Cardiac Amyloid in Patients with Familial Amyloid Polyneuropathy Consists of Abundant Wild-Type Transthyretin

Yazaki, Masahide; Tokuda, Takahiko; Nakamura, Akihiro; Higashikata, Takeo; Koyama, Jun; Higuchi, Kenichi; Harihara, Yasu; Baba, Satoshi; Kametani, Fuyuki; Ikeda, Shu‐ichi

doi:10.1006/bbrc.2000.3203

Cited by 155 publications

(132 citation statements)

References 20 publications

(21 reference statements)

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“…These findings were originally obtained from the patients with non-Val30Met ATTRs who possibly had substantial amyloid deposition on the myocardium before operation (61)(62)(63). However, a similar finding has been observed in typical FAP patients with Val30Met ATTR (64) and in the pathogenesis of this form of cardiac amyloidosis, wild-type TTR is regarded as playing a central role (65). It is, therefore, critical to clarify the severity of cardiac amyloid deposition when considering liver transplantation in FAP patients.…”

Section: Table 3 Attrs Producing Severe Amyloid Heart Disease As a Psupporting

confidence: 59%

Cardiac Amyloidosis: Heterogenous Pathogenic Backgrounds

Ikeda

2004

Intern. Med.

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Cardiac amyloidosis is a fatal disorder which develops on the basis of the different pathologic conditions in systemic amyloidosis: the most common underlying disease is immunoglobulin light chain-derived primary amyloidosis and the next is transthyretin-related hereditary amyloidosis; the latter disorder, typically represented by familial amyloid polyneuropathy, was long regarded as an endemic disease. However, this disorder has now been shown to involve a highly variable clinical picture due to a large number of transthyretin gene mutations, and many patients with diverse ancestors suffer from severe cardiac amyloidosis. Additionally, senile systemic amyloidosis is now noted as a cause of cardiac dysfunction in elderly individuals. Echocardiogram and myocardial technetium-99m-pyrophosphate scintigraphy can provide characteristic findings. Immunohistochemistry on tissue amyloid, biochemical analysis of serum and urine proteins, and DNA sequencing are usually employed to determine the disease-related amyloid fibril protein.Although systemic amyloidosis has become treatable, the prognosis of each patient who received up-to-date and effective, but nevertheless stressful, therapy depends on the severity of cardiac involvement by amyloid deposition.

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Section: Table 3 Attrs Producing Severe Amyloid Heart Disease As a Psupporting

confidence: 59%

Cardiac Amyloidosis: Heterogenous Pathogenic Backgrounds

Ikeda

2004

Intern. Med.

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“…However, a similar finding was reported in typical FAP patients with Val30Met TTR type (27). Wild-type TTR is regarded as playing a central role in the pathogenesis of this form of cardiac amyloidosis (22): wild-type TTR is inherently amyloidogenic, causing senile systemic amyloidosis (28), and conversion of normal TTR to the amyloid fibril conformation may be promoted after liver transplantation using a preexisting template of variant TTR-derived amyloid deposits in the myocardium. Therefore, it is critical to clarify the severity of cardiac amyloid deposition when considering liver transplantation in FAP patients.…”

Section: Discussionsupporting

confidence: 74%

“…In Japan, 2 patients with Val30Leu TTR type FAP underwent LDLT, but both died approximately one year after the operations. Autopsy revealed heavy deposition of amyloid on the myocardium in these two patients (22). Serious cardiac involvement by amyloid is known to be one cardinal feature in FAP patients with non-Val30Met TTR type (16,23), and this severe phenotype of cardiac amyloidosis has been suggested to be responsible for the poor post-transplant prognosis in these FAP patients.…”

Section: Discussionmentioning

confidence: 81%

Ten Years of Experience with Liver Transplantation for Familial Amyloid Polyneuropathy in Japan: Outcomes of Living Donor Liver Transplantations

et al. 2005

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Object We summarize 10 years of experience with liver transplantation for FAP patients in Japan and review the current opinions regarding this treatment for FAP.Methods and Patients All basic report data on patients at the time of transplantation were registered with the Japanese Liver Transplantation Society (JLTS). Based on the JLST report data, more detailed information on FAP patients was requested from each center.Results Living

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“…However, emerging clinical data suggest that this procedure is substantially less effective against other familial TTR mutations for reasons that are unclear. Furthermore, transplantation is not an option for treating senile systemic amyloidosis, which results from deposition of WT TTR (33,34). Nor would this approach be useful for ameliorating CNS-selective amyloidosis because the TTR deposited in these tissues is synthesized in the choroid plexus.…”

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confidence: 99%

Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis

Green

Foss

Kelly

2005

Proc. Natl. Acad. Sci. U.S.A.

110

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The misfolding of transthyretin (TTR), including rate-limiting tetramer dissociation and partial monomer denaturation, is sufficient for TTR misassembly into amyloid and other abnormal quaternary structures associated with three amyloid diseases: senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. Small molecules can bind to one or both of the unoccupied TTR thyroid hormone-binding sites, stabilizing the native tetramer more than the dissociative transition state, thereby raising the kinetic barrier for tetramer dissociation. Herein we demonstrate that genistein, the major isoflavone natural product in soy, works in this fashion and is an excellent inhibitor of transthyretin tetramer dissociation and amyloidogenesis, reducing acid-mediated fibril formation to <10% of that exhibited by TTR alone. Genistein also inhibits the amyloidogenesis of the most common familial amyloid polyneuropathy and familial amyloid cardiomyopathy mutations in TTR: V30M and V122I, respectively. Genistein additionally inhibits tetramer dissociation under physiological conditions thought to lead to slow amyloidogenesis in humans. Furthermore, this natural product exhibits highly selective binding to TTR in plasma over all of the other plasma proteins. Isothermal titration calorimetry shows that genistein binds to TTR with negative cooperativity (K d1 ‫؍‬ 40 nM, Kd2 ‫؍‬ 1.4 M). The benefits of using a nutraceutical such as genistein to treat orphan diseases such as the TTR amyloidoses include known oral bioavailability and safety data. It is conceivable that some patients could benefit from simply increasing their intake of soy products or supplements.amyloidogenesis inhibitor ͉ kinetic stabilization F or many years nutritionists and dieticians have noted the health benefits of a soy-based diet, citing the much lower incidence of cancer, including breast cancer, in Asian countries (1-4). The isoflavone genistein (compound 1 in Fig. 1), found in various soy foods at concentrations of 1.9-229 g͞g, is the component of soy implicated in cancer chemoprevention (5). An additional 71-968 g͞g of genistein is present as its O-glucoside conjugate, genistin (2), which is rapidly deglycosylated by intestinal bacteria in vivo. Genistein is being evaluated in preliminary trials for treatment of breast, prostate, and uterine cancers (6, 7), as well as for osteoporosis (8), cardiovascular disease (9), and treatment of menopausal symptoms (10). Toxicity studies reveal that this isoflavone does not appear to cause adverse health effects, even at the relatively high concentrations used (11-13). The isoflavone daidzein (3), lacking the hydroxyl group at the 5 position of genistein, is also found in soy foods, but no chemoprotective effects have been attributed to it.Transthyretin (TTR) is a tetrameric protein composed of identical 127-aa ␤-sheet sandwich subunits (14, 15). TTR functions to transport holo-retinol-binding protein and thyroxine (T4) in the blood and cerebrospinal fluid (16,17). Under denaturing con...

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Cardiac Amyloid in Patients with Familial Amyloid Polyneuropathy Consists of Abundant Wild-Type Transthyretin

Cited by 155 publications

References 20 publications

Cardiac Amyloidosis: Heterogenous Pathogenic Backgrounds

Cardiac Amyloidosis: Heterogenous Pathogenic Backgrounds

Ten Years of Experience with Liver Transplantation for Familial Amyloid Polyneuropathy in Japan: Outcomes of Living Donor Liver Transplantations

Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis

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