A Review of the HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients With Inherited Primary Arrhythmia Syndromes

Introduction

The following is a review of some of the major features of the expert consensus document on inherited primary arrhythmia syndromes presented at Heart Rhythm 2013 and soon to be published in the HeartRhythm journal.¹

This document represents the work of the Heart Rhythm Society (HRS), the European Society of Cardiology (EHRA), and the Asia Pacific Heart Rhythm Society (APHRS). The document was also endorsed in June by the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), the Pediatric and Congenital Electrophysiology Society (PACES), and the Association for European Pediatric and Congenital Cardiology (AEPC). The opinions that resulted in the work were derived from expert consensus, extensive literature review, clinical experience, and registry data, and not from clinical trials or randomized trials. 

The need for this consensus work has been driven by the fact that clinicians are constantly finding new pathogenic genetic mutations, and that the prevalence and complexity of caring for the patients with these mutations is growing. Within these new guidelines are some diagnostic re-definitions of syndromes, plus revised treatment recommendations. In addition, lifestyle changes that should be recommended are included. Finally, there is an in-depth discussion of the need for and proposed structure of specialty clinics for inherited arrhythmia syndrome patients. 

The recommendations contained in the document follow the standard structure of such guidance documents, with Class I corresponding to “is recommended”, Class IIa being “can be useful”, Class IIb being  “may be considered”, and Class III indicating a treatment “should not” be done or “is not recommended”. The syndromes discussed in this review are: long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, early repolarization, and progressive cardiac conduction disease.

Long QT Syndrome (LQTS)

Long QT syndrome (LQTS) is the most common inherited arrhythmia, occurring at a rate of 1 in 2,000 births worldwide.²  Thirteen genetic forms of LQTS have been identified. The most frequently occurring are LQTS 1-3. 

Manifestations of LQTS include arrhythmic events and electrocardiographic abnormalities. Arrhythmic events are caused by torsades de pointes VT, which can progress to ventricular fibrillation (VF) and lead to sudden death. Torsades itself can cause syncope and cardiac arrest. Events are triggered by different means in each of the more commonly seen LQTS types. Patients with LQT1 are more likely to experience events because of physical or emotional stress, while LQT2 events are associated with rest or sudden noises, and LQT3 events occur at rest or during sleep. 

The prolongation of the QT interval is the most easily identified ECG abnormality, although prolongation is not always seen. Abnormally shaped T waves are also often seen. 

The consensus statement states that the diagnosis of LQTS is made unequivocally when a pathogenic mutation of one of the LQTS genes is found, or a LQTS risk score ≥3.5 is present with no secondary cause for a QT prolongation, or a QTc of 500 ms is found in repeated ECGs in the absence of a secondary cause for QT prolongation. In addition, LQTS can be diagnosed with a QTc of 480-499 ms in repeated ECGs in unexplained syncope in the absence of a secondary cause for QT prolongation and in the absence of a pathogenic mutation (Table 1).

Management of the LQTS patient may include lifestyle changes, use of beta-blockers, use of sodium channel blockers, possible left cardiac sympathetic denervation, and ICD implantation. Specific guidelines are outlined in Table 2. Figure 1 summarizes the appropriate use of ICD therapy.

Notable with this consensus statement is the change related to sports participation in LQTS. The authors felt that this should be determined on a case-by-case basis. They reiterated that type 1 is triggered by swimming and diving, so exercise should definitely be avoided for this group. However, they believed that non type 1 is considered low risk. For those with borderline QT prolongation and no history of cardiac symptoms, and no family history of multiple sudden cardiac death (SCD), participation might be allowed after full evaluation and with proper precautions taken. Proper evaluation should be conducted by a clinical expert in inherited arrhythmias, not just any pre-participation sports physician. It should be noted that not all current guidelines are in agreement about the sports participation issue.

Brugada Syndrome (BrS)

The consensus recommendations for Brugada syndrome (BrS) diagnosis have been re-defined, in that diagnosis may now be made on the basis of the ECG alone. Definitive BrS is a type 1 ST segment elevation noted either spontaneously or after administration of an IV sodium channel blocking agent. The ST finding has to be observed in at least one R precordial lead placed in a standard or superior position up to the 2nd intercostal space (Figure 2). In the past, BrS was defined as an ECG abnormality in combination with other clinical issues.

Brugada syndrome prevalence is higher in Asia, and 8-10 times more frequent in males.³ Clinical manifestations of BrS include VF or aborted SCD, syncope, nocturnal agonal respiration, palpitations, and chest discomfort. The complete list of recommendations related to diagnosis and interventions is found in Tables 3 and 4. The ICD implantation guideline summary is shown in Figure 3. 

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

The prevalence of this rare adrenergic-induced bidirectional and polymorphic VT is unclear. Often the first episode of the disease is seen in those under 20, and it is brought on by physical activity or emotional stress. Episodes are often mistaken for a seizure disorder.

The consensus statement recommendation for diagnosis states that diagnosis be made when there is known pathogenic mutation, or in the presence of a structurally normal heart, a normal resting ECG, and unexplained exercise- or catecholamine-induced bidirectional VT of polymorphic ventricular beats or VT before the age of 40 (Table 5).

Therapeutic interventions include lifestyle changes, use of beta-blockers, and possible ICD implantation, or use of flecainide or left cardiac sympathetic denervation (Table 6). ICD therapy is often problematic; inappropriate ICD shocks may increase sympathetic tone and may trigger shockable arrhythmias. ICDs should be programmed with long delays for shock delivery and with high cutoff rates because of this.

Short QT Syndrome (SQTS)

Short QT syndrome (SQTS) is one of the rarer channelopathies. The largest series of these patients reported in the literature over the last 10 years had about 60 cases.⁴  SQTS is diagnosed in the presence of a QTc ≤330 ms. It can also be diagnosed in the presence of a QTc <360 ms and one or more of the following: a pathologic genetic mutation, a family history of SQTS, family history of sudden cardiac death before the age of 40, or cardiac arrest in the absence of structural heart disease. 

Implantation of an ICD is considered a Class I (recommended) intervention for symptomatic patients with a diagnosis of SQTS who: are survivors of a cardiac arrest and/or have documented spontaneous VT with or without syncope. Class IIb (may be considered) interventions include ICD implantation, quinidine, or sotalol in asymptomatic patients with a diagnosis of SQTS and a family history of SCD.

Early Repolarization (ER)

Early repolarization (ER) is a common ECG finding, defined as J-point and ST segment elevation in two or more contiguous leads. The finding is present in between 1% and 13% of the normal population.¹ However, within the last five years, reports began linking this finding to sudden death.

The genetic substrate for this syndrome has not been clearly defined. For that reason and because of the great prevalence of this ECG finding, labeling of individuals with ER is only done cautiously. Those with ER who are considered to definitely have the syndrome are those who have survived a cardiac arrest. Those at high risk may have a familial history of SCD, arrhythmic syncope, and ECG amplitude and morphology (Table 7).

Data from preparticipation athletic screening programs has shown ER to be present in up to 15-20% of subjects. If this is all that is found, it is generally not of concern. However, if the patient has early repolarization in two or more contiguous inferior and/or lateral leads, and experiences exercise-induced syncopal symptoms, further evaluation is needed.

Therapeutic intervention with ICD implantation is considered Class I (recommended) for those with ER who have survived a cardiac arrest. Class II (‘can be useful’ and ‘may be considered’) recommendations include the use of isoproterenol, quinidine, and ICD implantation in specific situations (Table 8).

Progressive Cardiac Conduction Disease (PCCD)

Progressive cardiac conduction disease is a disorder that may be either structural or functional, and is considered to be a degenerative disease or an exaggerated aging process which affects primarily the conduction tissue.⁵ The disease may occur with a structurally normal heart or with associated familial cardiomyopathy.

PCCD is usually diagnosed in patients <50 years old with unexplained progressive conduction abnormalities and a structurally normal heart with no skeletal myopathies. The Class I or recommended therapeutic intervention is pacemaker implantation if either of the following is present: intermittent or permanent third-degree or high-grade AV block; or symptomatic Mobitz I or II second-degree AV block. Class IIa recommendations, or those that can be considered useful include: pacemaker implantation in patients with a diagnosis of PCCD and the presence of bifascicular block with or without first-degree AV block; and ICD implantation in adult patients diagnosed with PCCD with a mutation in the lamin A/C gene with left ventricular dysfunction and/or nonsustained VT.

Those with PCCD may have a prolonged P-wave duration, PR interval and QRS widening plus an axis deviation, all of which may progress over time. Those with lamin A/C mutation may also have atrial and ventricular arrhythmias and possibly heart failure. Diagnosis is made with a history, family history, ECG, 2D echocardiogram, possible MRI, and genetic testing.

Inherited Arrhythmia Clinics

The consensus statement has recommended that the evaluation of all patients (probands) plus first degree relatives who have a diagnosed or suspected inherited cardiovascular disease thought to be a potential cause of SCD, should take place in a dedicated clinic with appropriately trained staff. They believe a multidisciplinary team is needed to assist with the medical and psychological consequences of possible diagnoses. A team might consist of a clinic coordinator, a nurse specialist, a genetic counselor, a physician specialist, a psychologist, physical and occupational therapists, a social worker, and a cardiothoracic surgeon.

Conclusion

The defining of inherited primary arrhythmia syndromes and determination of appropriate treatments will continue to evolve. The development of expert consensus statements such as this one helps all of us to catch up with the most recent data and, hopefully, continually improve the care our patients receive.

Disclosures: The author reports no conflicts of interest regarding the content herein. Outside the submitted work, the author reports honoraria from St. Jude Medical and Medtronic for speaking engagements, stocks in Boston Scientific and Medtronic, and course expenses reimbursed by Medtronic.

References

1. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes. Heart Rhythm. Article in press. 
2. Schwartz PJ, Stramba-Badiale M, Crotti L, et al. Prevalence of the congenital long-QT syndrome. Circulation. 2009;120:1761-1767.
3. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference. Heart Rhythm. 2005;2:429-440.
4. Giustetto C, Schimpf R, Mazzanti A, et al. Long-term follow-up of patients with short QT syndrome. J Am Coll Cardiol. 2011;58:587-595. 
5. Schott JJ, Charpentier F, Le Marec H. Progressive cardiac conduction disease. In: Gussak I, Antzelevitch C, eds. Electrical Diseases of the Heart. London: Springer-Verlag. 2008:564-576.