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Early Diagnosis of Cardiac Amyloidosis by Carpal Tunnel Surgery Is It All in the Wrist?*

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Early Diagnosis of Cardiac Amyloidosis by Carpal Tunnel Surgery Is It All in the Wrist?* JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 72, NO. 17, 2018 ª 2018 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER EDITORIAL COMMENT Early Diagnosis of Cardiac Amyloidosis by Carpal Tunnel Surgery Is it All in the Wrist?* Mathew S. Maurer, MD,a Frederick L. Ruberg, MDb ver the past several years, cardiac amyloid- Historically, diagnosis of cardiac amyloidosis O osis has been increasingly recognized by required a cardiac biopsy demonstrating histological providers, emerging from its characteriza- evidence of amyloid deposits by Congo Red staining. tion as a rare and unusual cause of heart failure. More recently, cardiac involvement could be diag- The disease has long enjoyed a “zebra” cachet owing nosed by a histological identification of amyloidosis to its confusing nomenclature (AL for light-chain from another body site in the context of supportive amyloidosis and ATTR for transthyretin disease), noninvasive cardiac imaging findings as determined challenging diagnostic approach, and perceived rar- by echocardiography, magnetic resonance imaging, or ity. Caused by myocardial deposition of amyloid nuclear scintigraphy (bone avid tracers) (6).Ofthese fibrils composed of misfolded protein, clinicians also noninvasive tests, only nuclear imaging has the learn that cardiac amyloidosis is a disease with no capacity to definitively demonstrate ATTR cardiac effectivetreatment.Indeed,theclassicalteaching amyloidosis without a tissue biopsy (7).Although was that AL cardiac amyloidosis with concomitant conclusively shown to be highly sensitive and specific heart failure conferred a median survival of 6 to among patients with suspected amyloidosis (8),to 12 months (1). Unfortunately, many practicing clini- date, no screening studies using nuclear imaging have cians adhere to this dogma embracing a mindset of been reported. However, ATTR amyloidosis has been therapeutic nihilism. Why diagnose what you cannot demonstrated in up to 13% of patients with heart fail- treat? Recent advances have dramatically altered the ure and preserved ejection fraction with increased LV therapeutic landscape, rendering systemic amyloid- wall thickness (9), 16% of patients with severe aortic osis with cardiac involvement a treatable disease, stenosis undergoing transcutaneous valve replace- affording patients an array of therapeutic options ment (10), 5% of patients with presumed hypertrophic (2–5). It is clear that early recognition of amyloidosis cardiomyopathy (11), and in 1% to 2% of subjects is critical because current treatment strategies sup- undergoing bone scintigraphy for noncardiac reasons press precursor protein production or stabilize the (12). These observations challenge the conception that protein preventing misfolding, but do not directly ATTR amyloidosis, in particular, is a rare disease. target existing amyloid deposits. SEE PAGE 2040 *Editorials published in the Journal of the American College of Cardiology Because amyloidosis is a systemic disease with reflect the views of the authors and do not necessarily represent the deposition that has also classically been associated with views of JACC or the American College of Cardiology. carpal tunnel syndrome (CTS) (13),Sperryetal.(14) in From the aDivision of Cardiology, Department of Medicine, Center for this issue of the Journal hypothesized that screening Advanced Cardiac Care, Columbia University Medical Center, New York, for unsuspected cardiac amyloidosis could be accom- New York; and the bSection of Cardiovascular Medicine, Department of plished through histological testing of flexor retinac- Medicine, and Amyloidosis Center, Boston University School of Medicine, Boston Medical Center, Boston Massachusetts. Dr. Maurer is supported ulum specimens collected during carpal tunnel release by a K24 Award from the National Institute on Aging (AG036778); has surgery. The overall rationale was to characterize the fi received grants from P zer and Eidos Therapeutics; and has served on proportion of patients with systemic amyloidosis advisory boards for Pfizer, Alnylam, Eidos, and Akcea. Dr. Ruberg has received consulting income from GlaxoSmithKline; and research funding undergoing carpal tunnel release with the implication from Eidos Therapeutics. that by early identification patients could receive ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2018.09.003 2052 Maurer and Ruberg JACC VOL. 72, NO. 17, 2018 Carpal Tunnel Surgery Screening for Cardiac Amyloidosis OCTOBER 23, 2018:2051– 3 treatment at an earlier stage of disease. In this prospec- andislowerinATTRamyloidosisthanmatchedcon- tive cohort study, a total of 98 patients (mean age 68 trols (17). Although mechanistically attractive as a years) were recruited from the 319 carpal tunnel release means to also identify preclinical disease, it remains to surgeries performed at a single center with broad in- be seen whether measurable instability of circulating clusion criteria of all men >50 years of age and women TTR associates with fibril formation and subsequent >60 years of age. Only those with known amyloidosis or amyloid deposition. CTS related to rheumatoid arthritis or trauma were In addition, there a number of caveats to consider excluded. Tenosynovium specimens were tested for when drawing conclusions from these data. Impor- amyloidosis with Congo Red staining and those that tantly, only those with a positive biopsy went on to were positive (10 patients or 10.2%) were confirmed by further testing, with the assumption that the biopsy mass spectrometry with further testing by echocardi- of tenosynovium is highly sensitive and specificfor ography, cardiac-specific biomarkers, free light chains/ identification of systemic amyloidosis. However, the immunofixation electrophoresis, and nuclear imaging limited tissue sample evaluable for amyloidosis after to definethepresenceofcardiacamyloidosis.Ofthese, CTS surgery may be an explanation for the lower yield 1 case of AL cardiac amyloidosis, 1 case of wild-type of amyloidosis (10%) when compared with lumbar ATTR cardiac amyloidosis, and 1 case of hereditary spine specimens (15). Thus, we do not know whether ATTR amyloidosis with polyneuropathy were identified some of the patients with negative biopsies may and treated with disease-modifying therapy. Thus, actually also have systemic amyloidosis. Alterna- undiagnosed systemic amyloidosis was found in 10% tively, as the authors acknowledge, we do not know of patients undergoing carpal tunnel release surgery what proportion of ATTR amyloidosis patients with of whom 3 patients were subsequently treated with positive biopsies, but negative nuclear scans, will amyloidosis-specifictherapy. develop cardiac involvement. Serial imaging studies There are a number of additional interesting points in this population may address this issue. Interest- raised by this study. First, there is a common concep- ingly, the authors identified amyloidosis in a similar tion that bilateral CTS is more common in systemic proportion of men and women, likely as a result of amyloidosis and can be used as a clinical sign to detect their unbiased recruitment strategy. This finding is disease. Although the authors did observe that 100% of discordant from reported referral population studies patients with positive biopsies had bilateral surgeries, and current clinical practice, wherein wild-type ATTR so did 83% of the negative biopsies, reducing the cohorts are almost exclusively male (18). These data specificity of this criteria to identify early systemic support the hypothesis that active ascertainment of amyloidosis. More interestingly, lumbar spinal steno- amyloidosis by screening might show that the true sis was noted in 60% of the positive cohort, which is proportion of sex distribution in systemic amyloid- concordant with other data that demonstrate nearly all osis is closer to even. Finally, as acknowledged by the subjects undergoing clinically indicated lumbar spine authors, the proportion of African Americans in study decompression for spinal stenosis have amyloid was small (approximately 5%), thus the data here deposits and almost one-half have evidence of TTR cannot be seen to inform understanding of the asso- by immunohistochemistry (15).Third,amonoclonal ciation between genotype and the prevalence of gammopathy was noted in 4 of 7 patients with ATTR amyloid disease in this population. amyloidosis, similar to reported data showing that We commend Sperry et al. (14) for a well-conducted 40% to 50% of subjects with wild-type ATTR have a pilot study that should be seen as a justification for concomitant monoclonal gammopathy of unknown larger screening efforts. The advent of contemporary significance (16). The high coincidence of monoclonal therapies for both AL and ATTR amyloidosis now gammopathy underscores the requirement to carefully render the disease treatable, particularly if adminis- characterize the precursor protein by tissue biopsy in tered early. It remains to be determined which such subjects and not rely on nuclear scintigraphy screening methodology will prove the best approach, alone. Fourth, the authors tested the concentration of but given the emerging nature of amyloidosis, a native or tetrameric TTR and stability of the TTR pro- screening algorithm will likely be incorporated into tein in the serum of all patients and found that there everyday clinical practice in the near future. were no differences either concentration or stability between cases with amyloidosis and controls. As ADDRESS FOR CORRESPONDENCE: Dr. Matthew S. acknowledged
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