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Blood pressure regulation and arterial hypertension Endothelial dysfunction Ľudovít Paulis For a teaching session, please email me at: [email protected]

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Page 1: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Blood pressure regulation and

arterial hypertension

Endothelial dysfunction

Ľudovít Paulis

For a teaching session, please email me at: [email protected]

Page 2: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

High blood pressure

Why is high blood pressure so important?

Because it causes death!

Causes of mortality in the Slovak Republic

54.5

23.3

5.9

5.7

5.4

0 10 20 30 40 50 60

Cardiovascular diseases

Cancer

Accidents and poisoning

Respiratory diseases

GI diseases

%

Page 3: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Consequences of arterial hypertesion

Jalta - 4. 2 1945

1

2

3

Winston Churchill (1)24.01.65

Hypertensive encephalopathy

+ dementia

Josif Stalin (3)05.03.53

Stroke

Franklin D. Roosevelt (2)12.04.45

Apoplex

Stroke, Renal insufficiency

Page 4: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Survival in hypertension

0

20

40

60

80

100

0 1 2 3 4 5

Years after diagnosis

Su

rviv

al

(%)

Gudbrandsson , Acta Med Scand

1981;210(Suppl):650

Farmer et al. , Arch Intern Med

1963;112:118

Keith et al. , Am J Med Sci

1939;196:332-343

Page 5: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

AT1-Receptor-Blockers

Alpha-1-Blockers

1950

1960

1970

1980

1990

2000

Diuretics

Beta Blockers

Reserpine

(1949)

Captopril (1981)

Losartan (1995)

Verapamil (1963)

Calcium Antagonists

Nifedipine (1975)

ACE-Inhibitors

Propranolol (1965)

Furosemide (1964)

Prazosin (1977)

HCTZ (1958)

Direct Renin Inhibitors

Aliskiren

(2007)

Page 6: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

CV continuum

Hypertension

Diabetes

Dyslipidaemia

Central Obesity

Arteriosclerosis

Vascular remodeling

LVH

> IM thickness

Lacunar infarcts

Microalbuminuria

MI, Angina

Stroke

Congestive Cardiac Failure

Renal Failure

Peripheral Artery DiseaseNon-fatal

recurrent

events

CHF

CRF

Dialysis

Dementia

GenesLife style Death

Modified after Dzau et al. Circulation 2006;114:2850-2870

Stop or delay the

progression

of vascular disease

Page 7: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

† Survival for 75-yr-olds. Roger et al JAMA 2004‡ Brenner H Lancet 2002

Men WomenSurvival%

100

80

60

40

20

0

Time (year)0 1 2 3 4 5 6 7 8 9 10

Time (year)0 1 2 3 4 5 6 7 8 9 10

1996-2000

Prostate cancer† Breast cancer‡

1991-19951985-19901979-1984

Temporal trends in 5-year survival after heart failure diagnosis in men

and women

Survival%

100

80

60

40

20

0

Page 8: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Cost model based on 29 million adults in 5 EU countries(13% of population) with BP >160/95 mm Hg and a further

46 million (21%) with BP 140/90-160/95 mm Hg

Hansson et al Blood Press 2002

Annual acute management costs of inadequately

treated hypertension

CV event Events (000s)

Costs (billion Euros)

Cost associated with uncontrolled BP

Acute MI

Heart failure

Stroke

All (95% CI)

442

815

964

2220

2.22

2.99

5.09

10.3 (9.8,10.8)

Events (000s)

Costs (billion Euros)

Cost saving if BP target attained

19

122

141

281

0.09

0.45

0.72

1.26 (0.80,1.90)

Page 9: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

The major aim of a therapy?

To reduce mortality and extend survival

High

blood

pressure

Mortality

Marker of mortality

Primary end-point

Left ventricular hypertrophy

Myocardial fibrosis

Atherosclerosis

Endothelial dysfunction

Ischemic heart disease

Stroke

Heart failure

Secondary end-point

Only a syndrome?

Disease

Quality of life

and to increase QUALYs

Page 10: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Blood pressure

Under blood pressure we usually mean the pressure in medium-

sized arteries, where it is also measured (a. brachialis) directly

(invasively) or indirectly (non-invasively)

Arterial blood pressure at rest is oscillating between 60-90 mm Hg

during the diasystole and 100-140 mm Hg during the systole. Mean

arterial pressure is then 90-100 mm Hg

In other parts of the vascular tree, the blood pressure is different:

behind precapillaries 30 mm Hg, at the venous end of capillaries 22

mm Hg, in the right atrium 0-8/2-10 mm Hg, in the right ventricle 15-

30/0-8 mm Hg, in the pulmonary artery 15-30/3-12 mm Hg and in the

left ventricle 100-140/3-12 mm Hg

Arterial blood pressure is accessible to non-invasive measurement

and moreover it influences the pressure conditions in all organs.

Probably therefore it closely correlates with cardiovascular morbidity

and mortality and attracts the attention of cardiologists and

physicians

Page 11: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Blood pressure determinants

BP = Flow x Peripheral resistance

Cardiac output = Stroke volume x Heart rate

Preload Contractility Afterload

Venous compliance

Compliance of large arteries

Inner diameter of resistant arteries

IVF volume

Na+ content Renal excretory capacity

Sympathetic Renin Ang II Aldosterone

Parasympathetic Local vasodilators (NO)

Page 12: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Blood pressure regulation

• Central

– Centers in mesencefalon and medulla oblongata afferented from superior centers (cortex, limbic system via hypothalamus) and from baroceptors with efferentation to sympathetic and parasympathetic nervous system

• Baroreflex (Hypotension activates sympathetic nervous system)

• Bainbridge reflex (High ventricular filling activates sympathetic)

• Acute stress reaction

– Renin-angiotensin-aldosterone system

• Chronic stress reaction

• Local

– Myogenous (Protective vasoconstriction)

– Metabolic (Metabolic products induce dilation – renal adenosine causes constriction)

– Humoral (NO, EDHF vs. ET, EDCF)

– Neurogenous (Axon reflex)

Page 13: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Impaired BP regulation: Hypertension

• Repeatedly increased blood pressure over 160/95 mm Hg (borderline hypertension over 140/90 mm Hg), however the value is arbitrary

• Types:

– Unstable

– Fixed

– Non-dipping

• Pathophysiology :

– Hyperdynamic

– Hyperresistant

• Etiology:

– Primary

– Secondary

Page 14: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,
Page 15: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,
Page 16: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,
Page 17: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,
Page 18: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,
Page 19: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,
Page 20: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,
Page 21: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,
Page 22: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,
Page 23: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,
Page 24: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Renal hypertension

BP = Flow x Peripheral resistance

Cardiac output = Stroke volume x Heart rate

Preload Contractility Afterload

Venous compliance

Compliance of large arteries

Inner diameter of resistant arteries

IVF volume

Na+ content Renal excretory capacity

Renin Ang II AldosteroneRenal ischemia

Decreased Na load in DT Renal parenchyma reduction (glomerulonephritis, gestational

nephropathy)

Tumor producing renin

Page 25: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Endocrine hypertension

BP = Flow x Peripheral resistance

Cardiac output = Stroke volume x Heart rate

Preload Contractility Afterload

Venous compliance

Compliance of large arteries

Inner diameter of resistant arteries

IVF volume

Na+ content Renal excretory capacity

Sympathetic Aldosterone

PhaeochromocytomaGlucocorticoids MineralcorticoidsCushing syndrome

Adrenogenital syndrome ACTH

Conne syndrome

Page 26: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Neurogeneus hypertension

BP = Flow x Peripheral resistance

Cardiac output = Stroke volume x Heart rate

Preload Contractility Afterload

Venous compliance

Compliance of large arteries

Inner diameter of resistant arteries

IVF volume

Na+ content Renal excretory capacity

Sympathetic

Encephalitis

Page 27: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Essential hypertension: Stress

BP = Flow x Peripheral resistance

Cardiac output = Stroke volume x Heart rate

Preload Contractility Afterload

Venous compliance

Compliance of large arteries

Inner diameter of resistant arteries

IVF volume

Na+ content Renal excretory capacity

Sympathetic Renin Ang II Aldosterone

Stress

Page 28: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Essential hypertension: Salt

BP = Flow x Peripheral resistance

Srdcový výdaj = Vývrhový objem x Srdcová frekvencia

Preload Contractility Afterload

Venous compliance

Large arteries compliance

Inner diameter of resistant arteries

IVF volume

Na+ content Renal excretory capacity

Renin Ang II Aldosterone

Page 29: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Essential hypertension:

Endothelial dysfunction

BP = Flow x Peripheral resistance

Cardiac output = Stroke volume x Heart rate

Preload Contractility Afterload

Venous compliance

Compliance of large arteries

Inner diameter of resistant arteries

IVF volume

Na+ content Renal excretory capacity

Sympathetic Renin Ang II Aldosterone

Local dilators (NO)

Page 30: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Endothelial dysfunctionHealthy endothelium produces endothelial factors (NO, EDHF, PGI2) which:

– Inhibit platelet aggregation and adhesion

– Inhibit activation of monocytes and lymphocytes

– Inhibit mitogenesis and proteosynthesis

– Relax vascular smooth muscle

Injured endothelium:– Allows the subendothelial penetration of lipids and exposes highly thrombogenic

tissue factors to circulating platelets

– Does not produce sufficient NO and PGI2, expresses adhesive molecules and after activation releases ET, PGH and TX, and increases superoxide production

– Superoxide produced by endothelium and fagocytes migrated subendothelial deactivates NO

– The loss of NO leads to increased platelet activation, smooth muscle proliferation and production of collagen by fibroblasts

Activated cells in the neointimal layer:– Accumulate lipid particles (foam cells) forming thus lipid plaque

– Cause hyperplasia of the artery (smooth muscle cells)

– Increase stiffness and narrowing of the arteries and (fibroblasts)

– Induce thrombogenesis (dysfunctional endothelium and platelets)

In conditions of turbulent blood flow the plaque may rupture leading to:– Artery occlusion: brain/myocardial/leg infarction

– Form a thromboembolization

Page 31: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Lewis SM, Collier IC, Heitkemper MM: Medical-

surgical nursing: assessment and management of

clinical problem, ed 4, 1995, St Louis

Endothelial dysfunction

Page 32: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Complications: Target organ damage

• Blood vessels:

– Over 1 mm in diameter: atherosclerosis (endothelial injury, exposure of subendothelial tissue, penetration of monocytes, production of cytokines, accumulation of lipids in foam cells, activation of fibroblasts to enhanced production of ECM, stimulation of smooth muscle hyperplasia, adherence and aggregation of thrombocytes: thrombogenesis, plaque rupture, aneurysm development)

– Less than 1 mm in diameter: arteriosclerosis (hyaline remodelation of arterial media, decreased stiffness, narrowing, aneurysm development)

– Results of vessel remodeling: increase in peripheral resistance (fixation of hypertension), development of aneurysms, renal ischemia and damage (fixation of hypertension), ischemic heart disease, peripheral arterial disease

– Fundoscopy provides an indication of the arteriolar damage occurring elsewhere and may be used for the classification of hypertensive disease progress. It might distinguish between hypertensive retinopathy (cotton wool exudates) and diabetic retinopathy (hard exudates, lipid deposites and microaneurysms)

Page 33: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Complications: Target organ damage

• Brain:

– Cerebrovascular incidents: Stroke, brain infarction, TIA

– Neurological complications: Hypertension encephalopathy

• Kidney:

– Renal ischemia and loss of renal parenchyma: Chronic renal failure (fixation of hypertension)

• Heart:

– Left ventricular hypertrophy (ECG, echo), IHD, fibrosis, increased stiffness, atrial dilation, heart failure

Page 34: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

NormalLV structure and function

Hypertension HF

Overt heart failure

SmokingDyslipidaemiaDiabetes

ObesityDiabetes

LV remodelling

LVH

MISystolic

dysfunction

Diastolicdysfunction

Subclinical LV

dysfunction

Time: decades Time: months

Death

Progression from hypertension to heart failure

Page 35: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Influence of LVH on incident heart failure

Gardin et al Am J Cardiol 2001

Cardiovascular Health Study: a prospective, longitudinal, population-based study in 2506 subjects with 6-7 years follow-up

LV mass (g) Quartiles

Kaplan-Meier curves for incident heart failure free survival by LV mass gender-specific quartiles

Time to incident HF (days)

% free of incident HF

84

86

88

90

92

94

96

98

100

0 1000 2000

4

3

1, 2

Page 36: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Coronary heart disease risk factors

0

10

20

30

40

50

Rate of CHD over 8 years%

LVH

no LVH

Kannel J hypertens 1991

high cholesterol

hypertension

glucose intolerance

smoking

-

-

-

-

+

-

-

-

+

+

-

-

+

+

+

-

+

+

+

+

Page 37: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Clinics

Aim of investigation of hypertensive patient:

• to obtain accurate and representative measurements of blood pressure

(staging), blood pressure may be low in heart failure

• to identify contributory factors and any underlying cause (secondary

hypertension): search for signs of aortic coarctation, renal disease,

endocrinopathies

• to assess other risk factors and quantify cardiovascular risk

• to detect any complications (target organ damage) that are already present: to

search for atherosclerosis and arteriosclerosis (carotid arteries sonography,

fundoscopy), left ventricular hypertrophy, diastolic dysfunction, IHD, renal failure

• to identify comorbidity that may influence the choice of antihypertensive therapy:

dyslipidemia, obesity, hyperinsulinemia and insuline resistance

=CXR, ECG, echo, ambulatory blood pressure, U, Cr and E, protein levels, glucose

levels, glucose tolerance, lipid profile

Page 38: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Prevention

• Risk factors:

– Age over 60

– Male sex

– Positive family history

– Impaired glucose tolerance

– Dyslipidemia

– Obesity

– Lack of exercise

– Smoking

– High salt intake

– Heavy consumption of alcohol

– Impaired intrauterine growth

Page 39: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Cardiovascular risk markers

Age Sex

High blood pressure

Hereditary Smoking

↑ Cholesterol levels

↓ Glucose tolerance

Obesity

↑ Fibrinogen levels

Diabetes mellitus

Drugs

Left ventricular hypertrophy and fibrosis

Sedentary life style

Stress

↓ HDL/LDL Ratio

Modifiable Behavioral

Labormarkers Clinical manifestations and organ damage

↑ Homocysteine level

↑ PAI-1 concentration

↑ CRP

↑ BNP-Spiegel

↑ Dimethylarginine Arterial remodeling and stiffness

Proteinuria and renal damage

…and more???

Page 40: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Treatment

• Generally, treatment should be initiated at 160/95 mm Hg and target blood

pressure values are 130/85 mm Hg

• The higher risk, the more benefit from the treatment. Therefore, the threshold

values for treatment decrease with the number of comorbidities. E.g. in DM the

threshold is set to 140/90 mm Hg and target blood pressure values are 120/80

mm Hg (HOT).

• Major classes of antihypertensive treatment:

– Diuretics

– ACE inhibitors and AT receptor blockers

– Beta-blockers

– Calcium antagonists

Page 41: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

BP treatment

BP = Flow x Peripheral resistance

Cardiac output = Stroke volume x Heart rate

Preload Contractility Afterload

Venous compliance

Compliance of large arteries

Inner diameter of resistant arteries

IVF volume

Na+ content Renal excretory capacity

Sympathetic Renin Ang II Aldosterone

Parasympathetic Local vasodilators (NO)

Calcium antagonists Diuretics Beta-blockers ACE-inhibitors

Page 42: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Which drug is the best?

Diuretics

Cheap

Most effective in afro-american and elderly

Calcium antagonists

Cheap

Negative effects

Effective in BP lowering

Beta-blockers

Cardioprotective

Cave in DM and asthma

Effective in hyperdynamic hypertension

in young

Cause erectile dysfunction

ACE inhibitors

Cardioprotective, renoprotective

Expensive

May be used in asthma and IHD

Page 43: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,
Page 44: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,
Page 45: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,
Page 46: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,
Page 47: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,
Page 48: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,
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Page 50: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,
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Page 52: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Current problemsThere is some theoretical background suggesting, that ACE-inhibitors might be

superior to other antihypertensives

No trial has shown that one of the classes of antihypertensives could reduce

morbidity and mortality more than other and thus provide any beneficial effect

beyond blood pressure reduction.

A meta-analysis of 17 RCTs found that diuretics or β-blockers reduced the risk of

coronary heart disease by 16%, stroke by 38%, cardiovascular death by 21% and

all cause mortality by 13%. Another systematic review found that the effects of ACE

inhibitors and calcium antagonists were similar.'

Trials in hypertension are hard to perform: a large number of patients and a long

time of surveillance is needed

The choice of antihypertensive treatment is economically extremely important: large

number of patients

In the future individual therapeutic strategies and the use of adjuvant drugs may be

expected

Page 53: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Endothelium-protective substances:

new perspectives in hypertension

treatment• Endothelium-protective substances (statins, melatonin, antioxidants, drugs

containing thiol group, acetylsalicylic acid) show a small antihypertensive effect

• However, they are interesting because:

– The beneficial effect of however this effect might extend beyond the

potential of pure blood pressure reduction

– The side effects of these substances are rare and mild

• In future studies, the potential of these drugs as adjuvant treatment of

hypertension will be investigated

Page 54: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Experimental hypertension

• Models of experimental hypertension

– Spontaneously hypertensive rats (SHR):

• Model of essential hypertension

– NO-deficient hypertension (L-NAME-induced)

• Model of endothelial dysfunction

– Dahl salt-sensitive rats

• Model of salt-sensitive hypertension

• Techniques

– Tail-cuff plethysmography (non-invasive blood pressure measurement)

– Morphometry of the LV and aorta (determination of hypertrophy and fibrosis)

– NO-synthase activity, markers of oxidative stress

– Immunoblotting and immunohistochemistry

– Polymerase chain reaction

Page 55: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Melatonin and blood pressure

• Melatonin deficit hypertension

• Melatonin BP: – Experimental hypertension

– Healthy volunteers

– Patients with essential hypertension

• Other means: – Antisympathetic action

– Normalization of lipid profile

– Extraordinary antioxidant properties

• High chance of melatonin intake by cardiovascular patients

Simko and Paulis, J Pineal Res 42:319–322, 2007

Page 56: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Comparison of the effect of melatonin

on SHR and L-NAME hypertension

* *+

*+

**

0

1

2

3

4

5

6

7

8

9

WKY

SHR

SHR+Spi

SHR+Cap

SHR+Sim

SHR+Mel

NO

S a

cti

vit

y i

n t

he L

V (

pkat/

g)

**

*

*

*

*+

*+

*+

*+

100

110

120

130

140

150

160

170

180

0 1 2 3 4 5(week of experiment)

Sy

sto

lic

blo

od

pre

ss

ure

(m

m H

g)

Ctrl LN LN + Mel Mel

*****

*+

*+

*+

*+*

+

*+

*+

*+

100

120

140

160

180

0 1 2 3 4 5

(week of treatment)

Systo

lic b

loo

d p

ressu

re (

mm

Hg

)

SHR SHR+Mel SHR+Cap

SHR+Spi WKY SHR + Sim

**

0

1

2

3

4

5

6

7

8

9

Ctrl LN LN + Mel Mel

NO

S a

cti

vit

y i

n t

he

LV

(p

ka

t/g

)

Paulis et al. J Hypertens, 2009Simko et al. J Hypertens, 2009

Page 57: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

The effect of melatonin on the

remodeling of the left ventricle

* *

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Ctrl LN LN + Mel Mel

Re

lati

ve

LV

we

igh

t (m

g/g

)

**

*+

* *

0.0

0.5

1.0

1.5

2.0

2.5

WKY

SHR

SHR+Spi

SHR+Cap

SHR+Sim

SHR+Mel

Rela

tive L

V w

eig

ht

(mg

/g)

*+****

0.0

0.1

0.2

0.3

0.4

0.5

0.6

WKY

SHR

SHR+Spi

SHR+Cap

SHR+Sim

SHR+Mel

LV

hyd

roxyp

roli

n c

on

ten

t (m

g)

Paulis et al. and Simko et al. J Hypertens, 2009

+

*

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

Ctrl LN LN + Mel Mel

LV

hy

dro

xy

pro

lin

co

nc

en

tra

tio

n (

mg

/g)

Page 58: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Hypertrophy vs. fibrosis

+++

*

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

Ctr-4 LN-4 SR Arg Spi Ctr-7

LV

W/B

W [

mg

/g]

*

* **

0.0

0.1

0.2

0.3

0.4

0.5

0.6

Ctr-4 LN-4 SR Arg Spi Ctr-7

LV

Hyp

co

nte

nt

[ug

]

Paulis et al. Acta Physiol 194:45-55, 2008

Page 59: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Structure vs. function

Weber, Hypertension 38:588-591, 2001 Brilla et al. Circulation 102:1388-1393, 2000

Page 60: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Classical RAAS

Renin

Angiotensinogen

Angiotensin I

Angiotensin II

Angiotensin II type 1 receptor

(AT1R)

Angiotensin converting

enzyme (ACE)

Aldosterone

Vasoconstriction

(systemic, renal)

Hypertrophy

Inflammation

Na+ and water

retention

Renin inhibitors

ACE inhibitors

AT1R blockers

Aldosterone receptor

antagonists

Page 61: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Novel RAAS

Renin

Angiotensinogen

Angiotensin I

Vasoconstriction

(systemic, renal)

Hypertrophy

Inflammation

Na+ and water

retention

Renin inhibitors

(Pro)Renin Receptor

antagonists

Prorenin

(Pro)Renin Receptor

PLZF

PI3K

Akt

MAPKs

Proliferation/Hypertrophy

Apoptosis

Fibrosis

Page 62: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Novel RAAS

Renin

Angiotensinogen

Angiotensin I

Angiotensin II

AT1R

Angiotensin

converting

enzyme (ACE)

Vasoconstriction

(systemic, renal)

Hypertrophy

Inflammation

Na+ and water

retention

Renin inhibitors

ACE inhibitors

AT1R blockers

Chymase, Tonin, Cathepsin G

Bradykinine

Inactive

Vasodilation

AT2R

Vasodilation

Apoptosis

NO production

Reduced proliferation

Neurotrophic effects

AT2R agonist

Page 63: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Study design

⚫ Prospective, randomized, double-blind, double-dummy,

multicentre, parallel-group trial

E R

(n=7,800)

Placebo

Run-in

Telmisartan 80 mg

Ramipril 10 mg

Telmisartan 80 mg + Ramipril 10 mg

(n=7,800)

(n=7,800)

E

(n=3,000)Placebo

(n=3,000)Run-in

Telmisartan 80 mg

PlaceboR

5.5 years

Unger T. Am J Cardiol 2003; 91 (Suppl):28G–34G

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ONTARGET: Key Baseline Characteristics

Ramipril Telmisartan Combination

N 8576 8542 8502

Age 66.4 66.4 66.5

% females 27.2 26.3 26.5

% CAD 74.4 74.5 74.7

% Stroke/TIA 21.0 20.6 20.9

% Diabetes 36.7 38.0 37.9

BP 141.8 / 82.1 141.7 / 82.1 141.9 / 82.1

Statins 61.0 62.0 61.8

Antiplatelet 80.5 81.1 81.1

-blockers 56.5 56.9 57.4

ONTARGET Investigators NEJM 358(15): 1547-59 (2008)

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Time to Permanent Discontinuation

of Study MedicationONTARGET

Years of Follow-up

Cu

mu

lative

Ha

za

rd R

ate

s

0.0

0.1

0.2

0.3

0.4

0 1 2 3 4

Telmisartan

Ramipril

# at Risk Yr 1 Yr 2 Yr 3 Yr 4

T 8542 7954 7384 6909 6478R 8576 7796 7165 6681 6254

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ONTARGET: Reasons for Permanently

Stopping Study MedicationsRam

N=8576

Telmi

N=8542

Telmi vs. Ram

RR p

Hypotension 149 229 1.54 0.0001

Syncope 15 19 1.27 0.4850

Cough 360 93 0.26 <0.0001

Diarrhea 12 19 1.59 0.20

Angioedema 25 10 0.40 0.0115

Renal Impairment 60 68 1.14 0.46

Any

Discontinuation

2099 1962 0.94 0.02

Page 67: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Time to Primary OutcomeONTARGET

Years of Follow-up

Cu

mu

lative

Ha

za

rd R

ate

s

0.0

0.0

50

.10

0.1

50

.20

0.2

5

0 1 2 3 4

Telmisartan

Ramipril

# at Risk Yr 1 Yr 2 Yr 3 Yr 4

T 8542 8176 7778 7420 7051

R 8576 8214 7832 7473 7095

ONTARGET Investigators NEJM 358(15): 1547-59; 2008

Page 68: Blood pressure regulation and arterial hypertension Endothelial … · 2020. 3. 16. · Blood pressure Under blood pressure we usually mean the pressure in medium-sized arteries,

Novel RAAS

Renin

Angiotensinogen

Angiotensin I (1-10)

Angiotensin II (1-8)

AT1R

Vasoconstricti

on (systemic,

renal)

Hypertrophy

Inflammation

Na+ and water

retention

ACE,

Chymase,

Tonin,

Cathepsin G

Bradykinine

Inactive

Vasodilation

AT2R

Angiotensin 1-9

Angiotensin 1-7

ACE2

ACE2

ACE

Angiotensin III (2-8)

Angiotensin IV (3-8)

AMPA

AMPM

AT4R

(IRAP)

MASVasodilation

Anti-

proliferation

Anti-

inflammation