Caffeine metabolism and heart health

Monday, November 14, 2022. Author FitnessGenes

Caffeine and heart

What are the effects of caffeine on the cardiovascular system?

When discussing the effects of caffeine, it is important to distinguish between those effects that are short-term or acute, and manifest shortly (minutes to hours) after drinking a cup of coffee, from those that are long-term or chronic, which occur when someone habitually drinks coffee over longer periods (years to decades). 

Let’s take a look at these individually.

 

- Acute effects of caffeine

In the first hour after drinking a cup of coffee, our heart rate increases and our blood vessels (including the coronary arteries supplying the heart) temporarily become narrower (known as vasoconstriction).

These effects occur because caffeine is a sympathomimetic, meaning it stimulates our sympathetic nervous system (which is responsible for our body’s fight-or-flight response). Two key hormones involved in the fight-or-flight response are adrenaline and noradrenaline, and caffeine is shown to elevate circulating levels of these hormones, thereby stimulating our sympathetic nervous system. Similarly, caffeine also inhibits the adenosine receptor and a cellular enzyme called phosphodiesterase, which leads to vasoconstriction and increases in heart rate.  

The combination of vasoconstriction and increased effects may cause a small, transient rise in blood pressure after ingesting caffeine. On this note, a 2011 meta-analysis of controlled trials in people with hypertension (high blood pressure) found that a 200-300 mg dose of caffeine (equivalent to about 2-3 8oz cups of coffee) led to a 5.7 and 8.1 mm Hg rise in diastolic and systolic blood pressure, respectively. This rise in blood pressure was observed in the first 1-3 hours after consuming caffeine. 

 

Source:Voskoboinik, A., Koh, Y., & Kistler, P. M. (2019). Cardiovascular effects of caffeinated beverages. Trends in cardiovascular medicine, 29(6), 345-350.

 

Importantly, however, the same meta-analysis found that our bodies adapt to habitual caffeine consumption and that acute rises in blood pressure were not present after 2 weeks. One of these adaptations to regular caffeine consumption is an increase in the activity of CYP1A2, the enzyme which breaks down caffeine. By breaking down caffeine more quickly, habitual caffeine consumers experience less pronounced acute cardiovascular effects of a given caffeine dose. 

In extremely high doses, caffeine may cause an irregular heartbeat (known as arrhythmia) and also reduce blood flow to the heart. These doses are extremely high, however, and most evidence suggests that typical caffeine intake is not associated with an increased risk of arrhythmia.

 

- Chronic effects

Studies of the longer term effects of caffeine consumption have been largely based on observational studies investigating the relationship between various cardiovascular health parameters (e.g. blood pressure, incidence of heart attack) and consumption of caffeinated-drinks such as tea and coffee. 

The drawback of this method is that we cannot be certain whether it is caffeine per se, or another nutrient within coffee,tea, etc.,that is responsible for any long-term cardiovascular effects. 

With this caveat in mind, some studies have shown that habitual caffeine consumption is associated with a reduced risk of cardiovascular disease such as heart failure, coronary artery disease, and heart failure. The underlying mechanisms behind this association are not clear, but may be partly due to the fact that long term caffeine consumption can enhance production of nitric oxide, a molecule that dilates blood vessels. 

Of course, the exact acute and chronic cardiovascular effects of caffeine depend on various factors, such as the dose of caffeine and how it’s consumed, as well as individual variables, such as whether or not someone is a regular caffeine consumer and how quickly they break down caffeine based on their genetics. 

As we’ll explore in later sections, there is some evidence that the chronic caffeine intake has differing cardiovascular effects depending on how fast you break down caffeine i.e. whether you are a fast, intermediate, or slow metaboliser.

 

Is drinking coffee bad for my heart?

Most studies have not found a link between caffeine consumption and negative cardiovascular outcomes, such as high blood pressure or risk of heart disease.

In fact, several large recent studies report that regular caffeine intake is associated with a 8-39% reduction in death from any cause, including cardiovascular disease. (A good summary of these studies is available in this editorial in the journal Nutrients). 

For example, a 2022 study which followed 468,469 UK Biobank participants for a median of 11 years found that, compared to non-coffee-drinkers, people consuming 0.5 - 3 cups of coffee per day had a 17% lower risk of death due to cardiovascular disease. 

Furthermore, some subjects also underwent cardiovascular magnetic resonance imaging to assess structural and functional changes to the heart and blood vessels over time. The researchers found that drinking coffee was associated with favourable structural changes to the cardiovascular system, including higher stroke volume (i.e. greater volume of blood pumped out of the ventricles with each heartbeat), and reduced arterial stiffness. Both of these factors may partly explain why those drinking 0.5-3 cups of coffee per day had a lower risk of cardiovascular mortality. 

Drinking more than 3 cups of coffee a day was initially found to increase the risk of cardiovascular mortality (including a higher risk of heart attack), but this association disappeared after controlling for factors such as age, sex, non-European ethnicities, body mass index, smoking, physical activity, deprivation, alcohol intake and diet. This suggests that drinking 3 or more cups of coffee a day is safe and unlikely to harm your cardiovascular health.

 

Source: Kistler, P. M., Chieng, D., Canovas, R., Kaye, D. M., Morton, J. B., Lee, G., ... & Kalman, J. M. (2022). Regular coffee intake is associated with improved mortality in prevalent cardiovascular disease. Journal of the American College of Cardiology, 79(9_Supplement), 1490-1490.

 

Another UK Biobank study, which focussed on people with preexisting arrhythmia and other cardiovascular diseases, found that drinking coffee did not increase mortality risk. In fact, as illustrated in the graph above, those with cardiovascular disease drinking 2-3 cups of coffee per day had an 8% lower mortality risk. Similarly, people with arrhythmia drinking 1 cup of coffee per day had a 15% lower mortality risk compared to non-consumers.

As with virtually any drug, nutrient, or intervention in public health, the cardiovascular benefits of habitually consuming coffee (and other caffeinated beverages) vary according to dose. A 2014 meta-analysis found a U-shaped relationship, with a dose of 3-5 cups of coffee a day associated with the greatest reduction in risk of cardiovascular disease. The reduction in cardiovascular risk then decreases when drinking more than this. Importantly, as is shown in the graph below, heavy coffee consumption was still safe and was not linked to an increased risk of cardiovascular disease.

It is also important to note here that while people who do not consume caffeine appear to have a relatively higher cardiovascular risk compared to light-to-moderate caffeine consumers, this effect may be due to reverse causation. Specifically, people with cardiovascular health problems tend to limit their caffeine intake.

 

Source: Ding, M., Bhupathiraju, S. N., Satija, A., van Dam, R. M., & Hu, F. B. (2014). Long-term coffee consumption and risk of cardiovascular disease: a systematic review and a dose–response meta-analysis of prospective cohort studies. Circulation, 129(6), 643-659.

 

Despite these findings, the effects of caffeine/coffee consumption on cardiovascular risk are likely to vary between individuals depending on various factors, including genetic differences. As we’ll explain in later sections, there is some evidence that the change in cardiovascular risk of moving from moderate to heavy coffee consumption may be influenced by your CYP1A2 gene variants and how fast you metabolise caffeine.

 

How is caffeine metabolised?

What happens when you drink a cup of coffee or other caffeinated beverage?

Caffeine is quickly absorbed via the gut and enters the bloodstream within minutes. It reaches a peak concentration in the bloodstream between 30 and 120 minutes after ingestion. The half life of caffeine is typically between 4 and 6 hours, although, as we’ll find out, there is considerable variation between people depending on how fast they break down caffeine. 

The vast majority (over 95%) of caffeine is broken down or “metabolised” by a liver enzyme known as cytochrome P450 1A2 (CYP1A2). This enzyme converts caffeine into paraxanthine (about 84% of caffeine is broken down into this metabolite), theobromine (12%), and theophylline (4%). 

These metabolites are then further broken down by various liver enzymes and the breakdown products excreted in the urine by the kidneys. 

Source: Rodak, K., Kokot, I., & Kratz, E. M. (2021). Caffeine as a Factor Influencing the Functioning of the Human Body—Friend or Foe?. Nutrients, 13(9), 3088.

 

The activity of our CYP1A2 enzyme determines how fast we break down caffeine. This, in turn, is affected by various lifestyle and genetic factors, which cause people to break down caffeine at different rates.

Smoking, heavy caffeine use, and high intakes of Brassica vegetables (e.g. broccoli, kale) are shown to activate or induce (i.e increase the production of) the CYP1A2 enzyme, leading to faster breakdown of caffeine. 

By contrast, alcohol, oestrogen-containing oral contraceptives, high intakes of apiaceous vegetables (e.g. carrots, parsnips, celery), and quercetin (found in red wine, onions, grapes) are all shown to downregulate and reduce the activity of CYP1A2, thereby slowing the breakdown of caffeine. 

As we’ll elaborate on in the following section, variants of our CYP1A2 gene (which encodes the CYP1A2 enzyme) also affect how quickly we metabolise or breakdown caffeine.

 

How do CYP1A2 gene variants affect caffeine metabolism?

The CYP1A2 enzyme responsible for breaking down caffeine is coded for by your CYP1A2 gene. 

Variants of the CYP1A2 gene can alter the inducibility of the enzyme - that is, how effectively the production and activity of the CYP1A2 enzyme can be increased. Greater inducibility and higher activity of the CYP1A2 enzyme leads to faster breakdown of caffeine and faster generation of its metabolites, paraxanthine, theobromine, and theophylline.

More specifically, a well-studied SNP (Single Nucleotide Polymorphism), designated rs762551, causes an A → C change in the DNA code of the CYP1A2 gene, giving rise to two different CYP1A2 variants or alleles: the ‘A’ allele and the ‘C’ allele. (These alleles are also known as the *1A and *1F alleles, respectively). 

The ‘A’ (or *1A) allele causes increased inducibility and higher activity of the CYP1A2 enzyme, resulting in faster breakdown of caffeine. By contrast, the ‘C’ (or *1F) allele causes reduced inducibility and lower enzyme activity, leading to slower breakdown of caffeine

The rs762551 SNP and resultant 'A' and 'C' alleles therefore give rise to three possible CYP1A2 genotypes and caffeine metaboliser types:

  • Fast metabolisers (AA or 1A/1A genotype) - these people break down caffeine more quickly.
  • Intermediate metabolisers (AC or 1A/1F genotype) - these people break down caffeine more slowly than fast metabolisers, but quicker than slow metabolisers.
  • Slow metabolisers (CC or 1F/1F genotype) - these people break down caffeine slowly.

(It’s worth pointing out that some studies more simply classify people into fast (AA) and slow (AC + CC) metabolisers based on CYP1A2 genotype).

 

Source: Millard, J. T., Passang, T., Ye, J., Kline, G. M., Beachy, T. M., Hepburn, V. L., & Klinkerch, E. J. (2018). Genotype and phenotype of caffeine metabolism: A biochemistry laboratory experiment. Journal of Chemical Education, 95(10), 1856-1860.

 

As illustrated in the graph above, which is taken from an experiment whereby subjects consumed a 200 mg dose of caffeine, fast metabolisers (the bottom curve with triangle data points) have lower peak caffeine concentrations in blood (and saliva) and a shorter half life of caffeine in the bloodstream. This is because they more quickly break down caffeine due to higher CYP1A2 enzyme activity. 

By contrast, slow metabolisers (the top curve with circular data points) have higher peak caffeine concentrations and a longer half life of caffeine, due to slower breakdown of caffeine by the CYP1A2 enzyme. 

Due to differences in the rate of caffeine breakdown, fast, intermediate, and slow metabolisers may have different cardiovascular risks when consuming higher amounts of caffeine per day.

 

How do CYP1A2 variants affect risk of cardiovascular disease?

There are conflicting findings on whether your CYP1A2 genotype and caffeine metabolism speed have an impact on your cardiovascular risk when habitually consuming caffeinated beverages such as coffee.

One large study analysed the CYP1A2 genotypes of 347,077 people enrolled in the UK Biobank study and followed them to see who developed cardiovascular diseases such as coronary artery disease, stroke, and peripheral vascular disease. 

The researchers did not find a link between CYP1A2 genotype and risk of cardiovascular disease. Moreover, there was no significant interaction between CYP1A2 genotype and coffee consumption when it came to cardiovascular risk. Couched in simpler terms: fast metabolisers (with the AA or *1A/*1A CYP1A2 genotype) had a similar cardiovascular risk to intermediate (AC or *1A/*1F genotype) and slow (CC or *1F/*1F) metabolisers at all levels of coffee consumption. This is illustrated in the Forest plot below. 

 

Source: Zhou, A., & Hyppönen, E. (2019). Long-term coffee consumption, caffeine metabolism genetics, and risk of cardiovascular disease: a prospective analysis of up to 347,077 individuals and 8368 cases. The American journal of clinical nutrition, 109(3), 509-516.

 

In contrast to the above study, earlier smaller studies have found a link between CYP1A2 genotype, caffeine consumption, and risk of cardiovascular disease, including heart attack (myocardial infarction) and high blood pressure (hypertension). We’ll discuss these findings below.

 

- Heart attack (myocardial infarction)

A 2006 study published in JAMA compared the CYP1A2 genotypes and coffee consumption patterns of 2,014 people in Costa Rica who had suffered a non-fatal heart attack (cases) to those of 2,014 healthy controls. 

If CYP1A2 genotype / metaboliser type and caffeine intake do not affect risk of heart attack, we would expect to see a fairly equal distribution of CYP1A2 genotypes and caffeine intakes between cases and controls. 

The researchers found that fast metabolisers with the AA (or 1A/1A) CYP1A2 genotype did not have an increased risk of heart attack (i.e an increased odds of being a case as opposed to a control) when “moving” from less than 1 cup of coffee a day to 1, 2-3, and 4 or more cups of coffee per day. 

By contrast, intermediate (AC or 1A/1F genotype) and slow (CC or 1F/1F genotype) metabolisers had an increased risk of heart attack when  “increasing” their coffee intake. Compared to those drinking less than 1 cup of coffee per day, those consuming 2-3 and 4 or more cups of coffee per day had a 1.36 and 1.64 times higher odds of heart attack. 

(Note that this was not a prospective trial which followed the same individuals over time to see how changes in caffeine consumption affected their risk of developing a heart attack. Consequently, the terms “moving” and “increasing” are in inverted commas). 

 

Source: El-Sohemy, A., Cornelis, M. C., Kabagambe, E. K., & Campos, H. (2007, October). Coffee, CYP1A2 genotype and risk of myocardial infarction. In Genes & Nutrition (Vol. 2, No. 1, pp. 155-156). BioMed Central.

 

The graph above shows how the risk (or, more accurately, odds ratio) of heart attack changes with increasing coffee consumption in both fast and intermediate+slow caffeine metabolisers aged under 50 years old. As can be seen by comparing the left and right-hand sides of the above graph, the risk (odds ratio) of heart attack is significantly higher when drinking 4 or more cups of coffee per day (compared to <1 cup), but only for intermediate (*1A/*1F) and slow (*1F/*1F) genotypes. 

An obvious question to ask is why might slow and intermediate metabolisers in this study have an increased risk of heart attack with higher caffeine intakes?

The authors speculated that it may be due to the inhibitory effects of caffeine on the adenosine receptor, which impairs dilation of the coronary arteries, thereby reducing blood flow to the heart. These effects would be predicted to be longer lasting in slow and intermediate metabolisers, as these individuals break down caffeine more slowly. 

A complementary question is why do fast metabolisers seem to be protected against the apparent cardiovascular risks of heavy coffee consumption. One possibility is that rapid breakdown of caffeine unmasks the beneficial effects of other compounds in coffee, such as chlorogenic acid and caffeic acid, both of which are antioxidants that may protect the heart.

 

- High blood pressure (hypertension)

An Italian study from 2009 followed 553 white individuals with stage 1 hypertension, defined in this study as having a systolic blood pressure between 140 and 159 mm Hg and a diastolic blood pressure between 90 and 99 mm Hg, which can be managed with lifestyle adjustments. 

The researchers were interested in seeing who went on to develop more severe hypertension requiring treatment with anti-hypertensive medication, and whether this was related to an individual’s CYP1A2 genotype and coffee intake. 

After following subjects for an average of 8.2 years, they found that, compared to nonconsumers/abstainers, intermediate (AC or *1A/*1F CYP1A2 genotype) and slow (CC or *1F/1F) caffeine metabolisers consuming coffee had an increased risk of developing hypertension requiring medication

Specifically, intermediate and slow metabolisers drinking 1-3 and 4 or more cups of coffee per day had a 1.72 and 3.00 times higher risk of developing hypertension, respectively. 

By contrast, fast metabolisers (i.e. those with the AA or *1A/*1A CYP1A2 genotype) who regularly drank coffee were observed to have a reduced risk of developing severe hypertension compared to abstainers. Those consuming 4 or more cups of coffee had a 0.36 times risk (hazard ratio) of hypertension. These results can be seen in the graph below.

 

Source: Palatini, P., Ceolotto, G., Ragazzo, F., Dorigatti, F., Saladini, F., Papparella, I., ... & Santonastaso, M. (2009). CYP1A2 genotype modifies the association between coffee intake and the risk of hypertension. Journal of hypertension, 27(8), 1594-1601.

 

The authors posited that the increased risk of hypertension in intermediate and slow metabolisers with heavier caffeine intake was due to the blood pressure raising effects of caffeine.

As explained previously, we know that caffeine temporarily elevates blood pressure, a phenomenon partly due to caffeine’s stimulatory effect on the sympathetic nervous system and release of the hormones adrenaline and noradrenaline. These hormones cause an increase in heart rate and narrowing of blood vessels (vasoconstriction), both of which can raise blood pressure. 

Accordingly, as caffeine is broken down more slowly in intermediate and slow metabolisers, caffeine’s stimulation of the sympathetic nervous system and adrenaline and noradrenaline release would be predicted to last longer, leading to more prolonged rises in blood pressure. 

In line with this, the researchers found that levels of adrenaline (epinephrine) were significantly higher in the urine of intermediate and slow metabolisers drinking 4 or more cups of coffee per day. This difference in urinary adrenaline level was not seen in fast metabolisers, as illustrated in the graph below. 

 

Source: Palatini, P., Ceolotto, G., Ragazzo, F., Dorigatti, F., Saladini, F., Papparella, I., ... & Santonastaso, M. (2009). CYP1A2 genotype modifies the association between coffee intake and the risk of hypertension. Journal of hypertension, 27(8), 1594-1601.

 

Relative to intermediate and slow metabolisers, fast metabolisers break down caffeine more quickly. Accordingly, the blood-pressure-raising effects of caffeine are likely to be much shorter lived in fast metabolisers. 

Furthermore, the authors suggest that by breaking down caffeine more quickly, the beneficial blood-pressure-lowering effects of other compounds in coffee (such as chlorogenic and caffeic acid) are unmasked. More specifically, these compounds can enhance the production of nitric oxide (NO), a molecule that acts to dilate blood vessels, which may help to lower blood pressure.

Another study found that smoking affects the impact of CYP1A2 genotype on risk of hypertension. Fast metabolisers were found to be 35% less likely to have hypertension compared to slow metabolisers, but only in non-smokers. This is partly because smoking is known to induce and increase the activity of the CYP1A2 enzyme, thereby blunting any differences in activity between slow and fast metabolisers due to genetics. 

The same study found that those with the highest tertile of CYP1A2 activity experienced greater drops in blood pressure after quitting smoking. This would tentatively suggest that, with respect to blood pressure, fast metabolisers (with higher CYP1A2 activity) stand to benefit more from quitting smoking.

 

How do CYP1A2 variants affect the acute (short-term) cardiovascular effects of caffeine?

Some small studies have found that fast metabolisers with the AA (*1A/*1A) CYP1A2 genotype experience smaller transient rises in blood pressure when consuming caffeine

For example, one study gave fast and intermediate metabolisers tablets of caffeine at a dose of 6mg/kg bodyweight and then measured changes in blood pressure after 1 hour. Although both groups experienced rises in diastolic blood pressure (DBP), this increase was less pronounced in fast metabolisers. 

Furthermore, only the intermediate metabolisers (with the AC or *1A/*1F CYP1A2 genotype) experienced rises in systolic blood pressure (SBP) after consuming caffeine. This is illustrated in the uppermost graph below. 

 

Source: Soares, R. N., Schneider, A., Valle, S. C., & Schenkel, P. C. (2018). The influence of CYP1A2 genotype in the blood pressure response to caffeine ingestion is affected by physical activity status and caffeine consumption level. Vascular pharmacology, 106, 67-73.

 

As expected, rises in blood pressure after ingesting caffeine also depended on whether a person habitually consumes caffeine. When researchers split the intermediate metabolisers (AC genotype) into non-habitual caffeine users (NC) and habitual caffeine users C), they found that only non-habitual users experienced increases in systolic blood pressure. This is shown in the bottom-right graph above.

As explained earlier, this is likely because, despite having CYP1A2 gene variants linked to slower caffeine metabolism, regular caffeine consumption can induce and increase the activity of the CYP1A2 enzyme, leading to faster breakdown of caffeine. 

Interestingly, regular physical activity also seemed to modulate the effects of caffeine on blood pressure. As can be seen in the bottom-left graph above, increases in systolic blood pressure after consuming caffeine  were only observed in those in intermediate metabolisers (AC genotype) who were sedentary (S). 

Active (A) individuals did not experience a rise in systolic blood pressure, which is likely due to the beneficial adaptations to the cardiovascular system that accompany exercise. Specifically, people who exercise regularly have increased activity (or “tone) of the vagus nerve, a key component of our parasympathetic nervous system that acts to reduce heart rate and reduce blood pressure. 

Another randomised trial, which gave fast, intermediate, and slow metabolisers either caffeinated or decaffeinated coffee, found that slow metabolisers (CC or *1F/*1F genotype) experienced a greater rise in blood pressure (11.8 +/- 5.9 mm Hg) compared to intermediate and fast metabolisers (4.1 +/- 5.5 mm Hg). Importantly, this was only seen in people who did not habitually consume much caffeine (<90 mg caffeine per day). This again suggests that habitual caffeine use can increase CYP1A2 activity and attenuate the acute blood-pressure-raising effects of caffeine.  

 

How do CYP1A2 variants affect blood sugar levels?

Several studies have found that coffee consumption may reduce the risk of developing Type II diabetes in the long term

For example, a 2021 meta-analysis of studies in the US population found an inverse relationship between the amount of coffee consumed and risk of diabetes. In other words, the more cups of coffee consumed per day, the lower the risk of Type II diabetes (as illustrated in the graph below). 

 

Source: Di Maso, M., Boffetta, P., Negri, E., La Vecchia, C., & Bravi, F. (2021). Caffeinated Coffee Consumption and Health Outcomes in the US Population: A Dose–Response Meta-Analysis and Estimation of Disease Cases and Deaths Avoided. Advances in Nutrition, 12(4), 1160-1176.

 

In the short-term, however, there is evidence that caffeine can reduce insulin sensitivity and lead to rises in blood sugar levels. Furthermore, these rises in blood sugar levels may differ according to CYP1A2 genotype. 

One longitudinal study followed subjects over 6 years and assessed who developed impaired fasting glucose - a term, also known as prediabetes, that describes elevated fasting blood glucose levels. If left uncontrolled, prediabetes can develop into diabetes. 

The study found that heavy caffeine drinkers (defined as more than 3 cups per day) were more likely to develop prediabetes compared to abstainers and moderate drinkers (1- 3 cups per day).

 

Source: Palatini, P., Benetti, E., Mos, L., Garavelli, G., Mazzer, A., Cozzio, S., ... & Casiglia, E. (2015). Association of coffee consumption and CYP1A2 polymorphism with risk of impaired fasting glucose in hypertensive patients. European journal of epidemiology, 30(3), 209-217.

 

When analysing the different CYP1A2 genotypes, intermediate (with the AC or *1A/1F genotype) and slow ( CC or *1F/*1F) metabolisers were much more likely than fast metabolisers to develop prediabetes when consuming caffeine. This is shown in the Kaplan-Meier curves above. 

Compared to abstainers, intermediate and slow metabolisers drinking >3 cups of coffee a day had a 2.78 times higher risk of prediabetes. This association was not seen in fast metabolisers. 

The authors speculated that this difference may be due to caffeine’s stimulation of adrenaline, which has opposite effects to insulin and acts to raise blood glucose levels. Due to slower breakdown of caffeine, intermediate and slow metabolisers would be expected to release more adrenaline, resulting in higher blood sugar levels.

 

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