| 1. |
- Maurer, Mathew S., et al.
(author)
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Genotype and Phenotype of Transthyretin Cardiac Amyloidosis THAOS (Transthyretin Amyloid Outcome Survey)
- 2016
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 68:2, s. 161-172
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Journal article (peer-reviewed)abstract
- Background: Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis.Objectives: The goal of this study was to describe ATTR in the United States by using data from the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry.Methods: Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared with data from patients from other regions of the world (ROW) (n = 2,140). The focus was on the phenotypic expression and survival in the majority of U.S. subjects with valine-to-isoleucine substitution at position 122 (Val122Ile) (n = 91) and wild-type ATTR (n = 189).Results: U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%), and more often of African descent (25.4% vs. 0.5%) than the ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 (85%) of 107 patients with Val122Ile were from the United States, where Val122Ile subjects were younger and more often female and black than patients with wild-type disease, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a transthyretin mutation, were independently associated with higher mortality from a multivariate analysis of survival.Conclusions: In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult male subjects with a cardiac-predominant phenotype. Val122Ile is the most common transthyretin mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. (Transthyretin-Associated Amyloidoses Outcome Survey [THAOS]; NCT00628745)
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| 2. |
- Solomon, Scott D., et al.
(author)
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Effects of Patisiran, an RNA Interference Therapeutic, on Cardiac Parameters in Patients With Hereditary Transthyretin-Mediated Amyloidosis : Analysis of the APOLLO Study
- 2019
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In: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 139:4, s. 431-443
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Journal article (peer-reviewed)abstract
- Background: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease that presents with cardiomyopathy or polyneuropathy. The APOLLO study assessed the efficacy and tolerability of patisiran in patients with hATTR amyloidosis. The effects of patisiran on cardiac structure and function in a prespecified subpopulation of patients with evidence of cardiac amyloid involvement at baseline were assessed.Methods: APOLLO was an international, randomized, double-blind, placebo-controlled phase 3 trial in patients with hATTR amyloidosis. Patients were randomized 2:1 to receive 0.3 mg/kg patisiran or placebo via intravenous infusion once every 3 weeks for 18 months. The prespecified cardiac subpopulation comprised patients with a baseline left ventricular wall thickness 13 mm and no history of hypertension or aortic valve disease. Prespecified exploratory cardiac end points included mean left ventricular wall thickness, global longitudinal strain, and N-terminal prohormone of brain natriuretic peptide. Cardiac parameters in the overall APOLLO patient population were also evaluated. A composite end point of cardiac hospitalizations and all-cause mortality was assessed in a post hoc analysis.Results: In the cardiac subpopulation (n=126; 56% of total population), patisiran reduced mean left ventricular wall thickness (least-squares mean difference SEM: -0.90.4 mm, P=0.017), interventricular septal wall thickness, posterior wall thickness, and relative wall thickness at month 18 compared with placebo. Patisiran also led to increased end-diastolic volume (8.3 +/- 3.9 mL, P=0.036), decreased global longitudinal strain (-1.4 +/- 0.6%, P=0.015), and increased cardiac output (0.38 +/- 0.19 L/min, P=0.044) compared with placebo at month 18. Patisiran lowered N-terminal prohormone of brain natriuretic peptide at 9 and 18 months (at 18 months, ratio of fold-change patisiran/placebo 0.45, P<0.001). A consistent effect on N-terminal prohormone of brain natriuretic peptide at 18 months was observed in the overall APOLLO patient population (n=225). Median follow-up duration was 18.7 months. The exposure-adjusted rates of cardiac hospitalizations and all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups, respectively (Andersen-Gill hazard ratio, 0.54; 95% CI, 0.28-1.01).Conclusions: Patisiran decreased mean left ventricular wall thickness, global longitudinal strain, N-terminal prohormone of brain natriuretic peptide, and adverse cardiac outcomes compared with placebo at month 18, suggesting that patisiran may halt or reverse the progression of the cardiac manifestations of hATTR amyloidosis.
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| 3. |
- Barroso, Fabio A., et al.
(author)
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Characteristics of patients with autonomic dysfunction in the Transthyretin Amyloidosis Outcomes Survey (THAOS)
- 2022
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In: Amyloid. - : Taylor & Francis. - 1350-6129 .- 1744-2818. ; 29:3, s. 175-183
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Journal article (peer-reviewed)abstract
- Background: Autonomic dysfunction is common in transthyretin amyloidosis (ATTR amyloidosis), but its frequency, characteristics, and quality-of-life (QoL) impact are not well understood.Methods: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal survey of patients with ATTR amyloidosis, including patients with inherited (ATTRv) and wild-type (ATTRwt) disease and asymptomatic patients with TTR mutations (ClinicalTrials.gov: NCT00628745). In a descriptive analysis, characteristics and Norfolk QoL-DN total (TQoL) scores at enrolment were compared in patients with vs without autonomic dysfunction (analysis cut-off: 1 August 2020).Results: Autonomic dysfunction occurred in 1181/2922 (40.4%) symptomatic patients, and more commonly in ATTRv (1107/1181 [93.7%]) than ATTRwt (74/1181 [6.3%]) amyloidosis. Time (mean [SD]) from ATTR amyloidosis symptom onset to first autonomic dysfunction symptom was shorter in ATTRv (3.4 [5.7] years) than ATTRwt disease (9.7 [10.4]). In ATTRv disease, patients with vs without autonomic dysfunction had worse QoL (TQoL, 47.3 [33.2] vs 16.1 [18.1]); in ATTRwt disease, those with vs without autonomic dysfunction had similar QoL (23.0 [18.2] vs 19.9 [20.5]).Conclusions: Autonomic dysfunction was more common and presented earlier in symptomatic ATTRv than ATTRwt amyloidosis and adversely affected QoL in ATTRv disease. These THAOS findings may aid clinicians in diagnosing and treating patients with ATTR amyloidosis.Trial registration: ClinicalTrials.gov: NCT00628745.
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| 4. |
- Caponetti, Angelo Giuseppe, et al.
(author)
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Sex-Related Risk of Cardiac Involvement in Hereditary Transthyretin Amyloidosis : Insights From THAOS
- 2021
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In: JACC. Heart failure. - : Elsevier. - 2213-1779 .- 2213-1787. ; 9:10, s. 736-746
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Journal article (peer-reviewed)abstract
- Objectives: Because patients with ATTRv cardiomyopathy are more likely to be male, this analysis aimed to increase information on associations between sex and genotype, phenotype, and degree of myocardial involvement in ATTRv amyloidosis.Background: Transthyretin amyloid cardiomyopathy is a progressive, fatal disease that occurs due to accumulation of wild-type or variant (ATTRv) transthyretin amyloid fibrils in the myocardium.Methods: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing global longitudinal observational survey of patients with ATTR amyloidosis and asymptomatic carriers with TTR mutations. Data from THAOS (data cutoff: January 6, 2020) were analyzed to determine any sex-based differences in genotype, phenotype, and presence of cardiac and neurological symptoms in patients with ATTRv amyloidosis and in patients with ATTRv amyloidosis and cardiomyopathy.Results: There were 2,790 patients with ATTRv amyloidosis enrolled in THAOS, with male patients more likely to have symptoms of cardiac involvement and a cardiac phenotype. Male prevalence was greater in patients with more severe cardiac manifestations of disease, as assessed with N-terminal pro–B-type natriuretic peptide, left-ventricular (LV) ejection fraction, mean LV wall thickness divided by height, and LV mass index divided by height. Sex, age at disease onset, and genotype category were identified by multivariate analyses as risk factors for the development of cardiomyopathy (defined as increased LV septum thickness divided by height).Conclusions: In this analysis, myocardial involvement was more frequent and pronounced in male patients with ATTRv amyloidosis, suggesting that there may be biological characteristics that inhibit myocardial amyloid infiltration in females or facilitate it in males.
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| 5. |
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| 6. |
- Coelho, Teresa, et al.
(author)
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THAOS - The Transthyretin Amyloidosis Outcomes Survey : initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis
- 2013
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In: Current Medical Research and Opinion. - : Informa Healthcare. - 0300-7995 .- 1473-4877. ; 29:1, s. 63-76
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Journal article (peer-reviewed)abstract
- Background: Transthyretin (TTR) amyloidosis is a rare, life-threatening, systemic, autosomal dominant condition occurring in adults, with two main forms: hereditary (associated with TTR gene mutations) and wild-type. Studies indicate considerable heterogeneity in disease presentation, with predominantly polyneuropathic, predominantly cardiac, or mixed phenotypes. Methods: THAOS - the Transthyretin Amyloidosis Outcomes Survey - is the first global, multicenter, longitudinal, observational survey that collects data on the natural history of TTR amyloidosis (ClinicalTrials.gov: NCT00628745). This paper presents data on signs and symptoms, neurological and cardiac assessments, biomarkers and quality of life in the patients enrolled in THAOS from its inception in December 2007 to September 2011. Results: At the time of this analysis, data were available from 611 symptomatic patients with hereditary TTR amyloidosis, 67 symptomatic patients with wild-type TTR amyloidosis, and 274 currently asymptomatic individuals with a TTR mutation. Nineteen countries were participating in the registry. The largest patient groups came from Portugal (n = 453), the USA (n = 129), Italy (n = 70), and Japan (n = 68). Predominant symptom presentation in patients with hereditary TTR amyloidosis differed according to the underlying disease-causing mutation (polyneuropathy for Val30Met, cardiomyopathy for Val122Ile and Leu111Met, and mixed for Glu89Gln). However, each mutation was associated with clear multisystem involvement. Similarly, although cardiomyopathy was predominant in patients with wild-type TTR amyloidosis, many also showed symptoms consistent with neuropathy. Quality of life in patients with hereditary TTR amyloidosis, but not asymptomatic carriers of disease-causing mutations, was severely impaired relative to that of the age-matched general US population. Conclusions: This preliminary analysis highlights the considerable phenotypic heterogeneity for neurological and cardiac manifestations in patients with hereditary and wild-type TTR amyloidosis and the necessity of providing multidisciplinary care. THAOS registry data will help better characterize the diverse presentation and course of TTR amyloidosis worldwide and aid in improving and standardizing diagnosis and treatment.
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| 7. |
- Damy, Thibaud, et al.
(author)
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Clinical, ECG and echocardiographic clues to the diagnosis of TTR-related cardiomyopathy
- 2016
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In: Open heart. - : BMJ Publishing Group Ltd. - 2053-3624. ; 3:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: Signs of cardiac transthyretin (TTR) amyloidosis (ATTR) in patients with echocardiographic increase in interventricular septal thickness (IVST) are lacking.OBJECTIVES: To identify clinical and ECG/echocardiographic signs associated with increased IVST in ATTR.METHODS: Analysis of patients with baseline echocardiography in the Transthyretin Amyloidosis Outcomes Survey (THAOS) registry (N=1682). Patients were categorised into IVST classes according to the American Society of Echocardiography classification adapted to gender (ie, normal, mild, moderate, severe); then into two combined IVST classes (normal-mild and moderate-severe).RESULTS: 425 patients were included: 336 with a TTR mutation (m-TTR) and 89 with wild-type TTR (WT-TTR). 72% were men. Median (25th, 75th centile) age was 62 (45, 72) years. Non-Val30Met and WT-TTR were frequent in moderate (41% and 35%) and severe (50% and 33%) IVST classes. Median IVST was 15?mm (14, 16) (moderate) and 20?mm (18, 22) (severe). In the combined moderate-severe class, 85% of patients were ?55?years of age; 81% were men; 86% had blood pressure <140?mm?Hg; and 77% had increased right ventricle thickness (?7?mm). Up to 66% of patients had cardiac sparkling. Systolic dysfunction (left ventricular ejection fraction <50%), restrictive pattern and low voltage were less frequent, and observed in 49%, 18% and 33% of patients, respectively.CONCLUSIONS: Increased IVST, especially in men ?55?years with normal systolic blood pressure, increase in right ventricle free wall and valve thicknesses, and sparkling, should alert practitioners to the possibility of ATTR. Absence of restrictive pattern and low voltage should not rule out the suspicion.TRIAL REGISTRATION NUMBER: NCT00628745 (clinicaltrials.gov).
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| 8. |
- Damy, Thibaud, et al.
(author)
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Transthyretin cardiac amyloidosis in continental Western Europe : An insight through the Transthyretin Amyloidosis Outcomes Survey (THAOS)
- 2019
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In: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 43:5, s. 391-400
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Journal article (peer-reviewed)abstract
- Aims: Transthyretin amyloidosis (ATTR amyloidosis) is a heterogeneous disorder with cardiac, neurologic, and mixed phenotypes. We describe the phenotypic and genotypic profiles of this disease in continental Western Europe as it appears from the Transthyretin Amyloidosis Survey (THAOS).Methods and results: THAOS is an ongoing, worldwide, longitudinal, observational survey established to study differences in presentation, diagnosis, and natural history in ATTR amyloidosis subjects. At data cut-off, 1411 symptomatic subjects from nine continental Western European countries were enrolled in THAOS [1286 hereditary (ATTRm) amyloidosis; 125 wild-type ATTR (ATTRwt) amyloidosis]. Genotypes and phenotypes varied notably by country. Four mutations (Val122Ile, Leu111Met, Thr60Ala, and Ile68Leu), and ATTRwt, were associated with a mainly cardiac phenotype showing symmetric left ventricular (LV) hypertrophy, normal diastolic LV dimensions and volume, and mildly depressed LV ejection fraction (LVEF). Morphologic and functional abnormalities on echocardiogram were significantly more severe in subjects with cardiac (n = 210), compared with a mixed (n = 298), phenotype: higher median (Q1-Q3) interventricular septal thickness [18 (16-21) vs. 16 (13-20) mm; P = 0.0006]; and more frequent incidence of LVEF <50% (38.1 vs. 17.5%; P = 0.0008). Subjects with cardiac mutations or ATTRwt (or cardiac or mixed phenotype) had a lower survival rate than subjects in other genotype (or the neurologic phenotype) categories (P < 0.0001, for both).Conclusion: ATTR amyloidosis genotypes and phenotypes are highly heterogeneous in continental Western Europe. A geographic map of the different disease profiles and awareness that a subset of subjects have a dominant cardiac phenotype, mimicking hypertrophic cardiomyopathy, at presentation can facilitate the clinical recognition of this underdiagnosed disease.Trial registration: ClinicalTrials.gov: NCT00628745.
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| 9. |
- Denfeld, Quin E., et al.
(author)
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Assessing and managing frailty in advanced heart failure: An International Society for Heart and Lung Transplantation consensus statement
- 2024
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In: The Journal of Heart and Lung Transplantation. - : Elsevier. - 1053-2498 .- 1557-3117. ; 43:1
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Journal article (peer-reviewed)abstract
- Frailty is increasingly recognized as a salient condition in patients with heart failure (HF) as previous studies have determined that frailty is highly prevalent and prognostically significant, particularly in those with advanced HF. Definitions of frailty have included a variety of domains, including physical performance, sarcopenia, disability, comorbidity, and cognitive and psychological impairments, many of which are common in advanced HF. Multiple groups have recently recommended incorporating frailty assessments into clinical practice and research studies, indicating the need to standardize the definition and measurement of frailty in advanced HF. Therefore, the purpose of this consensus statement is to provide an integrated perspective on the definition of frailty in advanced HF and to generate a consensus on how to assess and manage frailty. We convened a group of HF clinicians and researchers who have expertise in frailty and related geriatric conditions in HF, and we focused on the patient with advanced HF. Herein, we provide an overview of frailty and how it has been applied in advanced HF (including potential mechanisms), present a definition of frailty, generate suggested assessments of frailty, provide guidance to differentiate frailty and related terms, and describe the assessment and management in advanced HF, including with surgical and nonsurgical interventions. We conclude by outlining critical evidence gaps, areas for future research, and clinical implementation. J Heart Lung Transplant 2024;43:1-27 (c) 2023 International Society for Heart and Lung Transplantation. All rights reserved.
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| 10. |
- Dispenzieri, Angela, et al.
(author)
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Clinical and genetic profile of patients enrolled in the Transthyretin Amyloidosis Outcomes Survey (THAOS) : 14-year update
- 2022
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In: Orphanet Journal of Rare Diseases. - : BioMed Central (BMC). - 1750-1172. ; 17:1
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Journal article (peer-reviewed)abstract
- Background: Transthyretin amyloidosis (ATTR amyloidosis) is a rare, life-threatening disease caused by the accumulation of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in the heart, peripheral nerves, and other tissues and organs.Methods: Established in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal observational study of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This descriptive analysis examines baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2021).Results: This analysis included 3779 symptomatic patients and 1830 asymptomatic gene carriers. Symptomatic patients were predominantly male (71.4%) and had a mean (standard deviation [SD]) age of symptom onset of 56.3 (17.8) years. Val30Met was the most common genotype in symptomatic patients in South America (80.9%), Europe (55.4%), and Asia (50.5%), and more patients had early- versus late-onset disease in these regions. The majority of symptomatic patients in North America (58.8%) had ATTRwt amyloidosis. The overall distribution of phenotypes in symptomatic patients was predominantly cardiac (40.7%), predominantly neurologic (40.1%), mixed (16.6%), and no phenotype (2.5%). In asymptomatic gene carriers, mean (SD) age at enrollment was 42.4 (15.7) years, 42.4% were male, and 73.2% carried the Val30Met mutation.Conclusions: This 14-year global overview of THAOS in over 5000 patients represents the largest analysis of ATTR amyloidosis to date and highlights the genotypic and phenotypic heterogeneity of the disease.ClinicalTrials.gov Identifier: NCT00628745.
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| 11. |
- Gentile, Luca, et al.
(author)
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A 15-year consolidated overview of data in over 6000 patients from the Transthyretin Amyloidosis Outcomes Survey (THAOS)
- 2023
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In: Orphanet Journal of Rare Diseases. - : BioMed Central (BMC). - 1750-1172. ; 18:1
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Journal article (peer-reviewed)abstract
- Background: Transthyretin amyloidosis (ATTR amyloidosis) is a progressive, multisystemic, life-threatening disease resulting from the deposition of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in various tissues and organs.Methods: Established in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal, observational study of patients with ATTR amyloidosis, including both hereditary and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This analysis describes the baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2022), providing a consolidated overview of 15-year data from the THAOS registry.Results: This analysis included 4428 symptomatic patients and 1707 asymptomatic gene carriers. The majority of symptomatic patients were male (70.8%) with a mean (standard deviation [SD]) age at symptom onset of 56.6 (17.9) years. Compared with the 14-year analysis, V30M remained the most prevalent genotype in Europe (62.2%), South America (78.6%), and Japan (74.2%) and ATTRwt remained most common in North America (56.2%). Relative to the 14-year analysis, there was an increase of mixed phenotype (from 16.6 to 24.5%) and a reduction of predominantly cardiac phenotype (from 40.7 to 31.9%). The proportion of patients with predominantly neurologic phenotype remained stable (from 40.1 to 38.7%). Asymptomatic gene carriers were 58.5% female with a mean age at enrollment of 41.9 years (SD 15.5).Conclusions: This overview of > 6000 patients enrolled over 15 years in THAOS represents the largest registry analysis of ATTR amyloidosis to date and continues to emphasize the genotypic and phenotypic heterogeneity of the disease. Nearly a quarter of the symptomatic population within THAOS was mixed phenotype, underscoring the need for multidisciplinary management of ATTR amyloidosis.
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| 12. |
- Gertz, Morie, et al.
(author)
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Avoiding misdiagnosis : expert consensus recommendations for the suspicion and diagnosis of transthyretin amyloidosis for the general practitioner
- 2020
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In: BMC Family Practice. - : BMC. - 1471-2296. ; 21:1
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Journal article (peer-reviewed)abstract
- Background Transthyretin amyloidosis (also known as ATTR amyloidosis) is a systemic, life-threatening disease characterized by transthyretin (TTR) fibril deposition in organs and tissue. A definitive diagnosis of ATTR amyloidosis is often a challenge, in large part because of its heterogeneous presentation. Although ATTR amyloidosis was previously considered untreatable, disease-modifying therapies for the treatment of this disease have recently become available. This article aims to raise awareness of the initial symptoms of ATTR amyloidosis among general practitioners to facilitate identification of a patient with suspicious signs and symptoms. Methods These consensus recommendations for the suspicion and diagnosis of ATTR amyloidosis were developed through a series of development and review cycles by an international working group comprising key amyloidosis specialists. This working group met to discuss the barriers to early and accurate diagnosis of ATTR amyloidosis and develop a consensus recommendation through a thorough search of the literature performed using PubMed Central. Results The cardiac and peripheral nervous systems are most frequently involved in ATTR amyloidosis; however, many patients often also experience gastrointestinal and other systemic manifestations. Given the multisystemic nature of symptoms, ATTR amyloidosis is often misdiagnosed as a more common disorder, leading to significant delays in the initiation of treatment. Although histologic evaluation has been the gold standard to confirm ATTR amyloidosis, a range of tools are available that can facilitate early and accurate diagnosis. Of importance, genetic testing should be considered early in the evaluation of a patient with unexplained peripheral neuropathy. Conclusions A diagnostic algorithm based on initial red flag symptoms and manifestations of cardiac or neurologic involvement will facilitate identification by the general practitioner of a patient with clinically suspicious symptoms, enabling subsequent referral of the patient to a multidisciplinary specialized medical center.
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| 13. |
- Kristen, Arnt V., et al.
(author)
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Impact of genotype and phenotype on cardiac biomarkers in patients with transthyretin amyloidosis - Report from the Transthyretin Amyloidosis Outcome Survey (THAOS)
- 2017
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:4
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Journal article (peer-reviewed)abstract
- Aim: Cardiac troponins and natriuretic peptides are established for risk stratification in light-chain amyloidosis. Data on cardiac biomarkers in transthyretin amyloidosis (ATTR) are lacking.Methods and results: Patients (n = 1617) with any of the following cardiac biomarkers, BNP (n = 1079), NT-proBNP (n = 550), troponin T (n = 274), and troponin I (n = 108), available at baseline in the Transthyretin Amyloidosis Outcomes Survey (THAOS) were analyzed for differences between genotypes and phenotypes and their association with survival. Median level of BNP was 68.0 pg/mL (IQR 30.5–194.9), NT-proBNP 337.9 pg/mL (IQR 73.0–2584.0), troponin T 0.03 μg/L (IQR 0.01–0.05), and troponin I 0.08 μg/L (IQR 0.04–0.13). NT-proBNP and BNP were higher in wild-type than mutant-type ATTR, troponin T and I did not differ, respectively. Non-Val30Met patients had higher BNP, NT-proBNP and troponin T levels than Val30Met patients, but not troponin I. Late-onset Val30Met was associated with higher levels of troponin I and troponin T compared with early-onset. 115 patients died during a median follow-up of 1.2 years. Mortality increased with increasing quartiles (BNP/NT-proBNP Q1 = 1.7%, Q2 = 5.2%, Q3 = 21.7%, Q4 = 71.3%; troponin T/I Q1 = 6.5%, Q2 = 14.5%, Q3 = 33.9%, Q4 = 45.2%). Three-year overall-survival estimates for BNP/NT-proBNP and troponin T/I quartiles differed significantly (p<0.001). Stepwise risk stratification was achieved by combining NT-proBNP/BNP and troponin T/I. From Cox proportional hazards model, age, modified body mass index, mutation (Val30Met vs. Non-Val30Met) and BNP/NT-proBNP (Q1–Q3 pooled vs. Q4) were identified as independent predictors of survival in patients with mutant-type ATTR.Conclusions: In this ATTR patient cohort, cardiac biomarkers were abnormal in a substantial percentage of patients irrespective of genotype. Along with age, mBMI, and mutation (Val30Met vs. Non-Val30Met), cardiac biomarkers were associated with surrogates of disease severity with BNP/NT-proBNP identified as an independent predictor of survival in ATTR.
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| 14. |
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| 15. |
- Plante-Bordeneuve, Violaine, et al.
(author)
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The Transthyretin Amyloidosis Outcomes Survey (THAOS) registry : design and methodology
- 2013
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In: Current Medical Research and Opinion. - : Informa Healthcare. - 0300-7995 .- 1473-4877. ; 29:1, s. 77-84
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Journal article (peer-reviewed)abstract
- Background: Transthyretin (TTR) amyloidosis - the most common type of hereditary amyloidosis - also has an acquired form and is observed in geographically dispersed populations. TTR amyloidosis is marked by considerable clinical heterogeneity, and the main phenotypes are neurologic and cardiovascular. Methods: THAOS is an international, noninterventional, longitudinal, observational registry designed to evaluate overall survival in patients, better understand genotype-phenotype relationships and the natural history of TTR amyloidosis, and evaluate the effects of liver transplantation and other treatments on disease progression in TTR amyloidosis. All individuals with a confirmed TTR mutation with or without a diagnosis of TTR amyloidosis and patients with wild-type TTR amyloidosis are eligible to be enrolled in the registry. Purpose: To describe the design and methodology of the recently established registry. Procedures for data collection are outlined and a minimum set of assessments for the standard evaluation of all subjects with TTR amyloidosis is described. Demographic information, TTR genotype, medical history, family history of the disease, and transplant history are assessed at baseline. On return visits, signs and symptoms of the disease are evaluated, general examinations are conducted, and laboratory data, measures of neurologic and cardiovascular function, and quality of life are assessed according to the standard of care for patients. Visits on at least a biannual basis are recommended. The registry will remain open for a period of at least 10 years. Results: The initial experience suggests that the registry is characterized by a comprehensive set of data elements which can be completed by providers from the various clinical backgrounds who administer care to individuals with TTR amyloidosis. Conclusion: As of September 2011, 30 centers in 15 of the 19 countries participating in the THAOS registry have enrolled 975 patients. Such data provide a representative sample of the global TTR amyloidosis patient population, including asymptomatic TTR variant carriers, which can inform the natural history of the disease and offer the potential to evaluate novel therapeutic modalities in diverse patient subpopulations.
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| 16. |
- Rapezzi, Claudio, et al.
(author)
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Efficacy of Tafamidis in Patients With Hereditary and Wild-Type Transthyretin Amyloid Cardiomyopathy : Further Analyses From ATTR-ACT
- 2021
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In: JACC. Heart failure. - : Elsevier. - 2213-1779 .- 2213-1787. ; 9:2, s. 115-123
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Journal article (peer-reviewed)abstract
- Objectives: Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM), this study aimed to determine whether there is a differential effect between variant transthyretin amyloidosis (ATTRv) and wild-type transthyretin (ATTRwt).Background: ATTR-CM is a progressive, fatal disorder resulting from mutations in the ATTRv or the deposition of denatured ATTRwt.Methods: In pre-specified analyses from ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial), baseline characteristics, all-cause mortality, and change from baseline to month 30 in 6-min walk test distance and Kansas City Cardiomyopathy Questionnaire Overall Summary score were compared in patients with ATTRwt and ATTRv.Results: There were 335 patients with ATTRwt (201 tafamidis, 134 placebo) and 106 with ATTRv (63 tafamidis, 43 placebo) enrolled in ATTR-ACT. Patients with ATTRwt (vs. ATTRv) had less advanced disease at baseline and a lower rate of disease progression over the study. The reduction in all-cause mortality with tafamidis compared with placebo was not different between ATTRwt (hazard ratio: 0.706 [95% confidence interval (CI): 0.474 to 1.052]; p = 0.0875) and ATTRv (hazard ratio: 0.690 [95% CI: 0.408 to 1.167]; p = 0.1667). Tafamidis was associated with a similar reduction (vs. placebo) in the decline in 6-min walk test distance in ATTRwt (mean ± SE difference from placebo, 77.14 ± 10.78; p < 0.0001) and ATTRv (79.61 ± 29.83 m; p = 0.008); and Kansas City Cardiomyopathy Questionnaire Overall Summary score in ATTRwt (12.72 ± 2.10; p < 0.0001) and ATTRv (18.18 ± 7.75; p = 0.019).Conclusions: Pre-specified analyses from ATTR-ACT confirm the poor prognosis of untreated ATTRv-related cardiomyopathy compared with ATTRwt, but show the reduction in mortality and functional decline with tafamidis treatment is similar in both disease subtypes. (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy [ATTR-ACT]; NCT01994889)
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| 17. |
- West, Jay B., et al.
(author)
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Comparison and evaluation of retrospective intermodality image registration techniques
- 1997
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In: SPIE - The International Society for Optical Engineering. - : SPIE - International Society for Optical Engineering. ; , s. 332-347
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Conference paper (peer-reviewed)abstract
- All retrospective image registration methods have attached to them some intrinsic estimate of registration error. However, this estimate of accuracy may not always be a good indicator of the distance between actual and estimated positions of targets within the cranial cavity. This paper describes a project whose principal goal is to use a prospective method based on fiducial markers as a ’gold standard’ to perform an objective, blinded evaluation of the accuracy of several retrospective image-to-image registration techniques. Image volumes of three modalities – CT, MR, and PET – were taken of patients undergoing neurosurgery at Vanderbilt University Medical Center. These volumes had all traces of the fiducial markers removed, and were provided to project collaborators outside Vanderbilt, who then performed retrospective registrations on the volumes, calculating transformations from CT to MR and/or from PET to MR, and communicated their transformations to Vanderbilt where the accuracy of each registration was evaluated. In this evaluation the accuracy is measured at multiple ’regions of interest,’ i.e. areas in the brain which would commonly be areas of neurological interest. A region is defined in the MR image and its centroid C is determined. Then the prospective registration is used to obtain the corresponding point C’ in CT or PET. To this point the retrospective registration is then applied, producing C’ in MR. Statistics are gathered on the target registration error (TRE), which is the disparity between the original point C and its corresponding point C’. A second goal of the project is to evaluate the importance of correcting geometrical distortion in MR images, by comparing the retrospective TRE in the rectified images, i.e., those which have had the distortion correction applied, with that of the same images before rectification. This paper presents preliminary results of this study along with a brief description of each registration technique and an estimate of both preparation and execution time needed to perform the registration.
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