Coronary heart disease (CHD) assessment during a routine physical exam can be either cursory or comprehensive or somewhere in between. Several famous U.S. clinics offer executive physicals which take from one to three days and represent the ultimate physical exam experience. One clinic even has a branch in Toronto dedicated to such exams. Such exams are not available or affordable for most individuals but the merits of extensive use of scans in such physicals can be debated because of both false positives and radiation exposure. If the motivation for the physical includes primary prevention of CHD, then it should include assessment of the risk of or presence of atherosclerosis and the risk factors for its progression. Given the undesirable radiation exposure from the coronary calcium electron beam tomography (EBT) scan, a compromise appears to reside in the assessment of emerging and novel risk factors and a shift in emphasis away from LDL cholesterol as a primary indicator and target for therapy. In fact, the recent Cholesterol Review, which appeared in this Newsletter, detailed some of the shortcomings of the present assessment system and in particular the failure of the Framingham Risk Score (10- year risk of fatal or non-fatal heart attack) or total cholesterol (TC) or LDL cholesterol to correlate with the presence or progression of atherosclerosis. This seems like a serious flaw in the assessment protocol given that as atherosclerosis progresses, the risk of symptomatic heart disease or other serious vascular problems increases. Furthermore, as discussed in the above- mentioned Research Review, neither TC nor LDL correlates at all with the risk of sudden cardiac death which is responsible for about 50% of all fatal cardiac events. Also, approximately 50% of individuals who experience a heart attack have either normal or even low LDL.1 Thus the interest seen in the recent literature concerning other methods of assessing risk that might provide better prediction of CHD, CHD related events and silent atherosclerosis and in addition provide guidance in interventions that provide an alternative to LDL lowering.

For the individual with no health complaints or concerns, the physical examination presumably has as its goal the primary prevention of chronic diseases such as cancer, diabetes and heart disease. Scheduling routine, periodic physical examinations is considered to be the sign of a prudent person. It is almost an article of faith that preventing the incidence of a disease or detecting signs of imminent incidence or signs of an early stage is preferable to treating the disease once it has become symptomatic, although the impact of early detection on mortality is often debated and there are those that maintain that for asymptomatic individuals, a too comprehensive examination runs the risk of false positives and unnecessary invasive diagnostic procedures and makes this conventional wisdom questionable. Nevertheless, the weight of evidence is probably on the side of early detection and aggressive primary prevention. In the context of this review, one reason is that there is considerable evidence that lifestyle including diet holds the key to the primary prevention of both CHD and type 2 diabetes and that the measures suggested by large prospective studies can reduce the risk by between 80% and 90%. These are huge reductions but this may not be generally appreciated or recognized in mainstream medicine even though the studies originate from premier U.S. institutions and were done by epidemiologists considered among the best in the world. The challenge then appears to be discovering risk factors present in an individual that are elevated but modifiable and convincing this individual to take them very seriously and act accordingly. The fear associated with not doing anything coupled with knowledge that the chances of more or less complete success are very high if action is taken may be enough to motivate some or most individuals. This review in part is concerned with the selection of the risk factors to assess, bearing in mind that these factors must be easily evaluated in the office setting and must be associated with interventions that have been shown effective, practical and feasible.

During a routine physical examination, it is probably true that most patients are merely passive observers while the physician makes the choice of what to do and what tests to order. While this is entirely normal and appropriate, it can work to the patient's disadvantage if the assessment of CHD risk is traditional, i.e. blood pressure, TC, HDL and LDL, smoking, fasting blood sugar, and weight for a given build and height. Some physicians will use some of this data to calculate the 10-year Framingham Risk Score, and if it is low, pay little attention to a more comprehensive assessment of CHD risk. A much more complete picture would result from additional blood tests and a few questions about psychological stress and depression. The additional blood tests come under the heading of emerging or non-traditional risk factors and are viewed with suspicion by some physicians since they do not appear in the guidelines they have come to depend on. But the informed patient can attempt to insist on at least the additional blood tests and if necessary comparing the results at home with what are thought to be threshold values for significant risk. Threshold values are even available in books written by well-known cardiologists who believe there is merit in going well beyond the traditional assessment and treating individual risk factors independent of overall risk.2

Over 250 risk factors have been identified for CHD. Two recent attempts to reduce the list to manageable length have come up with either 10 or 30 factors that are suggested as potentially improving the predictive power of the assessment protocol and addressing the problem of the under-diagnosis of silent atherosclerosis.3,4 But the evaluation of many of the factors in these lists is complex and more suited to the research rather than the primary care setting.

This review will examine emerging and non-traditional risk factors for CHD that could be added to a physical examination at no or minimal inconvenience and the commonly recommended reference values will be discussed along with interventions suggested by cardiologists to deal with elevated risk. Some of the material contained in this review is in an article by your editor which is in press in the journal Medical Hypotheses.5 We will first look at non-traditional risk factors that meet the criteria outlined above.

INSULIN RESISTANCE AND COMPENSATORY HYPERINSULINEMIA

That insulin resistance and the associated compensatory hyperinsulinemia are directly involved in the development of atherosclerosis, obesity, type 2 diabetes and coronary heart disease does not appear to be in dispute. The association between insulin resistance and coronary artery disease has been found to be both highly significant and independent of the effects of blood lipids, hypertension and smoking, and in addition, insulin resistance correlates strongly with carotid intima-media thickness which is also a measure of the extent of atherosclerosis.6 Much evidence supports insulin resistance and inflammation as fundamental hormonal and metabolic disturbances responsible for the cluster of disorders that the metabolic syndrome encompasses.7- 9 What is at issue here is the role given by the National Cholesterol Education Program (NCEP) ATP III guidelines10,11 to the metabolic syndrome and insulin resistance. The metabolic syndrome is a secondary component of the NCEP ATP III CHD risk assessment. It is defined as having three of the following: fasting glucose equal to greater than 6.2 mmol/L (110 mg/L), waist circumference > 102 cm (40 in) for men and 88 cm (35 in) for women, triglycerides equal to greater than 1.7 mmol/L (150 mg/dL), blood pressure equal to greater than 130/85 mm Hg, and HDL < 1.036 mmol/L (40 mg/dL for men and <1.295 mmol/L (50 mg/dL) for women. The World Health Organization and the International Diabetes Federation have definitions which differ significantly with that given by ATP III.12 But it appears important to distinguish between the metabolic syndrome and insulin resistance as a stand-alone factor. The problem is the inadequacy of fasting glucose for identifying those with insulin resistance and the fact that individuals with serious problems identified by one or more of the above criteria may still fail to be diagnosed as having the metabolic syndrome using the "any three" approach and perhaps fail to have their problem or problems adequately appreciated or treated. If LDL levels are not elevated and the 10-year risk is low, the question of the metabolic syndrome may not even be addressed since the question comes up in the guidelines after therapeutic lifestyle changes have been initiated, but this would be indicated only if LDL was above the goal set by the guidelines. Attention is first directed to triglyceride levels in connection with the question of the metabolic syndrome in spite of its relevance in connection with that aspect of dyslipidemia (high TG, low HDL) associated not only with insulin resistance but also with enhanced risk of CHD.13,14 Also, neither the metabolic syndrome nor high TGs are considered major risk factors in the ATP III guidelines.

Gerald Reaven, one of the world's leading metabolic syndrome researchers, has recently addressed these issues in several publications and takes the position that diagnosing the metabolic syndrome has neither pedagogical nor clinical utility.12,15 In connection with identifying insulin resistance, Reaven points out that one study of about 500 apparently healthy individuals found that impaired fasting glucose had a very low sensitivity of about 10% for identifying those with insulin resistance. He also points out that impaired fasting glucose accounts for only 5-15% of the variance in insulin mediated glucose disposal in the population at large. Thus fasting glucose, even if it is embedded in the metabolic syndrome risk factor assessment and guideline design, cannot be regarded as a satisfactory surrogate for insulin resistance. Reaven also points out that the sensitivity for identifying insulin resistant individuals can be increased about threefold by measuring the plasma glucose after an oral glucose load and using the American Diabetic Association criterion for impaired glucose tolerance and recommends this approach.15

In the research setting, the gold standard for identifying insulin resistance is the euglycemic hyperinsulinemic clamp technique, a complicated procedure inappropriate in primary care. Approaches more suited to the office practice employ one of the following: (a) the 2-hour oral glucose tolerance test (OGTT) with either fasting and 2-hour blood glucose and insulin determinations, or a series of determinations that allow an average so-called steady state glucose value or the area under the glucose-time curve to be determined; (b) the use of the fasting insulin and glucose values in an simple equation (fasting insulin in µU/mL times the fasting glucose in mmol/L and divided by 22.5) to give the HOMA-IR measure which then has a cut-off for indicating insulin resistance; (c) the triglyceride (TG) to HDL ratio. The latter two approaches use just data normally collected in physical examinations although how widespread the knowledge is in the primary care community concerning currently favoured cut-offs or even the equation used to calculate the HOMA-IR, appears unknown. While not perfect, HOMA-IR correlates fairly well with the results from the euglycemic clamp technique,16 and is in fact used in studies to identify individuals with insulin resistance.

INFLAMMATION IS OF SECONDARY IMPORTANCE IN CURRENT GUIDELINES

It appears to be generally accepted that inflammation is a cardiovascular risk factor and a cause of atherosclerosis.17 The current protocol for judging CHD risk does not directly consider inflammation. This is compounded by the use of guidelines that tend to deemphasize or ignore insulin resistance and in addition completely ignore psychological stress, both of which also appear to operate on the cardiovascular system through an inflammatory mechanism.18 C- reactive protein as a biomarker for inflammation was suggested a decade ago and numerous studies have shown that serum levels are related to cardiovascular risk.19 In addition, data suggest that high-sensitivity CRP (hsCRP) is a stronger predictor of cardiovascular events than LDL.20 Based on the consistency of prognostic data for hsCRP in connection with CHD and the practicality of its use in the primary care setting, it has recently been proposed that serious consideration be given to adding hsCRP to risk score algorithms for global risk assessment.21 The debate concerning this has recently been reviewed by Ridker who takes the position that hsCRP screening should be used in primary prevention for those at 5% to 20% 10-year risk based the Framingham Risk Score.22 The JUPITER trial which was examining the use of a statin drug which lowers hsCRP in a group of individuals with low LDL (< 130 mg/dL) who have elevated hsCRP levels (>2 mg/L) was recently prematurely terminated because the reduction in CHD events was sufficiently large to render continuing testing unethical. The fact that this occurred so soon after the intervention suggests that the benefit derived from inflammation reduction, not cholesterol lowering. The CRP lowering effect of statins is one of many non- cholesterol lowering aspect of these drugs. Part of the rationale for this study came from the observation that half of all heart attacks and strokes in the U.S. occur among those who have normal or even low levels of LDL.1

Diet, sedentary lifestyle, overweight and obesity, psychological stress and depression, and chronic infections such as mild gum disease are common causes of chronic low-level inflammation, frequently called silent inflammation since it is generally not accompanied by the classical inflammatory symptoms. This is type of inflammation that impacts long term primary prevention of CVD. Most of these causes are amenable to intervention as will be discussed in Part II. There are of course many causes of inflammation that are far from silent such as physical injuries, respiratory and other symptomatic infections, allergies, arthritis etc., but many of these sources of inflammation are not also not chronic. The most common non-silent sources of chronic inflammation are arthritis and rheumatoid arthritis.

PSYCHOLOGICAL STRESS, DEPRESSION AND INFLAMMATION

It has been recognized for some time that psychological stress and depression increase the risk of atherosclerosis, CHD and adverse CHD events.23-25 The INTERHEART study which recently reported has provided new and highly significant evidence of the importance of stress and depression as risk factors for first heart attack (myocardial infarct or MI) in a case-control study involving 52 countries and 10 geographical regions including North America.26 It was found that the odds ratio (OR) for risk of first MI associated with psychosocial factors was 3.25 with smoking at 2.87, hypertension at 1.91, and diabetes at 2.37. A surrogate marker for cholesterol was used in the analysis which gave for the apolipoprotein B/apolipoprotein A-1 ratio (ApoB/ApoA-1) an OR of 2.87. These results applied with statistical significance to men and women, old and young and in all regions studied. It should be noted in connection with these results that other than age, no component of the Framingham Risk Score has an adjusted hazard ratio > 3.0 and most in fact are between 1.6 and 2.0.22 The population attributable risk (PAR) is the relative risk weighted by the prevalence in the population being studied and provides an indication of the percentage of the population at risk. The PAR associated with psychosocial factors was 32.5% but varied considerably with gender and from country to country. In North America, the PAR associated with psychosocial factors was 63.7% for men and 32.7% for women. The factors included work stress, stress at home, general stress, financial stress, stressful life events, and depression. These were quantified by the use of a questionnaire professionally administered. Similar results were recently reported where a relative risk of 2.63 for incident CHD was found for patients with a high level of psychosocial stress when compared to those with low levels.27

In addition there is now some evidence from EBT and angiography studies that psychological stress and depression are implicated as risk factors for the presence and progression of atherosclerosis. While two recent cross-sectional studies found null results,28,29 both looked only at the current situation and one was criticized as underpowered.30 On balance the evidence from a number of studies appears to point to a significant association, especially as regards such characteristics as anger, hostility and major depression.31-39

There is also indirect evidence regarding the positive association between stress and coronary calcification from studies that revealed correlations between the CACS and the abnormal diurnal behaviour of cortisol levels.40 Impaired cortisol response has been found to characterize individuals with coronary artery disease.41 Thus there is evidence pointing to abnormal cortisol control (dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis) in connection with the adverse effects of psychological stress, and this in turn points to inflammation as a component of the biological mechanism.42-44 An association between cardiac pathology, the acute phase response and the over-activity of the sympathetic limb of the autonomic nervous system with concomitant inflammation has also been observed and discussed.7,45,46 The close connection between the inflammatory consequences of psychological stress and insulin resistance, obesity, atherosclerosis, and type 2 diabetes has recently been reviewed in considerable detail by Black.47 The frequent parallel development of atherosclerosis and type 2 diabetes also suggests that primary prevention of the latter includes the former.

These results appear significant. Studies found psychosocial stress to have an odds ratio comparable to diabetes. Since diabetes is considered a CHD-equivalent risk factor in current protocols, this result underscores the potential importance of psychological factors in risk assessment and intervention.

FIBRINOGEN

Plasma fibrinogen is a vital component of the coagulation process and a major determinant of blood viscosity and flow. There is considerable evidence that elevated levels of this blood component are associated with increased risk of cardiovascular disorders including CHD, stroke and other incidents related to blood clots. The relationship between high levels of fibrinogen and atherosclerosis and thrombosis is complex but it is thought that fibrinogen also plays a key role in the process of atherosclerotic plaque formation. Epidemiologic studies have established that elevated plasma fibrinogen levels are an independent and modifiable risk factor for coronary heart disease.48,49 Individuals in the upper quintile of plasma fibrinogen as compared to the lowest quintile have a 1.5 fold greater odds of an adverse CHD event as compared to individuals judged by the lowest to the highest quintile of total cholesterol.50 Thus fibrinogen is commonly included in the blood tests ordered by physicians who include emerging risk factors in their assessment of CHD risk.

OMEGA-3 INDEX

The Omega-3 Index is one of the latest emerging risk factors, in particular for sudden cardiac death (SCD). The common definition of SCD requires death to occur within an hour of the onset of the episode. SCD accounts for about half the deaths associated with adverse CHD events.51 In this context, the omega-3 fatty acids are thought to be directly involved in the mechanism of arrhythmia which is the principal dysfunction associated with SCD. This index consists of the concentration of the long-chain omega-3 fatty acids EPA and DHA i.e. EPA + DHA, expressed as a percentage of the total phospholipids in the red blood cells. In prospective cohort and case- control studies, when equal to less than 4% was used as a reference, an index value of equal to greater than 8% was associated with greatest sudden cardiac death (SCD) risk reduction with a remarkably low OR of approximately 0.1, i.e. a 90% lower risk, and an approximate inverse linear relationship of the OR and the Omega-3 Index between these two limits has been observed.52-54 Since the blood or tissue omega-3 fatty acid content is considered an indication of inflammation status, this risk factor goes beyond simply introducing a measure of SCD risk related to arrhythmia.55 Commercial laboratories offer this test and there is also a mail-in test available in the U.S. Nevertheless, the assay is not commonly done in routine physical exams and it is probably safe to state that knowledge of this risk factor and the existence of an assay is far from common among primary care physicians.

VISCERAL ADIPOSITY

This translates into excess abdominal fat, the apple shape or the beer-belly, and is one of the metabolic syndrome risk factors and a well-established risk factor for CHD. Some regard abdominal fat as organ-like in the sense that it is involved in the secretion of inflammatory substances. The best way to assess the risk associated with excess visceral adipose tissue appears controversial.56 There is some evidence that the waist-to-hip ratio may be superior to waist circumference.57,58 It has also been suggested that waist circumference be combined with triglyceride levels and there is evidence that when the former is enlarged and the latter elevated, the EWET factor or so-called hypertriglyceridemic waist, that this becomes a very good indicator of risk for coronary artery disease.59

OTHER RISK FACTORS

Two other emerging risk factors need mentioning. They are lipoprotein(a) and homocysteine. Homocysteine will not be discussed since while the evidence is strong that it is a risk factor, a number of intervention studies using folic acid alone or in combination with vitamin B6 and B12 have proved uniformly disappointing with a vast collection of statistically insignificant results for a variety of endpoints such as cardiovascular disease, CHD, stroke and all-cause mortality.60 Lipoprotein(a) is a cholesterol-rich lipoprotein similar in structure to LDL cholesterol but containing an additional molecular component thought to be involved in the mechanism of thrombosis. Thus some regard lipoprotein(a) as a risk factor for both CHD in general and as well clot formation. However, while lipoprotein(a) has been documented as a risk factor for CHD, there is no consensus as regards the mechanisms whereby this risk is conferred.61

A PROPOSED APPROACH TO CHD RISK ASSESSMENT

The risk factors and serum markers that are consistent with the theme of inflammation, insulin resistance and psychological stress are as follows.

• Psychological stress and depression
• Elevated TG/HDL ratio or the combination of high TGs and low HDL.
• Evidence of insulin resistance from an unfavourable HOMA-IR calculation based on fasting insulin and glucose, or a positive test for insulin resistance based on the oral glucose tolerance test.
• Omega-3 Index, a blood test based index that examines omega-3 status.
• Waist-to-hip ratio (WHR), or waist circumference (WC) and TG levels used together.
• C-Reactive protein (i.e. high sensitivity CRP or hsCRP)

To these can be added hypertension, elevated fibrinogen, current smoking and diagnosed diabetes, the latter normally considered a risk factor equivalent to existing CHD. Total and LDL cholesterol have been omitted for reasons set out above and because the TG/HDL ratio should provide a satisfactory measure of the blood lipid associated risk and is tied in with insulin resistance and the prevalence of small, dense LDL particles which are thought to be the dangerous LDL component. This set of factors is consistent with the primary care setting in that, aside from stress assessment, blood work and simple measurements are all that are required.

THRESHOLDS AND INTERVENTIONS

While the thresholds for elevated risk given below are mainly obtained from the literature, the interventions provided are mostly those suggested by the cardiologists Dr. Stephen Sinatra and James Roberts, who have been a strong advocate of using emerging risk factors in CHD assessment in what is termed "The New Cardiology Risk Assessment.2 They call these "interventions that work for us."

Psychological Stress and Depression
The assessment of chronic stress and depression in non-pathological cases is a big problem but there is growing interest in the cardiology community regarding this aspect of the risk picture, which is termed behavioural cardiology, and which involves addressing both assessment and therapy.25 This interest may accelerate the development of user-friendly questionnaires that can be administered by office or nursing staff. One of the serious problems associated with stress as a risk factor is that in many cases where the origin is work-related or domestic, the root cause may difficult or impossible to eliminate (changing jobs, avoiding toxic boss-worker relationships, solving marital problems, overcoming the stress of separation and divorce, etc, etc. may be next to impossible for many). Eliminating the root cause of depression may even be more difficult. While therapy is an obvious route to take, it may be that the only practical solution is to attempt to neutralize the inflammatory effects of stress and depression, an area that deserves research attention.

Psychological stress probably is never an issue during a physical exam unless the physician asks probing questions, something unlikely since this is somewhat outside the area of expertise of most in the primary care field. However, requests for tranquilizers or sedatives might prompt questions that would reveal a serious problem. It is probably more common that a patient will present with signs of depression or actually cite depression as an important problem or even the reason for the office visit. While one standard response is pharmaceutical based, it is far from clear that antidepressants will in general significantly reduce the depression induced chronic inflammation or diminish the adverse vascular effects of this inflammation. However, the selective serotonin uptake inhibitors (SSRIs) have been shown to have anti-inflammatory properties.62 In fact, in one study, significant declines in CRP were found independent of the antidepressant action of standard doses of SSRIs.63 However, there is some evidence that another class of antidepressant, the tricyclics, can increase ischemic heart disease.64 Nevertheless, for both chronic psychological stress and depression, it appears important to get at the root causes and attempt to attenuate them through therapy or by directly eliminating them. But as pointed out above, the latter may be impossible if the root of the problem is work related or domestic stress. Obviously, this is a difficult but very important area. One should not forget that there is good evidenced that psychosocial stress is approximately equivalent to diabetes in terms of CHD risk. The following self-administered stress test may prove useful.

If the answers to the following questions are (a) quite a bit; (b) very much; or (c) extremely, the indication would be for evaluated stress. These are adapted from Lamyre and Tessier.65

• I feel rushed and do not seem to have enough time.
• I have chronic physical aches and pains such as a sore back, headache and stiff neck.
• I feel overworked, preoccupied or tormented.
• If feel confused. My thoughts are either muddled, not focused or I lack concentration.
• I feel as if I had a great weight on my shoulders.
• I experience difficulty in controlling my reactions, emotions, moods or gestures.
• I feel stressed-out.

There is also an online stress test complete with analysis of the results that has been used in the medical resident-intern setting as well as in comprehensive physicals at Wellmax Center for Preventive Medicine, which offers about as complete a physical as one could ever want. It takes 3-4 days! This evaluation tool can be accessed for a nominal fee (ESSI Stress Map at http://www.essisystems.com. An important and probably underappreciated approach to the treatment of depression is physical exercise. In fact, aerobic exercise has been shown to be as effective as antidepressants in some situations. This subject, along with many other exercise- brain benefits, has been treated in detail in a new book by John J. Ratey, M.D., a psychiatrist who is on the faculty of Harvard Medical school.66

Fasting TG/HDL Ratio
Only a limited number of studies are available. This ratio is also sensitive to the units used. When the units mg/dL are used, Sinatra gives a ratio of 4 (1.7 in mmol/L) as the threshold for elevated risk. A recent study puts high risk at > 3 (1.3) and medium risk at 2.5-3 (1.1-1.3).67 The ratio will always be available from the standard fasting blood lipid profile since triglyceride levels are needed to calculate LDL which is not directly measured. Interventions to lower TG levels include niacin (20-50% decrease), fibrates (20-50% decrease), and fish oil (20-50% decrease). Some statin drugs also reduce TGs. To raise HDL, niacin appears the provide benefit with a 15-35% elevation. Exercise and reduced carbohydrate diets influence the TG and HDL levels in the desired direction.2,68

Insulin Resistance
Given the inconvenience of the oral glucose tolerance test which requires a fasting blood sample and then another at 2 hours after glucose intake, the HOMA-IR seems like the most convenient approach. It uses the fasting blood insulin and glucose values. The equation is fasting insulin in µU/mL times the fasting glucose in mmol/L divided by 22.5. There does not appear to be a consensus regarding the threshold for identifying insulin resistance, but the value of the index of > 2-2.5 appears indicative. However, the use of the HOMA model for older men has been questioned and it has also been found that in Koreans, the model has limited validity for subjects with lower BMI and in lean type 2 diabetics with insulin secretion problems. An alternative is the oral glucose tolerance test. The American Diabetes Association definition of impaired glucose tolerance can be use to identify individuals with insulin resistance.15 The definition requires a plasma glucose level of 140 to 199 mg/dL (7.8-11.0 mmol/L) two hours after a 75 g oral glucose challenge for an individual initially fasting. Sinatra uses a fasting insulin level > 17 µg/L as a threshold. Interventions that improve insulin sensitivity which include weight loss, exercise, and restricting carbohydrates, especially sugary or high-glycemic carbohydrates. Suggested supplements, according to Sinatra and Roberts, include alpha-lipoic acid, coenzyme Q-10, cinnamon, magnesium and chromium picolinate.

Omega-3 Index
Oral EPA and DHA from either fish oil or from preparations containing the purified fatty acids have been repeatedly and consistently shown to increase this index. Typical daily doses for someone who has a low value are in the range of 1-3g/d of purified fish oil. Purified preparations typically contain more EPA than DHA in a ratio of around 2 to 1 and typical pharmaceutical grade preparations purified by molecular distillation will contain about 400 mg of EPA and 200 DHA per gram of oil. Cod liver oil provides somewhat less. Safety even at relatively high doses does not appear to be an issue.69

Waist-to-Hip Ratio (WHR) or Waist Circumference
The best way to assess risk associated with visceral adipose tissue appears controversial.56 There is some evidence that the waist-to-hip ratio may be superior to waist circumference.57,58 It has also been suggested that waist circumference be combined with triglyceride levels and there is evidence that when the former is enlarged and the latter elevated, the EWET factor or so-called hypertriglyceridemic waist, that this becomes a very good indicator of risk for coronary artery disease.59,70 In the World Health Organisation (WHO) definition of metabolic syndrome, they use a risk threshold for the WHR of > 0.9 for men and > 0.85 for women. For the waist circumference thresholds, the ATP III guidelines give > 102 cm (40 in) for men and > 88 cm (35 in) for women. The comparable numbers from the International Diabetes Federation are equal to greater than 94 cm (37 in) for men and equal to greater than 80 (31.5 in) cm for women. For the EWET, i.e. the combination of elevated waist circumference and triglycerides, one threshold suggested for men is equal to greater than 90 cm (35.5 in) and 177 mg/dL (2 mmol/L).59 However, a common threshold recommended in general for triglycerides is equal to greater than 150 mg/dL (1.7 mmol/L) above which concern is appropriate. Interventions appear limited. Obviously, exercise and weight reduction are indicated.

High Sensitivity C-Reactive Protein
The reason for the designation "high sensitivity is that historically CRP was measured with a limit of sensitivity that rendered it useless in this context. A commonly quoted threshold for elevated risk is >1.5 mg/L. One problem with CRP is that it can be temporarily elevated by an infection. Thus elevated values call for one or more repeat measurements to attempt to eliminate this potential false alarm. The calls for CRP to be added to the standard risk profile become louder each year as the evidence accumulates regarding the value of this indicator of inflammation in the context of CHD risk. CRP can be lowered by statins, exercise, low dose aspirin, and fish oil. In addition, Sinatra and Roberts recommend nattokinase and coenzyme Q-10. Diets considered non-inflammatory or anti-inflammatory also reduce CRP.

Fibrinogen
Sinatra and Roberts give 180-350 mg/dL as the healthy range. To lower fibrinogen, they suggest fish oil, garlic, bromelain, ginger and/or green tea and nattokinase. Nattokinase is available from health food stores or by eating the Japanese preparation natto, which is made from fermented soybeans and sold in Asian food stores.

CONCLUSIONS

The basic philosophy underlying the above discussion is that it is more important to recognize and deal with individual risk factors, place less emphasis on global risk assessment such as APT III or the traditional Framingham Risk Score and focus on inflammation and insulin resistance. Such an approach seems to have a better chance of dealing with underlying causes such as inflammation and insulin resistance before they manifest their adverse effects in symptomatic heart disease or diabetes, the latter being in fact a pre-CHD disorder carrying a huge increase in risk of eventually developing and dying from CHD. A good general reference for the subject of emerging or novel risk factors is Sinatra and Robert's book.2

INTRODUCTION

Part I provided a basis for the view that chronic, systemic low-level inflammation is an important risk factor associated with the development of insulin resistance, diabetes, atherosclerosis and coronary heart disease (CHD). Furthermore, the presence of the metabolic syndrome is a risk factor for all of the above. Thus it seems reasonable that primary prevention of CHD should focus on inflammation and the various aspects of the metabolic syndrome and this was systemized in Part I with a list of risk factors, their thresholds and potential interventions. If one has diagnosed metabolic syndrome, then the challenge is reversing it or in a broader context, normalizing as many of the criteria as possible. If one does not qualify for this diagnosis, then preventing the metabolic syndrome is the challenge along with maintaining all the criteria in the normal range. In addition, attention must be paid to the other risk factors discussed in Part I. The goal of the suggested prevention program is the normalization of risk factors discussed in Part I and this is strongly associated with the goal of preventing insulin resistance, type 2 diabetes, and vascular disease including CHD.

In the context of primary prevention of CHD, non-pharmaceutical interventions appear limited to diet, exercise, supplements and the minimization of psychological stress and depression. Diet is highly controversial and political, but the importance of exercise not even debatable, and dealing with psychological stress and depression is clearly challenging, given that its root causes frequently are not easily eliminated.

Part II will mostly deal with the issue of diet since strong arguments can be advanced that dietary factors play a key role in that they are associated with unfavourable levels of many of the risk factors discussed in Part I. The question of what is the best diet for 21st century homo sapiens is highly controversial with a wide range of distinctly different options along with their proponents and detractors. Government agencies have their recommendations as do a number of medically related organizations such as the American Heart Association, the various diabetes associations, the National Cholesterol Education Program (NECP), etc. The diversity of approaches to diet is evident to anyone browsing the diet section of a large bookstore. Some view diets as a weight loss tool; others take a boarder view that encompasses overall nutrition and disease prevention. In the context of this review, the central issue is the relationship between diet and inflammation. Are there diets or food patterns that raise inflammatory markers? Are there specific macronutrients that alter the inflammation balance? Since inflammation leads to insulin resistance which leads to diabetes which leads to cardiovascular disease (CVD) in general and CHD in particular, a lifestyle including diet that reduces the risk of type 2 diabetes is also of considerable interest. Such a diet will also be strongly associated with reducing the risk of acquiring the characteristic manifestations of the metabolic syndrome. In fact, it can be argued that the focus on cholesterol as the major risk factor for CHD and the primary target for therapy has provided a serious distraction from the real challenge in the primary prevention of CHD, i.e. the prevention of low-level systemic inflammation, insulin resistance and type 2 diabetes.

The connection between diet and heart disease has been the subject of countless studies, many of which were poorly designed and yielded meaningless results, and vast controversy has simmered for more than 30 years. The fat-heart disease hypothesis, which was initially advanced on the basis of selected data, became official science, an article of faith in medical and nutritional science, even though it remained a mere hypothesis under constant attack and under ordinary circumstances would have been relegated to the status of a weak and perhaps insignificant association of little importance. That this did not happen is a long story told most convincingly by Gary Taubes in his recent magnum opus titled Good Calories, Bad Calories. Challenging the Conventional Wisdom on Diet, Weight Control and Disease (Knopf, 2007).

Diet studies that try to sort out the impact of the individual macronutrients, i.e. fat, protein and carbohydrate, can be classified roughly into two groups. In one, the total number of calories remains constant whereas in the other, the energy intake is decreased. In the former, if the energy from one macronutrient category is decreased, this deficit must be made up by increasing the intake of another category. Thus more than one variable is always being changed. Within the major categories of fat, and carbohydrate, the composition of each can be changed by substitution while maintaining a fixed energy intake, or substitutions can be made along with a decrease in intake and thus energy. Studies that change the distribution of calories between fat, carbohydrate and protein and at the same time reduce energy intake are hard to interpret because of the two or more factors are changed at the same time. In some studies, exercise and even meditation and stress reduction are added to dietary changes which add significantly to the confusion. Randomized dietary intervention studies suffer from an unknown extent of compliance and those that are highly controlled are of necessity very short-term, and observation (follow-up) studies require multiple assessments with validated questionnaires in order to make sure that changes over time in diet patterns are taken into account. One of the most realistic approaches to dietary questions involves looking at patterns rather than the three macronutrients, since people eat meals, and in addition, alcohol in general and wine in particular, occupies a unique position in diet and lifestyle and is not normally considered part of one of the three macronutrients.

This review will focus on dietary patterns, inflammation and the risk of the metabolic syndrome, type 2 diabetes and CHD. It will be seen that there are dietary patterns and a certain lifestyle that have been found to provide dramatic risk reductions, reductions that in some cases are greater than anything that has been accomplished with pharmaceutical intervention. Furthermore, these diet patterns and lifestyle features also are associated with low levels of inflammation, insulin resistance, and favourable levels of the risk factors discussed in Part I.

DIETARY PATTERNS, AND RISK OF DIABETES AND CHD

Two large and important prospective follow-up studies from Harvard reported in 2000 and 2001.1,2 They endeavoured to determine the optimum dietary pattern for the prevention of CHD in men and women in the age group 38-63. These studies were part of the men's Health Professional Follow-up (44,875 men) and the Nurses' Health Study (69,047 women). The least favourable and the most favourable dietary patterns were termed "Western" and "prudent." The former was characterized by higher intake of red meat, processed meat, refined grains, sweets and deserts, French fries and high-fat dairy products. The prudent diet pattern consisted of higher intakes of vegetables, fruit, legumes, whole grains, fish and poultry. Fatal or nonfatal heart attack was the endpoint indicating CHD. At the end of the follow-up period, the highest adherence to the prudent pattern combined with the lowest adherence to the Western pattern showed a 50% reduction in CHD as compared to the combined lowest prudent patter and highest Western pattern group. A similar comparison for women found a 36% reduction.

Data from the Nurses' Health study was also used to investigate the proportion of coronary events that could potentially be prevented by adherence to a set of dietary and behavioral guidelines.3 The low-risk diet was high in cereal fiber, marine omega-3 fatty acids and folate, had a high ratio of polyunsaturated fat to saturated fat, was low in trans-fats, and had a low glycemic load. Behavioral guidelines required a body mass index of < 25 (not overweight) no smoking, moderate to vigorous exercise for at least one hour a day, and at least ˝ of an alcoholic drink per day. During fourteen years of follow-up, women who adhered to the low-risk guidelines had an 83% reduction in the risk of CHD and 82% of the coronary events in the total study cohort could be attributed to lack of adherence to this low-risk diet and lifestyle pattern.

Diabetes is a major risk factor for CHD. Thus diet and lifestyle factors that are effective in preventing CHD would be expected to impact the risk of diabetes. Put another way, preventing type 2 diabetes should be an important component of CHD prevention. In a study from the Nurses' Health Study, closely related to that described above which used essentially the same low-risk behavioural pattern (folate and fish omitted), a remarkable 91% reduction was found in the risk of developing type 2 diabetes over the 16 year follow-up.4 On the other hand, for men in the Health Professionals Follow-up Study, a high score for the Western dietary pattern combined with low physical activity almost doubled the risk of developing type 2 diabetes. Obesity carried an eleven-fold increase in risk.5

A new study that relates to the issue of diet patterns and the risk of CVD has just reported.6 The cohort was again from the Nurses' Health Study, and the follow-up was over 24 years with diet assessment carried out 7 times during this period with food frequency questionnaires. The main outcomes measured were nonfatal MI, CHD death and stroke, and the study examined the impact of adherence to the DASH diet pattern on these endpoints. Historically the DASH diet (Dietary Approaches to Stop Hypertension) was designed to examine the hypothesis that blood pressure lowering would result from a diet high in fruits and vegetables, moderate in low-fat dairy products, and low in animal protein but with substantial plant protein from legumes and nuts. Subsequent variations included sodium restriction and substituting part of the carbohydrate content with either plant protein or unsaturated fat.

In this study, adherence to the DASH diet was established by a score that depended on the intake of fruits, vegetables except potatoes, nuts and legumes, and whole grains. Negative points were given for the intake of sodium, red and processed meats and sweetened beverages. When the fifth vs. the first quintile for the adherence score were compared, there was a 27% relative risk reduction in total CHD, a 22% reduction in nonfatal MI, and a 34% reduction in fatal CHD events. These results were adjusted for a large number of confounders and were all statistically significant as were the trends for risk reduction across the quintiles. The DASH pattern differs somewhat from the patterns discussed above in that women with high scores consumed more fiber, and the intake of polyunsaturated and monosaturated fat was lower. Nevertheless the similarities with the prudent diet are noteworthy and highlight the importance of high fruit, vegetable, legume and nut intake.

It is interesting to compare the above results with those from the Woman's Health Initiative Randomized Controlled Dietary Modification Trial.7 In this trial, the dietary intervention involved reducing fat intake to 20% of calories by increasing the intake of fruits and vegetables to 5 serving per day and grains to at least 6 servings per day. It was assumed that the reduction of fat intake would be accompanied by a reduction in saturated fat intake, which in fact did occur (12.4% to 9.5% of total energy). Weight loss was not a goal, and there appears to have been no emphasis on whole grains vs. refined grains if one judges from the indicated intakes for the intervention and comparison groups. In fact, after three years, the intervention resulted in small increases in triglycerides and small reductions in HDL. This highlights the magnitude of the emphasis on fat reduction in this study. The comparison group was given a copy of Dietary Guidelines for Americans. After a mean of 8.1 years of follow-up, this intervention did not reduce the risk of CHD, stroke or CVD in postmenopausal women. Nevertheless, the reduction of dietary fat in general and saturated fat in particular is one of the pillars of mainstream medicine's approach to reducing the risk of CHD and the changes that occurred during this study were in keeping with the mainstream guidelines.

CHD AND THE MEDITERRANEAN DIET

The diets which exhibited significant risk reduction for CHD and diabetes resemble the Mediterranean diet. The Mediterranean diet is generally characterized as having a high intake of vegetables, legumes, fruits, nuts and cereals (that traditionally were largely unrefined) and a high intake of olive oil but a low intake of saturated fats, a moderately high intake of fish, a low-to- moderate intake of locally produced dairy products, mostly cheese and yogurt, a low intake of meat and poultry and regular but moderate intake of alcohol, mostly in the form of wine with meals. Interest focused on this diet when it was observed that in countries like Greece, and in particular Crete, when the traditional diet was consumed, the incidence of heart disease was very low as compared to European countries or the U.S. Interest was further stimulated by several randomized, controlled trials of Mediterranean style diets for secondary prevention of cardiac events. One of the most famous, the Lyon Diet Heart Study, found a 68% decrease in cardiac death and non-fatal MI over four years of follow-up when the comparison was with the Step I NCEP control diet. The Mediterranean diet had augmented omega-3 fats in the form of alpha- linolenic acid. This large secondary protective effect was found in spite of little or no change in cholesterol levels among the intervention diet participants, an observation that surprised those committed to the LDL hypothesis. In the GISSI-Prevention Study of over 11,000 post-MI patients, 1g/day of omega-3 fish-oil supplementation was added to the Mediterranean diet. A 30% decrease in CV deaths and a 46% decrease in sudden deaths were found. While these secondary prevention results are of great importance to individuals with CHD, this review is concerned with primary prevention.

With regard to the issue of dietary omega-3 fatty acids, there do not appear to be any randomized clinical trials, and with one exception, prospective cohort studies have only indirectly provided information. For example, in the Nurses' study, eating fish five times a week cut the risk of CHD mortality by 45% and in the Physicians Health Study, the relative risk of sudden death was lower among men with higher blood levels of omega-3 fatty acids.8

There have been two large prospective studies that directly addressed the connection between the Mediterranean diet and mortality. Both used a 9- or 10-point adherence scale for the Mediterranean diet. In one study involving a Greek population the risk of total mortality was reduced by 25% for a two-point increase in this score. The authors point out that magnitude in the reduction of mortality with greater adherence to a Mediterranean diet was compatible with the reported survival advantage of adult Mediterranean populations over North American and northern European populations.9 Another large prospective study of a U.S. population of average age 62 years examined the association between adherence to a Mediterranean diet and mortality. The decrease in all cause and CVD mortality for those with the highest conformity as compared to the lowest was 20-25%.10

A case-control study from Spain also found that the degree of adherence to a Mediterranean diet was as important factor associated with significantly decreasing the risk of a first MI. This study also supported the exclusion of high glycemic load foods.11

DIETARY PATTERNS AND THE METABOLIC SYNDROME

Dietary strategy that eliminates or reduces the risk of the metabolic syndrome not only addresses non-traditional risk factors but also the etiology of CHD at an early stage in its natural history. The following studies are of interest.

• In a study from Greece that used a national health and nutrition survey, it was found that individuals who consumed a Mediterranean diet had a 19% risk reduction of the risk of having the metabolic syndrome and if even a little or moderate physical activity was present, the risk reduction improved to 25%.12
• In another study from Greece, a dietary pattern characterized by cereals, fish, legumes, vegetables and fruits was inversely associated with waist circumference, systolic blood pressure, triglycerides and positively associated with HDL levels and resulted in a 13% risk reduction for the metabolic syndrome.13
• In a study of women 40-60 years of age in Tehran, Iran, a diet pattern characterized by high intake of fruit, vegetables, poultry, and legumes was associated with reduced risk of insulin resistance and the metabolic syndrome whereas a diet high in refined grains, red meat, butter, processed meat, and high-fat dairy products and low amounts of vegetables and low-fat dairy products was associated with a greater risk of this syndrome. This study was jointly carried out by nutritional epidemiologists from Harvard and Isfahan University in Iran.14

DIET, INFLAMMATION AND INSULIN RESISTANCE

Diets considered beneficial in the context of CHD should not only decrease the risk of hard events (fatal and non-fatal MI), but also decrease the risk of atherosclerosis or its progression, since this, after all, impacts directly on the origins of the problem. The primary prevention of hard events is a common and convenient endpoint for studies, but the prevention of diabetes, the metabolic syndrome, insulin resistance, and inflammation which may be the root cause of it all, seems essential. Thus the impact of diet on markers of CHD risk, and in particular the non- traditional risk factors, is of considerable interest and has been the subject of a number of studies.

In a review published in the Journal of the American College of Cardiology in 2006, dietary strategies were examined in connection with inflammation reduction.15 A highly inflammatory diet was high in refined starches, sugar and saturated and trans-fats, and poor in natural antioxidants and fiber from fruits, vegetables, whole grains, and poor in omega-3 fatty acids. Such a diet pattern may cause the activation of the innate immune system, most likely by an excessive production of pro-inflammatory cytokines associated with the reduced production of anti- inflammatory cytokines. It was concluded that the Western dietary patterns "warm up inflammation" and the prudent dietary patterns "cool it down." A number of studies support this view. For example:

• A Mediterranean diet supplemented with olive oil was found to have beneficial effects on cardiovascular risk factors. When compared to a low-fat diet, significant beneficial changes over 3 months were found for insulin resistance (decrease in the HOMA index), fasting insulin, fasting glucose, HDL, C-reactive3 protein (CRP) and interleukin-6 (a cytokine with associated with inflammation).16
• In a study of the Mediterranean-style diet on markers of vascular inflammation in a cohort with the metabolic syndrome, compared to those on a control diet, patients consuming the intervention diet experienced significantly reduced levels of CRP and several inflammatory interleukins, and as well reduced insulin resistance and improved endothelial function. Adherence to this diet also resulted in a significant number of patients being reclassified as not having the metabolic syndrome.17
• In a study of 5 dietary patterns, the Mediterranean pattern and one called the Alternate Healthy Eating Index which was similar to the prudent diets discussed above, both produced lower concentrations of biomarkers of inflammation and endothelial dysfunction as compared to diets similar to the Western pattern. For the Mediterranean and Alternate Healthy Eating Index patterns, the decreases from baseline in CRP were 24% and 30% whereas for interleukin-6 they were 16% and 31%.18
• In a study of the prudent diet pattern and insulin resistance, it was found that in comparison with a traditional Western or a northern European diet pattern, the prevalence of insulin resistance as indicated by the HOMA score was 47% lower.19
• A comparison of high to low adherence to a Mediterranean diet pattern found that high adherence resulted in a decrease in the HOMA Index of insulin resistance from 2.7 to 2.3 units, a change which reflected improved insulin sensitivity.20
• The traditional Mediterranean diet augmented with either extra olive oil or nuts was found in a randomized trial to significantly reduce LDL oxidation. The authors considered this additional evidence for recommending this diet pattern for the prevention of CHD.21

Other examples and a detailed discussion can be found in recent reviews.15,22,23 The bottom line appears to be that if one is seeking an anti-inflammatory diet which also increases or maintains insulin sensitivity, evidence points to the Mediterranean diet or the prudent diet, both of which were also strongly implicated in the reduction of CHD risk in the studies discussed above.

METABOLIC AND INFLAMMATORY EVENTS AFTER A MEAL ARE ALSO IMPORTANT

The medical term for the period in time after a meal is called post-prandial. While derived from the Latin word for breakfast, it applies to any meal. The American culture currently favors a diet high in extensively processed, calorie dense, nutrient depleted foods which frequently results in exaggerated supra-physiological post-prandial spikes in blood glucose and lipids. This result, called post-prandial dysmetabolism, induces immediate oxidative stress, inflammation, endothelial dysfunction and an enhanced tendency toward clot formation. The oxidative stress is in direct proportion to the post-prandial increases in serum glucose and triglycerides. This is an important phenomenon since post-prandial dysmetabolism is an independent predictor of future CV events even in non-diabetic individuals. Epidemiologic studies indicate that eating patterns such as characterize the traditional Mediterranean diet will blunt the post-prandial increase in glucose, triglycerides and inflammation and this provides additional support for this diet pattern in the context of the primary prevention of CHD.24

LOW-FAT, HIGH-FAT, LOW-CARB, HIGH-CARB????

This discussion has so far avoided for the most part the question of the macronutrient balance reflected by the four diet types described in the heading to this section. In fact, the diets thus far discussed place emphasis on the selection of fats and carbohydrates rather than the percentages of energy derived from carbohydrates, fats and proteins. This approach in fact addresses a serious defect in some dietary recommendations which do not differentiate the types of fat nor do they take into account different carbohydrate sources such as refined grains and sugar in comparison with low glycemic vegetables and fruits. Furthermore, there is a large range in total fat content in so-called low-fat diets, and likewise, "low-carbohydrate" to one group of researchers can be high-carbohydrate to another. It appears that the types of fat and carbohydrate appear to play a key role in the cardio-protective nature of both the prudent and Mediterranean diet patterns.

It is also noteworthy that the prudent diet that produced a significant decrease in the risk of CHD and diabetes also highlighted only the nature of carbohydrates and fats, not the relative contributions to energy intake. In addition, the Mediterranean diet cannot be characterized as low or high in either of these macronutrient classes. In fact, the traditional Mediterranean diet typically contains 30-40% fat and 15% protein, which means the energy input from carbohydrates is approximately 45-55%. At 55% carbohydrate, it would actually approach a high-carbohydrate diet. But if one compares the modern Western diet with the Mediterranean diet, the former is high in carbohydrates derived from refined grains, sucrose and fructose and low in fiber, just the opposite of the cardioprotective diets. In addition, the fats in the Mediterranean diet will be higher in monounsaturated and polyunsaturated fat and also higher in omega-3 fatty acids derived both from plant and marine sources. Studies discussed above suggest that the cardioprotection of these diet patterns derives in part from being less inflammatory, less likely to induce insulin resistance, and less likely to cause postprandial dysmetabolism, and as well, less likely to lead to type 2 diabetes.

This then sums up the dietary guidance provided by the studies discussed above and provides the incentive for thinking in terms of dietary patterns rather than high and low fat or carbohydrate and rather concentrating on selecting the types of each that appear to provide the greatest benefit.

CARBOHYDRATE RESTRICTION

The discussion thus far in this review concerning diet and the risk factors for CHD has concentrated on dietary patterns and in particular the merits of the prudent and Mediterranean diets. However, in Part I, carbohydrate restriction was suggested by Dr. Stephen Sinatra as the appropriate intervention for unfavourable TG/HDL ratio and/or the presence of insulin resistance. A high TG/HDL ratio and the frequent presence of small LDL particles have been termed atherogenic dyslipidemia and is part of the clinical picture generally presented by those with the metabolic syndrome. While dietary measures demonstrated to reverse or reduce the risk of the metabolic syndrome were discussed above, individuals with very high TG and very low HDL perhaps need to take more aggressive action and this appears to be the restriction of carbohydrate intake as well as the selection of sources in keeping with the prudent or Mediterranean diet principles.

However, a recent comprehensive review of this subject by Volek et al25 points out that discussion or even acknowledgement of carbohydrate restriction as an effective lifestyle modification to treat atherogenic dyslipidemia is absent from much of the current literature and researchers examining the cellular mechanisms of strongly elevated TGs generally disregard carbohydrate restriction as a potent modulator of TG levels. Volek et al take the position that progress in dealing with elevated TG levels and atherogenic dyslipidemia will depend on putting the historical controversies aside. One is also reminded of the Atkins Diet, which in spite of a number of favourable studies which have shown that the major concerns voiced by nutritional experts are unfounded and the diet in fact provides a significant improvement in CV risk factors, it is still is considered an insignificant if not potentially dangerous fad diet. Recent studies however suggest that it is in fact a satisfactory and safe diet for inducing weight loss and a diet that significantly improves the TG/HDL: ratio.26-28

This subject will be explored more fully in the upcoming review on weight reduction. However, individuals with the metabolic syndrome or even just an unfavourable TG/HDL ratio of > 3 to 3.5 might consider not only the Mediterranean diet approach but also restricting carbohydrates and especially those associated with sugars, refined starches, rice and potatoes.

DIETARY OMEGA-3 AND OMEGA-6 FATTY ACIDS AND CVD

A popular notion has been that omega-6 fatty acids (n-6 FAs) are inflammatory and omega-3 fatty acids (n-3 FAs) are anti-inflammatory. The arguments in favour of this involve the metabolic products of the two classes of fatty acid and the competition for enzymatic pathways. Since the typical Western diet tends to be heavy in n-6 FAs and light to very light in n-3 FAs, this aspect of modern diets has been postulated as contributing to the incidence of CVD. A recent paper by Harvard's Walter Willett provides a modern perspective concerning the importance of both of these fatty acids in the prevention of CVD.29

The principal actors in these two classes of polyunsaturated fatty acid are linoleic acid (LA), alpha-linolenic (ALA), arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). LA and AA are n-6 FAs and ALA, EPA and DHA belong to the n-3 class. Aside from marine sources, dietary intake of these two classes of FA is mostly through LA and ALA. LA is metabolized to AA and ALA to EPA and DHA, the latter two FAs also being supplied directly by fish and fish oils. In connection with risk factors of interest in this review, Willett makes the following points with regard to the n-6 FAs.

• Compared to all other classes of fatty acid, intake of LA produces the most favourable blood lipid changes as reflected by the lowest ratio of LDL to HDL and by the fact that LA increases HDL levels.
• While there have been relatively few studies regarding n-6 FAs and inflammation in humans, nevertheless, they show that consumption of n-6 FAs does not appear to increase inflammatory factors and may reduce some indicators of systemic inflammation.
• There is strong evidence that LA consumption improves insulin resistance and decreases the incidence to type 2 diabetes.

Thus studies of the intakes of n-6 and n-3 FAs and CHD events assume great interest, given that it is the balance of risk and benefit that is important. Willett points out that studies do not find a positive association between LA consumption and the risk of CHD. In addition, both ALA and LA consumption were associated with lower incidence of fatal CHD and the ratio of dietary ALA to LA was also not associated with the risk of fatal CHD. Finally, a higher intake of LA did not reduce the strong inverse relation between the consumption of n-3 FAs derived from fish (EPA and DHA) and the risk of sudden death.

Willett concludes that it is better to consider the intake of n-3 and n-6 FAs individually rather than worry about the ratio, and that the reduction of n-6 intake to alter the n-6/n-3 ratio in a direction thought beneficial may actually increase the incidence and mortality rates of CHD and type 2 diabetes. In North America, the n-6 FA intake is generally high, and thus this advice translates into the importance of concentrating on an adequate n-3 FA intake.

PROBLEM OF BEING OVERWEIGHT OR OBESE

There is no doubt that being overweight or obese adds very significantly to the risk of CHD. The waist-to-hip ratio or the waist circumference attempts to quantify the problem and these measures in fact appear better than the body mass index (BMI--height in inches times 703 divided by the weight in pounds squared). The overweight individual has a BMI between 25 and 30 and obesity is generally defined as a BMI > 30.

There have been countless studies that have examined various diets in the context of weight loss. Typically the results have been modest and difficult to sustain. There are complex metabolic, genetic and psycho-physiologic factors at work here. But it must be recognized that in selecting a diet, the goals should include not only weight control or loss, but also address the issues of inflammation, insulin resistance and the classical dyslipidemia that is characterized by elevated triglycerides and low HDL and as well exaggerated postprandial elevations of blood glucose and triglycerides. Diets that normalize these factors should confer benefit independent of weight loss.

CONCLUSIONS

The current emphasis on LDL cholesterol as the primary risk factor and the primary target for intervention may well have had the unintended result that taking statin drugs provides a false sense of security and the notion that the problem of prevention has now been solved with a pill. But as discussed in Part III of the Cholesterol Review (IHN February 2008), in the context of primary prevention for individuals free of CHD the impact of statins is small for younger men and negligible for women and the elderly.30,31 Also, the connection between CHD risk and cholesterol in younger men may be partly due to confounding by the presence of exaggerated blood pressure response to stress.32 Only industry supported studies have found any benefit at all, and the numbers need to treat to prevent one adverse event are very high. On the other hand, the dietary and lifestyle approach indicated by a considerable body of research should produce significant if not sensational risk reduction for both CHD and diabetes. The NCEP approach is to recommend diet changes (reduce saturated fat to < 7% of calories, cholesterol to < 200 mg/day, increase the intake of soluble fiber and plant stanols/sterols), manage weight and exercise and after three months see if LDL goals are met. If not, institute drug therapy. But drug therapy in fact will be almost always the ultimate result since the recommended lifestyle interventions will frequently not produce the large changes in LDL necessary to meet the goals set by NCEP, especially the most recent goals.

Almost all the enthusiasm for LDL lowering derives from statin trials that involve individuals with established CHD or those at very high risk such as diabetics. The fact that there is a small absolute benefit and a large relative risk reduction has been accepted by an amazing number of medical and nutritional scientists as proof that it is the level of LDL that is the important and causative factor and the candidate to be the prime target for intervention. This view (actually an error in logic) ignores the multitude of beneficial actions of these drugs that have nothing to do with LDL lowering and these benefits would also be dose dependent and thus create an illusion of the lower the LDL the better. This has been discussed in the Cholesterol Research Review and in Part I of this review. The recent highly publicized failure of the trial involving a combination of two cholesterol lowering drugs has brought a number of critics of the LDL hypotheses out of the woodwork and has heated up the debate (see the June, 2008 issue of the IHN newsletter and as well Business Week, January 17, 2008, which presents a number of interesting comments from respected academic physicians. Google cholesterol Business Week).

In Part II the case has been made for specific dietary measures and exercise as an approach most likely to produce large and significant risk reduction not only for CHD but also for diabetes and the metabolic syndrome. In addition, this offers an approach the problem of preventing, reversing or retarding atherosclerosis as the major goal of the intervention in the context of primary prevention in asymptomatic individuals, especially younger individuals where atherosclerosis is in its early stages. Evidence provided in Part I based on coronary calcium scans suggests that measuring LDL cholesterol is not very successful in identifying asymptomatic individuals at risk which is of course why there is an ever increasing call for expanding the calcium scan to lower and lower risk individuals.

Finally, in Part I an approach to identifying chronic stress was discussed. The reduction or elimination of chronic psychological stress and/or depression is an important component of any CHD prevention program, but this is a complex issue and is beyond the scope of this review. Individuals with significant depression or chronic stress should seek professional help. However, it is not clear that the pharmaceutical approach to depression will impact the CHD risk.

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