Presentation is loading. Please wait.

Presentation is loading. Please wait.

RANOLAZINE A NEW DRUG WITH A CLASS ACTION The anti heart failure action Pasquale Perrone Filardi Università Federico II di Napoli ELEVEN INTERNATIONAL.

Similar presentations


Presentation on theme: "RANOLAZINE A NEW DRUG WITH A CLASS ACTION The anti heart failure action Pasquale Perrone Filardi Università Federico II di Napoli ELEVEN INTERNATIONAL."— Presentation transcript:

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

2 Ischemia Oxygen free radicals Zaza et al Pharm &Ther 2008 Heart failure Post-MI remodeling Pathological conditions with increased I NaL

3 Positive feedback during ischaemia increases the imbalance between myocardial O2 supply and demand Ca 2+ overload Ischemia O 2 supply/ MVO 2 O 2 supply/ MVO 2Ischemia Late I Na Late I Na [Na + ] i [Na + ] i extravascular compression extravascular compression ( O 2 supply) extravascular compression extravascular compression ( O 2 supply) Contracture ( LVEDP) Contracture Deleterious Positive Feedback Cycle X NCX Arrhythmias

4 4 Ischaemia Late I Na Na + overload Ca ++ overload Ranolazine NCX Hasenfuss G, Maier LS. Clin Res Cardiol 2008;97: Maier LS. Cardiol Clin 2008;26: Mechanical dysfunction Diastolic tension Electrical dysfunction Arrhythmias O 2 supply & demand ATP consumption ATP formation NCX: sodium-calcium exchanger Ranolazine: mechanism of action

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

6 ControlRAN Time (min) * B) Time to onset of contracture Control RAN EDP (mmHg) 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 EDP (mmHg) Control Ranolazine (10µM) Time (min) Ranolazine Control Contracture ( LVEDP) MVO 2 MVO 2 O 2 - Supply O 2 - Supply Wang, JPET 321: , 2007.

7 RPP (mmHg/min) ,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: , 2007.

8 Wu Y et al. J Pharmacol Exp Ther 2009;330: RANOLAZINE ATTENUATES THE INCREASE OF END-DIASTOLIC PRESSURE DUE TO PALMITOYL-L-CARNITINE –INDUCED INCREASE OF LATE I NA

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

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

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

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

13

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:

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

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 Figuredo et al. J Cardiovasc Pharmacol Ther Oct 5. [Epub ahead of print] EFFECTS OF RANOLAZINE ON DIASTOLIC FUNCTION IN 22 PATIENTS WITH CHRONIC ANGINA

20 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

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 I NA is increased in diastolic and systolic heart failure Ranoolazine reduces late I NA 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 I Na is involved in the Long QTS GeneChannel LQT1 KCNQ1, KvLQT1 I Ks I Ks LQT2 KCNH2, HERG I Kr I Kr LQT3 KCNQ1, KvLQT1 Late I Na Late I Na LQT4 KCNH2, HERG Ca i, Late I Na ? Ca i, Late I Na ? LQT5 KCNE1, minK I Ks I Ks LQT6 KCN2, MiRP1 I Kr I Kr LQT7* KCNJ2, Kir2.1 I K1 I K1 LQT8** CACNA1C, Ca v 1.2 I Ca I Ca LQT9 CAV3, Caveolin-3 Late I Na Late I Na LQT10 SCN4B, NavB4 Late I Na Late I Na LQT11 AKAP9, Yotiao I Ks I Ks LQT12 SNTA1, -1 Syntrophin Late I Na Late I Na 50 ms 5 pA Normal 50 ms Enhanced ( KPQ) I NaL

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

28

29 L'aumento di I NaL rallenta il rilassamento Sodium Current 0 0 (Upstroke) 1 2 (Plateau) 3 4 Peak Normal 0 Late I Na Peak Abnormal Twitch PhasicPhasicTonic Late I Na Belardinelli, L P (mmHg) coronary flow (ml/min) Ao LV

30

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

32

33

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

35

36

37

38

39

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

41

42

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

44

45

46

47

48

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

50

51


Download ppt "RANOLAZINE A NEW DRUG WITH A CLASS ACTION The anti heart failure action Pasquale Perrone Filardi Università Federico II di Napoli ELEVEN INTERNATIONAL."

Similar presentations


Ads by Google