MUNI MED Lékařská fakulta Masarykovy univerzity CIRCULATORY SYSTEM - x Left atrium, left ventricle x 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 ARTERIAL BLOOD PRESSURE - DEFINITION X P = Q X R 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 isovolumic relaxation Isovolumic contraction Ejection Rapid inflow Atrial systole Diastasis 120n Aortic value opens _ 100 E *H E V 60H 3 A-V valve to 40 -| doses °- 20-0- =^130-| 1 W-\ > 50-1 ~-- Aortic pressure ^Atrial pressure Ventricular pressure Ventricular volume Electrocardiogram Phonocardiogram Systole Systole HEAR STR urwL/ o 11 / x Dimension: N.m2 (Pa) - same as in blood pressure, axial vector fluid shear stress: t = 4t]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 ieNOS I Endothelial Repair Focal Region of Decreased * » j « i iCytoskeletal/Cellular Shear Around Curvature _____,. ___, Alignment in Direction of Flow T Reactive Oxygen Species TLeukocyte Adhesion TLipoprotein Permeability f Inflammation Atherosclerotic Plaque 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) CARDIAC AND VENOUS FUNCTION CURVE right atrial pressure, mmHg RENAL FUNCTION CURVE x Provided the renal functions are untouched, the increase in CO or resistance can be compensated by lowering of circulating volume CO S N O -0) C I.J CO ._ Z £ n E i= O 2 c □ x c angiotenzin II sympatikus aldosteron ADH, endotelin tromboxan 50 NO, CO, NMDA CD iS ^ N O ■Ö c 1? 3 dopamin kininy, ANP prostacyklin 1,+eceptory CO — Z c "co-ra 2 N £ 0 Diu re x nor J 100 150 Stfednf arteriäini tlak (mm Hg) 50 150 This can be disturbed under pathological conditions -hypervolemia Part of circulatory system % ml Pulmonary circulation 9% 450 Heart 7% 350 Arteries 13% 650 1 Arterioles and , capillaries 7% 350 Venules, venes and venous sinuses 64% 3200 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 R, = 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 + prostacyclins + histamine + bradykinin + p02, pC02,pH + adenosine + catecholamines + cGMP, cAMP Vasoconstriction + endothelin + ATM + ADH + catecholamines + thromboxane A2 + Ca2+ ^Ca++—> ^Cyclooxyg endothelium Acetylcholine ATP Adenosine Bradykinin Histamine L-arginine Vessel lumen ARTERIAL WALL ELASTICITY (ELASTIC ARTERIES) Elastic arteries . ttttt Stiff arteries y Systolic/pulse pressure * Diastolic flow 7t Systolic/pulse pressure üj Diastolic flew x Worsens with age x Loss of elasticity (arterial stiffness) leads to isolated systolic hypertension BLOOD PRESSURE REGULATION x Several interconnected systems x Regulation of: + heart rate + cardiac contractility + peripheral resistance + circulating volume VEGETATIVE REGULATION OF THE BLOOD PRESSURE fastest regulation afferentation - baroreceptors in glomus caroticum, arcus aortae; central and peripheral chemoreceptors centre - nucleus tractus solitarii (NTS), area postrema, rostral ventrolateral medulla (RVLM) with imidazolin receptors Efferentation - heart (esp. |31 and M2 receptors), vessels (esp. al receptors), kidney (al, a2, 31) Circulating catecholamines Medulla oblongata Spinal cord Ganglion Resistance vessel JUXTAGLOMERULAR APPARATUS Three inputs: • NaCI in distal tubule • Stretching of afferent artery • Sympathetic nervous system RENIN ANGIOTENSIN A AnrioEtitfin I $1 inter Angiotonsi nngen Klti i i Kutirry —► AjigHtEcnsin II I T -Aldosterone Sillium hS Wjilcr I Ifrurt 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 Ang2-10 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 3d 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(iPAI-l) Vasodilation Anti proliferation J. Ang I AT1 Vasoconstriction Hypertrophy Proliferation TNE "Thirst T Na* retention TPAI-1 (it-PA) T Oxidation Inflammation Growth Vasoconstriction Thrombosis ACE i Angiotensinogen Ang I AT2 NO Anti pro I iteration Vasodilation Anti-inflammation Antigrowth Antioxidative AT4 //YV*1 Laminin /I \ MPal-1 T NO J- ET J. TIMP-1 Maintenance of vascular intergrity AT (1-7) J. BP J. Growth tPGs TNO Source: Fuster V, Walsh FAr HarririgLo n F.P,: Hurst's The Heart, Utfi Edition: irVwvy.acce&smerJicine.corn Copyright © The McGraw-Hill Companies, Inc. All rights reserved. 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 Hi E 1(> E ■ £> 3 (A » □. "D o ao D 70 Bah 2 pm - n=58 BP drops by -10-20% at night („dipping") Hypertonics „non-dippers" have approx. 2,5x higher odds of cardiovascular events than „dippers" Exaggerated dipping may lead into tissue ischemia, including brain In some „non-dippers" there may be disturbed melatonin secretion (shift work...), often, the absence of the drop results from sleep apnea or secondary hypertension Exsessive dipping: vegetative dysbalance, drugs CARDIOVASCULAR EVENTS DURING 24-H CYCLE nWUnlAAWOOnrVfLc l ACM I O nnUIMn ~t+-U P I nrr 180 -i £ 160 0 ^ 140 is 80 o 60 A 40 -J o Stroke (n = 1,167) Myocardial infarction (n = 2,999) Early morning blood pressure surge - - I 18.00 0.00 Time of day 06.00 -30 50 45 ■40 o 35 * B) C O 25 £ as h20 1 9 15 P o o -10 -5 12.00 x The incidence of myocardial infarctions and cerebral strokes peaks before noon x The patients with sleep apnea syndrom make an exception OBSTRUCTIVE SLEEP APNEA Opened Upper Airway Closed Upper Airway Clear and open upper airway allows air to flow freely to and from the lungs. Snoring and apnoeas (breathing pauses) are observed when the 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 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 P APNEA x Respiratory activity alternates with apnoeic pauses with no respiratory effort + Technically, a result of high hysteresis and high inertia („wrongly set thermostat") + Hypercapnia -> hyperventilation -> hypocapnia -> apnea -> hypercapnia x Causes: respiratory centre diseases drugs (e.g. opiates) heart failure (stimulation of respiratory centre mediated by pulmonary J-receptors vs. inhibition by hypocapnia x Cheyne-Stokes breathing Microawakening occurs at the top of crescendo phase ->decrescendo Aside of CSA, this also occur in altitude sickness, alkalosis x Prevalence: approximately 1 % same as in central hypoventilation SLEEP APNEA SYNDROMES Obstructive Sleep Apnea I}. V,-,,,., Airfluw EfTon W ii: Mil. 'i Eft™__J, Oj-iil^i-miiwi Central Sleep Apnea 'jijiit-——A xOSA + more likely during REM phase + chest movements during apnoeic pauses + BP is very variable sympathetic activation vs. lower left ventricle output in Muller manoeuvre treatment: continuous overpressure ventilation (CPAP) x csa + more likely during NREM phase + no chest movements during apnoeic pauses + BP not much variable treatment: adaptive overpressure ventilation (ASV), recently phrenic nerve stimulation NORMAL BLOOD PRESSURE AND HYPERTENSION A. veškerá populace fyziologická populační variabilita X morbidita / mortalita polygenní — ""komplexní porucha O c j-j o hypertenze monogen ni poruchy i i—r systolický krevní tlak (mmHg) B. zdravá populace O 1SD 1SD " referenční 1 interval [95%) I 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 systolický 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 re no parenchymatous 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 ^ x Disturbed renal function curve - hypervolemia -1 x Arterial stiffness c V arterial resistance 4y 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 HYPERTENSION 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 STROKE' E 120 H i i -s ! Achieved diastolic blood pressure illS rnrn Mr 105-1 14 mm Hj 90-104 mm Hg <% mm Hg 15-24 25-34 35-44 A|fi (y) 45-54 55*4 65-74 A: Systolic 11 I s _ ~ —I— 120 140 Uki.;:I syskVi:: :::oorJ pressure (rum hig) A: Systolic blood pressure B: Diastolic blood pressure 11 -I I 70 I BO I Ukue]I [iiil5l[]liC tjliKXj pressure (mm Hg) B: Diastolic blood pressure linear correlation in SBP, exponential in DBP ao 90 loo no Usual systolic blood pressure (mm H|J Usual diastolic blood pf^SSUre (mm HtfJ GENETICS OF ESSENTIAL HYPERTENSION rjCMir i ioo nu u99ci^ i iwr lj i lcu i iti/ioiom 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 Lowering of CO x Lowering of vascular resistance x Adjustment of renal function curve Potential sites of action for antihypertensive drugs 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 BLOOD PRESSURE - RIVA-ROCCI METHOD SYSTEMIC ARTERIAL PRESSURE CUFF PRESSURE SYSTOLIC AMBULATORY BLOOD PRESSURE MONITORING x ABPM („blood pressure Ho Iter") x Intermittent monitoring x Measurements by oscillometric 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 intra r e :l Iransir ision Plethysmograph Inflatable lingGr cuff Continuous noninvasive blood pressure measurement ABPM INDICATIONS 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