4. Infarction Flashcards
Infarction
• Infarct: area of ____ necrosis caused by occlusion of vascular supply to tissue
• Infarction: process by which infarcts occur
• Classification:
– ____ (hemorrhagic) vs white (anemic)
– ____ (septic) or bland
• Important cause of illness
– 40% of all deaths in US consequence of CVD; most of these due to myocardial or ____ infarct
• Causes of infarcts (mostly arterial):
– ____ thrombus and embolism
– Complication of ____
– Less common causes:
• Extrinsic compression of a vessel (e.g., ____)
• Edema in a confined space
• Blood vessel twisting (e.g., ____, bowel volvulus)
– Venous blockade (e.g., thrombus)
• May cause infarct, more commonly ____; ____ channels restore venous outflow and arterial inflow
ischemic
red
infected
cerebral
arterial atherosclerosis tumor testicular torsion congestion bypass
• Clinical consequences of an infarct: – Inconsequential – Tissue necrosis – Organ dysfunction – Death • Note: Partial occlusion (e.g., \_\_\_\_) – leads to ischemia and typically results in \_\_\_\_ and occasionally \_\_\_\_ – Ischemic necrosis of extremities problem in \_\_\_\_ population (gangrene)
• Clinical consequece of infarction influenced by: – Vascular supply • \_\_\_\_: kidney, spleen, heart • \_\_\_\_: lungs, liver – Rate occlusion develops • Slowly developing occlusions leads to development of \_\_\_\_ blood supply – Tissue vulnerability to hypoxia • \_\_\_\_>\_\_\_\_>\_\_\_\_ – \_\_\_\_ content of blood (normal individual vs anemic or cyanotic pt)
• Results in ischemia, and ultimately coagulative necrosis • Infarcts occur from \_\_\_\_ occlusion • Ischemic necrosis of extremities - diabetic • Vascular supply ○ Some organs are endoarterial - single blood supply § More susceptible to infarction than dual supply ○ Dual supply • Rate of occlusion ○ Rapid occlusion > rapid anoxia > immediate death § No chance for collateral development ○ Slowly develops > ischemia develops and collateral BV develop > important for myocardial infarcts • \_\_\_\_ can survive low O2 over longer periods • If patient is already compromised (\_\_\_\_, Hb problems) > patient more susceptible to ischemic event
stenosis
atrophy
necrosis
diabetic
single dual collateral neurons myocardium fibroblasts oxygen
total
fibroblasts
anemia
Classification of infarcts
• White (anemic, pale) infarcts
– Arterial occlusions in ____ organs
– Tissue with ____ circulation (heart, kidney, brain)
– Tissue ____ limits seepage of blood from adjoining vascular beds
– ____ necrosis
It occurs in tissues that because of its density, there is limited seepage of blood from adjacent blood vessels. Without that seepage, adjoining vascular beds cannot provide any blood supply. So this infarcted tissue is not
going to be perfused by seepage of blood from the adjacent vessels that are still receiving blood. The tissue will die as a result of coagulative necrosis, which is the result of the drop in ____ and denaturation of ____ enzymes. There is no-or-limited autolysis and no heterolysis, which usually occurs because of inflammation, but there is no ____ because no blood supply.
solid
end-arterial
density
coagulative
pH
proteolytic
inflammation
White infarcts (continued):
– Tend to be ____-shaped with occluded vessel at ____ and periphery of organ forming ____
– Lateral margins ____—blood flow from adjacent vessels
– Margins may be hemorrhagic (acute) and eventually hyperemic (inflammation)
– Main histologic finding: ____ necrosis
– Inflammation at the margins; why?
– Fate of infarct: repair—____
– Complications: ____ infarction: microbes seed necrotic tissue
– Exceptions: Brain infarct leads to ____ necrosis– ____
wedge apex base irregular ischemic (coagulative) scar septic liquefactive abscess
Classification of infarcts
• Red (hemorrhagic) infarcts
– Tissue with ____ blood supply (e.g., lung, liver)
– ____ tissue where blood can collect in infarcted zone (e.g. lung)
– Arterial or venous occlusion
– ____ necrosis
– Hemorrhage due to bleeding into infarct from ____ vessels
• Tissue with dual blood supply
• Tissue with extensive ____ circulation
dual "loose" ischemic coagulative adjacent collateral
Examples of infarcts • White infarcts: – \_\_\_\_ – \_\_\_\_ • Red infarcts: – \_\_\_\_
renal
heart
pulmonary
- Kidneys connected to bladder via ____
- ____ artery that enters each kidney, perfusing the cortex and medulla
- Functional unit = ____ (glomeruli, tubules)
ureters
renal
nephron
Renal Infarct: Coagulative necrosis
• Morphological changes:
• Gross:
• ____/firm, tissue retains ____ outline
• Microscopic:
• cell architecture ____; reveal structure of living tissue but lacks clear ____
• Lacks cell boundaries
– ____
• nucleus
– ____
– karyorrhexis
– ____
• Fate: necrotic tissue removed by ____
* TR: normal live kidney * BR: eosinophilic (lost mRNA that normally take up hematoxylin), retains its basic cell architecture, cannot find cell borders, and no nuclei (all \_\_\_\_)
pale basic remains definition eosinophilia pyknosis karyolysis phagocytes karyolysis
- R: no ____, no nuclei, ____
- Fate of infract > removed by ____
- Dead tissue is one of the most potent inducers of ____ reaction (occuring in adjacent tissue that is being perfused)
cell borders
eosinophilia
phagocytes
inflam
• TL: left side, ____ necrosis: pale, eosino, no nuclei; right side: ____ zone, would see BV, nucleated cells (phagocytes: PMNs, macro’s) that are surrounding infarcted tissue > ____
• BL: presence of inflammatory cells, top-left: eosinophilic
• Cannot repair/resolve until you remove the ____
○ Kidney with limited ____ ability > healing is by scar (____ cells)
○ Reduced in ____
○ Remodeling of structure bc of tensile strength of collagen that distorts it > ____ phenotype
coag necrosis hyperemic heterolysis etiology proliferative stable function bread-and-butter
Myocardial infarct
• Complete occlusion of major branch of ____ artery
• Gross: initially ____
* Firm and pale appearance * Remaining live tissue becomes \_\_\_\_
coronary
pale
hypertrophic
Myocardial infarction • Complete occlusion of major branch of coronary artery • Histopath: – \_\_\_\_ – Loss of structure: • Nuclei • \_\_\_\_ disks • Cell demarcation • Inflammatory infil
* TR: normal histology, presence of intercalated disks allow the smooth muscles to work as one unit * BR: middle of infarct; eosino, some intercalated disks but they're \_\_\_\_ down; limited number of nuclei * Will ultimately become \_\_\_\_
eosinohpilia
intercalated
breaking
phagocytosed
- L: dead myocardial cells, with inflam cells interdispersed that are degrading/digesting the ____ cells
- Will resolve/heal with a thin ____ tissue
myocardial
connective/scar
- Once dead tissue is removed, ____ will occur
- R: thin white band on right is a thin ____ tissue layer, chalky (____ calcification); this part of the heart will ____ out
fibrosis
connective
dystrophic
blow
- Who is more likely to survive a MI > ____ will be more likely to survive (65 > 45)
- Coronary artery will form sudden occlusion, and the blood supply downstream is blocked (45); no ____ circulation formation
- In the 65 y.o, developing artherosclerosis for longer, as development there is a gradual decrease in perfusion > the BV respond by developing ____ > allow the blood to bypass the blockade and provide downstream circulation > these channels develop further, so once total occlusion of major vessel occurs, there will still be ____ to that tissue (____)
older collateral collaterals BF compromised
- Five lobes
- Air is conducted from ____ > R/L ____ > ____ > ____ bronchioles > ____ bronchioles > alveolar ____ > alveolar ____ > alveoli
- Alveoli open up into the sac
- ____ within the lung
- Alveolar ____
trachea bronchi bronchioles terminal respiratory ducts sacs
surfactant
macrophages
Pulmonary infarcts
• Often result of emboli in
____ artery; ____ lead to clinical symptoms
• Infarction occurs if ____ arteries inadequately compensate
• Often associated with ____
Dual blood supply to lung: ____ and ____ arteries
* Typically an embolism is going to result in a blockade of a pulmonary artery. All the small subsets of these (embolism) actually are of clinical significance. Most of them are small, they are around the periphery, the patient doesn't even know they have it. In roughly 10% of these, emboli are actually present with clinical symptoms and the infarction occurs. The blockade itself may not be a major problem, unless it involves a large amount of tissue, but this infarct here (right picture: circled in red) is due to a small amount of tissue. * Within the lesion > RBC in alveoli, but infarcted > here, the secondary BS was inadequate to perfuse the tissue
pulmonary 10% bronchial CHF pulmonary bronchial
- ____ necrosis
* Can see ____ outline, but no ____ in pneumocytes, and you have RBC (hemorrhagic, red)
coag
basic
nuclei
Shock:
Systemic ____ of tissue due to profound hemodynamic and metabolic disturbance leading to failure of circulatory system to maintain appropriate ____ and perfuse vital ____
– Cause:
• Reduced ____
• Reduced ____ volume
– Consequences:
• Impaired tissue perfusion and cellular ____
• dysfunction of multiple organs
– Initially ____, prolonged shock leads to ____ tissue injury
– Not simply low bp; although hypotension may also be a ____ sign in shock
hypoperfusion blood supply organs cardiac output circulating hypoxia reversible irreversible late
Common forms of shock • \_\_\_\_shock • \_\_\_\_ shock • \_\_\_\_ shock • Anaphylactic shock • Loss of vascular tone: – \_\_\_\_—secondary to spinal cord injury – Associated with \_\_\_\_
• Shock is also the final pathway for several lethal events: – \_\_\_\_ – Extensive trauma/burns – \_\_\_\_ – Pulmonary embolism – \_\_\_\_
* Anaphylactic - \_\_\_\_-mediated * Exansguination - loss of large amounts of blood * The lethal outcome of myocardial infarction often involves shock
cardiogenic hypovolemic septic neurogenic anesthesia exsanguination myocardial infarcation sepsis
immune
• Cardiogenic shock: – Results from low \_\_\_\_ due to \_\_\_\_ failure: • Myocardial damage: Infarction (MI) • Ventricular \_\_\_\_ • Outflow obstruction: \_\_\_\_ embolism • Extrinsic compression: cardiac \_\_\_\_
• Cardiogenic Shock
◦ A reduction in cardiac output due to many underlying causes:
‣ Infarct
‣ Inflammation
‣ Cardiac Tamponade (pressure on the heart due to fluid build up between the myocardium and the ____)
◦ This decreased cardiac output leads to decreased tissue perfusion, leading to anoxic injury which in turn effects many organs including:
‣ Heart (causing a change to ____)
‣ Renal (leading to further decreased cardiac output, in particular ____)
‣ ____ damage (leading to vascular permeability and altered blood volume, which contributes
further to this cycle)
◦ The decreased cardiac output also contributes to a decrease in blood pressure, resulting (via the renin-
angiotensin-aldosterone system) in ____, further decreases tissue perfusion
cardiac output pump arrhythmia pulmonary tamponade
cardiac lining anaerobic glycolysis metabolic acidosis endothelial cell vasoconstriction
• Hypovolemic shock:
– Results from low ____ output due
to loss of ____ or ____ volume:
• Hemorrhage
• Fluid loss:
– External: ____, excessive urine formation, ____, dehydration
– Internal: increase in ____ permeability (burns, trauma)
Explanation of figure:
External fluid loss, for example hemorrhage, leads to decreased blood volume that results in decreased ____ return, which in turn results in decreased cardiac output, and this results in decreased perfusion of the tissue and anoxic injury to the peripheral organs.
Likewise, internal fluid loss results from exposure to endotoxin, burns, trauma, anaphylaxis, and leads to increased ____ permeability. These results in decreased blood volume, decreased venous return, decreased cardiac output, decreased perfusion, and anoxic cell injury. So they all follow.
cardiac blood plasma diarrhea vomiting microvasculature venous vascular
Hypovolemic shock
It gets more complicated, as the tissue throughout the body becomes anoxic, that leads to ____ damage. Once you are in this cycle, you cannot get out of it.
To make matters worse, as the tissue becomes anoxic (all the tissue b/c total perfusion is disrupted), the patient goes into ____ failure, which results in loss of proteins and altered sodium retention.
This will contribute ultimately to changes in electrolyte balance, thus putting the patient in ____.
Likewise, the anoxia is going to contribute into widespread ____ within muscles, further contributing to metabolic acidosis, and the heart is going to deteriorate resulting in heart failure, and this will in turn feedback all the aforementioned succession of events. This keeps cycling both ways and patient CANNOT get out of this. The patient goes into shock and there is no recovery. So there is a ____ component and a ____ component to it, therefore it becomes a difficult situation to manage.
endothelial
renal
metabolic acidosis
glycolysis
metabolic
vascular
Stages of Shock
• Non-progressive phase (compensatory signs):
– Reflex compensatory mechanisms activated:
• E.g., release of ____, renin-angiotensin-aldosterone and ____ stimulation
– perfusion of vital organs maintained:
• Via ____, peripheral and cutaneous ____, ____ fluid conservation
• Progressive stage
– Tissue hypoperfusion>widespread ____
– circulatory and metabolic imbalances worsen; ____
• Irreversible stage (refractory)
– Severe cellular and tissue injury
– Correction of hemodynamic defects does not ____ situation
– ____ not possible
ADH sympathetic tachycardia vasoconstriction renal
hypoxia
acidosis
improve
survival
• When a patient goes into shock, there are three phases:
◦ 1) Non Progressive Phase (Compensatory Phase)
‣ In this stage, they are able to respond to small changes in mean ____ pressure (drop in 10-15mmHg
of mean arterial pressure).
‣ They respond to this drop in pressure by either increasing ____, or by activating the ____ system in the kidney (increasing blood volume and heart rate and causing vasoconstriction)
‣ So during these early stages, the patient can respond and restore arterial pressure via these reflex ____ mechanisms, maintaining perfusion through the increased HR, vasoconstriction, and renal fluid conservation.
arterial
heart rate
renin angiotensin aldosterone
compensatory
◦ 2) Progressive Phase
‣ This phase is defined by a greater decline in the mean arterial pressure
‣ ____ output is altered, and they have a weak ____ rate
‣ Patient suffers from severe widespread tissue hypoperfusion, leading to hypoxia, which causes tissue damage
‣ The ability to maintain ____ at this point is compromised (metabolic imbalances such as acidosis get worse) and the patients start to exhibit lots of clinical manifestations (____, clammy, cold, rapid respiratory rate with shallow respirations, altered metabolism exhibited by a decrease in core ____, increase thirst, acidosis, low urine output, ____ signs, cardiovascular changes – tachycardia, weak pulse, low cardiac output, low BP)
urinary pulse circulation pale temperature neurological
◦ 3) Irreversible Phase (Refractory Phase)
‣ This phase is ____. The perfusion is terrible, and the anoxic injury has completely set in (even if circulation is re-established with medications/treatment, it is still fatal)
fatal
Septic shock – High (20%) mortality rate • #1 cause of ICU death • Rising incidence: – \_\_\_\_ improvement – increasing numbers of \_\_\_\_ hosts – Increasing prevalence of \_\_\_\_ resistant organisms in hospitals
– Due to systemic response to microbial infection:
• Overwhelming microbial infection (septicemia)
– ____
– Gram–
– ____
– Old term: ____ shock no longer applies
• ____ infection may trigger septic shock
• Overview of pathogenesis:
– Cells associated with innate immunity, endothelial cells and mediators activate complex inflammatory responses
– Tissue ____ due to decreased vascular tone:
• Systemic ____ and blood ____ (arterial and venous)
– Wide spread endothelial activation and injury
– Changes in metabolism that suppress cellular function
– Net effect: multiple organ dysfunction with high morbidity and mortality
◦ This form of shock is due to a systemic response to ____ infection (note that the infection doesn’t have to be ____, only the response to it).
◦ This form of shock used to be called endotoxic shock (they thought it was only due to gram negative organisms, which we now know is not true - ____ organisms and fungal infections can also cause it)
◦ This form of shock starts with an infection (local or systemic), induces an excessive host response (involving the vascular responses we have previously learned about - but they are overwhelming and activate ____ immunity including neutrophils,
macrophages, endothelial cells, inflammatory mediators, complement system, etc). The end result of this response is severe tissue hypoperfusion due to decreased vascular tone (the ____ are taking the brunt of the injury here)
◦ The excessive response leads to cellular damage, initially involving the endothelium and eventually it becomes widespread throughout the body. It will cause metabolic changes at the cellular level, leading to multi organ dysfunction (with high mortality
rate).
◦ Death is often the end result of septic shock (due to vascular damage, loss of vascular tone, organ damage, and loss of organ function)
life support
immunocompromised
multidrug
gram+
fungal
endotoxic
local
hypoperfusion
vasodilation
pooling
local
systemic
gram+
innate
blood vessels
Sepsis continuum
septic shock~severe sepsis
Systemic Inflammatory Response Syndrome (SIRS): Patient presents with ____ or more of the following criteria.
- temperature > ____°C or < ____°C
- heart rate > ____ beats/minute
- respiration > ____/min or PaCO2 < ____mm Hg (low)
- leukocyte count > ____/mm3, < ____/mm3 or > ____% immature (band) cells
• Sepsis is part of a continuum (____ –> SEPSIS –> SEVERE ____ –> ____)
◦ Sirs (Systemic Inflammatory Response Syndrome)
‣ Must exhibit at least two of the following criteria (but will often exhibit more than two)
• Altered leukocyte count (could be ____ which is an increase in WBC count) – (or the WBC count could decrease if the supply is exhausted, in which case the patient will exhibit an increase in ____ cells)
‣ Once an infection is confirmed by the physician, they can be moved to the next stage
◦ Sepsis
◦ Severe Sepsis/Septic Shock
‣ For our purposes, we will think of severe sepsis as equivalent to septic shock
‣ Severe sepsis is when the patient exhibits severe ____, high levels of ____ (due to the glycolytic metabolism), and they are starting to show signs of sustained end organ damage
two 38 36 90 20 32 12,000 4,000 10
SIRS sepsis septic shock leukocytosis band
hypotension
lactic acid
Major factors contributing to pathophysiology of septic shock:
– Inflammatory mediators:
• ____ immune cells activated by microbial components
• Cytokines, PAF, complement, activation of coagulation by microbial components
• Net effect is a ____-inflammatory state
– Endothelial activation/injury:
• ____-induced damage (ROS, cytokines)
• ____-induced activation/damage
• 3 major consequences: ____ permeability, ____, ____ leading to hypercoagulable state (DIC)
– Metabolic abnormalities:
• Septic patients exhibit ____ resistance, hyperglycemia and an array of altered metabolism due to cytokines, hormones (e.g., glucagon and glucocorticoids)
• Impairment of ____ expression
– Organ dysfunction
• Decreased blood delivery (O2 and nutrient deprivation)
• Systemic ____, interstitial edema and small vessel thrombosis
• Mitochondrial dysfunction (____)
• High levels of cytokines
* Infection > inflam response, complement activation > but in compromised patients > exuberant response > neutro's/macro's produced cytokines, ROS, complement, products from microbes > direct or indirect endothelial damage > change in vascular permeabiltiy, vasodilation and thrombosis of microcircualtion (upon thrombi formation, block circulation > infarctitions, but bc there are so many > consume clotting factors > hemorrhage at location of thrombi) * Starts as inflam mediators, but for some reason, rather than protective its in a hyperinflam state > harmful * Endothelial cells damaged and vasculature compromised * GLUT4 - insulin-responsive, grabs \_\_\_\_ from cell surface so cell can metabolize; impairment > related to action of cytokines
innate
hyper
leukocyte microbial vascular vasodilation thrombosis
insulin
GLUT4
hypotension
oxidative stress
glucose
