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Caffeine—Not Just Coffee Drinking—Reduces Heart Disease Risk. (Yes, You Read That Correctly.) Conventional Wisdom Proven Wrong Again.

Caffeine—Not Just Coffee Drinking—Reduces Heart Disease Risk.  (Yes, You Read That Correctly.) Conventional Wisdom Proven Wrong Again.

The plot of the classic 1973 comedy Sleeper revolves around a health-food store owner who falls asleep only to wake up two centuries later in a hospital where his doctors are discussing his case. To watch, click here.  The dialogue goes as follows:

Dr. Melik: This morning for breakfast he requested something called “wheat germ, organic honey and tiger’s milk.”
Dr. Aragon: [chuckling] Oh, yes. Those are the charmed substances that some years ago were thought to contain life-preserving properties.
Dr. Melik: You mean there was no deep fat? No steak or cream pies or… hot fudge?
Dr. Aragon: Those were thought to be unhealthy… precisely the opposite of what we now know to be true.
Dr. Melik: Incredible.

Conventional Wisdom Is Often Proven Wrong; and It Can Be Hard to Believe When It Is

Although the above scene is funny, it illustrates a good point: Conventional wisdom is often eventually proven wrong, and when it is, it may be so surprising that people find it hard to believe, so it takes a while before the information disproving it is disseminated among the community, and finally, widely adopted and accepted. In medicine, and quite often in my profession of cardiology, I have frequently seen our thought leaders hold onto conventional wisdom regarding diet for far too long.

Caffeine Can Reduce Your Risk of Heart Disease? Really?

When I first heard about a recent study claiming that caffeine—not coffee—could reduce your risk of heart disease[1], I will confess my first thought was, “No way! That is crazy!” It just seems incredible and unbelievable on its face since it is counterintuitive. This is because it hardly takes medical training to know that caffeine’s primary function is that of a stimulant: It raises your heart rate and blood pressure, which are not normally good things; therefore, the conventional wisdom was that caffeine must increase your risk of heart disease. Secondly, it is well known that caffeine taken in excessive quantities can cause death, usually by inducing cardiac arrhythmias (abnormal heart rhythms). Caffeine intoxication typically involves doses of about two grams of caffeine to require hospitalization; doses ranging from five grams and up have been reported to be lethal[2]. If an average cup of strong coffee contains 100 mg of caffeine, this would mean consuming fifty cups of coffee in short order. People have died by overdosing on energy drinks, which typically contain higher amounts of caffeine per fluid ounce than coffee, but also contain other added stimulants, which potentiate the caffeine’s effect.

The Previous Caffeine-Heart Disease Theory Was Not Evidence-Based

Other than the previous knowledge that overdose by caffeine (caffeine intoxication), which does cause arrhythmias, a reassessment by multiple investigators of moderate, or even heavy, caffeine consumption has simply failed to show any statistical evidence of deleterious cardiac consequences, such as heart failure or arrhythmias[3],[4],[5]. This was simply conventional wisdom and was assumed for generations.

We Already Know Coffee Drinking Can Lower Heart Disease Risk

After years of cardiologists telling their patients to drink decaf (based on the theory that coffee contains caffeine, which must necessarily increase heart disease risk), studies began appearing in the medical literature that concluded that drinking coffee was associated with a decrease in cardiovascular disease (CVD) risk. This association that was observed had been put down to the fact that coffee contains a plethora of antioxidant polyphenols such as caffeic, ferulic, and chlorogenic acids. Polyphenols in general are known to reduce CVD risk; however, studies have shown that chlorogenic acid specifically has potential cardiovascular benefits related to decreasing blood pressure[6], improving endothelial function (the lining of the arteries), and increasing nitric oxide bioavailability[7]. But now, this recent article comes along and introduces a provocative theory: Caffeine also helps reduce CVD risk. But how?

How Can Caffeine Possibly Reduce Heart Disease Risk?

The authors of the study think caffeine works to lower CVD risk by directly reducing the amount of circulating LDL cholesterol. And obviously, if you can do that, you lower the risk of CVD. What is interesting is that they think caffeine does this in two ways: (1) by reducing the amount of an enzyme called PCSK9; and (2) by increasing expression of a gene coding for the LDL-C receptor (LDLR). These two work together. The LDL-C molecule binds to the LDL-C receptor in a lock-and-key fashion and the LDLR transports it out of the circulation, for further processing, thus ensuring that LDL-C blood levels do not rise too high. PCSK9 is an enzyme that functions by binding to the LDLR to degrade, and thus remove, LDL receptors from the liver (where most of them are).

Scheme showing the interaction between PCSK9 and the LDLR on a hepatocyte. A: Available PCSK9 binds to the LDLR and results in internalization of the receptor, followed by lysosomal degradation. B: Without available PCSK9, LDL cholesterol is internalized by the LDLR into the hepatocyte. The LDLR circulates afterwards back to the surface. (Image courtesy Valentin Schlegel, et al. Copyright 2017, Creative Commons license CC BY 4.0.

The effect is then that there are fewer LDLRs left for the LDL-C molecules to bind to in the liver, and thus, LDL-C blood concentrations stay higher because they are not being removed. The discovery of PCSK9 was extremely important because it led to the development of two drugs that could block it—Repatha and Praluent—providing important alternatives to patients for whom statins were ineffective in lowering their LDL cholesterol. The problem is that these medications are expensive and must be administered by injection. The implication of this research is that simply by consuming moderate amounts of caffeine, significant reductions in LDL-C can be obtained, therefore reducing your risk of heart disease.

So , if you are like billions of people around the world who love their latte, want to espresso themselves, or end their night with a flat white, this is great news for you! The only thing I will say that might kill your coffee buzz (but hopefully will not) is that you should not have boiled, unfiltered coffee, as that raises your heart disease risk, as the boiling brings out fats from the coffee beans that you do not want to be drinking. But all other methods of preparation, followed by normal filtration, keep these unwanted by-products out of your coffee cup, delivering only the healthy part of the brew to you.

The moral of the story is, sometimes it is important to question conventional wisdom: It is only by challenging old theories, by retesting old medications in new clinical contexts that science is advanced. You never know: the results may surprise you, and just might provide valuable insights that could eventually change the course of accepted clinical practice. It was not so long ago that many of my colleagues simply followed conventional wisdom and told their patients that to prevent heart disease, all they had to do was to avoid eating egg yolks, look for “low-fat” on the label when shopping, and use margarine and Crisco. They never recommended olive oil or said a word about the real culprit—carbs. Now we know better, don’t we?

[1] Lebeau, P.F., Byun, J.H., Platko, K. et al. Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance. Nat Commun 13, 770 (2022).
[2] Willson C. The clinical toxicology of caffeine: A review and case study. Toxicol Rep. 2018;5:1140-1152. Published 2018 Nov 3. doi:10.1016/j.toxrep.2018.11.002
[3] Voskoboinik A, Kalman JM, Kistler PM. Caffeine and Arrhythmias: Time to Grind the Data. JACC Clin Electrophysiol. 2018 Apr;4(4):425-432. doi: 10.1016/j.jacep.2018.01.012. PMID: 30067480.
[4] Voskoboinik A, Koh Y, Kistler PM. Cardiovascular effects of caffeinated beverages. Trends Cardiovasc Med. 2019 Aug;29(6):345-350. doi: 10.1016/j.tcm.2018.09.019. Epub 2018 Oct 4. PMID: 30301595.
[5] Patil H, Lavie CJ, O'Keefe JH. Cuppa joe: friend or foe? Effects of chronic coffee consumption on cardiovascular and brain health. Mo Med. 2011 Nov-Dec;108(6):431-8. PMID: 22338737; PMCID: PMC6181718.
[6] Mubarak A, Bondonno CP, Liu AH, Considine MJ, Rich L, Mas E, Croft KD, Hodgson JM. Acute effects of chlorogenic acid on nitric oxide status, endothelial function, and blood pressure in healthy volunteers: a randomized trial. J Agric Food Chem. 2012 Sep 12;60(36):9130-6. doi: 10.1021/jf303440j. Epub 2012 Sep 4. PMID: 22900702.
[7] Jiang R, Hodgson JM, Mas E, Croft KD, Ward NC. Chlorogenic acid improves ex vivo vessel function and protects endothelial cells against HOCl-induced oxidative damage, via increased production of nitric oxide and induction of Hmox-1. J Nutr Biochem. 2016 Jan;27:53-60. doi: 10.1016/j.jnutbio.2015.08.017. Epub 2015 Aug 24. PMID: 26386740.


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