Advanced Nutrition Diet and Cardiovascular Disease 1 MargiAnne Isaia, MD MPH

DIET AND CARDIOVASCULAR DISEASE DISEASE END POINTS: Coronary Artery Disease Atherosclerosis Hypertension (high blood pressure) Peripheral Artery Disease Cerebral Artery Disease

DIET AND CARDIOVASCULAR DISEASE ESTABLISHED RISK FACTORS Non-modifiable: age, family history, gender, genetics Modifiable Hypertension Dyslipidemia one or combination increased Total C (≥ 200-240 mg/dL ) increased LDL-C (≥ 130-160 mg/dL ) decreased HDL-C (< 35 mg/ dL) HDL:LDL ratio < o.4 increased TG ( ≥ 200 mg/dL) Diabetes Obesity: BMI ≥ 30, central or abdominal obesity: Waist circumference: M ≥ 40 in; F ≥ 35 in Physical inactivity Smoking

DIET AND CARDIOVASCULAR DISEASE EMERGING RISK FACTORS High small, dense LDL-C greater atherogenic potential, enter through the arterial wall, more sensitive to oxidation Metabolic syndrome precursor for DM Lipoprotein (a) LDL-C particle with the apo B-100 modified chemically, genetically determined, poorly cleared by LDL-C receptors Increased Homocysteine Increased thrombogenic and hemostatic factors pro-clotting factors Inflammation Oxidative stress Emerging risk factors – some modified by the diet, some not

DIET AND CARDIOVASCULAR DISEASE ATHEROSCLEROSIS Stimuli that triggers: Increased LDL-C Oxidative stress Smoking Hypertension Hyperglycemia Obesity Insulin resistance Inflammation

DIET AND CARDIOVASCULAR DISEASE PATHOGENESIS OF CARDIOVASCULAR DISEASE Atherosclerosis: Formation of fatty streak Thrombosis Inflammation These processes must all happen in order or simultaneously to result in a calcified plaque Ruptured plaque eventually can cause blocks in big arteries or break up into clots and block micro vessels

DIET AND CARDIOVASCULAR DISEASE ENDOTHELIAL DYSFUNCTION The first step in Atherosclerosis Normal endothelium relations with the vascular tone related platelet and leukocyte adhesion inhibition of smooth muscle cell migration/ proliferation barrier to lipoproteins and other plasma components Abnormal endothelium vasoconstriction increased platelet/leukocyte adhesion smooth muscle cells migration and proliferation increased lipid deposition and clearance Abnormal endothelium in conditions that trigger Atherosclerosis hLDL-C, Hypertension, Diabetes, Smoking Indicator of endothelial damage = hadhesion molecules in blood

The first step in Atherosclerosis DIET AND CARDIOVASCULAR DISEASE ENDOTHELIAL DYSFUNCTION The first step in Atherosclerosis

DIET AND CARDIOVASCULAR DISEASE ENDOTHELIAL DYSFUNCTION The first step in Atherosclerosis

DIET AND CARDIOVASCULAR DISEASE ATHEROSCLEROSIS STAGE 1 Vascular injury / Inflammation Atherosclerotic triggers cause endothelial cell damage Adhesion molecules, such as: VCAM-1, ICAM-1, e-Selectin, p-Selectin are expressed by endothelial cells that are damaged These adhesion molecules bind to leukocytes (monocytes) and help them migrate into the intima (pro-inflammatory cytokines facilitate this process)

DIET AND CARDIOVASCULAR DISEASE ATHEROSCLEROSIS STAGE 2: Fatty streak formation

DIET AND CARDIOVASCULAR DISEASE ATHEROSCLEROSIS Stage 2: Fatty streak formation

DIET AND CARDIOVASCULAR DISEASE ATHEROSCLEROSIS Stage 2: Fatty streak formation Monocytes migrated within the intima become macrophages LDL-C migrates through the endothelium is highly instable- lipid peroxidation – oxidized LDL-C Ox LDL-C acts on macrophages and stimulates cytokines production is treated as foreign, not recognized by Apo B-100 Macrophages exhibit increased expression of scavenger receptors LDL-C uptake can be regulated by the cell Ox LDL-C uptake cannot be regulated, included in that cell unlimitedly (“foam cell”) “Foam cells” aggregate and become fatty streak Fatty streak recruits more pro-inflammatory cytokines This triggers smooth muscle cells of arterial walls to proliferate Fibro-proliferative response and Ca deposition – progression to complex plaque Repair processes may become so large that lumen is lost, blood flow is reduced

DIET AND CARDIOVASCULAR DISEASE ATHEROSCLEROSIS Stage 3: Thrombosis T Lymphocytes secrete cytokines that inhibit collagen formation by smooth muscle cells stimulate collagen breaking enzyme production End result = weakening of fibrous plaque Platelets adhere to damaged blood vessels Activated platelets release Tx A2 Tx A2 causes platelets aggregation and Tx A3 causes platelets anti-aggregation Tx A2 triggers clotting process to form clot/thrombus for normal endothelium: balance thrombosis -anti-thrombosis Thrombus formation results in blocking the vessel

DIET AND CARDIOVASCULAR DISEASE ATHEROSCLEROSIS

DIET AND CARDIOVASCULAR DISEASE ATHEROSCLEROSIS Normal platelets in flowing blood Platelets adhering to sub endothelial space (platelets adhering to damaged endothelium and undergoing activation) Aggregation of platelets into a thrombus

DIET AND CARDIOVASCULAR DISEASE BLOOD VESSELS Normal blood vessel - Prevention Minimal & moderate change Compensatory expansion - lumen is retained - Aggressive Lifestyle intervention reverse Cholesterol transport from fatty streak HDL-C involved Advanced CHD Lumen is compromised - Surgical approach

DIET AND CARDIOVASCULAR DISEASE ATHEROSCLEROSIS MARKERS LDL-C Ox LDL-C Adhesion molecules, pro-inflammatory cytokines: these are markers of inflammation - common ones: CRP, VCAM-1, e-Selectin, IL-1, IL-6, TNF-a Haemostatic and thrombogenic factors: these are markers of thrombosis tendency - common ones: Factor VII a if increased - clotting tendency increased Tissue Plasminogen Activator, tPA ability for fibrinolysis Plasminogen Activator Inhibitor-1, PAI-1 prevents fibrinolysis Fibrinogen if increased, blood viscosity increased

DIET AND CARDIOVASCULAR DISEASE ELEVATED HOMOCYSTEINE Plasma Homocysteine in healthy individuals: - 5 to15 micromol/L Elevated plasma Homocysteine concentrations are found in: Genetic abnormalities, aging, renal disease, low intake of vitamin B6, B 12 and folate Elevated plasma Homocysteine concentrations (> 15 micromol/L) are associated with: increased risk of coronary artery disease, stroke, venous thromboembolism Mechanism Disruption of arterial wall Treatment Increase folate intake INFLAMMATORY MEDIATORS C-reactive protein (CRP) An acute phase reactant and a marker for underlying systemic inflammation Identifies patients likely to benefit from Aspirin and other anti-inflammatory agents Soluble Intercellular Adhesion Molecule 1 (ICAM-1) Vascular Cell Adhesion Molecule 1 (VCAM-1)

Mechanisms by which Diet potentially influences risk of CHD DIET AND CARDIOVASCULAR DISEASE Mechanisms by which Diet potentially influences risk of CHD Intermediary Biological Mechanisms Lipid Levels LDL-C HDL-C TG Lipoprotein (a) Blood pressure Diet Thrombotic tendency Risk of CHD Cardiac Rhythm Endothelial Function Systemic Inflammation Insulin Sensitivity Oxidative Stress Homocysteine level

REFERENCES Shils M. et al “Modern Nutrition in Health and Disease”, 10th Edition www.pubmed.org 5th ICVN, Loma Linda, USA, 2008 National Cholesterol Education Program, Detection Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), NIH Pub No 01-3670, 2001 www.nhlbi.nih.gov Report of a Joint WHO/FAO Expert Consultation. Diet, Nutrition and The Prevention of Chronic Diseases. Geneva 2003

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