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BioRxiv : the Preprint Server For... May 2024ATTR amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made of transthyretin, a protein integral to transporting retinol and thyroid...
ATTR amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made of transthyretin, a protein integral to transporting retinol and thyroid hormones. Transthyretin is primarily produced by the liver and circulates in blood as a tetramer. The retinal epithelium also secretes transthyretin, which is secreted to the vitreous humor of the eye. Because of mutations or aging, transthyretin can dissociate into amyloidogenic monomers triggering amyloid fibril formation. The deposition of transthyretin amyloid fibrils in the myocardium and peripheral nerves causes cardiomyopathies and neuropathies, respectively. Using cryo-electron microscopy, here we determined the structures of amyloid fibrils extracted from cardiac and nerve tissues of an ATTRv-V30M patient. We found that fibrils from both tissues share a consistent structural conformation, similar to the previously described structure of cardiac fibrils from an individual with the same genotype, but different from the fibril structure obtained from the vitreous humor. Our study hints to a uniform fibrillar architecture across different tissues within the same individual, only when the source of transthyretin is the liver. Moreover, this study provides the first description of ATTR fibrils from the nerves of a patient and enhances our understanding of the role of deposition site and protein production site in shaping the fibril structure in ATTRv-V30M amyloidosis.
PubMed: 38798361
DOI: 10.1101/2024.05.14.594028 -
Revue Medicale Suisse May 2024Amyloidosis is a systemic infiltrative disease characterized by deposition of misfolded proteins in tissues, notably affecting the heart. According to type of protein,...
Amyloidosis is a systemic infiltrative disease characterized by deposition of misfolded proteins in tissues, notably affecting the heart. According to type of protein, various types are known with the most prevalent being light-chain and transthyretin amyloidosis. Prognosis is dismal with progression to severe heart failure without disease-modifying treatment. Latter having dramatically improved over the last decade, prompt diagnosis is of paramount importance. Recognition of early signs followed by multidisciplinary approach is essential for optimal patient management.
Topics: Humans; Amyloidosis; Prognosis; Cardiomyopathies; Amyloid Neuropathies, Familial; Disease Progression; Heart Failure
PubMed: 38783670
DOI: 10.53738/REVMED.2024.20.875.1010 -
Arquivos Brasileiros de Cardiologia 2024Transthyretin amyloidosis (ATTR) is an infiltrative disease caused by abnormal protein deposition mainly in the heart and peripheral nervous system. When it affects the...
BACKGROUND
Transthyretin amyloidosis (ATTR) is an infiltrative disease caused by abnormal protein deposition mainly in the heart and peripheral nervous system. When it affects the heart, the disease presents as restrictive cardiomyopathy; when it affects the peripheral and autonomic nervous system, it manifests as polyneuropathy, and is called familial amyloid polyneuropathy (FAP). There are two ATTR subtypes: wild-type ATTR, where there is no mutation, and mutant ATTR (ATTRm), which is characterized by a mutation in the gene encoding the transthyretin protein (TTR). In both subtypes, cardiac involvement is the major marker of poor prognosis.
OBJECTIVES
To assess the prevalence of subclinical cardiac involvement in a sample of patients with TTR gene mutation by using pyrophosphate scintigraphy and strain echocardiography; to compare scintigraphy and strain findings; to evaluate the association between neurological manifestations (FAP) and subclinical cardiac involvement; and to analyze whether there is an association between any specific mutation and cardiac involvement.
METHODS
This is a cross-sectional study with carriers of the TTR gene mutation, without cardiovascular symptoms or changes in electrocardiographic or conventional echocardiographic parameters. All patients underwent pyrophosphate scintigraphy and strain echocardiography. Subclinical cardiac involvement was defined as a Perugini score ≥ 2, heart-to-contralateral lung (H/CL) ratio ≥ 1.5 at 1 h, H/CL ≥1.3 at 3 h, or global longitudinal strain (GLS) ≤ -17%. Descriptive and analytical analyses were performed and Fisher's exact test and Mann-Whitney test were applied. A value of p < 0.05 was considered significant.
RESULTS
The 23 patients evaluated had a median age of 51 years (IQR 37-57 years), 15 (65.2%) were female, 12 (52.2%) were Pardo, nine (39.1%) had systemic arterial hypertension, and nine (39.1%) had a previous diagnosis of FAP. Of the nine patients with FAP, 8 (34.8%) were on tafamidis. The associated mutations were Val142IIe, Val50Met, and IIe127Val. The median GLS in the sample was -19% (-16% to -20%). Of the 23 patients, nine (39.1%; 95% CI = 29-49%) met criteria for cardiac involvement, six (26%) by the GLS-based criteria only. There was no association between having FAP and being an asymptomatic carrier, as assessed by strain echocardiography and pyrophosphate scintigraphy (p = 0.19). The prevalence of systemic arterial hypertension, diabetes mellitus, dyslipidemia, smoking, and reduced GLS did not differ between groups. Septal e' wave velocity was the only variable that significantly differed between individuals with and without reduced GLS, with an area under the ROC curve of 0.80 (95% CI = 0.61-0.98, p = 0.027). The best diagnostic accuracy was achieved with a septal e' velocity ≤ 8.5 cm/s. There was no association between mutation type and preclinical cardiac involvement, nor between tafamidis use and lower degree of cardiac involvement (37.5% versus 40.0%, p = 0.90).
CONCLUSION
Subclinical cardiac involvement was common in a sample of TTR mutation carriers without cardiac involvement. Reduced left ventricular GLS was the most frequent finding. There was no association between the presence of amyloid polyneuropathy and subclinical cardiac involvement. Type of mutation was not associated with early cardiac involvement. In this sample, the use of tafamidis 20 mg/day was not associated with a lower prevalence of subclinical cardiac involvement.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Amyloid Neuropathies, Familial; Cross-Sectional Studies; Echocardiography; Prealbumin; Radionuclide Imaging; Reference Values; Statistics, Nonparametric
PubMed: 38775614
DOI: 10.36660/abc.20230216 -
Circulation. Cardiovascular Imaging May 2024Extracellular volume fraction (ECV) is a marker for myocardial fibrosis and infiltration, can be quantified using cardiac computed tomography (ECV), and has prognostic...
BACKGROUND
Extracellular volume fraction (ECV) is a marker for myocardial fibrosis and infiltration, can be quantified using cardiac computed tomography (ECV), and has prognostic utility in several diseases. This study aims to map out regional differences in ECV to obtain greater insights into the pathophysiological mechanisms of ECV expansion and its clinical implications.
METHODS
Three prospective cohorts were included: patients with aortic stenosis (AS) and coexisting AS and transthyretin cardiac amyloidosis were referred for a transcatheter aortic valve replacement and had ECG-gated CT angiography and Technetium-99m-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy to differentiate between the 2 cohorts. Controls had CT angiography and cardiac magnetic resonance demonstrating no significant coronary artery disease or infarction. Global and regional ECV was analyzed, and its association with mortality was assessed for patients with AS.
RESULTS
In 199 patients, controls (n=65; 66% male), AS (n=115), and coexisting AS and transthyretin cardiac amyloidosis (n=19) had a global ECV of 26.1 (25.0-27.8%) versus 29.1 (27.5-31.1%) versus 37.4 (32.5-46.6%), respectively; <0.001. Across cohorts, ECV was higher at the base (versus apex), the inferoseptum (versus anterolateral wall), and the subendocardium (versus subepicardium); <0.05 for all. Among patients with AS, epicardial ECV, rather than any other regional value or global ECV, was the strongest predictor of mortality at a median of 3.9 (max 6.3) years (adjusted hazard ratio, 1.21 [95% CI, 1.08-1.36]; =0.002).
CONCLUSIONS
Regional differences in ECV suggest a predilection for fibrosis and amyloid infiltration at the base, subendocardium, inferior wall, and septum more than the anterior and lateral myocardium. ECV can predict long-term mortality with the subepicardium demonstrating the strongest discriminatory power.
REGISTRATION
URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03029026 and NCT03094143.
Topics: Humans; Aortic Valve Stenosis; Male; Female; Aged; Prospective Studies; Computed Tomography Angiography; Aged, 80 and over; Myocardium; Fibrosis; Amyloid Neuropathies, Familial; Predictive Value of Tests; Prognosis; Coronary Angiography; Transcatheter Aortic Valve Replacement; Aortic Valve; Cardiomyopathies; Middle Aged
PubMed: 38771906
DOI: 10.1161/CIRCIMAGING.123.015996 -
Journal of Korean Medical Science May 2024Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an under-recognized cause of heart failure (HF) with clinical phenotypes that vary across regions and genotypes. We...
BACKGROUND
Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an under-recognized cause of heart failure (HF) with clinical phenotypes that vary across regions and genotypes. We sought to characterize the clinical characteristics of ATTR-CM in Asia.
METHODS
Data from a nationwide cohort of patients with ATTR-CM from six major tertiary centres in South Korea were analysed between 2010 and 2021. All patients underwent clinical evaluation, biochemical laboratory tests, echocardiography, and transthyretin (TTR) genotyping at the time of diagnosis. The study population comprised 105 Asian ATTR-CM patients (mean age: 69 years; male: 65.7%, wild-type ATTR-CM: 41.9%).
RESULTS
Among our cohort, 18% of the patients had a mean left ventricular (LV) wall thickness < 12 mm. The diagnosis of ATTR-CM increased notably during the study period (8 [7.6%] during 2010-2013 vs. 22 [21.0%] during 2014-2017 vs. 75 [71.4%] during 2018-2021). Although the duration between symptom onset and diagnosis did not differ, the proportion of patients with HF presenting mild symptoms increased during the study period (25% NYHA class I/II between 2010-2013 to 77% between 2018-2021). In contrast to other international registry data, male predominance was less prominent in wild-type ATTR-CM (68.2%). The distribution of TTR variants was also different from Western countries and from Japan. Asp38Ala was the most common mutation.
CONCLUSION
A nationwide cohort of ATTR-CM exhibited less male predominance, a proportion of patients without increased LV wall thickness, and distinct characteristics of genetic mutations, compared to cohorts in other parts of the world. Our results highlight the ethnic variation in ATTR-CM and may contribute to improving the screening process for ATTR-CM in the Asian population.
Topics: Humans; Male; Female; Aged; Republic of Korea; Amyloid Neuropathies, Familial; Cardiomyopathies; Prealbumin; Middle Aged; Cohort Studies; Echocardiography; Asian People; Genotype; Mutation; Heart Failure; Aged, 80 and over
PubMed: 38769922
DOI: 10.3346/jkms.2024.39.e163 -
Circulation May 2024
Topics: Humans; Amyloid Neuropathies, Familial; Prealbumin; Biomarkers; Male; Female; Aged; Middle Aged; Amyloid
PubMed: 38768274
DOI: 10.1161/CIRCULATIONAHA.123.067225 -
Journal of the American Heart... May 2024Although tafamidis treatment improves prognosis in patients with wild-type transthyretin amyloid cardiomyopathy, an optimal surrogate marker monitoring its therapeutic...
BACKGROUND
Although tafamidis treatment improves prognosis in patients with wild-type transthyretin amyloid cardiomyopathy, an optimal surrogate marker monitoring its therapeutic effect remains unclear. This study investigated the association between changes in cardiac biomarkers, high-sensitivity cardiac troponin T (hs-cTnT) and B-type natriuretic peptide (BNP) during the first year after tafamidis treatment and clinical outcomes.
METHODS AND RESULTS
In 101 patients with wild-type transthyretin amyloid cardiomyopathy receiving tafamidis at our institution, change in cardiac biomarkers from baseline to 1 year after tafamidis administration and its association with composite outcomes (composite of all-cause death and hospitalization attributable to heart failure) was assessed. During the follow-up period (median, 17 months), 16 (16%) patients experienced composite outcomes. The hs-cTnT level significantly decreased at 1 year after tafamidis treatment, unlike the BNP level. The frequencies of increased hs-cTnT and BNP levels were significantly higher in those with composite outcomes than in those without (44% versus 15%; =0.01). Kaplan-Meier survival analysis showed that patients in whom both hs-cTnT and BNP levels increased at 1 year after tafamidis had a higher probability of composite outcomes compared with those with decreased hs-cTnT and BNP levels (log-rank <0.01). Cox regression analysis identified increased hs-cTnT and BNP levels at 1 year after tafamidis administration as an independent predictor of higher cumulative risk of composite outcomes.
CONCLUSIONS
Deterioration in cardiac biomarkers during the first year after tafamidis treatment predicted a worse prognosis, suggesting the utility of serial assessment of cardiac biomarkers for monitoring the therapeutic response to tafamidis in patients with wild-type transthyretin amyloid cardiomyopathy.
Topics: Humans; Male; Female; Biomarkers; Natriuretic Peptide, Brain; Aged; Amyloid Neuropathies, Familial; Benzoxazoles; Troponin T; Cardiomyopathies; Treatment Outcome; Time Factors; Middle Aged; Aged, 80 and over; Heart Failure; Retrospective Studies; Prealbumin
PubMed: 38761073
DOI: 10.1161/JAHA.124.034518 -
Journal of the American College of... Jul 2024
Topics: Humans; Amyloid Neuropathies, Familial; Cardiomyopathies; Walking; Male; Aged
PubMed: 38750977
DOI: 10.1016/j.jacc.2024.04.041 -
Kardiologiia Apr 2024To estimate the prevalence of amyloid cardiomyopathy (CM) caused by transthyretin amyloidosis (ATTR) and immunoglobulin light chain (AL) amyloidosis among patients aged...
AIM
To estimate the prevalence of amyloid cardiomyopathy (CM) caused by transthyretin amyloidosis (ATTR) and immunoglobulin light chain (AL) amyloidosis among patients aged >65 years with interventricular septal (IVS) hypertrophy of ≥14 mm.
MATERIAL AND METHODS
From January through August 2023, 60 patients (mean age 7.2±7.3 years, 34 (56.67%) men) were enrolled. Patients meeting the inclusion criteria underwent an echocardiographic study with determining the myocardial longitudinal strain, myocardial scintigraphy with 99mTc-pyrfotech, myocardial single-photon emission computed tomography, measurement of N-terminal fragment of brain natriuretic peptide and troponin I, and the immunochemical study of serum and urine proteins with measurement of free light chains. In the presence of grades 2 and 3 radiopharmaceutical uptake according to scintigraphy, a molecular genetic study was performed for differential diagnosis of wild-type transthyretin amyloidosis (wtATTR) and hereditary/variant (hATTR) ATTR-CM.
RESULTS
According to data of myocardial scintigraphy with 99mTc-pyrfotech, grade 3 uptake in the absence of monoclonal secretion was detected in 5 (8.3%) cases and grade 2 radiotracer uptake in the absence of monoclonal secretion was detected in 6 (10%) patients. Myeloma complicated by AL amyloidosis and primary AL amyloidosis were found in 5 (8.3%) patients.
CONCLUSION
Among patients aged ≥65 years with IVS hypertrophy ≥14 mm, amyloid CM was detected in 20% of cases (12 patients), including 5 cases (8.3%) of AL amyloidosis and 7 cases (11.7%) of ATTR amyloidosis.
Topics: Humans; Male; Female; Russia; Aged; Amyloid Neuropathies, Familial; Prevalence; Hypertrophy, Left Ventricular; Echocardiography; Immunoglobulin Light-chain Amyloidosis; Tomography, Emission-Computed, Single-Photon; Cardiomyopathies
PubMed: 38742516
DOI: 10.18087/cardio.2024.4.n2611