Long presentation on mechanism of action of levosimendan 07.11.2014

Mechanism of action and pharmacology of levosimendan

Classic treatmentsfor acute heart failure

INOTROPE

Diuretic

If more contractility is required

Vasodilator

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

'Old school' inotropic drugs

Pollesello et al. Inter. J. Cardiol. 2016;203:543-48

‘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

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

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?

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



• Calcium dependent binding to cTnC• Opening of KATP channels on smooth muscle cells in

vasculature• Opening of KATP channels in cardiac mitochondria

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.

Ca2+

Levosimendan binds selectivelyto calcium saturated cardiac troponin C

Levosimendan

Pollesello P et al. J Biol Chem 1994;269:28584–90

Calcium sensitization directly affects contractile fibres

Papp Z et al. J Cardiovasc Pharmacol 2005;46:369–76

*p<0.05

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

Levosimendan: no increase in calcium transient

Lancaster MK, Cook SJ. Eur J Pharmacol 1997;339:97–100

Levosimendan: no increase in oxygen consumption (1)

Kaheinen P et al. J Cardiovasc Pharmacol 2004;43:555–61

Cha

nge

in

Levosimendan: no increase in oxygen consumption (2)

Ukkonen H et al. Clin Pharmacol Ther 1997;61:596–607

Levosimendan: no attenuation by beta-blockers

Haikala H et al. Cardiovasc Res 1997;34:536–46

LIDO: no effect of concomitant beta-blockers

Follath F et al. Lancet 2002;360:196–202

• Calcium dependent binding to cTnC• Opening of KATP channels on smooth

muscle cells in vasculature• Opening of KATP channels in cardiac

mitochondria



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.

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)

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

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

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

• Calcium dependent binding to cTnC• Opening of KATP channels on smooth

muscle cells in vasculature• Opening of KATP channels in cardiac

mitochondria



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…”

Cardioprotection

KATP channels opening

Zingman LV et al. J Appl Physiol 2007;103:1888–93

Levosimendan opens mitochondrial KATP channels in cardiomyocytes

Kopustinskiene DM et al. Biochem Pharmacol 2004;68:807–12

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

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

Levosimendan has a pre-conditioning effect

StunningIschaemia Reperfusion

ischemic preconditioning

Control

LVDPor dP/dT

levosimendan preconditioning

Infarctsize

du Toit EF et al. Br J Pharmacol 2008;154:41–50

*p<0.05 vs. control


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

Metzsch et al. Acta Anaesthesiol Scand 2007;51:86 -93


The pre-conditioning effect of levosimendanis enhanced by beta-blockers

Metzsch et al. Acta Anaest Scand 2010;54:103-110

*P<0.05

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

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

StunningIschaemia Reperfusion

Ischaemicpost-conditioning

Control

LVDPor dP/dT

levosimendanpostconditioning

Infarctsize

Levosimendan has a post-conditioning effect

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

Levosimendan has a post-conditioning effect in vivo

Hönisch A et al. Basic Res Cardiol 2010;105:155–67

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.

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

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

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)

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)

…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

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

…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

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

Levosimendan stops and reverses theremodelling of cardiac tissue in HF

Louhelainen et al. Br J Pharmacol 2007;150:851-61

*P<0.05

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.

Evidence for apoptosis prevention

Maytin & Colucci . Am J Cardiol 2005;96:26G-31G5-HD = 5-hydroxydecanoic acid;H2O2 = hydrogen peroxide

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

Inflammation (7 of 7)

A broad spectrum of neurohormonal and inflammatory markers are released during heart failure

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)

Cohen-Solal et al. J Am Coll Cardiol 2009; 53:2343-8

Levosimendan protects against inflammation


• Calcium dependent binding to cTnC• Opening of KATP channels on smooth muscle

cells in vasculature• Opening of KATP channels in cardiac

mitochondria

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

Levosimendan and its active metabolite

Szilagyi et al. Eur J Pharmacol 2004; 486:67-74

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)

Levosimendan and its active metabolitereach similar free plasma concentrations

Kivikko et al. Int J Clin Pharm & Ther 2002;40:465-71

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

Levosimendan and its active metabolite elicit an inotropic effect with similar potency and efficacy

Szilagyi et al. Eur J Pharmacol 2004;486:67-74

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

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

Long presentation on mechanism of action of levosimendan 07.11.2014

Healthcare

Transcript of Long presentation on mechanism of action of levosimendan 07.11.2014