The Structural Understanding of Transthyretin Misfolding and the Inspired Drug Approaches for the Treatment of Heart Failure Associated With Transthyretin Amyloidosis.
Ontology highlight
ABSTRACT:
SUBMITTER: He S
PROVIDER: S-EPMC7930814 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Transthyretin (TTR) amyloidogenesis involves the formation, aggregation, and deposition of amyloid fibrils from tetrameric TTR in different organs and tissues. While the result of amyloidoses is the accumulation of amyloid fibrils resulting in end-organ damage, the nature, and sequence of the molecular causes leading to amyloidosis may differ between the different variants. In addition, fibril accumulation and toxicity vary between different mutations. Structural changes in amyloidogenic TTR have been difficult to identify through X-ray crystallography; but nuclear magnetic resonance spectroscopy has revealed different chemical shifts in the backbone structure of mutated and wild-type TTR, resulting in diverse responses to the cellular conditions or proteolytic stress. Toxic mechanisms of TTR amyloidosis have different effects on different tissues. Therapeutic approaches have evolved from orthotopic liver transplants to novel disease-modifying therapies that stabilize TTR tetramers and gene-silencing agents like small interfering RNA and antisense oligonucleotide therapies. The underlying molecular mechanisms of the different TTR variants could be responsible for the tropisms to specific organs, the age at onset, treatment responses, or disparities in the prognosis.
| S-EPMC8658192 | biostudies-literature
Project description: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.
| S-EPMC6540104 | biostudies-literature
Project description:Transthyretin (TTR) is an essential transporter of a thyroid hormone and a holo-retinol binding protein, found abundantly in human plasma and cerebrospinal fluid. In addition, this protein is infamous for its amyloidogenic propensity, causing various amyloidoses in humans, such as senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. It has been known for over two decades that decreased stability of the native tetrameric conformation of TTR is the main cause of these diseases. Yet, mechanistic details on the amyloidogenic transformation of TTR were not clear until recent multidisciplinary investigations on various structural states of TTR. In this review, we discuss recent advancements in the structural understanding of TTR misfolding and amyloidosis processes. Special emphasis has been laid on the observations of novel structural features in various amyloidogenic species of TTR. In addition, proteolysis-induced fragmentation of TTR, a recently proposed mechanism facilitating TTR amyloidosis, has been discussed in light of its structural consequences and relevance to acknowledge the amyloidogenicity of TTR.
| S-EPMC8122960 | biostudies-literature
Project description:Cardiac amyloidosis (CA) is considered a rare disease with poor prognosis and limited therapeutic options. However, non-biopsy diagnostic modalities as well as emerging therapies are challenging this long-held belief. Radionuclide bone scintigraphy is increasingly being used in the diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CA). As such, it is expected that the number of patients diagnosed with ATTR-CA will continue to rise. Emerging therapies decrease the progressive morbidity and mortality associated with ATTR-CA. The importance of early recognition of ATTR-CA is imperative as prompt initiation of these novel agents is essential to maximize their therapeutic potential. Herein, we outline the current approach to diagnosis of ATTR-CA and review the therapeutic management of the disease.
| S-EPMC7297649 | biostudies-literature
Project description:Heart failure with preserved ejection fraction (HFpEF) comprises half of the heart failure population. A specific, but underdiagnosed, cause for HFpEF is transthyretin-derived (ATTR) amyloidosis. This article reviews the clinical characteristics of cardiac ATTR amyloidosis. The clinical suspicion of cardiac ATTR amyloidosis is strong if pronounced left ventricular hypertrophy is present in the absence of hypertension. Scintigraphy with a diphosphonate tracer is a diagnostic tool for the early detection of cardiac ATTR amyloidosis with high sensitivity and specificity. First treatment options for ATTR amyloidosis recently emerged, and showed a reduction in morbidity and mortality, especially if treatment was started in the early stages of disease. In light of these results, screening for ATTR amyloidosis in the general HFpEF population with left ventricular hypertrophy might be useful.
| S-EPMC7479537 | biostudies-literature
Project description:Hereditary transthyretin amyloidosis (ATTRv) is a severe, adult-onset autosomal dominant inherited systemic disease predominantly affecting the peripheral and autonomic nervous system, heart, kidney and the eyes. ATTRv is caused by mutations of the transthyretin (TTR) gene, leading to extracellular deposition of amyloid fibrils in multiple organs including the peripheral nervous system. Typically, the neuropathy associated with ATTRv is characterised by a rapidly progressive and disabling sensorimotor axonal neuropathy with early small-fibre involvement. Carpal tunnel syndrome and cardiac dysfunction frequently coexist as part of the ATTRv phenotype. Although awareness of ATTRv polyneuropathy among neurologists has increased, the rate of misdiagnosis remains high, resulting in significant diagnostic delays and accrued disability. A timely and definitive diagnosis is important, given the emergence of effective therapies which have revolutionised the management of transthyretin amyloidosis. TTR protein stabilisers diflunisal and tafamidis can delay the progression of the disease, if treated early in the course. Additionally, TTR gene silencing medications, patisiran and inotersen, have resulted in up to 80% reduction in TTR production, leading to stabilisation or slight improvement of peripheral neuropathy and cardiac dysfunction, as well as improvement in quality of life and functional outcomes. The considerable therapeutic advances have raised additional challenges, including optimisation of diagnostic techniques and management approaches in ATTRv neuropathy. This review highlights the key advances in the diagnostic techniques, current and emerging management strategies, and biomarker development for disease progression in ATTRv.
| S-EPMC9148983 | biostudies-literature
Project description:Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal condition that requires early diagnosis, management, and specific treatment. The availability of new disease-modifying therapies has made successful treatment a reality. Transthyretin amyloid cardiomyopathy can be either age-related (wild-type form) or caused by mutations in the TTR gene (genetic, hereditary forms). It is a systemic disease, and while the genetic forms may exhibit a variety of symptoms, a predominant cardiac phenotype is often present. This document aims to provide an overview of ATTR-CM amyloidosis focusing on cardiac involvement, which is the most critical factor for prognosis. It will discuss the available tools for early diagnosis and patient management, given that specific treatments are more effective in the early stages of the disease, and will highlight the importance of a multidisciplinary approach and of specialized amyloidosis centres. To accomplish these goals, the World Heart Federation assembled a panel of 18 expert clinicians specialized in TTR amyloidosis from 13 countries, along with a representative from the Amyloidosis Alliance, a patient advocacy group. This document is based on a review of published literature, expert opinions, registries data, patients' perspectives, treatment options, and ongoing developments, as well as the progress made possible via the existence of centres of excellence. From the patients' perspective, increasing disease awareness is crucial to achieving an early and accurate diagnosis. Patients also seek to receive care at specialized amyloidosis centres and be fully informed about their treatment and prognosis.
| S-EPMC10607607 | biostudies-literature
Project description:Structural characterization of misfolded protein aggregates is essential to understanding the molecular mechanism of protein aggregation associated with various protein misfolding disorders. Here, we report structural analyses of ex vivo transthyretin aggregates extracted from human cardiac tissue. Comparative structural analyses of in vitro and ex vivo transthyretin aggregates using various biophysical techniques revealed that cardiac transthyretin amyloid has structural features similar to those of in vitro transthyretin amyloid. Our solid-state nuclear magnetic resonance studies showed that in vitro amyloid contains extensive nativelike β-sheet structures, while other loop regions including helical structures are disrupted in the amyloid state. These results suggest that transthyretin undergoes a common misfolding and aggregation transition to nativelike aggregation-prone monomers that self-assemble into amyloid precipitates in vitro and in vivo.
| S-EPMC7306164 | biostudies-literature
Project description:Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of heart failure (HF) and mortality worldwide. Advances in non-invasive diagnosis, coupled with the development of effective treatments, have shifted ATTR-CA from a rare and untreatable disease to a relatively prevalent condition that clinicians should consider on a daily basis. Amyloid fibril formation results from age-related failure of homoeostatic mechanisms in wild-type ATTR (ATTRwt) amyloidosis (non-hereditary form) or destabilizing mutations in variant ATTR (ATTRv) amyloidosis (hereditary form). Longitudinal large-scale studies in the United States suggest an incidence of cardiac amyloidosis in the contemporary era of 17 per 100 000, which has increased from a previous estimate of 0.5 per 100 000, which was almost certainly due to misdiagnosis and underestimated. The presence and degree of cardiac involvement is the leading cause of mortality both in ATTRwt and ATTRv amyloidosis, and can be identified in up to 15% of patients hospitalized for HF with preserved ejection fraction. Associated features, such as carpal tunnel syndrome, can preceed by several years the development of symptomatic HF and may serve as early disease markers. Echocardiography and cardiac magnetic resonance raise suspicion of disease and might offer markers of treatment response at a myocardial level, such as extracellular volume quantification. Radionuclide scintigraphy with 'bone' tracers coupled with biochemical tests may differentiate ATTR from light chain amyloidosis. Therapies able to slow or halt ATTR-CA progression and increase survival are now available. In this evolving scenario, early disease recognition is paramount to derive the greatest benefit from treatment.
| S-EPMC9897687 | biostudies-literature
Project description:BackgroundNuclear imaging modalities using 123Iodine-metaiodobenzylguanidine (123I-MIBG) and bone seeking tracers identify early cardiac involvement in ATTRm amyloidosis patients. However, little is known whether results from 123I-MIBG scintigraphy actually correlate to markers for either cardiac autonomic neuropathy or cardiomyopathy.MethodsAll TTR mutation carriers and ATTRm patients who underwent both 123I-MIBG and 99mTechnetium-hydroxymethylene diphosphonate (99mTc-HDP) scintigraphy were included. Cardiomyopathy was defined as NT-proBNP > 365 ng/L, and cardiac autonomic neuropathy as abnormal cardiovascular reflexes at autonomic function tests. Late 123I-MIBG heart-to-mediastinum ratio (HMR) < 2.0 or wash-out > 20%, and any cardiac 99mTc-HDP uptake were considered as abnormal.Results39 patients (13 carriers and 26 ATTRm patients) were included in this study. Patients with cardiomyopathy, with or without cardiac autonomic neuropathy, had lower late HMR than similar patients without cardiomyopathy [median 1.1 (range 1.0-1.5) and 1.5(1.2-2.6) vs 2.4 (1.4-3.8) and 2.5 (1.5-3.7), respectively, P < 0.001]. Late HMR and wash-out (inversely) correlated with NT-proBNP r = - 0.652 (P < 0.001) and r = 0.756 (P < 0.001), respectively. Furthermore, late HMR and wash-out (inversely) correlated with cardiac 99mTc-HDP uptake r = - 0.663 (P < 0.001) and r = 0.617 (P < 0.001), respectively.ConclusionIn case of heart failure, 123I-MIBG scintigraphy reflects cardiomyopathy rather than cardiac autonomic neuropathy in ATTRm patients and TTR mutation carriers. 123I-MIBG scintigraphy may already be abnormal before any cardiac bone tracer uptake is visible.
| S-EPMC7599160 | biostudies-literature