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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
Pathological conditions with increased INaL
Zaza et al Pharm &Ther 2008
Heart failure
Post-MI
remodeling
Oxygen free
radicals
Ischemia
Positive feedback during ischaemia increases the
imbalance between myocardial O2 supply and demand
Ischemia
 O2 supply/ MVO2
X
 extravascular compression
( O2 supply)
Contracture
( LVEDP)
 Late INa
Deleterious Positive
Feedback Cycle
 [Na+]i
NCX
Ca2+ overload
Arrhythmias
Ranolazine: mechanism of action
Ischaemia
↑ Late INa
Ranolazine
Na+ overload
NCX
Ca++ overload
Electrical dysfunction
Arrhythmias
Mechanical dysfunction
↑Diastolic tension
O2 supply & demand
↑ ATP consumption
↓ ATP formation
NCX: sodium-calcium exchanger
Hasenfuss G, Maier LS. Clin Res Cardiol 2008;97:222-26.
4
Maier LS. Cardiol Clin 2008;26:603-14.
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
Time Course of Changes in LV End - diastolic Pressure
(EDP) During Low Flow Ischemia
A) Time – dependent changes in EDP
Control
70
Control
EDP (mmHg)
60
Ranolazine (10µM)
50
40
Ranolazine
30
20
Contracture
( LVEDP)

 MVO2
 O2 - Supply
10
0
0
10
20
Time (min)
B) Time to onset of contracture
C) Average EDP (30min period)
*
30
30
20
EDP (mmHg)
Time (min)
30
10
0
Control
Wang, JPET 321:213-220, 2007.
RAN
*
20
10
0
Control
RAN
EFFECTS OF RANOLAZINE ON STUNNING MYOCARDIUM IN
ISCHEMIA REPERFUSION INJURY
RPP (mmHg/min)
35,000
25,000
15,000
Control
Ranolazine (10 µM)
5,000
0
Hwang, JPET 321:213-220, 2007.
10
20
30
Time (min)
40
50
60
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
Wu Y et al. J Pharmacol Exp Ther 2009;330:550-7.
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
RANOLAZINE IMPROVES MECHANICAL EFFICIENCY IN A CANINE MODEL OF
CHRONIC HEART FAILURE
Chandler MP et al. Circ. Res. 2002;91;278-280
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.
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
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 PATIENTS
Betocchi 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
EFFECTS OF RANOLAZINE ON DIASTOLIC FUNCTION IN 22 PATIENTS WITH
CHRONIC ANGINA
Figuredo et al. J Cardiovasc Pharmacol Ther. 2010 Oct 5. [Epub ahead of print]
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)
incidenza cumulativa (%) a 12 mesi
30
P=0,009
29
25
23,7
20
15
10
5
0
Placebo
RANOLAZINA
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
Normal
5
pA
50 ms
Enhanced (KPQ)
50 ms
INaL
INaL
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
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
Abnormal
Normal
0
0
Ao
Late I Na
Late INa
Peak
Peak
1
P (mmHg)
Sodium
Current
0 (Upstroke)
3
4
Phasic
Phasic
Tonic
Twitch
Belardinelli, L. 2007
coronary flow (ml/min)
2 (Plateau)
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.