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Corresponding Author: Dr. Andrew Krahn, Hearts in Rhythm Organization, Room 220, 1033 Davie St. Vancouver BC, V6E 1M7, Phone 604-682-2344 x 63260, Fax 604-806-9474.
Inherited arrhythmia syndromes are rare genetic conditions which predispose seemingly healthy individuals to sudden cardiac arrest and death. The Hearts in Rhythm Organization (HiRO) is a multidisciplinary Canadian network of clinicians, researchers, patients, and families that aims to improve care for patients and families with inherited cardiac conditions, focused on those that predispose to arrhythmia and sudden cardiac arrest/death. The field is rapidly evolving as research discoveries expand. A streamlined, practical guide for providers to diagnose and follow pediatric and adult patients with inherited cardiac conditions represents a useful tool to improve health system utilization, clinical management, and research related to these conditions.
This review provides consensus care pathways for 7 conditions including the 4 most common inherited cardiac conditions that predispose to arrhythmia, with scenarios to guide investigation, diagnosis, risk stratification, and management. These include Brugada syndrome (BrS), long QT syndrome (LQTS), arrhythmogenic right ventricular cardiomyopathy and related arrhythmogenic cardiomyopathies (ARVC/ACM), and catecholaminergic polymorphic ventricular tachycardia (CPVT). In addition, an approach to sudden cardiac arrest (SCA), sudden unexpected death (SUD), and first-degree family members of affected individuals is provided. Referral to specialized cardiogenetic clinics should be considered in most cases. The intention of this review is to offer a framework for the process of care that is useful for both experts and non-experts, and related allied disciplines such as hospital management, diagnostic services, coroners, and pathologists, in order to provide high quality, multidisciplinary standardized care.
Inherited arrhythmia syndromes are a rare and complex group of genetic conditions which predispose seemingly healthy individuals to sudden cardiac arrest and death. Brugada syndrome (BrS), long QT syndrome (LQTS), arrhythmogenic right ventricular cardiomyopathy (ARVC) and catecholaminergic polymorphic ventricular tachycardia (CPVT) are four of the most common inherited arrhythmia syndromes, each with unique but overlapping clinical presentations and genetic associations. An additional subset of presumed inherited arrhythmia syndromes presents with unexplained cardiac arrest (UCA) or sudden cardiac death (SCD), wherein an event in a seemingly healthy individual occurs without a clear underlying etiology.
The Hearts in Rhythm Organization (HiRO) is a Canadian network focused on clinical excellence, research, and patient and family involvement, with an intention to promote guideline-recommended multidisciplinary care for families affected by inherited cardiogenetic syndromes. Members include adult and pediatric physicians, genetic counselors, nurses, administrative and clerical staff, trainees, patients, and family members. The current document presents a summary of the HiRO consensus on the process of care related to the management of the 7 most common referral conditions. This is intended to complement the extensive and rapidly changing literature on best practices for specific clinical problems.
The specific HRS/EHRA/APHRS consensus statement regarding inherited arrhythmias has not been updated since 2013
HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013.
Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2018;72:e91-e220. doi: 10.1016/j.jacc.2017.10.054
Stiles MK, Wilde AAM, Abrams DJ, Ackerman MJ, Albert CM, Behr ER, Chugh SS, Cornel MC, Gardner K, Ingles J, et al. 2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families. Heart Rhythm. 2021;18:e1-e50. doi: 10.1016/j.hrthm.2020.10.010
European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases.
. In general, management includes risk mitigation based on lifestyle, medical, interventional, and device therapies, which all require shared decision making. Many patients benefit from simple drug avoidance, and guidance on safe physical activity, depending on the underlying syndrome and personal risk. Conservative management measures are suggested for patients who are asymptomatic or only have provoked ECG changes (ex. during exercise or fever). Invasive interventions, such as implantable cardioverter defibrillator (ICD) implantation, are reserved for those at highest risk.
HiRO has a key goal of providing access to expert care for patients and families at risk, which includes provision of a clinic toolkit for new or growing clinics. While guidelines recommend multidisciplinary care, the practical process of care including nature and frequency of testing, the timing and oversight of genetic testing, and the related custody of the variants that arise, are frequent queries that arise from mentored new clinics. Community healthcare practitioners are often the first point of contact for many suspected inherited arrhythmia cases, and follow-up and family care also often falls on these providers. However, a streamlined practical guide for healthcare providers to diagnose and follow patients with suspected inherited arrhythmia syndromes does not otherwise exist.
This review intends to provide HiRO expert consensus on care pathways to guide investigation, diagnosis, risk stratification, and follow-up of patients and family members with suspected or confirmed inherited arrhythmia syndromes, SCD, and UCA. These care pathways are applicable to pediatric and adult patients. Each scenario is supported by a hypothetical patient presentation to demonstrate how to utilize each care pathway to support clinical decision making.
METHODS
To achieve these goals, these care pathways were created to support general management of patients and families with inherited arrhythmia syndromes. Expert adult and pediatric physicians, nurses, and genetic counselors across the Canadian HiRO network were surveyed to understand current local care pathways at inherited arrhythmia clinics. From those results, focus groups were formed to draft algorithms which were then circulated and presented at the annual HiRO symposium for final approval. A discrete care pathway was developed for consideration of Brugada syndrome (BrS), long QT syndrome (LQTS), arrhythmogenic right ventricular cardiomyopathy (ARVC) and related arrhythmogenic cardiomyopathies (ACM), catecholaminergic polymorphic ventricular tachycardia (CPVT), sudden cardiac death (SCD), and unexplained cardiac arrest (UCA). Steps are colour-coded to denote starting points, action/tests, results, diagnoses, and research participation opportunities (Figures 2-5, 7-9).
It is important to note that individual cases are more complex than a summative care path, and clinical presentations are often not straightforward, requiring multidisciplinary expertise to navigate the cardiovascular and genetic nuances. The Hearts in Rhythm Organization (HiRO) firmly believes in guideline recommended multidisciplinary team care of patients and families, and provides publicly available patient and provider resources, enabling expert care (www.heartsinrhythm.ca).
BRUGADA SYNDROME
Background
Brugada syndrome (BrS) is classically seen in young adult males who are at risk of arrhythmic syncope or cardiac arrest particularly during sleep or at rest. Patients may also be incidentally diagnosed in the context of an abnormal ECG. BrS is defined as a 12-lead ECG with coved ST elevation and T-wave inversion in the right precordial leads (Figure 1)
. A definite diagnosis requires spontaneous Type 1 ECG changes in leads V1-V2, with a probable diagnosis reached with a provoked Type 1 ECG pattern (either with fever or sodium-channel blocker challenge). Loss-of-function variants in the SCN5A gene are the most common culprits in BrS; however, while family histories corroborate a genetic component to BrS, a single genetic culprit is often not identified suggesting inheritance is polygenic in nature
Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.
. Clinical risk and management is in part determined by the presence of a Type 1 pattern, whether spontaneous or provoked, or incidental or symptomatic (Figure 2).
Figure 2Care pathway for diagnosis and management of Brugada syndrome., *Consider sodium channel blocker challenge in very selected cases (Require medication listed on Brugadadrugs.org to avoid). Drug-induced Type 1 pattern & no family history ≠ Brugada syndrome (Shanghai criteria).
Provocation of a Type 1 pattern can be achieved by sodium channel blocker (ex. procainamide or ajmaline) challenge. Sodium channel blocker challenge use is somewhat controversial due to the lack of a gold standard comparison and variability in sensitivity and specificity across sodium channel blockers
. Ajmaline is not available in Canada, so procainamide is most commonly used. A positive sodium channel blocker challenge supports the diagnosis of BrS and risk management strategies can be implemented to reduce risk of SCD or syncope. However, sodium channel blocker challenges should be approached with caution and assessed on a case-by-case basis. These tests generally have a low detection rate but the balance of risk with a missed provoked Type 1 pattern supports pursuing comprehensive testing. Further, the specific agent used can impact results, with ajmaline more likely to provoke a Type 1 pattern with a greater probability of false positive
Yield and Pitfalls of Ajmaline Testing in the Evaluation of Unexplained Cardiac Arrest and Sudden Unexplained Death: Single-Center Experience With 482 Families.
. A 24-hour holter monitor is not routinely included in the initial IA clinic visit but may be considered in cases at clinic discretion. Electrophysiology (EP) studies are generally discouraged in BrS because of limited discriminative power but may be considered in specific cases. Consultation with an inherited arrhythmia specialist is recommended. It is important to note that a confirmed BrS diagnosis, while helpful to guide clinical care, could also have both psychological and practical (ex. insurance) implications; notably, the absolute risk of an inducible Type 1 pattern is not well understood, so the absolute benefit of a diagnosis is unclear
Management of BrS includes lifestyle, pharmacological, and interventional components. The highest risk patients are those with spontaneous Type 1 ECG pattern and a history of cardiac arrest or arrhythmic syncope; in these patients, ICD implantation should be considered
. In patients who receive appropriate ICD shocks, quinidine therapy and/or EP study and ablation may be considered. We recommend an inherited arrhythmia specialist is consulted in these cases.
Illustrative Case:
A 35-year-old man had an ECG performed for routine screening, which incidentally found a Type 2 Brugada pattern (Figure 1). He did not report any personal history of associated symptoms such as syncope, but his father died suddenly in his sleep at age 50, and an autopsy was not performed. In light of the Type 2 Brugada ECG pattern and positive family history, the patient was referred for a sodium channel blocker challenge. Prior to completing the test, the implications of a positive result were discussed with the patient. In this case, the patient was referred to a specialized inherited arrhythmia clinic where a sodium channel blocker challenge provoked a Type 1 pattern. Risk management strategies were initiated including avoidance of certain drugs (www.brugadadrugs.org), aggressive treatment of fever with acetaminophen and lifestyle management (Table 1). In coordination with a genetic counsellor, SCN5A genetic testing was also pursued. However, an actionable variant was not identified, as is common with most BrS cases
. The patient was considered low risk, so conservative management focused on risk avoidance was recommended (Table 1). Given the patient was asymptomatic, an ICD was not recommended. An echocardiogram or cardiac MRI would typically be offered to assess for any structural heart disease. Follow-up should be with the IA clinic every 1-2 years, including an ECG with high leads, review of genetic classification and family screening, and re-education regarding drug avoidance and fever management.
Table 1Clinical management of inherited arrhythmia syndromes.
Lifestyle
Pharmacologic
Intervention
ARVC*
Avoid competitive or frequent high-intensity endurance exercise
Beta-blocker: definite phenotype positive ARVC; consider if inappropriate ICD shocks Amiodarone/sotalol: consider with symptomatic arrhythmias ± ICD Flecainide: combination with beta-blockade in patients with refractory arrhythmias
Consider ICD: use risk calculator https://arvcrisk.com/ Catheter ablation: symptomatic arrhythmias refractory to treatment
BrS
Treat fever with Tylenol Drug avoidance (www.brugadadrugs.org & illicit substances) Carry Brugada ECG
Consider quinidine if ICD shocks
ICD recommended: all symptomatic Type 1 (provoked or unprovoked) Catheter ablation: consider with EP study if appropriate ICD shocks
CPVT
Avoid triggers Physical activity safety plan
First line: Beta-blocker Second line: flecainide
LCSD or ICD recommended: symptomatic probands despite optimal medical therapy
LQTS
Avoid QT prolonging medications (www.qtdrugs.org), illicit substances, and triggers (ex. sudden noises) Physical activity safety plan Emphasize importance of beta-blocker adherence
Beta-blocker: prefer non-selective agents, evaluate efficacy with exercise test Mexiletine: consider in LQT2 and LQT3
ICD recommended: breakthrough syncope/LQT on beta-blocker Consider LCSD: high-risk patients, breakthrough cardiac events or medical/device treatment intolerance/refusal
With no identified pathogenic or likely pathogenic genetic variant in the proband, cascade genetic testing for family members is not available. Most cases of gene-negative BrS will be sporadic, however cardiac screening in first-degree family members is still recommended. The proband’s mother, siblings and children were referred to an IA clinic and underwent 12-lead ECG with standard and high lead placement, and review of personal and family history. All relatives had normal cardiac evaluations, with no Brugada pattern identified on ECG, and were discharged from clinic. In this scenario, negative genetic testing in the proband and absence of a phenotype in other relatives reduces suspicions that the father’s death was related to BrS, although this cannot be ruled out. However, it is important to note that as the father died over the age of 40, if BrS was the culprit, the subsequent risk to family members is not definitively increased
Congenital long QT syndrome (LQTS) is characterized by prolonged repolarization, with the greatest risk of arrhythmia generally occurring at elevated heart rates. The Schwartz score is used to stratify patients into unlikely (≤1.5 points), possible (2-3 points), or probable (≥3.5 points) LQTS groups based on history and ECG findings (Figure 3; Supplemental Table S1)
A systematic approach to measuring the QT interval can improve reliability and detection of prolonged QT intervals. The tangent method is widely used by inherited arrhythmia specialists as a reliable method at a wide range of heart rates
. In this method, the end of the QT interval is defined as the intercept of the tangent line from the steepest slope of the T-wave and the isoelectric line. Correction of the QT interval for heart rate is most often done using Bazett’s formula, however its performance characteristics may be suboptimal, particularly at extremes of heart rates, but no broadly accepted alternative is in practice
Individualized corrected QT interval is superior to QT interval corrected using the Bazett formula in predicting mutation carriage in families with long QT syndrome.
. Notably, there is an important overlap of QT interval distributions in genetic LQTS and the general population. This underlies the difficulty in establishing a diagnosis of LQTS using the baseline ECG. The probability of LQTS using the QTc measured using the tangent or the threshold methods as well as age and sex can be estimated using a recent case-control study (https://www.qtcalculator.org/)
. Importantly, the diagnosis of LQTS is based on persistent QTc prolongation, highlighting the importance of repeated ECGs in patients where LQTS is suspected.
The exercise test is a mainstay of LQTS diagnosis, with a Bruce or modified Bruce protocol recommended for evaluation. As heart rate increases, prolongation of the corrected QT interval can be exacerbated, and underlying repolarization abnormalities revealed. The QT interval at 4-minutes in recovery is the single most useful measure in LQTS on exercise testing
. A 24-hour holter monitor is not routinely included in the initial IA clinic visit but may be considered in cases at clinic discretion. Of all inherited arrhythmia syndromes, the genetic basis of LQTS is best understood and as such plays a large role in confirming or ruling out a diagnosis, especially in cases with low-intermediate probability. Around 80% of gene-positive LQTS cases result from a mutation in the KCNQ1, KCNH2, which encode voltage-gated potassium channels, or SCN5A gene, which encodes voltage-gated sodium channel
. As a result, genetic testing is also recommended in patients with possible LQTS, following genetic counseling.
Pharmacologic management of LQTS includes avoidance of QT prolonging medications and initiation of beta-blocker therapy; these two factors together drastically reduce the risk of cardiac arrest or sudden death
High efficacy of beta-blockers in long-QT syndrome type 1: contribution of noncompliance and QT-prolonging drugs to the occurrence of beta-blocker treatment "failures.
. A wide variety of medications can prolong the QT interval and predispose to life-threatening ventricular arrhythmia such as Torsade de Pointes; they should be avoided where possible. A full list can be found at www.crediblemeds.org, or the related smartphone app. Beta-blocker therapy in LQTS provides exceptional risk reduction. Adequate blockade and dosage should be assessed by exercise test 4-6 weeks after initiation and/or dose titration. A 15-20% reduction of maximum heart rate at similar workload is considered adequate beta-blockade; however, small and gradual dose titration is recommended to limit adverse effects and support compliance. Mexiletine can be considered in LQTS Type 2 or 3 (Table 1). Primary prevention ICD plays a limited role in LQTS, however may be considered for those on adequate beta-blocker therapy with breakthrough syncope or prolonged QTc interval on ECG. In those with unlikely or possible LQTS, expert judgment may inform the decision to follow and reassess in select cases based on clinical and family context.
Illustrative Case:
A 45-year-old man underwent an ECG as part of employment screening and was incidentally found to have a QTc interval of 475ms. He was not taking any medications known to prolong the QT interval. He reported no history of syncope, but his brother died suddenly at age 27, and a structural cause of death was not identified on autopsy. As such, with a QTc interval of 475ms and unexplained sudden death in a first degree relative under the age of 30, this patient’s Schwartz score was 2.5, suggesting possible LQTS.
He was referred to a local inherited arrhythmia clinic where a repeat resting ECG showed a QTc interval of 470 ms, and exercise stress testing showed QTc prolongation of 490 msec extending into the recovery period. The shared decision to pursue genetic testing was made by the clinic electrophysiologist, genetic counselor, and patient.
In this case, a Long QT gene panel was performed, and a pathogenic KCNQ1 variant was identified, confirming the patient’s diagnosis of LQTS. Following the positive genetic test result, beta-blocker therapy was initiated with nadolol as the preferred agent, and bisoprolol or propranolol alternatives. A treadmill test was performed on beta blocker to target a 15-20% reduction in peak heart rate. Recommended follow-up includes a 12-lead ECG and exercise test every 1-2 years; if the patient is stable and/or low-risk, test review without clinic visit or a virtual clinic visit can be considered. With regards to first-degree family member screening, some inherited arrhythmia clinics lead with genetic testing when a known pathogenic variant has been identified in the family, and only perform phenotypic testing (ECG, exercise stress test) in carriers of the variant. Other clinics choose to concurrently complete phenotypic testing in all first-degree family members. Regardless, all first-degree family members of an affected proband should be referred for evaluation, especially in the setting of an identified pathogenic variant. Published decision aids on cascade screening can help with family counseling and decision making
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by fibrofatty infiltration of the ventricular myocardium which results in an increased arrhythmogenic risk. The desmosomes connecting myocardial cells are often abnormal, reducing the strength and integrity of cell-to-cell connections and thus increasing the likelihood of ventricular arrhythmias. As such, unlike other inherited arrhythmia syndromes, imaging (echocardiogram or contrast enhanced cardiac magnetic resonance [CE-CMR]) plays a role in the diagnosis and risk stratification of ARVC (Figure 4).
Figure 4Care pathway for diagnosis and management of arrhythmogenic right ventricular cardiomyopathy.
. Scores should be re-calculated in patients with follow-up testing, especially in previously borderline patients, as ARVC can be progressive, and severity may change over time. Nomenclature has recently evolved to arrhythmogenic cardiomyopathy (ACM), expanding the diagnosis to include diverse phenotypes such as biventricular and left ventricular dominant arrhythmogenic cardiomyopathies, and other genetic forms of cardiomyopathy whose clinical phenotypes can overlap with ARVC
. In 2020, the Padua diagnostic criteria were published to include the broader spectrum of ACM, however the 2010 Task Force Criteria remain most widely accepted and utilized by specialists
. Both systems separate clinical findings into major and minor criteria and focus on 12-lead ECG, 24-hour Holter monitor, cardiac imaging (echocardiogram and/or CE-CMR), and family history. Signal averaged ECG (SAECG) is becoming less important in the diagnosis of ACM, as understanding of the disease evolves and genetic testing expands
The majority of experimental and clinical evidence supports that a reduction in high-intensity endurance exercise reduces both ventricular arrhythmia and heart failure risk
Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers.
. A conservative safe level is usually 30-minutes of brisk walking daily; however, limiting intensity may provide more protection from ventricular arrhythmia compared to duration of exercise
. There is evidence to suggest that phenotype-negative, genotype-positive patients also benefit from exercise limitation in terms of long-term outcomes
. Close follow-up is warranted for patients that continue to exercise.
Medical and interventional management strategies in ACM include beta-blockers and primary ICD implant, respectively. Beta-blocker therapy is recommended for patients with definite phenotype-positive ACM. Primary prevention ICD implantation can be considered in high-risk patients. A validated prediction model to assess the risk of ventricular arrhythmias is available at www.arvcrisk.com, which can be useful to inform shared decision-making surrounding ICD use
Arrhythmic risk prediction in arrhythmogenic right ventricular cardiomyopathy: external validation of the arrhythmogenic right ventricular cardiomyopathy risk calculator.
. Ablation may be considered in symptomatic arrhythmias refractory to treatment where primary prevention ICD is not indicated.
In terms of follow-up, re-evaluation of the prediction model at each clinic visit is imperative for accurate ongoing risk stratification. ACM is usually progressive, so it is important to maintain an accurate clinical picture of the severity of disease to support both prognosis and risk management strategies. Further, reclassification of genetic variants may impact diagnosis strength and arrhythmia risk.
Illustrative Case:
A 24-year-old male college athlete presented with a sudden cardiac arrest while playing hockey and received a secondary prevention ICD. An echocardiogram showed LVEF of 50% and regional RV akinesia with reduced RV ejection fraction at 39%, which was confirmed by cardiac MRI. His 12-lead ECG showed T-wave inversion in V1-V4, and a 24-Holter monitor reported 712 PVCs. As such, this patient would meet the 2010 task force criteria for definite ARVC, with one major criterion for ARVC (T-wave inversion) and two minor criteria (RV morphological features and >500 PVC/24 hours). The patient was then started on beta-blocker therapy and counseled to stop high-level hockey and reduce his exercise intensity. Psychological support was offered in light of the significant lifestyle alteration associated with the diagnosis. The patient met with a genetic counselor and proceeded with genetic testing, which was negative. First-degree relatives were referred to the clinic for cardiac evaluation. With no identified pathogenic or likely pathogenic genetic variant in the proband, cascade genetic testing for family members was not possible, but surveillance cardiac evaluation was recommended.
The proband was seen for annual evaluation and remained clinically stable over the next 3 years. Eventually, repeat genetic testing was offered, which identified a pathogenic FLNC variant, a gene more recently associated with arrhythmogenic cardiomyopathy (ACM), which had not been included on the original gene panel. Following this, first-degree relatives were offered genetic testing for this variant. Relatives who tested negative for the familial variant were discharged from ongoing evaluation. Family members who tested positive for the FLNC variant continued to be followed by the specialty IA clinic every 1-2 years to monitor for early signs of disease.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by rapid polymorphic and bidirectional ventricular tachycardia in the setting of sudden adrenergic stimuli and is one of the least prevalent inherited arrhythmia syndromes
Kazemian P, Gollob MH, Pantano A, Oudit GY. A novel mutation in the RYR2 gene leading to catecholaminergic polymorphic ventricular tachycardia and paroxysmal atrial fibrillation: dose-dependent arrhythmia-event suppression by β-blocker therapy. The Canadian journal of cardiology. 2011;27:870.e877-810. doi: 10.1016/j.cjca.2011.02.003
. The resting ECG most often does not show any abnormalities, so a detailed history and provocative testing must be completed to reach a diagnosis (Figure 5). Symptoms usually present first in children and young adults, although they may be subtle or nonspecific such as presyncope or palpitations. Further, the context of adrenergic stimuli may vary, from physical exercise, swimming, rollercoaster ride or emotional stress
. A delayed diagnosis or overlooked warning signs are not uncommon and may have catastrophic consequences, especially as a missed opportunity for very effective interventions that can prevent sudden cardiac arrest or death
Catecholaminergic polymorphic ventricular tachycardia in children: analysis of therapeutic strategies and outcomes from an international multicenter registry.
Exercise testing is the mainstay of CPVT diagnosis to mimic adrenergic stimulation in a clinical setting. However, the sensitivity of standard Bruce protocols wherein effort is gradually increased is low. Depending on the specific genetic variant, over 70% of gene-positive patients may have a non-diagnostic exercise test
. A new burst exercise testing protocol, more closely mimicking the sudden onset of adrenergically triggered arrhythmias, may improve the sensitivity of exercise testing although further analysis is needed to support its diagnostic role
The underlying etiology of CPVT is characterized by abnormal Ca2+ handling at the sarcoplasmic reticulum. As such, the most common genetic variants are within the RyR2 gene encoding the ryanodine receptor, and up to 60% of patients with CPVT present with pathogenic variants
Kazemian P, Gollob MH, Pantano A, Oudit GY. A novel mutation in the RYR2 gene leading to catecholaminergic polymorphic ventricular tachycardia and paroxysmal atrial fibrillation: dose-dependent arrhythmia-event suppression by β-blocker therapy. The Canadian journal of cardiology. 2011;27:870.e877-810. doi: 10.1016/j.cjca.2011.02.003
. Interestingly, de novo mutations are commonly seen in CPVT probands, however a thorough family screening should still be undertaken as siblings of a de novo proband carry a 1-2% risk of harbouring the same mutation as a result of parental germline mutation
. Further, false paternity is an uncommon occurrence, but should be carefully considered in all genetic conditions.
Management of CPVT focuses on avoiding potential triggers where possible and ensuring safety plans are in place when engaging in stimulating activities. When a diagnosis is confirmed, non-selective beta-blockers (nadolol or propranolol) are the first line pharmacological treatment and flecainide is an effective adjunct. Left cardiac sympathectomy is also effective. ICD use is more limited compared to other inherited arrhythmia conditions, as the adrenergic response to an ICD shock may exacerbate the trigger of CPVT. However, ICDs may be considered in probands that remain symptomatic despite optimal medical therapy.
Illustrative Case:
A 12-year-old girl presented after a near-drowning experience. She jumped off a high diving board and was found immediately unresponsive. After the lifeguard removed her from the pool, she spontaneously regained consciousness. She reported no prodrome to the event other than feeling quite frightened upon jumping. However, she had experienced intermittent palpitations over the past 3 years, but as they were always associated with stressful situations, she dismissed them. She had no family history of sudden death or cardiac arrest.
Her 12-lead resting ECG was normal but a standard exercise test showed infrequent polymorphic premature ventricular contractions (PVCs) at peak exercise. She was re-tested with the burst exercise protocol showing frequent bidirectional PVCs and a short run of non-sustained polymorphic ventricular tachycardia (VT) at peak exercise (Figure 6). As such, she had a likely diagnosis of CPVT. She underwent genetic testing which revealed a pathogenic variant in the RyR2 gene, supporting the diagnosis. She was started on nadolol (non-selective beta-blocker) and repeat exercise testing a few days later showed only PVCs but no couplets or VT. Repeat exercise testing 6-months later revealed 25% reduction in peak heart rate and only rare PVCs; this was the desired therapeutic result. A follow-up 12-lead ECG and exercise test was recommended annually.
Figure 6An example of bidirectional VT seen on an exercise stress test in a patient with CPVT, best depicted in lead III.
Upon first-degree relative screening, neither parent was found to carry the same pathogenic variant, suggesting a de novo mutation. While this finding effectively rules out CPVT in her parents, it brings forward a question regarding screening of her two siblings. Her siblings carry a 1% risk of inheriting the RyR2 variant due to the potential of germline mosaicism
The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: a comprehensive open reading frame mutational analysis.
. As such, in this case her siblings should be evaluated with a 12-lead ECG, exercise test (standard or burst), and targeted genetic testing may be considered. Given the potentially catastrophic consequences of a missed diagnosis, erring on the side of caution is advocated in these scenarios.
SUDDEN UNEXPECTED DEATH & SUDDEN CARDIAC ARREST
Background
Sudden cardiac arrest (SCA) and sudden unexpected death (SUD) are the two most feared manifestations of inherited arrhythmia syndromes. In general, SCA and SUD are defined as cardiac arrest or death within an hour of symptom onset, or with no identifiable prodrome such as during sleep. Automated external defibrillators (AEDs) are important in resuscitating SCA to avoid SUD. Advocacy for public availability of AEDs, especially in potentially risky settings such as swimming pools or sports facilities, helps save lives. Only a very small subset of SCA and SUD are related to inherited arrhythmia syndrome, so thorough evaluation is important given the wide differential diagnosis. However, inherited arrhythmia syndromes remain an important differential given the familial nature and prognostic implications, especially when events occur in young individuals.
Ischemic, structural, toxic, or metabolic causes of SCA are more common than inherited arrhythmia syndromes and should be ruled out first (Figure 7). Once excluded, a thorough history should be obtained including a three-generation family history. Any potential warning signs (such as syncope without prodrome) and suspicious deaths or deaths at a young age in other family members should be defined as well as possible. Comprehensive phenotypic testing should be completed and used to guide genetic testing. Broad panel genetic testing can be offered if no phenotype is found and should be led by a genetic counselor in conjunction with a specialized inherited arrhythmia clinic
. In a subset of patients, a clear etiology may not initially be found; phenotypic testing should be repeated every 2-3 years as diagnostic findings may be intermittent and clinical knowledge evolves. For example, short coupled ventricular fibrillation (SCVF) was recently identified in 6% of previously unexplained SCA
Short-coupled ventricular fibrillation represents a distinct phenotype among latent causes of unexplained cardiac arrest: a report from the CASPER registry.
. SCVF is initiated by short-coupled premature ventricular contractions, although it is currently unclear if it is a distinct entity or a sub-phenotype of ventricular fibrillation. This discovery also has treatment implications as quinidine was identified to be an effective pharmacological management, not usually prescribed in other etiologies of SCA. A thorough evaluation of SCA probands also has implications on the utility of family screening (Figure 8). If no cause can be found, the yield of family screening is low (3%)
In the case of SUD, a diagnosis requires a different path of investigation as the proband cannot be prospectively evaluated (Figure 9). Any available cardiac testing prior to the SUD should be tracked and reviewed by an expert. An autopsy should be performed especially if the deceased was under the age of 35. Once these other causes are ruled out, SUD is sometimes referred to as sudden arrhythmic death syndrome (SADS). In these cases, 40% of people will have a negative autopsy and inherited arrhythmia syndromes are the top differential in the absence of structural pathology
. As most young, seemingly healthy individuals do not have extensive cardiac testing performed prior to a fatal event, post-mortem broad panel genetic testing often plays a very important role in diagnosis after SUD. Through advocacy and education, saving autopsy tissue for genetic testing has become common practice in many jurisdictions, but efforts remain necessary to ensure this is common practice.
Figure 9Care pathway for diagnosis and management of sudden unexpected death.
. Nevertheless, an identified variant in any family greatly streamlines evaluation and assists in preventing further tragedies for affected families. Where possible, either premortem or prospective clinical testing should guide which genetic panel is tested. Management of those with a positive diagnosis, whether phenotypic and/or genotypic, depends on the syndrome found as outlined above.
Illustrative Case (Sudden Cardiac Arrest):
A 31-year-old man experienced sudden cardiac arrest during a local marathon. He was successfully resuscitated by a bystander with an AED available on the racecourse, and was subsequently transferred to the hospital. Unfortunately, no ECG tracings were available for review but a presumptive diagnosis of SCA was made. His initial in-hospital ECG, echocardiogram, and cardiac MRI showed no abnormalities, and coronary angiogram ruled out coronary artery disease and anomalous coronary artery anatomy. An ICD was implanted given his SCA.
After discharge, he was assessed at the local inherited arrhythmia clinic for a full workup. His family history was notable as his paternal cousin was found unresponsive after a single motor vehicle accident, and his paternal grandfather died suddenly at age 45. Aside from the SCA, the patient did not report any history of arrhythmia symptoms. Further, his 12-lead ECG, Holter monitor, and exercise testing did not reveal any abnormalities. A procainamide challenge was negative for a Type 1 Brugada pattern, though suspicion was low because of the adrenergic context. Broad panel genetic testing was completed, which revealed a VUS in the KCNQ1 gene, often associated with LQTS. First-degree family members were referred for screening but were not offered genetic testing given that the VUS identified in the proband was not considered a diagnostic genetic result.
Two years later, he was seen again for scheduled follow-up with repeated clinical testing and review of genetic variant classification. New data identified the KCNQ1 variant to be relatively common within the general population, and the variant was downgraded to likely-benign. The patient subsequently had an appropriate ICD shock while out for a brisk walk. Rhythm strip analysis revealed ventricular fibrillation triggered by a PVC with a coupling interval of 300ms, which was successfully terminated by ICD shock. As such, the patient received a diagnosis of SCVF and quinidine therapy was initiated. As SCVF is a newly described diagnosis, the implications of this diagnosis on family screening are not yet well understood. SCVF is not typically familial, and no culprit gene has been identified, with the exception of a founder haplotype near the gene DPP6 in patients of Dutch ancestry. First degree family members with an abnormal phenotype should continue to be followed, while those with normal phenotypes can be discharged.
Illustrative Case (Sudden Unexpected Death):
A 14-year-old boy was referred after his 42-year-old mother was tragically found dead in her bedroom, presumed to have died in her sleep. An autopsy did not identify a structural or toxic cause of death. Upon review, the family history was positive for sudden death in a distant maternal cousin, however limited details surrounding this were available. Broad panel genetic testing of the saved blood sample was performed, but a pathogenic variant was not identified. The family consented for the remaining sample to be stored for research purposes, with permission to contact if new information arose. Given the undetermined but potentially inherited cause of SUD in his mother, the boy along with his two younger maternal half-siblings underwent a comprehensive phenotypic evaluation including a 12-lead ECG, high-lead ECG, signal averaged ECG, Holter monitor, exercise stress test, and echocardiogram, which were reassuring. He was counseled to return for a follow-up visit in 3-5 years to re-evaluate his own phenotype testing and potentially perform further genetic testing depending on new information at the time.
If a pathogenic variant had been identified in the post-mortem sample, this would greatly streamline family member screening, and those who did not carry the variant would not need to be followed. Those who do carry the variant would undergo phenotypic testing and be followed as per the specific pathway relating to the likely diagnosis.
CONCLUSION
A systematic and comprehensive approach to the evaluation of patients and families at risk for inherited arrhythmia syndromes is central to diagnostic clarity and precision therapy. Missed diagnoses can have catastrophic consequences, and overdiagnosis is also a concern. There are characteristic findings associated with each syndrome and clinical pathways that will help better understand and diagnose these conditions. Importantly, not all cases are straightforward, the phenotype and genotype diagnostic effort can take time and multidisciplinary expert consultation is key to care for patients and families.
FUNDING SOURCES
The National Hearts in Rhythm Oragnization is funded by the Canadian Institutes of Health Research (RN380020-406814; Principal Investigator: Dr Krahn). Dr Krahn receives support from the Sauder Family and Heart and Stroke Foundation Chair in Cardiology (Vancouver, BC), the Paul Brunes Chair in Heart Rhythm Disorders (Vancouver, BC), and the Paul Albrechtsen Foundation (Winnipeg, MB).
DISCLOSURES
The authors have no disclosures.
ACKNOWLEDGEMENTS
We are deeply appreciative of the work of the HiRO (Hearts in Rhythm Organization) study coordinators across Canada and of our patients and their families who participate in research to advance our understanding and care of inherited arrhythmia conditions.
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Inherited arrhythmia syndromes are rare genetic conditions which predispose seemingly healthy individuals to sudden cardiac arrest and death. The Hearts in Rhythm Organization (HiRO) is a multidisciplinary Canadian network of clinicians, researchers, patients, and families that aims to improve care for inherited cardiac conditions. This review provides consensus care pathways for the 7 most common conditions and presentations to guide investigation, diagnosis, risk stratification, and management.
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