Director of the Israeli Institute for Quality in Medicine Israeli Medical Association July 1st, 2016

The differential effect of Atherosclerosis on end organ damage in adult and elderly patients with CVRF: New Algorithm for Hypertension Diagnosis and Treatment R. Zimlichman, FAHA, FASH, FESC, FESH Chief Dept. of Medicine and Hypertension Institute and Director of The Brunner Institute for Cardiovascular Research Sackler Faculty of Medicine, Tel-Aviv University. The E. Wolfson Medical Center Director of the Israeli Institute for Quality in Medicine Israeli Medical Association July 1st, 2016 1

Age is the predominant factor for CVD The population of the western world is aging, by 2030 there will be 71 million individuals over 65. Aging increases CV morbidity and mortality even in the absence of CVRF s. The risk of death from heart disease in the eighth decade is 60 times greater than in the 4 th decade. With aging the risk of overt, subclinical and silent (e.g. asymptomatic coronary atherosclerosis), disease increases dramatically. 2

The CV system aims to provide sufficient pressure and flow to the tissues at rest and during exercise. It s performance requires: Power and stroke capacity of the heart (Left Ventricle). Capacitance and inertial properties of the aorta (Aorta). Resistance capacity of the microcirculation (Resistance vessels, precapillaries). 3

Demographic Aspects During the recent decades longevity extended significantly. Life-span is now longer by more than 20 years compared to several decades ago. What are the consequences? 4

Aging. 5

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1970 7

Essential (?) Hypertension Secondary hypertension will not be discussed here. It is another disease that one of it s manifestations is hypertension. Essential Hypertension is a misnomer- Blood pressure does not come by itself. It has a reason, pathogenesis and specific mechanisms of progression. Hypertension is a result of various pressor contributors to blood pressure like: o RAS, o Aldosterone, o Catecholaminergic system (SNS), o Humoral/metabolic effects (Obesity etc.) And their balance with vasodilator factors. 8

Contributors to Hypertension 9 Physiologic Morbid obesity Excess dietary sodium Excessive alcohol Sleep Apnea Humoral contributors to hypertension RAAS Aldosterone and mineralocorticoid Ht SNS Concurrent medications NSAIDs (low GFR) Sympathomimetics Illicit drugs Increased artery stiffness isolated systolic hypertension

Hypertensives Within Age Group (%) Age Distribution of Hypertensives in US 10 Population: NHANES III and the 1991 Census 30 26% 74% 25 20 47.4 million hypertensives 26.0% of US population 21.3 23.7 19.2 15 13 10 9.5 9.6 5 3.7 0 18 29 30 39 40 49 50 59 60 69 70 79 80+ Age Groups (y) Franklin SS. J Hypertension. 1999;17(suppl 5):S29-S36.

Population With Hypertension (millions) Increased Prevalence of Hypertension in the United States from 1988-1994 (NHANES III) to 1999-2000 NHANES 11 100 80 60 40 50 30% increase, p<.001 65 20 0 1988-1994 1999-2000 National Health and Nutrition Survey (NHANES) Nearly 1 in 3 Adults (31%) in the US Has Hypertension Fields, et al. Hypertension. 2004;44:398f

1976-98 Cumulative Incidence of HTN in Women and Men Aged 65 Years 12 Risk of Hypertension % 100 80 Men Women 60 40 20 0 0 2 4 6 8 10 12 14 16 18 20 Years of Follow-up Vasan, et al. JAMA.2002;287:1003

Residual lifetime risk to develop hypertension 13 Vasan et al, JAMA 2002, 287, 1003

Pathogenesis of Systolic and Diastolic Hypertension Stroke Volume SYSTOLIC HYPERTENSION Central Artery Stiffness Arteriolar Constriction DIASTOLIC HYPERTENSION Inhibits Promotes 14

Arterial stiffening Gradual decrease in arterial elasticity that occurs in all subjects. The major cause for arterial stiffening is age, (Physiological aging, premature, pathological aging). Rate of progression of arterial stiffening is enhanced with presence of risk factors. Accumulation of Risk Factors, genetic properties and other mechanisms can magnify rate of arterial stiffening. 15

Blood Pressure: Generated by Ventricular Contraction Figure 15-4: Elastic recoil in the arteries 16

The heart pumps in short spurts. The compliant aorta stores this energy during ejection and releases it during diastole so that flow into the periphery continues throughout the cardiac cycle 17

DBP (mm Hg) DBP (mm Hg) SBP (mm Hg) SBP (mm Hg) Mean SBP and DBP by Age and Race/Ethnicity for Men and Women (US Population Age 18 Years, NHANES III) 18 150 150 130 130 110 Pulse pressure 110 Pulse pressure 80 80 70 70 0 18-29 30-39 40-49 50-59 60-69 70-79 80+ Men, Age (y) 0 18-29 30-39 40-49 50-59 60-69 70-79 80+ Women, Age (y) Burt VI, et al. Hypertension. 1995;25:305-313.

Artery Elasticity Index Hg x ml x 10) Large Artery Elasticity 25 20 15 10 5 0 15 25 35 45 55 65 75 age (years) 19

Artery elasticity index Hg x ml x 100) Small Artery Elasticity 12 10 8 6 4 2 0 15 25 35 45 55 65 75 age (years) 20

blood pressure systolic blood pressure 160 150 140 130 120 110 100 15 25 35 45 55 65 75 age (years) 21

vascular resistence x sec x 10-5 ) systemic vascular resistence 2000 1800 1600 1400 1200 1000 800 15 25 35 45 55 65 75 age (years) 22

Large artery arterial elasticity index Figure 1. Large artery arterial elasticity index by age group 18 16 14 12 10 8 6 4 2 0 0 1 2 3 4 5 6 7 8 Age group (decades) 23

Small artery arterial elasticity index Figure 2. Small artery arterial elasticity index by age group 9 8 7 6 5 4 3 2 1 0 0 1 2 3 4 5 6 7 8 age group (decades) 24

Elasticity (mmhg) Age Related Loss of Arterial Elasticity (Normotensives, free from obvious disease) 25 C1 and C2 decrease with age, the slope of C2 being greater. The change in C2 was independent of BP and may represent a more sensitive marker of the aging process. C1 (x 10) C2 (x 100) 25 20 15 10 5 0 20 40 60 75 Age (years) McVeigh, Gary E.; Bratteli, Christopher W.; Morgan, Dennis J.; Alinder, Cheryl M.; Glasser, Stephen P.; Finkelstein, Stanley M.; Cohn, Jay N. Age-Related Abnormalities in Arterial Compliance Identified by Pressure Pulse Contour Analysis. HYPERTENSION 33:1392-1398, June 1999.

Elasticity (mmhg) Elasticity Decreases as the Hypertensive State Increases Average and 95% Confidence Intervals 25 26 20 15 10 C1 C2 5 0 1 2 3 4 Normotensive No Family History Normotensive Family History Hypertensive Treated, Controlled Hypertensive Untreated, Uncontrolled Prisant, L.M., Resnick, L.M., Hollenberg, S.M. Arterial Elasticity Among Normotensive Subjects and Treated and Untreated Hypertensive Subjects, Blood Pressure Monitoring 6:233-237, 2001, Ref: 131

Why is aortic pressure pulsatile? With each ejection the aortic volume increases by one stroke volume 27

If aortic compliance were to decrease, pulse pressure will increase. 28

Aging reduces aortic compliance Pulse pressure naturally increases with age 120/80 Systolic hypertension >140 Compliance = volume/ pressure 29

Correlation between number of risk factors and arterial distensibility N = 803, mean age 30 y 30 Brachial artery distensibility ( % / mm Hg) 7.5 7 6.5 6 Linear trend P < 0.0001 Brachial artery distensibility occurs long before clinical manifestations of CVD appear 5.5 0 1 2 3 4 Number of CV risk factors 5 Bogalusa Heart Study Urbina EM et al. Am J Hypertens. 2005;18:767-71.

Peripheral arterial stiffness is associated with subclinical N = 256 atherosclerosis 50 40 P < 0.0001 for trend 31 Thigh arterial compliance* 30 20 10 0 Q1 Q2 Q3 Q4 MRI results Quartile of abdominal aorta wall thickening *Maximum volume change X 50 Brachial pulse pressure Herrington DM et al. Circulation. 2004;110:432-7.

Distribution of Hypertension Subtype in the Untreated Hypertensive Population by Age (NHANES III) 32 ISH (SBP 140 mm Hg and DBP <90 mm Hg) SDH (SBP 140 mm Hg and DBP 90 mm Hg) IDH (SBP <140 mm Hg and DBP 90 mm Hg) 100 } Diastolic Hypertension 17% 16% 16% 20% 20% 11% Frequency of hypertension subtypes in all untreated hypertensives (%) 80 60 40 20 0 <40 40-49 50-59 60-69 70-79 80+ Age (y) Numbers at top of bars represent the overall percentage distribution of untreated hypertension by age. Franklin et al. Hypertension. 2001;37: 869-874.

Demography, Hypertension type Young-26% Elderly- 74% Franklin SS, 1999? % 80-90%????, 2016 33

Hypertension type changes with age Arterial Stiffening Alpha: Variable Ageing + CVRF s 34

Hypertension type changes with age In Young Subjects? Humoral contribution Ageing + CVRF s 35

Hypertension type changes with age Arterial Stiffening Humoral contribution Ageing 36

Hypertension type changes with age Arterial Stiffening Humoral contribution Ageing Young subjects: Humoral factors Respond best to humoral blockers: -ACE/ARB -Mineralocorticoid antagonists? -BB? Stiff Arteries Respond best to: -CCB s -Diuretics 37

Stiffness becomes predominant gradually with age Young Elderly Transition zone: both humoral and stiffening present Young, fast stiffeners (premature stiffening Elderly, slow stiffeners 38

JNC Reclassification of BP Based on Risk ategory SBP (mm Hg) JNC VI DBP (mm Hg) Category JNC 7 SBP (mm Hg) 39 DBP (mm Hg) Optimal Normal Hi-normal <120 and 80 Normal <120 and 80 120-129 130-139 and 80-84 or 85-89 Prehypertension 120-139 or 80-89 Hypertension Stage 1 140-159 or 90-99 Stage 1 140-159 or 90-99 Stage 2 Stage 3 160-179 180 or or 100-109 110 Stage 2 160 or 100 Source for JNC VI: Arch Intern Med. 1997;157:2413-2446. Adapted with permission from Chobanian AV et al. Hypertension. 2003;42:1206-1252.

JNC Reclassification of BP Based on Risk ategory SBP (mm Hg) JNC VI DBP (mm Hg) Category JNC 7 SBP (mm Hg) 40 DBP (mm Hg) Optimal Normal Hi-normal <120 and 80 Normal <120 and 80 120-129 130-139 and 80-84 or 85-89 Prehypertension 120-139 or 80-89 Hypertension Stage 1 140-159 or 90-99 Stage 1 140-159 or 90-99 Stage 2 Stage 3 160-179 180 or or 100-109 110 Stage 2 160 or 100 Source for JNC VI: Arch Intern Med. 1997;157:2413-2446. Adapted with permission from Chobanian AV et al. Hypertension. 2003;42:1206-1252.

2013 ESH-ESC Guidelines for the management of Hypertension Evaluation of global CV risk Organ Damage 41

2013 ESH-ESC Guidelines for the management of Hypertension Evaluation of global CV risk Organ Damage 42

Is there a J curve for increased CV events? 43 CV events DBP

Is there a J curve for increased CV events? 44 CV events Do we really lower DBP or stiffening does it by itself??? DBP

BP-Lowering Treatment Trialists Comparisons of Different Active Treatments BP Difference (mm Hg) Relative Risk RR (95% CI) Major CV events ACEI vs D/BB CA vs D/BB ACEI vs CA CV mortality ACEI vs D/BB CA vs D/BB ACEI vs CA Total mortality ACEI vs D/BB CA vs D/BB ACEI vs CA 2/0 1/0 1/1 2/0 1/0 1/1 2/0 1/0 1/1 1.02 (0.98, 1.07) 1.04 (0.99, 1.08) 0.97 (0.95, 1.03) 1.03 (0.95, 1.11) 1.05 (0.97, 1.13) 1.03 (0.94, 1.13) 1.00 (0.95, 1.05) 0.99 (0.95, 1.04) 1.04 (0.98, 1.10) 0.5 Favors 1.0 Favors 2.0 First Listed Second Listed Blood Pressure Lowering Treatment Trialists Collaboration. Lancet. 2003;362:1527-1535. 45

BP-Lowering Treatment Trialists Comparisons of Different Active Treatments BP Difference (mm Hg) Relative Risk RR (95% CI) Major CV events ACEI vs D/BB CA vs D/BB ACEI vs CA CV mortality ACEI vs D/BB CA vs D/BB ACEI vs CA Total mortality ACEI vs D/BB CA vs D/BB ACEI vs CA 2/0 1/0 1/1 2/0 1/0 1/1 2/0 1/0 1/1 1.02 (0.98, 1.07) 1.04 (0.99, 1.08) 0.97 (0.95, 1.03) 1.03 (0.95, 1.11) 1.05 (0.97, 1.13) 1.03 (0.94, 1.13) 1.00 (0.95, 1.05) 0.99 (0.95, 1.04) 1.04 (0.98, 1.10) 0.5 Favors 1.0 Favors 2.0 First Listed Second Listed Blood Pressure Lowering Treatment Trialists Collaboration. Lancet. 2003;362:1527-1535. 46

Algorithm Hypertension type changes with age Arterial Stiffening Humoral contribution Ageing Determine the type of Ht Young, Humoral / / Elderly, Stiff Age Diastolic Pressure Pulse Pressure ISH/DSH/SDH Arterial Stiffness (PWV, Central P, Aug Index) Young subjects: Humoral factors Respond best to humoral blockers: ACE ARB -BB? Stiff Arteries Respond best to: -CCB s -Diuretics 47

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