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New Mechanistic Approaches to Myocardial Ischemia. New mechanistic approaches to myocardial ischemia. Rho kinase inhibition (fasudil) Metabolic modulation (trimetazidine) Preconditioning (nicorandil) Sinus node inhibition (ivabradine) Late Na + current inhibition (ranolazine). - PowerPoint PPT Presentation
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New Mechanistic Approaches to Myocardial Ischemia
New mechanistic approaches to myocardial ischemia
• Rho kinase inhibition (fasudil)
• Metabolic modulation (trimetazidine)
• Preconditioning (nicorandil)
• Sinus node inhibition (ivabradine)
• Late Na+ current inhibition (ranolazine)
Rho kinase inhibition: Fasudil
Adapted from Seasholtz TM. Am J Physiol Cell Physiol. 2003;284:C596-8.
Rho kinase triggers vasoconstriction through accumulation of phosphorylated myosin
Ca2+ Ca2+
PLC
SR Ca2+
Receptor
Agonist
Myosin
Myosin-P
Myosin phosphatase
PIP2
IP3
MLCK
VOC ROC
Ca2+
Calmodulin
Rho
Rho kinase
Fasudil
Metabolic modulation (pFOX): Trimetazidine
• O2 requirement of glucose pathway is lower than FFA pathway
• During ischemia, oxidized FFA levels rise, blunting the glucose pathway
FFA Glucose
Acyl-CoA
Acetyl-CoA
Pyruvate
Energy for contraction
Myocytes
β-oxidation
Trimetazidine
MacInnes A et al. Circ Res. 2003;93:e26-32.Lopaschuk GD et al. Circ Res. 2003;93:e33-7.
Stanley WC. J Cardiovasc Pharmacol Ther. 2004;9(suppl 1):S31-45.pFOX = partial fatty acid oxidationFFA = free fatty acid
Metabolic modulation (pFOX) and ranolazine
• Clinical trials showed ranolazine SR 500–1000 mg bid (~2–6 µmol/L) reduced angina
• Experimental studies demonstrated that ranolazine 100 µmol/L achieved only 12% pFOX inhibition– Ranolazine does not inhibit pFOX at clinically relevant doses
• Inhibition of fatty acid oxidation does not appear to be a major antianginal mechanism for ranolazine
MacInnes A et al. Circ Res. 2003;93:e26-32.Antzelevitch C et al. J Cardiovasc Pharmacol
Therapeut. 2004;9(suppl 1):S65-83.Antzelevitch C et al. Circulation. 2004;110:904-10.pFOX = partial fatty acid oxidation
Preconditioning: Nicorandil
Nitrate-associated effects• Vasodilation of coronary epicardial arteries
Activation of ATP-sensitive K+ channels• Ischemic preconditioning• Dilation of coronary resistance arterioles
IONA Study Group. Lancet. 2002;359:1269-75.Rahman N et al. AAPS J. 2004;6:e34.
N O
O NO2
HN
Sinus node inhibition: Ivabradine
• If current is an inward
Na+/K+ current that activates pacemaker cells of the SA node
• Ivabradine– Selectively blocks If in a
current-dependent fashion– Reduces slope of diastolic
depolarization, slowing HR
DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22.
40
20
0
–20
–40
–60
0.5
Potential (mV)
Control Ivabradine 0.3 µM
Time (seconds)
SA = sinoatrial
Late Na+ current inhibition: Ranolazine
Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.Belardinelli L et al. Eur Heart J Suppl. 2004;(6 suppl I):I3-7.
Myocardial ischemia
Late INa
Na+ Overload
Ca2+ Overload
Mechanical dysfunction LV diastolic tension
Contractility
Electrical dysfunctionArrhythmias
Ranolazine
Na+ and Ca2+ during ischemia and reperfusion
Tani M and Neely JR. Circ Res. 1989;65:1045-56.
Na+
(μmol/g dry)
Ca2+
(μmol/g dry)
Time (minutes)
Rat heart model
Ischemia Reperfusion90
60
30
0
12
8
4
00 10 20 30 40 50 60
Intracellular levels
SodiumCurrent
0
Late
Peak
0
Late
Peak
SodiumCurrent
Na+
ImpairedImpairedInactivationInactivation
ImpairedImpairedInactivationInactivation
Na+
Ischemia
Myocardial ischemia causes enhanced late INa
Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;(8 suppl A):A10-13.Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7.
Late Na+ accumulation causes LV dysfunction
Fraser H et al. Eur Heart J. 2006.
Isolated rat hearts treated with ATX-II, an enhancer of late INa
LV dP/dt(mm Hg/sec, in thousands)
LV-dP/dt
LV+dP/dt
(-)
(+)
Time (minutes)
ATX-II 12 nM(n = 13)A
TX
-II
Ranolazine 8.6 µM(n = 6)
Ran
ola
zin
e
10 20 30 40 50
-4
-3
-2
-1
0
1
2
3
4
5
6
Na+/Ca2+ overload and ischemia
Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.
Late Na+ current
Diastolic wall tension (stiffness)
Intramural small vessel compression( O2 supply)
O2 demand
Na+ overload
Ca2+ overload
Myocardial ischemia
LV end diastolic pressure
Baseline 15 30 45 600
10
20
30
40
50
60
70
Vehicle (n = 10)Ranolazine 10 µM (n = 7)
*
*
Reperfusion time (minutes)
mm
Hg
LV -dP/dt (Relaxation)
Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7.Gralinski MR et al. Cardiovasc Res. 1994;28:1231-7.*P < 0.05
Vehicle Ranolazine
Baseline 30 60 75 90
-1000
-800
-600
-400
-200
0**
*
*
mm
Hg
/sec
Reperfusion time (minutes)
Vehicle (n = 12)Ranolazine 5.4 µM (n = 9)
Isolated rabbit hearts
Late INa blockade blunts experimental ischemic LV damage
Ranolazine: Key concepts
• Ischemia is associated with ↑ Na+ entry into cardiac cells – Na+ efflux in recovery by Na+/Ca2+ exchange results
in ↑ cellular [Ca2+]i and eventual Ca2+ overload – Ca2+ overload may cause electrical and mechanical
dysfunction
• ↑ Late INa is an important contributor to the [Na+]i - dependent Ca2+ overload
• Ranolazine reduces late INa
Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.Belardinelli L et al. Eur Heart J Suppl. 2004;(6 suppl I):I3-7.
Myocardial ischemia: Sites of action of anti-ischemic medication
Consequences of ischemia
Ca2+ overloadElectrical instabilityMyocardial dysfunction(↓systolic function/ ↑diastolic stiffness)
Ischemia
↑ O2 DemandHeart rateBlood pressurePreloadContractility↓ O2 Supply
Development of ischemia
Traditionalanti-ischemicmedications:β-blockersNitratesCa2+ blockers
Courtesy of PH Stone, MD and BR Chaitman, MD. 2006.
Ranolazine
Summary
• Ischemic heart disease is a prevalent clinical condition
• Improved understanding of ischemia has prompted new therapeutic approaches– Rho kinase inhibition– Metabolic modulation– Preconditioning– Inhibition of If and late INa currents
• Late INa inhibition and metabolic modulation reduce angina with minimal or no pathophysiologic effects– Mechanisms of action are complementary to traditional agents