Download Which pressures and where

Hypertension
Lectures from Pathological
Physiology
Study materials from Pathological
Physiology, school year 2008 - 2016
© Oliver Racz
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Syllabus
Repetition of physiology & basic terms
Microcirculation, perfusion & blood pressure
Regulators of perfusion & blood pressure
Central role of kidneys in regulation of circulating
volume & blood pressure
Hypertension – classification, forms
Primary hypertension
Secondary forms of hypertension
Monogenic forms of hypertension and the
genomic background of common hypertension
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Repetition of physiology, basic terms- 1
What is blood pressure (BP) ?
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Moving force of blood flow to overcome the
hemodynamic (peripheral) resistance
Force, exerted by blood on vessel wall in
arterial circulation
P = F/S = N/m2 (Pascals, Pa)
1 mmHg = 0,133 kPa
For the body the tissue perfusion is
essential = oxygen supply
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Repetition of physiology, basic terms- 2
Determinants of BP
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Heart function (pump) - catch 22
Circulating volume
Elasticity and tension of vessel wall
Which pressures and where ?
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sBP, dBP, mean arterial pressure
Mean filling pressure
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Blood pressure
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Repetition of physiology, basic terms – 3
Mean arterial BP
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= dBP + pulse pressure/3
150/90; Mean = 90 + (60/3) = 110
= CO * TPR
(total peripheral resistance = microcirculation!)
Peripheral resistance is the opposite of perfusion !
Determinant of CO is the venous return!
Mean filling pressure is cca 7 mmHg
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Experiment: Arterial pressure after heart arrest
This is determining the filling of right ventricle =
venous return
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The distribution of blood in
circulation
Region
%
Heart
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Pulmonary
circulation
Arteries
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Arterioles,
capillaries
Venous part of
circulation
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Microcirculation
Resistance arterioles  0,5 – 0,15 mm
4 – 5 branchings to terminal arterioles  10 mm
Capillaries
Blood flow velocity in aorta ( 3 – 4 cm2) 0,2 – 0,3 m/s
In capillaries 0,3 mm/s  3000 – 4000 cm2
Only one third of them is open  1000 cm2
The hemodynamic resistance is directly proportional
to the length of vessel and indirectly proportional to
the 4th square of vessel diameter
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Increase of diameter by 1,2 – resistance decreases to 50 %,
1,8-fold increase - decrease to 10 %
and conversely !!!
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Examples of changes in resistance without
changes of BP
Hypoxia
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Vasodilatation
Venous return 
Cardiac output 
Hyperkinetic
circulation without
pressure change
A-V shunts
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Decrease of TPR
Amputation of LE
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Increase of TPR
No change in BP
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Overview of blood pressure
regulators
Baroreceptors
Chemoreceptors
Ischemic response of CNS
Immediate reaction - limited effectivity
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Overview of blood pressure
regulators
Pressure relaxation of vessel wall
Fluid shift (Frank – Starling)
Renin – angiotensin – aldosterone system
(& its antagonists – natriuretic hormones)
Antidiuretic hormone
Slower reaction, limited effectivity
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Regulation of microcirculation
Extremely complicated mechanisms
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Metabolic – hypoxia, ATP, pH, etc.
Para-, autocrine – NO, CO (endothel)
Ion equilibrium (contractility of muscle cells)
Transport systems, channels, their regulators &
receptors
Tissue („bed“)specific!
Regulation of „individual demand“
Signals for higher systems
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Overview of blood pressure
regulators
LONG TERM, ALMOST UNLIMITED
EFFECTIVITY
kidney – regulation of volume
Proofs – kidney crosstransplantations
between HT & NT rats, human kidney
transplantations
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The effectivity of blood pressure regulators
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Goldblatt and his experiments
Bright 1832: Large, heavy heart
and scarred kidney
Harry Goldblatt, a recipient of
final-year prize at McGill, 1916
Cleveland 1928 - 1934
Goldblatt H et al: Studies on
experimental hypertension I. J
Exp Med 59, 1934, 347-379
Clamp on a. renalis
The discovery of renovascular
hypertension
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Autoregulation of blood flow and glomerular
filtration in kidneys
renal blood flow
ml/min
glomerular
filtration,
ml/min
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Constant filtration achieved by regulation
of vas afferens a efferens tonus
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Natriuresis
Filtration does not depend on blood
pressure, diuresis & natriuresis strongly
depends !!!
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Constant perfusion – variable
excretion
Perfusion is 1,3 l/min
 25 % CO
Daily filtrate
(180 l)  25 mol = 0,5 kg
sodium (kilogramm salt)
Excretion  250 mmol,
5 g Na or 10 g salt, 1 %
Resorbtion
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2/3 proximal tubules
1/4 Henle loop
1/12 distal tubules
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Pressure diuresis
Kidney blood flow does not depend on BP
Diuresis & natriuresis depend
Pressure increase by 10 – 20 mmHg –
twofold increase of diuresis
Rapid response – begins in 1 minute
Mechanism – reabsorbtion of sodium
Regulated by macula densa
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Hypertension is always connected with
change of kidney pressure diuresis !!!
Natriuréza
Natriuréza
Hypertension is not a „disease“ of heart
Hypertension is not a „disease“ of peripheral resistance
Hypertension is a distrubance of volume equlibrium – the kidneys are
not able excrete excess water and salt at normal pressure
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100
150
200
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Definition & diagnostics of
hypertension
Scipione Riva-Rocci: Un nuovo
sfigmomanometro. Gazetta Med Torino, 47, 981
– 1001, 1896
Long term increase of systolic blood pressure ≥
140 mmHg & diastolic blood pressure ≥ 90
mmHg (confirmed by repeated measurements),
or the use of antihypertensive therapy
Classic sphygmomanometers, digital & 24 hour
monitoring of BP, continuous monitoring
Lege artis (white coat HT)
Measure in everybody (The Chernobyl Effect)
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Classification of hypertension
According to values of BP, see 
According to its etiology (pathogenesis)
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primary (95 %?)
secondary forms of hypertension (5%?)
According to the stage of disease
1. Only hypertension
2. Manifest damage of organs – heart hypertrophy,
nephropathy & changes of ocular fundus =
remodelation of small vessels
3. Heart and kidney failure, hemorrhagic stroke
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WHO/ISH 1999 (JNC VI)
CATEGORY
sBP
dBP
Optimal
< 120
< 80
Normal
< 130
< 85
High normal
130 - 139
85 - 89
Mild HT (I)*
140 – 159
90 – 99
Middle (II)
160 – 179
100 – 109
Severe (III)
≥ 180
≥100
*And also borderline 140 – 149/90 - 94
Isolated systolic > 140/<90
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CATEGORY
sBP
dBP
< 120
< 80
Prehypertension
120 - 139
80 - 89
Hypertension I
140 – 159
90 – 99
Hypertension II
≥ 160
≥ 100
Normal
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Circadian changes of BP
24 hour monitoring
Decrease after 8 p.m.
11 p.m. – 05 a.m. by 20 % (20 – 30 mmHg)
Increase in the morning, maximum before noon
Regulator: kidneys or catecholamines ? (both)
New term – non-dippers, bad prognosis
Surprise if the treatment is bad – nocturnal
hypotension
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Epidemiology of hypertension
20 and more % of adult population
Already in children (2 – 5%) – very bad
prognosis
Treatment often not ideal
Association with salt intake – no hypertension in
aboriginal people from New Guinea & Amazonia
who do not use salt
Deficiency of Ca, Mg
Association with obesity
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Some more epidemiological data
Age:
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20 – 30
40 – 50
60 & more
< 10 %
 25 %
 33 %
Sex
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Up to age 50 y.
After 50 y.
f/m 0,6 – 0,7
f/m1,1 – 1,2
Weight
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Normal
Obesity
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8 – 15 %
15 – 35 %
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Primary hypertension
The cause and the pathogenesis is not
fully clear
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Our old and simple explanation
Disturbance of pressure diuretic curve of kidneys
Kitchen salt ?
Dysfunction of endothel ?
Hypertension as a „complex“ disease
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Monogenic diseases (also HT, rare)
Diseases caused by external factors
Genetic background and external factors
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Reaction of circulation on physical and
psychical stress
HYPERTENSION
150
???
NORMOTENSION
100
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„Kidney“ theory of primary
hypertension
Key role of kidneys in volume regulation –
the excretion of Na and water is strongly
pressure dependent.
Primary hypertension is caused by
disturbance of this function ???
Why and how ???
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Natriuresis
Change in pressure diuresis curve – 1
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200
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Natriuresis
Change in pressure diuresis curve – 2
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Hypertension is a complex disease
Gene polymorphism
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External factors
Renin, ACE, AT
NOS
Kallikreine
Endotheline
Na-K ATPase
Adducin
More than 50
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NaCl (10 g instead of
0,5)
Stress
Deficiency of Ca, Mg
Obesity
Smoking, alcohol
And many others
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Problems with genetic
background of complex diseases
How strong is the effect?
(gene polymorphism with small and big effect)
What is the occurrence of allele in population
(1-2 % or 30-40 %)
Epistasis = Interaction between genes and their
products
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A1/A2 = 1, B1/B2 = 2
how much is A2 + B2 ?
In genetics from -10 to +10
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Monogenic hypertension – 1
problems with aldosterone
Some forms of congenital adrenal hyperplasia
Hyperaldosteronism responding to glucocorticoids (AD)
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The gene for aldosterone production is connected to the
regulatory sequence of glucocorticoid synthesis. Aldosterone
production controlled by ACTH. Renin, angiotensin low,
hypokaliemia. (increased Na reabsorbtion without reason)
Pseudohyperaldosteronism caused by defect of 11-bhydroxysteroid dehydrogenase
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Mineralocorticoid receptor sensitive to cortisol (glucocorticoid
acts as mineralo – increased Na reabsorption without
reason)
Mutation of gene for mineralocorticoid receptor
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Ser810leu, receptor sensitive to progesterone. The explanation
of preeklampisa?!)
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Monogenic hypertension – 2
sodium transport
Increased stimulation of Na-K ATPase (transporter)
caused by mutation of adducin gene (cytoskeletal
protein)
Liddle sy (AD). Gain of function mutation of the gene for
one subunit of sodium channel ENaC. A common
mutation in Africa?
Cys825Thr polymorphysm of gene for b subunit of a G
protein activating Na/H antiporter
Other mutations of Na-transport systems
Background of salt sensitivty???
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Monogenic hypertension – 3
other possibilities
Polymorphysm of ACE gene. Big gene, 26 exons, 17.
chromosome
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Insertion/deletion of 287 bp in the 16th intron
ID and DD have higher ACE activity than DD
Epistatic interactions with other genes – e.g. with gene for
angiotensin receptor.
Polymorphysm of angiotensinogen gene
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Met235thr – higher risk of coronary events and HT. No salt
sensitivity
Polymorphysm of NOS gene
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NO is an important antagonist of different vasoconstricting factors.
An important mediator of pressure diuresis.
And many others
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Secondary hypertension - 1
Renal
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Renoparenchymal (decrease of nephron number)
Renovascular (stenosis of a. renalis – RAAS)
Endocrine
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Phaeochromocytoma – paroxysmal HT
Conn, Cushing, other diseases of adrenal cortex
Acromegaly
HT during gravidity, EPH gestosis
(preeclampsia)
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Secondary hypertension - 2
Cardiovascular
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Coarctation of aorta (upper part of body)
Isolated systolic: loss of flexibility of vessel wall
in advanced age
Isolated systolic in aortal regurgitation & AV
shunts
Neurogenic
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High intracranial pressure – transitory
Lead intoxication
Iatrogenic
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Secondary hypertension - ???
How to classify hypertension
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Associated with obesity ?
Associated with insuline resistance ?
Associated with Type 2 diabetes mellitus ?
Associated with sleep apnoea syndrome ?
How to classify stress hypertension ?
A LOT OF PRIMARY HTs ARE
NONDIAGNOSED CONNs ?
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Natural history of hypertension
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Natural history of hypertension
yes, but...
Most cases of deaths occur in patients
wihth mild hypertension
Moderately elevated risk*high number of
patients
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Factors influencing prognosis
1 – CVS risk factors
II. Other factors
I. Basic factors
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 sBP and dBP
age m > 55, f > 65 y.
smoking
cholesterol > 6,5
mmol/l
diabetes mellitus
+ Family history
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 HDL CH  LDL CH
iGT
obesity
 fibrinogen
certain socioeconomic,
ethnic groups
certain geographic
regions
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Factors influencing prognosis
2 – organ damage
left heart hypertrophy
proteinuria and/or  creatinine
USG or RTG confirmed atherosclerotic
plaques (a. carotis, iliaca, femoralis, aorta)
generalised or focal narrowing of retinal
arteries
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Factors influencing prognosis
3 – other clinical conditions
cerebrovascular
diseases
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ischemic stroke
TIA
hemorrhagic stroke
diseases of heart
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myocardial infarct
angina pectoris
heart failure
revascularsation
diseases of kidneys
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vascular diseases
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dissecting aneurysma
symptomatic vascular
diseases
advanced retinopathy
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diabetic nephropathy
microalbuminuria in DM
kidney failure
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bleeding, exsudation
papillar oedema
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