Hypertension Lectures from Pathological Physiology Study materials from

Hypertension Lectures from Pathological Physiology Study materials from Pathological Physiology, school year 2020 – 2021 © Oliver Racz 27/02/2021 kvs 2107 e 1

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 27/02/2021 kvs 2107 e 2

Repetition of physiology, basic terms- 1 What is blood pressure (BP) ? n n n 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/m 2 (Pascals, Pa) 1 mm. Hg = 0, 133 k. Pa For the body the tissue perfusion is essential = oxygen supply 27/02/2021 kvs 2107 e 3

Repetition of physiology, basic terms- 2 Determinants of BP n n n Heart function (pump) - catch 22 Circulating volume Elasticity and tension of vessel wall Which pressures and where ? n n s. BP, d. BP, mean arterial pressure Mean filling pressure 27/02/2021 kvs 2107 e 4

Blood pressure 27/02/2021 kvs 2107 e 5

Repetition of physiology, basic terms – 3 Mean arterial BP § § § = d. BP + 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 mm. Hg n n 27/02/2021 Experiment: Arterial pressure after heart arrest This is determining the filling of right ventricle = venous return kvs 2107 e 6

The distribution of blood in circulation 27/02/2021 kvs 2107 e 7

Microcirculation Resistance arterioles 0, 5 – 0, 15 mm 4 – 5 branchings to terminal arterioles 10 mm Capillaries Blood flow velocity in aorta ( 3 – 4 cm 2) 0, 2 – 0, 3 m/s In capillaries 0, 3 mm/s 3000 – 4000 cm 2 Only one third of them is open 1000 cm 2 The hemodynamic resistance is directly proportional to the length of vessel and indirectly proportional to the 4 th square of vessel diameter n n n Increase of diameter by 1, 2 – resistance decreases to 50 %, 1, 8 -fold increase - decrease to 10 % and conversely !!! 27/02/2021 kvs 2107 e 8

Examples of changes in resistance without changes of BP Hypoxia n n Vasodilatation Venous return Cardiac output Hyperkinetic circulation without pressure change A-V shunts n Decrease of TPR Amputation of LE n Increase of TPR No change in BP 27/02/2021 kvs 2107 e 9

Overview of blood pressure regulators Baroreceptors Chemoreceptors Ischemic response of CNS Immediate reaction - limited effectivity 27/02/2021 kvs 2107 e 10

Overview of blood pressure regulators LOCAL Pressure relaxation of vessel wall Fluid shift (Frank – Starling) HORMONAL Renin – angiotensin – aldosterone system (& its antagonists – natriuretic hormones) Antidiuretic hormone Slower reaction, limited effectivity 27/02/2021 kvs 2107 e 11

Regulation of microcirculation Extremely complicated mechanisms n n Metabolic – hypoxia, ATP, p. H, 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 27/02/2021 kvs 2107 e 12

A SIMPLE MODEL OF BLOOD PRESSURE REGULATION THE OUTPUT FROM CENTRAL HEATING UNIT (HEART) DEPENDS ON THE DEMAND OF PERIPHERAL UNITS (TISSUES, ORGANS) kvs 21 edent 13 26. 2. 2021

Overview of blood pressure regulators LONG TERM, ALMOST UNLIMITED EFFECTIVITY kidney – regulation of volume Proofs – kidney crosstransplantations between HT & NT rats, human kidney transplantations 27/02/2021 kvs 2107 e 14

The effectivity of blood pressure regulators 27/02/2021 kvs 2107 e 15

Goldblatt and his experiments Bright 1832: Large, heavy heart and scarred kidney Harry Goldblatt, a recipient of final-year prize at Mc. Gill, 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 27/02/2021 kvs 2107 e 16

Autoregulation of blood flow and glomerular filtration in kidneys renal blood flow ml/min glomerular filtration, ml/min 50 27/02/2021 100 kvs 2107 e 150 200 17

Constant filtration achieved by regulation of vas afferens a efferens tonus 27/02/2021 kvs 2107 e 18

Natriuresis Filtration does not depend on blood pressure, diuresis & natriuresis strongly depends !!! 50 27/02/2021 100 kvs 2107 e 150 200 19

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 n 27/02/2021 kvs 2107 e 2/3 proximal tubules 1/4 Henle loop 1/12 distal tubules 20

Pressure diuresis Kidney blood flow does not depend on BP Diuresis & natriuresis depend Pressure increase by 10 – 20 mm. Hg – twofold increase of diuresis Rapid response – begins in 1 minute Mechanism – reabsorbtion of sodium Regulated by macula densa 27/02/2021 kvs 2107 e 21

Hypertension is always connected with change of kidney pressure diuresis !!! 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 27/02/2021 kvs 2107 e 22

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 mm. Hg & diastolic blood pressure ≥ 90 mm. Hg (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) 27/02/2021 kvs 2107 e 23

Classification of hypertension According to values of BP, see According to its etiology (pathogenesis) n n primary (95 %? ) secondary forms of hypertension (5%? ) According to the stage of disease 1. 2. 3. 27/02/2021 Only hypertension Manifest damage of organs – heart hypertrophy, nephropathy & changes of ocular fundus = remodelation of small vessels Heart and kidney failure, hemorrhagic stroke kvs 2107 e 24

CATEGORY s. BP d. BP < 120 < 80 Prehypertension 120 - 139 80 - 89 Hypertension I 140 – 159 90 – 99 Hypertension II ≥ 160 ≥ 100 Normal 27/02/2021 kvs 2107 e 25

Circadian changes of BP 24 hour monitoring Decrease after 8 p. m. 11 p. m. – 05 a. m. by 20 % (20 – 30 mm. Hg) 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 27/02/2021 kvs 2107 e 26

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 27/02/2021 kvs 2107 e 27

Some more epidemiological data Age: n n n 20 – 30 40 – 50 60 & more < 10 % 25 % 33 % Sex n n Up to age 50 y. After 50 y. f/m 0, 6 – 0, 7 f/m 1, 1 – 1, 2 Weight n n Normal Obesity 27/02/2021 8 – 15 % 15 – 35 % kvs 2107 e 28

Primary hypertension The cause and the pathogenesis is not fully clear n n Our old and simple explanation Disturbance of pressure diuretic curve of kidneys Kitchen salt ? Dysfunction of endothel ? Hypertension as a „complex“ disease Ø Ø Ø Monogenic diseases (also HT, rare) Diseases caused by external factors Genetic background and external factors 27/02/2021 kvs 2107 e 29

Reaction of circulation on physical and psychical stress HYPERTENSION 150 ? ? ? NORMOTENSION 100 27/02/2021 kvs 2107 e 30

„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 ? ? ? 27/02/2021 kvs 2107 e 31

Natriuresis Change in pressure diuresis curve – 1 50 27/02/2021 100 kvs 2107 e 150 200 32

Natriuresis Change in pressure diuresis curve – 2 50 27/02/2021 100 kvs 2107 e 150 200 33

Hypertension is a complex disease Gene polymorphism n n n n External factors Renin, ACE, AT NOS Kallikreine Endotheline Na-K ATPase Adducin More than 50 27/02/2021 n n n kvs 2107 e Na. Cl (10 g instead of 0, 5) Stress Deficiency of Ca, Mg Obesity Smoking, alcohol And many others 34

Monogenic hypertension – 1 problems with aldosterone Some forms of congenital adrenal hyperplasia Hyperaldosteronism responding to glucocorticoids (AD) n 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 n Mineralocorticoid receptor sensitive to cortisol (glucocorticoid acts as mineralo – increased Na reabsorption without reason) Mutation of gene for mineralocorticoid receptor n Ser 810 leu, receptor sensitive to progesterone. The explanation of preeklampisa? !) 27/02/2021 kvs 2107 e 35

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 ENa. C. A common mutation in Africa? Cys 825 Thr polymorphysm of gene for b subunit of a G protein activating Na/H antiporter Other mutations of Na-transport systems Background of salt sensitivty? ? ? 27/02/2021 kvs 2107 e 36

Monogenic hypertension – 3 other possibilities Polymorphysm of ACE gene. Big gene, 26 exons, 17. chromosome n n n Insertion/deletion of 287 bp in the 16 th 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 n Met 235 thr – higher risk of coronary events and HT. No salt sensitivity Polymorphysm of NOS gene n NO is an important antagonist of different vasoconstricting factors. An important mediator of pressure diuresis. And many others 27/02/2021 kvs 2107 e 37

Secondary hypertension - 1 Renal n n Renoparenchymal (decrease of nephron number) Renovascular (stenosis of a. renalis – RAAS) Endocrine n n n Phaeochromocytoma – paroxysmal HT Conn, Cushing, other diseases of adrenal cortex Acromegaly HT during gravidity, EPH gestosis (preeclampsia) 27/02/2021 kvs 2107 e 38

Secondary hypertension - 2 Cardiovascular n n n 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 n n High intracranial pressure – transitory Lead intoxication Iatrogenic 27/02/2021 kvs 2107 e 39

Secondary hypertension - ? ? ? How to classify hypertension n n 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 ? 27/02/2021 kvs 2107 e 40

Natural history of hypertension 27/02/2021 kvs 2107 e 41

Factors influencing prognosis 1 – CVS risk factors II. Other factors I. Basic factors n n n s. BP and d. BP age m > 55, f > 65 y. smoking cholesterol > 6, 5 mmol/l diabetes mellitus + Family history 27/02/2021 n n n kvs 2107 e HDL CH LDL CH i. GT obesity fibrinogen certain socioeconomic, ethnic groups certain geographic regions 42

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 27/02/2021 kvs 2107 e 43

Factors influencing prognosis 3 – other clinical conditions cerebrovascular diseases n n n ischemic stroke TIA hemorrhagic stroke diseases of heart n n myocardial infarct angina pectoris heart failure revascularsation diseases of kidneys n n n vascular diseases n n dissecting aneurysma symptomatic vascular diseases advanced retinopathy n n 27/02/2021 diabetic nephropathy microalbuminuria in DM kidney failure kvs 2107 e bleeding, exsudation papillar oedema 44