„The heart cannot become ill as then it would stop beating“

1. „The heart cannot become ill as then it would stop beating“ Hippokrates of Chios (460-370 B.C.)

2. MORTALITY respiratory diseases injury, pois. cancer gastrointestinal diseases 8,1 6,2 19,3 4,1 7,9 other 30,6 23,8 other cardiovascular diseases ischemic heart disease CARDIOVASCULAR DISEASES 54,4

3. TOTAL AND CARDIOVASCULAR MORTALITY Country Total Country Cardiovascular 1. Russia 2300 2. Latvia 2041 3. Belarus 1748 4. Ukraine 1720 5. Hungary 1671 6. Lithuania 1640 7. Romania 1602 8. Bulgaria 1453 9. Poland 1422 10. Slovakia 1407 1. Russsia 1065 2. Latvia 1040 3. Romania 928 4. Bulgaria 846 5. Belarus 811 6. Ukraine 805 7. Hungary 768 8. Lithuania 746 9. Poland 687 10. Czech Rep. 666 BUT: Sweden 826 BUT: SpainFrance 308 240

4. TOTAL AND CARDIOVASCULAR MORTALITY Czech Republic 1984 – 1997 Men, 25 – 64 yrs/ 100 000 inhabitants 1984 1993 change signif. 907,1 704,8 -13,5% p < 0,001 TOTAL MORTALITY CARDIOVASCULASR MORTALITY CEREBROVASCULAR MORTALITY CORONARY MORTALITY 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 et al., 1997

5. MYOCARDIAL INFARCTION history „ We have investigated a total of 95 cases of myocardial infarction during the last ten years... ……by a month after the beginning of infarction 40% of patients died, by one year it was 60%“. Herles, ČLČ 1938

6. MYOCARDIAL INFARCTIONhistory - in-hospital mortality Staněk, 2003

7. MYOCARDIAL INFARCTIONhistory of diagnosis 1910 - clinical description Obrazcov and Straženko 1918 - ECG, ST elevation Pardee 1928 - ECG - localization Parkinson and Bedford 1954 - enzymes, transaminases La Due et al. 1960 - creatine kinase Dreyfuss et al.

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

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

10. CARDIAC HYPOXIA / ISCHEMIA BLOODSUPPLY CARDIAC CELL OXYGEN DEMAND OXYGEN SUPPLY contractility coronary blood flow heart rate arteriovenous oxygen difference wall stress

11. 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

12. MYOCARDIAL ISCHEMIA Braunwald, 2008

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

14. HYPOXIC (ISCHEMIC) INJURY degree of injurydepends on: • intensity • duration • tolerance

15. HOW TO REDUCE MYOCARDIAL INJURY ?

16. CARDIAC PROTECTION possibilities • early reperfusion • protective phenomena • natural high tolerance

17. CARDIAC PROTECTION background • today, early reperfusion remains the most important intervention for reducing infarct size • new adjunctive therapiesare required to reduce myocardial injury and improve clinical outcomes in patients with IHD

18. CARDIAC PROTECTION adjunctive strategies - history POSTC. LATE PRECOND. PRECONDITIONING PHARMACOLOGICAL PROTECTION ADAPTATION TO CHRONIC HYPOXIA 1960 1970 1980 1990 2000 years

19. CARDIAC PROTECTION ADAPTATION infarct size recovery of contractile function arrhythmias systemic hypertension ! pulmonary hypertension RV hypertrophy

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

21. PRECONDITIONING AND POSTCONDITIONING CONTROLS PRECONDITIONING POSTCONDITIONING 30 * * 20 IA/AR % 10 0 C POST PRE Zhao et al., 2003

22. INNER MITOCHONDRIAL MEMBRANEMPT pore

23. ISCHEMIA / REPERFUSION INJURY consequences • production of oxygen radicals • increase of osmotic gradient – cell swelling • activation of Na/H exchanger • calcium overload • inflammatory response • opening of mitochondrial pores

24. troponin I (μg/ml) creatinkinase (IU/l) BLOCKADE OF MPT PORE cyclosporin - patients * * Piot a spol. 2008

25. CARDIAC PROTECTION possibilities • early reperfusion • protective phenomena • natural high tolerance

26. NATURAL HIGH CARDIAC TOLERANCE TO ISCHEMIA • cold-blooded animals • high altitude populations • immature heart • females until menopause

27. TOLERANCE TO ISCHEMIA isolated rat heart

28. Mount Everest (8850 m) barom.pressure 226 mm Hg PO2air 47 mm Hg art. saturation 18 % transition amniotic fluid - air changes of ambient temperature termination of transplacental nutrition OXIDATIVE STRESS Sea level (0 m) barom. pressure 760 mm Hg PO2 air 160 mm Hg art. saturation 97 %

29. SEX DIFFERENCES ISCHEMIC HEART DISEASE • premenopausal women the onset of IHD occurs 10 years later than in men, myocardial infarction even 20 years later • after menopause 10-fold increase of IHD (in men 4.5-fold) Duvall, 2003

30. * * % < 55 < 55 56 - 64 65 - 74 > 75 age SEX DIFFERENCES acute coronary syndrome with ST elevation Rosengren et al., 2004 (Euro Heart Survey)

31. ATHEROSCLEROTIC CHANGES Fejfar, WHO Annual Report, 1972

32. AGEING OF CARDIOMYOCYTESage 20-90 years WOMEN MEN LV – myocyte loss - 45mil/year LV – number unchanged RV – myocyte loss - 19mil/year RV – number unchanged Anversa et al., 2005

33. MYOCYTE CROSS-SECTION AREAincrease during life (monkey) MALES FEMALES 8% 51% Zhang et al. 2007

34. estrogen vascular endothelial cells smooth muscle cells cardiomyocytes cell proliferation cell migration vasodilatation cell migration LDL chol - oxidation resistance to insulin ischemia/reperfusion injury cardiac hypertrophy EFFECT OF ESTROGEN ON THE HEART Menazza and Murphy, 2016

35. EXPERIMENTAL AND CLINICAL CARDIOLOGY Cardiology is the scientific discipline, where the association between theory and clinical practice is not only the proclamatory phrase, but existing fact; it namely represents almost continuous chain of knowledge from the molecule up to the patient´s bed

36. MYOCARDIAL PROTECTION AT A CROSSROADS „...over the past 30 years, hundreds of experimental interventions have been reported to protect the ischemic myocardium in experimental animals; however, with the exception of early reperfusion, none has been translated into clinical practice.“ Bolli et al., 2005

37. CARDIAC PROTECTION BARRIERS TO TRANSLATING EXPERIMENTAL INTERVENTIONS INTO CLINICAL THERAPIES at the experimental level at the clinical level • adequate models • healthy animals • focus on molecular and cellular mechanisms • failure to publish negative results • methods available to measure infarct size • onset of protection • lack of biosenzors • multiplicity of factors • premature clinical evaluation Bolli et al. 2005, Dirksen et al. 2007

38. RELATIONSHIP BETWEEN EXPERIMENTAL AND CLINICAL CARDIOLOGY XXI. century clinical cardiology experimental cardiology „evidence based medicine“ molecular and cellular aspects

39. We are living in the era of molecular medicine and the influence of basic research on clinical practice is steadilly increasing

40. I do hope that the period of divergence in the approach of experimental and clinical cardiologists to the solution of serious problems comes to the end; this will lead to the prosperity of our beloved discipline

41. HEALTHY HEART Keith Haring