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