C2. Ventricular arrhythmias/ SCD- full Flashcards
(30 cards)
Headings pneumonic
IVICOT
Headings (list)
Introduction
Ventricular arrhythmias
Inherited arrhythmia syndromes
CPVT and heart failure
Other conditions
Treatment
Introduction subheadings (list)
Definition
Arrhythmias, VT and VF
ESC recommendations (2019)
Treatment
(Intro) Definition
● SCD accounts for approx 50% of all CV deaths
● Widely adopted WHO definition = sudden unexpected death either within 1h of
the onset of symptoms (witnessed) or within 24h of having been observed alive
(unwitnessed)
● Majority of SCD attributable to VF/VT causing mechanical pump failure ->
circulatory arrest
● But small proportion attributable to bradyarrhythmias
(Intro) Arrhythmias, VT and VF
● Arrhythmias = variations from sinus rhythm that are not physiological. VAs include:
● VT = 3 or more consecutive beats with rate >100 bpm, can deteriorate into…
● VF = asynchronous rhythm with undulations that are irregular in timing and morphology, fatal within mins if untreated
● Both can cause cardiac arrest
(Intro) ESC recommendations (2019)
● European Society of Cardiology recommendations (2019) for medical
management of VA to prevent SCD
● Acute management = treat reversible causes of VA (electrolyte imbalance,
drug-induced, ischaemia, thrombosis) & cardioversion
● Long-term management = optimal treatment of underlying cardiac disease &
anti-arrhythmic drugs (NB: ONLY BB have shown reduction in all-cause mortality)
(Intro) Treatment
● Gold standard for prevention of SCD in pts with VA/high risk = implantable
cardioverter-defibrillator (ICD), which detects and terminates arrhythmias
● But in pts with recurrent VT episodes, multiple ICD shocks are painful/cause
psych distress, reducing quality of life
● Effective primary/secondary prevention of arrhythmias is much more desirable
● Broad-brush approach to VA prevention is likely to be neither effective nor efficien
● In about 25% SCD patients, death is the first presentation of cardiac disease -
better identification of at-risk pts required
Ventricular arrhythmias subheadings (list)
Epidemiology
Triggers - EADs and DADs
Transient inward current and EADs/ DADs
Fowler 2020 and NCX exchange
Bögelholz 2016 and NCX mediated calcium extrusion
(VAs) Epidemiology
● Western world, CAD is responsible for 75-80% SCD cases (can be thought of as SCD secondary to MI)
● But in the young, SCD associated with 1) primary electrical disease 2) cardiomyopathies 3) coronary anomalies 4) myocarditis
● Pathologies converge on induction of VAs to cause SCD
● Ventricular arrhythmias arise from abnormal impulse generation or abnormal conduction, persistent VA requires both triggered activity AND substrate in heart to maintain ectopic beat propagation
● Most pathological arrhythmias induced by DAD (spontaneous diastolic Ca release -> activates INCX -> depolarisation to threshold) ● Figure 1
(VAs) Triggers - EADs and DADs
● Most pathological arrhythmias induced by DAD (spontaneous diastolic Ca release -> activates INCX -> depolarisation to threshold)
● Mechanisms of EAD/DAD. When amplitude of AD is sufficient to reach threshold, spontaneous AP fires in non-pacemaking tissue = extrasystole
● How does SNS cause triggered activity? Via DADs
● cAMP -> PKA -> enhances ICaL (phosphorylates LTCC), enhances SR Ca uptake (phospholamban) and Ca release (RyR), shortens APD (IKr, IKs)v
● Figure 2
(VAs) Transient inward current and EADs/ DADs
● Some of the first evidence that intracellular calcium transients such as those described were capable of causing arrhythmias, came prior to our knowledge of calcium sparks themselves.
● Early researchers noted the occurrence of transient inward current in response to arrhytmogenic stimuli.
● The transient inward current described is capable of either augmenting early afterdepolarisations (EADs) or generating de novo delayed afterdepolarisations (DADs).
● EADs are produced due to the interaction between calcium currents and repolarising potassium currents.
● Both the EADs and DADs are sufficient to precipitate further aberrant electrical activity and arrhythmias.
(VAs) Fowler 2020 and NCX exchange
● Fowler et al in 2020, where they used myocytes isolated from rabbit models of heart failure with reduced ejection.
● The heart failure myocytes had increased occurrence of these late calcium events.
● Current clamp recordings showed that there was a prolongation of the cardiac action potential relative to control rabbits.
● Whilst these results would appear to show that late calcium sparks during the cardiac action potential contribute to EADs, it is important to note that the coronary ligation model used in the rabbits is not representative of the broad spectrum of clinical heart failure.
● Spontaneous Ca2+ release from the SR elevates intracellular Ca2+ concentration which can activate Na+-Ca2+ exchange.
● The activation of Na+-Ca2+ exchange can cause afterdepolarisations, due to the electrogenic nature of the protein, if this occurs in late systole this can result in EADs.
(VAs) Bögelholz 2016 and NCX mediated calcium extrusion
● The potential for NCX to initiate these DADs relevant to arrhythmias was described by Bögelholz et al in 2016 who artificially over-expressed the NCX protein in mice and subjected the atrial cardiomyocytes to atrial pacing designed to induce fibrillation.
● Patch clamp experiments in the current clamp mode showed no significant increase in DADs.
● However, the number of spontaneous action potentials triggered by DADs was increased nearly 20-fold compared to wild-type mice.
● Whilst these results show that NCX mediated calcium extrusion may be sufficient to cause arrhythmogenesis, it is important to note that the model of overexpression is unlikely to represent normal physiology.
● Further experiments could test whether cardiospecific knockouts of NCX in atrial myocytes prevented any DADs.
Inherited arrhythmia syndromes subheadings (list)
Table 1
Sanguinetti 1996 and long QT syndrome
Kyndt 2001 and Brugada Syndrome
(Inherited) Table 1- syndromes, pattern of inheritance, and gene
Long QT syndrome, Autosomal dominant, KCNQ1, KCNH2, SCN5A
Brugada syndrome, Autosomal dominant, SCN5A
Catecholaminergic polymorphic ventricular tachycardia, Autosomal dominant/ recessive, RYR2/ CASQ2
(Inherited) Sanguinetti 1996 and long QT syndrome
● Sanguinetti et al in 1996 built on work that had previously identified KvLQT1 as the ion channel mutated in LQT1.
● This channel is now known as KCNQ1.
● The authors transfected Chinese hamster ovary cells with cDNA for the channel, and showed the unique Iks-like properties of the channel under voltage clamp conditions.
● The authors then co-transfected the minK cDNA, and showed that coasembly of these proteins was sufficient to replicate the Iks channel properties, whereby depolarising stimuli were followed by a brief delay then a repolarising outward potassium current.
● It would have been interesting for the authors to perform site-directed mutagenesis to visualise whether mutations in this gene were sufficient to reduce the repolarising current.
(Inherited) Kyndt 2001 and Brugada Syndrome
● Kyndt et al studied the implications of mutations on the current flow through these channels in 2001.
● The authors first identified a family of patients with Brugada syndrome, and performed exome sequencing of the SCN5A gene, before identifying a novel G1406R mutation in the gene.
● The authors then cloned the wild-type and mutant SCN5A genes before transfecting them in COS-7 cells.
● This enabled whole-cell patch clamping of the cells, in response to depolarising steps.
● The authors observed significantly reduced current through the SCN5A channels, demonstrating the loss of function.
● If this experiment were to be repeated, it would be more sensible to make hiPSCs from the skin of these Brugada syndrome patients, and measure whole cell currents under these situations.
CPVT and heart failure subheadings (list)
Mutations to RYRs apparatus including calsequestrin and triadin
Jiang 2004
RyR2 mutations and flecainide
Hilliard 2010 and flecainide
Shan 2010 and ryanodine receptor in chronic heart failure
(CPVT and HF) Mutations to RYRs apparatus including calsequestrin and triadin
● CPTV is an inherited condition that causes cardiac arrhythmias.
● The disease is caused by a variety of different mutations in the ryanodine receptor apparatus, including calsequestrin and triadin.
● However, the most common mutation that causes CPVT1 is to the RyR2 channel itself.
(CPVT and HF) Jiang 2004
● Jiang et al in 2004 showed that these RyR2 mutations were gain of function.
● The authors transfected either wild-type or CPVT-mutant RyR2s into HEK293 cell lines and loaded them with fluo3-AM.
● Under confocal line-scan microscopy, the occurrence of Ca2+ sparks was significantly higher in HEK cells transfected with CPVT-mutant RyR2 channels.
● However, the use of the embryonic kidney line raises questions as to the validity of these results in myocytes.
● Nonetheless, these findings have been supported by more recent studies in isolated ventricular myocytes from both humans and mouse models.
(CPVT and HF) RyR2 mutations and flecainide
● RyR2 mutations can increase the sensitivity of the ryanodine receptor to calcium concentrations on the cytosolic side of the SR membrane.
● The unifying feature of CPVT mutations is that their deleterious effects are only present upon sympathetic nervous system activation, often during exercise, and resulting in sudden cardiac death.
● One of the most promising new drugs in the treatment of CPVT is the class 1c anti-dysrhythmic, flecainide.
● Several clinical trials have shown that combination therapy of flecainide with beta blockers is effective at reducing the recurrence of tachycardias, particularly during exercise.
(CPVT and HF) Hilliard 2010 and flecainide
● The mechanism of action for flecainide was initially controversial, given that the drug is traditionally thought to blockade voltage gated sodium channels.
● However, Hilliard et al in 2010 identified another potential mechanism of action by comparing Wistar rats with Casq2-/- models of CPVT.
● Flecainide reduced the amplitude and intensity of the calcium sparks in the CPVT model.
● This was sufficient to prevent arrhythmogenic calcium waves. ● These findings were supported by Kryshtal et al in 2021 who used a similar experimental design in the presence of the voltage-gated sodium channel (VGSC) blocker tetrodotoxin (TTX).
● Flecainide administration had the same effect on calcium sparks in the presence or absence of TTX.
● Furthermore, using a modified version of flecainide (NM-FL) that was unable to block RyR2 channels did not improve symptoms in the CPVT mice model.
● These results together suggest that RyR2 blockade and inhibition of Ca2+ is the primary mechanism of action for flecainide.
● However, this must be treated with caution given that the two studies described, used only one mouse model of one of the many mutations capable of causing CPVT.
(CPVT and HF) Shan 2010 and ryanodine receptor in chronic heart failure
● The ryanodine receptor is not just affected by genetic aberrations in CPVT, instead there can be modulation by intracellular kinases.
● This can occur particularly in prolonged conditions such as chronic heart failure.
● Shan et al in 2010 used a mice model of a constitutively hyperphosphorylated RyR2.
● The authors developed a RyR2 S2808D knockin mice model.
● The authors found that mimicking chronic PKA phosphorylation with isoproterenol caused cardiomyopathy with significantly reduced ejection fraction in the knockin mice.
● When these channels were isolated and recorded in the presence of 150nM calcium, the single channel patch clamp recordings in lipid bilayers showed that these channels had a greater open probability.
● After myocardial infarction, these mice were more pre-disposed to ventricular tachycardia and death following the LAD ligation model of MI.
● Together, these findings demonstrate that the chronic hyperphosphorylation of RyR2 in heart failure predisposes to the development of arrhythmia due to increased open probability of the RyR2 channel.
● It would have been interesting for the authors to study calcium transients with calcium dyes in myocytes isolated from the canine models, to determine the frequency of arrhythmogenic events.
Other conditions subheadings (list)
Hypertrophic cardiomyopathy
Ischaemic heart disease
