What Is the Connection Between Cholesterol and Inflammation?

Understanding how cholesterol and inflammation affect the body and what to do about high cholesterol

Cholesterol has long been seen as a key culprit in cardiovascular disease—an umbrella term for the conditions that affect the heart and blood vessels. The American Heart Association (AHA) recognizes many factors contribute to the development of heart disease, such as blood pressure, blood sugar, weight, and cholesterol. But what actually is cholesterol?

What Is Cholesterol?

Cholesterol is a waxy, fatty substance produced by the liver, but it also occurs in foods. It comes in two main types: low-density lipoprotein (LDL), aka bad cholesterol, and high-density lipoprotein (HDL), aka good cholesterol. According to the Centers for Disease Control and Prevention, cholesterol in blood is important for maintaining good health because it performs vital functions, like making hormones and breaking down fatty foods. But, too much cholesterol can be a bad thing. This is because higher LDL levels combined with lower HDL levels put people at risk of cardiovascular diseases like coronary heart disease and heart attack, as well as stroke, so the AHA.

What About Inflammation?

Inflammation is the flood of white blood cells and chemicals that our immune system unleashes to ward off damage or infection. In a 2018 review published in Nutrients, researchers identified inflammation as a primary source of chronic diseases, such as cardiovascular disease (CVD). Cholesterol wouldn't be nearly as dangerous without this process, which is thought to play an essential role in atherosclerosis, the hardening that occurs when LDL cholesterol builds up in the arteries.

When high levels of cholesterol occur in the bloodstream, excess LDL cholesterol begins to seep into the inner wall of the artery. This triggers an inflammatory response, which actually speeds up the accumulation of cholesterol in the artery wall. This, in turn, produces more inflammation—and on and on. Eventually, the deposited cholesterol hardens into a plaque, which can rupture and lead to the blood clots that cause heart attacks and strokes—an event that inflammation also appears to help along.

Some experts now believe that inflammation is the link between many diseases and conditions that affect the heart and brain. "Inflammation is the common denominator in nearly all of the diseases we deal with," said James O'Keefe, MD, director of preventive cardiology at the Mid America Heart Institute in Kansas City, Mo. "Heart disease, diabetes, dementia—they're all tied to inappropriate, low-grade, chronic inflammation."

Measuring Inflammation

Our growing understanding of inflammation's role in atherosclerosis doesn't diminish the importance of cholesterol—you still have to keep that "bad," LDL number down and the "good," HDL number up—but it does present another way to anticipate cardiovascular disease.

Studies show that a substance known as C-reactive protein (CRP), one of the so-called markers released by cells during the inflammation process, may be more effective than cholesterol in gauging the risk of heart attack and other cardiovascular events. CRP was even reported as "the most clinically useful" biological marker of atherosclerosis in a 2021 review published in the journal European Cardiology Review. And a 2018 review study published in Frontiers in Immunology confirmed the predictive role CRP plays in the development of cardiovascular disease and a number of other inflammation-related conditions.

A CRP test specifically designed to measure the risk for cardiovascular disease, known as a high-sensitivity C-reactive protein (hsCRP) assay, was approved by the FDA in 1999, and the test has become nearly as routine as the cholesterol test. Some doctors have even begun to administer the hsCRP test, which requires a simple blood workup, as part of their annual physical exams.

The importance of CRP is still a matter of dispute, however. "One of the issues and controversies regarding CRP as a risk factor for cardiovascular disease has been whether it is simply a marker, or whether the higher levels actually cause heart attack and stroke," said Alex Reiner, MD, an epidemiologist at the University of Washington School of Public Health and Community Medicine. There's some evidence for both explanations, and according to Dr. Reiner, "It's very difficult to tease that out. It can work both ways, and my guess is, it probably does."

According to a study published the journal Atherosclerosis in 2021, CRP levels may be modifiable through lifestyle adjustments. This study examined a group of individuals with established cardiovascular disease. What the researchers found was that lifestyle adjustments, such as stopping smoking, increasing physical activity, and losing weight, were all associated with decreases in CRP levels.

Dr. Reiner is one of a group of researchers across the United States who has turned to genes to establish a link between inflammatory markers and the risk of cardiovascular events. Dr. Reiner and others have identified genetic variations that predict CRP levels, and variations that predict heart attack and other events, but they have yet to find a single gene that predicts both. If it exists, this gene would prove the connection between CRP and cardiovascular disease. "That would be the holy grail," said Dr. Reiner.

Implications for Treatment

Though the exact role of inflammatory markers is yet to be determined, if your CRP test uncovers high levels of CRP (defined by the AHA as over 3 mg/L), it is probably a sign that you should address your risk for cardiovascular disease, even if you have normal cholesterol. Your doctor may start you on aspirin therapy or, more likely, a statin.

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A 2017 meta-analysis published in Current Cardiology Reviews showed that statins had positive effects on reducing inflammation and they lowered the levels of inflammatory markers, including CRP. Even though some statins showed stronger effects on inflammation than others, the meta-analysis concluded that overall, statins are still effective treatments for inflammation.

While statins are frequently used, further research has found additional medications that may aid in reducing inflammation and CRP levels. A study published in 2021 in Frontiers in Cardiovascular Medicine explains the use of a medication called colchicine. Multiple clinical trials have examined additional drugs beyond statins on their effect to lower inflammation in CVD. An immunotherapy medication called canakinumab also showed promising effects on inflammation, according to a 2017 study published in The New England Journal of Medicine.

But medications aren't a silver bullet. As with cholesterol, inflammation should be managed through multiple steps, such as maintaining a healthy weight, exercising, quitting smoking, and following a healthy diet.

Inflammation appears to be aggravated by a poor diet, as was demonstrated in a 2020 study published in the Journal of the American College of Cardiology. High-calorie, high-fat meals are concerning because they cause a sudden spike in CRP and other inflammatory markers. "The inflammation is due to a fundamental problem of using the wrong fuel for the engine," said Dr. O'Keefe. "We're not designed to burn this stuff, and when we do, it throws off all these inflammatory by-products." To keep inflammation to a minimum, Dr. O'Keefe recommended a restricted-calorie diet (similar to the Mediterranean diet), consisting of fruits and vegetables, lean protein, nuts, vinegar, tea, and fish oil, as well as low to moderate alcohol intake.

"The key to restoring good health to America is getting people to tune in to the connection between the dynamic, hour-to-hour nature of inflammation and their general health and well-being—of their heart, their brain, their blood," said Dr. O'Keefe. "From a health standpoint, nothing is more important than keeping those inflammation levels down."

Is Inflammation Overhyped?

Not everyone is convinced that inflammation is the next big thing in cardiac care. The role of inflammation and the value of CRP continues to be investigated. Supporters of the inflammation theory admit that it is unlikely to become more important than cholesterol.

The connection between cholesterol and cardiovascular disease is by now so well established that inflammatory markers like CRP, while they may prove useful to test and treat, will not take the place of cholesterol any time soon, said Alan Daugherty, PhD, the director of the Cardiovascular Research Center at the University of Kentucky.

"If you gave physicians a choice between doing a test for cholesterol or CRP," said Daugherty, "I'm fairly certain that more than 90% would take the LDL cholesterol measurement." Treatment for inflammation, added Daugherty, will continue to take a backseat to cholesterol-based treatments for the foreseeable future. "I very much doubt it will ever be a substitute for cholesterol-lowering, but it might very well be an add-on," said Daugherty.

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