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Mechanisms of Fibril Formation and Cellular Response
Published in Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin, XIth International Symposium on Amyloidosis, 2007
Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin
For proper treatment of patients with amyloid cardiomyopathy it is essential to ascertain a definitive diagnosis. This is particularly critical for elderly patients who may have immunoglobulin light chain amyloidosis (AL), hereditary transthyretin amyloidosis (ATTR), or senile cardiac amyloidosis (1,2). When diagnosis of amyloidosis is made by endomyocardial biopsy, immunohistochemistry has been the standard method to differentiate these types of amyloidosis (3,4). Unfortunately, immunohistochemistry, especially for kappa and lambda light chain amyloid, is often not definitive. When a monoclonal immunoglobulin protein is found in serum or urine, it is usually assumed that the patient has AL amyloidosis; however, instances of AL amyloidosis in patients who have an amyloidogenic transthyretin (TTR) mutation have been documented. In addition, senile cardiac amyloidosis may occur in patients who also have a circulating monoclonal protein. For these reasons, we have added biochemical analysis of amyloid fibrils obtained from endomyocardial biopsies to our regimen of diagnostic techniques.
Human Amyloidogenic Light Chains Directly Invoke Oxidant Stress and Result in Impaired Cardiomyocyte Function
Published in Gilles Grateau, Robert A. Kyle, Martha Skinner, Amyloid and Amyloidosis, 2004
Daniel A. Brenner, Mohit Jain, David R. Pimentel, Wang Bo, Lawreen H. Connors, Martha Skinner, Carl S. Apstein, Ronglih Liao
This study suggests for the first time that cardiac dysfunction in amyloid cardiomyopathy is directly mediated by LC protein-induced cardiomyocyte oxidant stress and alterations in cellular redox status, independent of fibril deposition. Antioxidant therapies or treatment strategies aimed at eliminating circulating LC proteins may therefore be beneficial in the treatment of this fatal disease.
A real-life cohort study of immunoglobulin light-chain (AL) amyloidosis patients ineligible for autologous stem cell transplantation due to severe cardiac involvement or advanced disease
Published in Amyloid, 2020
Anne F. Brunger, Hans L. A. Nienhuis, Johan Bijzet, Wilfried W. H. Roeloffzen, Edo Vellenga, Bouke P. C. Hazenberg
Treatment-related toxicity grade 3 or more was observed in 36 (51%) of the 71 patients that eventually received chemotherapy (Table 5). Of the 31 patients treated with bortezomib, 15 patients (48%) developed toxicity grade 3 or more. Bortezomib was discontinued in 6 patients (19%). Three patients (9%) were switched from a bortezomib- to a lenalidomide-based regimen. Three patients (9%) (all with amyloid cardiomyopathy) developed severe heart failure, leading to death. Nine of the 16 patients treated with an IMID (55%) developed toxicity grade 3 or more, of which 3 patients (19%) discontinued treatment. Twelve of the 27 patients treated with other regimens (44%) developed toxicity grade 3 or more. Treatment was discontinued in 5 patients (19%) and postponed in 2 patients (7%). One patient (4%) (with renal involvement) developed end-stage renal failure, for which hemodialysis was started, but eventually still led to death. One patient (4%) (with amyloid cardiomyopathy) developed severe heart failure, leading to death.
Treatment of ATTR cardiomyopathy with a TTR specific antisense oligonucleotide, inotersen
Published in Amyloid, 2019
Noel R. Dasgupta, Merrill D. Benson
Transthyretin (TTR) cardiomyopathy can occur as the result of an inherited mutation in transthyretin (ATTRm) or due to deposition of normal transthyretin in older individuals (ATTRWT). TTR cardiomyopathy is a rapidly fatal disease with median survival quoted as 2–4 years from the time of diagnosis to death [1,2]. Natural history studies in untreated patients have shown a decrease in 6-min walk test distance of 25.8 m and left ventricular ejection fraction (LVEF) by 3.2% and a 1816 pg/dl increase in N terminal b-type natriuretic peptide (NT-pro-BNP) for each 6 month interval over a 2-year period in ATTRWT patients and patients with the V122I mutation [3]. Additionally left ventricular mass (LVM) on MRI has been reported to increase up to 8% over a 1-year time period in hereditary patients without treatment [4]. Antisense oligonucleotide (ASO) suppresses hepatic synthesis of both mutant and wild-type TTR. We previously published data showing stabilization of amyloid cardiomyopathy after 1 year of therapy with inotersen [5]. We now report our 2-year results on the ASO, inotersen.
Response: Suhr OB: commentary to Isabel Conceição et al. early diagnosis through targeted follow-up of identified carriers of TTR gene mutations
Published in Amyloid, 2019
While there is evidence of an association between fibril type and V30M phenotype, which could be determined using scintigraphy, categorization of patients by this means alone has some limitations. The key challenge to implementing this form of categorization is the lack of resources, skills and expertise to do so. Scintigraphy is not widely available across all regions and many centres have limited knowledge on how to accurately perform scintigraphy and determine whether uptake reflects Type A or B. Moreover, DPD uptake in scintigraphy may be lower than previously thought in V30M patients, and therefore may be limited in its ability to detect and type amyloid fibrils in such patients [7]. Despite this, scintigraphy is a valuable tool for the diagnosis of ATTR amyloid cardiomyopathy.