blood pressure regulation and arterial hypertension endothelial … · 2020. 3. 16. · blood...
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Blood pressure regulation and
arterial hypertension
Endothelial dysfunction
Ľudovít Paulis
For a teaching session, please email me at: [email protected]
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
%
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
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
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)
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
† 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
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)
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
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
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)
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)
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
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
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
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
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
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
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)
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
Lewis SM, Collier IC, Heitkemper MM: Medical-
surgical nursing: assessment and management of
clinical problem, ed 4, 1995, St Louis
Endothelial dysfunction
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)
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
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
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
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
-
-
-
-
+
-
-
-
+
+
-
-
+
+
+
-
+
+
+
+
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
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
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???
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
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
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
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
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
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
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
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
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)
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
Structure vs. function
Weber, Hypertension 38:588-591, 2001 Brilla et al. Circulation 102:1388-1393, 2000
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
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
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
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
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)
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
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
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
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