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ELEVEN INTERNATIONAL SYMPOSIUM HEART FAILURE & Co

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Presentation on theme: "ELEVEN INTERNATIONAL SYMPOSIUM HEART FAILURE & Co"— Presentation transcript:

1 ELEVEN INTERNATIONAL SYMPOSIUM HEART FAILURE & Co
Caserta, 29 – 30 aprile 2011 RANOLAZINE A NEW DRUG WITH A CLASS ACTION The anti heart failure action Pasquale Perrone Filardi Università Federico II di Napoli

2 Pathological conditions with increased INaL
LB Rome Menarini Pathological conditions with increased INaL v Zaza et al Pharm &Ther 2008 Oxygen free radicals Heart failure Post-MI remodeling Ischemia 2

3 extravascular compression
Positive feedback during ischaemia increases the imbalance between myocardial O2 supply and demand Ischemia  O2 supply/ MVO2 X extravascular compression ( O2 supply)  Late INa Deleterious Positive Feedback Cycle Contracture ( LVEDP)  [Na+]i NCX Ca2+ overload Arrhythmias 3

4 Ranolazine: mechanism of action
Ischaemia ↑ Late INa Ranolazine Na+ overload NCX Ca++ overload Mechanical dysfunction ↑Diastolic tension Electrical dysfunction Arrhythmias O2 supply & demand ↑ ATP consumption ↓ ATP formation NCX: sodium-calcium exchanger Hasenfuss G, Maier LS. Clin Res Cardiol 2008;97: Maier LS. Cardiol Clin 2008;26: 4 4

5 Late INa is increased in failing myocytes Leading to QT prolonagtion, EADs and beat-to-beat variation in APD canine human Valdivia ,Journal of Molecular and Cellular Cardiology 38 (2005) 475–483 Maltsev et al. Eur J Heart Fail 2007 5

6 Time Course of Changes in LV End - diastolic Pressure (EDP) During Low Flow Ischemia
A) Time – dependent changes in EDP 70 Control Control 60 Contracture ( LVEDP)  MVO2  O2 - Supply Ranolazine (10µM) 50 EDP (mmHg) 40 Ranolazine 30 20 10 10 20 30 Time (min) Control RAN 10 20 30 Time (min) * B) Time to onset of contracture Control RAN 10 20 30 EDP (mmHg) C) Average EDP (30min period) * Wang, JPET 321: , 2007.

7 LB Rome Menarini v EFFECTS OF RANOLAZINE ON STUNNING MYOCARDIUM IN ISCHEMIA REPERFUSION INJURY 35,000 25,000 RPP (mmHg/min) 15,000 Control Ranolazine (10 µM) 5,000 10 20 30 40 50 60 Time (min) Hwang, JPET 321: , 2007. 7

8 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.

9 RANOLAZINE ATTENUATES THE INCREASE OF VENTRICULAR STIFFNESS DUE TO PALMITOYL-L-CARNITINE –INDUCED INCREASE OF LATE INA Wu Y et al. J Pharmacol Exp Ther 2009;330:550-7.

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

11 RANOLAZINE IMPROVES MECHANICAL EFFICIENCY IN A CANINE MODEL OF CHRONIC HEART FAILURE
Chandler MP et al. Circ. Res. 2002;91;

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

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

14 Ranolazine reduces the increase in diastolic tension in LV trabeculae from human failing heart
Sossalla S et al. J Mol Cell Cardiol 2008; 45: 14

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

16 EFFECTS OF VERAPAMIL ON DIASTOLIC FUNCTION IN RELATION TO AGE IN NORMAL INDIVIDUALS
Arrighi,J, Perrone-Filardi P, et al. Circulation 1994; 90:

17 EFFECTS OF DILTIAZEM ON DIASTOLIC FUNCTION IN CAD PATIENTS
Betocchi S, Perrone Filardi P, et al. Am J Cardiol 1996;78:

18 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

19 Effects of ranolazine on diastolic function in 22 patients with chronic angina
Figuredo et al. J Cardiovasc Pharmacol Ther Oct 5. [Epub ahead of print]

20 Ranolazine significantly reduced the primary end point among the high-risk cohort of patients with BNP>80 pg/ml in the MERLIN trial 21% (RRR) P=0,009

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

22 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

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

24

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

26 Late INa is involved in the Long QTS
50 ms 5 pA Normal Enhanced (KPQ) INaL Gene Channel LQT1 KCNQ1, KvLQT1  IKs LQT2 KCNH2, HERG  IKr LQT3  Late INa LQT4  Cai,  Late INa ? LQT5 KCNE1, minK LQT6 KCN2, MiRP1 LQT7* KCNJ2, Kir2.1  IK1 LQT8** CACNA1C, Cav1.2  ICa LQT9 CAV3, Caveolin-3 LQT10 SCN4B, NavB4 LQT11 AKAP9, Yotiao LQT12 SNTA1, -1 Syntrophin 26

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

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

29 L'aumento di INaL rallenta il rilassamento
LB Rome Menarini v L'aumento di INaL rallenta il rilassamento Normal Abnormal Ao Sodium Current Late I Na Late INa P (mmHg) Peak LV Peak 1 2 (Plateau) 0 (Upstroke) 3 4 coronary flow (ml/min) Twitch Phasic Tonic Belardinelli, L. 2007 29

30

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

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

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

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

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

36

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

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

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

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

42

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

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

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

47

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

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

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


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