Examining the Science Underlying Myocardial Ischemia

1
Examining the Science Underlying Myocardial
Ischemia
2
Severe obstruction (angina, no rupture) vs mild
obstruction (no angina, likely to rupture)

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

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

• Plaque rupture
• Acute MI
• Unstable angina
• Sudden death

• Exertional angina
• () ETT

Revascularization Anti-anginal Rx
Pharmacologic stabilization Early identification
of high-risk?
Courtesy of PH Stone, MD.
3
Major cardiac events occur in non-target areas
following successful PCI
20
15
Hazardrate ()
10
Non-target lesion event
5
Target lesion event
0
1
2
3 Year
4
5
Substantial number of cardiac events could be
prevented if non-obstructive, high-risk lesions
were identified
Cutlip DE et al. Circulation. 20041101226-30.
4
Local determinants of the natural history of
individual coronary lesions
Opportunities for identification and intervention
Local factors
Shear stress
Quiescent, stable plaque No symptoms

• Proliferation
• Inflammation
• Remodeling

Quiescence
Inflammation
Thin cap Fibroatheroma MI, sudden death
Proliferation Calcification
Fibrotic/ scarred plaque Angina
Courtesy of PH Stone, MD and R Gerrity, PhD.
5
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.
2007492379-93.
6
The spectrum of CAD
ESS endothelial shear stress
Chatzizisis YS et al. J Am Coll Cardiol.
2007492379-93.
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Ventricular arrhythmogenesis in ischemic
myocardium

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

• Clinical or subclinical susceptibility
• Structural substrate present

High risk of transient acute ischemia reperfusion

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

• Triggers
• VPC
• VT
• Reentry

Ventricular fibrillation

VPC ventricular premature contraction VT
ventricular tachycardia
Adapted from Luqman N et al. Int J Cardiol.
2007119283-90.
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Causes and consequences of myocardial ischemia
New understanding
?O2 demand
Na and Ca2 overload
Electrical instability Myocardial dysfunction
Heart rate Blood pressure Preload Contractility
?O2 supply
Belardinelli L et al. Heart. 200692(suppl
IV)iv6-14.
9
Overview of the sodium channel
Na
Na
Na
Resting closed
Inactivated
Activated
out
Na
Na
in
Na
Na
Na
Na 140 mM
Na
Na
10mM
Ca2
Ca2
in
Ca2
Ca2
Na
Ca2
Ca2
out
Na/Ca2 Exchanger
Na
Ca2
Courtesy of L Belardinelli, MD.
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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

0
Sodiumcurrent
Late
Peak
Belardinelli L et al. Heart. 200692(suppl
IV)iv6-14.
11
Myocardial ischemia causes enhanced late INa
0
Ischemia
Sodiumcurrent
Late
Peak
Enhanced late INa appears to be a major
contributor to increased intracellular Na during
ischemia
Belardinelli L et al. Heart. 200692(suppl
IV)iv6-14.
12
Role of altered ion currents in adverse
consequences of myocardial ischemia
Disease(s) and pathological states linked to
imbalance of O2 supply/demand
?Late INa
?Na entry (Nai)
NCX
?Cytosolic Ca2

• Mechanical dysfunction
• Abnormal contraction and relaxation
• ?Diastolic tension

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

Nai intracellular NaNCX Na/Ca2
exchanger APD action potential duration
Belardinelli L et al. Heart. 200692(suppl
IV)iv6-14.
13
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

Exacerbates ischemia
MVO2 myocardial oxygen consumption
Courtesy of PH Stone, MD.
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Late INa inhibition blunts Ca2 accumulation
0.30
12
ATX-II
RAN
0.25
Indo fluorescence(F405/F485 ratio)
8

LV work(L/min per mm Hg)

0.20

4

0.15
ATX-II
RAN
0.10
0
0
10
20
30
40
50
0
10
20
30
40
50
Time of perfusion (min)
ATX-II alone (n 11) ATX-II ranolazine 4 µM
(n 9) or 9 µM (n 9)

P lt 0.05 vs ATX-II aloneATX-II sea anemone
toxin (selectively ?late INa)
Fraser H et al. J Mol Cell Cardiol.
2006411031-8.
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Ranolazine blunts sotalol-induced action
potential prolongation in dogs
Transmembrane action potentials (superimposed)
Control
50 mV
1 sec
Antzelevich C et al. Circulation 2004110904-10.