Faculty Disclosure

1. Faculty Disclosure Amy J. Arouni, MD, FACC Dr. Arouni has listed no financial interest/arrangement that would be considered a conflict of interest.

2. Chocolate and Wine for the Heart?A Cardiologist’s Perspective Amy J. Arouni, MD, FACC Associate Professor of Internal Medicine, Division of Cardiology The Cardiac Center of Creighton University

3. Objectives • Elucidate the earliest mechanisms and manifestations of atherosclerosis • Discuss the role of polyphenols in reducing the risk of cardiovascular disease • Specifically discuss the roles of dark chocolate and red wine in the prevention of cardiovascular disease

4. Atherosclerosis is initiated when LDLs accumulate in the intima and activate the endothelium. Leukocyte adhesion molecules and cytokines promote recruitment of monocytes and T cells. Monocytes differentiate into macrophages. Ross, R. N Engl J Med 1999;340:115-126.

5. Macrophages up-regulate receptors. Scavenger receptors mediate lipoprotein internalization, which leads to foam-cell formation. Toll-like receptors transmit activating signals that lead to the release of cytokines, proteases, and vasoactive molecules. Ross, R. N Engl J Med 1999;340:115-126.

6. T cells in lesions mount T helper responses with secretion of inflammatory cytokines that add to local inflammation and plaque growth. Intensified inflammatory activation may lead to local proteolysis, plaque rupture, and thrombus formation, which causes ischemia and infarction. Ross, R. N Engl J Med 1999;340:115-126.

7. The First Step is of Atherosclerosis is Endothelial Dysfunction • Functional impairment of the vascular endothelium in response to injury occurs long before the development of structural atherosclerotic changes. • The endothelium is a continuous, smooth, nonthrombogenic surface of all blood vessels. • In its healthy state, it has a highly selective permeability. • It synthesizes and releases a broad range of vasoactive substances, including nitric oxide.

8. NO is Released in Response to Shear Stress or Receptor Dependent Agonists

9. NO is Synthesized by eNOS fromL-arginine

10. NO causes Smooth Muscle Cell Relaxation

11. NO Inhibits Leukocytes, Platelets, and Smooth Muscle Cells

12. Impaired Endothelial Function Predicts Future Coronary Events • Reduced eNOS expression and/or NO bioavailability is associated with endothelial dysfunction and eventually atherosclerotic disease. • Endothelial dysfunction in the forearm circulation correlates with coronary vascular dysfunction. • Endothelial dysfunction is predictive of future coronary events.

14. “The French Paradox” • 2002: The average French person consumed 108 grams of animal fat. • The average American consumed 72 grams. • The French eat 4 times as much butter, 60 % more cheese and nearly 3 times as much pork as Americans. • 1999: According to data from the British Heart Foundation, death among males 35-74 was 230 per 100,000 in the US, but only 83 per 100,000 in France.

15. French Paradox: Relation Between Coronary Mortality and Intake of Dairy Fat in Different Countries Böhm M et al. Nephrol. Dial. Transplant. 2004;19:11-16

16. Relation Between Coronary Mortality and Intake of Ethanol or Wine in Different Countries Böhm M et al. Nephrol. Dial. Transplant. 2004;19:11-16

17. Long term treatment of cultured endothelial cells with red wine and grape juice induces eNOS expression and causes an increase in NO production. • In humans, one dose of red wine increased vascular NO production, and endothelium-dependent vasodilation is enhanced after consumption of wine by healthy people. • In two studies, the effect was stronger when alcohol was removed from the wine. • But, Karatzi found that endothelium dependent dilation in CAD patients was enhanced by de-alcoholated red wine, but decreased by regular red wine.

18. Rapid activation of eNOS and endothelium dependent vasodilation has also been demonstrated for grape juice. • Alcohol is probably not relevant for activating the eNOS system, but may independently offer some cardiovascular protection. • The polyphenolic compounds in red wine, in addition to ethanol, may play an active role in limiting the initiation and progression of atherosclerosis.

19. Polyphenols 101 • Polyphenolic substances in wine are usually subdivided into two groups, the flavonoids and nonflavonoids. • The most common flavonoids in red wine are flavonols such as quercetin and flavon-3-ols such as tannins and catechin. • Among the nonflavonoids, resveratrol is best known.

20. . Szmitko P E , Verma S Am J Physiol Heart Circ Physiol 2005;288:H2023-H2030

21. Flavanol Concentrations in Food

22. In patients with CAD, eating food rich in flavanols, particularly short- and long-term consumption of black tea and red wine, mostly improves endothelial function. • In healthy smokers, green tea exerts similar effects. • In line with these findings, cocoa induces NO-dependent vasodilation in the finger or forearm circulation of healthy humans or patients with cardiovascular risk factors, including diabetes.

24. Cocoa May Exert Additional Beneficial Effects • Platelet Function • Insulin Resistance • Blood Lipids

25. Some Chocolate has a lot More Flavonoids than Others • The more nonfat cocoa solids a chocolate product contains, the more flavanoids it contributes. • Chocolate products can have other types of fat added ("milk fat" or "partially hydrogenated vegetable oil" or coconut or palm oil---saturated oils), in addition to "cocoa butter.“

26. Some Chocolate has a lot More Flavonoids than Others • What about the fat found in the cacao bean? • Cacao contains some saturated fat. • Most of it is stearic acid – which doesn't elevate blood cholesterol as much as other saturated fatty acids. • The other fatty acids in cocoa butter are monounsaturated fat plus another saturated fat called palmitic fatty acid. • If the chocolate contains fat ingredients other than cocoa butter, it might contain the more harmful saturated fats and trans fats.

27. Summary • Although initial data on the polyphenolic compounds’ effects on atherosclerosis is favorable, caution is mandatory. • The high caloric load of wine and commercially available chocolate may induce weight gain, a risk factor for hypertension, diabetes, and dyslipidemia. • Alcohol-related diseases exact a high personal and societal cost.

28. Summary • Current evidence suggests that the flavanol content of many fruits and vegetables may have benefit for the prevention of atherosclerosis. • Potential mechanisms include augmentation of nitric oxide production, inhibition of ACE, inhibition of vasoconstriction, and anti-oxidant effects. • However, pro-oxidative effects of supplementation with large quantities of polyphenols cannot be excluded.