Channelopathies and their role in Sudden Cardiac Arrest

There is much debate regarding screening for cardiac disease in our athletic population. Prevalence of inherited cardiac disease is estimated at 3% in the general population (Francesca Girolami, 2017). We try to screen for hypertrophic obstructive cardiomyopathy during cardiac auscultation with a Valsalva maneuver but we have no physical exam test for channelopathies. Channelopathies are alterations in ion channels that can lead to arrhythmias and sudden cardiac death (Priya Chockalingam, 2015). Two of the most studied channelopathies are congenital long QT syndrome and Brugada syndrome (BrS). Less known are catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (Priya Chockalingam, 2015).

Although the majority are inherited through an autosomal dominant mode, these arrhythmias are difficult to manage because they can be autosomal recessive or exist due to a sporadic mutation (Priya Chockalingam, 2015). This has led to developments in next generation sequencing techniques to detect mutations (Priya Chockalingam, 2015).

The yield for genetic tests also varies based on arrhythmia type. For example, Long QT syndrome testing provides a yield of 75% while short QT syndrome is less than 20% (Silvia Priori, 2013). The gold standard to detect mutations is direct DNA sequencing (Ackerman, 2004). However, due to its limitation in large scale gene sequencing, next generation DNA sequencing has been created to help overcome some of these barriers (Ackerman, 2004). The purpose of these DNA sequencing advancements is to provide a commercially available genetic test for inherited cardiac diseases.

Genetic tests are currently available for structural cardiomyopathies including hypertrophic cardiomyopathy, diastolic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy (Francesca Girolami, 2017). Tests are also available for LQTS, Brugada Syndrome, CPVT, and short QT syndrome (Francesca Girolami, 2017). The Canadian guidelines published in 2011 regarding the use of genetic testing recommend a physician work in conjunction with a genetic counsellor prior to ordering testing (Michael Gollob, 2011). In this review of Long QT syndrome, Brugada syndrome, and Catecholaminergic Polymorphic Ventricular Tachycardia, we want to look in to the ECG findings and indications for genetic testing for these arrhythmias.

Long QT syndrome

Long QTc can be diagnosed based on multiple criteria. A QTc >500ms seen in repeated EKGs with no secondary causes meets criteria (Figure 1) (Silvia Priori, 2013). In the setting of syncope, a QTc of 480-499 also meets criteria (Silvia Priori, 2013). The alterations in ion channels in Long QTc is seen in one out of 2000 live births in Caucasians (Silvia Priori, 2013; Michael Ackerman S. P., 2011). These ion channel alterations lead to a delay in repolarization of the myocardium, which causes QT prolongation and T wave abnormalities (Michael Ackerman C. M., 2013). The Long QT syndrome (LQTS) has a clear genotype-phenotype relationship (Priya Chockalingam, 2015). Patients with LQTS type 1 have symptoms with exercise and type 2 have symptoms with emotion triggers (Priya Chockalingam, 2015). The LQTS type 2 is thought to be due to a mutation in the potassium channel HERG (also known as KCNH2) (Ackerman, 2004). One of the challenges in LQTS is there are many silent carriers for the mutation who have a normal QTc on their EKG. However,those patients who are silent carriers and have QTc <500ms are less likely to have episodes of sudden cardiac death (Peter Schwartz, 2009).