Septal Midwall Late Gadolinium Enhancement in Ischemic Cardiomyopathy and Nonischemic Dilated Cardiomyopathy—Characteristics and Prognosis
2023; Elsevier BV; Volume: 201; Linguagem: Inglês
10.1016/j.amjcard.2023.06.042
ISSN1879-1913
AutoresMarthe A.J. Becker, Anne‐Lotte C.J. van der Lingen, Jan H. Cornel, Peter M. van de Ven, Albert C. van Rossum, Cornelis P. Allaart, Tjeerd Germans,
Tópico(s)Cardiomyopathy and Myosin Studies
ResumoSeptal midwall late gadolinium enhancement (LGE) is a characteristic finding on cardiac magnetic resonance imaging (CMR) in nonischemic dilated cardiomyopathy (DCM) and is associated with adverse events. Its significance in ischemic cardiomyopathy (ICM) is unknown. With this multicenter observational study, we aimed to study the characteristics of septal midwall LGE and evaluate its prognostic value in ICM. A total of 1,084 patients with an impaired left ventricular (LV) ejection fraction (<50%) on LGE-CMR, either because of ICM (53%) or DCM, were included retrospectively. Septal midwall LGE was defined as midmyocardial stripe-like or patchy LGE in septal segments and was present in 10% of patients with ICM compared with 34% of patients with DCM (p <0.001). It was significantly associated with larger LV volumes and lower LV ejection fraction, irrespective of etiology. The primary endpoint was all-cause mortality and secondary endpoint was ventricular arrhythmias (VAs), including resuscitated cardiac arrest, sustained VA, and appropriate implantable cardioverter-defibrillator (ICD) therapy. During a median follow-up of 2.7 years, we found a significant association between septal midwall LGE and mortality in patients with DCM (hazard ratio [HR] 1.92, p = 0.03), but not in patients with ICM (HR 1.35, p = 0.39). Risk of VAs was significantly higher in patients with septal midwall LGE on CMR, both in DCM (HR 2.80, p <0.01) and in ICM (HR 2.70, p <0.01). In conclusion, septal midwall LGE, typically seen in DCM, was also present in 10% of patients with ICM and was associated with increased LV dilation and worse function, irrespective of etiology. When present, septal midwall LGE was associated with adverse outcome. Septal midwall late gadolinium enhancement (LGE) is a characteristic finding on cardiac magnetic resonance imaging (CMR) in nonischemic dilated cardiomyopathy (DCM) and is associated with adverse events. Its significance in ischemic cardiomyopathy (ICM) is unknown. With this multicenter observational study, we aimed to study the characteristics of septal midwall LGE and evaluate its prognostic value in ICM. A total of 1,084 patients with an impaired left ventricular (LV) ejection fraction (<50%) on LGE-CMR, either because of ICM (53%) or DCM, were included retrospectively. Septal midwall LGE was defined as midmyocardial stripe-like or patchy LGE in septal segments and was present in 10% of patients with ICM compared with 34% of patients with DCM (p <0.001). It was significantly associated with larger LV volumes and lower LV ejection fraction, irrespective of etiology. The primary endpoint was all-cause mortality and secondary endpoint was ventricular arrhythmias (VAs), including resuscitated cardiac arrest, sustained VA, and appropriate implantable cardioverter-defibrillator (ICD) therapy. During a median follow-up of 2.7 years, we found a significant association between septal midwall LGE and mortality in patients with DCM (hazard ratio [HR] 1.92, p = 0.03), but not in patients with ICM (HR 1.35, p = 0.39). Risk of VAs was significantly higher in patients with septal midwall LGE on CMR, both in DCM (HR 2.80, p <0.01) and in ICM (HR 2.70, p <0.01). In conclusion, septal midwall LGE, typically seen in DCM, was also present in 10% of patients with ICM and was associated with increased LV dilation and worse function, irrespective of etiology. When present, septal midwall LGE was associated with adverse outcome. In patients with heart failure, cardiac magnetic resonance (CMR) imaging is the imaging modality of choice to differentiate between ischemic and nonischemic etiology,1Ponikowski P Voors AA Anker SD Bueno H Cleland JGF Coats AJS Falk V González-Juanatey JR Harjola VP Jankowska EA Jessup M Linde C Nihoyannopoulos P Parissis JT Pieske B Riley JP Rosano GMC Ruilope LM Ruschitzka F Rutten FH van der Meer P ESC Scientific Document Group2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.Eur Heart J. 2016; 37: 2129-2200Crossref PubMed Google Scholar using late gadolinium enhancement (LGE).2Gonzalez JA Kramer CM Role of imaging techniques for diagnosis, prognosis and management of heart failure patients: cardiac magnetic resonance.Curr Heart Fail Rep. 2015; 12: 276-283Crossref PubMed Scopus (34) Google Scholar,3Mahrholdt H Wagner A Judd RM Sechtem U Kim RJ Delayed enhancement cardiovascular magnetic resonance assessment of non-ischaemic cardiomyopathies.Eur Heart J. 2005; 26: 1461-1474Crossref PubMed Scopus (668) Google Scholar Typically, subendocardial or transmural contrast enhancement in a coronary artery territory identifies the presence of ischemic heart disease, whereas septal midwall LGE is deemed a characteristic finding in patients with nonischemic dilated cardiomyopathy (DCM).3Mahrholdt H Wagner A Judd RM Sechtem U Kim RJ Delayed enhancement cardiovascular magnetic resonance assessment of non-ischaemic cardiomyopathies.Eur Heart J. 2005; 26: 1461-1474Crossref PubMed Scopus (668) Google Scholar,4McCrohon JA Moon JC Prasad SK McKenna WJ Lorenz CH Coats AJ Pennell DJ Differentiation of heart failure related to dilated cardiomyopathy and coronary artery disease using gadolinium-enhanced cardiovascular magnetic resonance.Circulation. 2003; 108: 54-59Crossref PubMed Scopus (911) Google Scholar In addition to its diagnostic value, the presence of LGE, and in particular septal midwall LGE, in patients with DCM is associated with adverse events, including mortality and ventricular arrhythmias (VAs).5Assomull RG Prasad SK Lyne J Smith G Burman ED Khan M Sheppard MN Poole-Wilson PA Pennell DJ Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy.J Am Coll Cardiol. 2006; 48: 1977-1985Crossref PubMed Scopus (912) Google Scholar, 6Becker MAJ Cornel JH van de Ven PM van Rossum AC Allaart CP Germans T The prognostic value of late gadolinium-enhanced cardiac magnetic resonance imaging in nonischemic dilated cardiomyopathy: a review and meta-analysis.JACC Cardiovasc Imaging. 2018; 11: 1274-1284Crossref PubMed Scopus (152) Google Scholar, 7Halliday BP Gulati A Ali A Guha K Newsome S Arzanauskaite M Vassiliou VS Lota A Izgi C Tayal U Khalique Z Stirrat C Auger D Pareek N Ismail TF Rosen SD Vazir A Alpendurada F Gregson J Frenneaux MP Cowie MR Cleland JGF Cook SA Pennell DJ Prasad SK Association between midwall late gadolinium enhancement and sudden cardiac death in patients with dilated cardiomyopathy and mild and moderate left ventricular systolic dysfunction.Circulation. 2017; 135: 2106-2115Crossref PubMed Scopus (223) Google Scholar In contrast, the absence of septal midwall LGE in patients with DCM is a predictor of left ventricular (LV) reverse remodeling with functional recovery of LV function.6Becker MAJ Cornel JH van de Ven PM van Rossum AC Allaart CP Germans T The prognostic value of late gadolinium-enhanced cardiac magnetic resonance imaging in nonischemic dilated cardiomyopathy: a review and meta-analysis.JACC Cardiovasc Imaging. 2018; 11: 1274-1284Crossref PubMed Scopus (152) Google Scholar,8Kubanek M Sramko M Maluskova J Kautznerova D Weichet J Lupinek P Vrbska J Malek I Kautzner J Novel predictors of left ventricular reverse remodeling in individuals with recent-onset dilated cardiomyopathy.J Am Coll Cardiol. 2013; 61: 54-63Crossref PubMed Scopus (102) Google Scholar,9Masci PG Schuurman R Andrea B Ripoli A Coceani M Chiappino S Todiere G Srebot V Passino C Aquaro GD Emdin M Lombardi M Myocardial fibrosis as a key determinant of left ventricular remodeling in idiopathic dilated cardiomyopathy: a contrast-enhanced cardiovascular magnetic study.Circ Cardiovasc Imaging. 2013; 6: 790-799Crossref PubMed Scopus (116) Google Scholar Interestingly, evaluation of LGE-CMR in patients with heart failure with reduced ejection fraction demonstrated that septal midwall enhancement can also occur in patients with systolic heart failure because of ischemic cardiomyopathy (ICM).10Kim J Kochav JD Gurevich S Afroz A Petashnick M Volo S Diaz B Okin PM Horn E Devereux RB Weinsaft JW Left ventricular geometric remodeling in relation to non-ischemic scar pattern on cardiac magnetic resonance imaging.Int J Cardiovasc Imaging. 2014; 30: 1559-1567Crossref PubMed Scopus (12) Google Scholar However, little is known about the incidence, characteristics, and predictive value of septal midwall LGE in patients with ICM. This study aimed to describe the characteristics of septal midwall LGE in patients with myocardial dysfunction because of ICM compared with patients with DCM. In addition, we studied the prognostic value of the presence of septal midwall LGE on the occurrence of VA and all-cause mortality during follow-up. Data from consecutive patients who underwent CMR imaging including LGE between 2014 and 2018 were retrospectively collected from 2 centers. CMR was performed either in hospitalized patients with decompensated heart failure for diagnosis of underlying etiology, or in patients referred from the outpatient clinics for viability assessment before elective revascularization or for prognostic evaluation before implantable cardioverter-defibrillator (ICD) implantation for prevention of sudden cardiac death. Patients with impaired LV systolic function, defined as LV ejection fraction (LVEF) <50%, either because of DCM or ICM were included (Figure 1). Patients with a history of significant obstructive coronary artery disease (coronary stenosis ≥70% or fractional flow reserve <0.80), a history of myocardial infarction or revascularization, or an ischemic LGE-pattern of sufficient severity to the degree of LV dysfunction, were classified as ICM. DCM was defined as LV dysfunction in the absence of obstructive coronary artery disease, primary valvular heart disease, or severe arterial hypertension, according to current guidelines.1Ponikowski P Voors AA Anker SD Bueno H Cleland JGF Coats AJS Falk V González-Juanatey JR Harjola VP Jankowska EA Jessup M Linde C Nihoyannopoulos P Parissis JT Pieske B Riley JP Rosano GMC Ruilope LM Ruschitzka F Rutten FH van der Meer P ESC Scientific Document Group2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.Eur Heart J. 2016; 37: 2129-2200Crossref PubMed Google Scholar,11Elliott P Andersson B Arbustini E Bilinska Z Cecchi F Charron P Dubourg O Kühl U Maisch B McKenna WJ Monserrat L Pankuweit S Rapezzi C Seferovic P Tavazzi L Keren A Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.Eur Heart J. 2008; 29: 270-276Crossref PubMed Scopus (2038) Google Scholar Exclusion criteria were acute myocarditis, hypertrophic or infiltrative cardiomyopathy, arrhythmogenic cardiomyopathy, or congenital heart disease. Incomplete CMR scans or scans in which quantitative analysis was impossible because of poor quality were also excluded. The primary endpoint was all-cause mortality. Secondary endpoint was a composite of sudden cardiac arrest, sustained VAs, or appropriate ICD therapy, including anti-tachycardia pacing and shock. Clinical and demographic data regarding baseline characteristics were obtained from electronic medical records. Informed consent was not required by the local ethics committee. For follow-up, medical records of all patients were evaluated for occurrence of endpoints until October 2019. Additionally, the National Health and Social Care Information Service was independently consulted for survival status for patients lost to follow-up. The study was conducted in accordance with the Declaration of Helsinki Ethical Principles and the local ethics review committee approved the data collection and management of this study. CMR scans were performed on 1.5 Tesla whole body scanners (Siemens, Erlangen, Germany, and GE Healthcare, Chicago, Illinois) with dedicated phased array cardiac receiver coil. Functional imaging was performed using retrospective electrocardiogram-gated steady-state free precession cine imaging with breath-holding in standard 3 long-axis views and a stack short-axis slices, covering the entire ventricles. Contrast images were acquired approximately 10 to 15 minutes after intravenous gadolinium administration using a T1-weighted inversion recovery-prepared gradient echo sequence with optimized inversion time. The presence and pattern of gadolinium hyperenhancement were assessed visually by experienced and CMR-certified physicians. LGE was considered present if the hyperenhancement was seen in 2 perpendicular views or 2 serial slices. LGE-pattern was considered ischemic if it was subendocardial or transmural in the territory of a coronary artery, otherwise, it was classified as a nonischemic pattern.3Mahrholdt H Wagner A Judd RM Sechtem U Kim RJ Delayed enhancement cardiovascular magnetic resonance assessment of non-ischaemic cardiomyopathies.Eur Heart J. 2005; 26: 1461-1474Crossref PubMed Scopus (668) Google Scholar Septal midwall LGE was defined as stripe-like or patchy midmyocardial hyperenhancement in the interventricular septum or right ventricular insertion points. LV volumes and LVEF were calculated by manual delineation of the endocardial border at end-diastole and end-systole from short-axis cine-image stacks, using dedicated software (Mass, Medis, Leiden, The Netherlands; Argus Function, Siemens, Erlangen, Germany; and Circle Cardiovascular Imaging Inc., Version 5.6, Calgary, Canada). Papillary muscles were excluded from the myocardium and included in the blood pool. Continuous variables are presented as mean ± SD if data were normally distributed, or as median and interquartile range otherwise. Categorical data are summarized as frequencies and percentages. The independent samples t test or Mann–Whitney U test was used for comparison between groups for continuous data, depending on whether distribution was normal or not. Chi-square test was used for binary variables and ordinal data were compared using Mann–Whitney U test. Unknown or missing data were excluded from analysis. Mortality rates were calculated using Kaplan–Meier curves and between-group differences were assessed using log-rank test. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were obtained using Cox regression. Univariable Cox regression analyses were performed including clinical data and CMR data possibly associated with time to mortality. Patients still alive at end of follow-up were censored. Similar Cox regressions were performed for time to VAs. Patients that died during follow-up without a ventricular arrhythmic event were censored for the secondary end point at date of death. Patients lost during follow-up were excluded. Parameters with p <0.10 in univariable analysis were entered in a stepwise multivariable Cox regression analysis using a backward elimination procedure. A 2-sided significance level of 5% was used for all analyses. Statistical analyses were performed in SPSS (version 24.0; IBM Corporation, Armonk, New York). A total of 1,084 consecutive patients with LGE-CMR were included, 575 patients (53%) with ICM and 509 patients (47%) with DCM. Table 1 lists patient characteristics stratified by etiology. Patients with ICM were older compared with patients with DCM (65 ± 10 and 60 ± 13 years, respectively, p <0.001), were more often male (83% and 57%, p <0.001), and had more preserved New York Heart Association (NYHA) functional classes compared with patients with DCM (p <0.01). An ICD was implanted in 305 patients (28%), including cardiac resynchronization therapy in 97 patients, after a median period of 11 (1–26) weeks after CMR.Table 1Patient characteristicsTotalN=1084ICMN=575 (53%)DCMN=509 (47%)p-valueMale sex766 (71%)476 (83%)290 (57%)<0.001Age (years)63±1265±1060±13<0.001BMI (kg/m2)26.7±4.527.0±4.126.4±4.90.04NYHA functional class0.009*Mann-Whitney U-test, missing values were excluded from analysis. ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin-II receptor blocker; BMI = body mass index; CAD = coronary artery disease; CRT-D = cardiac resynchronization therapy-ICD; DCM = dilated cardiomyopathy; ICD = implantable cardioverter defibrillator; ICM = ischaemic cardiomyopathy; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association functional class. Class I389 (36%)210 (50%)179 (42%) Class II278 (26%)129 (31%)149 (35%) Class III154 (14%)70 (17%)84 (20%) Class IV27 (3%)9 (2%)18 (4%) Missing236 (22%)Risk factors Smoking (current/former)341 (31%)211 (37%)130 (27%)0.001 Hypertension473 (44%)294 (52%)179 (37%)<0.001 Hypercholesterolemia263 (24%)197 (35%)66 (14%)<0.001 Diabetes mellitus208 (19%)145 (25%)63 (13%)<0.001 Familial history of CAD307 (28%)157 (28%)150 (31%)0.25 Chronic renal dysfunction198 (18%)123 (22%)75 (15%)0.01Medication β-blocker847 (78%)467 (82%)380 (77%)0.03 ACEi/ARB888 (82%)479 (84%)409 (83%)0.30 MRA431 (40%)199 (35%)232 (47%)<0.001 Diuretics450 (42%)218 (38%)232 (47%)0.01Devices Total305 (28%)160 (28%)145 (29%)0.10 ICD208 (19%)139 (24%)69 (14%)0.001 CRT-D97 (9%)21 (4%)76 (15%)<0.001 Primary prevention215 (20%)100 (17%)115 (23%)0.001Renal dysfunction defined as eGFR <60 ml/min/1,73 m2. Mann-Whitney U-test, missing values were excluded from analysis.ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin-II receptor blocker; BMI = body mass index; CAD = coronary artery disease; CRT-D = cardiac resynchronization therapy-ICD; DCM = dilated cardiomyopathy; ICD = implantable cardioverter defibrillator; ICM = ischaemic cardiomyopathy; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association functional class. Open table in a new tab Renal dysfunction defined as eGFR <60 ml/min/1,73 m2. LGE was present in 97% of patients with ICM compared with 44% of patients with DCM (p <0.001). Septal midwall LGE was seen in 55 patients with ICM (10%) and in 172 patients (34%) with DCM. LV volumes were significantly larger and LVEF was significantly lower in the presence of septal midwall LGE, irrespective of underlying etiology (all p <0.001; Figure 2, Table 2). NYHA functional class tended to be higher in patients with septal midwall LGE present (p <0.001 in DCM, p = 0.09 in ICM).Table 2Findings at cardiac magnetic resonance imaging in patients with ischemic cardiomyopathy and nonischemic dilated cardiomyopathyICMDCMNo septal midwall LGE (N = 520)Septal midwall LGE (N = 55)p-valueNo septal midwall LGE (N = 337)Septal midwall LGE (N = 172)p-valueLVEDVi (mL/m2)109 [90-132]141 [104-166]<0.001105 [89-124]125 [106-154]<0.001LVESVi (mL/m2)66 [52-90]102 [68-124]<0.00167 [51-85]89 [65-123]<0.001LVSV (mL)81 ± 2471 ± 240.00273 ± 2471 ± 230.56LVEF (%)39 [30-45]28 [18-36]<0.00136 [28-44]28 [20-38]<0.001LGE present500 (96%)55 (100%)0.1454 (16%)172 (100%)<0.001Ischemic pattern497 (96%)55 (100%)0.1139 (12%)29 (17%)0.10CMR = cardiac magnetic resonance imaging; DCM = dilated cardiomyopathy; ICM = ischemic cardiomyopathy; LGE = late gadolinium enhancement; LVEDVi = indexed left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction; LVESVi = indexed left ventricular end-systolic volume; LVSV = left ventricular stroke volume. Open table in a new tab CMR = cardiac magnetic resonance imaging; DCM = dilated cardiomyopathy; ICM = ischemic cardiomyopathy; LGE = late gadolinium enhancement; LVEDVi = indexed left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction; LVESVi = indexed left ventricular end-systolic volume; LVSV = left ventricular stroke volume. Data of 7 patients were lost to follow-up of the primary endpoint. During a median follow-up period of 2.7 (2.0 to 3.5) years, 123 patients (11%) died. Mortality rate was higher in patients with ICM than patients with DCM (14% and 9%, respectively, HR 1.68, (95% CI 1.17 to 2.43), p <0.01; Figure 3). CMR-variables associated with all-cause mortality in ICM included indexed LV end-diastolic volume (LVEDVi) and LVEF, respectively HR 1.11 per 10 ml increase (1.06 to 1.17), p <0.001 and HR 0.59 per 10% increase (0.47 to 0.73), p <0.001. There was no significant association between all-cause mortality and the presence of septal midwall LGE in patients with ICM (HR 1.35, (95% CI 0.69 to 2.59), p = 0.39) (Figure 3, Supplementary Table 1). Furthermore, NYHA functional class, age, and renal dysfunction were associated with the primary end point at univariable analysis. At multivariable analysis, LVEDVi and renal dysfunction remained independent predictors of all-cause mortality in patients with ICM (Supplementary Table 1). In patients with DCM, septal midwall LGE was significantly associated with shorter time to all-cause mortality at univariable regression analysis (HR 1.92, (95% CI 1.07 to 3.44), p = 0.03) (Figure 3), and NYHA functional class, smoking and the male gender (Supplementary Table 2). At multivariable analysis, only NYHA functional class and male gender remained independently associated with all-cause mortality in patients with DCM. For the composite secondary endpoint, 151 patients were lost and excluded from analysis. Of the remaining patients (485 with ICM and 448 with DCM), a total of 75 ventricular arrhythmic events occurred, 46 (9%) in patients with ICM compared with 29 (6%) in patients with DCM (p = 0.09). In both etiologies, the presence of septal midwall LGE was significantly associated with shorter time to VAs at univariable regression analysis (HR 2.70, (95% CI 1.34 to 5.44), p <0.01), in patients with ICM (Figure 4, Supplementary Table 3), and HR 2.80 (95% CI 1.34 to 5.87), p <0.001 in patients with DCM (Figure 4, Supplementary Table 4). Moreover, LVEDVi and LVEF were in both etiologies associated with the secondary endpoint at univariable analysis (in ICM LVEDVi per 10 ml HR 1.14 (1.07 to 1.21), p <0.001 and LVEF per 10% HR 0.62 (0.46 to 0.82), p <0.001. In DCM LVEDVi per 10 ml HR 1.11 (1.05 to 1.18), p <0.001 and LVEF per 10% HR 0.42 (0.29 to 0.60), p <0.001). In patients with ICM, secondary prevention ICD was an independent predictor of VA (HR 5.04 (2.60 to 9.80), p <0.001) whereas in patients with DCM, LVEF remained an independent predictor (HR 0.46 (0.31 to 0.68), p <0.001) (Supplementary Tables 3 and 4). This retrospective multicenter CMR study in patients with myocardial dysfunction and reduced LVEF demonstrated that septal midwall LGE, a characteristic finding in patients with DCM, was also present in 10% of patients with ICM. Presence of septal midwall LGE was associated with structural myocardial changes, including increased LV dilation and lower LVEF, irrespective of underlying etiology. During follow-up, there was a significant association between septal midwall LGE presence and increased all-cause mortality in patients with DCM but not in patients with ICM. Interestingly, the composite secondary ventricular arrhythmic endpoint was significantly associated with the presence of septal midwall LGE, irrespective of underlying etiology. This suggests that analysis of septal midwall LGE may be valuable to improve identification of heart failure patients who will benefit from preventive ICD implantation. The typical gadolinium hyperenhancement in the midwall of the interventricular septum, which showed good agreement with histopathological myocardial fibrosis,12Gulati A Jabbour A Ismail TF Guha K Khwaja J Raza S Morarji K Brown TD Ismail NA Dweck MR Di Pietro E Roughton M Wage R Daryani Y O'Hanlon R Sheppard MN Alpendurada F Lyon AR Cook SA Cowie MR Assomull RG Pennell DJ Prasad SK Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy [published correction appears in JAMA 2013;310:99].JAMA. 2013; 309: 896-908Crossref PubMed Scopus (0) Google Scholar,13Venero JV Doyle M Shah M Rathi VK Yamrozik JA Williams RB Vido DA Rayarao G Benza R Murali S Glass J Olson P Sokos G Biederman RW 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.ESC Heart Fail. 2015; 2: 150-159Crossref PubMed Scopus (0) Google Scholar was first described by McCrohon et al4McCrohon JA Moon JC Prasad SK McKenna WJ Lorenz CH Coats AJ Pennell DJ Differentiation of heart failure related to dilated cardiomyopathy and coronary artery disease using gadolinium-enhanced cardiovascular magnetic resonance.Circulation. 2003; 108: 54-59Crossref PubMed Scopus (911) Google Scholar as a characteristic finding exclusively seen in patients with DCM. Since then, several studies described the diagnostic value of LGE-CMR for differentiation of ischemic or nonischemic origin in patients with heart failure, based on the various LGE patterns.3Mahrholdt H Wagner A Judd RM Sechtem U Kim RJ Delayed enhancement cardiovascular magnetic resonance assessment of non-ischaemic cardiomyopathies.Eur Heart J. 2005; 26: 1461-1474Crossref PubMed Scopus (668) Google Scholar,4McCrohon JA Moon JC Prasad SK McKenna WJ Lorenz CH Coats AJ Pennell DJ Differentiation of heart failure related to dilated cardiomyopathy and coronary artery disease using gadolinium-enhanced cardiovascular magnetic resonance.Circulation. 2003; 108: 54-59Crossref PubMed Scopus (911) Google Scholar Myocardial fibrosis roughly consists of 2 types: (1) local replacement fibrosis, of which the production is stimulated after damage of myocytes and necrosis (e.g., ischemia) to maintain structure and integrity; and (2) interstitial or reactive fibrosis, characterized by a diffuse expansion of the extracellular matrix because of excessive collagen deposition.14Barison A Grigoratos C Todiere G Aquaro GD Myocardial interstitial remodelling in non-ischaemic dilated cardiomyopathy: insights from cardiovascular magnetic resonance.Heart Fail Rev. 2015; 20: 731-749Crossref PubMed Google Scholar,15Li L Zhao Q Kong W Extracellular matrix remodeling and cardiac fibrosis.Matrix Biol. 2018; 68–69: 490-506Crossref PubMed Scopus (180) Google Scholar This interstitial fibrosis is found in myocardial remodeling14Barison A Grigoratos C Todiere G Aquaro GD Myocardial interstitial remodelling in non-ischaemic dilated cardiomyopathy: insights from cardiovascular magnetic resonance.Heart Fail Rev. 2015; 20: 731-749Crossref PubMed Google Scholar, 15Li L Zhao Q Kong W Extracellular matrix remodeling and cardiac fibrosis.Matrix Biol. 2018; 68–69: 490-506Crossref PubMed Scopus (180) Google Scholar, 16Souders CA Bowers SL Baudino TA Cardiac fibroblast: the renaissance cell.Circ Res. 2009; 105: 1164-1176Crossref PubMed Scopus (746) Google Scholar, 17González A Schelbert EB Díez J Butler J Myocardial interstitial fibrosis in heart failure: biological and translational perspectives.J Am Coll Cardiol. 2018; 71: 1696-1706Crossref PubMed Scopus (298) Google Scholar and is considered an adaptive response to normalize increased wall stress and preserve cardiac output in cardiac dysfunction.14Barison A Grigoratos C Todiere G Aquaro GD Myocardial interstitial remodelling in non-ischaemic dilated cardiomyopathy: insights from cardiovascular magnetic resonance.Heart Fail Rev. 2015; 20: 731-749Crossref PubMed Google Scholar Diffuse interstitial fibrosis can be seen in early stages of DCM on myocardial biopsy,18aus dem Siepen F Buss SJ Messroghli D Andre F Lossnitzer D Seitz S Keller M Schnabel PA Giannitsis E Korosoglou G Katus HA Steen H T1 mapping in dilated cardiomyopathy with cardiac magnetic resonance: quantification of diffuse myocardial fibrosis and comparison with endomyocardial biopsy.Eur Heart J Cardiovasc Imaging. 2015; 16: 210-216Crossref PubMed Scopus (191) Google Scholar however, was also demonstrated in remote myocardium in patients with end-stage heart failure because of ICM,19Beltrami CA Finato N Rocco M Feruglio GA Puricelli C Cigola E Quaini F Sonnenblick EH Olivetti G Anversa P Structural basis of end-stage failure in ischemic cardiomyopathy in humans.Circulation. 1994; 89: 151-163Crossref PubMed Google Scholar demonstrating myocardial remodeling beyond the infarcted area. Myocardial remodeling is potentially reversible with targeted treatment.20Hoogwerf BJ Renin-angiotensin system blockade and cardiovascular and renal protection.Am J Cardiol. 2010; 105: 30A-35AAbstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar However, it can also precede focal irreversible replacement fibrosis.14Barison A Grigoratos C Todiere G Aquaro GD Myocardial interstitial remodelling in non-ischaemic dilated cardiomyopathy: insights from cardiovascular magnetic resonance.Heart Fail Rev. 2015; 20: 731-749Crossref PubMed Google Scholar,16Souders CA Bowers SL Baudino TA Cardiac fibroblast: the renaissance cell.Circ Res. 2009; 105: 1164-1176Crossref PubMed Scopus (746) Google Scholar Prolonged exposure to various triggers (e.g., mechanical stress, microvascular dysfunction, or inflammation) results in increased synthesis of fibrosis, and subsequently causes geometrical changes, including increased ventricular dilation and severe dysfunction.10Kim J Kochav JD Gurevich S Afroz A Petashnick M Volo S Diaz B Okin PM Horn E Devereux RB Weinsaft JW Left ventricular geometric remodeling in relation to non-ischemic scar pattern on cardiac magnetic resonance imaging.Int J Cardiovasc Imaging. 2014; 30: 1559-1567Crossref PubMed Scopus (12) Google Scholar The close relation between septal midwall LGE and structural LV changes has been previously demonstrated in patients with DCM.12Gulati A Jabbour A Ismail TF Guha K Khwaja J Raza S Morarji K Brown TD Ismail NA Dweck MR Di Pietro E Roughton M Wage R Daryani Y O'Hanlon R Sheppard MN Alpendurada F Lyon AR Cook SA Cowie MR Assomull RG Pennell DJ Prasad SK Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy [published correction appears in JAMA 2013;310:99].JAMA. 2013; 309: 896-908Crossref PubMed Scopus (0) Google Scholar,21Lehrke S Lossnitzer D Schöb M Steen H Merten C Kemmling H Pribe R Ehlermann P Zugck C Korosoglou G Giannitsis E Katus HA 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.Heart. 2011; 97: 727-732Crossref PubMed Scopus (179) Google Scholar Our results demonstrate a similar relation in patients with ICM as well, in line with a previous report.10Kim J Kochav JD Gurevich S Afroz A Petashnick M Volo S Diaz B Okin PM Horn E Devereux RB Weinsaft JW Left ventricular geometric remodeling in relation to non-ischemic scar pattern on cardiac magnetic resonance imaging.Int J Cardiovasc Imaging. 2014; 30: 1559-1567Crossref PubMed Scopus (12) Google Scholar The geometrical changes and the additional increase in NYHA functional class suggest that septal midwall LGE represents an advanced stage of heart failure with considerable remodeling, rather than being a tool for differentiation between an ischemic and nonischemic etiology. However, the incidence of septal midwall LGE in patients with ICM is particularly low, at 10% in the present study. This may be an underestimation since involvement of the septal segments in myocardial infarction results in subendocardial or transmural hyperenhancement on CMR, hampering visualization of septal midwall LGE. The prognostic value of septal midwall LGE presence was previously demonstrated in DCM.5Assomull RG Prasad SK Lyne J Smith G Burman ED Khan M Sheppard MN Poole-Wilson PA Pennell DJ Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy.J Am Coll Cardiol. 2006; 48: 1977-1985Crossref PubMed Scopus (912) Google Scholar,7Halliday BP Gulati A Ali A Guha K Newsome S Arzanauskaite M Vassiliou VS Lota A Izgi C Tayal U Khalique Z Stirrat C Auger D Pareek N Ismail TF Rosen SD Vazir A Alpendurada F Gregson J Frenneaux MP Cowie MR Cleland JGF Cook SA Pennell DJ Prasad SK Association between midwall late gadolinium enhancement and sudden cardiac death in patients with dilated cardiomyopathy and mild and moderate left ventricular systolic dysfunction.Circulation. 2017; 135: 2106-2115Crossref PubMed Scopus (223) Google Scholar,22Iles L Pfluger H Lefkovits L Butler MJ Kistler PM Kaye DM Taylor AJ Myocardial fibrosis predicts appropriate device therapy in patients with implantable cardioverter-defibrillators for primary prevention of sudden cardiac death.J Am Coll Cardiol. 2011; 57: 821-828Crossref PubMed Scopus (252) Google Scholar To the extent of our knowledge, the present study is the first to demonstrate a similar prognostic effect of septal midwall LGE presence on VA in patients with ICM as well. Previously, poor outcome in patients with ICM was associated with LVEF,23Di Bella G Siciliano V Aquaro GD Molinaro S Lombardi M Carerj S Landi P Rovai D Pingitore A Scar extent, left ventricular end-diastolic volume, and wall motion abnormalities identify high-risk patients with previous myocardial infarction: a multiparametric approach for prognostic stratification.Eur Heart J. 2013; 34: 104-111Crossref PubMed Scopus (45) Google Scholar which is correlated to the extent of ischemic LGE.24Nijveldt R Beek AM Hirsch A Stoel MG Hofman MB Umans VA Algra PR Twisk JW van Rossum AC Functional recovery after acute myocardial infarction: comparison between angiography, electrocardiography, and cardiovascular magnetic resonance measures of microvascular injury.J Am Coll Cardiol. 2008; 52: 181-189Crossref PubMed Scopus (281) Google Scholar However, the close correlation between advanced myocardial remodeling and septal midwall LGE indicates an advanced disease state, which would imply worse prognosis. The substrate of VA remains debatable. Septal midwall fibrosis itself may act as arrhythmogenic substrate for a re-entry circuit.25Piers SR Tao Q van Huls van Taxis CF Schalij MJ van der Geest RJ Zeppenfeld K Contrast-enhanced MRI-derived scar patterns and associated ventricular tachycardias in nonischemic cardiomyopathy: implications for the ablation strategy.Circ Arrhythm Electrophysiol. 2013; 6: 875-883Crossref PubMed Scopus (129) Google Scholar In contrast, the increased wall stress because of LV dilation and myocardial remodeling10Kim J Kochav JD Gurevich S Afroz A Petashnick M Volo S Diaz B Okin PM Horn E Devereux RB Weinsaft JW Left ventricular geometric remodeling in relation to non-ischemic scar pattern on cardiac magnetic resonance imaging.Int J Cardiovasc Imaging. 2014; 30: 1559-1567Crossref PubMed Scopus (12) Google Scholar may directly induce VA.26Hansen DE Craig CS Hondeghem LM Stretch-induced arrhythmias in the isolated canine ventricle. Evidence for the importance of mechanoelectrical feedback.Circulation. 1990; 81: 1094-1105Crossref PubMed Google Scholar Additionally, of interest for future research is the assessment of the value of septal midwall LGE in patients with ICM for the prediction of LV functional improvement after revascularization,27Allman KC Shaw LJ Hachamovitch R Udelson JE Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis.J Am Coll Cardiol. 2002; 39: 1151-1158Crossref PubMed Scopus (1120) Google Scholar since in DCM the absence of midwall LGE was associated with reverse remodeling.8Kubanek M Sramko M Maluskova J Kautznerova D Weichet J Lupinek P Vrbska J Malek I Kautzner J Novel predictors of left ventricular reverse remodeling in individuals with recent-onset dilated cardiomyopathy.J Am Coll Cardiol. 2013; 61: 54-63Crossref PubMed Scopus (102) Google Scholar Several limitations should be kept in mind when interpreting these data. This is a retrospective observational study and suffers from the biases inherent to this design. Diagnosis of ischemic origin or DCM as cause of myocardial dysfunction was based on clinical results. Since genetic testing is not routinely performed, a combined type of cardiomyopathy including both an ischemic origin and underlying DCM cannot be ruled out in this real-life cohort representing the current clinical practice. Furthermore, the retrospective nature of this study limited the analysis of cardiovascular death in particular, rather than all-cause mortality. Septal midwall LGE was stratified as a binary variable, without quantification of the extent. However, the additional value of LGE-extent remains unclear, since the results in previous studies with patients with DCM differ substantially.12Gulati A Jabbour A Ismail TF Guha K Khwaja J Raza S Morarji K Brown TD Ismail NA Dweck MR Di Pietro E Roughton M Wage R Daryani Y O'Hanlon R Sheppard MN Alpendurada F Lyon AR Cook SA Cowie MR Assomull RG Pennell DJ Prasad SK Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy [published correction appears in JAMA 2013;310:99].JAMA. 2013; 309: 896-908Crossref PubMed Scopus (0) Google Scholar,28Perazzolo Marra M De Lazzari M Zorzi A Migliore F Zilio F Calore C Vettor G Tona F Tarantini G Cacciavillani L Corbetti F Giorgi B Miotto D Thiene G Basso C Iliceto S Corrado D Impact of the presence and amount of myocardial fibrosis by cardiac magnetic resonance on arrhythmic outcome and sudden cardiac death in nonischemic dilated cardiomyopathy.Heart Rhythm. 2014; 11: 856-863Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar,29Halliday BP Baksi AJ Gulati A Ali A Newsome S Izgi C Arzanauskaite M Lota A Tayal U Vassiliou VS Gregson J Alpendurada F Frenneaux MP Cook SA Cleland JGF Pennell DJ Prasad SK Outcome in dilated cardiomyopathy related to the extent, location, and pattern of late gadolinium enhancement.JACC Cardiovasc Imaging. 2019; 12: 1645-1655Crossref PubMed Scopus (144) Google Scholar In addition, we hypothesized that midwall LGE is a result of prolonged LV remodeling, including increased interstitial fibrosis. Unfortunately, LGE-CMR is unable to visualize diffuse interstitial fibrosis because it depends on focal macroscopic differences. T1-mapping may be an appropriate tool for the quantification of interstitial fibrosis, however, this is no standard sequence and therefore mostly missing in this retrospective CMR study cohort. Additionally, the present study lacks histopathological data on remodeling in ICM, although this was demonstrated in earlier studies. Future studies focusing on the remodeling process and, in particular, on potential therapeutic targets in both patients with ICM and DCM are therefore recommended. In conclusions, septal midwall LGE, a frequent and characteristic finding of CMR in patients with DCM, was also present in 10% of patients with systolic heart failure caused by ischemic heart disease. The presence of septal midwall LGE was related to advanced myocardial remodeling, including more severe LV dilation and worse LV systolic function, irrespective of underlying cause. Importantly, the presence of septal midwall LGE was significantly associated with the occurrence of ventricular arrhythmic events, both in ICM and DCM. In patients with DCM, septal midwall LGE was also associated with increased all-cause mortality, whereas no such correlation was seen in patients with ICM. Evaluation of septal midwall LGE presence may further guide the selection of patients for preventive ICD implantation. The authors have no conflicts of interest to declare. Download .docx (.02 MB) Help with docx files Table S1. Cox regression analysis for the primary end point of all-cause mortality in patients with ICMTable S2. Cox regression analysis for the primary end point of all-cause mortality in patients with DCMTable S3. Cox regression analyses for the secondary end point of ventricular arrhythmic events in patients with ICMTable S4. Cox regression analyses for the secondary end point of ventricular arrhythmic events in patients with DCM
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