HYPERTENSION CIRCULATORY SYSTEM x Left atrium, left ventricle Arteries, arterioles Systemic capillaries x Portal circulation Venules, venes Right atrium, right ventricle x Pulmonary arteries x Pulmonary capillaries x Pulmonary venes x Lymphatic vessels Jugular ^uln {alio njbcldvlun -vein from arm-s) Superior vena cava Inlerl-or vena cava — HtfpdMc Jjcf lal vein-Ren-cri vein ili-ac vein Carotid artery fdlw fyv^ctSJldFi cnt#ry lo opim*} Pulmctidy vein 4-,-jrra -Mesenteric ait-erles. Renal artery Blac artery VESSEL CAPACITY AND RESISTANCE Part of circulatory system % ml Pulmonary circulation 9% 450 Heart 7% 350 Arteries 13% 650 Arterioles and capillaries 7% 350 Venules, venes and venous sinuses 64% 3200 ARTERIAL BLOOD PRESSURE - DEFINITION x p = qr>TR x Analogous to Ohm's law defining voltage x Tensor in moving viscous fluid x Vessel wall is challenged by its radial member (i.e. pointing towards the endothelium) + Systolic - on the top of the pulse curve + Diastolic - on the bottom of the pulse curve + Pulse - pulse curve amplitude + Mean - average pressure during the cycle Isovokimic relaxation Isovolumic contraction Ejection Rapid inflow Atrial systole Aortic pressure , Atrial pressure ■" Ventricular pressure Ventricular volume Electrocardiogram Phonocardiogram Systole Systole SHEAR STRESS x Dimension: N.m2 (Pa) - same as in blood pressure, axial vector fluid shear stress: X = 4l]Q/I 37I wall tension (Laplace) Sites with low and/or variable shear stress (sharp turns, bifurcations) are especially prone to the onset of atherosclerosis Laminar Flow Regions of Disrupted Flow Risk Factors: Hypertension Smoking Hypercholesterolemia Diabetes Mellitus leNOS I Endothelial Repair Focal Req ion of Decreased ...... . . — . iCytoskeletal/Cellular Shear Around Curvature *.,._____,. ___< rr„ Alignment in Direction of Flow T Reactive Oxygen Species tLeukocyte Adhesion TLipoprotein Permeability T Inflammation _ Atherosclerotic Plaque RESISTANCE x R [kg.s^.m4]: can be obtained from Hagen-Poiseuill law: R = 8xr|xd/7ix r4,where: r| = viscosity d = lenght of the segment r = radius R,= 5 R,= 10 R3 = 20 PERIPHERAL RESISTANCE x The resistance increases inversely to the radius at the power of 4 x The decrease in radius is most evident in arterioles x The smooth muscle tone in the wall of arterioles changes depending on many factors - this controls peripheral resistance (^peripheral arterioles") VASCULAR SMOOTH MUSCLE TONE Vasodilatation + NO - produced in the endothelium by constitutive (eNOS) and inducible (iNOS) synthase cGMP, cAMP prostacyclins catecholamines histamine bradykinin p02, pC02 ,pH + + + + + + Vasoconstriction + Endothelin + Ca2+ + ATM + ADH + catecholamines ARTERIAL WALL ELASTICITY (ELASTIC ARTERIES) Elasti c a rterie s St iff a rte ries y Systol i dp ulse p ressu re * Sy sto lie/pulse p ress u re * Diastolic flow Diastolic flow x Worsens with age x Loss of elasticity (arterial stiffness) leads to isolated systolic hypertension CARDIAC OUTPUT x Q: is equal to cardiac output (CO) - anatomic shunts CO = SV (stroke volume) x f SV= EDV (enddiastolic volume) - ESV (endsystolic volume) EF [%] = SV/EDV • CO is physiologically equal to venous return (depends on circulating volume) • In very high HR the CO paradoxically decreases (the ventricles are not filled efectively) RENAL FUNCTION CURVE x Provided the renal functions are untouched, the increase in CO or resistance can be compensated by lowering of circulating volume NO, CO, NMDA *S 4 N O -<1> C |S 3 cl dopamin kininy, ANP prostacyklin 1,-teceptory eza/Nati 0 □ X 1 J 50 150 This can be disturbed under pathological conditions -hypervolemia BLOOD PRESSURE REGULATION x Several interconnected systems x Regulation of: + heart rate + cardiac contractility + peripheral resistance + circulating volume VEGETATIVE REGULATION OF THE BLOOD PRESSURE x fastest regulation x afferentation - baroreceptors in glomus caroticum, arcus aortae; central and peripheral chemoreceptors x centre - nucleus tractus solitarii (NTS), area postrema, rostral ventrolateral medulla (RVLM) with imidazolin receptors x Efferentation - heart (esp. pi and M2 receptors), vessels (esp. al receptors), kidney (al, a2, 31) x Circulating catecholamines Resistsnco vessel JUXTAGLOMERULAR APPARATUS Three inputs: • NaCI in distal tubule • Stretching of afferent artery • Sympathetic nervous system RENIN ANGIOTENSIN ALDOSTERONE Angiotensin I An (■iutc-nif i n Renin —>■ Angiotensin II I Angiottnui n cfiiivcrling ± 1 f fll " T -Aldosterone Sntfiiim hS Wjiicr ^trenfion 1 EntrcHKud (IF VflsrjtiinslHellen If curt Renin (and prorenin) binds the (pro)renin receptor (PRR) The binding increases the enzymatic activity of renin and leads to receptor activation (involved in central BP regulation) Renin also cleaves angiotensin I (dekapetide) from angiotensinogen ACE AND ACE 2 Ang 1-9 < Angl t-\ ACE2 (-\ AP (-1 I Ang 1-7 j ^- [ Ang II ] -> [ Ang III Ang 2-10 CE < > f (_An gill Angiotensin I (Ang I) can be then transformed into several products Through ACE action, Ang II and Ang III with vasoconstriction effects are formed ACE also degrades bradykinin (pharmacologic inhibition of ACE leads to angioedema) Through the action of ACE 2, angiotensin 1-7 is formed, having vasodilatation and antiproliferation effect on vessel wall (contributing to the decrease of peripheral resistance - Mas receptors ANGIOTENSIN II RECEPTORS AND SYSTEMIC EFFECTS OF ALDOSTERONE_ Renin Chymase K+ ATM JW renal Endothelin - Aldosterone Heart Interstitial fibrosis Heart failure Kidney I Salt and fluid retention K+secretion Congestion Electrolyte imbalance Other effects (endothelial dysfunction, platelet aggregation) T Bradykinin TNO TPGs Tt-PA(4.PAI-1) Vasodilation Anti proliferation 4. Ang I at1 Vasoconstriction Hypertrophy Proliferation TNE t Thirst TNa+ retention TPAI-1 (4t-PA) t Oxidation Inflammation Growth Vasoconstriction Thrombosis ACE I Angiotensinogen Ang I AT2 MO Anti proliferation Vasodilation Anti-inflammation Antigrowth Antioxidative AT4 ■ Laminin I Pal-1 TNOJ-ETJ.TIMP-1 Maintenance of vascular intergrity Sou ret: Fuster V, Walsh RAr Harrington RA: Hurst's The Heart, Copyright © The McGraw-Hill Companies, Inc. All rights reserved. at (1-7) -I BP 4. Growth tPGs TNO x AT 2 receptors are mostly involved in fetal development Ang III is mostly involved in aldosterone secretion and in the CNS CIRCADIAN RHYTHMICITY OF THE BP 110 X £ 10! § 01 90 S? ■D O 80 o CD & AM 2 pm n=5$ BP drops by -10-20% at night (^dipping") Hypertonics „non-dippers" have approx. 2,5x higher odds of cardiovascular events than „dippers" In some „non-dippers" there may be disturbed melatonin secretion (shift work...), often, the absence of the drop results from obstructive sleep apnea CARDIOVASCULAR EVENTS DURING 24-H CYCLE 180 -i ----Stroke {n = 1,167) E 160 o 140 CM 0) s120 en J 100 > i5 o to > 9 £ ü 80 60 40 20 0 Myocardial infarction (n = 2,999) Early morning blood pressure surge 18.00 0.00 06.00 Time of day r 12.00 r50 45 -40 35 -30 -2b 20 -15 -10 -5 0 a 03 c O 4—* OS c o o x The incidence of myocardial infarctions and cerebral strokes peaks before noon x The patients with sleep apnea make an exception OBSTRUCTIVE SLEEP APNEA Opened Upper Airway Closed Upper Airway Clear and open upper airway Snoring and apnoeas (breathing allows air to flow freely to and pauses) are observed when the from the lungs. upper airway collapses. Intermittent apnea (up to 60 s) with hypoxia leading into SNS activation at night Caused by the loss of muscle tone in upper airways (soft palate) - associated with snoring x 4-30% of men (underdiagnosed), up to 9% of women Risk factors: obesity, high neck circumference, alcohol intake (having central myorelaxant properties) Effects: higher BP and risk of cardiovascular events at night chronic stress, cognitive disorders (memory), sleepiness, headache NORMAL BLOOD PRESSURE AND HYPERTENSION A. veškerá populace O C O — fyziologická populační variabilita X morbidita / mortalita polygenní "komplexní" porucha hypertenze t t—r systolický krevní tlak (mmHg) B. zdravá populace 1 monogen m poruchy ■' m \ 1SD / referenční 1 " Interval 1 [95%) BP is continuous parameter with characteristic population distribution Setting the border of "normality" is always arbitrary -»"reference interval" (contains 95% of healthy population, excluding outlying 5%) In parameters with normal (Gaussian) distribution mean + 2SD In other parameters generally median [2.5%-97.5% quantile] general population does not to have optimal values of the parameter! Value-associated mortality is often taken into account Reference interval may be adjusted based on prospective studies tolicky krevní tlak (mmHg) HYPERTENSION + BP > 140/90 mmHg (during day) in an adult regardless the age after >10min of rest repeatedly min. 2x out of 3 measurements in several days x In diabetes and in chronic renal failure, the BP should be <130/80mmHg x Ideal BP in an adult - SBP<120 and DBP<80mmHg + stage of hypertension x mild 140 - 179/90 - 104 x moderate 180 - 199/105 -114 x high > 200/115 x isolated systolic hypertension SBP >160 with DBP <90 mmHg x resistant >140/90 with the combination of 3 antihypertensives + stage of end-organ damage I - increased BP without affecting the end-organ II - organ involvement - LV hypertrophy, microalbumin-/proteinuria, aortic calcification III - organ failure: heart failure, renal insufficiency, cerebral stroke PATH OG EN ESIS x essential - 90-95% + Concommitant dysregulation of several mechanisms x secondary - 5-10% renal x renovascular x renoparenchymatous endocrine x adrenal gland * prim, hyperaldosteronism * Cushingsyndrome * pheochromocytoma x others * Acromegaly * Hyperthyroidism Other causes * Aortic coarctation NTIAL HYPERTENSION SNS activation ■—> increased CO NaCI income RAAS activation "=>vasoconstriction \ 1 x Disturbed renal function curve - hypervolemia -1 x Arterial stiffness c V arterial resistance Hypertension HEART AND VESSEL REMODELATION x Consequence of long-term hypertension x In fact a compensatory mechanism + heart - reacts to increased preload in hypervolemia or afterload in peripheral resistance + vessels - compensate higher CO, arterial stiffness and/or hypervolemia by higher resistance x RAAS components - (pro)renin, angiotensin, aldosterone - play an important role CONSEQUENCES OF x Heart + hypertrophy x Kidney + nephrosclerosis x Brain + encephalopathy + dementia + hemorrhagic stroke x Vessel wall + atherosclerosis (esp. of heart and brain) Normal heart Hypertensive heart Thickening in —1 walls of ventricles METABOLIC SYNDROME x Hypertension x Dyslipidemia x Insulin resistance x Central obesity + Often accompanied by: x hyperuricemia > long-term increase of HR > | fibrinogen x long-term | CRP > | oestrogens P AND MORTALITY - TOTAL, IHD AND STROK A: Systolic; hlaod pressure B: Diastolic blood pressure g Achieved diastolic blood pressure ;l i5 mm Ms 105-1 14 mm Hj 90-104 mm Hjj <90 rnm Hg 35-H4 Ase (y) — ^ 81 -1— 13« '.40 IKS U^|.;:I ihvsIci:: rMoo[i pressura (mm 4gj A: Systolic blood pressure h 7G I BO I usual diastolic blood pressure (mm HgJ Br Diastolic biood pressure linear correlation in SBP, exponential in DBP si 1 1Ü 2 5 ! ii: 2 usual systolic blood nrer^urr; (r SO 90 100 usual diastolic blood GENETICS OF ESSENTIAL HYPERTENSION x Usually polygenic x Ratio of heritable vs. all factors in overall variability 20-70% (most studies approx. 40%) + Only small proportion (several percents) is identified + Usually variants in: SNS RAAS sodium transport mechanisms vasodilatory mechanism Most of total heritability is unidentified ("missing heritability") + Rare monogenic forms (mineralocorticoid overproduction, Liddle syndrome) THERAPEUTIC STRATEGIES x Lowering of SNS activity x Lowering of CO x Lowering of vascular resistance x Adjustment of renal function curve Potential sites of action for antihypertensive drugs CNS: beta blockers alpha2 agonists CID Blood vessels; alpha^ receptor blockers calcium channel blockers vasodilators AT| receptor antagonists ACE inhibitors Heart: beta blockers Kidney: diuretics beta blockers ACE inhibitors MEASURING THE BP - METHODS x Invasive (veins, pulmonary circulation, heart chambers) + Catheter with a fluid x Non-invasive 4 Occasional 4 Ambulatory 4 Continual (digital fotoplethysmography) BLOOD PRESSURE - OSCILLOMETRY METHOD • By oscillometry, the mean blood pressure is measured accurately, SBP and DBP are estimated Cu tV i ni Uii iuit CufFdeflation BLOOD PRESSURE - RIVA-ROCCI METHOD SYSTEMIC ARTERIAL PRESSURE CUFF PRESSURE 110- I 90- E E 70- LU QC => 50- GO 00 — LU tr 30- CL _ 10- SYSTOLIC PRESSURE DIASTOLIC PRESSURE INFLATION BULB SPHYGMOMANOMETER CUFF ARTERIAL PRESSURE PULSES • SBP and DBP are exact mean blood pressure is estimated AMBULATORY BLOOD PRESSURE MONITORING x ABPM („blood pressure Holter") x Intermittent monitoring x Measurements by oscillometry method in approx. 15 min interval (30-60 min at night) x Alternative: continual BP monitoring using digital fotoplethysmography (Pefiaz method) + A detector measures the intensity of light passing through the finger, uses negative feedback loop A change in blood flow in digital arteries leads into the change in light intensity; change of cuff pressure needed for correction = change of blood pressure + Cannot be used in peripheral vasoconstriction ^„ ABPM INDICATION x Diagnostics of collapses (together with Holter ECG) x Pharmacoresistant hypertension x Paroxysmal hypertension (often in pheochromocytoma) x White coat hypertension - values in home environment are typically lower than in clinical environment -therefore, the limits are stricter: <135/85 during the day, <120/70 at night - more than 40% of values above those limits point to arterial hypertension - according to prospective studies, the ABPM has better prognostic ability to predict cardiovascular events than occasional measurement CHANGES IN BP DURING 24 HOURS