HUEC 7005 2006 10 02 v2

HUEC 7005: Molecular and Clinical Nutrition II: 

HUEC 7005: Molecular and Clinical Nutrition II October 2: Nutrition and Atherosclerotic Cardiovascular Disease November 6: Bioactives and Cardiovascular Disease November 20: Bioactives and Diabetes November 27: Bioactives and Cancer December 4: Class Presentations

Nutrition and Atherosclerotic Cardiovascular Disease: 

Nutrition and Atherosclerotic Cardiovascular Disease

Atherosclerosis: 

Atherosclerosis

Plaque Rupture with Thrombus: 

Plaque Rupture with Thrombus Lipids Online

The “Lipid Hypothesis,” Atherosclerosis and Diet: 

The “Lipid Hypothesis,” Atherosclerosis and Diet 1800’s Arteriosclerosis was well recognized but its pathological significance was not established. Theories encompassed disturbed arterial metabolism and adherent blood clots that changed into arteriosclerotic plaques. 1909 A.I. Ignatowski reports the successful production of atherosclerosis in rabbits by feeding meat, milk, and eggs. 1910 Adolf Windaus showed that atheromatous lesions contained 6 times as much free cholesterol and 20 more esterified cholesterol.

The “Lipid Hypothesis,” Atherosclerosis and Diet: 

The “Lipid Hypothesis,” Atherosclerosis and Diet 1913 Anitschkow and Chalatow demonstrate that the lesions in rabbits resulted from fat and cholesterol in the diet. 1950 Malmros, among others, correlate the war-time drop in CHD mortality with the concomitant drop in the consumption of milk, butter and eggs.

The “Lipid Hypothesis,” Atherosclerosis and Diet: 

The “Lipid Hypothesis,” Atherosclerosis and Diet 1950 John Gofman identified low-density lipoprotein cholesterol and high density lipoprotein cholesterol using ultracentrifuge. In addition, they found that 101 of 104 men with MI had elevated LDL – a finding they had also observed in their cholesterol-fed atherosclerotic rabbits. They also observed an inverse relationship between HDL and risk of coronary artery disease. 1952 Laurence Kinsel found that ingestion of plant foods and avoidance of animal fat decreased blood cholesterol levels.

The “Lipid Hypothesis,” Atherosclerosis and Diet: 

The “Lipid Hypothesis,” Atherosclerosis and Diet 1961 The American Heart Association began encouraging people to follow a “prudent diet”. 1964 Konrad Bloch and Feodor Lynen received the Nobel Prize in Medicine for the work on the metabolism of cholesterol and fatty acids 1970 Keys publishes compendium describing results from Seven Countries Study. 1985 Michael Brown and Joseph Goldstein shared the Nobel Prize in Medicine for their work on LDL receptor and LDL receptor pathway

Seven Countries Study: CHD Events are Correlated with % of Calories from Fat: 

Seven Countries Study: CHD Events are Correlated with % of Calories from Fat Keys, 1970

Seven Countries Study: CHD Events are Better Correlated with Saturated Fat: 

Seven Countries Study: CHD Events are Better Correlated with Saturated Fat Keys, 1970

Relationship Between Saturated Fat and CHD Deaths is Confirmed in 20 Country Study : 

Relationship Between Saturated Fat and CHD Deaths is Confirmed in 20 Country Study Stamler, 1979

CHD Mortality is Highly Correlated withMilkfat Consumption: 

CHD Mortality is Highly Correlated with Milkfat Consumption Turpeinen, 1976

Diet and CVD: 

Diet and CVD Dietary Guidelines for Healthy American Adults (1996) “…the AHA has issued seven policy statements on diet and CHD as reliable new information has become available*. In each of these statements emphasis was placed on consumption of total fat, saturated fat and certain unsaturated fatty acids, dietary cholesterol, and sodium because of their significant contribution to risk of CHD.” *(from years 1961-1988)

AHA Dietary Guidelines, 1996: 

AHA Dietary Guidelines, 1996 Elimination of cigarette smoking Appropriate levels of caloric intake and physical activity to prevent obesity 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 For those who drink consumption should not exceed 2 drinks per day Consumption of 55% to 60% of calories as complex carbohydrates

AHA Dietary Guidelines, 2000: 

AHA Dietary Guidelines, 2000 Consume a Healthy Eating Pattern Including Foods From All Major Food Groups Major guidelines: Consume a variety of fruits and vegetables and grain products, including whole grains. Include fat-free and low-fat dairy products, fish, legumes, poultry, and lean meats. Maintain A Healthy Body Weight Major guidelines: Match intake of energy (calories) to overall energy needs; limit consumption of foods with a high caloric density and/or low nutritional quality, including those with a high content of sugars. Maintain a level of physical activity that achieves fitness and balances energy expenditure with energy intake; for weight reduction, expenditure should exceed intake.

AHA Guidelines, 2000: 

AHA Guidelines, 2000 Achieve A Desirable Blood Cholesterol and Lipoprotein Profile Major guidelines: Limit the intake of foods with a high content of saturated fatty acids, trans fatty acids and cholesterol. Substitute grains and unsaturated fatty acids from vegetables, fish, legumes, and nuts. Achieve A Desirable Blood Pressure Major guidelines: Limit the intake of salt (sodium chloride) to <6 g per day. Limit alcohol consumption (no more than 1 drink per day for women and 2 drinks per day for men). Maintain a healthy body weight Consume a dietary pattern that emphasizes vegetables, fruits, and low-fat or fat-free dairy products.

AHA Recommendations, 2006: 

AHA Recommendations, 2006 Choose lean meats and poultry without skin and prepare them without added saturated and trans fat. Select fat-free, 1 percent fat, and low-fat dairy products. Cut back on foods containing partially hydrogenated vegetable oils to reduce trans fat in your diet. Cut back on foods high in dietary cholesterol. Aim to eat less than 300 milligrams of cholesterol each day. Cut back on beverages and foods with added sugars. Choose and prepare foods with little or no salt. Aim to eat less than 2,300 milligrams of sodium per day. If you drink alcohol, drink in moderation. That means one drink per day if you’re a woman and two drinks per day if you’re a man. Follow the American Heart Association recommendations when you eat out, and keep an eye on your portion sizes.

Evolution and Progression of Coronary Atherosclerosis: 

Evolution and Progression of Coronary Atherosclerosis Adapted from Fuster, 1992

Endothelial Dysfunction: 

Endothelial Dysfunction Increased endothelial permeability to lipoproteins and plasma constituents mediated by NO, PDGF, AG-II, endothelin. Up-regulation of leukocyte adhesion molecules (L-selectin, integrins, etc). Up-regulation of endothelial adhesion molecules (E-selectin, P-selcting, ICAM-1, VCAM-1). Migration of leukocytes into artery wall mediated by oxLDL, MCP-1, IL-8, PDGF, M-CSF. Ross, NEJM; 1999

Formation of Fatty Streak: 

Formation of Fatty Streak SMC migration stimulated by PDGF, FGF-2, TGF-B T-Cell activation mediated by TNF-a, IL-2, GM-CSF. Foam-cell formation mediated by oxLDL, TNF-a, IL-1,and M-CSF.. Platelet adherence and aggregation stimulated by integrins, P-selectin, fibrin, TXA2, and TF. Ross, NEJM; 1999

Formation of Advanced, Complicated Lesion: 

Formation of Advanced, Complicated Lesion Fibrous cap forms in response to injury to wall off lesion from lumen. Fibrous cap covers a mixture of leukocytes, lipid and debris which may form a necrotic core. Lesions expand at shoulders by means of continued leukocyte adhesion and entry. Necrotic core results from apoptosis and necrosis, increased proteolytic activity and lipid accumulation. Ross, NEJM; 1999

Development of Unstable Fibrous Plaque: 

Development of Unstable Fibrous Plaque Rupture or ulceration of fibrous cap rapidly leads to thrombosis. Occurs primarily at sites of thinning of the fibrous cap. Thinning is a result of continuing influx of and activation of macrophages which release metalloproteinases and other proteolytic enzymes. These enzymes degrade the matrix which can lead to hemorrhage and thrombus formation Ross, NEJM; 1999

Key Events in Cardiovascular Disease: 

Key Events in Cardiovascular Disease

Suggested Risk Factors for CVD: 

Suggested Risk Factors for CVD LDL Oxidation LDL-C Anti-OxLDL OxLDL LDL Oxid. Lag Time Negative LDL HDL-C Paraoxonase F2-Isoprostanes TBARS ORAC Endothelial Injury Triglycerides/VLDL Non-HDL-C apoA-1/apoB HDL-2/HDL-3 LDL size Postprandial TG IDL Chylo. Remnants Blood Pressure Homocysteine Thrombi Formation Factor VII Fibrinogen PAI-1 Factor VIII Tissue Plasminogen Activator D-Dimer Plasmin-Antiplasmin Complex Prothrombin Fragment 1+2 In vitro Platelet Activation Inflammatory Response C-Reactive Protein IL-6 Lp-PLA2/ PAF acetylhydrolase Endothelial Dysfunction von Willibrand’s Factor P-Selectin sICAM-1 sVCAM-2 Assymetric Dimethyl Arginine Nitrate/Nitrite Plaque Instability Plasma Metaloproteinase-9

Risk Factors for CVD Affected by Diet?: 

Risk Factors for CVD Affected by Diet? LDL Oxidation LDL-C Anti-OxLDL OxLDL LDL Oxid. Lag Time Negative LDL HDL-C Paraoxonase F2-Isoprostanes TBARS ORAC Endothelial Injury Triglycerides/VLDL Non-HDL-C apoA-1/apoB HDL-2/HDL-3 LDL size Postprandial TG IDL Chylo. Remnants Blood Pressure Homocysteine Thrombi Formation Factor VII Fibrinogen PAI-1 Factor VIII Tissue Plasminogen Activator D-Dimer Plasmin-Antiplasmin Complex Prothrombin Fragment 1+2 In vitro Platelet Activation Inflammatory Response C-Reactive Protein IL-6 Lp-PLA2/ PAF acetylhydrolase Endothelial Dysfunction von Willibrand’s Factor P-Selectin sICAM-1 sVCAM-2 Assymetric Dimethyl Arginine Nitrate/Nitrite Plaque Instability Plasma Metaloproteinase-9

Risk Factors for CVD Affected by Diet?: 

Risk Factors for CVD Affected by Diet? LDL Oxidation LDL-C Anti-OxLDL OxLDL LDL Oxid. Lag Time HDL-C Paraoxonase F2-Isoprostanes TBARS ORAC Endothelial Injury Triglycerides/VLDL Non-HDL-C apoA-1/apoB HDL-2/HDL-3 LDL size Postprandial TG IDL Chylo. Remnants Blood Pressure Homocysteine Thrombi Formation Factor VII Fibrinogen PAI-1 Tissue Plasminogen Activator Plasmin-Antiplasmin Complex Prothrombin Fragment 1+2 In vitro Platelet Activation Inflammatory Response C-Reactive Protein Endothelial Dysfunction von Willibrand’s Factor P-Selectin sICAM-1 sVCAM-2 Assymetric Dimethyl Arginine Nitrate/Nitrite Plaque Instability

Modifying Risk Factors Affect Disease Outcome?: 

Modifying Risk Factors Affect Disease Outcome? LDL Oxidation LDL-C Anti-OxLDL OxLDL LDL Oxid. Lag Time HDL-C Paraoxonase F2-Isoprostanes TBARS ORAC Endothelial Injury Triglycerides/VLDL Non-HDL-C apoA-1/apoB HDL-2/HDL-3 LDL size Postprandial TG IDL Chylo. Remnants Blood Pressure Homocysteine Thrombi Formation Factor VII Fibrinogen PAI-1 Tissue Plasminogen Activator Plasmin-Antiplasmin Complex Prothrombin Fragment 1+2 In vitro Platelet Activation Inflammatory Response C-Reactive Protein Endothelial Dysfunction von Willibrand’s Factor P-Selectin sICAM-1 sVCAM-2 Assymetric Dimethyl Arginine Nitrate/Nitrite Plaque Instability

Modifying Risk Factors Affect Disease Outcome?: 

Modifying Risk Factors Affect Disease Outcome? LDL Oxidation LDL-C HDL-C Endothelial Injury Triglycerides/VLDL Blood Pressure Thrombi Formation Inflammatory Response Endothelial Dysfunction Plaque Instability

CHD Risk Factors - Plasma Lipids: 

CHD Risk Factors - Plasma Lipids Plasma cholesterol levels are powerful predictors for future development of CHD. LDL cholesterol: high levels increase one’s risk for CHD. HDL cholesterol: high levels decrease one’s risk for CHD. Plasma triglycerides: More controversial - high triglycerides are associated with low HDL.

CHD Mortality is Correlated withPlasma Cholesterol Levels: 

CHD Mortality is Correlated with Plasma Cholesterol Levels LaRosa et al, 1990 Six Year CHD Mortality from MRFIT

Primary Pathway for Diet Modificationto Protect Against CVD: 

Primary Pathway for Diet Modification to Protect Against CVD Lower LDL-Cholesterol Decrease levels of LDL-C raising fatty acids

Effect of Fatty Acid Classes on LDL-C: 

Effect of Fatty Acid Classes on LDL-C Mensink et al, AJCN, 2003

Effect of Individual SFA on LDL-C: 

Effect of Individual SFA on LDL-C Mensink et al, AJCN, 2003

LDL Review: 

Surface Monolayer Phospholipids (25%) Free Cholesterol (15%) Protein (22%) Hydrophobic Core Triglyceride (5%) Cholesteryl Esters (35%) LDL Review Cholesterol and Atherosaclerosis, Grundy) * * * * * * I125

SFA Decreases LDL Clearance: 

SFA Decreases LDL Clearance Nicolosi et al, Arteriosclerosis, 1990

LDL Cellular Metabolism: 

LDL Cellular Metabolism Cholesterol and Atherosaclerosis, Grundy)

Hepatic LDL-Receptor is Down Regulated by SFA: 

Hepatic LDL-Receptor is Down Regulated by SFA Fox et al, JBC, 1987

Hepatic LDL-R Levels are Correlated with Plasma Lipids in High SFA Diets: 

Hepatic LDL-R Levels are Correlated with Plasma Lipids in High SFA Diets Fox et al, JBC, 1987

Mechanism for Saturated Fat Effects on LDL-R: 

Mechanism for Saturated Fat Effects on LDL-R Cholesterol and Atherosaclerosis, Grundy) 1. SFA are poor substrates for acyl coenzyme A: cholesterol acyl transferase

Mechanism for Saturated Fat Effects on LDL-R: 

Mechanism for Saturated Fat Effects on LDL-R Cholesterol and Atherosaclerosis, Grundy) 2. SFA alter membrane fluidity affecting receptor recycling

Primary Pathway for Diet Modificationto Protect Against CVD: 

Primary Pathway for Diet Modification to Protect Against CVD Lower LDL-Cholesterol Decrease levels of LDL-C raising fatty acids Decrease dietary cholesterol intake

Effect of Dietary Cholesterol on LDL-C: 

Effect of Dietary Cholesterol on LDL-C Weggemans et al, AJCN, 2002 1 egg (~200 mg chol/day) ↑ LDL-C by 3.9 mg/dL

Dietary Cholesterol Decreases LDL Clearance: 

Dietary Cholesterol Decreases LDL Clearance Nicolosi et al, Arteriosclerosis, 1990

Mechanism of Effects of Dietary Cholesterol: 

Mechanism of Effects of Dietary Cholesterol Cholesterol and Atherosaclerosis, Grundy) 1. Increased hepatic cholesterol content

Primary Pathway for Diet Modificationto Protect Against CVD: 

Primary Pathway for Diet Modification to Protect Against CVD Lower LDL-Cholesterol Decrease levels of LDL-C raising fatty acids Decrease dietary cholesterol intake Increase soluble fiber intake

Addition of Soluble Fiber to Diet: 

Addition of Soluble Fiber to Diet Meta analysis (Brown, AJCN, 1999) predicts 1.4 mg/dl LDL-C reduction per gram of oat bran soluble fiber

Modified Wheat Bran(Converted Insoluble Fiber to Soluble Fiber): 

Modified Wheat Bran (Converted Insoluble Fiber to Soluble Fiber) *Significantly different from AAD (P<0.05) **Significantly different from AAD (P<0.01) +Significantly different from OB (P<0.001)

Mechanism of Soluble Fiber in LDL Lowering: 

Mechanism of Soluble Fiber in LDL Lowering Increased binding of bile acids in the intestinal lumen

Soluble Fiber Mechanism for LDL Lowering: 

Soluble Fiber Mechanism for LDL Lowering Cholesterol and Atherosaclerosis, Grundy) + Soluble Fiber

Mechanism of Soluble Fiber in LDL Lowering: 

Mechanism of Soluble Fiber in LDL Lowering Increased binding of bile acids in the intestinal lumen Formation of thick unstirred water layer next to mucosa – reduce absorption of bile acids Reduce rate of glucose absorption leading to decreased insulin and reduced hepatic cholesterol production Fermentation of soluble fibers may lead to production of short-chain fatty acids which may inhibit hepatic cholesterol synthesis

Primary Pathway for Diet Modificationto Protect Against CVD: 

Primary Pathway for Diet Modification to Protect Against CVD Lower LDL-Cholesterol Decrease levels of LDL-C raising fatty acids Decrease dietary cholesterol intake Increase soluble fiber intake Increase plant sterol/stanol intake

Phytosterols/stanols: 

Phytosterols/stanols Plant analogs to cholesterol Present in diet at ~ 160-360 mg/day Poorly absorbed by gut Hydrogenation to stanols further decreases absorption Added to products (margarine) to be consumed at ~2-4 g/day

Stanols Lower Total Cholesterol, LDL Cholesterol and the TC/HDL Ratio: 

Stanols Lower Total Cholesterol, LDL Cholesterol and the TC/HDL Ratio

Dietary Cholesterol is Absorbed in Mixed Micelles: 

Dietary Cholesterol is Absorbed in Mixed Micelles

Cholesterol Absorption: 

Lymph Enterocyte Intestinal Lumen Cholesterol Absorption Cholesterol NPC1L1 Cholesteryl Ester ABCG5/G8 ACAT

Phytosterols Displace Cholesterol from Mixed Micelles: 

Phytosterols Displace Cholesterol from Mixed Micelles

Plant Sterols and Stanols: 

Plant Sterols and Stanols Sterol/Stanol Dietary Cholesterol

Plant Sterols and Stanols: 

Lymph Enterocyte Intestinal Lumen Plant Sterols and Stanols Cholesterol Cholesteryl Ester ABCG5/G8 ACAT NPC1L1

Phytosterol Mechanism for LDL Lowering: 

Phytosterol Mechanism for LDL Lowering Cholesterol and Atherosaclerosis, Grundy) + Phytosterols

Rationale for Dietary Fat Recommendations: 

Rationale for Dietary Fat Recommendations ¯ Coronary Heart Disease ¯ LDL-C  Total Fat = ¯SFA, TFA, Cholesterol

We Can Predict the Amount of Risk Reduction Associated with Changes in Lipids: 

We Can Predict the Amount of Risk Reduction Associated with Changes in Lipids p = 1 - exp(-eu) u = [log(t) - μ]/σ μ = 4.4181 + m σ = exp(-0.3155 - 0.2784 x m) m = a-1.4792 x log(age) - 0.3758 x diabetes a = 11.1122 - 0.9119 x log (SBP) - 0.2767 x smoking - 0.7181 x log (cholesterol/HDL) - 0.5865 x ECG-LVH Anderson et al, Circulation, 1991

Estimated Changes in CHD Risk Associated with Replacement of 5% SFA with CHO or PUFA/MUFA: 

Estimated Changes in CHD Risk Associated with Replacement of 5% SFA with CHO or PUFA/MUFA

Women’s Health Initiative: 

Women’s Health Initiative

Why are Estimated Changes in CHD Risk Smaller When Based on FA’s Effect on Plasma Lipids?: 

Why are Estimated Changes in CHD Risk Smaller When Based on FA’s Effect on Plasma Lipids? Fatty acids affects CHD risk through additional mechanisms apart from changing plasma lipid levels. (We do not fully understand the mechanism by which FA affect CHD development.)

Lyon Diet-Heart Study: 

Lyon Diet-Heart Study Percent without event Year Mediterranean Standard Diet de Lorgeril et al, 1999 A Mediterranean type diet reduced CVD events compared to standard low-fat diet instruction This reduction in events occurred despite no significant differences in plasma lipid levels

Change in Risk Associated with Increasing LDL 30 mg/dl or Decreasing HDL 10 mg/dl: 

Change in Risk Associated with Increasing LDL 30 mg/dl or Decreasing HDL 10 mg/dl

Previous Diet Recommendations: 

Previous Diet Recommendations Average American Diet 37% fat; 16% SFA; 14% MUFA Step 1 Diet 30% fat; 8% SFA; 15% MUFA Step 2 Diet 25% fat; 5% SFA; 13% MUFA

Changes in Lipids with Step 1 and Step 2 Diets: 

Changes in Lipids with Step 1 and Step 2 Diets

High MUFA vs Low Carb: 

High MUFA vs Low Carb Average American Diet 37% fat; 16% SFA; 14% MUFA Step 1 Diet 30% fat; 8% SFA; 15% MUFA High MUFA Diet 37% fat; 8% SFA; 22% MUFA

Effect of Diets on LDL and HDL Cholesterol Lowering: 

Effect of Diets on LDL and HDL Cholesterol Lowering

Hemostasis: 

Hemostasis

Thrombogenic Risk Factors: 

Fibrinogen: Upper tertile for fibrinogen associated with 2.3-fold increase in risk for myocardial infarction. Factor VII: 25% increase in factor VIIc is associated with a 55% increase in risk of a fatal CHD events within 5 years. Plasminogen activator inhibitor-1: Reduced fibrinolytic activity observed in CHD, MI, and diabetic complications have been attributed to elevated PAI-1 levels. Thrombogenic Risk Factors

Changes in Hemostasis Factors withStep 1 and Step 2 Diets: 

Changes in Hemostasis Factors with Step 1 and Step 2 Diets

Diet Effects on Thrombogenic Factors: 

Diet Effects on Thrombogenic Factors Increase in fibrinogen due to reductions in total fat in diet Decrease in factor VII due to reductions in saturated fat in diet

Highly Atherogenic Lipoproteins:Lipoprotein [a]: 

Highly Atherogenic Lipoproteins: Lipoprotein [a] Lipoprotein[a] is an LDL-like particle with a unique apoprotein[a] attached Taken up by foam cell precursors and accumulates in atherosclerotic plaque May interfere with thrombolysis Lp[a] is an independent risk factor for CHD, especially in the presence of high LDL. Up to 20% of premature CHD is thought to be due to elevated levels of Lp[a].

Diet Effects on Lipoprotein[a]: 

Diet Effects on Lipoprotein[a]

Highly Atherogenic Lipoproteins:Small, Dense LDL: 

Highly Atherogenic Lipoproteins: Small, Dense LDL LDL can be classified into two subclasses (“A” and “B”) based on size LDL subspecies is a marker for a common genetic trait that effects lipoprotein metabolism and increases CHD risk. A gene responsible has been located on chromosome 19, near the genes for the LDL receptor and insulin receptor. Pattern B (small, dense LDL) is associated with mild to moderate elevations in triglycerides, low HDL and insulin resistance 50% of men with heart disease express this trait. When in combination with high insulin and high apoB, the presence of a pattern B LDL phenotype increases CHD risk 18-fold.

Diet Effects on LDL size: 

Diet Effects on LDL size Other studies have shown that the prevalence of pattern B phenotype is directly related to the percent of carbohydrate in the diet.

Other CVD Risk Factors: Postprandial Lipemia: 

Other CVD Risk Factors: Postprandial Lipemia During the metabolism of dietary triglycerides, atherogenic lipoprotein remnants are formed from chylomicrons. Postprandial triglyceridemia increases factor VII levels Increased postprandial triglyceridemia is associated with increased risk for CVD However, postprandial TG clearance is influenced by many factors which are themselves associated with CVD.

Effect of Dietary fat on Postprandial Lipemia: 

Effect of Dietary fat on Postprandial Lipemia

Effect of Dietary Fat on Postprandial Lipemia: 

Effect of Dietary Fat on Postprandial Lipemia

Effect of Dietary Fat on Postprandial Factor VII: 

Effect of Dietary Fat on Postprandial Factor VII 0 hr. 4 hr. 8 hr.

Other CVD Risk Factors: C-Reactive Protein: 

Other CVD Risk Factors: C-Reactive Protein C-Reactive Protein (CRP) is a systemic marker of inflammation High levels of CRP is an independent risk factor for CVD CRP may be a marker for the extent of existing atherosclerotic burden and/or may be a direct contributing factor to the atherosclerotic process.

hs-CRP and Risk of Future MI: Analysis Stratified by Smoking Status: 

hs-CRP and Risk of Future MI: Analysis Stratified by Smoking Status Ridker PM et al. N Engl J Med 1997;336:973-979. 1 Relative Risk of Future MI Quartile of CRP 2 3 4 All Patients Nonsmokers

hs-CRP Adds to the Predictive Value of Total Cholesterol in Determining Risk of First MI: 

hs-CRP Adds to the Predictive Value of Total Cholesterol in Determining Risk of First MI Ridker PM et al. Circulation 1998;97:2007-2011. 1998 Lippincott Williams & Wilkins. Adjusted Relative Risk CRP >75th percentile TC >75th percentile – + – + – + – + P = 0.02 P = 0.001 P = 0.002

hs-CRP Adds to Predictive Value of TC:HDL Ratio in Determining Risk of First MI: 

hs-CRP Adds to Predictive Value of TC:HDL Ratio in Determining Risk of First MI

Potential Mechanisms Linking CRP to Atherothrombosis: 

Potential Mechanisms Linking CRP to Atherothrombosis Confounding by cigarette consumption Innocent bystander - Acute phase response Cytokine surrogate - IL-6, TNF-, IL-1 Direct effects of CRP - Innate immunity - Complement activation - CAM induction Prior infection - Chlamydia, H pylori, CMV Marker for subclinical atherosclerosis - EBCT / IMT / ABI Marker for insulin resistance/ obesity Marker for endothelial dysfunction Marker for dysmetabolic syndrome Marker for plaque vulnerability

Effect of Dietary Fat on CRP: 

Effect of Dietary Fat on CRP

Physiological Marker of Disease Progression - Brachial Artery Flow Mediated Dilation: 

Physiological Marker of Disease Progression - Brachial Artery Flow Mediated Dilation Impaired brachial artery vasodilation predicts coronary endothelial dysfunction Endothelium-dependent vasodilation is influenced by LDL-C, HDL-C, postprandial lipemia, antioxidants, Type 2 diabetes and blood pressure 60 seconds Baseline

Change in FMD over Time: 

Change in FMD over Time

Effect of Low-Fat Diets on Endothelial FunctionSubgroup Analysis: 

Effect of Low-Fat Diets on Endothelial Function Subgroup Analysis

Why are Estimated Changes in CHD Risk Smaller When Based on FA’s Effect on Plasma Lipids?: 

Why are Estimated Changes in CHD Risk Smaller When Based on FA’s Effect on Plasma Lipids? Fatty acids affects CHD risk through additional mechanisms apart from changing plasma lipid levels. (We do not fully understand the mechanism by which FA affect CHD development.)

Why are Estimated Changes in CHD Risk Smaller When Based on FA’s Effect on Plasma Lipids?: 

Why are Estimated Changes in CHD Risk Smaller When Based on FA’s Effect on Plasma Lipids? Fatty acids affects CHD risk through additional mechanisms apart from changing plasma lipid levels. (We do not fully understand the mechanism by which FA affect CHD development.) Diets low in saturated fat and cholesterol are characterized by the presence of additional nutrients which are protective for CHD. (We do not fully understand the relative importance of specific foods and nutrients on CHD risk.)

Saturated Fat Levels are Inversely Correlated with Levels of Other Potentially Beneficial Foods: 

Saturated Fat Levels are Inversely Correlated with Levels of Other Potentially Beneficial Foods Adapted from Ascherio et al, 1996

Dietary Components and CHD RiskSummary of the Nurses’ and Women’s Health Studies: 

Dietary Components and CHD Risk Summary of the Nurses’ and Women’s Health Studies Vit E (Supplement vs no Supplement) Margarine (<1 tsp/mo vs >4 tsp/d) Alcohol (1 drink/d vs none) Nuts (5 servings/wk vs almost never) Folic Acid (>545 ug/d vs <190 ug/d) Fiber (23 g/d vs 12 g/d) Whole grains (>1.7 serv vs <0.25 serv) Eggs (<1/wk vs >1/d) Saturated Fat (10.7% vs 18.8%) Total Fat (29.1% vs 46.1%) Fruit (3.8 serv vs 0.6 serv) Vegetables (6.8 serv vs 1.5 serv) Multivariate Adjusted Risk

High Blood Pressure: 

High Blood Pressure Leading cause of heart attack, stroke, kidney disease Affects 50 million adults Higher in African Americans (32%) Increases with age in men and women After age 60, affects 50-80%

The DASH Diet: 

The DASH Diet Nutrient Targets: Reduced saturated fat, total fat, and cholesterol Increased potassium, calcium, magnesium, fiber, and protein Achieved by: Increasing fruits, vegetables, and low-fat dairy products Including whole grains, poultry, fish, and nuts Reducing fats, red meat, sweets, and sugar-containing beverages

Blood Pressure Effects of DASH Diet: 

Blood Pressure Effects of DASH Diet

Effect of Sodium Level and DASH Diet on Diastolic BP: 

Effect of Sodium Level and DASH Diet on Diastolic BP

Effect of DASH Diet and Sodium Intake on Systolic Blood Pressure: 

Effect of DASH Diet and Sodium Intake on Systolic Blood Pressure

Comparison of DASH Diet to Single Dosesof BP-Lowering Medications: 

Comparison of DASH Diet to Single Doses of BP-Lowering Medications Treatment SBP/DBP change Captopril (ACE Inhibitor) 6/5 Atenolol (beta-blocker) 8/7 Prazosin 9/6 Diltiazem (Channel blocker) 10/9 Hydrochlorthiazide 11/5 DASH Diet 11/6

Summary and Conclusions: 

Summary and Conclusions Diet’s impact on CVD development extend beyond dietary fatty acids and cholesterol. Components in foods may affect CVD risk through both well established mechanisms (lipids and blood pressure) as well as through newer, emerging risk factors. While basic, mechanistic studies are important in furthering our understanding of the relationship between bioactive components and CVD, it still remains to be demonstrated that affecting these risk factors and metabolic pathways necessarily alters the course of disease progression.

Class Presentation: 

Class Presentation Each episode of MythBusters focuses on two or three (occasionally more) urban legends, popular beliefs, or Internet rumors. Each show requires complex preparation and building to test the myth. By the end of each episode, the MythBusters conclude each myth to be "Busted", "Plausible", or "Confirmed".

Urban Legends Tested: 

Urban Legends Tested Can the unaided human voice shatter glass? Can a penny dropped from a tall building kill a person at ground level? Is it possible to build a functioning, inconspicuous car ejector seat? Did Ben Franklin's kite experiment really take place? Does a duck's quack echo? Can a rotating ceiling fan decapitate a person? Can diving underwater protect a person from gunfire? Is it possible to break off a lock by shooting it with a gun?

Your Assignment: 

Your Assignment Conduct you own Nutrition Mythbusting. Identify a product with a clearly stated or implied health claim (OK with me by 11/6). Identify the ingredients/nutrients which serve as the basis for the claim Identify the implied “mechanism” – the bit of truth - which supports the claim Determine if the claims are “plausible” or “busted” through literature reviews Prepare 10 minute Powerpoint presentation on your findings

“Health Benefits” of Extra Virgin Coconut Oil: 

“Health Benefits” of Extra Virgin Coconut Oil The numerous health benefits of coconut oil are finally again reaching the mainstream. Reducing your risk of heart disease ... Promoting weight loss when and if you need it ... Supporting your immune system health ... Reducing your risk of cancer and degenerative diseases ... Supporting a healthy metabolism ... Providing an immediate energy source for you ...

Contact Information: 

Contact Information Contact Dr. Lefevre regarding the class project as follows: To E-mail: lefevrm@pbrc.edu To make an appointment, contact Ms. Cathy Huey at 763-0923