Caffeine and heart disease: What is the link?
- A recent study uncovered how caffeine reduces the risk of cardiovascular disease.
- Researchers found that caffeine lowers blood proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, which, in turn, lowers “bad” cholesterol, or low-density lipoprotein (LDL) cholesterol.
- High levels of LDL cholesterol contribute to the development of coronary heart disease.
- Researchers are developing new caffeine derivatives as potential therapies to treat cardiovascular disease.
Cardiovascular disease, also known as heart disease, affects the body’s heart and blood vessels. An estimated 18.2 million adults aged 20 years and older have coronary artery disease in the United States.
About 361,000 people in the U.S. died in 2019 from coronary heart disease, with 20% of deaths occurring in adults under 65 years.
Coronary heart disease occurs when fatty deposits or plaques consisting of cholesterol, calcium, and fibrin — a substance that causes blood clotting — accumulate in blood vessels.
Plaque buildup, or atherosclerosis, in arteries causes narrowing, which may cause a partial or total blockage, leading to heart attack, stroke, or tissue death in the extremities, which people know as gangrene.
Scientists currently believe that high blood pressure, diabetes, smoking, and high cholesterol may cause damage to the arteries’ inner lining.
Elevated LDL cholesterol levels contribute to atherosclerosis, while high levels of high-density lipoprotein (HDL), or “good” cholesterol, may be protective.
HDL carries LDL away from the arteries, transporting it from the blood to the liver, where the LDL cholesterol is broken down and eliminated from the body.
High LDL or low HDL levels alongside elevated triglycerides — the most common type of fat in the body that stores excess energy — increase the risk for heart attack and stroke risk.
Sterol regulatory element-binding protein 2 (SREBP2) regulates LDL cholesterol levels in the body.
When cholesterol and calcium levels in a cell decrease, it activates SREBP2. This protein then moves to the cell nucleus and activates genes that influence cholesterol production.
These gene regulators of cholesterol production include:
- 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase, which controls the rate of cholesterol production
- LDL receptors, which transport LDL cholesterol from the blood into cells
- PCSK9, which controls the number of LDLRs
Dr. Robert Greenfield, MD, an Emeritus Lipid Consultant at MemorialCare Heart & Vascular Institute at Orange Coast Medical Center in Fountain Valley, CA, spoke with Medical News Today.
He explained that PCSK9 protects the liver from getting too much cholesterol. “The liver has the ability to create receptors on its surface — let’s call them ‘parking spots’ for LDL or ‘bad’ cholesterol.”
He continued, “When an LDL molecule decides to park in the parking spot, the liver is then able to absorb that cholesterol […] into the liver cell to make bile, vitamin D, and other substances. To avoid too much LDL from entering the liver, and too many parking spots being available, it also manufactures this molecule called PCSK9.”
Dr. Greenfield added, “PCSK9 goes out to the parking spots or LDLRs that are on the surface of the liver, and actually [destroys] them, so the amount of LDLRs are kept in check.”
Current cholesterol treatments
Medical professionals treat high cholesterol with lifestyle changes, such as a nutritious diet and exercise alone or in combination with medications. These medications reduce high cholesterol through various mechanisms.
Statins are the gold standard of treatment and block cholesterol production in the liver by inhibiting HMG-CoA reductase. Other medication classes are available to treat high cholesterol in those who do not respond to statins or have intolerable side effects.
These other drugs include:
- adenosine triphosphate-citrate lyase inhibitors, which block the production of cholesterol
- bile acid sequestrants, which increase the elimination of cholesterol from the intestine
- ezetimibe, which limits cholesterol absorption in the intestine
- niacin, which decreases the production of cholesterol in the liver
- fibrates and omega-3 fatty acid ethyl esters, which lower triglycerides
- PCSK9 inhibitors, which block the PCSK9 protein
Dr. Matthew J. Budoff, a professor of medicine and program director of cardiac computed tomography at David Geffen School of Medicine at University of California, Los Angeles, in an American Journal of Managed Care Peer Exchange, explains:
“PCSK9 is a protein developed in the liver. It ‘kills’ the LDL receptors on the liver. […] The LDL floats in our bloodstream [and] does not get taken up by the liver, [which causes] our LDL levels to stay elevated.”
He adds, “If you block PCSK9, […] we lower that protein [and] end up with many more LDL receptors, and the liver can then lower LDL. It’s pretty remarkable and consistent that the PCSK9 inhibitors lower LDL by an additional 50% to 60% LDL.”
Statins lower LDL to a lesser degree, by about 30–50%. However, PCSK9 inhibitors are injectable medications that are expensive.
Despite the availability of different treatment options, some people have difficulties reaching cholesterol goals because of side effects or the lack of access due to medication costs. Therefore, finding new, more cost-effective ways to influence cholesterol levels is an urgent necessity.
Caffeine blocks SREBP2 activation
Recent research suggests that people consuming caffeine in nonalcoholic beverages in doses greater than 600 milligrams (mg) per day may reduce cardiovascular risk.
This led researchers at McMaster University in Canada to investigate the mechanism behind caffeine’s cardioprotective effect.
The team published their results in the journal Nature Communications. The study consisted of a series of experiments in liver cells and mice and found that caffeine:
- blocked PCSK9 gene expression and PCSK9 protein production in liver cells
- prevented SREBP2 activation and the expression of PCSK9 in the liver cells
- inhibited the secretion of PCSK9 proteins and increased LDLRs in mice
Together, these actions increased LDL cholesterol transport from the blood to liver cells.
The authors also tested how a 400 mg caffeine dose affected PCSK9 levels in healthy, fasting volunteers. At 2 hours, caffeine reduced PCSK9 levels by 25% at 2 hours and 21% at 4 hours.
Fasting participants in the control group who did not consume caffeine did not experience changes in PCSK9 levels at these time intervals.
Dr. Greenfield commented on the results of the study, “So the idea that caffeine may be something beneficial and trying to figure out why it’s beneficial was really important. Caffeine seems […] to shut off the production of PCSK9.”
He elaborated, “That’s a good thing because if there is less PCSK9, [there will be] more liver receptors, and [a greater] ability to clear excess cholesterol from our blood.”
The 400 mg dose of caffeine that participants consumed in the study is the Food and Drug Administration (FDA)-recommended maximum dose of caffeine per day, according to Dr. Greenfield.
He stated, “An 8-ounce cup of coffee [contains] between 80 [and] 100 milligrams of caffeine, […] which […] comes out to […] 4 or 5 cups a day.” However, caffeine intake may cause palpitations or jitteriness, which may be bothersome to some people.
The researchers of this study are developing xanthines — similar molecules to caffeine — which inhibit PCSK9 to a greater extent, without the side effects observable with caffeine.
Dr. Jakob Magolan, co-author and associate professor in the Department of Biochemistry & Biomedical Sciences at McMaster, elaborates, “We are excited to be pursuing this new class of medicines — or nutraceuticals — for the potential treatment and prevention of cardiovascular disease.”
Dr. Richard Austin, Ph.D., senior author and professor in the Department of Medicine at McMaster and a member of the Hamilton Centre for Kidney Research at The Research Institute of St. Joe’s Hamilton, explains:
“Coffee and tea drinkers have another important health reason to rejoice — minus the sugar. These findings now provide the underlying mechanism by which caffeine and its derivatives can mitigate the levels of blood PCSK9 and thereby reduce the risk of cardiovascular disease.”
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