Investigation of Sudden Cardiac Death
Mary N. Sheppard in Practical Cardiovascular Pathology, 2022
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that can degenerate into cardiac arrest and sudden death. The typical presentation is a child between the age of 4 and 12 years presenting with sudden exercise-related syncope or cardiac arrest, often related to swimming, and tending to be worse in males. Sudden Arrhythmia Death Syndrome autopsy series find CPVT almost as commonly as long QT syndrome so, given it is much rarer than LQTS, it is clearly much more severe. Cases in infancy (sudden infant death) are rare, and milder or later presenting forms in mid-adult life are being increasingly recognized. Many syncopal episodes in fact occur during ‘wakeful rest’. The resting 12-lead ECG is normal. The diagnosis is made by exercise testing, after the exclusion of structural heart disease, by documenting premature ventricular contractions usually at heart rates over 100 beats per minute on exercise testing, which progress to polymorphic VT, and sometimes to the classic ‘bidirectional VT’ which is pathognomonic. Calcium channels are involved in the excitation-contraction coupling (ECC) process. The cardiac ryanodine receptor (RyR2) is a calcium channel that regulates calcium ion release from the sarcoplasmic reticulum. Activation of RyR2 facilitates binding of calcium ions to contractile proteins of the heart muscle, which activates systolic contraction of the cardiac myocytes. To maintain a regular heartbeat, the activity of RyR2 must be tightly-regulated. Abnormal leak of calcium ions through dysregulated RyR2 can cause an altered membrane potential which, in turn, introduces irregular contractile and electrical activity, resulting in cardiac arrhythmia and SCD. Approximately 60% of patients with CPVT have a mutation in the RyR2 gene and in a subgroup of patients with ACM. The mutations are highly penetrant. CPVT2 is autosomal recessive and very uncommon, caused by calsequestrin mutations (CASQ2).
Genetically Determined Ventricular Arrhythmias
Andrea Natale, Oussama M. Wazni, Kalyanam Shivkumar, Francis E. Marchlinski in Handbook of Cardiac Electrophysiology, 2020
CPVT is a rare idiopathic ventricular arrhythmia that arises as a consequence of mutation in genes responsible for myocardial calcium handling and is characterized by bidirectional and polymorphic VT. Ventricular arrhythmias are usually triggered by exercise or adrenergic stimuli.13
Cardiac and cardiovascular disorders
Angus Clarke, Alex Murray, Julian Sampson in Harper's Practical Genetic Counselling, 2019
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is triggered in those susceptible, as might be expected, by exercise or stress. This is mostly autosomal dominant (especially RYR2) but a recessive form exists.
Targeting pathological leak of ryanodine receptors: preclinical progress and the potential impact on treatments for cardiac arrhythmias and heart failure
Published in Expert Opinion on Therapeutic Targets, 2020
Patrick Connell, Tarah A. Word, Xander H. T. Wehrens
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited, stress-induced arrhythmia disorder with a high incidence of sudden cardiac death. Caused in up to 60% of patients by mutations in RyR2, CPVT leads to diastolic Ca2+ leak in the presence of beta-adrenergic stimulation. This leak stimulates activation of the Na+/Ca2+-exchanger, resulting in delayed afterdepolarizations (DADs) and triggered activity, which can lead to potentially fatal ventricular tachyarrhythmias [2]. Mutated RyR2 results in diastolic leak in CPVT only when exposed beta-adrenergic stimulation and not at rest [12]. It has been shown that beta-adrenergic stimulation reduces the affinity of FKBP12.6, a channel-stabilizing accessory protein, to CPVT-mutant RyR2 channels [12]. In addition, it has been shown that activation of CaMKII by beta-adrenergic stimulation or exercise can exacerbate SR Ca2+ leak through mutant RyR2 channels [24,25]. This mechanism is likely to play a major role since ventricular tachycardia is only observed at faster heart rates in CPVT patients [26]. Recent work has also shown that CaM plays an important role in CPVT-related RyR2 dysfunction associated with select RyR2 mutations, as CaM binding affinity is decreased, and spontaneous Ca2+ leak is increased in these models [27,28].
Precision medicine in cardiac electrophysiology: where we are and where we need to go
Published in Expert Review of Precision Medicine and Drug Development, 2020
Ashish Correa, Syed Waqas Haider, Wilbert S. Aronow
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a rare congenital arrhythmia syndrome characterized by a predisposition to develop polymorphic VT (that can degenerate into VF) during physical activity, exercise, stress, or other states of adrenergic stimulation [59,60]. Patients present with syncope, seizures, or SCD with exercise, stress, or strenuous physical activity. Physical examination, EKG and postmortem gross pathology and microscopic examination of the heart tend to be normal [61]. However, a characteristic evolving EKG pattern is seen with increased adrenergic stimulation (or catecholamine infusion) – initially premature ventricular contractions (PVCs), followed by bigeminy and then polymorphic VT, typically with an alternating bidirectional pattern, which can degenerate into VF.
Cardiac arrhythmias in pregnant women: need for mother and offspring protection
Published in Current Medical Research and Opinion, 2020
Theodora A. Manolis, Antonis A. Manolis, Evdoxia J. Apostolopoulos, Despoina Papatheou, Helen Melita, Antonis S. Manolis
CPVT is a rare inherited cardiac arrhythmia caused by an imbalance in the homeostasis of intracellular calcium, and characterized by catecholamine-sensitive polymorphic VT, which can present with palpitations and/or syncope and can lead to SCD83. Patients with CPVT typically have a normal resting ECG and a structurally normal heart. Polymorphic VT is triggered by exertion or emotional stress. CPVT is caused by mutations in the cardiac ryanodine receptor (RyR2) gene, responsible for the autosomal dominant form, or in the sarcoplasmic reticulum protein calsequestrin 2 gene (CASQ2), responsible for the recessive form. Beta blockers remain the cornerstone of therapy in these patients, aided by flecainide, which has an adjunctive role in those not responding to beta blocker84. Implantation of a defibrillator and/or cardiac sympathetic denervation might also be alternative therapeutic options in certain cases.
Related Knowledge Centers
- Arrhythmia
- Calcium
- Cardiac Arrest
- Mutation
- Protein
- Syncope
- Ventricular Fibrillation
- Cardiac Muscle
- Ventricular Tachycardia
- Genetic Disorder