Download VBWG07_MIR_S02 (15 slides

Examining the
Science Underlying
Myocardial Ischemia
Severe obstruction (angina, no rupture) vs
mild obstruction (no angina, likely to rupture)
Severe fibrotic plaque
• Severe obstruction
• No lipid
• Fibrosis, Ca2+
Exertional angina
• (+) ETT
Revascularization
Anti-anginal Rx
Vulnerable plaque
• Minor obstruction
• Eccentric plaque
• Lipid pool
• Thin cap
Plaque rupture
• Acute MI
• Unstable angina
• Sudden death
Pharmacologic stabilization
Early identification of high-risk?
Courtesy of PH Stone, MD.
Major cardiac events occur in non-target areas
following successful PCI
20
15
Hazard
10
rate (%)
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. 2004;110:1226-30.
Local determinants of the natural history
of individual coronary lesions
Opportunities for identification and intervention
Shear stress
Local factors
Quiescent,
stable plaque
• Proliferation
• Inflammation
• Remodeling
No symptoms
Inflammation
Thin cap
Fibroatheroma
MI, sudden death
Fibrotic/
scarred plaque
Angina
Courtesy of PH Stone, MD and R Gerrity, PhD.
Proposed classification scheme for
atherosclerotic plaque
Plaque
trajectory
Histopathology
Progression
rate
Vascular
remodeling
Proclivity
to rupture
Clinical
manifestation
Quiescent
plaque
Small lipid core
Minimal
Compensatory
expansive
remodeling
Low
Asymptomatic
Stenotic
plaque
Small lipid core
Gradual
Constrictive
remodeling
Low
Stable angina
High-risk
plaque
Large lipid core
Increased
Excessive
expansive
remodeling
High
ACS
Thick fibrous cap
Very thick fibrous
cap
Thin and inflamed
fibrous cap
Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.
The spectrum of CAD
ESS = endothelial shear stress
Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93.
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
Triggers
• VPC
• VT
• Reentry
+
VPC = ventricular premature contraction
VT = ventricular tachycardia
Substrate
• Vulnerable ischemic zone
• Intracoronary thrombus
• Autonomic influence
• Hemodynamic compromise
Ventricular
fibrillation
Adapted from Luqman N et al. Int J Cardiol. 2007;119:283-90.
Causes and consequences of myocardial
ischemia: New understanding
O2 demand
Na+ and Ca2+ overload
Heart rate
Blood pressure
Preload
Contractility
Electrical instability
Myocardial dysfunction
Ischemia
O2 supply
Development of ischemia
Consequences of ischemia
Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.
Overview of the sodium channel
Na+
Na+
Resting
closed
Na+
Inactivated
Activated
out
[Na+]
= 140 mM
[Na+]
~10mM
Na+
Na+
Na+ Na+
Na+ Na+
in
Na+
out
in
Ca2+Ca2+
Ca2+Ca2+
2+
Ca2+ Ca
Na+/Ca2+
Exchanger
Na+
Ca2+
Courtesy of L Belardinelli, MD.
Origin of late INa
0
Sodium
current
Peak
Late
• 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.
Myocardial ischemia causes enhanced late INa
0
0
Sodium
current
Peak
Late
Ischemia
Sodium
current
Late
Peak
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
Disease(s) and pathological states linked to imbalance
of O2 supply/demand
Late INa
Na+ entry ([Na+]i)
NCX
Cytosolic Ca2+
Electrical instability
• Afterpotentials
• Beat-to-beat APD
• Arrhythmias (VT)
[Na+]i = intracellular [Na+]
NCX = Na+/Ca2+ exchanger
APD = action potential duration
Mechanical dysfunction
• Abnormal contraction and relaxation
• Diastolic tension
Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14.
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.
Late INa inhibition blunts Ca2+ accumulation
0.30
12
ATX-II
RAN
0.25
Indo
fluorescence
(F405/F485
0.20
ratio)
*
*
8
LV work
(L/min per
mm Hg)
*
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 < 0.05 vs ATX-II alone
ATX-II = sea anemone toxin (selectively late INa)
Fraser H et al. J Mol Cell Cardiol. 2006;41:1031-8.
Ranolazine blunts sotalol-induced action
potential prolongation in dogs
Transmembrane action potentials (superimposed)
Control
d-Sotalol
50 mV
+ Ranolazine 5 uM
+ Ranolazine 10 uM
1 sec
Antzelevich C et al. Circulation 2004;110:904-10.