Effect of Ranolazine Monotherapy on Glycemic Control in Subjects ...
RANOLAZINE A NEW DRUG WITH A CLASS ACTION The anti heart failure action
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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
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Ischemia
Oxygen free
radicals
Zaza et al Pharm &Ther 2008
Heart failure
Post-MI remodeling
Pathological conditions with increased INaL
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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
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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
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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
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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.
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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.
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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
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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
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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
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Chandler MP et al. Circ. Res. 2002;91;278-280
RANOLAZINE IMPROVES MECHANICAL EFFICIENCY IN A CANINE MODEL OF CHRONIC HEART FAILURE
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Rastogi S et al. Am J Physiol Heart Circ Physiol 2008; 295: H2149–H2155
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Rastogi S et al. Am J Physiol Heart Circ Physiol 2008; 295: H2149–H2155
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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.
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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
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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
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EFFECTS OF DILTIAZEM ON DIASTOLIC FUNCTION IN CAD PATIENTSBetocchi S, Perrone Filardi P, et al. Am J Cardiol 1996;78:451-457
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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
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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
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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
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Ranolazine significantly reduced the primary end point among the high-risk cohort of patients with BNP>80 pg/ml
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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
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Hwang H et al. Circulation. 2009;120 suppl 1:S16–S21
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Global left ventricular function, as assessed by the myocardial performance index, was significantly improved on drug therapy (p < 0.0001)
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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
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Hwang H et al. Circulation. 2009;120 suppl 1:S16–S21
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Hwang H et al. Circulation. 2009;120 suppl 1:S16–S21
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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
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Rastogi S et al. Am J Physiol Heart Circ Physiol 2008; 295: H2149–H2155
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Rastogi S et al. Am J Physiol Heart Circ Physiol 2008; 295: H2149–H2155
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Rastogi S et al. Am J Physiol Heart Circ Physiol 2008; 295: H2149–H2155
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Sossalla S et al. Basic Res Cardiol 2011; 106:263–272
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Sossalla S et al. Basic Res Cardiol 2011; 106:263–272
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Sossalla S et al. Basic Res Cardiol 2011; 106:263–272
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Sossalla S et al. Basic Res Cardiol 2011; 106:263–272
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Sossalla S et al. J Am Coll Cardiol 2010;55: 2330–42
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Sossalla S et al. J Am Coll Cardiol 2010;55: 2330–42
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Sossalla S et al. Journal of Molecular and Cellular Cardiology 2008; 45:32–43
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Sossalla S et al. Journal of Molecular and Cellular Cardiology 2008; 45:32–43
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Sossalla S et al. Journal of Molecular and Cellular Cardiology 2008; 45:32–43
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Wu Y et al. J Pharmacol Exp Ther 2009;330:550-7.
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Wu Y et al. J Pharmacol Exp Ther 2009;330:550-7.
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Wu Y et al. J Pharmacol Exp Ther 2009;330:550-7.