Gian Piero Perna Il valore aggiunto di Levosimendan nella terapia dell’insufficienza cardiaca.
Long presentation on mechanism of action of levosimendan 07.11.2014
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Transcript of Long presentation on mechanism of action of levosimendan 07.11.2014
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Mechanism of action and pharmacology of levosimendan
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Classic treatmentsfor acute heart failure
INOTROPE
Diuretic
If more contractility is required
Vasodilator
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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-blockersaldosterone-ant.
p.o. diureticsdigitalis
morphine
mechanical support
hospitalization
ACEi/ARB
ChronicHeart Failure
AcuteDecompensatedHeart Failure
CardiogenicShock
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'Old school' inotropic drugs
Pollesello et al. Inter. J. Cardiol. 2016;203:543-48
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‘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
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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
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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?
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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
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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
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Actin
Tropomyosin
TnI
TnT
Ca2+
cTnCMyosin head (S1 fragment)
ATP pocket RLC
ELC
New target: cardiac contractile proteins
Solaro RJ, Rüegg CJ. Circ Res 1982;51:290-4.
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Ca2+
Levosimendan binds selectivelyto calcium saturated cardiac troponin C
Levosimendan
Pollesello P et al. J Biol Chem 1994;269:28584–90
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Calcium sensitization directly affects contractile fibres
Papp Z et al. J Cardiovasc Pharmacol 2005;46:369–76
*p<0.05
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Levosimendan: effects on contractility and relaxation in vivo
Masutani S et al. J Pharmacol Exp Ther 2008;325:236–47Ess = left ventricular contractility;
LS = levosimendan
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Levosimendan: no increase in calcium transient
Lancaster MK, Cook SJ. Eur J Pharmacol 1997;339:97–100
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Levosimendan: no increase in oxygen consumption (1)
Kaheinen P et al. J Cardiovasc Pharmacol 2004;43:555–61
Cha
nge
in
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Levosimendan: no increase in oxygen consumption (2)
Ukkonen H et al. Clin Pharmacol Ther 1997;61:596–607
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Levosimendan: no attenuation by beta-blockers
Haikala H et al. Cardiovasc Res 1997;34:536–46
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LIDO: no effect of concomitant beta-blockers
Follath F et al. Lancet 2002;360:196–202
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• 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
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Levosimendan causes vasodilatation
Erdei N et al. Br J Pharmacol 2006;148:696–702GLI = glibenclamide
Ø: 100 m
*P<0.05
Gödény et al. Pharmacol Rep. 2013;65(5):1304-10.
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Levosimendan increases diastoliccoronary 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)
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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
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Levosimendan (Levo) reduced myocardial infarct sizeGlyburide (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
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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
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• 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
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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 channelsrepresents 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…”
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Cardioprotection
KATP channels opening
Zingman LV et al. J Appl Physiol 2007;103:1888–93
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Levosimendan opens mitochondrial KATP channels in cardiomyocytes
Kopustinskiene DM et al. Biochem Pharmacol 2004;68:807–12
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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
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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
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Levosimendan has a pre-conditioning effect
StunningIschaemia Reperfusion
ischemic preconditioning
Control
LVDPor dP/dT
levosimendan preconditioning
Infarctsize
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du Toit EF et al. Br J Pharmacol 2008;154:41–50
*p<0.05 vs. control
Levosimendan has a pre-conditioning effect
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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 Dosemicromol/kg
n Incidenceof VF (%)
Incidenceof VF (%)
%
Control 10 40 83 10
Levosimendan 0.1 10 0* 30* 70*
Milrinone 0.1 10 60 50 20
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Metzsch et al. Acta Anaesthesiol Scand 2007;51:86 -93
Levosimendan has a pre-conditioning effect
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The pre-conditioning effect of levosimendanis enhanced by beta-blockers
Metzsch et al. Acta Anaest Scand 2010;54:103-110
*P<0.05
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Pre-conditioning in coronary artery bypass grafting
Tritapepe et al. Br J Anaesth 2009;102:198-206Tritapepe et al. Br J Anaesth 2006;96:694-700
*P<0.05
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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
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StunningIschaemia Reperfusion
Ischaemicpost-conditioning
Control
LVDPor dP/dT
levosimendanpostconditioning
Infarctsize
Levosimendan has a post-conditioning effect
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Post-conditioning in ischaemic hearts ex vivo
du Toit et al. Br J Pharmacol 2008154:41-50I-PostC = ischaemic post-conditioningLevo-Post = levosimendan post-conditioning
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Levosimendan has a post-conditioning effect in vivo
Hönisch A et al. Basic Res Cardiol 2010;105:155–67
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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.
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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
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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
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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)
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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)
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…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
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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
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…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
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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
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Levosimendan stops and reverses theremodelling of cardiac tissue in HF
Louhelainen et al. Br J Pharmacol 2007;150:851-61
*P<0.05
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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.
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Evidence for apoptosis prevention
Maytin & Colucci . Am J Cardiol 2005;96:26G-31G5-HD = 5-hydroxydecanoic acid;H2O2 = hydrogen peroxide
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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
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Inflammation (7 of 7)
A broad spectrum of neurohormonal and inflammatory markers are released during heart failure
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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 32Parissis et al. Am J Cardiol 2005;96:423-6. 3Avgeropoulou et al. Eur J Heart Fail 2005;7:882-74Kyrzopoulos et al. Int J Cardiol 2005;99:409-13
5Gegenhuber et al.,Clin Chem 2004;50:454-4556Nicklas et al. Am J Cardiol 1999;83:12(I)-15(I)7Nieminen et al. J Am Coll Cardiol 2000;36:1903-128Sundberg et al. Am J Cardiol 1995;75:1061-69Binkley et al. Circulation 2000;102(suppl II)
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Cohen-Solal et al. J Am Coll Cardiol 2009; 53:2343-8
Levosimendan protects against inflammation
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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
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Pollesello P, Papp Z. J Cardiovasc Pharmacol 2007;50:257-63
Molecular targets, mechanisms of actionand 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 fractionAnti-stunning
Opening of KATP channels on
smooth muscle cells in vasculature
Membranehyper-polarization
Vasodilation in all vascular beds (also coronary and
peripheral circulation)
Lower pre- and afterloadAnti-ischaemic
Tissue perfusion
Opening of KATPmito channels in
cardiomyocytes
Protection of mitochondria in
ischaemia-reperfusion
Pre-conditioningAnti-apoptotic
CardioprotectionAnti-ischaemic
Long-term benefits
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Levosimendan and its active metabolite
Szilagyi et al. Eur J Pharmacol 2004; 486:67-74
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Kivikko et al. Int J Clin Pharm & Ther 2002;40:465-71
Levosimendan and its active metabolite: duration of action
Parameter Levosimendan OR-1896
t1/2 (h)Cmax (ng/ml)Tmax (h)Protein binding (%)
1.3 ± 0.162.6 ± 8.4
n/a97 (95–98)
77 ± 95.5 ± 0.6
72 (48–120)42 (33–49)
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Levosimendan and its active metabolitereach similar free plasma concentrations
Kivikko et al. Int J Clin Pharm & Ther 2002;40:465-71
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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
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Levosimendan and its active metabolite elicit an inotropic effect with similar potency and efficacy
Szilagyi et al. Eur J Pharmacol 2004;486:67-74
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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
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Heart failure medications: a place for SIMDAX
SIMDAXi.v. diuretics (e.g. furosemide)
i.v. vasodilatory (e.g. nitroprusside)i.v. inotropes (e.g. levosimendan) i.v. vasopressors (e.g. noradrenaline)
b-blockersaldosterone-ant.
p.o. diureticsdigitalis
morphine
mechanical support
hospitalization
ACEi/ARB
ChronicHeart Failure
AcuteDecompensatedHeart Failure
CardiogenicShock