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RANOLAZINE A NEW DRUG WITH A CLASS ACTION The anti heart failure action

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. Oxygen free radicals. Pathological conditions with increased I NaL.

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RANOLAZINE A NEW DRUG WITH A CLASS ACTION The anti heart failure action

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  1. ELEVEN INTERNATIONAL SYMPOSIUM HEART FAILURE & Co Caserta, 29 – 30 aprile 2011 RANOLAZINE A NEW DRUG WITH A CLASS ACTION The anti heartfailureaction Pasquale PerroneFilardi Università Federico II di Napoli

  2. Oxygen free radicals PathologicalconditionswithincreasedINaL Zaza et al Pharm &Ther 2008 Heart failure Post-MI remodeling Ischemia

  3. 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

  4. Electrical dysfunction Arrhythmias Mechanical dysfunction ↑Diastolic tension O2 supply & demand ↑ATP consumption ↓ATP formation Ranolazine: mechanism of action Ischaemia ↑ Late INa Ranolazine Na+ overload NCX Ca++ overload NCX: sodium-calcium exchanger Hasenfuss G, Maier LS. Clin Res Cardiol 2008;97:222-26. Maier LS. Cardiol Clin 2008;26:603-14. 4

  5. Late INa is increased in failing myocytesLeading 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

  6. Time Course of Changes in LV End - diastolic Pressure (EDP) During Low Flow Ischemia B) Time to onset of contracture C) Average EDP (30min period) * 30 30 20 * Time (min) 20 10 EDP (mmHg) 10 0 Control RAN 0 Control RAN A)Time – dependent changes in EDP Control 70 Control 60 Contracture ( LVEDP)   MVO2  O2 - Supply Ranolazine (10µM) 50 40 EDP (mmHg) Ranolazine 30 20 10 0 0 10 20 30 Time (min) Wang, JPET 321:213-220, 2007.

  7. EFFECTS OF RANOLAZINE ON STUNNING MYOCARDIUM IN ISCHEMIA REPERFUSION INJURY 35,000 25,000 RPP (mmHg/min) 15,000 Control (10 µM) Ranolazine 5,000 0 10 20 30 40 50 60 Time (min) Hwang, JPET 321:213-220, 2007.

  8. RANOLAZINE ATTENUATES THE INCREASE OF END-DIASTOLIC PRESSURE DUE TO PALMITOYL-L-CARNITINE –INDUCED INCREASE OF LATE INA Wu Y et al. J PharmacolExpTher 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 PharmacolExpTher 2009;330:550-7.

  10. EFFECTS OF RANOLAZINE ON lvend-diastolicpressurePOST 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;278-280

  12. RastogiS et al. AmJPhysiolHeart CircPhysiol2008; 295: H2149–H2155

  13. RastogiS et al. AmJPhysiolHeart CircPhysiol2008; 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: 32-43.

  15. EFFECTS OF RANOLAZINE ON FORCE AMPLITUDE AND DIASTOLIC FORCE ON ATRIAL MYOCITES FROM ATRIAL FIBRILLATION AND SYNUS RYTHM PATIENTS SossallaS et al. J Am CollCardiol 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: 213-219

  17. EFFECTS OF DILTIAZEM ON DIASTOLIC FUNCTION IN CAD PATIENTS Betocchi S, PerroneFilardi P, et al. AmJCardiol 1996;78:451-457

  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 Figuredoet al. J CardiovascPharmacolTher. 2010 Oct 5. [Epubahead of print]

  20. Ranolazinesignificantlyreduced the primary end pointamong the high-riskcohortofpatientswith 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. Global left ventricular function, as assessed by the myocardial performance index, was significantly improved on drug therapy (p < 0.0001)

  25. Late INa is involved in the Long QTS Normal Enhanced (KPQ) 5 pA 50ms 50 ms INaL INaL

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

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

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

  29. RastogiS et al. AmJPhysiolHeart CircPhysiol2008; 295: H2149–H2155

  30. RastogiS et al. AmJPhysiolHeart CircPhysiol2008; 295: H2149–H2155

  31. RastogiS et al. AmJPhysiolHeart CircPhysiol2008; 295: H2149–H2155

  32. Sossalla S et al. Basic Res Cardiol2011; 106:263–272

  33. Sossalla S et al. Basic Res Cardiol2011; 106:263–272

  34. Sossalla S et al. Basic Res Cardiol2011; 106:263–272

  35. Sossalla S et al. Basic Res Cardiol2011; 106:263–272

  36. SossallaS et al. JAmCollCardiol 2010;55: 2330–42

  37. SossallaS et al. JAmCollCardiol 2010;55: 2330–42

  38. SossallaS et al. Journal of Molecular and Cellular Cardiology2008; 45:32–43

  39. SossallaS et al. Journal of Molecular and Cellular Cardiology2008; 45:32–43

  40. SossallaS et al. Journal of Molecular and Cellular Cardiology2008; 45:32–43

  41. Wu Y et al. J PharmacolExpTher 2009;330:550-7.

  42. Wu Y et al. J PharmacolExpTher 2009;330:550-7.

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