Ischaemia and infarction Flashcards
a) Define ischaemia
b) what is meant to an inadequate quality of blood
c) Define infarction
d) causes of ischaemia (5)
a) Inadequate local blood supply to an organ (insufficitent quantity of blood)
b) Inadequate oxygen carrying capacity of blood in anaemia or inadequate oxygenation in heart/lung failure
c) Necrosis due to ischaemia. The localised area of necrosis is an infarct
d) i) external narrowing or occlusion of vessels (tumours, compression) ii) Internal narrowing or occlusion of vessels (atherosclerosis, thrombosis, embolism) iii) spasm of vessel (eg because of cold) iv) capillary blockage (sickle cell disease, cerebral malaria v) shock
a) define shock
b) Types of shock (4) and examples of causes
c) concequences of ischaemia to cells
d) effects these consequences have on the cells (6)
a) Circulatory failure with low arterial blood pressure, which causes impaired perfusion of tissues
b) Cardiogenic - myocardial infarction, arrythmia, outflow obstruction (pulmonary embolus), external compression
Hypovolaemic - haemorrhage, severe burns
Septic - bacteria (gram-positive or negative)
Anaphylactic - generalised type 1 hypersensitivity
c) Hypoxia, poor supply of nutrients (glucose, aas), failure to remove waste products of metabolism. These changes lead to reduced aerobic respiration and also reduced anaerobic
d) i) damage to mitochondria (depletion of cellular ATP, accumulation of ROS) ii) dysfunction and damage to cell membranes, causing defects in permeability (plasma membrane, lysosomal membrane) iii) influx of Ca2+ iv) protein mis-folding v) damage to DNA
Morphological changes in ischaemic cell injury
a) example of how long different tissues take to show morphological changes in ischaemia
b) Overview of the morphological changes that occur
a) myocardial cells stop contracting 1 minute after blood supply is occluded. Ultrastructural changes take 30 minutes. Histological changes take 4-12 hours
b) Changes occur sequentially, at a rate that depends on the susceptibility of the cells affected
Reversible changes will revert to normal is the cause of ischaemia is resolved
Irreversible changes indicate impending cell death. In ischaemia, death mainly occurs by necrosis, although apoptotic pathways may also be activated
Point of no return vbetween reversible and irreversible is ill-defined, but relates to the severity of damage to mitochondria and cell membranes
a) reversible cell injury (ultrastructural (5) and histological (2))
b) irreversible cell injury (key changes and causes, ultrastructural (4) and histological (3))
a) Ultrastructural - i) cell swelling ii) plasma membrane blebs (rounded outpouchings) iii) swelling of organells (eg endoplasmic reticulum, mitochondria) iv) nuclear chromatin clumping v) lipid vacuoles in cytoplasm if cells metabolise fat (hapatocytes, myocardial cells)
Histological - i) cell swelling ii) fatty change
b) Key morphological features of necrosis - denaturation of cytoplasmic proteins and enzymatic digestion of the cell contents
Caused by - brakdown of lysosomal membranes, allowing enzymes to leak into the cytoplasm, and breakdown of the cell membrane, leading to extracellular leakage of cell contents (can induce acute inflammation, with inflammatory cells introducing more lysosomal enzymes, which enter the dying cells through the disrupted membrane)
Ultrastructural - i) breakdown of plasma membrane ii) breakdown of nuclear membrane iii) breakdown of organelle membranes, including lysosome rupture iv) mitochondrial disruption and deposits of electron-dense material (proteins and calcium)
Histological - i) increased cytoplasmic eosinophilia, due to loss of RNA (reducing binding of haematoxylin) and denaturation of proteins (increased binding of eosin) ii) cytoplasm may appear moth eaten, reflecting enzymatic digestion iii) nuclei may be shrunken (pyknosis), pale (karyolysis) or fragmented (karyorrhexis)
a) what type of necrosis occurs due to ischaemia
b) how to clinically provide early evidence of cell death (example in myocardial infarction)
a) Coagulative necrosis. This is because protein denaturation in the cytoplasm is typically more prominent than enzymatic digestion, so necrotic tissue preserves its architecture and firmness for several days
b) damage to the plasma membrane of necrotic cells allows the cell contents to leak into the blood. Elevated levels of cell-specific proteins are typically detectable before morphological changes appear (hence useful clinically)
In MI, histological changes don’t appear for 4-12 hours, but elevated levels of enzymes specific to cardiac muscles are detectable in the blood after 2 hours
Factors affecting the outcome of ischaemia
a) Susceptibilty of cells
b) Susceptibility of organs
a) Determined by cellular metabolic rate and oxygen demand. Neurons (very sensitive) - irreversibly damaged by only 3 minutes of anoxia. Renal proximal tubular epithelium (sensitive) - ion reabsorption function is rapidly impaired. Myocardium (sensitive) - irreversible damage after 20 minutes of anoxia, but functional impairment (with risk of arrhythmia) within one minute. Skeletal muscle (less sensitive) - capabale of some anoxic work. Fibroblasts and macrophages (insensitive)
b) Determined by the anatomy of the blood supply to the organ
Collateral circulation, may reduce susceptibility (eg venous circulation, some arterial systems like the gut, may develp is there is slowly progressive arterial narrowing like in the coronary arteries)
Organs with dual blood supply, if one is blocked, the other may suffice (eg lungs are supplied by pulmonary and bronchial arteries, liver is supplied by hepatic portal vein and hepatic artery, brain is supplied by circle of Willis)
Single vessel (functional end arteries), very susceptible to ischaemis (eg kidney, spleen)
Factors affecting the outcome of ischaemia
a) size of block
b) degree of block
c) demandn of tissue
d) general adequacy of circulatory system
e) speed of onset
f) persistence of the block
a) the larger the vessel blocked, the greater the volume of ischaemic tissue
b) stenosis vs occlusion
c) blood supply may become inadequate on exertion (eg heart or leg muscles), induced hypothermia can reduce effects of brain ischaemia
d) outcome may be worse is there is co-existing anaemia, heart failur, impaired oxygenation of blood etc
e) slow onset may allow development of collateral circultion (eg coronary arteries), sudden ischaemia leaves no time for adaptation and causes infarction
f) some thrombi may be unstable, leading to transient ischaemia (eg in brain), other blockages may be stable, giving persistent ischaemia
a) ischaemic reperfusion injury
b) microscopic appearance of infarcts (3)
a) If blood flow is restored to ischaemic tissue, in some cells reversible injury may become irreversible. Folowing coronary artery occlusion, reperfusion may eb achieved by thrombolysis (eg using streptokinase), angioplasty, coronary artery bypass grafting. The mechanisms underlying reperfusion injury include generation of fresh mediators of cell injury (free radicals, calcium overload), and initiation of acute inflammation, by delivery of neutrophils and complement proteins
b) i) infarcted tissue shows coagulative necrosis (histological changes usually appear after 4-12 hours, there may be earlier biochemical evidence of cell damage)
ii) acute inflammation develops at the viable margins within 24 hours
iii) some tissues (eg liver) may attempt regeneration, although usually the infarct becomes organised. By around three to five days, macrophages start to appear and granulation tissue begins to develop. Over the following six to eight weeks the infarct is replaced by a non-functional fibrous scar.
Macroscopic appearances of infarcts (7)
i) In acute tissue anoxia there may be capillary dilation, even haemorrhage. Hence the infarct is red and poorly defined in the early stages
ii) In solid tissue (heart, kidney, spleen), the infarct becomes pale and well demarcated quite rapidly (within 24 hours). These are pale infarcts
iii) some infarcts may remain red due to haemorrhage (red infarcts), eg arterial occlusion (in spongy tissue, such as the lung or in tissues with collateral blood supplies like the gut) or generally in venous occlusion
iv) the shape of the infarct is determined by the blood supply to the tissue. Infarcts are usually cone-shaped, with the apex at the point of occlusion and the base at the organ surface (look wedge-shaped in two dimensions)
v) in the early stages, the margins of pale infarcts may appear red (showing acute inflammation and/or granulation tissue) and there may be a fibrinous exudate on the surface of the organ. Eventually the infarct is replaced by grey scar tissue
vi) in some tissue (lung) there is a risk of secondary infection, leading to one type of septic infarct, which may progress to an abscess
vii) in the brain, infarcts undergo liquefactive necrosis. The necrotic cells are digested quickly and form a cyst containing liquid, surrounded by reactive glial cells
Specific examples of infarction
a) Myocardial infarction (causes and effects)
b) Pulmonary infarction (causes and effects)
c) Cerebral infarction (causes and effects)
a) Causes - usually coronary artery atherosclerosis, complicated by thrombosis. Predominantly affects the left ventricle
Effects - dysrhythmia, sudden death, cardiogenic shock, rupture of the infarct, mural thrombosis on the endocardium lining the infarct, scarring may lead to cardiac aneurysm, which often contains mural thrombus, adaptation to inadequate cardiac output (dilation, hypertrophy), heart failure
b) Causes - thromboembolism from pelvic or leg veins
Effects - may be silent (if small), impaired lung function, pressure overload on right heart and possibly right heart failure, infection (septic infarcts, abcess)
c) Causes - cerebral artery thrombosis, embolism from the heart (thrombus) or from atheroma (usually in common carotid arteries - thrombus or plaque), shock (common in the elderly)
Effects - liquefactive necrosis and cyst formation, clinically there is sudden onset of inadequate cerebral function (a stroke)
