trigger 3 - hypertrophic cardiomyopathy Flashcards
bundles of what make up cardiac myocytes
myofibrils
sarcomeres
repeating units making up myofilaments
region between two Z-lines
composed of thick and thin filaments
myosin ATPase
enzyme that hydrolyses ATP required for actin and myosin cross-bridge formation
3 proteins that make up thin filaments
actin
tropomyosin
troponin
troponin complex
attached to tropomyosin
contains troponin C - binding site for calcium
when calcium binds to troponin C…
conformational change in troponin complex
myosin head exposed
length-dependent activation
stretching the sarcomere increases the affinity of Troponin-C (TNC) for Ca2+
types of cardiac action potential
non-pacemaker A.P. - fast response
pacemaker A.P. - slow response
where are pacemaker action potentials found
sinoatrial node
atrioventricuar node
compare length of duration of between neural/skeletal APs and cardiac APs
neural = 1 ms skeletal = 2-5 ms
cardiac = 200-400 ms
compare role of Calcium in depolarization of neural/skeletal APs to cardiac APs
depolarisation of:
neural/skeletal: - caused by opening of Na+ channels
non-pacemaker cardiac: - caused by opening of Na channels, Ca influx prolongs duration of AP causing plateau phase
pacemaker cardiac: - Ca2+ involved in initial depolarisation
3 examples of non-pacemaker action potentials in the heart
purkinje cells
atrial myocytes
ventricular myocytes
phase 4
non-pacemaker AP
resting membrane potential = -90mV
K+ channels are open - K+ leaves cell making it more negative inside
both fast Na channels and slow L-type Na channels are closed
phase 0
non-pacemaker AP
rapid depolarisation (by AP in adjacent cell) -70mV Na+ influx through fast Na+ channels K+ channels close membrane potential gets more positive
phase 1
non-pacemaker AP
(small rapid dip after peak on graph)
initial re-polarisation
opening of special/transient K+ channels
short-lived outward K+ hyperpolarisation
however, Ca influx through slow channels delays this repolarisation
phase 2
non-pacemaker
plateau phase
Ca2+ influx through long-lasting L-type channels
open when membrane depolarises to -40mV
phase 3
non-pacemaker
repolarisation
K+ efflux
Ca2+ channels inactivation
maintenance of resting membrane potential in cardiac
K+ channels open - K+ leaves cell making it more -ve
Na+ and Ca2+ channels closed, cannot enter cell
-90mV
antiarrythmic drugs
alter fast-response action potentials
alter (ERP) - effective refractory period
block specific ion channels
effective refractory period (ERP)
stimulation of cell cannot initiate action potential
during phases 0, 1, 2, 3, and early 4
fast Na channels close and stay inactivated after phase 1
protects the heart by preventing multiple APs
at a high HR, the rate would be unable to properly fill and ventricular ejection would reduce
non-pacemaker cells to pacemaker cells
they can transform under certain conditions
e.g. hypoxia, membrane depolarisation, fast Na channels close
Ca2+ still influxing - same as pacemaker
no true resting membrane potential
pacemaker action potentials
why is depolarisation slow in pacemaker cells
no fast Na+ channels
depolarisation current carried by slow Ca2+ influx
3 phases of SA node action potentials
0, 3, 4
phase 4
pacemaker
spontaneous depolarisation
triggers action potential once threshold potential is reached (-30/-40mV)
phase 0
pacemaker
depolarisation phase
incline on graph
phase 3
pacemaker
repolarisation
(decline on graph)
complete repolarisation = around -60mV
phase 3 to phase 4
pacemaker
when -60mV (repolarisation) has been reached
slow Na+ channels open creating ‘funny current’ and Na+ influx
cause membrane to spontaneously depolarise and initiate phase 4
T-type (transient) Ca2+ channel
pacemaker
opens when membrane potential reaches -50mV during depolariation
influx of Ca2+ causes more depolarisation of membrane to -40mV
causes L-Type Ca2+ channels to open
more Ca2+ influx causes membrane to reach threshold potential (-30/-40mV)
what kind of state is necessary for pacemaker cells to become activated
hyperpolarised
-ve voltage needed at end of phase 3
cause of phase 0 depolarisation
pacemaker
mainly by increased conductance of Ca2+ through L-type Ca2+ channels that open near the end of phase 4
what happens to ‘funny’ and T-type Ca2+ channels near the end of phase 4 (initial depolarisation of pacemaker)
funny currents decline - Na channels close
Ca2+ currents through T-type channels decline - channels close
penetrance
probability that a person carrying a disease-associated genotype will develop the disease within a given time period
penetrance calculation
number of individuals displaying symptoms, divided by the number of individuals with a disease causing mutation x 100
incomplete penetrance
when thenumber of individuals who display clinical features of the condition is less than those who carry the mutation.
complete penetrance
if a person carrying a disease-associated genotype always develops the conditon
expressivity
measures the extent to which a given genotype is expressed at the phenotypic level
physical symptoms of cardiomyopathy
fatigue dizzyness - reduced O2 to the brain breathlessness - fluid build up around lungs chest pains - reduced O2 to the heart unusual heart beat - palpatations
hypertrophic cardiomyopathy
ventricle walls become thicker (mainly left and septum)
muscle cells are in disarray - disorganised
stiffness make it harder to relax and fill with blood and contract and pump blood out
HOCM
hypertrophic obstructive cardiomyopathy
if the thickening of the heart muscle obstructs blood flow out of the heart
causes of HCM
single genetic mutation
inheritance pattern of HCM
autosomal dominant
mutated gene is found on a non-sex chromosome
beta-blockers and HCM
can prevent arrhythmias
reduce symptoms of obstruction
ICD
Implantable Cardioverter Defibrillator
detect and correct any dangerous arrhythmias
- could cause cardiac arrest
ARVC - Arrhythmogenic Right Ventricular Cardiomyopathy
disorder of the myocardium (heart muscle wall)
parts of myocardium break down over time - increase risk of abnormal heart beat
proteins that make up desmosomes affected
autosomal dominant with variable penetrance
the child of an affected parent will have 50% chance of inheriting the abnormal gene, but will not then necessarily go on to have the condition
MRI
magnetic resonance imaging
why may MRI need to be used instead of ECG for diagnosis of ARVC
signs on an echocardiogram can be very subtle in the early stages of the condition
ablation
if medication doesnt seem to work, the part of the heart causing palpations is targeted and cauterised using wires passing through the heart
mechanism to prevent sudden cardiac death
implantable cardiac defribrillator (ICD)
describe the contractions of vascular smooth muscle (VSM)
slow, sustained and tonic (maintained for a few mins)
describe cardiac muscle contractions
rapid and short duration
MLCK
myosin light chain kinase
enzyme that phosphorylates myosin light chains in the presence of ATP (leads to cross-bridge formation between myosin heads and actin)
noradrenaline from sympathetic nerve binds to which receptors in the heart?
beta-1 and beta-2
acetylcholine from parasympathetic nerve binds to which receptor type in the hearT?
M2
P wave on ECG (first small hump)
atrial depolarisation
trigger for heart contraction
QRS complex
ventricle depolarisation
bradychardia
slow HR
why is efficiency so important in economic evaluation (why are health heed and effectiveness not enough?)
scarcity of resources
3 main types of economic evaluation
- cost-effective analysis (CEA)
- Cost-utiltiy analysis (CUA)
- Cost-benefit analysis (CBA)
cost-effective analysis
effectiveness measured in natural units
e.g. £ per case detected
cost-utility analysis
effectiveness measured in preference-based units
£ per Quality-Adjusted Life-Year (QALY)
cost benefit analysis
effectiveness also measured and valued in £
net benefit in £
QALY
quality adjusted life year
measure of diseased burden on quality and quantity of life
morbidity
quality of life
what should you state to make a good economic evaluation
the perspective of the analysis
e.g. patient, patient’s family, primary care, health system,
society
sensitivity analysis
to see if the results are sensitive to different assumptions
vary input variables or assumptions
why might false-positives occur?
sample contamination
advantage of direct detection methods
good for multicoloured labelling
- less prone to non-specific background labelling
fewer steps
limitation of direct detection
lower sensitivity
requires primary antibody to be specifically labelled
advantage of indirect detection
higher sensitivity
more versatile
immunoglobulin
antibody e.g. IgG
antigens
proteins or polysacchardies within or on the surface of cells
what makes immunnohistochemistry so precise
antibodies bind specifically to the antigen that triggered the antibody’s pr
direct detection method
antibody attached directly to indicator molecule e.g. fluorescent molecules or HRP enzyme
excess added washed away
substrate added to localise reaction
indirect method
primary antibody added first e.g. IgG - binds to and recognises antigen of interest
excess antibody washes away
a linking antibody added to mixture - recognises the primary antibody - retains one antigen binding site
substrate added to localise reaction
why is PCR important in diagnosis
early stages of processing DNA for sequencing
do detecting the presence or absence of a gene to help identify pathogens during infection
3 steps of PCR
- denaturing - break H-bonds in double-helix
- annealing - lower the temp to enable primers to attach by H-bonds to template DNA
- extension - raise temp and new DNA is made- taq DNA polymerase enzyme
why is electrophoresis used after PCR
to check the quantity and size of DNA fragments produced
Taq DNA polymerase enzyme
adds DNA bases to the template strand in 5’ to 3’ direction
taken from thermophilic bacteria - thermus aquaticus
stable at high tempertures
optimum temp = 72
5 steps of traditional cloning methods
- vector preparation
- insert preparation
- ligation
- transformation
- colony screening
vector preparation
restriction enzymes digested by vector (plasmid)
dephosphorylation of vector prevents self-ligation
‘sticky ends’ - more compatible
purification of desired fragments recommended for successful ligation
insert preparation
restriction digestion
blunt end creation
purification
