Transcript Coronary Blood Flow

Ischemic Heart Disease and
Myocardial Infarction
Pathophysiology of Myocardial
Ischemia
Bio-Med 350
September 2004
Physiology and Pathophysiology of
Coronary Blood Flow / Ischemia
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Basic Physiology / Determinants of MVO2
Autoregulatory Mechanisms / Coronary Flow
Reserve
Pathophysiology of Coronary Ischemia
and Atherosclerosis
Clinical Syndromes


Stable Angina
Acute Coronary Syndromes
– Unstable Angina
– Acute MI (UA, AMI)
Coronary Arteries
Normal Anatomy
Basic Principles

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myocardial cells have to do only 2 things:
contract and relax; both are aerobic, O2
requiring processes
oxygen extraction in the coronary bed is
maximal in the baseline state; therefore to
increase O2 delivery, flow must increase
large visible epicardial arteries are conduit
vessels not responsible for resistance to flow
(when normal)
Basic Principles
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
small, distal arterioles make up the major
resistance to flow in the normal state
atherosclerosis (an abnormal state) affects the
proximal, large epicardial arteries
once arteries are stenotic (narrowed)
resistance to flow increases unless distal,
small arterioles are able to dilate to
compensate
Myocardial Ischemia:
Occurs when myocardial oxygen demand exceeds
myocardial oxygen supply
Myocardial Ischemia:
Occurs when myocardial oxygen demand exceeds
myocardial oxygen supply
MVO2 = Myocardial Oxygen Demand
MVO2 determined by:
Heart Rate
Contractility
Wall Tension
MVO2 (Myocardial Oxygen Demand)
Increases directly in proportion to heart
rate
 Increases with increased contractility
 Increases with increased Wall Tension:
i.e. increases with increasing preload
or afterload

Heart Rate
10
8
MVO2
cc/min
/100g
6
4
2
100
150
Heart Rate (BPM)
200
Contractility
10
Norepinephrine
Control
MVO2
(cc/min
/100g)
5
0
Peak Developed Tension (g/cm2)
Wall Tension
Is related to
Pressure x Radius
Wall Thickness
Defined as: Force per unit area generated in the LV
throughout the cardiac cycle
Afterload - LV systolic pressure
Preload - LV end-diastolic pressure or volume
Myocardial Ischemia:
Occurs when myocardial oxygen demand exceeds
myocardial oxygen supply
Myocardial Oxygen Supply
Determined by:
Coronary Blood Flow
&
O2 Carrying Capacity
( Flow = Pressure / Resistance)
 Coronary perfusion pressure
 Coronary vascular resistance
 Oxygen saturation of
the blood
 Hemoglobin content
of the blood
Coronary Blood Flow
Proportional to perfusion pressure / resistance

Coronary Perfusion
pressure
=
Diastolic blood
pressure, minus
LVEDP

Coronary Vascular
resistance

external compression
intrinsic regulation




Local metabolites
Endothelial factors
Neural factors (esp.
sympathetic nervous
system)
Endocardium and CFR
Diastole
Systole
Endocardium vs Epicardium
Greater shortening / thickening, higher
wall tension: increased MVO2
 Greater compressive resistance
 ? Decreased Perfusion Pressure
 Less collateral circulation
 Net Result is more compensatory
arteriolar vasodilatation at baseline and
therefore decreased CFR

Autoregulatory Resistance
Major component of resistance to flow
 Locus at arteriolar level
 Adjusts flow to MVO2
 Metabolic control

 Oxygen
 Adenosine
, ADP
 NO (nitric oxide)
 Lactate , H+
 Histamine, Bradykinin
Autoregulatory Resistance
Involves 3 different cells
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Myocardial muscle cell - produces byproducts
of aerobic metabolism (lactate,adenosine, etc)
Vascular endothelial cell (arteriole) - reacts to
metabolic byproducts
Vascular smooth muscle cell (arteriole) signaled by endothelial cell to contract (vessel
constriction) or relax (vessel dilation)
Autoregulation of Coronary
Blood Flow

Oxygen

Acts as
vasoconstrictor
 As O2 levels drop
during ischemia: precapillary vasodilation
and increased
myocardial blood
supply

Adenosine



Potent vasodilator
Prime mediator of
coronary vascular
tone
Binds to receptors on
vascular smooth
muscle, decreasing
calcium entry into cell
Adenosine
During hypoxemia, aerobic metabolism
in mitochondria is inhibited
 Accumulation of ADP and AMP
 Production of adenosine
 Adenosine vasodilates arterioles
 Increased coronary blood flow

Autoregulatory Resistance
200
Adenosine
Flow
cc/100g
/min
100
0
Control
60
80
100
115
130
Coronary Perfusion Pressure (mmHg)
Autoregulators

Other endothelialderived factors
contribute to
autoregulation

Dilators include:
 EDRF (NO)
 Prostacyclin

Constrictors include:
 Endothelin-1
Coronary Flow Reserve
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Arteriolar autoregulatory vasodilatory capacity in
response to increased MVO2 or pharmacologic
agents
Expressed as a ratio of Maximum flow / Baseline
flow
~ 4-5 / 1 (experimentally)
~ 2.25 - 2.5 (when measured clinically)
Coronary Flow Reserve

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Stenosis in large epicardial (capacitance) vessel 
decreased perfusion pressure  arterioles
downstream dilate to maintain normal resting flow
As stenosis progresses, arteriolar dilation becomes
chronic, decreasing potential to augment flow and
thus decreasing CFR
Endocardial CFR < Epicardial CFR
As CFR approaches 1.0 (vasodilatory capacity
“maxxed out”), any further decrease in PP or increase
in MVO2  ischemia
Coronary Flow Reserve
5
Maximum Flow
4
Coronary 3
Blood
Flow
2
Resting Flow
1
0
25
50
75
Epicardial % Diameter Stenosis
100
Endocardium and Collaterals
Epicardium
Endocardium
Coronary Steal
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
A
Sub-epicardium
B
Sub-endocardium
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Vasodilator Rx (Ado)
R2 decreases
Flow increases to A
R3 - no reserve
Increased flow across
R1 GRT
P1-2
No change in P1
P2
Flow to B is
dependant on P2 and
Prevalence of CAD in Modern
Society
70
60
Age(years)
50
% Donors
70%
40
50%
30
<25
25-40
>40
20
10
25%
0
Clevelend Clinic Cardiac Transplant
Donor IVUS Data-Base
Risk Factors
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family History
cigarette smoking
diabetes mellitus
hypertension
hyperlipidemia
sedentary life-style
obesity
elevated homocysteine, LP-a ?
Coronary lesions in Men and Women,
Westernized and non-Westernized diets
Relationship between fat in diet and
serum cholesterol
Atherosclerotic Plaque
Evolution from Fatty Streak
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Fatty streaks present
in young adults
Soft atherosclerotic
plaques most
vulnerable to
fissuring/hemorrhage
Complex interaction of
substrate with
circulating cells
(platelets,
macrophages) and
neurohumoral factors
Plaque progression….

Fibrous cap
develops when
smooth muscle cells
migrate to intima,
producing a tough
fibrous matrix which
glues cells together
Intra-vascular Ultrasound (IVUS)
Atherosclerotic Plaque
Physiologic Remodeling
Coronary atherosclerosis
Stable Angina - Symptoms
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mid-substernal chest pain
squeezing, pressure-like in quality (closed fist =
Levine’s sign)
builds to a peak and lasts 2-20 minutes
radiation to left arm, neck, jaw or back
associated with shortness of breath, sweating, or
nausea
exacerbated by exertion, cold, meals or stress
relieved by rest, NTG
Symptoms and Signs:
Coronary Ischemia
Stable Angina - Diagnosis
Exercise Treadmill Test
Stable Angina - Diagnosis
Thallium Stress Test
Stable Angina - Treatment
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Risk factor modification (HMG Co-A Reductase inhibitors =
Statins)
Aspirin
Decrease MVO2
 nitrates
 beta-blockers
 calcium channel blockers
 ACE-inhibitors
Anti-oxidants (E, C, Folate, B6)?
Stable Angina - Treatment
Mechanical Dilation:
Angioplasty, Stent, etc.
Treatment of Stable Angina STENTS
Stable Angina - Treatment
Coronary Artery Bypass Grafting Surgery
(CABG)
Schematic of an Unstable Plaque
Unstable Plaque:
More Detail…….
Cross section of a
complicated plaque
Journey down a coronary…
Angiogram in unstable angina:
eccentric, ulcerated plaque
Angiogram in unstable angina:
after stent deployment
Acute Coronary Syndrome
Terminology
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Pathophysiology of all 3 is the same
Unstable Angina (UA)
 ST depression, T Wave inversion or normal
 No enzyme release
Non-Transmural Myocardial Infarction (NTMI or SEMI)
 ST depression, T Wave inversion or normal
 No Q waves
 CPK, LDH + Troponin release
Transmural Myocardial Infarction (AMI)
 ST elevation
 + Q waves
 CPK, LDH + Troponin release
Pathophysiology of the Acute
Coronary Syndrome (UA,MI)
Plaque vulnerability and extrinsic
triggers result in plaque rupture
 Platelet adherence, aggregation and
activation of the coagulation cascade
with polymerization of fibrin
 Thrombosis with sub-total (UA, NTMI) or
total coronary artery occlusion (AMI)

Pathophysiology of Acute
Coronary Syndromes
Pathophysiology of Acute
Coronary Syndromes
“Vulnerable Plaque”
Coronary Stenosis Severity Prior to
Myocardial Infarction
% Stenosis
68%
14%
18%
>70
50-70
<50
Falk et al, Circulation 1995; 92: 657-71
Acute Coronary Syndrome
Unstable Angina / Myocardial Infarction
Symptoms
new onset angina
 increase in frequency, duration or
severity
 decrease in exertion required to provoke
 any prolonged episode (>10-15min)
 failure to abate with >2-3 S.L. NTG
 onset at rest or awakening from sleep

Unstable Angina High Risk Features
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prolonged rest pain
dynamic EKG changes (ST depression)
age > 65
diabetes mellitus
left ventricular systolic dysfunction
angina associated with congestive heart
failure, new murmur, arrhythmias or
hypotension
elevated Troponin i or t
Unstable Angina / NTMI
Pharmacologic Therapy
ASA and Heparin beneficial for acute
coronary syndromes ( UA, NTMI, AMI)
 Decrease MVO2 with Nitrates, Betablockers, Ca channel blockers, and Ace
inhibitors
 consider platelet glycoprotein 2b / 3a
inhibitor and / or low molecular weight
heparin

Anti-Platelet Therapy
Three principle pathways of platelet
activation with >100 agonists: ( TXA2,
ADP, Thrombin )
 Final common pathway for platelet
activation / aggregation involves
membrane GP II b / III A receptor
 Fibrinogen molecules cross-bridge
receptor on adjacent platelets to form a
scaffold for the hemostatic plug

Platelet GP IIB/ IIIA Inhibitors
with Acute Coronary Syndromes
Odds Ratios and 95% CI for Composite Endpoint
( Death,Re- MI at 30days )
Placebo (% ) Rx ( % )
PURSUIT
15.7
14.2
PRISM
7.1
5.8
11.9
8.7
11.7
12.0
(vs Heparin)
PRISM PLUS
(+ Heparin)
PARAGON
(high dose)
0.2
Rx better
1
4
Placebo better
Low Molecular Weight Heparin
in Acute Coronary Syndromes
Odds Ratios and 95% CI for Composite Endpoint
( Death, MI, Re-angina or Revasc at 6-14 days )
UH / Placebo
(%)
Rx
(%)
FRISC
10.3
5.4
FRIC
7.6
9.3
ESSENCE
19.8
16.6
TIMI 11b
16.6
14.2
0.2
LMWH Better
1
UH Better
4
Acute Myocardial Infarction
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total thrombotic occlusion of epicardial coronary
artery  onset of ischemic cascade
prolonged ischemia  altered myocardial cell
structure and eventual cell death (release of enzymes
- CPK, LDH, Troponin)
altered structure  altered function (relaxation and
contraction)
consequences of altered function often include
exacerbation of ischemia (ischemia begets ischemia)
Acute Myocardial Infarction

wavefront phenomenon of ischemic evolution endocardium to epicardium

If limited area of infarction  homeostasis achieved
If large area of infarction (>20% LV )  Congestive heart
failure
If larger area of infarction (>40% LV)  hemodynamic collapse


AMI - Wavefront Phenomenon
Acute Myocardial Infarction

Non-transmural /
sub-endocardial

Non-occlusive
thrombus or
spontaneous reperfusion
 EKG – ST depression
 Some enzymatic
release – troponin i
most sensitive

Transmural

total, prolonged
occlusion
 EKG - ST elevation
 Rx - Thrombolytic
Therapy or Cath Lab
/ PTCA
Cardiac enzymes: overview
Legend: A. Early CPK-MB isoforms after acute MI
B. Cardiac troponin after acute MI
C. CPK-MB after acute MI
D. Cardiac troponin after unstable angina
Markers of MI: Troponin I
Diagnosis of MI:
Role of troponin i



Troponin I is highly
sensitive
Troponin I may be
elevated after
prolonged
subendocardial
ischemia
See examples
below
Causes of Troponin elevation

Any cause of prolonged (>15 – 20
minutes) subendocardial ischemia
 Prolonged
angina pectoris
 Prolonged tachycardia in setting of CAD
 Congestive heart failure (elevated LVEDP
causing decreased subendocardial
perfusion)
 Hypoxia, coupled with CAD
 “aborted” MI (lytic therapy or spontaneous
clot lysis)
EKG diagnosis of MI

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ST segment
elevation
ST segment
depression
T wave inversion
Q wave formation
Consequences of Ischemia
(Ischemia begets Ischemia)
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chest pain
systolic dysfunction (loss of contraction)
 decrease cardiac output
 decrease coronary perfusion pressure
diastolic dysfunction (loss of relaxation)
 higher pressure (PCWP) for any given volume
 dyspnea, decrease pO2, decrease O2 delivery
 increased wall tension (increased MVO2)
All 3 give rise to stimulation of sympathetic nervous system with subsequent
catecholamine release- increased heart rate and blood pressure (increased MVO2)
Ischemic Cycle
Ischemia / infarction
Diastolic Dysfunction
Systolic Dysfunction
chest pain
pulmonary
congestion
pO2
LV diastolic pressure
cardiac output
wall tension
catecholamines
(heart rate, BP)
MVO2
Treatment of Acute Myocardial Infarction



aspirin, heparin, analgesia, oxygen
reperfusion therapy
 thrombolytic therapy (t-PA, SK, n-PA, r- PA)
 new combinations ( t-PA, r-PA + 2b / 3a inhib)
 cath lab (PTCA, stent)
decrease MVO2
 nitrates, beta blockers and ACE inhibitors
 for high PCWP - diuretics
 for low Cardiac Output - pressors (dopamine, levophed,
dobutamine; IABP; early catheterization
TIMI Flow Grades
TIMI 0 Flow = no penetration of contrast beyond stenosis
(100% stenosis, occlusion)
TIMI 1 Flow = penetration of contrast beyond stenosis
but no perfusion of distal vessel
(99% stenosis, sub-total occlusion)
TIMI 2 Flow = contrast reaches the entire distal vessel but either
at a decreased rate of filling or clearing versus
the other coronary arteries (partial perfusion)
TIMI 3 Flow = contrast reaches the distal bed and clears at an
equivalent rate versus the other coronary arteries
(complete perfusion)
GUSTO
30 Day Mortality
p-values
t-PA vs. t-PA + SK
t-PA vs. SK (IV)
t-PA vs. SK (SQ)
t-PA vs. Combo SK
10
0.04
0.003
0.009
0.001
8
6
7 .2
7 .4
7 .0
6 .3
4
2
0
SK + SQ
H e p a r in
N:
9,796
S K + IV
H epera n
10,376
A c c e l. t-P A
10,344
t-P A + S K
10,327
GUSTO
90 min Patency
% of Patients
TIM I 3
100
TIM I 2
81 % *
80
60
73 %
56 %
61 %
40
20
N:
p < 0.001
p < 0.001
0
SK + SQ
H epa rin
295
SK + IV
H epa rin
282
A ccel. t-P A
t-P A + SK
291
297
p = < 0.001 for Accelerated t-PA vs. all other arms
TIMI Flow Grade Versus
Mortality (GUSTO)
Mortality
p=0.01
12
9
% of
Patients
9.7
p=0.05
9.9
6
7.9
3
4.3
0
N
TIMI 0
TIMI 1
TIMI 2
TIMI 3
259
81
342
447
Coronary Steal
Role of Collaterals
Adenosine
Rest
Flow
P2
collateral
Flow
P1
P2
collateral
Assumptions
Collateral resistance
P1 drops with vasodil
P2 bed with no vaso
dilator reserve
P1
Changing Paradigm – The Concept
of Physiologic Remodeling