Physicians' Press - Innovative Medical Publishing

The Importance of a Mediterranean Diet and ACE Inhibitors
in Primary and Secondary Cardiovascular Risk Reduction

From: Dyslipidema Essentials, by James O’Keefe, Jr, MD (Director of Preventive Medicine, Mid-America Heart Institute, Kansas City, MO) and Christie Ballantyne, MD (Clinical Director, Section of Atherosclerosis, Baylor College of Medicine)

Overview

Increasing evidence suggests that a Mediterranean-style diet may play an important role in the prevention of clinical cardiovascular disease. In contrast to the standard American Heart Association Step I and Step II Diets, which emphasize restriction of total fat, saturated fat, and cholesterol, the Mediterranean diet includes up to 30% of calories from fat, predominantly in the form of monounsaturated and omega-3 fatty acids.

The Lyon Diet Heart Study was a randomized trial of 605 post-MI patients comparing a Mediterranean diet providing increased levels of alpha-linolenic acid (from olive oil and canola oil) to usual dietary instruction. Patients in the Mediterranean diet group were instructed to consume more fish, bread, and root and green vegetables; eat less meat; have fruit at least once daily; and use canola-based margarine and olive oil as a fat source. After 4 years, patients on the Mediterranean diet showed a 70% reduction in all-cause mortality (p=0.03). The rate of cardiovascular death and nonfatal MI was 1.32 per 100 patient years in the treated group compared to 5.55 per 100 patient years in the control group (p=0.001).

Further evidence for the cardioprotective benefits of omega-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) from fish or fish oil supplements come from the GISSI Prevention study and Diet and Reinfarction Trial (DART). The GISSI Prevention study randomized 11,324 Italian men and women (who presumably were eating a Mediterranean diet) with MI within the preceding 3 months to omega-3 fatty acids (850-882 mg/d), vitamin E (300 mg/d), both, or neither. After 3.5 years, the omega-3 group had a significant 20% reduction in all-cause mortality and 45% reduction in sudden cardiac death (Lancet 1999;354:447). In DART, 2033 men with prior MI were randomized to receive different types of dietary advice to prevent another MI. After 2 years, the group told to increase their omega-3 intake by eating oily fish (e.g., salmon, herring, mackerel) at least twice weekly had a 29% reduction in overall mortality (p < 0.05) (Lancet 1989;2:757). These studies suggest that the type of fat, not only the amount, determines cardiovascular health.

Recommendation

It is reasonable to recommend a Mediterranean diet as an alternative to the standard AHA low-fat diet as part of a comprehensive program to reduce cardiovascular risk. Table 1 describes basic components of a Mediterranean diet, and Table 2 offers guidelines on how to incorporate these steps into everyday living.

MEDITERRANEAN-STYLE DIET (Tables 1,2)

Table 1. Basic Components of a Mediterranean Diet
Component	Benefit
Omega-3–rich¹ fish 1-2 times per week or omega-3 supplements²	Reduces all-cause mortality and sudden cardiac death post-MI; lowers triglycerides (high doses) and blood pressure; improves insulin resistance; boosts the immune system; may help prevent cancer, arthritis, depression, Alzheimer’s disease.
Monounsaturated cooking oils (olive, flaxseed, or canola)	Does not increase LDL cholesterol or decrease HDL cholesterol (unlike high saturated fat or highly refined carbohydrate intake). “Metabolically neutral” calorie source for people with insulin resistance.
Fresh fruit and vegetables (5-10 servings per day); aim for a wide variety	High concentrations of vitamins, minerals, fiber, and phytochemicals³ help prevent heart disease, stroke, and many types of cancer (colon, stomach, prostate).
Vegetable protein from nuts and beans 1-2 times per week	Lowers LDL cholesterol; improves digestion; may reduce CAD and certain cancers. Nuts are an excellent source of protein, monounsaturated fat, fiber, and minerals. Beans contain high-quality protein, fiber, potassium, and folic acid.⁴
Limit saturated fats to < 10-20 grams per day	Saturated fats increase LDL cholesterol, which promotes atherosclerosis and increases the risk of CAD and stroke. Saturated fats are also linked to certain cancers.
Avoid trans fats	Trans fats are manufactured from vegetable oils and are used to enhance the taste and extend the shelf-life of fast foods, French fries, packaged snacks, commercial baked goods, and most margarines. Trans fats may be more atherogenic than saturated fats. Food manufacturers are not required to list trans fats on food labels; instruct patients to avoid foods with “hydrogenated” or “partially hydrogenated” vegetable oil as first or second ingredient—these contain trans fats.
Increase dietary to fiber to 20-30 grams per day	Lowers LDL cholesterol; improves insulin resistance; reduces the risk of heart disease and diabetes; protects against colon cancer, and possibly breast cancer, irritable bowel syndrome, diverticulitis and hemorrhoids; prevents constipation.
At least one source of high-quality protein with every meal	Produces satiety that lasts longer than high carbohydrate meals (reduces hunger and cravings); maintains muscle mass and bone strength. Lack of protein increases the risk of breast cancer, diabetes, and osteoporosis.
Adapted from the Omega Diet, by A. Simopoulos, MD
1. The typical American diet consists of an unhealthy ration (>15:1) of omega-6:omega-3 essential fatty acids, favoring excessive production of proinflammatory, prothrombotic, and vasconstrictive mediators of the arachidonic acid cascade (e.g., leukotrienes, thromboxane). Increasing consumption of omega-3 essential fatty acids helps regulate inflammation, thrombogenicity, arrhythmogenicity, and vascular tone. 2. Omega-3 supplements should be considered for patients with documented CAD, especially if risk factors for sudden death are present (LV dysfunction, LVH, ventricular dysrhythmias). 3. Phytochemicals are naturally occuring chemicals found in plants - many of them plant pigments - that act as free radical scavengers and protease inhibitors, among others. Examples include lycophene, beta-carotene, indoles, thiocyanates, lutein, resveratrol, ellagic acid, genistein, and allium. 4. Folic acid lowers homocysteine levels, a by-product of methoionine metabolism associated with atherosclerosis.

Table 2. How to Incorporate a Mediterranean Diet into Daily Living
Step	Choose	Go Easy On	Avoid
Eat omega-3 rich food 1-2 times per week	Salmon, trout, herring, water-packed tuna, sardines, mackerel, flaxseed, spinach, purslane, concentrated fish oil supplements	Raw shellfish (due to danger of infection risk, including hepatitis A and B)	Deep-fried fish, fish sticks, fish from seriously contaminated water
Switch vegetable oils	Flaxseed oil, extra virgin cold pressed olive oil or canola oil (check the label), mayonnaise made from olive oil or canola oil	High-oleic safflower, sunflower, or soybean oil	Corn oil, safflower oil, sunflower oil, palm oil, peanut oil, any other kind of oil, mayonnaise that isn’t made from olive oil or canola oil
Load up on fresh fruit and vegetables	Fresh fruit: 3 to 5 daily. Fresh vegetables: 4 to 6 daily. Aim for a wide variety.	Fruit juice (no more than 1-2 cups per day), dried fruit, canned fruit	Vegetables or fruit prepared in heavy cream sauces or butter
Add nuts and beans 1-2 times per week	Soybeans, kidney beans, lentils, navy beans, split peas, all other kinds of beans, nuts of all kinds (especially almonds, Brazil nuts, pecans, walnuts, other tree nuts)	Heavily salted nuts	Stale or rancid nuts
Limit saturated fats to 10-20 grams per day; eat at least one source of high-quality protein with every meal	Fish, lean cuts of fresh meat with fat trimmed off, chicken and turkey without skin, nonfat or lowfat dairy products (skim milk, yogurt, low-fat cottage cheese), dark chocolate, egg whites or egg substitute, omega-3–enriched eggs	Processed lowfat meats (bologna, salami, other luncheon meats), 2% milk, “lite” cream cheese, part-skim mozzarella cheese, milk chocolate, egg yolks (3-4 per week)	Prime-grade fatty cuts of meat, goose, duck, organ meats (liver, kidneys), sages, bacon, full-fat processed meats, hot dogs, whole milk, cream, full-fat cheeses, cream cheese, sour cream, ice cream
Say “no” to trans fats	Stanol-enriched margarine (Benecol, Take Control)	Commercial peanut butter, water crackers and other crackers that contain no fat, bagels	Fast food, French fries and other deep-fried food, chips and other packaged snacks, most commercial baked goods (doughnuts, cakes, pies, cookies, croissants, crackers, and so on), most margarines
Add more fiber; aim for 20-30 grams per day	Whole-grain breads and cereals, oats, brown rice, whole grain pasta, potatoes with skin (baked, boiled, or steamed), whole-grain bagels	Pasta, white rice, mashed instant potatoes, plain bagels, dinner rolls, egg noodles	Sweetened cereals, white bread, crackers, table sugar, honey, syrup, candy, and all highly processed foods, especially those made with white flour and sugar
Drink at least 64 ounces of water per day	Each day, drink 8 glasses of pure, non-chlorinated water. Additional drinks: skim milk (up to 4 glasses); pure fruit juice (up to 2 glasses); tea, especially green tea (up to 4 cups); a smoothie made with plain nonfat yogurt and fresh fruit	Coffee (regular or decaf), 1% or 2% milk, artificially sweetened fruit juice (the tip-off is “corn syrup” in the label), sports drinks, artificially flavored soft drinks, alcohol (no more than 1 drink daily for women, 2 drinks daily for men)	Sugared soft drinks, milkshakes, excess alcohol

ACE INHIBITORS IN PRIMARY AND SECONDARY PREVENTION OF ATHEROSCLEROTIC VASCULAR DISEASE AND DIABETES

Angiotensin converting enzyme (ACE) inhibitors block the conversion of angiotensin I to angiotensin II and inhibit the breakdown of bradykinin, resulting in physiologic benefits that confer unique cardioprotective and renoprotective properties to this class of drugs. ACE inhibitors have been shown to improve prognosis in a wide variety of cardiovascular disorders, including hypertension, heart failure, asymptomatic LV dysfunction, MI, post-coronary revascularization procedures, and proteinuric nephropathy. Most recently, compelling data from the Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated an important role for ACE inhibitors in the primary and secondary prevention of atherosclerotic vascular disease and in the development of new-onset diabetes mellitus (NEJM 2000;342:145). In this large randomized trial, involving 9,297 patients with either atherosclerotic arterial disease (prior MI, prior stroke, or peripheral arterial disease) or diabetes plus one additional risk factor (hypertension, elevated total cholesterol, depressed HDL cholesterol, smoking, or microalbuminuria), patients receiving ramipril (10 mg/d) had a 22% reduction in a composite endpoint of MI, stroke, or death from cardiovascular disease. Additionally, significant risk reduction was noted for most individual endpoints, including all-cause mortality (16%), MI (20%), stroke (32%), cardiac arrest (38%), and revascularization procedures (15%). Also noted was a reduction in the development of new-onset diabetes mellitus by 34% (p < 0.001). The beneficial effects of ramipril in HOPE were observed consistently among all subgroups—with and without diabetes, hypertension, or cardiovascular disease; older or younger than age 65—and were independent of the effects of concomitant cardiovascular medications (such as aspirin, beta-blockers, lipid-lowering agents, or other blood pressure drugs). Ramipril has recently been approved to reduce the risk of MI, stroke, and death from cardiovascular causes in patients 55 years or older at high risk of developing a major cardiovascular event because of a history of coronary artery disease, stroke, peripheral arterial disease, or diabetes that is accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria). Ramipril can be used in addition to other needed treatment, including antihypertensive, antiplatelet, and lipid-lowering therapy. The recommended starting dose is 2.5 mg once daily for 1 week, increased to 5 mg once daily for the next 3 weeks, then increased as tolerated to a maintainence dose of 10 mg once a day (which may be given in 2 divided doses for patients who have hypertension or who are post-MI). Potential mechanisms for improved cardiovascular prognosis with ACE inhibitors are shown in Table 3. ACE inhibitors are generally safe, well-tolerated, and affordable. Patients with atherosclerotic vascular disease, diabetes, or insulin resistance should therefore be considered for ACE inhibitor therapy unless they have an intolerable cough, systolic blood pressure consistently below 100-110 mmHg, or renal failure (creatinine > 2.5 mg/dL). Angiotensin receptor blockers are not equivalent to ACE inhibitors, but nevertheless may be a reasonable alternative for patients who are intolerant to ACE inhibitor therapy.

Table 3. Potential Mechanisms for Improved Cardiovascular Prognosis with ACE Inhibitors
Mechanism	Comments
Blood pressure lowering	ACE inhibitors lower blood pressure, which can reduce the risk of MI, heart failure, and stroke by 15-30%. However, the cardioprotective effects of ACE inhibitors appear to extend beyond blood pressure lowering; in the HOPE study, blood pressure was reduced by only 3/2 mmHg, which might be expected to account for about 40% of the reduction in stroke and 25% of the reduction in MI reported in HOPE (NEJM 2000;342:145). The unique cardioprotective benefits of ACE inhibitors are especially apparent in high-risk patients with hypertension and type 2 diabetes; in two trials, one comparing fosinopril vs. felodipine (Diabetes Care 1998;21:597) and the other comparing enalapril vs. nisoldipine (NEJM 1998;338:645), chronic ACE inhibitor therapy decreased cardiovascular events by almost 50% compared to calcium antagonists despite similar blood pressure reductions.
Improved endothelial function	Endothelial dysfunction plays a critical role in atherogenesis and thrombosis, and is the final common pathway through which cardiovascular risk factors like hypercholesterolemia, diabetes, cigarette smoking, and hypertension contribute to vascular inflammation and atherosclerosis. ACE inhibitors improve endothelial dysfunction by blocking the production of angiotensin II and preventing the breakdown of bradykinin, shifting the balance in favor of vasodilatation (decreased endothelin, increased nitric oxide/prostacyclin), fibrinolysis (decreased PAI-1, increased t-PA) and reduced platelet aggregation (8 nitric oxide/prostacyclin). Although other antihypertensive medications lower blood pressure as well as ACE inhibitors, they are not as effective at improving endothelial function (JACC 2000;35:60).
Reduction in LVH and arterial wall mass	Left ventricular hypertrophy (LVH) increases the risks of sudden death, CAD, heart failure, and life-threatening ventricular dysrhythmias. Regression of LVH substantially lowers these risks. ACE inhibitors are the most effective antihypertensive agents for the prevention and regression of LVH (JAMA 1996;275:1507), both by lowering blood pressure and blocking the formation of angiotensin II/aldosterone, which stimulates myocyte hypertrophy and extracellular matrix (collagen) formation. One longitudinal study showed that ACE inhibition reduced left ventricular mass by 40% over 3 years (Am J Hypertens 1998;11:631). Hypertension and insulin resistance also promote smooth muscle hypertrophy, hyperplasia, and increased fibrous tissue deposition within arterial walls, leading to reduced arterial compliance and endothelial dysfunction. ACE inhibition facilitates the reversal of these processes and the normalization of arterial wall structure and function.

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