43 Preventive Cardiology

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From: Essential Cardiology: Principles and Practice, 2nd Ed.

Edited by: C. Rosendorff © Humana Press Inc., Totowa, NJ

Since the inaugural edition of this book, an increased awareness in preventing and treating heart disease has been spawned by revisions of cholesterol, hypertension and diabetes guidelines. As national guidelines have recently dictated, there is a trend in the direction of “the lower the better”

for each of these risk factors. However, the past several years have also witnessed the emergence of diagnostic biomarkers of atherothrombosis that include C-reactive protein and noninvasive surrogates of atherosclerosis, such as carotid intima-media thickness and coronary calcification.

In contrast, therapies that were previously deemed to have an important role in offsetting coronary heart disease (CHD) risk (e.g., antioxidant vitamins and hormone replacement therapy) have been shown to exert no beneficial impact. As our understanding of cardiovascular preventive measures continues to evolve, the goal of this chapter is to focus on the most important advances in this rela- tively new field with an emphasizes on clinical endpoint data influencing both initial and secondary cardiovascular events.

IDENTIFICATION OF HIGH CHD RISK

In 2001, the National Cholesterol Education Program (NCEP) published a strategy for identify- ing high-risk subjects defined as coronary risk equivalence based on preexisting vascular disease, diabetes mellitus or a high Framingham risk score (1). While the Framingham risk score is useful in this regard, there are at least two groups at high risk who are not currently classified as a risk equivalent. These include impaired renal function (e.g., glomerular flow rate (GFR) <60 mL/min) and metabolic syndrome. To this end, the National Kidney Foundation has endorsed a target low-density lipoprotein (LDL) goal of less than 100 mg/dL in renal insufficient patients, irrespective of other CHD risk factors (http://www.kidney.org/professionals/doqi/kdoqi/toc.htm). Moreover, recent data evaluating metabolic syndrome (Table 1) have also identified significant increased all- cause mortality attributable to the presence of this syndrome (Fig. 1) (2). A second shortcoming relates to the omission of other factors not considered in calculating Framingham risk (e.g., family history of premature CHD). Despite these concerns, nearly 75% of CHD can still be explained by traditional risk factors included in the Framingham risk score (3). As such, the focus of intensive therapies should continue to be aimed at reducing LDL cholesterol (LDL-C), blood pressure, and elevated glucose.

LDL-C: HOW LOW SHOULD WE GO?

Barring monogenic abnormalities that result in inborn errors of lipoprotein metabolism, total cholesterol (TC) and LDL-C approx 70 and 30 mg/dL, respectively, at birth. These levels nearly double between 6 and 12 mo of age (4), providing the foundation for “physiologic” TC and LDL-C anticipated in humans throughout life. In fact, it has been well established that CHD risk begins to accentuate as TC levels exceed 150 mg/dL and that societies at the lowest risk of CHD also maintain

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physiologic lipid levels (non-HDL <100 mg/dL). Early clinical trials focused on proving the cholesterol hypothesis, that is, whether lowering TC and LDL-C reduces CHD event rates. During the past several years, however, the aim has been to refine how low LDL-C can safely and effectively be reduced. To that end, recent data suggest that even the present designated acceptable target goal for LDL-C in CHD or CHD risk equivalents (e.g., 100 mg/dL or less) may still be too high. Two trials that have tested this hypothesis are the REVERSAL (Reversal of Atherosclerosis with Aggres- sive Lipid Lowering) and PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis) trials (5,6). In both studies, LDL-C was reduced to either the NCEP target (~100 mg/dL) or lower (60–80 mg/dL). REVERSAL demonstrated halting of atheromatous progression in the intensively treated (80 mg/d atorvastatin) compared to the conventionally treated group (40 mg/d pravastatin) as assessed by intravascular ultrasound (IVUS). The PROVE-IT study found a 16% reduction in CHD death or major endpoint (p = 0.005) between the groups (n = 4162) (Fig. 2).

Two larger clinical endpoint trials whose anticipated release is 2005, TNT (Treat to New Targets) and SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocys- teine) are expected to seal the fate as to whether further LDL-C cutpoints are warranted. These data coupled with the demonstration that hypertensive subjects (without necessarily CHD risk equivalence) benefit from LDL lowering below 100 mg/dL as suggested in ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), suggest that cutpoints may be lowered at various designated risks (7). For example, Table 2 shows present target LDL-C and non-HDL cutpoints of the present NCEP guidelines and potential anticipated changes for the next revision pending results of ongoing trials.

Fig. 1. Unadjusted Kaplan-Meier hazard curves. Bottom of legend: RR, relative risk; CI, confidence interval.

Curves for men with vs without the metabolic syndrome based on factor analysis (men in the highest quarter of the distribution of the metabolic syndrome factor were considered to have the metabolic syndrome). Median follow-up (range) for survivors was 11.6 (9.1–13.7) yr. Relative risks were determined by age-adjusted Cox proportional hazards regression analysis. (From ref. 2. Copyright 2002 American Medical Association.)

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HDL-C: AN EMERGING THERAPEUTIC TARGET

Although it is well recognized that HDL-C is inversely correlated with CHD and that risk is aug- mented even in the setting of a “normal” LDL-C, NCEP has assigned HDL-C as a tertiary therapeutic target owing to the relative paucity of data demonstrating an independent effect of HDL raising on reducing CHD event rates. That may change however, in view of recent data and development of newer HDL-raising drugs. In HATS (HDL Atherosclerosis Intervention Trial) (n = 160), the combination of niacin (2–4 g/d) and simvastatin (10–20 mg/d), which increased HDL by 30% and decreased LDL by 35%, blunted progression of arteriographic disease and reduced CHD events by more than 70% (8). More recently, five weekly intravenous injections of an ApoA-I mimetic, resulted in 4% reduction in atheroma volume as assessed by IVUS (Fig. 3), supporting proof of con- cept that HDL is a primary mediator of reverse cholesterol transport and that reversal of coronary atherosclerosis may reflect efficiency of this process (9). Thus, if ongoing clinical trials demonstrate that the rise in HDL-C (that results, for example, from cholesterol ester transport protein [CETP] inhibition), translates into reduced CHD event rates, it is likely that NCEP will reassess HDL raising as an additional primary or secondary therapeutic target.

NONLIPID CHD BIOMARKERS

Though nonlipid biomarkers represent potentially important contributors to enhanced CHD event rates, there are currently limited data demonstrating that reduction of these parameters con- fers additional benefits beyond that achieved through hygienic and pharmacotherapies aimed at

Table 2

Present NCEP Guidelines and Proposed Revisions

Present guidelines Proposed revisions

LDL goal LDL goal

Risk category (mg/dL) non-HDL (mg/dL) non-HDL

CHD and CHD risk equivalents^a <100 <130 <70^b <100

Multiple CHD risk factors (2+) <130 <160 <100^c <130

0–1 risk factor <160 <190 <130 <160

aMay include renal insufficiency (50% or greater reduction in GFR) and metabolic syndrome in future revisions.

bBased on REVERSAL and PROVE-IT data. Pending results of TNT and SEARCH.

cBased on ASCOT.

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improving lipids, blood pressure, and glycemic control. The most extensively studied of these ather- ogenic markers are homocysteine and C-reactive protein. Personality factors such as mental stress and depression have also been evaluated in CHD risk assessment and deserve mention.

Homocysteine

The metabolism of homocysteine begins with its precursor, the essential amino acid methionine.

Methionine is converted to homocysteine following intermediary metabolism to S-adenosylmethio- nine and S-adenosylhomocysteine. Cystathione -synthase initiates a series of reactions that con- verts homocysteine to cysteine; Vitamin B₆ serves as cofactor for these reactions. Alternatively, homocysteine may be remethylated via transfer of a methyl group from 5-methyltetrahydrofolate, a reaction catalyzed by methionine synthase (MS) with vitamin B₁₂ as cofactor or by transfer of a methyl group by betaine (Fig. 4). An excess of homocysteine may result from abnormalities in the genes encoding cystathione -synthase or 5,10 methyltetrahydrofolate reductase (MTHFR).

Cystathione -synthase deficiency is an autosomal recessive disorder characterized by connec- tive tissue abnormalities, including skeletal and ocular deformaties that may be the consequence of homocysteine induced alterations in matrix protein (e.g. collagen, fibrillin) crosslinking; it bears clinical resemblance to Marfan’s syndrome. However, in contrast to Marfan’s, there is neither joint laxity, aortic root enlargement, nor mitral valve prolapse. Pulmonary emboli represents a common

Fig. 4. Simplified scheme of homocysteine metabolism, focusing on remethylation. MS, methionine synthase;

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cause of death and may occur in up to 50% of untreated cases by age 30. Despite genotypic heteroge- neity between North American and European populations, a common polymorphism in the MTHFR gene (677C T) has been associated with a 16% increased likelihood of CHD (10).

Acquired causes of elevated homocysteine include systemic diseases such as renal failure (reduced catabolism of homocysteine), psoriasis, acute lymphoblastic leukemia (increased cell turnover), and hypothyroidism. Transplant recipients also have elevated levels owing to cyclosporine inhibition of folate-induced remethylation. Pharmaceuticals that have an impact on homocysteine include those that interfere with folate-induced remethylation (e.g., methotrexate, anticonvulsants) or folate absorption (bile-acid sequestrants) as well as substances that block methionine synthase (nitric oxide) or increase SAM (niacin). As homocysteine levels exceed 10 μmol/L, the risk of CHD events increases. Homocysteine is believed to be directly injurious to the endothelium by facilitating LDL modification (11). However, while observational studies have suggested that intake of folate and vitamins B₆ and B₁₂reduce stroke incidence (12), at least one recent randomized study failed to show clinical benefit in stroke survivors (13).

C-Reactive Protein

C-reactive protein (CRP) predicts CHD independent of LDL-C and has gained increased rec- ognition in CHD risk assessment. Using high-sensitivity assays, three categories of risk have been defined: low (<1 mg/L), intermediate (1–3 mg/dL), and high (>3 mg/L) the latter of which raises the 10-yr Framingham Risk to the CHD equivalent range (14) (Fig. 5).

However, a recent AHA position statement did not endorse widespread screening, in part because of the lack of evidence demonstrating the independent benefit of CRP lowering on CHD event rate reduction (15). CRP is hepatically synthesized in response to the upregulation of peripheral cyto- kines, including interleukin-6 (IL-6) elaborated by adipocytes. As such, elevated CRP is tightly correlated with body mass index, obesity (16), and other measures of metabolic syndrome. Therapies that reduce CRP levels include weight-reducing measures (e.g., diet and exercise), and medications including lipid-lowering drugs (statins, niacin), aspirin (325 mg/d), and thiazolidene diones (TZDs).

The extent to which reducing elevated CRP in otherwise normolipidemic impacts on initial CHD events is the subject of a clinical trial (e.g., JUPITER); positive outcome may elevate the utility of CRP screening for intermediate risk patients in the future.

Mental Stress

A paradigm of how acute mental stress may lead to CAD events is shown in Fig. 6. A paradoxical vasoconstrictor response following intracoronary acetylcholine was observed in patients asked to

Fig. 5. Multivariable-adjusted relative risks of cardiovascular disease according to levels of C-reactive protein and the estimated 10-yr risk based on the Framingham risk score as currently defined by the National Choleste- rol Education Program and according to levels of C-reactive protein and categories of LDL cholesterol. To con- vert values for LDL cholesterol to mmol/L, multiply by 0.02586. (From ref. 14. Copyright 2002 Massachusetts Medical Society.)

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perform mental arithmetic (17). Other studies have extended these findings by demonstrating wall motion abnormalities, transient reduction in ventricular function, and silent ischemia in response to mental stress (18). Most recently, these findings have been extended to include a reduced likelihood of silent ischemia during high positive emotional periods (e.g., happiness) compared with negative emotions such as tension, frustration, and sadness.

Depression

As many as 20% of myocardial infarction (MI) survivors experience major depression and the risk of mortality quadruples within the first year following a CHD event (19). A recent meta-analysis suggests that depression may be a predictor of initial CHD events, even after adjusting for other covariates (20). An overactive hypothalamic-pituitary-adrenocortical axis in depressed subjects leads to enhanced cortisol production and mediation of proatherothrombotic activity (e.g., platelet activation and systemic inflammation) (21,22) coupled with reduced heart rate variability, which are believed to contribute to accelerated CHD event rates (23). Tricyclic antidepressants are often contraindicated in CHD patients owing to potential deleterious CV effects including tachyarrhyth- mias, prolongation of the QT interval and orthostatic hypotension. In contrast, selective serotonin reuptake inhibitors (SSRIs) have few if any untoward cardiovascular side effects and are the drugs of choice (24).

DIAGNOSTIC STRATEGIES

Of the numerous emerging noninvasive diagnostic tools under evaluation, carotid intima-media thickening and coronary calcification have been the most investigated to date.

Carotid Intima-Media Thickness

Measurement of common carotid artery (CCA) intima-media thickness (IMT) remains the most validated noninvasive surrogate for detection of early atherosclerosis because of its high reproduc- ibility and low variability. CCA IMT is highly correlated with existing CHD and predictive of future CHD events in subjects without symptomatic disease (25). The mean CCA IMT in 55-yr-old men and women are 0.70 and 0.64 mm, respectively, with an average annual cross-sectional change approximating 0.008 mm/yr (26). However, high-risk groups such as FH may have up to a fivefold greater rate of CCA IMT progression compared to the lower-risk subjects. Statin therapy may reduce or reverse CCA IMT progression and it appears that the lower LDL (or non-HDL) achieved, the greater the effect, mirroring similar observations using IVUS (27).

Coronary Artery Calcification

Another noninvasive method employed for detection of subclinical CHD is scanning for coronary artery calcification (Fig. 7). While the majority of published studies to date have evaluated

Fig. 6. Pathophysiologic model of mental stress as a trigger of myocardial ischemia and infarction. (From ref. 64.)

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electron-beam CT, helical or multislice CT scanners are more readily available in hospitals and are being more widely used. Although the degree of calcification correlates with anatomic abnormalities as assessed by coronary arteriography, highly calcified vessels are often stable and are not predictive as the culprit lesion in acute coronary syndromes (ACS) or MI. Nevertheless, high calcium scores (age and gender adjusted calcium exceeding the 75th percentile) are associated with a greater presence of noncalcified, highly thrombogenic lipid-rich lesions at high risk of rupture/

erosion, which result in a fourfold or greater increased likelihood of MI. Because of significant retest variability in calcium scores, a standardized measuring system was recently developed by the International Consortium for Standardization in Coronary Artery Calcium. This new standard uses 100 mg/cc as the threshold for a positive scan and is applicable across the spectrum of devices used to measure coronary calcium. While calcium scanning is presently not recommended as a screening tool for diagnosing CHD based on the 2000 ACC/AHA Consensus Statement, recent data suggest that this test may be most useful in modifying CHD risk prediction with Framingham risk scores in the intermediate range (10–20%) but not at lower risk ranges. Nonetheless, the highest scores (>300) were associated with the greatest likelihood of CHD events across all strata of Fram- ingham risk (Fig. 8) (28). The ongoing Multi-Ethnic Study of Atherosclerosis (MESA) will eval- uate the utility of coronary calcium scanning in 6000 men and women to determine the association of baseline risk factors with the progression of coronary calcium, and association of progression of coronary calcium with clinical CVD events. It will be equally important to assess the impact of intensive secondary preventive therapies on calcium progression rates and confirm whether intensive lipid lowering regresses calcified lesions in hyperlipidemic subjects as previously suggested (29).

HYGIENIC THERAPIES: THE OBESITY EPIDEMIC

Poor diet and inactivity are now responsible for 400,000 deaths in the US, accounting for 1 in 6 deaths and second only to tobacco as the leading preventable cause of mortality (Table 3) (30).

In fact, since 1990, death rates resulting from obesity have climbed 33% compared to the approx 9% increase related to smoking. Based on current trends, poor hygienic measures will overtake tobacco as the top cause of preventable death by 2010. Likely explanations include fast-food life-

Fig. 7. Electron-beam computed tomographic image obtained in a 49-yr-old man. The patient’s total calcium score is 70. Three areas of calcification (arrows) are visible in the regions of the coronary arteries—one in the left anterior descending artery and two in the left circumflex artery. (From ref. 65.)

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styles, increases in food portion sizes, decline in school physical education programs, and seden- tary activities including more weekly hours spent on computers and television. Obesity, defined as body mass index (BMI) >30 kg/m², is epidemic in the US with nearly half of the states reporting an obesity prevalence of at least 20% (Fig. 9) (31). Moreover, with aging, intrinsic basal metabolic rate (BMR) defined as energy expenditure at rest falls at an approximate rate of 5 Kcal/d per year.

Not surprisingly, weight gain in adults has averaged approx 10 lb during the past decade. Thus, even before discussing specific dietary measures, reduction in total caloric intake and or increased energy expenditure should be a top priority in CHD risk reduction strategies.

NUTRITIONAL ASPECTS OF PREVENTIVE CARDIOLOGY Important Lessons From Our Paleolithic Ancestors

Barring monogenic abnormalities (e.g., FH), a diet low in saturated and trans fats translates into a low risk of CHD, as exemplified by today’s industrialized societies. A comparison of the dietary composition of the foods consumed by the descendants of modern preliterate societies (e.g., our paleolithic ancestors) with present Westernized countries is outlined in Table 4.

The reduced percentage of fat consumed in Stone Age societies reflects a predominantly low intake of saturated fat and, of course, no trans fats. Wild game, the primary source of fat in Stone Age societies, has been found to contain considerably less carcass fat (4%) compared with domes- ticated livestock (30%). Equally important was the absence of dairy products from the diet of our paleolithic ancestors; the processing of milk products was developed during the agricultural revo-

Fig. 8. Predicted 7-year event rates from COX regression model for CHD death or nonfatal MI for categories of Framingham risk score or coronary artery calcium score (CACS). (From ref. 28. Copyright 2004 American Medical Association.)

Table 3

Trends in Percentage of Total Preventable Deaths in the US Between 1990 and 2000

1990 2000

Tobacco use 19% 18.1%

Poor diet/physical inactivity 14% 16.6%

Alcohol consumption 5% 3.5%

Microbial agents 4% 3.1%

Toxic agents 3% 2.3%

Car accidents 1% 1.8%

Gun-related deaths 2% 1.2%

AIDS 1% 0.8%

Drug use <1% 0.7%

Data from ref. 30.

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lution within the past 5000 yr. Harvesting of tobacco also occurred during this period. Thus, not only was the relative intake of fat reduced in these preagrarian societies, but the percentage of saturated fat consumption was also low, as reflected in the polyunsaturated to saturated fat (P:S) ratio. It is noteworthy that fiber intake was considerably higher and sodium intake lower compared with modern-day societies. Taken together, the earlier dietary habits support the notion that atherothrombosis was an uncommon occurrence.

Impact of Dietary Fat in Cardiovascular Disease Prevention SATURATED FAT

It has been well established that diets high in saturated fat (>40% of caloric intake) are associated with an increased tendency to atherothrombosis. Nearly 35 yr ago, Connor demonstrated the impact of saturated fatty acids on coagulation and thrombosis (32). Saturated fatty acids may also inhibit LDL-C receptor activity, thereby raising LDL-C (33). In general, for each 1% rise in saturated fat there is a 2.7 mg/dL increase in total cholesterol. Of the major saturated fats, only stearate is believed to have a neutral effect on cholesterol levels.

T^RANS FATTY ACIDS

Trans fatty acids are present in animal and dairy fats and in polyunsaturated vegetable oils that are (partially) hydrogenated to increase product stability and shelf-life. Substitution of trans fatty acids for cis fatty acids (e.g., oleic acid) raises LDL, TG, and Lp(a) and reduces HDL (34). Trans fats represent ~20% of total dietary fat; common sources include shortening used in baked products

Fig. 9. Prevalence of obesity between 1991 and 2000 among adults in the United States. (From ref. 66. Copy- right 2000 American Medical Association.)

Table 4

Comparison Between Late Paleolithic and Contemporary American Diets Contemporary Energy (%) Late paleolithic diet american diet

Carbohydrate 46 46

Fat 21 42

Protein 33 12

P:S ratio 1.4:1 0.44

Cholesterol (mg) 520 300–500

Fiber (g) 100–150 <20

Sodium (mg) <700 2300–6900

Modified from ref. 60, 61.

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Spain) compared with North America. The primary fatty acid, oleate, reduces VLDL-C and LDL- C and may reduce macrophage uptake of LDL-C by inhibiting oxidation. In addition to olive oil, the Mediterranean diet also includes a high concentration of fruits and vegetables (an excellent source of antioxidant vitamins and flavonoids), supplemented with fish, poultry, and occasionally red meat. Alcoholic beverages (particularly red wine) and nuts are consumed in the Mediterranean diet. Milk products, when consumed, are often in the form of grated cheese added to pasta. Eggs (up to 4) are also consumed weekly. In addition to its palatability, the Mediterranean diet has been the only diet to demonstrate CHD reduction. In the Lyon Diet Heart Study, subjects randomized to this diet experienced a 73% reduction in CAD deaths and nonfatal MI and a 70% reduction in overall mortality during the initial 27-mo period (38)with benefits extending to 4 yr (Fig. 10). It has also been suggested that diabetic patients benefit from a Mediterranean rather than a high-carbohydrate, low-fat diet. As carbohydrate intake exceeds 65% of total caloric intake, VLDL-C production is increased, thereby raising plasma TG level. Even 55% carbohydrate diets have been associated with elevated TG, reduced HDL levels, and potential deterioration of glycemic control (39). In addition to olive oil, other important sources of monounsaturated fats are avocados and nuts (40). Avocados are rich in vitamins E and C, while nuts provide a rich source of antioxidants, including the phytonutrient ellagic acid (walnuts, pecans), Vitamin E (almonds, peanuts), and omega-3 fatty acids (walnuts).

DIETS RICHIN OMEGA-3 FATTY ACIDS

Omega-3 fatty acids are long-chain polyunsaturated fats that contain the first double bond at the third position adjacent to the methyl terminal of the molecule. As a precursor of arachidonic acid, they may be incorporated through the cyclooxygenase or leukotriene pathway (Fig. 11), providing both antiplatelet and antiinflammatory effects. The clinical impact of these fatty acids was demonstrated in Greenland Eskimos whose diet of predominantly fatty fish was enriched with omega-3s (e.g., whale, salmon, herring, and mackerel). Dyerberg and Bang (40a) found that these individuals had a increased bleeding time and a low incidence of CAD and astutely attributed these effects to a high content of omega-3 fatty acids such as eicosapentanoic acid (EPA) (C20:5-3) and dicosahexanoic acid (C22:4-3). In addition, significant TG lowering (20–50%) was also observed owing to reduced hepatic VLDL-C secretion. Both observational (e.g., Diet and Reinfarction Trial) (41) and randomized clinical trials (e.g., GISSI) (42) of patients with CHD, omega-3 fatty acid sup- plementssignificantly reduced CV events (death, nonfatal heart attacks,nonfatal strokes). Omega- 3 fatty acids are believed to reduce sudden cardiac death by inhibiting L-type calcium channels and voltage-dependent sodium currents (43). In view of the cardioprotective effects of fish, the AHA/

ACC has endorsed consumption of 1 g of omega-3-containing fish daily either in the form of fish- oil capsules or consumption of oily fish (44). Table 5 lists the content of omega-3 among fish consumed in the US. Generally, for each 1 g of EPA/DHA, there is also a 10% reduction in TG; often 2 to 4 g are needed in hyperTG patients. High doses should be used particularly cautiously in CHD patients receiving aspirin (>162 mg/d) and/or clopidogrel. Fish-oil capsules should be refrigerated or frozen after opening to minimize oxidation and fishy odor eructation. Capsules recently tested by Consumer Reports are free of mercury and other contaminants.

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WEIGHT-LOSS DIETS: LOW-CARBVS LOW-FAT

Weight loss is most sustainable if performed on a gradual basis. Small changes in diet and exercise patterns will enhance the likelihood of achieving the recommended reductions approximating 1 lb/wk. Table 6 provides examples of modest hygienic measures that enable a net negative balance of 500 kcal/d in an average 70-kg adult. A primary concern with various weight-loss programs is the induction phase, where water loss accounts for the precipitous weight drop. For example, in low-carbohydrate, high-protein diets, weight loss is rapid because for each gram of glycogen depleted, 2 to 4 g of intracellular water are mobilized, resulting in rapid weight (e.g., water) loss.

If carbohydrate restriction is severe (less than 60 g), ketosis ensues, leading to nausea, reduced appetite, and hyperuricemia as ketones compete with uric acid for renal tubular excretion (45).

Diets low in total and saturated fat were popularized by Pritikin; he reduced his dietary fat intake following an MI and reportedly had minimal evidence of coronary disease on postmortem exami- nation. The Lifestyle Heart Trial also evaluated the efficacy of a very-low-fat diet (10% of caloric intake) in concert with lifestyle changes (aerobic exercise, stress management training, smoking cessation, and group support) on arteriographic progression in patients with preexisting CAD. The dietary component of the treated (experimental) group consisted primarily of fruits, vegetables, grains, legumes, and soybean products. Red meat, poultry, and fish consumption was not permitted.

After 1 yr, the experimental group evidenced reduced progression and slight regression of lesions (46). At the 5-yr follow-up, total fat intake represented 8.5% of calories, LDL-C was reduced 20%,

Fig. 10. Survival curves between the experimental and control groups in the Lyon Diet Heart Study. (From ref. 67.)

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and reduced coronary arteriographic progression compared to the control group became more apparent. Nevertheless, there were still 25 cardiac events among the 28 experimental patients during the 5-yr follow-up period (47). As the TG level in the experimental group was elevated (mean TG = 258 mg/dL), these results suggest that intensive lifestyle measures may not be sufficient in optimizing CAD event reduction. Other low-fat nonpharmacologic trials, including the St. Thomas Arteriographic Regression Study (STARS) (27% fat),and the Heidelberg Exercise/Diet Study (<20%

fat), also resulted in reduced arteriographic progression of CAD in patients assigned to the intervention group. While evidence supports reduction of total fat intake to less than 40% of total caloric burden, it remains unclear whether very-low-fat diets (<10% fat) as consumed in the Lifestyle Heart Diet offer any advantages to more palatable diets offered by the Mediterraneans (25–35% fat), the paleolithic diet (21% fat; see above), or an American Heart Association diet supplemented with lipid-lowering therapy. The combination of intensive diet, exercise, and lipid-lowering agents may yield the most favorable responses on TC, LDL, and TG(Fig. 12) but the relative impact on CAD event rates has been established only for a Mediterranean approach.

Fig. 11. Eicosanoid and platelet-activating factor. (From ref. 68.)

Table 5

Total Fat and Content of Highest Omega-3-Containing Fish (Grams per 3.6-oz Serving)

Omega-3

Fish Total fat content per 100 g

Sardines, in sardine oil 15.5 3.3

Atlantic mackerel 13.9 2.5

Pacific herring 13.9 1.7

Atlantic herring 9.0 1.6

Lake trout 9.7 1.6

Anchovy 4.8 1.4

Chinook salmon 10.4 1.4

Sablefish 15.3 1.4

Bluefish 6.5 1.2

Sockeye salmon 8.6 1.2

Atlantic salmon 5.4 1.2

Pink salmon 8.6 1.2

Modified from ref. 62.

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CARDIOPROTECTIVE NUTRIENTS

In recent years, polyphenols found in a variety of foods have been linked to cardioprotective health. This broad group of antioxidant compounds includes flavonoids, which are plant-derived pigments responsible for bright colored chemical components present in fruits and vegetables.

Epidemiologic studies have evaluated the clinical significance of two flavonoid subclasses, flav- an-3-ols (e.g., catechins) and flavanols (e.g., quercetin, myricetin), the former of which represent powerful antioxidants with greater potency than vitamins A, C, and E. In the Zutphen elderly prospective study of 800 seniors (65–84 yr old), the highest intake of catechins was inversely associated with CHD death after adjustment for other covariates (RR = 0.48; 95% CI: 0.28, 0.82), so that for each 50-mg intake there was a corresponding 25% reduction in CHD events (48). Rich sources of catechins are listed in Table 7; quercetin and myricetin are also potent antioxidants. In a prospective study of 10,000 Finnish men and women, a 20% reduced incidence of type 2 diabetes mellitus coincided withhigher quercetin andmyricetin intake; quercetin was also found to be inversely related to CHD mortality (49). Most recently, a major fraction of the total flavonoid content was analyzed in more than 40 different foods (50). In the US, the mean daily intake of these antioxidants approximated 60 mg/d with the majority obtained from three primary sources, apples (32%), choco- late (18%), and grapes (18%). Examples of the flavonoid content in selected nuts is shown in Fig. 13.

Fig. 12. Total serum cholesterol values before and after cholesterol-lowering drug therapy and then with the addition of the Pritikin diet and exercise program for both primary and secondary prevention groups. All three values were significantly different (p < 0.01) for both groups. (From ref. 69. Copyright 1997 Excerpta Medica, Inc.)

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In the Nurses Study of 86,000 women aged 34 to 59, frequent intake of nuts (1 oz or greater at least 5 times weekly) was associated with a 35% reduction in fatal CAD events and nonfatal MI compared with women who did not (or rarely) consume nuts (51). Overall, the most concentrated source of antioxidant units were found in cinnamon, and two recent studies suggest that polyphenolic polymers potentiate insulin action, which in turn may improve glycemic control in diabetic patients (52, 53). Taken together, identification of potential cardioprotective nutrients provides an excellent oppor- tunity to further explore the critical yet underemphasized role of diet in the prevention of CHD.

Impact of Exercise in Cardiovascular Disease Prevention

Individuals with a high aerobic capacity have a lower incidence of CAD compared with seden- tary subjects. While it has been widely touted that the most well-conditioned athletes present with the lowest case-fatality rates of MI (54), moderate levels of physical activity have also been associated with favorably reduced rates. These activities must persist throughout life; a high school athlete who foregoes exercise in later life is not protected from the subsequent development of CAD (55). Exercise is beneficial throughout all age groups. In fact, regular exercise in the elderly (walking or cycling for 20 min three times weekly) resulted in a 30% reduction in CHD and total mortality. In addition, moderate physical activity may also reduce stroke rates. In the Harvard Alumni Health Study, an approx 50% reduction in stroke was observed in men (mean age = 58 yr)

Raspberries 9

Apples, with skin 9

High quercetin-containing foods

Cocoa powder 20

Onions, cooked, boiled 19

Cranberries, raw 14

Onions, raw 13

Lingonberries, raw 12

Spinach, raw 4.9

Apples, with skin 4.4

Barley 3.8

Celery 3.5

Broccoli, raw 3.2

Blueberries 3.1

High myricetin-containing foods

Cranberries, raw 4.3

Rutabagas 2.13

Black currant juice 1.9

Tea, green, brewed 1.1

Blueberries 0.82

Red table wine 0.7

Grape juice 0.6

Grapes, black, green, or white 0.45

Tea, black, brewed 0.45

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who expended 2000 to 3000 kcal of energy weekly. This can easily be achieved with one hour of brisk walking (3–4 mph) daily. We also recommend wearing a pedometer with a minimum of 10,000 steps taken daily. Finally, light weight lifting exerts an additional 20 to 25% reduction in CHD event rates and is independent of other cardioprotective measures (56).

ABCs of CHD Prevention

In addition to quitting smoking, physical activity, and weight management, other important considerations in maximizing secondary preventive efforts are antiplatelet agents, angiotensin- converting enzyme (ACE) inhibitors, -blockers, and cholesterol-lowering therapies (covered in more depth in previous chapters).

ANTIPLATELET AGENTS

Aspirin reduces the risk of CHD by 20 to 25% in high-risk patients and remains the first-line antiplatelet drug because of its relative safety, low cost, and cost-effectiveness. However, the FDA recently denied Bayer’s petition for routine aspirin use in primary prevention because of the lack of data demonstrating reduction in CHD mortality or ischemic stroke. Previous studies have indicated that the platelet ADP inhibitor clopidogrel reduces CHD events by 10% compared with aspirin in acute coronary syndromes or non-ST segment elevation MI (57). Moreover, in patients under- going percutaneous coronary intervention (PCI), the combination of clopidogrel and aspirin was shown to be more effective in reducing MI or CHD death than aspirin alone (OR 0.23, 95% CI 0.11–

0.49, p = 0.0001). In the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial (n = 12,000), the combination of aspirin and clopidogrel treated for 9 mo (in subjects not having PCI) resulted in a 20% reduction in the primary endpoint (MI, CVA, CHD death). While risk of bleeding was generally higher, the most favorable combination included use of low-dose (75 mg/d) aspirin. In the smaller subgroup of PCI subjects (n = 2100), pretreatment with clopidogrel resulted in a 30% reduction in the primary endpoint. Continuation of clopidogrel for up to 1 yr following PCI continued to show benefit, as indicated by a 27% reduction in MI and stroke. Ongoing studies will determine whether longer-term combination treatment (e.g., 1–3 yr) remains cardioprotective. In addition to use for ACS and as pre- and post-PCI therapy, 75 mg/d clopidogrel is a suitable replacement for aspirin in allergic or sensitive patients and in those who have experienced atherothrombotic events on aspirin.

ACE INHIBITORS

Randomized controlled trials in MI survivors have revealed significant reductions in recurrent cardiovascular events and mortality (20–25%) with ACE inhibitor use. The HOPE study extended the benefit of ACE inhibition using ramipril in high-risk subjects (CHD and diabetics) even without markedly compromised EF (>40%). Most recently, the EUROPA (Reduction Cardiac Events with Perindopril in Stable Coronary Artery) study showed that ACE inhibition resulted in 20%

Fig. 13. Flavonoid content in selected nuts (mg/100 mg proanthocyanidins). (Adapted from ref. 50.)

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reduction in CHD death and MI in patients with stable coronary heart disease and without CHF. In this population, ACE inhibition is cost-effective, as 4 yr of therapy is expected to prevent one event for every 50 treated patients (58).

bbbbb-Blockers

-Blockers are very effective agents for reducing recurrent MI events (15–25%), sudden cardiac death (30–35%), and overall mortality (20%). Hemodynamically stable post-MI patients with compromised ventricular function (<40%) also benefit from -blocker use.

Potential Cumulative Effect of Secondary Preventive Measures The impact of established strategies on offsetting CHD events is shown in Table 8.

Among high-risk patients, defined as an annual CHD event rate of 4%, employing all these strategies along with smoking cessation would reduce the risk by an estimated 80% and thereby reduce event rates to a level observed in low-risk subjects. Overall and with few exceptions, CHD remains largely avertable in the US and even among genetically susceptible individuals, effective strategies are now available to prevent initial and recurrent CHD events (59).

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