Cardiac Amyloidosis
2011; Lippincott Williams & Wilkins; Volume: 124; Issue: 9 Linguagem: Galês
10.1161/circulationaha.110.010447
ISSN1524-4539
Autores Tópico(s)Parathyroid Disorders and Treatments
ResumoHomeCirculationVol. 124, No. 9Cardiac Amyloidosis Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBCardiac AmyloidosisA Treatable Disease, Often Overlooked Rodney H. Falk Rodney H. FalkRodney H. Falk From the Cardiac Amyloidosis Program, Brigham and Women's Hospital and Harvard Vanguard Medical Associates, Boston, MA. Originally published30 Aug 2011https://doi.org/10.1161/CIRCULATIONAHA.110.010447Circulation. 2011;124:1079–1085Case presentation: A 55-year-old woman, who had previously been very physically active, noted a gradual decrease in exercise tolerance over a period of 3 to 4 months to the extent that she had to rest briefly after climbing a single flight of stairs. She had consulted a dermatologist 6 months earlier because of recurrent, small bruises of her eyelids, but no cause had been found. An ECG suggested an old myocardial infarction with an unusual axis (Figure 1), and a cardiology consultation described symmetrical left ventricular hypertrophy on the echocardiogram with normal left ventricular ejection fraction, normally functioning valves, and mild right ventricular hypertrophy. There was no family history of cardiovascular or neurological disease. Physical examination revealed mild elevation of the jugular venous pressure, normal heart sounds, no murmurs, and mild peripheral edema with clear lung fields and a mildly congested liver. Blood pressure was 110/65 mm Hg. There was 1+ proteinuria. Serum protein electrophoresis revealed no abnormal bands, but serum immunofixation revealed a monoclonal spike determined to be IgGλ. A bone marrow biopsy demonstrated 5% to 10% monotypical plasma cells staining for λ light chains. Serum-free light chains showed an elevation in free λ with an abnormal κ/λ ratio. Brain natriuretic peptide was 1019 pg/mL (normal <100), and troponin I was 0.07 ng/mL (normal 95% of cases. An excess of λ or (less commonly) κ in a patient with suspected or biopsy-proven cardiac amyloidosis points to AL as the most likely type.Transthyretin Cardiac AmyloidosisCardiac amyloidosis may also be caused by the deposition of amyloid derived from a mutation of the hepatically expressed protein transthyretin. Transthyretin is a small protein composed of 127 amino acid subunits. More than 100 point mutations have been described, most of which are amyloidogenic. Mutant transthyretin has a tendency to form unstable monomers that misfold, forming amyloid deposits that preferentially affect the heart and nervous system. Neural involvement results in a progressive sensorimotor neuropathy, often with a degree of autonomic neuropathy. Intriguingly, congestive heart failure may be absent or mild even when cardiac infiltration is severe. This observation led to the postulate that rapidly progressive congestive heart failure in AL amyloid has a toxic component caused by circulating free light chains, whereas transthyretin is predominantly an infiltrative cardiomyopathy.6 Amyloidogenic light chain toxicity has subsequently been confirmed in animal experiments.7A particularly common variant of transthyretin is found in patients of African descent. Approximately 4% of the African American population is heterozygous for a valine-isoleucine substitution at position 122. This mutation results in cardiac amyloidosis with onset in the late 60s and is characterized by progressive congestive heart failure not infrequently associated with clinically significant tricuspid regurgitation.8 Neuropathy is rare but can occur late in the disease, and, unlike senile systemic amyloid, women are commonly affected. An intriguing observation of a higher percentage of isoleucine-122 patients in heart failure trials than in the general population9 raises the question of whether this mutation contributes to the development of heart failure in the setting of other etiologies of heart failure, perhaps related to small amyloid deposits.Small amounts of amyloid deposits are detected in the ventricles of 50% to 80% of patients aged >80 years. These are usually derived from wild-type transthyretin and have little or no clinical significance. In contrast, massive myocardial infiltration with wild-type–derived amyloid, although relatively uncommon, leads to progressive congestive heart failure and is referred to as senile cardiac (or senile systemic) amyloidosis. For unclear reasons, this disorder is overwhelmingly a disease of men, usually aged >70 years, with a male to female ratio of ≈20:1.10 Although autopsy of patients with senile systemic amyloid shows pulmonary deposits, renal amyloid is very uncommon in this disease, and clinically apparent neuropathy in wild-type transthyretin is almost never present. Reticence to perform endomyocardial biopsy in older patients, coupled with misdiagnosis of amyloid heart disease as hypertensive heart disease, almost certainly results in the underdiagnosis of both isoleucine-122 mutant transthyretin amyloidosis and senile cardiac amyloidosis. 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid, a bone scanning agent, has been found to be avidly taken up by the heart in transthyretin amyloidosis. Dicarboxypropane diphosphonate imaging has been proposed as a simple noninvasive test for determining the presence of transthyretin cardiac amyloidosis and helping to distinguish it from AL amyloidosis of the heart, in which the uptake is usually less.11TreatmentThe aim of treatment of any of the forms of cardiac amyloidosis is 2-fold: therapy of congestive heart failure and prevention of further amyloid deposition. Pharmacological removal of preexisting amyloid deposits is not yet feasible, although recent preliminary data in a transgenic mouse model suggest that a combined pharmacological and antibody approach holds promise.12 There are only subtle differences in the therapy of heart failure due to light chain amyloid and that of transthyretin amyloidosis, but the treatment of the underlying disease is completely different. In AL amyloidosis, possibly because of an associated autonomic neuropathy, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are rarely tolerated and may provoke profound hypotension even when prescribed in small doses. β-Blockade is of no proven use and may aggravate hypotension, whereas calcium channel blockers generally worsen congestive heart failure. Thus, diuretics are virtually the only therapy available to treat heart failure in this condition, although spironolactone or eplerenone is generally well tolerated and should probably be prescribed. β-Blockers and angiotensin-converting enzyme inhibitors may be better tolerated in transthyretin-derived amyloidosis, but there is little evidence that they have any impact on the outcome.Treatment of the underlying plasma cell dyscrasia in AL amyloidosis is the purview of a hematologist skilled in the management of amyloidosis.13 Therapy to reduce amyloid production may worsen congestive heart failure even if not known to be directly cardiotoxic. High-dose dexamethasone used in combination with any of the 3 major drugs used for the therapy of AL amyloidosis (melphalan, lenalidomide, and/or bortezomib) may cause significant fluid retention. In a patient with incipient to overt congestive heart failure, dexamethasone should be started at a relatively low dose and increased with each cycle to the maximally tolerated dose. This often necessitates adjustment of diuretic dosing throughout the therapeutic cycles and mandates vigilant cardiology follow-up. Melphalan is not cardiotoxic and, although bortezomib showed minimal cardiotoxicity in clinical trials of myeloma patients, subjects with congestive heart failure were generally excluded. However, bortezomib use is occasionally associated with worsening fluid retention and congestive heart failure.14 Lenalidomide is also generally not considered cardiotoxic, but a recent study suggested that N-terminal pro-brain natriuretic peptide and troponin levels may increase during therapy with lenalidomide, despite a decrease in free light chains, suggesting a negative effect on the heart.15High-dose chemotherapy with autologous stem cell transplantation has been shown to be effective in AL amyloidosis, but patients with cardiac amyloidosis fare worse than those who are free of cardiac involvement. In a comparative trial of this therapy compared with oral melphalan and dexamethasone, there was no statistical difference in outcome between the 2 groups.16 Patients with cardiac amyloidosis fared slightly better with less aggressive therapy. However, outcomes with aggressive therapy are highly dependent on the level of experience of the treating center. Careful selection of patients with cardiac amyloidosis by a cardiologist experienced in the disease, in conjunction with a skilled treating hematologist, may offer a high likelihood of successful aggressive therapy, with a good chance of a complete hematologic remission. Patients with AL cardiac amyloidosis deemed suitable for high-dose chemotherapy can be characterized by a combined clinical assessment and evaluation of serum troponin and N-terminal pro-brain natriuretic peptide.17Therapy for transthyretin amyloidosis is, at present, purely symptomatic. Fortunately, most patients initially respond well to careful therapy of heart failure. In the author's experience, these patients are sensitive to overdiuresis, resulting in a rapid increase in creatinine despite the absence of amyloid deposition in the kidney. This may reflect worsening of an already low cardiac output seen in advanced disease, which is a function of small left ventricular cavity and stroke volume. Patients with senile cardiac amyloidosis not uncommonly progress to complete heart block, and permanent pacing becomes necessary. Although standard criteria for biventricular pacing (prolonged QRS duration and ejection fraction <35%) are often not met, it is my policy to use biventricular pacing in these patients because right ventricular pacing-induced dyskinesis in a patient with a small left ventricular cavity further reduces cardiac output.There are several investigational approaches to the management and treatment of transthyretin amyloidosis. Tafamadis, an investigational drug, has been shown to prevent breakdown of the transthyretin molecule and hence should decrease or prevent amyloid deposition. Preliminary data from a clinical trial suggest that it slowed the progression of peripheral neuropathy in mutant transthyretin amyloidosis,17a and a trial in amyloid cardiomyopathy is in progress. Other drugs to stabilize the molecule are in the preclinical stage.18 New approaches, utilizing small interfering RNA technology19 and oligosense oligonucleotides, are also being investigated for the treatment of transthyretin amyloidosis.20Patient Follow-UpThe patient described at the beginning of this article was offered a choice of high-dose chemotherapy with autologous stem cell transplantation or a bortezomib/dexamethasone combination. She opted for the latter, with the understanding that it may have less severe side effects but may possibly be less effective. She proved to be an excellent responder to therapy, tolerating it well, and, after 2 months of therapy, her free light chain measurement returned to normal, suggestive of excellent disease suppression. She is being followed with frequent clinical evaluations and free light chain measurements with an option of continuation of bortezomib or chemotherapy with autologous stem cell transplantation should the disease become active again. A complete hematologic response such as this is seen in ≈40% of previously untreated patients who receive this regimen,21 but the recurrence rate is uncertain. Cardiac symptoms, although improving, often persist, and echocardiographic improvement is uncommon.ConclusionsOver the past decade, options for therapy of cardiac amyloidosis have expanded, and new therapies, particularly for transthyretin amyloidosis, are being actively investigated. A high index of suspicion for the disease and early diagnosis with precise typing of amyloid deposits are critical to improved outcomes. Referral to a center specializing in the disease is of great value so that the precise diagnosis can be confirmed and treatment tailored to the clinical status of the individual patient by physicians experienced in both the diagnosis and treatment of this uncommon, but now potentially treatable, disorder.DisclosuresNone.FootnotesThe online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.110.010447/-/DC1.Correspondence to Rodney H. Falk, MD, Department of Cardiology, Harvard Vanguard Medical Associates, 133 Brookline Ave, Boston MA 02215. E-mail [email protected]orgReferences1. Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med. 2003; 349:583–596.CrossrefMedlineGoogle Scholar2. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol. 1995; 32:45–59.MedlineGoogle Scholar3. Kristen AV, Dengler TJ, Hegenbart U, Schonland SO, Goldschmidt H, Sack FU, Voss F, Becker R, Katus HA, Bauer A. Prophylactic implantation of cardioverter-defibrillator in patients with severe cardiac amyloidosis and high risk for sudden cardiac death. Heart Rhythm. 2008; 5:235–240.CrossrefMedlineGoogle Scholar4. Dubrey SW, Cha K, Anderson J, Chamarthi B, Reisinger J, Skinner M, Falk RH. The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement. QJM. 1998; 91:141–157.CrossrefMedlineGoogle Scholar5. Maceira AM, Joshi J, Prasad SK, Moon JC, Perugini E, Harding I, Sheppard MN, Poole-Wilson PA, Hawkins PN, Pennell DJ. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation. 2005; 111:186–193.LinkGoogle Scholar6. Dubrey SW, Cha K, Skinner M, LaValley M, Falk RH. Familial and primary (AL) cardiac amyloidosis: echocardiographically similar diseases with distinctly different clinical outcomes. Heart. 1997; 78:74–82.CrossrefMedlineGoogle Scholar7. Shi J, Guan J, Jiang B, Brenner DA, Del Monte F, Ward JE, Connors LH, Sawyer DB, Semigran MJ, Macgillivray TE, Seldin DC, Falk R, Liao R. Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway. Proc Natl Acad Sci U S A. 2010; 107:4188–4193.CrossrefMedlineGoogle Scholar8. Connors LH, Prokaeva T, Lim A, Theberge R, Falk RH, Doros G, Berg A, Costello CE, O'Hara C, Seldin DC, Skinner M. Cardiac amyloidosis in African Americans: comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. Am Heart J. 2009; 158:607–614.CrossrefMedlineGoogle Scholar9. Buxbaum J, Alexander A, Koziol J, Tagoe C, Fox E, Kitzman D. Significance of the amyloidogenic transthyretin Val 122 Ile allele in African Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. Am Heart J. 2010; 159:864–870.CrossrefMedlineGoogle Scholar10. Ng B, Connors LH, Davidoff R, Skinner M, Falk RH. Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-associated amyloidosis. Arch Intern Med. 2005; 165:1425–1429.CrossrefMedlineGoogle Scholar11. Perugini E, Guidalotti PL, Salvi F, Cooke RMT, Pettinato C, Riva L, Leone O, Farsad M, Ciliberti P, Bacchi-Reggiani L, Fallani F, Branzi A, Rapezzi C. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol. 2005; 46:1076–1084.CrossrefMedlineGoogle Scholar12. Bodin K, Ellmerich S, Kahan MC, Tennent GA, Loesch A, Gilbertson JA, Hutchinson WL, Mangione PP, Gallimore JR, Millar DJ, Minogue S, Dhillon AP, Taylor GW, Bradwell AR, Petrie A, Gillmore JD, Bellotti V, Botto M, Hawkins PN, Pepys MB. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature. 2010; 468:93–97.CrossrefMedlineGoogle Scholar13. Comenzo RL. How I treat amyloidosis. Blood. 2009; 114:3147–3157.CrossrefMedlineGoogle Scholar14. Hacihanefioglu A, Tarkun P, Gonullu E. Acute severe cardiac failure in a myeloma patient due to proteasome inhibitor bortezomib. Int J Hematol. 2008; 88:219–222.CrossrefMedlineGoogle Scholar15. Dispenzieri A, Dingli D, Kumar SK, Rajkumar SV, Lacy MQ, Hayman S, Buadi F, Zeldenrust S, Leung N, Detweiler-Short K, Lust JA, Russell SJ, Kyle RA, Gertz MA. Discordance between serum cardiac biomarker and immunoglobulin-free light-chain response in patients with immunoglobulin light-chain amyloidosis treated with immune modulatory drugs. Am J Hematol. 2010; 85:757–759.CrossrefMedlineGoogle Scholar16. Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007; 357:1083–1093.CrossrefMedlineGoogle Scholar17. Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM, McConnell JP, Litzow MR, Gastineau DA, Tefferi A, Inwards DJ, Micallef IN, Ansell SM, Porrata LF, Elliott MA, Hogan WJ, Rajkumar SV, Fonseca R, Greipp PR, Witzig TE, Lust JA, Zeldenrust SR, Snow DS, Hayman SR, McGregor CG, Jaffe AS. Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood. 2004; 104:1881–1887.CrossrefMedlineGoogle Scholar17a. Coelho T, Maia L, Martins da Silva A, Waddington Cruz M, Planté-Bordeneuve V, Lozeron P, Suhr OB, Campistol J, Conceiçao I, Schmidt H, Trigo P, Packman J, Grogan DR. A comprehensive evaluation of the disease-modifying effects of tafamidis in patients with transthyretin type familial amyloid polyneuropathy. Presented at: American Academy of Neurology Annual Meeting; April 2011; Honolulu, HI.Google Scholar18. Kolstoe SE, Mangione PP, Bellotti V, Taylor GW, Tennent GA, Deroo S, Morrison AJ, Cobb AJ, Coyne A, McCammon MG, Warner TD, Mitchell J, Gill R, Smith MD, Ley SV, Robinson CV, Wood SP, Pepys MB. Trapping of palindromic ligands within native transthyretin prevents amyloid formation. Proc Natl Acad Sci U S A. 2010; 107:20483–20488.CrossrefMedlineGoogle Scholar19. Kurosawa T, Igarashi S, Nishizawa M, Onodera O. Selective silencing of a mutant transthyretin allele by small interfering RNAs. Biochem Biophys Res Commun. 2005; 337:1012–1018.CrossrefMedlineGoogle Scholar20. Benson MD, Kluve-Beckerman B, Zeldenrust SR, Siesky AM, Bodenmiller DM, Showalter AD, Sloop KW. Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotides. Muscle Nerve. 2006; 33:609–618.CrossrefMedlineGoogle Scholar21. Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010; 28:1031–1037.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Ream S, Ma J, Rodriguez T, Sarabia-Gonzalez A, Alvarado L, Dwivedi A and Mukherjee D (2023) Ethnic/racial differences in risk factors and clinical outcomes among patients with amyloidosis, The American Journal of the Medical Sciences, 10.1016/j.amjms.2022.12.009, 365:3, (232-241), Online publication date: 1-Mar-2023. Bogunovic N, Farr M, Pirl L, Piper C, Rudolph V and Roder F (2022) Multi-parametric speckle tracking analyses to characterize cardiac amyloidosis: a comparative study of systolic left ventricular longitudinal myocardial mechanics, Heart and Vessels, 10.1007/s00380-022-02047-6, 37:9, (1526-1540), Online publication date: 1-Sep-2022. Santarelli M, Genovesi D, Scipioni M, Positano V, Favilli B, Giorgetti A, Vergaro G, Landini L, Emdin M and Marzullo P (2021) Cardiac amyloidosis characterization by kinetic model fitting on [18F]florbetaben PET images, Journal of Nuclear Cardiology, 10.1007/s12350-021-02608-8, 29:4, (1919-1932), Online publication date: 1-Aug-2022. Bézard M, Oghina S, Vitiello D, Kharoubi M, Kordeli E, Galat A, Zaroui A, Guendouz S, Gilles F, Shourick J, Hamon D, Audard V, Teiger E, Poullot E, Molinier-Frenkel V, Lemonnier F, Agbulut O, Le Bras F, Damy T and den Uil C (2021) Dexamethasone is associated with early deaths in light chain amyloidosis patients with severe cardiac involvement, PLOS ONE, 10.1371/journal.pone.0257189, 16:9, (e0257189) Zach D, Ablasser K, Kolesnik E, Hoeller V, Fruhwald F, Prüller F, Reiter C, Beham‐Schmid C, Lipp R, Rainer P, Zirlik A, Wölfler A and Verheyen N (2021) Advanced isolated light chain amyloid cardiomyopathy with negative immunofixation and normal free light chain ratio, ESC Heart Failure, 10.1002/ehf2.13381, 8:4, (3397-3402), Online publication date: 1-Aug-2021. Clemmensen T, Eiskjær H, Ladefoged B, Mikkelsen F, Sørensen J, Granstam S, Rosengren S, Flachskampf F and Poulsen S (2020) Prognostic implications of left ventricular myocardial work indices in cardiac amyloidosis, European Heart Journal - Cardiovascular Imaging, 10.1093/ehjci/jeaa097, 22:6, (695-704), Online publication date: 10-May-2021. Nakayama S, Kinugasa S, Hirose T, Miyake Y,
Referência(s)