angina associated with congestive heart failure, new murmur

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 ArteriesNormal 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 IschemiaOccurs when myocardial
oxygen demand exceeds myocardial oxygen supply
7
Myocardial IschemiaOccurs 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
10
8
MVO2
cc/min /100g
6
4
2
100 150
200
Heart Rate (BPM)
10
Contractility
10
Norepinephrine
Control
MVO2 (cc/min /100g)
5
0
Peak Developed Tension (g/cm2)
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 IschemiaOccurs when myocardial
oxygen demand exceeds myocardial oxygen supply
13
Myocardial Oxygen Supply
Determined by
Coronary Blood Flow O2 Carrying
Capacity
( Flow Pressure / Resistance)

• Oxygen saturation of the blood
• Hemoglobin content of the blood

• Coronary perfusion pressure
• Coronary vascular resistance

14
Coronary Blood FlowProportional 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
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)

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

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Adenosine

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

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Autoregulatory Resistance
200
Adenosine
Flow cc/100g /min
Control
100
0
60
130
100
115
80
Coronary Perfusion Pressure (mmHg)
22
Autoregulators

• Other endothelial- derived factors contribute to
  autoregulation
• Dilators include
• EDRF (NO)
• Prostacyclin
• Constrictors include
• Endothelin-1

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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)

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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 lt 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
5
Maximum Flow
4
Coronary Blood Flow
3
2
Resting Flow
1
100
0
50
75
25
Epicardial Diameter Stenosis
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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
Sub-epicardium
B
Sub-endocardium
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Prevalence of CAD in Modern Society
70
60
Age(years)
50
70
lt25
40
Donors
25-40
50
30
gt40
20
25
10
0
Clevelend Clinic Cardiac Transplant Donor IVUS
Data-Base
29
Risk Factors

• family History
• cigarette smoking
• diabetes mellitus
• hypertension
• hyperlipidemia
• sedentary life-style
• obesity
• elevated homocysteine, LP-a ?

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Coronary lesions in Men and Women,Westernized
and non-Westernized diets
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Relationship between fat in diet and serum
cholesterol
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Atherosclerotic PlaqueEvolution 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

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Plaque progression.

• Fibrous cap develops when smooth muscle cells
  migrate to intima, producing a tough fibrous
  matrix which glues cells together

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Intra-vascular Ultrasound (IVUS)
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Atherosclerotic Plaque
36
Physiologic Remodeling
37
Coronary atherosclerosis
38
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

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Symptoms and Signs Coronary Ischemia
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Stable Angina - DiagnosisExercise Treadmill Test
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Stable Angina - DiagnosisThallium Stress Test
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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 - TreatmentMechanical
DilationAngioplasty, Stent, etc.
44
Treatment of Stable Angina -STENTS
45
Stable Angina - TreatmentCoronary Artery Bypass
Grafting Surgery (CABG)
46
Schematic of an Unstable Plaque
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Unstable Plaque More Detail.
48
Cross section of acomplicated plaque
49
Journey down a coronary
50
Angiogram in unstable anginaeccentric,
ulcerated plaque
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Angiogram in unstable angina after stent
deployment
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Acute Coronary SyndromeTerminology

• 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
Coronary Stenosis Severity Prior to Myocardial
Infarction
Stenosis
14
68
gt70
18
50-70
lt50
Falk et al, Circulation 1995 92 657-71
58
Acute Coronary SyndromeUnstable Angina /
Myocardial InfarctionSymptoms

• new onset angina
• increase in frequency, duration or severity
• decrease in exertion required to provoke
• any prolonged episode (gt10-15min)
• failure to abate with gt2-3 S.L. NTG
• onset at rest or awakening from sleep

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Unstable Angina - High Risk Features

• prolonged rest pain
• dynamic EKG changes (ST depression)
• age gt 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 gt100 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 )
Placebo ( ) Rx ( )
15.7 14.2 7.1 5.8 11.9
8.7 11.7 12.0
PURSUIT PRISM (vs Heparin) PRISM PLUS
( Heparin) PARAGON (high dose)
0.2
1
4
Rx better
Placebo better
63
Low Molecular Weight Heparin in Acute Coronary
Syndromes
UH / Placebo Rx () ()
Odds Ratios and 95 CI for Composite Endpoint
( Death, MI, Re-angina or Revasc at 6-14 days )
10.3 5.4 7.6
9.3 19.8 16.6 16.6 14.2
FRISC FRIC ESSENCE TIMI 11b
0.2
1
4
LMWH Better
UH Better
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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 (gt20 LV ) ?
  Congestive heart failure
• If larger area of infarction (gt40 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 MIRole 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 (gt15 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
Diastolic Dysfunction
Systolic Dysfunction
chest pain
cardiac output
LV diastolic pressure
pulmonary congestion pO2
catecholamines
wall tension
(heart rate, BP)
MVO2
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
30 Day Mortality
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
N 9,796 10,376 10,344 10,327
78
GUSTO
90 min Patency
of Patients
81
73
61
56
p lt 0.001
p lt 0.001
N 295 282 291 297
p lt 0.001 for Accelerated t-PA vs. all other
arms
79
TIMI Flow Grade Versus Mortality (GUSTO)
Mortality
12
p0.01
9
9.7
p0.05
of Patients
9.9
6
7.9
3
4.3
0
TIMI 0 TIMI 1 TIMI 2
TIMI 3
N 259 81 342
447
80
Coronary Steal Role of Collaterals
Assumptions Collateral resistance P1 drops with
vasodil P2 bed with no vaso dilator reserve
Rest
Adenosine
Flow
Flow
P1
P2
collateral
P1
P2
collateral
81
Changing Paradigm The Concept of Physiologic
Remodeling