Monoclonal Gammopathy of Uncertain Significance and Transthyretin Cardiac Amyloidosis
2019; Lippincott Williams & Wilkins; Volume: 12; Issue: 9 Linguagem: Inglês
10.1161/circimaging.119.009493
ISSN1942-0080
AutoresAna Devesa, Álvaro Aceña-Navarro, Ana María Pello Lázaro, Miguel Orejas, Elham Askari, Ángel Merino, G. Lapeña, Felipe Navarro del Amo, Borja Ibáñez, José Tuñón,
Tópico(s)IgG4-Related and Inflammatory Diseases
ResumoHomeCirculation: Cardiovascular ImagingVol. 12, No. 9Monoclonal Gammopathy of Uncertain Significance and Transthyretin Cardiac Amyloidosis Free AccessCase ReportPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplementary MaterialsFree AccessCase ReportPDF/EPUBMonoclonal Gammopathy of Uncertain Significance and Transthyretin Cardiac AmyloidosisCoexistence Is Possible Ana Devesa-Arbiol, MD, Álvaro Aceña-Navarro, MD, PhD, Ana M. Pello-Lázaro, MD, PhD, Miguel Orejas Orejas, MD, PhD, Elham Askari, MD, Ángel Merino, MD, Gregoria Lapeña, MD, Felipe Navarro del Amo, MD, PhD, Borja Ibañez, MD, PhD and José Tuñón-Fernández, MD, PhD Ana Devesa-ArbiolAna Devesa-Arbiol Ana Devesa Arbiol, MD, Fundación Jiménez Díaz. Avda. Reyes Católicos 2, 28040 Madrid, Spain. Email E-mail Address: [email protected] Cardiology Department, Fundación Jiménez Díaz, Madrid, Spain (A.D.-A., A.A.-N., A.M.P.-L., M.O.O., E.A., A.M., G.L., F.N., B.I., J.T.-F.). , Álvaro Aceña-NavarroÁlvaro Aceña-Navarro Cardiology Department, Fundación Jiménez Díaz, Madrid, Spain (A.D.-A., A.A.-N., A.M.P.-L., M.O.O., E.A., A.M., G.L., F.N., B.I., J.T.-F.). , Ana M. Pello-LázaroAna M. Pello-Lázaro Cardiology Department, Fundación Jiménez Díaz, Madrid, Spain (A.D.-A., A.A.-N., A.M.P.-L., M.O.O., E.A., A.M., G.L., F.N., B.I., J.T.-F.). , Miguel Orejas OrejasMiguel Orejas Orejas Cardiology Department, Fundación Jiménez Díaz, Madrid, Spain (A.D.-A., A.A.-N., A.M.P.-L., M.O.O., E.A., A.M., G.L., F.N., B.I., J.T.-F.). , Elham AskariElham Askari Cardiology Department, Fundación Jiménez Díaz, Madrid, Spain (A.D.-A., A.A.-N., A.M.P.-L., M.O.O., E.A., A.M., G.L., F.N., B.I., J.T.-F.). , Ángel MerinoÁngel Merino Cardiology Department, Fundación Jiménez Díaz, Madrid, Spain (A.D.-A., A.A.-N., A.M.P.-L., M.O.O., E.A., A.M., G.L., F.N., B.I., J.T.-F.). , Gregoria LapeñaGregoria Lapeña Cardiology Department, Fundación Jiménez Díaz, Madrid, Spain (A.D.-A., A.A.-N., A.M.P.-L., M.O.O., E.A., A.M., G.L., F.N., B.I., J.T.-F.). , Felipe Navarro del AmoFelipe Navarro del Amo Cardiology Department, Fundación Jiménez Díaz, Madrid, Spain (A.D.-A., A.A.-N., A.M.P.-L., M.O.O., E.A., A.M., G.L., F.N., B.I., J.T.-F.). , Borja IbañezBorja Ibañez Cardiology Department, Fundación Jiménez Díaz, Madrid, Spain (A.D.-A., A.A.-N., A.M.P.-L., M.O.O., E.A., A.M., G.L., F.N., B.I., J.T.-F.). Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (B.I.). and José Tuñón-FernándezJosé Tuñón-Fernández Cardiology Department, Fundación Jiménez Díaz, Madrid, Spain (A.D.-A., A.A.-N., A.M.P.-L., M.O.O., E.A., A.M., G.L., F.N., B.I., J.T.-F.). Originally published27 Aug 2019https://doi.org/10.1161/CIRCIMAGING.119.009493Circulation: Cardiovascular Imaging. 2019;12:e009493Case DescriptionAn 85-year-old man wearing a pacemaker because of previous history of atrial flutter with paroxysmal atrioventricular block was admitted presenting with syncope. Relevant past history included hypertension, rheumatoid arthritis, and a low-risk IgG kappa monoclonal gammopathy of uncertain significance. ECG at arrival showed an atrial fibrillation with spontaneously controlled ventricular rate (Figure 1).Download figureDownload PowerPointFigure 1. Electrocardiogram showing atrial fibrillation with spontaneously controlled ventricular rate with an embryonic R wave in precordial leads and low voltages in member leads.The pacemaker recorded multiple episodes of nonsustained ventricular tachycardia at 300 bpm. An echocardiogram showed concentric hypertrophy with enlarged atrium and mild pericardial effusion (Figure 2; Movies I through IV in the Data Supplement).Download figureDownload PowerPointFigure 2. Transthoracic echocardiogram.A, Long parasternal axis showing severe, asymmetrical hypertrophy, with greater values in the septum (black asterisk). B, Four-chamber view. The ventricular pacemaker electrode can be seen in the right atrium (red asterisk). Mild pericardial effusion is also observed (red arrow). AV indicates aortic valve; LA, left atrium; LV, left ventricle; RA, right atrium; and RV, right ventricle.Differential diagnosis included hypertensive, hypertrophic, and infiltrative cardiomyopathies. A coronary angiography showed no stenotic lesions. A cardiac magnetic resonance imaging showed concentric left ventricular hypertrophy with maximum thickness at the septum (16 mm) with a rapid washout of gadolinium after injection. A diffuse subendocardial enhancement and interatrial septum gadolinium uptake was observed. In the presence of conduction disorders in the ECG, these data suggested an infiltrative cardiomyopathy such as cardiac amyloidosis (CA; Figure 3).Download figureDownload PowerPointFigure 3. Cardiac magnetic resonance imaging.A, Four-chamber view showing marked hypertrophy at the septum (white asterisk). Red asterisk shows pericardial effusion. B, A 2-chamber view shows late gadolinium enhancement in the atrial wall (white arrows). Black arrows show diffuse subendocardial late gadolinium enhancement and a noncoronary pattern. LA indicates left atrium; LV, left ventricle; RA, right atrium; and RV, right ventricle.An abdominal fat biopsy and a bone marrow biopsy were negative for amyloid. A complete workup for systemic light-chain (AL) amyloidosis showed no signs of progression. Scintigraphy with 99-technetium-1,1-diphosphonopropane-2,3-dicarboxylic acid (Tc-99-DPD) showed an intense radiotracer uptake (grade 3 of Perugini) in the myocardial wall affecting both ventricles (Figure 4).Download figureDownload PowerPointFigure 4. 99-Technetium-1,1-diphosphonopropane-2,3-dicarboxylic acid scintigraphy shows an intense radiotracer uptake (grade 3 of Perugini) in the left ventricle. A less marked uptake is also seen in the right ventricle.DPD scintigraphy shows an intense radiotracer uptake (grade 3 of Perugini) in the left ventricle (Figure 4). A less marked uptake is also seen in the right ventricle.An endomyocardial biopsy was performed and showed deposition of amyloid material by Congo Red staining. Transthyretin amyloidosis (ATTR) was confirmed using immunohistochemistry (Figure 5).Download figureDownload PowerPointFigure 5. Histologic study.A, Staining with hematoxylin-eosin revealed an extracellular deposit of amorphous and homogeneous eosinophilic material between myocardial cells. B, Congo red stain evidencing amorphous material with green apple birefringence after the use of polarized light. C, Immunohistochemical staining for A amyloid shows no expression. D, Immunohistochemical staining for P amyloid shows intense expression. E, Immunohistochemical staining for transthyretin revealing intense and diffuse expression.A genetic study was performed to distinguish between wild-type and hereditary forms of ATTR, and results were negative for hereditary forms. At the time of writing, the patient remains asymptomatic, with cessation of ventricular tachycardia with β-blockers.DiscussionATTR is nowadays considered the most frequent type of CA1; moreover, in the presence of monoclonal gammopathy of uncertain significance, AL CA should be discarded. Amyloid A amyloidosis (AA) (associated to rheumatoid arthritis) would rarely affect the heart. ECG was concordant with amyloid cardiomyopathy with the classical pattern of pseudoinfarction in precordial leads and low voltages in member leads. Echocardiography suspicion will be based on biventricular hypertrophy with speckling appearance of the myocardium, left atrial dysfunction, and signs of elevated filling pressures.2 Pericardial effusion and dilated vena cava are often seen. Left ventricular hypertrophy not justified by poorly controlled arterial hypertension or by significant aortic stenosis should be grounds for complementary studies. We must rule out hypertrophic cardiomyopathy and infiltrative diseases such as CA. Differential diagnosis should be made by specific techniques such as cardiac magnetic resonance imaging (a difficulty in nulling the myocardium after gadolinium uptake and a subendocardial enhancement are characteristics of CA) and technetium-derived scintigraphy. Perugini grades of uptake in scintigraphy are 3: grade 1 (myocardial uptake is lower than bone's), grade 2 (similar uptake), and grade 3 (myocardial uptake is higher than bone's). The new algorithms for diagnosis of ATTR suggest that in the presence of clinical and compatible echocardiographic and magnetic resonance imaging findings, a radiotracer uptake grade 2 to 3 on a technetium-derived scintigraphy, in the absence of a monoclonal protein in serum or urine, has a 100% positive predictive value for ATTR.3 However, the presence of a monoclonal protein should lead to an invasive diagnosis. It is to consider that elevated free ALs can also be seen in patients with renal dysfunction, where the K/L ratio is usually normal. Fat pad biopsy has a low yield in ATTR. Negative findings in extracardiac biopsies do not exclude a diagnosis of CA, and evidence of amyloid deposition in a myocardial biopsy is still the gold standard for diagnosis. Although this is not a risk-free technique, the result may motivate a change in the patient's prognosis and treatment. In this particular case with coexistence of ATTR with monoclonal gammopathy of uncertain significance (which occurs in 23% of cases4), histological study of myocardial samples was essential for the differential diagnosis between ATTR and AL. This differentiation is crucial for the prognosis because AL has a poor prognosis and may require active treatment. On the contrary, new treatments are in development for ATTR.AcknowledgmentsWe acknowledge Oliver Shaw (Instituto de Investigación sanitaria (IIS) - Fundación Jiménez Díaz, Madrid, Spain) for his assistance in editing this article.DisclosuresNone.FootnotesThe online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIRCIMAGING.119.009493.Ana Devesa Arbiol, MD, Fundación Jiménez Díaz. Avda. Reyes Católicos 2, 28040 Madrid, Spain. Email [email protected]comReferences1. González-López E, Gallego-Delgado M, Guzzo-Merello G, de Haro-Del Moral FJ, Cobo-Marcos M, Robles C, Bornstein B, Salas C, Lara-Pezzi E, Alonso-Pulpon L, Garcia-Pavia P. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction.Eur Heart J. 2015; 36:2585–2594. doi: 10.1093/eurheartj/ehv338CrossrefMedlineGoogle Scholar2. Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis.Circulation. 2012; 126:1286–1300. doi: 10.1161/CIRCULATIONAHA.111.078915LinkGoogle Scholar3. Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, Wechalekar AD, Berk JL, Quarta CC, Grogan M, Lachmann HJ, Bokhari S, Castano A, Dorbala S, Johnson GB, Glaudemans AW, Rezk T, Fontana M, Palladini G, Milani P, Guidalotti PL, Flatman K, Lane T, Vonberg FW, Whelan CJ, Moon JC, Ruberg FL, Miller EJ, Hutt DF, Hazenberg BP, Rapezzi C, Hawkins PN. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis.Circulation. 2016; 133:2404–2412. doi: 10.1161/CIRCULATIONAHA.116.021612LinkGoogle Scholar4. Geller HI, Singh A, Mirto TM, Padera R, Mitchell R, Laubach JP, Falk RH. Prevalence of monoclonal gammopathy in wild-type transthyretin amyloidosis.Mayo Clin Proc. 2017; 92:1800–1805. doi: 10.1016/j.mayocp.2017.09.016CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Warner A (2021) Advances in the treatment of transthyretin cardiac amyloidosis: Current and emerging therapies, Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 10.1002/phar.2639, 41:12, (1081-1091), Online publication date: 1-Dec-2021. September 2019Vol 12, Issue 9 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCIMAGING.119.009493PMID: 31451004 Originally publishedAugust 27, 2019 Keywordshypertensionradionuclide imaginghumanspathologyamyloidPDF download Advertisement SubjectsCardiomyopathyHypertrophyNuclear Cardiology and PET
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