Sudden Cardiac Death and Arrhythmias

Login or register to view PDF.
Abstract

Sudden cardiac death (SCD) and arrhythmia represent a major worldwide public health problem, accounting for 15–20 % of all deaths. Early resuscitation and defibrillation remains the key to survival, yet its implementation and the access to public defibrillators remains poor, resulting in overall poor survival to patients discharged from hospital. Novel approaches employing smart technology may provide the solution to this dilemma. Though the majority of cases are attributable to coronary artery disease, a thorough search for an underlying cause in cases where the diagnosis is unclear is necessary. This enables better management of arrhythmia recurrence and screening of family members. The majority of cases of SCD occur in patients who do not have traditional risk factors for arrhythmia. New and improved large scale screening tools are required to better predict risk in the wider population who represent the majority of cases of SCD.

Disclosure
The authors have no conflicts of interest to declare.
Correspondence
Neil T Srinivasan, Department of Cardiac Electrophysiology, Barts Heart Centre, St Bartholomew’s Hospital, London, EC1A 7BE, UK. E: neil.srinivasan@nhs.net
Received date
07 March 2018
Accepted date
30 April 2018
Citation
Arrhythmia & Electrophysiology Review 2018;7(2):111–7.
DOI
https://doi.org/10.15420/aer.2018.15.2

An estimated 180,000–300,000 sudden cardiac deaths (SCD) occur in the US annually.1,2 Worldwide, sudden and unexpected cardiac death is the most common cause of death,2 accounting for 17 million deaths every year with SCD accounting for 25 % of these. The accepted definition of SCD is death that occurs within one hour of onset of symptoms in witnessed cases, and within 24 hours of last being seen alive when it is unwitnessed.2 The majority of deaths are unwitnessed, with VF being the final underlying mechanism.2–5 The majority of patients are found in asystole or pulseless electrical activity (PEA) and heart block is increasingly noted as an aetiology.

Despite the decline in cardiovascular deaths over the past several decades,6 due to improved preventative strategies, the incidence of SCD as a proportion of overall cardiovascular deaths has increased.2 This has occurred because in-hospital mortality has declined more rapidly,2 highlighting the need for better risk stratification methods and preventative strategies.

Medical therapy with class Ic agents or amiodarone to prevent SCD has been shown to be to be ineffective.7,8 The major advance in the prevention of SCD has been the development of the ICD.9 Secondary prevention trials, Antiarrhythmic Versus Implantable Defibrillator (AVID),10 Canadian Implantable Defibrillator Study (CIDS)11 and Cardiac Arrest Study of Hamburg (CASH),12 have demonstrated statistically significant improvement in survival rates with ICD implantation compared with drug therapy in this patient population.

The Multicenter Automatic Defibrillator Implantation Trial (MADIT)13 and the Multicenter Unsustained Tachycardia Trial (MUSTT)14 studies enrolled patients post MI, comparing primary prevention with an ICD against standard medical therapy in patients with a reduced ejection fraction (EF) (<35 % and <40 %, respectively), plus either documented or induced ventricular tachycardia (VT) and demonstrated a 58–59 % relative risk reduction in death. Subsequently MADIT II15 showed a 28 % relative risk reduction in 2-year mortality in post-MI patients with an EF of <30 % without the requirement for documented or induced VT. The Defibrillators in Non-Ischemic Cardio-myopathy Treatment Evaluation (DEFINITE)16 study compared the benefit of ICD against standard therapy in patients with heart failure, EF ≤35 % and premature ventricular contractions or non-sustained ventricular tachycardia (NSVT), demonstrating a strong trend towards reduced mortality with ICD. While the Sudden Cardiac Death in Heart Failure Trial (SCD-HEFT),17 which enrolled patients with both ischaemic and non-ischaemic cardiomyopathy with New York Heart Association class II or III and EF of ≤35 %, showed a benefit of ICD when comparing ICD with standard medical therapy. What is interesting within these primary prevention trials is that apart from a low EF, no other significant major risk predictors identify who will benefit from an ICD. The major studies have used an EF cut-off between ≤30–40 %; however, the median populations within these studies tend to have far lower EF, and subgroup analysis of patients closer to the cutoff often shows no clear benefit.3,13,15,17,18 Additionally, in the ‘high risk’ population studies, such as MADIT II15 and SCD-HeFT,17 <40 % of patients received appropriate ICD shock therapy during the first 4 years of follow up. Finally, the recent Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) showed prophylactic ICD implantation in patients with non-ischaemic cardiomyopathy in patients >68 years was not associated with a reduced long-term mortality.19

Using these studies to guide prescription of ICDs means that we have only targeted a subgroup of patients where the incidence of events is high and, therefore, they have been labelled as high risk (Figure 1). The challenge for clinicians lies in the fact most episodes of SCD occur in individuals who, prior to the event, have no known cardiac disease and are not perceived high risk by traditional measures, or occurs as a first presentation of an undiagnosed underlying cardiac condition (Figure 2B).3 Thus, the vast majority of SCD events occur in patients who are considered at ‘low risk’ of events.3 Although the incidence within this group of patients is low, they cumulatively account for the greatest number of events (Figure 1). Finally, the indications for primary prevention in less common conditions, such as hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), long QT syndrome (LQT), Brugada syndrome and early repolarisation, remain less clear, with few if any definite risk markers beyond patient symptoms.3,20

Figure 1: Incidence and Occurrence of Sudden Cardiac Death Over 1 Year

Open in new tab
Open ppt

Sudden Cardiac Arrest: Chain of Survival

The majority of cardiac arrests occur outside of hospital, with poor outcomes. In the UK survival to admission may be as low as 8.1 % and survival to discharge as low as 3.2 % for out-of-hospital cardiac arrest.21 The first step to improving outcomes involves the chain of survival:

1. immediate recognition of cardiac arrest and activation of the emergency response system;

2. early CPR with an emphasis on chest compressions;

3. rapid defibrillation;

4. effective advanced life support; and

5. integrated post-cardiac arrest care.

The importance of early recognition and CPR is emphasised by the finding that prompt and immediate bystander response, CPR and early automated defibrillation to an out-of-hospital cardiac arrest by lay members in the community is an important public health initiative that can drive improvements in outcome. Every minute without CPR reduces the chance of survival by 7–10 %. A study of 30,381 cardiac arrests in Sweden found that CPR performed before the arrival of emergency medical services (EMS) more than doubled survival at 30 days.22 Additionally, standardised EMS care, as well as standardised and integrated post-resuscitation care, play a major role in improving outcomes. A study in Oslo where improvements were made to EMS care with an emphasis on uninterrupted and good CPR, followed by goal-directed post-resuscitation care, including therapeutic hypothermia and percutaneous coronary intervention (PCI), doubled survival, with survival as high as 35 % in cases of bystander-witnessed VT/VF arrests.23 In cases of refractory VT/VF, early coronary intervention with extracorporeal membrane oxygenation and uninterrupted mechanical defibrillation during PCI has been shown to produce good outcomes.24 These findings emphasise the importance of a cohesive public health strategy, with public education and engagement in CPR, early access to EMS and focused post-resuscitation care.25

The importance of early bystander defibrillation is emphasised by the fact the early use of public automated defibrillator devices (AEDs) in cases of out-of-hospital cardiac arrest significantly improves outcome.26,27 However, this requires significant political and strategic will to implement, with a need for both widespread and organised access to such devices, as well as public education with regard to their availability. At present, despite campaigns to raise public awareness and make AEDs more publicly available, many public spaces have no available AED. Where they are available, their use may be as low as 1.7 % in out-of-hospital cardiac arrests,28 highlighting the need to re-engage with the public and for better regional planning to close this weak link in the chain of survival, which is the biggest contributor to poor survival rates. New and novel approaches implementing smart technology to detect cardiac arrest and drone networks with automated defibrillators may be the future to improving outcomes.29

Establishing a Diagnosis

Initial Assessment and Management of Patients Who Survive a Cardiac Arrest

Assessment of patients who survive an out-of-hospital cardiac arrest involves a thorough history of the nature of events, including collateral history. The causes of SCD are shown in Figure 2, with ischaemic heart disease being the most common cause. Symptoms prior to the event, such as chest pain, palpitations and breathlessness syncope or pre-syncope, should be assessed. Risk factors, such as hypertension, diabetes, hyperlipidaemia and smoking, should be sought. A drug history should be attained, along with specific questions relating to recreational drug use and use of psychiatric drugs that may prolong the QT interval. Additionally precipitating factors, such as exercise and emotional stress, should be looked for, as well as family history.

Figure 2: Causes of Sudden Cardiac Death

Open in new tab
Open ppt

The 12-lead ECG remains the hallmark of initial non-invasive evaluation. Where there is evidence of ischaemia, prompt coronary intervention should be performed. However, even in the absence of ischaemic changes on the ECG, up to 29 % of patients with out-of-hospital cardiac arrest will have a culprit lesion, and PCI in this setting is associated with a two-fold outcome in cerebral performance category.30 Thus, all patients should have ischaemia assessed both through the 12-lead ECG and through invasive coronary angiography. The ECG should also be closely analysed for evidence of inherited cardiac conditions and structural cardiac abnormalities. Common inherited cardiac conditions to look for on an ECG include Brugada syndrome, long and short QT and early repolarisation. Additionally, structural cardiac abnormalities, such as HCM, ARVC and dilated cardiomyopathy (DCM), may also present with characteristic ECG changes.

Imaging in the form of echocardiography and MRI play an important role in the assessment of structural causes of out-of-hospital cardiac arrest. Echocardiography is the mainstay of initial assessment, allowing assessment of regional wall motion abnormalities, overall ventricular function, valvular heart disease and heart muscle disorders, such as HCM, ARVC and DCM. Increasingly cardiac MRI (cMRI) is also used to provide additional information to echocardiography, through the ability to provide greater information about tissue wall characterisation, and may contribute to the diagnosis in 50 % of cases and provide a decisive diagnosis in 30 % of cases.31

Patients Where the Cardiac Arrest is Apparently Unexplained: The Barts Protocol

Where cases of ischaemic heart disease are excluded, EF is preserved and repolarisation disorders are not apparent on the resting ECG, further assessment is required. This may increase the diagnostic yield and provide a diagnosis in nearly half of patients where an initial diagnosis is unclear.32 Figure 3 describes the Barts Protocol for Assessment of such patients, and Table 1 details the diagnostic criteria.

Table 1: Diagnostic Criteria of Inherited Arrhythmia Syndromes

Open in new tab
Open ppt

Figure 3: The Barts Protocol for Assessment of<br />
Unexplained Cardiac Arrest in the Context of Unobstructed Coronary Vessels

Open in new tab
Open ppt

Provocation Testing

Initial assessment involves a lying and standing ECG to look for evidence of QT prolongation during brief tachycardia induced by standing, which may expose concealed LQT1 and LQT2 phenotypes.33,34 This is followed by exercise testing to look for QT prolongation on exercise or a failure to shorten the QT interval on exercise, which is a prominent feature of the exercise ECG in LQT1 patients.34 Figure 4 shows an example of QT prolongation on exercise along with the tangent method for measuring the QT interval. During treadmill testing particular attention should also be paid to the recovery ECG during the first 1–4 minutes, as LQT2 patients may only exhibit QT prolongation in the recovery phase of exercise where sympathetic withdrawal may provoke late QT lengthening.34,35 A QTc >445 ms at 4 minutes of recovery has been shown to have a sensitivity of 92 % and specificity of 88 % in identifying LQT1 and LQT2 individuals.35 Exercise testing may also expose polymorphic or bidirectional VT, which may hint at a diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT) as demonstrated in Figure 5A, though this test is neither sensitive nor specific for the condition.

Figure 4: Exercise Stress Test ECG in Long-QT Syndrome

Open in new tab
Open ppt

Figure 5: Catecholaminergic Polymorphic Ventricular Tachycardia and Early Repolarisation Syndrome

Open in new tab
Open ppt

Additionally, we routinely record the ECG in the standard and high-right precordial positions36 to look for characteristic evidence of type 1 Brugada ECG change.37 We also perform provocative testing using ajmaline at a dose of 1 mg/kg over 5 minutes, with the ECG right precordial leads in the high and standard positions, though the sensitivity and specificity of this is debated.36 Figure 6 shows an example of a positive ajmaline challenge test.

Figure 6: Ajmaline Challenge Testing

Open in new tab
Open ppt

Imaging

Echocardiography and cMRI form the mainstay of assessment to look for evidence of structural cardiac causes. cMRI is increasingly proving to be useful through the ability to detect morphological abnormalities and characterise tissue fibrosis, which provides vital clues to the pathogenesis of sudden cardiac arrest.31 Increasingly, where patients do not have a history or ECG changes that warrant immediate coronary intervention, cardiac CT is being used to look at the coronary anatomy and anomalous coronary artery courses, thus negating the need to conventional angiography.

Other Tests/Investigations

Electrophysiological testing has not been shown to influence management or predict outcome in cardiac arrest survivors,38 and its role in management and risk prediction in inherited conditions, such as Brugada syndrome, is debated.39 We only perform this in cases where pre-excitation is suspected. Genetic testing is useful where a clear diagnosis is established or the pre-test probability is high, such that a positive test will influence the management not only of the patient but of their family. Cardiac biopsy may have a role in diagnosing inflammatory or infiltrative diseases, such as myocarditis or sarcoidosis, but is increasingly less used with the advent of advanced imaging modalities, such as cMRI and PET-CT, which we only perform when the imaging findings are in doubt in cases of suspected sarcoidosis.

Management of Patients after Stabilisation from Cardiac Arrest

While implantation of an ICD remains the mainstay of management in most patients who survive an out-of-hospital cardiac arrest, in patients who cannot have an ICD due to clinical reasons or where patients are undecided about having an ICD, the ZOLL® LifeVest may be considered as a bridge to ICD implantation or until the arrhythmic risk subsides.40 In patients who have an ICD implanted, further appropriate ICD therapy is seen in >23 % of cases.32 Identifying the cause of the cardiac arrest is important as this may allow directed therapy that reduces the risk of future cardiac arrest, and may also allow for the identification and prevention of the same, potentially inherited, condition in first-degree relatives.

Ischaemic Cardiomyopathy

Ischaemia is the underlying aetiology in the majority of cases, and arrhythmia management is based on adequate secondary prevention and ensuring adequate revascularisation has occurred. Beta-blockers remain the mainstay of management to prevent further shocks, with additional use of amiodarone or class IB agents, if necessary, to avoid shocks and treat VT storms. Increasingly the use of VT ablation is being performed with success rates >75 % in some cohorts.41

Long QT Syndrome

In patients with LQT, beta-blockers remain the mainstay of treatment, with propranolol, bisoprolol and nadolol being the most effective in shortening the QT interval. Evidence suggestes metoprolol is not as effective.42,43 In patients with LQT3, the addition of oral mexiletine to block late sodium currents may be helpful in patients with a QT interval >500 ms and syncope/pre-syncope or ICD therapy.44 In patients with ongoing ICD therapy despite medical therapy, or with markedly prolonged QT intervals >550 ms where risk becomes higher,20 left cardiac sympathectomy may be effective.45 Additionally, the avoidance of drugs that prolong the QT interval should be emphasised. This list is frequently changing and should be checked by patients and physicians: crediblemeds.org.46

Brugada Syndrome and Early Repolarisation Syndrome

Avoidance of fever, including the use of anti-pyretics and avoidance of drugs that precipitate arrhythmia and type 1 ECG change, is the mainstay of treatment in Brugada syndrome (brugadadrugs.org).47 Acute VT storms respond well to isoproterenol infusion and hydroquinidine can be used as an oral alternative in patients with recurrent ICD therapy.20 Increasingly, epicardial substrate ablation is showing promise48 and may become a major component in patient management.

Early repolarisation syndrome responds in a similar manner to Brugada syndrome, with isoproterenol infusion and hydroquinidine being useful treatments. In some patients with early repolarisation syndrome, VT/VF is triggered by closely coupled ectopic beats (Figure 5B and C), and suppression of these using either beta-blockade, calcium channel blockers or ablation may be useful.

Catecholaminergic Polymorphic Ventricular Tachycardia

Beta-blockers are the first-line drug of choice in preventing ectopy and arrhythmia in this patient cohort. The addition of flecainide is thought to prevent cellular calcium overload in CPVT and may be useful in patients with recurrent syncope, VT or ICD therapy. Verapamil has also been shown to be effective.20 Implantation of an ICD should be avoided in these patients, if possible, because the sympathetic drive associated with a shock can precipitate arrhythmia whether or not the original shock is appropriate or inappropriate. Additionally, there are case reports of ventricular ectopic ablation in CPVT, which may prevent the Purkinje triggers in these patients.49 Finally, left cardiac sympathectomy may be effective in preventing arrhythmia and ICD shocks in cases resistant to medical therapy.45

Idiopathic Ventricular Fibrillation

Management of recurrent arrhythmia in this subset of patients is largely empirical. Recurrence of arrhythmia and appropriate shocks may occur in up to 29 % of patients, and therapy with hydroquinidine50 may be helpful in reducing ICD therapy.51 As with patients with early repolarisation, short coupled ventricular premature beats may be a common arrhythmia trigger in this cohort of patients, often via Purkinje firing, and ablation of these may prove successful in abolishing further arrhythmia.52

Structural Heart Disease

Management of cardiomyopathies is best performed in specialist clinics, where the multitude of symptoms, as well as family screening and follow up, can be performed by physicians with an expertise in the field. Beta-blockers and amiodarone remain the mainstay of treatment for recurrent ventricular arrhythmia in HCM and DCM. Sotolol is the initial drug of choice during the active arrhythmia phase of ARVC, followed by amiodarone or beta-blockers. Catheter ablation may prove useful in reducing arrhythmia burden in ARVC53 and DCM.

Family Screening

Family screening in cases where the diagnosis is clear, or where a clear pathogenic genetic mutation is identified, is necessary to exclude a diagnosis in first-degree relatives, and to manage their risk accordingly. Additionally, screening the family members of victims from unexplained sudden death may identify a disease phenotype that is latent in the proband,54 and may aid in diagnosing and managing the risk to relatives.55 Our screening of family members follows the Barts Protocol.

Conclusion

SCD and arrhythmia continues to represent a major international public health problem and is still the biggest killer worldwide, despite huge improvements in cardiovascular care in the past 30 years. The majority of patients do not survive to hospital discharge, highlighting the need for larger and better public health initiatives to improve the chain of survival. Importantly, the majority of events occur in patients without traditional risk factors for cardiac events, highlighting the need for new and better markers of arrhythmic risk. In patients who survive to arrival at hospital, a thorough assessment of the underlying aetiology is required, and where the diagnosis is unclear, further testing including provocation testing and cMRI is warranted. Management of further arrhythmic events is dependent on the underlying aetiology and screening of family members may aid not only in establishing a diagnosis but also in managing arrhythmic risk of first-degree relatives.

References
  1. Chugh SS, Reinier K, Teodorescu C, et al. Epidemiology of sudden cardiac death: clinical and research implications. Prog Cardiovasc Dis 2008;51:213–28.
    Crossref | PubMed
  2. Adabag AS, Luepker RV, Roger VL, Gersh BJ. Sudden cardiac death: epidemiology and risk factors. Nat Rev Cardiol 2010;7:216–25.
    Crossref | PubMed
  3. Myerburg RJ, Reddy V, Castellanos A. Indications for implantable cardioverter-defibrillators based on evidence and judgment. J Am Coll Cardiol 2009;54:747–63.
    Crossref | PubMed
  4. Rea TD, Page RL. Community approaches to improve resuscitation after out-of-hospital sudden cardiac arrest. Circulation 2010;121:1134–40.
    Crossref | PubMed
  5. Estes NA. Predicting and preventing sudden cardiac death. Circulation 2011;124:651–6.
    Crossref | PubMed
  6. Niemeijer MN, van den Berg ME, Leening MJG, et al. Declining incidence of sudden cardiac death from 1990–2010 in a general middle-aged and elderly population: the Rotterdam study. Heart Rhythm 2015;12:123–9.
    Crossref | PubMed
  7. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–37.
    Crossref | PubMed
  8. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324:781–8.
    Crossref | PubMed
  9. Nanthakumar K, Epstein AE, Kay GN, et al. Prophylactic implantable cardioverter-defibrillator therapy in patients with left ventricular systolic dysfunction: a pooled analysis of 10 primary prevention trials. J Am Coll Cardiol 2004;44:2166–72.
    Crossref | PubMed
  10. Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med 1997;337:1576–83.
    Crossref | PubMed
  11. Connolly SJ, Gent M, Roberts RS, et al. Canadian implantable defibrillator study (CIDS): a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation 2000;101:1297–302.
    Crossref | PubMed
  12. Kuck KH, Cappato R, Siebels J, Rüppel R. Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: the cardiac arrest study Hamburg (CASH). Circulation 2000;102:748–54.
    Crossref | PubMed
  13. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996;335:1933–40.
    Crossref | PubMed
  14. Buxton AE, Lee KL, Fisher JD, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. N Engl J Med 1999;341:1882–90.
    Crossref | PubMed
  15. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877–83.
    Crossref | PubMed
  16. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004;350:2151–8.
    Crossref | PubMed
  17. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–37.
    Crossref | PubMed
  18. Moss AJ, Fadl Y, Zareba W, et al. Survival benefit with an implanted defibrillator in relation to mortality risk in chronic coronary heart disease. Am J Cardiol 2001;88:516–20.
    Crossref | PubMed
  19. Køber L, Thune JJ, Nielsen JC, et al. Defibrillator implantation in patients with nonischemic systolic heart failure. N Engl J Med 2016;375:1221–30.
    Crossref | PubMed
  20. 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: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013;10:1932–63.
    Crossref | PubMed
  21. Lyon RM, Cobbe SM, Bradley JM, Grubb NR. Surviving out of hospital cardiac arrest at home: a postcode lottery? Emerg Med Jl 2004;21:619–24.
    Crossref | PubMed
  22. Hasselqvist-Ax I, Riva G, Herlitz J, et al. Early cardiopulmonary resuscitation in out-of-hospital cardiac arrest. N Engl J Med 2015;372:2307–15.
    Crossref | PubMed
  23. Lund-Kordahl I, Olasveengen TM, Lorem T, et al. Improving outcome after out-of-hospital cardiac arrest by strengthening weak links of the local chain of survival; quality of advanced life support and post-resuscitation care. Resuscitation 2010;81:422–6.
    Crossref | PubMed
  24. Yannopoulos D, Bartos JA, Raveendran G, et al. Coronary artery disease in patients with out-of-hospital refractory ventricular fibrillation cardiac arrest. J Am Coll Cardiol 2017;70:1109–17.
    Crossref | PubMed
  25. Boyce LW, Vliet Vlieland TP, Bosch J, et al. High survival rate of 43% in out-of-hospital cardiac arrest patients in an optimised chain of survival. Neth Heart J 2014;23:20–5.
    Crossref | PubMed
  26. Pollack RA, Brown SP, Rea T, et al. Impact of bystander automated external defibrillator use on survival and functional outcomes in shockable observed public cardiac arrests. Circulation 2018;epub ahead of press.
    Crossref | PubMed
  27. Murakami Y, Iwami T, Kitamura T, et al. Outcomes of out-of-hospital cardiac arrest by public location in the public-access defibrillation era. J Am Heart Assoc 2014;3:e000533.
    Crossref | PubMed
  28. Deakin CD, Shewry E, Gray HH. Public access defibrillation remains out of reach for most victims of out-of-hospital sudden cardiac arrest. Heart 2014;100:619–23.
    Crossref | PubMed
  29. Boutilier JJ, Brooks SC, Janmohamed A, et al. Optimizing a drone network to deliver automated external defibrillators. Circulation 2017;135:2454–65.
    Crossref | PubMed
  30. Dumas F, Bougouin W, Geri G, et al. Emergency percutaneous coronary intervention in post–cardiac arrest patients without ST-segment elevation pattern. JACC Cardiovasc Interv 2016;9:1011–8.
    Crossref | PubMed
  31. Rodrigues P, Joshi A, Williams H, et al. Diagnosis and prognosis in sudden cardiac arrest survivors without coronary artery disease: utility of a clinical approach using cardiac magnetic resonance imaging. Circ Cardiovasc Imaging 2017;10:e006709.
    Crossref | PubMed
  32. Herman AR, Cheung C, Gerull B, et al. Outcome of apparently unexplained cardiac arrest: results from investigation and follow-up of the prospective cardiac arrest survivors with preserved cardiac arrest survivors with preserved ejection fraction registry. Circ Arrhythm Electrophysiol 2016;9:e003619.
    Crossref | PubMed
  33. Viskin S, Postema PG, Bhuiyan ZA, et al. The response of the QT interval to the brief tachycardia provoked by standing: a bedside test for diagnosing long QT syndrome. J Am Coll Cardiol 2010;55:1955–61.
    Crossref | PubMed
  34. Wong JA, Gula LJ, Klein GJ, et al. Utility of treadmill testing in identification and genotype prediction in long-QT syndrome. Circ Arrhythm Electrophysiol 2010;3:120–5.
    Crossref | PubMed
  35. Chattha IS, Sy RW, Yee R, et al. Utility of the recovery electrocardiogram after exercise: a novel indicator for the diagnosis and genotyping of long QT syndrome? Heart Rhythm 2010;7:906–11.
    Crossref | PubMed
  36. Obeyesekere MN, Klein GJ, Modi S, et al. How to perform and interpret provocative testing for the diagnosis of Brugada syndrome, long-QT syndrome, and catecholaminergic polymorphic ventricular tachycardia. Circ Arrhythm Electrophysiol 2011;4:958–64.
    Crossref | PubMed
  37. Brugada R, Campuzano O, Sarquella-Brugada P, et al. Brugada Syndrome. Methodist Debakey Cardiovasc 2014;10:25–8.
    PubMed
  38. Poole JE, Mathisen TL, Kudenchuk PJ, et al. Long-term outcome in patients who survive out of hospital ventricular fibrillation and undergo electrophysiologic studies: evaluation by electrophysiologic subgroups. J Am Coll Cardiol 1990;16:657–65.
    Crossref | PubMed
  39. Krahn AD, Healey JS, Chauhan V, et al. Systematic assessment of patients with unexplained cardiac arrest: cardiac arrest survivors with preserved ejection fraction registry (CASPER). Circulation 2009;120:278–85.
    Crossref | PubMed
  40. Wäßnig N, Günther M, Quick S, et al. Experience with the wearable cardioverter-defibrillator in patients at high risk for sudden cardiac death. Circulation 2016;134:635–43.
    Crossref | PubMed
  41. Tung R, Boyle NG, Shivkumar K. Catheter ablation of ventricular tachycardia. Circulation 2011;123:2284–8.
    Crossref | PubMed
  42. Chockalingam P, Crotti L, Girardengo G, et al. Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: higher recurrence of events under metoprolol. J Am Coll Cardiol 2012;60:2092–9.
    Crossref | PubMed
  43. Steinberg C, Padfield GJ, Al-Sabeq B, et al. Experience with bisoprolol in long-QT1 and long-QT2 syndrome. J Interv Card Electrophysiol 2016;47:163–70.
    Crossref | PubMed
  44. Schwartz PJ, Priori SG, Locati EH, et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate: implications for gene-specific therapy. Circulation 1995;92:3381–6.
    Crossref | PubMed
  45. Odero A, Bozzani A, De Ferrari GM, Schwartz PJ. Left cardiac sympathetic denervation for the prevention of life-threatening arrhythmias: the surgical supraclavicular approach to cervicothoracic sympathectomy. Heart Rhythm 2010;7:1161–5.
    Crossref | PubMed
  46. Woosley RL, Heise CW, Romero, KA. QTdrugs List. Available at: crediblemeds.org (Accessed 11 May 2018).
  47. Postema PG, Wolpert C, Amin AS, et al. Drugs and Brugada syndrome patients: review of the literature, recommendations and an up-to-date website (www.brugadadrugs.org). Heart Rhythm 2009;6:1335–41.
    Crossref | PubMed
  48. Nademanee K, Veerakul G, Chandanamattha P, et al. Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation 2011;123:1270–9.
    Crossref | PubMed
  49. Kaneshiro T, Naruse Y, Nogami A, et al. Successful catheter ablation of bidirectional ventricular premature contractions triggering ventricular fibrillation in catecholaminergic polymorphic ventricular tachycardia with RyR2 mutation. Circ Arrhythm Electrophysiol 2012;5:e14–7.
    Crossref | PubMed
  50. Visser M, van der Heijden JF, van der Smagt JJ, et al. Long-term outcome of patients initially diagnosed with idiopathic ventricular fibrillation: a descriptive study. Circ Arrhythm Electrophysiol 2016;9:e004258.
    Crossref | PubMed
  51. Belhassen B, Glick A, Viskin S. Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation 2004;110:1731–7.
    Crossref | PubMed
  52. Knecht S, Sacher F, Wright M, et al. Long-term follow-up of idiopathic ventricular fibrillation ablation: a multicenter study. J Am Coll Cardiol 2009;54:522–8.
    Crossref | PubMed
  53. Philips B, Madhavan S, James C, et al. Outcomes of catheter ablation of ventricular tachycardia in arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Arrhythm Electrophysiol 2012;5:499–505.
    Crossref | PubMed
  54. Honarbakhsh S, Srinivasan N, Kirkby C, et al. Medium-term outcomes of idiopathic ventricular fibrillation survivors and family screening: a multicentre experience. Europace 2017;19:1874–80.
    Crossref | PubMed
  55. Quenin P, Kyndt F, Mabo P, et al. Clinical yield of familial screening after sudden death in young subjects: the French experience. Circ Arrhythm Electrophysiol 2017;10:e005236.
    Crossref | PubMed