1. Hearth failure Doc.Dr Emir Fazlibegović,ESC,FESC Prof.Dr Mustafa Hadžiomerović, ESC,FESC 5th International Congress of cardiologysts and angyologysts of Bosnia and Herzegovina,Sarajevo 2010.

2. WHAT IS HEART FAILURE? “HF is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood. The cardinal manifestations of HF are dyspnea and fatigue, which may limit exercise tolerance, and fluid retention, which may lead to pulmonary and peripheral edema. “HF is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood. The cardinal manifestations of HF are dyspnea and fatigue, which may limit exercise tolerance, and fluid retention, which may lead to pulmonary and peripheral edema. Both abnormalities can impair the functional capacity and quality of life of affected individuals, but they may not necessarily dominate the clinical picture at the same time.” Evaluation and Management of Chronic Heart Failure in the Adult A Report of the ACC/AHA Task Force on Practice Guidelines February 2002 Supply is less then demand Supply is less then demand Failure of the heart as a pump Failure of the heart as a pump

3. Systolic/Diastolic – does it matter? Systolic: heart cannot contract normally and cannot pump enough blood into the arteries (EF<40%) heart cannot contract normally and cannot pump enough blood into the arteries (EF<40%) Diastolic: heart cannot relax and fill normally and cannot pump enough blood into the arteries (EF>40%) heart cannot relax and fill normally and cannot pump enough blood into the arteries (EF>40%)

4. Left, right, or both? Right Heart Failure Results in increased, systemic venous congestion and peripheral oedema Results in increased, systemic venous congestion and peripheral oedema Left Heart Failure Results in pulmonary congestion Results in pulmonary congestion

5. Different etiology – so what? Many causes but clinical manifestations similar Many causes but clinical manifestations similar – Coronary artery disease is the underlying cause of HF in approximately two thirds of patients with ischemic left ventricular systolic dysfunction. –The remainder have nonischemic causes, e.g. hypertension, valvular disease, myocardial toxins, or myocarditis –or may have no discernible cause (e.g., idiopathic dilated cardiomyopathy).

6. Compensated phase Compensated phase –Supply temporarily meets the altered demand, no or very mild symtoms and signs Decompensated heart failure: Decompensated heart failure: –new or worsening symptoms/signs of dyspnoea, fatigue or oedema leading to hospitalisation or unscheduled medical care PHASE

7. Terminology or just semantics? Congestive Heart Failure (CHF) Heart failure with extra fluid in vessels and tissues Heart failure with extra fluid in vessels and tissues Acute heart failure (AHF) sudden initial episode of HF, severe symptoms; frequent pulmonary edema sudden initial episode of HF, severe symptoms; frequent pulmonary edema Chronic heart failure (CHF) – (chronic HF) Slow process of myocardium destruction, often unnoticed, mild to moderate symptoms; frequent peripheral edema, may follow acute insult Slow process of myocardium destruction, often unnoticed, mild to moderate symptoms; frequent peripheral edema, may follow acute insult Acute exacerbation of chronic heart failure Immediate and massive decompensation of the previously existing chronic heart Immediate and massive decompensation of the previously existing chronic heart

8. Current indication Acutely Decompensated Severe Low-output Chronic -24 hours? -Abruptly -Suddenly Symptomatic NYHA III-IV Cardiac – -EF<40% -CI<2.0 l/min/m 2 -Cold Pre-existing Congestive Heart Failure (CHF)

9. Acute heart failure: –sudden onset of symptoms or signs of heart failure in a patient with no history of heart failure and previously normal cardiac function ONSET

10. ONSET Exacerbation of chronic heart failure: –patient with established diagnosis of heart failure who develops increasing signs or symptoms of the disease after a period of relative stability

11. Conceptual differences between acute and chronic heart failure Chronic heart failure: Chronic heart failure: –neurohumoral disease that responds to neurohumoral intervention –Remodeling, RAAS, cateholamines, PDE Acute heart failure: Acute heart failure: –haemodynamic disease that responds to haemodynamic interventions

12. Classification and causes of heart failure Acute de novo heart failure Acute de novo heart failure –Myocardial infarction –Arrhythmias –Valve destruction –Myocarditis –Hypertensive crisis –Cardiac surgery Decompensated chronic heart failure Decompensated chronic heart failure –Myocardial ischaemia –Arrhythmias –Malcompliance –Infections –Salt overload –Hypertension Pulmonary oedema Low output heart failure (congestion) Cardiogenic shock

13. Differences between acute heart failure and decompensated Chronic HF Haemodynamics : AHF: RV +/- LV, normovolaemic Decompensation of Chronic HF: both RV and LV, increased EDV, hypervolaemic Prognosis : AHF: potentially reversible, stunning, sepsis Decompensation of Chronic HF: chronic disease

14. DIAGNOSIS Framingham Criteria Major Criteria Parox. Nocturnal dyspnea Parox. Nocturnal dyspnea Orthopnea Orthopnea  JVP  JVP Pulmonary rales Pulmonary rales Third heart sound Third heart sound Cardiomegaly Cardiomegaly Pulmonary edema Pulmonary edema Minor Criteria Peripheral edema Peripheral edema Night cough Night cough Dyspnea on exertion Dyspnea on exertion Hepatomegaly Hepatomegaly Pleural effusion Pleural effusion Heart rate>120/min Heart rate>120/min Wight loss > 4.5 kg in 5 days Wight loss > 4.5 kg in 5 days

15. Classification ONSETETIOLOGY PATOPHYSIO LOGY LOCATIONNYHADIAGNOSIS ACUTECHRONICISCHEMICTOXICINFALMATORYREUMATOIDIDIOPATICSYSTOLICDIASTOLICLEFTRIGHTIIIIIIIV HEART FAILURE Cardiac insufficiency CARDIOMIO PATHY Cardiac dysfunction

16. Treatment of Decompensated CHF Decompensated HF Patient Edema (+) Warm Extremities SBP > 90 mm Hg Decompensated HF Patient Edema (+) Cold Extremities SBP > 90 mm Hg Decompensated HF Patient Edema (-) Cold Extremities SBP > 90 mm Hg Optimization of therapy: Increase ACEI doses IV diuretics Other PO or IV vasodilators (nitroprusside) Levosimendan Decompensated HF Patient Edema (+) or (-) Cold Extremities SBP < 90 mm Hg Dobutamine/ Dopamine/ Norepinephrine Add Levo? 67%20%5%8% Inadequate response: Increasing BUN Persisting edema Persisting dyspnea Low-output HFCardio shockHigh output

17. Calcium-Induced Conformational Changes in Troponin Complex Actin TnT cTnC TnI Tm TnI cTnC TnI cTnC TnI Tm TnT Tm Actin Tm TnT Myosin head Ca 2+ Myosin head Myofilament length

18. Levosimendan Calcium sensitisation through binding to troponin C Calcium sensitisation through binding to troponin C – increases cardiac contractility and efficiency Opening of ATP-sensitive potassium channels in vascular smooth muscles Opening of ATP-sensitive potassium channels in vascular smooth muscles – pulmonary, coronary, systemic vasodilation

19. Calcium Sensitization by Levosimendan No increase in cAMP No increase in i/c calcium No increase in energy consumption No arrhythmogenicity No impairment in relaxation Anti-stunning effect No antagonism by  -blockers

20. Heart Failure LIDO study –203 patients with severe HF, levo vs. dobut CASINO study –299 patients low-output HF, levo vs. dobut vs. placebo. REVIVE-2 study –600 patients. Levo vs placebo. Higher early mortality, but no difference at 90 days. SURVIVE trial 1327 patients, levo vs. dobutamine: No mortality difference at 180 days.

21. IHD and Cardiac surgery RUSSLAN study RUSSLAN study –504 patients with recent MI, levo vs. placebo. Trend to lower mortality at 180 days. Small studies in cardiac surgery show levosimendan increases cardiac output and lowers SVR Small studies in cardiac surgery show levosimendan increases cardiac output and lowers SVR

23. Mostar study in 20 patients NYHA III-IV aged 43-84, average 69 aged 43-84, average 69 All patients treated with ACE inhibitors, diuretic, beta blockers, aldosterone blockers, statins, and cardiotonics (digoxin chronically and dobutamin, dopamine in the shortly crisis period). All patients treated with ACE inhibitors, diuretic, beta blockers, aldosterone blockers, statins, and cardiotonics (digoxin chronically and dobutamin, dopamine in the shortly crisis period). on follow-up 1-3 day after infusion and 3 and 6 month, and 1-2-3 year after. on follow-up 1-3 day after infusion and 3 and 6 month, and 1-2-3 year after.

24. Levosimendan and NYHA

25. Mean=-1.0000 Std Dev=0.6124 P< 0.0001

26. EFLV in patients with levosimendan

27. Levosimendan and EFLV Mean=15.7059 Std Dev=14.3952 P= 0.0004 Mean=15.7059 Std Dev=14.3952 P= 0.0004

28. Levosimendan and ENDLV

29. Levosimendan and FS

30. Distrubtion of FS with levosimendan Med=0.0818 SD=0.0915 P= 0.002

31. Conclusion 1 Experience from our practice shows that single dose of Levosimendan in patients with decompensated advanced heart failure produces significant improvement, which reflects in extension of life. Experience from our practice shows that single dose of Levosimendan in patients with decompensated advanced heart failure produces significant improvement, which reflects in extension of life.

32. Conclusion 2 Conclusion 2 Use of Levosimendan seams to be beneficial demonstrated by great benefit in the quality of life with better systolic function without any arrythmogenic effect. Use of Levosimendan seams to be beneficial demonstrated by great benefit in the quality of life with better systolic function without any arrythmogenic effect.

33. Conclusion 3 Conclusion 3 There are probably other benefits masked by uknown lusitropic and pleotropic influences of Levosimendan in the physiology and pathophysiology of heart and others systems of body. There are probably other benefits masked by uknown lusitropic and pleotropic influences of Levosimendan in the physiology and pathophysiology of heart and others systems of body.

34. Conclusion 4 Conclusion 4 Almost all cases of death are results of co-morbidity disease, and are not related to levosimendan effect Almost all cases of death are results of co-morbidity disease, and are not related to levosimendan effect In the future In the future ICD device ICD device Cardiac surgery Cardiac surgery Transplantation Transplantation