Systemic

hypertension

Assoc Prof Serban Balanescu, MD

Mancia G et al. Eur Heart J 2013;34:2159-2219.
 Major CV disease is related to systemic
hypertension
- Framingham Study; mean FU - 36 years -

Coronary Stroke Peripheral Heart failure

45
disease artery
disease
40
(incidence per 1000)

35

30
Normotensive
CV Risk

Hypertensive
25

20

15

10

men Women Men Women Men Women Men Women

Kannel WB. Eur Heart J 1992;13 (suppl G).

 Risk of MACE occurs when BP > 120/80 mmHg
Cummulated rate of AMI, stroke, heart failure or CV death
Womens Health Initiative trial (n = 60.785)

OR = 2.89; Hypertension: BP > 140/90 mmHg

CI 95%: 2.52 3.32 (n = 21.187)

OR: 1.66; Borderline: BP between 120/80 si 139/89 mmHg

CI 95%: 1.44 1.92 (n = 23.596)

Normotensive: BP < 120/80 mmHg

(n = 16.002)

Hsia J et al. Circulation 2007;115:855-60.

 CV risk depends on both systolic and diastolic BP
Meta-analysis of 61 prospective studies; n = 1 million pts.
BP > 115 / 75 mmHg increases CV risk; BP with every 20/10 mmHg doubles CV risk

Lewington S et al for the Prospective Studies Collaboration. Lancet. 2002;360:1903-13.

 HT classification depending on BP measures

Mancia G et al. Eur Heart J 2013;34:2159-2219.

 Epidemiology facts
The most frequent chronic disease in SUA

The first reason for medical visit

Highest number of drug prescriptions

major risk factor for stroke and coronary disease

The first risk factor for CV death in the world

60 million people in USA; more than 1 billion people in the world

Only about one third of patients have controlled BP according to their CV risk

Although incidence of CAD and stroke is reduced in the last 20 years, incidence of heart

failure and chronic renal disease increases

estimated costs for high BP treatment in USA in 2008: 69.4 billion USD *

Chobanian AV et al. JNC VII. JAMA 2003;289:2560-72. * Rosamond W et al. Heart Disease and Stroke Statistics 2008 Update. Circulation 2007;117
 Prevalence of high BP in the world
DBP 90 and/or SBP 140 or controlled with anti-hypertensive drugs.

Germany1
Finland1
Spain1
England1
Sweden1
Romania4 40.1%
Italy1
Japan2
Egypt3
USA1
Canada1
South Corea3
Taiwan3
0 10 20 30 40 50 60 70
Prevalence (%)

1. Wolf-Maier K, et al. JAMA. 2003;289:2363-2369.

2. Data on file. Pfizer Inc, New York, NY.
3. Risk factor data for hypertension. WHO Collaborating Centre on Surveillance of Cardiovascular Disease Web site. Disponibil la: www.cvdinfobase.ca.
4. Dorobantu M et al. Rev Rom Cardiol 2006;21:179-89.
 Mortality distribution determined by the
main ten CV risk factors

High BP
Smoking
Dyslipidemia
Underweight
Unprotected sex
Low input of vegetables/fruits
BMI Mortality in undeveloped countries
Sedentary lifestyle Mortality in emerging economies
Alcohol abuse Developed countries
Lack of hygiene

0 1 2 3 4 5 6 7 8

Attributable mortality in millions (total 55.9 millions)

The World Health Report 2002: reducing risks, promoting healthy life. Geneva, Switzerland: World Health Organization; 2002.
 Causes of systemic HT
Primary hypertension Secondary hypertension:
> 95% of HT patients Chronic renal disease (CKD):
Renal disease: ex: CGN, all renal chronic failure
Reno-vascular

Endocrine:
primary hyperaldosteronism

Deoxycorticosterone excess
Cushing Sdr
Pheocromocytoma

Acromegaly
Hyperthyroidism
Hyper-parathyroidism

Congenital disease :
Coarctation of the aorta

In women:
Oral contraceptives
Pregnancy HT: eclampsia and pre-eclampsia
 Pathophysiology of primary HT
Na Nephron Stress Genetic Obesity Endothelial
excess number factors dysfunction

Renal Sympathetic Excess of Alterare Hiper-

Na retention hyperactivity renin ald. membrana cel. insulinism

Hyper- Venous
Fumat
volemia constriction

Preload contractility Vasoconstriction Hypertrophy

Blood pressure = CARDIAC OUTPUT x VASCULAR RESISTANCE

High blood pressure = Cardiac output and / or Vascular resistance

Kaplan NM. In Clinical Hypertension. 7th ed. 1998;p 45.

 HT Role of genetic factors
genes load the gun, but environmental factors pull the trigger

Contribution genetic f.
gene mutations implicated in HT:

Glucocorticoid receptor

angiotensinogen

Lipoprotein-lipase: insulin resistance

Contribution aquired RF
rare monogenic mutations:

18 HO steroids

mineralocorticoids

Congenital bilateral adrenal hyperplasia

polycystic renal disease

Contribution genetic + aquired RF
Liddle sdr, Gitelman sdr (hipo K+)

BP determining factors in general population

Vascular mechanisms: endothelial dysfunction

Vasoconstriction: Vasodilatation:
Angiotensin II - ACE NO (EDRF)
Endothelin Prostacyclin
Plasma cathecolamines Bradykinin
Thromboxane Ach
 Hormonal mechanisms: RAAS

Plasma RAAS: ~ 10% of total RAAS activity; 90% tissue RAAS activity
 Tissue RAAS:
~ 90% of total RAAS activity

Tissue ACE: local activation implicated in target organ damage in HT:

myocardium, vessels and kidney.
Dzau VJ et al. Am J Cardiol 2001;88(suppl):1L-20L.
 Effect of HT and transmural pressure
gradient on development of AS
Transmural pressure

Penetration - Endothelial SMC effects

retention of Effects
lipoproteins

NO Endothelin Proliferation

Accelerated
atherosclerosis
Rakugi H et al. Am Heart J 1996;132:213-221.
 Clinical examination of the HT patient
History Clinical exam
HT duration; highest BP BP measurement

Identify secondary HT Signs for secondary HT

Risk factors for CVD Ex: goitre in hyperthyroidism, Cushing sdr

Symptoms for target organ disease Signs for target organ disease

anti HT treatment Assess abdominal obesity and

Classes of medication metabolic sdr

Efficacy

Adverse reactions, tolerance, persistence

heredo-collateral history

Mancia G et al. Eur Heart J 2007;28:1462-536.

 Ambulatory BP monitoring (ABPM) and
home BP measurement
ABPM per 24h Home BP
May improve diagnostic assessment in Home self measurements
treated pts Purpose:
Indications: To assess medication effect at trough
To improve treatment adherence
High BP variability at the office measures
High office BP in pts with low CV risk Not useful if it induces:
Major difference between office BP and home Anxious reactions

BP Self administration of drugs

Resistant HT Normal BP considered lower than

Suspicion of orthostatic hypotension office BP: < 130-135 / 85 mmHg
Sleep apnoea sdr
Increased BP in pregnancy with suspicion of
preeclampsia

Mean normal values: < 125-130/80

mmHg; on day time < 130-135/85
Mancia G et al. Eur Heart J 2007;28:1462-536.
ABPM in a female patient with HT
ABPM 6 weeks after treatment
 Hypertension is frequently associated to other
CV risk factors

Insulin resistance

Obesity (BMI >30)

Cholesterol >240 mg/dL

Smoking

LVH by echo

Sedentary lifestyle

HDL-C <40 mg/dL

Diabetes mellitus

0 10 20 30 40 50 60

Prevalence (%)
Kaplan N. Am J Cardiol 1995;76:595-597.
 Identifying subclinical organ damage

Heart: Kidney:
Standard ECG: LVH criteria Reduction of glomerular filtration rate

Echocardiography: LVH, diastolic (GFR): Cockroft Gault or MDRD formulas

dysfunction Microalbuminuria or frank proteinuria

(qualitative and quantitative measures)

Peripheral arteries:
carotid Doppler for intima-media thickness Brain:
and asymptomatic AS plaques Funduscopic exam in severe HT

Pulse wave velocity in systolic HT hemorrhage, exsudate, papillary edema:

high CV risk
Ankle brachial index
MRI or CT: silent cerebral infarcts,

ischemic lacunar areas, microhemorrhage

in amyloidosis
Mancia G et al. Eur Heart J 2007;28:1462-536.
concentric LVH: worst progosis
LVH by echo and ECG

Diastolic dysfunction: E < A

 MAVI: LVH prognostic value
N = 1033 HT pts; mean BP = 154/92 mmHg; mean FU 3 years.
Adverse CV events: AMI, stroke, CV death, heart failure or kidney failure.

LVH by echocardiography
Verdecchia P et al. JACC 2001;38:1829-35.
LVH reduction lowers CV mortality in primary HT

N = 941 pts with baseline LVH on ECG in LIFE study; mean FU = 4.8 years;
LVH reduction assessed by echocardiography

RR 28%;
RR 38%; P = 0.002
P = 0.001

RR 22%;
P = 0.009

combined endpoint: CV death or MI or stroke

Devereux RB et al. JAMA 2004;292:2350-6.

 Microalbuminuria increases mortality in treated
HT patients
adjusted relative risk for mortality (95% CI)

0 0.55

0.56 0.85
M
0.86 1.69
Albumin / creatinin

RR = 1.6
ratio (mg / mmol)

1.70 CI 95% = 1.0 2.6

p = 0.009
0 0.55

0.56 0.85
F
0.86 1.69

1.70

0.0 1.0 2.0 3.0

Romundstad S et al. Circulation 2003;108:2783-9.

 Carotid intima media thickness

Measures media thickness IMT normal values:

Marker of early AS Age <30 30 - 50 >50
Normal value: 0.36 0.9 in adults
Women <0,50 <0,65 <0,70
IMT of M > F at same age
Males <0,55 <0,70 <0,80
Constant age increase 0.08 mm/year

Correlated with AS risk factors

COMMON
Strong prognostic value for AMI and
CAROTID
stroke
Distant
Marker for efficacy of anti-AS wall

medication
 Availability, prognostic value and costs of some
investigations used to stratify risk in HT
Method Prognostic value Availability Cost

Standard ECG ++ ++++ +

Echocardiography +++ +++ ++

Carotid intima/media +++ +++ ++

thickness
Ankle-brachial index ++ ++ +

Coronary calcium score (CT) + + ++++

Endothelial dysfunction ++ + +++

Cerebral lacunar lesions ? ++ ++++

(CT)
Creatinin clearance +++ ++++ +

Microalbuminuria +++ ++++

Mancia G et al. 2007 Guidelines for the management of arterial hypertension. Eur Heart J 2007;28:1462-536.
+
 Clinical variables use for risk stratification

Mancia G et al. Eur Heart J 2013;34:2159-219.

 Europe: risk for fatal cardiovascular
disease at 10 year in high-risk countries

High risk defined by the

risk of fatal CVD at 10
years 5%

Used in European countries

with the exception of those at
low risk (Belgium, France,
Greece, Italy, Luxembourg,
Spain, Switzerland, Portugal)

Catapano AL et al. Eur Heart J 2016;37:2999-3058.

Mancia G et al. Eur Heart J 2013;34:2159-219.
 Variables used for risk stratification

Mancia G et al. Eur Heart J 2013;34:2159-219.

 Variables used for risk stratification

Mancia G et al. Eur Heart J 2013;34:2159-219.

 Variables used for risk stratification

Mancia G et al. Eur Heart J 2013;34:2159-219.

 Variables used for risk stratification

Mancia G et al. Eur Heart J 2013;34:2159-219.

 The main complications of HT

Renal disease: STROKE:

prevalence proportional with BP 80% ischemic, 20% hemorrhagic

level prevalence proportional with BP

correlated with risk CV death level, stronger than for CAD

accelerates ahterogenesis 60% of pts with stroke have HT

increasing incidence vs CAD and The highest risk for stroke in HT:

stroke between 40 50 years (x4)

acute increase of BP after stroke
HT treatment lowers stroke
incidence with 35 40%

Heart Failure:
continuous increase in incidence vs CAD and stroke
Incidence is 2 x higher in M and 3 x higher in F with HT
90% of pts with HF have had HT
50% of HT pts with HF have diastolic HF
Treatment of systemic HT
 Non-pharmacological intervention or lifestyle changes
To be recommended in all patients:
Including those on medication

First therapeutic intervention in pts with high normal BP to reduce risk to develop full-

blown high BP

Well known interventions to reduce BP and CV risk:

Abstinence from smoking

Body weight reduction

Excessive alcohol consumption

Moderate intensity physical exercise for at least 30 min / day at least 6 days /week

Low salt diet

Increased raw vegetables and fruit consumption; reduce fat ingestion (mainly non-saturated)

Needs professional help and frequent check-up (ex stop smoking) + regular advice

Long term compliance may be low and effect on BP is variable

Close FU and prompt medical treatment may be necessary, if no effect on BP

Mancia G et al. Eur Heart J 2007;28:1462-536.

 The main anti-hypertensive medication
classes

Opie LH, Gersh BJ. Drugs for the Heart. 6th ed, 2005;185.
 Treatment associations between different
anti-HT medication classes
Thiazides

Beta blockers AT1 blockers

Alpha blockers Ca channel

blockers

ACE inhibitors
Recommended association

Possible association
Mancia G et al. Eur Heart J 2007;28:1462-536.
 Generic treatment methods in systemic HT

NHS NICE Clinical Guideline 34 - 2006. Management of hypertension in adults in primary care.
Downloaded from: http://guidance.nice.org.uk/CG34/quickrefguide/pdf/English/download.dspx
 Number of drugs used to control BP in
ALLHAT
1 drug 2 drugs 3 drugs % controlled
<140/90 mm Hg
100

80
% patients

60

40

20

0
Baseline 6 months 1 year 3 years 5 years

Cushman et al. J Clin Hypertens 2002;4:393-404.

Proof of efficiency for anti-HT medication
All medications are efficient to lower HT complications vs placebo

comparative trials between different classes could NOT demonstrate that for the same
reduction of BP different reduction of HT complications can be obtained

favourable effects independent from BP reduction (to reduce stroke, heart failure, and
coronary disease) were obtained with some medication classes:
Effects are lower than simple BP reduction per se

favourable effects independent form BP reduction appear early to prevent subclinical target
organ damage, appearance of DM, CKD or atrial fibrillation

Purposes for ANTI HTA medication

Main purpose: long term maximal reduction of CV risk

Supposes BP reduction and other RF control

Non diabetic pts: BP < 140 / 90 mmHg or lower, if tolerated

Diabetics and others with very high CV risk (stroke, MI, CKD, proteinuria): BP 130/80 mmHg
 BP treatment lowers risk for MACE
- Meta analysis of 29 studies; n = 162.341 -

Studies Events / nr pts BP difference Relative risk

(Mean, mm Hg) (95% CI) p
Stroke
ACEI vs placebo 5 473/9111 660/9118 -5/-2 0.72 (0.64-0.81) .33
Ca bloc vs placebo 4 76/3794 119/3688 -8/-4 0.62 (0.47-0.82) .90

Coronary disease
ACEI vs placebo 5 667/9111 834/9118 -5/-2 0.80 (0.73-0.88) .91
Ca bloc vs placebo 4 125/3794 156/3688 -8/-4 0.78 (0.62-0.99) .34

CV events
ACEI vs placebo 5 1283/9111 1648/9118 -5/-2 0.78 (0.73-0.83) .42
Ca bloc vs placebo 3 280/3382 337/3274 -8/-4 0.82 (0.71-0.95) .54

CV death
ACEI vs placebo 5 488/9111 614/9118 -5/-2 0.80 (0.71-0.89) .29
Ca bloc vs placebo 4 107/3382 135/3274 -8/-4 0.78 (0.61-1.00) .43

0.5 0.8 1.0 2.0

Turnbull F for the Blood Pressure Lowering Treatment Trialists Collaboration. Lancet 2003;362:1527-1535.
 Comparative effects of different anti-HT
medication classes

Meta analysis of 29 RCT

N = 162.341 pts

Blood Pressure Lowering Treatment Trialists Collaboration. Lancet 2003;362:1527-35.

 General principles in HT treatment

The main benefits of HT treatment are due reduction of BP per se

Of the 5 classes of anti HT drugs multiple combinations may be used, with the
exception of a beta-blocker + thiazide diuretic in metabolic sdr
Almost all pts need combination therapy, so what drug is selected first is not
always relevant
The preference for a certain class of medication should consider:
Individual tolerance
Effect on other CV risk factors, except HT
subclinical organ damage (ex. Renal disease) or DM can be preferably treated with some classes
Cost of therapy for the individual or for the health system

Pay attention to adverse reactions that may lower treatment adherence

Long acting medication > 24h and single day administration should be preferred

Mancia G et al. 2007 Guidelines for the management of arterial hypertension. Eur Heart J 2007;28:1462-536.
 Selective use of medication in HT
Subclinical organ damage Clinical event
LVH: ACEI, Ca block, ARBs Previous stroke: any, except BB

Asymptomatic AS: Ca block, ACEI Previous MI: BB, ACEI, ARBs

Microalbuminuria: ACEI, ARBs Angina: BB, Ca block

Renal dysfunction: ACEI, ARBs Heart failure: diuretic, ACEI,

Specific subgroups BB, ARBs,

anti-aldosterone
Systolic HT: diuretics, Ca block
Atrial fibrillation:
Metabolic Sdr: ACEI, ARBs, Ca block
Recurrent: ARBs, ACEI
DM: ACEI, ARBs
Permanent: BB, Ca bloc non-dihydropiridine
Pregnancy: Ca block, methyl dopa, BB
Tachyarrhythmia: BB
Blacks: diuretics, Ca block
Proteinuria/ ESRD: ACEI, ARBs, diuretic
Glaucoma: BB
Peripheral artery disease: Ca block
Cough due to ACEI: ARBs
LV dysfunction: ACEI
 Resistant hypertension
Up to 2 / 3 of HT pts do not reach their target BP when treated

Definition: BP > 140 / 90 mmHg despite at least three anti HT drugs (including a diuretic),

after secondary HT was excluded

Causes:
Lack of adherence to prescribed therapy

No significant lifestyle changes (weight increase, alcohol abuse)

Administration of some drugs or substances that increase BP (liquorice, corticoids, NSAIDs, cocaine, etc)

Sleep apneea sdr

Ignored secondary HT

Volemic overload: inadequate diuretic, progressive renal failure, Na intake, hyperaldosteronism

Treatment:
Diagnosis of the cause

Administration of more than 3 classes medication, including an aldosterone-receptor blocker

Mancia G et al. Eur Heart J 2007;28:1462-536.

 EUROASPIRE II: just half of pts with
cardiovascular disease reach their BP goals
Percentage of patients with BP < 140/90 mmHg on
anti hypertensive medication
Hungary
Czech Republic
Belgium
Spain
Greece
Poland
Ireland
Finland
Italy
Holland
UK
France
Slovenia
Sweden
Germany
Romania*
Total
0 20 40 60 80

EUROASPIRE Study Group. Eur Heart J 2001;22:554-572. * Dorobantu M et al. Rev Rom Cardiol 2006;21:179-89.