• Coronary heart disease (CHD) is the leading cause of mortality in the US, in both males and females.
• 60% of all costs associated with CHD are hospitalization costs.
• CHD is a multi-factor disease. The more the risk factors the higher the chance of getting it.
• Steps in Atherogenesis:
• (1) Infiltration of LDL into arterial wall.
• (2) Entrapment of LDL into arterial wall.
• (3) Modification of LDL.
• (4) Uptake of modified LDL by Mf ’s (secretes TNFa ) – uptake by scavenger receptor (unregulated) rather than regulated LDL R.
• formation of foam cells (also secrete enzymes that degrade capsule Þ bleeding into artery walls)
• formation of fatty streaks
• (5) Conversion of fatty streaks to fibrous plaques.
• Risk factors:
• (1) Cigarette smoking – destabilizes (increase of the core lipid pool and weakening of the overlying fibrous cap) plaques leading to damage. Recent studies show that smoking is more likely to lead to sudden cardiac death and acute MI, and less likely to lead to stable angina.
• (2) Hypertension – both a systolic and diastolic risk factor.
• (3) Diet – a decrease in fat and cholesterol can lead to plaque regression.
• (4) Exercise – as big a factor as smoking. Has a graded beneficial effect (more you do, better it is). Do 30 mins/day.
• (5) Obesity – 1/3 of US adults are obese, ½ of US adults are overweight. Obesity in childhood leads to Ý morbidity in adulthood. Though 90-95% of patients regain lost weight in 7 years, even a small (5 lbs) loss can ß LDL, Ý HDL, ß blood sugar.
• (6) Stress – psychosocial stress is a potent risk factor.
• (7) Cholesterol

• Cholesterol Hypothesis:
• Increasing the dietary consumption of cholesterol and saturated fats elevates serum levels of total and LDL cholesterol which in turn increases the likelihood of acquiring CHD. This relationship between cholesterol and CHD is continuous, graded, and independent of the presence of other risk factors.
• Reducing dietary consumption of cholesterol and saturated fats lowers serum cholesterol, which in turn reduces the likelihood of acquiring CHD. This was shown both in primary prevention trials (pts with high cholesterol but no CHD) and secondary prevention trials (pts with histories of CHD).
• The use of HMG CoA reductase inhibitors (Statins) results in a significant reduction of total cholesterol, LDL, and fatal CHD. 1% reduction in total cholesterol level = 2% reduction in CHD risk. And, 1% increase in HDL = 3% decrease in CHD risk.
• Atherosclerosis is a systemic disease. It may be possible to have one vascular bed be a marker of disease for another.
• Most people who have MIs have average cholesterol levels. Most lesions that cause problems are NOT stenotic, it is the small lesions that suddenly destabilize that cause an MI, not the 99% slow stenosing artery which has time to grow collaterals.
• Many internists and cardiologists consistently fail to investigate their patient’s risk factors.
• Atherogenic Dyslipidemia – borderline high-risk LDL, Ý TGs, small LDL particles (more likely to be oxidized), ß HDL cholesterol.

• Female patients – women are underscreened, present later in evolution of disease, less aggressively evaluated, CHD worse prognosis than men. CHD rates rise rapidly after menopause due to lack of the cardioprotective estrogen. In women >50 years HDL is a stronger predictor of CHD mortality than total cholesterol. Postmenopausal estrogen replacement therapy (ERT) reduces cardiovascular disease risk in women by ß LDL and Ý HDL.
• What does estrogen (and ERT) do? Upregulate LDL receptors, lowers lipoprotein a, improves endothelial function, reduces likelihood of coronary artery spasm, Ý the production of the vasodilating prostaglandin I₂, Ý insulin sensitivity thus lower it, reduces plasma fibrinogen and plasminogen activator inhibitor levels.
• Lipoprotein(a) – LP(a) consists of LDL linked by a disulfide bond to apoprotein(a) (Apo(a)). Apo(a) is homologous to plasminogen (protease which breaks down fibrin clots), thus inhibiting plasminogen by blocking its receptor sites Þ increases clot formation. LP(a) is thus an independent risk factor which cannot be modified by diet, exercise, etc.
• LP(a) may also be active as an atherogenic lipoprotein. LP(a) gets oxidized like LDL, and if uptaken by Mf s Þ foam cells.
• There is thus a link between atherogenesis and thrombogenesis.
• Elderly – hardly any CHD studies. TC, LDL, and HDL are risk factors. Serum lipid levels and CHD mortality not related.
• Homocysteine – Builds up in the blood whe cystathionine B Synthetase doesn’t work/deficient. Though mechanism unclear it increases the risk for CHD. It is probably an independent risk factor though its been linked to others (smoking, hypercholesterolemia, blood pressure). Levels are lowered by folate, B12, B6 – but no studies show effect of lowering it.
• Diabetes – CHD is leading cause of death among diabetics, 80% of all mortality. Characterized by the
• Deadly Quartet : obesity, hypertension, hyperuricemia, and hypertriglyceridemia (small LDL particles (more likely to be oxidized) and increased triglycerides).
• Aggressive lipid lowering in diabetics produces same beneficial effects on cardiovascular outcomes as in non-diabetics.

Summary of Cholesterol Medications 

• Factors raising serum cholesterol:
• (1) Saturated Fats in diet (most important by far)
• (2) Cholesterol in diet
• (3) Obesity
• Three Types of Dietary Fat
• (1) Saturated fat (all single bonds) – hydrogenated – meat, lard, butterfat, dairy fats, coconut oil, palm oil.
• (2) Monounsaturated fat (one double bond) – canola oil, olive oil.
• (3) Polyunsaturated (multiple double bonds) – vegetable oils and fish.
• Saturated fats have hypercholesterolemic effects. Suppress activity of LDL receptors.
• Substitution of polyunsaturated and/or monounsaturated fats for saturated fat, lower total and LDL cholesterol.
• cis vs. trans:
• Cis – Both hydrogens on the same side of the double bond. Liquid at room temperature.
• Trans – Hydrogens on different sides of the double bond. Semi-solid to solid at room temperature. Higher melting point, more stable, smoother, more spreadable.
• Beware: trans FAs act like saturated fats (Ý LDL, Ý total cholesterol, ß HDL); food industry often uses them
• Produced by bacterial action in ruminant animals, therefore present in animal tissue and milk
• Can also be formed as a side product of hydrogenation process – called isomerization
• Butter raises cholesterol, saturated fat, and trans fat more than margarine
• Omega FAs:
• Omega 3 fatty acids – Long chain polyunsaturated FAs whose first double bond is located 3 carbons away from the methyl end of the molecule.
• Linolenic acid (18C, essential FA) Þ eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA).
• Omega 6 fatty acids – Long chain polyunsaturated FAs whose first double bond is located 6 carbons away from the methyl end of the molecule.
• Linoleic acid (18C, other essential FA) Þ arachidonic acid.
• Both Linolenic acid and Linoleic acid (omegas) undergo desaturation and chain elongation to form polyunsaturated 20 carbon products.
• Omega 3 deficiency – visual impairment and behavioral disturbances, learning deficiency.
• Omega 6 deficiency – drying/flaking skin, impaired wound healing, growth retardation, fatty liver, reproductive failure.
• Other effects:
• Omega 6 are hypocholesterolemic, effects of omega 3 on cholesterol are inconsistent and mixed.
• Omega 3 relates more to cardiovascular physiologic effects: suppressing thromboxane production and enhancing prostacyclin production thereby decreasing platelet aggregation and adhesion, promoting vasodilation, decreasing leukotriene production and several interleukins thereby decreasing inflammatory response, decreasing blood pressure. Intake of omega 3 lowers elevated plasma triglyceride levels (70-80%).

• Complex mixture of substances that despite being chemically different share the common physiological characteristic of resisting human enzymatic digestion.
• Most fibers are carbohydrates (cellulose, hemicelluloses, pectins, gums, mucilages), only non-carbohydrate is lignin (phenolic compound).
• Two types of fiber:
• (1) Soluble – gums, mucilages, pectins, some hemicelluloses (citrus fruits, fruits, oats, barely, beans/peas)
• (2) Insoluble – cellulose, lignin, some hemicelluloses (whole grains, wheat, corn, potatoes, cauliflower)
• Note: in processed whole grains the fiber-rich bran portion is removed
• Functions of fiber:
• (1) Insoluble fiber acts as a bulking agent - Ý stool weight and water content, thus rapid transit time. No effect on blood cholesterol or lipoporteins.
• (2) Soluble fiber is hypocholesterolemic - ß total cholesterol and LDL. Mechanism for this may be that soluble fiber binds cholesterol and bile acids in GI and increases fecal excretion.
• (3) Soluble fiber enhances production of small chain FAs via microbial fermentation in colon. May affect hepatic cholesterol synthesis.
• Recommendations: 20-35 g dietary fiber/day for adults.

• Antioxidant Nutrients
• LDL becomes oxidized Þ speeds formation of atherosclerotic lesions.
• Vitamin C, Vitamin E, b -carotene inhibit LDL oxidation.
• Nurses Health Study/Health Professionals Study: Vit E supplement associated with ~40% decrease of CHD.
• Homocysteine
• one of many reasons for elevated homocysteine Þ suboptimal folic acid and/or vitamin B₁₂.
• Phytochemicals
• non-nutrient chemicals in plants which have beneficial properties.
• Example: "French paradox" – French who eat high fat diet and drink red wine Þ low CHD.
• Phytochemical composition of red wine: flavonoid (most common, quercetin) and non-flavonoid phenols.
• Flavonoids can inhibit cyclo-oxygenase (ß platelet aggregation), and inhibit LDL oxidation.

• Percent daily values based on a 2000 Kcal diet, with:
• 30% from fat = 65 g
• 10% from saturated fat = 20 g
• < 300 mg cholesterol
• < 2400 mg sodium
• 25 g dietary fiber
• Terminology:
• Fat-free = < 0.5 g total fat
• Low-fat = £ 3.0 g total fat
• Cholesterol-free = < 2.0 mg cholesterol AND £ 2.0 g saturated fatty acids
• Low-Cholesterol = £ 20.0 mg cholesterol

• In 1996, American Heart Association recommends the following population-wide dietary and lifestyle goals:
• Elimination of cigarette smoking.
• Appropriate levels of caloric intake and physical activity to prevent obesity and reduce weight in those who are overweight.
• Consumption of 30% or less of the day’s total calories from fat.
• Consumption of 8% to 10% of total calories from saturated fatty acids.
• Consumption of up to 10% of total calories from polyunsaturated fatty acids.
• Consumption of up to 15% of total calories from monounsaturated fatty acids.
• Consumption of less than 300 mg/d of cholesterol.
• Consumption of no more than 2.4 g/d of sodium.
• Consumption of 55% to 60% of calories as complex carbohydrates.
• For those who drink and those for whom alcohol (ethanol) is not contraindicated, consumption should not exceed 2 drinks (1 to 2 oz of ethanol) per day.