CARDIAC MAGNETIC RESONANCE IMAGING IN DILATED AND ARRHYTHMOGENIC CARDIOMYOPATHIES: AN INSIGHT INTO CLINICAL AND PATHOLOGICAL SIGNIFICANCE OF LATE GADOLINIUM ENHANCEMENT

Background: Cardiomyopathies are an important and heterogeneous group of diseases of the heart muscle in which tissue characterization has been extensively studied only ex-vivo so far. Cardiac magnetic resonance (CMR) can provide in vivo the detection of post-contrast deposition (so called Late Gadolinium Enhancement, LGE). The role of LGE in the differential diagnosis of cardiac diseases has advanced through the years, in particular thanks to its capability to differentiate post-ischemic scar (with subendocardial or transmural coronary artery-related deposition) versus non-ischemic scar of different aetiologies. Among cardiomyopathies, the prognostic significance of LGE pattern is not well established, with the exception of hypertrophic cardiomyopathy. Detection in vivo of LGE in different cardiomyopathies has been used as a surrogate of fibrosis, even if the real basis of contrast deposition is not well understood. To this regard, dilated cardiomyopathy (DCM) is characterized by diffuse interstitial fibrosis with or without replacement-type fibrosis, which are associated with worse prognosis. Another myocardial disease in which CMR offers the capability of a non-invasive tissue characterization is Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), an inherited heart muscle disease with progressive loss of myocardium and replacement by fibrofatty tissue. The extensively application of CMR to these cardiomyopathies and its comparison with traditional invasive and non-invasive techniques for diagnostic and prognostic purposes has been limited so far. Aim: in order to assess the clinical significance of LGE in DCM and ARVC, the following lines were pursued: 1) in patients with DCM the diagnostic and the prognostic value of LGE, in particular evaluating the possible different significance of various LGE patterns, total amount of LGE against survival, heart failure and ventricular arrhythmias; 2) in patients with ARVC the comparison between CMR findings and: 1a) traditional electrocardiographic features; 1b) scar detction by endocardial voltage mapping (EVM), and 1c) the prognostic significance of LGE; 3) the significance of CMR tissue abnormalities by comparing LGE and specimen heart and/or endomyocardial biopsy (EMB) findings in DCM and ARVC. Material and Methods: Between January 2007 and December 2010 we prospectively evaluated two different groups of patients referred to our Tertiary Referral Centre for a complete invasive and non-invasive evaluation for unexplained left ventricle (LV) dilatation (DCM Group, A) and for suspected ARVC (ARVC Group, B). DCM Group (A): we prospectively evaluated 210 patients referred for unexplained LV dilatation with subacute-chronic onset (≥ 1 month), with or without previous history of heart failure, who underwent during the same hospitalization to a complete screening including CMR with LGE, angiography and EMB. ARVC group (B): we prospectively evaluated 52 patients who were referred to our Tertiary Centre for susptected ARVC and in which the diagnosis was reached according to 1994 Task Force Criteria and 2010 Modified Criteria. Data on clinical history, ECG, ECG Holter monitoring, echocardiography, CMR and EMB in selected cases were collected. In a subgroup of patients an electrophysiological study with EVM was performed. For each subject enrolled, a clinical, ECG and echocardiographic follow-up was obtained. Results: Group A. On the basis of coronary angiography, patients were divided into two groups: ischemic (99 patients) and DCM (111 patients). Ischemic group patients were then excluded from the analysis. Compared to angiography, CMR showed an excellent accuracy (96.5%) for the identification of non-ischemic versus ischemic aetiology for LV dilatation. In the DCM group (111 patients) LGE was present (with a non-ischemic pattern) in 67 cases (60.4%) and absent in 44 (39.6%); no differences between RV and LV volumes and ejection fraction (EF) were found between the two groups. Out of 67 patients with positive LGE, a “gray” pattern was present in 12 patients (17.9%), a midwall/subepicardial stria in 49 (73.1%), a septal junction pattern (anterior and/or posterior) either isolated in 4 (5.9%) or associated with other patterns in 25 patients (37.3%) and finally a spotty (“patchy”) pattern in 2 (2.9%). Among patients with positive LGE, the extent of LGE was 6.3%+/-8.8% of LV mass. Fifty-eight patients underwent to EMB: 33/58 patients (56.9%) showed replacement-type fibrosis, of this subgroup 23 patients (69.7%) showed LGE on CMR. Out of 13/58 patients (22%) without replacement-type fibrosis on EMB, LGE was present in 9/13 (69.2%) patients: in this subgroup the most frequent LGE pattern was midwall/subepicardial stria (n=8/9; 89%) and one patient (11%) showed a “patchy” LGE pattern . Compared to EMB, CMR showed a low accuracy for fibrosis detection. The range of follow-up in LGE group was 8 years-1 month. Kaplan-Meier curves for composite end-point and ventricular arrhythmias showed a significant differences between patients with and without LGE on CMR (Wilcoxon-Breslow: p< 0.05). The amount of LGE%, by univariate analysis, was strongly associated with ventricular arrhythmias (HR 1.05, 95% CI 1.02 to 1.08; p<0.0001). This association was unchanged in multivariate analysis adjusted for a EF<30% (model 5): HR 1.067, 95% CI 1.034 to 1.1; p<0.0001.With an associated HR of 2.5, the presence of LGE was among the strongest multivariate predictors for the combined end point, surpassed only by age < 49 years. ROC curve analysis revealed a LGE percentage of 3.5 as optimal discriminator for the occurrence of ventricular arrhythmic events with an associated HR of 4.11 (95% CI 1.3 to 12.7; p<0.001). Group B: On the basis of clinical and CMR evaluation, 24 patients (46%) were defined as “classic ARVC phenotype”; 14 (27%) as “left dominant phenotype”, and finally 14 (27%) as “biventricular ARVC phenotype”. Comparison between ECG and CMR showed that ECG indexes of LV dilatation are ST-segment elevation and T-wave inversion beyond V3 (p<0.05); among tissue characterization parameters, only LV LGE has an identifiable ECG abnormality, i.e. ST segment elevation (p<0.05). On EVM, endocardial voltages of RV was abnormal in 21/23 (91%) patients, with a total of 45 electroanatomic scars (EAS). RV LGE was found in 9/23 (39%) patients, with a total of 23 RV LGE scars: there was a mismatch in 24 RV scars, with 22 EAS not confirmed by LGE. In 9/12 (75%) patients with abnormal RV EVM/normal RV LGE, ≥1 LGE were identified in the LV. The patients of ARVC group enrolled for the follow-up were 52 (34 males; mean age 33+/-15 years). The mean LV ejection fraction was 57+/-8%; the mean fractional area change of RV was 39+/-10%. The mean follow-up was 25.6 months (range 38+/-4 months). Considering only the major events (aborted sudden death/ ventricular fibrillation; sudden death; non sudden death/heart transplantation) these occurred in 12 (7 in the LGE group, 5 in the non-LGE group).Kaplan-Meier curves did not show difference between LGE presence/absence for all events and major events. Kaplan-Meier curves did not show difference between three phenotypes detected by CMR both for all events and major events. Conclusions: CMR can provide a wide range of information in DCM and ARVC, beyond traditional imaging modalities. In the setting of DCM, CMR shows high accuracy in the detection of non-ischemic aetiology compared with angiography. LGE identifies the patients with increased risk of ventricular arrhythmic events. Compared to EMB, CMR with LGE imaging shows low accuracy for fibrosis detection, probably due to resolution power of CMR. However, an integrated approach with CMR and EMB may be useful in cases with negative EMB/positive LGE to identify epicardial lesion, which are not caught by EMB due to its endocardial approach. In the setting of ARVC, CMR confirms its superiority in assessing the full spectrum of morpho-functional and tissue abnormalities of a disease that should be as a biventricular cardiomyopathy. The ECG indexes able to identify LV dilatation are ST-segment elevation and T-wave inversion beyond V3; as far as tissue characterization parameters are concerned, LV LGE was associated to ST segment elevation. The correlation between EVM and CMR confirms that EVM allows an accurate identification of RV EAS in patients with ARVC and supports its clinical use for substrate-based mapping and catheter ablation of RV tachycardias as well as for imaging-guided EMB. Currently available LGE CMR appears to visualize unsatisfactorily RV scars and this limits its usefulness in ARVC diagnosis and guiding interventional RV procedures. However, the high prevalence of LV involvement in ARVC patients is in keeping with the current perspective of biventricular disease and points out the diagnostic relevance of LV scar detection by LGE CMR.Introduzione: Le cardiomiopatie rappresentano un gruppo eterogeneo di malattie del muscolo cardiaco la cui caratterizzazione tissutale finora è stata eseguita prevalentemente mediante analisi ex vivo. La risonanza magnetica cardiaca (RMC), grazie all’utilizzo di apposite sequenze e all’impiego di un mezzo di contrasto (gadolinio, visibile come Late Gadolinium Enhancement, LGE), rende possibile una caratterizzazione tissutale in vivo. L’analisi della sede ed estensione dell’LGE permette di differenziare la cicatrice miocardica post-infartuale (LGE sub endocardico o trans murale) rispetto ad altre cicatrici di tipo non ischemico. Nelle diverse cardiomiopatie, il significato prognostico dei depositi di LGE non è del tutto chiarito, se non in parte per la cardiomiopatia ipertrofica. In generale la presenza di LGE nel contesto di una cardiomiopatia viene identificato con la presenza di fibrosi miocardica, nonostante il meccanismo di deposito del gadolinio non sia uguale nelle diverse eziologie di cardiomiopatie, non necessariamente associate a fibrosi miocardica. Nell’ambito delle cardiomiopatie, la cardiomiopatia dilatativa (non dovuta ad una eziologia ischemica) (CMD) si caratterizza da un punto di vista istologico per la presenza di fibrosi interstiziale, con o senza fibrosi sostitutiva, entrambe associate ad una prognosi infausta. Una diversa patologia miocardica in cui la RMC offre una eccezionale capacità di caratterizzazione tissutale è la Cardiomiopatia Aritmogena del Ventricolo Destro (CAVD), una miocardiopatia dovuta ad una progressiva atrofia miocardica con successiva sostituzione fibroadiposa. Benché la RMC stia consolidando il suo ruolo nella pratica clinica, non è stata ancora eseguita una applicazione estensiva della RMC in queste due differenti cardiomiopatie a scopo diagnostico e prognostico, ed ancor più manca una analisi sistematica delle correlazioni tra i diversi quadri radiologici ed i tradizionali parametri invasivi e non-invasivi di queste cardiomiopatie. Scopo dello Studio: al fine di valutare il significato clinico e prognostico dell’LGE nelle CMD e nella CAVD sono state perseguite le seguenti linee di ricerca: 1) nei pazienti affetti da CMD il significato prognostico dell’LGE nelle DCM, con particolare riferimento ad un end-point di eventi combinati ed all’outcome aritmico; 2) nei pazienti affetti da CAVD il confronto tra i diversi aspetti alla RMC ed 1a) i quadri elettrocardiografici; 1b) il confronto con dati ottenuti dal mappaggio endocavitario del ventricolo destro (“Endocardial Voltage Mapping”, EVM); 1c) il significato prognostico dell’LGE; 3) il significato della alterazioni di caratterizzazione tissutale alla RMC confrontati con i dati istologici dei pazienti con biopsia endomiocardica (BEM) o che sono andati incontro a decesso/trapianto cardiaco nei due gruppi. Materiali e Metodi: tra il Gennaio 2007 e il Dicembre 2010 sono stati arruolati prospetticamente i pazienti riferiti presso il nostro Centro per una valutazione invasiva per il riscontro di una dilatazione del ventricolo sinistro (Gruppo CMD, A) o per sospetta CAVD (Gruppo CAVD, B). Gruppo CMD (A): sono stati valutati 210 riferiti per riscontro di dilatazione ventricolare con esordio subacuto-cronico (≥ 1 mese), con o senza pregressa storia di scompenso cardiaco, che durante la stessa ospedalizzazione sono stati sottoposti a coronarografia, RMC con contrasto e BEM. Gruppo CAVD (B): 52 soggetti riferiti presso il nostro Centro per sospetta CAVD e la cui diagnosi è stata raggiunta in accordo con i correnti criteri clinico-strumentali recentemente modificati. Durante la stessa ospedalizzazione sono stati sottoposti RMC con contrasto e studio elettrofisiologico con EVM e BEM in casi selezionati. Ogni paziente appartenente ad entrambi i gruppi è stato sottoposto ad un follow-up clinico-strumentale. Resultati: Gruppo A. Sulla base dei risultati della coronarografia i pazienti sono stati suddivisi in due gruppi in base alla presenza o meno di coronaropatia: in 99 è stato definita una eziologia ischemica alla base della disfunzione ventricolare, 111 non mostravano alcuna coronaropatia (gruppo CMD). Il gruppo dei soggetti ischemici è stato escluso dalla successive analisi. Rispetto all’angiografia coronarica, la RMC ha dimostrato un’ottima accuratezza diagnostica (96.5%) nell’escludere una eziologia ischemica. Nel gruppo A la presenza di un LGE di tipo non-ischemico è stata riscontrata in 67 casi (60.4%) mentre era assente in 44 (39.6%). Nessuna differenza nei volumi ventricolari e funzione sistolica è stata riscontrata nei due sottogruppi. Nei 67 pazienti con LGE era presente un pattern di tipo “gray” in 12, tipo stria “midural”/epicardica in 49 (73.1%), alla giunzione settale tra ventricolo destro e sinistro isolatamente in 4 (5.9%), associato ad altri pattern in 25 (37.3%), ed infine tipo “patchy” in 2 casi (2.9%). Nei pazienti con LGE, l’estensione media era pari al 6.3%+/-8.8% della massa del ventricolo sinistro. In 58 casi è stata eseguita la BEM: 33/58 pazienti (56.9%) mostravano aspetti di fibrosi sostitutiva; di questi, 23/33 (69.7%) mostravano anche LGE alla RMC. In 13/58 casi (22%) si riscontrava una BEM negativa: in questo sottogruppo di soggetti era presente un LGE in 9/13 (69.2%): nella maggioranza dei casi (8/9 pari all’89%) l’LGE era tipo stria “midmural”/epicardica, in uno solo (11%) tipo “patchy”. Nel gruppo A il range del follow-up è 8 anni-1 mese. Le curve di sopravvivenza Kaplan-Meier per eventi combinati ed aritmie ventricolari maggiori hanno mostrato una differenza significativa tra i due gruppi di pazienti con una prognosi peggiore nel gruppo con LGE (Wilcoxon-Breslow: p< 0.05). La quantità totale di LGE si è dimostrata associata alle aritmie ventricolari (HR 1.05, 95% CI 1.02-1.08; p<0.0001); tale correlazione rimaneva anche all’analisi multivariata aggiustata per una frazione d’eiezione inferiore al 30% (HR 1.067, 95% CI 1.034-1.1; p<0.0001).I pazienti con LGE mostravano un rischio di 2.5 per la comparsa di aritmie ventricolari e mediante l’analisi della curva ROC la percentuale di LGE pari a 3.5% è risultato il miglior valore predittivo di eventi aritmici (HR 4.11 (95% CI 1.3-12.7; p<0.001). Gruppo B. Sulla base dei risultati della RMC, 24 soggetti (46%) sono stati definiti affetti da un forma “classica”, 14 (27%) “dominante sinistra”, e 14 (27%) “biventricolare”. Analizzando la correlazione tra ECG e RMC, gli unici predittori della dilatazione del ventricolo sinistro sono risultati la presenza di un sopraslivellamento del tratto ST e le T invertite oltre V3 (p