Advertisement

European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus on risk assessment in cardiac arrhythmias: use the right tool for the right outcome, in the right population

Open AccessPublished:June 15, 2020DOI:https://doi.org/10.1016/j.hrthm.2020.05.004

      Introduction

      Patients with cardiac diseases or conditions with high risk of developing cardiac diseases undergo risk assessment by cardiologists, primary care physicians, and scientists based on referral for more advanced risk assessment strategies, institution of preventive treatments, counselling of patients and their relatives, and selection of patients for scientific trials. The various methods used for risk assessment differ with respect to availability, complexity, and usefulness in different patient populations. Parameters associated with increased risk of e.g. death may also be associated with higher risk of other adverse outcomes. However, risk assessment strategies including specific methods for risk assessment and risk scores should be used only for the purposes for which they are validated.
      This expert consensus statement of the European Heart Rhythm Association (EHRA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Heart Rhythm Society (LAHRS) summarizes the consensus of the international writing group based on a thorough review of the medical literature regarding risk assessment in cardiac arrhythmias. To create a tool for clinicians to perform rational and evidence-based risk stratification, this task force was set down by EHRA, HRS, LAHRS, and APHRS, including representatives from each of the four societies.
      With this document, we intend to describe and review status of performing risk assessment in different patient populations with cardiac diseases or conditions with high risk of developing such. Our objectives are to raise awareness of using the right risk assessment tool for a given outcome in a given population, and to provide physicians with practical proposals that may lead to improvement of patient care in this regard. For quick reference, sub-chapters start with a short section on consensus statements. The document concludes with a summary of consensus statements.

       Evidence review

      Members of the Task Force were asked to perform a detailed literature review using PubMed and EMBASE, weigh the strength of evidence for or against a particular treatment or procedure, and include estimates of expected health outcomes for which data exist. Patient-specific modifiers, comorbidities, and issues of patient preference that might influence the choice of particular tests are considered, as are frequency of follow-up and cost-effectiveness. In controversial areas, or with regard to issues without evidence other than usual clinical practice, consensus was achieved by agreement of the expert panel after thorough deliberations. This document was prepared by the Task Force and peer-reviewed by official external reviewers representing EHRA, HRS, APHRS, and LAHRS.
      Consensus statements are evidence-based and derived primarily from published data or determined through consensus opinion if no data available. Current systems of ranking level of evidence are becoming complicated in a way that might compromise their practical utility.
      • Benhorin J.
      • Bodenheimer M.
      • Brown M.
      • Case R.
      • Dwyer Jr., E.M.
      • Eberly S.
      • et al.
      Improving clinical practice guidelines for practicing cardiologists.
      In contrast to guidelines, we opted for an easier user-friendly system of ranking using ‘coloured hearts’ that should allow physicians to easily assess the current status of the evidence and consequent guidance (Table 1). This EHRA grading of consensus statements does not have separate definitions of the level of evidence. The categorization used for consensus statements must not be considered directly similar to the one used for official society guideline recommendations which apply a classification (Class I–III) and level of evidence (A, B, and C) to recommendations used in official guidelines.
      Table 1Scientific rationale of consensus statements
      Definitions related to a treatment or procedureConsensus statement instructionSymbol
      Scientific evidence that a treatment or procedure is beneficial and effective. Requires at least one randomized trial, or is supported by strong observational evidence and authors’ consensus (as indicated by an asterisk).‘Should do this’
      General agreement and/or scientific evidence favor the usefulness/efficacy of a treatment or procedure. May be supported by randomized trials based on a small number of patients or not widely applicable.‘May do this’
      Scientific evidence or general agreement not to use or recommend a treatment or procedure.‘Do not do this’
      The categorization for our consensus document should not be considered directly similar to the one used for official society guideline recommendations, which apply a classification (I–III) and level of evidence (A, B, and C) to recommendations.
      Thus, a green heart indicates a ‘should do this’ consensus statement or indicated risk assessment strategy based on at least one randomized trial or supported by strong observational evidence that it is beneficial and effective. A yellow heart indicates general agreement and/or scientific evidence favoring a ‘may do this’ statement or the usefulness/efficacy of a risk assessment strategy or procedure. A ‘yellow heart’ symbol may be supported by randomized trials based on a small number of patients or not widely applicable. Risk assessment strategies for which there is scientific evidence of no benefit or potential harm and should not be used (‘do not do this’) are indicated by a red heart.
      Finally, this consensus document includes evidence and expert opinions from several countries. The risk assessment approaches discussed may therefore include tests not approved by governmental regulatory agencies in all countries.

       Relationships with industry and other conflicts

      All members of the writing group, as well as reviewers, have disclosed any potential conflicts of interest. Details are available in supplementary material online.
      All consensus statements were voted upon by the writing committee independently and reached the predefined level of ≥75% consensus for inclusion in consensus statement tables. Each partner society officially reviewed the document, and all reviewer comments were addressed. Each partner society approved the final document and consensus statements.

      General tools for risk assessment, strengths, limitations, and pretest probability

       Value of clinical history and characteristics including clinical risk scores such as CHA2DS2-VASc

      Clinical assessment of the patient with cardiac arrhythmias starts with a good clinical history and basic investigations for an underlying etiological factor for the arrhythmia or its associated complication(s). In addition, an assessment of the risks and benefits of any therapeutic intervention should be made, and appropriate management initiated.
      Following on from clinical history and assessment, there is a proposal toward a more integrated and holistic approach to arrhythmia management, as evident in guidelines. Such an integrated approach requires multidisciplinary teams of healthcare professionals, patient involvement, access to treatment options, and decision-support tools to optimize the patient journey. Many proposals have been made towards the operationalization of such an integrated approach to risk assessment and practical management in cardiac arrhythmias, which has been of varying complexity. As an example, the management of atrial fibrillation (AF) has been simplified into the ABC pathway (‘A’ Avoid stroke with Anticoagulation; ‘B’ Better symptom management, with patient-centered and symptom-directed decisions on rate or rhythm control; ‘C’ Cardiovascular and comorbidity risk management), which has been shown to be associated with improved clinical outcomes and reduced healthcare costs.
      • Lip G.
      The ABC pathway: an integrated approach to improve AF management.
      • Proietti M.
      • Romiti G.F.
      • Olshansky B.
      • Lane D.A.
      • Lip G.
      Improved outcomes by integrated care of anticoagulated patients with atrial fibrillation using the simple ABC (Atrial Fibrillation Better Care) pathway.
      • Pastori D.
      • Pignatelli P.
      • Menichelli D.
      • Violi F.
      • Lip G.
      Integrated care management of patients with atrial fibrillation and risk of cardiovascular events: the ABC (Atrial fibrillation Better Care) pathway in the ATHERO-AF study cohort.
      • Pastori D.
      • Farcomeni A.
      • Pignatelli P.
      • Violi F.
      • Lip G.Y.
      ABC (Atrial fibrillation Better Care) pathway and healthcare costs in atrial fibrillation: the ATHERO-AF study.
      • Yoon M.
      • Yang P.S.
      • Jang E.
      • Yu H.T.
      • Kim T.H.
      • Uhm J.S.
      • et al.
      Improved population-based clinical outcomes of patients with atrial fibrillation by compliance with the simple ABC (Atrial Fibrillation Better Care) pathway for integrated care management: a nationwide cohort study.
      This makes a strong argument for using the right approaches and clinical tools for patient assessment, but using them appropriately for the reasons they were first proposed (e.g. stroke risk scores to assess stroke risk, and not other outcomes).
      Taking AF as an illustrative example with regard to using the right score for the right reason there are many risk factors for stroke (but the more common and validated ones have been used to formulate risk stratification tools).
      • Lip G.
      • Freedman B.
      • De Caterina R.
      • Potpara T.S.
      Stroke prevention in atrial fibrillation: past, present and future. Comparing the guidelines and practical decision-making.
      The most common in use is the CHA2DS2-VASc score,
      • Borre E.D.
      • Goode A.
      • Raitz G.
      • Shah B.
      • Lowenstern A.
      • Chatterjee R.
      • et al.
      Predicting thromboembolic and bleeding event risk in patients with non-valvular atrial fibrillation: a systematic review.
      but it is not meant to include every possible stroke risk factor, and was designed to be simple, reductionist and practical to help decision-making for stroke risk. As with all clinical scores based on clinical factors, the CHA2DS2-VASc score only performs modestly for predicting high-risk patients who sustain events. The use of more clinical factors and biomarkers improves prediction (at least statistically), but the practical added value is marginal and less impressive in real-world cohorts.
      • Lip G.Y.H.
      • Banerjee A.
      • Boriani G.
      • Chiang C.E.
      • Fargo R.
      • Freedman B.
      • et al.
      Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report.
      ,
      • Rivera-Caravaca J.M.
      • Marin F.
      • Vilchez J.A.
      • Galvez J.
      • Esteve-Pastor M.A.
      • Vicente V.
      • et al.
      Refining stroke and bleeding prediction in atrial fibrillation by adding consecutive biomarkers to clinical risk scores.
      Use of simplified scores to artificially categorize patients into low-, moderate-, and high-risk strata can be problematic, as in the real-world patients do not necessarily fall into three neat categories of risk. Also, not all risk factors carry equal weight, hence, the move to focus the initial decision-making on identifying low-risk patients who do not need antithrombotic therapy first, following which stroke prevention can be offered to AF patients with ≥1 stroke risk factors.
      • Lip G.Y.H.
      • Banerjee A.
      • Boriani G.
      • Chiang C.E.
      • Fargo R.
      • Freedman B.
      • et al.
      Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report.
      Stroke risk is also highly dynamic, and although logistically challenging, a clinical reassessment may be needed every 4–6 months to optimize risk re-assessment.
      • Yoon M.
      • Yang P.S.
      • Jang E.
      • Yu H.T.
      • Kim T.H.
      • Uhm J.S.
      • et al.
      Dynamic changes of CHA2DS2-VASc score and the risk of ischaemic stroke in Asian patients with atrial fibrillation: a nationwide cohort study.
      • Chao T.F.
      • Liao J.N.
      • Tuan T.C.
      • Lin Y.J.
      • Chang S.L.
      • Lo L.W.
      • et al.
      Incident co-morbidities in patients with atrial fibrillation initially with a CHA2DS2-VASc score of 0 (males) or 1 (females): implications for reassessment of stroke risk in initially ‘low-risk’ patients.
      • Chao T.F.
      • Lip G.Y.H.
      • Liu C.J.
      • Lin Y.J.
      • Chang S.L.
      • Lo L.W.
      • et al.
      Relationship of aging and incident comorbidities to stroke risk in patients with atrial fibrillation.
      As the CHA2DS2-VASc is a cluster of common cardiovascular risk factors, it is predictive of death, cardiovascular hospitalizations, and other adverse outcomes that the CHA2DS2-VASc score was not designed for. Also, given that many components of the CHA2DS2-VASc score are associated with incident AF, the CHA2DS2-VASc score is used to predict new onset AF, again something it was not designed for. Another misuse of the CHA2DS2-VASc score is the prediction of bleeding risk. Nevertheless, formal comparisons show that the CHA2DS2-VASc (and older CHA2DS2) score are inferior to a formal bleeding risk score such as the HAS-BLED score, for the prediction of major bleeding in AF patients.
      • Apostolakis S.
      • Lane D.A.
      • Buller H.
      • Lip G.Y.
      Comparison of the CHADS2, CHA2DS2-VASc and HAS-BLED scores for the prediction of clinically relevant bleeding in anticoagulated patients with atrial fibrillation: the AMADEUS trial.
      Indeed, bleeding risk is also highly dynamic, and the appropriate use of bleeding risk scores such as HAS-BLED is to address modifiable bleeding risk factors (e.g. uncontrolled hypertension, labile INR, concomitant aspirin, or NSAID use) then to schedule the ‘high-risk’ patients for early and more frequent follow-up visits (e.g. 4 weeks rather than 4 months).
      • Chao T.F.
      • Lip G.Y.H.
      • Lin Y.J.
      • Chang S.L.
      • Lo L.W.
      • Hu Y.F.
      • et al.
      Incident risk factors and major bleeding in patients with atrial fibrillation treated with oral anticoagulants: a comparison of baseline, follow-up and delta HAS-BLED scores with an approach focused on modifiable bleeding risk factors.
      Only focusing on modifiable bleeding risk factors is an inferior strategy for bleeding risk assessment, compared to the HAS-BLED score.
      • Borre E.D.
      • Goode A.
      • Raitz G.
      • Shah B.
      • Lowenstern A.
      • Chatterjee R.
      • et al.
      Predicting thromboembolic and bleeding event risk in patients with non-valvular atrial fibrillation: a systematic review.
      We should use the scores only for the purposes they were designed for. Attention to appropriate methodology, statistics, etc., as well as other clinical states, merits consideration e.g. sudden death prediction (or failed ablation, device infection, etc.), Charlson Comorbidity Index, frailty, etc.—but using the right score designed for that purpose.
      If appropriately used, some of these (simplified) tools help with clinical management. Indeed, the value of a medical test is measured by its accuracy as well as how it impacts medical decisions and ultimately patient health. As medical tests are considered and new ones emerge, they should be considered and evaluated in a framework of accuracy and patient impact.
      • Ferrante di Ruffano L.
      • Hyde C.J.
      • McCaffery K.J.
      • Bossuyt P.M.
      • Deeks J.J.
      Assessing the value of diagnostic tests: a framework for designing and evaluating trials.
      A test must not only be accurate, but also feasible. Tests that are difficult to reproduce, subject to technical failures, or difficult to interpret are likely to impact patient care as a consequence of a primary failure to produce a definitive and actionable result.

       Electrocardiographic methods including monitoring

      Tabled 1
      Electrocardiographic methods including monitoringClassReferences
      Twelve-lead electrocardiogram (ECG) should be obtained in all patients undergoing evaluation for known or suspected heart disease.
      • Goldberger J.J.
      • Cain M.E.
      • Hohnloser S.H.
      • Kadish A.H.
      • Knight B.P.
      • Lauer M.S.
      • et al.
      American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society scientific statement on noninvasive risk stratification techniques for identifying patients at risk for sudden cardiac death: a scientific statement from the American Heart Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on Epidemiology and Prevention.
      The 12-lead ECG provides diagnostic and prognostic information in patients with inherited high-risk syndromes including long QT syndrome (LQTS), short QT syndrome, Brugada syndrome, and arrhythmogenic cardiomyopathy (ACM) and should be obtained.
      • Goldberger J.J.
      • Cain M.E.
      • Hohnloser S.H.
      • Kadish A.H.
      • Knight B.P.
      • Lauer M.S.
      • et al.
      American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society scientific statement on noninvasive risk stratification techniques for identifying patients at risk for sudden cardiac death: a scientific statement from the American Heart Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on Epidemiology and Prevention.
      Exercise ECG provides diagnostic and prognostic information for patients with LQTS ACM, hypertrophic cardiomyopathy (HCM), catecholaminergic polymorphic ventricular tachycardia, and documented or suspected arrhythmias related to exertion, and should be obtained.
      • Goldberger J.J.
      • Cain M.E.
      • Hohnloser S.H.
      • Kadish A.H.
      • Knight B.P.
      • Lauer M.S.
      • et al.
      American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society scientific statement on noninvasive risk stratification techniques for identifying patients at risk for sudden cardiac death: a scientific statement from the American Heart Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on Epidemiology and Prevention.
      Ambulatory ECG evidence of non-sustained ventricular tachycardia provides prognostic information in ischemic cardiomyopathy, ACM, and HCM and should be obtained.
      • Goldberger J.J.
      • Cain M.E.
      • Hohnloser S.H.
      • Kadish A.H.
      • Knight B.P.
      • Lauer M.S.
      • et al.
      American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society scientific statement on noninvasive risk stratification techniques for identifying patients at risk for sudden cardiac death: a scientific statement from the American Heart Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on Epidemiology and Prevention.
      The signal-averaged ECG and QRS fragmentation may aid in the diagnosis of ACM.
      • Verrier R.L.
      • Klingenheben T.
      • Malik M.
      • El-Sherif N.
      • Exner D.V.
      • Hohnloser S.H.
      • et al.
      Microvolt T-wave alternans physiological basis, methods of measurement, and clinical utility—consensus guideline by International Society for Holter and Noninvasive Electrocardiology.
      The signal-averaged ECG and QRS fragmentation may be useful in risk stratification of Brugada syndrome.
      • Verrier R.L.
      • Klingenheben T.
      • Malik M.
      • El-Sherif N.
      • Exner D.V.
      • Hohnloser S.H.
      • et al.
      Microvolt T-wave alternans physiological basis, methods of measurement, and clinical utility—consensus guideline by International Society for Holter and Noninvasive Electrocardiology.
      Heart rate variability, heart rate turbulence, signal-averaged ECG, and T wave alternans analysis, when used in combination with additional clinical, electrocardiographic, and structural measures, may be useful for identifying high- and low-risk groups among patients with acquired structural heart disease.
      He art rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology.

       Electrocardiographic methods

      The ECG is the gold standard for risk assessment in patients with or at risk of developing cardiac arrhythmias. The 12-lead ECG is inexpensive and widely available. Risk stratification with the ECG is limited in general by its low positive predictive value (PPV) determined to a large extent by the low prevalence of cardiovascular events in the general population. However, the prognostic significance of the ECG is enhanced in patients with heart disease.

       P wave and PR interval

      The prognostic value of P wave characteristics has been examined in subjects enrolled in clinical trials of AF for prediction of the development of AF, where maximum P wave duration was a significant independent risk marker for the development of AF over 10 years.
      • De Bacquer D.
      • Willekens J.
      • De Backer G.
      Long-term prognostic value of p-wave characteristics for the development of atrial fibrillation in subjects aged 55 to 74 years at baseline.
      This observation was confirmed by epidemiologic/population studies (including ARIC and the Copenhagen ECG studies) that showed increased risk of AF in patients with prolonged P wave duration and PR interval prolongation,
      • Cheng M.
      • Lu X.
      • Huang J.
      • Zhang S.
      • Gu D.
      Electrocardiographic PR prolongation and atrial fibrillation risk: a meta-analysis of prospective cohort studies.
      • Magnani J.W.
      • Johnson V.M.
      • Sullivan L.M.
      • Gorodeski E.Z.
      • Schnabel R.B.
      • Lubitz S.A.
      • et al.
      P wave duration and risk of longitudinal atrial fibrillation in persons >/= 60 years old (from the Framingham Heart Study).
      • Nielsen J.B.
      • Kuhl J.T.
      • Pietersen A.
      • Graff C.
      • Lind B.
      • Struijk J.J.
      • et al.
      P-wave duration and the risk of atrial fibrillation: results from the Copenhagen ECG Study.
      and summarized in a review by Nikolaidou et al.
      • Nikolaidou T.
      • Ghosh J.M.
      • Clark A.L.
      Outcomes related to first-degree atrioventricular block and therapeutic implications in patients with heart failure.
      Moreover, a prolonged P wave duration was determined as a sensitive predictor of post-operative AF in patients undergoing coronary artery bypass grafting (CABG).
      • Buxton A.E.
      • Josephson M.E.
      The role of P wave duration as a predictor of postoperative atrial arrhythmias.
      The definition of an abnormal P wave varies greatly depending on how it is measured, and definitions vary depending on whether P wave area, duration, terminal forces in lead V1 or signal-averaged P wave are analysed. Abnormal P wave morphology was associated with incident stroke in the Multi-Ethnic Study of Atherosclerosis.
      • Kamel H.
      • Soliman E.Z.
      • Heckbert S.R.
      • Kronmal R.A.
      • Longstreth Jr., W.T.
      • Nazarian S.
      • et al.
      P-wave morphology and the risk of incident ischemic stroke in the Multi-Ethnic Study of Atherosclerosis.
      The prognostic significance of PR interval prolongation, which is variably defined as PR intervals greater than 196–220 ms, is controversial and depends on the patient population studied. Most studies show that PR interval prolongation is not associated with increased mortality in healthy middle-aged individuals during medium term follow-up. On the other hand, a number of reports show worse survival in patients with suspected heart failure (acute and chronic) or heart disease [coronary artery disease (CAD)]. Additionally, PR prolongation and P wave prolongation predict increased risk of AF and the greater degrees of PR prolongation and P wave duration predicted higher risks of AF.
      • Nikolaidou T.
      • Pellicori P.
      • Zhang J.
      • Kazmi S.
      • Goode K.M.
      • Cleland J.G.
      • et al.
      Prevalence, predictors, and prognostic implications of PR interval prolongation in patients with heart failure.
      ,
      • Aro A.L.
      • Anttonen O.
      • Kerola T.
      • Junttila M.J.
      • Tikkanen J.T.
      • Rissanen H.A.
      • et al.
      Prognostic significance of prolonged PR interval in the general population.
      An increased PR interval is also associated with poor cardiovascular outcomes in patients with AF.
      • Andrade J.G.
      • Roy D.
      • Wyse D.G.
      • Dorian P.
      • Talajic M.
      • Leduc H.
      • et al.
      ECG features associated with adverse cardiovascular outcomes in patients with atrial fibrillation: a combined AFFIRM and AF-CHF analysis.
      Several studies have shown that PR prolongation in patients undergoing cardiac pacing or receiving cardiac resynchronization therapy (CRT) is an independent predictor of worse prognosis and lower probability of reverse remodelling as well as an increased risk of AF, death, and hospitalization.
      • Januszkiewicz L.
      • Vegh E.
      • Borgquist R.
      • Bose A.
      • Sharma A.
      • Orencole M.
      • et al.
      Prognostic implication of baseline PR interval in cardiac resynchronization therapy recipients.
      ,
      • Rickard J.
      • Karim M.
      • Baranowski B.
      • Cantillon D.
      • Spragg D.
      • Tang W.H.W.
      • et al.
      Effect of PR interval prolongation on long-term outcomes in patients with left bundle branch block vs non-left bundle branch block morphologies undergoing cardiac resynchronization therapy.
      There are no data indicating whether the degree of PR prolongation portends a worse outcome compared to patients who have lesser degrees of PR prolongation, nor is there information on its prognostic value in acute inferior wall myocardial infarction (MI).

       QRS, QT interval, and T-wave

      Over the years, a number of ECG techniques have been developed to assess risk of ventricular tachyarrhythmias (VTs). These have the advantage of being non-invasive and, often, inexpensive. For almost all of these techniques, there are conflicting data, and not one technique has proven beneficial in patients with structural heart disease. Moreover, studies have varied in their reporting of sudden arrhythmic death vs. total mortality. Among the risk predictors shown to have value are QRS widening and fragmentation, QT prolongation, T-wave abnormalities, and ventricular ectopy. Although the prognostic value of each ECG parameter in isolation is limited, in combination with additional ECG, imaging, and genetic testing, these parameters can contribute to effective risk stratification.

       QRS

      QRS prolongation has been associated with all-cause mortality in heart failure patients, implantable cardioverter-defibrillator (ICD) shocks, and inducibility of sustained VT. QRS prolongation in patients on Class IC antiarrhythmic drugs is a predictor of pro-arrhythmia, and should be monitored, particularly during exercise. QRS prolongation predicts risk in patients with myotonic dystrophy and in Brugada syndrome. Additional prognostic information from the QRS is obtained from the signal-averaged ECG, which amplifies the QRS, averages multiple complexes to reduce noise, and filters out the T-wave in order to detect late potentials, and provides evidence of slow conduction substrate that associates with risk of re-entry tachyarrhythmias.
      • Goldberger J.J.
      • Cain M.E.
      • Hohnloser S.H.
      • Kadish A.H.
      • Knight B.P.
      • Lauer M.S.
      • et al.
      American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society scientific statement on noninvasive risk stratification techniques for identifying patients at risk for sudden cardiac death: a scientific statement from the American Heart Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on Epidemiology and Prevention.
      The signal-averaged ECG has been used to detect risk of ventricular arrhythmias in post-infarction patients, ACM, and Brugada syndrome. Although its specificity is limited, its negative predictive value is high, particularly in survivors of inferior wall myocardial infarction. The signal-averaged ECG is not useful in patients with underlying bundle branch block. QRS fragmentation, which includes abnormally notched narrow and wide QRS complexes, is associated with the presence of myocardial scar and is also associated with mortality in patients with cardiomyopathy and with Brugada syndrome.
      • Das M.K.
      • Zipes D.P.
      Fragmented QRS: a predictor of mortality and sudden cardiac death.
      The presence of an unprovoked type 1 Brugada syndrome pattern is associated with increased risk as is discussed later in the document.

       QT interval

      Measurement of the QT interval can be complicated by QRS prolongation and by the need to correct for heart rate, as has been described elsewhere.
      • Rautaharju P.M.
      • Surawicz B.
      • Gettes L.S.
      • Bailey J.J.
      • Childers R.
      • Deal B.J.
      • et al.
      Heart Rhythm Society. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: Part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: endorsed by the International Society for Computerized Electrocardiology.
      Despite these limitations, prolongation of the heart rate-corrected QT interval (QTc) has been associated with mortality in several population studies.
      • Elming H.
      • Holm E.
      • Jun L.
      • Torp-Pedersen C.
      • Kober L.
      • Kircshoff M.
      • et al.
      The prognostic value of the QT interval and QT interval dispersion in all-cause and cardiac mortality and morbidity in a population of Danish citizens.
      ,
      • Dekker J.M.
      • Crow R.S.
      • Hannan P.J.
      • Schouten E.G.
      • Folsom A.R.
      • Study A.
      Heart rate-corrected QT interval prolongation predicts risk of coronary heart disease in black and white middle-aged men and women: the ARIC study.
      In congenital long QT syndrome (LQTS), the length of the QT interval is a major predictor of risk of cardiac events, including sudden cardiac death (SCD). When initiating QT-prolonging drugs such as sotalol or dofetilide, a QT interval of 500 ms or higher should prompt reduction or discontinuation of the offending drug(s).

       QT dispersion

      This measure of ventricular repolarization heterogeneity is typically defined from the 12-lead ECG as the QTmax − QTmin. It has been used to predict a wide variety of events, including ventricular pro-arrhythmia, VTs, although the sensitivity, specificity, and accuracy are poorly defined and highly dependent on the patient population studied.
      • Chieng T.M.
      • Hau Y.W.
      • Lim C.W.
      Ventricular tachyarrhythmias prediction methods and its prognostic features: a review.

       T wave

      T wave inversions are common and may be non-specific or may signal important abnormalities such as ischemia or hypertrophy. Widespread deep T wave inversions in combination with QT prolongation, such as may occur in acute stress cardiomyopathy, can be associated with torsades de pointes. Abnormal T wave notching can be a clue to abnormal repolarization and is often seen in patients with QT prolongation. Computerized T-wave analytic techniques such as principal component analysis, T-wave residuum, flatness, asymmetry, and notching have been developed in an effort to detect and quantify abnormal repolarization and may have particular value in identifying patients with LQTS.
      • Prenner S.B.
      • Shah S.J.
      • Goldberger J.J.
      • Sauer A.J.
      Repolarization heterogeneity: beyond the QT interval.
      ,
      • Porta-Sanchez A.
      • Spillane D.R.
      • Harris L.
      • Xue J.
      • Dorsey P.
      • Care M.
      • et al.
      T-wave morphology analysis in congenital long QT syndrome discriminates patients from healthy individuals.
      Moreover, it has been shown that adding T-wave morphology characterizations to age, gender, and QTc in a support vector machine model can improve LQTS diagnosis.
      • Hermans B.J.M.
      • Bennis F.C.
      • Vink A.S.
      • Koopsen T.
      • Lyon A.
      • Wilde A.A.M.
      • et al.
      Improving long-QT syndrome diagnosis by a polynomial-based T-wave morphology characterization.
      However, these additional analytic techniques are not used in routine clinical practice.
      The Tpeak-end interval, measured from the peak to the end of the T-wave, thought to reflect heterogeneity of repolarization in the heart, has been associated with arrhythmic risk in various populations.
      • Panikkath R.
      • Reinier K.
      • Uy-Evanado A.
      • Teodorescu C.
      • Hattenhauer J.
      • Mariani R.
      • et al.
      Prolonged Tpeak-to-tend interval on the resting ECG is associated with increased risk of sudden cardiac death.
      However, considerable controversy remains as to how it should be measured and applied.
      • Malik M.
      • Huikuri H.
      • Lombardi F.
      • Schmidt G.
      Zabel M; on behalf of e-Rhythm Study Group of EHRA. Conundrum of the Tpeak-Tend interval.
      T-wave alternans is a beat-to-beat alternation of T wave morphology. When seen with the naked eye, it usually accompanies marked QT prolongation and is a harbinger of imminent torsades de pointes. Analysis of more subtle T-wave alternans has been used for assessing abnormal and heterogeneous repolarization to predict mortality and arrhythmic risk. Abnormal microvolt T-wave alternans assessed using the spectral method during graded exercise has a high negative predictive value and has been used to identify a subgroup of patients with reduced ejection fraction who are not likely to benefit from defibrillator implantation.
      • Verrier R.L.
      • Klingenheben T.
      • Malik M.
      • El-Sherif N.
      • Exner D.V.
      • Hohnloser S.H.
      • et al.
      Microvolt T-wave alternans physiological basis, methods of measurement, and clinical utility—consensus guideline by International Society for Holter and Noninvasive Electrocardiology.
      Microvolt T-wave alternans analysis cannot be performed when the rhythm is AF, and patients with ventricular pacing have not been studied extensively.

       Early repolarization

      Early repolarization pattern, highly prevalent in the overall population, defined as an elevation of the J point of at least 0.1 mV, may occur in the anteroseptal or inferolateral leads. In 2008, Haissaguerre reported an association of inferolateral early repolarization with increased risk of idiopathic ventricular fibrillation (VF) in a case–control study
      • Haissaguerre M.
      • Derval N.
      • Sacher F.
      • Jesel L.
      • Deisenhofer I.
      • de Roy L.
      • et al.
      Sudden cardiac arrest associated with early repolarization.
      and subsequently confirmed in other case–control studies. Exercise testing or isoproterenol testing improved the pattern of repolarization, and the pattern was accentuated with exposure to beta-adrenergic blockers. In a meta-analysis of population-based studies, inferolateral early repolarization was associated with increased risk of arrhythmic death, but the risk was still quite low in general (70/100 000 patient-years).
      • Wu S.H.
      • Lin X.X.
      • Cheng Y.J.
      • Qiang C.C.
      • Zhang J.
      Early repolarization pattern and risk for arrhythmia death: a meta-analysis.
      It appears that individuals at highest risk have early repolarization in multiple (especially inferior) leads, with high voltage (at least 0.2 mV), and with notching or horizontal/down-sloping ST segments. Early repolarization is especially prevalent in young men, particularly young black men, and in athletes.
      • Aagaard P.
      • Baranowski B.
      • Aziz P.
      • Phelan D.
      Early repolarization in athletes: a review.
      Because the absolute risk of arrhythmic death is so low, asymptomatic individuals with early repolarization, even those with higher risk ECG patterns, do not require further evaluation except when there is a strong family history of sudden cardiac death or when the J point elevation is associated with Brugada syndrome (discussed later in this document) or short QT syndrome (SQT).

       Ambulatory electrocardiographic monitoring

      In 1984, Bigger et al. showed that ventricular ectopy recorded on a Holter monitor, especially when combined with a low left ventricular ejection fraction (LVEF), predicted a higher risk of mortality in post-infarction patients compared to those without ectopy.
      • Bigger Jr., J.T.
      • Fleiss J.L.
      • Kleiger R.
      • Miller J.P.
      • Rolnitzky L.M.
      The relationships among ventricular arrhythmias, left ventricular dysfunction, and mortality in the 2 years after myocardial infarction.
      Non-sustained VT is also associated with increased risk in patients with arrhythmogenic and hypertrophic cardiomyopathy (HCM). Other data that can be extracted from ambulatory monitoring include heart rate, heart rate variability, and heart rate turbulence measurements, which can predict mortality risk at least in ischemic cardiomyopathy (ICM), but have not been incorporated into clinical practice.
      He art rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology.
      ,
      • Schmidt G.
      • Malik M.
      • Barthel P.
      • Schneider R.
      • Ulm K.
      • Rolnitzky L.
      • et al.
      Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction.

       Imaging

      Tabled 1
      Imaging (echo, computed tomography (CT), magnetic resonance imaging (MRI), perfusion)ClassReferences
      Echocardiography should be used to evaluate EF for risk assessment for primary prevention of sudden cardiac death and the presence of structural heart disease. Alternatively, MRI or cardiac CT can be used.
      • Solomon S.D.
      • Zelenkofske S.
      • McMurray J.J.
      • Finn P.V.
      • Velazquez E.
      • Ertl G.
      • et al.
      Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both.
      ,
      • Gula L.J.
      • Klein G.J.
      • Hellkamp A.S.
      • Massel D.
      • Krahn A.D.
      • Skanes A.C.
      • et al.
      Ejection fraction assessment and survival: an analysis of the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).
      Cardiac MRI is useful in assessing etiology-driven risk of VT and for the presence of scar or myocardial inflammation.
      • Di Marco A.
      • Anguera I.
      • Schmitt M.
      • Klem I.
      • Neilan T.G.
      • White J.A.
      • et al.
      Late gadolinium enhancement and the risk for ventricular arrhythmias or sudden death in dilated cardiomyopathy: systematic review and meta-analysis.
      • Coleman G.C.
      • Shaw P.W.
      • Balfour P.C.
      • Gonzalez J.A.
      • Kramer C.M.
      • Patel A.R.
      • et al.
      Prognostic value of myocardial scarring on CMR in patients with cardiac sarcoidosis.
      • Greulich S.
      • Deluigi C.C.
      • Gloekler S.
      • Wahl A.
      • Zürn C.
      • Kramer U.
      • et al.
      CMR imaging predicts death and other adverse events in suspected cardiac sarcoidosis.
      Cardiac positron emission tomography may be useful for the assessment of etiology-driven risk of ventricular arrhythmias and the presence of scar or myocardial inflammation in patients without CAD.
      • Naruse Y.
      • Sekiguchi Y.
      • Nogami A.
      • Okada H.
      • Yamauchi Y.
      • Machino T.
      • et al.
      Systematic treatment approach to ventricular tachycardia in cardiac sarcoidosis.
      ,
      • Blankstein R.
      • Osborne M.
      • Naya M.
      • Waller A.
      • Kim C.K.
      • Murthy V.L.
      • et al.
      Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis.

       Risk assessment of ventricular tachyarrhythmia using imaging modalities

      Evaluation for the presence of structural heart disease (SHD) is important for patients suspected of being at risk for sudden cardiac death. Left ventricular ejection fraction remains the key independent parameter for risk stratification of sudden cardiac death and to guide implantation of an ICD.
      • Solomon S.D.
      • Zelenkofske S.
      • McMurray J.J.
      • Finn P.V.
      • Velazquez E.
      • Ertl G.
      • et al.
      Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both.
      ,
      • Gula L.J.
      • Klein G.J.
      • Hellkamp A.S.
      • Massel D.
      • Krahn A.D.
      • Skanes A.C.
      • et al.
      Ejection fraction assessment and survival: an analysis of the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).
      Randomized controlled trials have shown a survival benefit from ICDs in patients with SHD and an EF ≤35%.
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • Daubert J.P.
      • Higgins S.L.
      • Klein H.
      • et al.
      Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia.
      • Moss A.J.
      • Zareba W.
      • Hall W.J.
      • Klein H.
      • Wilber D.J.
      • Cannom D.S.
      • et al.
      Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction.
      • Bardy G.H.
      • Lee K.L.
      • Mark D.B.
      • Poole J.E.
      • Packer D.L.
      • Boineau R.
      • et al.
      Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
      Although EF is currently the only proven imaging modality demonstrated to risk stratify for sudden cardiac death, only 1–5% of patients with ICDs, implanted based upon a low EF, require therapies each year and the large majority of patients who receive ICDs will not have ICD therapies over the 3-year period after implantation.
      • Moss A.J.
      • Greenberg H.
      • Case R.B.
      • Zareba W.
      • Hall W.J.
      • Brown M.W.
      • et al.
      Long-term clinical course of patients after termination of ventricular tachyarrhythmia by an implanted defibrillator.
      ,
      • Stecker E.C.
      • Vickers C.
      • Waltz J.
      • Socoteanu C.
      • John B.T.
      • Mariani R.
      • et al.
      Population-based analysis of sudden cardiac death with and without left ventricular systolic dysfunction: two-year findings from the Oregon Sudden Unexpected Death Study.
      In addition, up to 70% of all sudden cardiac deaths in the community occur in individuals with EF >35%.
      • Stecker E.C.
      • Vickers C.
      • Waltz J.
      • Socoteanu C.
      • John B.T.
      • Mariani R.
      • et al.
      Population-based analysis of sudden cardiac death with and without left ventricular systolic dysfunction: two-year findings from the Oregon Sudden Unexpected Death Study.
      • Gorgels A.P.
      • Gijsbers C.
      • de Vreede-Swagemakers J.
      • Lousberg A.
      • Wellens H.J.
      Out-of-hospital cardiac arrest-the relevance of heart failure. The Maastricht Circulatory Arrest Registry.
      • Stevens S.M.
      • Reinier K.
      • Chugh S.S.
      Increased left ventricular mass as a predictor of sudden cardiac death: is it time to put it to the test?.
      Although the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure (DANISH) trial showed that primary prevention ICD in the setting of severe non-ICM did not reduce all-cause mortality in patients on optimal medical therapy for heart failure, ICD implantation was associated with a 50% reduction in arrhythmic death. Of note, within this non-ICM population, younger patients (<68 years old) experienced a mortality benefit of 36% if treated with an ICD.
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • Haarbo J.
      • Videbæk L.
      • Korup E.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      Ejection fraction is most readily evaluated with echocardiography (recommendation level: green), given both lower cost, availability of equipment, and available expertise; however, cardiac MRI or CT can also be used to evaluate EF and SHD, particularly if obtained in combination of other assessment aims, such as CAD or if there is controversy over the quantified EF with echo (recommendation level: green). The imaging modality used to estimate EF has not been shown to determine benefit from ICD.
      • Gula L.J.
      • Klein G.J.
      • Hellkamp A.S.
      • Massel D.
      • Krahn A.D.
      • Skanes A.C.
      • et al.
      Ejection fraction assessment and survival: an analysis of the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).
      Additional parameters beyond EF remain to be tested in large studies. Cardiac MRI with late gadolinium enhancement (LGE) can provide important prognostic information and may allow for more accurate assessment of scar. Presence and location of scar can portend a higher risk of sustained VT.
      • Di Marco A.
      • Anguera I.
      • Schmitt M.
      • Klem I.
      • Neilan T.G.
      • White J.A.
      • et al.
      Late gadolinium enhancement and the risk for ventricular arrhythmias or sudden death in dilated cardiomyopathy: systematic review and meta-analysis.
      • Coleman G.C.
      • Shaw P.W.
      • Balfour P.C.
      • Gonzalez J.A.
      • Kramer C.M.
      • Patel A.R.
      • et al.
      Prognostic value of myocardial scarring on CMR in patients with cardiac sarcoidosis.
      • Greulich S.
      • Deluigi C.C.
      • Gloekler S.
      • Wahl A.
      • Zürn C.
      • Kramer U.
      • et al.
      CMR imaging predicts death and other adverse events in suspected cardiac sarcoidosis.
      ,
      • Piers S.R.
      • Tao Q.
      • van Huls van Taxis C.F.
      • Schalij M.J.
      • van der Geest R.J.
      • Zeppenfeld K.
      Contrast-enhanced MRI-derived scar patterns and associated ventricular tachycardias in nonischemic cardiomyopathy: implications for the ablation strategy.
      ,
      • White J.A.
      • Fine N.M.
      • Gula L.
      • Yee R.
      • Skanes A.
      • Klein G.
      • et al.
      Utility of cardiovascular magnetic resonance in identifying substrate for malignant ventricular arrhythmias.
      In a study of 452 non-ICM patients with New York Heart Association Class II or II and EF <35%, ICD implantation was only associated with reduced mortality in the population that had presence of scar on cardiac MRI.
      • Gutman S.J.
      • Costello B.T.
      • Papapostolou S.
      • Voskoboinik A.
      • Iles L.
      • Ja J.
      • et al.
      Reduction in mortality from implantable cardioverter-defibrillators in non-ischaemic cardiomyopathy patients is dependent on the presence of left ventricular scar.
      Cardiac positron emission tomography (PET) may elucidate areas of inflammation which may identify inflammatory cardiomyopathies and sarcoidosis, a condition that is associated with higher risk of ventricular arrhythmias in patients without CAD (increased F-2-fluorodeoxyglucose uptake) or can be used to identify sympathetic denervation (carbon-11-metahydroxyephedrine imaging) or regions of inflammation. Greater sympathetic denervation on PET in a prospective study of ICM patients was a better predictor of ICD shocks than EF.
      • Fallavollita J.A.
      • Heavey B.M.
      • Luisi A.J.
      • Michalek S.M.
      • Baldwa S.
      • Mashtare T.L.
      • et al.
      Regional myocardial sympathetic denervation predicts the risk of sudden cardiac arrest in ischemic cardiomyopathy.
      Uptake of iodine-123 meta-iodobenzylguanidine (MIBG) to evaluate heart to mediastinum ration (H/M ratio) has shown mixed results in predicting arrhythmic death with some studies suggesting additional prognostic benefit for this parameter, while others have not demonstrated additional value.
      • Buxton A.E.
      • Lee K.L.
      • Fisher J.D.
      • Josephson M.E.
      • Prystowsky E.N.
      • Hafley G.
      A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators.
      ,
      • Brembilla-Perrot B.
      • Suty-Selton C.
      • Beurrier D.
      • Houriez P.
      • Nippert M.
      • de la Chaise A.T.
      • et al.
      Differences in mechanisms and outcomes of syncope in patients with coronary disease or idiopathic left ventricular dysfunction as assessed by electrophysiologic testing.
      Importantly, the value of these additional parameters in determining risk of sustained VT, VF, or benefit from ICD in various population remains to be clarified. Finally, routine use of viability assessment using PET to guide revascularization in order to reduce risk of SCD remains an area of investigation. In patients with an EF <35% and CAD amenable to revascularization, routine use of PET to guide revascularization was not beneficial in reducing overall mortality.
      • Panza J.A.
      • Ellis A.M.
      • Al-Khalidi H.R.
      • Holly T.A.
      • Berman D.S.
      • Oh J.K.
      • et al.
      Myocardial viability and long-term outcomes in ischemic cardiomyopathy.

       Imaging modalities for atrial arrhythmias

      Echocardiography (transthoracic or transoesophageal) is a valuable tool in patients who present with atrial arrhythmias, specifically atrial flutter and AF, to evaluate for the presence of structural heart disease, left atrial enlargement, and valvular heart disease in order to better define treatment options. Cardiac MRI or CT may also be used if images obtained at echocardiography are not reliable. However, routine use of echocardiography, including atrial strain or atrial function in patients who do not have atrial arrhythmias to assess risk for the development of AF or atrial flutter is not warranted, unless other structural cardiac abnormalities are suspected.

       Invasive electrophysiological study

      Tabled 1
      Invasive electrophysiological study (EPS)ClassReferences
      EPS is indicated in patients with syncope and previous myocardial infarction, or other scar-related conditions when syncope remains unexplained after non-invasive evaluation.
      • Olshansky B.
      • Hahn E.A.
      • Hartz V.L.
      • Prater S.P.
      • Mason J.W.
      Clinical significance of syncope in the electrophysiologic study versus electrocardiographic monitoring (ESVEM) trial. The ESVEM Investigators.
      EPS may be considered in patients with syncope and asymptomatic sinus bradycardia, in a few instances when non-invasive tests (e.g. ECG monitoring) have failed to show a correlation between syncope and bradycardia.
      • Priori S.G.
      • Blomstrom-Lundqvist C.
      • Mazzanti A.
      • Blom N.
      • Borggrefe M.
      • Camm J.
      • et al.
      2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC).

      Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation 2018;138:e272–e391.

      • Gann D.
      • Tolentino A.
      • Samet P.
      Electrophysiologic evaluation of elderly patients with sinus bradycardia: a long-term follow-up study.
      EPS may be considered in patients with EF ≤40%, without a primary prophylactic ICD indication, and non-sustained VT in ICM (MUSTT criteria) to ascertain the presence of sustained VT events.
      • Buxton A.E.
      • Fisher J.D.
      • Josephson M.E.
      • Lee K.L.
      • Pryor D.B.
      • Prystowsky E.N.
      • et al.
      Prevention of sudden death in patients with coronary artery disease: the Multicenter Unsustained Tachycardia Trial (MUSTT).
      EPS may be helpful in patients with syncope and presence of a cardiac scar, including those with a previous myocardial infarction, or other scar-related conditions, when the mechanism of syncope remains unexplained after non-invasive evaluation.
      • Buxton A.E.
      • Lee K.L.
      • Fisher J.D.
      • Josephson M.E.
      • Prystowsky E.N.
      • Hafley G.
      A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators.
      ,
      • Priori S.G.
      • Blomstrom-Lundqvist C.
      • Mazzanti A.
      • Blom N.
      • Borggrefe M.
      • Camm J.
      • et al.
      2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC).
      ,

      Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation 2018;138:e272–e391.

      ,
      • Buxton A.E.
      • Fisher J.D.
      • Josephson M.E.
      • Lee K.L.
      • Pryor D.B.
      • Prystowsky E.N.
      • et al.
      Prevention of sudden death in patients with coronary artery disease: the Multicenter Unsustained Tachycardia Trial (MUSTT).
      EPS may be considered in patients with syncope and bifascicular block, when the mechanism of syncope remains unexplained after non-invasive evaluation.
      • Brembilla-Perrot B.
      • Suty-Selton C.
      • Beurrier D.
      • Houriez P.
      • Nippert M.
      • de la Chaise A.T.
      • et al.
      Differences in mechanisms and outcomes of syncope in patients with coronary disease or idiopathic left ventricular dysfunction as assessed by electrophysiologic testing.
      ,
      • Priori S.G.
      • Blomstrom-Lundqvist C.
      • Mazzanti A.
      • Blom N.
      • Borggrefe M.
      • Camm J.
      • et al.
      2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC).
      ,

      Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation 2018;138:e272–e391.

      ,
      • Hilfiker G.
      • Schoenenberger A.W.
      • Erne P.
      • Kobza R.
      Utility of electrophysiological studies to predict arrhythmic events.
      EPS may be considered for risk stratification of SCD in patients with tetralogy of Fallot who have one or more risk factors among LV dysfunction, non-sustained VT and QRS duration exceeding 180 ms.
      • Brembilla-Perrot B.
      • Suty-Selton C.
      • Beurrier D.
      • Houriez P.
      • Nippert M.
      • de la Chaise A.T.
      • et al.
      Differences in mechanisms and outcomes of syncope in patients with coronary disease or idiopathic left ventricular dysfunction as assessed by electrophysiologic testing.
      ,
      • Priori S.G.
      • Blomstrom-Lundqvist C.
      • Mazzanti A.
      • Blom N.
      • Borggrefe M.
      • Camm J.
      • et al.
      2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC).
      ,

      Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation 2018;138:e272–e391.

      ,
      • Hilfiker G.
      • Schoenenberger A.W.
      • Erne P.
      • Kobza R.
      Utility of electrophysiological studies to predict arrhythmic events.
      EPS may be considered in patients with congenital heart disease and non-sustained VT to determine the risk of sustained VT or identify SVT that could be ablate.
      • Brembilla-Perrot B.
      • Suty-Selton C.
      • Beurrier D.
      • Houriez P.
      • Nippert M.
      • de la Chaise A.T.
      • et al.
      Differences in mechanisms and outcomes of syncope in patients with coronary disease or idiopathic left ventricular dysfunction as assessed by electrophysiologic testing.
      ,
      • Priori S.G.
      • Blomstrom-Lundqvist C.
      • Mazzanti A.
      • Blom N.
      • Borggrefe M.
      • Camm J.
      • et al.
      2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC).
      ,

      Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation 2018;138:e272–e391.

      ,
      • Hilfiker G.
      • Schoenenberger A.W.
      • Erne P.
      • Kobza R.
      Utility of electrophysiological studies to predict arrhythmic events.
      EPS may be considered in asymptomatic patients with spontaneous type 1 Brugada ECG pattern, or drug-induced type 1 ECG pattern and additional risk factors.
      • Mankbadi M.
      • Hassan S.
      • McGee M.
      • Jan B.
      • Mangal S.
      • Altier J.
      • et al.
      Brugada syndrome: the role of risk stratification in selecting patients for implantable cardioverter-defibrillator placement.
      • Brugada J.
      • Campuzano O.
      • Arbelo E.
      • Sarquella-Brugada G.
      • Brugada R.
      Present status of Brugada syndrome: JACC state-of-the-art review.
      • Sroubek J.
      • Probst V.
      • Mazzanti A.
      • Delise P.
      • Hevia J.C.
      • Ohkubo K.
      • et al.
      Programmed ventricular stimulation for risk stratification in the Brugada syndrome: a pooled analysis.
      EPS is not recommended for additional risk stratification in patients with either long or short QT, catecholaminergic VT or early repolarization.
      • Priori S.G.
      • Blomstrom-Lundqvist C.
      • Mazzanti A.
      • Blom N.
      • Borggrefe M.
      • Camm J.
      • et al.
      2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC).
      ,

      Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation 2018;138:e272–e391.

      EPS is not recommended for risk stratification in patients with ischemic or non-ischemic DCM who meet criteria for ICD implantation.
      • Priori S.G.
      • Blomstrom-Lundqvist C.
      • Mazzanti A.
      • Blom N.
      • Borggrefe M.
      • Camm J.
      • et al.
      2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC).
      ,

      Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation 2018;138:e272–e391.

      Currently, there are a few indications to perform an electrophysiological study (EPS) to further assess the risk of arrhythmias in at-risk cardiac patients. Such patients include those with structural heart disease, LVEF >35%, pre-syncope, syncope, palpitations, or markedly abnormal ECG suggesting severe conduction disease. These patients can be considered for an EPS to assess the risk of ventricular arrhythmias and sudden cardiac death to decide on need of an ICD, or to identify conduction disturbances or supraventricular tachycardias that can be treated with ablation or pacing.
      • Priori S.G.
      • Blomstrom-Lundqvist C.
      • Mazzanti A.
      • Blom N.
      • Borggrefe M.
      • Camm J.
      • et al.
      2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC).
      ,

      Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation 2018;138:e272–e391.

      Patients with ICM without a primary indication for an ICD, EF ≤40%, and non-sustained VT on ambulatory cardiac monitoring are candidates for an EPS according to the findings in the MUSTT trial,
      • Buxton A.E.
      • Fisher J.D.
      • Josephson M.E.
      • Lee K.L.
      • Pryor D.B.
      • Prystowsky E.N.
      • et al.
      Prevention of sudden death in patients with coronary artery disease: the Multicenter Unsustained Tachycardia Trial (MUSTT).
      in which, 35% of patients with inducible sustained VT had a significantly lower risk of death with an ICD.
      • Buxton A.E.
      • Lee K.L.
      • Fisher J.D.
      • Josephson M.E.
      • Prystowsky E.N.
      • Hafley G.
      A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators.
      The MADIT trial initially also utilized an EPS in post-MI patients with an EF ≤30%, and non-sustained VT events to implant an ICD, and showed survival benefit with the ICD.
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • Daubert J.P.
      • Higgins S.L.
      • Klein H.
      • et al.
      Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia.
      However, MADIT-II subsequently eliminated the need for an EPS in post-MI patients with an EF ≤30% and similarly showed the life-saving benefit of the ICD in a broader patient cohort.
      • Moss A.J.
      • Zareba W.
      • Hall W.J.
      • Klein H.
      • Wilber D.J.
      • Cannom D.S.
      • et al.
      Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction.
      Therefore, post-MI patients with an EF ≤30% do not currently need to undergo an EPS to guide decisions on whether to implant an ICD.
      In patients with heart failure and EF ≤ 35%, an EPS is not recommended for risk assessment for the decision on ICD indication. Some centers perform an EPS for inducibility to better characterize induced, sustained VT events, and their response to anti-tachycardia pacing, which may potentially help to tailor ICD programming. Furthermore, in patients who have syncope of uncertain origin, an EPS could identify ventricular arrhythmias or document electrical conduction disorders.
      • Brembilla-Perrot B.
      • Suty-Selton C.
      • Beurrier D.
      • Houriez P.
      • Nippert M.
      • de la Chaise A.T.
      • et al.
      Differences in mechanisms and outcomes of syncope in patients with coronary disease or idiopathic left ventricular dysfunction as assessed by electrophysiologic testing.
      ,
      • Priori S.G.
      • Blomstrom-Lundqvist C.
      • Mazzanti A.
      • Blom N.
      • Borggrefe M.
      • Camm J.
      • et al.
      2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC).
      ,

      Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation 2018;138:e272–e391.

      ,
      • Hilfiker G.
      • Schoenenberger A.W.
      • Erne P.
      • Kobza R.
      Utility of electrophysiological studies to predict arrhythmic events.
      In the case of channelopathies, there is no indication for an EPS, except for Brugada syndrome. In Brugada syndrome, EPS may be useful in asymptomatic patients with spontaneous or drug-induced type 1 pattern, especially when there is a family history of sudden death.
      • Mankbadi M.
      • Hassan S.
      • McGee M.
      • Jan B.
      • Mangal S.
      • Altier J.
      • et al.
      Brugada syndrome: the role of risk stratification in selecting patients for implantable cardioverter-defibrillator placement.
      • Brugada J.
      • Campuzano O.
      • Arbelo E.
      • Sarquella-Brugada G.
      • Brugada R.
      Present status of Brugada syndrome: JACC state-of-the-art review.
      • Sroubek J.
      • Probst V.
      • Mazzanti A.
      • Delise P.
      • Hevia J.C.
      • Ohkubo K.
      • et al.
      Programmed ventricular stimulation for risk stratification in the Brugada syndrome: a pooled analysis.

       Implantable loop recorders

      Tabled 1
      Implantable cardiac devicesClassReferences
      An ILR is indicated in the evaluation of patients with infrequent recurrent syncope of uncertain origin especially when ambulatory monitoring is inconclusive.
      • Solbiati M.
      • Casazza G.
      • Dipaola F.
      • Barbic F.
      • Caldato M.
      • Montano N.
      • et al.
      The diagnostic yield of implantable loop recorders in unexplained syncope: A systematic review and meta-analysis.
      • Ibrahim O.A.
      • Drew D.
      • Hayes C.J.
      • McIntyre W.
      • Seifer C.M.
      • Hopman W.
      • et al.
      Implantable loop recorders in the real world: a study of two Canadian centers.
      • Sanna T.
      • Diener H.C.
      • Passman R.S.
      • Di Lazzaro V.
      • Bernstein R.A.
      • Morillo C.A.
      • et al.
      Cryptogenic stroke and underlying atrial fibrillation.
      An ILR is indicated in patients with syncope and high-risk criteria in whom a comprehensive evaluation did not demonstrate a cause of syncope or lead to a specific treatment, and who do not have conventional indications for primary prevention ICD or pacemaker.
      • Solbiati M.
      • Casazza G.
      • Dipaola F.
      • Barbic F.
      • Caldato M.
      • Montano N.
      • et al.
      The diagnostic yield of implantable loop recorders in unexplained syncope: A systematic review and meta-analysis.
      • Ibrahim O.A.
      • Drew D.
      • Hayes C.J.
      • McIntyre W.
      • Seifer C.M.
      • Hopman W.
      • et al.
      Implantable loop recorders in the real world: a study of two Canadian centers.
      • Sanna T.
      • Diener H.C.
      • Passman R.S.
      • Di Lazzaro V.
      • Bernstein R.A.
      • Morillo C.A.
      • et al.
      Cryptogenic stroke and underlying atrial fibrillation.
      An ILR can be considered in patients with palpitations, dizziness, pre-syncope, frequent premature ventricular complexes (PVCs)/non-sustained VT, and in those with suspected AF, and following AF ablation.
      • Solbiati M.
      • Casazza G.
      • Dipaola F.
      • Barbic F.
      • Caldato M.
      • Montano N.
      • et al.
      The diagnostic yield of implantable loop recorders in unexplained syncope: A systematic review and meta-analysis.
      • Ibrahim O.A.
      • Drew D.
      • Hayes C.J.
      • McIntyre W.
      • Seifer C.M.
      • Hopman W.
      • et al.
      Implantable loop recorders in the real world: a study of two Canadian centers.
      • Sanna T.
      • Diener H.C.
      • Passman R.S.
      • Di Lazzaro V.
      • Bernstein R.A.
      • Morillo C.A.
      • et al.
      Cryptogenic stroke and underlying atrial fibrillation.

       Implantable loop recorder to diagnose unexplained syncope/atrial fibrillation with cryptogenic stroke

      The implantable loop recorder (ILR) provides long-term continuous monitoring and improves the diagnosis in patients with unexplained syncope.
      • Edvardsson N.
      • Frykman V.
      • van Mechelen R.
      • Mitro P.
      • Mohii-Oskarsson A.
      • Pasquie J.L.
      • et al.
      PICTURE Study Investigators. Use of an implantable loop recorder to increase the diagnostic yield in unexplained syncope: results from the PICTURE registry.
      In a meta-analysis of 49 studies that included 4381 participants, the diagnostic yield for the detection of arrhythmogenic syncope was 26.5%.
      • Solbiati M.
      • Casazza G.
      • Dipaola F.
      • Barbic F.
      • Caldato M.
      • Montano N.
      • et al.
      The diagnostic yield of implantable loop recorders in unexplained syncope: A systematic review and meta-analysis.
      Moreover, the CRYSTAL-AF trial
      • Sanna T.
      • Diener H.C.
      • Passman R.S.
      • Di Lazzaro V.
      • Bernstein R.A.
      • Morillo C.A.
      • et al.
      Cryptogenic stroke and underlying atrial fibrillation.
      revealed that the ILR can detect subclinical AF following cryptogenic stroke. Still, any benefit of these findings needs to be confirmed in large randomized trials. Early use of the ILR has been advocated by the European guidelines
      • Brignole M.
      • Moya A.
      • de Lange F.J.
      • Deharo J.C.
      • Elliott P.M.
      • Fanciulli A.
      • et al.
      ESC Scientific Document Group. 2018 ESC Guidelines for the diagnosis and management of syncope.
      and in the American guidelines following inconclusive non-invasive monitoring.
      • Shen W.K.
      • Sheldon R.S.
      • Benditt D.G.
      • Cohen M.I.
      • Forman D.E.
      • Goldberger Z.D.
      • et al.
      2017 ACC/AHA/HRS Guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.
      The indications for ILR have been expanded in the current guidelines (Table 2).
      Table 2High-risk and low-risk criteria for syncope at initial evaluation (Adapted from 2018 ESC Guidelines for the diagnosis and management of syncope
      • Brignole M.
      • Moya A.
      • de Lange F.J.
      • Deharo J.C.
      • Elliott P.M.
      • Fanciulli A.
      • et al.
      ESC Scientific Document Group. 2018 ESC Guidelines for the diagnosis and management of syncope.
      )
      Syncopal events
      Low-risk
       Associated with prodrome typical or reflex syncope (e.g. light-headedness, feeling of warmth, sweating, nausea, vomiting)
       After sudden unexpected unpleasant sight, sound, smell, or pain
      Sudden loud sounds (as an alarm clock) may trigger VF in some long QT syndrome patients.
       After prolonged standing or crowded, hot places
       During a meal or postprandial
       Triggered by cough, defecation, or micturition
       With head rotation or pressure on carotid sinus (e.g. tumor, shaving, tight collars)
       Standing from supine/sitting position
      High-risk
       Major
      New onset of chest discomfort, breathlessness, abdominal pain, or headache
      Syncope during exertion or when supine
      Sudden onset palpitation immediately followed by syncope
      Presence of structural heart disease especially left ventricular dysfunction and/or history of myocardial infarction
       Minor (high-risk only if associated with structural heart disease or abnormal ECG):
      No warning symptoms or short (<10 s) prodrome
      Family history of sudden cardiac death at young age
      Syncope in the sitting position
      ECG, electrocardiogram; VF, ventricular fibrillation.
      a Sudden loud sounds (as an alarm clock) may trigger VF in some long QT syndrome patients.

       Implantable loop recorder to diagnose atrial and ventricular arrhythmia events

      While the ILR can be useful to detect atrial and ventricular arrhythmias, a large cohort study indicated that most of the current use of ILRs is primarily in patients with unexplained syncope (84%), followed by palpitations (13%), and suspected AF (12%).
      • Ibrahim O.A.
      • Drew D.
      • Hayes C.J.
      • McIntyre W.
      • Seifer C.M.
      • Hopman W.
      • et al.
      Implantable loop recorders in the real world: a study of two Canadian centers.
      Another smaller study specifically studying the risk of SCD and arrhythmias in patients with hemodialysis, found that 20% of these patients had SCD or bradyarrhythmia events necessitating pacemaker implantation, and 33% of these patients had an arrhythmic endpoint. Interestingly, the median time to event was 2.6 years, confirming the need for long-term monitoring. Surprisingly, however, bradyarrhythmias were very commonly diagnosed in this cohort suspected to be at high risk for ventricular arrhythmias and sudden cardiac death.
      • Roberts P.R.
      • Zachariah D.
      • Morgan J.M.
      • Yue A.M.
      • Greenwood E.F.
      • Phillips P.C.
      • et al.
      Monitoring of arrhythmia and sudden death in a hemodialysis population: the CRASH-ILR Study.
      Further studies are needed to establish the role of ILR in risk stratification.

       Wearables/direct to consumer

      Tabled 1
      Wearables/direct to consumerClassReferences
      Wearables may provide diagnostic data that contribute to disease detection and management when integrated into the clinical context and physician judgement.
      • Cheung C.C.
      • Krahn A.D.
      • Andrade J.G.
      The emerging role of wearable technologies in detection of arrhythmia.
      ,
      • Bumgarner J.M.
      • Lambert C.T.
      • Hussein A.A.
      • Cantillon D.J.
      • Baranowski B.
      • Wolski K.
      • et al.
      Smartwatch algorithm for automated detection of atrial fibrillation.
      The direct to consumer or wearable technology market, comprised of devices that monitor physiological parameters such as heart rate and sleep pattern, is anticipated to grow to 929 million connected devices by 2021.
      • Liu S.
      Number of Connected Wearable Devices Worldwide from 2016 to 2022. 2019.
      These devices encompass wristbands, glasses, in-ear monitors, chest straps, and smart phone-enabled recording electrode systems or electronic shirts, with varying capacity to monitor heart rate, heart rhythm, blood pressure, physical activity, respiratory rate, blood glucose, and sleep patterns.
      • Valiaho E.S.
      • Kuoppa P.
      • Lipponen J.A.
      • Martikainen T.J.
      • Jantti H.
      • Rissanen T.T.
      • et al.
      Wrist band photoplethysmography in detection of individual pulses in atrial fibrillation and algorithm-based detection of atrial fibrillation.
      • Brasier N.
      • Raichle C.J.
      • Dorr M.
      • Becke A.
      • Nohturfft V.
      • Weber S.
      • et al.
      Detection of atrial fibrillation with a smartphone camera: first prospective, international, two-centre, clinical validation study (DETECT AF PRO).
      • Verbrugge F.H.
      • Proesmans T.
      • Vijgen J.
      • Mullens W.
      • Rivero-Ayerza M.
      • Van Herendael H.
      • et al.
      Atrial fibrillation screening with photo-plethysmography through a smartphone camera.
      For heart rate monitoring, most wearable devices use photoplethysmography (PPG) technology, meaning they are inherently less accurate than conventional electrocardiography monitoring techniques. Accuracy of various devices varies, with correlation to reference standard ECG monitoring ranging from 0.76 to 0.99.
      • Gillinov S.
      • Etiwy M.
      • Wang R.
      • Blackburn G.
      • Phelan D.
      • Am G.
      • et al.
      Variable accuracy of wearable heart rate monitors during aerobic exercise.
      Recent advances in wearable ECG acquisition include use of direct electrode recording that represents a regulatory approved medical device generating a lead I like rhythm strip, blurring the lines between consumer and medical devices.
      • Wang R.
      • Blackburn G.
      • Desai M.
      • Phelan D.
      • Gillinov L.
      • Houghtaling P.
      • et al.
      Accuracy of wrist-worn heart rate monitors.
      A growing body of evidence suggests that these technologies can be harnessed to facilitate arrhythmia detection in the appropriate context. Although marketed as consumer devices, many wearable devices may generate health data comparable to that of medical grade ECG monitors, with several devices migrating to approved medical use.
      • Cheung C.C.
      • Krahn A.D.
      • Andrade J.G.
      The emerging role of wearable technologies in detection of arrhythmia.
      Despite this promise, there are clear concerns regarding accuracy, particularly false positives in asymptomatic patients where device-based alerts can raise unwarranted concern and generate low yield screening for disease, with associated costs. Wearable technologies represent an important frontier in health evaluation, with the potential to provide readily accessible health data for large segments of the population, including those not captured by conventional monitoring techniques. Though intended for personal use focused on health promotion and physical activity, wearable technologies promise to invert the traditional paradigm of healthcare delivery, with data collection and health queries often initiated by consumers and not providers. Providers may see wearables as accessible risk stratification tools for detection of AF in high-risk cohorts (such as high CHADS2-VASC2 score patients), and patients may equally present for evaluation after device-based observations that call into question whether they are at risk. The confluence of these factors is illustrated in the recently presented Apple Heart Study, wherein 419 297 participants were recruited in only 8 months to participate in an AF screening study that deployed a PPG-based algorithm followed by a 7-day patch if AF was suspected.
      • Perez M.V.
      • Mahaffey K.W.
      • Hedlin H.
      • Rumsfeld J.S.
      • Garcia A.
      • Ferris T.
      • et al.
      Large-scale assessment of a smartwatch to identify atrial fibrillation.
      Using a complex tachogram algorithm, 2126 individuals were sent irregular pulse notifications and prompted for a telemedicine visit and 7-day ECG patch. The authors reported a PPV of 84% for each irregular pulse notification, and 71% for each irregular tachogram. The burden of notifications and the performance of the technology showed promise to inform AF detection in the broader public. Similarly, the Huawei Heart Study evaluated 187 912 individuals that used smart devices to monitor their pulse rhythm, with notification of suspected AF in 424 participants, with a strong relationship between advancing age and detecting AF. The predictive value of the algorithm in the 62% of notified participants that pursued medical evaluation was promising (87%).
      • Guo Y.
      • Wang H.
      • Zhang H.
      • Liu T.
      • Liang Z.
      • Xia Y.
      • et al.
      Mobile photoplethysmographic technology to detect atrial fibrillation.
      Studies evaluating PPG-based wearables in conjunction with machine-learning algorithms have shown promise in arrhythmia detection, such as AF.
      • Bumgarner J.M.
      • Lambert C.T.
      • Hussein A.A.
      • Cantillon D.J.
      • Baranowski B.
      • Wolski K.
      • et al.
      Smartwatch algorithm for automated detection of atrial fibrillation.
      Studies to date have not focused on ventricular arrhythmia detection. Future wearables will benefit from improved reliability and accuracy, collect additional health and fitness parameters, support chronic disease management, and provide real-time connectivity and feedback that may supplant conventional medical monitoring. Wearables have the potential to become truly disruptive in our healthcare sector, with large segments of the population accessing cardiac monitoring that the physician must interpret. Currently, we have no data on how the information provided by PPG-based wearables will affect management and outcomes of patients, or how risk scores derived in other populations such as the CHA2DS2-VASc score apply in these previously undetected subjects.

       Biomarkers, tissue, genetics

      Tabled 1
      Biomarkers, tissue, geneticsClassReferences
      Genetic testing should be considered in several inherited arrhythmic diseases associated with an increased risk of ventricular arrhythmia and SCD.
      • Ackerman M.J.
      • Priori S.G.
      • Willems S.
      • Berul C.
      • Brugada R.
      • Calkins H.
      • et al.
      HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA).
      • Haugaa K.H.
      • Dan G.A.
      • Iliodromitis K.
      • Lenarczyk R.
      • Marinskis G.
      • Osca J.
      • et al.
      Management of patients with ventricular arrhythmias and prevention of sudden cardiac death-translating guidelines into practice: results of the European Heart Rhythm Association survey. Europace: european pacing, arrhythmias, and cardiac electrophysiology: journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the.
      • Anastasakis A.
      • Papatheodorou E.
      • Ritsatos K.
      • Protonotarios N.
      • Rentoumi V.
      • Gatzoulis K.
      • et al.
      Sudden unexplained death in the young: epidemiology, aetiology and value of the clinically guided genetic screening.
      MRI with LGE to detect fibrosis and scar may be useful in assessing the risk of arrhythmic events in AF patients and patients with cardiomyopathies.
      • Margulescu A.D.
      • Nunez-Garcia M.
      • Alarcon F.
      • Benito E.M.
      • Enomoto N.
      • Cozzari J.
      • et al.
      Reproducibility and accuracy of late gadolinium enhancement cardiac magnetic resonance measurements for the detection of left atrial fibrosis in patients undergoing atrial fibrillation ablation procedures.
      • Pontecorboli G.
      • Figueras I.
      • Carlosena A.
      • Benito E.
      • Prat-Gonzales S.
      • Padeletti L.
      • et al.
      Use of delayed-enhancement magnetic resonance imaging for fibrosis detection in the atria: a review.
      • Halliday B.P.
      • Cleland J.G.F.
      • Goldberger J.J.
      • Prasad S.K.
      Personalizing risk stratification for sudden death in dilated cardiomyopathy: the past, present, and future.
      Plasma NT-proBNP may be useful in differentiating patients with higher vs. lower burden of AF.
      • Goetze J.P.
      • Mogelvang R.
      • Maage L.
      • Scharling H.
      • Schnohr P.
      • Sogaard P.
      • et al.
      Plasma pro-B-type natriuretic peptide in the general population: screening for left ventricular hypertrophy and systolic dysfunction.
      • Darkner S.
      • Goetze J.P.
      • Chen X.
      • Henningsen K.
      • Pehrson S.
      • Svendsen J.H.
      Natriuretic propeptides as markers of atrial fibrillation burden and recurrence (from the AMIO-CAT Trial).
      • Sinner M.F.
      • Stepas K.A.
      • Moser C.B.
      • Krijthe B.P.
      • Aspelund T.
      • Sotoodehnia N.
      • et al.
      B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies.
      • Kemp Gudmundsdottir K.
      • Fredriksson T.
      • Svennberg E.
      • Al-Khalili F.
      • Friberg L.
      • Frykman V.
      • et al.
      Stepwise mass screening for atrial fibrillation using N-terminal B-type natriuretic peptide: the STROKESTOP II study.
      • Sepehri Shamloo A.
      • Bollmann A.
      • Dagres N.
      • Hindricks G.
      • Arya A.
      Natriuretic peptides: biomarkers for atrial fibrillation management.
      Plasma CRP or other inflammatory markers may be useful in risk assessment, for identifying individuals with increased risk of future AF and for identifying individuals with high degree of atrial fibrosis.
      • Engelmann M.D.
      • Svendsen J.H.
      Inflammation in the genesis and perpetuation of atrial fibrillation.
      • Nyrnes A.
      • Njolstad I.
      • Mathiesen E.B.
      • Wilsgaard T.
      • Hansen J.B.
      • Skjelbakken T.
      • et al.
      Inflammatory biomarkers as risk factors for future atrial fibrillation. An eleven-year follow-up of 6315 men and women: the Tromso study.
      • Henningsen K.M.
      • Therkelsen S.K.
      • Johansen J.S.
      • Bruunsgaard H.
      • Svendsen J.H.
      Plasma YKL-40, a new biomarker for atrial fibrillation?.
      The use of biomarkers, tissue biopsy, and genetic assessment can be used for risk assessment in patients suspected of specific arrhythmias or syndromes. The utility of using these tools broadly spans determining arrhythmic risk, refining a clinical diagnosis and estimating prognosis.

       Biomarkers

      Cardiac myocytes express and secrete natriuretic hormones that have a central function on blood pressure regulation, blood volume, and plasma sodium balance. Levels of B-type natriuretic peptide (BNP) and its stable N-terminal peptide pro-BNP (NT-proBNP) are increased in AF.
      • Goetze J.P.
      • Mogelvang R.
      • Maage L.
      • Scharling H.
      • Schnohr P.
      • Sogaard P.
      • et al.
      Plasma pro-B-type natriuretic peptide in the general population: screening for left ventricular hypertrophy and systolic dysfunction.
      AF burden has been shown to be associated with increased NT-proBNP.
      • Darkner S.
      • Goetze J.P.
      • Chen X.
      • Henningsen K.
      • Pehrson S.
      • Svendsen J.H.
      Natriuretic propeptides as markers of atrial fibrillation burden and recurrence (from the AMIO-CAT Trial).
      In a large meta-analysis consortium, BNP and C-reactive protein (CRP) associate with AF but only BNP was superior to well-known clinical variables in AF risk prediction.
      • Sinner M.F.
      • Stepas K.A.
      • Moser C.B.
      • Krijthe B.P.
      • Aspelund T.
      • Sotoodehnia N.
      • et al.
      B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies.
      Inflammatory processes and fibrosis are central to pathogenesis of AF,
      • Engelmann M.D.
      • Svendsen J.H.
      Inflammation in the genesis and perpetuation of atrial fibrillation.
      ,
      • Nattel S.
      Molecular and cellular mechanisms of atrial fibrosis in atrial fibrillation.
      and the inflammatory marker CRP is associated with longer AF duration and atrial remodelling.
      • Watanabe T.
      • Takeishi Y.
      • Hirono O.
      • Itoh M.
      • Matsui M.
      • Nakamura K.
      • et al.
      C-reactive protein elevation predicts the occurrence of atrial structural remodeling in patients with paroxysmal atrial fibrillation.
      CRP levels are elevated in patients with permanent AF compared to persistent AF patients and are predictive of recurrent AF after catheter ablation,
      • Henningsen K.M.
      • Nilsson B.
      • Bruunsgaard H.
      • Chen X.
      • Pedersen B.K.
      • Svendsen J.H.
      Prognostic impact of hs-CRP and IL-6 in patients undergoing radiofrequency catheter ablation for atrial fibrillation.
      ,
      • Henningsen K.M.
      • Therkelsen S.K.
      • Bruunsgaard H.
      • Krabbe K.S.
      • Pedersen B.K.
      • Svendsen J.H.
      Prognostic impact of hs-CRP and IL-6 in patients with persistent atrial fibrillation treated with electrical cardioversion.
      indicating that CRP levels can be used to identify AF subtypes and evaluate prognosis. Higher levels of CRP correlated to an increased risk of developing AF in general and after acute myocardial infarction.
      • Nyrnes A.
      • Njolstad I.
      • Mathiesen E.B.
      • Wilsgaard T.
      • Hansen J.B.
      • Skjelbakken T.
      • et al.
      Inflammatory biomarkers as risk factors for future atrial fibrillation. An eleven-year follow-up of 6315 men and women: the Tromso study.
      ,
      • Aronson D.
      • Boulos M.
      • Suleiman A.
      • Bidoosi S.
      • Agmon Y.
      • Kapeliovich M.
      • et al.
      Relation of C-reactive protein and new-onset atrial fibrillation in patients with acute myocardial infarction.
      Similarly, the plasma protein YKL-40 may have diagnostic and prognostic use in AF patients
      • Henningsen K.M.
      • Therkelsen S.K.
      • Johansen J.S.
      • Bruunsgaard H.
      • Svendsen J.H.
      Plasma YKL-40, a new biomarker for atrial fibrillation?.
      because plasma serum chondrex (YKL-40) is associated with atrial fibrosis severity in patients with lone AF.
      • Canpolat U.
      • Aytemir K.
      • Hazirolan T.
      • Ozer N.
      • Oto A.
      Serum YKL-40 as a marker of left atrial fibrosis assessed by delayed enhancement MRI in lone atrial fibrillation.
      Patients who experience recurrent AF following ablation have significantly increased YKL-40 baseline levels, although plasma YKL-40 is not an independent predictor of recurrent AF.
      • Henningsen K.M.
      • Therkelsen S.K.
      • Johansen J.S.
      • Bruunsgaard H.
      • Svendsen J.H.
      Plasma YKL-40, a new biomarker for atrial fibrillation?.
      ,
      • Henningsen K.M.
      • Nilsson B.
      • Johansen J.S.
      • Chen X.
      • Pehrson S.
      • Svendsen J.H.
      Plasma YKL-40 is elevated in patients with recurrent atrial fibrillation after catheter ablation.
      Increasing levels of YKL-40 have been shown to associate with a two-fold increased risk of future AF.
      • Marott S.C.W.
      • Benn M.
      • Johansen J.S.
      • Jensen G.B.
      • Tybjærg-Hansen A.
      • Nordestgaard B.G.
      YKL-40 levels and atrial fibrillation in the general population.
      Other simple AF biomarkers include body weight and blood pressure, which are also major intervention targets.

      Van Wagoner DR, Piccini JP, Albert CM, Anderson ME, Benjamin EJ, Brundel B, et al. Progress toward the prevention and treatment of atrial fibrillation: a summary of the Heart Rhythm Society Research Forum on the Treatment and Prevention of Atrial Fibrillation, Washington, DC, December 9-10, 2013. Heart Rhythm 2015;12:e5–e29.

      • Fenger-Gron M.
      • Overvad K.
      • Tjonneland A.
      • Frost L.
      Lean body mass is the predominant anthropometric risk factor for atrial fibrillation.
      • Sandhu R.K.
      • Conen D.
      • Tedrow U.B.
      • Fitzgerald K.C.
      • Pradhan A.D.
      • Ridker P.M.
      • et al.
      Predisposing factors associated with development of persistent compared with paroxysmal atrial fibrillation.
      • Frost L.
      • Benjamin E.J.
      • Fenger-Grøn M.
      • Pedersen A.
      • Tjønneland A.
      • Overvad K.
      Body fat, body fat distribution, lean body mass and atrial fibrillation and flutter. A Danish cohort study.
      • Zhuang J.
      • Lu Y.
      • Tang K.
      • Peng W.
      • Xu Y.
      Influence of body mass index on recurrence and quality of life in atrial fibrillation patients after catheter ablation: a meta-analysis and systematic review.
      • Abed H.S.
      • Samuel C.S.
      • Lau D.H.
      • Kelly D.J.
      • Royce S.G.
      • Alasady M.
      • et al.
      Obesity results in progressive atrial structural and electrical remodeling: implications for atrial fibrillation.

       Tissue diagnostics

      Tissue diagnostics can be beneficial to differentiate various infiltrative myopathic processes that can contribute to the risk for arrhythmic events. Fibrosis and scarring are well-recognized substrates for arrhythmia both in atria and ventricles.
      • Nattel S.
      Molecular and cellular mechanisms of atrial fibrosis in atrial fibrillation.
      Fibrosis may be assessed in atria as well as in ventricular myocardium and its quantification can be used in evaluating the risk of arrhythmia in AF and cardiomyopathies.
      • Pontecorboli G.
      • Figueras I.
      • Carlosena A.
      • Benito E.
      • Prat-Gonzales S.
      • Padeletti L.
      • et al.
      Use of delayed-enhancement magnetic resonance imaging for fibrosis detection in the atria: a review.
      ,
      • Halliday B.P.
      • Cleland J.G.F.
      • Goldberger J.J.
      • Prasad S.K.
      Personalizing risk stratification for sudden death in dilated cardiomyopathy: the past, present, and future.
      Specific patterns of scarring can assist in refinement of the diagnosis for infiltrative myopathies, hypertrophic cardiomyopathy, sarcoidosis, ACM, and amyloidosis. The development and validation of advanced imaging techniques including bio-metabolic imaging (sarcoid), and contrast enhanced cardiac MRI (amyloid) have largely replaced the need for invasive diagnostics.

       Genetics

      The majority of clinically applicable genetic testing is intended to be driven by phenotype and the pre-test probability of specific diagnosis determines the utility of genetic investigation.
      • Ackerman M.J.
      • Priori S.G.
      • Willems S.
      • Berul C.
      • Brugada R.
      • Calkins H.
      • et al.
      HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA).
      Due to incomplete penetrance of genetic arrhythmia syndromes, harbouring a genetic variant with known pathogenicity is almost never solely enough to meet diagnostic criteria for a particular syndrome.
      • Priori S.G.
      • Wilde A.A.
      • Horie M.
      • Cho Y.
      • Behr E.R.
      • Berul C.
      • et al.
      HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes.
      For LQTS, part of the diagnostic framework (along with the ECG biomarker of QT prolongation) can include a positive genetic test.
      • Priori S.G.
      • Wilde A.A.
      • Horie M.
      • Cho Y.
      • Behr E.R.
      • Berul C.
      • et al.
      HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes.
      Moreover, understanding the genetic diagnosis is important for treatment and prognostication. For example, patients with Jervell and Lange-Nielsen and Timothy Syndrome patients (LQT8) have more malignant clinical courses,
      • Schwartz P.J.
      • Spazzolini C.
      • Crotti L.
      • Bathen J.
      • Amlie J.P.
      • Timothy K.
      • et al.
      The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome.
      ,
      • Splawski I.
      • Timothy K.W.
      • Sharpe L.M.
      • Decher N.
      • Kumar P.
      • Bloise R.
      • et al.
      Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism.
      and for LQT1 the arrhythmic risk depends partly on which region of the channel the mutation affects.
      • Barsheshet A.
      • Goldenberg I.
      • O-Uchi J.
      • Moss A.J.
      • Jons C.
      • Shimizu W.
      • et al.
      Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to beta-blocker therapy in type 1 long-QT syndrome.
      In catecholaminergic polymorphic ventricular tachyarrhythmia (CPVT),
      • Leenhardt A.
      • Lucet V.
      • Denjoy I.
      • Grau F.
      • Ngoc D.
      • Coumel P.
      Catecholaminergic polymorphic ventricular tachycardia in children: a 7-year follow up of 21 patients.
      genetic testing of suspected individuals has a moderately high yield.
      • Ackerman M.J.
      • Priori S.G.
      • Willems S.
      • Berul C.
      • Brugada R.
      • Calkins H.
      • et al.
      HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA).
      Identification of an at risk first-degree relative of a CPVT affected individual is essential due to the high penetrance but more so the lethality of this syndrome.
      • Priori S.G.
      • Wilde A.A.
      • Horie M.
      • Cho Y.
      • Behr E.R.
      • Berul C.
      • et al.
      HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes.
      ,
      • Sumitomo N.
      • Harada K.
      • Nagashima M.
      • Yasuda T.
      • Nakamura Y.
      • Aragaki Y.
      • et al.
      Catecholaminergic polymorphic ventricular tachycardia: electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death.
      Similar to LQT1, CPVT due to RYR2 mutations may have some degree of risk depending on where in the ryanodine receptor the mutation falls.
      • van der Werf C.
      • Nederend I.
      • Hofman N.
      • van Geloven N.
      • Ebink C.
      • Frohn-Mulder I.M.
      • et al.
      Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives.
      Brugada syndrome can be particularly difficult to clinically diagnose and the utility of genetic testing for improving diagnosis is poor. For patients who are clinically diagnosed with Brugada syndrome the yield of genetic testing is ∼30%,
      • Kapplinger J.D.
      • Tester D.J.
      • Alders M.
      • Benito B.
      • Berthet M.
      • Brugada J.
      • et al.
      An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing.
      the majority of whom harbor SCN5a mutations, a gene associated with a plethora of arrhythmia syndromes.
      • Liu M.
      • Yang K.C.
      • Dudley Jr., S.C.
      Cardiac sodium channel mutations: why so many phenotypes?.
      ,
      • Eckhardt L.L.
      Phenotype, genotype, and cellular physiology: need for clarity in characterization.
      Genetic testing can be useful for family members of an appropriately genotype identified proband but is not recommended in the absence of a diagnostic ECG.
      • Ackerman M.J.
      • Priori S.G.
      • Willems S.
      • Berul C.
      • Brugada R.
      • Calkins H.
      • et al.
      HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA).
      Using genetics as part of diagnostic criteria for arrhythmogenic cardiomyopathies will be discussed later in the document. Lastly, genetics in AF is a developing area, but certain primary electrical sudden death syndromes have increased AF association as discussed in patients with inherited rhythm disease (long QT syndrome/short QT syndrome/catecholaminergic polymorphic ventricular tachyarrhythmia/Brugada syndrome) section. For families with a substantial number of AF cases or in early onset AF,
      • Weng L.C.
      • Lunetta K.L.
      • Muller-Nurasyid M.
      • Smith A.V.
      • Theriault S.
      • Weeke P.E.
      • et al.
      Genetic interactions with age, sex, body mass index, and hypertension in relation to atrial fibrillation: the AFGen consortium.
      • Weng L.C.
      • Preis S.R.
      • Hulme O.L.
      • Larson M.G.
      • Choi S.H.
      • Wang B.
      • et al.
      Genetic predisposition, clinical risk factor burden, and lifetime risk of atrial fibrillation.
      • Ahlberg G.
      • Refsgaard L.
      • Lundegaard P.R.
      • Andreasen L.
      • Ranthe M.F.
      • Linscheid N.
      • et al.
      Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation.
      • Roselli C.
      • Chaffin M.D.
      • Weng L.C.
      • Aeschbacher S.
      • Ahlberg G.
      • Albert C.M.
      • et al.
      Multi-ethnic genome-wide association study for atrial fibrillation.
      genetic testing can be considered but the yield is low.

       Artificial intelligence

      Machine learning is a broad term of artificial intelligence derived from the extraction of patterns from large data sets. The marriage with healthcare analytics and decision processes has been rapidly forwarded with computerized medical records and the creation of large data warehouses.
      A deep neural network was created to analyse raw ECG data from an ambulatory heart monitor and classify it into 12 categories based upon the presence of arrhythmia. Machine learning performed very well with an average under the reviewer operating characteristic curve (ROC) of 0.97 and an average F1 score (mean of the PPV and sensitivity) of 0.837; a score better than an average cardiologist (0.780).
      • Hannun A.Y.
      • Rajpurkar P.
      • Haghpanahi M.
      • Tison G.H.
      • Bourn C.
      • Turakhia M.P.
      • et al.
      Cardiologist-level arrhythmia detection and classification in ambulatory electrocardiograms using a deep neural network.
      Machine learning has been applied to standard ECG characteristics in sinus rhythm to predict incident AF using the eight independent ECG leads (leads I, II, V1–6) through a convolutional neural network.
      • Attia Z.I.
      • Noseworthy P.A.
      • Lopez-Jimenez F.
      • Asirvatham S.J.
      • Deshmukh A.J.
      • Gersh B.J.
      • et al.
      An artificial intelligence-enabled ECG algorithm for the identification of patients with atrial fibrillation during sinus rhythm: a retrospective analysis of outcome prediction.
      The ROC area under the curve for the detection of AF was 0.87 (0.86–0.88) using the internal validation dataset and 0.87 (0.86–0.88) using the testing dataset.
      In an analysis of the Atrial Fibrillation Prediction Database, a machine learning approach based upon heart rate variability predicted onset of AF with sensitivity of 100%, specificity of 95.6%, and accuracy of 96.2%.
      • Ebrahimzadeh E.
      • Kalantari M.
      • Joulani M.
      • Shahraki R.S.
      • Fayaz F.
      • Ahmadi F.
      Prediction of paroxysmal Atrial Fibrillation: a machine learning based approach using combined feature vector and mixture of expert classification on HRV signal.
      Machine learning based upon ECG characteristics identified left ventricular dysfunction with an area under the curve of 0.93, sensitivity of 86.3%, and specificity of 85.7% including risk of left ventricular dysfunction in those without.
      • Attia Z.I.
      • Kapa S.
      • Lopez-Jimenez F.
      • McKie P.M.
      • Ladewig D.J.
      • Satam G.
      • et al.
      Screening for cardiac contractile dysfunction using an artificial intelligence-enabled electrocardiogram.
      Machine learning has shown accuracy in predicting mortality and risk stratification of patients with CAD.
      • Motwani M.
      • Dey D.
      • Berman D.S.
      • Germano G.
      • Achenbach S.
      • Al-Mallah M.H.
      • et al.
      Machine learning for prediction of all-cause mortality in patients with suspected coronary artery disease: a 5-year multicentre prospective registry analysis.
      Machine learning has also been shown to accurately discriminate between athletic hearts compared to hypertrophic cardiomyopathy hearts.
      • Narula S.
      • Shameer K.
      • Salem Omar A.M.
      • Dudley J.T.
      • Sengupta P.P.
      Machine-learning algorithms to automate morphological and functional assessments in 2D echocardiography.
      Machine learning has great potential in this area of risk assessment because of the large amount of data contained in the large ECG and clinical datasets available to determine rules.

      How to assess risk for atrial fibrillation in specific populations

       Patients of advanced age

      There is agreement that the prevalence of AF in the general population in the Western world is in the order of 1–2%.
      • Schnabel R.B.
      • Yin X.
      • Gona P.
      • Larson M.G.
      • Beiser A.S.
      • McManus D.D.
      • et al.
      50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study.
      • Andrade J.G.
      • Deyell M.W.
      • Lee A.Y.
      • Macle L.
      Sex differences in atrial fibrillation.
      • Staerk L.
      • Sherer J.A.
      • Ko D.
      • Benjamin E.J.
      • Helm R.H.
      Atrial fibrillation: epidemiology, pathophysiology, and clinical outcomes.
      It is estimated that in 2010 there were 33.5 million people in the world with AF of which 20.9 million were men and 12.6 million were women.
      • Chugh S.S.
      • Havmoeller R.
      • Narayanan K.
      • Singh D.
      • Rienstra M.
      • Benjamin E.J.
      • et al.
      Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study.
      During the past 20 years, the age-adjusted prevalence rates of AF increased for both men and women and similarly the corresponding incidence rates have increased.
      • Chugh S.S.
      • Havmoeller R.
      • Narayanan K.
      • Singh D.
      • Rienstra M.
      • Benjamin E.J.
      • et al.
      Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study.
      • Stefansdottir H.
      • Aspelund T.
      • Gudnason V.
      • Arnar D.O.
      Trends in the incidence and prevalence of atrial fibrillation in Iceland and future projections.
      • Miyasaka Y.
      • Barnes M.E.
      • Gersh B.J.
      • Cha S.S.
      • Bailey K.R.
      • Abhayaratna W.P.
      • et al.
      Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence.
      • Kloosterman M.
      • Crijns H.
      • Mulder B.A.
      • Groenveld H.F.
      • Van Veldhuisen D.J.
      • Rienstra M.
      • et al.
      Sex-related differences in risk factors, outcome, and quality of life in patients with permanent atrial fibrillation: results from the RACE II study.
      • Cheng X.
      • Hu Q.
      • Gao L.
      • Liu J.
      • Qin S.
      • Zhang D.
      Sex-related differences in catheter ablation of atrial fibrillation: a systematic review and meta-analysis.
      Age is a major risk factor for the development of AF and in persons younger than 55 years a prevalence of AF around 0.5% is seen whereas in persons older than 85 years AF prevalence is around 15% (Figure 1).
      • Andrade J.G.
      • Deyell M.W.
      • Lee A.Y.
      • Macle L.
      Sex differences in atrial fibrillation.
      A stepwise increase in AF prevalence with increasing age has been found in several studies.
      • Murphy N.F.
      • Simpson C.R.
      • Jhund P.S.
      • Stewart S.
      • Kirkpatrick M.
      • Chalmers J.
      • et al.
      A national survey of the prevalence, incidence, primary care burden and treatment of atrial fibrillation in Scotland.
      ,
      • Rodriguez C.J.
      • Soliman E.Z.
      • Alonso A.
      • Swett K.
      • Okin P.M.
      • Goff Jr., D.C.
      • et al.
      Atrial fibrillation incidence and risk factors in relation to race-ethnicity and the population attributable fraction of atrial fibrillation risk factors: the Multi-Ethnic Study of Atherosclerosis.
      Studies in a multi-ethnic cohort from the United States has shown large variation in AF prevalence among various race-ethnicity groups in which AF associated hospitalizations were lower in Hispanics, Chinese, and black Americans compared to white Americans.
      • Rodriguez C.J.
      • Soliman E.Z.
      • Alonso A.
      • Swett K.
      • Okin P.M.
      • Goff Jr., D.C.
      • et al.
      Atrial fibrillation incidence and risk factors in relation to race-ethnicity and the population attributable fraction of atrial fibrillation risk factors: the Multi-Ethnic Study of Atherosclerosis.
      The predominant contributor to the increasing AF prevalence is our aging populations, more widespread use and availability of screening tools, and improved treatment for various heart diseases that enhance longevity.
      Figure thumbnail gr1
      Figure 1A depiction of the atrial fibrillation prevalence distribution found by each study published to date.
      • Andrade J.
      • Khairy P.
      • Dobrev D.
      • Nattel S.
      The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms.