1
Systemic arterial
hypertension (SAH)
Blood pressure (BP) regulation
The problem of defying „normal“ BP
Pathogenesis of SAH (primary vs. secondary)
SAH as an example of „complex“ disease
2
Pressure - hypertensions
• arterial
• systemic
• pulmonary
• primary
• secondary
• pre-capillary
• post-capillary
• hyperkinetic
• local
• aortic coarctation
• venous
• systemic
• congestive heart
failure
• local
• portal
3
Systemic arterial hypertension (SAH)
• Paul Dudley White (1931):
• “The treatment of the hypertension
itself is a difficult and almost
hopeless task in the present state of
our knowledge and in fact, for ought
we know the hypertension may be
an important compensatory
mechanism which should not be
tampered with even if it were
certain that we could control it.”
• original hypothesis
• systemic arterial hypertension
(SAH) is a compensatory
mechanism of the arterial narrowing
• nowadays
• SAH is the process leading to the
arterial disease
4
SAH = chronic elevation of BP
• BP>140/90 mmHg increases the
incidence of cerebral, heart and renal
events
• initially
• pressure overload of the left ventricle causing the
LV hypertrophy,
• mild cognitive dysfunction,
• microalbuminuria
• later
• CHD (acceleration of atherogenesis),
• myocardial infarction (plaque rupture),
• (congestive) heart failure,
• arrhythmia (atrial fibrillation due to dilation),
• stroke,
• renal failure (nephrosclerosis, proteinuria),
• retinopathy,
• vascular dementia
• aortic dissection
• …
• SAH is often associated with insulin
resistance, overweight / obesity and
dyslipidaemia = METABOLIC SYNDROM
• see further the pathogenic relationship
5
Vessels – morphology & function
• prototypic structure
• intima
• endothelium + basal membrane
• media
• SMC, elastin
• adventicia
• collagen
• parameters of blood circulation influenced
by blood vessels
• velocity and resistance = SMC
• pulse wave = elastin
• limitation of the stretch = collagen
• types of vessels
• capacitance (e.g. aorta, carotids, large limb
vessels)
• elastin (conservation of energy)
• resistance
• variable resistance
• nutritional – terminal
• regulation of perfusion by
capillaries
• capillaries
• filtration, diffusion
• capacitance venules and veins
• shunts (AV anastomoses)
• bypasses capillaries
• lymphatic
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Factors ensuring blood flow
continuity – vessel elasticity
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„Windkessel“ efekt
• The walls of large elastic arteries (eg. aorta, common carotid, subclavian, & their
larger branches, plus pulmonary artery) contain elastic fibers which are composed of
elastin.
• nndbd The rate of blood entering these elastic arteries significantly exceeds that
leaving them due to arterial peripheral resistance
• This results in a net storage of blood during systole which unloads during diastole
• Windkessel Effect Accomplishes the following:
• Decreases pulse pressure during cardiac cycle
• Increased efficiency of pumping of the left ventricle.
• Provides more continuous flow
• Contributes to organ perfusion during diastole when cardiac ejection ceases
• Specifically helps the perfusion of the coronary arteries during diastole
8
Blood flow
• arteries
• pulsatile, discontinuous
• pressures
• arterial
• systolic
• physiologically increases
with age and with
‘stiffening’ of arteries
• diastolic
• marker of the total
peripheral resistance (TPR)
• pulse
• difference between SBP
and DBP
• significant parameter of
mortality
• contributes to the ‘shear
stress’
• mean arterial pressure
(MAP)
• integral of the curve of
fluctuations
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Blood pressure (BP)
• BP = force moving fluid through circulation and, at the same
time, force applied on the vessel wall
• BP is a result of physical properties of the circulation (=
compliance) and its distension by circulating volume
• P = Q  R (Ohm’s law)
• Q = flow ~ CO (cardiac output) = SV (stroke volume)  f (frequency)
• SV = EDV – ESV (end-diastolic and end-systolic volumes)
• EDV  preload  filling of the heart, i.e. venous return, i.e. effective
circulating volume
• ESV  afterload and contractility
• R = resistance = k    d /   r4
•  = blood viscosity
• CAVE: anemia (), polyglobulia, paraproteinemia ()
• d = vessel length
• r = vessel radius
• CAVE: action of vasopressors
(e.g. AT2, endothelin, vasopressin,
catecholamines, …) and
vasodialtors (e.g., PGI, NO,
adenosin, …)
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BP regulation
• BP changes periodically due to
rhythmical ejection of blood from
heart
• SBP, DBP, MAP
• MAP=DBP+1/3(SBP-DBP)
• P = Q  R  BP is regulated via
changes of Q or R or both
• regulatory systems
• (1) neural
• (2) humoral
• regulation effectiveness
• (1) short-term regulation
• operates mainly with CO (f and
contractility) and r
• r – resistance vessels (=
arterioles) which modulates
influx into microcirculation
• (2) long-term regulation
• operates mainly via changes of
circulating volume (Na and H2O
reabsorption)
• extent of regulation
• (1) systemic = baroreflex, endocrine
hormones
• (2) local = auto-/paracrine mediators
• responsible for the fixation of
hypertension (vasoconstriction as a
defence against hyperperfusion, later
hypertrophy of the vessel wall)
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BP neuroregulation - baroreflex
• main short-term (but
permanent) regulation of BP
• afferent pathways
• signalling into prim. cardiovascular
centre (n. tractus solitarii) from:
• baroreceptors in the aortic arch
• chemoreceptors in carotid bodies
• efferent pathways
• variations in activity of efferent
sympathetic neurons (-adrenergic
stimulation)
• (in)activation of efferent
parasympathetic neurons (n. vagus)
• stimulation of vasopressin release
from hypothalamus
• stimulation of renin release form
juxtaglom. apparatus of kidneys
• intermittent hypoxia (see further
obstructive sleep apnoea)
• since peripheral (and partly central)
chemoreceptors have afferents also
to the vasomotor centre 
activation of SNS by hypoxia (during
sleep)
• gradual fixation of hypertension by
increase of peripheral resistance
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The arterial baroreflex circuit
The arterial baroreceptors are mechanoreceptors located in the carotid sinuses (innervated by the glossopharyngeal nerve, IX) and
aortic arch (innervated by the vagus nerve, X) that respond to stretch elicited by increase in arterial pressure. Primary baroreceptor
afferents provide monosynaptic excitatory input to the nucleus of the solitary tract. Barosensitive NTS neurons initiate a
sympathoinhibitory pathway that involves a projection from the NTS to interneurons in the caudal ventrolateral medulla (CVL) that
send an inhibitory projection to sympathoexcitatory neurons located in the rostral ventrolateral medulla. The baroreflexcardioinhibitory
pathway involves a direct input from the NTS to a group of vagal preganglionic neurons located in the ventrolateral
portion of the nucleus ambiguus (NA). These neurons project to the cardiac ganglion neurons that elicit bradycardia. The baroreflex,
via the NTS, also inhibits secretion of arginine vasopressin by magnocellular neurons of the supraoptic (SON) and paraventricular
(PVN) nuclei of the hypothalamus, in part by inhibiting noradrenergic cells of the A1 group.
13
Obstructive sleep apnoea (OSA)
• periodical collapse and obstruction
of airways during sleep
• disposition: short thick neck, oral
cavity anatomy, receding jaw,
obesity!!
• 10-60s lasting apnoea with variable
frequency (up to 1 in 30s)
• affects ~ 4% middle age people
• consequences: daily tiredness,
morning headache, memory
impairment, mood changes,
hypertension
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Humoral BP regulation
• (1) kidney / adrenal
cortex  RAAS – main
long-term regulation
• (2) hypothalamus /
posterior pituitary 
vasopressin (ADH)
• via V2 receptors
• auxiliary role, main role
is the regulation of
osmolality
• (3) adrenal medulla 
epinephrine
• (4) heart atria (right) 
ANP
• (5) others
• glucocorticoids
• insulin
• thyroid hormones
• growth hormone
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RAAS
• 1-vasoconstriction
• 2-vasoconstriction in limited
extent and inhibition of
formation and release of renin
• 3-preferentialy vasoconstriction
• 4-contraction
• 5 and 6-Na+ reabsorption
• 7-vasoconstriction
• 8 –effect unknown
• enzymatic cascade of
reaction leading to the
ATII formation
• systemic effect
• vasopressor effect
• activation of PLC  PIP2
cleaved to IP3 and DAG 
mobilization of intracellular
Ca
• stimulation of aldosterone
release from adrenal
cortex
• local effects of systemic
ATII + locally formed ATII
• long-term effects esp. in
vessel wall and kidney
• hypertrophy and
remodeling of vessel wall
a myocardium
• hypertrophy of glomeruli
and proliferation of
mesangial cells in kidney
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Effect of AT II in kidneys
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Kidneys - diuretics
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BP variability
 smoking
 alcohol
 caffeine
 sodium (genetics)
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BP circadian rhythmicity
measured as an ambulatory
blood pressure – continuous
24hrs monitoring
effect of
catecholamines and
cortisol cycling
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Principle of the circadian rhythm
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„Molecular clock“
• inner biological rhythmicity is caused by negative and positive
feedbacks between transcription of clock genes (CGs), their
translation, postransl. modification and degradation
• their products - proteins – then serve as transcription factors of
other hundreds of genes (CCGs) in n. suprachiasmaticus and
peripherally
• they synchronize the body according to external environment
• hypothalamus
• clock genes (CGs)
• Clock
• BMal1 (Mop3), BMal2
• Per1, Per2 (Period)
• Cry1, Cry2 (Cryptochrome)
• Rev – Erb-α
• CK1Є CK1δ (caseinkinase)
• clock-controlled genes (CCGs)
• Per 3
• AVP (arginin vasopresin)
• Dbp (D-element binding
protein)
• peripheral organs
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The problem of normal  high BP
• BP is a continuous trait
with characteristic
population distribution
• decision about “normality” is
always arbitrary 
“reference interval” (incl.
95% of healthy population)
• x  2SD for parameters with
normal distribution
• median [2.5% - 97.5%
quintile] for others
• however, common values
in a given population
needn’t to be optimal!
• therefore morbidity and
mortality associated with
some values are taken into
account
• BP in a given subjects is a
product of:
• genetic factors
• environmental factors
• activity of endogenous
regulatory mechanisms
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BP vs. cardiovascular
mortality• BP is a major determinant of CV mortality
• hypertension is one of the most
important risk factors of atherosclerosis
• Framingham study – identification of main CV
risk factors –  TK,  cholesterol,  triglycerides,
 HDL, smoking, obesity, diabetes, physical
inactivity,  age, gender (male) and psychosocial
factors
• original cohort (from 1948)
• 5,209 subjects (aged 32 – 60 yrs) from
Framingham, Massachusetts, USA
• detail examination every 2 years
• II. cohort (from 1971)
• 5,124 adult offspring
• III. cohort
• 3,500 grandchildren of original
participants
• every BP increase of 20mmHg SBP and
10mmHg DBP roughly doubles the risk of
CVD
• both chronic (atherogenesis – mechanical
damage of endothelium) and acute MI(plaque
rupture)
• late clinical manifestation of long-term
untreated / decompensated hypertension
were then taken into account for definition
of cut-off values of BP
• however in the presence of co-morbidities it is
necessary to accommodate (personalise)
these cut-offs
• it is often recommended to maintain lower BP
than 140/90
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SAH definition and criteria
• criteria used depend on the
environment and type of
measurement
• SAH criteria
• BP  140/90 mmHg in adult of any
age in the rest (>10 min)
repeatedly at least 2-times from 3
independent measurements on
several occasions
• diabetics and renal failure patients
<130/80mmHg
• ideally SBP<120 and DBP<80mmHg
• SAH grades
• mild 140 – 179/90 – 104
• moderate 180 – 199/105 - 114
• severe  200/115
• isolated systolic hypertension SBP
>160 with DBP <90 mmHg
• resistant BP 140/90 with
combination of 3 antihypertensives
• SAH stages
• I – simple increase of BP without
organ changes
• II – left ventricular hypertrophy
and/or
microalbuminuria/proteinuria
and/or calcification of aorta
• III – complications: heart failure
and/or renal failure and/or heart
attack and/or stroke
BUT careful in older people !!!
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SAH forms/classification
• secondary (~5%) =  BP is a symptom of another
another primary disease
• (A) renal
• renovascular (due to renal artery stenosis or fibromuscular
dysplasia of renal artery)
• renoparenchymatous (due to glomerulonephritis or diabetic
nephropathy)
• (B) endocrine
• prim. hyperaldosteronism (due to adrenal adenoma)
• pheochromocytoma
• Cushing’s syndrome (due to adrenal or pituitary adenoma)
• acromegaly (due to pituitary adenoma)
• (C) monogenic forms of hypertension
• mutations in genes affecting renal handling of Na (see further genetics)
• essential (primary, idiopathic, ~95%) = many pathogenic
mechanisms are known, but the very etiology is not
• prime suspects are the kidneys:
• abnormal renal handling of Na
•  endogenous sympathetic activity also plays a role
• essential SAH is not just simple hemodynamic abnormality, in ~80% of cases in
young and middle age SAH clusters with other metabolic disorders under the
condition called METABOLIC SYNDROME (see further)
• obesity
• insulin resistance / impaired glucose tolerance / diabetes
• dyslipidaemia
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Pathogenic classification of SAH
• SAH risk factors
• modifiable
• obesity
• salt consumption
(NaCl)
• lack of physical
exercise
• chronic stress
• high alcohol intake
• „French paradox“
( for CVD)
• smoking
• caffeine
• unmodifiable
• genetics
• P=QR  SAH can develop due to
• (1) volume expansion
• changes in natriuresis (i.e. any factors that lead
to Na+ retention) will lead to pressure diuresis
(i.e. increase in systemic BP)
• initially:  venous return,  CO,  BP
• later: vessel and heart stretch lead to remodeling, 
periph. resistance (R),  CO
• vascular stiffening, glomerulosclerosis,
microangiopathy, LV hypertrophy
• etiology
• primary hyperaldosteronism
• SIADH
• monogenic forms of SAH
• but also common genetic variants!
• m. Cushing
• renoparenchymatous: loss of filtration capacity,
tubulointersitial damage, Goldblatt 1K1C
• (2) increase of peripheral resistance
• the site od increased R can be anywhere above
renal arterioles
• etiology
• renovascular: unilateral renal artery stenosis
(Goldblatt 2K1C) or intra-renal stenosis
• isolated systolic hypertension in older people
• (3) mixed causes (constitution to both sodium
retention and increased RAAS and sympathetic
tone
• etiology
• obesity, stress
27
Salt sensitivity/intake (NaCl)
• for the 99.8 of their time (~3.5 mil yrs) humans
consumed little Na+ (30mmol = 1.8g) but more K+
• today 170-260mmol (=10-15g of NaCl) that is 10-15×
higher
• ethnicity matters!!!
• increased salt-sensitivity (i.e. tendency to retain salt and,
subsequently, responsibility to the salt restriction) is more
apparent in some populations (e.g. blacks) while in others
not
• populations that lived in areas with limited access to the salt
(i.e. inland sub-Saharan Africa) and thus low intake
developed more efficient reabsorption of Na
• the trait is still maintained in different (affluent) environment
- “slave’s gene”
• on the contrary, majority of European populations have
generally high salt intake but not all are hypertonics
• evidently different sensitivity (= salt wasting) and efficient
excretion
• dietary salt reduction is the most commonly
recommended intervention, however, sometimes with
limited or no effect (not harmful though)
• vessel remodeling „fixates“ hypertension and high BP
becomes less reversible
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MS - why obesity increases BP
• relationship between BMI and
SBP or DBP is nearly linear
• approx. 78% of primary SAH in men
and 65% in women can be ascribed
to excess weight gain
• even in obese normotensives BP
rises to some extent
• 10 kg (22 lb) of weight loss will
reduce SBP by 5-20 mm Hg
• distribution of fat is an important
consideration – visceral rather
than subcutaneous obesity!!!
• pathogenic mechanisms
• (1) physical compression of the
kidneys by fat in and around the
kidneys
• activation of RAAS
• (2) increased sympathetic nervous
system activity
• renal afferent nerves
• effect of renal denervation
• RAAS dependent
• RAAS-independent (leptin, MCR4
etc.)
• obese leptin deficient individuals are
not hypertensive
• (3) abnormalities of ANF
(deficiency)
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Cardiovascular sympatho-excitatory
actions of leptin
30
Chronic stress and BP
• predefined series of reactions
aimed to fight or flight
• lack of counterbalancing
physical activity today
• chronic phase – dominance
of glucocorticoids
• initially reactive  of BP leads
later to the active
remodelation of vessel wall
and thus “fixation” of
hypertension
• epidemiologically proven by the
studies comparing groups of
subjects of similar age, gender,
education and social background
but different profession (= level
of stress) living in the same
geographical area (nuns vs.
primary school teachers, air
traffic controllers vs. gardeners
etc.)
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Peripheral modulation of GC availability
• peripheral tissue-specific modulation of cortisol availability by enzymes catalyzing
interconversions of active and inactive forms of GCs
• (a) 11β hydroxysteroid dehydrogenase type 1 (11βHSD1)
• act as a reductase regenerating cortisol from cortisone   intracellular cortisol concentration
• mainly in liver and adipose tissue
• expression of 11βHSD1 is higher in visceral than subcutaneous fat!  visceral fat is therefore more flexible pool of energy
substrate
• often co-localises with GR (e.g. in liver and adipose tissue) and thus locally amplifies the GC action
• 11βHSD1 overexpressing mice develop obesity, while 11βHSD1 knock-out mice are protected from overeatinginduced
obesity
• liver and fat-tissue specific inhibitors of 11βHSD1 could be used for treatment of metabolic syndrome and obesity
• pathology associated with 11βHSD1
• Cushing syndrome – higher expression of 11βHSD1 in visceral fat – normally first source of substrate, but higher
suppression with GC, while enhanced GC action leads to lipolytsis in adipose tissue, the fat cumulates in visceral
• congenital deficiency of 11βHSD1 (apparent cortison reductase deficiency)  compensatory over-activation of HPA
axis  adrenal androgen excess, oligomenorhea, hirsutism in women
• overexpression of 11βHSD1 in subcutaneous tissue (congenital or acquired) leads to lipodystrophy
• 11βHSD1 plays a role in the pathogenesis of polycystic ovary syndrome
• regulation: starvation, cortisol, other hormones
• (b) 11β hydroxysteroid dehydrogenase
type 2 (11βHSD2)
• act as a dehydrogenase degrading cortisol to
cortisone   intracellular corticol concentration
• mainly in kidney
• by degrading cortisol 11βHSD2 enables tissuespecific
preferential action of aldosterone on MR
even though concentration of plasma cortisol
>>> aldosterone
• pathology associated with 11βHSD2
• congenital deficiency of 11βHSD2
(apparent mineralocorticoid excess) 
monogenic form hypertension
• 11βHSD2 is expressed in placenta (maintains lower
cortisol in fetal circulation than in maternal) –
deficient action contributes to pregnancy pathologies
(preeclampsia, IUGR, ...) and possibly to fetal
metabolic programming
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Genetics of ESAH
• proved by studies (population, twins,
adoption) – heritability of BP ~30-60%
depending on definition of phenotype
• “candidate genes” approach –
pathogenesis-based approach
• SNS, RAAS (rennin, AGT, ATR1, ACE, …),
endothelin, TXA, ANP, NO synthase, …
• so far only several unequivocal genetic factors
identified and confirmed
• genome-wide association studies (GWAS)
• monogenic forms of EH
• (1) glucocorticoids-suppressed
hyperaldosteronism
• mutations in the promoter of the gene for
aldosterone synthase  production of
aldosterone is not regulated by ATII but ACTH
(therapy by glucocorticoids to suppress ACTH)
• (2) Liddle’s syndrome
• mutations in the genu for Na-channel subunit,
 increased reabsorption of Na in the kidney
proximal tubule
• (3) apparent mineralocorticoid excess (AME)
• mutations in the enzyme 11βHSD2 degrading
cortisol in kidneys  locally increased activity
of cortisol  mineralocorticoid effect in higher
concentrations
• (4) pseudohyperaldosteronism
• mutations in the gene encoding
mineralocorticoid receptor  aldosterone
resistance
• (5) adrenogenital syndrome/congenital
adrenal hyperplasia (CAH)
• defect of 11--hydroxylase or 17-hydroxylase
 excess of mineralocorticoids
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Ethiopatogenetic heterogeneity
of SAH form clinical perspective
• Essential SAH is quite likely HETROGENOUS DISEASE developing
due to various sets of abnormalities – multifactorial or complex
disease – with contribution of both environmental and genetic
factors
• different patients will thus have been treated differently in the future -
PHARMACOGENETICS
• (1) factors influencing cardiac output
•  activity of SNS,  insulin sensitivity,  baroreflex sensitivity, activation of
the hypothalamus (CRH) - pituitary (ACTH) - adrenal (GC and aldosteron)
axis,  left ventricle mass
• (2) factors influencing circulating volume
•  plasma levels of RAAS components (i.e. rennin, ACE, AGT), variability in
enzymes synthesizing steroids (aldosteron synthase),  salt (Na) sensitivity
(central osmoreceptors and tubuluglomerular feed-back),  insulin
sensitivity, atrial natriuretic peptide (ANP)
• (3) factors influencing peripheral resistance
•  activity of SNS,  plasma levels of RAAS components,  activation of ATR1
(genet. variability), kalikrein-kinine system, balance between levels of para/autocrine
vasopressor (endothelin, TXA) and vasodilating mediators (NO,
adenosine)
• (4) factors influencing compliance, hypertrophy and vascular
remodelation
• growth factors and their receptors, oxidant stress, transport processes on
plasma membranes (Na+/H+ transport)
• (5) others
•  number of nephrons, foetal programming
34
Time matters in SAH
• initially transitional
changes lead to
• short-term responses
such as myogenic reflex
• long-term responses such
as vascular remodeling
35
„Fixation“ of SAH
• SAH changes shear stress
and circumferential wall
stress (stretch)
• SAH accelerates changes
otherwise seen during
aging
• endothelial cell damage
• increased vascular
smooth muscle cell
growth and migration
• inflammation
• fibrosis (extracellular
matrix deposition),
contraction and
calcification
• stiffness of arteries results
in increased aortic pulse
pressure and pulse wave
velocity (PWV)
36
Consequences of SAH
• pressure overload
hypertrophy –
pathological LVH
• hypertrophy of
cardiomyocytes
• myocardial fibrosis
• not present in
physiological heart
hypertrophy in
exercise training
• media of coronary
arteries
• impaired coronary
vasodilator reserve
37
Diagnostics of SAH
• (1) random BP
• after at least 10min. rest, sitting, dominant arm, with supported
forearm, tonometer in the height of hear, adequately wide and long
cuff
• for arm circumference <33cm = 12cm, for arm 33-41cm = 15cm, for art
>41cm = 18cm
• classic tonometer – auscultation
• digital – oscilometric
• dopplerometry
• (2) invasive BP measurement – catheter filled with fluid
• (3) ambulatory BO monitoring (AMBP)
• 24-h BP record (or 48-h)
• record every 15–30min during the day,
every 30–60min during the night
• indications
• suspect „white coat syndrome“
• resistant hypertension
• episodic hypertension
• autonomous neuropathy
• therapy monitoring
• unexpected collapses
38