Examining the Science Underlying Myocardial Ischemia

Severe obstruction (angina, no rupture) vs mild obstruction (no angina, likely to rupture)

RevascularizationAnti-anginal Rx

Exertional angina• (+) ETT

Severe fibrotic plaque• Severe obstruction• No lipid• Fibrosis, Ca2+

Pharmacologic stabilizationEarly identification of high-risk?

Plaque rupture• Acute MI• Unstable angina• Sudden death

Vulnerable plaque• Minor obstruction• Eccentric plaque• Lipid pool• Thin cap

Courtesy of PH Stone, MD.

Major cardiac events occur in non-target areas following successful PCI

Hazardrate (%)

Cutlip DE et al. Circulation. 2004;110:1226-30.

Substantial number of cardiac events could be preventedif non-obstructive, high-risk lesions were identified

Target lesion event

Non-target lesion event

0

5

10

15

20

1 2 3Year

4 5

Local determinants of the natural history of individual coronary lesionsOpportunities for identification and intervention

Courtesy of PH Stone, MD and R Gerrity, PhD.

Quiescent,stable plaque No symptoms

Fibrotic/scarred plaque Angina

Thin capFibroatheroma MI, sudden death

Quiescen

ce

Inflammation

Proliferation

Calcification

Local factorsLocal factorsShear stress

•Proliferation•Inflammation•Remodeling

Proposed classification scheme for atherosclerotic plaque

Plaque trajectory Histopathology

Progression rate

Vascular remodeling

Proclivity to rupture

Clinical manifestation

Quiescent plaque

Small lipid core

Thick fibrous cap

Minimal Compensatory expansive remodeling

Low Asymptomatic

Stenotic plaque

Small lipid core

Very thick fibrous cap

Gradual Constrictive remodeling

Low Stable angina

High-risk plaque

Large lipid core

Thin and inflamed fibrous cap

Increased Excessive expansive remodeling

High ACS

Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.

The spectrum of CAD

Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.ESS = endothelial shear stress

Substrate• Vulnerable ischemic zone• Intracoronary thrombus• Autonomic influence• Hemodynamic compromise

Ventricular arrhythmogenesis in ischemic myocardium

Adapted from Luqman N et al. Int J Cardiol. 2007;119:283-90.

VPC = ventricular premature contractionVT = ventricular tachycardia

Risk factors• Age• Heredity• Gender• Smoking• Lipids• Hypertension• Diabetes• Obesity

•Clinical or subclinical susceptibility •Structural substrate present

High risk of transient acute ischemia reperfusion

Triggers• VPC• VT• Reentry

+ Ventricular fibrillation

Causes and consequences of myocardial ischemia: New understanding

Consequences of ischemia

Electrical instabilityMyocardial dysfunctionIschemia

Heart rateBlood pressurePreloadContractility

Development of ischemia

O2 demand

O2 supply

Na+ and Ca2+ overload

Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.

Overview of the sodium channel

out

in

out

in

Na+/Ca2+

Exchanger

Ca2+

Ca2+

Ca2+

Ca2+

Na+

Na+

Na+

Na+Na+

Na+

Na+

Restingclosed

Na+

ActivatedActivatedInactivated

Na+

Na+

Na+ Ca2+

Ca2+

[Na+]= 140 mM ~10mM

Courtesy of L Belardinelli, MD.

Ca2+

[Na+]

Origin of late INa

• During the plateau phase of the action potential, a small proportion of sodium channels either do not close, or close and then reopen

• These late channel openings permit a sustained Na+ current to enter myocytes during systole

Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.

Sodiumcurrent

0

Late

Peak

Sodiumcurrent

0

Late

Peak

0

Late

Peak

Sodiumcurrent

Ischemia

Myocardial ischemia causes enhanced late INa

Enhanced late INa appears to be a major contributor to increased intracellular Na+ during ischemia

Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.

Role of altered ion currents in adverse consequences of myocardial ischemia

[Na+]i = intracellular [Na+]NCX = Na+/Ca2+ exchanger APD = action potential duration Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.

Disease(s) and pathological states linked to imbalance of O2 supply/demand

Cytosolic Ca2+

NCX

Late INa

Na+ entry ([Na+]i)

Mechanical dysfunction• Abnormal contraction and relaxation• Diastolic tension

Electrical instability• Afterpotentials• Beat-to-beat APD• Arrhythmias (VT)

Diastolic relaxation failure adversely affects myocardial O2 supply and demand

• Sustained contraction of ischemic tissue during diastole:– Increases MVO2

– Compresses intramural small vessels• Reduces myocardial blood flow

Courtesy of PH Stone, MD.

Exacerbates ischemia

MVO2 = myocardial oxygen consumption

Fraser H et al. J Mol Cell Cardiol. 2006;41:1031-8.

Late INa inhibition blunts Ca2+ accumulation

Time of perfusion (min)

ATX-II alone (n = 11)

ATX-II + ranolazine 4 μM (n = 9) or 9 μM (n = 9)

*P < 0.05 vs ATX-II aloneATX-II = sea anemone toxin (selectively late INa)

Indo fluorescence(F405/F485

ratio)

0.30

0.25

0.20

0.15

0.100 10 20 30 40 50

LV work(L/min per

mm Hg)

12

8

4

0

ATX-II

RAN

0 10 20 30 40 50

RAN

ATX-II

**

*

*

Ranolazine blunts sotalol-induced action potential prolongation in dogs

Antzelevich C et al. Circulation 2004;110:904-10.

Control

d-Sotalol

+ Ranolazine 5 uM

+ Ranolazine 10 uM

50 mV

1 sec

Transmembrane action potentials (superimposed)