Cum Grano Salis Cardiac Sarcoidosis As A Perfect Mimic Of Arrhythmogenic Right Ventricular Cardiomyopathy

HomeCirculation: Cardiovascular ImagingVol. 14, No. 7Cum Grano Salis: Cardiac Sarcoidosis as a Perfect Mimic of Arrhythmogenic Right Ventricular Cardiomyopathy Free AccessCase ReportPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toSupplementary MaterialsFree AccessCase ReportPDF/EPUBCum Grano Salis: Cardiac Sarcoidosis as a Perfect Mimic of Arrhythmogenic Right Ventricular Cardiomyopathy Giulia Saturi, MD, Angelo Giuseppe Caponetti, MD, Ornella Leone, MD, Luigi Lovato, MD, Simone Longhi, MD, PhD, Maddalena Graziosi, MD, PhD, Raffaello Ditaranto, MD, Mauro Biffi, MD, Nazzareno Galiè, MD and Elena Biagini, MD, PhD Giulia SaturiGiulia Saturi Cardiology Unit, Cardio-Thoracic-Vascular Department, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy (G.S., A.G.C., S.L., M.G., R.D., M.B., N.G., E.B.). Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy (G.S., A.G.C., R.D., N.G.) *G. Saturi and A. Giuseppe Caponetti contributed equally. Search for more papers by this author , Angelo Giuseppe CaponettiAngelo Giuseppe Caponetti Cardiology Unit, Cardio-Thoracic-Vascular Department, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy (G.S., A.G.C., S.L., M.G., R.D., M.B., N.G., E.B.). Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy (G.S., A.G.C., R.D., N.G.) *G. Saturi and A. Giuseppe Caponetti contributed equally. Search for more papers by this author , Ornella LeoneOrnella Leone Cardiovascular Pathology Unit, Department of Pathology, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy (O.L.). Search for more papers by this author , Luigi LovatoLuigi Lovato Cardio-Thoracic Radiology Unit, Cardio-Thoracic-Vascular Department, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy (L.L.) Search for more papers by this author , Simone LonghiSimone Longhi https://orcid.org/0000-0002-7512-1179 Cardiology Unit, Cardio-Thoracic-Vascular Department, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy (G.S., A.G.C., S.L., M.G., R.D., M.B., N.G., E.B.). Search for more papers by this author , Maddalena GraziosiMaddalena Graziosi Cardiology Unit, Cardio-Thoracic-Vascular Department, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy (G.S., A.G.C., S.L., M.G., R.D., M.B., N.G., E.B.). Search for more papers by this author , Raffaello DitarantoRaffaello Ditaranto Cardiology Unit, Cardio-Thoracic-Vascular Department, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy (G.S., A.G.C., S.L., M.G., R.D., M.B., N.G., E.B.). Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy (G.S., A.G.C., R.D., N.G.) Search for more papers by this author , Mauro BiffiMauro Biffi https://orcid.org/0000-0003-4590-8584 Cardiology Unit, Cardio-Thoracic-Vascular Department, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy (G.S., A.G.C., S.L., M.G., R.D., M.B., N.G., E.B.). Search for more papers by this author , Nazzareno GalièNazzareno Galiè Cardiology Unit, Cardio-Thoracic-Vascular Department, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy (G.S., A.G.C., S.L., M.G., R.D., M.B., N.G., E.B.). Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy (G.S., A.G.C., R.D., N.G.) Search for more papers by this author and Elena BiaginiElena Biagini Correspondence to: Elena Biagini, MD, PhD, Cardiology Unit, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Giuseppe Massarenti N9, Bologna 40138, Italy. Email E-mail Address: [email protected] https://orcid.org/0000-0003-0295-0440 Cardiology Unit, Cardio-Thoracic-Vascular Department, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy (G.S., A.G.C., S.L., M.G., R.D., M.B., N.G., E.B.). Search for more papers by this author Originally published30 Jun 2021https://doi.org/10.1161/CIRCIMAGING.120.012355Circulation: Cardiovascular Imaging. 2021;14Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 30, 2021: Ahead of Print A forty-four-year-old man, overweight (body mass index, 27.5 kg/m2), former smoker, and with hypertension came to medical attention for dyspnea and reduced exercise tolerance. No comorbidities or family history for cardiac disease or sudden death were present. Physical examination and blood tests were normal. The ECG showed respiratory sinus arrhythmia, anterior and inferior pseudonecrosis pattern, incomplete right bundle branch block with terminal activation delay detectable as positive terminal wave in V1 through V3 in III and aVR, small and round s wave in the lateral leads (I, aVL, and V6), and negative T waves in V1 through V6 (Figure 1A). The echocardiogram showed mild left ventricular (LV) hypertrophy with systolic dysfunction (interventricular septum [IVS] and posterior wall, 13 and 12 mm, respectively; indexed end-diastolic volume, 51 mL/m2; ejection fraction [EF], 48%) and severe right ventricular (RV) dilation and dysfunction (end-diastolic area, 49 cm2; fractional area change, 17%; tricuspid annular plane systolic excursion, 10 mm; Figure 1B through 1D). Coronary angiography excluded significant coronary artery disease. Cardiac magnetic resonance confirmed severe RV dilation (132 mL/m2) and systolic dysfunction (RV EF, 32%) with localized dyskinetic areas in the free and diaphragmatic walls, as well as in the outflow tract. The LV was moderately hypokinetic (LV EF, 44%) with a moderate increase of septal and lateral wall thickness (IVS, 14 mm; Movies I and II in the Data Supplement). Native T1 mapping, performed using a modified Look-Locker inversion recovery sequence, showed increased values particularly in the medium IVS (1100 ms; normal values, 980±25 ms). T2-weighted images (short-tau inversion recovery) showed diffuse edema of the RV and right side of the IVS, whereas a patchy distribution was present in the left side of the IVS and in the LV lateral and inferior walls. Late gadolinium enhancement using a phase-sensitive inversion recovery was present in all the aforementioned segments. Rest perfusion-weighted images documented septal hypoperfusion (Figures 2A through 2F and 3A). Patient phenotype fulfilled the diagnostic 2010 Task Force criteria for arrhythmogenic RV cardiomyopathy with mild LV involvement and signs of acute myocarditis. However, the unusual high inflammatory burden at cardiac magnetic resonance and the patchy, focal LV involvement triggered further diagnostic workup and an endomyocardial biopsy (EMB) was performed. Unexpectedly, severe diffuse inflammatory process characterized by non-necrotizing granulomas and isolated giant cells was detected, compatible with cardiac sarcoidosis; moderate-to-severe myocardial fibrosis was also present (Figure 4A through 4H). High-resolution computed tomography scan showed no signs of pulmonary or lymph node involvement. After administering a high dose of corticosteroid therapy, the patient underwent a positron emission tomography with 18F-fluorodeoxyglucose that showed no signs of active inflammation. The patient was discharged, and after 1 month, cardiac magnetic resonance and EMB were repeated. Mild improvement of biventricular function (RV EF, 38%; LV EF, 52%) and an important global reduction of edema were detected. In particular, there was a marked reduction of wall thickness (IVS, 11 mm) and a decrease of native T1 mapping values (mean value, 990 ms with a maximum value of 1042 ms in the IVS; Figure 3B) with normal T2 mapping values confirming the edema resolution (mean value, 57 ms; normal values, <60 ms). Persistent patchy late gadolinium enhancement indicated the presence of myocardial fibrosis in the RV, IVS, and inferior LV wall (Figure 5A through 5F). EMB showed resolution of granulomatous myocarditis: only few focal macrophages and mild-to-moderate myocardial and subendocardial fibrosis were detected (Figure 6A through 6C). Due to the persistence of RV dysfunction and the presence of diffuse fibrosis, a dual-chamber implantable cardioverter defibrillator was implanted for primary prevention of sudden cardiac death. At 1-year follow-up, the patient was New York Heart Association class II, LV EF was 50%, and RV fractional area change was 28%. Interrogation of the implantable defibrillator showed periods of nonsustained ventricular tachycardia.Download figureDownload PowerPointFigure 1. Electrocardiogram and echocardiogram at first evaluation. A, Standard 12-lead ECG. B, Echocardiogram parasternal long-axis view. C, Parasternal short-axis view focusing the right ventricular outflow tract. D, Apical 4-chamber view.Download figureDownload PowerPointFigure 2. Cardiac magnetic resonance at first clinical presentation. A, Short-axis end-diastolic cine image. B, T2-weighted short-axis view. C, Late gadolinium enhancement short-axis view. D, Four-chamber end-diastolic cine image. E, T2-weighted 4-chamber view. F, Late gadolinium enhancement 4-chamber view.Download figureDownload PowerPointFigure 3. Cardiac magnetic resonance T1 mapping sequence. A, First cardiac magnetic resonance. B, Cardiac magnetic resonance at 1-mo follow-up.Download figureDownload PowerPointFigure 4. Endomyocardial biopsy. A and B, Severe and diffuse inflammatory process: (A) Azan Mallory trichrome 25× and (B) CD68+ macrophages in brown, CD3 T lymphocytes in red 25×. C and D, Macrophagic granulomas and giant cells, surrounded by T lymphocytes and severe myocardial fibrosis: (C) Azan Mallory trichrome 50× and (D) double CD68/CD3 immunostaining 50×. E–G, Isolated and well-defined granulomas with epithelioid pattern and absence of necrotizing or caseating areas: (E and F) Azan Mallory trichrome 200× and (G) double CD68/CD3 immunostaining 200×. H, Giant cells show asteroid bodies (arrow) in the cytoplasm, hematoxylin-eosin: H 400×. CD indicates cluster differentiation.Download figureDownload PowerPointFigure 5. Cardiac magnetic resonance at 1-mo follow-up. A, Short-axis end-diastolic cine image. B, T2-weighted short-axis view. C, Late gadolinium enhancement short-axis view. D, Four-chamber end-diastolic cine image. E, T2-weighted 4-chamber view. F, Late gadolinium enhancement 4-chamber view.Download figureDownload PowerPointFigure 6. Endomyocardial biopsy at 1-mo follow-up. A and B, Moderate subendocardial and mild myocardial fibrosis: (A) Azan Mallory trichrome, 25× and (B) Azan Mallory trichrome, 100×. C, Inflammation resolution with only few residual macrophages (in brown) in a limited fibrotic area, CD68 immunostaining, 200×. CD indicates cluster differentiation.Sarcoidosis is a multisystem inflammatory disorder characterized by epithelioid noncaseating granulomas as histological hallmark. Lungs are frequently involved, but heart, skin, eyes, kidney, lymph nodes, and central nervous system can be affected as well. Cardiac involvement has been reported in 25% of patients with systemic sarcoidosis although the isolated cardiac presentation is rare but possible. Cardiac sarcoidosis foreshadows a worse prognosis and accounts for substantial mortality and morbidity. It predominantly involves the LV, and clinical features include atrioventricular blocks, arrhythmias, or heart failure; primary RV involvement is rare and difficult to diagnose.1Arrhythmogenic right ventricular cardiomyopathy is a primary, genetically based, heart muscle disease that shares with sarcoidosis a challenging diagnosis due to the rarity of these conditions, the patchy and nonischemic regional wall motion abnormalities, and the inflammatory phase fluctuations.2 Furthermore, a possible interplay in the molecular substrate has been reported since sarcoidosis may exhibit a similar pattern of reduced plakoglobin staining in the absence of any mutations linked to ARVC. Moreover, several studies have demonstrated the leading role of inflammation in ARVC as trigger for fibrofatty infiltration or consequence of the apoptotic process. This inflammatory theory has been confirmed by histology (inflammatory cell infiltrates in 60%–74% of ARVC) and by resonance imaging studies. The diagnosis of ARVC is based on a scoring system that combines clinical, instrumental, histopathologic, and genetic tools.2 However, none of these findings have a specific or unique diagnostic value, and the algorithm identifies more a right-sided cardiomyopathy phenotype rather than a definite etiology. Cardiac sarcoidosis can closely mimic ARVC, and in doubtful cases, EMB can provide the definite diagnosis. In a prospective study conducted by Vasaiwala et al3 on consecutive patients with suspected ARVC evaluated by a standard protocol including EMB, a histological evidence of sarcoidosis was found in 15% of the patients with a definite diagnosis of ARVC.In this clinical case, a disproportionate inflammation and the patchy LV and IVS distribution at cardiac magnetic resonance raised the suspicion of an alternative etiology and led to the correct diagnosis of cardiac sarcoidosis.Keeping in mind a global vision of the patient with a cardiomyopathy-oriented attitude and identifying red flags and discrepancies in the different phenotypes can be crucial to guide the clinical decision-making.4Sources of FundingNone.Supplemental MaterialsData Supplement Movies I and IIDisclosures None.Footnotes*G. Saturi and A. Giuseppe Caponetti contributed equally.The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCIMAGING.120.012355.For Sources of Funding and Disclosures, see page 664.Correspondence to: Elena Biagini, MD, PhD, Cardiology Unit, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Giuseppe Massarenti N9, Bologna 40138, Italy. Email elena.[email protected]comReferences1. Birnie DH, Nery PB, Ha AC, Beanlands RS. Cardiac sarcoidosis.J Am Coll Cardiol. 2016; 68:411–421. doi: 10.1016/j.jacc.2016.03.605CrossrefMedlineGoogle Scholar2. Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MG, Daubert JP, et al.. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modificawtion of the task force criteria.Circulation. 2010; 121:1533–1541. doi: 10.1161/CIRCULATIONAHA.108.840827LinkGoogle Scholar3. Vasaiwala SC, Finn C, Delpriore J, Leya F, Gagermeier J, Akar JG, Santucci P, Dajani K, Bova D, Picken MM, et al.. Prospective study of cardiac sarcoid mimicking arrhythmogenic right ventricular dysplasia.J Cardiovasc Electrophysiol. 2009; 20:473–476. doi: 10.1111/j.1540-8167.2008.01351.xCrossrefMedlineGoogle Scholar4. Protonotarios A, Elliott PM. Arrhythmogenic cardiomyopathy: a disease or Merely a phenotype?Eur Cardiol. 2020; 15:1–5. doi: 10.15420/ecr.2019.05CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Makhdumi M, Assar M, Meyer D and Roberts W (2022) Cardiac sarcoidosis diagnosed after orthotopic heart transplantation and clinically mimicking arrhythmogenic right ventricular cardiomyopathy, Cardiovascular Pathology, 10.1016/j.carpath.2021.107390, 56, (107390), Online publication date: 1-Jan-2022. July 2021Vol 14, Issue 7Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCIMAGING.120.012355PMID: 34187167 Originally publishedJune 30, 2021 Keywordsmyocarditisexercise tolerancesarcoidosisinflammationarrhythmogenic right ventricular dysplasiaPDF download Advertisement SubjectsCardiomyopathyMagnetic Resonance Imaging (MRI)