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Canadian Journal of Cardiology

Left Atrial Function and Sudden Cardiac Death

      The Prevention of Sudden Cardiac Death

      Sudden cardiac death (SCD), presumed to be due to a cardiac arrhythmia or haemodynamic catastrophe, is defined as occurring within an hour of the onset of symptoms, or as an unwitnessed death occurring within 24 hours of being asymptomatic.
      • Al-Khatib S.M.
      • Stevenson W.G.
      • Ackerman M.J.
      • et al.
      2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.
      The incidence of SCD in the general population internationally ranges from 50 to 100 per 100,000 persons per year.
      • Wong C.X.
      • Brown A.
      • Lau D.H.
      • et al.
      Epidemiology of sudden cardiac death: global and regional perspectives.
      Approaches to the prevention of SCD may be divided into 2 categories: the prevention of the conditions leading to SCD, and the identification of those at increased risk of SCD followed by their treatment with interventions to reduce that risk. The placement of an implantable cardioverter-defibrillator (ICD) has been established to be effective in reducing the risk of SCD due to ventricular tachyarrhythmia (SCD-VA) in selected patients and is recommended in various society guidelines.
      • Al-Khatib S.M.
      • Stevenson W.G.
      • Ackerman M.J.
      • et al.
      2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.
      • Bennett M.
      • Parkash R.
      • Nery P.
      • et al.
      Canadian Cardiovascular Society/Canadian Heart Rhythm Society 2016 implantable cardioverter-defibrillator guidelines.
      The risk of SCD-VA and the competing risks of nonsudden death and sudden death from noncardiac causes must be considered in each patient before ICD implantation to ensure that an ICD has a reasonable probability of increasing life expectancy.
      Left ventricular ejection fraction (LVEF) is a useful marker of SCD-VA risk, but in isolation it has limited precision in predicting those most likely to benefit from an ICD.
      • 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.
      • Exner D.V.
      • Kavanagh K.M.
      • Slawnych M.P.
      • et al.
      Noninvasive risk assessment early after a myocardial infarction the REFINE study.
      Only a minority of those with SCD have impaired LVEF, and only a fraction of those with impaired LVEF experience SCD.
      • Myerburg R.J.
      • Kessler K.M.
      • Castellanos A.
      Sudden cardiac death. Structure, function, and time-dependence of risk.
      The development of a more refined assessment of SCD risk with the use of additional risk markers is an area of ongoing research. In the current issue of the Canadian Journal of Cardiology, Lydell et al. present one such study, in which they investigated whether indices of left atrial function may be of value in determining the risk of SCD-VA.
      • Lydell C.P.
      • MIkami Y.
      • Homer K.
      • et al.
      Left atrial function using cardiovascular magnetic resonance imaging independently predicts life-threatening arrhythmias in patients referred to receive a primary prevention implantable cardioverter defibrillator.

      Study Design and Main Findings

      Lydell et al. performed a retrospective study of 203 subjects with either ischemic cardiomyopathy (ICM) or nonischemic cardiomyopathy (NICM). All subjects underwent both the implantation of a primary-prevention ICD and preimplantation cardiac magnetic resonance imaging (CMRI) from which left atrial volumes and function were assessed. The study population was followed for a median of 4.5 years, with 80% followed for more than 2.7 years. The primary end point was either SCD or an appropriate ICD shock. Thirty-five subjects (17%) reached the primary end point, with the majority of these events (33/35) being ICD shocks. The authors performed univariate analysis and identified a statistically significant association between the primary end point and larger indexed left atrial (LA) volumes, lower LA emptying fractions (LAEFs), and lower indexed LA conduit volumes (LACV). Of these parameters, they selected LAEF for further analysis with the use of a survival probability approach. They identified an LAEF threshold of 30% below which the probability of the primary end point was significantly increased. They then dichotomised the study population with this threshold and performed a multivariate analysis, which found that subjects with an LAEF of ≤ 30% had a 4.7-fold higher risk (P = 0.002) of the primary end point.
      They also performed a subgroup analysis by cardiomyopathy type. The rate of the primary end point was similar in both ischemic and nonischemic groups. In a multivariate analysis, LAEF ≤ 30% was significantly associated with the primary end point in the ICM group (hazard ratio [HR] 6.3; P = 0.02) but not in the NICM group. When analysed as a continuous variable, LAEF did have a significant association with the primary end point in the NICM group (HR 0.81 per 5% LAEF increment; P = 0.04).

      Strengths and Weaknesses

      Lydell et al. demonstrated a clear association between LA function and appropriate ICD therapy in their cohort. An important strength of their methodology is that the measurements of left atrial volume and function that they used may be readily performed from standard CMRI cine sequences.
      There are, however, important caveats to consider in their study. A more detailed description of device programming and the presence of cardiac resynchronization and mitral valve disease in their study population would help with the interpretation of their findings.
      • Deif B.
      • Ballantyne B.
      • Almehmadi F.
      • et al.
      Cardiac resynchronization is pro-arrhythmic in the absence of reverse ventricular remodelling: a systematic review and meta-analysis.
      Consideration of electrocardiographic characteristics known to be associated with SCD in their analysis would have been interesting to understand if LA function provides further information above these markers of SCD risk.
      • Das M.K.
      • Maskoun W.
      • Shen C.
      • et al.
      Fragmented QRS on twelve-lead electrocardiogram predicts arrhythmic events in patients with ischemic and nonischemic cardiomyopathy.

      Previous Research in This Area

      This study adds to previous work on LA parameters as predictors of SCD and all-cause mortality. Key elements of selected studies in this area are described in Table 1.
      Table 1Summary of studies of between left atrial (LA) imaging parameters and sudden cardiac death
      ReferenceStudy designStudy populationPrimary end pointVariables with statistically significant association with primary end point in multivariable modelling
      Rijnierse et al.
      • Rijnierse M.T.
      • Kamali Sadeghian M.
      • Schuurmans Stekhoven S.
      • et al.
      Usefulness of left atrial emptying fraction to predict ventricular arrhythmias in patients with implantable cardioverter defibrillators.
      Retrospective, patients referred for a primary-prevention ICD, ICM and NICM, assessed by CMRIn = 229; 69% ICMFirst appropriate device therapyLAEF, total LV scar volume
      Assessed with the use of late gadolinium enhancement.
      Negishi et al.
      • Negishi K.
      • Negishi T.
      • Zardkoohi O.
      • et al.
      Left atrial booster pump function is an independent predictor of subsequent life-threatening ventricular arrhythmias in nonischaemic cardiomyopathy.
      Retrospective, patients with NICM referred for a primary prevention ICD, assessed by TTEn = 124First appropriate device therapyMitral A-wave velocity
      Pellicori et al.
      • Pellicori P.
      • Zhang J.
      • Lukaschuk E.
      • et al.
      Left atrial function measured by cardiac magnetic resonance imaging in patients with heart failure: clinical associations and prognostic value.
      Retrospective, patients with a new diagnosis of heart failure, assessed by CMRIn = 664Hospitalization for heart failure or all-cause mortalityLAEF
      Gulati et al.
      • Gulati A.
      • Ismail T.F.
      • Jabbour A.
      • et al.
      Clinical utility and prognostic value of left atrial volume assessment by cardiovascular magnetic resonance in nonischaemic dilated cardiomyopathy.
      Retrospective, patients with NICM, assessed by CMRIn = 483All-cause mortality or cardiac transplantationLA volume indexed to BSA
      BSA, body surface area; CMRI, cardiac magnetic resonance imaging; ICD, implantable cardioverter-defibrillator; ICM, ischemic cardiomyopathy; LAEF, left atrial ejection fraction; LV, left ventricular; NICM, nonischemic cardiomyopathy; TTE, transthoracic echocardiography.
      Assessed with the use of late gadolinium enhancement.
      The studies examining SCD and arrhythmic end points reported that LA volume was not a significant predictor. Reports that atrial fibrillation, the end-stage manifestation of poor LA function, is a predictor for SCD also support the idea that LA function is more important than size in predicting ventricular arrhythmia.
      • Goldenberg I.
      • Vyas A.K.
      • Hall W.J.
      • et al.
      Risk stratification for primary implantation of a cardioverter-defibrillator in patients with ischemic left ventricular dysfunction.
      Lydell et al. point out that the mechanisms responsible for the association have yet to be fully elucidated. Increased LA volume and reduced LAEF have been strongly associated with increased LV end-diastolic pressure, which may be the result of diastolic dysfunction associated with fibrosis.
      • Posina K.
      • McLaughlin J.
      • Rhee P.
      • et al.
      Relationship of phasic left atrial volume and emptying function to left ventricular filling pressure: a cardiovascular magnetic resonance study.
      • Appleton C.P.
      • Galloway J.M.
      • Gonzalez M.S.
      • Gaballa M.
      • Basnight M.A.
      Estimation of left ventricular filling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease. Additional value of analyzing left atrial size, left atrial ejection fraction and the difference in duration of pulmonary venous and mitral flow velocity at atrial contraction.
      In this sense, LA function can be considered to be a further indirect measure of the burden of arrhythmic substrate in the LV. Yet LAEF has been found to be a predictor of SCD independently from LV scar volume assessed by means of CMRI, suggesting that it is a surrogate for proarrhythmic factors beyond scar burden.
      • Rijnierse M.T.
      • Kamali Sadeghian M.
      • Schuurmans Stekhoven S.
      • et al.
      Usefulness of left atrial emptying fraction to predict ventricular arrhythmias in patients with implantable cardioverter defibrillators.
      Further research is needed in this area and should include the study of a more diverse population than that included in this study, namely, those that are not currently considered candidates for a primary-prevention ICD.

      Future Directions in SCD Risk Stratification

      LA function is one of a steadily expanding list of novel risk markers (Table 2). These markers have been found to be of some prognostic value but have not been widely used clinically and are not recommended as part of routine evaluation by current guidelines.
      • Bennett M.
      • Parkash R.
      • Nery P.
      • et al.
      Canadian Cardiovascular Society/Canadian Heart Rhythm Society 2016 implantable cardioverter-defibrillator guidelines.
      The REFINE-ICD study (NCT00673842) is testing the utility of a primary-prevention ICD in patients with the presence of these electrophysiologic risk markers in the setting of a previous myocardial infarction.
      • Exner D.V.
      • Kavanagh K.M.
      • Slawnych M.P.
      • et al.
      Noninvasive risk assessment early after a myocardial infarction the REFINE study.
      Table 2Emerging risk markers for sudden cardiac death
      • Zaman S.
      • Goldberger J.J.
      • Kovoor P.
      Sudden death risk-stratification in 2018-2019: the old and the new.
      • van der Bijl P.
      • Delgado V.
      • Bax J.J.
      Noninvasive imaging markers associated with sudden cardiac death.
      ModalityMarker
      ImagingLeft ventricular ejection fraction
      Mechanical dispersion by speckle-tracking echocardiography
      Left atrial emptying function
      Volume of denervated myocardium by 11C-HED positron-emission tomography (PET)
      Metabolism perfusion mismatch by 18F-FDG PET
      Left ventricular scar mass and extent of peri-infarct zone by cardiac magnetic resonance imaging with gadolinium enhancement
      Reversible perfusion defects by single photon–emission computed tomographic myocardial perfusion imaging
      ElectricalInducible ventricular arrhythmia by programmed ventricular stimulation
      Microvolt T-wave alternans
      Heart rate turbulence and variability
      QRS fragmentation and duration
      Signal averaged electrocardiography (late potentials)
      OtherB-type natriuretic peptide
      Genetic markers

      Conclusion

      The use of markers such as LAEF and others may assist in risk-stratifying those individuals who would benefit most from ICD therapy beyond the accepted criteria using LVEF and heart failure severity. More research is needed to understand the pathophysiology of LA dysfunction and how it relates mechanistically to arrhythmic risk. The utility of these risk markers and to whom they should be applied also deserve further study. Ideally, future studies would have a prospective design and include a wide range of putative risk markers. This work may ultimately help us to move SCD risk stratification away from dichotomising patients on the basis of LVEF toward a multifactorial assessment that allows patients to be located in a continuous spectrum of SCD risk.

      Disclosures

      Dr Parkash receives grant funding from Medtronic and Abbott and is a CANet Network Investigator. Dr Lee has no conflicts of interest to disclose.

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