Ischemia
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Ischemic Heart Disease and Myocardial Infarction
Pathophysiology of Myocardial Ischemia
Bio-Med 350
September 2004
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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 Ischemia:Occurs when myocardial oxygen demand exceeds
myocardial oxygen supply
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Myocardial Ischemia:Occurs when myocardial oxygen demand exceeds
myocardial oxygen supply
MVO2 = Myocardial Oxygen Demand
MVO2 determined by:
Heart RateContractilityWall 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
100 150 200
cc/min/100g
MVO2
2
10
6
8
4
Heart Rate (BPM)
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Contractility
Peak Developed Tension (g/cm2)
MVO2(cc/min/100g)
10
0
5
Norepinephrine
Control
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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 pressurePreload - LV end-diastolic pressure or volume
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Myocardial Ischemia:Occurs when myocardial oxygen demand exceeds
myocardial oxygen supply
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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
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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
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
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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
Coronary Perfusion Pressure (mmHg)
Flowcc/100g/min
60 130100 11580
Control
Adenosine
0
200
100
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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 < 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
1
5
3
4
2
Epicardial % Diameter Stenosis
1000 50 7525
Maximum Flow
Resting Flow
CoronaryBloodFlow
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Endocardium and Collaterals
Epicardium
Endocardium
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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
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0
10
20
30
40
50
60
70
<25
25-40
>40
Age(years)
25%
50%
70%
% Donors
Clevelend Clinic Cardiac TransplantDonor IVUS Data-Base
Prevalence of CAD in Modern Society
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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 =
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
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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 Dilation:
Angioplasty, 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 PlaqueSchematic 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 angina:eccentric, 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
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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)
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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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>70
50-70
<50
% Stenosis68%
18%
14%
Coronary Stenosis Severity Prior to Myocardial Infarction
Falk et al, Circulation 1995; 92: 657-71
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Acute Coronary SyndromeUnstable 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
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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
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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 >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
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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 )
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
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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
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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 (>20% LV ) Congestive heart
failure If larger area of infarction (>40% LV) hemodynamic collapse
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AMI - Wavefront Phenomenon
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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
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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 MI:Role 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 (>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)
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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
chest pain
Diastolic Dysfunction Systolic Dysfunction
cardiac output
catecholamines
MVO2
wall tension
LV diastolic pressurepulmonarycongestionpO2
(heart rate, BP)
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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
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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)
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GUSTO
7.2 7.46.3
7.0
0
2
4
6
8
10
SK + SQHeparin
SK + IVHeperan
Accel. t-PA t-PA + SK
N: 9,796 10,376 10,344 10,327
p-values t-PA vs. t-PA + SK 0.04t-PA vs. SK (IV) 0.003t-PA vs. SK (SQ) 0.009t-PA vs. Combo SK 0.001
30 Day Mortality
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GUSTO
0
20
40
60
80
100
SK+ SQHeparin
SK + IVHeparin
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
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TIMI Flow Grade Versus Mortality (GUSTO)
0
12
6
3
9% ofPatients
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
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Coronary Steal Role of Collaterals
P1 P1P2 P2
Rest AdenosineAssumptionsCollateral resistanceP1 drops with vasodilP2 bed with no vaso dilator reserve
Flow Flow
collateral collateral
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Changing Paradigm – The Concept of Physiologic Remodeling