This document discusses the pathophysiology of myocardial ischemia and infarction. It describes how myocardial oxygen demand can exceed supply, leading to ischemia. Factors that determine oxygen demand and supply are explored, including heart rate, contractility, wall tension, coronary blood flow, oxygen carrying capacity of blood, and autoregulatory resistance in arterioles. The progression and vulnerability of atherosclerotic plaque is summarized. Clinical syndromes like stable angina and acute coronary syndromes (unstable angina and myocardial infarction) are defined and their presentations, diagnoses, and treatment approaches are overviewed.

1. Ischemic Heart Disease and
Myocardial Infarction
Pathophysiology of Myocardial
Ischemia
Bio-Med 350
September 2004

2. 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)

3. Coronary Arteries
Normal Anatomy

4. 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)

5. 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

6. Myocardial Ischemia:
Occurs when myocardial oxygen demand exceeds
myocardial oxygen supply

7. Myocardial Ischemia:
Occurs when myocardial oxygen demand exceeds
myocardial oxygen supply
MVO2 = Myocardial Oxygen Demand
MVO2 determined by:
Heart Rate
Contractility
Wall Tension

8. 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

9. Heart Rate
100 150 200
cc/min
/100g
MVO2
2
10
6
8
4
Heart Rate (BPM)

10. Contractility
Peak Developed Tension (g/cm2)
MVO2
(cc/min
/100g)
10
0
5
Norepinephrine
Control

11. 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

12. Myocardial Ischemia:
Occurs when myocardial oxygen demand exceeds
myocardial oxygen supply

13. Myocardial Oxygen Supply
Determined by:
Coronary Blood Flow & O2 Carrying Capacity
 Oxygen saturation of
the blood
 Hemoglobin content
of the blood
( Flow = Pressure / Resistance)
 Coronary perfusion pressure
 Coronary vascular resistance

14. 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)

15. Endocardium and CFR
Diastole
Systole

16. 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

17. 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

18. Autoregulatory Resistance
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)
Involves 3 different cells

19. Autoregulation of Coronary
Blood Flow
Oxygen
 Acts as
vasoconstrictor
 As O2 levels drop
during ischemia: pre-
capillary 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

20. Adenosine
During hypoxemia, aerobic metabolism
in mitochondria is inhibited
Accumulation of ADP and AMP
Production of adenosine
Adenosine vasodilates arterioles
Increased coronary blood flow

21. Autoregulatory Resistance
Coronary Perfusion Pressure (mmHg)
Flow
cc/100g
/min
60 130100 11580
Control
Adenosine
0
200
100

22. Autoregulators
Other endothelial-
derived factors
contribute to
autoregulation
 Dilators include:
EDRF (NO)
Prostacyclin
 Constrictors include:
Endothelin-1

23. 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)

24. 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

25. Coronary Flow Reserve
1
5
3
4
2
Epicardial % Diameter Stenosis
1000 50 7525
Maximum Flow
Resting Flow
Coronary
Blood
Flow

26. Endocardium and Collaterals
Epicardium
Endocardium

27. Coronary Steal
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
A
B
Sub-epicardium
Sub-endocardium

28. 0
10
20
30
40
50
60
70
<25
25-40
>40
Age(years)
25%
50%
70%
% Donors
Clevelend Clinic Cardiac Transplant
Donor IVUS Data-Base
Prevalence of CAD in Modern
Society

29. Risk Factors
family History
cigarette smoking
diabetes mellitus
hypertension
hyperlipidemia
sedentary life-style
obesity
elevated homocysteine, LP-a ?

30. Coronary lesions in Men and Women,
Westernized and non-Westernized diets

31. Relationship between fat in diet and
serum cholesterol

32. 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

33. Plaque progression….
Fibrous cap
develops when
smooth muscle cells
migrate to intima,
producing a tough
fibrous matrix which
glues cells together

34. Intra-vascular Ultrasound (IVUS)

35. Atherosclerotic Plaque

36. Physiologic Remodeling

37. Coronary atherosclerosis

38. 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

39. Symptoms and Signs:
Coronary Ischemia

40. Stable Angina - Diagnosis
Exercise Treadmill Test

41. Stable Angina - Diagnosis
Thallium Stress Test

42. 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)?

43. Stable Angina - Treatment
Mechanical Dilation:
Angioplasty, Stent, etc.

44. Treatment of Stable Angina
-STENTS

45. Stable Angina - Treatment
Coronary Artery Bypass Grafting Surgery
(CABG)

46. Schematic of an Unstable PlaqueSchematic of an Unstable Plaque

47. Unstable Plaque:
More Detail…….

48. Cross section of a
complicated plaque

49. Journey down a coronary…

50. Angiogram in unstable angina:
eccentric, ulcerated plaque

51. Angiogram in unstable angina:
after stent deployment

52. 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

53. 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)

54. Pathophysiology of Acute
Coronary Syndromes

55. Pathophysiology of Acute
Coronary Syndromes

56. “Vulnerable Plaque”

57. >70
50-70
<50
% Stenosis
68%
18%
14%
Coronary Stenosis Severity Prior to
Myocardial Infarction
Falk et al, Circulation 1995; 92: 657-71

58. 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

59. 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

60. 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

61. 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

62. Platelet GP IIB/ IIIA Inhibitors
with Acute Coronary Syndromes
Odds Ratios and 95% CI for Composite Endpoint
( Death,Re- MI at 30days )
0.2 1 4
PURSUIT
PRISM
(vs Heparin)
PRISM PLUS
(+ Heparin)
PARAGON
(high dose)
15.7 14.2
7.1 5.8
11.9 8.7
11.7 12.0
Placebo (% ) Rx ( % )
Rx better Placebo better

63. 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 )
0.2 1 4
FRISC
FRIC
ESSENCE
TIMI 11b
10.3 5.4
7.6 9.3
19.8 16.6
16.6 14.2
UH / Placebo Rx
(%) (%)
LMWH Better UH Better

64. 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)

65. 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

66. AMI - Wavefront Phenomenon

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

68. 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

69. Markers of MI: Troponin I

70. Diagnosis of MI:
Role of troponin i
♥ Troponin I is highly
sensitive
♥ Troponin I may be
elevated after
prolonged
subendocardial
ischemia
♥ See examples below

71. 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)

72. EKG diagnosis of MI
ST segment
elevation
ST segment
depression
T wave inversion
Q wave formation

73. 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)

74. Ischemic Cycle
Ischemia / infarction
chest pain
Diastolic Dysfunction Systolic Dysfunction
cardiac output
catecholamines
MVO2
wall tension
LV diastolic pressurepulmonary
congestion
pO2
(heart rate, BP)

75. 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

76. 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)

77. GUSTO
7.2 7.4
6.3
7.0
0
2
4
6
8
10
SK + SQ
Heparin
SK + IV
Heperan
Accel. t-PA t-PA + SK
N: 9,796 10,376 10,344 10,327
p-values t-PA vs. t-PA + SK 0.04
t-PA vs. SK (IV) 0.003
t-PA vs. SK (SQ) 0.009
t-PA vs. Combo SK 0.001
30 Day Mortality

78. GUSTO
0
20
40
60
80
100
SK+ SQ
Heparin
SK + IV
Heparin
Accel. t-PA t-PA + SK
TIMI 3 TIMI 2
p < 0.001 p < 0.001
56 % 61 %
81 % *
73 %
% of Patients
N: 295 282 291 297
p = < 0.001 for Accelerated t-PA vs. all other arms
90 min Patency

79. TIMI Flow Grade Versus
Mortality (GUSTO)
0
12
6
3
9
% of
Patients
TIMI 0 TIMI 1 TIMI 2 TIMI 3
N 259 81 342 447
Mortality
4.3
7.9
9.99.7
p=0.01
p=0.05

80. Coronary Steal
Role of Collaterals
P1 P1P2 P2
Rest Adenosine
Assumptions
Collateral resistance
P1 drops with vasodil
P2 bed with no vaso
dilator reserve
Flow Flow
collateral collateral

81. Changing Paradigm – The Concept
of Physiologic Remodeling