MORTALITA 8,1 6,2 19,3 4,1 7,9 30,6 23,8 respirační onemocnění úrazy, otravy nádory zažívací onemocnění 8,1 6,2 19,3 4,1 7,9 jiné 30,6 23,8 jiné choroby srdce a cév ischemická choroba srdeční CHOROBY SRDCE A CÉV 54,4

CELKOVÁ A KARDIOVASKULÁRNÍ MORTALITA Země Celková Země Kardiovaskulární 1. Rusko 2300 2. Lotyšsko 2041 3. Bělorusko 1748 4. Ukrajina 1720 5. Maďarsko 1671 6. Litva 1640 7. Rumunsko 1602 8. Bulharsko 1453 9. Polsko 1422 10. Slovensko 1407 1. Rusko 1065 2. Lotyšsko 1040 3. Rumunsko 928 4. Bulharsko 846 5. Bělorusko 811 6. Ukrajina 805 7. Maďarsko 768 8. Litva 746 9. Polsko 687 10. Česká republika 666 ALE: Švédsko 826 ALE: Španělsko Francie 308 240

CELKOVÁ A KARDIOVASKULÁRNÍ MORTALITA Česká republika 1984 – 1997 Muži, 25 – 64 let, na 100 000 obyvatel 1984 1993 změna význ. 907,1 704,8 -13,5% p < 0,001 CELKOVÁ MORTALITA KARDIOVASKULÁRNÍ CEREBROVASKULÁRNÍ KORONÁRNÍ 383,5 308,4 -19,6% p < 0,001 76,5 55,3 -27,7% p < 0,001 237,9 194,7 -18,2% p < 0,001 Škodová a spol., 1997

INFARKT MYOKARDU historie „ Celkem jsme v uplynulém desetiletí vyšetřili 95 případů infarktu myokardu. ……Do měsíce po vzniku infarktu zemřelo celkem 40% a do roka 60%“ Herles, ČLČ 1938

INFARKT MYOKARDU hospitalizační mortalita lůžko Staněk, 2003

DESET NEJVĚTŠÍCH OBJEVŮ KARDIOLOGIE 20. STOLETÍ EKG Framinghamská studie – hlavní rizikové faktory Lipidová hypotéza aterosklerózy Koronární jednotky Echokardiografie Trombolytická léčba Srdeční katetrizace Operace na otevřeném srdci Automatické implantabilní defibrilátory Koronární angioplastika Mehta a Khan, Texas Heart Institute J., 2002

CARDIOVASCULAR DISEASES ontogenetic development and risk factors age GOUT DIABETES HYPERTENSION PHYS. INACTIVITY SMOKING STRESS CHOLESTEROL OVERNUTRITION GENETIC FACTORS Fejfar, 1975

EPIDEMIOLOGY OF CVD trends in children (USA) cigarette smoking (36 %) physical activity calorie consumption (28 %) diabetes type II Pearson, 2000

CARDIAC HYPOXIA / ISCHAEMIA BLOOD SUPPLY CARDIAC CELL OXYGEN SUPPLY OXYGEN DEMAND contractility coronary blood flow heart rate arteriovenous oxygen difference wall stress

DEVELOPMENT OF ISCHEMIC INJURY ONSET OF SEVERE HYPOXIA Reduced oxygen availability Acute contractile failure Reduction of mitochondrial oxidative metabolism Disturbances of transmembrane ionic balance Reduced ATP production Reduction of creatine phosphate stores Reduction of amplitude and duration of action potential Leakage of potassium ST-segment changes Accumulation of sodium and chloride ions Catecholamine release Stimulation of glycogenolysis Increase in glycolytic flux Development of intracellular acidosis Inhibition of fatty acid oxidation Utilization of glycogen Slowing of glycolytic flux Increasing depletion of energy stores Cell swelling Increase in cytosolic calcium ions Possible exhaustion of glycogen reserves Inhibition of glycolysis Severe depletion of ATP and creatine phosphate Ultrastructural changes, eg. mitochondrial swelling Possible onset of contracture SECONDS MINUTES ONSET OF IRREVERSIBLE DAMAGE? Lysosomal changes and activation of hydrolases Increasing cellular edema Loss of mitochondrial respiratory control Nonspecific electrocardiographic changes Major ultrastructural changes Complete depletion of energy reserves Loss of mitochondrial components Membrane injury and cellular disruption Cellular autolysis HOURS CELL DEATH AND TISSUE NECROSIS Hearse, 1979

MYOCARDIAL INFARCTION Perfused tissue Infarcted area (IA) (tetrazolium-negative) Surviving tissue (tetrazolium-positive) Area at risk (AR) = Infarcted + Surviving

ISCHEMIC IMPAIRMENT OF VENTRICULAR CONTRACTION central ischemic zone adjacent area uninvolved myocardium paradoxical motion (systolic bulging, dyskinesis) reduced contraction (akinesis or hypokinesis) compensatory hyperfunction

NEW ISCHEMIC SYNDROMES silent ischemia stunning hibernation

? SILENT ISCHEMIA (Stern and Tzivoni, 1978) ECG and functional ischemic changes are not always accompanied by chest pain ? increased treshold for pain milder form of ischemia release of pain modifiers (e.g. ß endorfins)

STUNNING (Heyndrickx et al., 1975 Braunwald and Kloner, 1982) „Mechanical dysfunction that persists after reperfusion despite absence of irreversible damage restoration of normal or near-normal coronary flow“ Bolli, 1990

MECHANISMS PROPOSED FOR MYOCARDIAL STUNNING oxyradical hypothesis generation of oxygen free radicals calcium hypothesis calcium overload decreased responsiveness of myofilaments to calcium

CLINICAL RELEVANCE OF MYOCARDIAL STUNNING unstable angina acute myocardial infarction with early reperfusion open heart surgery cardiac transplantation

HIBERNATION „…a persistent contractile dysfunction that is associated with reduced coronary flow but preserved myocardial viability.“ Bolli, 1992 ONCE CORONARY FLOW IS RESTORED, THE DYSFUNCTION IS COMPLETELY REVERSED

HIBERNATION vs. STUNNING contractile dysfunction + + + + reversibility blood flow N

MYOCARDIAL INFARCTION Perfused tissue Infarcted area (IA) (tetrazolium-negative) Surviving tissue (tetrazolium-positive) Area at risk (AR) = Infarcted + Surviving

ZÁNIK SRDEČNÍ BUŇKY nekróza apoptóza

NEKRÓZA energeticky nezávislý proces poškození více buněčných organel edém buňky aktivace lysozomálních enzymů autolytický rozklad buňky zánětlivá reakce

APOPTÓZA svraštění buňky kondensace jádra přestavba bílkovin cytoskeletu rozpad do membránou obalených fragmentů (apoptotická tělíska)

APOPTÓZA a ischemická choroba srdeční 1 - 97% ? častější na okraji ložiska rozvoj po okluzi apoptózy 4,5 hod. nekrózy 24 hod.

REPERFUSION INJURY „…those metabolic, functional, and structural consequences of restoring coronary arterial flow… …that can be avoided or reversed by modification of conditions of reperfusion.“ Rosenkranz and Buckberg, 1983

ISCHEMIA / REPERFUSION INJURY previous ischemic damage is fundamental for development of reperfusion injury; degree of reperfusion injury positively correlates with the duration of ischemia

MECHANISMS OF REPERFUSION INJURY FACTORS USEFUL OR ESSENTIAL FOR NORMAL CELLS - re-energization - pH normalization FACTORS HARMFUL IF DECREASED SELF-DEFENSE SYSTEM - oxygen radicals - proteases FACTORS ACTIVATED BY ISCHEMIA-INDUCED CHANGES - neutrophils - complement system - other factors of inflammatory reaction „NO-REFLOW“ PHENOMENON

The appropriate term should be REPERFUSION INJURY Clear evidence that reperfusion causes injury to the myocardium - phenomenon called „reperfusion injury“ - is still lacking The appropriate term should be „ISCHEMIA – REPERFUSION INJURY“

CARDIAC TOLERANCE TO OXYGEN DEPRIVATION depends on: AGE SEX

TOLERANCE TO ISCHEMIA isolated rat heart

GENDER DIFFERENCE IN CARDIAC TOLERANCE TO OXYGEN DEPRIVATION (adult rats) * recovery of contractility (%) MALES FEMALES Ostadal et al. 1984

HOW TO INCREASE CARDIAC TOLERANCE TO OXYGEN DEPRIVATION ? PATHOPHYSIOLOGY Adaptation Preconditioning PHARMACOLOGY O2 consumption O2 supply CARDIOPLEGIA HYPERTHERMIA

ADAPTATION TO CHRONIC HYPOXIA PROTECTION OF THE ISCHEMIC HEART history PRECONDITIONING ADAPTATION TO CHRONIC HYPOXIA 1960 1970 1980 1990 years

clinical – epidemiological CARDIAC PROTECTION ADAPTATION TO CHRONIC HYPOXIA ISCHEMIC PRECONDITIONING Hurtado, 1960 Murry et al., 1986 clinical – epidemiological observation experimental study

TYPICAL PRECONDITIONING PROTOCOL Sustained test occlusion Measurement of infarct size Preconditioning stimulus Reperfusion Reperfusion

COMPARISON OF CARDIOPROTECTION BY CHRONIC HYPOXIA AND PRECONDITIONING INFARCT SIZE ARRHYTHMIAS * * * * IS/AR (%) total number of PVCs * * controls hypoxia ischemic preconditioning

„Second window of protection“ PRECONDITIONING „Second window of protection“ Delayed phase of protection (24 – 48 h after preconditioning) (Marban et al. 1993)

ADAPTATION TO CHRONIC HYPOXIA Protective effects: infarct size recovery of contractile function arrhythmias hypertension Adverse effects: pulmonary hypertension RV hypertrophy

COMPARISON OF CARDIOPROTECTION BY CHRONIC HYPOXIA AND PRECONDITIONING + ++ duration +++ mechanism ??? ?

CLINICAL RELEVANCE OF ISCHEMIC PRECONDITIONING angioplasty angina cardiac surgery preconditioning – mimetic drugs ?

CLINICAL RELEVANCE OF ADAPTATION TO CHRONIC HYPOXIA high altitude populations high altitude tourism and sports chronic ischemic heart disease chronic obstructive and restrictive lung disease congenital cyanotic cardiac malformations

KARDIOVASKULÁRNÍ ONEMOCNĚNÍ Ontogenetický vývoj rizikových faktorů (Fejfar 1975) dna diabetes hypertenze ” fyzická aktivita kouření stres “ cholesterol přejídání genetické faktory

ISCHEMIE MYOKARDU cévní resistence frekvence koronární průtok DODÁVKA O2 SPOTŘEBA O2 kontraktilita transportní kapacita krve pro O2 napětí ve stěně komory