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Long presentation on mechanism of action of levosimendan 07.11.2014

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Mechanism of action and pharmacology of the novel cardioprotective inodilator levosimendan

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Long presentation on mechanism of action of levosimendan 07.11.2014

  1. 1. Mechanism of action and pharmacology of levosimendan
  2. 2. Classic treatments for acute heart failure INOTROPE Diuretic If more contractility is required Vasodilator
  3. 3. Heart failure medications ACEi = angiotensin converting enzyme inhibitor i.v. diuretics (e.g. furosemide) i.v. vasodilatory (e.g. nitroprusside) i.v. inotropes (e.g. levosimendan) i.v. vasopressors (e.g. noradrenaline) b-blockers aldosterone-ant. p.o.diuretics digitalis morphine mechanical support ACEi/ARB Chronic Heart Failure Acute Decompensated Heart Failure Cardiogenic Shock
  4. 4. 'Old school' inotropic drugs Pollesello et al. Inter. J. Cardiol. 2016;203:543-48
  5. 5. ‘Old school’ inotropes enhance contractility, but at a price • Increase in myocardial oxygen consumption, increased risk for ischaemia • Reduced effects in patients on beta-blockers • Arrhythmias due to the high level of intracellular calcium • Acceleration of myocardial remodelling and apoptosis • Worsened mid- to long-term clinical prognosis
  6. 6. Dobutamine does not reduce mortality Tacon et al. Inten. Care Med. 2011;38:359-367 There are strong indications from this meta-analysis that dobutamine worsens outcomes in patients with severe heart failure Effect of dobutamine on mortality in heart failure (vs. placebo or standard care) OR 1.47
  7. 7. The emergence of a new inotrope • The development of levosimendan arose from an appreciation of the desirability of an inotrope that would not increase intracellular calcium or myocardial oxygen consumption • But is levosimendan just a good inotrope or is it a new therapeutic concept for AHF?
  8. 8. Levosimendan: a triple mechanism of action • Calcium dependent binding to cTnC • Opening of KATP channels on smooth muscle cells in vasculature • Opening of KATP channels in cardiac mitochondria cTNC = cardiac troponin C
  9. 9. cTNC = cardiac troponin C Levosimendan: a triple mechanism of action • Calcium dependent binding to cTnC • Opening of KATP channels on smooth muscle cells in vasculature • Opening of KATP channels in cardiac mitochondria
  10. 10. Actin Tropomyosin TnI TnT Ca2+ cTnC Myosin head (S1 fragment) ATP pocket RLC ELC New target: cardiac contractile proteins Solaro RJ, Rüegg CJ. Circ Res 1982;51:290-4.
  11. 11. Ca2+ Levosimendan binds selectively to calcium saturated cardiac troponin C Levosimendan Pollesello P et al. J Biol Chem 1994;269:28584–90
  12. 12. Calcium sensitization directly affects contractile fibres Papp Z et al. J Cardiovasc Pharmacol 2005;46:369–76 *p<0.05
  13. 13. Levosimendan: effects on contractility and relaxation in vivo Masutani S et al. J Pharmacol Exp Ther 2008;325:236–47 Ess = left ventricular contractility; LS = levosimendan
  14. 14. Levosimendan: no increase in calcium transient Lancaster MK, Cook SJ. Eur J Pharmacol 1997;339:97–100
  15. 15. Levosimendan: no increase in oxygen consumption (1) Kaheinen P et al. J Cardiovasc Pharmacol 2004;43:555–61 Changein
  16. 16. Levosimendan: no increase in oxygen consumption (2) Ukkonen H et al. Clin Pharmacol Ther 1997;61:596–607
  17. 17. Levosimendan: no attenuation by beta-blockers Haikala H et al. Cardiovasc Res 1997;34:536–46
  18. 18. LIDO: no effect of concomitant beta-blockers Follath F et al. Lancet 2002;360:196–202
  19. 19. • Calcium dependent binding to cTnC • Opening of KATP channels on smooth muscle cells in vasculature • Opening of KATP channels in cardiac mitochondria cTNC = cardiac troponin C Levosimendan: a triple mechanism of action
  20. 20. Levosimendan causes vasodilatation Erdei N et al. Br J Pharmacol 2006;148:696–702 GLI = glibenclamide Ø: 100 m *P<0.05 Gödény et al. Pharmacol Rep. 2013;65(5):1304-10.
  21. 21. Levosimendan increases diastolic coronary flow velocity Kaheinen P et al. J Cardiovasc Pharmacol 2001;37:367–74 Effects of levosimendan on the diastolic coronary flow velocity in isolated guinea- pig hearts in the presence (black) and absence (open) of 0.1 microM glibenclamide (n=6, ** p≤0.01)
  22. 22. Levosimendan increases blood perfusion Pagel PS et al. Br J Pharmacol 1996;119:609–15 Blood flow (lighter bars) and calculated vascular resistance (darker bars) in the small intestine. Data are represented as % change from control. (a) significant (p<0.05) difference from baseline, (abc) significant difference from both low and middle doses, (d) significant difference from the corresponding value in the levosimendan groupi
  23. 23. Levosimendan (Levo) reduced myocardial infarct size Glyburide (Glb) pretreatment abolished this effect Levosimendan: anti-ischaemic effect in an in vivo dog model Kersten JR et al. Anesth Analg 2000;90:5–11 *p<0.05 vs. controls
  24. 24. Levijoki J et al. Eur J Pharmacol 2001;419:243–8; Louhelainen M et al. Br J Pharmacol 2007;150:851–61 Levosimendan: reduction in mortality in heart failure preclinical models
  25. 25. • Calcium dependent binding to cTnC • Opening of KATP channels on smooth muscle cells in vasculature • Opening of KATP channels in cardiac mitochondria cTNC = cardiac troponin C Levosimendan: a triple mechanism of action
  26. 26. Cardioprotective significance of mitochondrial KATP channels in cardiomyocytes McCully JD, Levitsky S. Arch Biochem Biophys 2003;420:237–45 “…opening of the KATPmito channels play a predominant role in the modulation of myocardial infarction following ischemia and reperfusion. The pharmacological opening of KATPmito channels represents a modality for enhancing myocardial protection. Moreover, opening of the KATPmito channels plays a role in the reduction of myocardial cell necrosis and apoptosis induced by ischemia–reperfusion injury by the modulation of [Ca2+]mito accumulation and the stabilization of mitochondrial inner membrane volume and permeability, which would prevent the efflux of cytochrome C and activation of pro-apoptotic proteins…”
  27. 27. Cardioprotection KATP channels opening Zingman LV et al. J Appl Physiol 2007;103:1888–93
  28. 28. Levosimendan opens mitochondrial KATP channels in cardiomyocytes Kopustinskiene DM et al. Biochem Pharmacol 2004;68:807–12
  29. 29. Cardioprotection • Short-term cardioprotection (3 effects) – pre-conditioning – post-conditioning – anti-stunning • Long-term cardioprotection (4 effects) – anti-ischaemic – anti-remodelling – anti-apoptotic – anti-inflammatory
  30. 30. Pre-conditioning (1of 7) Mitochondria are the major effectors of cardioprotection by procedures that open the mitochondrial ATP- sensitive potassium channel (mitoKATP), including ischemic and pharmacological preconditioning. Garlid AO et al. Am J Physiol Heart Circ Physiol. 2013;305:H960-8
  31. 31. Levosimendan has a pre-conditioning effect Stunning Ischaemia Reperfusion ischemic preconditioning Control LVDP or dP/dT levosimendan preconditioning Infarct size
  32. 32. du Toit EF et al. Br J Pharmacol 2008;154:41–50 *p<0.05 vs. control Levosimendan has a pre-conditioning effect
  33. 33. Papp et al. J Cardiovasc Pharmacol Therapeut 2006;11:129-35 Improved survival with levosimendan in canine ischaemia-reperfusion MI model *P<0.05 Occlusion Reperfusion Survival Group Dose micromol/kg n Incidence of VF (%) Incidence of VF (%) % Control 10 40 83 10 Levosimendan 0.1 10 0* 30* 70* Milrinone 0.1 10 60 50 20
  34. 34. Metzsch et al. Acta Anaesthesiol Scand 2007;51:86 -93 Levosimendan has a pre-conditioning effect
  35. 35. The pre-conditioning effect of levosimendan is enhanced by beta-blockers Metzsch et al. Acta Anaest Scand 2010;54:103-110 *P<0.05
  36. 36. Pre-conditioning in coronary artery bypass grafting Tritapepe et al. Br J Anaesth 2009;102:198-206 Tritapepe et al. Br J Anaesth 2006;96:694-700 *P<0.05
  37. 37. Post-conditioning (2 of 7) The cardioprotective ischaemic-reperfusion protocol applied at onset of reperfusion, termed 'post-conditioning' is, as well as pre- conditioning, associated with significant cardioprotection that can be applied at the point of reperfusion treatment in the catheterization laboratory or operating room. Granfeldt et al. Cardiovasc Res 2009;83:234-46
  38. 38. Stunning Ischaemia Reperfusion Ischaemic post-conditioning Control LVDP or dP/dT levosimendan postconditioning Infarct size Levosimendan has a post-conditioning effect
  39. 39. Post-conditioning in ischaemic hearts ex vivo du Toit et al. Br J Pharmacol 2008154:41-50 I-PostC = ischaemic post-conditioning Levo-Post = levosimendan post-conditioning
  40. 40. Levosimendan has a post-conditioning effect in vivo Hönisch A et al. Basic Res Cardiol 2010;105:155–67
  41. 41. Stunning (3 of 7) Camici et al. Circulation 2006;117:103-14 Acute myocardial ischaemia rapidly impairs contractile function.This dysfunction can persist for several hours after transient non-lethal ischaemia but eventually is followed by full functional recovery. This phenomenon is known as myocardial stunning. In patients with CAD, repeated episodes of demand ischaemia may lead to cumulative stunning that could be a substrate in the development of chronic postischemic LV dysfunction.
  42. 42. Levosimendan has an anti-stunning effect In a 24 patient group with ACS the total number of hypokinetic segments decreased in the levosimendan group vs placebo Sonntag et al. J Am Coll Cardiol 2004;43:2177 -82
  43. 43. Ischaemia (4 of 7) • Ischaemia/reperfusion injury is a substantial aggravating factor in human acute heart failure – leads to higher rate of cardiomyocyte apoptosis – causes fibrosis
  44. 44. Levosimendan protects against ischaemia Levijoki et al. Eur J Pharmacol 2001;419:243-248 …and increases survival in animal models Ischaemic Heart Failure Model (Coronary ligation infarct model)
  45. 45. Levosimendan protects against ischaemia …by increasing diastolic coronary flow velocity Kaheinen et al. J Cardiovasc Pharmacol 2001;37:367-374 Effects of levosimendan on the diastolic coronary flow velocity in isolated guinea-pig hearts in the presence (black) and absence (open) of 0.1 microM glybenclamide (n=6, ** p  0.01)
  46. 46. …by increasing the blood perfusion in the heart muscle Levosimendan protects against ischaemia *p<0.05 vs. controls Kersten JR et al. Anesth Analg 2000;90:5–11
  47. 47. Blood flow (lighter bars) and calculated vascular resistance (darker bars) in the small intestine. Data are represented as % change from control. (a) significant (p<0.05) difference from baseline, (abc) significant difference from both low and middle doses, (d) significant difference from the corresponding value in the levosimendan groupi Pagel PS et al. Br J Pharmacol 1996;119:609–15 Levosimendan protects against ischaemia …by increasing organ perfusion
  48. 48. …and is associated with increase in survival in clinical studies Moiseyev et al. Eur Heart J 2002;18:1422-32 RUSSLAN study (n=504) Use of levosimendan is safe in ischaemic patients
  49. 49. Remodelling (5 of 7) • Remodelling = molecular, cellular and interstitial changes in the failing heart, which are manifested clinically as changes in size, shape and function of the heart resulting from cardiac load or injury • Leads to non-reversible myocardial damage – loss of cardiomyocytes – fibrosis of myocardium • Fibrotic myocardium has lost its normal contractile function Cohn et al. J Am Coll Cardiol 2000;25:569-82
  50. 50. Levosimendan stops and reverses the remodelling of cardiac tissue in HF Louhelainen et al. Br J Pharmacol 2007;150:851-61 *P<0.05
  51. 51. Apoptosis (6 of 7) van Empel et al. Cardiovasc Res 2005; 67:21-9 Human heart failure is preceded by a process termed cardiac remodelling in which heart chambers progressively enlarge and contractile function deteriorates. Programmed cell death (apoptosis) of cardiac muscle cells has been identified as an essential process in the progression to heart failure. Unlike necrosis, apoptosis is an orderly regulated process and, by inference, a logical therapeutic target if intervention occurs at an early stage.
  52. 52. Evidence for apoptosis prevention Maytin & Colucci . Am J Cardiol 2005;96:26G-31G 5-HD = 5-hydroxydecanoic acid; H2O2 = hydrogen peroxide
  53. 53. Evidence for prevention of cardiac apoptosis Louhelainen et al. Br J Pharmacol 2007;150:851-61HS = high salt; levo = levosimendan; LS = low salt *P<0.05 vs. Dahl HS # P<0.5 vs. Dahl LS
  54. 54. Inflammation (7 of 7) A broad spectrum of neurohormonal and inflammatory markers are released during heart failure
  55. 55. Levosimendan protects against inflammation In HF patients, levosimendan at therapeutic doses reduces the plasma levels of B-natriuretic peptide1-5, interleukin 62-5, endothelin-I6, A- natriuretic peptide and renin7,8, prevents the increase of norepinephrine and epinephrine levels7 and preserves heart rate variability9. 1Moertl et al. Eur J Heart Fail 2005 Aug 3 2Parissis et al. Am J Cardiol 2005;96:423-6. 3Avgeropoulou et al. Eur J Heart Fail 2005;7:882-7 4Kyrzopoulos et al. Int J Cardiol 2005;99:409-13 5Gegenhuber et al.,Clin Chem 2004;50:454-455 6Nicklas et al. Am J Cardiol 1999;83:12(I)-15(I) 7Nieminen et al. J Am Coll Cardiol 2000;36:1903-12 8Sundberg et al. Am J Cardiol 1995;75:1061-6 9Binkley et al. Circulation 2000;102(suppl II)
  56. 56. Cohen-Solal et al. J Am Coll Cardiol 2009; 53:2343-8 Levosimendan protects against inflammation
  57. 57. Levosimendan: a triple mechanism of action • Calcium dependent binding to cTnC • Opening of KATP channels on smooth muscle cells in vasculature • Opening of KATP channels in cardiac mitochondria
  58. 58. Pollesello P, Papp Z. J Cardiovasc Pharmacol 2007;50:257-63 Molecular targets, mechanisms of action and pharmacological effects of levosimendan Molecular targets Mechanisms of action Pharmacological effects Therapeutic effects Selective binding to the calcium- saturated form of cardiac troponin C Calcium sensitization of contractile proteins Positive inotropy Increased ejection fraction Anti-stunning Opening of KATP channels on smooth muscle cells in vasculature Membrane hyper-polarization Vasodilation in all vascular beds (also coronary and peripheral circulation) Lower pre- and afterload Anti-ischaemic Tissue perfusion Opening of KATPmito channels in cardiomyocytes Protection of mitochondria in ischaemia-reperfusion Pre-conditioning Anti-apoptotic Cardioprotection Anti-ischaemic Long-term benefits
  59. 59. Levosimendan and its active metabolite Szilagyi et al. Eur J Pharmacol 2004; 486:67-74
  60. 60. Kivikko et al. Int J Clin Pharm & Ther 2002;40:465-71 Levosimendananditsactivemetabolite:durationof action Parameter Levosimendan OR-1896 t1/2 (h) Cmax (ng/ml) Tmax (h) Protein binding (%) 1.3 ± 0.1 62.6 ± 8.4 n/a 97 (95–98) 77 ± 9 5.5 ± 0.6 72 (48–120) 42 (33–49)
  61. 61. Levosimendan and its active metabolite reach similar free plasma concentrations Kivikko et al. Int J Clin Pharm & Ther 2002;40:465-71
  62. 62. Levosimendan and its active metabolite elicit vasodilation by the same mechanism and with similar potency and efficacy Erdei et al. Br J Pharmacol 2006;148:696-702
  63. 63. Levosimendan and its active metabolite elicit an inotropic effect with similar potency and efficacy Szilagyi et al. Eur J Pharmacol 2004;486:67-74
  64. 64. The long-lasting effects of levosimendan are explained by the persistence of its active metabolite Lilleberg et al. Eur J Heart Fail 2007; 9:75–82
  65. 65. Heart failure medications: a place for SIMDAX SIMDAX i.v. diuretics (e.g. furosemide) i.v. vasodilatory (e.g. nitroprusside) i.v. inotropes (e.g. levosimendan) i.v. vasopressors (e.g. noradrenaline) b-blockers aldosterone-ant. p.o.diuretics digitalis morphine mechanical support ACEi/ARB Chronic Heart Failure Acute Decompensated Heart Failure Cardiogenic Shock

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