Targeting Inflammation in Cardiovascular Disease


Inflammation is the body’s natural way of protecting itself from harm. When fatty, cholesterol-rich plaque accumulates within the arterial walls, the immune system perceives it to be a foreign invader and sends white blood cells to attack, resulting in chronic low-grade arterial inflammation. It’s now believed that heart attacks and stroke are linked to this smoldering inflammation: As the plaque continues to accumulate over time, it narrows the coronary arteries and reduces blood flow to the heart muscle, ultimately leading to plaque rupture and heart attack.

Statin medications have been used for decades with great success to prevent cardiovascular disease: In lowering the accumulation of lipid, they significantly reduce cardiovascular risk. For years now, taking statins and adopting a healthier lifestyle have been the keystones in the prevention of cardiac disease. Now, however, scientists are hypothesizing that specifically targeting different inflammatory pathways may also help prevent and treat cardiovascular disease. By zeroing in on various molecular triggers, they are finding ways to effectively close these pathways and reduce arterial inflammation.

A 2016 study identified the mechanism behind the surge in cardiovascular inflammation that takes place following a heart attack. As a result of this discovery, the Massachusetts researchers were able to develop a potential strategy for suppressing inflammation within atherosclerotic plaques—an approach to target the immune cells’ contribution to cardiovascular disease.

The researchers found sympathetic nerve fibers are activated within the arterial lining in response to a heart attack, leading to the increased expression of adhesion molecules on the endothelial cells that line atherosclerotic plaques. Those molecules attract inflammatory white blood cells and cause them to stick to the plaques, increasing the risk for another heart attack.

Halting the expression of those adhesion molecules, therefore, could greatly reduce the chances of another heart attack. And the scientists discovered a way to do just that by means of nanoparticle-delivered RNA interference.

In the 2016 study, a series of experiments with a mouse model of atherosclerosis revealed that after a heart attack, the activity of sympathetic nerve fibers within the animals’ aortas caused the increased expression of several adhesion molecules. By targeting five of these adhesion molecules with nanoparticles, they not only reduced the recruitment of inflammatory immune cells to aortal plaques in the mice, but they also lowered the expression of inflammatory proteins (called cytokines and enzymes). This was key, as the researchers found that the increased expression of cytokines and enzymes contributed to the rupture of arterial plaque, which then triggered a heart attack.

By applying this treatment before an induced heart attack in the mice, they were able to reduce subsequent inflammatory changes, while applying it after a heart attack cut the recruitment of inflammatory cells in half and improved the recovery of heart function. Once this novel approach is translated, the scientists believe it may help to “cool down” inflammation in patients with vascular disease, which would not only protect them from a second heart attack, but also help the heart to recover.

With inflammation playing a major role in heart attack and stroke, and as patients with elevated inflammatory biomarkers, such as high sensitivity C-reactive protein (hsCRP) are at increased vascular risk, novel drugs directed at specific targets in the inflammatory cascade are now in various testing phases.

An injectable, anti-inflammatory, monoclonal antibody that blocks the body’s production of the pro-inflammatory interleukin-I (IL-1) cytokine is currently being investigated in an international, 10,000-patient, randomized clinical trial. Researchers want to see whether neutralizing the IL-1 cytokine can reduce rates of recurrent heart attack, stroke, and death among heart attack patients who remain at high risk due to a persistent elevation of hsCRP.

While inflammation is an important part of the body’s maintenance repair system, too much of it can have devastating effects on the body. Will the careful lowering of chronic inflammation result in fewer cardiac events in the next decade? That answer will be available within the next few years upon the publication of large trial results directly testing the inflammatory hypotheses of atherosclerosis.

And if the answer is yes, it will herald the dawn of a new era in which the treatment of chronic vascular disease moves beyond the reduction of LDL-cholesterol alone, and anti-inflammatory therapies become the cornerstone of lowering vascular event rates.

For more information about Dr. Nahrendorf’s research, please contact Partners HealthCare Innovation by clicking here.

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