ARTÉRIOVÁ HYPERTENZIA Doc. MUDr. Marian Sninčák, Ph.D., mim. profesor Klinika geriatrie a ošetrovateľstva LF UPJŠ a VŠOÚG sv. Lukáša v Košiciach, n.o. Centrum pre výskum, diagnostiku a liečbu hypertenzie

Agenda Tlak krvi-fyziológia (regulácia), patofyziológia Artériová hypertenzia(vysoký TK) a jeho následky Artériová hypertenzia-klinické rysy Liečba artériovej hypertenzie (v staršom veku, s ohľadom na výskyt CMP a demencie)

1. TLAK KRVI A JEHO REGULÁCIA

Čo je tlak krvi? Tlak krvi je sila, tlak na steny artérií krvnej cirkulácie v celom tele

Tlak krvi Horné (vrchné) číslo = systolický tlak krvi (STK)- srdce pracuje počas STK Tlak prostredníctvom krvi na cievnu stenu počas komorovej kontrakcie Dolné číslo = diastolický tlak krvi (DTK)- relaxácia počas DTK Tlak prostredníctvom krvi na cievnu steny počas ventrikulárnej relaxácie Meranie v mm Hg (millimeters of mercury) Heart work during SBP Relaxation during DBP

Tlak krvi: optimálne hodnoty STK < 120 mmHg a DTK < 80 mmHg According to EHS/EKS, 2007 EHS/EKS, 2007

Definície a klasifikácia hladín tlaku krvi (mmHg) 85-89 a/alebo 130-139 Vysoký normálny 80-84 120-129 Normálny <80 a <120 Optimálny Diastolický Systolický Kategória 90-99 a/alebo 140-159 Stupeň 1 hypertenzie 100-109 a/alebo 160-179 Stupeň 2 hypertenzie Stupeň 3 hypertenzie ≥180 a/alebo ≥110 <90 a ≥140 Izolovaná systolická hypertenzia

Čo je artériová hypertenzia? AH môže byť definovaná ako “Perzistentne vysoký artériový tlak krvi” “The continuous relationship between the level of blood pressure and cardiovascular risk makes any numerical definition and classification of hypertension arbitrary.” 1 Hypertension can be defined as persistently high arterial blood pressure. The continuous relationship between the level of blood pressure and cardiovascular risk makes any numerical definition and classification of hypertension arbitrary and in fact whenever guidelines are updated we see a change in the numerical definition. 1 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. Journal of Hypertension 2003 vol21 no6 p1011-1063.

Artériová hypertenzia Je tiež nazývaná ako vysoký TK Artériová hypertenzia je TK 140/90 mm Hg alebo vyšší 140 90

Tlak krvi (TK) Franck Tieto faktory sú cieľom antihypertenzných látok TK = CO x PCR Srdcový výdaj (Cardiac Output) CO = HR x SV Periférna cievna rezistencia The Franck equation: Blood Pressure is obtained by multiplying the CO by the PR, so BP directly depends on the work of the heart and the tension on the arterial wall. Blood pressure is linked to a variation of these factors. These factors are the targets of anti hypertensive drugs. BP is a cyclic phenomena: it varies between extreme values: -SBP, maximal is the BP during ventricular systole, and reflects the heart work -DBP,minimal,is the BP during diastole and reflects PR

Variácie TK Cirkadiánny rytmus Variácie podľa pozície tela vleže < vsede < vstoji Zvyšuje sa záťažou Stúpa vekom Muži > ženy Regulation of Blood Pressure Blood pressure varies during the cardiac cycle: systole: maximal; diastole: minimal. Maintaining a steady flow of blood from the head to the toes is vital for proper organ function. Blood pressure is regulated by neural, chemical, and renal controls that act continuously to modify and adjust cardiac output, peripheral resistance, and/or blood volume. But there are physiological variations in blood pressure.

Počet pacientov s prvou KV príhodou Cirkadiánny rytmus (najvyššie úrovne TK sú merané v skorých ranných hodinách) BP 15 18 21 00.00 06 09 12.00 Time (h) The highest levels of blood pressure are measured in the early morning hours, then the BP remains stable until evening when it starts to decline progressively, reaching a trough value at about midnight. Superimposed to this circadian rhythm, fluctuations in BP occur in response to various psychological stress and physical activities. The main determinant of this circadian variation in BP appears to be the sympathetic nervous system, although several other neurohormonal systems have been shown to follow a circadian rhythm with the peak in the morning. There is a marked diurnal variation in the onset of CV complications with the peak incidence of myocardial infarction, sudden cardiac death, and stroke occurring early in the morning when several CV risk factors reach the peak of the day.  circadian variations in BP, Hassler C. and col, Am J Cardiolvasc Drugs 2005; 5(1): 7-15 Počet pacientov s prvou KV príhodou 6.am to noon

Cirkadiánny rytmus TK ( T/P ratio) reflektuje antiHT účinnosť počas 24h, FDA odp. aspoň 50% Early morning rise in blood pressure is an important determinant of the CV risk, and should perhaps be considered as a therapeutic target. A true 24-hour blood pressure control should perhaps include an attenuation of the morning rise in BP as well as a normalization of both daytime and night-time BP  circadian variations in BP, Hassler C. and col, Am J Cardiolvasc Drugs 2005; 5(1): 7-15 TROUGH TO PEAK RATIO The T/P ratio Determines the decrease: In Blood Pressure at the end of the dosing interval (residual effect of the drug) In comparison to the maximum decrease in Blood Pressure after a drug intake T/P reflects the maintenance the maintenance of the efficacy during 24h T/P=1 =>100% The FDA recommend at least a T/P ratio 50%

REGULÁCIA TK

Regulácia TK (TK je cieľom 24h kontroly) Okamžitá regulácia (sek) Oneskorená regulácia (min-hod.) NERVOVÁ REGULÁCIA –baroreflex, odpoveď na potrebu organizmu HUMORÁLNA REGULÁCIA Sympatický systém Parasympatický systém Blood pressure is the object of 24-hr control. The immediate blood pressure regulation, (immediate being within seconds) is what we call the baroreflex: it answers to the needs of the body. The delayed blood pressure regulation, in minutes or hours is humoral depending mostly on the RAAS system. Hormóny (hlavne RAAS)

Sympatická stimulácia parasympatická stimulácia Regulácia TK : NERVOVÁ vekom sa stávajú baroreceptory menej senzitívne: posturálna hypotenzia V prípade ak BP AkBP Baroreceptory lokalizované v karotickom sinuse detekujú zmeny TK Nervová regulácia Sympatická stimulácia parasympatická stimulácia In the case of a decrease in blood pressure, the response is a sympathetic stimulation which transmits the order to the organs. In the case of an increase in blood pressure, it is the parasympathetic system. Baro-receptors become less sensitive with age: postural hypotension. BP BP

Regulácia TK : HUMORÁLNA BP BP Angiotenzín II Aldosterón Adrenalín ADH Antidiuretický hormón Humorálna regulácia Bradykinín (v pečeni) Inhibuje ho ACE Humoral blood pressure regulation involves RAAS: when BP decreases, renin secretion occurs and in turn, activation of the RAAS. Hypertensive humoral factors are: A II, aldosterone, adrenaline and ADH(or vasopressin) Bradykinin is hypotensive: is part of the kallicrein-bradykinin system. Bradykininogen in the liver, under the influence of kallicrein, tranforms bradykininogen into bradykinin which is hypotensive. Converting enzyme inactivates bradykinin. BP BP

Regulácia TK : HUMORÁLNA  BP Bradykinín BP = HR x SV x PR A II Aldosterón Adrenalín ADH  BP

2. VYSOKÝ TK A JEHO NÁSLEDKY

Endoteliálna dysfunkcia - Kardiovaskulárna remodelácia Vaskulárna remodelácia Kardiálna remodelácia KV remodelácia bola označená za veľký príspevok ku KV morbi-/mortalite Vaskulárna remodelácia, často v skorých štádiách poškodzuje isté orgány (mozog, obličky, srdce) Takže liečba by mala najprv redukovať TK, ale tiež zabezpečiť reverziu vaskulárnej remodelácie Cardiovascular remodeling has been established as a major contributor to CV morbi/mortality. Vascular remodeling, even at an early stage, may affect certain organs (i.e. brain, Kidney, heart). So the treatment should first reduce BP but also reverse the vascular remodeling.

RAAS Angiotenzín II Bradykinín The endothelium function is mainly under AII and bradykinin control, both depending on the RAAS system equilibrium. Kontrolujú a sú odpoveďou endoteliálnej funkcie Funkcia endotelu je najmä pod kontrolou AII a bradykinínu, oba závisia na rovnováhe RAAS

Endoteliálna dysfunkcia (najčastejšie pozorovaným defektom je zhoršenie VDL kapacity endotélia)  fibrinolýza  Anti-agregačné faktory  Inflamačné mediátory  Adhézne molekuly  Rastové faktory:proliferácia HTA  AII  Bradykinín  NO The most obvious defect observed is the impairment of the vasodilator capacity of the endothelium. The endothelium is not only a barrier separating the blood flow to the vessel. It is a very active structure and its regulates vascular homeostasis through the release of humoral factors that control relaxation and contraction; thrombogenesis and fibrinolysis, platelet activation and inhibition. Locally an imbalance of AII /bradykinin may affect the endothelium function. Note that not only hypertension, but also smoking, hypercholesterolemia, aging and diabetes may also alter the endothelium function. MÉDIA Vazokonstrikcia  Vazorelaxácia

KV remodelácia - definícia KV remodelácia spočíva vo všetkých pozorovaných zmenách v štruktúrach: -artérií srdca

Vaskulárna remodelácia-Intima ŠTRUKTURÁLNE ZMENY DYSFUNKCIA KLINICKÉ NÁSLEDKY Poškodenie endoteliálnych buniek NO ostatné faktory Zhoršenie a udržiavanie hypertenzia Diskontinuita endotélia Strata funkcie bariéry Riziko pre: Ateróm Formácia trombu

Vaskulárna remodelácia -Média ŠTRUKTURÁL. ZMENY DYSFUNKCIA KLINICKÉ NÁSLEDKY SMC hypertrophy Collagen M/L ratio Small arteries: PR hypersensitivity for the VC Large arteries:  AC Zhoršenie a udržiavanie hypertenzie Ischemické KV komplikácie Zhoršenie ATS Progresia poškodenia cieľových orgánov

Remodelácia kardiálna - Srdce Myocyte hypertrophy Changes in the myosine isoenzymatic profile Increase in the subendocardial collagen content

Remodelácia srdca - Srdce Štrukturálne zmeny myocytes hypertrophy  subendocardial collagen changes in myosin isoenzymatic profile Dysfunkcia  Cardiac distensibility  Conductibility  Contractility Klinické následky HĽK (LVH) Zlýhanie srdca Angina Dysrhytmia Hypertrophy of the myocytes, but they cannot multiply.

ATEROSKLERÓZA

Aterosklerotické lézie Hypertenzia Poškodenie endoteliálnych buniek Migration from the blood stream to the intima (sub endothelial) of: - low-density lipoprotein - monocytes Activation and Migration of smooth muscle cells from the media to the intima Synthesis of collagen Consequences: impaired endothelium function, and remodeling results in vascular atherosclerosis and plaque development The response-to-injury hypothesis of atherosclerosis states that some form of “injury” may occur to the lining endothelium and be responsible for the impairment of the barrier function of the endothelium. The agents responsible for this injury could be: dyslipidemia tobacco hypertension diabetes (they are all risk factors for atherosclerosis) The impairment of the barrier function of the endothelium (whatever the cause) allows for the migration of low-density lipoprotein (LDL) from the blood into the subendothelial space. It is transformed into oxidized LDL by free radicals. The impairment of the barrier function of the endothelium also allows for the migration of monocytes from the blood into the subendothelial layer where they are transformed into macrophages (differentiation). Aterosklerotické lézie

3. HYPERTENZIA Klinické rysy

Definitions and Classification of Blood Pressure Levels (mmHg) EHS/EKS, 2007 85-89 and/or 130-139 High Normal 80-84 120-129 Normal <80 and <120 Optimal Diastolic Systolic Category 90-99 and/or 140-159 Grade 1 Hypertension 100-109 and/or 160-179 Grade 2 Hypertension Grade 3 Hypertension ≥180 and/or ≥110 <90 and ≥140 Isolated Systolic Hypertension

Stratification of CV risk in four categories EHS/EKS, 2007 Blood pressure (mmHg) Other risk factors, OD or disease Normal SBP 120-129 or DBP 80-84 High normal SBP 130-139 or DBP 85-89 Grade 1 HT SBP 140-159 or DBP 90-99 Grade 2 HT SBP 160-179 or DBP 100-109 Grade 3 HT SBP ≥180 or DBP ≥110 No other risk factors Average risk Low added risk Moderate added risk High added risk 1-2 risk factors Very high added risk 3 or more risk factors, MS, OD or diabetes Established CV or renal disease SBP: systolic blood pressure; DBP: diastolic blood pressure; CV: cardiovascular; HT: hypertension. Low, moderate, high, very high risa refer to 10year risk of a CV fatal or non-fatal event. The term “added” indicates that in all categories risk is greater than average. OD: subclinical organ damage; MS: metabolic syndrome.

Meranie TK Patienti by mali sedieť Meranie po 5 min odpočinku SBP + DBP Dve alebo viac meraní po 2 min by mali byť spriemernené JNC-VII , JAMA May 21,2003; vol 289 N° 19 p 2560-2572

Symptómy Asymptomaticita väčšiny pacientov Môže zostať nedetekovaná mnoho rokov Bolesti hlavy sa môžu registrovať, ak STK stúpne nad 200 mmHg alebo ak je TK rapídne zvýšený Niekedy: Vertigo, tinitus, závraty Dizzines závraty

Prevalencia hypertenzie Italy 38% Spain 47% England 42% Germany 55% Canada 27% U.S.A. 28% Sweden ~30% = >1 billion individuals2 >7 million deaths/year1 1. WHO Report 2004; 2. Wolf-Maier K et al. Hypertension 2004.

Large number of untreated and uncontrolled patients Kontrola hypertenzie Sweden 6% Germany 8-23% Canada 16-17% Scotland 18% Finland 21% England 6-10% France 27% U.S.A. 27-29% Spain 5-16% Italy 9-23% BP<140/90 35-64 years Large number of untreated and uncontrolled patients 1. WHO Report 2004; 2. Wolf-Maier K et al. Hypertension 2004.

Etiológia hypertenzie Esenciálna hypertenzia 90 - 95% Sekundárna hypertenzia 5 - 10% Primary or Essential Hypertension accounts for approximately 95% of the hypertensive population. It has no single identifiable cause but may be affected by a number of factors.

Etiológia Primárna / Esenciálna hypertenzia 1) vek 2) genetika 3) Vplyvy prostredia a Excessive sodium intake. C Alcohol b Mental & Physical stress. d Weight e Physical inactivity – Less than 30min moderate daily activity 4) Rasa 6) Humorálne mechanizmy 5) Intrauterinné vplyvy 7) Inzulínová rezistencia Age -With age: the arteries lose their elasticity and the systolic blood pressure increases at rest. In young people arteries are supple and easily absorb the pressure of the blood pumped out by the heart. With age they lose their elasticity and the maxima (systolic) blood pressure increases at rest and even more during exertion or when experiencing emotion. Genetics Up to 40% of hypertension may be genetically determined. As has been indicated by family and adoption studies. Our environment also plays an important role as excessive sodium intake can increase blood pressure and mental & physical stress can also cause transient increases in blood pressure. Alcohol intake in large amounts (more than 6 units/day) tends to increase blood pressure (which will fall if consumption is reduced). People who drink no alcohol at all, on the other hand, tend to have a slightly higher blood pressure than people who drink in moderation. Weight is another important factor with obese patients having a higher blood pressure. The correlation is strong especially for central obesity. Physical inactivity is another factor leading to increased blood pressure. Our race is another determinant as in developed countries there is a 30-50% greater prevalence of hypertension in the black population compared with the Caucasion. There are also intrauterine influences for example a low birth weight increasing the risk of adult hypertension. And finally one also has to mention humoral mechanisms e.g renin-angiotensin system and insulin resistance with the diabetes-hypertension association This leads us to the other type of hypertension..

Etiológia Sekundárna hypertenzia Secondary hypertension is much less common than essential hypertension as it represents 5% of all hypertensive patients. Some of the possible aetiological factors leading to secondary hypertension are: renal disease, certain medications, pregnancy and hormonal imbalances. What should a pharmacist watch out for to realize a patient is hypertensive?

Hypertenzia : Rizikové faktory obesity diabetes smoking sedentary Esenciálna hypertenzia stress sex We call a risk factor of a disease, physiological characteristics (sex, age…), pathological characteristics (Hypertension, diabetes) or lifestyle habits (addiction to smoking, settled way of life) that are statistically related to an increased probability of developing this disease. Physiological or pathological characteristics or habits are statistically linked to an increased probability of developing hypertension: they are risk factors for hypertension. age dyslipidemia family history

Hypertenzia: príbuzné (spojené) komplikácie (hlavne sú postihnuté 4 orgány) 4 organs are mainly concerned

Hypertenzia: spojené komplikácie Srdce Mozog - LVH - CHF - Angina - MI Stroke Vysoký TK Obličky Oko 4 organs are mainly concerned Retinopathy Nephro- angio-sclerosis - Renal failure

Efekt STK na KV mortalitu Age-adjusted coronary heart disease death rates per 10,000 person-years by level of systolic and diastolic BP for men screened in the Multiple Risk Factor Intervention Trial (MRFIT) 81 48 CHD death rate per 10 000 person-years 37 44 35 38 31 26 25 25 24 25 25 17 21 14 160+ 13 10 This graph depicts 12-year follow-up data from the screenees (white men age 35-57) in the Multiple Risk Factor Intervention trial MRFIT). It clearly shows that systolic blood pressure is a more robust predictor of CHD mortality (other data also demonstrates this association for other CVD end points) than is diastolic blood pressure. At any level of DBP, risk increases as SBP increases. Note that the group with the highest risk are those > 160 mm Hg with the lowest DBP. These are the group with the widest pulse pressure. 13 12 12 140-159 Systolic BP (mm Hg) 9 9 100+ 9 120-139 90-99 80-89 <120 75-79 Diastolic BP (mm Hg) 70-74 <70 Neaton JD, Wentworth D. Arch Intern Med. 1992;152:56-64.

Artériová hypertenzia : Veľký KV RF The relationship between BP levels and risk of CV disease is continuous, consistent and independent of other risk factors1 due to suboptimal BP control2 62% of stroke 49% of CAD Treating HT means reducing the risk of CV disease3  5 mmHg SBP -14% stroke - 9% CAD - 7% all cause mortality 1. JNC-VII. Hypertension 2003. 2. WHO/ISH. J Hyperten 2003. 3. ESC Guidelines CVD. Eur J Cardiovasc Prev Rehabil. 2003

Artériová hypertenzia : Veľký KV RF Risk factors are clearly identified: Hypertension, lipids, deregulation of glucose plasma and smoking are the worst and most known. Kannel WB & al J Cardiovasc Pharmacol 1989; 13 (suppl 1): S4-S10 Wilson PWF & al Circulation 1998 : 1837-47

Riziko ICHS (CHD) iu mužov Age-adjusted annual incidence of CHD per 1000 Systolic blood pressure (mmHg) Age 65-94 Age 35-64 Diastolic blood pressure (mmHg) Age 65-94 Age 35-64 Blood Pressure and Risk for Coronary Heart Disease in Men Data from the Framingham Heart Study implicate rising systolic and diastolic blood pressure as risk factors for coronary heart disease. This is true for younger (yellow) and older (blue) age groups and for men and women (data not shown). Reference: The Framingham Study: an epidemiological investigation of cardiovascular disease. Section 34. Some risk factors related to the annual incidence of cardiovascular disease and death using pooled repeated biennial measurements: Framingham Heart Study, 30-year follow-up. Bethesda, MD: National Heart, Lung, and Blood Institute, 1987. Based on 30 year follow-up of Framingham Heart Study subjects free of coronary heart disease (CHD) at baseline Framingham Heart Study, 30-year Follow-up. NHLBI, 1987.

Záver Blood pressure Insulinoresistance Diabetes Hypertension is an important cardiovascular risk factor which is why it is necessary to control the blood pressure level perfectly.