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Cardiovascular Magnetic Resonance Visualization of Cardiac Amyloid Infiltration

2015; Lippincott Williams & Wilkins; Volume: 132; Issue: 16 Linguagem: Italiano

10.1161/circulationaha.115.018832

1524-4539

Frederick L. Ruberg, Reza Nezafat,

Advanced MRI Techniques and Applications

HomeCirculationVol. 132, No. 16Cardiovascular Magnetic Resonance Visualization of Cardiac Amyloid Infiltration Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCardiovascular Magnetic Resonance Visualization of Cardiac Amyloid InfiltrationChallenges and Opportunities Frederick L. Ruberg, MD and Reza Nezafat, PhD Frederick L. RubergFrederick L. Ruberg From Section of Cardiovascular Medicine and Amyloidosis Center, Department of Medicine, Boston Medical Center and Boston University School of Medicine, MA (F.L.R.); and Department of Medicine (Cardiovascular Division), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (R.N.). and Reza NezafatReza Nezafat From Section of Cardiovascular Medicine and Amyloidosis Center, Department of Medicine, Boston Medical Center and Boston University School of Medicine, MA (F.L.R.); and Department of Medicine (Cardiovascular Division), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (R.N.). Originally published11 Sep 2015https://doi.org/10.1161/CIRCULATIONAHA.115.018832Circulation. 2015;132:1525–1527Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: October 20, 2015: Previous Version 1 Cardiovascular magnetic resonance (CMR) is an indispensible clinical tool that can identify the cause of cardiomyopathy. Unlike other noninvasive imaging modalities, CMR leverages its intrinsic capacity to characterize tissue on the basis of fundamental MR properties (T1 and T2) and in so doing can differentiate normal from diseased myocardium. After the administration of the exogenous contrast agent gadolinium, which is retained in areas of increased interstitial space, intrinsic MR differences are accentuated, permitting selective visualization of fibrosis and infarction by means of late gadolinium enhancement (LGE). LGE, arguably one of the most important innovations in the history of CMR, works best when the border between normal and abnormal is distinct and the region of abnormality is sufficiently different so as to result in significant gadolinium accumulation, thereby shortening T1 and rendering a high signal intensity difference from normal myocardium.Article see p 1570In diffuse myopathic processes, as typified by cardiac amyloidosis, the discriminative capacity of LGE to differentiate the normal from the abnormal is challenged because the entire myocardium is abnormal and clear demarcation is absent. In cardiac amyloidosis, precursor proteins pathologically unfold to form amyloid fibrils that deposit in the myocardium, thereby increasing interstitial space and resulting in gadolinium accumulation. Although it is generally accepted that the most common types of cardiac amyloidosis, light-chain (AL) and transthyretin (ATTR), overlap in respect to their CMR manifestations,1,2 there are no reported data to effectively disentangle amyloid type and degree or stage of amyloid infiltration. For this reason, reported LGE characteristics in cardiac amyloidosis are quite varied, with diffuse, subendocardial, and transmural patterns reported.3 Furthermore, standard LGE imaging techniques are flawed in amyloidosis because there is a requirement that the MR technologist select a key parameter from visual inspection, the inversion time, to optimally suppresses signal from regions of normal myocardium. When nothing appears normal, inversion time selection can become an exercise in futility.Diffuse myocardial processes are perhaps better assessed by CMR through T1 mapping techniques that estimate the myocardial T1 tissue relaxation time in a pixel-wise manner to create a T1 map. T1 maps measured before (ie, native T1 map) and after gadolinium contrast can be used to noninvasively assess the myocardial extracellular volume fraction (ECV). Compared with control subjects, abnormal T1 and ECV differences have widely been described in patients with various cardiomyopathies, including hypertrophic, nonischemic dilated, and amyloid.4,5 In practice, LGE is relatively simple to perform and to interpret whereas T1/ECV is not, owing to the heterogeneity of acquisition and postprocessing techniques; however, performed correctly, the 2 techniques measure the same T1 variation, albeit with different contrast-to-noise ratio, and thus regions of LGE should correspond spatially to abnormal T1/ECV mapped areas.In this issue of Circulation, Fontana et al6 present a complete report of both T1/ECV mapping and LGE among patients with cardiac amyloidosis. This study, the largest series of CMR in cardiac amyloidosis yet reported, redefines our understanding of the continuum of infiltration in cardiac amyloidosis from early to late stage of disease and moves beyond a simple dichotomous interpretation of imaging information. The application of LGE and T1/ECV mapping in the same data set unifies contemporary noninvasive CMR assessment with hard clinical outcomes for the first time and, importantly, supports the use of a widely available LGE technique, phase-sensitive inversion recovery (PSIR), as the most accurate means by which to assess LGE in amyloidosis. The PSIR sequence removes the subjective inversion time selection variable from LGE imaging acquisition, thereby improving identification of hyperenhancement and eliminating the possibility of confounding by the wrong choice of inversion time. The implications of this report should change the practice of CMR in amyloidosis and, potentially, other diffuse cardiomyopathic processes.Fontana et al recruited a cohort of 250 consecutive patients with cardiac amyloidosis, 122 with ATTR and 119 with AL. In addition, 9 patients with TTR mutations but no apparent cardiac disease manifestation (ie, genotype positive, phenotype negative) were also recruited. Patients were followed up for 24±13 months, with mortality observed in a sizable proportion (27%). CMR imaging involved precontrast and postcontrast T1/ECV determination with standard magnitude inversion recovery (MAG-IR) LGE imaging in all patients and PSIR LGE imaging in 43% of patients. The authors then analyzed LGE images and categorized LGE pattern in a simple tripartite classification scheme (normal, subendocardial, transmural) while associating the observed LGE pattern with ECV and clinical outcomes. In this way, they were able to compare standard MAG-IR with PSIR, AL with TTR, and early with advanced disease. The patients were also characterized by echocardiography (although notably without longitudinal systolic strain) and serum cardiac biomarkers, including N-terminal pro-brain natriuretic peptide (but not troponin). To substantiate cardiac amyloidosis in the ATTR cohort, the authors reported imaging characteristics with Tc99m-DPD (3,3-diphosphono-1,2-propanodicarboxylicacid) scintigraphy.The principal findings of this report are as follows. First, there appeared to be a continuum of amyloid accumulation as determined by LGE pattern progressing from normal to transmural, the latter being more prevalent in ATTR, with robust ECV cut points that were not specific to amyloid type. Second, in a subset of 100 patients with postcontrast T1 maps as the "truth standard" for contrast accumulation in areas of presumptive amyloid deposition, the PSIR technique proved superior to conventional MAG-IR for accuracy in assignment of LGE pattern. Discordance between MAG-IR and PSIR was high (57%), an impressive observation given the expertise of this established amyloidosis and experienced CMR center, whereas PSIR and postcontrast T1 maps were not discordant. Third, a transmural LGE pattern was independently associated with mortality regardless of amyloid type and remained associated after adjustment for echocardiographic characteristics or N-terminal pro-brain natriuretic peptide (hazard ratio, 4.13; 95% confidence interval, 1.30–13.07; P<0.0001). Fourth and finally, 39% of patients with no LGE and no clinical manifestations of cardiac amyloidosis, as determined by CMR, echocardiography, or N-terminal pro-brain natriuretic peptide, had ECV measurements above the reported normal range (with results between 0.32 and 0.40), suggesting very early amyloid accumulation beneath the detection threshold of these other approaches.This study greatly informs our understanding of how amyloid cardiomyopathy progresses from early to advanced stage of infiltration while providing insight into conflicting prior reports of LGE and its relationship to survival. One important observation consistent with prior reports is that, among patients with transmural LGE, associated with the highest ECV and worst prognosis, myocardium retained more gadolinium than the blood pool, causing blood pool signal nulling and rendering the myocardium uniformly bright (called diffuse hyperenhancement).7 It is also notable that LGE pattern predicted survival regardless of amyloidosis type, although this appeared most striking in AL. Given this high discordance of PSIR from MAG-IR, the high concordance of PSIR with postcontrast T1 maps, and comparative simplicity and widespread availability of PSIR, the authors concluded that PSIR should replace MAG-IR as the LGE method of choice in cardiac amyloidosis.It is important to note that the methodology used to assess discordance between T1 maps, PSIR, and MAG-IR LGE was nonstandard. The use of postcontrast T1 as the truth standard method for visualization of extracellular space expansion is clearly challenging and subjective in cardiac amyloidosis. The low image contrast between amyloid-infiltrated and healthy myocardium renders accurate detection difficult. T1 measurements were performed with the shortened modified look-locker inversion recovery sequence with regions of interest drawn in the 4-chamber view at the level of the basal and mid inferoseptum. It is unclear whether the authors included or excluded areas of enhancement on LGE in these regions of interest for postcontrast T1 measurements, which may have biased ECV calculations. In addition, the T1 maps presented appear to be scaled to a broad T1 range (300–3300 milliseconds), rendering it difficult to visually identify the myocardial regional differences of up to 150 milliseconds that the authors report. Furthermore, this study uses an equilibrium ECV and a postcontrast T1 measurement that is rather cumbersome and somewhat outdated. The equilibrium technique may not add information compared with a single bolus infusion, now more commonly used in CMR studies to measure ECV. In respect to LGE transmurality assignment, it will be important to demonstrate reproducibility in a multicenter cohort, given the acknowledged challenging image quality. Finally, the limited subgroup sizes (PSIR versus non-PSIR, TTR versus AL) rendered relatively wide confidence intervals, particularly for the key association between transmural LGE and survival.It is also notable that among the ATTR patients, those with wild-type TTR and variant (mutated) TTR were included in the same ATTR categorization. This combination of potentially different disease trajectories may be problematic for survival interpretation. In respect to amyloid deposition, however, the data suggest that DPD uptake, LGE transmurality, and ECV are all positively associated, again supporting a continuum of infiltration in ATTR. Of the few patients with LGE-negative variant TTR, DPD uptake was abnormal (grade 1) in 3 of 4 with increased ECV, suggesting an interesting association between DPD grade and ECV in very-early-stage ATTR disease, a new finding not yet reported that may have important implications for screening of cardiac involvement in genotype carriers.Although this was a large series, cardiac amyloidosis was determined without cardiac biopsy in the vast majority of AL patients (94%) and most of the ATTR patients (71%), the latter of which were typically identified by DPD scintigraphy. This reflects the expertise and clinical practice of this referral center and is not dissimilar from other reports.8 Furthermore, although we are provided with treatment regimens for AL disease and hematological response status in broad terms, we are not provided with specific information such as free light chain or cardiac troponin concentrations that might help elucidate the component of direct toxicity of prefibrillar light chain proteins in respect to ECV and LGE. Finally, as is intrinsic in all contrast-enhanced CMR studies, patients with advanced renal disease (glomerular filtration rate <30 mL/min) were excluded, thereby affording a selection bias. For patients with advanced renal disease, native T1 mapping (data provided in Table 2), may provide useful prognostic and diagnostic information.9Although arguably redefining the CMR assessment of cardiac amyloidosis, how does one incorporate the findings of Fontana et al into the larger context of clinical assessment in systemic amyloid disease? For AL disease in particular, given the wealth of data supporting biomarker staging, treatment selection, and prognosis, CMR will probably still be viewed as an informative adjunct, used only in selected patients. Subsequent studies may prove that the primary utility, given the more precise and likely reproducible T1/ECV and PSIR findings, may be in following serial changes with specific therapies. Although obviously more expensive and difficult to measure, CMR biomarkers are more likely to reflect real changes in amyloid accumulation compared with serum biomarkers, particularly N-terminal pro-brain natriuretic peptide, that may fluctuate with volume status and creatinine clearance.Fontana et al have assembled a data set that significantly adds to our understanding of the utility of CMR in cardiac amyloidosis. These data strongly suggest that PSIR should replace MAG-IR for LGE determination in cardiac amyloidosis and that T1 mapping (however, we would submit using a contrast bolus rather than equilibrium technique) provides insight into the continuum of amyloid fibril deposition that occurs in this disease. We commend the authors on their accomplishment and anticipate that these conclusions will refine clinical practice.DisclosuresDr Ruberg acknowledges research support from Philips Medical Systems and the National Institutes of Health (R21AG050206-01 and U54TR001012). Dr Nezafat acknowledges research support from Samsung Electronics, the American Heart Association (15EIA22710040), and the National Institutes of Health (R01EB008743, R01HL129185-01, and R21HL127650-01).FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Frederick L. Ruberg, MD, Section of Cardiovascular Medicine, Boston Medical Center, 88 E Newton St, Boston, MA 02118. E-mail [email protected]References1. Dungu JN, Valencia O, Pinney JH, Gibbs SD, Rowczenio D, Gilbertson JA, Lachmann HJ, Wechalekar A, Gillmore JD, Whelan CJ, Hawkins PN, Anderson LJ. CMR-based differentiation of AL and ATTR cardiac amyloidosis.JACC Cardiovasc Imaging. 2014; 7:133–142. doi: 10.1016/j.jcmg.2013.08.015.CrossrefMedlineGoogle Scholar2. Austin BA, Tang WH, Rodriguez ER, Tan C, Flamm SD, Taylor DO, Starling RC, Desai MY. 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Kuetting D, Homsi R, Sprinkart A, Luetkens J, Thomas D, Schild H and Dabir D (2017) Quantitative assessment of systolic and diastolic function in patients with LGE negative systemic amyloidosis using CMR, International Journal of Cardiology, 10.1016/j.ijcard.2016.12.054, 232, (336-341), Online publication date: 1-Apr-2017. Pawar S, Haq M, Ruberg F and Miller E (2017) Imaging Options in Cardiac Amyloidosis: Differentiating AL from ATTR, Current Cardiovascular Imaging Reports, 10.1007/s12410-017-9399-z, 10:1, Online publication date: 1-Jan-2017. Lavatelli F and Merlini G (2016) Advances in proteomic study of cardiac amyloidosis: progress and potential, Expert Review of Proteomics, 10.1080/14789450.2016.1242417, 13:11, (1017-1027), Online publication date: 1-Nov-2016. Di Carli M, Geva T and Davidoff R (2016) The Future of Cardiovascular Imaging, Circulation, 133:25, (2640-2661), Online publication date: 21-Jun-2016. October 20, 2015Vol 132, Issue 16 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.115.018832PMID: 26362630 Originally publishedSeptember 11, 2015 Keywordscardiac magnetic resonance imagingamyloidEditorialsprognosisPDF download Advertisement SubjectsCardiomyopathyMagnetic Resonance Imaging (MRI)