This editorial refers to ‘Characteristics and clinical assessment of unexplained sudden cardiac arrest in the real-world setting: focus on idiopathic ventricular fibrillation’†, by V. Waldmann et al., on page 1981. In the absence of structural heart disease, an apparently unexplained cardiac arrest includes an eclectic compilation of latent causes, including long QT syndrome, Brugada syndrome, early repolarization syndrome, and several structural causes. After comprehensive assessment, about half of patients with unexplained cardiac arrest will have a specific aetiology identified, with the remaining indeterminate cases labelled ‘idiopathic ventricular fibrillation’ (IVF).1 In this issue of the journal, Waldmann et al. report the medical evaluation and outcomes among a Parisian cohort of 717 cardiac arrest survivors, focusing on those patients who remained undiagnosed after diagnostic testing.2 Among patients labeled IVF (49 patients), only 16% received a comprehensive assessment, defined as cardiac magnetic resonance (CMR), ergonovine challenge, and pharmacological testing. Although most patients underwent CMR (82%), genetic testing was performed in less than one-fifth and exercise testing in less than one-tenth of individuals. Importantly, family screening occurred in less than a quarter of patients. The authors’ findings highlight the importance of a comprehensive systematic evaluation of cardiac arrest survivors, and gaps in the current delivery of guideline-directed unexplained cardiac arrest assessment. Current guidelines in unexplained cardiac arrest evaluation The current guidelines provide direction but do not fully specify the necessary scope of investigations in a unexplained cardiac arrest survivor, and the Parisian experience reflects a systematic underinvestigation of unexplained cardiac arrest, probably due to both unfamiliarity and the breadth of diagnoses encountered in these patients.3–5 Although a comprehensive evaluation of first-degree relatives can be useful (Class IIa recommendation), no explicit recommendations are made for unexplained cardiac arrest survivors.3–5 Provocative drug challenges with sodium channel blockers (i.e. ajmaline) may be criticized for their poor specificity,6 and the sensitivity of the ergonovine test for coronary vasospasm is controversial.7 Thus, such investigations should only be performed in the appropriate clinical context at experienced multidisciplinary clinics, and in close collaboration with relevant partner experts from imaging, adult and paediatric electrophysiology, and medical genetics. A prospective, comprehensive assessment for structural and electrical diseases should be undertaken (Figure 1), with imaging, provocative tests, genetic testing, and family screening performed in parallel (i.e. diagnosed patients may still benefit from additional genetic testing and family screening). Waldmann et al. present rates of medical investigations ranging from 4% (signal-averaged ECG) to 82% (CMR).2 In the absence of a prospective, comprehensive evaluation of these individuals, we cannot know the true denominator among those labelled ‘idiopathic.’ How many patients could have received a diagnosis despite the apparently ‘unexplained’ cardiac arrest? Figure 1 View largeDownload slide Comprehensive evaluation of unexplained cardiac arrest. *Acetylcholine is used as an alternative agent to provoke coronary spasm. **Discretionary tests. ***Additional rare causes include malignant mitral valve prolapse, other infiltrative cardiomyopathies such as amyloidosis, and familial conduction system disease. MRI, magnetic resonance imaging; CT, computed tomography; PET, positron emission tomography; ARVC, arrhythmogenic right ventricular cardiomyopathy; HCM, hypertrophic cardiomyopathy; DCM, dilated cardiomyopathy including inherited cardiomyopathies; CPVT, catecholaminergic polymorphic ventricular tachycardia; ERS, early repolarization syndrome; SCIVF, short coupled idiopathic ventricular fibrillation. Figure 1 View largeDownload slide Comprehensive evaluation of unexplained cardiac arrest. *Acetylcholine is used as an alternative agent to provoke coronary spasm. **Discretionary tests. ***Additional rare causes include malignant mitral valve prolapse, other infiltrative cardiomyopathies such as amyloidosis, and familial conduction system disease. MRI, magnetic resonance imaging; CT, computed tomography; PET, positron emission tomography; ARVC, arrhythmogenic right ventricular cardiomyopathy; HCM, hypertrophic cardiomyopathy; DCM, dilated cardiomyopathy including inherited cardiomyopathies; CPVT, catecholaminergic polymorphic ventricular tachycardia; ERS, early repolarization syndrome; SCIVF, short coupled idiopathic ventricular fibrillation. Comprehensive evaluation after unexplained cardiac arrest A comprehensive evaluation has several key potential benefits. It can provide a diagnosis (and often ‘peace of mind’), manage or prevent recurrence, and facilitate family screening. Waldmann et al. should be commended for presenting their local data. With approximately one in eight patients receiving a complete evaluation, their findings highlight significant opportunity (and necessity) for improvement in translating evidence into the current healthcare delivery system. Advanced imaging and drug challenges to unmask latent channelopathies requires systematic broad testing to evaluate for a myriad of latent causes. In the Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER), a complete evaluation unmasked the cause of an apparently unexplained cardiac arrest in half of the cases, with each investigation providing incremental diagnostic yield.1 For example, in 174 patients with unexplained cardiac arrest receiving systematic exercise testing, epinephrine, and sodium channel blocker challenges, testing was frequently positive for long QT syndrome (18%), catecholaminergic polymorphic ventricular tachycardia (7%), and Brugada pattern (7%).8,9 Non-invasive testing was performed infrequently in the Parisian cohort (4% signal-averaged ECG, 8% exercise testing), despite the guidelines supporting their use.3–5 Electrophysiological studies were performed occasionally in the Parisian cohort (25%) and may be relevant in provoking bundle branch reentry,10 a novel occult cause of cardiac arrest being systematically investigated in the prospective EPS-ARREST study (NCT03079414). Advanced imaging is an important tool in the structural evaluation of patients with unexplained cardiac arrest after conventional testing is negative, with one-third of patients in the Parisian cohort receiving a diagnosis after CMR (and >80% of ‘IVF’ patients received CMR).2 These findings are consistent with the published experience for CMR, with 19% of patients receiving a diagnosis after CMR.11 Genetic testing was only performed in 18% of Parisian patients, despite studies showing that genetic testing can provide a diagnosis in 13–60% of patients after clinical evaluation.12 Among patients with unexplained cardiac arrest receiving genetic testing in CASPER, pathogenic variants were identified in 17% of patients along with frequent variants of unknown significance (18%).13 The emerging role of whole-exome sequencing may provide greater opportunities to identify genetic contributors in patients with a phenotype–genotype mismatch.14 Importance of family screening The importance of family screening after unexplained cardiac arrest cannot be overstated. Although arriving at a diagnosis in the affected individual is important, there are further benefits of family screening, including identifying relatives at risk, and to determine heritability and prevention planning. Among patients with sudden unexplained death syndrome (SUDS), expert consensus recommends that first-degree relatives, particularly obligate carriers and symptomatic relatives, should be prioritized for evaluation.3 In CASPER, family screening identified cardiac abnormalities in 30% of first-degree relatives.15 Genetic testing was performed in a quarter of family members, and disease-causing mutations were found in 20%.16 Waldmann et al. reported family screening in only 25% of patients.2 How many relatives would have benefited from comprehensive family screening? Arrhythmic outcomes Importantly, comprehensive evaluation and diagnosis may also allow for improved risk stratification and follow-up among patients with unexplained cardiac arrest. For example, a patient with early repolarization or Brugada syndrome should be informed that isoproterenol and quinidine are the treatment of choice for recurrent arrhythmia, with incorporation of these recommendations in their health record and ‘shock plan’. Waldmann et al. reported recurrent ventricular arrhythmias in 21.7% of patients over a median follow-up of 48.7 months (5.7% annual incidence rate).2 Patients with unexplained cardiac arrest in CASPER had a cumulative event rate (ICD shock or antitachycardia pacing) of 23% after 3.15 years follow-up.11 Patients receiving a diagnosis after comprehensive evaluation may be re-classified into a higher or lower risk group, and followed accordingly. Conversely, patients with no identifiable aetiology may have suffered a ‘one-and-done’ cardiac arrest, with a lower risk of recurrence. Further data are required in these uncommon diseases to better understand the natural history and merits of interventions based on diagnostic findings. Adoption of evidence into practice With a growing body of evidence supporting a comprehensive evaluation, it is necessary to develop the systems of care required to support these patients and facilitate the rapid adoption of evidence (and guidelines) into practice. What is the role of the physician experts at dedicated academic centres? The 2013 Consensus Statement on Inherited Arrhythmia Syndromes placed a Class I recommendation for the evaluation of patients and first-degree relatives with diagnosed or suspected inherited conditions to take place at a dedicated clinic (i.e. Inherited Arrhythmia Clinic).3 Clinical evaluation should be performed by a physician specialist in collaboration with genetic counsellors and allied health professionals. These recommendations recognize the emerging body of evidence and the role of the multidisciplinary clinics in incorporating this evidence into practice. With genetic testing becoming increasingly informative and expansive, involvement of genetic counsellors and/or medical geneticists is critical in the interpretation of both suspected and unexpected genetic results (i.e. variants of unknown significance). It is likely that the findings presented by Waldmann et al. are not limited to the Parisian health system, but reflect a systemic under-utilization of comprehensive evaluation and multidisciplinary inherited arrhythmia clinics. Role of patient advocacy In the face of gaps within our health system, it is common for patients and/or affected family members to draw attention to issues and gaps in care. In a qualitative survey of patient needs, patients seen at inherited arrhythmia clinics across Canada reported concerns including questions about their disease, access to specialists, and the lack of psychological support (unpublished data). Given the varying familiarity with inherited arrhythmia syndromes across our health system, patients and family members should be encouraged to seek answers from their physicians in the event of an unexplained cardiac arrest or sudden cardiac death. In Canada, the Hearts In Rhythm Organization (HiRO, www.heartsinrhythm.ca) represents a combined physician–patient partnership to standardize care for patients and family members affected by inherited arrhythmia syndromes. By creating shared protocols and resources between inherited arrhythmia clinics, HiRO strives to ensure access to deliberately cultivated expert care. Conclusion Significant challenges remain in ensuring that cardiac arrest survivors undergo a systematic evaluation. This will lead to informed prevention and management of recurrence, family screening, and the peace of mind that follows resolved uncertainty. Waldmann et al. highlight the many gaps in care, beginning with the scattered and incomplete evaluation of patients, to the limited genetic testing and family screening. Cardiac arrest survivors should undergo a comprehensive series of investigations, ranging from provocative drug challenges to genetic testing (Figure 1). By identifying a diagnosis in previously unexplained cardiac arrest, we can potentially modify arrhythmia recurrence, identify at-risk family members, and provide support for survivors and families. Conflict of interest: A.D.K. receives support from the Heart and Stroke Foundation of Canada, the Sauder Family, the Heart and Stroke Foundation Chair in Cardiology, and the Paul Brunes Chair in Heart Rhythm Disorders. C.C.C. has no relevant conflicts to disclose. References 1 Krahn AD , Healey JS , Chauhan V , Birnie DH , Simpson CS , Champagne J , Gardner M , Sanatani S , Exner DV , Klein GJ , Yee R , Skanes AC , Gula LJ , Gollob MH. Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER) . Circulation 2009 ; 120 : 278 – 285 . Google Scholar CrossRef Search ADS PubMed 2 Waldmann V , Bougouin W , Karam N , Dumas F , Sharifzadehgan A , Gandjbakhch E , Algalarrondo V , Narayanan K , Amet D , Jost D , Geri G , Lamhaut L , Beganton F , Ludes B , Bruneval P , Plu I , Hidden-Lucet F , Albuisson J , Lavergne T , Piot O , Leenhardt A , Lellouche N , Extramiana F , Cariou A , Jouven X , Marijon E , on behalf Paris-SDEC investigators. Characteristics and clinical assessment of unexplained sudden cardiac arrest in the real-world setting: focus on idiopathic ventricular fibrillation . Eur Heart J 2018 ; 39 : 1981 – 1987 . 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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
European Heart Journal – Oxford University Press
Published: Mar 23, 2018
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