Cardiotoxicology Flashcards
what is direct cardiovascular toxicity
direct effects on the myocardium
what is indirect cardiovascular toxicity
indirect effects through vasculature
what is the pathophysiology of non reversible damage
cell loss (necrosis, apoptosis)
what is the diagnosis of non reversible damage (3)
injury marker release, progressive contractile dysfunction, cardiac remodelling
what is the diagnosis of reversible damage (3)
no injury marker release, reversible contractile dysfunction, reversible arterial hypertension
what is the pathophysiology of reversible damage
cellular dysfunction
what is the manifestation of non reversible cardiovascular toxicity (3)
cardiomyopathy, MI, thrombosis
what is the manifestation of reversible cardiovascular toxicity (3)
temporary contractile dysfunction, vasoplastic angina, arterial hypertension
what happens to electricity of heart in cardiotoxicity
cardiac conduction and dysrhythmias - abnormalities in repolarization
what happens to ventricles of heart in cardiotoxicity
systolic/diastolic dysfunction - reduction in ventricular ejection
what happens to structure of heart in cardiotoxicity (2)
cardiac structural remodeling, fibrosis
what happens to function of heart in cardiotoxicity (2)
cardiomyopathies, heart failure
what happens to vasculature of body in cardiotoxicity
systemic and pulmonary vascular dysfunction and altered hemodynamics
what happens to blood of body in cardiotoxicity
hemostasis and thrombosis
what are the primary contractile cells
cardiomyocyte
what are cardiomyocytes
the primary contractile cells
can cardiomyocytes be replaced
no
what are the 4 main cells of the heart
cardiomyocytes, endothelial cells, epicardial cells, fibroblasts
which cell type is promoted with injury
fibroblasts
what are 3 ways to tell if you have cardiotoxicity
- changes in myocardial strain and biomarkers
- assessment of cardiac function
- determination of coronary blood flow reserve, stroke work, VO2 max
what is the most useful tool/machine to diagnose cardiac injury
echocardiography
why is echocardiography the best
safe, availability, reliability and low cost
what are 5 ways to diagnose cardiac injury (5)
MRI, ECG, echocardiography, SPECT, ultrasound
what are 4 markers of cardiac injury
CK-MB: creatine kinase
TnT or I-troponin
LDH (lactate dehydrogenase)
BNP B-type natriuretic peptide
when is CK-MB: creatine kinase released
lysis of cell
what does BNP B-type natriuretic peptide release cause
release water from water from body, vasodilation
which markers are more specific to the heart
TnT or I-troponin
and BNP B-type natriuretic peptide
which markers are less specific to the heart
CK-MB: creatine kinase
LDH (lactate dehydrogenase)
what is the most common way to test for ejection fraction
echocardiogram
what are 3 ways to test for ejection fraction
echocardiogram, MRI, nuclear medicine scan
what is left ventricular ejection fraction
the measure of % blood is being ejected from the left ventricle (% of blood leaving heart each time it contracts)
what are 6 examples of changes to vital signs that can happen in toxic syndromes
BP HR RR temp pupils skin (wet dry)
what can cause bradycardia (what are 7 places that are affected)
affects on the CNS or PNS, pacemaker cells or conduction system, changes to sympathetic outflow, enhanced vagal tone, altered Ca++ handling
what is the most common type of tachycardia
sinus
what does atropine do to HR
rise HR without inhibitory effect of vagal influence
what are direct effects that cause tachycardia
beta-adrenergic agonism
what are indirect effects that cause tachycardia
response to hypotension, hypoxia
what is an important channel for cardiotoxic events
hERG
what does the hERG gene do
encodes pore forming usbunit of the rapidly activating delayed rectifier cardiac K+ channel
what kind of channel does the hERG code for
voltage gated potassium channel
what is the role of the voltage gated potassium channel
contributes to repolarization of cardiac action potential
what is the common cause of withdrawal or restriction of drugs with the hERG
prolongation of the QT interval
what is the major effect of drugs that interact with this channel
blocks the channel so there is a loss of function
what is torsades de pointes + what causes it
lethal arrhythmia, often caused by drugs that block the hERG K+ channel
besides long QT, what can blocking of the hERG K+ channel lead to
early after depolarization
what are the 3 main mechanisms that xenobiotics cause hypertension
- CNS sympathetic over activity
- increased myocardial contractility
- increased peripheral resistance
what are the 4 main mechanisms that xenobiotics cause hypotension
- decreased peripheral resistance
- decreased myocardial contractility
- depletion of intravascular volume
- dysrhythmias
what are 3 general things that xenobiotic impact on cardiac contractility can result in changes to
- ejection fraction
- cardiac output
- blood pressure
what is afterload
the force that you have to push against in the arterial system
what is preload
the amount you have before pump, volume
do we often know the mechanisms of toxicity
no, often multiple factors
is ventricular or atrial fibrillation worse
ventricular
why can opioid receptor stimulation affect the heart
because OPR stimulation can inhibit B1 and B2 adrenergic receptor activity in cardiomyocytes
what are the physical effects of OPR stimulation on heart physiology
restrict inotropic and chronotropic effects, interfering with excitation-contraction coupling
what is infarction
dead tissue
what is ischemia
low oxygen or low blood flow
what are 2 main things that cocaine do to oxygen
increase demand decrease supply
how does cocaine decrease oxygen supply
by increasing thrombosis and vasoconstriction
how does cocaine increase oxygen demand
increasing HR BP contractility
what are the 2 major pathways that cocaine affects CVS
sympathetic output and local anesthetic effect
what can cocaine do to fat
it can accelerate atherosclerosis
what are 3 things that consequences of cannabis toxicity may stem from
- inhalation of combustion products
- direct THC effects
- indirect THC effects (acute anxiety, hallucinations, psychosis)
what are CB 1 receptors most associated with
adverse effects
what are CB 2 receptors most associated with
beneficial effects, anti inflammation
what is bad about lots of chemo agents
they have cardio toxic effects
what is doxorubicin
quinone containing anthracycline antibiotic
which is one of the most effective and commonly used anti cancer drugs
doxorubicin
what is a bad thing about doxorubicin
associated with increased risk of cardiomyopathy or congestive heart failure
what is the mechanism of doxorubicin anti tumor properties
inhibits topoisomerase and DNA synthesis
what can happen to HR with doxorubicin
tachycardia
what can happen to T wave with doxorubicin
flat
what can happen to voltage with doxorubicin
decrease
what can happen to myofibrils with doxorubicin
loss
what can happen to cytoplasm with doxorubicin
vacuolization
what can happen to mitochondria with doxorubicin
damage
what are 3 main things that COX makes
PGE2
PGI2
TXA2
what does PGE2 do
inflammatory response
what does PGI2 do
inhibits platelet adhesion, vasodilator
what does TXA2 do
vasoconstrictor, inflammatory response
how did COXIB cause thrombosis
promotes thrombosis by inhibiting COX-2 derived PGi2
how did COXIB cause platelet aggregation
inhibit COX2 block suppression of thrombin - augment platelet activation
overall, what does inhibition of COX-2 derived metabolites cause
augment response to thrombotic and hypertensive stimuli
which COX does COXIB inhibit
only COX 2
what is the effect of only inhibiting COX-2 with COXIB
TXA2 effects are exaggerated (Vascular tone, reduced cardioprotection)
what does COXIB do gradually
constant inhibition of neutrophils and platelets, promotes initiation and early progression of atherosclerosis
what is the 1 major problem with linking cause and effect
there is no ethical way to get human volunteers
what are 4 problems with using human volunteers (besides ethics)
- effect may not occur at the time of exposure
- variability in response (age gender health)
- complications of combined effects (like many drugs they may be taking)
- detailed toxicological information may not be available
what do outcomes depend on
reversibility of injury
what is our understanding of mechanisms like
limited but rapidly increasing
what is the hard thing to balance
cardioprotective response and adverse effect
what will comprehensive understanding of cardiotoxicity do
enhance therapy
what direction of K+ transport does the hERG channel move it
outside of the cell (repolarization, make more -ve)
