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ESC Heart Failure Apr 2024The prevalence of transthyretin-associated amyloidosis cardiomyopathy (ATTR-CM) has grown because of newer non-invasive diagnosis tools. Detecting the presence of... (Review)
Review
The prevalence of transthyretin-associated amyloidosis cardiomyopathy (ATTR-CM) has grown because of newer non-invasive diagnosis tools. Detecting the presence of extra-cardiac ATTR manifestations such as musculoskeletal pathologies considered 'red flags', when there is minimal or non-cardiac clinical involvement is primordial to carry out an early diagnosis. The aim of this systematic review is to examine the prevalence of musculoskeletal, ATTR-deposition-related co-morbidities in patients already diagnosed with ATTR-CM, specifically carpal tunnel syndrome, ruptured biceps tendon, spinal stenosis, and trigger finger. We performed a systematic review using PRISMA guidelines. Inclusion criteria were all studies in English and Spanish language and participants had to be patients diagnosed with ATTR-CM, by any diagnostic method, with the musculoskeletal co-morbidities subject of this review. The quality of the studies was based on the Risk of Bias Tool. This systematic review included 22 studies for final analysis. Carpal tunnel syndrome is reported in 21 studies, brachial biceps tendon rupture is reported in three, and spinal stenosis in eight studies. No articles that accomplished all the inclusion criteria for trigger finger were found. Regarding to the quality of the studies, all of them were categorized as being of high and moderate quality. The frequent association between ATTR-CM and carpal tunnel syndrome, ruptured biceps tendon, and lumbar spinal is confirmed, and the onset of these co-morbidities usually precedes the diagnosis of by years. This association defines them as red flags that should be search proactively due to the current treatment possibilities and the severity of the presentation of cardiac amyloidosis.
Topics: Humans; Prealbumin; Spinal Stenosis; Carpal Tunnel Syndrome; Trigger Finger Disorder; Amyloid Neuropathies, Familial; Cardiomyopathies; Morbidity
PubMed: 38130034
DOI: 10.1002/ehf2.14622 -
BMC Musculoskeletal Disorders Jan 2021Transthyretin and immunoglobulin light-chain amyloidoses cause amyloid deposition throughout various organ systems. Recent evidence suggests that soft tissue amyloid...
BACKGROUND
Transthyretin and immunoglobulin light-chain amyloidoses cause amyloid deposition throughout various organ systems. Recent evidence suggests that soft tissue amyloid deposits may lead to orthopedic conditions before cardiac manifestations occur. Pharmacologic treatments reduce further amyloid deposits in these patients. Thus, early diagnosis improves long term survival.
QUESTIONS/PURPOSES
The primary purpose of this systematic review was to characterize the association between amyloid deposition and musculoskeletal pathology in patients with common orthopedic conditions. A secondary purpose was to determine the relationship between amyloid positive biopsy in musculoskeletal tissue and the eventual diagnosis of systemic amyloidosis.
METHODS
We performed a systematic review using PRISMA guidelines. Inclusion criteria were level I-IV evidence articles that analyzed light-chain or transthyretin amyloid deposits in common orthopedic surgeries. Study methodological quality, risk of bias, and recommendation strength were assessed using MINORS, ROBINS-I, and SORT.
RESULTS
This systematic review included 24 studies for final analysis (3606 subjects). Amyloid deposition was reported in five musculoskeletal pathologies, including carpal tunnel syndrome (transverse carpal ligament and flexor tenosynovium), hip and knee osteoarthritis (synovium and articular cartilage), lumbar spinal stenosis (ligamentum flavum), and rotator cuff tears (tendon). A majority of studies reported a mean age greater than 70 for patients with TTR or AL positive amyloid.
CONCLUSIONS
This systematic review has shown the presence of amyloid deposition detected at the time of common orthopedic surgeries, especially in patients ≥70 years old. Subtyping of the amyloid has been shown to enable diagnosis of systemic light-chain or transthyretin amyloidosis prior to cardiac manifestations.
LEVEL OF EVIDENCE
Level IV.
Topics: Aged; Amyloid Neuropathies, Familial; Humans; Immunoglobulin Light-chain Amyloidosis; Orthopedic Procedures; Osteoarthritis, Hip; Osteoarthritis, Knee
PubMed: 33419417
DOI: 10.1186/s12891-020-03912-z -
BMC Neurology Feb 2021We aimed to compare neuropathic progression rate between hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and other peripheral neuropathies, including... (Meta-Analysis)
Meta-Analysis
BACKGROUND
We aimed to compare neuropathic progression rate between hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and other peripheral neuropathies, including diabetic peripheral neuropathy (DPN) and Charcot-Marie-Tooth disease (CMT).
METHODS
Literature searches identified studies reporting neuropathic progression, measured by Neuropathy Impairment Score (NIS) or NIS-Lower Limbs (NIS-LL). Our study also included unpublished data from a clinical registry of patients who were diagnosed with different peripheral neuropathies and seen at the Oregon Health & Science University (OHSU) during 2016-2020. Meta-analysis and meta-regression models examined and compared annual progression rates, calculated from extracted data, between studies of ATTRv-PN and other peripheral neuropathies.
RESULTS
Data were synthesized from 15 studies in which NIS and/or NIS-LL total scores were assessed at least twice, with ≥12 weeks between assessments, among untreated patients with ATTRv-PN or other peripheral neuropathies. Meta-analysis models yielded that the annual progression rate in NIS total scores was significantly different from zero for studies in ATTRv-PN and CMT (11.77 and 1.41; both P < 0.001), but not DPN (- 1.96; P = 0.147). Meta-regression models showed significantly faster annual progression in studies in ATTRv-PN, which statistically exceeded that in other peripheral neuropathies by 12.45 points/year for NIS, and 6.96 for NIS-LL (both P < 0.001).
CONCLUSIONS
Peripheral nervous function deteriorates more rapidly in patients with ATTRv-PN than for other peripheral neuropathies. These findings may improve understanding of the natural history of neuropathy in ATTRv-PN, facilitate early diagnosis, and guide the development of assessment tools and therapies specifically targeting neuropathic progression in this debilitating disease.
Topics: Amyloid Neuropathies, Familial; Disease Progression; Female; Humans; Male; Middle Aged; Polyneuropathies; Registries
PubMed: 33579211
DOI: 10.1186/s12883-021-02094-y -
Hellenic Journal of Cardiology : HJC =... 2019Light-chain amyloidosis and transthyretin-related amyloidosis (wild-type and mutated) are three main types of systemic amyloidosis associated with a clinically relevant... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Light-chain amyloidosis and transthyretin-related amyloidosis (wild-type and mutated) are three main types of systemic amyloidosis associated with a clinically relevant cardiac involvement. In this study, we compared prognosis in patients with different categories of cardiac amyloidosis using meta-analysis and present a systematic review.
METHODS
A systematic literature search was performed through Jan 1, 2018, and two reviewers independently extracted data and assessed risk of bias. We extracted MACE and death endpoint events and hazard ratios from regression models and performed a meta-analysis of the multiple prognosis association studies.
RESULTS
We observed that there were significant MACE differences between patients diagnosed with transthyretin amyloidosis and light-chain amyloidosis (OR: 2.09; 95% CI: 1.06-4.12; P = 0.03), and the same is true in the sub-comparison between AL and mATTR or wtATTR (AL vs. mATTR: OR: 1.72; 95% CI: 1.06-2.82; P = 0.03; AL vs. wtATTR: OR: 1.48; 95% CI: 0.85-2.58; P = 0.17). However, no significant difference was observed between two transthyretin types (P = 0.17). Overall death rate evaluated showed that compared with transthyretin-related amyloidosis, light-chain type showed a significant difference (P < 0.05). The prognostic analysis showed that types of amyloidosis, LVEF, NYHA, restrictive filling pattern, E-wave deceleration time, E/E' ratio, and low QRS voltage were predictors of cardiac-related mortality.
CONCLUSION
Patients diagnosed with light-chain amyloidosis has a poor prognosis compared with transthyretin-related amyloidosis, while no difference was proved in prognostic analysis between wild-type and mutated TTR amyloidosis. Some clinical factors related to the death prognosis, such as the LVEF, restrictive filling pattern, E-wave deceleration time, and E/E' ratio are important prognostic factors.
Topics: Adult; Aged; Aged, 80 and over; Amyloid Neuropathies, Familial; Cardiomyopathies; Case-Control Studies; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Middle Aged; Prealbumin; Prognosis; Ventricular Function, Left
PubMed: 30742933
DOI: 10.1016/j.hjc.2019.01.015 -
Journal of Neuromuscular Diseases 2021Hereditary peripheral neuropathies are inherited disorders affecting the peripheral nervous system, including Charcot-Marie-Tooth disease, familial amyloid...
BACKGROUND
Hereditary peripheral neuropathies are inherited disorders affecting the peripheral nervous system, including Charcot-Marie-Tooth disease, familial amyloid polyneuropathy and hereditary sensory and motor neuropathies. While the molecular basis of hereditary peripheral neuropathies has been extensively researched, interventional trials of pharmacological therapies are lacking.
OBJECTIVE
We collated evidence for the effectiveness of pharmacological and gene-based treatments for hereditary peripheral neuropathies.
METHODS
We searched several databases for randomised controlled trials (RCT), observational studies and case reports of therapies in hereditary peripheral neuropathies. Two investigators extracted and analysed the data independently, assessing study quality using the Oxford Centre for Evidence Based Medicine 2011 Levels of Evidence in conjunction with the Jadad scale.
RESULTS
Of the 2046 studies initially identified, 119 trials met our inclusion criteria, of which only 34 were carried over into our final analysis. Ascorbic acid was shown to have no therapeutic benefit in CMT1A, while a combination of baclofen, naltrexone and sorbitol (PXT3003) demonstrated some efficacy, but phase III data are incomplete. In TTR-related amyloid polyneuropathy tafamidis, patisiran, inotersen and revusiran showed significant benefit in high quality RCTs. Smaller studies showed the efficacy of L-serine for SPTLC1-related hereditary sensory neuropathy, riboflavin for Brown-Vialetto-Van Laere syndrome (SLC52A2/3) and phytanic acid-poor diet in Refsum disease (PHYH).
CONCLUSIONS
The 'treatable' variants highlighted in this project will be flagged in the treatabolome database to alert clinicians at the time of the diagnosis and enable timely treatment of patients with hereditary peripheral neuropathies.
Topics: Amyloid Neuropathies, Familial; Charcot-Marie-Tooth Disease; Hereditary Sensory and Motor Neuropathy; Humans
PubMed: 32773395
DOI: 10.3233/JND-200546 -
Journal of the American Heart... Oct 2020Background The emergence of specific therapies for transthyretin cardiac amyloidosis (CA) warrants the need for a systematic review of the literature. Methods and...
Background The emergence of specific therapies for transthyretin cardiac amyloidosis (CA) warrants the need for a systematic review of the literature. Methods and Results A systematic review of the literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search was performed on MEDLINE, PubMed, and Embase databases on November 29, 2019. Studies were selected based on the following predefined eligibility criteria: English-language randomized controlled trials (RCTs), non-RCTs, or observational studies, which included adult patients with variant/wild-type transthyretin-CA, assessed specific therapies for transthyretin-CA, and reported cardiovascular outcomes. Relevant data were extracted to a predefined template. Quality assessment was based on National Institute for Health and Care Excellence recommendations (RCTs) or a checklist by Downs and Black (non-RCTs). From 1203 records, 24 publications were selected, describing 4 RCTs (6 publications) and 16 non-RCTs (18 publications). Tafamidis was shown to significantly improve all-cause mortality and cardiovascular hospitalizations and reduce worsening in 6-minute walk test, Kansas City Cardiomyopathy Questionnaire-Overall Summary score, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) in variant/wild-type transthyretin-CA. Patisiran showed promising results in a subgroup analysis of patients with variant transthyretin-CA, which have to be confirmed in RCTs. Inotersen showed conflicting results on cardiac imaging parameters. The one study on AG10 had only a 1-month duration and cardiovascular end points were exploratory and limited to cardiac biomarkers. Limited evidence from noncomparative single-arm small non-RCTs existed for diflunisal, epigallocatechin-3-gallate (green tea extract), and doxycycline+tauroursodeoxycholic acid/ursodeoxycholic acid. Conclusions This systematic review of the literature supports the use of tafamidis in wild-type and variant transthyretin-CA. Novel therapeutic targets including transthyretin gene silencers are currently under investigation.
Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Cardiovascular Agents; Genetic Therapy; Humans
PubMed: 32969287
DOI: 10.1161/JAHA.120.016614 -
International Journal of Cardiology May 2024Cardiac amyloidosis is increasingly recognized as a significant contributor to cardiovascular morbidity and mortality. With the emergence of novel therapies, there is a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cardiac amyloidosis is increasingly recognized as a significant contributor to cardiovascular morbidity and mortality. With the emergence of novel therapies, there is a growing interest in prognostication of patients with cardiac amyloidosis using cardiac magnetic resonance imaging (CMR). In this systematic review and meta-analysis, we aimed to examine the prognostic significance of myocardial native T1 and T2, and extracellular volume (ECV).
METHODS
Observational cohort studies or single arms of clinical trials were eligible. MEDLINE, EMBASE and CENTRAL were systematically searched from their respective dates of inception to January 2023. No exclusions were made based on date of publication, study outcomes, or study language. The study populations composed of adult patients (≥18 years old) with amyloid cardiomyopathy. All studies included the use of CMR with and without intravenous gadolinium contrast administration to assess myocardial native T1 mapping, T2 mapping, and ECV in association with the pre-specified primary outcome of all-cause mortality. Data were extracted from eligible primary studies by two independent reviewers and pooled via the inverse variance method using random effects models for meta-analysis.
RESULTS
A total of 3852 citations were reviewed. A final nine studies including a total of 955 patients (mean age 65 ± 10 years old, 32% female, mean left ventricular ejection fraction (LVEF) 59 ± 12% and 24% had NYHA class III or IV symptoms) with cardiac amyloidosis [light chain amyloidosis (AL) 50%, transthyretin amyloidosis (ATTR) 49%, other 1%] were eligible for inclusion and suitable for data extraction. All included studies were single centered (seven with 1.5 T MRI scanners, two with 3.0 T MRI scanners) and non-randomized in design, with follow-up spanning from 8 to 64 months (median follow-up = 25 months); 320 patients died during follow-up, rendering a weighted mortality rate of 33% across studies. Compared with patients with AL amyloid, patients with ATTR amyloid had significantly higher mean left ventricular mass index (LVMi) (102 ± 34 g/m vs 127 ± 37 g/m, p = 0.02). N-terminal pro-brain natriuretic peptide (NT-proBNP), troponin T levels, mean native T1 values, ECV and T2 values did not differ between patients with ATTR amyloid and AL amyloid (all p > 0.25). Overall, the hazard ratios for mortality were 1.33 (95% CI = [1.10, 1.60]; p = 0.003; I = 29%) for every 60 ms higher T1 time, 1.16 (95% CI = [1.09, 1.23], p < 0.0001; I = 76%) for every 3% higher ECV, and 5.23 (95% CI = [2.27, 12.02]; p < 0.0001; I = 0%) for myocardial-to-skeletal T2 ratio below the mean (vs above the mean).
CONCLUSION
Higher native T1 time and ECV, and lower myocardial to skeletal T2 ratio, on CMR are associated with worse mortality in patients with cardiac amyloidosis. Therefore, tissue mapping using CMR may offer a useful non-invasive technique to monitor disease progression and determine prognosis in patients with cardiac amyloidosis.
Topics: Adult; Humans; Female; Middle Aged; Aged; Adolescent; Male; Cardiomyopathies; Stroke Volume; Ventricular Function, Left; Magnetic Resonance Imaging; Myocardium; Amyloid Neuropathies, Familial; Disease Progression; Magnetic Resonance Imaging, Cine; Predictive Value of Tests; Contrast Media; Observational Studies as Topic
PubMed: 38382853
DOI: 10.1016/j.ijcard.2024.131892 -
ESC Heart Failure Oct 2019The study aims to systematically assess the diagnostic performance of cardiac magnetic resonance (CMR) and nuclear scintigraphy (index tests) for the diagnosis and... (Comparative Study)
Comparative Study Meta-Analysis
AIMS
The study aims to systematically assess the diagnostic performance of cardiac magnetic resonance (CMR) and nuclear scintigraphy (index tests) for the diagnosis and differentiation of subtypes of cardiac amyloidosis.
METHODS AND RESULTS
MEDLINE and Embase electronic databases were searched for studies evaluating the diagnostic performance of CMR or nuclear scintigraphy in detecting cardiac amyloidosis and subsequently in differentiating transthyretin amyloidosis (ATTR) from immunoglobulin light-chain (AL) amyloidosis. In this meta-analysis, histopathological examination of tissue from endomyocardial biopsy (EMB) or extra-cardiac organs were reference standards. Pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were calculated, and a random effects meta-analysis was used to estimate diagnostic odds ratios. Methodological quality was assessed using a validated instrument. Of the 2947 studies identified, 27 met the criteria for inclusion. Sensitivity and specificity of CMR in diagnosing cardiac amyloidosis was 85.7% and 92.0% against EMB reference and 78.9% and 93.9% with any organ histology reference. Corresponding sensitivity and specificity of nuclear scintigraphy was 88.4% and 87.2% against EMB reference and 82.0% and 98.8% with histology from any organ. CMR was unable to reliably differentiate ATTR from AL amyloidosis (sensitivity 28.1-99.0% and specificity 11.0-60.0%). Sensitivity and specificity of nuclear scintigraphy in the differentiation of ATTR from AL amyloidosis ranged from 90.9% to 91.5% and from 88.6% to 97.1%. Pooled negative likelihood ratio and positive likelihood ratio for scintigraphy in this setting were 0.1 and 8, with EMB reference standard. Study quality assessed by QUADAS-2 was generally poor with evidence of bias.
CONCLUSIONS
Cardiac magnetic resonance is a useful test for diagnosing cardiac amyloidosis but is not reliable in further classifying the disease. Nuclear scintigraphy offers strong diagnostic performance in both the detection of cardiac amyloidosis and differentiating ATTR from AL amyloidosis. Our findings support the use of both imaging modalities in a non-invasive diagnostic algorithm that also tests for the presence of monoclonal protein.
Topics: Amyloid Neuropathies, Familial; Amyloidosis; Biopsy; Diagnosis, Differential; Heart Diseases; Heart Failure; Humans; Immunoglobulin Light-chain Amyloidosis; Magnetic Resonance Imaging; Prevalence; Radionuclide Imaging; Sensitivity and Specificity
PubMed: 31487121
DOI: 10.1002/ehf2.12511 -
Circulation. Genomic and Precision... Oct 2021The p.Val142Ile variant, predominantly found among people of African descent, is the most common cause of variant transthyretin amyloidosis and carriers predominantly...
BACKGROUND
The p.Val142Ile variant, predominantly found among people of African descent, is the most common cause of variant transthyretin amyloidosis and carriers predominantly develop a cardiomyopathy (variant transthyretin amyloidosis cardiomyopathy) phenotype. Yet, there are conflicting data on the prevalence and outcomes of p.Val142Ile variant carriers.
METHODS
We performed a systematic review of the prevalence and outcomes of p.Val142Ile variant transthyretin amyloidosis cardiomyopathy among subjects of African descent. We found 62 relevant articles after searching the MEDLINE databases from 1980 to 2020 that reported data for ≈150 000 subjects.
RESULTS
The reported worldwide prevalence of the p.Val142Ile variant is 0.3% to 1.6% in the general population. Among people of African descent, the reported prevalence from all studies ranges from 1.1% to 9.8%, but for studies with >1000 subjects, it is 3% to 3.5%. The prevalence of the p.Val142Ile variant in a region is dependent on the reported percentage of subjects who are of African descent in that region. p.Val142Ile variant transthyretin amyloidosis cardiomyopathy typically presents in the seventh to eighth decade of life and the majority of cases reported were male, with 25% to 38% diagnosed with atrial fibrillation. It was associated with a longitudinally worse quality of life and a lower adjusted survival compared with other types of transthyretin amyloidosis cardiomyopathy.
CONCLUSIONS
The p.Val142Ile variant is the most common variant of the transthyretin gene with most carriers being of African descent. The true penetrance is unknown but the p.Val142Ile variant is associated with increased rates of incident heart failure and portends a lower overall survival. Increased awareness could lead to earlier diagnosis and improved heart failure outcomes among those of African descent, which is of increasing importance given the advent of novel therapeutics for this disease.
Topics: Amino Acid Substitution; Amyloid Neuropathies, Familial; Cardiomyopathies; Female; Humans; Male; Mutation, Missense; Prealbumin; Prevalence; Risk Factors; Sex Factors
PubMed: 34461737
DOI: 10.1161/CIRCGEN.121.003356 -
JACC. Cardiovascular Imaging Jun 2020This study aimed to compare the diagnostic and prognostic performance of native T1 mapping (T1), extracellular volume (ECV) mapping, and late gadolinium enhancement... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
This study aimed to compare the diagnostic and prognostic performance of native T1 mapping (T1), extracellular volume (ECV) mapping, and late gadolinium enhancement (LGE) imaging for evaluating cardiac amyloidosis (CA).
BACKGROUND
CA is a progressive infiltrative process in the extracellular space that is often underdiagnosed and holds a poor prognosis. Cardiac magnetic resonance (CMR) offers novel techniques for detecting and quantifying the disease burden of CA.
METHODS
We searched PubMed for published studies using native T1, ECV, or LGE to diagnose and prognosticate CA. A total of 18 diagnostic (n = 2,015) and 13 prognostic studies (n = 1,483) were included for analysis. Pooled sensitivities, specificities, diagnostic odds ratios (DORs) of all diagnostic tests were assessed by bivariate analysis. Pooled hazard ratios (HRs) for mortality for the 3 techniques were determined.
RESULTS
Bivariate comparison showed that ECV (DOR: 84.6; 95% confidence interval [CI]: 30.3 to 236.2) had a significantly higher DOR for CA than LGE (DOR: 20.1; 95% CI: 9.1 to 44.1; p = 0.03 vs. ECV). There was no significant difference between LGE and native T1 for sensitivity, specificity, and DOR. HR was significantly higher for ECV (HR: 4.27; 95% CI: 2.87 to 6.37) compared with LGE (HR: 2.60; 95% CI: 1.90 to 3.56; p = 0.03 vs. ECV) and native T1 (HR: 2.04; 95% CI: 1.24 to 3.37; p = 0.01 vs. ECV).
CONCLUSIONS
ECV demonstrates a higher diagnostic OR for assessing cardiac amyloid than LGE and a higher HR for adverse events compared with LGE and native T1. In addition, native T1 showed similar sensitivity and specificity as ECV and LGE without requiring contrast material. Although limited by study heterogeneity, this meta-analysis suggests that ECV provides high diagnostic and prognostic utility for the assessment of cardiac amyloidosis.
Topics: Adult; Aged; Amyloid Neuropathies, Familial; Cardiomyopathies; Female; Gadolinium; Humans; Immunoglobulin Light-chain Amyloidosis; Magnetic Resonance Imaging; Male; Middle Aged; Myocardium; Predictive Value of Tests; Reproducibility of Results; Stroke Volume; Ventricular Function, Left
PubMed: 32498919
DOI: 10.1016/j.jcmg.2020.03.010