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International Journal of Molecular... May 2019Elevated pro-inflammatory biomarkers and cytokines are associated with morbidity and mortality in heart failure (HF). Preclinical and clinical studies have shown... (Review)
Review
Elevated pro-inflammatory biomarkers and cytokines are associated with morbidity and mortality in heart failure (HF). Preclinical and clinical studies have shown multiple inflammatory mechanisms causing cardiac remodeling, dysfunction and chronic failure. Therapeutics in trials targeting the immune response in heart failure and its effects did not result in evident benefits regarding clinical endpoints and mortality. This review elaborates pathways of immune cytokines in pathogenesis and worsening of heart failure in clinical and cellular settings. Besides the well-known mechanisms of immune activation and inflammation in atherosclerosis causing ischemic cardiomyopathy or myocarditis, attention is focused on other mechanisms leading to heart failure such as transthyretin (TTR) amyloidosis or heart failure with preserved ejection fraction. The knowledge of the pathogenesis in heart failure and amyloidosis on a molecular and cellular level might help to highlight new disease defining biomarkers and to lead the way to new therapeutic targets.
Topics: Amyloidosis; Heart Failure; Humans; Inflammation; Myocardial Ischemia; Prealbumin; Signal Transduction
PubMed: 31083399
DOI: 10.3390/ijms20092322 -
European Heart Journal Jul 2022Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly diagnosed at an early stage of the disease natural history, defined as National Amyloidosis Centre (NAC)... (Observational Study)
Observational Study
AIMS
Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly diagnosed at an early stage of the disease natural history, defined as National Amyloidosis Centre (NAC) ATTR Stage I. The natural history of early-stage ATTR-CM remains poorly characterized.
METHODS AND RESULTS
A retrospective multi-centre observational study of 879 patients with ATTR-CM, either wild-type TTR genotype or carrying the p.V142I TTR variant, and NAC ATTR Stage I biomarkers at the time of diagnosis who did not receive disease-modifying therapy for amyloidosis. Disease characteristics at diagnosis that were independently associated with mortality by Cox regression analysis were N-terminal pro-B-type natriuretic peptide (NT-proBNP), TTR genotype, and troponin T. Patients were categorized into NAC ATTR Stage Ia, defined as a furosemide equivalent diuretic requirement of <0.75 mg/kg and an NT-proBNP ≤500 ng/L or ≤1000 ng/L in the presence of atrial fibrillation, and NAC ATTR Stage Ib comprising all remaining Stage I patients. Median estimated survival among the 88% NAC ATTR Stage Ib patients was 75 (95% CI 57-93) months compared with >100 months in the 12% with Stage Ia disease [hazard ratio for death 5.06 (95% confidence interval 1.23-20.87); P = 0.025] despite significant cardiovascular morbidity at the time of diagnosis which increased during follow-up, including among patients diagnosed in NAC ATTR Stage Ia. Estimated survival among UK NAC ATTR Stage Ia patients was comparable to UK general population controls (P = 0.297).
CONCLUSION
Patients with NAC ATTR Stage I ATTR-CM can be further stratified according to NT-proBNP concentration and diuretic requirement at diagnosis. Patients with Stage Ia ATTR-CM have significant cardiovascular morbidity despite good short- and mid-term survival.
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Cardiovascular Diseases; Disease Progression; Diuretics; Humans; Prealbumin
PubMed: 35608040
DOI: 10.1093/eurheartj/ehac259 -
JBRA Assisted Reproduction Jun 2017Familial amyloid polyneuropathy was first described by Corino de Andrade in 1952 in Northern Portugal. It is a fatal autosomal dominant neurodegenerative disorder... (Review)
Review
Familial amyloid polyneuropathy was first described by Corino de Andrade in 1952 in Northern Portugal. It is a fatal autosomal dominant neurodegenerative disorder characterized by a progression of neurologic symptoms, beginning early in the reproductive life. The Transthyretin gene mutation originates a mutated protein that precipitates in the connective tissue as amyloid deposits. This disease is presently named Transthyretin-related hereditary amyloidosis. We performed an extensive review on this disease based on searches in Medical databases and in paper references. In this review, we briefly summarize the epidemiology and the mechanisms involved on amyloid deposition; we detailed how to evaluate the mechanisms implicated on the development of the major signs and symptoms associated with reproductive dysfunction; and we discuss the mechanisms involved in secondary sexual dysfunction after psychological treatments. Treatment of the disease is directed towards relieving specific symptoms in association with liver transplant, and molecular and genetic therapeutics. Although the current clinical trials indicate symptoms relief, no data on the reproductive function was reported. Thus, preimplantation genetic diagnosis is presently the only available technique that eradicates the disease as it avoids the birth of new patients.
Topics: Adult; Amyloid Neuropathies, Familial; Female; Humans; Male; Mutation; Peripheral Nerves; Prealbumin; Preimplantation Diagnosis
PubMed: 28609277
DOI: 10.5935/1518-0557.20170025 -
International Journal of Molecular... Mar 2019Transthyretin (TTR) amyloidoses (ATTR amyloidosis) are diseases associated with transthyretin (TTR) misfolding, aggregation and extracellular deposition in tissues as... (Review)
Review
Transthyretin (TTR) amyloidoses (ATTR amyloidosis) are diseases associated with transthyretin (TTR) misfolding, aggregation and extracellular deposition in tissues as amyloid. Clinical manifestations of the disease are variable and include mainly polyneuropathy and/or cardiomyopathy. The reasons why TTR forms aggregates and amyloid are related with amino acid substitutions in the protein due to mutations, or with environmental alterations associated with aging, that make the protein more unstable and prone to aggregation. According to this model, several therapeutic approaches have been proposed for the diseases that range from stabilization of TTR, using chemical chaperones, to clearance of the aggregated protein deposited in tissues in the form of oligomers or small aggregates, by the action of disruptors or by activation of the immune system. Interestingly, different studies revealed that curcumin presents anti-amyloid properties, targeting multiple steps in the ATTR amyloidogenic cascade. The effects of curcumin on ATTR amyloidosis will be reviewed and discussed in the current work in order to contribute to knowledge of the molecular mechanisms involved in TTR amyloidosis and propose more efficient drugs for therapy.
Topics: Amino Acid Substitution; Amyloid Neuropathies, Familial; Animals; Curcumin; Humans; Neuroprotective Agents; Prealbumin; Protein Folding
PubMed: 30875761
DOI: 10.3390/ijms20061287 -
International Journal of Molecular... Jun 2019Transthyretin (TTR) is a thyroid hormone-binding protein which transports thyroxine from the bloodstream to the brain. The structural stability of TTR in tetrameric form... (Review)
Review
Transthyretin (TTR) is a thyroid hormone-binding protein which transports thyroxine from the bloodstream to the brain. The structural stability of TTR in tetrameric form is crucial for maintaining its original functions in blood or cerebrospinal fluid (CSF). The altered structure of TTR due to genetic mutations or its deposits due to aggregation could cause several deadly diseases such as cardiomyopathy and neuropathy in autonomic, motor, and sensory systems. The early diagnoses for hereditary amyloid TTR with cardiomyopathy (ATTR-CM) and wild-type amyloid TTR (ATTRwt) amyloidosis, which result from amyloid TTR (ATTR) deposition, are difficult to distinguish due to the close similarities of symptoms. Thus, many researchers investigated the role of ATTR as a biomarker, especially its potential for differential diagnosis due to its varying pathogenic involvement in hereditary ATTR-CM and ATTRwt amyloidosis. As a result, the detection of ATTR became valuable in the diagnosis and determination of the best course of treatment for ATTR amyloidoses. Assessing the extent of ATTR deposition and genetic analysis could help in determining disease progression, and thus survival rate could be improved following the determination of the appropriate course of treatment for the patient. Here, the perspectives of ATTR in various diseases were presented.
Topics: Amyloidogenic Proteins; Amyloidosis; Biomarkers; Diagnosis, Differential; Disease Management; Humans; Mutation; Prealbumin; Protein Aggregates; Protein Aggregation, Pathological; Structure-Activity Relationship; Workflow
PubMed: 31216785
DOI: 10.3390/ijms20122982 -
Journal of Nuclear Cardiology :... Feb 2019Cardiac amyloidosis, once considered untreatable, is now gaining well-deserved attention due to advances in imaging and the recent approval of targeted breakthrough... (Review)
Review
Cardiac amyloidosis, once considered untreatable, is now gaining well-deserved attention due to advances in imaging and the recent approval of targeted breakthrough therapies. In this paper, we discuss the role of radionuclide imaging in the evaluation and management of patients with the most common form of amyloidosis-cardiac transthyretin amyloidosis (ATTR). We provide a comprehensive summary of the literature interspersed with our institutional experience as appropriate, to deliver our perspective.
Topics: Amyloid Neuropathies, Familial; Amyloidosis; Bone and Bones; Cardiomyopathies; Heart; Humans; Prealbumin; Radionuclide Imaging; Technetium Tc 99m Medronate; Technetium Tc 99m Pyrophosphate; Tomography, Emission-Computed, Single-Photon
PubMed: 30569412
DOI: 10.1007/s12350-018-01552-4 -
Cellular and Molecular Life Sciences :... Sep 2021Transthyretin (TTR) is an extracellular protein mainly produced in the liver and choroid plexus, with a well-stablished role in the transport of thyroxin and retinol... (Review)
Review
Transthyretin (TTR) is an extracellular protein mainly produced in the liver and choroid plexus, with a well-stablished role in the transport of thyroxin and retinol throughout the body and brain. TTR is prone to aggregation, as both wild-type and mutated forms of the protein can lead to the accumulation of amyloid deposits, resulting in a disease called TTR amyloidosis. Recently, novel activities for TTR in cell biology have emerged, ranging from neuronal health preservation in both central and peripheral nervous systems, to cellular fate determination, regulation of proliferation and metabolism. Here, we review the novel literature regarding TTR new cellular effects. We pinpoint TTR as major player on brain health and nerve biology, activities that might impact on nervous systems pathologies, and assign a new link between TTR and angiogenesis and cancer. We also explore the molecular mechanisms underlying TTR activities at the cellular level, and suggest that these might go beyond its most acknowledged carrier functions and include interaction with receptors and activation of intracellular signaling pathways.
Topics: Amyloidosis; Central Nervous System; Humans; Neurons; Prealbumin; Protein Aggregates; Reactive Oxygen Species; Thyroxine; Vitamin A
PubMed: 34297165
DOI: 10.1007/s00018-021-03899-3 -
Journal of Integrative Neuroscience Nov 2023Transthyretin (TTR) is secreted by hepatocytes, retinal pigment epithelial cells, pancreatic α and β cells, choroid plexus epithelium, and neurons under stress. The... (Review)
Review
Transthyretin (TTR) is secreted by hepatocytes, retinal pigment epithelial cells, pancreatic α and β cells, choroid plexus epithelium, and neurons under stress. The choroid plexus product is the main transporter of the thyroid hormone thyroxine (T4) to the brain during early development. TTR is one of three relatively abundant cerebrospinal fluid (CSF) proteins (Apolipoprotein J [ApoJ] (also known as clusterin), Apolipoprotein E [ApoE], and TTR) that interact with Aβ peptides , in some instances inhibiting their aggregation and toxicity. It is now clear that clusterin functions as an extracellular, and perhaps intracellular, chaperone for many misfolded proteins and that variation in its gene () is associated with susceptibility to sporadic Alzheimer's disease (AD). The function of ApoE in AD is not yet completely understood, although the allele has the strongest genetic association with the development of sporadic late onset AD. Despite and evidence of the interaction between TTR and Aβ, genomewide association studies including large numbers of sporadic Alzheimer's disease patients have failed to show significant association between variation in the gene and disease prevalence. Early clinical studies suggested an inverse relationship between CSF TTR levels and AD and the possibility of using the reduced CSF TTR concentration as a biomarker. Later, more extensive analyses indicated that CSF TTR concentrations may be increased in some patients with AD. While the observed changes in TTR may be pathogenetically or biologically interesting because of the inconsistency and lack of specificity, they offered no benefit diagnostically or prognostically either independently or when added to currently employed CSF biomarkers, i.e., decreased Aβ1-42 and increased Tau and phospho-Tau. While some clinical data suggest that increases in CSF TTR may occur early in the disease with a significant decrease late in the course, without additional, more granular data, CSF TTR changes are neither consistent nor specific enough to warrant their use as a specific AD biomarker.
Topics: Humans; Alzheimer Disease; Clusterin; Prealbumin; Apolipoproteins E; Biomarkers; Amyloid beta-Peptides
PubMed: 38176942
DOI: 10.31083/j.jin2206158 -
European Heart Journal Jun 2023
Topics: Humans; Prealbumin; Amyloid Neuropathies, Familial; Cardiomyopathies; Radionuclide Imaging
PubMed: 37282599
DOI: 10.1093/eurheartj/ehad281 -
Nutrients Apr 2019Skeletal muscle (SM) mass, the chief component of the structural compartment belonging to lean body mass (LBM), undergoes sarcopenia with increasing age. Decreased SM in... (Review)
Review
Skeletal muscle (SM) mass, the chief component of the structural compartment belonging to lean body mass (LBM), undergoes sarcopenia with increasing age. Decreased SM in elderly persons is a naturally occurring process that may be accelerated by acute or chronic nutritional deficiencies and/or inflammatory disorders, declining processes associated with harmful complications. A recently published position paper by European experts has provided an overall survey on the definition and diagnosis of sarcopenia in elderly persons. The present review describes the additional contributory role played by the noninvasive transthyretin (TTR) micromethod. The body mass index (BMI) formula is currently used in clinical studies as a criterion of good health to detect, prevent, and follow up on the downward trend of muscle mass. The recent upsurge of sarcopenic obesity with its multiple subclasses has led to a confused stratification of SM and fat stores, prompting workers to eliminate BMI from screening programs. As a result, investigators are now focusing on indices of protein status that participate in SM growth, maturation, and catabolism that might serve to identify sarcopenia trajectories. Plasma TTR is clearly superior to all other hepatic biomarkers, showing the same evolutionary patterns as those displayed in health and disease by both visceral and structural LBM compartments. As a result, this TTR parameter maintains positive correlations with muscle mass downsizing in elderly persons. The liver synthesis of TTR is downregulated in protein-depleted states and suppressed in cytokine-induced inflammatory disorders. TTR integrates the centrally-mediated regulatory mechanisms governing the balance between protein accretion and protein breakdown, emerging as the ultimate indicator of LBM resources. This review proposes the adoption of a gray zone defined by cut-off values ranging from 200 mg/L to 100 mg/L between which TTR plasma values may fluctuate and predict either the best or the worst outcome. The best outcome occurs when appropriate dietary, medicinal and surgical decisions are undertaken, resuming TTR synthesis which manifests rising trends towards pre-stress levels. The worst occurs when all therapeutic means fail to succeed, leading inevitably to complete exhaustion of LBM and SM metabolic resources with an ensuing fatal outcome. Some patients may remain unresponsive in the middle of the gray area, combining steady clinical states with persistent stagnant TTR values. Using the serial measurement of plasma TTR values, these last patients should be treated with the most aggressive and appropriate therapeutic strategies to ensure the best outcome.
Topics: Adipose Tissue; Aged; Biomarkers; Body Composition; Body Fluid Compartments; Body Mass Index; Humans; Inflammation; Liver; Muscle, Skeletal; Nutritional Status; Obesity; Prealbumin; Protein Deficiency; Sarcopenia
PubMed: 31010086
DOI: 10.3390/nu11040895