Cholesterol Crystals: The Neglected Heart Attack Risk Factor

In recent years, our understanding of how cholesterol and the lipoproteins that carry it affect heart health has exploded.

New research reveals another way cholesterol can raise your risk of heart attack: by forming needle-like “cholesterol crystals” that are buried deep inside arterial plaque, with potentially devastating consequences.

In this exclusive interview, Michael Ozner, MD, one of the leading preventive cardiologists in America, explains how cholesterol crystals are formed, why we should worry about them, and how exciting new research into how EPA from omega 3 fatty acids and medications can help reduce the risk of suffering a major cardiac event caused by cholesterol crystals.

LE: Let’s start at the beginning. What are cholesterol crystals?

MO: In my books, I’ve written a lot about the dangers of having excess atherogenic lipoproteins in the bloodstream. These atherogenic lipoproteins, which carry and transport cholesterol and triglycerides, have been shown to dramatically increase the risk of a heart attack or vascular disease because they can penetrate the arterial wall and begin the formation of arterial plaques. This is the first step in the atherosclerotic disease process.

These atherogenic lipoproteins are known as apo B lipoproteins (apolipoprotein B), and when the apo B blood levels are elevated there is an increased risk of heart attack. When apo B particles get into the arterial wall, they can get trapped, oxidized, and engulfed by a type of immune system cell called a macrophage.

As macrophages gather at the site of an arterial wall injury, this begins the process of arterial plaque formation. As macrophages engulf cholesterol, they become foam cells and over time these foam cells and macrophages undergo cell death, or apoptosis. When they die, they release their inner contents, which include cholesterol. As more cells die, the atherosclerotic plaque becomes super-saturated with cholesterol, and that cholesterol eventually forms a crystalline structure called a cholesterol crystal. These crystalline structures have sharp points like a needle that are capable of piercing the atherosclerotic cap, which can lead to a plaque rupture, and a devastating cardiac event such as heart attack and sudden cardiac death.

LE: It sounds like this explains the mechanism of plaque rupture, or what’s happening right before the plaque ruptures. Are these cholesterol crystals implicated in all plaque ruptures, or is this just one risk factor?

MO: The concept of cholesterol crystals has been known for years, but now there is excellent new research helping us understand how they contribute to atherosclerotic disease. There are other mechanisms that can cause plaques to rupture, but this is an important part of it. A recent study by cardiologist George Abela of Michigan State University of 286 heart attack subjects in an emergency room found that 89% of the patients had cholesterol crystals, with 84% showing crystals large enough to be measured and analyzed.¹

The mere presence of cholesterol crystals is a sign that a heart attack may be imminent since these crystals can pierce the fibrous cap of the atherosclerotic plaque, leading to plaque rupture. This means we may now have a way of identifying risk that a plaque may be about to rupture. But it’s important to understand this is just one way cholesterol crystals pose danger. In fact, there are two mechanisms by which they may pose a danger to your health.

LE: What’s the second one?

MO: The first I discussed was mechanical. The second has to do with the inflammatory milieu within cells. Cholesterol crystals increase inflammation within the plaque. They do this by activating the “inflammasome” within the macrophages, which in turn activates the inflammatory pathway and causes the release of IL-1 beta. This is an inflammatory cytokine that has been shown to increase vascular inflammation and the risk of plaque rupture.

So we have these two mechanisms, mechanical (crystals piercing plaques) and inflammatory, and both increase the risk of plaque rupture.

LE: Considering how dangerous they can be, is there a way to identify or measure cholesterol crystals?

MO: Unfortunately, it’s challenging right now to measure cholesterol crystals with a blood test. The study I mentioned earlier by Dr. Abela obtained material from within the coronary artery during the patient’s hospital stay. It was an invasive procedure that allowed them to examine the plaque and identify cholesterol crystals. Emerging non-invasive imaging modalities will potentially be able to accurately identify cholesterol crystals in human coronary arteries. A surrogate measure for cholesterol crystals might be testing for apolipoprotein B in the blood and fortunately the cost of this test has plummeted in recent years.

So, at this point in time, we can’t measure cholesterol crystals easily, but at least surrogate blood markers (like LDL and apolipoprotein B) can provide important information for those of us who are looking for ways to reduce the risk of heart attack and heart disease. We are learning more ways, both old and new, to decrease cholesterol within the plaques. When we reduce cholesterol within the plaque, we can decrease cholesterol crystal formation. If you think of a stable arterial plaque, it has very little inflammation and cholesterol inside it. These plaques are much less likely to rupture than the unstable plaques with an active inflammatory milieu and increased cholesterol concentration.

LE: In other words, to reduce cholesterol crystals, it is necessary to reduce dangerous cholesterol as much as possible. Is there a better way to do that?

MO: Anything that lowers cholesterol will reduce cholesterol crystals. When it comes to reducing cholesterol, we always start with lifestyle. Start by reducing saturated and trans fats in your diet. Get regular exercise. Medically, statin therapy will reduce cholesterol as well. And there are some new and emerging ways we can reduce cholesterol crystals, one of which is by taking omega-3 fatty acids, specifically the omega-3 fatty acid EPA.² Highly purified EPA has been shown to block cholesterol crystal formation within the cell membrane so it’s plausible we could use highly purified EPA to decrease the number of cholesterol crystals within plaque.

Further, we know that highly purified EPA, used on top of a statin, leads to increased plaque stability and plaque regression compared to the statin by itself. EPA (eicosapentaenoic acid) also lowers triglycerides and has a free radical scavenging and anti-inflammatory effect. There is continuing research on EPA, including the Reduce It Trial. This trial is looking at the role EPA plays in reducing elevated triglycerides in high-risk cardiac patients with well controlled cholesterol.

Topline results of the Reduce-It Trial were reported September 2018 and showed a highly significant 25% reduction in major adverse cardiovascular events (e.g. non-fatal heart attack and stroke and cardiovascular death) in those randomized to statin plus EPA versus statin without EPA.

Therefore triglycerides are a potentially atherogenic blood lipid that can lead to vascular plaque development and increase the risk of heart attack. Lowering triglycerides with a heart-healthy diet (e.g. Mediterranean diet), regular exercise and triglyceride lowering medications if indicated can lower cardiovascular disease risk.

Outside of EPA, there are other new and novel approaches being studied. A few studies have looked at cyclodextrin, a sugar-like substance as a potential therapy. One study showed that cyclodextrin was able to dissolve cholesterol crystals and decrease inflammation within the plaque.³ It’s promising at this stage, but a large-scale clinical trial has not been done so we await final results.

Finally, the CANTOS trial is a groundbreaking trial that’s looking at canakinumab, an injectable drug that blocks the action of IL-1 beta. This trial showed a significant reduction in cardiovascular events among patients who had inflammation, as measured by high sensitivity C-reactive protein levels, and were given canakinumab.⁴ This is an expensive drug, but it showed that if we can inhibit IL-1 beta, we can reduce the risk of cardiovascular events.

In conclusion, reducing cholesterol crystals formation by following a healthy diet and lifestyle and utilizing medications, when needed to lower cholesterol and triglycerides and reduce inflammation, can translate into a reduction in heart attack risk.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

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Michael Ozner, MD, FACC, FAHA, is one of America’s leading advocates for heart disease prevention. Dr. Ozner is a board-certified cardiologist, a fellow of both the American College of Cardiology and the American Heart Association, medical director of Wellness and Prevention at Baptist Health South Florida, a well-known regional and national speaker in the field of preventive cardiology, and a member of Life Extension’s Scientific Advisory Board. He is symposium director for Cardiovascular Disease Prevention, an annual international meeting dedicated to the treatment and prevention of heart attack and stroke. He was the recipient of the 2008 American Heart Association Humanitarian Award and was elected to Top Cardiologists in America by the Consumer Council of America. Dr. Ozner is also the author of The Great American Heart Hoax, Heart Attack Proof, and The Complete Mediterranean Diet.

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References

1. Abela GS, Kalavakunta JK, Janoudi A, et al. Frequency of Cholesterol Crystals in Culprit Coronary Artery Aspirate During Acute Myocardial Infarction and Their Relation to Inflammation and Myocardial Injury. Am J Cardiol. 2017 Nov 15;120(10):1699-707.
2. Mason RP, Jacob RF, Shrivastava S, et al. Eicosapentaenoic acid reduces membrane fluidity, inhibits cholesterol domain formation, and normalizes bilayer width in atherosclerotic-like model membranes. Biochim Biophys Acta. 2016 Dec;1858(12):3131-40.
3. Zimmer S, Grebe A, Bakke SS, et al. Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming. Sci Transl Med. 2016 Apr 6;8(333):333ra50.
4. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017 Sep 21;377(12):1119-31.