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Published on March 4, 2008

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Vitamins in the Prevention of Cardiovascular Diseases:  Vitamins in the Prevention of Cardiovascular Diseases Eva Lonn McMaster University Oxidation of LDL - Essential Step in Atherogenesis:  Oxidation of LDL - Essential Step in Atherogenesis Libby et al. Circulation 2002;105:1135-1143. E-Selectin, P-Selectin LDL OxLDL L-Selectin, Integrins VCAM-1, ICAM-1 M-CSF MCP-1 Macrophage Activation & Division Monocyte Intima Media Smooth Muscle Cell Migration Other inflammatory triggers Antioxidant Vitamins in CVD:  Antioxidant Vitamins in CVD Oxidized LDL is atherogenic Antioxidant Vitamins Vitamin E – major lipid soluble natural antioxidant Beta-carotene – lipid soluble Vitamin C – water soluble Ox LDL Foam Cells Direct cytotoxic to EC Attracts macrophages to the subintima Inflammation Increased Vascular Tone Procoagulant Food Sources of Antioxidants:  Food Sources of Antioxidants AHA Nutrition Committee. Circulation 1999;99:591-595. Vitamin E and Platelet Function:  Vitamin E and Platelet Function Scanning electron micrographs in controls, platelets from individuals supplemented with Vitamin E 200 IU and 400IU x 2 weeks Vitamin E reduces the release of platelet granules and inhibits platelet aggregation and adhesion Steiner M. Clin Cardiol 1993 Epidemiology Antioxidant Vitamins and CV Risk :  Epidemiology Antioxidant Vitamins and CV Risk Diets rich in fruit and vegetables associated with decreased CVD risk Randomized Trials of Antioxidant Vitamins:  Randomized Trials of Antioxidant Vitamins Vitamin E improves endothelial function, measured by FMD of the brachial artery, in people with type 1 DM Skyme-Jones RAP, et al. J Am Coll Cardiol; 2000 Vitamin E improves endothelial function, measured by FMD of the brachial artery, in people with type 1 DM Pinkney JH. Et al. Diabet Med; 1999 Vitamin E has no effect on endothelial function, measured by forearm venous occlusion plethysmography, in people with type 2 DM Pinkney JH. Et al. Diabet Med; 1999 Vitamin C improves endothelial function, measured by FMD of the brachial artery, shortly after administration, but the effect is lost with chronic administration Celermajer DS et al. J Am Coll Cardiol 2000 Endothelial Function Atherosclerosis Progression Trials:  Atherosclerosis Progression Trials * Decreased the benefit attained with Simvastatin+Niacin; Vit E+C+beta-carotene+selenium Slide9:  Effect of Vitamin E on Carotid Atherosclerosis Lonn EM, et al. Circulation 2001; 103:919-25. 0.025 0.020 0.015 0.010 0.005 0 Mean max. carotid IMT slope (mm/year) Placebo Vitamin E Not significant Nutrition Intervention Trial in Linxian (China):  Nutrition Intervention Trial in Linxian (China) 29,584 adults Intervention : 2x4 factorial design Beta-carotene + selenium + vitamin E group (30 mg) Lower mortality: RR=0.91 (0.84-0.99); p=0.03 mainly due to lower cancer rates 523 cerebrovascular deaths - lower rates in vitamin E arm - RR=0.90 Vitamin E in End-Stage Renal Disease:  Vitamin E in End-Stage Renal Disease * No differences in stroke, PVD, total mortality ,CV deaths Boaz M, et al. Lancet 2000;356:1318 The SPACE trial 196 patients with ESRD on hemodialysis with pre-existent CVD MI/Stroke/ PVD/UAP MI 33/99 15/97 17/99 5/97 Randomized Controlled Trials of Vitamin C :  Randomized Controlled Trials of Vitamin C 3 small randomized controlled clinical trials of vitamin C in CVD prevention: 538 patients admitted to a geriatric unit Vitamin C 200 mg/day; duration: 6 months 297 elderly people with low Vitamin C levels Vitamin C 150 mg/day; duration: 2 years 199 elderly patients Vitamin C 200 mg/day; duration: 6 months RRI = 8% (95% CI= -7% to 26%) Large Randomized Controlled Trials of Beta- Carotene:  Large Randomized Controlled Trials of Beta- Carotene Vivekananthan DP. Lancet 2003;361:2017 Effect of Beta-Carotene on All Cause Death:  Effect of Beta-Carotene on All Cause Death Vivekananthan DP. Lancet 2003;361:2017 Effect of Beta-Carotene on Cardiovascular Death:  Effect of Beta-Carotene on Cardiovascular Death Vivekananthan DP. Lancet 2003;361:2017 Large Randomized Trials of Vitamin E:  Large Randomized Trials of Vitamin E Vivekananthan DP. Lancet 2003;361:2017 Effects of Vitamin E on All Cause Death:  Effects of Vitamin E on All Cause Death Effect of Vitamin E on CV Death:  Effect of Vitamin E on CV Death Vivekananthan DP. Lancet 2003;361:2017 Effect of Vitamin E on Stroke:  Effect of Vitamin E on Stroke Vivekananthan DP. Lancet 2003;361:2017 Effect of Vitamin E on CV Death/ Fatal or Non-Fatal MI:  Effect of Vitamin E on CV Death/ Fatal or Non-Fatal MI Slide21:  HOPE: Effect of Vitamin E on Major Vascular Events 0.20 0.15 0.10 0.05 0 0 500 1,000 1,500 Proportion of Patients Days of follow-up Vitamin E Placebo RR: 1.05 (95% CI, 0.95-1.16) p=0.33 The HOPE Investigators. N Engl J Med 2000; 342:154-60. Slide22:  Effect of Vitamin E on Major Vascular Outcomes in Diabetic Patients 0.25 0.20 0.15 0.10 0.05 0 0 500 1,000 1,500 2,000 Kaplan-Meier Rate Days of follow-up Lonn E, et al. Diabetes Care 2002; 25:1919-27. Placebo Vitamin E RR: 1.03 (95% CI, 0.88-1.21) p=0.70 Effect of Vitamin E on Diabetic Complications Microvascular Disease:  Effect of Vitamin E on Diabetic Complications Microvascular Disease No effect on urinary albumin/ creatinine ratio No effect on the incidence of self-reported diabetes Slide24:  Effect of Vitamin E on Major Vascular Outcomes in Patients with Mild-Moderate Renal Insufficiency 0.30 0.20 0.10 0 0 Kaplan-Meier Rate Follow-up (Days) Mann J, et al. Kidney International 2004; 65:1375-80. Placebo Vitamin E 500 1000 1500 2000 RR: 1.03 (95% CI, 0.79-1.34) p=0.82 Slide25:  HOPE Extension 0.30 0.25 0.20 0.15 0.10 0.05 0 0 Kaplan-Meier Rate Time, y The HOPE and HOPE-TOO Investigators. JAMA 2005; 293:1338-47. Placebo 0.30 0.25 0.20 0.15 0.10 0.05 0 0 Time, y 1 2 3 4 5 6 7 1 2 3 4 5 6 7 Vitamin E Placebo Vitamin E Incident Cancer Major CV Events No. at Risk: Vitamin E 4761 4617 4441 4279 3946 2972 2168 1783 Placebo 4780 4638 4452 4266 3957 2895 2130 1754 4761 4548 4328 4130 3810 2874 2091 1714 4780 4571 4355 4142 3854 2883 2091 1732 Main HOPE Trial Ends Main HOPE Trial Ends Effect of Vitamin E on CV Outcomes and on All Cause Death :  Effect of Vitamin E on CV Outcomes and on All Cause Death Vitamin E Placebo (N=4761) (N=4780) Effect off Vitamin E on Heart Failure:  Effect off Vitamin E on Heart Failure HOPE-TOO Outcomes: Vitamin E Arm:  HOPE-TOO Outcomes: Vitamin E Arm Aspirin and Other Antiplatelets Beta-Blockers Lipid-Lowering Agents Diuretics Calcium Channel Blockers % Risk Increase No effect on cancer, major CV events or all-cause death Effect Beyond HOPE *Statistically significant Lonn E et al. JAMA 2005. *13% *19% *21% *40% Vitamin E increases the Risk of Developing Heart Failure after Myocardial Infarction: Results from the GISSI-Prevenzione Trial:  Vitamin E increases the Risk of Developing Heart Failure after Myocardial Infarction: Results from the GISSI-Prevenzione Trial Marchioli R et al. for the GISSI-Prevenzione Investigators. J Cardiovasc Med 2006:7:347-350. Vitamin E increases the Risk of Heart Failure after MI: Results from the GISSI-Prevenzione Trial:  Vitamin E increases the Risk of Heart Failure after MI: Results from the GISSI-Prevenzione Trial Marchioli R et al. for the GISSI-Prevenzione Investigators Meta-analysis of Antioxidant Supplements for Prevention of Gastrointestinal Cancers :  Bjelakovic G et al. Lancet 2004;364:1219-1228 Meta-analysis of Antioxidant Supplements for Prevention of Gastrointestinal Cancers 14 randomized trials; n-179525 No benefit for beta-carotene, vitamins A, C, E and selenium alone or in combination vs. placebo In some analyses beta-carotene increased mortality Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality:  Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality Miller ER et al. Ann Intern Med 2004;141 Conclusions:  Conclusions The available evidence derived from large RCTs shows no benefit for the use of antioxidant vitamin supplements in CV prevention. Antioxidant vitamins should not be used in CV prevention. The use of antioxidant vitamin supplements is associated with potential harm. The available evidence does not refute the “oxidative hypothesis of atherosclerosis”. There is a need for the study of new antioxidants and of novel strategies to reduce oxidative stress. Slide34:  AHA Science Advisory Antioxidant Vitamin Supplements and Cardiovascular Disease Penny M. Kris-Etherton, PhD, RD; Alice H. Lichtenstein, DSc; Barbara V. Howard, PhD; Daniel Steinberg, MD, PhD; Joseph L. Witztum, MD; for the Nutrition Committee of the American Heart Association Council on Nutrition, Physical Activity, and Metabolism Summary At this time, the scientific data do not justify the use of antioxidant vitamin supplements for CVD risk reduction. CVD risk reduction can be achieved by the long-term consumption of diets consistent with the AHA Dietary Guidelines; the long-term maintenance of a healthy body weight through balancing energy intake with regular physical activity; and the attainment of desirable blood cholesterol and lipoprotein profiles and blood pressure levels. No consistent data suggest that consuming micronutrients at levels exceeding those provided by a dietary pattern consistent with AHA Dietary Guidelines will confer additional benefit with regard to CVD risk reduction .. Circulation 2004; 110:637-641 Why Did the Randomized Controlled Trials of Antioxidant Vitamins Fail?:  Why Did the Randomized Controlled Trials of Antioxidant Vitamins Fail? “Fooled” by epidemiology Vitamin E dose used in trials Vitamin E preparation Did we do the right trials? Pro-oxidant in an oxidative milieu Displacement of gamma-tocopherol Decrease in HDL2 Homocysteine Production and Metabolism:  Methionine S-Adenosyl- methionine Acceptor Methylated Acceptor Protein (B12) Serine Glycine THF S-Adenosyl- homocysteine Homocysteine 5-Methyl THF 5,10-Methylene THF* MTHFR (B2 ) MS Homocysteine Production and Metabolism (B6) Folate Cycle DMG Betaine BHMT Cystathionine Serine Cysteine (B6) SO42- CBS Transsulfuration Methionine Cycle Remethylation * THF: Tetrahydrofolate Homocysteine Theory of Atherosclerosis:  Homocysteine Theory of Atherosclerosis Severe hyperhomocysteinemia with homocystinuria - rare inborn errors of metabolism caused by several different genetic deficiencies of enzymes in the metabolism homocysteine Clinical features: Variable, but early neurologic complications and arterial and venous thromboses are common Biochemical features: High levels of homocysteine (> 100 µmol/L) in plasma and urine Histopathological features: endothelial injury, arterial stenosis, SMC proliferation Homocysteine and Atherogenesis:  Homocysteine and Atherogenesis In experimental animal models and in human studies homocysteine Increases oxidative stress Causes endothelial dysfunction and vascular injury Increases inflammation Smooth muscle cell proliferation Enhances thrombogenicity Homocysteine and CVD:  Homocysteine and CVD Mild to moderate hyperhomocysteinemia is common Genetic factors – “thermolabile MTHFR” B Vitamin deficencies Increased methionine consumption Age Male sex Postmenopausal state Tobacco use Renal dysfunction Hypothyroidism Diabetes Severe inflammatory disorders Drugs Meta-analysis of Cross-Sectional and Retrospective Case-Control Studies:  Meta-analysis of Cross-Sectional and Retrospective Case-Control Studies 0.6 0.7 0.8 0.9 1 2 3 4 5 6 7 8 Coronary Artery Disease—Males Coronary Artery Disease—Females Study Alfthan Stampfer Pancharuniti Israelsson Wu Malinow Genest Ubbink von Eckardstein Summary, All Alfthan Wu Malinow Summary, All Odds Ratio (95% Confidence Interval) Boushey CJ et al. JAMA. 1995;274:1049-1057. CHD: OR=1.7 (1.5-1.9) CeVD: OR=2.5 (2.0-3.0) PAD: OR=6.8 (2.9-15.8) 5 μmol/L increase in tHcy similar risk to 0.5 mmol/L increase in LDL-C 5 μmol/L decrease in tHcy → 1/3 decrease in CHD risk Homocysteine, Mortality and CAD:  Homocysteine, Mortality and CAD 0.70 0.75 0.80 0.85 0.90 0.95 1.00 0 1 2 3 4 5 6 9.0–14.9 µmol/L n=335 15.0–19.9 µmol/L n=44 Years Proportion Surviving P<0.001 for trend Nygård O, et al. N Engl J Med. 1997;337:230-236. <9.0 µmol/L n=125 20.0 µmol/L n=19 Homocysteine A Modifiable CV Risk Factor:  Homocysteine A Modifiable CV Risk Factor Graded continuous relationship between homocysteine and CV risk Even mild to moderate elevations in homocysteine levels are associated with increased CV risk Evidence from mendelian randomization Mild to moderate elevations in homocysteine levels are common Homocysteine levels can be lowered with simple, safe and inexpensive therapy Folic Acid Lowers Homocysteine Concentrations:  Folic Acid Lowers Homocysteine Concentrations Homocysteine Lowering Trialists Collaboration. BMJ 1998;316:896-98. Potential Impact of Homocysteine Lowering Vitamin Therapy:  Potential Impact of Homocysteine Lowering Vitamin Therapy “The lowering of the population mean level of total homocysteine is estimated to have prevented 17,000 deaths from coronary causes each year” AHA 2005 Homocysteine – a component of the polypill Wald, Law 2003 HOPE-2 Study Design:  HOPE-2 Investigators. N Engl J Med. 2006;354: 157;1567-77. HOPE-2 Study Design Randomized Double-blind Main Study Objective: To evaluate the effects of homocysteine lowering with B Vitamins on major CV events HOPE-2: Baseline Characteristics:  HOPE-2: Baseline Characteristics Folate food-fortification status *2.5-mg folic acid/50-mg B6/1-mg B12 % Patients Fortification program HOPE-2: Baseline Prevalence of CVD:  HOPE-2: Baseline Prevalence of CVD Placebo Active* N = 5522 Other CVD history <10% *2.5-mg folic acid/50-mg B6/1-mg B12 HOPE-2: Baseline Prevalence of CV Risk Factors:  HOPE-2: Baseline Prevalence of CV Risk Factors Placebo Active* Patients (%) *2.5-mg folic acid/50-mg B6/1-mg B12 N = 5522 Plasma Homocysteine Levels:  Plasma Homocysteine Levels 0 1 2 3 4 5 0 2 4 6 8 10 12 14 16 Years Folic Acid + Vitamins B6 and B12 Placebo μmol/L 12.2 13.2 12.9 12.2 9.9 9.7 Difference in change from baseline in homocysteine levels of 3.3 µmol/L at 2 years and of 3.2 µmol/L at study end Plasma Folate, Pyridoxal and Vitamin B12 levels increased > 2 – 4 fold Primary Outcome and All-Cause Death:  Primary Outcome and All-Cause Death * All patients with this outcome are included Treatment Effect on the Primary Outcome CV Death, Myocardial Infarction or Stroke :  Treatment Effect on the Primary Outcome CV Death, Myocardial Infarction or Stroke Effect on CV Death and Myocardial Infarction:  Effect on CV Death and Myocardial Infarction 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0 1 2 3 4 5 Years 2764 2660 2515 2386 2246 1000 2758 2650 2506 2367 2227 978 No. at Risk Active Placebo Log-Rank P=0.823 Cardiovascular Death Myocardial Infarction Folic Acid + Vitamins B6 and B12 Placebo Proportion of Patients 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0 1 2 3 4 5 Years 2764 2699 2600 2501 2391 1084 2758 2702 2587 2486 2376 1059 No. at Risk Active Placebo Log-Rank P=0.585 Treatment Effect on Stroke:  Treatment Effect on Stroke Proportion of Patients 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0 1 2 3 4 5 Years 2764 2671 2562 2442 2315 1048 2758 2686 2560 2442 2326 1030 No. at Risk Active Placebo Log-Rank P=0.025 Folic Acid + Vitamins B6 and B12 Placebo Blood Pressure :  Blood Pressure * p=0.01 Secondary Outcomes:  Secondary Outcomes Other Outcomes:  Other Outcomes Renal HOPE-2: Study Design:  Renal HOPE-2: Study Design History of vascular disease or diabetes plus additional atherosclerotic risk factor(s) N = 5522 Randomized Double-blind Folic acid 2.5 mg + vitamins B6 50 mg + B12 1 mg qd n = 307 Placebo n = 312 Random sample with blood sample N = 3310 Estimated GFR (MDRD)* < 60 ml/min N = 619 Primary and secondary outcomes 5 years *eGFR according to the formula developed in the Modification of Diet in Renal Disease (MDRD) study Baseline Laboratory Values:  Baseline Laboratory Values * p<0.01 Plasma Homocysteine Levels in People with Renal Insufficiency:  Plasma Homocysteine Levels in People with Renal Insufficiency 0 1 2 3 4 5 0 2 4 6 8 10 12 14 16 Years Folic Acid + Vitamins B6 and B12 Placebo μmol/L Difference in change from baseline in homocysteine levels of 3.6 µmol/L at 2 years and of 3.8 µmol/L at study end 15.7 16.1 15.5 15.9 12.7 11.9 Plasma Folate, Pyridoxal and Vitamin B12 levels increased > 2 – 4 fold CV Event Rates (/100pyrs) in Patients with and without Renal Insufficiency:  CV Event Rates (/100pyrs) in Patients with and without Renal Insufficiency Risk of Major CV Events and Death by Quintiles of GFR:  Risk of Major CV Events and Death by Quintiles of GFR 1.Q ≥ 90.46 2.Q 80.14 to 90.45 3.Q 80.13 to 71.38 4.Q 80.13 to 71.38 5.Q <60.78 GFR ml/min Primary Outcome and All-Cause Death in Patients with Renal Insufficiency:  Primary Outcome and All-Cause Death in Patients with Renal Insufficiency * All patients with this outcome are included Treatment Effect on the Primary Outcome in Patients with Low GFR:  Treatment Effect on the Primary Outcome in Patients with Low GFR Years Proportion of Patients 0.0 0.10 0.20 0.30 0.40 0 1 2 3 4 5 312 295 276 246 220 112 307 279 258 234 204 100 No. at Risk Placebo Active Folic Acid + Vitamins B6 and B12 Placebo Secondary and Other Outcomes in Patients with Renal Insufficiency:  Secondary and Other Outcomes in Patients with Renal Insufficiency Treatment Effect on Heart Failure in Patients with Low GFR:  Treatment Effect on Heart Failure in Patients with Low GFR Years Proportion of Patients 0.0 0.05 0.10 0.15 0.20 0 1 2 3 4 5 312 300 281 262 241 122 307 280 260 244 218 109 No. at Risk Placebo Folate Folic Acid + Vitamins B6 and B12 Placebo Clinical Trials of Hcy Lowering:  Clinical Trials of Hcy Lowering Slide68:  Probability of No Recurrent Stroke by Treatment Group VISP O’Toole J. JAMA 2004;291:565-575 Cumulative Risk of Primary Endpoint by Treatment Group:  Cumulative Risk of Primary Endpoint by Treatment Group NORVIT Bøona KH et al. N Engl J Med 2006;354 Evidence from Randomized Controlled Trials:  Evidence from Randomized Controlled Trials Evidence from Randomized Controlled Trials:  Evidence from Randomized Controlled Trials How Can We Explain the Results of the Homocysteine Lowering Clinical Trials? :  How Can We Explain the Results of the Homocysteine Lowering Clinical Trials? Folate food fortification “Fooled” by epidemiology Studies underpowered to show a small (10% RRR) treatment effect Treatment with folic acid and B vitamins reduces Hcy but causes deleterious effects that offset potential benefits of Hcy lowering Cell proliferation DNA methylation → atherogenesis Asymmetric dimethylarginine → inhibits NOS → endothelial dysfunction Slide73:  Loscalzo J. N Engl J Med 2006;354:1629-1632 Homocysteine and the Methylation Cycle Conclusions:  Conclusions Current evidence from randomized controlled trials does not support the use of B vitamins in CV prevention Effects on stroke require further exploration especially in regions without mandatory folate food fortification and in subjects with high homocysteine levels Complementary and Alternative Medicines CAM:  Complementary and Alternative Medicines CAM http://nccamnih.gov-accessed Oct19th ,2006 CAM Therapies Included in the 2002 NHIS :  CAM Therapies Included in the 2002 NHIS Use of CAM:  Use of CAM CAM - Efficacy:  CAM - Efficacy Over the past few decades, thousands of studies of various dietary supplements have been performed. To date, however, no single supplement has been proven effective in a compelling way. http://nccamnih.gov-accessed Oct19th ,2006 CAM - Costs:  CAM - Costs The U.S. public spent an estimated $36 billion to $47 billion on CAM therapies in 1997. In 2002, sales of dietary supplements increased to an estimated $18.7 billion per year, with herbs/botanical supplements accounting for an estimated $4.3 billion in sales. http://nccamnih.gov-accessed Oct19th, 2006

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