care system.

For 15 years, Dr. Thorin, a researcher at the MHI Research Centre and a full professor at Université de Montréal, has been interested in the evolution of artery function during the aging process and in the underlying mechanisms of atherosclerosis. More specifically over the past five years, he has looked at the role of this particular protein. His work has led to a better understanding of the processes induced by angptl2 and that accelerate the progression of the disease.

First of all, angptl2 triggers very intense vascular inflammation and recruits leukocytes to adhere to the vascular endothelium, which is a single layer of cells lining the lumen of vessels and whose integrity is essential to good vascular function and blood flow. The adhesion of leukocytes, or the circulating cells of the immune system, is considered a trigger for atherosclerosis, especially when an abundance of these cells are rolled and tethered onto artery walls to eventually cause atheromatous plaque.

The second important component of this study is the demonstration that a one-month infusion of this protein in mice considerably increased circulating cholesterol levels. This discovery was unexpected, as angptl2 was not known to have an impact on cholesterol metabolism. This finding is all the more important because a high level of blood cholesterol promotes the development of atherosclerosis.

The study showed that the levels of this protein increased in the blood of patients with cardiovascular disease even though all of these patients were treated with a statin, which normalized their high baseline cholesterol levels. Statins are not a blanket solution, as they reduce cardiovascular events in only around 35 per cent of patients. High levels of angptl2 may therefore be a marker for at-risk subjects, which only future research will show. Previous studies indicated that angptl2 blood levels increase in subjects with certain autoimmune diseases as well as diabetes, obesity and cancer, or diseases that damage the small blood vessels and that are associated with chronic inflammation.

According to Dr. Anil Nigam, a cardiologist and specialist in cardiovascular disease prevention at the MHI and co-author of the study, “Prevention is the ideal solution to delay the onset of atherosclerosis, and an early blood marker such as angptl2—if future clinical studies confirm this finding—will serve as an important tool to identify at-risk subjects who do not present with any symptoms of atherosclerotic disease.”