Transthyretin Val30Met mutation in an African American with cardiac amyloidosis.
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ABSTRACT:
SUBMITTER: Schulze PC
PROVIDER: S-EPMC4938000 | biostudies-literature | 2010 Mar-Apr
REPOSITORIES: biostudies-literature
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Transthyretin Val30Met mutation in an African American with cardiac amyloidosis.
Schulze P Christian PC Maurer Mathew S MS
Congestive heart failure (Greenwich, Conn.) 20100301 2
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Project description:AimsMutant transthyretin (ATTRm) amyloidosis is a systemic disease caused by the deposition of amyloid fibrils derived from mutated transthyretin. Although cardiac involvement impacts the prognosis of patients with ATTRm amyloidosis, the incidence of cardiac events, such as bradyarrhythmia, ventricular tachycardia, and heart failure, has not been fully elucidated. The aim of this study was to evaluate the prognosis and predictors of clinical outcomes, including cardiac events, in patients with ATTRm amyloidosis in Japan.Methods and resultsWe evaluated 90 consecutive patients with ATTRm amyloidosis at Kumamoto University. ATTRm amyloidosis was diagnosed by the observation of both amyloid fibril deposition on tissue biopsy and a transthyretin mutation on sequential analysis. Sympathetic nerve activity was evaluated in 59 patients using 123-iodine metaiodobenzylguanidine (123 I-MIBG) imaging. The endpoint was a composite of all-cause death, hospitalization for heart failure, and implantation of a pacemaker, implantable cardioverter defibrillator, or cardiac resynchronization therapy defibrillator. Sixty-seven patients had the Val30Met mutation (74%). The composite endpoint occurred in 23 patients (26%): all-cause death (n = 6), hospitalization for worsening heart failure (n = 1), and implantation of an implantable cardioverter defibrillator (n = 6), cardiac resynchronization therapy defibrillator (n = 3), or pacemaker (n = 7). The 5-year incident rate for clinical outcomes was 19%. In a multivariate Cox hazard analysis, age [hazard ratio (HR): 1.07, 95% confidence interval (95% CI): 1.01-1.12, P = 0.015], PQ interval (HR: 1.01, 95% CI: 1.00-1.02, P = 0.042), interventricular septum thickness in diastole (HR: 1.25, 95% CI: 1.09-1.42, P = 0.001), and non-Val30Met mutation (HR: 4.31, 95% CI: 1.53-12.16, P = 0.006) were independent predictive factors of clinical outcomes. Kaplan-Meier analysis demonstrated a significantly higher probability of the composite endpoint in the non-Val30Met group than in the Val30Met group (log-rank test: P = 0.002) and in patients with left ventricular hypertrophy than in patients without left ventricular hypertrophy (log-rank test: P < 0.001). In patients who underwent 123 I-MIBG imaging, a delayed heart-to-mediastinum (HM) ratio <1.6 was a significant predictive factor of the composite endpoint (HR: 4.98, 95% CI: 1.73-14.37, P = 0.003) in the univariate Cox hazard analyses. Kaplan-Meier curve analysis showed that a delayed HM ratio <1.6 was associated with a poor prognosis (log-rank test: P = 0.001).ConclusionsNon-Val30Met mutation, septal hypertrophy, and a delayed HM ratio are useful predictors of clinical outcomes in patients with ATTRm amyloidosis in Japan. These results suggest that it is important to evaluate cardiac involvement in terms of morphological (left ventricular hypertrophy) and functional (cardiac denervation) perspectives using echocardiography and 123 I-MIBG imaging, respectively.
| S-EPMC6352919 | biostudies-literature
Project description:AimsWhether sodium-glucose co-transporter 2 inhibitors are effective for heart failure caused by ATTR-CA (transthyretin cardiac amyloidosis) remains uncertain. The aim of this study is to investigate the cardiovascular prognosis in ATTR-CA mice model with dapagliflozin treatment.Methods and resultsHumanized RBP4/TTRVal50Met and RBP4/TTR mice models were constructed with clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) techniques and multiple generations breeding. A total of 6 RBP4/TTR mice received placebo treatment, when 12 RBP4/TTRVal50Met received dapagliflozin (1 mg/kg/day, 6 mice) and placebo (6 mice) treatment. Fasting glucose, intraperitoneal glucose tolerance test, and plasma brain natriuretic peptide (BNP) concentration were measured at Day 0, Week 2, and Week 4. BNP, transforming growth factor-beta (TGF-β), collagen type I alpha 1 (COL1A1) protein levels, and Cola1, TGFβ1, TNFα, IL-1β, BNP relative quantities in cardiac, along with cardiac pathology examination including right ventricular collagen percentage, ventricular septum thickness, left ventricular wall thickness, and left ventricular internal diameter were measured at Week 4 after treatment procedure. All 18 mice completed the experiment. The baseline characteristics were balanced among three treatment groups. In placebo-treated mice, the cardiac BNP relative quantity was significantly higher in RBP4/TTRVal50Met mice than RBP4/TTR mice (RBP4[KI/KI], TTR [KI/KI]: 0.72 ± 0.46, RBP4[KI/KI], TTRVal50Met [KI/KI]: 1.44 ± 0.60, P = 0.043), indicating more significant heart failure progression in ATTR-CA mice than normal mice. In ATTR-CA mice, the cardiovascular prognosis measurements including heart failure (plasma BNP concentration and relative quantities of BNP), cardiac inflammation (relative quantities of Cola1, TGFβ1, TNFα, and IL-1β), and pathological changes (right ventricular collagen percentage, ventricular septum thickness, left ventricular wall thickness, and left ventricular internal diameter) were statistically comparable between those under dapagliflozin and placebo treatment.ConclusionsDapagliflozin did not improve cardiovascular prognosis including the progression of heart failure, cardiac inflammation, and pathological changes in ATTR-CA mice compared with placebo. The results of this study were not in support of dapagliflozin's therapeutic effects for ATTR-CA. More pre-clinical and clinical researches to validate these findings and demonstrate the underlying mechanisms are still required.
| S-EPMC10804162 | biostudies-literature
Project description:IntroductionHereditary transthyretin amyloidosis (ATTRv amyloidosis) is a clinically heterogeneous disease caused by mutations in the transthyretin (TTR) gene. The most common mutation, Val30Met, can manifest as an early- or late-onset disease.MethodsThe Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both inherited and wild-type disease and asymptomatic patients with TTR mutations. This is a descriptive analysis of symptomatic patients with ATTRv Val30Met amyloidosis with late- (age at least 50 years) vs. early-onset (age less than 50 years) disease in THAOS (data cutoff August 1, 2019).ResultsOf 1389 patients with ATTRv Val30Met amyloidosis, 491 (35.3%) had late-onset disease. Compared with early-onset, patients with late-onset were more likely to be male (66.2% vs. 53.6%) and have a longer mean (standard deviation [SD]) time from onset to diagnosis (3.8 [3.4] vs. 2.7 [4.1] years). Late-onset disease was associated with more severe neurological impairment at enrollment (median [10th, 90th percentile] derived Neuropathy Impairment Score in the Lower Limbs, 25.0 [4.0, 69.3] vs. 8.0 [0, 54.8]; Neurologic Composite Score, 42.0 [2.0, 155.0] vs. 21.0 [0, 102.0]). Cardiac findings were more prominent in late-onset disease. An overall interpretation of electrocardiogram as abnormal was reported in 72.1% of late-onset patients (vs. 44.3% early-onset). A left-ventricular septal thickness of at least 12 mm was reported in 69.7% of late-onset patients (vs. 14.6% early-onset). All differences were statistically significant (p < 0.001).ConclusionIn THAOS, late-onset ATTRv Val30Met amyloidosis is common, presenting with more severe neurologic and cardiac findings at enrollment. Heterogeneity of disease may make it more difficult to diagnose. Increased recognition of late-onset ATTRv Val30Met amyloidosis could lead to more timely diagnosis and improve patient outcomes.Trial registrationClinicalTrials.gov NCT00628745.
| S-EPMC8571445 | biostudies-literature
Project description:This phase II, open-label, single-treatment arm study evaluated the pharmacodynamics, efficacy, and safety of tafamidis in patients with non-Val30Met transthyretin (TTR) amyloidosis. Twenty-one patients with eight different non-Val30Met mutations received 20 mg QD of tafamidis meglumine for 12 months. The primary outcome, TTR stabilization at Week 6, was achieved in 18 (94.7%) of 19 patients with evaluable data. TTR was stabilized in 100% of patients with non-missing data at Months 6 (n = 18) and 12 (n = 17). Exploratory efficacy measures demonstrated some worsening of neurological function. However, health-related quality of life, cardiac biomarker N-terminal pro-hormone brain natriuretic peptide, echocardiographic parameters, and modified body mass index did not demonstrate clinically relevant worsening during the 12 months of treatment. Tafamidis was well tolerated. In conclusion, our findings suggest that tafamidis 20 mg QD effectively stabilized TTR associated with several non-Val30Met variants.
| S-EPMC3838581 | biostudies-literature
Project description:Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of heart failure (HF) and mortality worldwide. Advances in non-invasive diagnosis, coupled with the development of effective treatments, have shifted ATTR-CA from a rare and untreatable disease to a relatively prevalent condition that clinicians should consider on a daily basis. Amyloid fibril formation results from age-related failure of homoeostatic mechanisms in wild-type ATTR (ATTRwt) amyloidosis (non-hereditary form) or destabilizing mutations in variant ATTR (ATTRv) amyloidosis (hereditary form). Longitudinal large-scale studies in the United States suggest an incidence of cardiac amyloidosis in the contemporary era of 17 per 100 000, which has increased from a previous estimate of 0.5 per 100 000, which was almost certainly due to misdiagnosis and underestimated. The presence and degree of cardiac involvement is the leading cause of mortality both in ATTRwt and ATTRv amyloidosis, and can be identified in up to 15% of patients hospitalized for HF with preserved ejection fraction. Associated features, such as carpal tunnel syndrome, can preceed by several years the development of symptomatic HF and may serve as early disease markers. Echocardiography and cardiac magnetic resonance raise suspicion of disease and might offer markers of treatment response at a myocardial level, such as extracellular volume quantification. Radionuclide scintigraphy with 'bone' tracers coupled with biochemical tests may differentiate ATTR from light chain amyloidosis. Therapies able to slow or halt ATTR-CA progression and increase survival are now available. In this evolving scenario, early disease recognition is paramount to derive the greatest benefit from treatment.
| S-EPMC9897687 | biostudies-literature
Project description: Not available
| S-EPMC3501197 | biostudies-literature
Project description:This study reports the long-term results of trabeculectomy (LEC) for secondary glaucoma in hereditary transthyretin (ATTRv) amyloidosis patients and its correlation with prior vitrectomy. A retrospective case series was conducted involving 31 consecutive eyes of 20 ATTRv amyloidosis patients who underwent LEC between 2007 and 2020. The mean follow-up period was 73.2 ± 37.0 months (range: 20-181 months). Postoperative intraocular pressures (IOPs) were evaluated based on the following criteria: (a) IOP between 6 and 21 mmHg without additional glaucoma surgeries, except for laser suture lysis, (b) IOP between 6 and 15 mmHg without additional glaucoma surgeries, except for laser suture lysis, and (c) IOP between 6 and 21 mmHg without additional glaucoma surgeries, except for needling and laser suture lysis. Kaplan-Meier analysis revealed survival rates after LEC of 0.52 at 36 months, 0.42 at 60 months, and 0.25 at 84 months under criterion (a); 0.49 at 36 months, 0.27 at 60 months, and 0.11 at 84 months under criterion (b); and 0.76 at 36 months, 0.71 at 60 months, and 0.65 at 84 months under criterion (c). Eyes with a history of small gauge transconjunctival vitrectomy (SGTV) exhibited a tendency towards lower survival rates, although no statistically significant difference was observed (log-rank test; p = 0.193 under criterion (a) and p = 0.0553 under criterion (b)). Our findings suggest that LEC and additional needling procedures can provide some control over IOP; however, the overall postoperative outcomes of LEC for ATTRv amyloidosis remain unsatisfactory, even in the era of SGTV with reduced conjunctival scarring.
| S-EPMC10406936 | biostudies-literature
Project description:BackgroundWe have previously shown that transthyretin (TTR) amyloidosis patients have amyloid fibrils of either of two compositions; type A fibrils consisting of large amounts of C-terminal TTR fragments in addition to full-length TTR, or type B fibrils consisting of only full-length TTR. Since type A fibrils are associated with an older age in ATTRVal30Met (p.Val50Met) amyloidosis patients, it has been discussed if the TTR fragments are derived from degradation of the amyloid deposits as the patients are aging. The present study aimed to investigate if the fibril composition type changes over time, especially if type B fibrils can shift to type A fibrils as the disease progresses.Material and methodsAbdominal adipose tissue biopsies from 29 Swedish ATTRVal30Met amyloidosis patients were investigated. The fibril type in the patients´ initial biopsy taken for diagnostic purposes was compared to a biopsy taken several years later (ranging between 2 and 13 years). The fibril composition type was determined by western blot.ResultsAll 29 patients had the same fibril composition type in both the initial and the follow-up biopsy (8 type A and 21 type B). Even patients with a disease duration of more than 12 years and an age over 75 years at the time of the follow-up biopsy had type B fibrils in both biopsies.DiscussionThe result clearly shows that the amyloid fibril composition containing large amounts of C-terminal fragments (fibril type A) is a consequence of other factors than a slow degradation process occurring over time.
| S-EPMC8970372 | biostudies-literature
Project description:Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive disease characterized by the deposition of abnormal transthyretin protein fibrils in the heart, leading to cardiac dysfunction. Recent evidence suggests that sex differences may play a significant role in various steps of ATTR-CA, including clinical presentation, diagnostic challenges, disease progression, and treatment outcomes. ATTR-CA predominantly affects men, whereas women are older at presentation. Women generally present with a history of heart failure with preserved ejection fraction and/or carpal tunnel syndrome. When indexed, left ventricular (LV) wall thickness is equal, or even increased, than men. Women also have smaller LV cavities, more preserved ejection fractions, and apparently a slightly worse right ventricular and diastolic function. Given the under-representation on women in clinical trials, no data regarding sex influence on the treatment response are currently available. Finally, it seems there are no differences in overall prognosis, even if premenopausal women may have a certain level of myocardial protection. Genetic variations, environmental factors, and hormonal changes are considered as potential contributors to observed disparities. Understanding sex differences in ATTR-CA is vital for accurate diagnosis and management. By considering these differences, clinicians can improve diagnostic accuracy, tailor treatments, and optimize outcomes for both sexes with ATTR-CA.
| S-EPMC10942898 | biostudies-literature
Project description:Transthyretin-related cardiac amyloidosis is a progressive infiltrative cardiomyopathy that mimics hypertensive and hypertrophic heart disease and often goes undiagnosed. In the United States, the hereditary form disproportionately afflicts black Americans, who when compared with whites with wild-type transthyretin amyloidosis, a phenotypically similar condition, present with more advanced disease despite having a noninvasive method for early identification (genetic testing). Although reasons for this are unclear, this begs to consider the inadequate access to care, societal factors, or a biological basis. In an effort to improve awareness and explore unique characteristics, we review the pathophysiology, epidemiology, and therapeutic strategies for transthyretin amyloidosis and highlight diagnostic pitfalls and clinical pearls for identifying patients with amyloid heart disease.
| S-EPMC4874558 | biostudies-literature