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

This international consensus statement is the collaborative effort of three medical societies representing electrophysiology in North America, Europe and Asian-Pacific area: the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA) and the Asia Pacific Heart Rhythm Society. The objective of the consensus document is to provide clinical guidance for diagnosis, risk stratification and management of patients affected by inherited primary arrhythmia syndromes. It summarizes the opinion of the international writing group members based on their own experience and on a general review of the literature with respect to the clinical data on patients affected by channelopathies. This document does not address the indications of genetic testing in patients affected by inherited arrhythmias and their family members. Diagnostic, prognostic, and therapeutic implications of the results of genetic testing also are not included in this document because this topic has been covered by a recent publication [[1]] coauthored by some of the contributors of this consensus document, and it remains the reference text on this topic. Guidance for the evaluation of patients with idiopathic ventricular fibrillation, sudden arrhythmic death syndrome and sudden unexplained death in infancy, which includes genetic testing, are provided as these topics were not covered in the previous consensus statement. Developing guidance for genetic diseases requires adaptation of the methodology adopted to prepare guidelines for clinical practice. Documents produced by other medical societies have acknowledged the need to define the criteria used to rank the strength of recommendation for genetic diseases [[2]]. The most obvious difference encountered for inherited diseases is that randomized and/or blinded studies do not exist in this field. Therefore most of the available data derive from registries that have followed patients and recorded outcome information. As a consequence, all consensus recommendations are level of evidence (LOE) C (i.e., based on experts' opinions). The consensus recommendations in this document use the commonly used Class I, IIa, IIb and III classification and the corresponding language: "is recommended" for Class I consensus recommendation; "can be useful" for a Class IIa consensus recommendation; "may be considered" to signify a Class IIb consensus recommendation; and "should not" or "is not recommended" for a Class III consensus recommendation (failure to provide any additional benefit and may be harmful). Syncope: In the context of inherited arrhythmogenic disorders, the occurrence of "syncope" is an important indicator of arrhythmic risk. Although there is no definition to differentiate a syncopal episode caused by ventricular arrhythmias from an otherwise unexplained syncope, in the context of this document, the term "syncope" implies the exclusion of events that are likely due to vasovagal events such as those occurring during abrupt postural changes, exposure to heat and dehydration, emotional reactions to events such as blood drawing, etc. We refer to the guidelines of ESC and AHA/ACCF for the differential diagnoses of syncope [[3], [4]]. Symptomatic individuals: The term "symptomatic" refers to individuals who have experienced ventricular arrhythmias (usually ventricular tachycardia or resuscitated ventricular fibrillation), or syncopal episodes (see definition above). The presence of symptoms is, in some of the channelopathies, an independent predictor of cardiac arrest at follow-up. Arrhythmic events: The term refers to the occurrence of symptomatic or asymptomatic sustained or nonsustained spontaneous ventricular tachycardia, or unexplained syncope/resuscitated cardiac arrest. Concealed mutation-positive patients: This term is used to refer to individuals without clinical symptoms or phenotype of a channelopathy who carry the genetic defect present in clinically affected members of the family. When considering the guidance from this document, it is important to remember that there are no absolutes governing many clinical situations. The final judgment regarding care of a particular patient must be made by the health care provider and the patient in light of all relevant circumstances. Recommendations are based on consensus of the writing group following the Heart Rhythm Society's established consensus process. It is recognized that consensus does not mean unanimous agreement among all writing group members. We identified the aspects of patients' care for which a true consensus could be found. Surveys of the entire writing group were used. The authors received an agreement that was equal to or greater than 84% on all recommendations; most recommendations received agreement of 94% or higher. This statement is directed to all health care professionals who are involved in the management of (1) individuals who survived a cardiac arrest at a young age (usually defined as <40 years) in the absence of a clinical diagnosis of cardiac disease, despite extensive clinical assessment; (2) family members of individuals who died suddenly at young age with a negative autopsy; (3) in patients and family members in whom the diagnosis of a channelopathy is clinically possible, likely, or established; and (4) young patients with unexplained syncope. All members of this document writing group provided disclosure statements of all relationships that might present real or perceived conflicts of interest. Disclosures for all members of the writing group are published in Appendix A. LQTS is diagnosed: In the presence of an LQTS risk score ≥3.5 in the absence of a secondary cause for QT prolongation and/or In the presence of an unequivocally pathogenic mutation in one of the LQTS genes or In the presence of a QT interval corrected for heart rate using Bazett's formula (QTc) ≥500 ms in repeated 12-lead electrocardiogram (ECG) and in the absence of a secondary cause for QT prolongation. LQTS can be diagnosed in the presence of a QTc between 480–499 ms in repeated 12-lead ECGs in a patient with unexplained syncope in the absence of a secondary cause for QT prolongation and in the absence of a pathogenic mutation. The following lifestyle changes are recommended in all patients with a diagnosis of LQTS: Avoidance of QT-prolonging drugs (www.qtdrugs.org) Identification and correction of electrolyte abnormalities that may occur during diarrhea, vomiting, metabolic conditions or imbalanced diets for weight loss. Beta-blockers are recommended for patients with a diagnosis of LQTS who are: Asymptomatic with QTc ≥470 ms and/or Symptomatic for syncope or documented ventricular tachycardia/ventricular fibrillation (VT/VF). Left cardiac sympathetic denervation (LCSD) is recommended for high-risk patients with a diagnosis of LQTS inwhom: Implantable cardioverter defibrillator (ICD) therapy is contraindicated or refused and/or Beta-blockers are either not effective in preventing syncope/arrhythmias, not tolerated, not accepted or contraindicated. ICD implantation is recommended for patients with a diagnosis of LQTS who are survivors of a cardiac arrest. All LQTS patients who wish to engage in competitive sports should be referred to a clinical expert for evaluation of risk. Beta-blockers can be useful in patients with a diagnosis of LQTS who are asymptomatic with QTc ≤470 ms. ICD implantation can be useful in patients with a diagnosis of LQTS who experience recurrent syncopal events while on beta-blocker therapy. LCSD can be useful in patients with a diagnosis of LQTS who experience breakthrough events while on therapy with beta-blockers/ICD. Sodium channelblockers can be useful, as add-on therapy, for LQT3 patients with a QTc >500 ms who shorten their QTc by >40 ms following an acute oral drug test with one of these compounds. Except under special circumstances, ICD implantation is not indicated in asymptomatic LQTS patients who have not been tried on beta-blocker therapy. Patients affected by the long QT syndrome (LQTS) have been identified all over the world and in all ethnic groups. A possible exception is represented by a paucity of cases identified among black Africans and among African-Americans. Among Caucasians, the prevalence of LQTS has been established by a prospective ECG study, complemented by molecular screening, performed on over 44,000 infants at age 15–25 days [[5]]. LQTS disease-causing mutations were identified in 43% and 29% of the infants with a QTc exceeding 470 and 460 milliseconds (ms), respectively. These findings demonstrate a prevalence of about 1:2000 apparently healthy live births (95% CI, 1:1583 to 1:4350). This prevalence reflects only infants with an abnormally long QTc and does not take into account the significant number of "concealed mutation-positive patients." Since 1995, when the first three genes responsible for LQTS were identified [[6]-[8]], molecular genetic studies have revealed a total of 13 genetic forms of congenital LQTS caused by mutations in genes encoding potassium-channel proteins, sodium-channel proteins, calcium channel-related factors, and membrane adaptor proteins. Patients with LQT1, LQT2, and LQT3 genotypes with mutations involving KCNQ1, KCNH2, and SCN5A make up over 92% of patients with genetically confirmed LQTS. Up to 15%–20% of patients with LQTS remain genetically elusive [[1]]. Mutations in auxiliary β-subunits to KCNQ1 (KCNE1, LQT5) and KCNH2 (KCNE2, LQT6) are infrequent, but they result in clinical phenotypes similar to patients with mutations in their associated α-subunits of KCNQ1 and KCNH2. A recessive form of LQTS, the Jervell and Lange-Nielsen syndrome, involves the same (homozygous) or different (compound heterozygous) KCNQ1 mutations from both parents, is more virulent and is associated with deafness. Mutations in KCNJ2 (Kir2.1, LQT7) result in the neurologic musculoskeletal Andersen-Tawil syndrome with associated QT prolongation. The remaining LQTS genotypes (LQT4 and LQT8–13) have each been identified in just a few families or in single individuals. Common variants in the LQTS genes (single nucleotide polymorphisms [SNPs]), and in some cases unrelated genes, are thought to contribute to the variable penetrance of LQTS within affected family members having the same gene mutation [[9]]. The clinical manifestations of LQTS fall under two main categories: the arrhythmic events and the electrocardiographic (ECG) aspects. The arrhythmic events are due to runs of torsades de pointes VT, which, according to its duration, produces syncope, cardiac arrest, and—when it deteriorates into VF—sudden death. Among untreated patients, the natural history is represented by the occurrence of a number of syncopal episodes, eventually leading to sudden death. Sudden death as a first manifestation represents the main rationale for the treatment of asymptomatic patients. Atrial arrhythmias, specifically atrial fibrillation, are more frequent in LQTS patients compared to controls [[10], [11]]. The conditions associated with arrhythmic events are, to a large extent, gene-specific [[12]], with most arrhythmic events occurring during physical or emotional stress in LQT1, at rest or in association with sudden noises in LQT2 patients, and at rest or during sleep in LQT3 patients. The ECG alterations are important and numerous. While the prolongation of the QT interval is the hallmark of LQTS, it is not always present. Indeed, between 10% (LQT3) and 37% (LQT1) of genotype-positive patients have a QT interval within normal limits at rest [[13]]. Ventricular repolarization is not only prolonged but often presents bizarre morphologic alterations, some of which tend to be gene-specific [[14]]. Macroscopic T-wave alternans [[15]] is perhaps the most distinctive ECG pattern of LQTS, and is a marker of high cardiac electrical instability. Notches on the T-wave are rather typical for LQT2 and their presence is associated with a higher risk for arrhythmic events [[16]]. Long sinus pauses are not infrequent among LQT3 patients. The diagnosis of LQTS is mainly based on measurement of the QT interval corrected for heart rate (QTc) using Bazett's formula. When using a prolonged QTc to diagnose LQTS, one must exclude secondary causes of QTc prolongation that can occur with drugs, acquired cardiac conditions, electrolyte imbalance, and unbalanced diets. A scoring system has been established, which takes into account the age of the patient, medical and family history, symptoms, and QTc and provides a probability of the diagnosis of LQTS [[17], [18]]. Approximately 20%–25% of patients with LQTS confirmed by the presence of an LQTS gene mutation may have a normal range QTc [[13], [19]]. The use of provocative tests for QT measurement during change from a supine to standing position [[20]], in the recovery phase of exercise testing [[21], [22]], or during infusion of epinephrine [[23], [24]] has been proposed to unmask LQTS patients with normal QTc at resting ECG. These tests may be considered in uncertain cases. However, the clinical use of this test requires more extensive validation. Individuals at the extremes of the curve, those at very high or at very low risk, are easy to identify. For the larger group, in the gray area, risk stratification is difficult and can be fraught with errors in either direction. There are genetic and clinical clues that facilitate risk assessment. Specific genetic variants, such as the Jervell and Lange-Nielsen syndrome [[25]] and the extremely rare Timothy syndrome (LQT8) [[26]] are highly malignant, manifest with major arrhythmic events very early, and respond poorly to therapies. Within the most common genetic groups, specific locations, types of mutations, and degree of mutation dysfunction are associated with different risks. Mutations in the cytoplasmic loops of LQT1 [[27], [28]], LQT1 mutations with dominant-negative ion current effects [[29]], and mutations in the pore region of LQT2 [[29], [30]] are associated with higher risk, and the same is true even for some specific mutations with an apparently mild electrophysiological effect [[31]]. By contrast, mutations in the C-terminal region tend to be associated with a mild phenotype [[32]]. Clinically, there are several patterns and groups associated with differential risk. High risk is present whenever QTc >500 ms [[13], [33]] and becomes extremely high whenever QTc >600 ms. Patients with a diagnosis of LQTS who are identified by genetic testing as having two unequivocally pathogenic variants and a QTc >500 ms (including homozygous mutations as seen in patients with Jervell and Lange-Nielsen syndrome) are also at high risk, in particular when they are symptomatic. The presence of overt T-wave alternans, especially when evident despite proper therapy, is a direct sign of electrical instability and calls for preventive measures. Patients with syncope or cardiac arrest before age 7 have a higher probability of recurrence of arrhythmic events while on beta-blockers [[34]]. Patients who have syncope or cardiac arrest in the first year of life are at high risk for lethal events and may not be fully protected by the traditional therapies [[35], [36]]. Patients who suffer arrhythmic events despite being on full medical therapy are at higher risk. By contrast, it also is possible to identify patients at lower risk. Concealed mutation-positive patients are at low, but not zero, risk for spontaneous arrhythmic events. The risk for an arrhythmic event in this group has been estimated around 10% between birth and age 40 in the absence of therapy [[13]]. A major risk factor for patients with asymptomatic genetically diagnosed LQTS comes from drugs that block the IKr current and by conditions that lower their plasma potassium level. Among genotyped patients, LQT1 males, who are asymptomatic at a young age [[37]], are at low risk of becoming symptomatic later on in life, while females, and especially LQT2 females, remain at risk even after age 40. The aggressiveness to manage patients with LQTS is related in part to the risk for life-threatening arrhythmic events, as highlighted in Section 2.5. The AHA/ACC/ESC Guidelines for LQTS Therapy, published in 2006, are still relevant in 2012 [[2]]. Life-style modifications such as avoidance of strenuous exercise, especially swimming, without supervision in LQT1 patients, reduction in exposure to abrupt loud noises (alarm clock, phone ringing, etc) in LQT2 patients, and avoidance of drugs that prolong QT interval in all LQTS patients, should be routine. Participation of LQTS patients in competitive sports is still a matter of debate among the experts. Recently available retrospective data suggest that participation in competitive sports of some patients with LQTS may be safe [[38]]. Based on these data [[38]], which still need confirmation, low-risk patients, with genetically confirmed LQTS but with borderline QTc prolongation, no history of cardiac symptoms, and no family history of multiple sudden cardiac deaths (SCD), may be allowed to participate in competitive sports in special cases after full clinical evaluation, utilization of appropriate LQTS therapy and when competitive activity is performed where automated external defibrillators are available and personnel trained in basic life support [[38]]. This applies especially to patients genotyped as non-LQT1. In all patients with a high perceived risk (see Section 2.5) and in patients with exercise-induced symptoms, competitive sport should be avoided. Specific therapies available for patients with LQTS and indications for their use are described below. Beta-blockers are clinically indicated in LQTS, including those with a genetic diagnosis and normal QTc, unless there is a contraindication such as active asthma [[34], [35]]. Presently, there is no substantial evidence to favor cardioselective or noncardioselective beta-blockers; however, the former is preferred in those patients who suffer from asthma. Long-acting beta-blockers such as nadolol or sustained-release propranolol should be preferred as these medications can be given once or twice a day with avoidance of wide fluctuations in blood levels. Recent data also suggest that, particularly in symptomatic patients, these drugs may perform better than, for example, metoprolol [[39]]. While studies are not available to define the most effective dosage, full dosing for age and weight, if tolerated, is recommended. Abrupt discontinuation of beta-blockers should be avoided as this may increase the risk of exacerbation. ICD therapy is indicated in LQTS patients who are resuscitated from cardiac arrest [[40]]. ICD is often favored in patients with LQTS-related syncope who also receive beta-blockers [[41]]. Prophylactic ICD therapy should be considered in very-high-risk patients such as symptomatic patients with two or more gene mutations, including those with the Jervell and Lange-Nielsen variant with congenital deafness [[25]]. ICD therapy has life-time implications. Complications are not infrequent, especially in the younger age group, and risk/benefit considerations should be carefully considered before initiating this invasive therapy [[42], [43]]. Accordingly, LQT1 patients who experience a cardiac arrest while not receiving beta-blockers may only be treated with beta-blockers or with LCSD (see below) in settings when the implant of an ICD is likely to be associated with high risk, such as in infants and pediatric patients [[44], [45]]. LQTS-related sudden death in one family is not an for ICD in affected family members unless they have an of high risk for arrhythmic events recommendations for in patients diagnosed with long QT the associated with the implantation of an ICD in young when using a in asymptomatic patients. We suggest that ICD therapy not be used as therapy in an asymptomatic LQTS beta-blockers remain the therapy in LQTS patients. However, an ICD may be considered in those patients who are to be at very high risk, especially those with a contraindication to beta-blocker therapy. 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