Ischemic Heart Disease and

Myocardial Infarction

Pathophysiology of Myocardial
Ischemia
Bio-Med 350
September 2004
 Physiology and Pathophysiology of
Coronary Blood Flow / Ischemia

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
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

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 6
/100g
4

2
100 150 200
Heart Rate (BPM)
 Contractility
10
Norepinephrine

Control

MVO2
(cc/min 5
/100g)

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)

Oxygen saturation of
the blood
Coronary perfusion pressure
Coronary vascular resistance Hemoglobin content
of the blood
 Coronary Blood Flow
Proportional to perfusion pressure / resistance

Coronary Perfusion Coronary Vascular

pressure resistance
= external compression
Diastolic blood
intrinsic regulation
Local metabolites
pressure, minus Endothelial factors
LVEDP 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

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 Adenosine
Acts as Potent vasodilator
vasoconstrictor Prime mediator of
As O2 levels drop coronary vascular
during ischemia: pre- tone
capillary vasodilation Binds to receptors on
and increased vascular smooth
myocardial blood muscle, decreasing
supply 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 Control
/min
100

0
60 80 100 115 130

Coronary Perfusion Pressure (mmHg)

 Autoregulators

Other endothelial-
derived factors
contribute to
autoregulation
Dilators include:
EDRF (NO)
Prostacyclin
Constrictors include:
Endothelin-1
 Coronary Flow Reserve

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
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

4 Maximum Flow

Coronary 3
Blood
Flow
2
Resting Flow
1

0 25 50 75 100
Epicardial % Diameter Stenosis
Endocardium and Collaterals

Epicardium

Endocardium
 Coronary Steal
Vasodilator Rx (Ado)
R2 decreases
A Flow increases to A
Sub-epicardium
B
R3 - no reserve
Sub-endocardium 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
70%
40 <25
% Donors 50% 25-40
30
>40
20
10 25%
0

Clevelend Clinic Cardiac Transplant

Donor IVUS Data-Base
 Risk Factors
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
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
mid-substernal chest pain
squeezing, pressure-like in quality (closed fist =
Levines 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

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
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% >70
18% 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
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, Beta-
blockers, 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

(vs Heparin)

PRISM PLUS 11.9 8.7

(+ Heparin)

PARAGON 11.7 12.0

(high dose)

0.2 1 4
Rx better Placebo better
 Low Molecular Weight Heparin
in Acute Coronary Syndromes
Odds Ratios and 95% CI for Composite Endpoint UH / Placebo Rx
( Death, MI, Re-angina or Revasc at 6-14 days ) (%) (%)

FRISC 10.3 5.4

FRIC 7.6 9.3

ESSENCE 19.8 16.6

TIMI 11b 16.6 14.2

0.2 1 4
LMWH Better UH Better
 Acute Myocardial Infarction

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 / Transmural
sub-endocardial total, prolonged
Non-occlusive occlusion
thrombus or EKG - ST elevation
spontaneous re- Rx - Thrombolytic
perfusion Therapy or Cath
EKG ST depression Lab / PTCA
Some enzymatic
release troponin i
most sensitive
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

ST segment
elevation
ST segment
depression
T wave inversion
Q wave formation
 Consequences of Ischemia
(Ischemia begets Ischemia)
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 LV diastolic pressure cardiac output

congestion
pO2

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 0.04
t-PA vs. SK (IV) 0.003
10 t-PA vs. SK (SQ) 0.009
t-PA vs. Combo SK 0.001
8

7.2 7.4
6 7.0
6.3
4

0
SK + SQ SK + IV Accel. t-PA t-PA + SK
Heparin Heperan
N: 9,796 10,376 10,344 10,327
GUSTO 90 min Patency

% of Patients TIMI 3 TIMI 2

100
81 % *
80 73 %
56 % 61 %
60

40

20
p < 0.001 p < 0.001
0
SK+ SQ SK + IV Accel. t-PA t-PA + SK
Heparin Heparin
N: 295 282 291 297
p = < 0.001 for Accelerated t-PA vs. all other arms
 TIMI Flow Grade Versus
Mortality (GUSTO)
Mortality
12 p=0.01

9 9.7
% of 9.9 p=0.05
Patients
6
7.9
3
4.3
0
TIMI 0 TIMI 1 TIMI 2 TIMI 3
N 259 81 342 447
 Coronary Steal
Role of Collaterals
Assumptions
Rest Adenosine Collateral resistance
P1 drops with vasodil
Flow Flow P2 bed with no vaso
dilator reserve

P2 collateral P1 P2 collateral P1
Changing Paradigm The Concept
of Physiologic Remodeling