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PURPOSE: Amyloidosis is a heterogeneous group of diseases caused by abnormal extracellular deposition of insoluble proteins and can involve myocardium. One of the causes of myocardial involvement is TTR amyloidosis. Our objective has been to evaluate the situation of cardiac amyloidosis (CA) in our center and the role of nuclear medicine, and to review the state of the art of nuclear medicine in this entity. PATIENTS AND METHODS: We have evaluated retrospectively 186 patients with clinical suspicion of CA and analyzed the clinical characteristics, free light chains and immunofixation in serum and/or urine, and the most relevant biomarkers associated with transthyretin CA (C-ATTR) of these patients and compared them with the results of the 99mTc-DPD scintigraphy. RESULTS: We have verified the growing bibliographic evidence concerning C-ATTR. A total of 51 scintigraphies (27.4%) were positive, 2 (1.1%) indeterminate and 133 (71.5%) negative according to the Perugini score. ATTR was diagnosed in 22 (11.8%; 77.3% males; mean age, 79.4 years). Of these, 12 (75% men; 82.3 years) were ATTRwt (wild-type or age-associated) patients, 2 (50% men; 52 years) experienced ATTRv (variant or hereditary), and 8 (87.5% men; 82.3 years) were not classified because of the absence genetic test. The origin of amyloidosis could not be determined in 31 (16.7%; 80.7% males; 84.5 years). In 29 of them (93.6%), it was because there was no study of free light chains or immunofixation. CONCLUSIONS: Nuclear medicine is playing an increasing role in the diagnosis and classification of CA. However, the monitoring of these is still patchy.

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Familial amyloid polyneuropathy (FAP) is caused by mutations of the transthyretin (TTR) gene, predominantly expressed in the liver. Two compounds that knockdown TTR, comprising a small interfering RNA (siRNA; ALN-TTR-02) and an antisense oligonucleotide (ASO; IONIS-TTRRx), are currently being evaluated in clinical trials. Since primary hepatocytes from FAP patients are rarely available for molecular analysis and commercial tissue culture cells or animal models lack the patient-specific genetic background, this study uses primary cells derived from urine of FAP patients. Urine-derived cells were reprogrammed to induced pluripotent stem cells (iPSCs) with high efficiency. Hepatocyte-like cells (HLCs) showing typical hepatic marker expression were obtained from iPSCs of the FAP patients. TTR mRNA expression of FAP HLCs almost reached levels measured in human hepatocytes. To assess TTR knockdown, siTTR1 and TTR-ASO were introduced to HLCs. A significant downregulation (>80%) of TTR mRNA was induced in the HLCs by both oligonucleotides. TTR protein present in the cell culture supernatant of HLCs was similarly downregulated. Gene expression of other hepatic markers was not affected by the therapeutic oligonucleotides. Our data indicate that urine cells (UCs) after reprogramming and hepatic differentiation represent excellent primary human target cells to assess the efficacy and specificity of novel compounds.

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BACKGROUND: Portuguese type familial amyloid polyneuropathy (FAP) is a neuropathic amyloidosis caused by a mutant transthyretin (TTR). Varying degrees of renal involvement have been reported. Our aim was to assess the value of microalbuminuria (MA) for predicting clinical neurological disease and overt nephropathy in TTR-related amyloidosis. METHODS: All subjects had the TTR Val30Met mutation, and were recruited between 1993 and 1999. We have prospectively evaluated 22 asymptomatic gene carriers (7 male, 15 female; mean age 41.6+/-9.6 years) and 32 patients with neuropathy (14 male, 18 female; 36.8+/-8.8 years, on average, 33.0+/-9.3 years at the onset of neuropathy). We measured urinary albumin excretion every year, if asymptomatic, or every 6 months if already affected. Kidney biopsies were performed in patients with normal urinary albumin excretion, MA, and overt nephropathy, respectively. RESULTS: In asymptomatic carriers, persistent MA was detected in eight (36%) subjects. The presence of MA in asymptomatic gene carriers, compared with those having normal urinary albumin excretion, conferred a 4.8-fold risk of developing neuropathy, usually within the subsequent 3 years. Once neurological signs appeared, nephropathy, manifested as MA, progressed to overt nephropathy in one-half of subjects. In patients with neuropathy, 24 (75%) had MA during follow-up: evolution towards clinical renal disease occurred in 14 (58%) and renal failure occurred in five (21%), always after a course of MA. Proteinuria or renal failure without prior persistent MA were never observed in the present patient cohort. Histopathological evaluation did not reveal glomerular lesions other than amyloid deposits to explain abnormal urinary albumin excretion. The amount of mesangial and vascular-pole amyloid deposits was correlated with the degree of albuminuria. CONCLUSIONS: Microalbuminuria represents the first stage of clinical TTR amyloid nephropathy and is premonitory of neuropathy. Its presence identifies a subgroup of patients who are more prone to develop overt nephropathy. Screening of MA may be important to assess disease onset and to recommend liver transplantation in individuals at risk.

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