A. Causes of Death in USA (2000) [19]

1. Heart Disease (coronary artery disease, CAD) 710,760
2. Cancer 553,091
3. Cerebrovascular Disease / Stroke 167,661
4. Chronic Obstructive Pulmonary Disease (some asthma) 122,009
5. Accidents 97,900
6. Diabetes Mellitus (DM) 69,301
7. Pneumonia and Influenza 65,313
8. Alzheimer's Disease 49,558
9. Nephritis, nephrotic syndrome, and nephrosis 37,251
10. Septicemia 31,224
11. Other Major Causes
    1. Chronic liver disease and cirrhosis
    2. HIV / AIDS
    3. Suicide
12. Healthy lifestyle associated with reduced cardiovascular (CV) disease (CVD) risk [113,140]
13. Obesity is expected to overtake smoking as major contributor to death in USA in ~2006
14. Increased body weight and lack of physical activity are equal contributors to mortality [41]

B. Diet [94]

1. Overall Recommended Diet [1]
   1. High ratio polyunsaturated and monosaturated to saturated fats
   2. Abundance of fruits and vegetables
   3. High consumption of marine n-3 fatty acids [2]
   4. Whole grains, vegetables as main source of carbohydrates as part of low fat or preferably Mediterranean diet [4]
   5. High consumption of cereal fiber
   6. High consumption of folate
   7. Western diet associated with increased risk for obesity and type 2 DM [3]
   8. Carbohydrate restricted ("Atkins") diet is superior to fat restricted diet for obesity, for 3-12 months of diet [60,88,114,115,168]
   9. In general, carbohydrate restricted diet recommended over fat restricted diet [168]
   10. Mediterranean diet had similar weight loss to carbohydrate restricted diet and improved glycemic control and weight loss compared with fat-restricted diet [168]
   11. Similar weight loss 2.1-3.3kg at 1 year with "Atkins", "Ornish", Weight Watchers, Zone diets in obese persons [147]
   12. Diets high in plant sterols and fibers are probably most effective and may be as effective as low dose statins [126]
   13. Caloric restriction generally associated with beneficial effects on risk factors [67]
2. Mediterranean Diet
   1. Superior to low-fat diet for improvement in cardiac risk factors [47] and weight loss [168]
   2. Mediterranean diet reduces markers of metabolic syndrome and diabetes [142]
   3. Virgin olive oil contains monounsaturated fats (mainly oleic acid) and polyphenols, which increase HDL levels and are anti-oxidant [54]
   4. Associated with 25-50% improvement in morbidity and mortality in average and elderly persons [122,141]
   5. Replacement of some carbohydrate with iether protein or monounsaturated fat leads to reduction in blood pressure, improved lipid profiles, reduced CVD risk [136]
3. Fiber
   1. Recommended 30-40gm per day (metamucil)
   2. Reduces risk of irritable bowel syndrome, diverticulosis, hiatal hernia, hemmorhoids
   3. Very effective for prevention and treatment of constipation
   4. Appears to decrease risk of CAD by ~20%
   5. Improves glycemic control and lipid profile in type 2 DM [5]
   6. May reduce risk of hypertension (HTN)
   7. May protect against obesity by reducing insulin levels
   8. Associated with 27% reduced risk for colonic adenomas [6]
   9. Confilicting results on colon cancer risk: no effect [7,8,18] or 40% reduction [111]
   10. Metamucil (Psyllium) is recommended additive in high risk persons
4. Fruits and Vegetables
   1. Recommendation of at least 5 servings of fruits and vegetables per day
   2. Folate, fiber, potassium, flavenoids, other vitamins likely provide benefits
   3. Cruciferous and green leafy vegetables
   4. Citrus fruits and citrus fruit juices
   5. Green leafy vegetables and vitamin C rich fruits and vegetables reduce the following:
   6. Cardiovascular (CV) risk [9]
   7. Ischemic stroke risk
   8. Blood pressure (BP) and HTN risk [11,104]
   9. Gastrointestinal, including colorectal, cancers [102]
   10. Increased fruit and vegetable intake had no effect on breast cancer risk [12]
5. Fat Intake [94]
   1. <25% of total daily calories should be from fat
   2. <10% of total calories should come from saturated fats
   3. Fat intake should be reduced in ALL persons with high cholesterol (Chol) or CAD
   4. Reduced fat intake and increased fruits/vegetables for all patients with HTN [14]
   5. Reduced saturated fat intake and weight loss reduce diabetic complications [34]
   6. Reduce trans fatty acid (TFA) to <1% of daily energy intake: avoid fast foods, hydrogenated vegetable oils, all foods with high TFA [13,28]
   7. Mediterranean diet rich in omega-3 fatty acids reduces overall Chol [2] and is associated with reduced overall, coronary, and cancer mortality [122]
   8. Virgin olive oil has oleic acid and polyphenols (antioxidants) which increase HDL [54]
   9. Increased N-3 polyunsaturated fatty acid intake associated with ~25% reduction in MI and in sudden cardiac death [15,16]
   10. High blood levels of long chain N-3 fatty acids associated with >70% reduced risk of sudden cardiac death in men with no prior history of CAD [17]
   11. National Cholesterol Education Program guidelines should be followed
   12. Goal Chol levels for secondary prevention are probably around 100mg/dL [21]
   13. High intake of poly- and monounsaturated fats reduced gallstone risk in men [144]
6. Statins and Lipid Levels
   1. Statin therapy should be initiated in all patients with CAD, regardless of baseline Chol [66]
   2. Statins for any patient at high risk for heart disease or stroke [66]
   3. Statin use associated with ~50% reduced risk of initial myocardial infarction (MI) [10]
   4. Mediterranean diet potentiates Chol lowering effects of statins [2]
   5. Statins also associated with reduced nuclear cataract risk [155]
7. Alcohol Intake [104,161]
   1. Mild to moderate alcohol consumption is recommended: 0.3-2 drinks per day
   2. In this range, minimal adverse effects and overall mortality reductions
   3. This level can reduce risk of MI / angina >30%
   4. Associated with >40% reduced risk of death from MI [22.107]
   5. Associated with 20-50% reduced risk of developing heart failure [23,24]
   6. Associated with 20-50% stroke risk reduction [42]
   7. One to 3 drinks/day reduces DM2 risk ~30-50% [134]
   8. Associated with >40% reduced risk of dementia of any cause in age >55 years [27]
   9. Moderate alcohol intake (1-3 drinks/day) reduces diabetes mellitus risk ~30-50% [134]
   10. Similar or greater reductions in CAD risks found in diabetics who drink
   11. ~1.5X increased risk of breast cancer associated with >1 drink per day [29]
   12. Wine may provide benefits beyond alcohol content [30]
   13. No increase in hemorrhagic strokes at these levels of alcohol consumption
   14. Correlates with increases in HDL Chol and plasminogen activator levels
   15. Also reduces levels of systemic inflammatory markers [31]
   16. Execessive alcohol intake leads to premature death from accidents, liver disease, cancers
8. Alcohol Dehydrogenase (ADH) Polymorphisms [32]
   1. Three ADH isoenzymes exist in humans: ADH1, AHD2, ADH3
   2. ADH2 and ADH3 are polymorphic
   3. In white populations, ADH3 alleles occur as g1 and g2 with 2.5X different kinetics
   4. Persons with g1g1 (40%) have most rapid kinetics, g1g2 mid (45%), g2g2 (~15%) slowest
   5. G1G1 associated with increased risk of oropharyngeal cancer and end-organ damage
   6. G2G2 associated with increased risk of alcoholism itself
   7. G2G2 with mild alcohol consumption associated with reduced MI risk
9. Fish Consumption
   1. Fish contain cardioprotective long chain n-3 fatty acids
   2. At least once weekly appears to reduce sudden cardiac death by ~50%
   3. High intake of fish and omega-3 fatty acids associated with 10-50% reduced stroke risk in women [33]
10. Coffee Consumption
    1. Associated with reduced risk of DM2 (mechanism unclear) [135,150]
    2. Does not increase mortality, but may reduce CV and overall mortality [167]
11. Patients with DM should have aggressive diet and lifestyle modifications to prevent vascular complications including MI [34]
12. Improved diet and lifestyle has contributed to reduced CAD [35] and Type 2 DM [36] in women

C. Vitamins (Vit) [37]

1. Multivitamin tablets are recommended in healthy adults only to provide specific Vit
2. Specific Recommended Vitamins [38,39]
   1. Vit D + calcium to prevent bone and tooth loss in postmenopausal women as well as men >55 years, particularly if intake is below recommended levels [40,157]
   2. Vit D supplements reduce all-cause mortality in adults and older individuals: 400 IU/d for adults 50-70 years, 600 IU/d for >70 years old [165]
   3. Folate, Vit B12 and Vit B6 lower plasma homocysteine but do not prevent primary cardiac or overall vascular events or mortality [44,166]
   4. Increased folate intake associated with reduced risk of colon polyps and cancer
   5. Routine vitamin supplementation is not recommended for CAD or cancer prevention [123,124]
3. Antioxidant Vitamins
   1. Vit E - no clear efficacy for prevention of CAD or cancer; may increase mortality [148]
   2. Vit C - no efficacy in prevention of CAD or any other disease
   3. Vit C may increase antioxidant effects of Vit E
   4. ß-Carotene - no efficacy in preventing cancer or CAD
   5. High dose ß-carotene or Vit A supplements are harmful and should be avoided
   6. Vit A as excess can cause blindness, osteoporosis, other problems
   7. To date, antioxidant vitamins have not reduced cancer risk (slight increase possible) [145]
4. CAD
   1. Oxidized low density lipoprotein (LDL) is major contributor to atherosclerosis
   2. Antioxidants, particularly Vit E, can prevent LDL oxidation
   3. No benefit to 600 IU natural Vit E qod for prevention of CVD, cancer; no overall effect on mortality [149]
   4. Randomized studies show variable benefits of Vit E in CAD [1,43]
   5. No effect of supplementary Vit C or A for preventing CAD when given alone
   6. No general benefit of any vitamin or combination for cancer or CAD prevention [123,124]
5. Recommendations for Vitamin Supplements [37,38,39]
   1. Folate must also be taken by all pregnant women to reduce neural tube defects
   2. Data do not currently support folate+Vit B6 or Vit B12 for homocysteine reduction [44]
   3. Recommend adequate Vit D + Calcium intake in older persons
   4. Vit E intake probably optimal at ~100 IU/day and not more
   5. Vit B12 supplements may be helpful in elderly wtih diminished absorption
   6. Avoid high doses Vit A particularly during pregnancy
   7. Avoid massive doses of fat-soluble vitamins at any age

D. Body Weight [46]

1. Maintaining a healthy weight is critical to good health
2. Prevalance of obesity (BMI >30kg/m2) is ~20% in USA in 2000 and is increasing [48]
3. Healthy body mass index (BMI) is 19-25
   1. BMI is a measure of weight normalized for body surface area (height dependent)
   2. BMI = [weight(pounds)x703]/[height(inches) squared]
4. Relationship between BMI, Mortality, Disease
   1. Age and sex dependent
   2. Risks increase to up to 1.5X for death with increasing BMI
   3. Overweight have ~3 years and obese ~7 years reduction in lifespan [106]
   4. Smoking combines with overweight / obesity to reduce lifespan up to 13 years [106]
   5. Risks increase >6X for type 2 DM with increasing BMI
   6. BMI 23-24.9 for men, 22.0-23.4 for women associated with lowest mortality risk
   7. Increased BMI is most strongly associated with death from CAD
   8. Obesity increases risk for HTN 3-6 fold [104]
   9. Obesity increases risk for several types of cancer [102]
5. Weight Loss
   1. Weight reduction with BOTH caloric restriction AND excercise is preferred over either modality alone [49,129]
   2. Weight loss reduces BP in both men and women [50]
   3. Loss of 10 pounds sustained for >6 months reduced HTN risk 65% [50]
   4. If weight gain >10 pounds occurs after age 20, persons should change eating patterns and increase physical activity
   5. Reduced carbohydrate ("Atkins") diet is generally superior to others for weight loss and reduction of CV risk factors [60,88]
   6. Weight loss, reduced fat intake, and exercise in patients with impaired glucose tolerance reduced the risk of developing frank DM by 58% [51,52]
   7. This combination lifestyle modification was more effective at preventing DM than metformin [52]
6. Ratio of waste to hip circumference should not exceed 1.0 (men and women)
7. Weight loss combined with exercise and improved diet reduces blood pressure [113]

E. Exercise [53]

1. Overall goal of exercise is to maintain CV fitness and a healthy weight
2. Physical activity is decreasing among young people and must be encouraged [98]
3. Regular exercise reduces CV and overall mortality 30-50% [99]
4. Cardiorespiratory fitness is an independent mortality predictor in adults >60 years [164]
5. Primary care physician recommendations to patients lead to increased physical activity
6. Lifestyle changes are as effective as structured exercise
7. Sedentary lifestyle strongly associated with increased obesity and DM2 risk [110]
8. Exercise is critical for patients trying to and just after quitting smoking [55]
9. Goal is 20 minutes of exercise at least three times per week at target heart rate [56]
   1. Target heart rate on exercise treadmill testing is 220-Age x 70%
   2. Brisk walking >3 hours per week is sufficient excercise
   3. Long bouts of exercise are no more effective than short bouts for weight control
   4. At least 1 hour of walking per week associated with 50% reduced risk of CAD
   5. Increased exercise intensity does not appear to affect outcomes in overweight women [129]
10. Major Effects
    1. Exercise reduces weight regardless of genetic predispositions or eating habits [49]
    2. Reduces systolic (~4 mm Hg) and diastolic (~2.5 mm Hg) blood pressure [58,104]
    3. Reduces total Chol, triglycerides and increases HDL-Chol [105]
    4. Long term excercise reduces atherogenic activity of mononuclear cells
    5. Reduces HbA1c in Type 2 Diabetic patients by ~0.65% [61]
    6. Increases coronary endothelial function in patients with CAD [62]
    7. Improves endothelial vasodilator function and left ventricular diastolic function [103]
    8. Associated with 14-33% risk breast cancer reduction [130]
    9. Reduced risk of stroke >40% in women [64]
    10. Reduces progression of carotid atherosclerosis in men [65]
    11. Reduced risk of osteoporosis and osteoporotic fractures
    12. Reduced need for cholecystecomy in women independent of weight or weight loss
    13. Physical activity improves cognitive function and reduces decline in older women [143]
    14. Exercise at least 3 times per week associated with ~40% reduced incidence of dementia in 65 year old persons without baseline dementia [78]
11. Effects on DM [52,103]
    1. Exercise reduces weight, improves insulin sensitivity, reduces DM risk [68]
    2. Aerobic and resistance exercise both reduce HbA1c, and combination is best [163]
    3. Exercise in DM type 2 did not reduce LDL or raise HDL cholesterol, but reduced triglycerides [163]
    4. Weight loss, reduced fat intake, and exercise in patients with impaired glucose tolerance reduced the risk of developing frank DM 58% [51,52]

F. Aspirin (ASA) [43,70,71]

1. Recommended in all men and women without contraindications >40-50 years
2. COX1 blockade and overall antiplatelet activity of ASA similar in men and women [20]
3. CAD Prevention [45,63,71,72,73,156]
   1. MI reduction 15-30% in men
   2. Stroke (thromboembolic) reduction - 12-25% mainly in women
   3. CV mortality reduction mainly in men 14-17%
   4. Non-cardiac vascular death reduction 25% mainly in men
   5. ASA 75mg/d improves efficacy of aggressive HTN treatment
   6. Primary prevention with ASA 100mg po qod in women reduced stroke but not MI [63]
   7. Nonsteroidal anti-inflammatory drugs (NSAIDS) do not reduce the CV risk [75]
   8. ASA 75-81mg po qd is recommended for both primary and secondary CAD prevention [69]
4. Colonic Adenomas and Colon Cancer [108,109,133]
   1. ASA and NSAIDs reduce colorectal cancer (CRC) risk after 10-20 years
   2. ASA at least 300mg qd x 5 years associated with 25% reduced CRC risk at 10 years [87]
   3. ASA 325mg qd reduces number of new polyps ~40%
   4. ASA reduces number of CRC patients developing new polyps by ~40%
   5. ASA reduces number of >1cm as well as villous polyps ~40%
   6. ASA >650mg/week associated with reduction in colorectal adenomas 20-30% (dose dependent effect) in a prospective study in an average risk population [133]
   7. ASA (>14 pills/week) or NSAIDs for >10 years associated with ~50% reduced CRC risk in women [151]
   8. Regular use of ASA associated with ~35% reduction in risk of CRC expressing high levels of COX-2; no effect on CRC with weak or absent COX-2 [162]
   9. Overall, ASA, NSAID or COX2 inhibitors are not recommended for routine primary prevention of CRC [158,159,160]
5. ASA use associated with 20% reduced risk of breast cancer [138]
6. Dose [69,70]
   1. Primary CAD prevention: ASA 75-81 mg qd is strongly recommended
   2. Secondary CAD Prevention: ASA 75-160mg qd is now usually recommended
   3. Higher doses of ASA do not appear to have benefit, and increase bleeding risks [69]
   4. ASA 81-162mg qd + clopidogrel (Plavix® 75mg for secondary CV risk reduction is beneficial [25]
   5. ASA+clopidogrel in patients with multiple CVD risk factors as primary prevention is not beneficial and may cause harm [165]
   6. Slight increase in major bleeding with ASA+clopidogrel versus ASA alone [25]
7. Side Effects
   1. Risk of upper gastrointestinal bleeding increases with dose [151]
   2. Enteric coating or buffering does not appear to reduce bleeding risk
   3. Patient compliance is likely improved and bleeding risks reduced with 81mg po qd
8. Consider clopidogrel (Plavix®) in place of ASA for primary prevention or combined with ASA for secondary prevention of CAD, cerebral, or peripheral vascular disease [25,146]

G. Hormone Replacement Therapy (HRT) [79,80,81]

1. HRT at standard estrogen doses is longer be recommended routinely in healthy post- menopausal women with or without a uterus [100,137]
2. Typical Doses
   1. Conjugated equine estrogens (CEE such as Premarin®) 0.625mg/d
   2. Progestin: medroxyprogesterone acetate (MPA) 2.5mg/d
   3. Dose 0.3mg/d is as effective as 0.625mg/d at reducing cardiovascular events and is associated with reduced risk of stroke and of endometrial hyperplasia [82]
3. Overall Increase in Events [125]
   1. CAD risk increased by ~7/10,000 person-years
   2. Strokes and pulmonary embolism risk increased by ~8/10,000 person-years each [118]
   3. Invasive breast cancer risk increased by ~8-12/10,000 person-years or 1.2-2.0X [118,121,128]
   4. Global health index reduced overall
   5. Increase in ovarian cancer risk
   6. Three years after stopping combined HRT (5.6 years) had 1.27X increased breast ca risk [57]
   7. Three years after HRT (for 5.6 years), CV disease risk similar to no therapy [57]
4. Overall Reduction in Events
   1. Reduction in hip fractures of 5/10,000
   2. Reduction in CRC of 6/10,000
5. In women without menopause symptoms, HRT does not improve quality of life [35]
6. Congitive Function and Dementia
   1. A prospective study (4381 women) with HRT versus placebo showed no reduction in dementia risk [116] and no improvement in cognitive function [117] in women >65 years
   2. ERT/HRT cannot be recommended for prevention of demenia or congitive decline
7. Testosterone Supplements [26]
   1. Men 60-80 years often have low-normal serum testosterone levels (<13.7nmol/L)
   2. Testosterone supplements for 6 months did not affect functional status or cognition, but increased lean body mass and had mixed effects on metabolic parameters [26]
   3. Testosterone supplements in men with low-normal levels not recommended at this time

H. Selective Estrogen Receptor Modulators (SERMs) [85,86]

1. Mixed agonist/antagonist activity on estrogen receptors
2. Tamoxifen (TAM, Nolvodex®) [101]
   1. 30-50% reduction for new (mainly ER+) breast cancers when given over 4 years
   2. Causes endometrial hyperplasia, uterine cancer, thromboemboli, cataracts
   3. Mortality may be slightly increased with overall use
   4. No benefit in most women with >5 years treatment
3. Raloxifene (RAL, Evista®) [153]
   1. In osteopenic women, raloxifene associated with a ~55% reduction in new breast ca
   2. Reduced risk of breast Ca in women with high estrogen levels by 75% [89]
   3. Over 8 years, reduced new breast invasive breast cancer by 66% [77]
   4. In 5-year study, similar reduction in new invasive breast Ca to TAM, with reduced cataracts, thromboembolic events, and uterine cancers [153,154]
   5. Improvement in bone density and reduction in fracture risk
   6. Does not cause endometrial hyperplasia or cancer
4. Women with familial breast cancer and BRCA1 or BRCA2 mutations may consider prophylactic total mastectomy and TAM [83] or oopherectomy [84]
5. Strongly consider SERMs for all post-menopausal women at any increased breast cancer risk

I. Stroke Prevention [90]

1. Lifestyle Modification
   1. Stop smoking
   2. Increase physical activity
   3. Weight reduction
2. Alcohol Intake
   1. Moderate (1-2 drinks per day) consumption associated with ~50% stroke risk reduction
   2. Three-fold increased risk of stroke with >6 drinks per day
3. BP normalization
4. DM - good control is key to reduction in stroke risk
5. Cholesterol Reduction
   1. Aggressive reduction of cholesterol with statins reduces risk of stroke 20-30%
   2. Treatment with pravastatin post-MI in elderly with normal cholesterol reduced the incidence of recurrent MI, stroke, hospitalization, and death by 30-45% [91]
6. Aspirin
   1. Low dose: 75-81mg/d appears to reduce risk of thromboembolic stroke 10-30% [70]
   2. Dose >325mg/d increases risk of hemorrhagic stroke
7. Warfarin
   1. Patients with atrial fibrillation
   2. Post-MI with decreased cardiac function or ventricular thrombus
8. Screening for Carotid Stenosis
   1. Endarterectomy for symptomatic carotid stenosis >70% is cost effective [92]
   2. Endarterectomy for symptomatic carotid stenosis >50% in >75 year olds is beneficial [92]
   3. Endarterectomy treatment of asymptomatic stenosis >70% reduces stroke risk [93]
   4. Screening for asymptomatic carotid stenosis >60% is not cost effective
9. Lack of Association with Stroke:
   1. Diet
   2. Antioxidant vitamins
   3. Oral Contraceptive Agents

J. Osteoporosis [131]

1. All post-menopausal women are at risk and 1 in 6 women develop hip fractures after age 50
2. Caucasian, thin, and women with a family history are at increased risk
3. Routine bone mineral densitometry (BMD) screening is strongly recommended
4. Routine interventions are recommended unless specific contraindications exist
   1. Calcium (1000mg/day) + Vitamin D (400-800 IU/day) has been standard
   2. However, calcium+vitamin D showed an insignificant reduction in fractures in healthy postmenopausal women despite a small increase in hip bone density [74]
   3. Calcium+vitamin D also slightly increased risk of kidney stones (by 17%) [74]
   4. Bisphosphonates are most effective agents available
   5. Selective estrogen response modifiers (SERM) are also very effective
   6. Transdermal estrogen patch, particularly low dose, may be safe and do improve BMD [139]
5. External hip protector can prevent fractures in frail adults >70 years [95]

K. Suncreens

1. Sunscreens reduce UVB much more than UVA effects
2. Sun protection factor (SPF) is ratio of time required to produce minimal erythema of the skin covered by sunscreen product to time required for erythema on bare skin
3. Sunscreens do not apparently affect 25-hydroxyvitamin D3 levels
4. Clearly reduce sunburn, photoaging, actinic keratoses
5. Appear to reduce squamous but not basal cell carcinomas of the skin [96]
6. Reduces development of new nevi ~50% in white children [97]
7. Unclear if any effect on melanoma risk [132]
8. Strongly recommend routine use of SPF >15 in all persons

L. Dementia

1. Participation in cognitively stimulating activities reduces incidence of Alzheimer's by >30% [119]
2. Exercise at least 3 times per week associated with ~40% reduced incidence of dementia in 65 year old persons without baseline dementia [78]
3. Participation in leisure activities associated with 7% reduced risk of dementia [120]

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