COVID-19 and cardiovascular disease

COVID-19 and cardiovascular disease

OVERVIEW

  • People with cardiovascular disease are more likely to develop the more severe forms of COVID-19, which significantly increases the mortality rate of this disease.
  • In addition to being an important risk factor for COVID-19, cardiovascular disease can also be a consequence of SARS-CoV-2 coronavirus infection.
  • Patients with severe COVID-19 frequently have heart damage, which increases the severity of the infection and is life threatening.

COVID-19 is a respiratory disease caused by a new virus, the SARS-CoV-2 coronavirus. The COVID-19 epidemic began in December 2019 in Wuhan, Hubei Province, China, and has spread rapidly worldwide with more than 1,360,000 people affected and 75,973 deaths as of April 7, 2020. Although most patients infected with the virus do not have major symptoms, about 15% of them develop a much more severe form of the disease, including severe acute respiratory syndrome that requires mechanical ventilation. This severe form of COVID-19 is particularly dangerous for the elderly: while the mortality rate is around 1% among those aged 50 and under, it rises to 3.6% in those aged 60, to 8% for those aged 70 and up, and to 14.8% for those 80 years and older.

An aggravating factor: Chronic diseases
Data from previous outbreaks caused by coronaviruses similar to SARS-CoV-2 have shown that a large proportion of infected patients are affected by underlying chronic conditions. For example, during the 2002 severe acute respiratory syndrome (SARS) epidemic, the prevalence of type 2 diabetes and preexisting cardiovascular disease was 11 and 8%, respectively, and the presence of either of these chronic conditions was associated with a very large increase (almost 10 times) in the mortality rate. Similarly, in patients infected with Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 and presenting with severe symptoms, 50% suffered from hypertension and diabetes and up to 30% from heart disease.

The presence of these comorbidities (coexistence in the same patient of two or more diseases) is also observed during the current COVID-19 epidemic. In all the studies carried out to date, a significant proportion of patients were affected by a preexisting chronic condition, the most common being hypertension, type 2 diabetes and cardiovascular disease (Table 1).

PopulationComorbiditiesSource
99 infected patients
(Wuhan, China)
Cardiovascular disease (40 %)
Diabetes (12 %)
Chen et al. (2020)
191 infected patients
(Wuhan, China)
Hypertension (30 %)
Diabetes (19 %)
Cardiovascular disease (8 %)
Zhou et al. (2020)
138 infected patients
(Wuhan, China)
Hypertension (31 %)
Diabetes (10 %)
Cardiovascular disease (15 %)
Wang et al. (2020)
1099 infected patients
(China)
Hypertension (15 %)
Diabetes (7.4 %)
Cardiovascular disease (2.5 %)
Guan et al. (2020)
46,248 infected patients
(China, meta-analysis)
Hypertension (17 %)
Diabetes (8 %)
Cardiovascular disease (5 %)
Yang et al. (2020)
355 deceased patients
(Italy)
Hypertension (76 %)
Diabetes (36%)
Cardiovascular disease (33 %)
Atrial fibrillation (25 %)
Cancer (20 %)
Instituto Superiore di Sanita (2020)

In all cases, these chronic conditions are more frequently observed in patients with the more severe forms of COVID-19. For example, a study carried out in Wuhan showed that the proportion of patients with hypertension, type diabetes 2 and cardiovascular disease is almost twice as high in those who have developed a severe form of COVID-19. This contribution of chronic diseases to the burden imposed by COVID-19 seems particularly important in Italy, one of the countries hardest hit by COVID-19: data collected by the country’s health authorities show that 99% of people who have died from the disease had at least one chronic condition such as hypertension (76%), type 2 diabetes (36%), coronary heart disease (33%), atrial fibrillation (25%) or cancer (20%).

The impact of these chronic diseases is considerable, with the mortality rate of COVID-19 increasing by 5 to 10 times compared to people who do not have preexisting conditions (Figure 1).

Figure 1. Influence of preexisting chronic conditions on the COVID-19 mortality rate. From: The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team (2020).

People with a chronic condition, including cardiovascular disease, are therefore at much higher risk of developing a severe form of COVID-19, especially if they are older. Consequently, this population must be extra vigilant and avoid interacting with people who may have been in contact with the virus.

Heart damage
In addition to being an important risk factor for COVID-19, cardiovascular disease can also be a consequence of SARS-CoV-2 coronavirus infection. Studies carried out at the beginning of the pandemic observed clinical signs of cardiac injury (elevated blood level of cardiac Troponin I [hs-cTnI], abnormalities of electrocardiograms or cardiac ultrasounds) in 7.2% of infected patients, a proportion that reaches 22% in those affected by severe forms of COVID-19 and who required hospitalization in intensive care. In another study of 138 patients with COVID-19 in Wuhan, 36 patients with severe symptoms treated in intensive care units had significantly higher levels of myocardial injury markers than those not treated in intensive care units. Severe cases of COVID-19 therefore often present complications involving an acute myocardial injury, which seriously complicates the treatment of these patients. It is very likely that these cardiac injuries contribute to the mortality caused by COVID-19, since a study observed hs-cTnI values higher than the 99th percentile (which indicates a myocardial injury) in 46% of patients who had died from the disease, compared to only 1% of survivors. In addition, two recent studies (here and here) have found that the death rate of patients with cardiac injury is much higher than among those without, an increase that can be as high as 10 times in people with a history of cardiovascular disease (Figure 2).


Figure 2. Differences in mortality of patients with COVID-19 depending on the presence of preexisting cardiovascular disease and/or cardiac injury caused by infection. From Guo et al. (2020).

The mechanisms responsible for these heart lesions are very complex and involve several phenomena. On the one hand, poor functioning of the lungs can cause oxygen levels to become insufficient to keep the heart muscle working. This oxygen deficiency is all the more dangerous because the fever caused by the infection increases the body’s metabolism, which increases the workload of the heart. This imbalance between oxygen supply and demand therefore increases the risk of arrhythmia and heart damage.

Another factor involved in heart damage caused by respiratory viruses is what is known as a “cytokine storm”, a phenomenon characterized by an exaggerated inflammatory response following viral infection. The immune system goes berserk and indiscriminately attacks everything in the vicinity, including our own cells, which damages organ function and can increase susceptibility to bacterial infections. The heart is particularly sensitive to this uncontrolled inflammation given its close interaction with the lungs; the oxygenated blood from the lungs reaching the heart has been in direct contact with the foci of infection and therefore necessarily contains a greater concentration of the molecules produced by excess inflammation. When this blood is expelled from the left ventricle to the aorta, a portion of this oxygenated blood is immediately passed to the myocardium to feed the heart cells, with the result that these cells are exposed to abnormally high amounts of inflammatory molecules. An excess of inflammatory molecules can also cause thrombosis (clot formation), which blocks the flow of blood to the heart and causes a heart attack. Indeed, a recent study has shown that high levels of D-dimers, a marker of thrombosis, were associated with a very large increase (18 times) in the risk of mortality from COVID-19.

A clinical study led by Dr. Jean-Claude Tardif, Director of the MHI Research Center, has just been launched to determine whether a reduction in inflammation from viral infection with colchicine, an inexpensive and generally well tolerated anti-inflammatory medication, can prevent the excessive immune response and improve the course of the disease.

It should also be mentioned that in some rare cases, it seems that the heart is the first target of the SARS-CoV-2 virus and that cardiovascular symptoms are the first signs of infection. For example, although the first clinical signs of COVID-19 are usually fever and cough, the National Health Commission of China (NHC) reported that some patients first sought medical attention for heart palpitations and chest tightness rather than respiratory symptoms, but were subsequentlydiagnosed with COVID-19. Recent cases of acute myocarditis caused by COVID-19 in patients with no history of cardiovascular disease have also been recently reported, a phenomenon that had previously been observed for other coronaviruses, including MERS-CoV. A common feature of these viruses is to enter human cells by interacting with the surface protein ACE2 (angiotensin-converting enzyme 2), which is present in large quantities in the lungs, heart and cells of blood vessels. It is therefore possible that the virus uses this receptor to penetrate directly into the cells of the myocardium and cause heart damage. In line with this, it should be noted that analysis of heart tissue from patients who died during the 2002 SARS epidemic revealed the presence of viral genetic material in 35% of the samples. SARS-CoV-2 is very similar (75% identical) to this virus, so it is possible that a similar mechanism is at work.

COVID-19 and hypertension
The interaction of SARS-CoV-2, the virus that causes COVID-19, with the angiotensin-converting enzyme (ACE2) is intriguing, as this enzyme plays a key role in the development of hypertension, and it is precisely hypertensive people who present a more severe form of the infection. Since commonly prescribed antihypertensive drugs cause an increase in the amount of ACE2 on the surface of cells, there have been several texts on social media claiming that these drugs can increase the risk and severity of SARS-CoV-2 infection and should therefore be discontinued. It is important to mention that this hypothesis has no solid scientific basis and that all of the cardiology associations in the world still recommend hypertensive patients continue taking their drugs, whether they are inhibitors of ACE2 (captopril, enalapril, etc.) or angiotensin receptor antagonists (losartan, valsartan, telmisartan, etc.). On the contrary, preclinical studies seem rather to show that antihypertensive drugs could protect against pulmonary complications in patients infected with coronaviruses.

A new metabolite derived from the microbiota linked to cardiovascular disease

A new metabolite derived from the microbiota linked to cardiovascular disease

OVERVIEW

  • Metabolomic screening has identified a new metabolite associated with cardiovascular disease in the blood of people with type 2 diabetes.
  • This metabolite, phenylacetylglutamine (PAGln), is produced by the intestinal microbiota and the liver, from the amino acid phenylalanine from dietary proteins.
  • PAGln binds to adrenergic receptors expressed on the surface of blood platelets, which results in making them hyper-responsive.
  • A beta blocker drug widely used in clinical practice (Carvedilol) blocks the prothrombotic effect of PAGln.

A research group from the Cleveland Clinic in the United States recently identified a new metabolite of the microbiota that is clinically and mechanistically linked to cardiovascular disease (CVD). This discovery was made possible by the use of a metabolomic approach (i.e. the study of metabolites in a given organism or tissue), a powerful and unbiased method that identified, among other things, trimethylamine oxide (TMAO) as a metabolite promoting atherosclerosis and branched-chain amino acids (BCAAs) as markers of obesity.

The new metabolomic screening has identified several compounds associated with one or more of these criteria in the blood of people with type 2 diabetes: 1) association with major adverse cardiovascular events (MACE: myocardial infarction, stroke or death) in the past 3 years; 2) heightened levels of type 2 diabetes; 3) poor correlation with indices of glycemic control. Of these compounds, five were already known: two which are derived from the intestinal microbiota (TMAO and trimethyllysine) and three others that are diacylglycerophospholipids. Among the unknown compounds, the one that was most strongly associated with MACE was identified by mass spectrometry as phenylacetylglutamine (PAGln).

In summary, here is how PAGln is generated (see the left side of Figure 1):

  • The amino acid phenylalanine from dietary proteins (animal and plant origin) is mostly absorbed in the small intestine, but a portion that is not absorbed ends up in the large intestine.
  • In the large intestine, phenylalanine is first transformed into phenylpyruvic acid by the intestinal microbiota, then into phenylacetic acid by certain bacteria, particularly those expressing the porA
  • Phenylacetic acid is absorbed and transported to the liver via the portal vein where it is rapidly metabolized into phenylacetylglutamine or PAGln.

Figure 1. Schematic summary of the involvement of PAGln in the increase in platelet aggregation, athero-thrombosis and major adverse cardiovascular events. From Nemet et al., 2020.

Researchers have shown that PAGln increases the effects associated with platelet activation and the potential for thrombosis in whole blood, on isolated platelets and in animal models of arterial damage.

PAGln binds to cell sites in a saturable manner, suggesting specific binding to membrane receptors. The researchers then demonstrated that PAGln binds to G-protein coupled adrenergic receptors, expressed on the surface of the platelet cell membrane. The stimulation of these receptors by PAGln causes the hyperstimulation of the platelets, which then become hyper-responsive and accelerate the platelet aggregation and the thrombosis process.

Finally, in a mouse thrombus model, it has been shown that a beta blocker drug widely used in clinical practice (Carvedilol) blocks the prothrombotic effect of PAGln. This result is particularly interesting because it suggests that the beneficial effects of beta blockers may be partly caused by reversing the effects of high PAGln levels. The identification of PAGln could lead to the development of new targeted and personalized strategies for the treatment of cardiovascular diseases.

Optimism reduces the risk of cardiovascular disease and mortality

Optimism reduces the risk of cardiovascular disease and mortality

OVERVIEW

  • According to a meta-analysis of 15 studies, optimism was associated with a 35% lower risk of cardiovascular events and a 14% lower risk of mortality.
  • Another study published in 2019 suggests that optimism is associated with exceptional longevity (≥85 years) in two separate cohorts of men and women.
It is now well established that there is an association between negative emotions (anger, trauma), sociocultural factors, chronic stress and the development of heart problems. Much less is known about the potential impact of mental attitude on cardiovascular risk, but there has been more and more research on this topic in recent years.

Optimism is a mental disposition characterized by the general idea that good things will happen, or by the sense that thefuture will be favourable to us, since we can, if necessary, manage important problems. In empirical studies, optimism has been associated with greater success in school, work, sports, politics and interpersonal relationships. Studies have reported that optimistic people are less likely to suffer from chronic diseases and die prematurely than pessimistic people. For example, in a large prospective study, published in a prestigious scientific journal and involving more than 6,000 people, the most optimistic participants were 48% less likely to have heart failure than the least optimistic. Positive mental attitudes other than optimism, such as kindness, gratitude, and indulgence, and psychosocial factors other than pessimism, such as depression, anxiety, chronic stress, social isolation, and low self-esteem, can also have an effect on the risk of developing a chronic disease.

Optimism and cardiovascular disease
A meta-analysis of 15 studies published in 2019, including 229,391 participants, examined the association between optimism and cardiovascular events or all-cause mortality. After an average follow-up of 13.8 years, optimism was associated with a 35% lower risk of cardiovascular events and a 14% lower risk of mortality. In 12 of the 15 studies included in this meta-analysis, there was a linear relationship between the participants’ level of optimism and the decrease in the risk of cardiovascular events.

Optimism and longevity
Another study published in 2019 suggests that optimism is associated with exceptional longevity (≥85 years) in two separate cohorts of men and women. The data analyzed came from the Veterans Affairs Normative Aging Study (NAS) and the Nurses’ Health Study (NHS), with a follow-up after 30 years and 10 years, respectively. The most optimistic women in this study (top quintile) had an average lifespan 14.9% longer than the least optimistic women (bottom quintile). Similar results were obtained for men: the most optimistic had a lifespan 10.9% longer on average. The most optimistic participants were 1.5 times (women) and 1.7 times (men) more likely to live to age 85 than the least optimistic participants. These associations are independent of socio-economic status, health status, depression, social integration and health behaviours (e.g., smoking, diet, alcohol consumption).

In an editorial accompanying the publication of this study, Dr. Jeff C. Huffman concludes by answering the following question: Where does the field go from here?

“In terms of longitudinal studies, conducting studies that continue to examine the associations of more modifiable or state-based constructs with health outcomes will help to define clear, plausible, and important targets for intervention. These studies could also include more novel methods for assessing well-being, including ecological momentary assessment (Editor’s note: a method for assessing fluctuating and environmentally dependent psychological states) or Day reconstruction methods (Editor’s note: a method that assesses how people spend their time and how they experience the various activities and settings of their lives) that address the challenges with single or retrospective sampling.”

“Regarding intervention studies, interventions should focus on improving and measuring not only well-being, but also important additional downstream outcomes (e.g., physical activity and biomarkers) that are associated with health. Ongoing studies should also determine whether programs to promote psychological well-being might be best used alone or in conjunction with other, established behavioural interventions to boost their effect.”

Because a person’s level of optimism can be modified, these data suggest that optimism could be an important psychosocial resource for interventions to prevent or delay heart disease and prolong the lives of the elderly.

Choosing dietary sources of unsaturated fats has many health benefits

Choosing dietary sources of unsaturated fats has many health benefits

OVERVIEW

  • Unsaturated fatty acids, found mainly in vegetable oils, nuts, certain seeds and fatty fish, play several essential roles for the proper functioning of the human body.
  • While saturated fatty acids, found mainly in foods of animal origin, increase LDL cholesterol levels, unsaturated fats lower this type of cholesterol and thereby reduce the risk of cardiovascular events.
  • Current scientific consensus is therefore that a reduction in saturated fat intake combined with an increased intake of unsaturated fat represents the optimal combination of fat to prevent cardiovascular disease and reduce the risk of premature mortality.
Most nutrition experts now agree that a reduction in saturated fat intake combined with an increased intake of quality unsaturated fat (especially monounsaturated and polyunsaturated omega-3) represents the optimal combination of fat to prevent cardiovascular disease and reduce the risk of premature death. The current consensus, recently summarized in articles published in the journals Science and BMJ, is therefore to choose dietary sources of unsaturated fats, such as vegetable oils (particularly extra virgin olive oil and those rich in omega-3s such as canola), nuts, certain seeds (flax, chia, hemp) and fatty fish (salmon, sardine), while limiting the intake of foods mainly composed of saturated fats such as red meat. This roughly corresponds to the Mediterranean diet, a way of eating that has repeatedly been associated with a decreased risk of several chronic diseases, especially cardiovascular disease.

Yet despite this scientific consensus, the popular press and social media are full of conflicting information about the impact of different forms of dietary fat on health. This has become particularly striking since the rise in popularity of low-carbohydrate (low-carb) diets, notably the ketogenic diet, which advocates a drastic reduction in carbohydrates combined with a high fat intake. In general, these diets make no distinction as to the type of fat that should be consumed, which can lead to questionable recommendations like adding butter to your coffee or eating bacon every day. As a result, followers of these diets may eat excessive amounts of foods high in saturated fat, and studies show that this type of diet is associated with a significant increase in LDL cholesterol, an important risk factor for cardiovascular disease. According to a recent study, a low-carbohydrate diet (<40% of calories), but that contains a lot of fat and protein of animal origin, could even significantly increase the risk of premature death.

As a result, there is a lot of confusion surrounding the effects of different dietary fats on health. To get a clearer picture, it seems useful to take a look at the main differences between saturated and unsaturated fats, both in terms of their chemical structure and their effects on the development of certain diseases.

A little chemistry…
Fatty acids are carbon chains of variable length whose rigidity varies depending on the degree of saturation of these carbon atoms by hydrogen atoms. When all the carbon atoms in the chain form single bonds with each other by engaging two electrons (one from each carbon), the fatty acid is said to be saturated because each carbon carries as much hydrogen as possible. Conversely, when certain carbons in the chain use 4 electrons to form a double bond between them (2 from each carbon), the fatty acid is said to be unsaturated because it lacks hydrogen atoms.

These differences in saturation have a great influence on the physicochemical properties of fatty acids. When saturated, fatty acids are linear chains that allow molecules to squeeze tightly against each other and thus be more stable. It is for this reason that butter and animal fats, rich sources of these saturated fats, are solid or semi-solid at room temperature and require a source of heat to melt.

Unsaturated fatty acids have a very different structure (Figure 1). The double bonds in their chains create points of stiffness that produce a “crease” in the chain and prevent molecules from tightening against each other as closely as saturated fat. Foods that are mainly composed of unsaturated fats, vegetable oils for example, are therefore liquid at room temperature. This fluidity directly depends on the number of double bonds present in the chain of unsaturated fat: monounsaturated fats contain only one double bond and are therefore less fluid than polyunsaturated fats which contain 2 or 3, and this is why olive oil, a rich source of monounsaturated fat, is liquid at room temperature but solidifies in the refrigerator, while oils rich in polyunsaturated fat remain liquid even at cold temperatures.

Figure 1. Structure of the main types of saturated, monounsaturated and polyunsaturated omega-3 and omega-6 fats. The main food sources for each fat are shown in italics.

Polyunsaturated fats can be classified into two main classes, omega-3 and omega-6. The term omega refers to the locationof the first double bond in the fatty acid chain from its end (omega is the last letter of the Greek alphabet). An omega-3 or omega-6 polyunsaturated fatty acid is therefore a fat whose first double bond is located in position 3 or 6, respectively (indicated in red in the figure).

It should be noted that there is no food that contains only one type of fat. On the other hand, plant foods (especially oils, seeds and nuts) are generally made up of unsaturated fats, while those of animal origin, such as meat, eggs and dairy products, contain more saturated fat. There are, however, exceptions: some tropical oils like palm and coconut oils contain large amounts of saturated fat (more than butter), while some meats like fatty fish are rich sources of omega-3 polyunsaturated fats such as eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids.

Physiological roles of fatty acids
All fatty acids, whether saturated or unsaturated, play important roles in the normal functioning of the human body, especially as constituents of cell membranes and as a source of energy for our cells. From a dietary point of view, however, only polyunsaturated fats are essential: while our metabolism is capable of producing saturated and monounsaturated fatty acids on its own (mainly from glucose and fructose in the liver), linoleic (omega-6) and linolenic (omega-3) acids must absolutely be obtained from food. These two polyunsaturated fats, as well as their longer chain derivatives (ALA, EPA, DHA), play essential roles in several basic physiological functions, in particular in the brain, retina, heart, and reproductive and immune systems. These benefits are largely due to the degree of unsaturation of these fats, which gives greater fluidity to cell membranes, and at the same time facilitate a host of processes such as the transmission of electrical impulses in the heart or neurotransmitters in the synapses of the brain. In short, while all fats have important functions for the functioning of the body, polyunsaturated fats clearly stand out for their contribution to several processes essential to life.

Impacts on cholesterol
Another major difference between saturated and unsaturated fatty acids is their respective effects on LDL cholesterol levels. After absorption in the intestine, the fats ingested during the meal (mainly in the form of triglycerides and cholesterol) are “packaged” in structures called chylomicrons and transported to the peripheral organs (the fatty tissue and the muscles, mainly) where they are captured and used as a source of energy or stored for future use. The residues of these chylomicrons, containing the portion of excess fatty acids and cholesterol, are then transported to the liver, where they are taken up and will influence certain genes involved in the production of low-density lipoproteins (LDL), which serve to transport cholesterol, as well as their receptors (LDLR), which serve to eliminate it from the blood circulation.

And this is where the main difference between saturated and unsaturated fats lies: a very large number of studies have shown that saturated fats (especially those made up of 12, 14 and 16 carbon atoms) increase LDL production while decreasing that of its receptor, with the result that the amount of LDL cholesterol in the blood increases. Conversely, while polyunsaturated fats also increase LDL cholesterol production, they also increase the number and efficiency of LDLR receptors, which overall lowers LDL cholesterol levels in the blood. It has been proposed that this greater activity of the LDLR receptor is due to an increase in the fluidity of the membranes caused by the presence of polyunsaturated fats which would allow the receptor to recycle more quickly on the surface liver cells (and therefore be able to carry more LDL particles inside the cells).

Reduction of the risk of cardiovascular disease
A very large number of epidemiological studies have shown that an increase in LDL cholesterol levels is associated with an increased risk of cardiovascular diseases. Since saturated fat increases LDL cholesterol while unsaturated fat decreases it, we can expect that replacing saturated fat with unsaturated fat will lower the risk of these diseases. And that is exactly what studies show: for example, an analysis of 11 prospective studies indicates that replacing 5% of caloric intake from saturated fat with polyunsaturated fat was associated with a 13% decrease in the risk of coronary artery disease. A similar decrease has been observed in clinical studies, where replacing every 1% of energy from saturated fat with unsaturated fat reduced the risk of cardiovascular events by 2%. In light of these results, there is no doubt that substituting saturated fats with unsaturated fats is an essential dietary change to reduce the risk of cardiovascular disease.

A very important point of these studies, which is still poorly understood by many people (including some health professionals), is that it is not only a reduction of saturated fat intake that counts for improving the health of the heart and vessels, but most importantly the source of energy that is consumed to replace these saturated fats. For example, while the substitution of saturated fats by polyunsaturated fats, monounsaturated fats or sources of complex carbohydrates like whole grains is associated with a substantial reduction in the risk of cardiovascular disease, this decrease is completely abolished when saturated fats are replaced by trans fats or poor quality carbohydrate sources (e.g., refined flours and added sugars) (Figure 2). Clinical studies indicate that the negative effect of an increased intake of simple sugars is caused by a reduction in HDL cholesterol (the good one) as well as an increase in triglyceride levels. In other words, if a person decreases their intake of saturated fat while simultaneously increasing their consumption of simple carbohydrates (white bread, potatoes, processed foods containing added sugars), these sugars simply cancel any potential cardiovascular benefit from reducing saturated fat intake.


Figure 2. Modulation of the risk of coronary heart disease following a substitution of saturated fat by unsaturated fat or by different sources of carbohydrates. The values shown correspond to variations in the risk of coronary heart disease following a replacement of 5% of the caloric intake from saturated fat by 5% of the various energy sources. Adapted from Li et al. (2015).

Another implication of these results is that one should be wary of “low-fat” or “0% fat” products, even though these foods are generally promoted as healthier. In the vast majority of cases, reducing saturated fat in these products involves the parallel addition of simple sugars, which counteracts the positive effects of reducing saturated fat.

This increased risk from simple sugars largely explains the confusion generated by some studies suggesting that there is no link between the consumption of saturated fat and the risk of cardiovascular disease (see here and here, for example). However, most participants in these studies used simple carbohydrates as an energy source to replace saturated fat, which outweighed the benefits of reduced intake of saturated fat. Unfortunately, media coverage of these studies did not capture these nuances, with the result that many people may have mistakenly believed that a high intake of saturated fat posed no risk to cardiovascular health.

In conclusion, it is worth recalling once again the current scientific consensus, stated following the critical examination of several hundred studies: replacing saturated fats by unsaturated fats (monounsaturated or polyunsaturated) is associated with a significant reduction in the risk of cardiovascular disease. As mentioned earlier, the easiest way to make this substitution is to use vegetable oils as the main fatty substance instead of butter and to choose foods rich in unsaturated fats such as nuts, certain seeds and fatty fish (salmon, sardine), while limiting the intake of foods rich in saturated fats such as red meat. It is also interesting to note that in addition to exerting positive effects on the cardiovascular system, recent studies suggest that this type of diet prevents excessive accumulation of fat in the liver (liver steatosis), an important risk factor of insulin resistance and therefore type 2 diabetes. An important role in liver function is also suggested by the recent observation that replacing saturated fats of animal origin by mono- or polyunsaturated fats was associated with a significant reduction in the risk of hepatocellular carcinoma, the main form of liver cancer. Consequently, there are only advantages to choosing dietary sources of unsaturated fat.

Spicing up the prevention of cardiovascular disease with chili peppers

Spicing up the prevention of cardiovascular disease with chili peppers

OVERVIEW

  • The frequency of weekly consumption of chili peppers by 22,811 Italians from the Molise region was measured over an 8-year period.
  • At the same time, researchers identified deaths from cardiovascular disease, cancer or other causes that occurred during this period.
  • Results show that people who eat chilies 4 or more times per week have a 44% and 61% reduced risk of death from myocardial infarction or stroke, respectively, compared to those who never or very rarely eat them.

Chili peppers (Capsicum spp.) are native to South America, where they were already being cultivated for culinary purposes more than 6,000 years ago. Following the discovery of America by Europeans in the 15th century, these hot peppers were disseminated worldwide by Portuguese sailors (particularly in India and Asia), where they were quickly adopted and became essential ingredients in the culinary cultures of these countries.

The gastronomic value of chilies obviously comes from their spicy flavour, which distinctively enhances the taste of different dishes. This property is due to the presence of capsaicin (Figure 1), a phenolic compound that specifically interacts with certain receptors (TRPV1 for Transient Receptor Potential Vanilloid) involved in the pain signal generated by temperatures above 43ºC.

Figure 1. Molecular structure of capsaicin, the molecule responsible for the spicy taste of chili peppers.

By binding to the TRPV1 receptor present in the mouth, capsaicin therefore causes a feeling of heat or a burning sensation, which completely tricks the brain into believing that the mouth is literally “on fire”. The reason many people are attracted to these “painful” substances is still not understood, but could be related to the release of pleasure molecules (endorphins) to mitigate the effects of the “burn” detected by the brain.

In addition to their unique taste properties, a recent study suggests that chili peppers may have positive health effects, particularly for cardiovascular disease. Over an 8-year period, researchers followed just over 20,000 people recruited into the Moli-sani Project, a prospective study of residents of the Molise region of southeastern Italy. By analyzing deaths during this period according to the frequency of chili pepper consumption by participants, the researchers found that the risk of dying prematurely from all causes was reduced by 23% for hot pepper lovers (consumption 4 times per week). This decrease was particularly apparent for mortality linked to coronary heart disease (44%) and cerebrovascular disease (61%) (Figure 2). A downward trend was observed for cancer mortality, but the difference is not statistically significant.

Figure 2. Reduced risk of all-cause mortality and mortality related to various diseases among regular chili pepper consumers. Adapted from Bonaccio et al. (2019). N.S., not significant.

These observations are in agreement with previous studies that have observed a significant reduction (approximately 10–20%) of premature mortality among the largest consumers of spicy foods (here and here, for example).

As the editorial accompanying the article points out, although this type of population study does not directly establish a causal link between chili pepper consumption and mortality, it remains that the experimental data accumulated in recent years make this link biologically plausible. On the one hand, several studies have suggested that capsaicin may help prevent the development of obesity, an important risk factor for diabetes and cardiovascular disease. For example, epidemiological studies have observed that regular consumption of these peppers is associated with a reduction in the prevalence of obesity in certain populations, and clinical studies have observed a loss of abdominal fat following the administration of a supplement of capsinoids (capsaicin and related molecules) compared to placebo. This positive effect of capsaicin on body weight maintenance is mainly linked to a decrease in calorie intake, caused by decreased appetite and increased satiety.

On the other hand, it should be noted that capsaicin also influences other phenomena linked to an increased risk of cardiovascular disease, notably by improving the response to insulin, reducing the oxidation of low-density lipoproteins (LDL), and improving endothelial function. Studies have also suggested that people who season their food with hot peppers eat less salt and are less at risk for hypertension, the main risk factor for cardiovascular events.

Overall, these observations raise the interesting possibility that some minor dietary changes, such as the addition of chili peppers, may have positive impacts on health, particularly at the cardiovascular level. Of course, there should be no illusions: if a person’s diet is based on ultra-processed foods and contains very little fruit and vegetables, it is not by adding sriracha sauce or Tabasco that they will manage to decrease their risk of cardiovascular disease. But in the context of a diet known to be positive for the health of the heart and vessels, such as the Mediterranean diet (adopted by most of the participants of the study mentioned above), it is possible that the positive biological effects of chili peppers on body weight, blood sugar and reduced salt intake may accentuate the benefits associated with this diet and therefore have a positive impact on health.

Exercise reduces cardiovascular inflammation by modulating the immune system

Exercise reduces cardiovascular inflammation by modulating the immune system

OVERVIEW

  • Voluntary and regular exercise in mice decreases the number of inflammatory leukocytes (white blood cells) in the bloodstream.
  • Exercise causes a decrease in leptin (a digestive hormone) secreted by fat cells, which decreases the production of leukocytes by hematopoietic stem and progenitor cells in the bone marrow.
  • Cardiac patients who exercised four or more times a week had lower leptin and leukocyte blood levels.
  • These results suggest that a sedentary lifestyle contributes to cardiovascular risk through increased production of inflammatory leukocytes.

It is well established that regular exercise has many benefits for cardiovascular health, but the underlying mechanisms have not yet been fully identified and understood. A recent study published in Nature Medicine shows that in mice, voluntary exercise reduces the proliferation of hematopoietic stem and progenitor cells (HSPC), which has the effect of reducing the number of inflammatory leukocytes in the bloodstream. Remember that HSPC cells have the ability to transform into different types of cells that are involved in the immune response (leukocytes, lymphocytes, macrophages, etc.).

A sedentary lifestyle, chronic inflammation and abnormally high white blood cell count (leukocytosis) promote atherosclerosis, which can potentially cause myocardial infarction, stroke or heart failure.

To test whether regular exercise can modulate hematopoiesis, the researchers put mice in cages in the presence (or not for the control group) of an exercise wheel, where they could exercise at their will. Mice use these exercise wheels readily and with great zeal and are therefore not subjected to stress as when they are forced to exercise such as, for example, forced swimming that has already been used in other studies. After six weeks, mice that exercised voluntarily (doing about 20 times more physical activity than sedentary mice) reduced their body weight and increased their food intake.

Analyses have shown that exercise reduced the proliferation of hematopoietic stem and progenitor cells by 34%. The decrease in HSPC through exercise had the effect of reducing the number of inflammatory leukocytes (white blood cells) in the bloodstream. In addition, the mononuclear cells in the bone marrow of mice that exercised were less able to differentiate into granulocytes, macrophages, and pre-B cells. The researchers showed that the mechanism involves a decrease in the production of leptin (a hormone secreted during digestion to regulate fat stores and control the feeling of satiety) in fat tissues. The decrease in leptin in the bloodstream of mice had the effect of increasing the production of factors of quiescence and retention of hematopoietic stem cells in the bone marrow, and consequently of decreasing the number of leukocytes in the bloodstream (see figure below).

Figure. Schematic summary of the effects of exercise on leukocyte levels and the risk of cardiovascular disease. LepR+: expressing the leptin receptor. Adapted from Frodermann et al., 2019.

Leptin supplementation in mice that exercised (using subcutaneous micropumps) reversed the exercise-induced effects on hematopoiesis, proving that this digestive hormone is involved in this phenomenon.

The exercise wheel was removed from the mouse cage after six weeks. Three weeks later, the effect on leptin production faded, but the effects of exercise on hematopoiesis persisted, i.e. the leukocyte levels of exercise mice were still lower than that of sedentary mice. There is therefore a “memory” of the exercise, which was related to epigenetic changes, i.e. to a difference in the expression of certain genes without alteration of their DNA sequence.

A reduction in leukocyte levels in the blood can lead to an increased risk of infection, as has already been observed for high-intensity exercise. The researchers wanted to see if this was the case with the mice in their study. A component of the cell wall of bacteria (lipopolysaccharide) was injected into the stomachs of mice to induce an inflammatory response. The mice responded quickly by increasing the number of HSPC and defence cells (neutrophils, monocytes, B lymphocytes, T-cells) in the blood and at the site of infection. Mice who exercised reacted more than sedentary mice to lipopolysaccharide injection and had a lower mortality rate when real sepsis was provoked. It is therefore clear that regular voluntary exercise in mice does not decrease the emergency immune response to infection.

The researchers then wanted to find out if the decrease in leukocytes caused by exercise could reduce atherosclerosis and inflammation of atherosclerotic plaques. To do this they used a “knockout” mouse line in which the gene encoding apolipoprotein E was inactivated (Apoe–/–­­­­­). This protein carries lipids into the blood and is essential for their elimination. Inactivation of the Apoe gene causes hypercholesterolemia and atherosclerosis in mice. Apoe–/–­­­­­ mice that developed atherosclerosis were placed in cages containing an exercise wheel, which led to a decrease in leptin levels, a decrease in leukocytes, and a decrease in plaque size. The same beneficial effects of exercise on atherosclerosis were observed in a mouse line in which the gene encoding the leptin receptor was inactivated specifically at the level of stromal cells.

The researchers finally wanted to know if exercise could have beneficial effects on hematopoiesis in patients with cardiovascular disease. To do this, they checked whether there was an association between the amount of exercise and the blood levels of leptin or the number of leukocytes in 4,892 participants of the CANTOS study, who were all recruited after having a heart attack. Participants who exercised four or more times a week had significantly lower leptin blood levels. Another study (Athero-Express Study) also showed a favourable relationship between the amount of exercise and levels of leptin and leukocytes. The results of these two clinical studies, combined with those obtained in mice, indicate that physical activity has beneficial effects on leptin levels and leukocytosis in patients with cardiovascular disease.

This new study suggests that a sedentary lifestyle contributes to cardiovascular risk through an increased production of inflammatory leukocytes, and confirms the idea that physical activity reduces chronic inflammation. Let us recall the main recommendations of the World Health Organization’s (WHO) regarding physical activity for health:

“In order to improve cardiorespiratory and muscular fitness, bone health, reduce the risk of noncommunicable diseases and depression,

  1. Adults aged 18–64 should do at least 150 minutes of moderate-intensity aerobic physical activity throughout the week or do at least 75 minutes of vigorous-intensity aerobic physical activity throughout the week or an equivalent combination of moderate- and vigorous-intensity activity.
  2. Aerobic activity should be performed in bouts of at least 10 minutes duration.
  3. For additional health benefits, adults should increase their moderate-intensity aerobic physical activity to 300 minutes per week, or engage in 150 minutes of vigorous-intensity aerobic physical activity per week, or an equivalent combination of moderate- and vigorous-intensity activity.
  4. Muscle-strengthening activities should be done involving major muscle groups on 2 or more days a week.”

To learn more about the benefits, quantity and types of exercise, check out these articles:

How much exercise to live longer?

Exercise on an empty stomach to burn more fat

Can regular exercise compensate for long periods spent sitting?

Exercise benefits in cardiovascular disease: beyond attenuation of traditional risk factors