C2. Ventricular arrhythmias/ SCD- brief 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)
(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…
(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
(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
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
(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
(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.
(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.
(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.
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.
(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.
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.
(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.
(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.
(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.
(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.
Other conditions subheadings (list)
Hypertrophic cardiomyopathy
Ischaemic heart disease
