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      Addressing Common Questions Encountered in the Diagnosis and Management of Cardiac Amyloidosis

      research-article
      , MD 1 , , FRCP(UK) 2 , , MD 3 , , MD 4 , , MD 5
      Circulation
      cardiac amyloidosis, transthyretin, light chain

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          Abstract

          Advances in cardiac imaging have resulted in greater recognition of cardiac amyloidosis (CA) in everyday clinical practice, but the diagnosis continues to be made in patients with late stage disease, suggesting that more needs to be done to improve awareness of its clinical manifestations and the potential of therapeutic intervention to improve prognosis. Light chain CA (AL-CA) in particular, if recognized early and treated with targeted plasma cell therapy, can be managed very effectively. For patients with transthyretin amyloidosis, there are numerous therapies that are currently in late phase clinical trials. In this review we address common questions encountered in clinical practice regarding etiology, clinical presentation, diagnosis and management of cardiac amyloidosis, focusing on recent important developments in cardiac imaging and biochemical diagnosis. The aim is to show how a systematic approach to the evaluation of suspected CA can impact the prognosis of patients in the modern era.

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          Most cited references96

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          Molecular mechanisms of amyloidosis.

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            Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004.

            We undertook this study to develop uniformly accepted criteria for the definition of organ involvement and response for patients on treatment protocols for immunoglobulin light-chain amyloidosis (AL). A consensus panel was convened comprising 13 specialists actively involved in the treatment of patients with amyloidosis. Institutional criteria were submitted from each, and a consensus was developed defining each organ involved and the criteria for response. Specific criteria have been developed with agreed on definitions of organ and hematologic response as a result of discussions at the 10th International Symposium on Amyloid and Amyloidosis held in Tours, France, April 2004. These criteria now form the working definition of involvement and response for the purposes of future data collection and reporting. We report criteria that centers can now use to define organ involvement and uniform response criteria for reporting outcomes in patients with light-chain AL. Copyright (c) 2005 Wiley-Liss, Inc.
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              Safety and efficacy of RNAi therapy for transthyretin amyloidosis.

              Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin. We identified a potent antitransthyretin small interfering RNA, which was encapsulated in two distinct first- and second-generation formulations of lipid nanoparticles, generating ALN-TTR01 and ALN-TTR02, respectively. Each formulation was studied in a single-dose, placebo-controlled phase 1 trial to assess safety and effect on transthyretin levels. We first evaluated ALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretin amyloidosis and then evaluated ALN-TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthy volunteers. Rapid, dose-dependent, and durable lowering of transthyretin levels was observed in the two trials. At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a mean reduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms of transthyretin were lowered to a similar extent. For ALN-TTR02, the mean reductions in transthyretin levels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to 67.1% at 28 days (P<0.001 for all comparisons). These reductions were shown to be RNAi-mediated. Mild-to-moderate infusion-related reactions occurred in 20.8% and 7.7% of participants receiving ALN-TTR01 and ALN-TTR02, respectively. ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and nonmutant forms of transthyretin, establishing proof of concept for RNAi therapy targeting messenger RNA transcribed from a disease-causing gene. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov numbers, NCT01148953 and NCT01559077.).
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                Author and article information

                Journal
                0147763
                2979
                Circulation
                Circulation
                Circulation
                0009-7322
                1524-4539
                17 March 2017
                04 April 2017
                04 April 2018
                : 135
                : 14
                : 1357-1377
                Affiliations
                [1 ]Columbia University Medical Center
                [2 ]University College London & St. Bartholomew’s Hospital
                [3 ]Tufts Medical Center
                [4 ]Massachusetts General Hospital, Harvard University
                [5 ]University of Bologna
                Author notes
                Corresponding Author: Mathew S. Maurer, Columbia University Medical Center, New York Presbyterian Hospital, Clinical Cardiovascular Research Laboratory for the Elderly, 5141 Broadway, 3 Field West, Room 035, New York, N.Y. 10034, Phone: 212-30-9808, Fax: 212-932-4538, msm10@ 123456cumc.columbia.edu
                Article
                PMC5392416 PMC5392416 5392416 nihpa855616
                10.1161/CIRCULATIONAHA.116.024438
                5392416
                28373528
                552e5be1-e604-437f-b2c2-2aa18701c9aa
                History
                Categories
                Article

                transthyretin,light chain,cardiac amyloidosis
                transthyretin, light chain, cardiac amyloidosis

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