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Collaborative Prospective Studies of Cardiovascular Disease

Collaborative Prospective Studies of Cardiovascular Disease. Nathan D. Wong, PhD Professor and Director Heart Disease Prevention Program, Division of Cardiology. Objectives.

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Collaborative Prospective Studies of Cardiovascular Disease

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  1. Collaborative Prospective Studies of Cardiovascular Disease Nathan D. Wong, PhD Professor and Director Heart Disease Prevention Program, Division of Cardiology

  2. Objectives • Understand the design and structure of the major ongoing NIH and CDC-supported prospective epidemiologic studies of cardiovascular disease • Understand opportunities for research projects and collaboration for residents, cardiology fellows, and faculty.

  3. Framingham Heart Study • Longest running study of cardiovascular disease in the world • Began in 1948 with original cohort of 5,209 subjects aged 30-62 at baseline • Biennial examinations, still ongoing, most of original cohort deceased • Offspring cohort of 5,124 of children of original cohort enrolled in 1971, and more recently and still being enrolled to better understand genetic components of CVD risk are up to 3,500 grandchildren of the original cohort. • Routine surveillance of cardiovascular disease events adjudicated by panel of physicians

  4. Measurements • Standard risk factors since inception of study, except HDL-C began around 1970. • Serial ECGs (first to document high rate of unrecognized MIs) • M-mode echocardiograms in 1980’s, first large study to show prognostic importance of increased LV mass • Newer measures done in subsets include: Carotid ultrasound, bone denistometry, coronary artery calcium, and other novel risk factors and biomarkers (e.g. natriuretic peptides)

  5. Framingham Most Significant Milestones • 1960 Cigarette smoking found to increase the risk of heart disease • 1961 Cholesterol level, blood pressure, and electrocardiogram abnormalities found to increase the risk of heart disease • 1967 Physical activity found to reduce the risk of heart disease and obesity to increase the risk of heart disease • 1970 High blood pressure found to increase the risk of stroke • 1976 Menopause found to increase the risk of heart disease • 1978 Psychosocial factors found to affect heart disease • 1988 High levels of HDL cholesterol found to reduce risk of death • 1994 Enlarged left ventricle (one of two lower chambers of the heart) shown to increase the risk of stroke • 1996 Progression from hypertension to heart failure described

  6. ____________________________________________________________ Smoking Statement Issued in 1956 by American Heart Association ___________________________________________________________ “It is the belief of the committee that much greater knowledge is needed before any conclusions can be drawn concerning relationships between smoking and death rates from coronary heart disease. The acquisition of such knowledge may well require the use of techniques and research methods that have not hitherto been applied to this problem.” Circulation 1960; vol. 23 ___________________________________________________________

  7. CHD Risk by Cigarette Smoking. Filter Vs. Non-filter. Framingham Study.Men <55 Yrs. 14-yr. Rate/1000 210 206 210 119 112 59

  8. 9 Doubts about cholesterol as late as 1989

  9. Relative Risk of CHD by HDL and LDL-Cholesterol Men 50-70 Years of Age Framingham Study 4-Year Follow-up, The Framingham Study 25 mg/dl 55 mg/dl 85 mg/dl Morbidity Ratio: LDL-Cholesterol WB Kannel Am Heart J. 1985;110:1100-1107.

  10. Risk factors for long-term coronary prognosis after initial myocardial infarction: the Framingham Study.Wong ND, Cupples LA, Ostfeld AM, Levy D, Kannel WB. Am J Epidemiol. 1989 Sep;130(3):469-80.Links • Age-adjusted analyses showed the risk of reinfarction to be positively associated with blood pressure and serum cholesterol. Risk of coronary death was strongly associated with blood sugar level, systolic blood pressure, serum cholesterol, heart rate, diabetes, and interim reinfarction. In multivariable analyses, systolic pressure, serum cholesterol, and diabetes were predictive of reinfarction; relative weight was inversely associated with reinfarction. Systolic pressure, serum cholesterol, and the prevalence of diabetes persisted as independent predictors of coronary death. When adjustments were made for the effects of these variables, women were at only half the risk of coronary death compared with men.

  11. ______________________________________________________________________________________________________________________________________________________________ Lifetime Risk of CHD Increases with Serum Cholesterol ___________________________________________________________________________ Cholesterol 57 44 34 33 29 19 Framingham Study: Subjects age 40 years DM Lloyd-Jones et al Arch Intern Med 2003; 1966-1972

  12. ________________________________________________________ CK Friedberg on Hypertension: Diseases of the Heart 1996 ___________________________________________________________ “There is a lack of correlation in most cases between the severity and duration of hypertension and development of cardiac complications.” _______________________________________________________________

  13. Relation of Non-Hypertensive Blood Pressure to Cardiovascular DiseaseVasan R, et al. N Engl J Med 2001; 345:1291-1297 10-year Age- Adjusted Cumulative Incidence Hazard Ratio* SBPWomenMen <120/80 1.0 1.0 120-129 1.5 1.3 130-139 2.5 1.6 H.R. adjusted for age, BMI, Cholesterol, Diabetes and smoking *P<.001 10.1 7.6 5.8 4.4 2.8 1.9 Framingham Study: Subjects Ages 35-90 yrs.

  14. Risk of Myocardial Infarction withIsolated Systolic Hypertension Framingham Study 24 Yr. Follow-Up Men ages 45-54 yrs. Annual Incidence Per 10,000 WB Kannel Prev Cardiol 1998; 1:32-39

  15. Joint Influences of SBP and Pulse Pressure on CHD Risk Franklin SS….Wong ND et al, Circulation 1999 Franklin SS et al. Circulation. 1999;100:354-360.

  16. Franklin SS, Lopez VA, Wong ND, et al. Single Versus Combined Blood Pressure Components and Risk for Cardiovascular Disease. The Framingham Heart Study. Circulation Jan 2009 • BACKGROUND: -The utility of single versus combined blood pressure (BP) components in predicting cardiovascular disease (CVD) events is not established. We compared systolic BP (SBP) and diastolic BP (DBP) versus pulse pressure (PP) and mean arterial pressure (MAP) combined and each of these 4 BP components alone in predicting CVD events. • Methods and Results-In participants in the original (n=4760) and offspring (n=4897) Framingham Heart Study who were free of CVD events and BP-lowering therapy, 1439 CVD events occurred over serial 4-year intervals from 1952 to 2001. In pooled logistic regression with the use of BP categories, combining SBP with DBP and PP with MAP improved model fit compared with individual BP components (P<0.05 to P<0.0001). Significant interactions were noted between SBP and DBP (P=0.02) and between PP and MAP (P=0.01) in their respective multivariable models. Models with continuous variables for SBP+DBP and PP+MAP proved identical in predicting CVD events (Akaike Information Criteria=10 625 for both). Addition of a quadratic DBP(2) term to DBP and SBP further improved fit (P=0.0016). • Conclusions-Combining PP with MAP and SBP with DBP produced models that were superior to single BP components for predicting CVD, and the extent of CVD risk varied with the level of each BP component. The combination of PP+MAP (unlike SBP+DBP) has a monotonic relation with risk and may provide greater insight into hemodynamics of altered arterial stiffness versus impaired peripheral resistance but is not superior to SBP+DBP in predicting CVD events.

  17. Diseases of The HeartCharles K Friedberg MD, WB Saunders Co. Philadelphia, 1949 “The proper control of diabetes is obviously desirable even though there is uncertainty as to whether coronary atherosclerosis is more frequent or severe in the uncontrolled diabetic” ________________________________________________________________ ______________________________________________________________

  18. Risk of Cardiovascular Events in DiabeticsFramingham Study _________________________________________________________________ Age-adjusted Biennial Rate Age-adjusted Per 1000Risk Ratio Cardiovascular EventMen WomenMen Women Coronary Disease39 21 1.5** 2.2*** Stroke 15 6 2.9*** 2.6*** Peripheral Artery Dis. 18 18 3.4*** 6.4*** Cardiac Failure23 21 4.4*** 7.8*** All CVD Events 76 65 2.2*** 3.7*** Subjects 35-64 36-year Follow-up **P<.001,***P<.0001 _________________________________________________________________

  19. Risk of Coronary Heart Disease by Diabetic Status According to Level of Risk FactorsFramingham StudyWilson PWF, Kannel WB. Nutr. In Clin Care 1998 Women age 50 yrs. % Risk Factors HBP (160) No (120) YesYes Yes Yes Yes Chol (240) No (165) No Yes Yes Yes Yes Cig Smoker No No No Yes Yes Yes HDL-C (34) No (58) No No No Yes Yes ECG-LVH No No No No No Yes

  20. ______________________________________________________________________________________________________________________________ CVD Risk Imposed by ECG-LVH Framingham Study 36-yr. Follow-up _______________________________________________________________ Age-adjusted Risk Excess Risk Rate per 1000Ratioper 1000 Age Men Women Men Women Men Women 35-64164 135 4.7*** 7.4*** 129 117 65-94234 235 2.8*** 4.1*** 151 178 Biennial Rate per 1000. CVD=CHD, stroke, peripheral vascular disease, heart failure ***P<0.001 _____________________________________________________________

  21. __________________________________________________________________________________________________________________________ CVD Risk by Plasma Natriuretic Peptides _______________________________________________________________ Multivariate Hazard Ratio per SD Increment OutcomeBNPN-ANP Death1.27 (1.06-1.52)** 1.41 (1.14-1.74)*** Major CVD1.28 (1.03-1.59)* 1.30 (1.02-1.67)* Heart Failure 1.77 (1.31-2.41)*** 1.94 (1.37-2.75)*** AF1.66 (1.30-2.11)*** 1.72 (1.302.28)*** Stroke/TIA1.53 (1.16-2.02) ** 1.37 (0.99-1.89) CHD1.10 (0.89-1.37) 1.12 (0.88-1.42) Framingham Offspring Study Obesity-promoted natriuretic peptides are secreted from cardiomyocytes: They play a fundamental role in CV remodeling, volume homeostasis, and response to ischemia. TJ Wang et al. N Engl J Med 2004; 350:655-663.

  22. ____________________________________________________________ Lifetime Risk of Coronary Heart Disease in the Framingham Study ______________________________________________________________ Men Women At age 40 years: 48.6% 31.7% At age 70 years: 34.9% 24.2% Lloyd-Jones et al. Lancet 1999; 353:89-92 _________________________________________________________________

  23. Cardiovascular Health Study • 5,201 Medicare eligible individuals aged 65-102 at baseline enrolled beginning 1992 at six field centers. • Assessment of newer and older risk factors. • Ongoing follow-up of cardiovascular events and mortality • Subclinical disease measures included: • carotid B-mode ultrasound for carotid IMT at Year 2, Year 7, and Year 11 • m-mode echocardiographic measures of left ventricular mass and dimensions, left atrial dimension done at baseline (Year 2) (at UC Irvine) and follow-up (Year 7) examinations. • Ankle brachial index (ABI) for measurement of PAD • Pulmonary function (FVC and FEV1)

  24. Summary of Events • Combined Cohort at Baseline (N=5888) • Mean Age = 72 years58% Women16% African American31% had Cardiovascular Disease at entry Number of Events through June 30, 2002 • Angina 1064 • MI 696 • Heart Failure 1262 • Claudication 789 • Stroke 789 • TIA 212 • Death 2658

  25. Cardiovascular Health Study: Combined intimal-medial thickness predicts total MI and stroke Cardiovascular Health Study (CHS) (aged 65+): MI or stroke rate 25% over 7 years in those at highest quintile of combined IMT (O’Leary et al. 1999)

  26. Ankle Brachial Index as a Predictor of Cardiovascular Mortality in the CHS Study Newman A et al ATVB 1999

  27. CHS Representative Recent Publications • Association of carotid artery intima-media thickness, plaques, and C-reactive protein with future cardiovascular disease and all-cause mortality: the Cardiovascular Health Study. Circulation. 1;116 (32-38). 7-3-2007 • Brachial Flow-Mediated Dilation Predicts Incident Cardiovascular Events in Older Adults. The Cardiovascular Health Study. Circulation. 4-23-2007 • Relationship between brachial flow-mediated dilation and carotid intima-media thickness in an elderly cohort: The Cardiovascular Health Study. Atherosclerosis. 9-3-2007

  28. CHS publications continued • The association of alcohol consumption and incident heart failure: the Cardiovascular Health Study. J Am Coll.Cardiol. 2;48 (305-311). 7-18-2006 • Usefulness of aortic root dimension in persons > or = 65 years of age in predicting heart failure, stroke, cardiovascular mortality, all-cause mortality and acute myocardial infarction (from the Cardiovascular Health Study). Am J Cardiol. 2;97 (270-275). 1-15-2006 • Left atrial volume, geometry, and function in systolic and diastolic heart failure of persons >/=65 years of age (the cardiovascular health study). Am.J.Cardiol. 1;97 (83-89). 1-1-2006

  29. CHS publications (continued) • Blood pressure level and outcomes in adults aged 65 and older with prior ischemic stroke. J Am Geriatr Soc. 9;54 (1309-1316). 2006 • 10-year follow-up of subclinical cardiovascular disease and risk of coronary heart disease in the Cardiovascular Health Study. Arch.Intern.Med. 1;166 (71-78). 1-9-2006 • Metabolic syndrome and cardiovascular disease in older people: The cardiovascular health study. J Am Geriatr Soc. 9;54 (1317-1324). 2006 • Mortality and cardiovascular risk across the ankle-arm index spectrum: results from the Cardiovascular Health Study. Circulation. 3;113 (388-393). 1-24-2006

  30. CHS publications (cont.) • The association of microalbuminuria with clinical cardiovascular disease and subclinical atherosclerosis in the elderly: The Cardiovascular Health Study. Atherosclerosis. 10-19-2005 • Increased left ventricular mass is a risk factor for the development of a depressed left ventricular ejection fraction within five years: the Cardiovascular Health Study. J.Am.Coll.Cardiol. 12;43 (2207-2215). 6-16-2004 • The association between lipid levels and the risks of incident myocardial infarction, stroke, and total mortality: The Cardiovascular Health Study. J.Am.Geriatr.Soc. 10;52 (1639-1647). 2004

  31. Possible Topics for Future Papers • Prognosis associated with echo left atrial dimension—e.g., in relation to stroke • Papers examining relation of progression of LV mass in relation to future risk of cardiovascular events (CHD, CHF, stroke) • Predictors of progression of LV mass • Combination of increased CIMT and LV mass in relation to CHF or CHD events.

  32. Multiethnic Study of Atherosclerosis • 6,814 adults aged 45-80 enrolled at 6 field centers, including Caucasians, African-Americans, Hispanics, and Chinese beginning 2000. • Extensive assessment of standard and novel risk factors, unique blood cohort among 1000 subjects. • Multiple evaluations of carotid IMT, ABI, and coronary calcium. Ancillary studies of LV size and extracoronary measures of calcification (Harbor-UCLA) and abdominal aortic calcium (UC San Diego) in full or partial cohorts.

  33. MESA Study Design Features Four examinations approximately two years apart, exam 4 just completed Major risk factors measured at each exam Coronary calcium measured in entire cohort at Exam 1, ½ cohort at Exam 2, ½ cohort at Exam 3, and in about 1000 pts in Exam 4. Carotid IMT measured at Exam 1 and 2-3. Cardiac MRI measured at Exam 1 and 2-3 Ankle Brachial Index Pulse wave analysis Endothelial function measures Follow-up for CVD events and incident DM, mortality

  34. MESA Key Subclinical Disease Measures • Coronary calcium Agatston score and volume • LV size, thoracic aortic calcium, aortic valve calcium (ancillary study) • Abdominal aortic calcium (ancillary study), including aortic diameter • Ankle brachial index • ECG variables (LVH, Q-waves, long QT, AFIB) • Carotid Ultrasound (Common and Internal CIMT, max carotid stenosis) • Cardiac MRI (LV end diastolic mass, volumes, LVEF, stroke volume, aortic distensibility, cardiac output)

  35. MESA laboratory variables • Glucose, insulin, TG, HDL (including 8 subfractions), LDL (incl very small to large subfractions), mean LDL and HDL size, • Urinary albumin, creatinine, microalbuminuria, homocysteine • CD40 ligand, E-selectin, IL-2, IL-6, HS-CRP, MMP3, 9, TNF-alpha, PAI-1, HSV, CMV, H.Pylori, C. Pneumoniae • CETP activity and mass, SI-cam, Ox-LDL, D-dimer

  36. Other MESA Variables • Family history of MI, stroke • Cigarette, cigar, pipe, and chewing tobacco • Total light, moderate, and vigorous physical activity in minutes/wk and MetS • Medications: Statins, Anti-arrhythmics by class, beta-blockers, CCBs, Cox2 inhibitors, estrogen replacement therapy, oral anticoagulants

  37. Cumulative Incidence of Any Coronary Event: MESA Study (Detrano et al., NEJM 2008)

  38. Risk Factor-Adjusted Hazard Ratios by Coronary Calcium Score: MESA Study (Detrano et al., NEJM 2008)

  39. MESA ongoing papers in progress here at UCI • Metabolic syndrome, diabetes, and progression of coronary calcium • Abdominal aortic calcification and systemic atherosclerosis (relation to CAC, CIMT, and ABI) • Value of CAC vs. CIMT in predicting CHD events over FRS in Metabolic Syndrome and Diabetes (with Dr. Malik)

  40. Multiethnic Study of Atherosclerosis (MESA): CAC and CHD Events (Malik, Wong et al, AHA Nov 2007) Adjusted for Framingham Risk Score and Ethnicity

  41. Multiethnic Study of Atherosclerosis (MESA): Common CIMT and CHD Events (Malik, Wong et al AHA Nov. 2007) Adjusted for Framingham Risk Score and Ethnicity Results for Internal CIMT were similar.

  42. ROC Curve Analyses for CVD Events: FRS alone, FRS plus CIMT, or FRS plus CAC in those with Mets (without DM): MESA Study (Malik, Wong et al., AHA 2007) ROC FRS alone ROC FRS + CIMT ROC FRS + CAC ROC area FRS+CAC (0.7539) vs. FRS alone (0.6967), p = 0.0017 ROC area FRS + CIMT (0.6926) vs FRS alone (0.6967), p =0.6354 ROC area FRS+ CAC (0.7539) vs.FRS + CIMT (0.6925), p = 0.002

  43. ROC Curve Analyses for CVD Events:FRS alone, FRS plus CIMT, or FRS plus CAC in those with DM: MESA Study (Malik, Wong et al., AHA 2007) ROC FRS alone ROC FRS + CIMT ROC FRS + CAC ROC area FRS+CAC (0.7285) vs. FRS alone (0.6669), p = 0.0001 ROC area FRS + CIMT (0.6809) vs. FRS alone (0.6669), p =0.3258 ROC area FRS+ CAC (0.7285) vs.FRS + CIMT (0.6809), p = 0.0037

  44. Incidence and Progression of Coronary Calcium (mean 2.4 years between scans): Multiethnic Study of Atherosclerosis (n=5570) (Wong et al., AHA 2006) P<0.01 to p<0.001 between each group P<0.001 across groups P<0.001 across groups • % with new CAC among those free of CAC at baseline • % with progression of CAC (score change >0) • Mean adjusted change in CAC score among those with CAC at baseline

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