Systemic arterial hypertension
(SAH) as an example of pressure overload and HF etiology
Blood pressure (BP) regulation
The problem of defying „normal“ BP
Pathogenesis of SAH (primary vs. secondary)
SAH as an example of „complex“ disease
Pressure - hypertensions
• arterial
• systemic
• pulmonary
• primary
• secondary
• pre-capillary
• post-capillary
• hyperkinetic
• local
• aortic coarctation
• venous
• systemic
• congestive heart failure
• local
• portal
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
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
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 capillaries
• capillaries
• filtration, diffusion
• capacitance venules and veins
• shunts (AV anastomoses)
• bypasses capillaries
• lymphatic
Factors ensuring blood flow continuity –
vessel elasticity
„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
Qualitative aspects of pulse wave
PWV – measurement of pulse wave velocity
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
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, …)
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)
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
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.
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
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
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
Effect of AT II in kidneys
Kidneys - diuretics
BP variability
 smoking
 alcohol
 caffeine
 sodium (genetics)
BP circadian rhythmicity
measured as an ambulatory
blood pressure – continuous
24hrs monitoring
effect of
catecholamines and
cortisol cycling
Principle of the circadian rhythm
„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
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
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
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 !!!
SAH forms/classification
• secondary (~5%) =  BP is a symptom of 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
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
Renovascular and renoparenchymal hypertension
modely
(2K1C: 2 kidneys, 1 clip
(1K1C: 1 kidney, 1 clip
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 subSaharan
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
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)
Cardiovascular sympatho-excitatory actions of leptin
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.)
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 overeating-induced 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 cortisol
concentration
• mainly in kidney
• by degrading cortisol 11βHSD2 enables tissue-specific 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
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
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
Time matters in SAH
• initially transitional changes
lead to
• short-term responses such as
myogenic reflex
• long-term responses such as
vascular remodeling
„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)
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
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