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).

Figure 1. Long QT syndrome criteria (Priori, 2013)

Despite our awareness of the risk for sudden cardiac death from having long QT syndrome, most physicians are not prepared to calculate an accurate QTc. A study published in 2008 in Heart Rhythm Society looked at creating a uniform way to calculate the QT interval. They used the tangential method, which defines the QTc as the QT/√RR and any QTc over 450ms was considered abnormal Figure 2 (Pieter Postema, 2008). They then enrolled second year medical students, EP physicians, Cardiologists, and non-Cardiologists to read a series of EKGs and classify them as having long QTc or not (Pieter Postema, 2008). What they found was that the second year medical students who used the tangential method scored 80% on their classifications and Cardiologists and non-Cardiologists scored <25% (Pieter Postema, 2008).

Figure 2. Calculating QTC (Postema, 2008)

LQTS does not influence the heart on a beat-to-beat basis (Ackerman, 2004). However, if a patient is startled into exertion or there is a loud auditory stimuli, the heart can go into torsades de pointes, which will cause the patient to lose consciousness (Ackerman, 2004). If the heart does no return to a sinus rhythm spontaneously, patients require early defibrillation (Ackerman, 2004).

Current guidelines only recommend LQTS genetic testing in patients after cardiac arrest with long QT, syncopal episode with long QTC, asymptomatic individuals with prolonged QTc, and first degree relatives with genotype positive LQTS (Michael Gollob, 2011). The asymptomatic patients with prolonged QTc should first have structural heart disease ruled out, electrolyte abnormalities corrected, and evaluation for medications that prolong QTc (Michael Gollob, 2011). They do not recommend genetic testing if QTc is less than 460ms in women and 450ms in men (Michael Gollob, 2011).

Brugada syndrome

Brugada syndrome is more common in men and is due to an autosomal dominant inheritance (Silvia Priori, 2013). A loss of function mutation of the SCN5A gene is implicated in 20% of Brugada syndrome patients (Ackerman, 2004; Michael Gollob, 2011). However, over 70 mutations exist in the cardiac sodium channel and the SCN5A mutation leads to accelerated inactivation of the sodium channels (Antonio Bayes de Luna, 2012). Brugada syndrome is seen less frequently in children (Vincent Probst, 2007). Fever and high testosterone levels are thought to be associated with developing Brugada syndrome (Vincent Probst, 2007). Type I Brugada syndrome is defined as ST-segment elevation greater than or equal to 2mm in more than 1 lead among the right precordial leads (V1 and V2) (Figure 3) (Silvia Priori, 2013). Type I differs from Type II and III, which are identified by a saddleback pattern in V1 and V2 and no ST elevation is seen (Michael Gollob, 2011). These patients are at risk for polymorphic ventricular tachyarrhythmias (Michael Ackerman C. M., 2013).

Figure 3. Brugada syndrome criteria (Priori, 2013)

Genetic testing for BrS is recommended in patients who have family members with an identified causative mutation for Brugada syndrome (Michael Ackerman S. P., 2011). Another indication for testing is in patients with Brugada type I when a Cardiologist has suspicion for BrS based on history or physical exam. Patients who have persistent or induced with provocative testing type I Brugada ECG findings should also have genetic testing (Michael Ackerman S. P., 2011).

Figure 4. Identifying Brugada patterns (Bayes De Luna, 2012)

Catecholaminergic Polymorphic Ventricular Tachycardia

The EKG in CPVT is typically normal (Silvia Priori, 2013). Similar to Long QT syndrome, patients with CPVT usually present with syncope, seizures, or death (Michael Ackerman C. M., 2013). CPVT is responsible for 15% of autopsy negative episodes of sudden cardiac death in a young patient (Michael Ackerman C. M., 2013). Researchers have identified that changes in intracellular calcium release from the sarcoplasmic reticulum is responsible for CPVT (Michael Ackerman C. M., 2013). They have identified the RyR2 gain of function mutation in 60% of CPVT cases (Michael Ackerman C. M., 2013).

Figure 5. CPVT Criteria (Priori, 2013)

Indications for genetic testing are when a cardiologist has a clinical suspicion for CPVT based on family history, patient’s clinical history, and expressible phenotype during exercise EKG (Michael Ackerman C. M., 2013). Having exercise induced syncope or cardiac arrest in setting of a QTc <460ms should also be considered for CPVT testing (Michael Ackerman C. M., 2013).

Conclusion

Despite advancements in identifying genetic mutations that put patients at risk for sudden cardiac arrest, the commercial availability remains scarce and the price tag high. At this time, there are no guidelines that recommend screening for channelopathies for all youth participating in sports. As listed above, guidelines do exist based on family history, ECG findings, and history of arrest or syncope. If physicians suspect genetic testing would benefit a patient, a genetic counsellor should be involved.

References

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Antonio Bayes de Luna, J. B. (2012). Current electrocardiographic criteria for diagnosis of Brugada pattern: a consensus report. Journal of Electrocardiography, 433-442.

Francesca Girolami, G. F. (2017). Contemporary genetic testing in inherited cardiac disease: tools, ethical issues, and clinical applications. Journal of Cardiovascular Medicine, 1-11.

Michael Ackerman, C. M. (2013). Personalized Medicine: Genetic Diagnosis for Inherited Cardiomyopathies/Channelopathies. Revista Espanola de Cardiologia, 298-307.

Michael Ackerman, S. P. (2011). HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies. European Society of Cardiology, 1077-1109.

Michael Gollob, L. B. (2011). Recommendations for the Use of Genetic Testing in the Clinical Evaluation of Inherited Cardiac Arrhythmias Associated with Sudden Cardiac Death: CanadianCardiovascular Society/Canadian Heart Rhythm Society Joint Position Paper. Canadian Journal of Cardiology, 232-245.

Peter Schwartz, M. S.-B. (2009). Prevalence of the Congenital Long-QT Syndrome. Circulation, 1761-1767.

Pieter Postema, S. J. (2008). Accurate electrocardiographic assessment of the QT interval: Teach the tangent. Heart Rhythm Society, 1015-1018.

Priya Chockalingam, Y. M. (2015). Channelopathies – Emerging Trends in The Management of Inherited Arrhythmias. Indian Pacing and Electrophysiology Journal, 43-54.

Silvia Priori, A. W. (2013). Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. European Society of Cardiology, 1389-1406.

Vincent Probst, I. D. (2007). Clinical Aspects and Prognosis of Brugada Syndrome in Children. Circulation, 2042-2048.