The document discusses approaches for deciding whom to treat for hypertension. It compares strategies focused on lowering blood pressure versus slowing disease progression. Screening tests can identify early markers of cardiovascular disease to guide more aggressive prevention strategies in high-risk individuals before blood pressure thresholds are met. Future paradigms may target treatment to slow progression across the disease continuum rather than achieve discrete treatment goals.

1. How Should One Decide Whom to Treat for Hypertension? Jay N. Cohn, M.D. Professor of Medicine Director, Rasmussen Center for Cardiovascular Disease Prevention University of Minnesota Medical School Minneapolis, MN

2. CV Mortality Risk Doubles with Each 20/10 mm Hg BP Increment* *Individuals aged 40-69 years, starting at BP 115/75 mm Hg. CV, cardiovascular; SBP, systolic blood pressure; DBP, diastolic blood pressure Lewington S, et al. Lancet . 2002; 60:1903-1913. JNC VII. JAMA. 2003. CV mortality risk SBP/DBP (mm Hg) 0 1 2 3 4 5 6 7 8 115/75 135/85 155/95 175/105

3. Impact of “High-Normal” BP on CV Risk Data from the Framingham Heart Study 16 12 8 4 0 Optimal BP Normal BP 12 8 4 0 0 2 4 6 8 10 12 Years Optimal BP Normal BP High-normal BP Women Men Cumulative incidence of CV events (%) High-normal BP Vasan et al. N Engl J Med. 2001;345:1291-7. Optimal BP: <120/80 Normal BP: 120-129/80-84 High-normal BP: 130-139/85-89

4. Lower Is Better IHD Rates by SBP, DBP, and Age A: Systolic Blood Pressure 40-49 years 50-59 years 60-69 years 70-79 years 80-89 years Age at risk: IHD Mortality (Floating Absolute Risk and 95% CI) 256 128 64 32 16 8 4 2 1 120 140 160 180 Usual SBP (mm Hg) B: Diastolic Blood Pressure IHD Mortality (Floating Absolute Risk and 95% CI) 256 128 64 32 16 8 4 2 1 70 80 90 100 110 Usual DBP (mm Hg) Lewington et al. Lancet. 2002;360:1903-1913. Age at risk: 40-49 years 50-59 years 60-69 years 70-79 years 80-89 years

5. Hypothesis The apparent linear relationship between blood pressure and ischemic disease events as well as age and ischemic disease events does not necessarily mean that age or blood pressure cause events but that both markers capture a progressively higher proportion of people with early disease.

6. Blood Pressure and Likelihood of Disease 100 Frequency in Population (%) 50 0 75 100 125 150 175 200 Systolic Blood Pressure (mmHg) No Disease Possible Disease Likely Disease

7. Systolic BP Reduction and CVD Mortality  Systolic BP (control - experimental, mm Hg) Cardiovascular Mortality Odds Ratio Staessen JA et al. Lancet. 2001;358:1305 -1315. 1.50 1.25 1. 00 0.75 0.50 0.25 -5 0 5 10 15 20 25 P =.003 MIDAS/NICS/VHAS UKPDS C vs A INSIGHT HOT L vs H HOT M vs H MRC1 MRC2 SHEP HEP EWPHE RCT70-80 Syst-Eur STONE Syst-China UKPDS L vs H HOPE PART2/SCAT ATMH STOP1 CAPPP STOP2/CCBs STOP2/ACEIs NORDIL

9. Benefits of Intensive BP Reduction HOT Study * Mean BP from 6 months of follow-up to end of study. Hansson L et al. Lancet. 1998;351:1755-1762. Achieved DBP* (mm Hg) 85.2 83.2 81.1 P =0.05 for trend Number of MIs  90 143.7 85.2  85 141.4 83.2  80 138.7 81.1 Target DBP (mm Hg) Achieved SBP (mm Hg) Achieved DBP* (mm Hg) 100 80 40 0 20 60

10. Hypothesis The apparent linear relationship between the magnitude of drug-induced BP fall and the reduction of morbid events does not necessarily indicate that blood pressure reduction prevents events but that the drugs protect the arteries and heart (while also lowering blood pressure). A corollary: the greater the BP reduction from a drug the less the vascular disease - i.e., BP fall identifies a low-risk population.

11. Antihypertensive Drugs that Slow Disease Progression in Known Doses Vascular Cardiac Ramipril Enalapril Perindopril Captopril ?other ACEIs Carvedilol Amlodipine Metoprolol Valsartan Bucindolol Losartan Valsartan Hydrochlorothiazide Candesartan Spironolactone Eplerenone ISDN/hydralazine

12. Old Paradigm BP Cholesterol Disease Disease Treatment Treatment Normal Normal GOAL : Target Response

13. Current Paradigm DISEASE BP Cholesterol GOAL : ?Target Response TREATMENT

14. Pathophysiology of CV Continuum Genes Environment Ethnicity Diet Family Hx Exercise Polymorphisms Stress Proteomics Smoking Blood Vessel/ Heart Angiotensin Nitric Oxide Progression Aldosterone Norepinephrine Cytokines Structural Remodeling CAD Cerebrovascular Disease Heart Failure Renal Failure PVD Dementia

15. Genes, Ethnicity, Diet, Exercise, Smoking, Obesity, Lipids Small Artery Arterial Structural Cardiac Elasticity Abnormalities Abnormalities ( Endothelial Microalbumin LVM Dysfunction ) IMT BNP BP Retinal Vasculopathy ECG PNE Large Artery Elasticity AngII Exercise BP Resting BP Disease Drug Therapy RAAS Blockade Statins NO Enhancers Antihypertensives Antioxidants ?Antiinflammatories

17. † CVD designation is determined by the constellation of risk factors, early disease markers, and target-organ disease. CVD, cardiovascular disease. ASH Writing Group Definition and Classification of Hypertension ASH Writing Group 2005. Overtly present with or without CVD events Early signs present None None Target-organ Disease Overtly present with progression Overtly present Usually present None Early Disease Markers Many Many Several None or few Cardiovascular Risk Factors Marked and sustained BP elevations OR Advanced CVD † Sustained BP elevations OR Progressive CVD † Occasional or intermittent BP elevations OR Early CVD † Normal BP or rare blood pressure elevations AND No identifiable CVD † Descriptive Category Stage 3 hypertension Stage 2 hypertension Stage 1 hypertension Normal Classification

18. Early Markers for Hypertensive Vascular Disease Blood Pressure -Exaggerated response to exercise -Widened pulse pressure Vascular -Reduced small artery elasticity -Reduced large artery elasticity -Endothelial dysfunction -Increased pulsewave velocity -Increased carotid intima-medial thickness -Retinal vascular changes -Microalbuminuria Cardiac -Increased LV wall thickness -Increased LV volume -Increased LV mass -Abnormal ECG -B-type natriuretic peptide

19. R A S M U S S E N C E N T E R for CARDIOVASCULAR DISEASE PREVENTION

23. Results of Rasmussen Center Screening Frequency Rasmussen Score Low Risk 33% Modest Risk 36% High Risk 31%

24. Patient : 60-year-old female registered nurse Past History : negative except high cholesterol Family History : both parents smoked, no significant CV disease Physical Exam : Height 5’4” Weight 126 lb. HR 64 b/min BP 132/66 mmHg Screening Results : C 1 = 8.5 ml/mmHg x10 (abnormal) C 2 = 2.4 ml/mmHg x100 (abnormal) Exercise BP = 173/64 mmHg (abnormal) Retinal photo = A:V nicking (abnormal) Microalbumin = 0.86 mg/mmol (abnormal) LV ultrasound = increased mass (abnormal) Rasmussen score = 12 points Blood Chemistry : LDL 187 mg/dl; HDL 70 mg/dl Interpretation : Advanced CV Disease Treatment : Antihypertensive, statin

25. Patient : 62-year-old female florist Past History : Asymptomatic, plays tennis and golf Elevated cholesterol: Atorvastatin, 10 mg Family History : Negative Physical Exam : Height 5’5” Weight 128 lb. HR 74 b/min BP 140/80 mmHg Screening Results : C 1 = 8.7 ml/mmHg x10 (abnormal) C 2 = 1.6 ml/mmHg x100 (abnormal) Exercise BP = 182/80 mmHg (abnormal) Retinal photo = decreased A:V ratio (borderline) Microalbumin = 1.98 mg/mmol (abnormal) Rasmussen score = 9 points Blood Chemistry : LDL 137 mg/dl; HDL 129 mg/dl; CRP 0.13 mg/dl Interpretation : Advancing CV Disease Treatment : ACE/ARB; BP Control; Increase atorvastatin

26. Patient : 49-year-old male executive Past History : Overweight, elevated BP, asymptomatic, no therapy Family History : Hypertension, coronary disease Physical Exam : Height 5’8” Weight 240 lb. HR 76 b/min BP 144/84 mmHg Screening Results : C 1 = 16.1 ml/mmHg x10 (normal) C 2 = 6.4 ml/mmHg x100 (normal) Exercise BP = 154/74 mmHg (normal) All other tests normal Rasmussen score = 2 points (BP only) Blood Chemistry : LDL 172 mg/dl; HDL 38 mg/dl; FBS 108 mg/dl; CRP 1.0 mg/dl Interpretation : No CV Disease Treatment : Diet, ?statin

29. Risk Factors Biomarkers Cardiac and Vascular Structural Abnormalities Death Non-Fatal Morbid Events Recurrence Progression Primary Prevention Secondary Prevention Tertiary Prevention

32. Future Paradigm Early Disease Statin RAAS Blockade Antihypertensives NO donor/enhancer Innovative Therapy Slow Progression GOAL : ?Target Dose