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