Transcript Contemporary Management of Myocardial Ischemia

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
Rho kinase triggers vasoconstriction through accumulation of
phosphorylated myosin
Ca2+
Ca2+
Agonist
PLC
VOC
ROC
Receptor
PIP2
IP3
Fasudil
Rho
Rho kinase
SR Ca2+
Myosin
Myosin phosphatase
MLCK
Ca2+
Calmodulin
Myosin-P
Adapted from Seasholtz TM. Am J Physiol Cell Physiol. 2003;284:C596-8.
Metabolic modulation (pFOX): Trimetazidine
Myocytes
FFA
Glucose
Acyl-CoA
Pyruvate
β-oxidation
• O2 requirement of glucose
pathway is lower than FFA
pathway
• During ischemia, oxidized FFA
levels rise, blunting the glucose
pathway
Trimetazidine
Acetyl-CoA
Energy for contraction
MacInnes A et al. Circ Res. 2003;93:e26-32.
pFOX = partial fatty acid oxidation
Lopaschuk GD et al. Circ Res. 2003;93:e33-7.
FFA = free fatty acid
Stanley WC. J Cardiovasc Pharmacol Ther. 2004;9(suppl 1):S31-45.
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
pFOX = partial fatty acid oxidation
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.
Preconditioning: Nicorandil
Activation of ATP-sensitive K+ channels
• Ischemic preconditioning
• Dilation of coronary resistance arterioles
N
O
HN
O NO2
Nitrate-associated effects
• Vasodilation of coronary epicardial arteries
IONA Study Group. Lancet. 2002;359:1269-75.
Rahman N et al. AAPS J. 2004;6:e34.
Sinus node inhibition: Ivabradine
Control
Ivabradine 0.3 µM
40
20
0
–20
–40
–60
Potential (mV)
SA = sinoatrial
0.5
Time
(seconds)
• 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.
Late Na+ current inhibition: Ranolazine
Myocardial ischemia
 Late INa
Ranolazine
Na+ Overload
Ca2+ Overload
Mechanical dysfunction
 LV diastolic tension
 Contractility
Electrical dysfunction
Arrhythmias
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.
Na+ and Ca2+ during ischemia and reperfusion
Rat heart model
Intracellular levels
Ischemia
Reperfusion
90
Na+
(μmol/g dry)
60
30
0
12
Ca2+
(μmol/g dry)
8
4
0
0
10
20
30
40
50
60
Time (minutes)
Tani M and Neely JR. Circ Res. 1989;65:1045-56.
Myocardial ischemia causes enhanced late INa
0
0
Sodium
Current
Ischemia
Late
Sodium
Current
Late
Na+
Peak
Peak
Impaired
Inactivation
Na+
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
Isolated rat hearts treated with ATX-II, an enhancer of late INa
6
5
(+)
ATX-II
3
LV dP/dt
(mm Hg/sec, 2
in thousands) 1
Ranolazine 8.6 µM
(n = 6)
Ranolazine
4
LV+dP/dt
ATX-II 12 nM
(n = 13)
0
10
-1
-2
-3
-4
20
30
40
50
LV-dP/dt
(-)
Time (minutes)
Fraser H et al. Eur Heart J. 2006.
Na+/Ca2+ overload and ischemia
Myocardial
ischemia
Intramural small vessel compression
( O2 supply)
 Late Na+ current
 O2 demand
Na+ overload
 Diastolic wall tension (stiffness)
Ca2+ overload
Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.
Late INa blockade blunts experimental ischemic
LV damage
Isolated rabbit hearts
LV -dP/dt (Relaxation)
60
75
90
*
Baseline 30
70
*
LV end diastolic pressure
0
60
*
20
mm Hg/sec
30
-400
-600
-800
10
*
40
*
mm Hg
-200
*
50
-1000
0
Baseline 15
30
45
60
Reperfusion time (minutes)
Vehicle
*P < 0.05
Reperfusion time (minutes)
Vehicle (n = 10)
Ranolazine 10 µM (n = 7)
Ranolazine
Vehicle (n = 12)
Ranolazine 5.4 µM (n = 9)
Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7.
Gralinski MR et al. Cardiovasc Res. 1994;28:1231-7.
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 antiischemic medication
Development of ischemia
↑ O2 Demand
Heart rate
Blood pressure
Preload
Contractility
↓ O2 Supply
Traditional
anti-ischemic
medications:
β-blockers
Nitrates
Ca2+ blockers
Consequences of ischemia
Ischemia
Ca2+ overload
Electrical instability
Myocardial dysfunction
(↓systolic function/
↑diastolic stiffness)
Ranolazine
Courtesy of PH Stone, MD and BR Chaitman, MD. 2006.
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