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

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

3. DIET AND CARDIOVASCULAR DISEASE
ESTABLISHED RISK FACTORS
Non-modifiable: age, family history, gender, genetics
Modifiable
Hypertension
Dyslipidemia
one or combination
increased Total C (≥ mg/dL )
increased LDL-C (≥ 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

4. 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

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

6. 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

7. 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

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

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

10. 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)

11. DIET AND CARDIOVASCULAR DISEASE
ATHEROSCLEROSIS
STAGE 2: Fatty streak formation

12. DIET AND CARDIOVASCULAR DISEASE
ATHEROSCLEROSIS
Stage 2: Fatty streak formation

13. 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

14. 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

15. DIET AND CARDIOVASCULAR DISEASE
ATHEROSCLEROSIS

16. 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

17. 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

18. 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

19. 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)

20. 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

21. REFERENCES
Shils M. et al “Modern Nutrition in Health and Disease”, 10th Edition
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 , 2001
Report of a Joint WHO/FAO Expert Consultation. Diet, Nutrition and
The Prevention of Chronic Diseases. Geneva 2003

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