Module 1 Studies

Question 1

CICR - graded response (2)

Answer 1

• Stern, 1992: Local control model
• Cheng, 1993: Graded release is a result of stochastic opening of RyR channels which is reflected as Ca2+ sparks. Local SR depletion - rat heart experiments have shown long lasting Ca sparks can be generated that do not decline with time

Question 2

L-R Axis (3)

Answer 2

• Levin M, 1995 (diagram with Pitx2)
• Ocana, 2017: Prxx1a found in zebrafish
• Wang, 2010: Pitx2 represses left SAN development

Question 3

Tbx (1)

Answer 3

• Hoogars et al, 2007: Ectopic expression of Tbx3 in mice – imposes pacemaker phenotype in atria -> ectopic pacemakers

Question 4

SAN - Sympathetic response (2)

Answer 4

• DiFrancesco: voltage clamp experiments looking at how adrenaline accelerates the heart
• Froese et al 2012: stress induced bradycardia and loss of dynamic adjustment of HR to physiological demand in POPDC2 mutants mice

Question 5

Roles of repolarising currents in the ventricular myocyte (3)

Answer 5

• Hodgkin & Huxley: early inward, late outward, inactivation, activation, channel gating - linking structure, function and regulation of channels
• Armstrong’s experiments - TEA derivates blocking K channel activation at selectivity filter
• Aldrich and colleagues: K ball and chain

Question 6

VT: anti-arrhythmics (1)

Answer 6

• CAST trial: antiarrhythmic drugs to treat PVC following acute MI actually increase mortality (flecainide)

Question 7

VT: ICD trials (4)

Answer 7

• AVID (anti-arrhythmics vs ICD), in VF, VT w/syncope, VT with LVEF <40% patients – improved survival in ICD group
• CASH trial – ICD improved survival, benefit most marked with low EF (<35%)
• MADIT 1 and MADIT 2 (primary prevention) – mortality reduction of 50% and 40% respectively compared to control groups (AAD)

Question 8

VT: ICD trials, caveats (2)

Answer 8

• CABG-Patch (primary prevention for arrhythmias following CABG surgery) – no clear benefit compared to control group
• DANISH study – at a longer follow up (8 years) ICD event rates overlapped with control group

Question 9

Atrial tachycardia (2)

Answer 9

Mayer, 1906 – unidirectional block causing circuits in jellyfish tissue

• Linton et al, 2013: new entrainment criteria
• Can be applied to any pair of stationary catheters, after two different overdrive manoeuvres
• Does not require the catheters to be close to the circuit
• Simple to elicit by pacing from well separated locations
• Can also detect double loop reentry

Question 10

AF: Causes (3)

Answer 10

• Abed et al, 2013: Sheep fed high fat diets - increased epicardial fat and BMI associated with increased risk of AF – fat also seen to slow conduction
• Van der Velden, 2000: found gap junctional remodelling and altered localisation of gap junctions when exposed to high atrial rates (burst pacing) in goat model -> atrial fibrillation
• Iwasaki et al, 2014 – chronic OSA in rat model
  Altered Cx43 distribution and expression with OSA

Question 11

AF: Pharmacological treatments (2)

Answer 11

• 2016 ESC Guidelines for rate control: LVEF <40% - BB, amiodarone is option, then add digoxin. AVOID CCBs. LVEF >40% - BB or verapamil, then add digoxin
• AFFIRM study seems to suggest rate control is preferred over rhythm, but limitation of the study was it used anti-arrhythmics with bad side effects

Question 12

AF: Ablation (2)

Answer 12

• Pappone et al, 2000: First described circumferential pulmonary vein ostia ablation with good success (safe and effective)
• APAF Study – circumferential pulmonary vein ablation in patients with paroxysmal AF is better at reducing atrial tachyarrhythmia (AT) rates than anti-arrhythmic drugs (93% vs 35% AT free at 1 year). What are the limitations?

Question 13

AF: Anticoagulation (2)

Answer 13

• ARISTOTLE trial (Apixaban vs Warfarin in AF patients) – apixaban superior in preventing stroke/embolism, less bleeding and lower mortality
• RE-LY trial (Dabigatran vs Warfarin in AF patients) – Dabigatran at 150mg associated with lower rates of stroke but similar rates of haemorrhage