Physiological Aspects of Major Cardiovascular Pathologies: Arterial Hypertension Ischemic Heart Disease Assoc. Prof. MUDr. Markéta Bébarová, Ph.D. Dept. of Physiology, Faculty of Medicine, Masaryk University Ischemic Heart Disease Coronary Circulation •a. cor. sinistra (85%) •a. cor. dextra Ganong´s Review od Medical Physiology, 23rd edition Guyton and Hall. Textbook of Medical Physiology, 11th edition •epicardial coronary arteries •intramuscular arteries •plexus of subendocardial arteries Rozdíl v průtoku subendokardem a subepikardem hraje významnou roli u určitých typů koronární ischémie. Coronary Circulation •the resting blood flow: 225 ml/min (4-5% of CO) •increases at physical exertion, mental stress, … •O2 extraction is almost maximal already at rest, capillaries are open •The only possibility how to increase O2 supply is the coronary vasodilation! •metabolic vasodilation, sympathicus/parasympathicus Coronary Reserve •ability of coronary vessels to adapt blood flow to the actual cardiac work (ergometry) •the maximal blood flow / the resting blood flow •reduction of the coronary reserve: -relative coronary insufficiency (too high resting demands, high resting blood flow cannot be sufficiently increased) -absolute coronary insufficiency (~ ischemic heart disease) (the stenotic arteriosclerotic process) Reduced coronary reserve is a limiting factor of the cardiac output, thus, also of the effort of organism! Za stenózou je již v klidu vazodilatace, v důsledku snahy zabezpečit dostatečný krevní průtok. Při námaze je tím pádem koronární rezerva nedostatečná (část již vyčerpaná v klidu) a vznikají projevy ischemie myokardu. Ischemic Heart Disease •the most often cardiac disease in Western culture •about 1/3 of all deaths •causes of death: -acute coronary occlusion -ventricular fibrillation - - -slow, progressive weekening of contractility due to slowly increasing myocardial ischemia (the most often cause of the congestive heart failure) - = ischemic heart disease, coronary artery disease •vs. myocardial ischemia (a more general term; anaemia, hypotension, myocardial hypertrophy, thyreotoxicosis) ICHS vs. ischémie myokardu (obecnější pojem - i stavy, kdy nedostatečný přísun O2 vzniká na nekoronárním podkladu, např. anémie, hemoglobinopatie, hypotenze-pokles perfúzního tlaku, hypertrofie myokardu, tyreotoxikóza-vyšší metabolické nároky). Pokles stažlivosti se projeví již při omezení perfúze o 10-20procent. Ischémie myokardu vzniká při nerovnováze mezi nabídkou a poptávkou, která je dána: a) zvýšenými nároky myokardu, b) sníženou perfúzí přes koronární arterie, c) kombinací obou. Spotřeba O2 je dána: 1) napětím stěny LK, 2) inotropním stavem myokardu, 3) srdeční frekvencí. Extravaskulární tlak v srdci narůstá od epikardu k endokardu – zhoršená perfúze subendokardiálních vrstev. Porucha perfúze může mít podklad organický (ateroskleróza, trombus, embolie, arteriitida apod.) nebo funkční (koronární spazmy). V praxi nejčastěji kombinace faktorů (nasednutí trombu či spazmu na aterosklerotický plát, ať již hemodynamicky významný či nevýznamný. •pathogenesis: atherosclerotic process of one or more branches of the coronary circulation Ischemic Heart Disease http://www.medecine.unige.ch/recherche/groupes/b_donnees/sujet_591_4.html Více informací o aterosklerotickém procesu (obvykle je primárním momentem): 1. fáze (již v prvním a druhém deceniu) – v intimě nacházíme tukové proužky, 2. fáze (od třetího decenia) – stádium fibrózních plátů – výskyt významně koreluje s rizikovými faktory aterosklerózy (ovlivnitelné - hypertenze, hyperlipoproteinémie, kouření, cukrovka, stres, obezita, nedostatek fyzické aktivity + neovlivnitelné-věk, pohlaví, rodinná zátěž); nejprve dochází k akumulaci esterů cholesterolu v intimě, endotelem prostupují monocyty, které se mění v makrofágy a akumulují extracelulárně uložené tuky, čímž vznikají tzv. pěnové buňky, z médie migrují a proliferují buňky hladké svaloviny, část z nich se rovněž mění v pěnové buňky, pěnové buňky se po naplnění rozpadají a tuk je opět v ECT, vše se opakuje; nad lézí pak může dojít k porušení endotelu (zejména jeho retrakcí) a na obnažené místo nasedají trombocyty a monocyty. Aktivované trombocyty, makrofágy a buňky hladké svaloviny uvolňují chemotaktické působky mitogeny včetně třeba PDGF a ten stimuluje buňky hladké svaloviny a fibroblasty. Dále je významná účast lipoproteinů a lipidů, zejména LDL (low density). Transcelulární transport cholesterolu vázaného v LDL přes endotel se děje po vazbě na specifické receptory. Z intersticia se pak cholesterol dostává do buněk prostřednictvím vazby na receptor pro LDL, pak endocytózou do lyzosomů, kde se estery hydrolyzují a volný cholesterol je buňkou buď využit nebo je reesterifikován a ester je uložen. V posledním stádiu pokročilé aterosklerózy se uplatňují trombocyty nasedající na aterosklerotickou lézi zbavenou endotelu – uvolněním PDGF celý proces potencují. •pathogenesis: atherosclerotic process of one or more branches of the coronary circulation Ischemic Heart Disease http://int2.lf1.cuni.cz/pruvodce-pro-pacienty-pred-katetrizacnim-vysetrenim-srdce endothelial cells thrombocytes inflammatory cells lipid core smooth muscle cells thrombus rupture of thin fibrous cover http://www.thno.org/v03p0894.htm Více informací o aterosklerotickém procesu (obvykle je primárním momentem): 1. fáze (již v prvním a druhém deceniu) – v intimě nacházíme tukové proužky, 2. fáze (od třetího decenia) – stádium fibrózních plátů – výskyt významně koreluje s rizikovými faktory aterosklerózy (ovlivnitelné - hypertenze, hyperlipoproteinémie, kouření, cukrovka, stres, obezita, nedostatek fyzické aktivity + neovlivnitelné-věk, pohlaví, rodinná zátěž); nejprve dochází k akumulaci esterů cholesterolu v intimě, endotelem prostupují monocyty, které se mění v makrofágy a akumulují extracelulárně uložené tuky, čímž vznikají tzv. pěnové buňky, z médie migrují a proliferují buňky hladké svaloviny, část z nich se rovněž mění v pěnové buňky, pěnové buňky se po naplnění rozpadají a tuk je opět v ECT, vše se opakuje; nad lézí pak může dojít k porušení endotelu (zejména jeho retrakcí) a na obnažené místo nasedají trombocyty a monocyty. Aktivované trombocyty, makrofágy a buňky hladké svaloviny uvolňují chemotaktické působky mitogeny včetně třeba PDGF a ten stimuluje buňky hladké svaloviny a fibroblasty. Dále je významná účast lipoproteinů a lipidů, zejména LDL (low density). Transcelulární transport cholesterolu vázaného v LDL přes endotel se děje po vazbě na specifické receptory. Z intersticia se pak cholesterol dostává do buněk prostřednictvím vazby na receptor pro LDL, pak endocytózou do lyzosomů, kde se estery hydrolyzují a volný cholesterol je buňkou buď využit nebo je reesterifikován a ester je uložen. V posledním stádiu pokročilé aterosklerózy se uplatňují trombocyty nasedající na aterosklerotickou lézi zbavenou endotelu – uvolněním PDGF celý proces potencují. Ischemic Heart Disease Symptoms are usually provoked by physical exertion, cold, rapid increase of the blood pressure, etc. •symptoms (always when blood inflow demands exceed the capacity of stenotic artery): -pain behind the sternum (angina pectoris) -changes of ST segment and T wave on ECG due to sooner repolarization in the ischemic myocardial region, usually in the subendocardium - •pathogenesis: atherosclerotic process of one or more branches of the coronary circulation To, zda se ischemická depolarizace projeví jako elevace nebo deprese úseku ST závisí na tom, je-li ischemická zóna uložena subepikardiálně či subendokardiálně: 1.U námahové (stabilní) anginy ischemizuje především subendokardiální zóna, tedy na povrchovém EKG vidíme depresi ST. 2.U variantní (vazospastické) Prinzmetalovy anginy (dána ložiskovým spazmem epikardiální koronární arterie/í; obvykle u těchto pacientů nedochází k IM; bolest typicky v noci, několik minut) s těžkým spazmem či v rané fázi IM ischemizuje subepikard či celá stěna (transmurální ischemie) a na EKG tedy vidíme elevaci ST. •pathogenesis: atherosclerotic process of one or more branches of the coronary circulation Ischemic Heart Disease •acute coronary occlusion due to: -thrombus (rupture of the plaque) -embolus -local muscular spasm Guyton and Hall. Textbook of Medical Physiology, 11th edition •pathogenesis: atherosclerotic process of one or more branches of the coronary circulation Ischemic Heart Disease The degree of damage of the heart muscle is determined to a great extent by the degree of collateral circulation! •acute coronary occlusion due to: -thrombus (rupture of the plaque) -embolus -local muscular spasm Kolaterály jsou buď již předem otevřeny nebo se otevírají během minut po okluzi. Anastomózy mezi většími koronárkami neexistují, ale mezi malými větvemi jsou četné. Ty na okluzi větve reagují během sekund dilatací – ale pokryje obvykle max. polovinu potřeby. Následně se průtok moc nemění, ale pak se zase začne zvětšovat – na dvojnásobek 2. – 3. den, dosáhne normálního průtoku během zhruba měsíce – mnozí lidé se plně zotaví. K uzávěru může docházet i postupně, během mnoha let, postupným narůstáním aterosklerotického plátu. V tom případě se kolaterály vyvíjí postupně, jak se stav zhoršuje – nakonec už kolaterály nestačí a rozvíjí se srdeční selhání. Ischemic Heart Disease •Myocardial infarction = sudden closure of a coronary branch, usually by a thrombus originating on the strength of a rupture of the atherosclerotic plate, changes are irreversible •healing by a scar (a sign of non-conductive tissue remains on ECG – a deep Q wave) •symptoms: -severe unremitting pain behind sternum -heart failure (in the case of a bigger extent) -on ECG: ST elevation followed by T wave without any decrease to the isoelectric line (the Pardee´s sign) - http://www.wikiskripta.eu/index.php/Popis_EKG IM je stav ohrožující stav pacienta řadou komplikací, vyžaduje okamžitou intenzivní péči na koronární jednotce. Nekróza i jizva jsou nevodivé, tedy hluboké Q vzniká ihned a přetrvává, zatímco Pardeeho vlna postupně klesá k izoelektrické linii (vlna T nejdříve jde do negativity a po letech může být zpět nahoře). Z nekrotických buněk unikají enzymy (MB-isomer kreatinkinázy, MB-CK; troponin T; troponin I), jejichž hladiny lze měřit v séru a potvrdit tak diagnózu IM. -70 -90 -90 Ischemic Heart Disease •Myocardial infarction •TQ depression due to depolarization of RMP (accumulation of K+ in ECT) TQ depression Depolarizace v důsledku vyplavení K+ z buněk (IKATP kanály, vyplavování spolu s negativně nabitým laktátem a fosfáty, snížená činnost Na+/K+ pumpy) a jeho akumulaci v ECT. Zkrácení AN v důsledku zvýšené repolarizační síly (IKATP). Zpomalená depolarizace AN v důsledku depolarizace membrány a inaktivace INa kanálů. Depolarizace membrány v ischemickém ložisku působí v diastole proud od ischemického ložiska ke zdravému myokardu – diastolická TQ deprese, která se na EKG zobrazí jako ST elevace. Ischemic Heart Disease •Myocardial infarction •TQ depression due to depolarization of RMP (accumulation of K+ in ECT) •ST elevation due to shortening of AP and delayed depolarization TQ depression ST elev. -15 0 0 Negativnější napětí ve fázi 2 a 3 v ischemickém ložisku působí proud směrem do ložiska ischemie, tedy k elektrodě ležící nad infarktem – elevace ST úseku. Ischemic Heart Disease •Myocardial infarction Ganong´s Review od Medical Physiology, 23rd edition A B C D E A.Physiological tracing in lead I B.Myocardial infarction – acute phase – hours from infarction. C.Many hours till days from infarction. D.Late pattern - many days till weeks from infarction. E.Very late pattern – months till years from infarction. Ischemic Heart Disease •Treatment with drugs -Vasodilatory drugs (nitroglycerine, other nitrate drugs) -Beta-blockers (propranolol) Nitroglycerin a nitráty stimulují solubilní guanylylcyklázu k tvorbě cGMP v buňkách hladkého svalstva, čímž dochází k jejich relaxaci (jako NO). Betablokátory brání zvyšování srdeční frekvence a metabolismu v srdci v důsledku sympatikotonie (tělesná aktivita, emoce, stres) – decreased demands of the heart muscle. Ischemic Heart Disease •Surgical treatment coronarography Coronary Angioplasty http://www.ikem.cz/www?docid=1005912 Aortic-Coronary Bypass http://www.sedmstatecnych.cz/clanek/opravene-srdce-po-trech-letech/ Closure of a coronary artery Coronary anglioplasty: to open partially blocked coronary vessels before they will be completely occluded; a small catheter with a ballon is passed under radiographic guidance into the coronary system and pushed through the partial occlusion, then, the ballon is inflated with high pressure; bypass can follow if necessary; stents - prevention of restenosis. Bypass: In many patients, the constricted areas located at only a few discrete points, vessels elsewhere ar intact (or almost intact). A graft of subcutaneous vein from an arm or a leg is used and places from the root of aorta to the side of a peripheral coronary artery beyond the atherosclerotic blockage point. If the heart has already been severely damaged, the bypass procedure is likely to be of a little value. Arterial Hypertension Definition and Consequences Arterial hypertension - chronic increase of the systemic blood pressure. Symptoms indistinctive and nonspecific in the first stages of hypertension ® almost 50% of the hypertensive patients do not know about their hypertension! voverload of the left ventricle (hypertrophy, heart failure) varteriosclerosis increased risk of the myocardial infarction increased risk of the stroke the renal failure, etc. If not diagnosed in time and adequately treated, arterial hypertension results in: Hypertension significantly shortens the life span. The arterial hypertension means a chronic increase of the systemic blood pressure. Since symptoms are indistinctive and nonspecific in the first stages of hypertension, almost half of the patients do not know about their hypertension. Unfortunately, the end-organ damage induced by the hypertension starts already in these first stages. Hypertension causes namely overload of the left ventricle resulting in its hypertrophy and in the end, in the heart failure. Hypertension also considerably accelerates development of arteriosclerotic changes in vessels with increased risk of myocardial infarction, stroke, renal failure, and so on. Thus, hypertension definitely significantly shortens the life span. That is why the well-timed diagnosis and adequate treatment are so important. Considering occurrence of these life-threatening consequences of the arterial hypertension, it is crucial to really well establish the borders of physiological blood pressure and hypertension but it is not so easy. Definition and Consequences Arterial hypertension - chronic increase of the systemic blood pressure. Guidelines for the management of arterial hypertension. Eur Heart J 2007;28:1462-1536. The optimal physiological blood pressure is considered to be lower than 120 mmHg in the case of the systolic blood pressure and lower than 80 mmHg in the case of the diastolic blood pressure. Various grades of hypertension are distinguished, usually exactly according to the levels of systolic and diastolic blood pressure. To diagnose hypertension, the blood pressure has to be measured repeatedly; it should be elevated at least in case of two out of three measurements during at least two visits of the patient in your medical attendance (ordination, office). The blood pressure has to be measured in the right way (practicals). 24-hours Monitoring of Blood Pressure The blood pressure varies much during the day and night. Thus, 24-hours monitoring is often used during the diagnostic process of arterial hypertension and also during the control of antihypertensive treatment. You can see the characteristic drop of the blood pressure during night in a healthy subject. Definition and Consequences Arterial hypertension - chronic increase of the systemic blood pressure. Guidelines for the management of arterial hypertension. Eur Heart J 2007;28:1462-1536. prehypertension The blood pressure between 120-139/80-89 mmHg corresponds to the so called prehypertension which is not pharmacologically treated, however, non-pharmacological steps as a change of the lifestyle should be already applied in these patients. Definition and Consequences Arterial hypertension - chronic increase of the systemic blood pressure. Guidelines for the management of arterial hypertension. Eur Heart J 2007;28:1462-1536. Grade I hypertension starts at 140/90 mmHg. Definition and Consequences Guidelines for the management of arterial hypertension. Eur Heart J 2007;28:1462-1536. Stratification of cardiovascular risk However, the definition of hypertension may be variable and criteria are even more strict in patients with associated risk factors as you can see here. The level of total cardiovascular risk is estimated based both on levels of the systolic and diastolic blood pressure, and on presence of the additional risk factors, for example age (men >55 years, women >65 years), smoking, dyslipidaemia, increased plasma glucose (diabetes), abdominal obesity, family history of premature cardiovascular disease, or renal disease. In the case of higher cardiovascular risk, the treatment of hypertension starts at lower levels of the blood pressure tha at 140/90 mmHg. Definition and Consequences in children and adolescents – special percentile tables The blood pressure is moreover much dependent on the age as shown in this graph. These dashed lines correspond to the level where hypertension officially starts, 140/90 mm Hg. It is apparent that just one sharp level, where the hypertension starts, cannot be established in the population. Namely in children and adolescents, special percentile tables are used to consider the level of blood pressure. In the elderly, there is typically often present the so called isolated systolic hypertension (discussed later). Factors Determining Blood Pressure Ohm´s law U = I . R P = CO . TPR P arterial pressure CO cardiac output TPR total peripheral resistance v cardiac output (usually due to extracellular fluid) volume-loading (hyperdynamic) hypertension ↑ ↑ v total peripheral resistance resistance hypertension ↑ According to the Ohm´s law, the voltage is given by the product of the electric current and resistance. Analogically, the blood pressure is given by the product of the cardiac output and total peripheral resistance. Thus, the blood pressure may be increased either due to an increase of the cardiac output, usually because of the increased volume of the extracellular fluid. Then, it is called the volume-loading or hyperdynamic hypertension. The second possible cause of hypertension is the increased total peripheral resistance. In this case, it is called resistance hypertension. Nowadays, the terms volume-dependent and volume-independent hypertension are preferred in the clinical practise. In most cases, the pathophysiology of hypertension is not so clear, both changes mix. Moreover, every hypertension ends as the resistance one in fact. Factors Determining Blood Pressure Ohm´s law U = I . R P = CO . TPR v cardiac output (usually due to extracellular fluid) volume-loading (hyperdynamic) hypertension ↑ ↑ v total peripheral resistance resistance hypertension ↑ v compliance isolated systolic hypertension P arterial pressure CO cardiac output TPR total peripheral resistance The third factor which considerably influences the blood pressure is the compliance. The compliance expresses how big increase of the pressure will result from an increase of the vascular volume. A decreased compliance results in a higher increase of the pressure at a certain increase of the volume and causes the isolated systolic hypertension in the elderly which I will talk about later. The pathophysiology of hypertension might look easy according to this scheme but it is not. veins blood reservoire heart CO = SV . HR HR is guided by sympathetic and parasympathetic system SV depends on: 1.venous return (blood volume, tonus of veins) 2.contractility 3.peripheral pressure kidneys regulation of blood volume P = CO . TPR On this scheme, you can see the whole cardiovascular system. The cardiac output (CO) is one of the two key factors influencing the blood pressure. CO is due to the product of the stroke volume (SV) and heart rate (HR), thus, it is essentially dependent on the cardiac function. The heart rate is guided by the sympathetic and parasympathetic systems. The stroke volume depends on the venous return (preload), contractility and peripheral pressure (afterload). Contractility can be increased by the sympathetic system. The venous return is much related to the blood volume, thus, it notably depends on the renal function. The amount of blood kept in veins as the blood reservoire plays also the crucial role and may be influenced by venoconstriction and venodilatation. kidneys regulation of blood volume P = CO . TPR arterioles regulation of TPR heart CO = SV . HR HR is guided by sympathetic and parasympathetic system SV depends on: 1.venous return (blood volume, tonus of veins) 2.contractility 3.peripheral pressure veins blood reservoire also TPR (RAS) The second parameter essentially determining the blood pressure is the total peripheral resistance which is mainly given by the radius of arteriols. Many vasoconstrictive and vasodilatory signals exist and may influence the total peripheral resistance through the change of the vascular radius. Kidneys and their regulating substances as angiotensin II may participate on a change of the total peripheral resistance as well. P = CO . TPR Summary of most of the vasoconstrictive and vasodilatory signals in the body: The regulation of the total peripheral resistance is very complex. And it is only one of the parameters determining the blood pressure. Thus, it is not surprising that the pathophysiology of hypertension is so complex. arterioles regulation of TPR kidneys regulation of blood volume, also TPR (RAS) aorta and big elastic arteries compliance heart CO = SV . HR HR is guided by sympathetic and parasympathetic system SV depends on: 1.venous return (blood volume, tonus of veins) 2.contractility 3.peripheral pressure veins blood reservoire P = CO . TPR The compliance of the aorta and big elastic arteries also notably influences the blood pressure. arterioles regulation of TPR aorta and big elastic arteries compliance regulation of blood volume: -kidneys -thirst -ADH heart CO = SV . HR HR is guided by sympathetic and parasympathetic system SV depends on: 1.venous return (blood volume, tonus of veins) 2.contractility 3.peripheral pressure veins blood reservoire Pathophysiology of hypertension is very complex, thus, usually hard to be analyzed in a concrete patient! P = CO . TPR Regulation of the blood volume is also more complex, guided not just by kidneys and related hormones but also by the thirst and antidiuretic hormone which are stimulated by an increased osmolality of the body fluids. To finally summarize it, the pathophysiology of hypertension is very complex and usually hard to analyse in the concrete patient. Classification A.Essential (primary) hypertension B.Secondary (symptomatic) hypertension •„hypertension of an unknown origin“ •90 – 95% A.Essential (primary) hypertension •symptom of another primary disease with identifiable cause The arterial hypertension can be divided into two main groups, the essential (or primary) hypertension and the secondary (or symptomatic) hypertension. First, we will deal with the essential hypertension which is also called hypertension of an unknown origin and is much more common being present in 90-95% of the hypertensive patients. Essential Hypertension vstrong hereditary tendency in some patients (polygenic ground – genetic defects, often polymorphisms, causing abnormality/ies in a factor regulating the blood pressure) vprovoking factors: •excess weight gain, obesity – account for about 65-70% of the risk for developing of essential hypertension •sedentary lifestyle New clinical guidelines recommend increased physical activity and weight loss as the first step in treating most patients with the essential hypertension. •excessive sodium intake (interpopulation studies – Eskimos vs. people living in the North Japan) •stress (namely mental) A strong hereditary tendency is present at least in some patients with the essential hypertension (EH). The EH is a disease with the polygenic inheritance. In about 60% of these patients, an abnormality is present in the sodium excretion, which predisposes them to the volume-dependent type of hypertension. The rest 40% of patients with the essential hypertension show the non-volume dependent (formerly resistance) hypertension, likely because of a defect in e.g. a receptor for one of the vasoconstricting mediators or in their metabolism or so. To manifest as the hypertension, the hereditary tendency has to be supported by other, extrinsic factors. The most important seem to be the obesity (or excess weight gain), usually accompanied by the sedentary lifestyle. Stress and excessive sodium intake play also a role in pathogenesis of the essential hypertension. Essential Hypertension 583D0C5D Northern Japan Eskymos Sodium intake / day The interpopulation studies clearly showed that the incidence of hypertension correlates well with the level of sodium intake in an individual population. Note differences of both these characteristics between for example Eskymos or people from the New Guinea, and people from the Northern Japan. Essential Hypertension Sodium-loading renal function curves The sodium-loading renal function curves clearly demonstrate that in some hypertensive patients, there is increased sensitivity of the blood pressure to the increased sodium intake. This seems to be caused by structural or functional differences in the kidneys of these two types of hypertensive patients. The salt-sensitivity is not a fixed characteristic. It is age-dependent due to the gradual loss of functional units in the kidneys in people over 50 or 60 years of the age. Development of a dysfunction of the renin-angiotensin system may also change it. Under physiological conditons, the renin-angiotensin system can compensate the increase of the arterial blood pressure caused by increased sodium intake because its activation is decreased at such conditions and, thus, the renal retention of salt and water decreases. Definition and Consequences Arterial hypertension - chronic increase of the systemic blood pressure. Guidelines for the management of arterial hypertension. Eur Heart J 2007;28:1462-1536. The isolated systolic hypertension is often diagnosed in the elderly and is characterized by an increased systolic and pulse pressure but physiological diastolic pressure. Formerly, the old people with isolated systolic hypertension were not even treated because of a general opinion that the increased systolic bp is not so dangerous as the increased diastolic bp, and likely also because of the opinion that this is just a physiological change of the blood pressure coming with the increasing age. However, the increased systolic bp has been recently found to cause considerable end-organ damage as well. Isolated Systolic Hypertension Essential Hypertension vin the elderly vdue to: •age-dependent remodelling of the wall of elastic arteries (less elastic and more collagen fibres) v↑ systolic and pulse pressure ® ↑ stiffness, ~↓ compliance: 2. ® ↑ pulse wave velocity 1. ® ↓ distension of elastic arteries during the systole (physiologically accommodating the expansion of the volume after ejection of blood from the heart) ® steeply ↑ arterial systolic pressure + ↓ blood volume (and also pressure) in arteries during the diastole The isolated systolic hypertension originates mainly from the age-dependent remodelling of the wall of elastic arteries. They become to be less elastic, thus, more rigid, due to the decreased amount of the elastic and increased amount of the collagen fibres. Thus, the compliance of the aorta and big arteries decreases resulting in two main facts. First, the physiologically important distension of these arteries during the systole is decreased. Thus, the arterial systolic pressure steeply increases and, on the other hand, the blood pressure in arteries during the diastole is decreased due to lower blood volume flowing during diastole under these conditions. Second, as in other hypertensive patients, the pulse wave velocity is increased as you have heard or will hear soon in the practicals when you will estimate the pulse wave velocity in the aorta and in the arteries of your upper limb using sphygmographic records from several places on your body. Isolated Systolic Hypertension Essential Hypertension ↑ pulse wave velocity ® the secondary, reflected pulse wave comes back to the aorta and elastic arteries sooner and, thus, superimposes on the primary pulse wave still during the systolic phase ® ↑ systolic pressure and may even ↓ diastolic pressure primary wave reflected wave resulting wave Consequences of the increased pulse wave velocity: The primary pulse wave is going along the arterial walls from the root of aorta to the periphery, it reflects at places where arterias verge into arteriols and goes back to the aorta. In patients with the isolated systolic hypertension, the increased pulse wave velocity results in a premature return of the secondary (reflected) pulse wave back to the aorta which then superimposes on the primary pulse wave already during the systole. It is visible as the second peak on the sphygmogram. An augmentative pressure may be then subtracted from the record and the augmentative index may be calculated as the ratio of the augmentative pressure and the pulse pressure. This index increases with increasing age. Considering the superposition of the secondary wave on the primary wave in the systole, the systolic pressure increases and, on the contrary, the diastolic pressure decreases. Isolated Systolic Hypertension Essential Hypertension •endothelial dysfunction (↑ reactivity on vasoconstrictive mediators, namely the local ones as endothelins, thromboxane A2, …) vin the elderly vdue to: •age-dependent remodelling of the wall of elastic arteries (less elastic and more collagen fibres) v↑ systolic and pulse pressure Even an endothelial dysfunction with increased reactivity of the vessel wall on vasoconstrictive mediators, namely to the local vasoconstrictive mediators as endothelins, thromboxyne A2 etc., seems to play a role in pathogenesis of the isolated systolic hypertension. Essential Hypertension Treatment New clinical guidelines recommend increased physical activity and weight loss as the first step in treating most patients with EH. vvasodilatory drugs • ↓ TPR, some of them ↑ renal blood flow as well (ACEI) a.by inhibiting sympathetic nervous system (sympatolytics) b.by directly paralyzing the smooth muscle of the renal vasculature (vasodilatory agents or calcium channel blockers) c.by blocking action of the renin-angiotensin system on the renal blood vessels or tubules (inhibitors of angiotensin I-converting enzyme, ACEI) Decrease of sodium and increase of potassium intake, relaxation ... vnatriuretic (diuretic) drugs •↓ renal tubular reabsorption of salt and water ® ↓ CO (by blocking the active transport of sodium through the tubular wall) P = CO . TPR Treatment of essential hypertension: Therapy of essential hypertension is always lifetime. The first and very important step is the non-pharmacologic treatment. It is best started even in people with the so called prehypertension, thus, with the levels of blood pressure under the border for the grade I hypertension, so below 140/90 mmHg, but above the optimal blood pressure which is below 120/80 mmHg. However, the non-pharmacological treatment is the key part of treatment of all patients with the essential hypertension. Recommended are: weight loss, increase of the physical activity, decrease of sodium and increase of potassium intake, relaxation and so on. The blood pressure is assessed by the product of total peripheral resistance (TPR) and cardiac output (CO). Thus, either vasodilatory drugs are used to decrease the blood pressure by a decrease the total peripheral resistance. Alternatively, diuretic drugs decreasing the renal reabsorption of salt and water, thus, decreasing the cardiac output can be used. Besides the monotherapy, so besides the therapy with just one drug, the therapy with two, three or even four drugs is often used. Classification A.Essential (primary) hypertension B.Secondary (symptomatic) hypertension •„hypertension of an unknown origin“ •90 – 95% •symptom of another primary disease with identifiable cause Compared to the essential hypertension, the cause of hypertension can be identified in case of the secondary hypertension. Here, the hypertension is just a symptom of another disease. Secondary Hypertension 3.Coarctation of the aorta 4.Hypertension in preeklampsia 5. 5.Neurogenic hypertension •Renin-producing renal tumor 1.Renal hypertension •Acute and chronic diseases of the renal parenchyma •Prerenal causes - Renovascular hypertension •Postrenal causes (renal vein trombosis, urinary tract obstruction) •Sympatoadrenal hyperfunction (pheochromocytoma) 2.Endocrine hypertension •Adrenocortical hyperfunction (Cushing´s, Conn´s, adrenogenital sy) •Exogenic hormones (gluko-, mineralocorticoids, sympatomimetics) •Hyperthyroidism •Acromegaly 1.Renal hypertension Number of types of the secondary hypertension are known. First group is related to renal diseases, the second group to an impaired hormonal regulation. Some other types can be rarely distinguished. Regarding therapy, the primary cause of the disease has to be treated to decrease the blood pressure effectively and constantly. Renal hypertension Secondary hypertension vcirculus vitiosus in some cases (renal disease can cause hypertension and hypertension can again cause injury to the glomeruli and renal blood vessels) vnon-hypertensive kidney diseases (loss of whole nephrons) vhypertensive kidney diseases a.lesions ↓ GFR (due to ↑ renal vascular resistance – renovascular hypertension - or ↓ glomerular capillary filtration coefficient – e.g. chronic glomerulonephritis causing thickening of the membranes) b.lesions ↑ tubular reabsorption of sodium (hyperaldosteronism) c.patchy renal damage causing local ischemia (e.g. local arteriosclerosis; changes similar to „two-kidney“ Goldblatt hypertension) Once hypertension develops, GFR and urinary excretion rate return to the physiological values (pressure natriuresis and diuresis). Secondary hypertension Renovascular hypertension vexperimental „two-kidneys“ Goldblatt hypertension (arteficial constriction of one renal artery, the second kidney preserved) ↓ blood pressure in the kidney on the side of constriction (in clinics – e.g. stenosis of one renal artery due to atherosclerosis in the elderly or fibromuscular dysplasia in younger patients) 1.® ↓ GFR ® retention of salt and water in the ischemic kidney 2.® ↑ secretion of renin in the ischemic kidney ® ↑ angiotensin II ® vasoconstriction + retention of salt and water also in the second, healthy kidney Secondary hypertension Renin-producing renal tumor (primary hyperreninism) vbenign tumor from the juxtaglomerular cells vsevere hypertension ↑ secretion of renin ® ↑ angiotensin II ® 1.vasoconstriction (seconds) ® ↑ TPR 2.retention of salt and water (days) ® ↑ CO •Sympatoadrenal hyperfunction (pheochromocytoma) 2.Endocrine hypertension •Adrenocortical hyperfunction (Cushing´s, Conn´s, adrenogenital sy) •Exogenic hormones (gluko-, mineralocorticoids, sympatomimetics) •Hyperthyroidism Secondary hypertension 3.Coarctation of the aorta 4.Hypertension in preeklampsia 5. 5.Neurogenic hypertension •Renin-producing renal tumor 1.Renal hypertension •Acute and chronic diseases of the renal parenchyma •Prerenal causes - Renovascular hypertension •Postrenal causes (renal vein trombosis, urinary tract obstruction) •Acromegaly Secondary hypertension Adrenocortical hyperfunction (Cushing´s, Conn´s, adrenogenital sy) •unilateral aldosterone-producing adenoma (less often carcinoma) Conn´s syndrome •bilateral hyperplasia of zona glomerulosa ® ↑ absorption of sodium (primary hyperaldosteronism) ® hypokalemic alkalosis (causing periods of muscle weekness/paralysis, nephropathy) ® ↑ secretion of potassium and H+ ® osmotic absorption of water (eventually ↑ water intake) ® ↑ extracellular fluid ® ↑ CO ® hypertension ® pressure natriuresis/diuresis + ↓ renin Secondary hypertension Hyperthyroidism •stimulation of the thyroid tissue by autoantibodies (thyroid-stimulating immunoglobulin) - same receptors as TSH ® ↑ tissue metabolism ® metabolic vasodilatation + vasodilatation in the skin (↑ heat elimination) ® ↑ blood flow ® ↑ CO (including ↑ HR) •thyroid adenoma ® ↑ amount and affinity of cardiac (also other) β-receptors ® ↑ sensitivity to their chrono- and inotropic effects ® ↑ expression of α-isoform of MHC (higher ATPase activity than β-isoform) ® ↑ heart strength vmean pressure remains physiological but ↑ pulse pressure (systolic blood pressure - ↑ by 10 to 15 mmHg, diastolic blood pressure - ↓) •Sympatoadrenal hyperfunction (pheochromocytoma) 2.Endocrine hypertension •Adrenocortical hyperfunction (Cushing´s, Conn´s, adrenogenital sy) •Exogenic hormones (gluko-, mineralocorticoids, sympatomimetics) •Hyperthyroidism Secondary hypertension 3.Coarctation of the aorta 4.Hypertension in preeklampsia 5. 5.Neurogenic hypertension •Renin-producing renal tumor 1.Renal hypertension •Acute and chronic diseases of the renal parenchyma •Prerenal causes - Renovascular hypertension •Postrenal causes (renal vein trombosis, urinary tract obstruction) •Acromegaly Secondary hypertension Hypertension in preeklampsia (toxemia of pregnancy) vcauses not fully known thickening of the kidney glomerular membranes (autoimmune process?) ® ↓ glomerular filtration rate ® ↑ long-term level of the arterial pressure to preserve the physiological level of formation of urine vsalt-sensitive vthe most serious type of hypertension during pregnancy considering prognosis for both mother and the fetus vother types of hypertension during pregnancy: •hypertension which began before pregnancy •hypertension which starts in the first months of the pregnancy vone of the manifestations of the syndrome called preeklampsia which may develop in the last trimester If the pharmacological treatment is not successful, premature termination of the pregnancy is necessary.