BMS303 Lecture 5 Cardiac Arrythmias

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  • Created by: Mollie
  • Created on: 17-01-18 01:23
True or false, all cardiac arrhythmias are inherited?
False, they can also be acquired. They include several related syndromes such as LQT and SQT which can overlap
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Cav channels are formed of 24 transmembrane domains including 4 voltage sensors and how many P regions?
4
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Cav channels have a variety of regulatory and accessory subunits such as beta, alpha-2 and gamma, how do they alter the the activity of the alpha subunits?
By altering its sensitivity to voltage and to Ca itself
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L-type Cav channels are regulated by what type of voltages?
High voltages
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What gene codes for Cav 1.2 which is found in the heart brain and lungs?
CACNA1C
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What type of current is formed when Ca ions move into a cell; inwardly negative or outwardly positive?
Inwardly negative currents, the currents are similar to Na and have a positive Nernst potential
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How many alternative splicing loci are there for Cav 1.2 and how many possible variants of the protein can be made?
There are 12 alternative splicing variants and 42 variants can be made as multiple proteins with slightly different sequences of AA's and potentially slightly different properties can be formed
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What is the role of t-tubules close to the sarcoplasmic reticulum in the heart and muscles?
They allow Ca to move
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Cav 1.2 channels can be both voltage and Cav dependently inactivated, hence what are the two possible inactivation processes possible?
1) By potential as a more positive potential drives the channel to close 2) Calcium dependent inactivation, Ca entry via the channels results in negative feedback thus inhibiting the channels, both of these are regulated by beta subunits
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How is a 2:1 atrioventricular block in Timothy Syndrome characterised?
By a mismatch in timing between the atria and ventricles which results in an increased risk of arrhythmias and sudden cardiac death.
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How and why are the ECGs of Timothy Syndrome patients unusual?
Patients show higher QTc value, there are 2 P waves for every 1 QRS as a result of the atria contracting twice thus causing an atria-ventricular block. Due to atria contracting twice repol is delayed sometimes resulting in alternating T waves
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Due to the wide variety of symptoms seen in the gain of function disorder; Timothy Syndrome, it isn't always classed an LQTS. Give 4 phenotypic symptoms or observable areas affected resulting from Timothy Syndrome.
Immune deficiency, Round face, flat nose bridge, small upper jaw, thin upper lip, increased risk of autism, syndactyly, Arrhythmias/LQT
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When pressure is put on the cardiac system of Timothy Syndrome patients causing them to exhibit ventricular tachycardia, what major cardiac event does this increase the risk of?
Ventricular fibrilation
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In a study done on 17 children with Timothy Syndrome, 10 died during the study, 12/17 experienced life threatening arrhythmias. Why did the 7 survivors experience cognitive impairment?
Because Cav 1.2 is also found in the brain and impacts development
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What was concluded to be the cause of Timothy Syndrome upon finding it was common in 13 of the 17 patients seen but not in controls?
A new splice position seen at position G406R which is at the end of the first 6 TMDs which results in some but not all Cav 1.2 channels changing a highly conserved Glycine to Arginine
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What is different in the cardiac action potentials of patients with Timothy Syndrome compared to normal activation that result in an increased cardiac action potential plateau phase and QT interval?
Splice variants for Timothy Syndrome show activation similar to WT however inaction is slower and less efficient as there is less inactivation over the same period as a result Ca channels doesn't close as quickly as they should
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Why is there a pick up in inactivation of G406R Cav 1.2 splice variants at more positive potentials?
As a result of calcium dependent inactivation which is very pronounced in this splice variant
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What was concluded about the splice variant G406R following substituting Ca2+ for Ba2+ which eliminated calcium dependent inactivation?
That the splice variant has almost completely lost voltage dependent inactivation as there was some inactivation in the WT with Ba which would have been voltage dependent
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True or false, carriers of the G406R splice variant have normal calcium inactivation in all Ca 1.2 channels?
False, carriers will have a subpopulation of Ca1.2 channels which are not inactivating as they should and will this have some prolonged plateau phases and delayed QT intervals
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Heterozygous splice carriers are predicted to have a 17% longer cardiac action potential and while the model produced showed a small impact to Ca2+ currents there is a potential rise in associated heart conditions. What % of Ca1.2 are may be variant?
11%
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How many types of Brugada Syndrome are know of?
5, Brugada Syndrome is Short QT syndrome
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Give 2 examples of Brugada Syndrome and the channels they effect and how.
SQTS1-KCNH2-gain of function Ikr, SQTS2-KCNQ1-gain of function Iks, SQTS-CACNA1C alpha subunit-loss of function Ica
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What are the symptoms of Brugada Syndrome?
Short QT interval Males:
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Give an example of a mutation in CACNA1C channels is associated with Brugada Syndrome?
G490R which is between the first loop between 6+1, glycine to arginine at position 490. A39V is an N-terminal mutation substituting alanine to valine
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Cav currents recorded in the A39V CANAC1C mutants are about 25% smaller than WT currents, how does the G490R mutation affect currents?
They only allow tiny Ca currents through so the currents through the specific Ca channel is very slow. The reduced Ca results in earlier repolarisation
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Brugada Syndrome is likely to be due to mutant impact gating rather than trafficking; G490R and S481L(beta subunit) Cav1.2 mutants show similar expression to WT. What other mutant may impact for trafficking?
A39V could impact trafficking and account for the loss of current
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Card 2

Front

Cav channels are formed of 24 transmembrane domains including 4 voltage sensors and how many P regions?

Back

4

Card 3

Front

Cav channels have a variety of regulatory and accessory subunits such as beta, alpha-2 and gamma, how do they alter the the activity of the alpha subunits?

Back

Preview of the front of card 3

Card 4

Front

L-type Cav channels are regulated by what type of voltages?

Back

Preview of the front of card 4

Card 5

Front

What gene codes for Cav 1.2 which is found in the heart brain and lungs?

Back

Preview of the front of card 5
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