Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia
Year: 2020
Type: review
Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced cardiac channelopathy that has a high mortality in untreated patients. Our understanding has grown tremendously since CPVT was first described as a clinical syndrome in 1995. It is now established that the deadly arrhythmias are caused by unregulated 'pathological' calcium release from the sarcoplasmic reticulum (SR), the major calcium storage organelle in striated muscle. Important questions remain regarding the molecular mechanisms that are responsible for the pathological calcium release, regarding the tissue origin of the arrhythmic beats that initiate ventricular tachycardia, and regarding optimal therapeutic approaches. At present, mutations in six genes involved in SR calcium release have been identified as the genetic cause of CPVT: RYR2 (encoding ryanodine receptor calcium release channel), CASQ2 (encoding cardiac calsequestrin), TRDN (encoding triadin), CALM1, CALM2 and CALM3 (encoding identical calmodulin protein). Here, we review each CPVT subtype and how CPVT mutations alter protein function, RyR2 calcium release channel regulation, and cellular calcium handling. We then discuss research and hypotheses surrounding the tissue mechanisms underlying CPVT, such as the pathophysiological role of sinus node dysfunction in CPVT, and whether the arrhythmogenic beats originate from the conduction system or the ventricular working myocardium. Finally, we review the treatments that are available for patients with CPVT, their efficacy, and how therapy could be improved in the future.
Source: The Journal of Physiology
DOI: 10.1113/jp276757
Institutions: Vanderbilt University, Vanderbilt University Medical Center
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1855952650, Targeting intracellular calcium leak for ventricular arrhythmia prevention in structural heart disease, Towards Precision Medicine with Human iPSCs for Cardiac Channelopathies, Medical Scientist Training Program, Cardiac Calsequestrin (Casq2) function in excitation-contraction coupling and cardiac arrhythmias, Medical Scientist Training Program
OpenAlex ID: W3010459846