Pathology of myocardial ischemia and infarction Flashcards
1. Review the pathological manifestations of atherosclerotic coronary artery disease 2. Determinants of infarct size 3. Different pathological forms of MIs such as regional, diffuse, STEMI, NSTEMI 4. Gross and microscopic appearances of the different phases of an MI 5. Reperfusion myocardial injury 6. Clinical onsequences of MIs and thier pathological expressions
Definition of myocardial ischemia
A state in which O2 supply to the myocardium is insufficient to meet its needs as a result of inadequate perfusion
Factors influencing myocadial O2 supply
- diastolic perfusion pressure
- coronary vascular resistance
- O2 carrying capacity
Factors influencing myocardial O2 demand
- wall tension
- heart rate
- contractility
Balance between supply and demand
- when supply equals demand or increase in supply is met by the same increase in demand = no ischemia
- demand > supply –> ischemia
What are causes of coronary artery disease (10)
- Atherosclerosis/ thrombosis (most important)
- Coronary emboli
- Coronary vasospas
- Ostial narrowing
- Congenital anomalities of coronary artery
- Arthritis
- Post -cardiac transplant vasculopathy
- Spontaneous arterial dissection
- Complications of coronary catherization
- Cocaine abuse
Most common reason why coronary artery atheroscerosis causes myocardial ischemia
-most infarcts (90%) are caused by plaque erosion and subsequent thrombosis
Consequences of calcification of coronary arteries
1) Luminal narrowing
2) Inability to dilate
Composition of atherosclerotic plaque
- fibrous cap on the top - protective layer on surface (collagen and connective tissue and myofibroblasts -contractile and secretory part - make the matrix)
- function of matrix - protect bloodstream from seeing the atheroma
- atheroma = lipid core -if liberated in bloodstream causes instant thrombosis and sudden death
Compensation for narrowed lumen
-distal arterioles dilate
which plaques are the most dangerous (prone to rupture)
- not plaques with alot of calcium (although this does make them narrowed and less pliable)
- it is the soft plaques that are the most prone to rupture (and therefore to become a thrombus) - vulnerable plaque
Where plaque is most likely to rupture
- at the shoulder region
- where inflammatory cells accumulate and secrete cytokines and degredative enzymes (Matrix metaloproteinases and elastases)
- eats away at soft thin region around shoulder and ruptures plack
Two mechanism formation of thrombus
- Plaque fissure
2. Plaque rupture
Plaque fissure
- defect in the endothelium exposing underlying plaque tissue to flow of blood
- thrombus forms on exposed surface
Plaque rupture
- flap of fibrous cap has lifted
- exposes underlying atheroma and it spills into the lumen
- thrombus forms on exposed surface
Propagation of thrombus
1) Thrombus can remain relatively small
2) can enlarge and
i) remain stable
ii) become more fibrous and regress (brought into coronary artery wall)
iii) can block artery right in original position
3) can break off and float down into smaller vessel and occlude that (thrombo emboli)
- platelets that are part of the thrmbus contain platelets contain vasoactive factors - cause vasoconstriction in microvesicles (mechanical and chemical plug)
4) resolution –> rethrombosis and progressive stenosis
Infarction - definition
Cell/tissue death due to ischemia
Clinical definition of infarction
Evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia
Diagnosis of MI clinically
Rise and/or fall of cardiac biomarker (troponin) to >99th percentile + min 1 of:
1) symptoms of ischemia
2) ECG changes of new ischemia
- ST-T differences
3) Imaging evidence (new loss of viable myocardium, regional wall abnormality)
Timeline myocardial infarction
1) Myocardial dysfunction occur in 2 min from occlusion
2) Irreversible changes (necrosis) being approx 20 min following occlusion
3) Complete infarction may take 2-4 hours
Lethal cellular event in mi
-rapid drop in high energy phosphates
Real lethal event =
-cell membrane ion pumps don’t have a field to drive them (i.e. high energy phosphates) so fail
-membrane disruption because ions re-equilibrate across membrane and H2O follows
-cell death follows
How to detect myocardial necrosis
- by elevation of specific enzymes
i) CK-MB (rise 3-8 hr)
ii) Troponin (rise 3-4 hr)
Troponin vs. CK-MB
-troponin rise faster and detectable fo longer period of time
-troponin more specific than CK-MB (which is found in some other organs in small amounts)
(troponins virtually undetectable in absence of cardiac disease
Other causes of increased troponins
x
Area at risk
- when occlude a coronary artery put an area of the myocardial bed at risk (area at risk)
- more proximal occlude an artery = > area at risk
- infarcts almost always start in
Where do most infarcts start/ what parts can potentially be salvaged
- in the immediate subendocardial zone
- i.e. lateral borders of the heart seem to be predetemined
- it is the part from the lateral border on (i.e. the depth of the wall) that may be able to be salvaged
Wavefront phenomenon
Irreversible ischemic myocardial cell injury develops in an increasing number of cells as the duration of occlusion is prolonged
progresses Subendocardial –> subepicardium
Subendocardial region
-inner half of the myocardium
Why do most infarcts begin in the subendocardial region
1) Fewer collaterals than subepicardium
2) Vessels pass through more contracting myocardium
3) Increased wall tension relative to subepicardium
4) Higher metabolic demand of myocytes in the region
Non -ST elevation MI
- tends to be a subendocardial MI
- often see S-T depression
- management my be conservative or invasive including PCI/CABG
ST elevation MI
- transmural ischemia
- management involves either fibrinolyti therapy or primary PCI
2 groups of infarcts by morphology
1) Segmental
2) Diffuse
Segmental infarct
-single vessels coronary disease
Causes of diffuse infarct
1) Multivessel CAD
2) Prolonged hypotension
3) Prolonged hypoxia
4) Shock
5) Over administration of inotropic drugs
Percentage distribution of segmental MI’s
RCA -30%
Cx -20%
LAD -50%
What determines infarct size
- Severity x duration of ischemia
- Size of area at risk
- Collateral coronary circulation
- Reperfusion of ischemic area
- Pre-ischemic state of myocardum
- Conccurent cardiac physiology
- Global (systemic) conditions -i.e. if anemic, systemic hypertension
Histopathological sequence in myocardial infarction
1&2 Wavy fibres and interstitial edema
- Contraction bands
- membrane pumps break down
- SR liberates Ca2+= intraccellular Ca2+ overload
- filaments exposed to Ca2+ contract- hypercontraction state (almost like tetani)
- z lines bunched up together - Neutrophilic infiltrate
- neutrophils liberate degradative enzymes to dissolve dead tissue (so that can be removed by macrophage) - Coagulation necrosis (proteins in cells coagulate = cell death)
- heart is not dead all the way through often pathches of surviving myocytes (collaterals has something to do with this) - Macrophage phagocytosis of necrotic myocytes (garbage trucks take away dead debris - a few days later)
- Granulation Tissue formation
- Formation of collagenous scar
Features of Early infarct 1-3 days
- infarct turn pale (as no blood flowing through)
- myocardial pallor = mottling suggests non-reperfused early MI
- then begins to turn yellow (destruction of cell wall = liberation of lipids = yellow)
Features of resolving infarct 1-2 weeks
- infarct contracts and forms a scar
- gray gelatinous/proteinaceous
Infarct several weeks old
- scar/granulating tissue contracting
- progress until necrotic tissue ie replaced by a scar - can take a long time depending on how large the necrotic area is
Appearance of healed MI -several months old
-white (collagen) fibrous scars
Myocardial reperfusion injury
-reintroduction of oxygenated blood into a region of ischemia/necrosis
Consequences of myocardial reperfusion
1) If achieved early (>2hrs) myocardial salvage
2) If delayed (> 6 hrs) potential for enhanced cell death
3) Reperfused infarcts tend to be very hemorrhagic (most common cause of hemorrhagia post mi = reperfusion)
Agents of harmful side-effects in myocardial reperfusion/reperfusion injury
- oxygen radicals
- intracellular Ca2+ overload
Aim of reperfusion
-reduce the potential for the whole infarct
Why reperfusion may cause further injury
- reperfusion may introduce oxygen radicals
- thereby killing some of area meant to reperfuse
Clinical consequences of mi
1) Arrhythmias
2) Ventricular dysfunction
3) Myocardial stunning
4) Myocardial hibernation
5) Cardiogenic shock
6) Infarct extension
7) Infarct expansion (remodeling)
8) Ventricular aneurysm
Why MI can lead to arrhythmias
1) Decreased perfusion of conducting system tissues
2) Ischemia at the borders f the infarct - in the normal myocardium - this sensitizes the myocardial cells and promotes generation of ectopic arrhythemias
3) Accumulation of toxic metabolites (cellular acidosis)
4) Autonomic stimulation
Why MI can cause ventricular dysfunction
1) Decreased performance from loss of functional myocardium
2) Increased volume because can’t ejected all of volume = increased LVEDV and increase LVEDP
Myocardial stunning
- product of severe ischemia that falls short of myocardial necrosis
- persistent dysfunction even following restoration of normal myocardial blood flow
- gradual return of contractility of myocardium (several days -weeks)
- may be caused by reperfusion
Myocardial hibernation
- chronically impaired myocardial function due to persistently reduced blood supply
- some chronic cellular damage
- function may be restored by revascularization
Cardiogenic shock
- inadequate circulation as a consequence of primary pump failure
- severe arrhythmias
- proportional to infarct size
- contributes to global ischemia and reinfarction
Infarct extension (recurrent infarction)
-new infarction adjacent to or remote from original region
2-10 days from original event
Infarct expansion (remodelling)
- stretching/thinning of original infarct
- proportional to original infarct size
- usually antero-apical region (ventricular aneurysms) -occuring in LAD terrritory
Basis for physiological effects of infarct expansion: increased wall stress
-infarct expands ventricular radius
-infarct decreases ventricular thickness
-increased LVEDV –> LVEDP
wall stress = Px r/2h
Basis for physiological effect of infarct expansion
- increased wall stress
- Impairment of systolic contraction
- Increased probability of aneurysm formation
