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JACC. Cardiovascular Imaging Dec 2023Although transthyretin cardiac amyloidosis (ATTR-CA) is often underdiagnosed, clinical suspicion is essential for early diagnosis.
BACKGROUND
Although transthyretin cardiac amyloidosis (ATTR-CA) is often underdiagnosed, clinical suspicion is essential for early diagnosis.
OBJECTIVES
The aim of this study was to develop and validate a feasible prediction model and score to facilitate the diagnosis of ATTR-CA.
METHODS
This retrospective multicenter study enrolled consecutive patients who underwent Tc-DPD scintigraphy for suspected ATTR-CA. ATTR-CA was diagnosed if Grade 2 or 3 cardiac uptake was evidenced on Tc-DPD scintigraphy in the absence of a detectable monoclonal component or by demonstration of amyloid by biopsy. A prediction model for ATTR-CA diagnosis was developed in a derivation sample of 227 patients from 2 centers using multivariable logistic regression with clinical, electrocardiography, analytical, and transthoracic echocardiography variables. A simplified score was also created. Both of them were validated in an external cohort (n = 895) from 11 centers.
RESULTS
The obtained prediction model combined age, gender, carpal tunnel syndrome, interventricular septum in diastole thickness, and low QRS interval voltages, with an area under the curve (AUC) of 0.92. The score had an AUC of 0.86. Both the T-Amylo prediction model and the score showed a good performance in the validation sample (ie, AUC: 0.84 and 0.82, respectively). They were tested in 3 clinical scenarios of the validation cohort: 1) hypertensive cardiomyopathy (n = 327); 2) severe aortic stenosis (n = 105); and 3) heart failure with preserved ejection fraction (n = 604), all with good diagnostic accuracy.
CONCLUSIONS
The T-Amylo is a simple prediction model that improves the prediction of ATTR-CA diagnosis in patients with suspected ATTR-CA.
Topics: Humans; Prealbumin; Amyloid Neuropathies, Familial; Predictive Value of Tests; Cardiomyopathies; Heart
PubMed: 37389511
DOI: 10.1016/j.jcmg.2023.05.002 -
Orphanet Journal of Rare Diseases Nov 2023Transthyretin amyloidosis (ATTR amyloidosis) is a progressive, multisystemic, life-threatening disease resulting from the deposition of variant or wild-type (ATTRwt... (Observational Study)
Observational Study
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.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT00628745.
Topics: Adult; Female; Humans; Male; Middle Aged; Amyloid Neuropathies, Familial; Longitudinal Studies; Prealbumin; Registries; Surveys and Questionnaires
PubMed: 37946256
DOI: 10.1186/s13023-023-02962-5 -
Innere Medizin (Heidelberg, Germany) Sep 2023Transthyretin amyloidosis (ATTR) is a rare disease in which the protein transthyretin (TTR) is deposited in the form of amyloid fibrils in various tissues and organs... (Review)
Review
Transthyretin amyloidosis (ATTR) is a rare disease in which the protein transthyretin (TTR) is deposited in the form of amyloid fibrils in various tissues and organs and secondarily leads to functional impairment, especially in peripheral nerves and the heart. A differentiation is made between hereditary and sporadic forms. The hereditary variant is inherited in an autosomal dominant manner and usually occurs in the younger to middle-aged, while the sporadic form occurs in older age and has no known genetic cause. Typical signs of hereditary ATTR amyloidosis (ATTRv, v for variant) include a rapidly progressing sensorimotor and autonomic polyneuropathy (PNP), cardiac dysfunction as well as ocular and gastrointestinal symptoms. A carpal tunnel syndrome often precedes the manifestation. Various options (tafamidis, patisiran, inotersen or vutrisiran) are available for the treatment of patients with ATTRv with PNP in Germany, depending on the severity. In the sporadic variant of wild-type ATTR amyloidosis (ATTRwt), symptoms of progressive cardiomyopathy are usually prominent; however, neurological assessment of these patients often also reveals a concomitant sensory ataxic PNP. The tetramer stabilizer tafamidis can be used for treatment. Because of this complex presentation, the management of patients with ATTR amyloidosis should be performed in interdisciplinary centers specialized in amyloidosis.
Topics: Middle Aged; Humans; Prealbumin; Amyloid Neuropathies, Familial; Polyneuropathies; Cardiomyopathies; Germany
PubMed: 37555967
DOI: 10.1007/s00108-023-01570-6 -
European Journal of Heart Failure Nov 2023The value of disease-modifying therapies (such as tafamidis) in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) and severe heart failure symptoms has been...
AIM
The value of disease-modifying therapies (such as tafamidis) in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) and severe heart failure symptoms has been debated. This study assessed long-term all-cause survival in patients with New York Heart Association (NYHA) class III symptoms in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) long-term extension (LTE) study.
METHODS AND RESULTS
At the baseline of ATTR-ACT, 55/176 (31.3%) patients receiving tafamidis 80 mg and 63/177 (35.6%) receiving placebo had NYHA class III symptoms. After 30 months of treatment, patients could join an ongoing LTE study to receive open-label tafamidis. In an interim analysis of the LTE study (August 2021), all-cause mortality was lower among patients with NYHA class III symptoms who received continuous tafamidis in ATTR-ACT and the LTE study (hazard ratio 0.64; 95% confidence interval 0.41-0.99; median follow-up: 60 months), as compared with those who received placebo in ATTR-ACT and tafamidis in the LTE study (median follow-up: 56 months). Similar findings were observed in patients with NYHA class I/II symptoms at baseline (0.50; 0.35-0.73; tafamidis 80 mg n = 121; placebo n = 114; median follow-up of 61 and 60 months, respectively).
CONCLUSION
We observed reduced all-cause mortality with continuous tafamidis treatment compared with delayed tafamidis treatment (placebo then tafamidis) in patients with NYHA class III symptoms at baseline over a median follow-up of ∼5 years. These findings demonstrate the value of tafamidis treatment in patients with ATTR-CM and severe heart failure symptoms, and emphasize the importance of early treatment.
CLINICAL TRIAL REGISTRATIONS
ClinicalTrials.gov NCT01994889 and NCT02791230.
Topics: Humans; Amyloid Neuropathies, Familial; Prealbumin; Heart Failure; Cardiomyopathies
PubMed: 37434378
DOI: 10.1002/ejhf.2974 -
Innere Medizin (Heidelberg, Germany) Sep 2023Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed cause of heart failure and arrhythmia. This differential diagnosis should particularly be considered... (Review)
Review
Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed cause of heart failure and arrhythmia. This differential diagnosis should particularly be considered in older patients with left ventricular hypertrophy (LVH) who are also suffering from heart failure with preserved ejection fraction (HFpEF) or aortic valve stenosis. ATTR-CM is caused either by a genetic variation or by aging processes. The extracellular accumulation of amyloid fibrils in the heart causes a restrictive cardiomyopathy, which leads to typical heart failure symptoms as well as cardiac conduction and repolarization disturbances. Extracardiac problems such as a carpal tunnel syndrome can also be indicative for ATTR-CM. The disease can be diagnosed either by a myocardial biopsy or alternatively by a positive bone scintigraphy with the simultaneous exclusion of monoclonal proteins in blood and urine. Besides a symptomatic treatment, the transthyretin (TTR) stabilizer tafamidis is now available, which can significantly delay the disease progress. In the coming years, the approval of further drugs for the treatment of ATTR-CM is to be expected.
Topics: Aged; Humans; Amyloid Neuropathies, Familial; Cardiomyopathies; Heart Failure; Prealbumin; Stroke Volume; Tomography, X-Ray Computed; Benzoxazoles
PubMed: 37540258
DOI: 10.1007/s00108-023-01569-z -
Heart Failure Reviews Mar 2024Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive disease characterized by the deposition of abnormal transthyretin protein fibrils in the heart, leading to... (Review)
Review
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.
Topics: Humans; Female; Male; Cardiomyopathies; Prealbumin; Sex Characteristics; Amyloidosis; Heart; Amyloid Neuropathies, Familial
PubMed: 37566193
DOI: 10.1007/s10741-023-10339-w -
The American Journal of the Medical... Aug 2023
Topics: Humans; Prealbumin; Amyloidosis; Cardiomyopathies
PubMed: 37001694
DOI: 10.1016/j.amjms.2023.03.023 -
JACC. Cardiovascular Imaging Dec 2023
Topics: Humans; Predictive Value of Tests; Amyloid Neuropathies, Familial; Prealbumin
PubMed: 37589608
DOI: 10.1016/j.jcmg.2023.06.013 -
JAMA Oct 2023
Topics: Humans; Amyloid Neuropathies, Familial; Amyloidosis; Prealbumin
PubMed: 37768648
DOI: 10.1001/jama.2023.15087 -
American Journal of TherapeuticsDeposition of wild-type or mutant transthyretin (TTR) amyloid fibrils in the myocardium causes TTR amyloid cardiomyopathy (ATTR-CM). Targeted therapeutics for ATTR-CM...
BACKGROUND
Deposition of wild-type or mutant transthyretin (TTR) amyloid fibrils in the myocardium causes TTR amyloid cardiomyopathy (ATTR-CM). Targeted therapeutics for ATTR-CM include TTR stabilizers (tafamidis and diflunisal) and oligonucleotide drugs (revusiran, patisiran, and inotersen). TTR stabilizers prevent dissociation of transthyretin tetramers. Transthyretin monomers can misfold and form amyloid fibrils. TTR stabilizers thereby limit amyloid fibrils development and deposition. Oligonucleotide drugs inhibit hepatic synthesis of transthyretin, which decreases transthyretin protein levels and thus the amyloid fibril substrate.
AREAS OF UNCERTAINTY
To study the safety and efficacy of targeted therapeutics in patients with ATTR-CM, we performed a pooled analysis. A random-effects model with the Mantel-Haenszel method was used to pool the data.
DATA SOURCES
A literature search was performed using PubMed, Cochrane CENTRAL, and Embase databases using the search terms "cardiac amyloidosis" AND "tafamidis" OR "patisiran" OR "inotersen" OR "revusiran" OR "diflunisal."
THERAPEUTIC ADVANCES
We identified 6 studies that compared targeted therapeutics with placebo. One study was stopped prematurely because of increased mortality in the targeted therapeutics arm. Pooled analysis included 1238 patients, of which 738 patients received targeted therapeutics and 500 patients received placebo. When compared with placebo, targeted therapeutics significantly reduced all-cause mortality [OR 0.39, 95% confidence interval (CI): 0.16-0.97, P = 0.04]. Only 2 studies reported the effect on cardiovascular-related hospitalizations. There was a trend toward an improvement in global longitudinal strain (mean difference -0.69, 95% CI: -1.44 to 0.05, P = 0.07). When compared with placebo, there was no increase in serious adverse events with targeted therapeutics (OR 1.06, 95% CI: 0.78-1.44, P = 0.72).
CONCLUSION
Evidence from the pooled analysis revealed targeted therapeutics improve survival and are well-tolerated. These findings suggest a potential role for targeted therapeutics in the treatment of patients with ATTR-CM.
Topics: Humans; Amyloid Neuropathies, Familial; Prealbumin; Diflunisal; Oligonucleotides; Cardiomyopathies
PubMed: 37713689
DOI: 10.1097/MJT.0000000000001296