Hypertension

is The Most Important Preventable Cause

of Premature death

The Benefits of Antihypertensive Drugs

For Prevention of CV Mortality & Morbidity
Are Well Established
Lancet 2002;360:1347-60
 Germany 6.6-13.1%

Bulgary 1,1% Japan 20% Canada 13%

Greece 27%
England 21%

USA 25-29%

Korea 4,7%
Mexico 2,3%
France 16,1-18,5%
Indonesia 817%

Taiwan 2-5% Brazil 21.7%

Spain 25.7-35%
China 1.2-4.1%
South Africa 14,8%

PREVALENSI HIPERTENSI
 Update in hypertension
Global mortality 2000: impact of hypertension
and other health risk factors

High blood pressure (BP)

Tobacco
High cholesterol
Underweight
Unsafe sex
High BMI
Physical inactivity
High-mortality, developing region
Alcohol Low-mortality, developing region
Indoor smoke from fuels Developed region
Iron deficiency
0 1000 2000 3000 4000 5000 6000 7000 8000
Attributable mortality
(In thousands; total 55,861,000)

Adapted from Ezzati et al, Lancet, 2002.

 Prevalence of Hypertension
Hypertension is one of the most frequent clinical discorders.

70
prevalence of hypertension (%)

SBP > 140 mm Hg 65

60 64
DBP > 90 mm Hg
50 54

40 44

30
20 21
10 4 11
0
age (yrs) 18-29 30-39 40-49 50-59 60-69 70-79 80+

Franklin, S.S., J Hypertens 1999; 17 (suppl 5): S29-S36

 Pathogenesis of Hypertension
Excess sodium Reduced Stress Genetic Endothelium Obesity
intake Nephron number Alteration derived factors
Renal Decreased Sympathetic Renin
Sodium Filtration nervous Angiotensin
retension surface overactivity Excess
Cell membrane Hyperinsulinemia
alteration
Fluid Volume Venous
Constriction

Preload Contractility Functional ConstrictionStructural Hypertrophy

Blood Pressure = Cardiac Output (CO) X Peripheral Resistance (PR)

Hypertension Increased CO and/or Increased PR
Autoregulation

Kaplan NM, Clinical Hypertension 7th ed. 2002; 63

 Endothelial Dysfunction and Cardiovascular Disease

CHF Reocclusion
Vasospasm
Thrombosis and coronary/cerebral
coagulopathies Hypertension

Diabetic Endothelial
Angiopathies Reperfusion Injury
dysfunction

Hyperlipidemia
Peripheral Artery
Atherosclerosis disease

Immune Reaction Inflammatory Disease

J Cardiovasc Pharmacol, Vol 22 (Suppl.4), 1993

 THE CARDIOVASCULAR
CONTINUUM
Myocardial Sudden Death
infarction
Coronary Arrhythmia &
thrombosis loss of muscle

Myocardial Remodelling
ischaemia
Ventricular
CAD dilatation
STROKE
Atherosclerosis Congestive
LVH heart failure

Risk factors Death

smoking, HYPERTENSION,
cholesterol, diabetes
 Arterial Blood Pressure
Physiologic Factor Physical Factor

BP = CO x PVR - Arterial
Blood Volume
- Arterial
- CO = Heart rate x
Compliance
Stroke volume
- Peripheral Resistance

Arterial Blood Pressure

 Hypertension
Left Ventricle Hypertrophy (LVH)

Myocardial Impaired Impaired Ventricular

ischemia contractility LV filling dysrhythmias

Myocardial Congestive Congestive Ventricle

Infarction Heart failure Heart failure fibrillation

Death
 Left Ventricular Hypertrophy
(Normal Hypertension) ( Cardiac Hypertrophy) ( Cardiac Dilation)

Pressure is applied to Dilated Image

myocardium Contractile function is
reduced by dilation of
cardiac cavities

Dilated Image
Fibrosis
Enlarged myocardium
Heart Disease
in Hypertension
A Normal human heart of 350 g in weight from a 35 years old man male.

Olivetti,G., et.al. Cardiovascular Research 45 (2000)

An Hypertrophied human heart of 850 g in weight from a 40 year old
hypertensive male.

Olivetti,G., et.al. Cardiovascular Research 45 (2000)

 Angiotensin II

Hypercholesterol
AT 1 receptor Hyperinsulinemia
Estrogen deficiency

Vasoconstriction Angiogenesis ROS
Neurohumoral activation


Blood pressure Growth Apoptosis Inflammation

Endothelial Fatty streak Advance
Plaque
plaque rupture
dysfunction
At h e r o s c l e r o s i s
Eur Heart J Suppl 2003;5(suppl A) A9 A13.
 Endothelial Dysfunction and Cardiovascular Disease

CHF Reocclusion
Vasospasm
Thrombosis and coronary/cerebral
coagulopathies Hypertension

Diabetic Endothelial
Angiopathies Reperfusion Injury
dysfunction

Hyperlipidemia Peripheral Artery

Atherosclerosis disease

Immune Reaction Inflammatory Disease

J Cardiovasc Pharmacol, Vol 22 (Suppl.4), 1993

 Atherosclerosis
Atherosclerosis is an inflammatory disease of vascular
wall initiated and amplified by vascular oxidative stress
The important potential sources of oxidative stress in
vascular tissue are :
oxidized low-density lipoprotein (oxLDL)
nicotinamide adenine dinucleotide phosphate
(NADPH) oxidases, which produce superoxide
anion ( O2o ) : AngiotensinII induces mRNA
expression and NADPH Oxidase Superoxide
generation (Hypertension 1998;32:331-337)

Am J Cardiol 2001;87(suppl):25c-32c
 Atherosclerosis: A Progressive
Disease Plaque rupture

Adhesion Macrophage
Oxidized
Monocyte LDL-C molecule
LDL-C
Foam cell
CRP

Smooth muscle
cells

Endothelial Plaque instability

Inflammation Oxidation
dysfunction and thrombus

CRP=C-reactive protein; LDL-C=low-density lipoprotein cholesterol.

Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126.
Film Atherosclerosis
 The Aim of Treatment for
Hypertension

Prevention or to decrease
Myocardial infarction
Heart failure
Cerebro Vascular Desease
Aorta disease
Pheriperal Vascular disease
End Stage Renal Disease
Complication of Hypertension (1)

Hypertensive complication;
Accelerated malignant hypertension
Encephalopathy
Cerebral hemorrhage
Left ventricular hypertrophy
Congestive heart failure
Renal insufficiency
Aortic dissection
Complication of Hypertension (2)

Atherosclerotic complication;
Cerebral hemorrhage
Myocardial infarction
Coronary artery disease
Claudication syndromes
 Control of Blood Pressure and
Antihypertensive Sites of Action
BP is controlled
via changes in Sympathetic
Cardiac output Stimulation
Vasomotor tone
Plasma volume 1 3

Sympathetic Heart
Stimulation

Postcapillary Venules 1 -Blockers

12 (Capacitance Vessels)
1-Blockers
Sympathetic
Precapillary Arteriole 2
Stimulation
(Resistance Vessels) Vasodilators
1 3
Renin 12 ACE Inhibitors
4 Activates AT1-RA
Angiotensin
3 Sympathetic 4
Activates
3 Stimulation Diuretics
Kidney Aldosterone
Athero thrombosis: the major cause of TIA & ischaemic stroke

25%

30% - 75%

20%

20%
Cardiovascular events in men with high-normal blood pressure
 Hypertension

How to manage?
 JNC BP Classification : DBP
130

125 Stage 4
Severe Severe Severe
120 Stage 3 Stage 2
Hyper-
tensive
115 Stage 3

110 Moderate Moderate Moderate

DBP
( mmHg ) 105 Stage 2 Stage 2

100
Consider
Mild Mild Mild
therapy
95 Stage 1 Stage 1 Stage 1

90
High High High High
Normal Normal Normal Normal Prehyper
85
tension
Normal Normal Normal Normal
80
Optimal Optimal Normal

JNC I JNC II JNC III JNC IV JNC V JNC VI JNC VII

JNC I. JAMA. 1977;237:255-261 JNC IV. Arch Intern Med. 1988;148:1023-1038

JNC II. Arch Intern Med. 1980;140:1280-1285 JNC V. Arch Intern Med. 1993;153:154-183
JNC III. Arch Intern Med. 1984;144:1047-1057 JNC VI. Arch Intern Med. 1997;157:2413-2466
 JNC BP Classification : SBP
220
Stage 4
210

200 Stage 3
Stage 3
190 Stage 2
ISH ISH

180

SBP 170 Stage 2 Stage 2

( mmHg )
160

150 Borderline Borderline Stage 1 Stage 1 Stage 1

140
High High
No recommendations normal normal Prehyper
130 For SBP in JNC I tension
Or JNC II Normal Normal
120 Normal

110
Optimal Optimal Normal

JNC I JNC II JNC III JNC IV JNC V JNC VI JNC VII

JNC I. JAMA. 1977;237:255-261 JNC IV. Arch Intern Med. 1988;148:1023-1038
JNC II. Arch Intern Med. 1980;140:1280-1285 JNC V. Arch Intern Med. 1993;153:154-183
JNC III. Arch Intern Med. 1984;144:1047-1057 JNC VI. Arch Intern Med. 1997;157:2413-2466
 Important messages for the
management of Hypertension

Assess the risk

Treat to target
Lifestyle
Combination therapy
Pharmacotherapy
Compliance
ASSESS THE RISK
 Diabetes?
Chronic kidney disease?
Stroke?
High coronary disease risk?
Heart failure?
Post myocardial infarction?

NO YES

Treatment in the
Individualized
absence of specific
treatment
indication
TREAT TO TARGET
 CLASSIFICATION OF BLOOD PRESSURE
FOR ADULTS AGE 18 AND OLDER

Category Systolic (mm Hg) Diastolic (mm Hg)

Optimal < 120 and < 80

Normal < 130 and < 85
High normal 130 - 139 or 85 - 89
Hypertension
Stage 1 140 - 159 or 90 - 99
Stage 2 160 - 179 or 100 - 109
Stage 3 > 180 or > 110

JNC-V :
Stage 4 > 210 > 120
 JNC VII: Classification of blood pressure

Blood pressure Systolic BP Diastolic BP

classification (mm Hg) (mm Hg)
Normal <120 <80
and
Prehypertension 120-139 80-89
or

Stage 1 140-159 90-99

hypertension or
Stage 2 >160 >100
hypertension or

The JNC VII. JAMA 2003;289:2560-72

 BLOOD PRESSURE CONTROL

GOAL

Less than 140/90 mm Hg

or
Less than 130/80 mm Hg
(diabetes)
or
Less than 125/75 mm Hg
(protein uria >1g/day)
1999 WHO/ISH Hypertension Guidelines. J Hypertens 1999;17:151-183
ADA Position Statement. Diabetes Care 2002;25:S33-S49
 MORE INTENSIVE VS LESS INTENSIVE STRATEGIES

Number of patients Study

More intensive Less intensive
ABCD, UKPDS, HOT
7257 13151
Coronary heart disease RR 0.81 (0.67-0.98)

Stroke RR 0.80 (0.65-0.98)

Heart failure RR 0.78 (0.53-1.15)

Major cardiovascular events RR 0.85 (0.76-0.96)

Cardiovascular death RR 0.90 (0.75-1.09)

0.5 1.0 2.0

Favour Favour
Blood Pressure Lowering Treatment Trialist
more intensive less intensive
Collaboration. Lancet 2000;355:1955-64
LIFESTYLE MODIFICATION
Lifestyle Recommendations for Hypertension

Healthy diet:
High in fresh fruits, vegetables and low fat
dairy products, low in saturated fat and salt
Regular physical activity:
optimum 45-60 minutes of moderate
cardiorespiratory activity 4-5/week

Reduction in alcohol consumption

in those who drink excessively (<2 drinks/ day)
Weight loss (> 5 Kg)
in those who are over weight (BMI>25)

Smoke free environment

2003 Canadian Hypertension Education Program Recommendations.

PHARMACOTHERAPY
 Profile of an Ideal Combination
Antihypertensive Product

Scientific rationale and complimentary mechanisms of

action
Simple pharmacokinetics profiles
Maintains 24-hr BP control
Placebo-like tolerability
Superior to existing monotherapies
Work independent of special population status
Effect beyond BP reduction

Cardilogy
Treatment Algorithm for Adults with Systolic-Diastolic
Hypertension without another compelling indication

TARGET <140/90 mmHg

INITIAL TREATMENT AND MONOTHERAPY

Lifestyle modification
therapy

Long-acting Beta-
Thiazide ACE-I ARB DHP-CCB blocker

Alpha-blocker
as initial
monotherapy

2003 Canadian Hypertension Education Program Recommendations.

COMPLIANCE
 Recommendations for Improving Adherence to
Antihypertensive Prescription

Adherence can be improved by a multi-pronged approach

Simplify medication regimens to once daily dosing
Tailor pill-taking to fit patients daily habits
Encourage greater patient responsibility/ autonomy in
monitoring their BP management (including monitoring)
Educate patients and patients families about their
disease/treatment regimens

2003 Canadian Hypertension Education Program Recommendations.

 Additional suggestions for improving adherence to
antihypertensive prescription

Ask about side effects and record any that occur

Tailor pill taking into a usual daily routine (same time/place/situation)
Simplify drug and lifestyle regime
Ensure regime is affordable
Involve family and friends in lifestyle and medication adherence
Maintain regular BP follow-up
Consider self measurement of blood pressure

2003 Canadian Hypertension Education Program Recommendations.

 CONCLUSION
Regarding the treatment of hypertension,
the recommendations endorse:
Lifestyle modification (alone if effective to reach
the goal value)

Individualizing therapy

Treating to target BP

Using combination therapy

Promoting adherence