Dr Martin Juneau, M.D., FRCPCardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.28 May 2020
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.
| Food | Isoflavone content
(mg/100 g) |
| Natto | 82.3 |
Tempeh
| 60.6 |
| Soybeans (edamame) | 49.0 |
| Miso | 41.5 |
| Tofu | 22.1 |
| Soy milk | 10.7 |
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.
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.
Dr Martin Juneau, M.D., FRCPCardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.28 May 2020
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.
Dr Martin Juneau, M.D., FRCPCardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.27 May 2020
OVERVIEW
- A high proportion of patients with COVID-19 have clotting disorders that clinically manifest as venous thrombosis and pulmonary embolisms.
- These disorders are believed to be caused, at least in part, by a direct attack of the coronavirus on the endothelial cells that line the inside of blood vessels, causing abnormal formation of blood clots.
- The presence of these clots is particularly important in patients who develop severe complications from COVID-19 and contributes to the increased risk of mortality observed in this population.
As the COVID-19 pandemic progresses, it is becoming increasingly clear that the coronavirus responsible for this disease is a respiratory virus like no other. The lungs are, of course, the main organs affected by this virus, and most patients who develop severe complications or die from COVID-19 have serious lung damage. However, a large number of studies have reported several very specific clinical cases, which had so far never (or very rarely) been described for this type of viral infection, in particular severe damage to the heart, digestive system, kidneys, and brain.
Coagulation disorders
Data collected so far indicates that abnormal blood clot formation (thrombosis) is another unusual manifestation of COVID-19 that may play a very important role in the severity of the disease. Since the beginning of the pandemic, several physicians have reported an abnormally high incidence of phenomena linked to a decrease in blood circulation, such as a bluish tint to the lower limbs (e.g. toes) as well as deep vein thrombosis (phlebitis). The presence of these blood clots in the veins is extremely dangerous, as they can migrate into the bloodstream, reach the right ventricle of the heart, and subsequently block the pulmonary arteries to cause embolisms. In this sense, it should be noted that studies carried out in the Netherlands and France indicate that approximately 20–30% of patients with severe forms of COVID-19 are affected by these venous thrombosis and that pulmonary embolisms represent the most common complication of these coagulation disorders. This was confirmed by an autopsy study of 12 patients who died from COVID-19: of these patients, 7 presented with deep thrombosis, and 4 of them died of pulmonary embolism.
These pulmonary embolisms really seem to represent a “signature” of the coronavirus responsible for COVID-19. For example, a study reported the presence of pulmonary embolisms in 17% of patients with severe respiratory syndrome caused by COVID-19, while these embolisms are present in only 2% of patients also suffering from a severe respiratory syndrome, but not related to COVID-19. The contribution of these clots to the severity of COVID-19 is well illustrated by studies showing that high blood 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. In addition, 71% of patients who died from this disease were reported to have multiple blood clots scattered throughout their blood vessel network (disseminated intravascular coagulation), a phenomenon observed in only 0.6% of patients who survived the disease.
The coagulation disorders caused by the coronavirus are not limited to the veins, but also seem to affect the arteries. For example, one of the most surprising complications of COVID-19 is the observation of large-vessel strokes in young adults (under 50) living in New York. Studies in China have also documented the presence of these strokes in about 5% of patients; however, they were older than those affecting young New Yorkers. Taken together, these observations clearly show that bleeding disorders are a common consequence of infection with the SARS-CoV-2 coronavirus and contribute greatly to the development of serious complications of the disease.
Endothelial cells are targeted
One of the factors involved in this disruption of the normal coagulation process appears to be the direct action of the virus on the cells that line the blood vessels, called the endothelium. Under normal conditions, one of the main functions of this endothelium is to ensure good blood circulation, in particular by preventing the formation of blood clots. On the other hand, when these endothelial cells are damaged by physical (cut, wound) or biochemical (inflammation, pathogenic agents) aggressors, the rupture of the endothelial barrier allows the factors involved in coagulation to come into contact with the blood and form fibrin clots to restore the integrity of the endothelium.
In patients who develop severe forms of COVID-19, an exaggerated inflammatory response, often referred to as a “cytokine storm” (hypercytokinemia), is frequently observed. This high intensity inflammation makes the blood vessels very permeable and is therefore perceived by the body as an injury, which causes the activation of coagulation and the formation of clots. This process may be amplified by the presence of antiphospholipid antibodies, an autoimmune disorder also associated with an increased risk of thrombosis. It is also now known that the receptor that allows the entry of the coronavirus SARS-CoV-2 into cells is present in significant quantities on the surface of endothelial cells, so that the virus can directly attack the endothelium and cause damage that will trigger the activation of coagulation. This phenomenon was observed during an autopsy study recently published in the New England Journal of Medicine: by examining lung samples from patients who died of COVID-19, the researchers noted the presence of multiple viral particles in the blood vessels, as well as heavy damage to the structure of endothelial cells. This endothelial damage was accompanied by the presence of a large number of small clots obstructing blood flow in the pulmonary blood microvessels. These phenomena seem specific to COVID-19, because the parallel examination of the lungs of patients who died of influenza (H1N1) did not reveal any infection of the endothelial cells by the virus and showed a much lower incidence (9 times) of blood clots in the pulmonary vessels. This could explain why the mechanical ventilation of patients with severe forms of COVID-19 is often powerless to increase blood oxygen levels: not only is breathing compromised by the presence of fluid or pus in the pulmonary alveoli, but in addition, the damage inflicted on the endothelial cells and the presence of multiple clots obstructing the vessels prevent the blood from circulating and being oxygenated.
The impacts of these phenomena are obviously not exclusive to the lungs: every organ in the body is supplied with blood vessels, so that infection of the endothelium by the virus, combined with an increased formation of blood clots, can greatly contribute to the devastating effects of the virus on the functioning of several organs.
Dr Martin Juneau, M.D., FRCPCardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.19 May 2020
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.
Dr Martin Juneau, M.D., FRCPCardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.14 May 2020
OVERVIEW
- Obesity is normally associated with a decrease in the heart’s energy metabolism, but it is not clear how the heart adapts to cope with this energy deficit.
- Study participants who were obese had an average 14% lower phosphocreatine/ATP ratio than non-obese participants, but the total energy supply (ATP) delivered to the heart muscle was preserved by a compensatory mechanism that involves the acceleration of the enzymatic reaction catalyzed by creatine kinase.
- This adaptation mechanism has negative consequences for obese participants in situations where the workload of the heart increases.
- Obese participants who successfully lost weight (-11% on average) following a 6-month nutritional intervention saw their myocardial energy parameters return to values similar to those measured in non-obese participants.
Obesity is a major public health problem, which is growing so rapidly in our societies that it is now referred to as an “obesity epidemic” (see this article on the subject). Obesity is a significant risk factor for many cardiovascular diseases, including heart failure (HF) and especially heart failure with preserved ejection fraction (HFpEF). Heart failure is the inability of the heart to supply enough blood to deliver oxygen to tissues while maintaining normal filling pressures. People with HFpEF account for about half of people with heart failure, with the other half living with heart failure with reduced ejection fraction (HFrEF). In the United States, more than 80% of patients with HFpEF are overweight (BMI between 25 and 30) or obese (BMI > 30), twice as many as the general population. Obesity is now a risk factor for HFpEF almost as significant as hypertension. Yet hypertension has received much more attention to date than obesity as a cause of HFpEF.
The mechanisms by which obesity leads to HFpEF are multiple: cardiac overload, systemic inflammation, renal retention, insulin resistance, and alterations in cellular metabolism. The direct effects of obesity on heart muscle cells have recently become the subject of interesting studies. Studies published to date suggest that the accumulation of lipids in the heart has toxic effects that promote cardiac dysfunction in obese people. Obesity is normally associated with a decrease in the heart’s energy metabolism, but it is not clear how the heart adapts to cope with this energy deficit.
A study published in 2020 in the journal Circulation makes an important contribution to our understanding of the relationship between obesity and cardiac energy metabolism. The researchers recruited 80 volunteers who had no known cardiovascular disease, including 35 non-obese people (BMI: 24 ± 3 kg/m2) and 45 obese people (BMI: 35 ± 5 kg/m2). All participants were subjected to a battery of tests before and after the nutritional intervention with obese participants only, which aimed to make them lose weight. Among the various tests performed, nuclear magnetic resonance imaging (NMR) was used to assess cardiac function, abdominal visceral fat volume and in the liver, conventional phosphorus (31P) NMR spectroscopy was used to measure phosphocreatine and ATP (energy sources) at rest, and a more sophisticated variant of phosphorus NMR spectroscopy, called “31P saturation transfer”, was used to evaluate the enzymatic kinetics of creatine kinase, the enzyme that allows the rapid formation of ATP from phosphocreatine in muscle cells (ADP + phosphocreatine + H+ → ATP + creatine).
The study showed that obese participants had on average a phosphocreatine/ATP ratio 14% lower than non-obese participants, but that the total ATP supply delivered to the heart muscle was preserved by a compensatory mechanism that involves acceleration of the enzymatic reaction catalyzed by creatine kinase. Indeed, the resting creatine kinase catalytic constant, kfCKrest was 33% higher in obese participants than in non-obese participants.
The researchers suspected that this adaptation mechanism could have negative consequences in situations where the workload of the heart increases. To test this hypothesis, they induced an increase in cardiac output from the heart by administering dobutamine by infusion to the participants, while doing the imaging and NMR spectroscopy tests described above. In non-obese participants, both ATP delivery and kfCK increased in response to dobutamine infusion, by 80% and 86%, respectively. In contrast, there was no significant increase in ATP delivery and kfCK in obese participants under the same stress conditions imposed on the heart. In addition, the systolic increase caused by the increased heart workload was lower in obese participants (+16%) than in non-obese participants (+21%).
Impacts of weight loss
Of the 45 obese participants, 36 agreed to participate in a 6-month weight loss nutritional intervention, and of these 27 successfully lost weight (-11% of body weight and -23% of body fat, on average). This weight loss was associated with an improvement in several parameters, including a 13% decrease in blood cholesterol, a 9% decrease in fasting glucose, and a 41% reduction in insulin resistance. Weight loss has also been associated with reduced left ventricular end diastolic mass and volume, improved diastolic function, and increased ability to exercise. Weight loss in obese participants was associated with increased phosphocreatine/ATP ratio and decreased kfCkrest and ATP delivery. In fact, obese participants who were successful in losing weight saw their myocardial energy parameters return to values similar to those measured in non-obese participants.
These findings shed light on the likely cause of the exhaustion symptoms after an effort that are present in the majority of obese people. Fortunately, the decrease in cardiac energy capacity induced by obesity is reversible by weight loss, which represents new avenues for the treatment of cardiomyopathies associated with obesity.
