New Strategies of

Antihypertensive Drug Therapy,

in Particular in Relation to Central vs. Brachial BP

MeasurmentKim Eung Ju

Korea University Guro Hospital Cardiovascular Center

Seoul, Korea

Pathophysiological Significance of

Central Pressures

Central BP may Have

Predictive Value Independent of the

Corresponding Peripheral BP

Central Aorta

Systolic pr : a measure of cardiac afterload

Diastolic pr : a determinant of coronary perfusion

↑ Central PP has 2 components:

(1) ↑ SBP, a measure of cardiac afterload

(2) ↓ DBP (with the ↑ SBP), a measure of V-A stiffening

Components of Left Ventricular Load

3 components of LV load at theAscending aorta:

static component

1. Resistance

cyclic component

2. Stiffness

3. Wave reflection

- incident wave

- reflected wave

- reflected point

(distance from heart)

Reflection

Resistance

Stiffness

Adapted from WW Nichols.

Pulse Wave Amplification

(mmHg)

150

100

50

There is a progressive increase in SBP & PP, but a relatively constantDBP & MAP, as the pulse wave propagates distally along the arterial tree.

Cause of peripheral amplification: incident wave travels throughprogressively stiffer arteries and reflected wave in phase with the incidentwave, and thus reinforces it.

Remington. J Appl Physiol. 1956;9:433

Pulse Wave Amplification

(mmHg)

150

100

50

As central augmentation increases, secondary to increased arterialstiffness, peripheral amplification decreases.

↑Central PP

: more accurately reflect loading conditions of the LV myocardium,coronary arteries, & cerebral vasculature

: better relate to CV target organ damage and to CV events than brachialpressures

Remington. J Appl Physiol. 1956;9:433

Men Women

Normal Vascular Aging: Differential Effects

on Wave Reflection and Aortic PWV

The Anglo-Cardiff Collaborative Trial (ACCT) J Am Coll Cardiol 2005;46:1753– 60

Central SBP

N=4,001, Healthy normotensives

Distribution of Hypertension Subtype in the Untreated

Hypertensive Population by Age (NHANES III)

Franklin et al. Hypertension 2001;37:869–874

ISH (SBP≥140 mmHg and DBP<90mmHg)

SDH (SBP≥140 mmHg and DBP≥90mmHg)

IDH (SBP<140 mmHg and DBP≥90mmHg)

Numbers at top of bars represent the overall %

distribution of untreated hypertension by age

17% 16% 16% 20% 20% 11%100

80

60

40

20

0<40 40-49 50-59 60-69 70-79 80+

Frequency of

hypertension

subtypes in all

untreated

hypertensives (%)

Age, yr

Difference Between SBP and DBP in CHD Prediction,

as a Function of Age* (Framingham Heart Study)

Franklin et al. Circulation. 2001;103:1245-1249

Age (yr)

*Ages 20 to 79

Adjusted for age, sex & other risk factors

ß(S

BP

) -

ß(D

BP

)

ß(SBP) - ß(DBP)=1.49 + 0.029*age

( p=0.008)

+Favor

SBP

Favor

DBP

The age-related change in brachial BP indices that predict CV risk is evidence

for ↑ arterial stiffening and ↓ pressure amplification.

SBP

Epidemiological Evidence for Wave Reflection

as the 3rd Component of Cardiac Load

The heart only “sees” peak SBP at the ascending aorta

HeartLV -

Afterload

Ascend.

Aorta Peak SBP

Brachial Artery BPAge < 40 (IDH)

Age 40-49 (SDH)

Age ≥ 50-59 (ISH)

As arteries stiffen and wave amplification decreases with aging,

there is a gradual shift from DBP to SBP and eventually to PP as

predictors of CV risk.

Elements of Cardiovascular Risk

Central BP : 160/90 vs. 160/70

Increased central SBP = marker of cardiac afterload

(resistance + stiffness + reflection)

Decreased central DBP (contributing to ↑ PP) = marker

of ↑ ventricular-vascular stiffening, LVH & ↓LV

relaxation (“Stiffening disease” of heart & thoracic

aorta)

Therefore, the combination of ↑ cardiac afterload

presented to compromised LV (unable to handle the

load) leads to diastolic dysfunction & heart failure.Kass DA. Hypertension.2005;46:185-193.

Importance of Central Pressure:

Recent Clinical Findings

Central Pressures and Central Indices as

Markers and Predictors of Disease

Central hemodynamic variables have been

shown to be independently associated with

organ damage, incident cardiovascular

disease, and events both in the general

population and in various disease states.

Cross-Sectional and Longitudinal Studies Indicating the

Independent Value of Central Hemodynamics

as Markers of Disease and

Predictors of Surrogate CV End Points

Longitudinal Studies Indicating the Independent

Value of Central Hemodynamics

as Predictors of Events

Agabiti-Rosei et al. Hypertension. 2007;50:154-160.

Central BP More Strongly Relates to Vascular

Disease Than Does Peripheral BP:

The Strong Heart Study

Roman et al. Hypertension. 2007;50:197-203.

N=3520

Population-based

Cross-sectional study

Central BP Better Predicts CV Events

Than Does Peripheral BP:

The Strong Heart Study

Roman et al. Hypertension. 2007;50:197-203.

N=2403

Population-based

Longitudinal study (4.8 yr)

Total Cardiovascular Events and Procedures

ASCOT-BPLA Study

ASCOT-BPLA. Lancet 2005; 366: 895–906.

N=19,257 HTN

multicentre, prospective,

randomised controlled trial

mean follow-up 5.4 yr

HR=0.84 (95% CI 0.78-0.90),

p<0.0001

Atenolol ± thiazide

Amlodipine ± perindopril

Brachial and Central Aortic Systolic

Blood Pressure in the CAFÉ Study

115

120

125

130

135

140

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 AUC

133.9

133.2

125.5

P=.07

121.2

P<.0001

Amlodipine ± perindopril

Atenolol ± thiazide

mm

Hg

Brachial SBP

Diff Mean (AUC)= 0.7(-0.4,1.7)mm Hg

Central SBP

Diff Mean (AUC) =4.3(3.3,5.4) mm Hg

Time (Years)

Atenolol 86 243 324 356 445 372 462 270 339 128 85 1031

Amlodipine 88 248 329 369 475 406 508 278 390 126 101 1042

Time (Years)

Atenolol 86 243 324 356 445 372 462 270 339 128 85 1031

Amlodipine 88 248 329 369 475 406 508 278 390 126 101 1042

38

43

48

53

58

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6

mm

Hg

AUC

56.2

55.3

46.4

P=.06

43.4

P<.0001

Brachial PP

Diff Mean (AUC)= -0.9 (-1.9,0)mm Hg

Central PP

Diff Mean (AUC) =3(2.1, 3.9) mm Hg

Brachial and Central Aortic Pulse Pressure

in the CAFÉ Study

Amlodipine ± perindopril

Atenolol ± thiazide

Updated Cox proportional hazard model for the composite endpoint,

adjusted for age and baseline risk factors

Factor X2 P HR CI

Peripheral PP 3.83 0.050 1.10 1.00-1.22

Central PP 3.91 0.048 1.11 1.00-1.23

Augmentation 2.26 0.133 1.14 0.96-1.36

P1 height 3.04 0.081 1.17 0.98-1.40

Impact of Blood Pressure and

Central Aortic Hemodynamics on Clinical Outcomes

in the CAFÉ Study (Hazard/10 mm Hg)

CAFÉ study. Circulation. 2006;113:1213-1225.

Implications of Central BP Findings in

SHS & ASCOT

Noninvasively determined central BP predicted outcomesmore strongly than brachial BP in both studies.

The ASCOT (CAFÉ) results demonstrate that brachialBP is not always a good surrogate for the effect of BP–lowering drugs on arterial hemodynamics.

The ASCOT (CAFÉ) study suggests a mechanism bywhich different drug treatments in hypertension trialscould differentially affect central aortic pressures andthus clinical outcomes beyond brachial BP.

Effect of Different Antihypertensive

Drug Classes on Central Aortic Pressure

Morgan et al. Am J Hypertens 2004;17:118–123

Double-blind

crossover study

q 4wk

N=32

PERIN 4, 8mg or ENALA

20, 40mg

ATEN 25, 50mg

FELO or AMLO 5, 10mg

HCTZ 25, 50mgB = Brachial

A = Aortic

Review of Other Tirals

Benefit in terms of outcome in spite of little or no

difference of BP between groups.

HOPE : Ramipril vs Placebo

LIFE : Losartan vs Atenolol

ANBP2 : ACEi-based vs Diuretic-based regimen

These potential effects “beyond BP control” are perhaps

accounted for by protective properties of different drugs

that affect subclinical organ damage or intermediate end

points, such as arterial properties or central BP.

Thank you for your

attention !