Secondary prevention of coronary heart disease (CHD) should be initiated promptly after the first clinical manifestation of CHD; in patients with an acute coronary syndrome (ACS), it is during the initial stay in the coronary care unit (CCU). In these patients, prevention should focus on the reduction of risk of recurrent cardiac events and death; the two main causes of cardiac death in these patients are sudden cardiac death (SCD) and chronic heart failure (CHF), often as a result of new coronary event. The main mechanism for such recurrent events is myocardial ischemia resulting from atherosclerotic plaque erosion or ulceration usually associated with inflammation in young lipid-rich plaques containing more saturated and unsaturated fatty acids than cholesterol (see Chapters 6 and 7 ).
These priorities in secondary prevention differ from that of primary prevention, where the main targets are traditional risk factors (e.g., smoking, dyslipidemia, diabetes, overweight or obesity, high blood pressure) and surrogate markers. These should be reinforced and their control more stringent after an ACS, while others are added, mainly prevention of malignant arrhythmias, SCD, and other morbidities associated with left ventricular dysfunction. SCD accounts for more than 50% of cardiac mortality in these patients, is often unpredictable, and occurs largely out of hospital where therapeutic resources are most often not readily available.
This chapter covers these aspects of secondary prevention, focusing more on clinical outcome than on surrogate markers. Indeed, nutritional evaluation and personalized counseling are key to any prevention program as are exercise training, behavioral interventions such as support for smoking cessation, and drug therapy. The dietary prevention program is commonly initiated during hospitalization after a first CHD event; as hospital stays are getting shorter, the teaching takes place as soon as the patient is receptive within the first 48 hours and continued in cardiac prevention centers. Such programs are better developed under the guidance of a specialized dietitian and in close collaboration with the patient’s cardiologist and primary care physician to assure consistency and continuity in care after hospital discharge.
A list of simple dietary recommendations to introduce in daily life will be provided at the end of the chapter for the many patients and families who find a formal and drastic re-education program difficult, recognizing that these recommendations will be minimal and not intended to replace a more global approach.
The Mediterranean Diet: Rationale and Evidence for Its Benefit
There is now some consensus to recommend the Mediterranean diet pattern for the secondary prevention of CHD, as no other dietary pattern was successfully tested so far in ACS patients. Contrasting with standard dietary approaches, which aim for a reduction of low-density-lipoprotein cholesterol (LDL-C) levels, the Mediterranean diet was shown to improve survival, mainly by reducing death from CHD and also from other various chronic diseases including cancers. Furthermore, the Mediterranean diet may be effective in reducing coronary atherosclerosis and the risk of fatal complications of atherosclerosis such as sudden death and congestive heart failure. Finally, unlike drug therapies, no harmful side effect has been reported using that dietary pattern.
Prospective epidemiologic studies on CHD have shown important differences in mortality rates across various populations that could pertain to differences in dietary habits. Such is the case for relative protection against CHD and certain cancers in the Mediterranean populations that has been linked to dietary habits. ,
The epidemiologic studies, however, only provide associations between risk factors and clinical end points, not causal relationships; the associations can be confounded by several factors including the economic situation and availability of extended social support systems. Clearly, randomized trials are the only way to make sure that a given dietary pattern results in a significant protective effect against CHD complications.
Some dietary trials in primary or secondary prevention of CHD have reported significant reduction of CHD risk especially in terms of mortality while others did not. The successful trials in general tested dietary patterns characterized by a low intake of total, saturated and omega-6 polyunsaturated fats and an increased intake of omega-3 fatty acids without primarily aiming a reduction in blood cholesterol levels. Two of these trials also included a high intake of fresh fruits and vegetables, legumes, and cereals containing large amounts of fiber, antioxidants, minerals, vegetable proteins, and vitamins of the B group. The credibility of these trials was considerably reinforced by a number of studies showing major protective effects of most of these foods and nutrients with a particular emphasis on plant and marine omega-3 fatty acids.
The Lyon Diet Heart Study was a randomized single-blind secondary prevention trial aimed at testing whether an experimental Mediterranean diet could reduce the risk of recurrence of an ischemia outcome event after a first myocardial infarction. It showed a significant reduction in the rates of cardiovascular complications. Additionally, the trial suggested that the diet also protected from cancer. Although further trials are warranted to confirm the cancer data, they are in line with several studies suggesting that dietary factors are important in cancers and cancer prevention.
A recent and large observational study in a U.S. population provided strong evidence for a beneficial effect of good adherence to a Mediterranean dietary pattern on risk of all-cause mortality, including cardiovascular and cancer deaths. They back their conclusions on previous non-U.S. epidemiologic studies reporting similar mortality data with the Mediterranean diet. , In another study of 74,886 U.S. women followed for about 20 years, a greater adherence to the Mediterranean diet was associated with a lower risk of CHD complications and stroke.
These epidemiologic studies consistently confirm the results of the Lyon Diet Heart Study. Of interest, the Lyon Heart Study, showed no difference between groups in the main conventional risk factors, including blood cholesterol and blood pressure, suggesting that its protective effect is largely independent from conventional factors.
The diet scores that are used to assess conformity with the Mediterranean dietary pattern in the various epidemiologic studies are generally nonperforming and do not capture the various practical aspects of the traditional Mediterranean diets. Clinicians and patients should know some fundamentals of the Mediterranean diet are:
- 1
A high variety of raw, sometimes cooked, seasonal vegetables year-round, often associated with large amounts of onions, garlic, parsley, rosemary, oregano, thyme and other aromatic herbs.
- 2
Fruit year-round, both fresh and dried (during the summer, for consumption in winter, e.g., apricots and grapes).
- 3
Various nuts (almonds, hazelnuts), particularly walnuts that are rich in alpha-linolenic acid (ALA), the main plant omega-3 and a major characteristic of traditional Mediterranean diets. There are many other sources of ALA in Mediterranean diets, including many types of salads such as purslane and products from animals fed with ALA-rich feed such as linseed (rabbit, eggs and chicken, dairy products).
- 4
Grains, preferably whole, especially wheat under the form of bread, fermented with natural leaven and sometimes flavored with ALA-rich linseed. The wheat used in traditional Mediterranean diets (like the vegetables and fruit) does not contain pesticides as they are not products of industrial agriculture.
- 5
Fatty fish, including anchovy, sardine, mackerel, sea bream and red tuna, all rich in very-long chain (marine) omega-3 fatty acids. Another source of indispensable marine omega-3 fatty acids are eggs of linseed-fed chicken, and possibly moderate wine drinking for an effect similar to fish eating.
- 6
Olive oil, the main edible oil used around the Mediterranean area, low-saturated and rich-monounsaturated. However, the monounsaturated fat-saturated fat ratio used by the epidemiologists does not capture one major lipid characteristic of the Mediterranean diet, which is actually low in omega-6 and rich in omega-3 fatty acids. The omega-6/omega-3 ratio has been proposed as a major component of a healthy diet.
- 7
In contradiction with many experts, Mediterranean populations do traditionally eat dairy products, though made of goat and ewe milk and not cow milk. Importantly, these are consumed as the fermented forms of cheese and yogurt, and almost never as milk, butter, or cream.
- 8
Mediterranean populations are not vegetarian. They eat ALA-rich eggs and small amounts of meat, mainly lean meat such as rabbit, chicken, and duck. Beef or pork, or both, are also on the menu in the North of the area, while lamb is the preferred meat for festive meals in the South. It is also important to note that everywhere in the Mediterranean area the diet includes a lot of legumes and is therefore rich in vegetable proteins.
- 9
Moderate alcohol drinking, essentially during meals, is a major characteristic of the Mediterranean diet. The main alcoholic beverage is wine, particularly red wine, a major source of various polyphenols (actually wine is a mix of ethanol and polyphenols). South of the Mediterranean Sea, the main source of healthy polyphenols is not wine but fermented black tea (a mix of water and polyphenols). Thus most people living in the Mediterranean area are high consumers of various polyphenols whose health effects are still likely considerably underestimated by scientists and physicians; these have not yet been included in diet scores used by epidemiologists.
Questions arise on how effective is moderate drinking and on what cardiologists should tell their patients at risk of death.
The medical and scientific literature shows that moderate drinking (1-2 drinks/day for women and 2-4 drinks/day for men) is usually associated with a better life expectancy in the general population as well as in patients with established CHD. In the absence of a controlled trial, which is neither technically nor ethically feasible, the main question for physicians remains whether the inverse association between moderate drinking and CHD complications is a cause-effect relationship. Some consider that most studies reporting alcohol-related protection carry bias, the main one retained being the “sick quitter bias,” suggesting that non-drinkers (the referent group in most studies) include drinkers who recently quit because of an illness, resulting in a higher risk in so-called non-drinkers as compared to moderate drinkers. Previous prospective studies on light drinkers (rather than non-drinkers) as the referent group did not support such bias, and a recent study considering former drinkers and long-term abstainers separately, confirmed a true protective effect of moderate drinking compared with long-term abstainers. Limitations of this study included a small sample size, few former drinkers and few cardiac deaths, and a short follow-up resulting in less protective effect than in other populations and meta-analyses that showed with moderate drinking with 30% reduction in cardiac mortality and 20% reduction of all-cause mortality. Altogether these data strongly support a cause-effect relationship between moderate alcohol drinking and better survival. These figures are considerable in terms of public health and compare with those observed with preventive drug therapy.
In the absence of clinical trials and definitive epidemiologic evidence, one can rely somewhat on biological plausibility. Beside the well-known effects of alcohol on high-density-lipoprotein (HDL) cholesterol, hemostasis (through reduced platelet function and fibrinogen levels) and insulin resistance, recent data indicate that moderate drinking may have a direct protective effect on the ischemic myocardium, and positively interact with omega-3 fatty acids known to be highly protective in secondary prevention, especially against SCD.
Thus, cardiologists caring for high-risk post-acute myocardial infarction (AMI) patients should consider moderate alcohol drinking with a level of evidence similar to other measures to prevent sudden death, such as smoking abstention, regular physical exercise, a Mediterranean diet (of which wine drinking is one of the major characteristics), prophylactic drug therapy, revascularization procedures, and defibrillator (implantable cardioverter defibrillator) in candidate patients. Alcohol drinking may be as effective for this purpose as aggressive cholesterol lowering, since the effects of statins on SCD are not clearly documented.
Wine drinking and statins have different pleiotropic effects with respective pathophysiologic significance that remains to be better understood. Alcohol acts on platelet function and coagulation to influence thrombosis, on leukocyte function to impact on inflammation processes, and on the incidence of malignant ventricular arrhythmia, pathophysiologic mechanisms that are all important in acute coronary syndromes and SCD. The hazards of unsafe sex, violence, and accident representing the main alcohol-related morbidity and mortality among youngsters and among heavy drinkers, are much less of an issue in middle-aged or aging CHD patients. Finally, cardiologists should remember that moderate drinking is a social lubricant and a major characteristic of lifestyle, often associated with the feeling of “joie de vivre,” notably in Southern Europe, the cradle of the Mediterranean diet.
The recommendations for approaching the patients are as follows: (1) to screen for heavy present or past drinkers to caution them that there is a way of drinking that can be beneficial for health and one that can be deleterious, and that abstention is better than abuse, (2) to identify the non-drinkers who abstain on the misconception that any alcohol drinking is bad for health, explain that moderate drinking, especially but not exclusively wine in the context of the traditional Mediterranean diet, is a most effective way to prevent both fatal and nonfatal complications of CHD. This applies also in Northern Europe and in old age. Further studies are needed to fully understand the mechanisms of that protection.
The answer to the issue as to whether wine drinking is superior to other alcoholic beverages for the prevention of atherosclerotic complications is not known, but observational data and meta-analysis suggest that wine may actually be more protective than beer and spirits.
Dietary Prevention of Sudden Cardiac Death
SCD is usually defined as death from a cardiac cause occurring within 1 hour from the onset of symptoms. It is currently attributed to cardiac arrhythmia, although it is well recognized that classification based on clinical circumstances only is sometimes misleading. The magnitude of the problem is considerable, as SCD is a very common, often the first manifestation of CHD, and accounts for more than 50% of cardiovascular mortality in developed countries. , Most frequently, SCD occurs without prodromal symptoms and out of hospital. Because up to 80% of SCD patients suffer CHD, the epidemiology and potential preventive approaches of SCD should theoretically parallel those of CHD. In other words, any treatment which targets a reduction of CHD is preventive of SCD.
Fish, n-3 Fatty Acids, and Sudden Cardiac Death
The hypothesis that eating fish may protect against SCD is derived from the results of a secondary prevention trial, the Diet And Reinfarction Trial (DART), which showed a significant 30% reduction in total and cardiovascular mortality in patients having at least two servings of fatty fish/week. The authors suggested that the protective effect of fish might be explained by preventing ventricular fibrillation (VF), since the occurance of nonfatal was not influenced. This hypothesis was consistent with experimental evidence suggesting that n-3 polyunsaturated fatty acids (PUFA), the dominant fatty acids in fish oil and fatty fish, could prevant the occurrence of VF in the setting of myocardial ischemia and reperfusion in various animal models. , Using an elegant in vivo model of SCD in dogs, Billman and colleagues demonstrated a striking reduction of VF following the intravenous administration of pure n-3 PUFA, including both the long-chain fatty acids present in fish oil and alpha-linolenic acid, their parent n-3 PUFA found in some vegetable oils. The authors explained this protection to the electrophysiologic effects of free n-3 PUFA that partitioned into the phospholipids of the sarcolemma without covalently bonding any constituents of the cell membrane. These fatty acids when ingested are preferentially incorporated into membrane phospholipids. Nair and colleagues also showed that a very important pool of free non-esterified fatty acids localize in the normal myocardium, and that the amount of n-3 PUFA is increased by an n-3 PUFA-supplemented diet. Ischemia promptly releases phospholipases and lipases that promote the release of new fatty acids from phospholipids, including predominantly n-3 fatty acids that further increase the pool of antiarrhythmic free n-3 fatty acids. It is important to remember that the lipoprotein lipase is particularly active following the consumption of n-3 PUFA. A hypothesis to explain these antiarrhythmic effects is a modulation of several membrane ion channels during ischemia, including inhibitory effects on the fast sodium current, INa, and the L-type calcium current, ICaL.
Recent trials conducted in patients with ICD at high risk of VF on an ischemic or nonischemic cardiomyopathy provided, however, conflicting efficacy data on the prevention of SCD. The administration of omega-3 fatty acid in the diet is therefore recommended only in deficient patients, and not routinely in all ICD patients.
Other potential mechanisms for a benefit n-3 PUFA in SCD is a competing role in the formation of eicosanoids which are the precursors to a broad array of structurally diverse and potent bioactive lipids (including eicosanoids, prostaglandins, and thromboxanes), which are thought to play a role in ischemia and reperfusion induced , a reduction in heart rate variability. , Clinical studies have provided conflicting result on the efficacy of n-3 PUFA in CHD.
In a population-based case-control study, Siscovick and coworkers looked at the use of n-3 PUFA among patients with primary cardiac arrest, compared to age- and sex-matched controls. The data indicated that the intake of about 5 to 6 grams of n-3 PUFA per month (an amount provided by consuming fatty fish once or twice a week) was associated with a 50% reduction in the risk of cardiac arrest. The value of the data was reinforced by the measure of n-3 PUFA levels in the red blood cell membrane, and the results were consistent with those of many but not with all cohort studies. , Most studies, however, did not report on specific endpoint of SCD.
In a large prospective study that included more than 20,000 participants with a follow-up extending to 11 years, Albert and coworkers examined the hypothesis that fish intake could have antiarrhythmic properties and prevent SCD. In the study, the risk of SCD was 50% lower for men who consumed fish at least once a week than for those who had fish less than once a month. The consumption of fish was not related to non–sudden cardiac death, suggesting that the main protective effect of fish (or n-3 PUFA) could be related to an effect on arrhythmia. These results are consistent with those of DART but differ from those of the Chicago Western Electric Study, in which there was a significant inverse association between fish consumption and non–sudden cardiac death, but not with SCD. Several methodologic factors may explain the discrepancy between the two studies, one being the criteria to classify deaths in the latter study. Again these observations illustrate the limitations of observational studies and the need for randomized trials to provide clear demonstration of causal relationships.
The GISSI-Prevenzione trial addressed the issue of health benefits of foods rich in n-3 PUFA and of vitamin E supplement, among 11,324 patients who have survived an acute myocardial, patients survived for at least three months. All patients were advised to follow a Mediterranean type of diet and randomly assigned in a 2 × 2 factorial design trial to supplements of n-3 PUFA (0.8 g daily), vitamin E (300 mg daily), both or neither for 3.5 years. Secondary analyses included overall mortality, cardiovascular (CV) mortality, and SCD. Treatment with n-3 PUFA significantly lowered by 15% the risk of the primary end point composed of death, non-fatal AMI, or stroke. Overall mortality was reduced by 20%, CV mortality by 30%, SCD by 45%, the later accounted for most of the benefits seen in the primary composite end point. There was no differences across the treatment groups for nonfatal events, a result comparable to that of the DART study. In summary, the randomized GISSI trial, previous controlled trials, large-scale observational studies and experimental data all support an effect of n-3 PUFA to reduce SCD in patients with CHD. This protective effect of n-3 PUFA on SCD was greater in subgroups of patients more compliant to the Mediterranean diet, , suggesting a positive interaction between n-3 PUFA and some components of the Mediterranean diet not enriched in n-6 PUFA and low in saturated fats, but rich in plant oleic acid, various antioxidants and fibers, and moderate consumption of alcohol.
More, recent trials conducted in patients with ICD and left ventricular dysfunction following AMI or structural heart disease failed, however, to show a benefit of fish oil supplements at dosages similar to those tested in GISSI-Prevenzione. An explanation could be that patients enrolled these triats were not deficient in n-3 PUFA, which is a major risk factor for SCD. New studies are needed to investigate the real status of n-3 PUFA in these specific patients and the subgroups that can benefit.
In summary, existing evidence supports the theory that an intake of n-3 PUFA to an amount of approximately 1 g daily, either as supplements or by eating at least two large (about 200 g) servings of fatty fish/week, helps prevent SCD in secondary prevention. At present, there are no reasons to recommend intake exceeding 1 to 2 g of n-3 PUFA/day. The dosage to be recommended in high-risk patients and in secondary prevention of SCD warrants further investigation.
Saturated Fatty Acids, Oleic Acid, Trans Fatty Acids, and n-6 Fatty Acids
With regard to other dietary fatty acids, animal experiments clearly indicate that a diet rich in saturated fatty acids is associated with a high incidence of ischemia- and reperfusion-induced ventricular arrhythmia, whereas PUFA of either the n-6 or n-3 family reduce this risk. Most, but not all large epidemiologic studies have shown consistent associations between the intake of saturated fatty acids and CHD mortality. SCD was not, however, a recorded end point in most of these studies. A clear demonstration of a causal relationship between dietary saturated fatty acids and SCD would require the organization of a randomized trial, which would not be ethically acceptable. Thus, besides the effect of saturated fatty acids on blood cholesterol levels, the putative mechanism(s) by which saturated fats increase CHD mortality remain unclear. If experimental data, demonstrating a proarrhythmic effect of saturated fatty acids be confirmed in humans, the first treatment would be to drastically reduce the intake of saturated fats. This has been done in randomized dietary trials and, as expected, the rate of SCD decreased in the experimental groups. The beneficial effect cannot, however, be entirely attributed to the reduction of saturated fats as other potentially antiarrhythmic dietary factors, including n-3 PUFA, were also modified in these trials.
In contrast with n-3 PUFA, few data have been published so far in humans regarding the effect of n-6 PUFA on the risk of SCD. Roberts and colleagues reported that the percentage content of linoleic acid (LA; the dominant n-6 PUFA in the diet) in adipose tissue (an indicator of long-term dietary intake) was inversely related to the risk of SCD, suggesting that patients at risk of SCD may benefit from increasing their dietary intake of n-6 PUFA, in particular LA, as for n-3 PUFA, but with a lesser degree of efficacy in most experiments. Additionally, diets enriched in n-6 PUFA by increasing the LA content render the lipoproteins more susceptible to oxidation, which theoretically contrain-dicated considering the putative roled lipoprotein oxidation in the inflammatory process associated with atherosclerosis plaque rapture, and SCD. In fact, most diets high in n-6 PUFA have failed to improve the overall prognosis of patients with CHD. In the Los Angeles diet study, which was a mixed primary and secondary prevention trial, the substitution of saturated fat for n-6 PUFA, was associated with a reduction of SCD (18 vs. 27), but this benefit was offset by a higher total mortality rate particularly from cancer (85 vs. 71). Such negative effects were not reported with n-3 PUFA. Thus, despite the beneficial effect of n-6 PUFA on lipoprotein levels, which could, in theory, reduce SCD in the long term by reducing the development of atherosclerosis, it seems preferable not to increase the consumption of n-6 PUFA beyond the amounts required to prevent deficiencies in the essential n-6 fatty acid, LA (approximately 4% to 6% of the total energy intake), amounts that are found in the current average Western diet. A good substitute for saturated fat, is vegetable monounsaturated fat (oleic acid). The Mediterranean diet pattern, thus the contains the optimal fatty acid combination to prevent SCD by taking profit of the antiarrhythmic, antioxidant, and hypolipidemic effects of foods. ,
Finally, Roberts and colleagues reported no significant relationship between trans isomers of oleic and LA in adipose tissue and the risk of SCD, whereas Lemaitre and colleagues found that cell membrane trans isomers of LA but not of oleic acid are associated with a large increase in the risk of primary cardiac arrest.
Thus, although specific human data on the effect of saturated fatty acids on SCD are lacking, results of several trials show their intake should be reduced in the secondary prevention of CHD (at least to reduce platelet reactivity). Despite a possible beneficial effect on the risk of SCD, increasing consumption of n-6 PUFA should not be recommended in clinical practice for patients with established CHD. Diets including low intakes in saturated fatty acid (as well as trans isomers of LA) and n-6 PUFA (but enough to provide the essential LA) and high in n-3 PUFA and oleic acid (Mediterranean diet pattern) appear to be the best option to prevent both SCD and nonfatal AMI recurrence.
Alcohol and Sudden Cardiac Death
The question of the effect of alcohol on heart and vessel diseases has been the subject of discussion in recent years (see earlier discussion). The consensus is now that moderate alcohol drinking is associated with reduced cardiovascular mortality, although the exact mechanism or mechanisms by which alcohol is protective are still unclear. In contrast, chronic heavy drinking has been incriminated in the occurrence of atrial as well as ventricular arrhythmias in humans, an effect called “the holiday heart” because it is often associated with binge drinking by healthy people, specifically during the weekend. Studies in animals have shown varying and apparently contradictory effects of alcohol on cardiac rhythm and conduction, depending on the animal species, experimental model, and doses of alcohol. Given acutely to nonalcoholic animals, ethanol may even have antiarrhythmic properties. In humans, few studies have specifically investigated the effect of alcohol on SCD. The hyperadrenergic state resulting from binge drinking, as well as from withdrawal in alcoholics, seems to be the main mechanism by which alcohol induces arrhythmias in humans. In the British Regional Heart Study, the relative risk of SCD in heavy drinkers (>6 drinks/day) was twice as high as in occasional or light drinkers. However, the effect of binge drinking on SCD was more evident in men with no pre-existing CHD than in those with established CHD. In contrast, in the Honolulu Heart Program, the risk of SCD among healthy middle-aged men was positively related to blood pressure, serum cholesterol, smoking and left ventricular hypertrophy but inversely related to alcohol intake. The Physicians’ Health Study, which was the one study that looked at the risk of SCD in nonalcoholic, moderate “social” drinkers apparently free of CHD, reported a decreased risk of SCD. After controlling for multiple confounders, men who consumed 2 to 4 drinks/week or 5 to 6 drinks/week at baseline had a significantly reduced risk of SCD (by 60% to 80%) as compared with those who rarely or never consumed alcohol. Secondary analyses, one excluding the deaths that occurred within the first 4 years of follow-up to rule out the possibility that some abstainers did so because of early symptoms of heart diseases, and the other based on a new evaluation of alcohol intake after 7 years to minimize potential misclassifications at baseline, basically confirmed the potential protective effect of moderate drinking on the risk of SCD. Despite limitations (the selected nature of the cohort, an exclusively male study group, no information on beverage type and drinking pattern), this study suggests that a significant part of the cardioprotective effect of moderate drinking pertains to the prevention of SCD. Further research should be directed at understanding the mechanism or mechanisms by which moderate alcohol drinking may prevent ventricular arrhythmias and SCD.
In practice, current state-of-the knowledge supports the recommendation to drink one or two drinks/day, preferably wine during the evening meal, and never before driving a car or undertaking hazordous work.
Diet and the Risk of Heart Failure Following Acute Myocardial Infarction
The prevalence of chronic heart failure (CHF), which represents a most common terminal event in cardiac diseases, has steadily increased in many countries despite (and probably because of) considerable progress made in the management of acute and chronic CHD, which is nowadays the main cause of CHF in most countries. Most research effort on CHF focused on drug treatment, with little attention to nonpharmacologic management. Many unidentified factors may however, contribute to the rise in the prevalence of CHF and should be recognized and corrected when possible. Thus, CHF is now seen as a metabolic problem with endocrine and immunologic disturbances potentially contributing to the progression of the disease. ,
Nutrition and Chronic Heart Failure
While it is well appreciated that a high sodium diet is detrimental by promoting volume overload, little is known about other aspects of diet in CHF in terms of both general nutrition and micronutrients such as vitamins and minerals. Whereas the diagnosis and treatment of CHF is of first concern, it is also important to recognize and correct the traditional CHD risk factors such as high blood pressure, diabetes, malnutrition, and specific micronutrients deficiences that can entertain the disease process.
The importance for health of micronutrients is now fully recognized. These could be direct antioxidants such as zinc, or components of the antioxidant enzymes superoxide dismutase or glutathione peroxidase. It is now widely believed (but still not causally demonstrated) that diet-derived antioxidants could play a role in the development (and thus in the prevention) of CHF. For instance, clinical and experimental studies have suggested that CHF may be associated with increased free radical formation and reduced antioxidant defenses and that vitamin C can improve endothelial function in patients with CHF. In a recent trial, investigators have shown improved quality of life and left ventricular function in CHF patients receiving several antioxidant nutrients. Taken altogether, these data suggest, but do not prove, that antioxidant nutrients help prevent CHF in post-AMI patients.
While CHF can be caused by deficiency of micro- or macro-nutrients such as selenium, CHF per se is associated with symptoms that affect food intake such as tiredness, shortness of breath, and gastrointestinal complaints as nausea, loss of appetite, and early feeling of satiety. Drug therapy and excess urinary losses can do the same.
It has been shown that up to 50% of patients suffering from CHF are to some extent malnourished. Loss of weight is frequent and due to a variety of debilitating causes such as a higher metabolic rate at rest, a shift to increased catabolism with insulin resistance due to anabolic steroids, and loss of muscle bulk due to inactivity. , Levels of tumor necrosis factor-α (TNF-α), also known as cachectin, is elevated in many patients with CHF, , contributing also to the weight loss. Interestingly, TNF-α levels correlate with markers of oxidative stress in the failing heart suggesting a link between TNF-α and antioxidant defenses in CHF. Finally, cardiac cachexia becomes manifested as symptoms worsen and is a major predictor of imminent death. The pathophysiologic mechanisms that lead to cachexia remains unclear and so far, no specific treatment exist apart the treatment of the basic illness and correction of the associated biological abnormalities.
Deficiency in Specific Micronutrients
The deficiency in specific micronutrients should be of concern for physicians, because it can cause CHF, or at least aggravate it. The real prevalence of these deficiencies among patients with CHF and postinfarction patients and whether specific treatment will improve prognosis remain unclear. Indeed, a combination of minor deficiencies may be harmful, especially in the elderly. Many believe that the current evidence supports the conduct of a large-scale trial of dietary micronutrient supplementation in CHF.
Some relevant human data in CHF are:
- 1
Low serum and high urinary zinc levels, possibly as a result of diuretic use but no data on zinc supplementation in that context exist.
- 2
Whether the slight elevation in plasma copper and lower zinc compared with controls without differences in patients with CHF in dietary intake ; are contributors to development of CHF or simply markers of a chronic inflammation found in CHF , remains to be investigated.
- 3
Selenium deficiency documented etiologic as a factor in some nonischemic CHF syndromes, especially in low-selenium soil areas such as Eastern China and Western Africa.
- 4
Selenium deficiency as risk factor for peripartum cardiomyopathy.
- 5
In Western countries, cases of congestive cardiomyopathy associated with low antioxidant nutrients (vitamins and trace elements) in malnourished human immunodeficiency virus (HIV)-infected patients and in subjects on chronic parenteral nutrition.
- 6
In China, an endemic cardiomyopathy named Keshan disease apparently has direct consequence of selenium deficiency. The exact mechanisms for such failure with selenium deficiency are unknown; recent data suggest that selenium may be involved in skeletal and cardiac muscle deconditioning, and contribute to the symptoms of fatigue and low exercise tolerance associated with CHF. Indeed, in the Keshan area, the levels of selenium correlate better with the severity of CHF symptoms than the severity of left ventricular dysfunction assessed by echocardiography. Furthermore, raising selenium levels of the residents in this area to the levels found in nonendemic areas resulted in a significant decline in mortality rates without, however, reducing the prevalence of latent cases as detected by echocardiography. What we learned from the Keshan disease and other studies conducted elsewhere is a mild deficiency in selenium may influence the clinical severity of the disease.
These data are strong incentive to initiate studies testing the effects of natural antioxidants on the clinical severity of CHF. In the meantime, physicians could consider measuring selenium in patients with an exercise inability that is disproportionate to the severity of cardiac dysfunction.
- 7
Finally, low whole blood thiamine (vitamin B 1 ) levels have been documented in patients with CHF administered loop diuretics with alcohol abuse and in hospitalized elderly patients; thiamine supplementation significantly improved cardiac function and symptoms.
- 8
The presence of a low-grade systemic inflammation response syndrome (SIRS) in heart failure manifested by elevated circulating levels of cytokines and cytokine receptors is also a possible connection between diet and heart failure. , Since various anti-cytokine and immunomodulating agents may improve heart function and the clinical functional class in patients with advanced CHF, , a potential for dietary interventions exists. In that regard, it has been shown that supplementation with n-3 fatty acids (either fish oil or vegetable oil rich in n-3 fatty acid) reduces cytokine production in healthy volunteers. , An inverse exponential relationship exists between leukocyte n-3 fatty acid content and cytokine production by these cells, most of the reduction being due to a reduction in eicosapentaenoic acid in cell membrane to less than 1%, which is easily achieved with moderate n-3 fatty acid supplementation. Low-dose marine n-3 PUFA less than 1 g/day resulted and was associated with a marginally better prognosis in a recent randomized trial in CHF patients. Further studies are warranted to test whether higher dosages may influence the clinical course of CHF through an anti-inflammatory effect.
Diet and Plaque Inflammation, Erosion, and Rupture
For several decades, the primary and secondary prevention of CHD has focused on the reduction of the traditional risk factors of smoking, hypertension (HBP), and hypercholesterolemia, aiming to halt the progression of the disease and promoting atherosclerotic plaque regression. It has become clear that efficiency first means prevention of clinical events and complications such as SCD and CHF, and only second the slowing down of the atherosclerotic process and neutralization of plaque inflammation and erosion and rupture that precipitates thrombotic occlusion. Recent progress in the understanding of the cellular and biochemical pathogenesis of atherosclerosis suggests that prevention of inflammation and rupture (see Chapter 26 ).
Is Coronary Heart Disease an Inflammatory Disease?
Proinflammatory factors (including the free radicals produced by cigarette smoking), hyperhomocysteinemia, diabetes, peroxidized lipids, and high blood pressure contribute to injury of the vascular endothelium, altering its antiatherosclerotic and antithrombotic properties. The fundamental differences that exist between the unstable, lipid-rich and leukocyte-rich plaque and the stable, acellular lipid-poor fibrotic lesions for the propensity to rupture bears poor correlation with the severity of the lumen obstruction.
Previous work by Virchow, Ross, Libby, and ourselves emphasized the role of inflammation and leukocytes inpromoting ischemic acute events. It is now well accepted that one of the main mechanisms underlying the sudden onset of acute CHD syndromes, is erosion and/or rupture of an atherosclerotic lesion, , which triggers thrombotic complications and considerably enhances the risk of malignant ventricular arrhythmias. , Leukocytes have also been implicated in the occurrence of ventricular arrhythmias in clinical and experimental settings, , and can contribute to myocardial damage during both ischemia and reperfusion. Clinical and pathologic studies showed the importance of inflammatory cells and immune mediators in the occurrence of acute CHD events, , and prospective epidemiologic studies show a strong and consistent association between acute CHD and systemic inflammation markers. ,
Inflammation and Atherosclerosis: Many Questions
Although oxidized lipoproteins and vascular inflammation are considered to play an important role in CHD, no antioxidant and no anti-inflammatory treatments have been shown effective in randomized clinical trials. The same observation exists with inflammation; despite the role of macrophages and activated lymphocytes in atherosclerotic lesions, no anti-inflammatory drugs have been useful so far (see Chapter 25 ).
Nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids are ineffective, and patients with arthritis treated with these drugs have more CHD complications than those not exposed to these drugs. Potential explanations are a predisposition to insulin resistance and metabolic syndromes created by glucocorticoids, which are major risk factors for CHD. In patients with established CHD, high-dose dexamethasone-eluting stents do not reduce in-stent neointimal proliferation and restenosis, an experimental model of human accelerated coronary atherosclerosis. NSAIDs can be deleterious by causing an imbalance between prostacyclin and thromboxane A 2 and other mechanisms as well. , All these data and the perfect homeostasis that fits most individuals is highly complex and intriguing in the pathogenesis of atherosclerosis and CHD complications with so many pathophysiologic mechanisms and interactions. In this context, it is certainly relevant to question environmental factors including diet and the role of essential polyunsaturated fatty acids as mediators of inflammation in the development of CHD.
Inflammation, Atherosclerosis, and Essential Fatty Acids
All stages of the atherogenic process imply dynamic interactions between inflammatory cells, cytokines, and inflammatory eicosanoids within the arterial wall. According to the most popular theory to date, the conventional risk factors of CHD, including oxidized low-density lipoproteins (oxLDL), smoking, high blood glucose, and HBP, are harmful by initiating and promoting within the arterial wall the inflammation reaction associated with the atherogenic process. The earliest cellular event that can be detected in atherosclerosis is endothelial dysfunction that promotes monocytes rolling and adhesion to endothelial cells, and migration into the subendothelial space to the endothelium. This inflammatory response is facilitated by leukocyte-derived adhesion molecules expressed on the surface of endothelial cells. This process is thought to be driven by proinflammatory cytokines, and chemo-attractant chemokines and cytokines. Oxidized LDLs are thought to promote the accumulation of monocytes-macrphages into the subendothelium and the formation of foam cells. Foam cells are a hallmark of fatty streaks, the first (but still reversible) visible stage of atherosclerosis. A later stage of inflammation is characterized by fibrosis, a major feature of atherosclerosis produced by the proliferation of smooth muscle cells that migrate in the subendothelium from the muscular layer of the artery under the influence of various mitogenic and growth factors, such as the platelet-derived growth factor. Fibrosis is a repair process that contributes to irreversible sclerosis and coronary obstruction, but is not subject to thrombotic complications because fibrosis is, in theory, a stabilizing factor of the plaques.
Although the inflammation theory of atherosclerosis is well anchored, , it is partly speculative as it does not account for the failure of antioxidant and anti-inflammatory treatment , drugs to prevent CHD complications. New refinements in the theory are therefore required.
Of growing interest now are the effects of dietary fatty acids on immune parameters and on inflammatory process. Long-chain omega-6 PUFAs LA and even more arachidonic acid (AA) are potent inhibitors of lymphocyte function , as are omega-3 PUFAs. , These effects could be mediated partly by antagonizing inflammatory substances. Other nonessential dietary fatty acids, for instance the omega-9 family, can also be involved in the inflammation process.
Actually, omega-6 PUFAs are now seen as proinflammatory and omega-3 PUFAs as anti-inflammatory. Arachidonic acid, the major omega-6 PUFA in inflammatory cells, is the dominant substrate for eicosanoid synthesis that produces the major proinflammatory mediators potentially involved in CHD. , Blocking the initial step of AA synthesis in platelets at the level of cyclooxygenase-1 (COX-1) enzyme system does result in inhibition of platelet function. Most, but not all studies have suggested, however, that low doses of aspirin are as effective as the higher anti-inflammatory doses to prevent CHD complications, suggesting that the benefit derived pertains more to antithrombotic effects of the drug rather than anti-inflammatory effects. Nevertheless, controversies still persist on the best doses of aspirin that reduce CHD complications. It could also be that the optimal doses differ between populations. Indeed, recent data suggest that low-dose aspirin is not of major benefit in primary prevention, and also in specific patients such as diabetic patients with an asymptomatic vascular disease and cardiac transplanted patients. ,
The absence of a better efficacy of high doses of NSAIDs raises important questions on the inflammatory theory of atherosclerosis considering that platelets regulate a variety of inflammatory responses through their interaction with the endothelium beyond their role in hemostasis and thrombosis. They link inflammation, thrombosis, and atherosclerosis, highlighting the concept of atherothrombosis where thrombus formation is a starting point for progression of the disease through organization of residual thrombi. Apart from specific conditions such as accelerated coronary atherosclerosis after heart transplantation, , the availability of conclusive human data to support the atherothrombotic theory is somewhat limited.
A second question relates to the role of inflammatory eicosanoids (from any source) in vascular inflammation and CHD. Why do substances blocking AA metabolism and the production of inflammatory eicosanoids and exhibiting potent anti-inflammatory effects (such as NSAIDs) have no effects , on CHD complications?
A third crucial question is how meaningful is the metabolic competition between the different families of PUFAs (omega-6, omega-9, and omega-3) in the vascular and anti-inflammatory effect of NSAIDs. Could COX inhibition have the same clinical effect in patients with very different dietary intakes in omega-9, omega-6, and omega-3 fatty acids?
In view of the complexity of these questions, only certain aspects of the role of essential PUFAs in CHD through their pro- or anti-inflammatory properties will be discussed.
There are many recent reviews of the biology and metabolism of essential PUFAs. , Essential PUFAs are fatty acids that contain two or more double bonds; the nomenclature is based on the number of double bonds and the position of the first double bond counted from the methyl terminus of the acyl chain. Thus, an 18-carbon fatty acid with two double bonds in the acyl chain and with the first double bond on carbon number 6 from the methyl terminus is termed 18 : 2 omega-6 (or 18 : 2n-6). The common name of this fatty acid is linoleic acid (LA) and it is the simplest member of the omega-6 family of PUFAs. Linoleic acid can be further desaturated by insertion of a double bond between carbons 3 and 4 to yield alpha-linolenic acid (ALA; 18 : 3 omega-3 or 18 : 3n-3), the simplest member of the omega-3 family of fatty acids. Plants, but not mammals, have the desaturase enzymes required to synthesize LA and ALA. For this reason, LA and ALA are said to be “essential,” which means that they have to be supplied through our daily diet to cover our needs ( Fig. 31-1 ). Plant seed oils (and margarine) from corn, sunflower, and soybean are the main sources of LA in the Western diet. Nuts, canola oil, and green leafy vegetables are the main sources of ALA in the Western and Mediterranean diets. LA is the most important PUFA in the Western diet with an average intake between 12 and 20 g/day, and an LA to ALA ratio of 20 or 25 to 1 depending on the populations studied. The minimum intake of ALA for the prevention of cardiovascular disease (CVD) should be about 2 g/day and the preferred LA to ALA ratio of 4 or less. In many countries, however, the ALA intake is lower than 1 g/day. LA and ALA are the main PUFAs in the Western and Mediterranean diets and longer-chain PUFAs (with 20 carbons or more) are consumed in small amounts: from 50 mg (often) to 500 mg (rarely)/day for AA (20 : 4n-6) and for the long-chain omega-3 PUFAs mostly found in fish, eicosapentaenoic acid (EPA; 20 : 5n-3) and docosahexaenoic acid (DHA; 22 : 6n-3). Mammals are in theory able to synthesize EPA and DHA from ALA. In fact, in patients at high risk of CVD complications, a high ALA intake resulted in a significant increase in blood and tissue EPA levels, whereas the increase in DHA was low and not significant. Thus, DHA is often considered essential like LA and ALA, and it is prudent to provide for minimum amounts of it at least 200 to 500 mg DHA/day, depending on the associated amounts of ALA and EPA present in our daily diet. Unlike ALA (the precursor of EPA), oleic acid (18 : 1n-9) is consumed in substantial amounts in the typical Western diet and is not an essential fatty acid. Oleic acid is the precursor of eicosatrienoic acid (ETA; 20 : 3n-9), the main omega-9 PUFA potentially involved in inflammation by competing with AA (and EPA) at the COX and LOX (lipoxygenase) levels. However, there is little ETA in cell membranes, probably because of the overwhelming competition from dietary LA and ALA for the relevant desaturase and elongase enzymes. ETA is nonetheless assumed to decrease synthesis of leukotriene (LKT) B 4, a major inflammatory mediator, partly through a direct effect on LKTA 4 hydrolase ( Fig. 31-2 ). ETA also is a substrate for 5-LOX and may compete with AA for the formation of LKTA 4 , especially in case of severe LA restriction leading to elevated ETA concentrations. It is noteworthy that the Mediterranean diet is poor in LA and rich in oleic acid, which is another context where ETA concentrations are relatively high compared with the LA-rich Western diet. Thus, whatever the nutritional context (severe LA restriction or Mediterranean diet), and in partial analogy to the situation with EPA, elevated ETA concentrations can also alter the balance of eicosanoids produced by leukocytes toward a potentially less inflammatory mixture. The effect of ETA on COX is less clear than on 5-LOX although inhibition of endothelial (PGI 2 ) production has been ascribed to ETA. This could, at least theoretically, increase the risk of thrombosis. Thus, a traditional Mediterranean diet with high intakes in oleic acid and omega-3 PUFAs, from both vegetable and marine sources, and low intakes in saturated fatty acids and LA may be the best compromise to reduce the risks of both inflammation and thrombosis. This has been confirmed in clinical trials. In any case, as emphasized by several major investigators in the field, the background omega-6 PUFA content of the diet is a key issue when fortifying diets with either omega-9 and/or omega-3 fatty acids with a therapeutic or health-enhancing purpose. A key link between PUFAs and inflammation relates to the fact that the family of inflammatory mediators termed eicosanoids is generated from 20-carbon PUFAs released by cell-membrane phospholipids (see Fig. 31-2 ). Inflammatory cells are thought to typically contain a high proportion of the omega-6 AA and low proportions of the omega-3 EPA. In fact, the AA to EPA ratio is extremely dependent on the dietary habits of the populations in question. In persons following a typical Western diet (with a very high AA to EPA ratio), AA is the dominant substrate for eicosanoid synthesis. In contrast, in persons following a Mediterranean diet poor in omega-6 PUFAs (but rich in omega-9 oleic acid and omega-3 PUFAs), the relevance of AA and AA-derived eicosanoids is reduced. Eicosanoids include prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LKTs), and many other less studied substances (see Fig. 31-2 ). AA is mobilized from cell membranes under the effects of phospholipases and subsequently acts as a substrate for the enzymes that synthesize eicosanoids. The metabolization of AA by COX gives rise to the 2-series PGs and TXs. However, when EPA is the substrate for COX instead of AA, the eicosanoids that are produced belong to the 3-series, the properties of which are very different (less inflammatory, less vasoconstrictive, less prothrombotic) from those of the 2-series. Substances derived from ETA are less well characterized and their physiologic roles are not clearly determined.
There are two isoforms of COX: COX-1 is a constitutive enzyme and COX-2 is induced in inflammatory cells as a result of stimulation (for instance by cytokines produced by activated leukocytes) and accounts for the marked increase in eicosanoid production that occurs in activated cells. It is very important to understand that PGs are formed in a cell-specific manner (see Fig. 31-2 ). For instance, monocytes (and macrophages) produce large amounts of PGE 2 and PGF 2 , neutrophils produce moderate amounts of PGE 2 and mast cells produce PGD 2 . Arachidonic acid metabolization through the 5-LOX pathway gives rise to hydroxyl and hydroperoxyl derivatives and to the 4-series LKTs. Eicosapentaenoic acid (EPA) metabolization by the 5-LOX pathway gives rise to 5-series LKTs, which have a considerably lower inflammatory effect than 4-series LKTs.
One of the major inflammatory AA-derived 2-series PGs is PGE 2 . Its proinflammatory effects include fever, increased vascular permeability and vasodilatation, as well as increased pain and edema. PGE 2 induces COX-2, upregulates its own production by leukocytes, and induces the production of inflammatory cytokines (TNF, interleukins), which are other major mediators of inflammation that are able to recruit new leukocytes and again induce COX-2. However, PGE 2 was also found to inhibit 5-LOX, decreasing the production of the 4-series LKTs, and to induce 15-LOX, promoting the formation of lipoxins. The latter mediators have potent anti-inflammatory effects , indicating that the same compound, namely PGE 2 , possesses both pro- and anti-inflammatory actions, whereas PGE 3 derived from EPA may apparently be less active than PGE 2 . This may explain some puzzling data showing benefits from PGE 2 in some inflammatory compartments, especially those where 4-series LKTs exert damaging effects. In fact, one of the major inflammatory AA-derived eicosanoids of the 4-series LKTs is LKTB 4 , which increases vascular permeability, is a potent chemotactic agent for leukocytes, and increases the generation of reactive oxygen species and production of inflammatory cytokines. LKTB 4 was recently shown to play an important role in the atherosclerotic process (using the intima-media thickness as a surrogate marker of atherosclerosis) in certain patients with a specific polymorphism (variant 5-LOX genotypes). Interestingly, a protective effect of omega-3 PUFAs and a deleterious effect of omega-6 PUFAs were shown in that study, suggesting that contrary to the results of large randomized trials, where the protective effect of EPA plus DHA appeared to be confined to myocardial anti-arrhythmic effects, long-chain omega-3 PUFAs may also be able to slow down the progression of the atherosclerotic process. In addition, it is possible that incorporation of EPA and DHA in the plaque might have a stabilizing (anti-inflammatory) effect, as shown in a recent study, allowing prevention of acute ischemic events. This suggests that EPA plus DHA may inhibit the generation of metalloproteinases, , compounds that are potentially involved in plaque vulnerability and ulceration and subsequent thrombotic complications. Further studies are obviously needed to support this assumption.
The PGE 2 and 4-series LKTs story illustrates the complexity of the health effects of eicosanoids and the necessity to be careful when using potent pharmacologic agents to manage them. As shown with the anti-COX-2 (coxib) agents, the ultimate outcome may be less appealing than previously expected, with a tragic increased risk of CHD complications. ,
The EPA-derived 3-series of PGs and 5-series of LKTs are considerably less inflammatory than those derived from AA. Increased consumption of omega-3 PUFAs results in increased proportions of omega-3 PUFAs, especially EPA in inflammatory cell phospholipids, at the expense of AA. This was shown to result in decreased production of PGE 2 , TXB 2 , and LKTB 4 by inflammatory cells and, at the same time, increased production of PGE 3 , TXB 3 , and LKTB 5 . The functional significance of this is that the mediators derived from EPA are less potent than those derived from AA. It may be exaggerated, however, to say that EPA-derived eicosanoids are anti-inflammatory. Let it simply be said that they are less proinflammatory than the AA-derived eicosanoids.
Finally, recent studies have identified novel groups of mediators, termed E-series resolvins (for resolution phase interaction products) when derived from EPA by COX-2, and D-series resolvins (or docosatrienes and neuroprotectins) when derived from DHA by COX-2, which appear to have anti-inflammatory properties, especially during the resolution phase of the inflammatory process. The relevance of this specific anti-inflammatory activity for vascular inflammation associated with atherosclerosis remains to be confirmed.
Thus, the action of omega-3 PUFAs in antagonizing AA, the major inflammatory PUFA, appears to be a key anti-inflammatory effect of omega-3 PUFAs ( Box 31-1 ). Another major question is whether omega-3 PUFAs have real anti-inflammatory effects that may occur downstream of altered eicosanoid production.
BOX 31-1 
