European Journal of Heart Failure (2022) 24, 1183–1196 RESEARCH ARTICLE doi:10.1002/ejhf.2514 Combination of late gadolinium enhancement and genotype improves prediction of prognosis in non-ischaemic dilated cardiomyopathy Jesús G. Mirelis1,2,3* , Luis Escobar-Lopez1,2,3 , Juan Pablo Ochoa1,2,3 , María Ángeles Espinosa2,4, Eduardo Villacorta2,5,6 , Marina Navarro2,3,7, Guillem Casas2,8 , Nerea Mora-Ayestarán9 , Roberto Barriales-Villa2,10 , María Victoria Mogollón-Jiménez11, José M. García-Pinilla2,12 , Pablo E. García-Granja13 , Vicente Climent14 , Julian Palomino-Doza2,15, Ana García-Álvarez2,16,17, María Álvarez-Barredo2,18, Eva Cabrera-Borrego2,19, Tomás Ripoll-Vera20 , María Luisa Peña-Peña21, Elena Rodríguez-González4, María Gallego-Delgado2,5 , Josefa Gonzalez-Carrillo3,7, Ana Fernández-Ávila4, José F. Rodríguez-Palomares2,8 , Ramón Brugada2,22, Antoni Bayes-Genis2,23, Fernando Dominguez1,2,3, and Pablo García-Pavía1,2,3,17,24,25,* 1 Department of Cardiology, Hospital Universitario Puerta de Hierro, IDIPHISA, Madrid, Spain; 2 CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain; 3 European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN-GUARDHEART); 4 Department of Cardiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; 5 Inherited Cardiac Diseases Unit. Department of Cardiology, Instituto de Investigación Biomédica de Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y León (SACYL), Salamanca, Spain; 6 Departament of Medicine, Facultad de Medicina, Universidad de Salamanca, Salamanca, Spain; 7 Inherited Cardiac Disease Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain; 8 Inherited Cardiovascular Diseases Unit. Department of Cardiology. Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; 9 Department of Cardiology, Área del Corazón, Complejo Hospitalario de Navarra, Pamplona, Spain; 10 Inherited Cardiac Diseases Unit. Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña, Servizo Galego de Saúde (SERGAS), Universidade da Coruña, A Coruña, Spain; 11 Department of Cardiology, Complejo Hospitalario Universitario de Cáceres, Cáceres, Spain; 12 Heart Failure and Familial Heart Diseases Unit, Cardiology Department, Hospital Universitario Virgen de la Victoria, IBIMA, Malaga, Spain; 13 Department of Cardiology, Instituto de Ciencias del Corazón (ICICOR), Hospital Clínico Universitario Valladolid, Valladolid, Spain; 14 Inherited Cardiovascular Diseases Unit, Department of Cardiology, Hospital General Universitario de Alicante, Institute of Health and Biomedical Research, Alicante, Spain; 15 Inherited Cardiac Diseases Unit, Cardiology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación i+12, Madrid, Spain; 16 Cardiology Departament, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain; 17 Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; 18 Xenética Cardiovascular, Instituto de investigación Sanitaria de Santiago, Unidad de Cardiopatías Familiares, Department of Cardiology, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain; 19 Department of Cardiology, Hospital Universitario Virgen de las Nieves, Granada, Spain; 20 Inherited Cardiac Diseases Unit, Cardiology Department, Hospital Universitario Son Llatzer & IdISBa, Palma de Mallorca, Spain; 21 Inherited Cardiac Diseases Unit, Hospital Universitario Virgen del Rocío, Seville, Spain; 22 Department of Cardiology, Hospital Univesitari Dr. Josep Trueta, Girona, Spain; 23 Heart Institute. Hospital Universitari Germans Trias i Pujol. Badalona, Barcelona, Spain; 24 Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, Spain; and 25 Universidad Autónoma de Madrid, Madrid, Spain Received 24 August 2021; revised 15 March 2022; accepted 14 April 2022 ; online publish-ahead-of-print 22 May 2022 Aims Genotype and left ventricular scar on cardiac magnetic resonance (CMR) are increasingly recognized as risk markers for adverse outcomes in non-ischaemic dilated cardiomyopathy (DCM). We investigated the combined influence of genotype and late gadolinium enhancement (LGE) in assessing prognosis in a large cohort of patients with DCM. ..................................................................................................................................................................... Methods and Outcomes of 600 patients with DCM (53.3 ± 14.1 years, 66% male) who underwent clinical CMR and genetic testing results were retrospectively analysed. The primary endpoints were end-stage heart failure (ESHF) and malignant ventricular arrhythmias (MVA). During a median follow-up of 2.7 years (interquartile range 1.3–4.9), 24 (4.00%) and 48 (8.00%) patients had ESHF and MVA, respectively. In total, 242 (40.3%) patients had pathogenic/likely pathogenic variants (positive genotype) and 151 (25.2%) had LGE. In survival analysis, positive LGE was associated with MVA and ESHF *Corresponding author. Jesús G. Mirelis and Pablo García-Pavía, Department of Cardiology, Hospital Universitario Puerta de Hierro, Manuel de Falla, 2, Majadahonda, Madrid 28222, Spain. Email: pablo.garciap@uam.es; jesus.gmirelis@telefonica.net © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 1184 J.G. Mirelis et al. (both, p < 0.001) while positive genotype was associated with ESHF (p = 0.034) but not with MVA (p = 0.102). Classification of patients according to genotype (G+/G−) and LGE presence (L+/L−) revealed progressively increasing events across L−/G−, L−/G+, L+/G− and L+/G+ groups and resulted in opti- mized MVA and ESHF prediction (p < 0.001 and p = 0.001, respectively). Hazard ratios for MVA and ESHF in patients with either L+ or G+ compared with those with L−/G− were 4.71 (95% confidence interval: 2.11–10.50, p < 0.001) and 7.92 (95% confidence interval: 1.86–33.78, p < 0.001), respectively. ..................................................................................................................................................................... Conclusion Classification of patients with DCM according to genotype and LGE improves MVA and ESHF prediction. Scar assessment with CMR and genotyping should be considered to select patients for primary prevention implantable cardioverter-defibrillator placement. .......................................................................................................... Graphical Abstract Non-ischaemic dilated cardiomyopathy (NI DCM) patients with positive genotype and/or late gadolinium enhancement (LGE) show increased risk of ventricular arrhythmias and end-stage heart failure (ESHF) during follow-up. CI, confidence interval; HR, hazard ratio; LVEF, left ventricular ejection fraction; MVA, malignant ventricular arrhythmia. .......................................................................................................... Keywords Cardiac magnetic resonance • Dilated cardiomyopathy • End-stage heart failure • Genotype • Late gadolinium enhancement • Sudden cardiac death Introduction a common substrate for ventricular arrhythmias and is associated ........................ with a higher risk of sudden cardiac death (SCD).1,2 Non-ischaemic dilated cardiomyopathy (DCM) is characterized Recent studies suggest a genetic origin for DCM in ∼40% by left ventricular (LV) enlargement and systolic dysfunction that of patients, and several genotypes have been associated with cannot be attributed to abnormal loading conditions or coronary increased arrhythmogenicity or progression to end-stage heart artery disease. It has an estimated prevalence of 1:250 to 1:2500 failure (ESHF).3–8 and is the most frequent cause of heart failure in the young and the Myocardial scarring determined by late gadolinium enhancement leading cause of heart transplantation. Moreover, DCM constitutes (LGE) on cardiac magnetic resonance (CMR) imaging can be © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. LGE and genetics in non-ischaemic dilated cardiomyopathy 1185 observed in 25%–40% of patients with DCM and its presence in case it was performed. Infiltrative cardiomyopathies were excluded ........................................................................................................................................................................ has emerged as a strong risk marker for all-cause mortality and if phenotype was suggestive. ventricular arrhythmias.9–11 Despite advances in the identification of new risk markers, Cardiac magnetic resonance assessing prognosis in patients with DCM remains challenging, and clinical decisions about treatment options, for example, eligibil- Patients underwent CMR imaging on a 1/1.5/3.0 T magnetic resonance scanner for assessment of LVEF and myocardial scar between 2003 ity for implantable cardioverter-defibrillator (ICD) therapy, are and 2020. Steady-state free precession cine images were acquired largely based on the presence of significant LV dysfunction.12,13 in multiple short-axis and three long-axis views. LGE was per- LV ejection fraction (LVEF) has, however, limited sensitivity and formed using a segmented inversion-recovery gradient-echo tech- specificity in predicting clinical events in DCM, and the major- nique in identical views as cine-CMR 10–15 min after 0.15 mmol/kg ity of SCD events (in absolute numbers) in this setting occur in of gadolinium-contrast administration. Inversion times were optimized patients with LVEF ≥35%.11,14 Furthermore, emerging data from a to null normal myocardium. randomized controlled trial have questioned the clinical usefulness Cine and LGE images from all centres were centrally evaluated in of ICD implantation in patients with non-ischaemic DCM and LVEF a core laboratory by two CMR experts blinded to genotype and out- ≤35%.15 Thus, there is a need for more granularity and refinement comes using cvi42 CircleCVI software. When disagreement occurred, in risk stratification in patients with DCM. With this background, the most experienced expert opinion (JGM >10 years’ experience) the present study investigated the combined influence of geno- prevailed. An interobserver variability test was undertaken with 17 CMR studies and it showed interclass correlation of 0.88 (95% confi- type and myocardial scar on prognosis in a large cohort of patients dence interval [CI] 0.69–0.96). LV volume, mass, and LVEF were quan- with DCM. titatively measured from the stack of short-axis cine images using stan- dard techniques.18 The presence and location of hyperenhanced tissue on LGE, which was interpreted as representing scarred myocardium,19 Methods was determined by visual inspection. Scar size (extent) as a percent- age of LV myocardium was quantified with semi-automated planime- Study design try (manually corrected) using the full-width half-max thresholding This is a multicentre, retrospective, observational, and longitudinal method.20 Patients were classified according to presence/absence of study of consecutive genetically-evaluated patients with DCM recruited LGE as L+ or L−. from 20 Spanish hospitals. DCM was defined as the presence of LVEF Late gadolinium enhancement patterns were classified into seven <50% on echocardiogram at diagnosis in the absence of abnormal categories (linear midventricular, patchy midventricular, epicardial, loading conditions, coronary artery disease (by coronary angiography subendocardial, transmural, right ventricular (RV) insertion points, mul- or computed tomography), excessive alcohol consumption, or any tiple patterns or other distribution). Patients with LGE were grouped other identifiable cause.16 Only patients with age ≥15 years at the time according to LGE extent in three groups: <2.5%, ≥2.5% but <5% and of diagnosis were included. The study was approved by the Hospital ≥5% of total LV mass. Universitario Puerta de Hierro ethics committee and conformed to the principles of the Helsinki Declaration. The authors from each participating centre guarantee the integrity of data. Genotype Genetic variants were centrally classified as pathogenic (P), likely pathogenic (LP), unknown significance (VUS), or likely benign/benign Subjects (LB/B) after a systematic review by a cardiologist expert in cardio- Participating individuals were consecutive patients with DCM who vascular genetics (JPO) using modified criteria of the American Col- had been genetically tested using targeted next-generation sequencing lege of Medical Genetics and Genomics,21 as described in the data (NGS) panels at participating institutions or at an accredited genetics supplement. A variant was considered disease-causing if it affected a laboratory between 2015 and 2021, and who had CMR performed at DCM-related gene and was classified P/LP. Patients harbouring P/LP the participating institutions. Although gene panels could differ in the variants were considered ‘genotype-positive’ (G+), and patients har- number of genes examined, all the genes classified as having definitive bouring VUS/LB/B variants were considered ‘genotype-negative’ (G−). or strong evidence of implication in DCM according to the ClinGen Furthermore, a more restrictive classification was also undertaken DCM gene curation expert panel were evaluated in all cases except considering as G+ only those patients with variants in the genes with for FLNC that was evaluated in 88% of individuals.17 Additionally, we strong/definitive association with DCM as defined by ClinGen DCM included consecutive relatives with DCM who had CMR performed gene curation expert panel, or in DMD (a gene robustly associated with at participating institutions and who harboured a pathogenic or likely DCM with or without concomitant skeletal myopathy and not curated pathogenic genetic variant previously identified in a DCM proband in by the ClinGen curation panel). their family with a NGS panel including >50 cardiomyopathy-associated The frequencies of variants in the general population were extracted genes. from the gnomAD database v2.1.1.22 We also added the information Demographics, symptoms, 12-lead electrocardiogram, and of 5254 index cases with no evidence of structural cardiac disease transthoracic echocardiogram data were collected from clinical (channelopathies and aortic diseases) sequenced by NGS at Health in records at each participating centre using uniform methodology. Code Molecular Genetics Laboratory with a library that included all DCM was defined as familial if one or more relatives (in addition to the genes with genotype-positive variants detected in this study. This the proband) had DCM during life or at postmortem examination; cohort was used to obtain an ancestry-specific control set, minimizing sporadic case was used to indicate that there was no family history of the likelihood of incorrectly categorizing variants as disease-causing if DCM, and no cases of DCM were detected during familial screening they were present in Spanish controls. © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 1186 J.G. Mirelis et al. Outcomes Myocardial scar ........................................................................................................................................................................ The primary endpoints were a composite of ESHF events, and a Cardiac magnetic resonance was mainly performed on 1.5 T mag- composite of major ventricular arrhythmias (MVA). ESHF endpoint netic field scanners (587 patients; 97.8%), and a small number of included ventricular assist device implantation for refractory heart patients had CMR performed on 3 T (12 patients; 2%) or 1 T (1 failure, heart transplant, and ESHF mortality. MVA included SCD or patient; 0.2%) scanners. Mean LVEF at CMR was 37.0 ± 13.4%, aborted SCD, sustained ventricular tachycardia, and appropriate ICD and 329 (54.8%) patients had a LVEF ≤35%. Indexed LV volume interventions. Only appropriate ICD shocks to terminate ventricular was 127.5 ± 39.8 ml/m2 , with a mean LV mass of 76.7 ± 20.5 g/m2 . tachycardia or ventricular fibrillation episodes were considered for The right ventricle showed average normal size (indexed RV vol- the purpose of this study (anti-tachycardia pacing therapy was not considered). All patients had planned reviews at participating centres ume 79.7 ± 23.2 ml/m2 ) and mild systolic dysfunction (RV ejection every 6–12 months or more frequently if clinically indicated. The fraction 45.9 ± 15.2%). Left atrial indexed volumes were enlarged follow-up for each patient was calculated from the date of their CMR (49.6 ± 23.2 ml/m2 ). study to the occurrence of a study endpoint, death from another cause, Myocardial scar was present in 151 (25.2%) patients (L+), or the date of their most recent evaluation. whereas 449 (74.8%) patients did not show LGE on CMR (L−). Clinical characteristics of patients with and without LGE are described in online supplementary Table S3. Both groups exhibited Statistical analyses similar baseline echocardiographic LVEF, a similar percentage of Continuous variables are expressed as mean ± standard deviation patients with LVEF ≤35% and similar NYHA class, but patients (SD) or median (interquartile range, IQR), as appropriate. Groups with LGE had lower LVEF by CMR (34.3% vs. 37.9%, p = 0.004) were compared using Student’s t-test, or the Mann–Whitney, or the and were more frequently male (76.8% vs. 62.6%, p = 0.001) and ANOVA test, or the Kruskal–Wallis test when comparing more than probands (94.7% vs. 87.1%, p = 0.010). Moreover, patients with two groups. Non-continuous categorical variables were expressed as LGE had a higher rate of MRA at last evaluation (74.2% vs. 58.1%, counts (percentages) and compared using the Chi-squared test or p < 0.001) and received ICD and CRT more frequently (47.0% vs. Fisher’s exact test, as appropriate. The cumulative probability of an 22.3%, p < 0.001; and 17.94% vs. 8.5%, p = 0.001, respectively) event on follow-up was estimated using the Kaplan–Meier method, and the log-rank test was used to compare survival between groups. Hazard despite having LBBB less frequently (23.2% vs. 33.6%, p = 0.016) ratios of the L+ or G+ category and other parameters commonly used and similar pharmacological treatment at baseline. to predict outcomes in DCM including LVEF ≥35%, male sex, and New Median scar extent in patients with LGE was 4.7% (IQR York Heart Association (NYHA) class III–IV were estimated by Cox 1.4–12.5) of the LV mass. The distribution of scar patterns was as proportional hazards regression. Furthermore, Harrell’s C-statistic was follows: linear midventricular: 29.8%, patchy midventricular: 7.3%, used to assess predictive performance of those parameters with haz- epicardial: 25.8%, subendocardial: 3.3%, transmural: 7.2%, RV inser- ard ratios that were statistically significant. Analyses were performed tion points: 19.9%, multiple patterns or other distribution: 7.3%. using Stata Statistics version 15 (StataCorp LLC, College Station, TX, USA). A 2-sided p-value <0.05 defined statistical significance. Genotype A DCM-related P/LP disease-causing variant was identified in 242 Results (40.3%) individuals (G+). Of the 534 index cases, genetic testing identified a P/LP disease-causing variant in 176 (33.0%), no variant Subjects was identified in 229 (42.9%), and a VUS was detected in 129 cases A total of 600 patients met the inclusion criteria, of whom (24.2%). Four index cases (0.8%) harbored two disease-causing 534 (89.0%) were unrelated index cases and 66 (11.0%) were variants. relatives. Characteristics of the patients are presented in Table 1. Among the 236 cases (from the complete cohort including Male sex predominated (66.2%), mean age at CMR study was index and family members) with a unique P/LP variant, the most 53.3 ± 14.1 years, and the majority of patients were in NYHA class frequently involved gene was TTN, identified in 81 individuals I or II (69.3%) at baseline. Atrial fibrillation prevalence was 7.8%, (34.3%), followed by motor sarcomeric genes (n = 48, 20.3%), left bundle branch block (LBBB) was present in 31% of patients, cytoskeleton/Z-disk genes (n = 28, 11.9%), desmosomal genes and a third-degree atrioventricular block was found in 1%. Clinical (n = 21, 8.9%), nuclear envelope genes (n = 14, 5.9%), and other characteristics and outcomes according to gender and age (under genes (n = 44, 18.6%). or above median age) are provided in online supplementary Tables Eighteen individuals (3% of those included in the study) had P/LP S1 and S2. variants in genes not considered as definitive or strongly linked with Concerning medical treatment, 80% of the patients were DCM by the ClinGen curation panel or in DMD. The distribution of receiving beta-blockers and 85.2% angiotensin-converting enzyme affected genes in these 18 individuals classified as G− according to inhibitors (ACEI) or angiotensin receptor blockers (ARB) at initial the more ‘restrictive’ genetic classification was as follows: MYBPC3 evaluation. At last follow-up, 92.5% of patients were receiving (n = 12), PKP2 (n = 2), DSG2 (n = 1), DSC2 (n = 1), NKX2.5 (n = 1) beta-blockers, 68.3% ACEI/ARBs, 26.2% sacubitril/valsartan, and and PRDM16 (n = 1). 62.2% mineralocorticoid receptor antagonists (MRA). At last Distribution of P/LP per affected gene in G+ individuals and the evaluation, 171 patients had an ICD (28.5%) and 65 (10.8%) a complete list of P/LP variants can be found in online supplementary cardiac resynchronization therapy (CRT) device. Tables S4 and S5. © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. LGE and genetics in non-ischaemic dilated cardiomyopathy 1187 Table 1 Clinical characteristics of patients according to presence of late gadolinium enhancement and genotype Total (n = 600) L+/G+ (n = 67) L+/G− (n = 84) L−/G+ (n = 175) L−/G− (n = 274) p-value ............................................................................................................................................................... Demographics Male sex, n (%) 397 (66.2) 48 (71.6) 68 (81.0) 103 (58.9) 178 (65.0) 0.051 Age at CMR study, years 53.3 (14.1) 50.8 ± 12.8 57.1 ± 13.9 50.3 ± 15.2 54.6 ± 13.4 0.304 Duration of follow-up, years 2.70 (1.29–4.86) 3.21 (1.55–5.34) 2.64 (1.21–4.90) 2.87 (1.36–5.43) 2.38 (1.24–4.41) 0.303 Proband, n (%) 534 (89.0) 59 (88.1) 84 (100.0) 117 (66.9) 274 (100.0) 0.005 FH of DCM, n (%) 292 (48.7) 38 (56.7) 28 (33.3) 123 (70.3) 103 (37.6) 0.023 FH of SCD 1st degree relative, n (%) 65 (10.8) 8 (11.9) 3 (3.6) 28 (16.0) 26 (9.5) 0.905 FH of SCD non-1st degree relatives, n (%) 111 (18.5) 10 (14.9) 15 (17.9) 44 (25.1) 42 (15.3) 0.729 FH of skeletal myopathy, n (%) 7 (1.2) 1 (1.5) 1 (1.2) 2 (1.1) 3 (1.1) 0.807 Skeletal myopathy, n (%) 17 (2.8) 3 (4.5) 2 (2.4) 6 (3.4) 6 (2.2) 0.386 Previous SCD, n (%) 6 (1.0) 1 (1.5) 2 (2.4) 0 (0.0) 3 (1.1) 0.530 NYHA class III–IV at 1st evaluation, n (%) 184 (30.7) 24 (35.8) 25 (29.8) 45 (25.7) 90 (32.8) 0.988 NYHA class at 1st evaluation, n (%) 0.001 I 230 (38.3) 25 (37.3) 21 (25.0) 91 (51.7) 93 (34.1) II 186 (30.9) 18 (26.9) 38 (45.2) 39 (22.2) 91 (33.3) III 158 (26.3) 22 (32.8) 19 (22.6) 39 (22.2) 78 (28.6) IV 26 (4.3) 2 (3.0) 6 (7.1) 6 (3.4) 12 (4.4) Baseline ECG Sinus rhythm, n (%) 551 (91.8) 62 (92.5) 72 (85.7) 167 (95.4) 250 (91.2) 0.706 Atrial fibrillation, n (%) 47 (7.8) 5 (7.5) 12 (14.3) 8 (4.6) 22 (8.0) 0.513 AV block (third degree), n (%) 6 (1.0) 1 (1.5) 0 (0.0) 1 (0.6) 4 (1.5) 0.562 QRS duration, mm 114.0 ± 29.5 100.7 ± 22.2 116.3 ± 29.0 103.0 ± 23.0 125.5 ± 31.2 <0.001 LBBB, n (%) 186 (31.0) 5 (7.5) 30 (35.7) 24 (13.7) 127 (46.4) <0.001 Abnormal T-wave inversion, n (%) 229 (38.2) 32 (47.8) 39 (46.4) 56 (32.0) 102 (37.2) 0.076 Low QRS voltage limb leads, n (%) 64 (10.7) 18 (26.9) 10 (11.9) 28 (16.0) 8 (2.9) <0.001 Low QRS voltage precordial leads, n (%) 18 (3.0) 4 (6.0) 4 (4.8) 8 (4.6) 2 (0.7) 0.006 Baseline echocardiogram LVEF, % 33.6 ± 10.8 34.2 ± 10.0 33.3 ± 10.1 35.9 ± 11.5 32.1 ± 10.5 0.078 LVEF ≤35%, n (%) 335 (55.8) 37 (55.2) 50 (59.5) 74 (42.3) 174 (63.5) 0.130 LVEDD, mm 60.1 ± 7.7 59.6 ± 8.0 60.7 ± 8.1 59.4 ± 7.3 60.4 ± 7.8 0.589 MR moderate/severe, n (%) 188 (32.4) 23 (34.8) 26 (31.7) 51 (30.2) 88 (33.3) 0.988 RVSD (any degree), n (%) 109 (19.4) 13 (20.3) 20 (24.4) 29 (18.0) 47 (18.5) 0.432 Drug treatment at initial evaluation Beta-blockers, n (%) 480 (80.0) 55 (82.1) 65 (77.4) 136 (77.7) 224 (81.8) 0.674 ACEIs/ARBs, n (%) 511 (85.2) 52 (77.6) 67 (79.8) 147 (84.0) 245 (89.4) 0.003 Sacubitril/valsartan, n (%) 27 (4.5) 4 (6.0) 7 (8.3) 6 (3.4) 10 (3.6) 0.146 MRA, n (%) 236 (39.3) 26 (38.8) 32 (38.1) 60 (34.3) 118 (43.1) 0.326 Treatment at last evaluation Beta-blockers, n (%) 555 (92.5) 64 (95.5) 78 (92.9) 155 (88.6) 258 (94.2) 0.976 ACEI/ARB, n (%) 410 (68.3) 42 (62.7) 51 (60.7) 122 (69.7) 195 (71.2) 0.061 Sacubitril/valsartan, n (%) 157 (26.2) 18 (26.9) 31 (36.9) 40 (22.9) 68 (24.8) 0.213 MRA, n (%) 373 (62.2) 49 (73.1) 63 (75.0) 91 (52.0) 170 (62.0) 0.033 ICD, n (%) 171 (28.5) 33 (49.3) 38 (45.2) 49 (28.0) 51 (18.6) <0.001 CRT, n (%) 65 (10.8) 5 (7.5) 22 (26.2) 9 (5.1) 29 (10.6) 0.242 MRI baseline LVEDV, ml 241.1 ± 81.1 239.2 ± 70.7 256.0 ± 90.1 226.6 ± 7.3 246.2 ± 85.3 0.838 LV mass, g 145.3 ± 43.8 138.8 ± 41.1 158.4 ± 48.9 131.3 ± 35.7 151.8 ± 45.1 0.147 LVEF, % 37.0 ± 13.4 34.3 ± 12.8 34.3 ± 10.4 40.0 ± 13.0 36.6 ± 14.3 0.135 RVEDV, ml 151.4 ± 50.5 154.2 ± 48.9 155.4 ± 60.0 152.2 ± 49.1 149.0 ± 48.7 0.284 RV mass, g 40.1 ± 13.2 43.0 ± 15.5 43.9 ± 14.4 39.2 ± 12.7 38.9 ± 12.3 0.002 RVEF, % 45.9 ± 15.2 43.3 ± 16.0 44.8 ± 14.6 46.7 ± 15.0 46.3 ± 15.3 0.135 LA max vol, ml 94.4 ± 49.5 104.8 ± 47.9 108.6 ± 78.8 84.2 ± 38.2 94.0 ± 43.0 0.028 LAEF, % 40.1 ± 17.2 35.6 ± 18.6 35.6 ± 17.3 43.7 ± 15.8 40.3 ± 17.2 0.015 RA max vol, ml 69.3 ± 32.3 72.5 ± 34.8 81.0 ± 45.6 68.4 ± 65.5 ± 28.2 0.002 RAEF, % 35.6 ± 14.7 36.4 ± 14.8 31.7 ± 16.5 38.2 ± 13.8 34.9 ± 14.4 0.913 LVEDV index, ml/m2 127.5 ± 39.8 126.9 ± 37.0 131.6 ± 39.6 122.6 ± 35.0 129.6 ± 43.1 0.768 LV mass index, g/m2 76.7 ± 20.5 73.1 ± 18.1 81.5 ± 20.8 71.0 ± 17.0 79.8 ± 22.0 0.069 RVEDV index, ml/m2 79.6 ± 23.2 81.5 ± 23.3 79.9 ± 28.1 82.1 ± 23.1 77.7 ± 21.5 0.156 RV mass index, g/m2 21.1 ± 6.0 22.6 ± 7.0 22.5 ± 6.1 21.1 ± 6.0 20.3 ± 5.5 <0.001 LA max vol index, ml/m2 49.6 ± 23.2 55.2 ± 23.6 55.1 ± 32.3 45.4 ± 19.1 49.3 ± 21.6 0.025 RA max vol index, ml/m2 36.5 ± 16.0 38.3 ± 18.0 41.6 ± 22.5 36.9 ± 14.1 34.2 ± 13.8 0.001 LGE, n (%) 151 (25.2) 67 (100) 84 (100.0) 0 (0.0) 0 (0.0) <0.001 LGE mass, g 3.0 ± 8.7 11.7 ± 14.2 12.1 ± 14.0 0.0 ± 0.0 0.0 ± 0.0 <0.001 Percentage of LGE of LV mass, % 2.3 ± 6.8 9.7 ± 12.6 8.4 ± 10.0 0.0 ± 0.0 0.0 ± 0.0 <0.001 Values are mean ± standard deviation or median (interquartile range), unless otherwise indicated. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; AV, atrioventricular; CMR, cardiac magnetic resonance; CRT, cardiac resynchronization therapy; DCM, dilated cardiomyopathy; ECG, electrocardiogram; FH, family history; ICD, implantable cardioverter-defibrillator; LA, left atrial; LAEF, left atrial ejection fraction; LBBB, left bundle branch block; LGE, late gadolinium enhancement; LV, left ventricular; LVEDD, left ventricular end-diastolic diameter; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; MRA, mineralocorticoid receptor antagonist; MRI, magnetic resonance imaging; NYHA, New York Heart Association; RA, right atrial; RAEF, right atrial ejection fraction; RV, right ventricular; RVEDV, right ventricular end-diastolic volume; RVSD, right ventricular systolic dysfunction; SCD, sudden cardiac death. © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 1188 J.G. Mirelis et al. Table 2 Outcomes and events according to presence of late gadolinium enhancement and genotype Clinical events Total L+/G+ L+/G− L−/G+ L−/G− p-value (n = 600) (n = 67) (n = 84) (n = 175) (n = 274) ........................................................................................................................................... Heart failure on admission 159 (26.5) 21 (31.3) 33 (39.3) 26 (14.9) 79 (28.8) 0.325 Atrial fibrillation 127 (21.1) 18 (26.9) 26 (31.0) 42 (24.0) 41 (15.0) 0.001 Stroke 15 (2.5) 3 (4.5) 4 (4.8) 3 (1.7) 5 (1.8) 0.100 Appropriate ICD therapy 31 (5.2) 8 (11.9) 11 (13.1) 6 (3.4) 6 (2.2) <0.001 Aborted SCD 13 (2.2) 3 (4.5) 4 (4.8) 2 (1.1) 4 (1.5) 0.047 Heart transplant 15 (2.5) 5 (7.5) 2 (2.4) 7 (4.0) 1 (0.4) 0.001 LVAD implantation 5 (0.8) 3 (4.5) 1 (1.2) 0 (0.0) 1 (0.4) 0.004 All-cause mortality 19 (3.2) 4 (6.0) 7 (8.3) 3 (1.7) 5 (1.8) 0.007 HF-related mortality 8 (1.3) 2 (3.0) 4 (4.8) 1 (0.6) 1 (0.4) 0.007 MVA-related mortality 5 (0.8) 2 (3.0) 1 (1.2) 2 (1.1) 0 (0.0) 0.016 ESHF 24 (4.0) 8 (11.9) 6 (7.1) 8 (4.6) 2 (0.7) <0.001 MVA 48 (8.0) 14 (20.9) 15 (17.9) 12 (6.9) 7 (2.6) <0.001 Values are n (%). ESHF, end-stage heart failure; HF, heart failure; ICD, implantable cardioverter-defibrillator; LVAD, left ventricular assist device; MVA, malignant ventricular arrhythmia; SCD, sudden cardiac death. Clinical characteristics of G+ and G− patients can be found LGE pattern, was associated with an MVA event rate of 16.7%. ......................................................................................................... in online supplementary Table S6. G+ patients were younger Regarding ESHF events, although the number of events was lim- (50.5 ± 14.6 vs. 55.2 ± 13.5 years, p < 0.001) but G− patients ited to drive solid conclusions, again the rate of events diverged showed lower LVEF by CMR (36.1% vs. 38.4%, p = 0.039), wider depending on the LGE pattern (p = 0.005 for comparison among QRS (123.4 vs. 102.3 ms, p < 0.001) and higher rate of LBBB LGE patterns). Of note again, the RV insertion points pattern was (43.9% vs. 12.0%, p < 0.001). Treatment was similar in both groups, not benign, and this group exhibited an ESHF event rate of 13.3%. although more patients in the G+ group had an ICD implanted Clinical characteristics and outcomes according to the LGE pat- (33.9% vs. 24.9%, p = 0.016) and more G− patients received tern are presented in online supplementary Table S8. Regarding a CRT device (14.2% vs. 5.8% p = 0.001). Online supplemen- LGE extent, as expected, a higher LGE extent was associated with tary Table S7 provides outcomes according to genotype classifying increased MVA and ESHF (both p < 0.001 for comparison between patients as G+, G− and VUS. LGE extent groups), but this relationship seemed not to be lin- ear as the intermediate LGE extent group (LGE % of LV mass of 2.5%–5%) had a higher rate of events than the higher LGE extent Outcomes group (>5% of LV mass). Clinical characteristics and outcomes During a median follow-up of 2.7 (IQR 1.3–4.9) years, 24 (4.00%) according to LGE extern are presented in online supplementary and 48 (8.00%) patients had ESHF and MVA events, respectively. Table S9. Table 2 shows clinical outcomes in the entire cohort. On survival analysis, positive LGE was associated with MVA and ESHF (both log-rank test p < 0.001) and positive genotype was Combination of late gadolinium associated with ESHF (p = 0.034) but not with MVA (p = 0.102) enhancement and genotype (online supplementary Figures S1 and S2). By contrast, we did Classification of patients according to genotype (G+/G−) and LGE not observe a significant association between LVEF ≤35% and presence (L+/L−) revealed progressively increasing events across MVA (p = 0.482) or ESHF (p = 0.082) (online supplementary L−/G−, L−/G+, L+/G− and L+/G+ groups (Table 2) and resulted Figure S3). in optimized prediction of MVA (p < 0.001) and ESHF (p = 0.001) (Figures 1 and 2). Clinical characteristics of patients included in each group can be found in Table 1. Late gadolinium enhancement pattern Malignant ventricular arrhythmia events per group were as and extent follows: 20.9% in L+/G+, 17.9% in L+/G−, 6.9% in L−/G+, and Malignant ventricular arrhythmias and ESHF were highly different 2.6% in L−/G−. ESHF events per group were: 11.9% in L+/G+, depending on the underlying LGE pattern. While linear midven- 7.1% in L+/G−, 4.6% in L−/G+, and 0.7% in L−/G−. tricular, epicardial, transmural and ‘other patterns’ groups exhib- The hazard ratios for MVA according to L/G category and ited a MVA rate ranging from 20% to 27.3%, patients with patchy compared with L−/G− status were as follows: 7.82 (95% or endocardial patterns did not have any MVA event (p < 0.001 CI 3.16–19.39, p < 0.001) in L+/G+ patients, 7.29 (95% CI for comparison among LGE patterns). Of note, the LGE pres- 2.97–17.89, p < 0.001) in L+/G−, and 2.45 (95% CI 0.96–6.24, ence at RV insertion points, traditionally considered a more benign p = 0.060) in L−/G+. The hazard ratios for ESHF events compared © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. LGE and genetics in non-ischaemic dilated cardiomyopathy 1189 Figure 1 Kaplan–Meier curves of malignant ventricular arrhythmia (MVA) events according to presence of late gadolinium enhancement (LGE) and genotype. with L−/G− status were: 14.40 (95% CI 3.05–67.85, p = 0.001) respectively. Clinical characteristics of patients with DCM and ........................................................... in L+/G+, 9.37 (95% CI 1.89–46.45, p = 0.006) in L+/G−, and with L+ and/or G+ versus L−/G− peers were very similar despite 4.80 (95% CI 1.00–23.14, p = 0.050) in L−/G+. the finding that L−/G− patients had wider QRS interval, higher Genotype and LGE grouping in patients with DCM and LVEF rate of LBBB, lower LVEF and higher rate of LVEF ≤35% on >35% (n = 271, 45.2%) also resulted in improved MVA predic- echocardiogram (Table 3). tion (p = 0.002), with patients without LGE and with a nega- Classification of patients according to genotype (G+/G−) and tive genotype showing the lowest percentage of events during LGE presence (L+/L−) with the more restrictive genetic classifica- follow-up (Figure 3). Specifically, MVA events per groups were: tion approach yielded similar results, with increasing events across 25.7% in L+/G+, 12.8% in L+/G−, 4.6% in L−/G+, and 3.2% L−/G−, L−/G+, L+/G− and L+/G+ groups (online supplementary in L−/G−. By contrast, genotype and LGE grouping in patients Table S14) and optimized prediction of MVA (p < 0.001) and ESHF with DCM and with LVEF >35% did not improve ESHF predic- (p = 0.002) (Figure 5). The hazard ratios for MVA and ESHF accord- tion (Figure 3). Clinical characteristics and outcomes of patients ing to L/G category and L+ or G+ compared with L−/G− status with DCM and with LVEF >35%, LVEF ≤35% and with NYHA class using the restrictive genetic classification are presented in online III–IV included in each group can be found in online supplementary supplementary Table S15. Lastly, Figure 6 shows MVA and ESHF Tables S10–S13. during follow-up of L+ or G+ patients compared with the L−/G− Lastly, patients with either L+ or G+ showed increased MVA group, with similar findings to those from the more liberal genetic and ESHF during follow-up when compared with the L−/G− group classification. Clinical characteristics and total number of events (Figure 4). Hazard ratios for MVA and ESHF in patients with L+ of patients included in each L/G group with the restrictive genetic or G+ compared with those with L−/G− were 4.71 (95% CI classification approach can be found in online supplementary Tables 2.11–10.50, p < 0.001) and 7.92 (95% CI 1.86–33.78, p < 0.001), S14 and S16. © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 1190 J.G. Mirelis et al. Figure 2 Kaplan–Meier curves of end-stage heart failure (ESHF) events according to presence of late gadolinium enhancement (LGE) and genotype. Figure 3 Kaplan–Meier curves of malignant ventricular arrhythmias (MVA) (A) and end-stage heart failure (ESHF) (B) according to presence of late gadolinium enhancement (LGE) and genotype in dilated cardiomyopathy patients with left ventricular ejection fraction >35% included in the study (n = 271). © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. LGE and genetics in non-ischaemic dilated cardiomyopathy 1191 Figure 4 Kaplan–Meier curves of malignant ventricular arrhythmias (MVA) (A) and end-stage heart failure (ESHF) (B) in patients with late gadolinium enhancement (LGE) or genotype-positive versus patients without LGE and genotype-negative (n = 600). Late gadolinium enhancement disease and LVEF ≤35%, it is still contentious in patients with severe .............................................................................................. LV dysfunction and non-ischaemic DCM. and genotype grouping versus other Although LVEF ≤35% has been reported as an independent risk parameters marker of all-cause and cardiac death in DCM, it has also shown While MVA was higher in patients with L+ or G+ than in peers only modest ability in identifying DCM patients with higher risk of with L−/G−, we did not find LVEF ≤35%, male sex or NYHA class SCD and who would benefit from ICD implantation. In fact, the III–IV to be associated with MVA in our cohort (Table 4). Similar majority of SCD events in this patient population occur among findings were found with ESHF events with L+ or G+ being the those with LVEF ≥35% and the only randomized controlled trial sole parameter that was significantly associated with ESHF in our that has examined prophylactic ICD implantation in DCM patients cohort. Harrell’s C-statistics for predicting MVA and ESHF of L+ with LVEF ≤35% did not find improved survival in patients who or G+ in our cohort were 0.653 and 0.628, respectively. received an ICD.15 In the present study, the overall MVA rate was 8%, which is in line with previous studies,10 and 45.8% of MVA events occurred in patients with LVEF >35%. Furthermore, Discussion LVEF ≤35% was not associated with MVA events during follow-up, This study constitutes the largest cohort reported to date of confirming that using LVEF as the unique marker for predicting genotyped patients with DCM and with available CMR and clinical SCD is inadequate in DCM, and highlighting that other markers outcome data. It shows that both the presence of LGE and P/LP are needed to identify patients with DCM who would benefit from genetic variants are associated with worse clinical outcomes during ICD implantation. follow-up, and that classification of patients according to LGE The presence of myocardial scar determined by LGE on CMR and genotype improves the prediction of MVA and ESHF events. and the presence of positive genotype are two new markers Moreover, our results suggest that patients with DCM who do not proposed to identify DCM patients with increased susceptibility to exhibit LGE and who are G– have a favourable prognosis with a SCD. A recent study from our group analysing outcomes in 1005 very low number of arrhythmic and ESHF complications during genotyped DCM probands showed that those with P/LP variants follow-up (Graphical Abstract). had a worse clinical outcome than their G– peers.3 The present Predicting prognosis in non-ischaemic DCM is a challenging study expands previous findings by combining genetic results with aspect in the clinical care of these patients and has important con- CMR findings. sequences for clinical decisions, including indicating ICD implan- In our cohort, LGE was present in 25.2% of patients with DCM, tation and referral for heart transplantation evaluation. Current in line with what has been reported in other DCM series, and guidelines recommend LVEF for risk stratification of SCD and for the presence of LGE was strongly associated with both MVA and guiding ICD implantation in heart failure patients, but while this rec- ESHF.9–11 Our study adds to the available body of data from recent ommendation is widely accepted in patients with coronary artery prospective longitudinal studies and meta-analyses that support © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 1192 J.G. Mirelis et al. Table 3 Characteristics and outcomes of patients with late gadolinium enhancement or positive genotype versus those without late gadolinium and negative genotype L+ or G+ (n = 326) L−/G− (n = 274) p-value ........................................................................................................................................... Demographics Male sex, n (%) 219 (67.2) 178 (65.0) 0.550 Age at CMR, years 52.2 ± 14.7 54.6 ± 13.4 0.040 Duration of follow-up, years 2.70 (1.29–4.86) 2.17 (0.82–4.30) 0.127 Proband, n (%) 260 (79.8) 274 (100.0) <0.001 FH of DCM, n (%) 189 (58.0) 103 (37.6) <0.001 FH of SCD 1st degree relative, n (%) 39 (12.0) 26 (9.5) 0.331 FH of SCD non-1st degree relatives, n (%) 69 (21.2) 42 (15.3) 0.067 Previous SCD, n (%) 4 (1.2) 3 (1.1) 0.881 NYHA class III–IV at 1st evaluation, n (%) 94 (28.8) 90 (32.8) 0.288 NYHA class at first evaluation, n (%) 0.240 I 137 (41.9) 93 (33.9) II 95 (29.1) 91 (33.2) III 80 (24.5) 78 (28.5) IV 14 (4.3) 12 (4.4) Baseline ECG Sinus rhythm, n (%) 301 (92.3) 250 (91.2) 0.627 Atrial fibrillation, n (%) 25 (7.7) 22 (8.0) 0.870 AV block (third degree), n (%) 2 (0.6) 4 (1.5) 0.299 QRS duration, mm 105.4 ± 24.9 125.5 ± 31.2 <0.001 LBBB, n (%) 59 (18.1) 127 (46.4) <0.001 Abnormal T-wave inversion, n (%) 127 (39.0) 102 (37.2) 0.664 Low QRS voltage limb leads, n (%) 56 (17.2) 8 (2.9) <0.001 Low QRS voltage precordial leads, n (%) 16 (4.9) 2 (0.7) 0.003 Baseline echocardiogram LVEF, % 34.9 ± 10.9 32.1 ± 10.5 0.001 LVEF ≤35%, n (%) 161 (49.4) 174 (63.5) 0.001 LVEDD, mm 59.8 ± 7.6 60.4 ± 7.8 0.319 MR moderate/severe, n (%) 100 (31.5) 88 (33.3) 0.647 RVSD (any degree), n (%) 62 (20.2) 47 (18.5) 0.614 Drug treatment at initial evaluation Beta-blockers, n (%) 256 (78.5) 224 (81.8) 0.325 ACEI/ARB, n (%) 266 (81.6) 245 (89.4) 0.007 Sacubitril/valsartan, n (%) 17 (5.2) 10 (3.6) 0.357 MRA, n (%) 118 (36.2) 118 (43.1) 0.086 Treatment at last evaluation Beta-blockers, n (%) 297 (91.1) 258 (94.2) 0.157 ACEI/ARB, n (%) 215 (66.0) 195 (71.2) 0.171 Sacubitril/valsartan, n (%) 89 (27.3) 68 (24.8) 0.491 MRA, n (%) 203 (62.3) 170 (62.0) 0.955 ICD, n (%) 120 (36.8) 51 (18.6) <0.001 CRT, n (%) 36 (11.0) 29 (10.6) 0.857 MRI baseline LVEDV, ml 236.8 ± 77.2 246.2 ± 85.3 0.154 LV mass, g 139.8 ± 42.0 151.8 ± 45.1 0.001 LVEF, % 37.3 ± 12.6 36.6 ± 14.3 0.532 RVEDV, ml 153.4 ± 52.0 149.0 ± 48.7 0.292 RV mass, g 41.2 ± 13.9 38.9 ± 12.3 0.037 RVEF, % 45.5 ± 15.1 46.3 ± 15.3 0.494 LA max vol, ml 94.7 ± 54.4 94.0 ± 43.0 0.857 LAEF, % 39.9 ± 17.3 40.3 ± 17.2 0.818 RA max vol, ml 72.5 ± 35.2 65.5 ± 28.2 0.008 RAEF, % 36.2 ± 14.9 34.9 ± 14.4 0.251 LVEDV index, ml/m2 125.8 ± 36.7 129.6 ± 43.1 0.250 © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. LGE and genetics in non-ischaemic dilated cardiomyopathy 1193 Table 3 (Continued) L+/G+ (n = 326) L−/G− (n = 274) p-value ........................................................................................................................................... LV mass index, g/m2 74.1 ± 18.8 79.8 ± 22.0 0.001 RVEDV index, ml/m2 81.4 ± 24.4 77.7 ± 21.5 0.050 RV mass index, g/m2 21.8 ± 6.3 20.3 ± 5.5 0.003 LA max vol index, ml/m2 49.9 ± 24.5 49.3 ± 21.6 0.749 RA max vol index, ml/m2 38.4 ± 17.5 34.2 ± 13.8 0.001 LGE, n (%) 151 (46.3) 0 (0) <0.001 LGE mass, g 5.5 ± 11.2 0±0 <0.001 Percentage of LGE in LV mass, % 4.2 ± 8.9 0±0 <0.001 Clinical events Heart failure on admission, n (%) 80 (24.5) 79 (28.8) 0.235 Atrial fibrillation, n (%) 86 (26.4) 41 (15.0) 0.001 Stroke, n (%) 10 (3.1) 5 (1.8) 0.331 Appropriate ICD therapy, n (%) 25 (7.7) 6 (2.2) 0.003 Aborted SCD, n (%) 9 (2.8) 4 (1.5) 0.276 Heart transplant, n (%) 14 (4.3) 1 (0.4) 0.002 LVAD implantation, n (%) 4 (1.2) 1 (0.4) 0.247 All-cause mortality, n (%) 14 (4.3) 4 (1.5) 0.085 HF-related mortality, n (%) 7 (2.1) 1 (0.4) 0.058 MVA-related mortality, n (%) 5 (1.5) 0 (0) 0.040 ESHF, n (%) 22 (6.7) 2 (0.7) <0.001 MVA, n (%) 41 (12.6) 7 (2.6) <0.001 Values are mean ± standard deviation or median (interquartile range), unless otherwise indicated. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CMR, cardiac magnetic resonance; CRT, cardiac resynchronization therapy; DCM, dilated cardiomyopathy; ECG, electrocardiogram; ESHF, end-stage heart failure; FH, family history; HF, heart failure; ICD, implantable cardioverter-defibrillator; LA, left atrial; LAEF, left atrial ejection fraction; LBBB, left bundle branch block; LGE, late gadolinium enhancement; LVAD, left ventricular assist device; LVEDD, left ventricular end-diastolic diameter; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; MRA, mineralocorticoid receptor antagonist; MRI, magnetic resonance imaging; MVA, malignant ventricular arrhythmia; NYHA, New York Heart Association; RA, right atrial; RAEF, right atrial ejection fraction; RVEDV, right ventricular end-diastolic volume; RVSD, right ventricular systolic dysfunction; SCD, sudden cardiac death. Figure 5 Kaplan–Meier curves of malignant ventricular arrhythmia (MVA) (A) and end-stage heart failure (ESHF) (B) events according to presence of late gadolinium enhancement (LGE) and genotype applying the more restrictive genetic classification (n = 600). © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 1194 J.G. Mirelis et al. Figure 6 Kaplan–Meier curves of malignant ventricular arrhythmia (MVA) (A) and end-stage heart failure (ESHF) (B) in patients with late gadolinium enhancement (LGE) or genotype-positive versus patients without LGE and genotype-negative applying the more restrictive genetic classification (n = 600). Table 4 Hazard ratios and p-values for malignant ventricular arrhythmias and end-stage heart failure for selected parameters MVA ESHF .................................................. ................................................... HR 95% CI p-value HR 95% CI p-value ........................................................................................................................................... L+ or G+ 4.71 2.11–10.50 <0.001 7.92 1.86–33.78 <0.001 Male sex 1.39 0.73–2.62 0.303 0.73 0.32–1.65 0.457 NYHA class III–IV 0.76 0.39–1.49 0.410 1.43 0.61–3.35 0.420 LVEF ≤35% 0.82 0.46–1.44 0.482 0.48 0.21–1.10 0.082 CI, confidence interval; ESHF, end-stage heart failure; G+, genotype-positive; HR, hazard ratio; L+, presence of late gadolinium enhancement; LVEF, left ventricular ejection fraction; MVA, malignant ventricular arrhythmia; NYHA, New York Heart Association. ICD implantation in patients with DCM and with LGE on CMR more restrictive genetic approach did not alter the results. Accord- ................................................... irrespective of LVEF.11,23,24 ingly, our findings cannot be attributed to an overrepresentation of The main finding of our study is that combining LGE and variants in certain genes or to the classification as G+ of DCM genotype improves the prediction of outcomes in patients with patients with P/LP variants in disputed genes. DCM: those with LGE and/or a positive genotype clearly exhibited The LGE/genotype classification was also shown to be useful in worse outcomes as compared with the largest group of patients the more clinically challenging group of patients with DCM and (45.7% of the total cohort) who did not have LGE on CMR and with LVEF >35%, for whom current guidelines do not recommend who were G–. Of note, only 2.6% and 0.7% of patients in the latter ICD implantation. Among the 271 patients with LVEF >35% in group had MVA and ESHF events, respectively, suggesting that the the study (45.2%), those who had LGE or who were G+ had use of these markers could lead to a major improvement in the higher MVA occurrence than those who were L−/G−, with an selection of patients who would benefit from ICD implantation and absolute rate of MVA of 12.2% in patients either with LGE or G+ advanced heart failure care, although our findings would need to (n = 147) compared with 3.23% in those who were L− and G− be replicated in additional cohorts. (n = 124) (p < 0.001). Moreover, only 2 (1.6%) of the L−/G− The distribution of affected genes in our cohort was similar patients with LVEF >35% had ESHF events as opposed to 7.5% to that of previously reported genotyped cohorts, with 13.5% of those with either LGE or who had a positive genotype, which of patients showing variants in TTN, 3.3% in BAG3 and 2.3% in is also important information when planning clinical care and when LMNA.25,26 Classification of patients by LGE and genotype using a informing patients and families about prognosis. © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. LGE and genetics in non-ischaemic dilated cardiomyopathy 1195 Figure 7 Outcomes of patients associated with model-based implantable cardioverter-defibrillator (ICD) implantation strategies. The implications of implanting an ICD according to presence of late gadolinium enhancement (LGE), positive genotype or LGE presence and/or positive genotype, as compared with the implications of treating all patients as per current guidelines using left ventricular ejection fraction (LVEF) ≤35% threshold. Each bar represents the complete cohort (n = 600) and colour-coding represents the proportion of patients experiencing sustained ventricular arrhythmias (MVA) or absence of, as well as the placement versus the non-placement of an ICD. LGE presence and/or positive genotype approach optimizes ICD placement strategy by minimizing proportion of subjects with MVA but without ICD and maximizing the proportion of subject with MVA with ICD. Application of the recommended LVEF ≤35% threshold to guide CMR performed. As expected in the context of a registry study ....................................................................................... ICD implantation in our cohort would have theoretically led to 329 of this kind, the criteria to proceed with CMR evaluation and ICD implants (54.8% of patients) with 26 MVA events prevented but genotyping have evolved over time in the participating centres, and would also have missed 22 MVA events (sensitivity: 54.2%; positive we cannot discard that CMR and genotype results have influenced predictive value: 7.9%) (Figure 7). By contrast, if ICD implantation ICD implantation in some patients, and subsequentially impacted had been guided by our proposed LGE/genotype classification with on MVA events registered. As ICD shocks were a component of the any or both factors present irrespective of LVEF, it would have MVA event in our study, higher ICD implantations could have led resulted in a similar number of ICDs implanted (326 patients, to higher MVA events, as potentially some ventricular arrythmias 54.3%) but would have prevented 41 MVA and missed only 7 treated with ICD shocks could have terminated spontaneously. MVA events (sensitivity: 85.4%; positive predictive value: 12.6%), Also, although competitive events were rare (9 non-ESHF deaths improving substantially the performance of the recommended LVEF and 19 non-MVA deaths/heart transplants), a competitive risk ≤35% threshold and also the performance of LGE and genotype analysis was not performed. when applied individually (Figure 7). Furthermore, although the main DCM genes were evaluated Although our findings will need validation in additional cohorts, in all cases, not all patients underwent the same genetic analysis and ideally tested in prospective clinical trials, we believe that because the genes included in NGS panels varied between centres addressing prognosis in DCM with LGE/genotype has important and over time. Nevertheless, all patients had the most important clinical consequences and could improve patient selection and DCM-associated genes analysed and 88% of probands had also allocation of available resources. FLNC analysed, reflecting a complete genetic analysis according to current standards in a large majority of patients. Lastly, although this is the largest cohort of genotyped DCM Limitations patients with CMR and clinical outcomes information published so Significant limitations to this investigation are worth noting. This far, the number of patients included could still be considered limited is an observational retrospective study that was conducted at 20 and our findings would need to be replicated in validation cohorts. heart failure and inherited cardiac diseases units; as such, it is affected by an unavoidable degree of referral bias. Although the current standard at the participating institutions Conclusions is to consider CMR and genotyping evaluation for all patients In conclusion, we found that classification of patients according to with DCM, this registry includes data from consecutive patients genotype and LGE presence improves MVA and ESHF prediction in with DCM genotyped during a 5-year period who had a clinical DCM. Combination of scar assessment with CMR and genotyping © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 1196 J.G. 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