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
Sub-epicardium
 Flow increases to A
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 =
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

 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 Lab
 EKG – ST depression / 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

0
SK + SQ S K + IV A c c e l. t-P A t-P A + S K
H e p a r in H epera n

N: 9,796 10,376 10,344 10,327

GUSTO 90 min Patency

% of Patients
TIM I 3 TIM I 2
100
81 % *
80
73 %
56 % 61 %
60

40

20

p < 0.001 p < 0.001

0
SK + SQ SK + IV A ccel. t-P A t-P A + SK
H epa rin H epa rin
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