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Association of Late-Gadolinium Enhancement in Cardiac Magnetic Resonance with Mortality, Ventricular Arrhythmias, and Heart Failure in Patients with Non-Ischemic Cardiomyopathy: A Systematic Review and Meta-Analysis

Open AccessPublished:January 11, 2023DOI:https://doi.org/10.1016/j.hroo.2023.01.001

      Abstract:

      Background

      Late-gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) is a predictor of adverse events in patients with non-ischemic cardiomyopathy (NICM).

      Objectives

      This meta-analysis evaluated the correlation between LGE and mortality, ventricular arrhythmias (VA) and sudden cardiac death (SCD), and heart failure (HF) outcomes.

      Methods

      A literature search was conducted for studies reporting the association between LGE in NICM and the study endpoints. The primary endpoint was mortality. Secondary endpoints included VA and SCD, HF hospitalization, improvement in left ventricular ejection fraction (LVEF) to >35%, and heart transplant referral. The search was not restricted to time or publication status. The minimum follow-up duration was one year.

      Results

      A total of 46 studies and 10,548 NICM patients (4,610 with LGE, 5,938 without LGE) were included; mean follow-up was 3 years (13-71 months). LGE was associated with increased mortality (Odds ratio (OR) 2.9, 95% Confidence Interval (CI) 2.3-3.8, P<0.01) and VA and SCD (OR 4.6, 95% CI 3.5-6.0; P<0.01). LGE was associated with an increased risk of HF hospitalization (OR 3.4, 95% CI 2.3-5.0; P<0.01), referral for transplant (OR 5.1, 95% CI 2.5-10.4; P<0.01) and decreased incidence of LVEF improvement to >35% (OR 0.2, 95% CI 0.03-0.85; P=0.03).

      Conclusions

      LGE in NICM patients is associated with increased mortality, VA and SCD, and HF hospitalization and heart transplant referral during long-term follow up. Given these competing risks of mortality and HF progression, prospective randomized controlled trials are required to determine if LGE is useful for guiding prophylactic implantable cardioverter-defibrillator placement in NICM patients.

      Key words

      ABBREVIATIONS:

      (CRT-D) (Cardiac resynchronization therapy-defibrillation), (CRT-P) (Cardiac resynchronization therapy-pacing), (CMR) (Cardiac magnetic resonance), (CI) (Confidence interval), (HF) (Heart failure), (ICD) (Implantable cardioverter-defibrillator), (LVEF) (Left ventricular ejection fraction), (LGE) (Late-gadolinium enhancement), (NICM) (Nonischemic cardiomyopathy), (OR) (Odds ratio), (PRISMA) (Preferred Reporting of Items for Systematic Reviews And Meta-Analyses), (SCD) (Sudden cardiac death), (VA) (Ventricular arrhythmias)

      Introduction

      Non-ischemic cardiomyopathy (NICM) is a highly prevalent chronic disease that has been associated with increased morbidity and mortality through progressive pump failure and life-threatening arrhythmias.
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      Economics of chronic heart failure.
      With an estimated disease prevalence ranging between 0.05% to 5% of all patients seen in the inpatient and outpatient settings and accounting for 1-2% of all annual healthcare costs, NICM places a large burden on the healthcare system in the United States and worldwide.
      • Berry C.
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      ,

      Follath F. Nonischemic heart failure: epidemiology, pathophysiology, and progression of disease. J Cardiovasc Pharmacol. 1999;33 Suppl 3(SUPPL. 3). doi:10.1097/00005344-199906003-00004

      It is imperative to identify patients who are at elevated risk for disease progression and mortality.
      Late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) is a promising technique for risk stratification of patients with NICM. LGE is useful for the detection of myocardial scar and fibrosis in patients with ischemic cardiomyopathy (ICM).
      • Wu K.C.
      • Weiss R.G.
      • Thiemann D.R.
      • et al.
      Late Gadolinium Enhancement by Cardiovascular Magnetic Resonance Heralds an Adverse Prognosis in Nonischemic Cardiomyopathy.
      ,
      • Catalano O.
      • Moro G.
      • Perotti M.
      • et al.
      Late gadolinium enhancement by cardiovascular magnetic resonance is complementary to left ventricle ejection fraction in predicting prognosis of patients with stable coronary artery disease.
      While LGE is present in approximately 30-35% of patients with NICM, studies evaluating its association with clinical outcomes have mostly been limited to single-center observational studies.
      • Yang E.Y.
      • Shah D.J.
      Cardiac Magnetic Resonance in Nonischemic Cardiomyopathies.
      The goal of this systematic review and meta-analysis was to conduct a comprehensive evaluation of the association between LGE and clinical outcomes in patients with NICM. We examined the association of LGE with all-cause mortality, ventricular arrhythmias (VA) and sudden cardiac death (SCD), heart failure (HF) hospitalization, improvement of left ventricular ejection fraction (LVEF) to > 35% and referral for heart transplant in NICM patients.

      Methods

      Data Search

      This systematic review was performed in adherence to the guidelines of the PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta-analyses). The review was performed using a preplanned protocol in January 2022. The primary endpoint was mortality. Secondary endpoints included the composite of VA and SCD, HF hospitalization, interval improvement in LVEF to > 35%, and heart transplant referral. VAs were defined as the combined incidence of premature ventricular contractions (PVC), non-sustained and sustained ventricular tachycardia, and appropriate ICD shocks. The studies were inconsistent regarding the amount of PVCs that qualified as VAs.

      Search Strategy

      A systematic search was conducted using Ovid MEDLINE, EMBASE, Scopus, Web of Science, and Google Scholar for relevant literature that reported an association between LGE in CMR and VA, SCD, mortality, HF outcomes. The search was not restricted to time or publication status. Two independent reviewers (MA and MT) performed an electronic search using the following keywords: “late”, "gadolinium", “enhancement”, “enhanced”, “enhance”, “enhancer”, “enhancers”, “enhances”, “enhancing”, “nonischaemic”, “nonischemic”, “nonischemics”, “cardiomyopathy”, “dilated”, “sensitivity”, “specificity”, “Predictive Value of Tests”, “Diagnostic Value”, “Prediction”. The references of the included studies, other systematic reviews, and meta-analyses were also manually reviewed to obtain a comprehensive list of studies. After identifying relevant studies, the full texts of the selected articles were examined by both reviewers based on inclusion criteria. Disagreements were resolved by consensus.

      Study Selection

      Studies were selected using the PICO (patient/population, intervention, comparison and outcomes) format to include those that studied patients with NICM (Population), comparing LGE present (Intervention) to LGE absent (Comparison), and assessing for all-cause mortality, SCD, VA, appropriate ICD shock, SCD, HF hospitalization, referral for heart transplant, and improvement in LVEF to >35% in subjects with baseline LVEF ≤35% (Outcomes). Studies that did not separate mixed ischemic and NICM patient populations were excluded. LGE presence was assessed either by visual estimation (present/absent) or quantitatively. When quantitative analysis was performed, the mean signal intensity and standard deviation (SD) of the region of interest were measured, and enhanced myocardium was defined as myocardium with signal intensity >5 SD above the remote normal myocardial signal. Patients with hypertrophic cardiomyopathy were excluded.

      Data Extraction

      Two reviewers (MA and MT) independently extracted the study data using a predefined data extraction sheet. Variables that were extracted from the studies included: Lead author, year of publication, study design, all-cause mortality, SCD, total patients with LGE, total patients without LGE, VAs, HF hospitalization, referral for transplant, mean follow-up, mean age, mean LVEF, gender, left ventricular end-diastolic volume, and qualitative vs quantitative interpretation of LGE.

      Statistical analysis

      Meta-analysis was performed using Comprehensive Meta-Analysis software, version 3.

      Comprehensive Meta-Analysis Software (CMA). Accessed September 28, 2022. https://www.meta-analysis.com/?gclid=CjwKCAjwhNWZBhB_EiwAPzlhNtFfAiO5PI-wyIXrg8LfjOGG_Bi0X4Y9Ryt-FMOlwfERKT67Dh4ncRoC4fYQAvD_BwE

      We used a random-effects model to examine the association between LGE and outcomes, which were presented with an odds ratio (OR) with 95% confidence interval (CI) and Z-value. The extent of heterogeneity was determined by I2 (ranging from 0% to 100%). Statistical significance was considered with a P-value < 0.05 and all tests were 2-sided.

      Results

      Literature Search and Study Selection

      We identified 216 eligible studies from our literature search. After reviewing all studies in full text for relevance, 46 studies were identified to be eligible for meta-analysis for the outcomes of all-cause mortality (primary endpoint) and the composite of VAs, SCD and appropriate ICD therapy (secondary endpoint). For the secondary endpoints of HF hospitalization, referral for heart transplant, and EF improvement to >35%, 25 studies met inclusion criteria (Figure 1).
      Figure thumbnail gr1
      Figure 1PRISMA Flow Chart. Flow diagram depicts study selection for inclusion in the meta-analysis according to the PRISMA statement for reporting systematic reviews and meta-analyses.

      Study and Patient Characteristics

      This meta-analysis included prospective and retrospective (Table 1). A total of 10,548 patients (4,610 with LGE and 5938 without LGE) were reported in the studies evaluating the association between LGE and all-cause mortality, and the combined incidence of VAs, SCD, and appropriate ICD shocks. A total of 3,039 patients (1,265 with LGE and 1,774 without LGE) were reported in the studies evaluating the association between LGE and HF hospitalization, referral for heart transplant, and LVEF improvement. The mean duration of follow-up was 36 months (range 13- 71 months, Figure 1)
      TABLE 1Demographic data of the included studies:
      NameYearTypeLGE (N)No LGE (N)Mean Follow up (months)Mean Age (years)Mean LVEF (%)Male ( %)LGE reading
      Park
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      Delayed Hyperenhancement Magnetic Resonance Imaging Is Useful in Predicting Functional Recovery of Nonischemic Left Ventricular Systolic Dysfunction.
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      Cardiovascular Magnetic Resonance, Fibrosis, and Prognosis in Dilated Cardiomyopathy.
      2006pro3566325135.669.3V
      Wu
      • Wu K.C.
      • Weiss R.G.
      • Thiemann D.R.
      • et al.
      Late Gadolinium Enhancement by Cardiovascular Magnetic Resonance Heralds an Adverse Prognosis in Nonischemic Cardiomyopathy.
      2008pro273817552464.6SD
      Cheong
      • Cheong B.Y.C.
      • Muthupillai R.
      • Wilson J.M.
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      Prognostic Significance of Delayed-Enhancement Magnetic Resonance Imaging.
      2009retro3717852.8515257V
      Yokokawa
      • Yokokawa M.
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      The characteristics and distribution of the scar tissue predict ventricular tachycardia in patients with advanced heart failure.
      2009retro181120652458.6SD
      Cho
      • Cho J.R.
      • Park S.
      • Choi B.W.
      • et al.
      Delayed enhancement magnetic resonance imaging is a significant prognostic factor in patients with non-ischemic cardiomyopathy.
      2010retro423733.45626.660.8V
      Kono
      • Kono A.K.
      • Ishii K.
      • Kumagai H.
      • Taniguchi Y.
      • Kajiya T.
      • Sugimura K.
      Late gadolinium enhancement on cardiac magnetic resonance imaging: Is it associated with a higher incidence of nonsustained ventricular tachycardia in patients with idiopathic dilated cardiomyopathy?.
      2010pro181430.86121.359.4SD
      Looi
      • Looi J.L.
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      Characteristics and prognostic importance of myocardial fibrosis in patients with dilated cardiomyopathy assessed by contrast-enhanced cardiac magnetic resonance imaging.
      2010pro317232583275.7V
      Shimizu
      • Shimizu I.
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      Delayed enhancement cardiovascular magnetic resonance as a novel technique to predict cardiac events in dilated cardiomyopathy patients.
      2010pro114014.1593076.7V
      Iles
      • Iles L.
      • Pfluger H.
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      Myocardial fibrosis predicts appropriate device therapy in patients with implantable cardioverter-defibrillators for primary prevention of sudden cardiac death.
      2011retro313019532568.9SD
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      Use of cardiovascular magnetic resonance for risk stratification in chronic heart failure: Prognostic value of late gadolinium enhancement in patients with non-ischaemic dilated cardiomyopathy.
      2011retro7211222523975SD
      Armenta
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      Use of myocardial scar characterization to predict ventricular arrhythmia in cardiac resynchronization therapy.
      2012pro152225642283SD
      Gao
      • Gao P.
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      Prediction of Arrhythmic Events in Ischemic and Dilated Cardiomyopathy Patients Referred for Implantable Cardiac Defibrillator.
      2012pro4619216126.281V
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      Assessment of myocardial scarring improves risk stratification in patients evaluated for cardiac defibrillator implantation.
      2012pro372724524150V
      Leyva
      • Leyva F.
      • Taylor R.J.
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      Left ventricular midwall fibrosis as a predictor of mortality and morbidity after cardiac resynchronization therapy in patients with nonischemic cardiomyopathy.
      2012pro2077356622.361.9V
      Masci
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      2012pro507514.258.23465.6SD
      Gulati
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      Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy.
      2013pro142330645137.268.6V
      Kubanek
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      2013pro301412432371V
      Masci
      • Masci P.G.
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      Myocardial fibrosis as a key determinant of left ventricular remodeling in idiopathic dilated cardiomyopathy: A contrast-enhanced cardiovascular magnetic study.
      2013pro263224553733SD
      Muller
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      • Kramer U.
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      Prognostic Value of Contrast-enhanced Cardiac Magnetic Resonance Imaging in Patients with Newly Diagnosed Non-Ischemic Cardiomyopathy: Cohort Study.
      2013pro9491215143.371.4V
      Neilan
      • Neilan T.G.
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      CMR quantification of myocardial scar provides additive prognostic information in nonischemic cardiomyopathy.
      2013pro818129552665V
      Sramko
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      • Kubánek M.
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      Utility of combination of cardiac magnetic resonance imaging and high-sensitivity cardiac troponin T assay in diagnosis of inflammatory cardiomyopathy.
      2013retro281425442668.2V
      Almehmadi
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      • Joncas S.X.
      • Nevis I.
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      Prevalence of myocardial fibrosis patterns in patients with systolic dysfunction: prognostic significance for the prediction of sudden cardiac arrest or appropriate implantable cardiac defibrillator therapy.
      2014retro1076215.6623373SD
      Hasselberg
      • Hasselberg N.E.
      • Edvardsen T.
      • Petri H.
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      Risk prediction of ventricular arrhythmias and myocardial function in Lamin A/C mutation positive subjects.
      2014retro49295232V
      Machii
      • Machii M.
      • Satoh H.
      • Shiraki K.
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      Distribution of late gadolinium enhancement in end-stage hypertrophic cardiomyopathy and dilated cardiomyopathy: differential diagnosis and prediction of cardiac outcome.
      2014retro482436.26424.872V
      Marra
      • Perazzolo Marra M.
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      • Zorzi A.
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      Impact of the presence and amount of myocardial fibrosis by cardiac magnetic resonance on arrhythmic outcome and sudden cardiac death in nonischemic dilated cardiomyopathy.
      2014pro7661364932.578.8V
      Masci
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      Incremental prognostic value of myocardial fibrosis in patients with non-ischemic cardiomyopathy without congestive heart failure.
      2014pro6116723504379V
      Mordi
      • Mordi I.
      • Jhund P.S.
      • Gardner R.S.
      • et al.
      LGE and NT-proBNP identify low risk of death or arrhythmic events in patients with primary prevention ICDs.
      2014pro762030.5462778.1SD
      Nabeta
      • Nabeta T.
      • Inomata T.
      • Iida Y.
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      Baseline cardiac magnetic resonance imaging versus baseline endomyocardial biopsy for the prediction of left ventricular reverse remodeling and prognosis in response to therapy in patients with idiopathic dilated cardiomyopathy.
      2014pro3639115630.265SD
      Rodriguez
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      Long-term prognostic value of late gadolinium enhancement in a cohort of patients with nonischemic dilated cardiomyopathy.
      2014retro234131.556.229.175V
      Yamada
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      Prognostic impact of combined late gadolinium enhancement on cardiovascular magnetic resonance and peak oxygen consumption in ambulatory patients with nonischemic dilated cardiomyopathy.
      2014pro2532715533.570V
      Amzulescu
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      • Rousseau M.F.
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      Prognostic Impact of Hypertrabeculation and Noncompaction Phenotype in Dilated Cardiomyopathy: A CMR Study.
      2015pre639941552563V
      Barison
      • Barison A.
      • del Torto A.
      • Chiappino S.
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      Prognostic significance of myocardial extracellular volume fraction in nonischaemic dilated cardiomyopathy.
      2015pro3950245941XV
      Chimura
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      • Kiuchi K.
      • Okajima K.
      • et al.
      Distribution of Ventricular Fibrosis Associated With Life-Threatening Ventricular Tachyarrhythmias in Patients With Nonischemic Dilated Cardiomyopathy.
      2015retro1225361602963V
      Piers
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      Myocardial scar predicts monomorphic ventricular tachycardia but not polymorphic ventricular tachycardia or ventricular fibrillation in nonischemic dilated cardiomyopathy.
      2015pro553245562962V
      Tateishi
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      Prognostic impact of blood pressure response plus gadolinium enhancement in dilated cardiomyopathy.
      2015pro10510244502780V
      Venero
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      Mid wall fibrosis on CMR with late gadolinium enhancement may predict prognosis for LVAD and transplantation risk in patients with newly diagnosed dilated cardiomyopathy—preliminary observations from a high‐volume transplant centre.
      2015pro2110124517.667.7V
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      Prognostic Value of Late Gadolinium Enhancement in Nonischemic Cardiomyopathy.
      2016retro7134275025.356.2SD
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      2016retro374147.7563168SD
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      2016pro665225.2573257.6SD
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      2016retro26110444.354.126.561.9SD
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      LGE: late gadolinium enhancement, LVEF: Left ventricular ejection fraction, LVEDV: left ventricular end diastolic volume, (*) indexed by body surface area, Pro: prospective, Retro: retrospective, V: visual estimation, SD: standard deviation

      Association of LGE with all-cause mortality and VAs, SCD, and appropriate ICD shocks

      LGE was associated with an increased risk of all-cause mortality (OR 2.9, 95% CI 2.3-3.8, p <0.01; Figure 2). There was low heterogeneity (Chi2=51.26, df=32, p=0.017, I2=37%). LGE was also associated with an increased risk for the combined incidence of VAs, SCD, and appropriate ICD shocks (OR 4.6, 95% CI 3.5-6.0; P<0.01; Figure 3). There was low to moderate heterogeneity (Chi2=82.2, df=45, p=0.001, I2=45%).
      Figure thumbnail gr2
      Figure 2Association between LGE and mortality. LGE was associated with an increased risk of all-cause mortality (OR 2.9, 95% CI 2.3-3.8, P<0.01). There was low heterogeneity (Chi2=51.26, df=32, p=0.017, I2=37%).
      Figure thumbnail gr3
      Figure 3Association between LGE and ventricular arrhythmias/sudden cardiac death, LGE was associated with an increased risk for the combined incidence of VAs, SCD, and appropriate ICD shocks (OR 4.6, 95% CI 3.5-6.0; P<0.01). Heterogeneity was low to moderate: Chi

      Follath F. Nonischemic heart failure: epidemiology, pathophysiology, and progression of disease. J Cardiovasc Pharmacol. 1999;33 Suppl 3(SUPPL. 3). doi:10.1097/00005344-199906003-00004

      = 82.2, df =45 (P=0.001), I2 =45%.

      Association of LGE with HF Hospitalization, Referral for Transplant, and recovery of EF

      LGE was associated with an increased risk of HF hospitalization (OR 3.4, 95% CI 2.3-5.0, P<0.01; Figure 4). The heterogeneity was moderate (Chi2=49.5, df=21, p=0.001, I2=57%). LGE was associated with increased referral for heart transplant (OR 5.1, 95% CI 2.5-10.4, P<0.01; Figure 5). The heterogeneity was low (Chi2=4, df=9, p=0.87, I2=0%). LGE was associated with an increased risk for lack of improvement in LVEF to > 35% (OR 0.2, 95% CI 0.03-0.85, P=0.03; Figure 6). The heterogeneity was moderate to high (Chi2=30, df=4, p=0.001, I2=86%).
      Figure thumbnail gr4
      Figure 4Association between LGE and HF hospitalization: LGE was associated with an increased risk of HF hospitalization (OR 3.4, 95% CI 2.3-5.0, P<0.01). The heterogeneity was moderate (Chi2=49.5, df=21, p=0.001, I2=57%).
      Figure thumbnail gr5
      Figure 5Association between LGE and referral for heart transplant, LGE was associated with increased referral for heart transplant (OR 5.1, 95% CI 2.5-10.4, P<0.01). The heterogeneity was low (Chi2=4, df=9, p=0.87, I2=0%).
      Figure thumbnail gr6
      Figure 6Association between LGE and EF improvement to >35%, LGE was associated with an increased risk for lack of improvement in LVEF to > 35% (OR 0.2, 95% CI 0.03-0.85, P=0.03). The heterogeneity was moderate to high (Chi2=30, df=4, p=0.001, I2=86%).

      Discussion

      The major findings of this study are that LGE identifies NICM patients who are at increased risk for all-cause mortality and the combined incidence of VAs, SCD, and appropriate ICD shocks. LGE also identified NICM patients who are at increased risk for HF hospitalization, referral for heart transplant, and lack of improvement in LVEF. To our knowledge, this meta-analysis is the most comprehensive evaluation to date of the association of LGE and clinical outcomes in NICM.
      The initial AHA/ACC/HRS guidelines recommending defibrillator implantation in NICM were primarily based on the results of the SCD-HeFT trial published over a decade ago.

      Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death. Circulation. 2018;138(13):e272-e391. doi:10.1161/CIR.0000000000000549

      ,
      • Bardy G.H.
      • Lee K.L.
      • Mark D.B.
      • et al.
      Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
      However, the SCD-HeFT trial was conducted on a mixed population (52% ICM and 48% NICM). At 10-year follow-up of the SCD-HeFT population, there was no mortality benefit for ICD placement in the patients with NICM.
      • Poole J.E.
      • Olshansky B.
      • Mark D.B.
      • et al.
      Long-Term Outcomes of Implantable Cardioverter-Defibrillator Therapy in the SCD-HeFT.
      Similarly, the DANISH trial demonstrated no significant difference in all-cause mortality with ICD implantation in patients with NICM.
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • et al.
      Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure.
      However, in the DEFINITE trial ICD placement did not reduce mortality, but was associated with a reduction in sudden death from arrhythmia.
      • Kadish A.
      • Dyer A.
      • Daubert J.P.
      • et al.
      Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy.
      One possible explanation for these findings may be that NICM represents a heterogeneous group of diseases where certain disease etiologies place patients at higher cardiovascular risk than others.
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • et al.
      Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure.
      The lack of benefit of prophylactic ICD implantation in these studies highlights the need for additional risk stratification beyond LVEF, such as LGE. In one study, ICD placement was associated with a reduction in mortality only in patients with LGE (HR: 0.45 vs 1.22 for LGE and no LGE respectively, p <0.05).
      • Gutman S.J.
      • Costello B.T.
      • Papapostolou S.
      • et al.
      Reduction in mortality from implantable cardioverter-defibrillators in non-ischaemic cardiomyopathy patients is dependent on the presence of left ventricular scar.
      LGE may also be utilized to identify high risk patients that are excluded from current guidelines for ICD implantation. Although LVEF <35% is the current standard for recommending ICD implantation in NICM patients, it has low sensitivity (71.7%) and specificity (50.5%) for identifying patients at risk for SCD.
      • Goldberger J.J.
      • Subačius H.
      • Patel T.
      • Cunnane R.
      • Kadish A.H.
      Sudden cardiac death risk stratification in patients with nonischemic dilated cardiomyopathy.
      As a result, some high risk patients are not receiving ICD implantation due to not meeting LVEF criteria, while other low risk patients with LVEF<35% and no LGE are having ICDs implanted and are exposed to device complications such as inappropriate shocks, lead or pulse generator malfunction, and infection. One study demonstrated that LGE is associated with ventricular arrhythmias and sudden cardiac death even in patients with LVEF >35%.
      • di Marco A.
      • Brown P.F.
      • Bradley J.
      • et al.
      Improved Risk Stratification for Ventricular Arrhythmias and Sudden Death in Patients With Nonischemic Dilated Cardiomyopathy.
      The stark contrast in the utility of LVEF for predicting risk in NICM and ICM may be due to the fact that in ICM, a significant reduction in LVEF represents more extensive myocardial injury and scar formation. Several previous studies have suggested a strong correlation between reduction in LVEF and the extent of myocardial scarring in patients with ICM.
      • Nijveldt R.
      • Beek A.M.
      • Hirsch A.
      • et al.
      Functional Recovery After Acute Myocardial Infarction. Comparison Between Angiography, Electrocardiography, and Cardiovascular Magnetic Resonance Measures of Microvascular Injury.
      ,
      • Nijveldt R.
      • van der Vleuten P.A.
      • Hirsch A.
      • et al.
      Early Electrocardiographic Findings and MR Imaging-Verified Microvascular Injury and Myocardial Infarct Size.
      In comparison, the pathogenesis of myocardial fibrosis in NICM remains unclear and may occur in varying distributions of myocardial tissue.
      • Zeppenfeld K.
      Ventricular Tachycardia Ablation in Nonischemic Cardiomyopathy.
      While this development of fibrosis may not significantly impact LVEF, it may still place patients at risk for adverse events. In one study, the presence of LGE was not associated with initial low LVEF but it predicted subsequent worsening of LVEF over time.
      • Nabeta T.
      • Ishii S.
      • Ikeda Y.
      • et al.
      Late gadolinium enhancement for re-worsening left ventricular ejection fraction in patients with dilated cardiomyopathy.
      The existing literature has been mixed regarding whether LGE is associated with adverse left ventricular remodeling and differences in left ventricular dimensions.
      • Yang E.Y.
      • Shah D.J.
      Cardiac Magnetic Resonance in Nonischemic Cardiomyopathies.
      ,
      • Gulati A.
      • Jabbour A.
      • Ismail T.F.
      • et al.
      Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy.
      • Lehrke S.
      • Lossnitzer D.
      • Schöb M.
      • et al.
      Use of cardiovascular magnetic resonance for risk stratification in chronic heart failure: Prognostic value of late gadolinium enhancement in patients with non-ischaemic dilated cardiomyopathy.
      • Neilan T.G.
      • Coelho-Filho O.R.
      • Danik S.B.
      • et al.
      CMR quantification of myocardial scar provides additive prognostic information in nonischemic cardiomyopathy.

      Behera DR, v K AK, K K NN, et al. Prognostic value of late gadolinium enhancement in cardiac MRI of non-ischemic dilated cardiomyopathy patients. Indian Heart J. 2020;72(5):362-368. doi:10.1016/J.IHJ.2020.06.011

      In the present study, LGE identified NICM patients who are at increased risk for HF hospitalization, referral for heart transplant, and lack of improvement in LVEF. The clinical implications of these results are twofold. First, patients at high risk for HF progression may require close monitoring by a heart failure specialist and earlier referral to specialty centers for evaluation of advanced therapeutic options. Second, patients with LVEF <35% who do not have LGE may not need a prophylactic ICD or could be considered for a cardiac resynchronization therapy (CRT) pacemaker if they meet CRT criteria given the higher likelihood for left ventricular reverse remodeling. These findings await confirmation in adequately powered, prospective studies before withholding ICD therapy from patients that meet current guidelines. The available data on the utility of adding ICD therapy to CRT in NICM patients is conflicting as several studies have demonstrated no added mortality benefit,
      • Cleland J.G.F.
      • Daubert J.C.
      • Erdmann E.
      • et al.
      The CARE-HF study (cardiac resynchronisation in heart failure study): Rationale, design and end-points.
      • Looi K.L.
      • Gajendragadkar P.R.
      • Khan F.Z.
      • et al.
      Cardiac resynchronisation therapy: pacemaker versus internal cardioverter-defibrillator in patients with impaired left ventricular function.
      • Reitan C.
      • Chaudhry U.
      • Bakos Z.
      • et al.
      Long-Term Results of Cardiac Resynchronization Therapy: A Comparison between CRT-Pacemakers versus Primary Prophylactic CRT-Defibrillators.
      while the COMPANION trial reported the opposite result.
      • Doran B.
      • Mei C.
      • Varosy P.D.
      • et al.
      The Addition of a Defibrillator to Resynchronization Therapy Decreases Mortality in Patients With Nonischemic Cardiomyopathy.

      Study Limitations

      There are several limitations that need to be taken into consideration when assessing the results of this present study. Given that currently there are no standardized methods for defining the presence or extent of LGE, the interpretation of LGE varied across the studies included in this meta-analysis. The presence of LGE was defined in several ways, ranging from visual estimation to different threshold-based methods of analysis where the signal intensity of contrast-enhanced areas was compared to non-enhanced areas of myocardium.
      While our results suggest the presence of LGE has significant associations with clinical outcomes, we did not evaluate whether patterns of LGE result in differences in associated risk. There have been several studies demonstrating septal, subepicardial, and multiple LGE lesions to be independent predictors of cardiovascular outcomes.

      Behera DR, v K AK, K K NN, et al. Prognostic value of late gadolinium enhancement in cardiac MRI of non-ischemic dilated cardiomyopathy patients. Indian Heart J. 2020;72(5):362-368. doi:10.1016/J.IHJ.2020.06.011

      ,
      • Ota S.
      • Orii M.
      • Nishiguchi T.
      • et al.
      Implications of multiple late gadolinium enhancement lesions on the frequency of left ventricular reverse remodeling and prognosis in patients with non‐ischemic cardiomyopathy.
      ,
      • Halliday B.P.
      • Gulati A.
      • Ali A.
      • et al.
      Association Between Midwall Late Gadolinium Enhancement and Sudden Cardiac Death in Patients With Dilated Cardiomyopathy and Mild and Moderate Left Ventricular Systolic Dysfunction.
      However, we could not identify enough current literature on this topic to further investigate in this meta-analysis.
      Since there is a lack of standardization for defining the extent of LGE, we could not evaluate whether the extent of LGE correlates with differences in clinical outcomes. LGE extent can be interpreted in various ways, including summation of segments with hyperenhancement, percentage of involved myocardium, or absolute weight of enhanced myocardium.
      • Keil L.
      • Chevalier C.
      • Kirchhof P.
      • et al.
      CMR-Based Risk Stratification of Sudden Cardiac Death and Use of Implantable Cardioverter-Defibrillator in Non-Ischemic Cardiomyopathy.
      Interpretation is further complicated as different LGE quantification techniques have been shown to cause wide variations in results in a single patient.
      • Flett A.S.
      • Hasleton J.
      • Cook C.
      • et al.
      Evaluation of techniques for the quantification of myocardial scar of differing etiology using cardiac magnetic resonance.
      Perhaps it is because of these reasons that there is no current consensus on what extent of LGE is predictive of clinical events. Cut-off values of significance for LGE extent range as broadly as >5% to >17% and even results on the clinical significance of small areas of LGE have been mixed.

      Behera DR, v K AK, K K NN, et al. Prognostic value of late gadolinium enhancement in cardiac MRI of non-ischemic dilated cardiomyopathy patients. Indian Heart J. 2020;72(5):362-368. doi:10.1016/J.IHJ.2020.06.011

      ,
      • Shimizu I.
      • Iguchi N.
      • Watanabe H.
      • et al.
      Delayed enhancement cardiovascular magnetic resonance as a novel technique to predict cardiac events in dilated cardiomyopathy patients.
      • Pöyhönen P.
      • Kivistö S.
      • Holmström M.
      • Hänninen H.
      Quantifying late gadolinium enhancement on CMR provides additional prognostic information in early risk-stratification of nonischemic cardiomyopathy: A cohort study.
      • Assomull R.G.
      • Prasad S.K.
      • Lyne J.
      • et al.
      Cardiovascular Magnetic Resonance, Fibrosis, and Prognosis in Dilated Cardiomyopathy.
      • Halliday B.P.
      • Baksi A.J.
      • Gulati A.
      • et al.
      Outcome in Dilated Cardiomyopathy Related to the Extent, Location, and Pattern of Late Gadolinium Enhancement.
      LGE on CMR is only able to detect regional myocardial fibrosis. While this pattern is typical in ICM, where regional fibrosis is present, fibrosis patterns in NICM can occur either regionally or diffusely.

      Behera DR, v K AK, K K NN, et al. Prognostic value of late gadolinium enhancement in cardiac MRI of non-ischemic dilated cardiomyopathy patients. Indian Heart J. 2020;72(5):362-368. doi:10.1016/J.IHJ.2020.06.011

      ,
      • Kuruvilla S.
      • Adenaw N.
      • Katwal A.B.
      • Lipinski M.J.
      • Kramer C.M.
      • Salerno M.
      Late gadolinium enhancement on cardiac magnetic resonance predicts adverse cardiovascular outcomes in nonischemic cardiomyopathy: A systematic review and meta-analysis.
      Studies that utilized T1 mapping and extracellular volume fraction to detect diffuse myocardial fibrosis have shown this pattern to be significantly associated with adverse cardiovascular outcomes as well.
      • Puntmann V.O.
      • Carr-White G.
      • Jabbour A.
      • et al.
      T1-Mapping and Outcome in Nonischemic Cardiomyopathy: All-Cause Mortality and Heart Failure.
      Future studies should examine whether combined assessment of regional and diffuse fibrosis is useful for risk stratifying NICM patients.
      The definition of VAs varied between studies, and some studies included VAs that are not life threatening in the composite endpoint, such as PVCs and non-sustained VT.

      Conclusion

      LGE in NICM patients is associated with increased mortality, VA and SCD, HF hospitalization and heart transplant referral during long-term follow up. Given these competing risks of mortality and HF progression, prospective randomized controlled trials are required to determine if LGE is useful for guiding prophylactic implantable cardioverter-defibrillator placement in NICM patients who meet current guideline indications and NICM patients with less severe left ventricular dysfunction.
      Funding: None
      Conflict of interest: The authors report no relevant conflicts of interest.
      Guidelines Statement: The systematic review was conducted with a protocol in accordance with the Preferred Reporting of Items for Systematic reviews and Meta-Analyses (PRISMA) statement.

      Acknowledgement:

      None

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