| dc.description.abstract | Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal, stressed-induced cardiac channelopathy. CPVT is characterized by ventricular arrhythmias that are triggered by catecholamines released during exercise or stress in individuals with structurally normal hearts. Cardiac calsequestrin (Casq2)-associated CPVT, termed CPVT2 is the most severe and the second most common form of CPVT. Autosomal-recessive CPVT2 is a result of a decrease in Casq2 protein levels, altering the ability of the sarcoplasmic reticulum (SR) to buffer calcium. In 2016, the first autosomal-dominant mutation, K180R, was found in CASQ2. We have found that K180R causes CPVT by decreasing the dynamic buffering capabilities of the SR without affecting Casq2 protein levels. The decreased buffering causes a decrease in calcium release refractoriness, an increase in spontaneous calcium release events, and ultimately the development of CPVT.
Even with a better understanding of the molecular mechanisms of CPVT, the anatomical origin remains unclear. Given that the arrhythmia results in the formation of ventricular tachycardia, it has been suggested that CPVT originates in the ventricular cardiomyocytes of the working myocardium or in the Purkinje cells. Currently, experimental and modeling studies suggest that the ventricular cardiomyocytes and Purkinje cells both have the potential to be responsible for arrhythmia generation, but no conclusion has been reached. Using transgenic mice with tissue specific Casq2 expression, we have found that CPVT originates in ventricular cardiomyocytes, specifically, the subendocardial cardiomyocytes juxtaposed to Purkinje cells.
Having a better understanding of the molecular and tissue mechanisms of CPVT will help develop better treatments. Currently several therapeutic options exist, but many patients still experience symptoms. New models and methods are needed to uncover treatments for CPVT. One area that has shown promise is human induced pluripotent stem cells (hiPSC). Using CRISPR/Cas9, we generated a hiPSC line where Casq2 has been ablated and have found that cardiomyocytes generated from the hiPSCs have CPVT characteristics. The hiPSC line can advance our understanding of CPVT and serve as a tool for future drug screens. | |
