Evidence Based Cardiovascular Disease

1. Evidence Based Cardiovascular Disease Manju B. Reddy, PhD. Iowa State University Food Science and Human Nutrition

2. Global Causes of Death # 1cause http://www.who.int/cardiovascular_diseases

3. Projected global deaths by cause : Beaglehole and Bonita, 2008

4. Prevalence and Incidence The United States ranks 13th and 17th, among industrialized nations for the prevalence of CVD in women and men, respectively. More than 71 million Americans have at least one form of CVD.

5. Forms of CVD • Hypertension • Coronary Heart Disease (CHD) • Stroke • Rheumatic heart disease • Congestive heart failure

6. Percentage breakdown of deaths from CVD (United States:2004) *Not a true underlying cause. Source: NCHS and NHLBI

7. Deaths from Diseases of the Heart(United States: 1900–2005) NCHS and NHLBI

8. Pathology - Atherosclerosis Atherosclerosis is a major underlying cause of CVD • Fatty streaks: Earliest lesion (children) • Fibrous plaques: more complex lesion that can occlude the artery (extends into lumen) • Complicated lesion: Hemorrhage in the plaque

9. Progression of Atherosclerosis (From Harkreader H. Fundamentals. Philadelphia: W.B. Saunders, 2000)

10. (From Harkreader H. Fundamentals. Philadelphia: W.B. Saunders, 2000)

11. Plaque Formation Proliferation of smooth muscle cells Accumulation of smooth muscle cells in to connective tissue matrix Accumulation of lipid and cholesterol around the cells Plaque or atheromas: lipid deposits that develop in the innermost layer. Plaque forms in response to injuries of endothelium in artery wall (hypercholesterolemia, oxidized LDL, hypertension, smoking, obesity, diabetes, homocysteine, high cholesterol or high saturated fat diets)

12. Structure of Plaque

13. Risk Factors Non modifiable risk factors: • Age • Gender • Family history Modifiable risk factors: • Hyperlipidemia • Adiposity (BMI and Waist circumference) • Inactivity • Cigarette smoking • Hypertension • Diabetes • Atherogenic diet

14. Incidence of CVD by Age and Sex Risk is higher in males Less difference at older age

15. Lipids and Lipoprotein Risk Factors Total cholesterol: amount in all lipoprotein fractions (High) Total triglyceride: amount in all lipoprotein fractions (High) Chylomicrons: transport dietary fat and cholesterol from small intestine to liver and periphery VLDL: transport endogenous triglyceride and cholesterol LDL (bad cholesterol): major cholesterol transport lipoprotein (High) HDL (good cholesterol): reverse cholesterol transport (Low)

16. Cholesterol* Levels and Their Meanings *mg/dL NCEP STEPIII – NHLBI

17. Lipid lowering therapy and stroke RR= probability of the event : exposed /non exposed Example: Developing lung cancer is 10% in smokers vs 1% non-smokers RR = (10/100)/1/100 = 10 Smokers have 10% higher risk for developing cancer compared to non-smokers Corvol et al. Arch Intern Med. 2003:163:669

18. Associations of physical activity and waist circumference with CHD* Abdominal adiposity *Nurses’ health study 1986-2000 (n=88,393; 20-y follow up). RR= Relative Risk adjusted for age, parental history of CHD, postmenopausal status and hormone use, aspirin use, BMI and alcohol consumption Tricia et al. Circulation. 2006;113:499-506

19. Associations of BMI and waist circumference with CHD* *Nurses’ Health Study 1986-2000 (n=88,393; 20-y follow up). RR= Relative Risk adjusted for age, parental history of CHD, postmenopausal status and hormone use. aspirin use, and alcohol consumption Tricia et al. Circulation. 2006;113:499-506

20. CHD and Physical Activity 0.83 0.65 No training * Adjusted for age; n=44,452; US Men, Health Professional Follow-up Study Mahael et al. JAMA. 2002;288 (data collected 1994-2000)

21. Physical Activity, Smoking and CHD Lee et al. JAMA 2001, 285:1447-1454 N=39,372, healthy female professionals <45y

22. Hypertension • Antihypertensive drug use was more protective than lipid lowering drugs (RR=1.6 vs 1.1) in a Prospective Epidemiological study of Myocardial Infarction (PRIME) with 2,500 men with 5-y follow up (50-59 y) (Blacher et al. J Hyperten 2004;22:415-23) • Follow up report with 10-y follow up with 9,649 men showed similar results with CHD, CVD death and stroke (Blacher et al. 2009. J Human Hyperten)

23. CVD Mortality and Diabetes Hazard ratio = How often the event happens in one group compared to other group; Example: Cancer survival at any point of time in treatment group vs control group Hazard ratio Zeymer, U. Int J Cardiol. 2006, 11–20

24. Diet CVD Replacement of total, unsaturated, and even possibly saturated fats with refined, high-glycemic index carbohydrates is unlikely to reduce CHD risk and may increase risk in persons predisposed to insulin resistance Diet that will likely reduce the risk of CHD 1. rich in whole grains and other minimally processed carbohydrates 2. includes moderate amounts of fats (approximately 30%–40% of total energy), particularly unsaturated fats and omega-3 polyunsaturated fats from seafood and plant sources 3. lower in refined grains and carbohydrates 4. less packaged foods, baked goods, and fast foods containing trans fatty acids Mozaffarian, D. Current Atherosclerosis Reports 2005, 7:435–445

25. Percentage Change in Consumption by Kilocalories per Capita per Day in Selected Countries from 1980 to 2003, FAOSTAT Food Consumption Data Promoting Cardiovascular Health in the Developing World: A Critical Challenge to Achieve Global Health. Institute of Medicine (US) Committee on Preventing the Global Epidemic of Cardiovascular Disease: Meeting the Challenges in Developing Countries; Fuster V, Kelly BB, editors. Washington (DC): Academic Press, 2010

26. Diet and Lipoproteins Fiber Bile acids X Absorption Feces Cholesterol Bile acids • Saturated fat:  LDL receptor LDL uptake from blood   LDL in circulation • Fiber: Fiber binds bile acids and  re-absorption of cholesterol and  excretion in the feces.

27. Important qualities of carbohydrates in reducing CVD risk Mozaffarian D. Current Atherosclerosis Reports 2005,7:435–445

28. Adjusted Relative Risk of CHD according to the whole-grain foods .45 .89 .82 .77 .72 .76 .86 N=75,521 female nurses *Adjusted for BMI, smoking, alcohol, family history, hypertension/hypercholesterolemia, menopausal status, asiprin and multiple vitamin , activity, and energy intake use, Simin et al. Am J Clin Nutr 1999;70:412–9.

29. Diet and Heart Diseases Antioxidants • Protect from oxidative damage to LDL (oxidized LDL  atherosclerosis) • Protective effect of antioxidants (vit E, β carotene and C)

30. Beta carotene supplementation and CHD risk alpha-tocopherol, beta-carotene cancer prevention (ATBC) study. Tornwall et al. European Heart Journal. 2004, 25, 1171–1178

31. Fish Consumption on CHD Omega-3 fatty acids Precursors of eicosanoid synthesis  blood clotting  blood pressure  blood lipids Whelton , SP. Am J Cardiol 2004;93:1119–1123 – Meta analysis

32. Fish Consumption and CVD Wennberg, et al AJCN 2012

33. Other Risk Factors Homocysteine • High levels may promote atherosclerosis by damaging the inner lining of arteries and promoting blood clots •  homocysteine and folate intake – risk! • B6, B12 are also important Hyperhomocysteinemia is not a major risk factor for cardiovascular disease (AHA)

34. Metabolism of Homocysteine Protein synthesis THF Vitamin B12 Methionine X *THF-CH3 -CH3 Homocysteine Serine X B6 Cysteine *THF= tetrahydrofolate (folate containing co-enzyme)

35. Homocysteine and CVD Parameter Active group Placebo group Homocysteine (mmol/l) Baseline 15.9 ± 7.3 15.7 ± 5.7 2 years 12.7 ± 5.0 16.1 ± 5.2 5 years 11.9 ± 3.3 15.5 ± 4.5 Folate (nmol/l) Baseline 27.8 ± 12.3 28.7 ± 11.0 2 years 41.4 ± 9.2 26.1 ± 9.3 Vitamin B6 (nmol/l) Baseline 87.4 ± 128.8 64.5 ± 82.0 2 years 275.8 ± 175.3 80.3 ± 111.6 Vitamin B12 (pmol/l) Baseline 332.3 ± 161.7 323.2 ± 166.6 2 years 768.0 ± 196.9 320.9 ± 181.7 Mann et al. Nephrol Dial Transplant. 2008, 23: 645–653

36. C-Reactive Protein • Inflammation: Process by which the body responds to injury or an infection • Inflammation is involved with atherosclerosis • C-reactive protein (CRP) is one of the acute phase proteins that increase during systemic inflammation • hs-CRP and CVD risk < 1.0 mg/L Low risk 1.0 and 3.0 mg/L Moderate risk 3.0 mg/L High risk CDC and AHA recommend to measure CRP

37. Framingham Heart Study – CVD Risk • Population of interest - Individuals 30 to 74 y old and without CVD at the baseline examination – 10 y risk Predictors • Age • Diabetes • Smoking • Treated and untreated Systolic Blood Pressure • Total cholesterol • HDL cholesterol

38. Estimate of CVD in men – CVD Points

39. Calculating CVD Risk

40. Evidence Based Information • Selection of expert panel • Selection of topic and systemic search • Evidence rating and recommendation • Clinical recommendations • Research needs and future directions

41. Classification of CVD Risk in Women Risk Status Criteria High risk Established coronary heart disease Cerebrovascular disease Peripheral arterial disease Abdominal aortic aneurysm End-stage or chronic renal disease Diabetes mellitus 10-Year Framingham global risk 20% Mosca et al. Circulation, Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women: 2007 Update.

42. Classification of CVD Risk in Women Risk Status Criteria At risk>1 major risk factors for CVD, including: Cigarette smoking Poor diet Physical inactivity Obesity, especially central adiposity Family history of premature CVD (CVD at 55 years of age in male relative and 65 years of age in female relative) Hypertension Dyslipidemia Evidence of subclinical vascular disease (eg, coronary calcification) Metabolic syndrome Poor exercise capacity on treadmill test and/or abnormal heart rate recovery after stopping exercise Mosca et al. Circulation, Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women: 2007 Update.

43. Classification of CVD Risk in Women Risk Status Criteria Optimal risk Optimal risk Framingham global risk <10% and a healthy lifestyle, with no risk factors Mosca et al. Circulation, Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women: 2007 Update.

44. Classification Levels

45. Level of Evidence

46. Guidelines for prevention of CVD in Women: Clinical Recommendations A few examples…. 1. Life Style Interventions • Cigarette Smoking - should not smoke and should avoid environmental smoke (class I, level B) • Physical activity – minimum of 30 min brisk walking every day (class I, level B) Loose weight or sustain weight loss. 60- 90 min brisk walking every day (class I, level C)

47. Life Style interventions… • Dietary intake – Fruits and vegetable-rich diet, whole grain, high-fiber foods, fish (2x/wk), Saturated fat intake <10% of energy (<7%, if possible), cholesterol <300 mg/d, alcohol not more than 1 drink/d, sodium <2.3 g/d (1 tsp), and trans fatty acids <1% energy (class I, level B)

48. 2. Major Risk Factor Interventions A few examples….. • Blood Pressure • Optimal level and life style - <120/80 mm Hg through life style approaches (weight control, physical activity, alcohol, sodium, other healthy diet (class I, level B) • Pharmacotherapy – If >140/90 mm Hg or even lower with kidney disease or diabetes (class I, level A)

49. Lipids and lipoprotein levels • Optimal levels and life style approaches – LDL-C <100 mg/dL; HDL-C >50 mg/dL; TG <150 mg/dL; and non HDL-C <130 mg/dL (class I, level B) • Pharmacotherapy (high risk women) – drug therapy + life style approach in women with CHD (class I, level A) or atherosclerotic CVD or diabetes or 10 y absolute risk (class I, level B). Low HDL or elevated non-HDL – Niacin or fibrate therapy after LDL-C goal is reached (class IIa, level B) • Diabetes - Life style and pharmacotherapy (class I, level B) to achieve an HbA1c <7%

50. 3. Preventive Drug Interventions • Aspirin (75 -325 mg/d) in high risk women unless contraindicated (class I, level A). Other risk and healthy women, >65y age (81-100 mg/d) if BP is controlled (class IIa, level B)