Myocardial Infarction Flashcards
What is an infarction?
What is a myocardial infarction?
What is the metabolic reason this ocurs?
- Infarction
- the process by which necrosis (cell or tissue death) results from ischemia (loss of blood supply)
- Myocardial Infarction
- infarction of cardiac muscle
- etiology: lack of oxygen and various metabolits due to blockage of blood flow
What is the major causes of myocardial infarction?
- Atherosclerosis is major cause for MI
- Others
- coronary embolism
- congenital coronary anomaly
- coronary trauma
- coronary spasm
- drug use (cocaine)
- other factors (increase oxygen requirement)
- heavy exertion, fever, hyperthyroidism, or strong emotions
The heart utilizes what types of molecules as fuel?
It is is most likely to use what type of molecule in the experience of ischemia?
carbohydrates, amino acids, and fatty acids
During ischemia: high glucose utilization
Myocardial utilization of what types of fuels is concentration dependent?
lactate and fatty acids
Decrease in coronary blood flow increases what process?
What is the purpose of this?
glycolysis
-
Purpose: return the normal contractile function of the heart
- via glucose oxidation & glycogen resynthesis
- translocation of GLUT4 to the plasma membrane in situations of acute ischemia
Why do we see an elevation of free fatty acids in the plasma ater a MI?
- surge of catecholamin activity
- inhibition fo beta oxidation of lipids in mitochondria
- accumulation of intracellular acyl carnitine and acylcoenzyme A
In what situations do we see reduced myocardial uptake of free fatty acids during ischemia?
high glucose concentration
What is the reasoning behing the Glucose, insulin & potassium (GIK) treatment for a MI?
How effective is it?
- If the injury zone of infarction has a low membrane resting polarization, the intracellular potassium is proportionately decreased, if [K] outside the fiber remains constant
- the treatment with GIK forces potassium into the cell, thus restoring the normal resting potential
- Effectiveness
- A reduction of 28% in mortality
- even in patients who had received thrombolytic agents, the in-hospital death rate was reduced by over 60%
What is the concern with administering GIK treatment?
fear of myocardial acidosis as a result of increased lactate production
also, the research wasn’t supported b/c not profitable
What is the effect of increased NO in the infarcted myocardium?
How is the majority of NO produced?
What end-products increase in the blood following MI/coronary artery occlusion?
- Released primarily through inducible form of NO synthase (iNOS)
-
NO + Guanylate cyclase-heme-Fe –> cGMP
- NO binds to the heme group of Guanylate cycyase
- increase in cGMP produces the physiological & pharmacological effects
-
NO + Guanylate cyclase-heme-Fe –> cGMP
- Helps contratcile and metabolic functions of the infarcted heart
- necessary for the growth-promoting effect of vascular endothelial growth factor (VEGF) – important for develping collaterl arteries
- End products
- NO2 (nitrite)
- NO3 (nitrate)
- peroxynitrite & hydroxy-like intermediates
There is an increase in what 3 biological substances within the infarcted myocardium?
NO, prostacyclin, and thromboxane
What is the function of prostacyclin & thromboxane in
- Prostacyclin
- inhibit platelet aggregation
- coronary vasodilation
- prevents ventricular arrhythmias
- decreases infarct size
- Thromboxane
- promotes platelet aggregation
- causes vasoconstriction
- initiates ventricular arrhythmias
- increases infarct size
- increases production of NO and prostacyclin counteracts these effects
What is the relationship between NO and the COX systems?
NO synthase & cyclooxygenase (COX) form prostanoids from arachidonic acid
cross-talk between the systems – production of NO increases production of prostacyclin & thromboxane
How do the NSAIDs, Aspirin & celecoxib, influence NO, prostacyclin & thromboxane?
- acetylsalicylic acid (Aspirin), a COX1 and -2 (75mg/kg/day) inhibitor, reduces both prostaglandin & thromboxane formation
- does not influencemyocardial activity of iNOS
-
celecoxib, a COX2 selective inhibitor lowers myocardial prostacyclin production
- does not alter myocardial production of nitrit & nitrate
What cardiac biomarker levels are assessed for diagnosis of MI?
cardiac troponin
sensitive & accurate
What charcteristics make something a good biomarker?
What do you have to know about biomarkers for them to provide good information?
- indicators of normal & pthological processes
- Provide quantitative measurements
- used alone or in combination
- Information
- plasma concentration
- when it is release with relation to the injury
- How quickly they degrade/decline in cocentration
In addition to enzyme levels, what factors help identify a diagnosis?
- patient age
- sex
- prior history
- possivle drug use
What were the first 3 enzymes used to diagnose MI?
What were the benefits & challenges of using these enzymes?
- Aspartate aminotransferase (AST) & Alanine aminotransferase (ALT)
- appear slowly in plasma
- not specific to heart muscle
-
LDH
- released slowly into plasma
- tetrameric enzyme with two monomer types
- H(heart) and M(muscle) that combine to yield
- 5 LDH isozymes HHHH (I1), HHHM (I2), HHMM (I3), HMMM (I4), MMMM (I5)
- tissue-specific patterns in the expression of H and M genes
- LHD1 high in heart tissue & LDH5 high in liver
- it is possible to separate & detect isozymes by electrophoresis
- H(heart) and M(muscle) that combine to yield
What are the 3 isozymes of cratinine kinase?
CK-MM (skeletal muscle)
CK-BB (brain)
CK-MB (heart and skeletal muscle)
Describe how the levels of CK change with relation to a MI
How are the different isozyme detected?
appear within 4-6 hours of an MI
peaks at 24 hours
returns to baseline by 38-72 hours
detected by eletrophoresis
What is troponin?
At what timepoints following an MI do you see troponin?
Can elevated troponin be caused by anything other than a MI?
- Troponin
- complex of 3 proteins involved in muscle contraction in skeletal and cardiac muscle but not in smooth muscle
- Plasma levels of cardiac troponins I and T are sensitive and specific indicators of damage to heart muscle
- troponin levels rise within 2-6 hours after MI and remain elevated for 4-10 days
- In addition to MI, other heart muscle damage also elevates serum troponin level
What is an inherited cardiomyopathy?
What are the two classes?
-
Inhetited cardiomyopathy
- any structural or functional abnormality of the ventricular myocardium due ot an inherited cause
- Classes
- Cardiac energy metabolism – mutation in genes encoding enzymes/proteins involved in fatty acid oxidation & oxidative phosphorylation
- Mutations in genes encoding proteins involved in or affecting myocardial contraction, such as myosin, tropomyosin, the troponins, & cardiac myosin-binding protein C
- Familial Hypertrophic Cardiomyopathy
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What is Familial Hypertrophic Cardiomyopathy?
What is the mutation?
Clinical presentation?
- FHC
- thickening (hypertrophy) of the heart muscle
- Mutation
- cardiac beta myosin heavy chain gene
- may be a missense mutation or a formation of a hybrid heavy chain
- cardiac beta myosin heavy chain gene
- Clinical presentation
- large variation
- genetic heterogeneity (may have additional mutations in other genes)
- cardiac actin, cardiac troponins I & T, essential and regulatory myosin light chains, cardiac myosin-binding protein C, titin
- if additional mutation is also in betal chain, this may more severly affect the protein
Describe the biochemical basis for the 2 most common mutations associated with Familial Hypertrophic Cardiomyopathy.
- Missense mutation
- head & head-rod regions of myosin heavy chain
- mutatnt polypeptides caue formation of abnormal myofibrils, eventually resulting in compensatory hypertrophy
- Alter the charge of AA side chain
- Arginine is replace with glutamine, which presumably affects the conformation of the proetin more markedly than other substitutions
- significantly shorter life expectancy
Descibe dilated cariomyopathy
What mutations are associated with it?
- Dilated cardiomyopathy
- heart’s ability to pump blood is decreased b/c the LV is enlarged & weakened
- prevents the heart from relaxing & filling with blood as it should
- often starts in the LV and then spreads to the RV adn atria
- Mutations
- dystrophin
- muscle LIM protein (w/ cystein-rich domain detected in Lin-II, Isl-1, Mec-3)
- cyclinc response-element binding protein (CREB)
- desmin
- lamin have been implicated in the causation of this condition
