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.16 February 2021
- 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.
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.
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.
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.15 March 2018
Updated May 23, 2018
Nitrates (NO3–) and nitrites (NO2–) are mostly known to the public as undesirable residues of the agri-food chain as they are associated with potentially carcinogenic effects. Yet, these molecules are naturally found in fruits and vegetables (nitrates) as well as in the human body (nitrates and nitrites) where they contribute to important physiological functions, particularly in the cardiovascular system. Moreover, it has now been proven that dietary nitrates can be beneficial to cardiovascular health and sports performance, as will be discussed below.
Nitrates and Nitrites: Dangerous or Harmless?
During the curing process used to transform meats into charcuterie (ham, sausages, bacon, etc.), nitrite salt is added to stabilize the colour and taste of meats and to prevent the development of pathogenic microorganisms. Nitrite salt is in fact very effective in preventing the proliferation of bacteria, including the formidable Clostridium botulinum, which produces a powerful toxin that causes botulism, a very serious, sometimes deadly, paralytic illness. Nitrates and nitrites themselves are not carcinogenic; rather, it is N-nitroso compounds, such as nitrosamines, produced by the reaction between nitrites and meat protein that are. The curing process promotes the formation of nitrosamines due to the abundance of added nitrites, proteins and myoglobin whose heme group accelerates the reaction. Cooking at high temperatures (deep-frying) greatly accelerates the formation of nitrosamines. Government regulations limit the quantity of nitrites used to cure meats and requires the addition of neutralizing agents (antioxidants) in certain products, for example bacon. Nitrates naturally present in food mainly come from fruits and vegetables, which contain antioxidants, such as vitamin C and polyphenols that prevent the formation of N-nitroso compounds.
Up until about twenty years ago, nitrates and nitrites found in the human body were considered inert final products of the metabolism of nitric oxide (NO), a gas that acts as a signalling molecule and contributes to the regulation of blood flow and several other physiological functions. In the presence of oxygen, nitric oxide is produced in the endothelial cells that line blood vessels through the oxidizing reaction of the amino acid L-arginine into NO and L-citrulline. Several medications used to treat heart disease increase the signalling pathway of NO, either by increasing its bioavailability or by inhibiting its degradation. The most well-known are organic nitrates (e.g. nitroglycerine). They act by releasing NO rapidly and induce non-specific dilatation of both arteries and veins, which improves blood flow. Other pharmacological agents are phosphodiesterase-5 inhibitors, which are used to treat pulmonary hypertension and erectile dysfunction (e.g. sildenafil, better known by the brand name Viagra). Moreover, inhibitors of the HMG reductase enzyme (statins) and of the angiotensin-converting enzyme indirectly increase the bioavailability of NO.
Since 2001, we know that endogenous nitrites are an important alternative source of NO, particularly when oxygen levels are low, as is the case with blood microcirculation (see Figure 1). At that time, it was thought that the intake of nitrates and nitrites from food sources had no effect on blood vessels, since it was not thought that this intake could increase the circulating concentration of nitrites. We now know that dietary nitrates are quickly absorbed in the small intestine, about 75% of nitrates are excreted by the kidneys, and what is left becomes highly concentrated in the salivary glands (10 times the plasma concentration). When nitrates are secreted in saliva, they are converted to nitrites by the commensal bacteria, then swallowed with the saliva and absorbed into intestinal circulation. The circulating nitrites can be transformed into nitric oxide by different enzymes (reductases).
Figure 1. Formation and recycling of nitrates (NO3–), nitrites (NO2–) and nitric oxide (NO). Adapted from Woessner et al., 2017. In the presence of oxygen, endothelial nitric oxide synthase (eNOS) catalyzes the oxidation of L-arginine to NO. NO can also be quickly oxidized into nitrites and nitrates. A secondary source of vascular NO is obtained through diet. Consumption of foods high in inorganic nitrates (green leafy vegetables, beetroot) has been shown to increase plasma nitrate concentration,which can be secreted in saliva and reduced to nitrite by commensal bacteria in the mouth. Nitrites can then be further reduced to NO (and other biologically active nitrogen oxides) via several mechanisms that are expedited under hypoxic conditions. Hence, although some of the circulating nitrates and nitrites are excreted in the kidneys, they can also be recycled back to NO.
Dietary Sources of Nitrates
About 85% of dietary nitrates (NO3–) come from vegetables, and the rest mostly from drinking water. Dietary nitrites (NO2–) mostly come from cured meats (charcuterie). Vegetables can be grouped into 3 categories according to their nitrate content (see Table I). Vegetables high in nitrates (>1000 mg/kg) belong to the Brassicaceae (arugula), Chenopodiaceae (beetroot, spinach), Asteraceae (lettuce), and Apiaceae (celery) families. Most commonly eaten vegetables have medium levels of nitrates (100–1000 mg/kg), whereas onions and tomatoes contain very little nitrates (<100 mg/kg). Juicing vegetables is a popular and convenient way to increase vegetable consumption, and several commercial juices are available on the market. Whereas the nitrate content of homemade fresh juice is negligible, it increases dramatically after two days at room temperature, but remains low if stored in the refrigerator at 4 °C. The conversion of nitrates to nitrites in juices prepared at home is due to the presence of bacterial enzymes (reductases), which is less problematic in commercially prepared juices since they are lightly pasteurized.
Table I. Nitrate content in vegetables and water. Source: Lidder & Webb, 2012.
*Note: To facilitate the selection of vegetables to build a diet, the authors recommend using “nitrate units” (1 unit = 1 mmol) to ensure sufficient nitrate intake in order to benefit from the hypotensive effects or to improve exercise performance, and also to avoid consuming more nitrates than recommended (4.2 units for an adult weighing 70 kg).
The acceptable daily intake (ADI) established by the European Food Safety Authority for nitrates is 3.7 mg/kg (0.06 mmol/kg), which corresponds to about 260 mg (4.2 mmol) daily for an adult weighing 70 kg. This ADI was established by dividing the maximum harmless dose for rats and dogs by 100. According to estimations, Europeans consume 31–185 mg of nitrates daily and 0–20 mg of nitrites daily. Based on the moderate recommendation to eat 400 g of a variety of fruits and vegetables per day, the dietary intake of nitrates is about 157 mg/day. Several countries currently recommend a diet high in nitrates for people with heart disease. The DASH diet (Dietary Approach to Stop Hypertension), for example, with its emphasis on fruits and vegetables, whole grains, lean meats (poultry, fish) and nuts, provides a significant level of nitrates. In a clinical study, the DASH diet (rich in fruits and vegetables) lowered blood pressure in subjects with hypertension almost as much as a monotherapy with antihypertensive medication. In fact, it has been suggested that the cardioprotective effects of fruits and vegetables observed in epidemiological studies are caused by the high nitrate content of green leafy vegetables.
The choice of fruits and vegetables eaten can have an important impact on the quantity of dietary nitrates. For example, it is estimated that a DASH diet that only includes fruits and vegetables with low nitrate levels would provide 174 mg of nitrates and 0.41 mg of nitrites, whereas choosing fruits and vegetables high in nitrates can provide up to 1222 mg of nitrates and 0.35 of nitrites. This estimation indicates that the dietary intake of nitrates can vary up to about 700%, according to dietary choices. An excessive intake of nitrates, which is very rare, can cause methemoglobinemia, a disease or intoxication where the level of methemoglobin (a type of hemoglobin that cannot bind oxygen) is too high. Infants (<3 years) are much more susceptible than older children and adults to this disease. In children it is sometimes called “blue baby syndrome.” In adults, this intoxication is rare because their diet cannot contain nitrates in high enough quantities to cause the disease. However, infants can get sick by consuming 200 g of spinach high in nitrates/per day. The American Academy of Pediatrics recommends not giving children foods (purees) containing vegetables (e.g. spinach, beetroot, green beans, carrots) before the age of three months.
A prospective study published in 2018 revealed an association between urinary nitrate and the prevalence of heart disease and the risk of mortality. A concentration of nitrates in urine that was 10 times higher was associated with a 33% decreased risk of hypertension and a 39% decreased risk of stroke. However, there was no association between the concentration of nitrates in urine and the risk of myocardial infarction. Moreover, a ten-fold increase of urinary nitrates was associated with a reduction in all-cause mortality (–37%) and a reduction in cardiovascular mortality (–56%). Despite concerns that nitrates can be converted to nitrites and N-nitrosamines and become carcinogenic, nitrates in urine were not associated with cancer prevalence or cancer mortality. Future studies should evaluate whether nitrate supplements can prevent or reduce the prevalence of heart disease and premature death.
The Effect of Nitrates on Blood Pressure
A study published in 2008 (randomized, placebo-controlled, crossover design) evaluated the effects of a diet high in nitrates on blood pressure in healthy, non-smoking and physically active participants. A diet high in nitrates led to a significant decrease in average blood pressure (3.2 mm Hg) and diastolic blood pressure (3.7 mm Hg), when compared to a diet low in nitrates. In this study, the daily dose of nitrate supplements taken corresponded to that normally contained in 150–250 g from vegetables high in nitrates, such as spinach, beetroot and lettuce. The authors note that the decrease in blood pressure observed in their study was similar to that observed in the DASH study in the healthy group that ate a diet rich in fruits and vegetables, when compared with the group that consumed few fruits and vegetables. In another study, drinking 500 ml of beetroot juice led to an even more significant decrease in systolic (~10.4 mm Hg) and diastolic (~8 mm Hg) blood pressure, when compared to the group that ingested the placebo (500 ml of water, crossover study). This effect was temporally correlated with the transient increase in plasma nitrite concentration. Interrupting the enterosalivary conversion cycle of nitrates to nitrites (by asking participants to spit out all their saliva for 3 hours after ingesting beetroot juice) completely prevented the increase of plasma nitrite concentration, and the decrease in blood pressure. This latter finding confirms that the decrease in blood pressure caused by the consumption of beetroot juice is due to the conversion of nitrates found in beetroot juice to nitrites.
Hypertension, Type 2 Diabetes, Hypercholesterolemia, Obesity
Even though the effect of nitrates on the decrease in blood pressure in healthy subjects was consistently reported in several studies, this is not always the case in studies among subjects with a chronic disease. In a British study of 68 subjects with hypertension, the blood pressure of those who drank 250 ml of beetroot juice daily for a month was lower by 8 mm Hg, compared to those who consumed beetroot juice depleted of nitrates (placebo). In a similar study, also among hypertensive subjects, no decrease in blood pressure was observed, even though the consumption of beetroot juice resulted in a considerable increase in plasma nitrite concentration. In another study of diabetics, there were no effects of dietary nitrites (beetroot juice) on blood pressure, endothelial function, and insulin sensitivity. However, supplementing the diet with beetroot juice significantly reduced systolic blood pressure of overweight or obese participants, aged 55 to 70, when compared to supplementation with blackcurrant juice, which was very low in nitrates. Finally, a study among 69 participants with hypercholesterolemia showed that the intake of dietary nitrates improved vascular function when compared to the group that received the placebo. The reason for variability of the results obtained in these clinical studies is unknown. Length of the treatment, medications used to manage hypertension, methods used to measure blood pressure, and differences between cohorts (e.g. age, BMI, diminished response to NO in certain diseases) are among possible explanatory factors.
A recent study (randomized, placebo-controlled, crossover design) shows that dietary nitrate supplementation (beetroot juice) increases exercise performance in people with heart failure with reduced ejection fraction. Here is a summary of the study and the main results. After consuming 140 ml of concentrated beetroot juice, the plasma nitrate and nitrite concentration of subjects increased on average by 15 times (1469%) and 2 times (105%), respectively, and the concentration of nitric oxide (a gas) in breath increased by 60%. This effect was not observed with the placebo, a beetroot juice previously depleted of nitrates and that could not be differentiated from the original beetroot juice (packaging, colour, texture, taste and smell) by the study subjects. Two hours after consuming the beetroot juice, subjects exercised for a few minutes on an ergometer stationary bike in a semi-reclined position at various intensities. Respiratory gas exchange was measured continuously. Heart rate, blood pressure and perceived fatigue were evaluated during the last 30 seconds of each phase. Consumption of nitrates had no effect on the ventilatory response, or exercise efficiency, heart rate, and blood pressure. However, compared to the placebo group, the subjects that ingested the beetroot juice were able to reach peak oxygen consumption (VO2 peak) that was higher by 8%, and increased, on average, their duration of effort to exhaustion by 7%. These findings suggest that dietary nitrate intake could be a valuable addition to the management of exercise intolerance among patients with heart failure with reduced ejection fraction.
Nitrates and Athletic Performance
Several studies have been conducted on the impact of nitrate supplementation on the performance of amateur and competitive athletes. In one study, 10 young men drank concentrated beetroot juice or a placebo and, after 2.5 hours (to coincide with the maximum concentration of circulating nitrites), did moderate to high intensity physical activity. When compared to the placebo group, consuming 70 ml of beetroot juice had no effect on athletic performance, but ingesting 140 ml or 280 ml of juice reduced oxygen consumption during moderate physical activity by 1.7% and 3.0%, whereas average time–to-task failure(at very high intensity) increased from 8 min 18 s to 9 min 30 s (14%) and from 8 min 13 s to 9 min 12 s (12%), respectively. Such an increase (12–14%) can seem enormous, but in fact translates to about a 1 to 2% reduction in time to complete a race, for example. In an elite sport, a 1% difference is considered very significant, reducing the time it takes to race a 1,500-metre distance by about 2 seconds and that of a 3,000-metre distance by about 4–5 seconds, for example. Other studies have shown a reduction in oxygen consumption (for the same effort) and an improvement in performance for walking, running, rowing, and cycling, through nitrate supplementation (beetroot juice or NaNO3–). A meta-analysis of 17 of these studies shows that nitrates give a small advantage in performance for time to exhaustion tests, and have a slight beneficial, but not statistically significant, effect on performance during time trials. Another meta-analysis, published in 2016, including 26 randomized, placebo-controlled studies, indicates that nitrate supplementation significantly reduces oxygen consumption for a given effort during a moderate to high intensity exercise in healthy individuals, but not in people with a chronic disease.
Beetroot juice and other supplements with high nitrate levels are obviously not a cure-all. It is better to adopt a global approach to stay healthy, i.e. exercise daily and follow a healthy diet (Mediterranean for example) and eat several servings of fruits and vegetables every day, including green vegetables rich in nitrates, fibre, minerals and vitamins.