Ischemic Heart Disease and Myocardial Infarction

1
Ischemic Heart Disease and Myocardial Infarction

• Pathophysiology of Myocardial Ischemia
• Bio-Med 350
• September 2005

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)

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Coronary ArteriesNormal Anatomy
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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)

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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

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Myocardial IschemiaOccurs when myocardial
oxygen demand exceeds myocardial oxygen supply
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Myocardial IschemiaOccurs when myocardial
oxygen demand exceeds myocardial oxygen supply
MVO2 Myocardial Oxygen Demand
MVO2 determined by Heart Rate Contractility Wall
Tension
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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

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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)
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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
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Myocardial IschemiaOccurs when myocardial
oxygen demand exceeds myocardial oxygen supply
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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

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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)

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Endocardium and CFR
Diastole
Systole
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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

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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

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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)

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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)
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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

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Coronary Flow Reserve
5
Maximum Flow
4
Coronary Blood Flow
3
2
Resting Flow
1
100
0
50
75
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Epicardial Diameter Stenosis
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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
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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
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Physiologic Remodeling
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Coronary atherosclerosis
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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)?

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Stable Angina - TreatmentMechanical
DilationAngioplasty, Stent, etc.
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Treatment of Stable Angina -STENTS
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Stable Angina - TreatmentCoronary Artery Bypass
Grafting Surgery (CABG)
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Schematic of an Unstable Plaque
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Unstable Plaque More Detail.
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Cross section of acomplicated plaque
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Journey down a coronary
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Angiogram in unstable anginaeccentric,
ulcerated plaque
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Angiogram in unstable angina after stent
deployment
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Acute Coronary SyndromesTerminology

• 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

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Pathophysiology of the Acute Coronary Syndromes
(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)

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Pathophysiology of Acute Coronary Syndromes
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Pathophysiology of Acute Coronary Syndromes
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Vulnerable Plaque
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Coronary Stenosis Severity Prior to Myocardial
Infarction
Stenosis
14
68
gt70
18
50-70
lt50
Falk et al, Circulation 1995 92 657-71
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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

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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

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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

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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
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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)

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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

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AMI - Wavefront Phenomenon
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Acute Myocardial Infarction

• Transmural
• total, prolonged occlusion
• EKG - ST elevation
• Rx - Thrombolytic Therapy or Cath Lab / PTCA

• Non-transmural / sub-endocardial
• Non-occlusive thrombus or spontaneous
  re-perfusion
• EKG ST depression
• Some enzymatic release troponin i most sensitive

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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
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Markers of MI Troponin I
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Diagnosis of MIRole of troponin i

• Troponin I is highly sensitive
• Troponin I may be elevated after prolonged
  subendocardial ischemia
• See examples below

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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)

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EKG diagnosis of MI

• ST segment elevation
• ST segment depression
• T wave inversion
• Q wave formation

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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)
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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
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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