The cardiovascular benefits of soy

The cardiovascular benefits of soy

OVERVIEW

  • Asians have a much lower incidence of cardiovascular disease than North Americans, a difference that has been attributed, at least in part, to their high consumption of soybeans.
  • This protection is due to soy’s high content of isoflavones, a class of polyphenols that have several positive effects on the cardiovascular system.
  • A recent study carried out among 210,700 Americans (168,474 women and 42,226 men) has just confirmed this reduction in the risk of coronary heart disease associated with the consumption of soybeans, illustrating how this legume is an attractive alternative to meat as a source of protein.

It has been known for several years that people in Asian countries have a much lower incidence of cardiovascular disease than in the West. The study of migrant populations has shown that this difference is not due to genetic factors. For example, an analysis carried out in the 1970s revealed that the Japanese who had emigrated to California had twice the incidence of coronary heart disease than that of their compatriots who remained in Japan. It should be mentioned that these Asia-America differences are also observed for several types of cancer, in particular breast cancer. Asian women (China, Japan, Korea) have one of the lowest incidences of breast cancer in the world, but this cancer can become up to 4 times more common as a result of their migration to America, and its incidence even becomes similar to that of third generation Americans. The rapid rise in cardiovascular disease or cancer following migration to the West therefore suggests that abandoning the traditional lifestyle of Asians for the one in vogue in North America greatly favours the development of these diseases.

One of the differences between the Asian and North American lifestyles that has long interested researchers is the huge gap in soy consumption. While an average of 20 to 30 g of soy protein is consumed daily in Japan and Korea, this consumption barely reaches 1 g per day in the United States (Figure 1). It is proposed that this difference could contribute to the higher incidence of cardiovascular disease in the West for two main reasons:

  • Like all members of the legume family (lentils, peas, etc.), soy is an excellent source of fibre, vitamins, minerals, and polyunsaturated fats, nutrients known to be beneficial to heart and vessel health;
  • Soybeans are an exceptional source of isoflavones, a class of polyphenols found almost exclusively in this legume. The main isoflavones in soybeans are genistein, daidzein and glycitein (Figure 2), these molecules being present in varying amounts depending on the degree of processing of soybeans.

Figure 1. Comparison of the amounts of soybeans consumed daily by people in different countries. From Pabich and Materska (2019).

 


Figure 2. Molecular structures of the main isoflavones.
Note that equol is not present in soy products, but is rather generated by the gut microbiome following their ingestion.

The highest concentrations of isoflavones are found in the starting beans (edamame) and foods derived from fermented beans (natto, tempeh, miso), while foods from the pressing of beans (tofu, soy milk) contain slightly less (Table 1). These foods are commonly consumed by Asians and allow them to obtain isoflavone intakes varying from 8 to 50 mg per day, depending on the region, quantities clearly greater than those of the inhabitants of Europe and America (less than 1 mg per day). It should be noted, however, that soy is gradually becoming more and more popular in the West as an alternative to meat and that isoflavone intake can reach levels similar to Asians (18–21 mg per day) in certain groups of health-conscious people.


Table 1. The isoflavone content of various foods.
Source: United States Department of Agriculture, Nutrient Data Laboratory.

FoodIsoflavone content
(mg/100 g)
Natto82.3
Tempeh
60.6
Soybeans (edamame)49.0
Miso41.5
Tofu22.1
Soy milk10.7

The importance of a high intake of isoflavones comes from the multiple biological properties of this class of molecules. In addition to their antioxidant and anti-inflammatory activities, common to many polyphenols, a unique feature of isoflavones is their structural resemblance to estrogens, the female sex hormones, and it is for this reason that these molecules are often referred to as phytoestrogens. This estrogenic action has so far been mainly studied in relation to the development of hormone-dependent breast cancers. Since the growth of these cancers is stimulated by estrogens, the presence of phytoestrogens creates a competition that attenuates the biological effects associated with these hormones, especially the excessive growth of breast tissue (this mode of action is comparable to that of tamoxifen, a drug prescribed for several years against breast cancer). It is also important to note that, contrary to a very widespread misconception, the consumption of soybeans should not be discouraged for women who have survived breast cancer. On the contrary, many studies conducted in recent years clearly show that regular soy consumption by these women is absolutely safe and is even associated with a significant decrease in the risk of recurrence and mortality from this disease. It should be mentioned that despite the similarity of isoflavones to estrogens, studies indicate that soy does not interfere with the effectiveness of tamoxifen or anastrozole, two drugs frequently used to treat hormone-dependent breast cancers. Consequently, for people who have been affected by breast cancer, there are only benefits to incorporating soy into their diet.

Several data suggest that the positive effect of isoflavones on health is not limited to their anticancer action, and that the combination of the antioxidant, anti-inflammatory and estrogenic activities of these molecules may also contribute to the cardiovascular benefits of soy (Table 2).


Table 2. Main properties of isoflavones involved in reducing the risk of cardiovascular disease associated with soy consumption.

Cardiovascular effectsProposed mechanisms
Vasodilation of blood vesselsIsoflavones interact with a subtype of estrogen receptor present in the coronary arteries (Erβ), leading to the production of nitrous oxide (NO), a gas that induces vasodilation of blood vessels.
Lower cholesterol levels
Accelerated elimination of LDL and VLDL in the liver.
Isoflavones reduce LDL-cholesterol oxidation in diabetic patients.
AntioxydantEquol, a metabolite of daidzein formed by the intestinal microbiome, has a strong antioxidant activity.
Anti-inflammatoryIsoflavones promote the establishment of an intestinal microbiome enriched with bacteria that produce anti-inflammatory molecules (Bifidobacterium spp., for example).

A cardioprotective effect associated with soy consumption is also suggested by the results of an epidemiological study recently published in Circulation. By examining the eating habits of 210,700 Americans (168,474 women and 42,226 men), the researchers found that people with the highest isoflavone intake (about 2 mg per day on average) had a risk of coronary heart disease decreased by 13% compared to those with minimal intake (0.15 mg per day on average). A protective effect is also observed for tofu, with an 18% reduction in the risk of coronary heart disease for people who consume it once or more per week compared to those who ate it very rarely (less than once per month). Regular consumption of soy milk (once or more per week) is also associated with a slight decrease in risk, but this decrease is not statistically significant.

These reductions may seem modest, but it should be noted that the amounts of soybeans consumed by participants in this study are relatively small, well below what is commonly measured in Japan. For example, in a Japanese study that reported a 45% decrease in the risk of myocardial infarction in women who consumed the most soy, the isoflavone intake of these people was on average around 40 mg/day, i.e. 20 times more than in the American study (2 mg/day). It is therefore likely that the reductions in the risk of coronary heart disease observed in the United States represent a minimum and could probably be greater as a result of higher soy intake.

An interesting aspect of the decreased risk of coronary heart disease associated with tofu is that it is observed as much in younger women before menopause as in postmenopausal women, but only if they are not using hormone therapy (Figure 3). According to the authors, it is possible that after menopause, the estrogenic action of isoflavones compensates for the drop in estrogen levels and may mimic the cardioprotective effect of these hormones. In the presence of synthetic hormones, on the other hand, isoflavones are “masked” by excess hormones and therefore cannot exert their beneficial effects. For younger women, it is likely that the higher expression of the estrogen receptor before menopause promotes a greater interaction with isoflavones and allows these molecules to positively influence the function of blood vessels.

Figure 3. Association between risk of coronary heart disease and tofu consumption by hormonal status.
From Ma et al. (2020).

Taken together, these observations suggest that soy products have a positive effect on cardiovascular health and therefore represent an excellent alternative to meat as a source of protein. A recent study reports that these cardiovascular benefits can be even more pronounced following the consumption of fermented soy products such as natto, which is very rich in isoflavones, but given its texture (sticky, gooey), its strong smell (reminiscent of a well-made cheese), and its low availability in grocery stores, this food is foreign to our food culture and unlikely to be adopted by the North American population. Tofu is probably the most accessible soy-derived food given its neutral taste that allows it to be used in a wide variety of dishes, Asian-style or not. Soy milk is a less attractive alternative, not only because its consumption is not associated with a significant decrease in the risk of coronary heart disease, but also because these products often contain significant amounts of sugar.

To prevent cardiovascular disease, medication should not be a substitute for improved lifestyle

To prevent cardiovascular disease, medication should not be a substitute for improved lifestyle

OVERVIEW

  • Cardiovascular disease dramatically increases the risk of developing serious complications from COVID-19, again highlighting the importance of preventing these diseases in order to live long and healthy lives.
  • And it is possible! Numerous studies clearly show that more than 80% of cardiovascular diseases can be prevented by simply adopting 5 lifestyle habits (not smoking, maintaining a normal weight, eating a lot of vegetables, exercising regularly, and drinking alcohol moderately).

The current COVID-19 pandemic has exposed two major vulnerabilities in our society. The first is, of course, the fragility of our health care system, in particular everything related to the care of the elderly with a loss of autonomy. The pandemic has highlighted serious deficiencies in the way this care is delivered in several facilities, which has directly contributed to the high number of elderly people who have died from the disease. Hopefully, this deplorable situation will have a positive impact on the ways of treating this population in the future.

A second vulnerability highlighted by the pandemic, but much less talked about, is that COVID-19 preferentially affects people who present pre-existing conditions at the time of infection, in particular cardiovascular disease, obesity and type 2 diabetes. These comorbidities have a devastating impact on the course of the disease, with increases in the death rate of 5 to 10 times compared to people without pre-existing conditions. In other words, not only does poor metabolic health have a disastrous impact on healthy life expectancy, it is also a significant risk factor for complications from infectious diseases such as COVID-19. We are therefore not as helpless as we might think in the face of infectious agents such as the SARS-CoV-2 coronavirus: by adopting a healthy lifestyle that prevents the development of chronic diseases and their complications, we simultaneously greatly improve the probability of effectively fighting infection with this type of virus.

Preventing cardiovascular disease
Cardiovascular disease is one of the main comorbidities associated with severe forms of COVID-19, so prevention of these diseases can therefore greatly reduce the impact of this infectious disease on mortality. It is now well established that high blood pressure and high blood cholesterol are two important risk factors for cardiovascular disease. As a result, the standard medical approach to preventing these diseases is usually to lower blood pressure and blood cholesterol levels with the help of drugs, such as antihypertensive drugs and cholesterol-lowering drugs (statins). These medications are particularly important in secondary prevention, i.e. to reduce the risk of heart attack in patients with a history of cardiovascular disease, but they are also very frequently used in primary prevention, to reduce the risk of cardiovascular events in the general population.

The drugs actually manage to normalize cholesterol and blood pressure in the majority of patients, which can lead people to believe that the situation is under control and that they no longer need to “pay attention” to what they eat or be physically active on a regular basis. This false sense of security associated with taking medication is well illustrated by the results of a recent study, conducted among 41,225 Finns aged 40 and over. By examining the lifestyle of this cohort, the researchers observed that people who started medication with statins or antihypertensive drugs gained more weight over the next 13 years, an excess weight associated with an 82% increased risk of obesity compared to people who did not take medication. At the same time, people on medication reported a slight decrease in their level of daily physical activity, with an increased risk of physical inactivity of 8%.

These findings are consistent with previous studies showing that statin users eat more calories, have a higher body mass index than those who do not take this class of drugs, and do less physical activity (possibly due to the negative impact of statins on muscles in some people). My personal clinical experience points in the same direction; I have lost count of the occasions when patients tell me that they no longer have to worry about what they eat or exercise regularly because their levels of LDL cholesterol have become normal since they began taking a statin. These patients somehow feel “protected” by the medication and mistakenly believe that they are no longer at risk of developing cardiovascular disease. This is unfortunately not the case: maintaining normal cholesterol levels is, of course, important, but other factors such as smoking, being overweight, sedentary lifestyle, and family history also play a role in the risk of cardiovascular disease. Several studies have shown that between one third and one half of heart attacks occur in people with LDL-cholesterol levels considered normal. The same goes for hypertension as patients treated with antihypertensive drugs are still 2.5 times more likely to have a heart attack than people who are naturally normotensive (whose blood pressure is normal without any pharmacological treatment) and who have the same blood pressure.

In other words, although antihypertensive and cholesterol-lowering drugs are very useful, especially for patients at high risk of cardiovascular events, one must be aware of their limitations and avoid seeing them as the only way to reduce the risk of cardiovascular events.

Superiority of lifestyle
In terms of prevention, much more can be done by addressing the root causes of cardiovascular disease, which in the vast majority of cases are directly linked to lifestyle. Indeed, a very large number of studies have clearly shown that making only five lifestyle changes can very significantly reduce the risk of developing these diseases (see Table below).

The effectiveness of these lifestyle habits in preventing myocardial infarction is quite remarkable, with an absolute risk drop to around 85% (Figure 1). This protection is seen both in people with adequate cholesterol levels and normal blood pressure and in those who are at higher risk for cardiovascular disease due to high cholesterol and hypertension.

Figure 1. Decreased incidence of myocardial infarction in men combining one or more protective factors related to lifestyle. The comparison of the incidences of infarction was carried out in men who did not have cholesterol or blood pressure abnormalities (upper figure, in blue) and in men with high cholesterol levels and hypertension (lower figure, in orange). Note the drastic drop in the incidence of heart attacks in men who adopted all 5 protective lifestyle factors, even in those who were hypertensive and hypercholesterolemic. Adapted from Åkesson (2014).

Even people who have had a heart attack in the past and are being treated with medication can benefit from a healthy lifestyle. For example, a study conducted by Canadian cardiologist Salim Yusuf’s group showed that patients who modify their diet and adhere to a regular physical activity program after a heart attack have their risk of heart attack, stroke and mortality reduced by half compared to those who do not change their habits (Figure 2). Since all of these patients were treated with all of the usual medications (beta blockers, statins, aspirin, etc.), these results illustrate how lifestyle can influence the risk of recurrence.

Figure 2. Effect of diet and exercise on the risk of heart attack, stroke, and death in patients with previous coronary artery disease. Adapted from Chow et al. (2010).

In short, more than three quarters of cardiovascular diseases can be prevented by adopting a healthy lifestyle, a protection that far exceeds that provided by drugs. These medications must therefore be seen as supplements and not substitutes for lifestyle. The development of atherosclerosis is a phenomenon of great complexity, which involves a large number of distinct phenomena (especially chronic inflammation), and no drug, however effective, will ever offer protection comparable to that provided by a healthy diet, regular physical activity, and maintenance of a normal body weight.

Hydroxychloroquine and COVID-19: A potentially harmful effect on the heart

Hydroxychloroquine and COVID-19: A potentially harmful effect on the heart

Updated June 8, 2020

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the SARS-CoV-2 coronavirus strain that primarily, but not exclusively, affects the respiratory system. While in the majority of infected people the symptoms of the disease are relatively mild or moderate (cough, fever, dyspnea or difficulty breathing, digestive disorders, temporary loss of taste and smell, hives, vascular lesions on the fingertips and toes), they may worsen in some people who have one or more risk factors (diabetes, hypertension, obesity, cardiovascular disease, advanced age) into acute respiratory distress syndrome that requires hospitalization in an intensive care unit and can lead to death.

There is no vaccine or effective drug available to reduce the mortality associated with COVID-19. The use of an antiviral drug, remdesivir, which was urgently approved by the FDA on May 1, 2020, reduces the number of days in hospital in people with COVID-19, but does not significantly reduce mortality. As of May 15, 2020, more than 1,500 studies on various aspects of COVID-19 have been registered on ClinicalTrials.gov, including more than 885 intervention studies and randomized controlled studies, with 176 on the use of hydroxychloroquine.

Hydroxychloroquine
One of the first candidates tested for treating COVID-19 was hydroxychloroquine, a drug used for its anti-inflammatory properties in the treatment of rheumatoid arthritis and systemic lupus erythematosus. Prior to the current COVID-19 pandemic, it was already known that chloroquine and its derivatives, including hydroxychloroquine, have non-specific antiviral activity against several types of enveloped viruses (HIV, hepatitis C, dengue, influenza, Ebola, SARS, MERS) in vitro. Two recent studies (see here and here) have shown that hydroxychloroquine also inhibits infection with the SARS-CoV-2 virus in vitro, i.e. in cultured epithelial cells. Hydroxychloroquine, which has a better safety profile than chloroquine, has been shown to be a more potent SARS-CoV-2 inhibitor in vitro.

The results obtained in vitro do not necessarily imply that chloroquine and its derivatives have antiviral activity in humans. Indeed, studies have shown that in vivo chloroquine and/or hydroxychloroquine have no effect on viral replication or increase viral replication and the severity of illness caused by infection by influenza, dengue, Simliki forest virus, encephalomyocarditis virus, Nipah and Hendra viruses, Chikungunya virus, and Ebola virus (references here).

Initial results from studies on the use of hydroxychloroquine to treat COVID-19 are unclear. Chinese researchers have reported treating over 100 patients with beneficial effects, but have not released any data. French microbiologist Didier Raoult and his collaborators published two articles (see here and here) on the use of hydroxychloroquine (in combination with the antibiotic azithromycin) for the treatment of COVID-19, in which they concluded that this drug lowers viral load in nasal swabs. However, these studies were not randomized and they do not report essential clinical data, such as the number of deaths among participants. In addition, two other French groups (see here and here) report having found no evidence of antiviral activity of hydroxychloroquine/azithromycin or of clinical benefit in hospitalized patients with a severe form of COVID-19.

In an observational study conducted in New York City hospitals, hydroxychloroquine was administered to 811 patients out of a total of 1376 patients, with a follow-up lasting an average of 22.5 days after admission to the hospital. Analysis of the results indicates that among this large number of patients admitted to hospital with a severe form of COVID-19, the risk of having to be intubated or dying was not significantly higher or lower in patients who received hydroxychloroquine than in those who did not. The authors conclude that the results obtained do not support the use of hydroxychloroquine in the current context, except in randomized controlled trials, which remain the best way to establish the efficacy of a therapeutic intervention.

Cardiovascular risk: Prolongation of the QT interval
Although hydroxychloroquine and azithromycin are well-tolerated drugs, both can cause prolongation of the QT segment on the electrocardiogram (figure below). For this reason, cardiologists are concerned about the use of these two drugs in a growing number of clinical trials for the treatment of COVID-19 (see here, here, here and here). It should be noted that the prolongation of the corrected QT interval (QTc) is a recognized marker of an increased risk of fatal arrhythmias.

Figure. Normal and abnormal (long) QT interval on the electrocardiogram.

Hospital researchers in the United States assessed the risk of QTc prolongation in 90 patients who received hydroxychloroquine, 53 of whom were concomitantly given the antibiotic azithromycin. The most common comorbidities among these patients were hypertension (53%) and type 2 diabetes (29%). The use of hydroxychloroquine alone or in combination with azithromycin was associated with QTc prolongation. Patients who received the two drugs in combination had significantly greater QTc prolongation than those who received hydroxychloroquine alone. Seven patients (19%) who received hydroxychloroquine monotherapy saw their QTc increase to 500 milliseconds (ms) or more, and three patients (8%) saw their QTc increase by 60 ms or more. Among the patients who received hydroxychloroquine and azithromycin in combination, 11 (21%) saw their QTc increase to 500 milliseconds (ms) or more, and 7 (13%) saw their QTc increase by 60 ms or more. Treatment with hydroxychloroquine had to be stopped promptly in 10 patients, due to iatrogenic drug events (adverse reactions), including nausea, hypoglycemia and 1 case of torsades de pointes. The authors conclude that physicians treating their patients with COVID-19 should carefully weigh the risks and benefits of treatment with hydroxychloroquine and azithromycin, and monitor QTc closely if patients are receiving these drugs.

French doctors have also published the results of a study on the effects of hydroxychloroquine treatment on the QT interval in 40 patients with COVID-19. Eighteen patients were treated with hydroxychloroquine (HCQ) and 22 received hydroxychloroquine in combination with the antibiotic azithromycin (AZM). An increase in the QTc interval was observed in 37 patients (93%) after treatment with antiviral therapy (HCQ alone or HCQ + AZM). QTc prolongation was observed in 14 patients (36%), including 7 with a QTc ≥ 500 milliseconds, 2 to 5 days after the start of antiviral therapy. Of these 7 patients, 6 had been treated with HCQ + AZM and one patient with hydroxychloroquine only, a significant difference. The authors conclude that treatment with hydroxychloroquine, particularly in combination with azithromycin, is of concern and should not be generalized when patients with COVID-19 cannot be adequately monitored (continuous monitoring of the QTc interval, daily electrocardiogram, laboratory tests).

Update June 8, 2020
A randomized, placebo-controlled study suggests that hydroxychloroquine is not effective in preventing the development of COVID-19 in people who have been exposed to the SARS-CoV-2 virus. The study, conducted in the United States and Canada, was published in the New England Journal of Medicine. Of 821 participants, 107 developed COVID-19 during the 14-day follow-up. Among people who received hydroxychloroquine less than four days after being exposed, 11.8% developed the disease compared to 14.3% in the group who received the placebo, a non-significant difference (P = 0.35). Side effects (nausea, abdominal discomfort) were more common in participants who received hydroxychloroquine than in those who received a placebo (40% vs. 17%), but no serious side effects, including cardiac arrhythmia, were reported. Clinical trials are underway to verify whether hydroxychloroquine can be effective in pre-exposure prophylaxis.

Hydroxychloroquine and COVID-19: A potentially harmful effect on the heart

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.