Effects of cold on cardiovascular health

Effects of cold on cardiovascular health

OVERVIEW

  • Exposure to cold causes a contraction of blood vessels as well as an increase in blood pressure, heart rate, and the work of the heart muscle.
  • The combination of cold and exercise further increases stress on the cardiovascular system.
  • Cold temperatures are associated with increased cardiac symptoms (angina, arrhythmias) and an increased incidence of myocardial infarction and sudden cardiac death.
  • Patients with coronary artery disease should limit exposure to cold and dress warmly and cover their face when exercising.

Can the sometimes biting cold of our winters affect our overall health and our cardiovascular health in particular? For an exhaustive review of the literature on the effects of cold on health in general, see the summary report (in French only) recently published by the Institut national de santé publique du Québec (INSPQ). In this article, we will focus on the main effects of cold on the cardiovascular system and more specifically on the health of people with cardiovascular disease.

Brief and prolonged exposure to cold both affect the cardiovascular system, and exercise in cold weather further increases stress on the heart and arteries. Numerous epidemiological studies have shown that cardiovascular disease and mortality increase when the ambient temperature is cold and during cold spells. The winter season is associated with a greater number of cardiac symptoms (angina, arrhythmias) and cardiovascular events such as hypertensive crisis, deep venous thrombosis, pulmonary embolism, aortic ruptures and dissections, stroke, intracerebral hemorrhage, heart failure, atrial fibrillation, ventricular arrhythmia, angina pectoris, acute myocardial infarction, and sudden cardiac death.

Mortality from cold
Globally, more temperature-related deaths were caused by cold (7.29%) than heat (0.42%). For Canada, 4.46% of deaths were attributable to cold (2.54% for Montreal), and 0.54% to heat (0.68% for Montreal).

Intuition may lead us to believe that it is during periods of extreme cold that more adverse health effects occur, but the reality is quite different. According to a study that analyzed 74,225,200 deaths that occurred between 1985 and 2012 in 13 large countries on 5 continents, extreme temperatures (cold or hot) accounted for only 0.86% of all deaths, while the majority of cold-related deaths occurred at moderately cold temperatures (6.66%).

Acute effects of cold on the cardiovascular system of healthy people

Blood pressure. The drop in skin temperature upon exposure to cold is detected by skin thermoreceptors that stimulate the sympathetic nervous system and induce a vasoconstriction reflex (decrease in the diameter of the blood vessels). This peripheral vasoconstriction prevents heat loss from the surface of the body and has the effect of increasing systolic (5–30 mmHg) and diastolic (5–15 mmHg) blood pressure.

Heart rate. It is not greatly affected by exposure of the body to cold air, but it increases rapidly when, for example, the hand is dipped in ice water (“cold test” used to make certain diagnoses, such as Raynaud’s disease) or when very cold air is inhaled. Cold air usually causes a slight increase in heart rate in the range of 5 to 10 beats per minute.

Risk of atheromatous plaque rupture?
Post-mortem studies have shown that rupture of atheroma plaques (deposits of lipids on the lining of the arteries) is the immediate cause of over 75% of acute myocardial infarctions. Could cold stress promote the rupture of atheromatous plaques? In a laboratory study, mice exposed to cold in a cold room (4°C) for 8 weeks saw their blood LDL cholesterol level and the number of plaques increase compared to mice in the control group (room at 30°C). Furthermore, it is known that exposure to cold induces aggregation of platelets in vitro and increases coagulation factors in vivo in patients during colder days (< 20°C) compared to warmer days (> 20°C). Combined, these cold effects could help promote plaque rupture, but to date no study has been able to demonstrate this.

Risk of cardiac arrhythmias
Arrhythmias are a common cause of sudden cardiac death. Even in healthy volunteers, the simple act of dipping a hand in cold water while holding the breath can cause cardiac arrhythmias (nodal and supraventricular tachycardias). Could cold promote sudden death in people at risk for or with heart disease? Since arrhythmias cannot be detected post-mortem, it is very difficult to prove such a hypothesis. If it turns out that exposure to cold air can promote arrhythmias, people with coronary artery disease may be vulnerable to the cold since the arrhythmia would amplify the oxygenated blood deficit that reaches the heart muscle.

Effects of cold combined with exercise
Both cold and exercise individually increase the heart’s demand for oxygen, and the combination of the two stresses has an additive effect on this demand (see these two review articles, here and here). Exercising in the cold therefore results in an increase in systolic and diastolic blood pressure as well as in the “double product” (heart rate x blood pressure), a marker of cardiac work. The increased demand for oxygen by the heart muscle caused by cold weather and exercise increases blood flow to the coronary arteries that supply the heart. The rate of coronary blood flow increases in response to cold and exercise combined compared to exercise alone, but this increase is mitigated, especially in older people. Therefore, it appears that cold causes a relative lag between the oxygen demand from the myocardium and the oxygenated blood supply during exercise.

In a study carried out by our research team, we exposed 24 coronary patients with stable angina to various experimental conditions in a cold room at – 8°C, specifically a stress test with electrocardiogram (ECG) in cold without antianginal medication and an ECG at + 20°C. We then repeated these two ECGs after taking one drug (propranolol) that slows the heart rate, and then another drug (diltiazem) that causes dilation of the coronary arteries. The results showed that the cold caused mild to moderate ischemia (lack of blood supply) to the myocardium in only 1/3 of the patients. When ECG was done with medication, this effect was completely reversed. The two drugs have been shown to be equally effective in reversing this ischemia. The conclusion: cold had only a modest effect in 1/3 of patients and antianginal drugs are as effective in cold (- 8°C) as at + 20°C.

In another study in the same type of patients, we compared the effects of an ECG at – 20°C with an ECG at + 20°C. The results showed that at this very cold temperature, all patients presented with angina and earlier ischemia.

Hypertension
The prevalence of hypertension is higher in cold regions or during winter. Cold winters increase the severity of hypertension and the risk of cardiovascular events such as myocardial infarction and stroke in people with hypertension.

Heart failure
The heart of patients with heart failure is not able to pump enough blood to maintain the blood flow necessary to meet the body’s needs. Only a few studies have looked at the effects of cold on heart failure. Patients with heart failure do not have much leeway when the heart’s workload increases in cold weather or when they need to exert sustained physical effort. Cold combined with exercise further decreases the performance of people with heart failure. For example, in a study we conducted at the Montreal Heart Institute, cold reduced exercise time by 21% in people with heart failure. In the same study, the use of beta-blocker class antihypertensive drugs (metoprolol or carvedilol) significantly increased exercise time and reduced the impact of cold exposure on the functional capacity of patients. Another of our studies indicates that treatment with an antihypertensive drug from the class of angiotensin converting enzyme inhibitors, lisinopril, also mitigates the impact of cold on the ability to exercise in patients with heart failure.

Cold, exercise and coronary heart disease
It is rather unlikely that the cold alone could cause an increase in the work of the heart muscle large enough to cause a heart attack. Cold stress increases the work of the heart muscle and therefore the blood supply to the heart in healthy people, but in coronary patients there is usually a reduction in blood flow to the coronary arteries. The combination of cold and exercise puts coronary patients at risk of cardiac ischemia (lack of oxygen to the heart) much earlier in their workout than in warm or temperate weather. For this reason, people with coronary artery disease should limit exposure to cold and wear clothes that keep them warm and cover their face (significant heat loss in this part of the body) when working out outdoors in cold weather. In addition, the exercise tolerance of people with coronary heart disease will be reduced in cold weather. It is strongly recommended that coronary heart patients do indoor warm-up exercises before going out to exercise outdoors in cold weather.

Standing up is still doing a little exercise!

Standing up is still doing a little exercise!

OVERVIEW

  • Sedentary lifestyle is associated with a significant increase in the risk of cardiovascular disease, type 2 diabetes, certain types of cancer and an increased risk of dying prematurely.
  • A study of seniors (65 years and older) reported that simply standing for more than an hour a day, without necessarily exercising, is enough to significantly reduce this risk of premature death.

According to recent estimates from the World Health Organization, physical inactivity is directly responsible for around 10% of premature deaths worldwide, an impact similar to those of smoking and obesity. Canada is no exception to this trend, with barely 15% of the population doing the recommended minimum of 150 minutes of physical activity per week and only 5% doing so on a regular basis, i.e. being active for at least 30 minutes a day, five days a week. This sedentary lifestyle is particularly pronounced among older people (60 and over), with barely 10% of this age group being sufficiently active. As a result, it is estimated that the elderly spend on average more than 60% (10 hours and more) of their waking period in sedentary activities, totally devoid of physical activity (Figure 1).

Figure 1. Proportion of waking time spent in sedentary activities by age group. From Matthews et al. (2008).

This is far too much, as numerous studies have clearly shown that high levels of physical inactivity are associated with a significant increase in the risk of cardiovascular disease, type 2 diabetes, certain types of cancer and an increased risk of dying prematurely. There is no doubt that sitting or lying down doing nothing for too long is very bad for health and that itis absolutely necessary to break this bad habit to improve the health of the population.

Standing up is already better
Obviously, the best option to counter the harmful effects of a sedentary lifestyle is to be more physically active. For example, a recent study reports that around 30 minutes of moderate to vigorous physical activity per day (such as brisk walking) seems sufficient to completely cancel out the negative impact of a sedentary lifestyle on the risk of premature mortality.

A study of older people suggests that much lower levels of physical activity may also have positive health effects. In this study, nearly 6,000 American women, ages 63 to 97, wore a research accelerometer for seven days to get accurate measurements of time spent sitting, standing, or moving. During a follow-up period of 5 years on average, the researchers observed that the simple fact of spending more time in a standing position, without doing any other exercise, was enough to significantly decrease the risk of premature death. Compared to the most sedentary women (less than 45 min standing per day), participants who spent the most time standing had a 37% lower risk of death (Figure 2A). These positive effects of standing were even stronger when participants stood and moved at the same time (50% reduction in mortality) (Figure 2B).


Figure 2. Effect of standing (A) or standing with movement (B) on the risk of premature mortality. The values represent the comparison of the mortality rate between the most sedentary people (Q1) and those who are more active (Q4). From Jain et al. (2020).

These results are interesting because many elderly people develop several chronic diseases during aging that weaken them and prevent them from participating in moderate to vigorous physical activities. According to the study, however, these people can improve their health simply by switching from sitting to standing as often as possible.

The transition from sitting to standing requires activating the muscles of the legs and abdominals to lift the body and keep it in balance. These efforts immediately increase blood pressure, heart rate and vascular tone, and the required energy expenditure improves blood vessel function and lipid and carbohydrate metabolism. Although these physiological adaptations are obviously not of the same order as during higher intensity exercise, the results of the study clearly show that they have a positive effect on health and that standing, even without moving, is far better than sitting or lying down for long periods of time.

In short, these results confirm that a sedentary lifestyle is an abnormal behaviour, completely ill adapted to human physiology, and that one should avoid sitting and being inactive for too long as much as possible, regardless of the type of activity performed. And this is true for all ages, young and old alike.

Can exercise protect against respiratory infections?

Can exercise protect against respiratory infections?

OVERVIEW

  • Participants in more than 14 studies were randomly separated into two groups: one group who did not exercise and one who exercised regularly and under supervision.
  • Exercise did not reduce the incidence of acute respiratory infections.
  • Exercise appears to reduce the severity of symptoms associated with episodes of acute respiratory infections.
  • According to several other studies, exercise can improve the immune response to viruses, bacteria and other antigens. Regular physical activity and frequent exercise may reduce or delay the aging of the immune system.

COVID-19 caused by infection with the SARS-CoV-2 virus particularly affects people who have certain risk factors (advanced age, male) or a comorbidity such as chronic respiratory disease, obesity, cardiovascular disease, diabetes, hypertension and cancer (see this article). A healthy lifestyle, including eating well, not smoking, consuming alcohol in moderation, and exercising regularly, is the best way to prevent many diseases such as diabetes, cancer and cardiovascular disease. Also, certain conditions are associated with a decrease in immune activity, for example, stress, diabetes and the deficiency of certain dietary compounds like vitamin D and zinc. By its action on these conditions, exercise is likely to influence our resistance to infections.

Can exercise prevent acute respiratory infections, including COVID-19? Researchers at the Cochrane Library recently updated a systematic review of the effect of exercise on the occurrence, severity and duration of acute respiratory infections.  The systematic review included 14 studies of 1377 healthy individuals aged 18 to 85 who were followed for a median period of 12 weeks. The participants were randomly separated into two groups: one who did not exercise and one who exercised regularly. In most cases, the exercise was supervised and was performed at least three times per week. The exercise sessions lasted 30 to 45 minutes and consisted of moderate intensity exercise such as walking, cycling, treadmill or a combination of these exercises. Exercise did not have a significant effect on biochemical parameters, quality of life or number of injuries.

Exercise did not decrease the number of acute respiratory infections (ARI) episodes, nor the proportion of participants who had at least one episode of ARI during the study, or the number of days with symptoms during each of these episodes. On the other hand, exercise was associated with a decrease in symptom severity in two studies and in the number of days with symptoms during the total study duration (4 studies). The study authors indicate that certainty about the data is low and that data from ongoing or future studies may impact their conclusions.

Exercise and the immune system
The immune system is very responsive to exercise, depending on both the duration and the intensity of effort (see this review article). Exercise causes multiple micro-injuries to the muscles, triggering a local and systemic inflammation reaction. During a moderate to high intensity exercise session lasting less than 60 minutes, the number of leukocytes (white blood cells) and several cytokines (proteins produced by the immune system to stimulate the proliferation of defence cells) increases rapidly in the bloodstream. The increase in the number of neutrophils (a type of white blood cell) often lasts for up to 6 hours after the end of the exercise session. This physiological response to stress caused by exercise is followed, during the recovery period, by a drop in the number of leukocytes in the bloodstream to a level below that measured at the start of the exercise session.

Although exercise transiently increases markers of inflammation, including several cytokines (interleukins, chemokines, interferons, and others), at rest, people who exercise regularly have lower blood levels of these pro-inflammatory proteins than people who exercise little or not at all or who are obese. Regular exercise therefore appears to moderate the inflammatory response and promote an anti-inflammatory environment in the body. The persistent increase in markers of inflammation (chronic inflammation) is linked to several conditions and diseases, including obesity, osteoarthritis, atherosclerosis and cardiovascular disease, chronic kidney disease, liver disease, metabolic syndrome, insulin resistance, type 2 diabetes, chronic obstructive pulmonary disease, dementia, depression, and various types of cancers. In short, exercise reduces the negative effects on the immune system of a recognized factor that is diabetes and the associated insulin resistance.

It is known that in severe forms of COVID-19 an exaggerated inflammatory reaction called “cytokine storm” destroys the cells of the pulmonary endothelium that allow oxygenation of the blood and body. Could regular exercise that provides a less inflammatory environment protect us in the event of a SARS-CoV-2 virus infection? This has not been demonstrated, but it is certainly a hypothesis that will need to be examined. Moreover, it seems that in the elderly, immune aging (also called “immunosenescence”) is associated with a decline in the cells that regulate the immune response. It is because of this decline that we observe an increase in immune disorders such as autoimmune diseases and an increase in cancers. However, the cytokine storm would be secondary to the lack of control by these cells. A healthy immune system would be less likely to lack these “regulatory” cells.

Suppression of immunity in athletes: Myth or reality?
In recent decades, an idea has taken root in the scientific literature according to which aerobic exercise, particularly if it is vigorous and of long duration, can interfere with immunocompetence, i.e. the body’s ability to produce a normal immune response in response to exposure to an antigen. This idea is now increasingly questioned and has even been called a myth by some researchers. This hypothesis dates from the early 20th century, when fatigue was believed to contribute to infections that caused pneumonia, but it was not until the 1980s–1990s that studies verified this assertion with professional and amateur athletes. In general, it is increasingly certain that it is “psychological” stress rather than physical stress that is immunosuppressive. For example, a study in the 1980s among medical students showed that immune capacity collapsed within 24 to 48 hours of exams. The “mental” stress on the eve of competitions could be the comparison. Exercise is a great stress reliever for most people.

One of the studies indicated that one third of the 150 runners participating in the 1982 Two Oceans ultramarathon (56 km) in South Africa reported symptoms of upper respiratory tract infection (runny nose, sore throat, sneezing) within two weeks of the race. The control group reported half as many symptoms of upper respiratory tract infection than runners. Similar results were obtained from athletes who participated in the Los Angeles Marathon (42 km) in 1987. Among the 2311 participants who completed the race and who had not reported symptoms of infection in the week before the race, 12.9% reported symptoms of infection in the week following the race. Only 2.2% of participants who dropped out of the race (for reasons other than health reasons) reported symptoms of infection in the week after the race. Another study conducted at the same time did not find an association between aerobic exercise and the risk of upper respiratory tract infection for runs over shorter distances, namely 5 km, 10 km, and 21 km (half marathon). This suggested that the risk of infections increases only after exercising for a very long period of time.

The major problem with these studies is that they are questionnaire-based and none of the infections reported by athletes were confirmed in the laboratory. In a 2007 study, researchers took swabs and tested athletes who reported symptoms of upper respiratory tract infection over a period of 5 months. Only 30% of the cases reported by the participants were associated with the presence of viruses, bacteria, or mycoplasmas. These results suggest that the symptoms experienced by athletes in previous studies may not have been caused by infection, but rather by other causes, including allergies, asthma, inflammation of the mucous membranes, or trauma to the epithelial cells of the airways caused by increased breathing or exposure to cold air.

The decrease in leukocytes in the bloodstream that is observed after exercise has led to the so-called “open window” hypothesis that intense exercise causes transient immunosuppression during the recovery period. During this “open window”, athletes would be more susceptible to viral and bacterial infections. Another hypothesis would be that of the recruitment of white blood cells to repair small damage to the muscles. Indeed, tissue damage, whether mechanical or infectious, causes the release of cytokines, which “call” the defences to “see what happens.” Yet, contrary to the studies cited above, recent studies indicate that exercise is rather associated with a reduction in the incidence of infections. There are as many epidemiological studies that show that regular exercise is associated with a reduction in infections as there are that show that regular exercise is associated with an increase in infections, but the former are less taken into account than the latter in the literature on exercise immunology.

For example, a Swedish study of 1509 men and women aged 20 to 60 found that high levels of physical activity are associated with a reduced incidence of upper respiratory tract infections. Studies of ultramarathon runners, one of the most taxing sports, have shown that these people report fewer days of absence from school or work due to illness compared to the general population. For example, the average number of sick days reported annually was 1.5 days in a study of 1212 ultramarathon runners and 2.8 days in another study of 489 161-km ultramarathon runners, while that year the number of sick days reported in the American population was 4.4 days. An often overlooked aspect of outdoor exercise is its vitamin D intake with exposure to the sun. The longer the routes, the greater the exposure and endogenous skin production of vitamin D. Vitamin D intake would be beneficial for the regulatory cells of the immune system.

In summary, contrary to the immunosuppression (“open window”) hypothesis, regular exercise can be beneficial for the immune system, or at least not harmful. Exercise does not increase the risk of diagnosed opportunistic infections. Exercise can improve the immune response to viruses, bacteria, and other antigens. Regular physical activity and frequent exercise may reduce or delay the aging of the immune system.

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.

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

Exercise on an empty stomach to burn more fat

Exercise on an empty stomach to burn more fat

OVERVIEW

  • Sedentary men did supervised exercise 3 times a week for 6 weeks after ingesting either a sugary drink or a sugar-free placebo drink.
  • Participants who exercised on an empty stomach “burned” twice as much fat as those who consumed a sugary drink before exercise sessions.
  • Participants who exercised on an empty stomach also saw their insulin sensitivity improve more than those who ingested calories before the exercise sessions.

It is now well established that exercise in all its forms improves overall health. In addition to increasing cardiorespiratory capacity, regular exercise improves insulin sensitivity and reduces insulin secretion after meals. However, each individual’s response to similar exercises is very variable: some people become fitter or lose more weight or stabilize their blood sugar more than others. One of the factors that could be important is the timing of meals and exercise sessions. Muscles use energy in the form of sugars and fats, which can come from the last meal or from reserves in the body when fasting. The accumulation of too much fat in the muscles is problematic for health, because the fat-engorged muscles do not respond well to insulin, a hormone that stimulates the absorption of glucose by muscle, adipose and liver cells. Therefore, excess fat in the muscles can contribute to insulin resistance, hyperglycemia and increased risks of type 2 diabetes and other metabolic imbalances.

In a randomized controlled study, an international team tested the effect of the timing of meals on the metabolic benefits associated with exercise. Thirty sedentary and overweight or obese men were divided into three groups (see figure below): a control group that continued to live normally and two other groups that did supervised exercise in the morning (treadmill running), three times a week for six weeks, without breakfast; the second group ingested a vanilla-flavoured drink containing 20% sugar two hours before each exercise session, whereas the third group ingested a vanilla-flavoured placebo beverage containing water and no calories. After each morning exercise session, participants in both groups drank the beverage they had not received prior to the session. This means that all the runners ingested the same number of calories and did the same amount of exercise, only the timing of calorie consumption differed, i.e. before or after the exercise session.

Figure. Protocol schematic for the training study.  Adapted from Edinburgh et al., 2019.

The study was randomized and controlled, so participants did not know what type of drink they ingested before and after exercising. 83% of participants reported that they could not detect differences between the sugary and placebo drinks or were unable to identify which beverage contained sugar. It should be noted that the sugar used here, maltodextrin (partially hydrolyzed starch), has a very low sweetening power and is therefore difficult to detect.

Blood samples and biopsies of a muscle located in the thigh (vastus lateralis) were taken before and after the intervention in order to measure different metabolites and proteins of interest. Glucose, glycerol, triglycerides, HDL and LDL cholesterol, insulin, C-peptide, and fatty acids were measured in the blood, and phospholipid composition, protein content involved in glucose transport, insulin signalling and lipid metabolism were measured in the vastus lateralis muscle samples.

Not surprisingly, the control group did not improve their physical fitness or insulin sensitivity during these six weeks. On the contrary, the other two groups who exercised saw their fitness improved and their waistline decreased, although only a few of the participants lost weight.

The most striking finding of the study was that participants who exercised on an empty stomach “burned” twice as much fat as those who consumed a sugary drink before the exercise session. Yet participants in both groups who exercised expended the same number of calories.

Participants who ran on an empty stomach also saw their insulin sensitivity improve further and their muscles synthesized greater amounts of certain proteins (AMP-activated protein kinase, an energy sensor, and the glucose transporter GLUT4) involved in the response of muscle cells to insulin and the use of sugars.

Studies on exercise and metabolic health will need to consider the timing of meals in the future. Since it is not possible for everyone to exercise in the morning after the night fasting period, it will be interesting to check if it is possible to obtain the same metabolic benefits after a shorter daytime fasting period, for example, when exercising in the early evening after skipping lunch. However, it should not be forgotten that any physical activity (walking, housework, etc.), performed at any time of the day, is beneficial for health.