Choosing the right sources of carbohydrates is essential for preventing cardiovascular disease

Choosing the right sources of carbohydrates is essential for preventing cardiovascular disease

OVERVIEW

  • Recent studies show that people who regularly consume foods containing low-quality carbohydrates (simple sugars, refined flours) have an increased risk of cardiovascular events and premature mortality.
  • Conversely, a high dietary intake of complex carbohydrates, such as resistant starches and dietary fibre, is associated with a lower risk of cardiovascular disease and improved overall health.
  • Favouring the regular consumption of foods rich in complex carbohydrates (whole grains, legumes, nuts, fruits and vegetables) while reducing that of foods containing simple carbohydrates (processed foods, sugary drinks, etc.) is therefore a simple way to improve cardiovascular health.

It is now well established that a good quality diet is essential for the prevention of cardiovascular disease and the maintenance of good health in general. This link is particularly well documented with regard to dietary fat: several epidemiological studies have indeed reported that too high a dietary intake of saturated fat increases LDL cholesterol levels, an important contributor to the development of atherosclerosis, and is associated with an increased risk of cardiovascular disease. As a result, most experts agree that we should limit the intake of foods containing significant amounts of saturated fat, such as red meat, and instead focus on sources of unsaturated fat, such as vegetable oils (especially extra virgin olive oil and those rich in omega-3s such as canola), as well as nuts, certain seeds (flax, chia, hemp) and fish (see our article on this subject). This roughly corresponds to the Mediterranean diet, a diet that has repeatedly been associated with a lower risk of several chronic diseases, especially cardiovascular disease.

On the carbohydrate side, the consensus that has emerged in recent years is to favour sources of complex carbohydrates such as whole grains, legumes and plants in general while reducing the intake of simple carbohydrates from refined flour and added sugars. Following this recommendation, however, can be much more difficult than one might think, as many available food products contain these low-quality carbohydrates, especially the entire range of ultra-processed products, which account for almost half of the calories consumed by the population. It is therefore very important to learn to distinguish between good and bad carbohydrates, especially since these nutrients are the main source of calories consumed daily by the majority of people. To achieve this, we believe it is useful to recall where carbohydrates come from and how industrial processing of foods can affect their properties and impacts on health.

Sugar polymers
All of the carbohydrates in our diet come from, in one way or another, plants. During the photosynthetic reaction, in addition to forming oxygen (O2) from carbon dioxide in the air (CO2), plants also simultaneously transform the energy contained in solar radiation into chemical energy, in the form of sugar:

6 CO2 + 12 H2O + light → C6H12O6 (glucose) + 6 O2 + 6 H2O

In the vast majority of cases, this sugar made by plants does not remain in this simple sugar form, but is rather used to make complex polymers, i.e., chains containing several hundred (and in some cases thousands) sugar molecules chemically bonded to one another. An important consequence of this arrangement is that the sugar contained in these complex carbohydrates is not immediately accessible and must be extracted by digestion before reaching the bloodstream and serving as a source of energy for the body’s cells. This prerequisite helps prevent sugar from entering the blood too rapidly, which would unbalance the control systems responsible for maintaining the concentration of this molecule at levels just sufficient enough to meet the needs of the body. And these levels are much lower than one might think; on average, the blood of a healthy person contains a maximum of 4 to 5 g of sugar in total, or barely the equivalent of a teaspoon. Dietary intake of complex carbohydrates therefore provides enough energy to support our metabolism, while avoiding excessive fluctuations in blood sugar that could lead to health problems.

Figure 1 illustrates the distribution of the two main types of sugar polymers in the plant cell: starches and fibres.

Figure 1. The physicochemical characteristics and physiological impacts of starches and dietary fibres from plant cells. Adapted from Gill et al. (2021).

Starches. Starches are glucose polymers that the plant stores as an energy reserve in granules (amyloplasts) located inside plant cells. This source of dietary carbohydrates has been part of the human diet since the dawn of time, as evidenced by the recent discovery of genes from bacteria specializing in the digestion of starches in the dental plaque of individuals of the genus Homo who lived more than 100,000 years ago. Even today, a very large number of plants commonly eaten are rich in starch, in particular tubers (potatoes, etc.), cereals (wheat, rice, barley, corn, etc.), pseudocereals (quinoa, chia, etc.), legumes, and fruits.

Digestion of the starches present in these plants releases units of glucose into the bloodstream and thus provides the energy necessary to support cell metabolism. However, several factors can influence the degree and speed of digestion of these starches (and the resulting rise in blood sugar). This is particularly the case with “resistant starches” which are not at all (or very little) digested during gastrointestinal transit and therefore remain intact until they reach the colon. Depending on the factors responsible for their resistance to digestion, three main types of these resistant starches (RS) can be identified:

  • RS-1: These starches are physically inaccessible for digestion because they are trapped inside unbroken plant cells, such as whole grains.
  • RS-2: The sensitivity of starches to digestion can also vary considerably depending on the source and the degree of organization of the glucose chains within the granules. For example, the most common form of starch in the plant kingdom is amylopectin (70–80% of total starch), a polymer made up of several branches of glucose chains. This branched structure increases the contact surface with enzymes specialized in the digestion of starches (amylases) and allows better extraction of the glucose units present in the polymer. The other constituent of starch, amylose, has a much more linear structure which reduces the efficiency of enzymes to extract the glucose present in the polymer. As a result, foods with a higher proportion of amylose are more resistant to breakdown, release less glucose, and therefore cause lower blood sugar levels. This is the case, for example, with legumes, which contain up to 50% of their starch in the form of amylose, which is much more than other commonly consumed sources of starches, such as tubers and grains.
  • RS-3: These resistant starches are formed when starch granules are heated and subsequently cooled. The resulting starch crystallization, a phenomenon called retrogradation, creates a rigid structure that protects the starch from digestive enzymes. Pasta salads, potato salads, and sushi rice are all examples of foods containing resistant starches of this type.

An immediate consequence of this resistance of digestion-resistant starches is that these glucose polymers can be considered dietary fibre from a functional point of view. This is important because, as discussed below, the fermentation of fibre by the hundreds of billions of bacteria (microbiota) present in the colon generates several metabolites that play extremely important roles in the maintenance of good health.

Dietary fibre. Fibres are polymers of glucose present in large quantities in the wall of plant cells where they play an important role in maintaining the structure and rigidity of plants. The structure of these fibres makes them completely resistant to digestion and the sugar they contain does not contribute to energy supply. Traditionally, there are two main types of dietary fibre, soluble and insoluble, each with its own physicochemical properties and physiological effects. Everyone has heard of insoluble fibre (in wheat bran, for example), which increases stool volume and speeds up gastrointestinal transit (the famous “regularity”). This mechanical role of insoluble fibres is important, but from a physiological point of view, it is mainly soluble fibres that deserve special attention because of the many positive effects they have on health.

By capturing water, these soluble fibres increase the viscosity of the digestive contents, which helps to reduce the absorption of sugar and dietary fats and thus to avoid excessive increases in blood sugar and blood lipid levels that can contribute to atherosclerosis (LDL cholesterol, triglycerides). The presence of soluble fibre also slows down gastric emptying and can therefore decrease calorie intake by increasing feelings of satiety. Finally, the bacterial community that resides in the colon (the microbiota) loves soluble fibres (and resistant starches), and this bacterial fermentation generates several bioactive substances, in particular the short chain fatty acids (SCFA) acetate, propionate and butyrate. Several studies carried out in recent years have shown that these molecules exert a myriad of positive effects on the body, whether by reducing chronic inflammation, improving insulin resistance, lowering blood pressure and the risk of cardiovascular disease, or promoting the establishment of a diversified microbiota, optimal for colon health (Table 1).

A compilation of many studies carried out in recent years (185 observational studies and 58 randomized trials, which equates to 135 million person-years) indicates that consuming 25 to 30 g of fibre per day seems optimal to benefit from these protective effects, approximately double the current average consumption.

Table 1. Main physiological effects of dietary fibre. Adapted from Barber (2020).

Physiological effectsBeneficial health impacts
MetabolismImproved insulin sensitivity
Reduced risk of type 2 diabetes
Improved blood sugar and lipid profile
Body weight control
Gut microbiotaPromotes a diversified microbiota
Production of short-chain fatty acids
Cardiovascular systemDecrease in chronic inflammation
Reduced risk of cardiovascular events
Reduction of cardiovascular mortality
Digestive systemDecreased risk of colorectal cancer

Overall, we can therefore see that the consumption of complex carbohydrates is optimal for our metabolism, not only because it ensures an adequate supply of energy in the form of sugar, without causing large fluctuations in blood sugar, but also because it provides the intestinal microbiota with the elements necessary for the production of metabolites essential for the prevention of several chronic diseases and for the maintenance of good health in general.

Modern sugars
The situation is quite different, however, for several sources of carbohydrates in modern diets, especially those found in processed industrial foods. Three main problems are associated with processing:

Simple sugars. Simple sugars (glucose, fructose, galactose, etc.) are the molecules responsible for the sweet taste: the interaction of these sugars with receptors present in the tongue sends a signal to the brain warning it of the presence of an energy source. The brain, which alone consumes no less than 120 g of sugar per day, loves sugar and responds positively to this information, which explains our innate attraction to foods with a sweet taste. On the other hand, since the vast majority of carbohydrates produced by plants are in the form of polymers (starches and fibres), simple sugars are actually quite rare in nature, being mainly found in fruits, vegetables such as beets, or even some grasses (sugar cane). It is therefore only with the industrial production of sugar from sugar cane and beets that consumers’ “sweet tooth” could be satisfied on a large scale and that simple sugars became commonly consumed. For example, data collected in the United States shows that between 1820 and 2016, the intake of simple sugars increased from 6 lb (2.7 kg) to 95 lb (43 kg) per person per year, an increase of about 15 times in just under 200 years (Figure 2).

 

 

Figure 2. Consumption of simple sugars in the United States between 1820 and 2016.  From Guyenet (2018).

Our metabolism is obviously not adapted to this very high intake of simple sugars, far beyond what is normally found in nature. Unlike the sugars found in complex carbohydrates, these simple sugars are absorbed very quickly into the bloodstream and cause very rapid and significant increases in blood sugar. Several studies have shown that people who frequently consume foods containing these simple sugars are more likely to suffer from obesity, type 2 diabetes and cardiovascular disease. For example, studies have found that consuming 2 servings of sugary drinks daily was associated with a 35% increase in the risk of coronary heart disease. When the amount of added sugars consumed represents 25% of daily calories, the risk of heart disease nearly triples. Factors that contribute to this detrimental effect of simple sugars on cardiovascular health include increased blood pressure and triglyceride levels, lowered HDL cholesterol, and increased LDL cholesterol (specifically small, very dense LDLs, which are more harmful to the arteries), as well as an increase in inflammation and oxidative stress.

It is therefore necessary to restrict as much as possible the intake of simple sugars, which should not exceed 10% of the daily energy intake according to the World Health Organization. For the average adult who consumes 2,000 calories per day, that’s just 200 calories, or about 12 teaspoons of sugar or the equivalent of a single can of soft drink.

Refined flour.  Cereals are a major source of carbohydrates (and calories) in most food cultures around the world. When they are in whole form, i.e., they retain the outer shell rich in fibre and the germ containing several vitamins and minerals, cereals are a source of complex carbohydrates (starches) of high quality and beneficial to health. This positive impact of whole grains is well illustrated by the reduced risk of coronary heart disease and mortality observed in a large number of population studies. For example, recent meta-analyses have shown that the consumption of about 50 g of whole grains perday is associated with a 22–30% reduction in cardiovascular disease mortality, a 14–18% reduction in cancer-relatedmortality, and a 19–22% reduction in total mortality.

On the other hand, these positive effects are completely eliminated when the grains are refined with modern industrial metal mills to produce the flour used in the manufacture of a very large number of commonly consumed products (breads, pastries, pasta, desserts, etc.). By removing the outer shell of the grain and its germ, this process improves the texture and shelf life of the flour (the unsaturated fatty acids in the germ are sensitive to rancidity), but at the cost of the almost total elimination of fibres and a marked depletion of several nutrients (minerals, vitamins, unsaturated fatty acids, etc.). Refined flours therefore essentially only contain sugar in the form of starch, this sugar being much easier to assimilate due to the absence of fibres that normally slow down the digestion of starch and the absorption of released sugar (Figure 3).

Figure 3. Schematic representation of a whole and refined grain of wheat.

Fibre deficiency. Fortification processes partially compensate for the losses of certain nutrients (e.g., folic acid) that occur during the refining of cereal grains. On the other hand, the loss of fibre during grain refining is irreversible and is directly responsible for one of the most serious modern dietary deficiencies given the many positive effects of fibre on the prevention of several chronic diseases.

Poor-quality carbohydrates
Low-quality carbohydrate sources with a negative impact on health are therefore foods containing a high amount of simple sugars, having a higher content of refined grains than whole grains, or containing a low amount of fibre (or several of these characteristics simultaneously). A common way to describe these poor-quality carbohydrates is to compare the rise in blood sugar they produce to that of pure glucose, called the glycemic index (GI) (see box). The consumption of food with a high glycemic index causes a rapid and dramatic rise in blood sugar levels, which causes the pancreas to secrete a large amount of insulin to get glucose into the cells. This hyperinsulinemia can cause glucose to drop to too low levels, and the resulting hypoglycemia can ironically stimulate appetite, despite ingesting a large amount of sugar a few hours earlier. Conversely, a food with a low glycemic index produces lower, but sustained, blood sugar levels, which reduces the demand for insulin and helps prevent the fluctuations in blood glucose levels often seen with foods with a high glycemic index. Potatoes, breakfast cereals, white bread, and pastries are all examples of high glycemic index foods, while legumes, vegetables, and nuts are conversely foods with a low glycemic index.

Glycemic index and load
The glycemic index (GI) is calculated by comparing the increase in blood sugar levels produced by the absorption of a given food with that of pure glucose. For example, a food that has a glycemic index of 50 (lentils, for example) produces a blood sugar half as important as glucose (which has a glycemic index of 100). As a general rule, values below 50 are considered to correspond to a low GI, while those above 70 are considered high. The glycemic index, however, does not take into account the amount of carbohydrate in foods, so it is often more appropriate to use the concept of glycemic load (GL). For example, although watermelon and breakfast cereals both have high GIs (75), the low-carbohydrate content of melon (11 g per 100 g) equates to a glycemic load of 8, while 26 g of carbohydrates present in breakfast cereals result in a load of 22, which is three times more. GLs ≥ 20 are considered high, intermediate when between 11 and 19, and low when ≤ 10.

PURE study
Results from the PURE (Prospective Urban and Rural Epidemiology) epidemiological study conducted by Canadian cardiologist Salim Yusuf have confirmed the link between low-quality carbohydrates and the risk of cardiovascular disease. In the first of these studies, published in the prestigious New England Journal of Medicine, researchers examined the association between the glycemic index and the total glycemic load of the diet and the incidence of major cardiovascular events (heart attack, stroke, sudden death, heart failure) in more than 130,000 participants aged 35 to 70, spread across all five continents. The study finds that a diet with a high glycemic index is associated with a significant (25%) increase in the risk of having a major cardiovascular event in people without cardiovascular disease, an increase that reaches 51% in those with pre-existing cardiovascular disease (Figure 4). A similar trend is observed for the glycemic load, but in the latter case, the increased risk seems to affect only those with cardiovascular disease at the start of the study.

Figure 4. Comparison of the risk of cardiovascular events according to the glycemic index or the glycemic load of the diet of healthy people (blue) or with a history of cardiovascular disease (red). The median glycemic index values were 76 for quintile 1 and 91 for quintile 5. For glycemic load, the mean values were 136 g of carbohydrates per day for Q1 and 468 g per day for Q5. Note that the increased risk of cardiovascular events associated with a high glycemic index or load is primarily seen in participants with pre-existing cardiovascular disease. From Jenkins et al. (2021).

The impact of the glycemic index appears to be particularly pronounced in overweight people (Figure 5). Thus, while the increase in the risk of major cardiovascular events is 14% in thin people with a BMI less than 25, it reaches 38% in those who are overweight (BMI over 25).

 

Figure 5. Impact of overweight on the increased risk of cardiovascular events related to the glycemic index of the diet. The values shown represent the increased risk of cardiovascular events observed for each category (quintiles 2 to 5) of the glycemic index compared to the category with the lowest index (quintile 1). The median values of the glycemic indices were 76 for quintile 1; 81 for quintile 2; 86 for quintile 3; 89 for quintile 4; and 91 for quintile 5. Taken from Jenkins et al. (2021).

This result is not so surprising, since it has long been known that excess fat disrupts sugar metabolism, especially by producing insulin resistance. A diet with a high glycemic index therefore exacerbates the rise in postprandial blood sugar already in place due to excess weight, which leads to a greater increase in the risk of cardiovascular disease. The message to be drawn from this study is therefore very clear: a diet containing too many easily assimilated sugars, as measured using the glycemic index, is associated with a significant increase in the risk of suffering a major cardiovascular event. The risk of these events is particularly pronounced for people with less than optimal health, either due to the presence of excess fat or pre-existing cardiovascular disease (or both). Reducing the glycemic index of the diet by consuming more foods containing complex carbohydrates (fruits, vegetables, legumes, nuts) and fewer products containing added sugars or refined flour is therefore an essential prerequisite for preventing the development of cardiovascular disease.

Refined flours
Another part of the PURE study looked more specifically at refined flours as a source of easily assimilated sugars that can abnormally increase blood sugar levels and increase the risk of cardiovascular disease. Researchers observed that a high intake (350 g per day, or 7 servings) of products containing refined flours (white bread, breakfast cereals, cookies, crackers, pastries) was associated with a 33% increase in the risk of coronary heart disease, 47% in the risk of stroke, and 27% in the risk of premature death. These observations therefore confirm the negative impact of refined flours on health and the importance of including as much as possible foods containing whole grains in the diet. The preventive potential of this simple dietary change is enormous since the consumption of whole grains remains extremely low, with the majority of the population of industrialized countries consuming less than 1 serving of whole grains daily, well below the recommended minimum (half of all grain products consumed, or about 5 servings per day).

Wholemeal breads are still a great way to boost the whole-grain intake. However, special attention must be paid to the list of ingredients. In Canada, the law allows up to 5% of the grain to be removed when making whole wheat flour, and the part removed contains most of the germ and a fraction of the bran (fibres). This type of bread is superior to white bread, but it is preferable to choose products made from whole-grain flour which contains all the parts of the grain. Note also that multigrain breads (7-14 grains) always contain 80% wheat flour and a maximum of 20% of a mixture of other grains (otherwise the bread does not rise), so the number of grains does not matter, but what does matter is whether the flour is whole wheat or ideally integral, which is not always the case.

In short, a simple way to reduce the risk of cardiovascular events and improve health in general is to replace as much as possible the intake of foods rich in simple sugars and refined flour with plant-based foods containing complex carbohydrates. In addition to carbohydrates, this simple change alone will influence the nature of the proteins and lipids ingested as well as, at the same time, all the phenomena that promote the appearance and progression of atherosclerotic plaques.

Omega-3 fatty acid supplements are ineffective for the prevention of cardiovascular disease

Omega-3 fatty acid supplements are ineffective for the prevention of cardiovascular disease

OVERVIEW

  • The VITAL study in participants who did not have cardiovascular disease and the ASCEND study in diabetic patients did not show a beneficial effect of omega-3 fatty acid supplements on cardiovascular health.
  • The REDUCE-IT study reported a beneficial effect of an omega-3 fatty acid supplement (Vascepa®), while the STRENGTH study reported no effect of another supplement (Epanova®).
  • The divergent results of the REDUCE-IT and STRENGTH studies have raised scientific controversy, mainly about the questionable use of mineral oil as a neutral placebo in the REDUCE-IT study.
  • Overall, the results of the studies lead to the conclusion that omega-3 fatty acid supplements are ineffective in preventing cardiovascular disease, in primary prevention and most likely also in secondary prevention.

Consuming fish on a regular basis (1–2 times per week) is associated with a reduced risk of death from coronary heart disease (see these meta-analyses here and here). In addition, favourable associations between fish consumption and the risks of type 2 diabetes, stroke, dementia, Alzheimer’s disease and cognitive decline have also been identified.

A large number of studies have suggested that it is mainly omega-3 (O-3) fatty acids, a type of very long-chain polyunsaturated fatty acid found in high amounts in several fish species, that are the cause of the positive health effects of eating fish and other seafood. For example, a meta-analysis of 17 prospective studies published in 2021 indicates that the risk of dying prematurely was significantly lower (15–18%) in participants who had the most circulating O-3s, compared to those who had the least. In addition, favourable associations of the same magnitude were observed for cardiovascular and cancer-related mortality.

Since eating fish is associated with better cardiovascular health, why not isolate the “active ingredient”, i.e. the omega-3 fatty acids it contains and make supplements with them? This seemed like a great idea; the same pharmacological approach has been applied successfully to a host of plants, fungi and microorganisms, which has made it possible to create drugs. One such example is aspirin, a derivative of salicylic acid found in the bark of certain tree species, quinine extracted from the cinchona shrub (antimalarial), digitoxin extracted from purple digitalis (treatment of heart problems), paclitaxel from yew (anticancer), etc.

Are marine O-3 supplements just as or even more effective than the whole food from which they are extracted? Several randomized controlled studies (RCTs) have been carried out in recent years to try to prove the effectiveness of O-3s. Meta-analyses of RCTs (see here and here) indicate that O-3 supplements (EPA and DHA) have little or no effect in primary prevention, i.e. on the risk of developing cardiovascular disease or dying prematurely from cardiovascular disease or any other cause. In contrast, data from some studies indicated that O-3 supplements may have beneficial effects in secondary prevention, i.e. in people with cardiovascular disease.

In order to obtain a higher level of evidence, several large, well-planned and controlled studies have been carried out recently: ASCEND, VITAL, STRENGTH and REDUCE-IT. The VITAL study (VITamin D and omegA-3 TriaL) in 25,871 participants who did not have cardiovascular disease and the ASCEND study (A Study of Cardiovascular Events in Diabetes) in 15,480 diabetic patients did not demonstrate any beneficial effects of O-3 supplements on cardiovascular health.

The results of the REDUCE-IT (REDUction of Cardiovascular Events with Icosapent ethyl-Intervention Trial) and STRENGTH (Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia) studies were then published. The results of these studies were eagerly anticipated since they tested the effect of O-3 supplements on major strokes at high doses (3000–4000 mg O-3/day) in patients at risk treated with a statin to lower blood cholesterol, but who had high triglyceride levels.

The results of these two studies are divergent, which has raised scientific controversy. The REDUCE-IT study reported a significant reduction of 25% in the number of cardiovascular events in the group of patients who took daily O-3 supplementation (Vascepa®; ethyl-EPA), compared to the group of patients who took a placebo (mineral oil). The STRENGTH study reported an absence of effect of O-3 supplements (Epanova®; a mixture of EPA and DHA in the form of carboxylic acids) on major cardiovascular events in patients treated with a statin, compared to the group of patients who took a corn oil placebo.

Several hypotheses have been proposed to explain the different results between the two large studies. One of them is that the mineral oil used as a placebo in the REDUCE-IT study may have caused adverse effects that would have led to a false positive effect of the O-3 supplement. Indeed, mineral oil is not a neutral placebo since it caused an average increase of 37% of C-reactive protein (CRP), a marker of systemic inflammation in the control group, as well as a 7.4% increase in LDL cholesterol and 6.7% in apolipoprotein B compared to the group that took Vascepa. These three biomarkers are associated with an increased risk of cardiovascular events.

Two other hypotheses could explain the difference between the two studies. It is possible that the moderately higher plasma levels of EPA obtained in the REDUCE-IT study could be the cause of the beneficial effects seen in this study, or that the DHA used in combination with EPA in the STRENGTH study may have counteracted the beneficial effects of EPA.

To test these two hypotheses, the researchers responsible for the STRENGTH study performed post-hoc analyses of the data collected during their clinical trial. Patients were classified according to their plasma EPA level after 12 months of daily supplementation with O-3. Thus, in the first tertile, patients had an average plasma EPA concentration of 30 µg/mL, those in the second tertile: 90 µg/mL, and those in the third tertile: 151 µg/mL. The mean plasma concentration of EPA in the third tertile (151 µg/mL) is comparable to that reported in the REDUCE-IT study (144 µg/mL). Analyses show that there was no association between the plasma concentration of EPA or DHA and the number of major cardiovascular events. The authors conclude that there is no benefit to taking O-3 supplements for secondary prevention, but they suggest that more studies should be done in the future to compare mineral oil and corn oil as placebos and also to compare different formulations of omega-3 fatty acids.

Overall, the results of recent studies lead to the conclusion that O-3 supplements are ineffective in preventing cardiovascular disease, in primary prevention and most likely also in secondary prevention. It should be noted that, taken in large amounts, O-3 supplements can have unwanted effects. In fact, in both the STRENGTH and REDUCE-IT studies, the incidence of atrial fibrillation was significantly higher with the use of O-3 supplements. In addition, bleeding was more common in patients who took ethyl-EPA (Vascepa®) in the REDUCE-IT study than in patients who took the placebo. It therefore seems safer to eat fish once or twice a week to maintain good health than to take ineffective and expensive supplements.

Reducing calorie intake by eating more plants

Reducing calorie intake by eating more plants

OVERVIEW

  • Twenty volunteers were fed a low-fat or low-carbohydrate diet in turn for two weeks.
  • Participants on the low-fat diet consumed an average of nearly 700 fewer calories per day than with the low-carbohydrate diet, a decrease correlated with a greater loss of body fat.
  • Compared to the low-carbohydrate diet, the low-fat diet also led to lower cholesterol levels, reduced chronic inflammation, and lowered heart rate and blood pressure.
  • Overall, these results suggest that a diet mainly composed of plants and low in fat is optimal for cardiovascular health, both for its superiority in reducing calorie intake and for its positive impact on several risk factors for cardiovascular disease.

It is estimated that there are currently around 2 billion overweight people in the world, including 600 million who are obese. These statistics are truly alarming because it is clearly established that excess fat promotes the development of several diseases that decrease healthy life expectancy, including cardiovascular disease, type 2 diabetes, and several types of cancer. Identifying the factors responsible for this high prevalence of overweight and the possible ways to reverse this trend as quickly as possible is therefore essential to improve the health of the population and avoid unsustainable pressures on public health systems in the near future.

Energy imbalance
The root cause of overweight, and obesity in particular, is a calorie intake that exceeds the body’s energy needs. To lose weight, therefore, it is essentially a matter of restoring the balance between the calories ingested and the calories expended.

It might seem simple in theory, but in practice most people find it extremely difficult to lose weight. On the one hand, it is much easier to gain weight than to lose weight. During evolution, we have had to deal with periods of prolonged food shortages (and even starvation, in some cases) and our metabolism has adapted to these deficiencies by becoming extremely efficient at accumulating and conserving energy in the form of fat. On the other hand, the environment in which we currently live strongly encourages overconsumption of food. We are literally overwhelmed by an endless variety of attractive food products, which are often inexpensive, easily accessible, and promoted by very aggressive marketing that encourages their consumption. The current epidemic of overweight and obesity thus reflects our biological predisposition to accumulate reserves in the form of fat, a predisposition that is exacerbated by the obesogenic environment that surrounds us.

Eating less to restore balance
The body’s innate tendency to keep energy stored in reserve as fat makes it extremely difficult to lose weight by “burning” those excess calories by increasing the level of physical activity. For example, a person who eats a simple piece of sugar pie (400 calories) will have to walk about 6.5 km to completely burn off those calories, which, of course, is difficult to do on a daily basis. This does not mean that exercise is completely useless for weight loss. Research in recent years shows that exercise can specifically target certain fat stores, especially in the abdominal area. Studies also show that regular physical activity is very important for long-term maintenance of the weight lost from a low-calorie diet. However, there is no doubt that it is first and foremost the calories consumed that are the determining factors in weight gain. Moreover, contrary to what one might think, levels of physical activity have hardly changed for the last thirty years in industrialized countries, and the phenomenal increase in the number of overweight people is therefore mainly a consequence of overconsumption of food. Exercise is essential for the prevention of all chronic diseases and for the maintenance of general good health, but its role in weight loss is relatively minor. For overweight people, the only realistic way to lose weight significantly, and especially to maintain these losses over prolonged periods, is thus to reduce calorie intake.

Less sugar or less fat?
How do we get there? First, it’s important to realize that the surge in the number of overweight people has coincided with a greater availability of foods high in sugar or fat (and sometimes both). All countries in the world, without exception, that have adopted this type of diet have seen their overweight rates skyrocket, so it is likely that this change in eating habits plays a major role in the current obesity epidemic.

However, the respective contributions of sugar and fat to this increase in caloric intake and overweight are still the subjectof vigorous debate:

1) On the one hand, it has been proposed that foods high in fat are particularly obesogenic, since fats are twice as high in calories as carbohydrates, are less effective in causing a feeling of satiety, and improve the organoleptic properties of foods, which generally encourages (often unconscious) overconsumption of food. Therefore, the best way to avoid overeating and becoming overweight would be to reduce the total fat intake (especially saturated fat due to its negative impact on LDL-cholesterol levels) and replace it with complex carbohydrates (vegetables, legumes, whole-grain cereals). This is colloquially called the low-fat approach, advocated for example by the Ornish diet.

2) On the other hand, the exact opposite is proposed, i.e. that it would be mainly carbohydrates that would contribute to overconsumption of food and to the increase in the incidence of obesity. According to this model, carbohydrates in foods in the form of free sugars or refined flours cause insulin levels to rise markedly, causing massive energy storage in adipose tissue. As a result, fewer calories remain available in the circulation for use by the rest of the body, causing increased appetite and overeating to compensate for this lack. In other words, it wouldn’t be because we eat too much that we get fat, but rather because we are too fat we eat too much.

3) By preventing excessive fluctuations in insulin levels, a diet low in carbohydrates would thus limit the anabolic effect of this hormone and, therefore, prevent overeating and the accumulation of excess fat.

Less fat on the menu, fewer calories ingested
To compare the impact of low-carb and low-fat diets on calorie intake, Dr. Kevin Hall’s group (NIH) recruited 20 volunteers who were fed each of these diets in turn for two weeks. The strength of this type of cross-study is that each participant consumes both types of diets and that their effects can therefore be compared directly on the same person.

As shown in Figure 1, the two diets studied were completely opposite of each other, with 75% of the calories in the low-fat (LF) diet coming from carbohydrates versus only 10% from fat, while in the low-carb (LC) diet, 75% of calories were in the form of fat, compared to only 10% from carbohydrates. The LF diet under study consisted exclusively of foods of plant origin (fruits, vegetables, legumes, root vegetables, soy products, whole grains, etc.), while the LC diet contained mainly (82%) animal foods (meat, poultry, fish, eggs, dairy products).

Figure 1. Comparison of the amounts of carbohydrates, fats and proteins present in the low-carbohydrate (LC) and low-fat (LF) diets consumed by study participants. Adapted from Hall et al. (2021).

The study shows that there is indeed a big difference between the two types of diets in the number of calories consumed by participants (Figure 2). Over a two-week period, participants who ate an LF (low-fat) diet consumed an average of nearly 700 calories (kcal) per day less than an LC (low-carbohydrate) diet. This difference in calorie intake is observed for all meals, both at breakfast (240 calories less for the LF diet), at lunch (143 calories less), at dinner (195 calories less), and during snacks taken between meals (128 calories less). This decrease is not caused by a difference in the appreciation of the two diets by the participants, as parallel analyses did not find any difference in the level of appetite of the participants, nor in the degree of satiety and satisfaction generated by the consumption of either diet. However, the LF diet was composed exclusively of plant-based foods and therefore much richer in non-digestible fibres (60 g per day compared to only 20 g for the LC diet), which greatly reduce the energy density of meals (quantity of calories per g of food) compared to the high-fat LC diet. It is therefore very likely that this difference in energy density contributes to the lower calorie intake observed for the low-fat diet.

Overall, these results indicate that a diet consisting of plants, and thus low in fat and high in complex carbohydrates, is more effective than a diet consisting mainly of animal products, high in fat and low in carbohydrates, to limit calorie intake.

Figure 2. Comparison of the daily calorie intake of participants on a low-carbohydrate (LC) or low-fat (LF) diet. From Hall et al. (2021).

Weight loss
Despite the significant difference in calorie intake observed between the two diets, their respective impact on short-term weight loss is more nuanced. At first glance, the LC diet appeared to be more effective than the LF diet in causing rapid weight loss, with about 1 kg lost on average in the first week and almost 2 kg after two weeks, compared to only 1 kg after two weeks of the LF diet (Figure 3). However, further analysis revealed that the weight loss caused by the LC diet was mainly in the form of lean mass (protein, water, glycogen), while this diet had no significant impact on fat loss during this period. Conversely, the LF diet had no effect on this lean body mass, but did cause a significant decrease in body fat, to around 1 kg after two weeks. In other words, only the LF diet caused a loss of body fat during the study period, which strongly suggests that the decrease in calorie intake made possible by this type of diet may facilitate the maintenance of astable body weight and could even promote weight loss in overweight people.

Figure 3. Comparison of changes in body weight (top), lean mass (middle), and body fat (bottom) caused by low-carbohydrate and low-fat diets. From Hall et al. (2021).

Cardiovascular risk factors
In addition to promoting lower calorie intake and fat loss, the LF diet also appears to be superior to the LC diet in terms of its impact on several cardiovascular risk factors (Table 1):

Cholesterol. It is well established that LDL cholesterol levels increase in response to a high intake of saturated fat (see our article on the issue). It is therefore not surprising that the LF diet, which contains only 2% of all calories as saturated fat, causes a significant decrease in cholesterol, both in terms of total cholesterol and LDL cholesterol. At first glance, the high-fat LC diet (containing 30% of the daily calorie intake as saturated fat) does not appear to have a major effect on LDL cholesterol; however, it should be noted that this diet significantly modifies the distribution of LDL cholesterol particles, in particular with a significant increase in small and dense LDL particles. Several studies have reported that these small, dense LDL particles infiltrate artery walls more easily and also appear to oxidize more easily, two key events in the development and progression of atherosclerosis. In sum, just two weeks of a high-fat LC diet was enough to significantly (and negatively) alter the atherogenic profile of participants, which may raise doubts about the long-term effects of this type of diet on cardiovascular health.

Table 1. Variations in certain risk factors for cardiovascular disease following a diet low in carbohydrates or low in fat. From Hall et al. (2021).

Branched-chain amino acids. Several recent studies have shown a very clear association between blood levels of branched-chain amino acids (leucine, isoleucine and valine) and an increased risk of metabolic syndrome and type 2 diabetes, two very important risk factors for cardiovascular diseases. In this sense, it is very interesting to note that the levels of these amino acids are almost twice as high after two weeks of the LC diet compared to the LF diet, suggesting a positive effect of a diet rich in plants and poor in fats in the prevention of these disorders.

Inflammation. Chronic inflammation is actively involved in the formation and progression of plaques that form on the lining of the arteries and can lead to the development of cardiovascular events such as myocardial infarction and stroke. Clinically, this level of inflammation is often determined by measuring levels of high-sensitivity C-reactive protein (hsCRP), a protein made by the liver and released into the blood in response to inflammatory conditions. As shown in Table 1, the LF diet significantly decreases the levels of this inflammatory marker, another positive effect that argues in favour of a plant-rich diet for the prevention of cardiovascular disease.

In addition to these laboratory data, the researchers noted that participants who were fed the LF diet had a slower heart rate (73 vs. 77 beats/min) as well as lower blood pressure (112/67 vs. 116/69 mm Hg) than observed following the LC diet. In the latter case, this difference could be related, at least in part, to the much higher sodium consumption in the LC diet compared to the LF diet (5938 vs. 3725 mg/day).

All of these results confirm the superiority of a diet mainly composed of plants on all the factors involved in cardiovascular health, whether in terms of lipid profile, chronic inflammation, or adequate control of calorie intake necessary to maintain body weight.

A new metabolite derived from the microbiota linked to cardiovascular disease

A new metabolite derived from the microbiota linked to cardiovascular disease

OVERVIEW

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

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

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

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

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

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

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

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

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

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

The importance of maintaining normal cholesterol levels, even at a young age

The importance of maintaining normal cholesterol levels, even at a young age

OVERVIEW

  • A study of 400,000 middle-aged people (average age 51) shows that above-normal cholesterol levels are associated with a significant increase in the risk of cardiovascular disease in the decades that follow.
  • This risk is particularly high in people who were under the age of 45 at the start of the study, suggesting that prolonged exposure to excess cholesterol plays a major role in increasing the risk of cardiovascular disease.
  • Reducing cholesterol levels as early as possible, from early adulthood, through lifestyle changes (diet, exercise) can therefore limit the long-term exposure of blood vessels to atherogenic particles and thus reduce the cardiovascular events during aging.

It is now well established that high levels of cholesterol in the bloodstream promote the development of atherosclerosis and thereby increase the risk of cardiovascular events such as myocardial infarction and stroke. It is for this reason that the measurement of cholesterol has been part of the basic blood test for more than 30 years and that a deviation from normal values is generally considered a risk factor for cardiovascular disease.

Remember that cholesterol is insoluble in water and must be combined with lipoproteins to circulate in the blood. Routinely, the way to determine cholesterol levels is to measure all of these lipoproteins (what is called total cholesterol) and then distinguish two main types:

  1. HDL cholesterol, colloquially known as “good cholesterol” because it is involved in the elimination of cholesterol and therefore has a positive effect on cardiovascular health;
  2. LDL cholesterol, the “bad” cholesterol because of its involvement in the formation of atherosclerotic plaques that increase the risk of heart attack and stroke.

LDL cholesterol is difficult to measure directly and its concentration is rather calculated from the values determined for total cholesterol, HDL cholesterol and triglycerides using a mathematical formula:

[LDL cholesterol] = [Total cholesterol] – [HDL cholesterol] – [Triglycerides] / 2.2

However, this method has its limits, among other things because a large proportion of cholesterol can be transported by other types of lipoproteins and therefore does not appear in the calculation. However, it is very easy to measure all of these lipoproteins by simply subtracting HDL cholesterol from total cholesterol:

[Total cholesterol] – [HDL cholesterol] = [Non-HDL cholesterol]

This calculation makes it possible to obtain the concentration of what is called “non-HDL” cholesterol, i.e. all of the atherogenic lipoproteins [VLDL, IDL, LDL and Lp(a)] that are deposited at the level of the wall of the arteries and form atheromatous plaques that significantly increase the risk of cardiovascular problems. Although clinicians are more familiar with LDL cholesterol measurement, cardiology associations, including the Canadian Cardiovascular Society, now recommend that non-HDL cholesterol also be used as an alternative marker for risk assessment in adults.

Short-term risks
The decision to initiate cholesterol-lowering therapy depends on the patient’s risk of experiencing a cardiovascular event in the next 10 years. To estimate this risk, clinicians use what is called a “risk score” (the Framingham risk score, for example), a calculation based primarily on the patient’s age, history of cardiovascular disease, family history and certain clinical values ​​(blood pressure, blood sugar, cholesterol). For people who are at high risk of cardiovascular disease, especially those who have suffered a coronary event, there is no hesitation: all patients must be taken care of quickly, regardless of LDL or non-HDL cholesterol levels. Several clinical studies have shown that in this population, the main class of cholesterol-lowering drugs (statins) helps prevent recurrences and mortality, with an absolute risk reduction of around 4%. As a result, these drugs are now part of the standard therapeutic arsenal to treat anyone who has survived a coronary event or who has stable coronary heart disease.

The same goes for people with familial hypercholesterolemia (HF), a genetic disorder that exposes individuals to high levels of LDL cholesterol from birth and to a high risk for cardiovascular events before they even turn 40. A study has just recently shown that HF children who were treated with statins at an early age had a much lower incidence of cardiovascular events in adulthood (1% vs. 26%) than their parents who had not been treated early with statins.

Long-term risks
However, the decision to treat high cholesterol is much more difficult for people who do not have these risk factors. Indeed, when the risk of cardiovascular events over the next 10 years is low or moderate, the guidelines tolerate much higher LDL and non-HDL cholesterol levels than in people at risk: for example, when we usually try to keep LDL cholesterol below 2 mmol/L for people at high risk, a threshold twice as high (5 mmol/L) is proposed before treating people at low risk (Table 1). In this population, there is therefore a great deal of room for maneuver in deciding whether or not to start pharmacological treatment or to fundamentally change lifestyle habits (diet, exercise) to normalize these cholesterol levels.

Table 1. Canadian Cardiovascular Society guidelines for dyslipidemia treatment thresholds. *FRS = Framingham Risk Score. Adapted from Anderson et al. (2016).

 

This decision is particularly difficult for young adults, who are generally considered to be at low risk of cardiovascular events over the next 10 years (age is one of the main factors used for risk assessment and therefore the younger you are, the lower the risk). On the one hand, a young person, say in their early forties, who has above-normal LDL or non-HDL cholesterol, but without exceeding the recommended thresholds and without presenting other risk factors, probably does not have a major risk of being affected by a short-term cardiovascular event. But given their young age, they may be exposed to this excess cholesterol for many years and their risk of cardiovascular disease may become higher than average once they turn 70 or 80.

Recent studies indicate that it would be wrong to overlook this long-term negative impact of higher-than-normal non-HDL cholesterol. For example, it has been shown that an increase in non-HDL cholesterol at a young age (before age 40) remains above normal for the following decades and increases the risk of cardiovascular disease by almost 4 times. Another study that followed for 25 years a young population (average age of 42 years) who presented a low risk of cardiovascular disease at 10 years (1.3%) obtained similar results: compared to people with normal non-HDL cholesterol (3.3 mmol/L), those with non-HDL cholesterol above 4 mmol/L had an 80% increased risk of cardiovascular mortality.   As shown in Table 1, these non-HDL cholesterol values are below the thresholds considered to initiate treatment in people at low risk, suggesting that hypercholesterolemia that develops at a young age, even if it is mild and not threatening in the short term, may nevertheless have longer-term adverse effects.

This concept has just been confirmed by a very large study involving nearly 400,000 middle-aged people (average age 51) who were followed for a median period of 14 years (maximum 43 years). The results show a significant increase as a function of time in the risk of cardiovascular disease based on non-HDL cholesterol levels: compared to the low category (<2.6 mmol/L), the risk increases by almost 4 times for non-HDL cholesterol ≥ 5.7 mmol/L, as much in women (increase from 8% to 34%) as in men (increase from 13% to 44%) (Figure 1).

Figure 1. Increased incidence of cardiovascular disease based on non-HDL cholesterol levels. From Brunner et al. (2019).

The largest increase in risk associated with higher non-HDL cholesterol levels was observed in people who were under 45 years of age at the beginning of the study (risk ratio of 4.3 in women and 4.6 in men for non-HDL cholesterol ≥5.7 mmol/L vs. the reference value of 2.6 mmol/L) (Figure 2). In older people (60 years or more), these risk ratios are much lower (1.4 in women and 1.8 in men), confirming that it is prolonged exposure (for several decades) to high levels of non-HDL cholesterol that plays a major role in increasing the risk of cardiovascular disease.

Figure 2. Age-specific and sex-specific association of non-HDL cholesterol and cardiovascular disease. From Brunner et al. (2019).

According to the authors, there would therefore be great benefits in reducing non-HDL cholesterol levels as soon as possible to limit the long-term exposure of blood vessels to atherogenic particles and thus reduce the risk of cardiovascular events. An estimate based on the results obtained indicates that in people 45 years of age and under who have above-normal non-HDL cholesterol levels (3.7–4.8 mmol/L) and other risk factors (e.g. hypertension), a 50% reduction in this type of cholesterol would reduce the risk of cardiovascular disease at age 75 from 16% to 4% in women and from 29% to 6% in men. These significant reductions in long-term risk therefore add a new dimension to the prevention of cardiovascular disease: it is no longer only the presence of high cholesterol levels which must be considered, but also the duration of exposure to excess cholesterol.

What to do if your cholesterol is high
If your short-term risk of cardiovascular accident is high, for example, because you suffer from familial hypercholesterolemia or you combine several risk factors (heredity of early coronary artery disease, hypertension, diabetes, abdominal obesity), it is certain that your doctor will insist on prescribing a statin if your cholesterol is above normal.

For people who do not have these risk factors, the approach that is generally recommended is to modify lifestyle habits, particularly in terms of diet and physical activity. Several of these modifications have rapidly measurable impacts on non-HDL cholesterol levels: weight loss for obese or overweight people, replacing saturated fat with sources of monounsaturated fat (olive oil, for example) and omega-3 polyunsaturated fats (fatty fish, nuts and seeds), an increase in the consumption of soluble fibres, and the adoption of a regular physical activity program. This roughly corresponds to the Mediterranean diet, a diet that has repeatedly been associated with a decreased risk of several chronic diseases, particularly cardiovascular disease.

The advantage of adopting these lifestyle habits is that not only do they help normalize cholesterol levels, but they also have several other beneficial effects on cardiovascular health and health in general. Despite their well-documented clinical utility, randomized clinical studies indicate that statins fail to completely reduce the risk of cardiovascular events, both in primary and secondary prevention. This is not surprising, since atherosclerosis is a multifactorial disease, which involves several phenomena other than cholesterol (chronic inflammation in particular). This complexity means that no single drug can prevent cardiovascular disease alone. And it is only by adopting a comprehensive approach based on a healthy lifestyle that we can make significant progress in preventing these diseases.