Abstract
In this article, we discuss certain contemporary and controversial topics in cardiovascular (CV) nutrition including recent data regarding the health benefits of the Mediterranean diet, the role of saturated fatty acids, red meat and the microbiome in CV disease and the current role of personalized CV nutrition. Findings from the PREDIMED study now demonstrate the health benefits of the Mediterranean diet even in the absence of heart disease. The study highlighted that even small, sustained and easily implementable changes to diet can provide significant health benefits even in Mediterranean regions. Likewise, observational data in secondary prevention show that increased adherence to the Mediterranean diet is associated with good long-term clinical outcomes among subjects with stable coronary heart disease. The role of saturated fats in the development of CV disease remains controversial, although data suggest that these fats are associated with modestly increased risk of CV events. In contrast, the obesity epidemic currently driving the CV risk worldwide is in large part due to excess consumption of refined carbohydrates. Furthermore, a growing body of evidence suggests that the intestinal microbiome is highly sensitive to lifestyle choices and may play a pivotal role in modulating CV disease development. For example, recent evidence linking processed and unprocessed meats to increased CV risk pointed to the gut microbial metabolite trimethylamine N-oxide as a potential culprit. Finally, given the high interindividual variability in response to interventions including diet, personalized nutrition has potential to play a major role in tailoring diets based on genetic make-up to maximize health benefits. This approach is still in its infancy but is highly promising.
1
Introduction
Cardiovascular (CV) nutrition remains a cornerstone of a complete cardiac rehabilitation program. According to the most recent data from the World Health Organization, hypertension, high blood sugar, excess weight and hypercholesterolemia represent 4 of the 10 greatest risk factors for all-cause mortality worldwide . These risk factors highlight the vital role that nutrition plays in health and disease. The same can be said at the individual level. The contemporary patient with CV disease (CVD) not only has underlying heart disease but most often has multiple co-morbidities including obesity, diabetes, hypertension and dyslipidemia, all of which continue to play a role in long-term prognosis. Therefore, poor nutrition plays a major role in the initiation and maintenance of the atherosclerotic process, but diet has a major role in reversing heart disease.
In this article, we discuss several contemporary topics in CV nutrition, some of which are controversial, including recent findings regarding the Mediterranean diet (MED) and CV risk, the role of saturated fatty acids and red meat in CVD and personalized nutrition for CV prevention.
2
The Mediterranean diet: recent findings
Most dietary patterns that have been studied for their cardiometabolic properties (e.g. DASH, Mediterranean, Nordic diets) are based on similar principles, that natural, nutrient-rich foods should be prioritized over highly processed foods . The widely known MED has been largely investigated since its first description by Keys et al. . Briefly, this dietary pattern is rich in fruits and vegetables, legumes and grains, with moderate consumption of fish, low-fat dairy products, and alcohol and relies on extra-virgin olive oil (EVOO) as its main source of dietary fat . The nutritional composition of the MED is thus rich in monounsaturated fatty acids (MUFAs), primarily oleic acid, dietary fibers, and antioxidant compounds such as polyphenols, in addition to a high ratio of omega-3 to omega-6 polyunsaturated FAs. This dietary pattern is also characterized by low consumption of highly processed foods, red meats and vegetable oils other than EVOO, so it is poor in saturated FAs (SFAs), industrially produced trans fats and simple sugars.
Epidemiological and accumulating clinical studies have demonstrated the benefits of the MED and its constituents that act in synergy to prevent the development of CVD and its risk factors in the primary prevention setting. For example, a recent meta-analysis of epidemiological and prospective trials concluded that a two-point increase in adherence to the MED, measured by the MED score elaborated by Panagiotakos et al. was associated with a 10% reduction in all-cause mortality in healthy people of all age groups and in CV risk . On a practical level, a two-point increase in MED score requires a modest increase in consumption of beneficial foods including fruits, vegetables, legumes, grains and fish combined with a modest decrease in detrimental foods such as processed and unprocessed red meats. Such dietary modifications are thus attainable and implementable at the population level. As noted below, data regarding the benefits of the MED in secondary prevention are more limited but are wholly consistent with primary prevention studies.
The largely covered PREDIMED intervention trial and the plethora of post hoc-related analyses have revealed for the first time in a randomized controlled trial (RCT) the CV and cardiometabolic benefits of the MED in people without overt CVD but at high risk. The study involved 7447 Spanish participants with type 2 diabetes mellitus (T2DM) or at least 3 traditional CV risk factors who were randomized to receive a low-fat control diet or 1 of 2 MEDs (supplemented with large quantities of EVOO or mixed nuts). Adherence to a MED decreased the incidence of stroke, myocardial infarction (MI) or CV death by 30% . As well, adherence to a MED (particularly in the increased nut-consumption group) significantly reduced the prevalence of metabolic syndrome and diabetes in the context of an ad libitum diet . PREDIMED interventions positively affected other intermediate CV endpoints: they normalized levels of B-type natriuretic peptide, oxidized LDL, and lipoprotein(a) ; improved plasma antioxidant status ; and decreased the prevalence of hypertension .
However, conclusions from the PREDIMED trial require interpretation with caution . In reality, all 3 groups had similar baseline diets, which reflected a high degree of adherence, on average, to the MED . At the end of the trial, the proportion of energy intake from total fat was only slightly lower in the low-fat control group (37%) relative to the MED groups (41%), whereas that from saturated fat was similar among the groups . Although adherence to the MED was increased in the olive oil and nut groups, the major differences in terms of the control diet were the higher MUFA content (from increased EVOO consumption and nut consumption) and PUFA content (from nut consumption). Thus, correctly speaking, PREDIMED demonstrated that consumption of significant quantities of EVOO or nuts in addition to a MED reduced fatal and non-fatal CV endpoints relative to a MED alone. Nonetheless, PREDIMED demonstrated that minor and thus sustainable dietary modifications to already “healthy” habits can benefit CV health and lower event rates.
Since the publication of both the GISSI-Prevenzione and Lyon Diet Heart studies , no additional prospective RCTs have evaluated the impact of the MED or its constituents on the secondary prevention of CVD. Briefly, GISSI-Prevenzione demonstrated in 11,324 Italian subjects with recent MI that supplementation with fish oil (1 g EPA + DHA) reduced the risk of CV death relative to placebo by 17–30% after a mean follow-up of 3.5 years . In contrast, in the Lyon Diet Heart study, 423 patients with recent acute MI were randomized to a control diet (prudent Western diet) or a MED and followed for 45 months, on average . Similar to PREDIMED, the MED group received canola oil as a supplement to increase dietary content of alpha-linolenic acid. The study demonstrated that adherence to the MED reduced the composite endpoint of cardiac death and non-fatal MI by 72% ( P = 0.0001) and risk of cardiac death alone by 65% ( P = 0.01). Taken together, the results of PREDIMED, GISSI-Prevenzione and the Lyon Diet Heart studies demonstrate that as one moves from primary to secondary prevention of CVD and from targeted supplementation of a specific constituent to a holistic MED pattern, the benefits of a MED on hard clinical endpoints are even greater. Recent data from an observational study support this view. In a substudy of the STABILITY trial, which included over 15,000 patients with stable coronary heart disease (CHD), adherence to a MED was associated with reduced risk of major adverse cardiac events including CV death, non-fatal MI and non-fatal stroke in the context of optimal contemporary medical management . In contrast, adherence to a Western-type diet rich in refined grains, carbohydrates and deep-fried foods was not associated with poorer outcomes. As noted by the authors, these data suggest that consumption of healthy foods is more important than avoidance of less healthy foods for secondary prevention of CV events .
2
The Mediterranean diet: recent findings
Most dietary patterns that have been studied for their cardiometabolic properties (e.g. DASH, Mediterranean, Nordic diets) are based on similar principles, that natural, nutrient-rich foods should be prioritized over highly processed foods . The widely known MED has been largely investigated since its first description by Keys et al. . Briefly, this dietary pattern is rich in fruits and vegetables, legumes and grains, with moderate consumption of fish, low-fat dairy products, and alcohol and relies on extra-virgin olive oil (EVOO) as its main source of dietary fat . The nutritional composition of the MED is thus rich in monounsaturated fatty acids (MUFAs), primarily oleic acid, dietary fibers, and antioxidant compounds such as polyphenols, in addition to a high ratio of omega-3 to omega-6 polyunsaturated FAs. This dietary pattern is also characterized by low consumption of highly processed foods, red meats and vegetable oils other than EVOO, so it is poor in saturated FAs (SFAs), industrially produced trans fats and simple sugars.
Epidemiological and accumulating clinical studies have demonstrated the benefits of the MED and its constituents that act in synergy to prevent the development of CVD and its risk factors in the primary prevention setting. For example, a recent meta-analysis of epidemiological and prospective trials concluded that a two-point increase in adherence to the MED, measured by the MED score elaborated by Panagiotakos et al. was associated with a 10% reduction in all-cause mortality in healthy people of all age groups and in CV risk . On a practical level, a two-point increase in MED score requires a modest increase in consumption of beneficial foods including fruits, vegetables, legumes, grains and fish combined with a modest decrease in detrimental foods such as processed and unprocessed red meats. Such dietary modifications are thus attainable and implementable at the population level. As noted below, data regarding the benefits of the MED in secondary prevention are more limited but are wholly consistent with primary prevention studies.
The largely covered PREDIMED intervention trial and the plethora of post hoc-related analyses have revealed for the first time in a randomized controlled trial (RCT) the CV and cardiometabolic benefits of the MED in people without overt CVD but at high risk. The study involved 7447 Spanish participants with type 2 diabetes mellitus (T2DM) or at least 3 traditional CV risk factors who were randomized to receive a low-fat control diet or 1 of 2 MEDs (supplemented with large quantities of EVOO or mixed nuts). Adherence to a MED decreased the incidence of stroke, myocardial infarction (MI) or CV death by 30% . As well, adherence to a MED (particularly in the increased nut-consumption group) significantly reduced the prevalence of metabolic syndrome and diabetes in the context of an ad libitum diet . PREDIMED interventions positively affected other intermediate CV endpoints: they normalized levels of B-type natriuretic peptide, oxidized LDL, and lipoprotein(a) ; improved plasma antioxidant status ; and decreased the prevalence of hypertension .
However, conclusions from the PREDIMED trial require interpretation with caution . In reality, all 3 groups had similar baseline diets, which reflected a high degree of adherence, on average, to the MED . At the end of the trial, the proportion of energy intake from total fat was only slightly lower in the low-fat control group (37%) relative to the MED groups (41%), whereas that from saturated fat was similar among the groups . Although adherence to the MED was increased in the olive oil and nut groups, the major differences in terms of the control diet were the higher MUFA content (from increased EVOO consumption and nut consumption) and PUFA content (from nut consumption). Thus, correctly speaking, PREDIMED demonstrated that consumption of significant quantities of EVOO or nuts in addition to a MED reduced fatal and non-fatal CV endpoints relative to a MED alone. Nonetheless, PREDIMED demonstrated that minor and thus sustainable dietary modifications to already “healthy” habits can benefit CV health and lower event rates.
Since the publication of both the GISSI-Prevenzione and Lyon Diet Heart studies , no additional prospective RCTs have evaluated the impact of the MED or its constituents on the secondary prevention of CVD. Briefly, GISSI-Prevenzione demonstrated in 11,324 Italian subjects with recent MI that supplementation with fish oil (1 g EPA + DHA) reduced the risk of CV death relative to placebo by 17–30% after a mean follow-up of 3.5 years . In contrast, in the Lyon Diet Heart study, 423 patients with recent acute MI were randomized to a control diet (prudent Western diet) or a MED and followed for 45 months, on average . Similar to PREDIMED, the MED group received canola oil as a supplement to increase dietary content of alpha-linolenic acid. The study demonstrated that adherence to the MED reduced the composite endpoint of cardiac death and non-fatal MI by 72% ( P = 0.0001) and risk of cardiac death alone by 65% ( P = 0.01). Taken together, the results of PREDIMED, GISSI-Prevenzione and the Lyon Diet Heart studies demonstrate that as one moves from primary to secondary prevention of CVD and from targeted supplementation of a specific constituent to a holistic MED pattern, the benefits of a MED on hard clinical endpoints are even greater. Recent data from an observational study support this view. In a substudy of the STABILITY trial, which included over 15,000 patients with stable coronary heart disease (CHD), adherence to a MED was associated with reduced risk of major adverse cardiac events including CV death, non-fatal MI and non-fatal stroke in the context of optimal contemporary medical management . In contrast, adherence to a Western-type diet rich in refined grains, carbohydrates and deep-fried foods was not associated with poorer outcomes. As noted by the authors, these data suggest that consumption of healthy foods is more important than avoidance of less healthy foods for secondary prevention of CV events .
3
Controversies in cardiovascular nutrition
3.1
Saturated fatty acids
In the past 2 years, much confusion has surrounded the role of SFAs in the pathogenesis of CHD because of the publication of meta-analyses that have suggested deleterious effects on CV health falsely attributed to these fats over the past 40 years . The first meta-analysis of Chowdhury et al. concluded that their findings “did not yield clearly supportive evidence for current cardiovascular guidelines that encourage high consumption of polyunsaturated fatty acids and low consumption of saturated fats” . However, many experts in the field have criticized the authors’ methodology, notably, that one study in particular, the Sydney Diet Heart Study , should not have been included in the meta-analysis because the supplemented source of w-6 PUFAS was a trans fat-based margarine . Moreover, according to Dawczynski et al., in the analyses of circulating blood fatty acid composition, 2 studies finding negative associations between SFAs from dairy products (pentadecanoic acid (15:0) and heptadecanoic acid (17:0)) and MI should not have been included because dairy sources of SFAs do not reflect total SFA intake . By eliminating the 2 studies, Dawczynski et al. found a harmful association between SFA blood levels and coronary outcomes.
The meta-analysis by de Souza et al. also found no association between SFA intake and CV mortality or total CHD . However, a positive trend association between SFA intake and CHD mortality was found. The methodology of this meta-analysis is arguable. Indeed, the study included observational studies, conducted over a very broad time range, from 1981 to 2014, and in very heterogeneous populations. Moreover, the studies included did not all consider which macronutrient replaced the SFAs . In one study that focused on which macronutrient replaced SFAs; the risk of fatal CHD was decreased with SFAs replaced by PUFAs . Similarly, a pooled analysis of 11 prospective cohort studies found a 13% decrease in coronary events (hazard ratio [HR] 0.87, 95% CI 0.77–0.97) and a 26% decrease in coronary deaths (HR 0.74, 95% C 0.61–0.89) with a 5% lower energy intake from SFAs and a concomitant higher energy intake from PUFAs . A 7% increase in coronary events (HR 1.07, 95% CI 1.01–1.14) was found for intake of carbohydrates.
However, the meta-analysis of Mozaffarian et al., which included 8 RCTs and no observational studies, demonstrated a 10% reduction in risk of CHD events per 5% increase in energy intake from PUFAs, with absence of heterogeneity among studies . Also, a recently updated Cochrane systematic review of 15 RCTs addressing the same question concluded that reduced SFA intake resulted in a 17% decrease in CV events, with the greatest benefit observed by substituting SFAs with PUFAs . From these findings, the question is whether saturated fats are harmful and also whether in a balanced isocaloric diet, other types of fat or macronutrients are cardioprotective. To properly address this question, we need RCTs examining the replacement of saturated fat by other macronutrients as part of a globally cardioprotective diet. In fact, a recent RCT found an inverse association of SFAs replaced by MUFAs or PUFAs with CVD .
Adding to the complexity of this topic, SFAs appear to be a more heterogeneous group of FAs than was previously thought. According to a recent case-cohort study, the association of plasma phospholipid SFA intake and incident T2DM varied by length of the carbon chain of the fatty acid and number of carbon atoms (odd or even-chain) . Intake of even-chain SFAs [myristic acid (14:0), palmitic acid (16:0) and stearic acid (18:0)] was positively associated with T2DM, with only a trend found for stearic acid in multivariable models (HR 1.06, 95% CI 1.00–1.13) and in half the sensitivity analyses. Conversely, intake of odd-chain SFAs [pentadecanoic acid (15:0), heptadecanoic acid (17:0)] and longer-chain SFAs [arachidic acid (20:0), behenic acid (22:0), tricosanoic acid (23:0), lignoceric acid (24:0)] was inversely associated with T2DM. However, intake of plasma phospholipid SFAs was not well correlated with food intake. Intake of even-chain SFAs was mostly positively associated with alcohol consumption. More studies are needed to assess the association between SFA subgroup intake and CV risk. In summary, we have limited high-quality data evaluating the exact role of SFAs in the development of CVD. At this time, intake of saturated fat overall appears to be modestly associated with CV risk, although some SFAs may be more harmful than others and others may be protective.
3.2
Cholesterol
According to a recent systemic review and meta-analysis, intervention trials showed that dietary cholesterol intake increases levels of total cholesterol, LDL-C (except for cholesterol doses >900 mg/day) and HDL-C cholesterol and the LDL to HDL ratio . However, cohort studies show no association between cholesterol intake and the risk of CHD and stroke.
Whether cholesterol, saturated fat or both play a role in the development of CHD may remain unsolved. The first plausible explanation for the lack of convincing evidence is the complexity of measuring the food intake of individuals or populations. In observational studies, dietary intake is measured with food frequency questionnaires or dietary history interview . Correlations between food frequency questionnaire data and diet records, considered more accurate, rarely exceed 0.7 . Second, some nutrients may be more detrimental when eaten with other nutrients, cholesterol being eaten simultaneously with saturated fat, for example. In this context, food patterns may be more appropriate in determining protective foods habits than nutrients studied separately. Indeed, as noted previously, the MED has been shown to protect against CVD . Again, this dietary pattern is low in animal products and therefore low in cholesterol and saturated fat while being simultaneously high in MUFAs, primarily from olive oil . In contrast, the Western diet, which is high in saturated fat, cholesterol, and refined sugars, has greatly contributed to the obesity epidemic and the major increase in prevalence of CVD . In other words, the complete diet may have a more important role in health and disease than its individual constituents.
3.3
Carbohydrates
Total fat intake and types of fat have drawn much attention in the past years, but carbohydrates seem to be more detrimental. Carbohydrates, and especially refined starches such as white rice and major sources of added sugars, such as soft drinks, have been linked to the global obesity epidemic . Indeed, Mozaffarian et al. observed an association between weight gain and foods rich in carbohydrates such as potato chips, potatoes and sugar-sweetened beverages in the US population . As mentioned previously, CHD risk increases with SFAs replaced by carbohydrates . However, carbohydrates from whole grains appear to decrease the risk of CHD as opposed to refined starches and added sugars . This finding agrees with those from prospective cohort studies finding an association of sugar-sweetened beverages with CHD .
4
Red meat, processed meat and the microbiota
Although processed meat is clearly associated with all-cause mortality , CV mortality and CHD risk , the association of unprocessed red meat and mortality remains conflicting . The gut microbiota, this promising but still largely misunderstood organ, could explain in part these discrepancies. Indeed, Koeth et al. described a link between microbiota and synthesis of the proatherogenic compound trimethylamine- N -oxide (TMAO) from l -carnitine and choline present in red meats . Dietary l -carnitine supplementation in mice was associated with modification of gut flora leading to increased production of TMAO and development of atherosclerosis. This mechanism was not observed in mice treated with antibiotics – and thus depleted in gut microbiota – which suggests an obligatory role of the gut microbiota in TMAO production . Similarly, high plasma l -carnitine levels predicted prevalent CHD and incident major adverse cardiac events in humans . Finally, increased TMAO level was found independently associated with CV events at 3 years . Interestingly, a recent study found different gut microbiota composition in CHD patients and healthy subjects . Emoto et al. demonstrated that gut microbiota composition could be a diagnostic marker of CHD , but several unresolved issues and contradictions remain.
For instance, unprocessed meats and other food items associated with cardioprotective diets such as seafood, eggs, and nuts contain l -carnitine and choline and might lead to TMAO production, which is puzzling . Such inconsistencies could be explained by cardioprotective dietary patterns positively affecting the gut microbiota composition and mediating the production and cardiometabolic effect of TMAO. For instance, dietary habits that positively affect gut microbiota composition such as vegetarianism attenuated TMAO production with l -carnitine supplementation . Fig. 1 illustrates the interaction between lifestyle factors, genetics, the intestinal microbiome and development of CVD or its risk factors.
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