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Cardiovascular Effects of Ethanol

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  1. Cardiovascular Effects of Ethanol Samir Zakhari, Ph.D. National Institute on Alcohol Abuse and Alcoholism NIH Daria Mochly-Rosen, Ph.D. Stanford University School of Medicine RSA, June 2006

  2. Detrimental Effects (> 60 g/d) Cardiomyopathy Cardiac Arrhythmias Hypertension Increased risk of hemorrhagic stroke Beneficial Effects (< 30 g/d) Decreased risk of CAD Protection against CHF Ann Int Med, 136: 181, 2002 Decreased risk of IS JAMA,281:53, 1999; Stroke, 33:907,2002 Reduced mortality after MI JAMA, 285:1965, 2001 Protection against T2D Diabetes, 50:2390,2001 Goal: To Understand Cardiovascular Consequences of Alcohol Consumption RSA, June 2006

  3. Alcohol’s effects on: Heart Contractility Rhythmicity/Conductivity Blood cells Blood Vessels Coronary Arteries (Moderate Drinking) Cerebral Vessels (Stroke) Blood Pressure Outline RSA, June 2006

  4. Total volume of blood pumped by normal resting human heart in 70 years is: ~ 206 million liters ~ 50 million gallons 24 feet The Heart is a Pump RSA, June 2006

  5. TNF-  3       Alcohol’s sites of action  AP = action potential ATP = Adenosine triphosphate PLB = phospholamban NCX = Na+/Ca++ exchange RyR = ryanodine receptor SR = sarcoplasmic reticulum Adapted and modified from Bers, Nature, 2002 Acute/Chronic Alcohol Consumption Depresses Myocardial Contractility RSA, June 2006

  6. EDV − ESV EF = EDV EF = Ejection Fraction EDV = End Diastolic Volume ESV = End Systolic Volume Urbano-Marques et al., JAMA, 1995; Courtesy of Dr. Rubin ChronicAlcohol ConsumptionDecreases Cardiac Function in Males & Females RSA, June 2006

  7. Normal Alcoholic Modified from the National Geographic, 181:14, 1992 Alcoholic Cardiomyopathy Vulnerability to cardiomyopathy Is related to the presence of Angiotensin-converting enzyme DD genotype Fernandez-Sola et al., Ann. Intern. Med. 137:321, 2002 RSA, June 2006

  8. SA node AV node AV bundle Purkinje fibers Electrocardiogram (EKG) Left bundle branch Interventricular septum Electrical Impulse Formation and Conduction RSA, June 2006

  9. Arterial baroreceptors Carotid baroreceptors afferent Aortic baroreceptors Sympathetic efferents Θ Para- sympathetic efferents Alcohol impairs baroreceptor reflex function by blocking NMDA receptors within the NTS. El-Maas et al., JPET, 266:602, 1993 + Autonomic Nervous System Control of Heart RSA, June 2006

  10. Binge or Chronic Alcohol Consumption May Cause: • Atrial fibrillation • Prolonged Q-T interval • Inverted T waves • Heart block • Ventricular arrhythmias • Sudden cardiac death Normal Atrial fibrillation Alcohol-Induced Arrhythmias RSA, June 2006

  11. Alcohol’s effects on: Heart Contractility Rhythmicity/Conductivity Blood cells: e.g., platelets Blood Vessels Coronary Arteries (Moderate Drinking) Cerebral Vessels (Stroke) Blood Pressure Outline RSA, June 2006

  12. TxA2 Thrombin ADP aggregation R3 R1 R2 + + + + Plasma Membrane PLA2 PLC PIP2 PL PKC Alcohol AA + DAG TxA2 IP3 + Ca2+ Release of ADP Alcohol Inhibits Platelet Aggregation RSA, June 2006

  13. Alcohol’s effects on: Heart Contractility Rhythmicity/Conductivity Blood cells Blood Vessels Coronary Arteries (Moderate Drinking) Cerebral Vessels (Stroke) Blood Pressure Outline RSA, June 2006

  14. Coronary Arteries RSA, June 2006

  15. monocytes Blood Vessel LDL EC Intima Adh. Mol. MCP-1 cytokines inflammation Oxidation macrophage Foam cell LDL and Atherosclerosis RSA, June 2006

  16. Endo. Dysf. Plaque growth Plaque rupture Monocytes Macrophages Foam cells Atherosclerosis RSA, June 2006 Modified from Scientific American, May 2002

  17. Alcohol and Coronary Artery Disease • Honolulu Heart Study • Belfast, Northern Ireland • London Civil Servants • Kaiser-Permanente • Yugoslavia Heart Study • Busselton, Australia • Puerto Rico Heart Study • North Karelia Project • Zutphen Study • Albany Study • Thailand Heart Study • Nurses’ Health Study • British Regional Heart Study RSA, June 2006

  18. Moderate Drinking One Drink = 12 ounces of beer 5 ounces of wine 1.5 ounces of 80-proof distilled spirits RSA, June 2006

  19. Moderate Alcohol Consumption and Decreased Risk of CAD: Possible Mechanisms of Action • Increased HDL • Increased paroxonase activity • Decreased platelet agreggation • Increased fibrinolysis • Ischemia/reperfusion (PKC, • preconditioning) RSA, June 2006

  20. Alcohol Consumption Increases HDL Cholesterol 1983 Thornton et al., Lancet, 322:819-822 1984 Haskell et al., N. Eng. J. Med., 310:805-810 1986 Bertiere et al., Atherosclerosis, 61:7-14 1988 Valimaki et al., Eur. J. Clin. Invest., 18:472-480 1991 Rimm et al., Lancet, 338:464-468 1991 Stampfer et al., N. Eng. J. Med., 325:373-381 1993 Gaziano et al., N. Eng. J. Med., 329:1829-1834 1995 Marques-Vidal et al., Atherosclerosis, 115:225-232 2000 Silva et al., Circulation, 102:2347-2352 RSA, June 2006

  21. HDL PON1 Alcohol’s site of action Moderate Alcohol Consumption Increases Paraoxonase (PON1) Activity Activates Monocytes Ox-LDL phospholipid PON1 expression Atherosclerotic lesion Inactive Product LDL phospholipid In Serum & Macrophages RSA, June 2006

  22. TxA2 Thrombin ADP aggregation R3 R1 R2 + + + + Plasma Membrane PLA2 PLC PIP2 PL PKC Alcohol AA + DAG TxA2 IP3 + Ca2+ Release of ADP Alcohol Inhibits Platelet Aggregation RSA, June 2006

  23. Fibrin(ogen) degradation products Fibrin(ogen) PAI-1 Fibrinolysis Pmg Plasmin t-PA u-PA PmgR t-PAR u-PAR Endothelial Cell Fibrinolysis Coagulation Normal Hemostasis Alcohol Fibrinolysis Coagulation Fibrinolysis Regulation of Fibrinolysis and Normal Hemostasis by Endothelial Cells RSA, June 2006

  24. Infarct size (%) EtOH 0.1g/kg 80 Control 60 40 * * 20 0 0.1 - EtOH (g/ kg ) 10' 60' 90' Acute or Chronic Ethanol Consumption Confers Cardioprotection Against Ischemia/Reperfusion Injury • How does ethanol induce cardioprotection? • It mimics ischemic preconditioning • Ischemic Preconditioning: short bouts of ischemia and reperfusion before an ischemic event, which protect organs from the injury of subsequent prolonged ischemia RSA, June 2006 Courtesy of Dr. Mochly-Rosen

  25. Preconditioning Mechanisms • Activation of cell surface receptors (e.g., adenosine) • Activation of Na+/K+ ATPase channels • Activation of Protein Kinase C Epsilon (PKC) • Both upstream and downstream of Na+/K+ ATPase • Preconditioning compounds • Adenosine • Na+/H+ exchange (cariporide, eniporide) • Na+/K+ ATPase channel activator (diazoxide) RSA, June 2006 Courtesy of Dr. Mochly-Rosen

  26. Moderate Alcohol Decreases I/R Injury by Mimicking Preconditioning, a Natural Protection Mechanism Alcohol  Adenosine PIP2 PLC RACK Active PKC Adenosine A1 Receptor IP3 DAG  Alcohol I/R Injury Protection Inactive PKC RSA, June 2006

  27. Alcohol and Hemorrhagic Stroke Chronic heavy alcohol consumption increases the risk of hemorrhagic stroke http://stroke.ucsf.edu/Pages/images/hemorrhagic_stroke.jpg http://www.neuropat.dote.hu/jpeg/vascul/2thaver2.jpg RSA, June 2006

  28. Ischemic Stroke Alcohol and Ischemic Stroke Chronic alcohol consumption decreases the risk of ischemic stroke B http://stroke.ucsf.edu/Pages/images/hemorrhagic_stroke.jpg https://www.saintlukeshealthsystem.org/slhs/com/mahi/mm/images/illus_ischemic_stroke.jpg RSA, June 2006

  29. Systolic Diastolic 160 - 120 - ND = non drinkers SD = social drinkers LD = light drinkers MD = moderate drinkers HD = heavy drinkers Blood Pressure (mm Hg) 80 - 40 - 0 - ND SD LD MD HD Chronic Heavy Alcohol Consumption Causes Hypertension RSA, June 2006

  30. Mg++/Ca++ Alcohol’s site of action Some Factors that Affect Blood Pressure Venous Return Stroke Volume Reflexes From Carotid Sinus & Aortic Arch Cardiac Output Heart Rate Sympathetic Discharge Myocardial Contractility Systemic Arterial Pressure Peripheral Vascular Resistance Adrenal Medulla RSA, June 2006

  31. Detrimental Effects(> 60 g/d) Cardiomyopathy Decrease contractility Cardiac Arrhythmias Interferes with conductivity Increased risk of hemorrhagic stroke Decrease platelet aggregation Hypertension Hypertension Decrease baroreceptors reflex Beneficial Effects (< 30 g/d) Decreased risk of CAD Increase HDL, paraoxonase activity, fibrinolysis Decrease platelet aggregation Decreased risk of IS Decrease platelet aggregation Reduced mortality after MI Preconditioning, PKC SUMMARY: Cardiovascular Consequences of Alcohol Consumption RSA, June 2006