RANOLAZINEA NEW DRUG WITH A CLASS ACTION

The anti heart failure action

Pasquale Perrone FilardiUniversità Federico II di Napoli

ELEVEN INTERNATIONAL SYMPOSIUMHEART FAILURE & Co

Caserta, 29 – 30 aprile 2011

Ischemia

Oxygen free

radicals

Zaza et al Pharm &Ther 2008

Heart failure

Post-MI remodeling

Pathological conditions with increased INaL

Positive feedback during ischaemia increases the imbalance between myocardial O2 supply and demand

Ca2+ overloadCa2+ overload

Ischemia O2 supply/ MVO2

Ischemia O2 supply/ MVO2

Late INa

Late INa

[Na+]i

[Na+]i

extravascular compression

( O2 supply)

extravascular compression

( O2 supply)

Contracture

( LVEDP)

Contracture

( LVEDP)

Deleterious Positive Feedback Cycle

X

NCX

Arrhythmias

4

Ischaemia

↑ Late INa

Na+ overload

Ca++ overload

Ranolazine

NCX

Hasenfuss G, Maier LS. Clin Res Cardiol 2008;97:222-26.Maier LS. Cardiol Clin 2008;26:603-14.

Mechanical dysfunction↑Diastolic tension

Electrical dysfunctionArrhythmias

O2 supply & demand↑ ATP consumption

↓ ATP formation

NCX: sodium-calcium exchanger

Ranolazine: mechanism of action

Late INa is increased in failing myocytesLeading to QT prolonagtion, EADs and beat-to-beat variation in APD

Valdivia ,Journal of Molecular and Cellular Cardiology 38 (2005) 475–483Maltsev et al. Eur J Heart Fail 2007

canine human

Control RAN0

10

20

30

Tim

e (

min

)

*

B) Time to onset of contracture

Control RAN0

10

20

30

ED

P (

mm

Hg

)

C) Average EDP (30min period)

*

Time Course of Changes in LV End - diastolic Pressure (EDP) During Low Flow Ischemia

A) Time – dependent changes in EDP

ED

P (

mm

Hg

)

0 10 20 300

10

20

30

40

50

60

70Control

Ranolazine (10µM)

Time (min)

Ranolazine

Control

Contracture( LVEDP)

MVO2

O2 - Supply

Wang, JPET 321:213-220, 2007.

RP

P (

mm

Hg

/min

)

0 10 20 30 40 50 60

5,000

15,000

25,000

35,000

Control

Ranolazine

Time (min)

(10 µM)

EFFECTS OF RANOLAZINE ON STUNNING MYOCARDIUM IN ISCHEMIA REPERFUSION INJURY

Hwang, JPET 321:213-220, 2007.

Wu Y et al. J Pharmacol Exp Ther 2009;330:550-7.

RANOLAZINE ATTENUATES THE INCREASE OF END-DIASTOLIC PRESSURE DUE TO PALMITOYL-L-CARNITINE –INDUCED INCREASE OF LATE INA

Wu Y et al. J Pharmacol Exp Ther 2009;330:550-7.

RANOLAZINE ATTENUATES THE INCREASE OF VENTRICULAR STIFFNESS DUE TO PALMITOYL-L-CARNITINE –INDUCED INCREASE OF LATE INA

Hwang H et al. Circulation. 2009;120 suppl 1:S16–S21

EFFECTS OF RANOLAZINE ON LV END-DIASTOLIC PRESSURE POST CARDIOPLEGIA IN LANGENDORFF PERFUSED ISOLATED HEARTS

Chandler MP et al. Circ. Res. 2002;91;278-280

RANOLAZINE IMPROVES MECHANICAL EFFICIENCY IN A CANINE MODEL OF CHRONIC HEART FAILURE

Rastogi S et al. Am J Physiol Heart Circ Physiol 2008; 295: H2149–H2155

Rastogi S et al. Am J Physiol Heart Circ Physiol 2008; 295: H2149–H2155

Ranolazine reduces the increase in diastolic tension in LV trabeculae from human failing heart

Sossalla S et al. J Mol Cell Cardiol 2008; 45: 32-43.

Sossalla S et al. J Am Coll Cardiol 2010;55: 2330–42

EFFECTS OF RANOLAZINE ON FORCE AMPLITUDE AND DIASTOLIC FORCE ON ATRIAL MYOCITES FROM ATRIAL FIBRILLATION AND SYNUS RYTHM PATIENTS

EFFECTS OF VERAPAMIL ON DIASTOLIC FUNCTION IN RELATION TO AGE IN NORMAL INDIVIDUALS

EFFECTS OF VERAPAMIL ON DIASTOLIC FUNCTION IN RELATION TO AGE IN NORMAL INDIVIDUALS

Arrighi,J, Perrone-Filardi P, et al. Circulation 1994; 90: 213-219

EFFECTS OF DILTIAZEM ON DIASTOLIC FUNCTION IN CAD PATIENTSBetocchi S, Perrone Filardi P, et al. Am J Cardiol 1996;78:451-457

Ranolazine shortened a prolonged QTc interval and improved diastolic relaxation in patients with the LQT3-ΔKPQ mutation, a

gentic disorder that is known to cause an increase of late sodium current

Figuredo et al. J Cardiovasc Pharmacol Ther. 2010 Oct 5. [Epub ahead of print]

EFFECTS OF RANOLAZINE ON DIASTOLIC FUNCTION IN 22 PATIENTS WITH CHRONIC ANGINA

Placebo RANOLAZINA0

5

10

15

20

25

30

inc

ide

nza

cu

mu

lati

va

(%

) a

12

me

si 29

23,7

21% (RRR)

P=0,009

Ranolazine significantly reduced the primary end point among the high-risk cohort of patients with BNP>80 pg/ml in the MERLIN trial

Ranolazine significantly reduced the primary end point among the high-risk cohort of patients with BNP>80 pg/ml

CONCLUSIONS AND PERSPECTIVES

• Late INA is increased in diastolic and systolic heart failure

• Ranoolazine reduces late INA and improves diastolic function in experimental animal models and in ex vivo human myocardium

• Ranolazine also reduces post-ischemic contractile dysfunction

• In vivo human data are so far scarce yet encouraging and shall be considered as proof of concept

• Clinical studies are warranted to assess the effects of ranolazine on heart failure with preserved EF and on reperfusion (ACS) patients

Hwang H et al. Circulation. 2009;120 suppl 1:S16–S21

Global left ventricular function, as assessed by the myocardial performance index, was significantly improved on drug therapy (p < 0.0001)

Late INa is involved in the Long QTS

Gene Channel

LQT1 KCNQ1, KvLQT1 IKs

LQT2 KCNH2, HERG IKr

LQT3 KCNQ1, KvLQT1 Late INa

LQT4 KCNH2, HERG Cai, Late INa ?

LQT5 KCNE1, minK IKs

LQT6 KCN2, MiRP1 IKr

LQT7* KCNJ2, Kir2.1 IK1

LQT8** CACNA1C, Cav1.2 ICa

LQT9 CAV3, Caveolin-3 Late INa

LQT10 SCN4B, NavB4 Late INa

LQT11 AKAP9, Yotiao IKs

LQT12 SNTA1, -1 Syntrophin

Late INa

50 ms

5pA

Normal

50 ms

Enhanced (KPQ)

INaL

INaL

Hwang H et al. Circulation. 2009;120 suppl 1:S16–S21

Hwang H et al. Circulation. 2009;120 suppl 1:S16–S21

L'aumento di INaL rallenta il rilassamento

SodiumCurrent

0

0 (Upstroke)

12 (Plateau)

3

4

Peak

Normal0

Late INa

Peak

Abnormal

Twitch

Phasic Phasic

Tonic

Late I Na

Belardinelli, L. 2007P

(m

mH

g)

coro

nar

y fl

ow

(m

l/m

in)

Ao

LV

Rastogi S et al. Am J Physiol Heart Circ Physiol 2008; 295: H2149–H2155

Rastogi S et al. Am J Physiol Heart Circ Physiol 2008; 295: H2149–H2155

Rastogi S et al. Am J Physiol Heart Circ Physiol 2008; 295: H2149–H2155

Sossalla S et al. Basic Res Cardiol 2011; 106:263–272

Sossalla S et al. Basic Res Cardiol 2011; 106:263–272

Sossalla S et al. Basic Res Cardiol 2011; 106:263–272

Sossalla S et al. Basic Res Cardiol 2011; 106:263–272

Sossalla S et al. J Am Coll Cardiol 2010;55: 2330–42

Sossalla S et al. J Am Coll Cardiol 2010;55: 2330–42

Sossalla S et al. Journal of Molecular and Cellular Cardiology 2008; 45:32–43

Sossalla S et al. Journal of Molecular and Cellular Cardiology 2008; 45:32–43

Sossalla S et al. Journal of Molecular and Cellular Cardiology 2008; 45:32–43

Wu Y et al. J Pharmacol Exp Ther 2009;330:550-7.

Wu Y et al. J Pharmacol Exp Ther 2009;330:550-7.

Wu Y et al. J Pharmacol Exp Ther 2009;330:550-7.