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JACC. Heart Failure Feb 2021Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM), this study aimed to determine whether there is a differential effect between...
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).
Topics: Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin
PubMed: 33309574
DOI: 10.1016/j.jchf.2020.09.011 -
Journal of the Peripheral Nervous... Dec 2022Transthyretin-mediated amyloidosis (ATTR) is a rare, under-recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition... (Review)
Review
Transthyretin-mediated amyloidosis (ATTR) is a rare, under-recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition of amyloid transthyretin (TTR) fibrils in multiple organs and tissues throughout the body. TTR is predominantly synthesized by the liver and normally circulates as a homotetramer, while misfolded monomers aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to reduce the amount of TTR produced by the liver using drugs that directly target the TTR mRNA or gene. This narrative review focuses on how TTR gene silencing tools act to reduce TTR production, describing strategies for improved targeted delivery of these agents to hepatocytes where TTR is preferentially expressed. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed RNA silencers, cause selective degradation of TTR mRNA, while a TTR gene editing tool reduces TTR expression by introducing nonsense mutations into the TTR gene. Two strategies to facilitate tissue-specific delivery of these nucleic acid-based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low-density lipoprotein receptor-mediated uptake of unconjugated siRNA and are now used for CRISPR gene editing tools. Additionally, conjugating N-acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor-mediated uptake by the asialoglycoprotein receptor. In summary, ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor-targeted ligands (eg, GalNAc) and nanoparticle encapsulation (eg, LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis.
Topics: Humans; Amyloid Neuropathies, Familial; Liposomes; Liver; Prealbumin; RNA, Messenger; RNA, Small Interfering
PubMed: 36345805
DOI: 10.1111/jns.12519 -
JAMA Cardiology Mar 2023Tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations and minimized patient-reported health status deterioration at 30 months in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations and minimized patient-reported health status deterioration at 30 months in patients with transthyretin (ATTR) amyloidosis. However, the clinical significance of health status changes remains unclear, particularly in patients with New York Heart Association (NYHA) class III symptoms who experienced more cardiovascular-related hospitalizations than those with NYHA class I-II symptoms.
OBJECTIVE
To evaluate the health status of patients taking tafamidis with baseline NYHA class III symptoms.
DESIGN, SETTING, AND PARTICIPANTS
This randomized clinical trial post hoc analysis evaluated data for patients with transthyretin (ATTR) cardiac amyloidosis and NYHA class I-III symptoms at baseline who were enrolled in ATTR-ACT, a placebo-controlled study of tafamidis held at 48 sites in 13 countries.
INTERVENTIONS
Tafamidis meglumine, 80 mg or 20 mg (pooled cohort), vs placebo.
MAIN OUTCOMES AND MEASURES
Established thresholds for clinical benefit on the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) were used to define response groups (very large decline to very large improvement); the proportion of patients in each group was calculated within each baseline NYHA class.
RESULTS
Among 441 patients (264 tafamidis, 177 placebo), the mean (SD) age was 74.3 (7.0) years; 398 (90%) were male and 43 (10%) were female. Mean (SD) baseline KCCQ-OS scores were 67.3 (21.4) in the tafamidis group and 65.9 (21.7) in the placebo group (range: 0-100, with 100 indicating the best health). There was a significant shift toward better KCCQ-OS scores in patients receiving tafamidis (odds ratio for 10-point improvement 2.4; 95% CI, 1.6-3.4; P < .001). More patients taking tafamidis were alive and not worse at all time points (37% vs 15% at month 30). These findings were similar in patients with NYHA class III symptoms. In patients with NYHA class III symptoms alive at 30 months, improvements in health status were more common (35% vs 10%) and declines were less common (38% vs 57%) with tafamidis vs placebo.
CONCLUSIONS AND RELEVANCE
In ATTR-ACT, although patients with baseline NYHA class III symptoms had worse overall outcomes, treatment with tafamidis yielded better health status compared with placebo.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01994889.
Topics: Humans; Male; Female; Aged; Prealbumin; Amyloidosis; Benzoxazoles; Health Status
PubMed: 36723935
DOI: 10.1001/jamacardio.2022.5251 -
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 -
Journal of Clinical Pharmacology Jan 2020Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, rapidly progressive, life-threatening disease caused by deposition of abnormal transthyretin... (Randomized Controlled Trial)
Randomized Controlled Trial
Patisiran Pharmacokinetics, Pharmacodynamics, and Exposure-Response Analyses in the Phase 3 APOLLO Trial in Patients With Hereditary Transthyretin-Mediated (hATTR) Amyloidosis.
Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, rapidly progressive, life-threatening disease caused by deposition of abnormal transthyretin protein. Patisiran is an RNA interference therapeutic comprising a novel, small interfering ribonucleic acid (ALN-18328) formulated in a lipid nanoparticle targeted to inhibit hepatic transthyretin protein synthesis. The lipid nanoparticle also contains 2 novel lipid excipients (DLin-MC3-DMA and PEG -C-DMG). Here we report patisiran pharmacokinetics (PK), pharmacodynamics (PD), and exposure-response analyses from the phase 3 APOLLO trial, in which patients with hATTR amyloidosis with polyneuropathy were randomized 2:1 to receive patisiran 0.3 mg/kg or placebo intravenously every 3 weeks over 18 months. In patisiran-treated patients, mean maximum reduction in serum transthyretin level from baseline was 87.8%. Patisiran PK exposure was stable following chronic dosing. There were no meaningful differences in PK exposure, serum transthyretin reduction, and efficacy (change from baseline in modified Neuropathy Impairment Score+7) across all subgroups analyzed (age, sex, race, body weight, genotype status of valine-to-methionine mutation at position 30 [V30M] and non-V30M, prior use of tetramer stabilizers, mild/moderate renal impairment, and mild hepatic impairment). transthyretin reduction and efficacy were similar across the interpatient PK exposure range for ALN-18328. There was no trend in the incidence of adverse events or serious adverse events across the interpatient PK exposure range for all 3 analytes. Incidence of antidrug antibodies was low (3.4%) and transient, with no impact on PK, PD, efficacy, or safety. The patisiran dosing regimen of 0.3 mg/kg every 3 weeks is appropriate for all patients with hATTR amyloidosis.
Topics: Administration, Intravenous; Aged; Amyloid Neuropathies, Familial; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Liposomes; Liver; Male; Middle Aged; Nanoparticles; Polyneuropathies; Prealbumin; RNA, Small Interfering; RNAi Therapeutics; Treatment Outcome
PubMed: 31322739
DOI: 10.1002/jcph.1480 -
International Journal of Molecular... Dec 2022Amyloidoses are a group of diseases associated with deposits of amyloid fibrils in different tissues. So far, 36 different types of amyloidosis are known, each due to... (Review)
Review
Amyloidoses are a group of diseases associated with deposits of amyloid fibrils in different tissues. So far, 36 different types of amyloidosis are known, each due to the misfolding and accumulation of a specific protein. Amyloid deposits can be found in several organs, including the heart, brain, kidneys, and spleen, and can affect single or multiple organs. Generally, amyloid-forming proteins become prone to aggregate due to genetic mutations, acquired environmental factors, excessive concentration, or post-translational modifications. Interestingly, amyloid aggregates are often composed of proteolytic fragments, derived from the degradation of precursor proteins by yet unidentified proteases, which display higher amyloidogenic tendency compared to precursor proteins, thus representing an important mechanism in the onset of amyloid-based diseases. In the present review, we summarize the current knowledge on the proteolytic susceptibility of three of the main human amyloidogenic proteins, i.e., transthyretin, β-amyloid precursor protein, and α-synuclein, in the onset of amyloidosis. We also highlight the role that proteolytic enzymes can play in the crosstalk between intestinal inflammation and amyloid-based diseases.
Topics: Humans; Proteolysis; Amyloidosis; Amyloid; Amyloid beta-Protein Precursor; Protein Precursors; Prealbumin; Peptide Hydrolases
PubMed: 36614141
DOI: 10.3390/ijms24010699 -
European Journal of Heart Failure Feb 2021
Topics: Amyloid Neuropathies, Familial; Heart Failure; Humans; Prealbumin
PubMed: 33342016
DOI: 10.1002/ejhf.2080 -
Romanian Journal of Internal Medicine =... Mar 2023Transthyretin cardiac amyloidosis is a progressive disease known to cause heart failure, conduction anomalies, and arrythmias. Due to poor outcomes and mortality from... (Review)
Review
Transthyretin cardiac amyloidosis is a progressive disease known to cause heart failure, conduction anomalies, and arrythmias. Due to poor outcomes and mortality from severe cardiomyopathy, prevalence and incident rates are often underreported. As global longevity is increasing and rates of amyloidosis are also increasing, there is a need to improve diagnostic and therapeutic interventions. Previously, symptom management and transplantation were the mainstay of treatment for heart failure symptoms, but studies using RNAi and siRNA technologies have shifted the paradigm of therapeutic strategy in amyloid cardiomyopathy management. Additionally, early detection and clinical monitoring with numerous imaging and non-imaging techniques are being increasingly investigated. Here, we review the epidemiology, pathophysiology, diagnosis, and management of transthyretin amyloid cardiomyopathy.
Topics: Humans; Amyloidosis; Arrhythmias, Cardiac; Cardiomyopathies; Heart Failure; Prealbumin
PubMed: 36278951
DOI: 10.2478/rjim-2022-0018 -
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 -
Current Heart Failure Reports Oct 2022Transthyretin cardiac amyloidosis (ATTR-CM) is an infiltrative cardiomyopathy and an increasingly recognized cause of morbidity and mortality. There remains substantial... (Review)
Review
PURPOSE OF REVIEW
Transthyretin cardiac amyloidosis (ATTR-CM) is an infiltrative cardiomyopathy and an increasingly recognized cause of morbidity and mortality. There remains substantial delay between initial symptoms and diagnosis. With the recent emergence of various targeted therapies proven to reduce morbidity and mortality, there is an imperative to diagnose subclinical disease. Biomarkers may be well-suited for this role.
RECENT FINDINGS
Conventional markers of heart failure, such as natriuretic peptides and cardiac troponins, and estimated glomerular filtration rate are associated with risk in ATTR-CM. Circulating transthyretin (TTR) levels parallel TTR kinetic stability, correlate with disease severity, and may serve as indirect markers of ATTR-CM disease activity and response to targeted treatment. There is also growing evidence for the correlation of TTR to retinol-binding protein 4, a biomarker which independently associates with this disease. The rate-limiting step for ATTR pathogenesis is dissociation of the TTR homotetramer, which may be quantified using subunit exchange to allow for early risk assessment, prognostication, and assessment of treatment response. The protein species that result from the dissociation and misfolding of TTR are known as nonnative transthyretin (NNTTR). NNTTR is quantifiable via peptide probes and is a specific biomarker whose reduction is positively correlated with improvement in neuropathic ATTR amyloidosis. Neurofilament light chain (NfL) is released into the blood after axonal damage and correlates with neuropathic ATTR amyloidosis, but its clinical use in ATTR-CM is uncertain. Conventional markers of heart failure, transthyretin, retinol-binding protein 4, transthyretin kinetic stability, nonnative transthyretin, peptide probes, and neurofilament light chain have potential as biomarkers to enable early, subclinical diagnosis in patients with transthyretin cardiac amyloidosis.
Topics: Amyloid Neuropathies, Familial; Biomarkers; Cardiomyopathies; Heart Failure; Humans; Prealbumin; Troponin
PubMed: 35930129
DOI: 10.1007/s11897-022-00570-1