1. Respir. dis. Injury, poisoning Gastroint. dis. Cancer Other IHD Cardiovascular diseases MORTALITY

2. TOTAL AND CARDIOVASCULAR MORTALITY 1. Russia 2300 2. Latvia 2041 3. Belarus 1748 4. Ukraine 1720 5. Hungary 1671 6. Lithuania 1640 7. Rumania 1602 8. Bulgary 1453 9. Poland 1422 10. Slovakia 1407 1. Russia 1065 2. Latvia 1040 3. Rumania 928 4. Bulgary 846 5. Belarus 811 6. Ukraine 805 7. Hungary 768 8. Lithuania 746 9. Poland 687 10. Czech Republic 666 CountryTotalCountryCardiovascular BUT: Sweden826308 240 BUT: Spain France

3. TOTAL AND CARDIOVASCULAR MORTALITY Czech Republic 1984 – 1997 Men, 25 – 64 yrs/ 100 000 inhabitants TOTAL MORTALITY CARDIOVASCULASR MORTALITY CEREBROVASCULAR MORTALITY CORONARY MORTALITY Škodová et al., 1997 1984 1993 change signif. 907,1 704,8 -13,5% p < 0,001 383,5 308,4 -19,6% p < 0,001 76,5 55,3 -27,7% p < 0,001 237,9 194,7 -18,2% p < 0,001

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

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

6. CARDIAC ISCHEMIA vascular resistance transporting capacity of blood for O 2 coronary flow heart rate wall stress contractility O 2 SUPPLYO 2 CONSUMP.

7. HOURS MINUTES SECONDS 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 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 ONSET OF IRREVERSIBLE DAMAGE? CELL DEATH AND TISSUE NECROSIS Hearse, 1979 DEVELOPMENT OF ISCHEMIC INJURY

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

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

10. NEW ISCHEMIC SYNDROMES  silent ischemia  stunning  hibernation

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

12. 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

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

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

15. 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

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

17. 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

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

19. 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

20. 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“

21. CARDIAC TOLERANCE TO OXYGEN DEPRIVATION  AGE  SEX depends on:

22. TOLERANCE TO ISCHEMIA isolated rat heart

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

24. HOW TO INCREASE CARDIAC TOLERANCE TO OXYGEN DEPRIVATION ? PATHOPHYSIOLOGY PHARMACOLOGY CARDIOPLEGIA HYPERTHERMIA Adaptation O 2 consumption O 2 supply Preconditioning

25. PROTECTION OF THE ISCHEMIC HEART history 1960197019801990 PRECONDITIONING ADAPTATION TO CHRONIC HYPOXIA years

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

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

28. COMPARISON OF CARDIOPROTECTION BY CHRONIC HYPOXIA AND PRECONDITIONING total number of PVCs IS/AR (%) INFARCT SIZEARRHYTHMIAS controlshypoxiaischemic preconditioning * * *

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

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

31. COMPARISON OF CARDIOPROTECTION BY CHRONIC HYPOXIA AND PRECONDITIONING CHRONIC HYPOXIAPRECONDITIONING protection +++ duration ++++ mechanism ????

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

33. 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

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