Hypertension

Nani Hersunarti
Department of Cardiology and Vascular Medicine
Faculty of Medicine University of Indonesia
National Cardiovascular Center Harapan Kita

Pathogenesis of Hypertension
Excess sodium
intake

Reduced
Nephron number

Renal
Decreased Sympathetic
Sodium Filtration nervous
overactivity
retension surface

Fluid Volume

Stress

Genetic
Alteration

Endothelium
derived factors

Renin
Angiotensin
Excess
Cell membrane
alteration

Obesity

Hyperinsulinemia

Venous Constriction
Preload

Contractility

Functional Constriction

Structural 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

Cardiovascular Risk Factors

Modifiable

Non-modifiable

Diets high in fat, cholesterol, and/or calories

Age and gender

Smoking

Family history of CAD or other atherosclerotic

disease at early age
(<55 years men, <65 years women)

Excess alcohol consumption

Sedentary lifestyle and/or obesity
High blood pressure

Personal history of CAD or other atherosclerotic

disease

Raised LDL-cholesterol and triglyceride levels

Hyperglycaemia/diabetes
Thrombogenic factors
Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice.
Eur Heart J 2003; 24: 1601-10.

Hypertension Leads to Atherosclerosis

Local effects
(Prostaglandine, free
radicals, etc)

Hypertension

Endothelial damage

Systemic effects
(Renin-angiotensin,
catecholamine, vasopressin)

Platelet deposition
Mitogenic and migration
factors
Myointimal proliferation

Pressure natriuresis
Hypovolemia
Further increase in
vasopressors

Further rise in blood pressure

and Vascular damage
Dzau VJ. Hypertension. 2001;37:1047-1052

Progression of Atherosclerosis in
Hypertension
Alteration of endothelial function due to Hypertension
Deposition and oxidation of LDL; fatty streak formation
Thickening of arterial wall; remodeling of artery
Formation of fibrous cap over lipid core
Stable plaque

Unstable plaque

Increased growth

Plaque rupture

Stenosis

Thrombus/MI

Dzau VJ. Hypertension. 2001;37:1047-1052

Left Ventricular Hypertrophy : Molecular

FIBROBLASTS

MYOCYTES

Aldosterone

Ang II

Stretch (BP)

Corticoid receptor

Ang II
receptor

Mechano-receptors

Ang II

Intracellular Ca2+ signals

Intracellular Ca signals
2+

Genes for collagen

Genes for actin, myosin

INTERSTITIAL FIBROSIS

INTERSTITIAL FIBROSIS

Left ventricular hypertrophy

Abnormal stiffness left ventricular
Motz et al. Hypertension 1989;13:43-50
Weber et al. Circulation. 1991;83:1849-1865

The chain of events leading to end-stage heart disease

Myocardial
ischaemia

Coronary
thrombosis

Myocardial
infarction

Arrhythmias/
loss of muscle

Coronary artery
disease

Remodelling

Atherosclerosis
LVH

Ventricular
dilatation

Risk factors (cholesterol, high

blood pressure, diabetes,
insulin resistance)

Adapted from Dzau V, Braunwald E. Am Heart J 1991; 121: 1244-63.

Congestive heart
failure

End-stage heart
disease

The Progression from hypertension to heart

failure
LVH

Diastolic
dysfunction

Hypertension

CHF

MI

Death

Systolic
dysfunction

LV
Subclinical
Overt
Normal LV
Structure & Functionremodeling LV dysfunction Heart Failure
Time
(decades)
Vasan RS, Levy D. 1996. Arch Intern Med 156 : 1759-1796

Time
(months)

Patient Evaluation

Evaluation of patients with documented HTN has three

main objectives
1) Assess lifestyle and identify other CV risk factors or
concomitant disorders
2) Reveal identifiable causes of hypertension
3) Assess the presence or absence of target organ damage
and CVD

JNC VII. JAMA 2003;289:2560-2572

Patient Evaluation
Reveal identifiable causes of hypertension

Sleep Apnea
Drug-induced
Chronic kidney disease
Primary aldosteronism
Renal vascular disease

JNC VII. JAMA 2003;289:2560-2572

Chronic steroid therapy and

Cushings syndrome
Pheochromocytoma
Coarctation of the aorta
Thyroid or parathyroid
disorders

RISK STRATIFICATION AND TREATMENT

Blood Press
Stages (mmHg)

RISK GROUP A
No risk factors
TOD/CCD)

RISK GROUP B
(At least 1 Risk fc,
No including
Diabetes, No
TOD.CCD)

RISK GROUP C
(TOD/CCD and/or
Diabetes, with or without
Risk fc)

High normal
(130-139/85-89)

Life style modification

Life style
modification

Drugs therapy

Stages 1
(140-159/90-99)

Life style modification

(up to 12 months)
Drug therapy

Stages 2-3
(160/ 100)
JNC VII. JAMA 2003;289:2560-2572

Life style
Drugs therapy
modification (up to 6
months)
Drugs therapy

Drugs therapy

Lifestyle Modification
Modification

Approx. SBP reduction (mmHg)

Weight reduction/10 kg

5 10

Adopt DASH diet

8 14

Dietary Na+ restriction

28

Physical activity

49

Moderation of alcohol
consumption

24

http://hin.nhlbi.nih.gov/nhbpep_slds/menu.htm

Lifestyle Modification

Works best in motivated individuals

Initiate at prehypertension stage
Obesity risk for HTN and DM
If > 20% over ideal body weight (IBW) considered obese
IBW females = 100 lbs + 5 lb/every inch over 5
IBW females = 106 lbs + 6 lb/every inch over 5

3500 calories = 1lb

Decrease intake by 500 cal/day
Increase exercise and activity

JNC VII. JAMA 2003;289:2560-2572

Lifestyle Modification
Sodium restriction and other diet aids
Usual salt intake 10 gm/d = 4 gm Na+
Reduce to 2.4 gm Na+/day
Caution salt substitutes contain K+

Reducing alcohol consumption

Exercise/Activity
30-40 minutes 3-4x/wk, optimal 5x/wk
Stress reduction

JNC VII. JAMA 2003;289:2560-2572

Guideline recommendations for BP goals

ESH/ESC* and JNC 7** recommend the following BP goals:
<140/90mmHg for essential hypertension
<130/80mmHg for hypertensive patients with diabetes

Most patients with hypertension will require two or more antihypertensive agents
to achieve BP goal
The initiation of therapy with more than one drug increase the likelihood of
achieving BP, produces greater BP reduction at lower doses, resulting in fewer
side effects

*ESH/ESC: European Society of Hypertension/European Society of Cardiology

**JNC 7: Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, seventh report

Guidelines Committee. J Hypertens 2003; 21: 1011-53.

Chobanian AV, et al. JAMA 2003; 289: 2560-72.

Treatment initiation: WHO/ISH 1999

SBP 140-180 mmHg or DBP 90-110 mmHg on several occasions
(Grades 1 and 2 hypertension)
Assess other risk factors, TOD and ACC
Initiate lifestyle measures
Stratify absolute risk

Very high

High

Begin drug
treatment

Begin drug
treatment

Medium

Low
Monitor BP
and other risk
factors for
6-12 months

Monitor BP
and other risk
factors for
3-6 months
SBP 140 or
DBP 90
Begin drug
treatment

SBP, systolic blood pressure; DBP, diastolic blood pressure; TOD, target
organ damage; ACC, associated clinical conditions, including
cardiovascular disease and renal disease

SBP <140 or
DBP <90
Continue to
monitor

SBP 150 or
DBP 95
Begin drug
treatment

SBP <150 or
DBP <95
(borderline)
Continue to
monitor

1999 WHO/ISH Guidelines for the Management of Hypertension.

J Hypertens 1999;17:151-183

Clinical trial and guideline basis for compelling

indications for individual drug classes

JNC VII. JAMA 2003;289:2560-2572

European Society
Of Hypertension

Diuretic

Beta blocker

AT1 receptor
blocker

Alpha blocker

Calcium
antagonist

Possible combination
of different classes
of anti hypertension
drugs
Journal. Of Hypertension 2003

Most rational
combination

ACE inhibitor

Proven beneficial in trials

Causes of Resistant HTN

Improper BP measurement
Excess sodium intake
Inadequate diuretic therapy
Medication
Inadequate doses
Compliance
Drug interactions
OTC/herbals/dietary supplements
Excess alcohol intake
Identifiable causes of HTN

Promote Patient Compliance

Educate pt regarding proper use of medicine as well as disease
state
Include social support networks
Include the patient in decision making
Avoid drugs with numerous side effects
Simplify the drug regimen
Minimize the # of pills, frequency, and inconvenience

Provide positive reinforcement

Maintain continuity of care and avoid polypharmacy
Individualize treatment

Followup and Monitoring

Patients should return for follow up and adjustment of medications until the
BP goal is reached.
More frequent visits for stage 2 HTN or with complicating comorbid conditions.
Serum potassium and creatinine monitored 12 times per year.

JNC VII. JAMA 2003;289:2560-2572

Follow up and Monitoring

(continued)
After BP at goal and stable, follow up visits at 3- to 6-month intervals.
Low dose aspirin should be considered only when BP is controlled because
of the increased risk of hemorrhagic stroke when hypertension is not
controlled
Comorbidities, such as heart failure, associated diseases, such as
diabetes, and the need for laboratory tests influence the frequency
of visits.

JNC VII. JAMA 2003;289:2560-2572

Thank You

Additional Considerations in Antihypertensive

Drug Choices
Potential unfavorable effects
Thiazide diuretics should be used cautiously in gout or a history of significant
hyponatremia.
BBs should be generally avoided in patients with asthma, reactive airways
disease, or second- or third-degree heart block.
ACEIs and ARBs are contraindicated in pregnant women or those likely to
become pregnant.
ACEIs should not be used in individuals with a history of angioedema.
Aldosterone antagonists and potassium-sparing diuretics can cause
hyperkalemia.

Strategies for Improving Adherence to Regimens

Clinician empathy increases patient trust, motivation, and adherence to
therapy.
Physicians should consider their patients cultural beliefs and individual
attitudes in formulating therapy.

JNC VII. JAMA 2003;289:2560-2572

Follow-up and Monitoring

Patients should return for f/u as frequently as needed until BP is at
goal
More frequently for those with Stage II HTN or comorbid
conditions
Laboratory markers at least semi-annually
More often if necessary due to specific drug
After BP goal achieved continue f/u every 3-6 months
Continually monitor for side effects or adverse drug reactions

JNC VII. JAMA 2003;289:2560-2572

New NCEP ATP III LDL-C:Goals and Cut off points

Risk Category

LDL-C Goal

Initiate TLC

< 100mg/dL
(Optional goal: < 70 mg/dL)

100 mg/dL

100 mg/dl
(< 100 mg/dL: Consider drug
option)

Moderately high risk: 2+ risk

factors
(10 yr risk 10%-20%)

< 130 mg/dL

130 mg/dL

130 mg/dl
(< 100-129 mg/dL: Consider drug
option)

Moderate high risk: 2+ risk factors

(10 yr risk<10%)

< 130 mg/dL

130 mg/dL

160 mg/dL

Lower risk:
0-1 risk factor

< 160 mg/dL

160 mg/dL

190 mg/dL
(160-189 mg/dL: LDL lowering drug
optional)

High risk: CHD or CHD risk

equivalents
(10 yr risk >20%)

Consider Drug Therapy

NCEP=National Cholesterol Education Program; ATP III=Adult Treatment Panel III

Adapted from Grundy SM et al Circulation 2004;110:227239; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
JAMA 2001;285:24862497.

Changes to NCEP ATP III LDL-C Goals

Risk Category
CHD or CHD risk equivalents
(10-year risk >20%)

2+ risk factors
(10-year risk 20%)

Publication

LDL-C Goal

ATP III

<100 mg/dl (2.5 mmol/L)

Modification

Optional goal of <70 mg/dl (1.8 mmol/L)

ATP III

<130 mg/dl (3.4 mmol/L)

Modification

Optional goal of <100 mg/dl (2.5

mmol/L)
for 10%20% risk group

NCEP=National Cholesterol Education Program; ATP III=Adult Treatment Panel III

Adapted from Grundy SM et al Circulation 2004;110:227239; Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults JAMA 2001;285:24862497.

NCEP ATP III : LDL-C Goals (2004 Updates)

High Risk

LDL-C level

190

Lower

High Risk

Risk

Risk

2 risk

2 risk

< 2 risk

equivalents

factors

factors

factors

( 10-yr risk

( 10-yr risk

( 10-yr risk

>20% )

10-20% )

<10% )

Target

160
mg/dL

Target

100
mg/dL

100

Moderate

CHD or CHD risk

160

130

Moderately

Target

Target

130

130

mg/dL

mg/dL

or
optional

100
mg/dL**

or
optional

70

70

mg/dL*

* Therapeutic option in very high-risk patients and in patients with high TG, non-HDL-C<100 mg/dL;
** Therapeutic option; 70 mg/dL = 1.8 mmol/L; 100 mg/dL = 2.6 mmol/L;
130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L
Grundy SM et al. Circulation 2004; 110:227-239

Recent Trials for NCEP ATP III

HPS
Primary end point result
Simvastatin 40 mg vs placebo

Heart Protection Study

N=20,536
Implications for
NCEP guidelines
Optional lower LDL-C goal; statin therapy and the elderly

The majority of high-risk patients require intensive LDL-lowering therapy

Statin therapy should be initiated in all patients with both CVD and
diabetes, regardless of LDL-C baseline level, with a goal of < 70 mg/dL
Statin therapy is effective in persons 6580 years of age and should be
intensive in cases of established CVD

*The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Trial. Schwartz GG et al. JAMA. 2001;285:1711-1718.
Grundy SM et al. Circulation. 2004;110:227-239.

Recent Trials for NCEP ATP III

ASCOT-LLA
Primary end point result
Atorvastatin 10 mg vs
placebo

Anglo-Scandinavian Cardiac
Outcomes Trial Lipid
Lowering Arm

N=10,305
Implications for
NCEP guidelines
Statin therapy for moderately high-risk persons and the elderly

LDL-lowering drug therapy should be used in persons with a 10-year risk of

10% to 20% and LDL-C level of 100 to 129 mg/dL (2.63.3 mmol/L) at
baseline, to achieve an LDL-C goal of < 100 mg/dL
ASCOT supports the use of statin therapy in older, high-risk persons without
established CVD

*The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Trial. Schwartz GG et al. JAMA. 2001;285:1711-1718.
Grundy SM et al. Circulation. 2004;110:227-239.

Monitoring Drug Therapy

Example: Beta blocker
Therapeutic
Dependent on any presenting
symptoms

Subjective

Objective

BP and HR
Laboratory data

Toxic
Fatigue, Lethargy
Confusion
Depressed
Shortness of breath

BP, HR and RR
Depression Scale
Auscultation/PFT

Recent Trials for NCEP ATP III

PROSPER
Primary end point result
Pravastatin 40 mg vs placebo

Prospective Study of
Pravastatin in the Elderly at Risk

N=5,804
Implications for
NCEP guidelines
Statin therapy is effective in older, high-risk persons and should be
intensive in cases of established CVD

Statin therapy is effective in older, high-risk persons and should be

intensive in cases of established CVD

*The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Trial. Schwartz GG et al. JAMA. 2001;285:1711-1718.
Grundy SM et al. Circulation. 2004;110:227-239.

Anti atherosclerotic effect of ACE inhibition

Rationale

Anti-atherosclerotic effects

Plaque rupture reduction

Improvement in vascular endothelial function

Enhanced fibrinolysis

Modulation of neurohormonally-induced arterial

vasoconstriction

Blood pressure lowering

LV hypertrophy reduction

Angiotensin II reduction / bradykinin increase

Enhancement of
endothelial
NO production
Lipid
antioxidant
activity

Endothelial
Ca antagonist
Cell
Actions
Cytoprotection

Remodeling of
Atherosclerotic
Membrane
Structure
R.P. Mason. Atheroscleros 165 (2002)

Inhibition of
SMC
Migration and
Proliferation

Modulation of
ECM
Metabolism

The BHS recommendations for combining blood pressurelowering drugs

Older (eg 55 years)
or black

Younger (eg <55 years)

and non-black
Step 1

Step 2

Step 3

Step 4
Resistant
hypertension

A or B

C or D
A (or B)

C or D

Add: either alpha-blocker or spironolactone or other diuretic

A: ACE inhibitor or ARB

C: Calcium-channel blocker
BHS, British Hypertension Society; ACE, angiotensin-converting enzyme;
ARB, angiotensin II receptor blocker

B: Beta-blocker
D: Diuretic (thiazide)
Brown MJ, et al. J Hum Hypertens 2003;17:81-86

Hypertension treatment strategy: ESH/ESC 2003

Consider:
Untreated BP level
Presence or absence of TOD and risk factors
Choose between:
Two-drug combination
at low dose

Single agent
at low dose
If goal BP not achieved
Previous agent
at full dose

Switch to different
agent at low dose

Previous combination
at full dose

Add a third drug

at low dose

If goal BP not achieved

Two- to three-drug
combination
BP, blood pressure; TOD, target organ damage

Full-dose
monotherapy

Three-drug combination
at effective doses
ESH/ESC Guidelines 2003. J Hypertens 2003;21:1011-1053