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Clinical Cardiology Sep 2022Transthyretin amyloid cardiomyopathy (ATTR-CM) is a debilitating and life-threatening condition with a heterogeneous clinical presentation. Recent guidelines from the... (Review)
Review
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a debilitating and life-threatening condition with a heterogeneous clinical presentation. Recent guidelines from the United States and Europe have been published to guide clinical practice and to facilitate management conformity by covering current diagnostic and treatment strategies for patients with ATTR-CM. These guidelines highlight the importance of an early diagnosis to optimize therapeutic outcomes, specifying the use of tests and imaging techniques to allow accurate, noninvasive diagnosis of ATTR-CM. However, as regional practice variations across Asia may limit access to healthcare, availability of specific tests, and expertise in assessing diagnostic images, there is an ongoing need to provide an Asian perspective on these clinical guidelines. This review article provides practical recommendations for the diagnosis and monitoring of patients with ATTR-CM in Asia, highlighting the need for additional guidelines to support a broad and diverse population, consider differing healthcare systems and diagnostic testing availability, and provide a flexible yet robust algorithm.
Topics: Amyloid Neuropathies, Familial; Asia; Cardiomyopathies; Early Diagnosis; Humans; Monitoring, Physiologic; Prealbumin
PubMed: 35795903
DOI: 10.1002/clc.23882 -
Biomolecules Aug 2022The plasma protein transthyretin (TTR), a transporter for thyroid hormones and retinol in plasma and cerebrospinal fluid, is responsible for the second most common type...
The plasma protein transthyretin (TTR), a transporter for thyroid hormones and retinol in plasma and cerebrospinal fluid, is responsible for the second most common type of systemic (ATTR) amyloidosis either in its wild type form or as a result of destabilizing genetic mutations that increase its aggregation propensity. The association between free calcium ions (Ca) and TTR is still debated, although recent work seems to suggest that calcium induces structural destabilization of TTR and promotes its aggregation at non-physiological low pH in vitro. We apply high-resolution NMR spectroscopy to investigate calcium binding to TTR showing the formation of labile interactions, which leave the native structure of TTR substantially unaltered. The effect of calcium binding on TTR-enhanced aggregation is also assessed at physiological pH through the mechano-enzymatic mechanism. Our results indicate that, even if the binding is weak, about 7% of TTR is likely to be Ca-bound in vivo and therefore more aggregation prone as we have shown that this interaction is able to increase the protein susceptibility to the proteolytic cleavage that leads to aggregation at physiological pH. These events, even if involving a minority of circulating TTR, may be relevant for ATTR, a pathology that takes several decades to develop.
Topics: Amyloidosis; Calcium; Humans; Prealbumin; Proteolysis
PubMed: 36008960
DOI: 10.3390/biom12081066 -
Heart Failure Reviews Nov 2022Transthyretin (TTR) is a tetrameric transport protein mainly synthesized by the liver and choroid plexus. ATTR amyloidosis is characterized by the misfolding of TTR... (Review)
Review
Transthyretin (TTR) is a tetrameric transport protein mainly synthesized by the liver and choroid plexus. ATTR amyloidosis is characterized by the misfolding of TTR monomers and their accumulation within tissues as amyloid fibres. Current therapeutic options rely on the blockade of TTR production, TTR stabilization to maintain the native structure of TTR, amyloid degradation, or induction of amyloid removal from tissues. "Amyloid seeds" are defined as small fibril fragments that induce amyloid precursors to assume a structure rich in β-sheets, thus promoting fibrillogenesis. Amyloid seeds are important to promote the amplification and spread of amyloid deposits. Further studies are needed to better understand the molecular structure of ATTR seeds (i.e. the characteristics of the most amyloidogenic species), and the conditions that promote the formation and multiplication of seeds in vivo. The pathological cascade may begin months to years before symptom onset, suggesting that seeds in tissues might potentially be used as biomarkers for the early disease stages. Inhibition of amyloid aggregation by anti-seeding peptides may represent a disease mechanism and treatment target in ATTR amyloidosis, with an additional benefit over current therapies.
Topics: Amyloid; Amyloid Neuropathies, Familial; Amyloidosis; Biomarkers; Carrier Proteins; Humans; Prealbumin
PubMed: 35386059
DOI: 10.1007/s10741-022-10237-7 -
Circulation Jul 2019
Topics: Amyloid Neuropathies, Familial; Heart; Humans; Prealbumin; Quality of Life
PubMed: 31549879
DOI: 10.1161/CIRCULATIONAHA.119.041015 -
European Journal of Internal Medicine May 2024Transthyretin amyloid cardiomyopathy (ATTR-CM) has been traditionally considered a rare and inexorably fatal condition. ATTR-CM now is an increasingly recognized cause... (Review)
Review
Transthyretin amyloid cardiomyopathy (ATTR-CM) has been traditionally considered a rare and inexorably fatal condition. ATTR-CM now is an increasingly recognized cause of heart failure (HF) and mortality worldwide with effective pharmacological treatments. Advances in non-invasive diagnosis, coupled with the development of effective treatments, have transformed the diagnosis of ATTR-CM, which is now possible without recourse to endomyocardial biopsy in ≈70 % of cases. Many patients are now diagnosed at an earlier stage. Echocardiography and cardiac magnetic resonance have enabled identification of patients with possible ATTR-CM and more accurate prognostic stratification. Although radionuclide scintigraphy with 'bone' tracers has an established diagnostic value, the diagnostic performance of the bone tracers validated for non-invasive confirmation of ATTR-CM may not be equal. Characterising the wider clinical phenotype of patients with ATTR-CM has enabled identification of features with potential for earlier diagnosis such as carpal tunnel syndrome. Therapies able to slow or halt ATTR-CM progression and increase survival are now available and there is also evidence that patients may benefit from specific conventional HF medications. Cutting-edge research in the field of antibody-mediated removal of ATTR deposits compellingly suggest that ATTR-CM is a truly reversible disorder, bringing hope for patients even with advanced disease. A wide horizon of possibilities is unfolding and awaits discovery.
Topics: Humans; Cardiomyopathies; Amyloid Neuropathies, Familial; Heart Failure; Echocardiography; Prealbumin; Magnetic Resonance Imaging
PubMed: 38184468
DOI: 10.1016/j.ejim.2024.01.001 -
Journal of the American College of... Jul 2016
Topics: Amyloid; Amyloid Neuropathies, Familial; Amyloidosis; Cardiomyopathies; Humans; Prealbumin
PubMed: 27386770
DOI: 10.1016/j.jacc.2016.05.020 -
JACC. Heart Failure Feb 2019
Topics: Alzheimer Disease; Amyloidosis; Brain; Heart Failure; Humans; Prealbumin
PubMed: 30704604
DOI: 10.1016/j.jchf.2018.12.014 -
Circulation Nov 2022
Topics: Humans; Prealbumin; Amyloidosis; Cognition
PubMed: 36441817
DOI: 10.1161/CIRCULATIONAHA.122.062532 -
BMC Nephrology Jul 2019Patients who develop acute kidney injury (AKI) have significantly higher short-term outcomes including in-hospital mortality. The development of AKI has been associated...
Patients who develop acute kidney injury (AKI) have significantly higher short-term outcomes including in-hospital mortality. The development of AKI has been associated with long-term consequences including progression to chronic kidney disease (CKD) and higher rates of cardiovascular disease (CVD) and mortality. In recent years there has been a growing push for the discovery of novel methods to diagnose AKI at earlier stages, and for an improvement in risk stratification and prognosis following AKI.Wang and colleagues assessed the association of total serum indoxyl sulfate (IS) levels, a protein bound uremic toxin, with 90-day mortality after hospital-acquired AKI (HA-AKI). These authors found that serum IS levels were significantly elevated in patients with HA-AKI (2.74 ± 0.75 μg/mL) compared to healthy subjects (1.73 ± 0.11 μg/ml, P < 0.001) and critically ill patients (2.46 ± 0.35 μg/ml, P = 0.016).The mechanisms of this relationship remain unclear, with a limited understanding of cause-specific mortality associated with either the high or low-IS group. One limitation of this current study is an understanding of the acceptable or expected higher level in IS during episodes of AKI. IS levels remained persistently elevated at day 7 compared to β2-microglobulin and serum creatinine which were both lower at 7 days. It is unclear, however, if levels of β2-microglobulin and serum creatinine were lower for other reasons, such as if any patients with AKI required dialysis.This work provides an important addition to the field of AKI research, specifically in the evaluation of readily measurable biomarkers and outcomes after AKI. Moving forward, further validation in studies of acute kidney injury are needed to develop a better understanding of IS levels at the time of AKI diagnosis and trends during the course of AKI.
Topics: Acute Kidney Injury; Creatinine; Humans; Indican; Prealbumin; Renal Dialysis
PubMed: 31345164
DOI: 10.1186/s12882-019-1465-0 -
Common transthyretin-derived amyloid fibril structures in patients with hereditary ATTR amyloidosis.Nature Communications Nov 2023Systemic ATTR amyloidosis is an increasingly important protein misfolding disease that is provoked by the formation of amyloid fibrils from transthyretin protein. The...
Systemic ATTR amyloidosis is an increasingly important protein misfolding disease that is provoked by the formation of amyloid fibrils from transthyretin protein. The pathological and clinical disease manifestations and the number of pathogenic mutational changes in transthyretin are highly diverse, raising the question whether the different mutations may lead to different fibril morphologies. Using cryo-electron microscopy, however, we show here that the fibril structure is remarkably similar in patients that are affected by different mutations. Our data suggest that the circumstances under which these fibrils are formed and deposited inside the body - and not only the fibril morphology - are crucial for defining the phenotypic variability in many patients.
Topics: Humans; Amyloid; Amyloid Neuropathies, Familial; Cryoelectron Microscopy; Prealbumin; Proteostasis Deficiencies
PubMed: 37993462
DOI: 10.1038/s41467-023-43301-3