scholarly journals Cardiac Amyloidosis: Diagnostic Tools for a Challenging Disease

2021 ◽  
Vol 11 (3) ◽  
pp. 111-121
Author(s):  
Marco Giuseppe Migliaccio ◽  
Franco Iodice ◽  
Marco Di Mauro ◽  
Angela Iannuzzi ◽  
Roberta Pacileo ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Cardiac Tissue ◽  
Diastolic Heart Failure ◽  
Target Therapy ◽  
Clinical Signs ◽  
Restrictive Cardiomyopathy ◽  
Diagnostic Tools ◽  
Transthyretin Amyloidosis ◽  
Amyloid Fibril Formation ◽  
Immunoglobulin Light Chain Amyloidosis

Amyloidosis is a group of diseases in which amyloid fibrils build up in tissues, leading to organ dysfunction. Cardiac involvement is observed in immunoglobulin light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) and, when it occurs, the prognosis worsens. Cardiac tissue infiltration can lead to restrictive cardiomyopathy with clinical signs of diastolic heart failure, without reduction of ejection fraction (HFpEF). The aim of multiple and less invasive diagnostic tests is to discern peculiar characteristics and reach the diagnosis without performing an invasive endomyocardial biopsy. These diagnostic tools allow early diagnosis, and they are crucial to best benefit from target therapy. In this review article, we describe the mechanism behind amyloid fibril formation, infiltration of tissues, and consequent clinical signs, focusing on the diagnostic tools and the red flags to obtain a diagnosis.

scholarly journals Cardiac Amyloidosis

2021 ◽  
Author(s):  
Csilla Andrea Eötvös ◽  
Giorgia Pastiu ◽  
Iulia Zehan ◽  
Cerasela Goidescu ◽  
Roxana Chiorescu ◽  
...  
Keyword(s):  
Protein Misfolding ◽  
Cardiac Amyloidosis ◽  
Clinical Laboratory ◽  
Specific Treatment ◽  
Restrictive Cardiomyopathy ◽  
Al Amyloidosis ◽  
Transthyretin Amyloidosis ◽  
Immunoglobulin Light Chain Amyloidosis ◽  
The Many ◽  
Definition Of

Amyloidosis represents a heterogeneous group of disorders caused by amyloid fibril deposition in the extracellular space in different organs. Among the many types of amyloidosis cardiac involvement occurs almost exclusively with immunoglobulin light chain amyloidosis (AL amyloidosis) or transthyretin amyloidosis (ATTR amyloidosis). When present cardiac amyloidosis (CA) has a significant impact on disease prognosis. The typical clinical presentation in CA is that of a restrictive cardiomyopathy. Clinical suspicion of CA is based on clinical, laboratory and electrocardiographic findings. The diagnosis is confirmed using echocardiography, cardiac magnetic resonance imaging, biopsy, and/or bone scintigraphy. A precise definition of amyloidosis type is essential for choosing the specific treatment for this condition. Treatment of CA has two components: general treatment of congestive HF, and specific treatment of the underlying protein misfolding disorder.

scholarly journals Sequence-independent recognition of the amyloid structural motif by GFP protein family

2020 ◽  
Vol 117 (36) ◽  
pp. 22122-22127 ◽  
Author(s):  
Sherry C. S. Xu ◽  
Josephine G. LoRicco ◽  
Anthony C. Bishop ◽  
Nathan A. James ◽  
Welby H. Huynh ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Fluorescent Protein ◽  
Protein Localization ◽  
Fibril Formation ◽  
Structural Motif ◽  
Diagnostic Tools ◽  
Lag Phase ◽  
Dependent Manner ◽  
Amyloid Fibril Formation

Cnidarian fluorescent protein (FP) derivatives such as GFP, mCherry, and mEOS2 have been widely used to monitor gene expression and protein localization through biological imaging because they are considered functionally inert. We demonstrate that FPs specifically bind amyloid fibrils formed from many natural peptides and proteins. FPs do not bind other nonamyloid fibrillar structures such as microtubules or actin filaments and do not bind to amorphous aggregates. FPs can also bind small aggregates formed during the lag phase and early elongation phase of fibril formation and can inhibit amyloid fibril formation in a dose-dependent manner. These findings suggest caution should be taken in interpreting FP-fusion protein localization data when amyloid structures may be present. Given the pathological significance of amyloid-related species in some diseases, detection and inhibition of amyloid fibril formation using FPs can provide insights on developing diagnostic tools.

scholarly journals Diagnostic algorithm in transthyretin amyloidosis with cardiomyopathy

2020 ◽  
Vol 26 (2) ◽  
pp. 5-20
Author(s):  
Mariana Gospodinova ◽  
Elena Kinova ◽  
Iana Simova ◽  
Yoto Yotov ◽  
Marina Garcheva ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Early Recognition ◽  
Multimodality Imaging ◽  
Diagnostic Algorithm ◽  
Restrictive Cardiomyopathy ◽  
Wild Type ◽  
Transthyretin Amyloidosis ◽  
Life Threatening ◽  
Timely Treatment ◽  
Centres Of Expertise

Transthyretin cardiac amyloidosis is a restrictive cardiomyopathy ((ATTR-CM), caused by an extracellular deposition of insoluble amyloid fibrils in the myocardium. It is a life threatening disease with life expectancy of 2 to 6 years after diagnosis. There are two types – hereditary and wild type. Recent data reveal that the wild type ATTR-CM is a common cause of heart failure with preserved ejection fraction, especially in elderly men. Hereditary ATTR amyloidosis is not so rare in Bulgaria. Five different mutations have been diagnosed, the most common being p.Glu89Gln, identified in 62 unrelated families with 117 patients and 72 mutation carriers. ATTR-CM diagnosis is often delayed or even missed, however its early recognition has become very important as a new drug, which is a transthyretin stabilizer is now available and other drugs are under development. Updated knowledge about the clinical presentation, diagnostic algorithm, available and future therapeutic options for ATTR-CM are a prerequisite for an early identification, timely treatment and better prognosis of the affected patients. The diagnosis requires a multidisciplinary approach with the participation of experienced specialists, multimodality imaging, well equipped histopathological and genetic laboratories. Establishing centres of expertise could improve the management of the patients with ATTR-CM.

scholarly journals Cardiac Amyloidosis Therapy: A Systematic Review

2021 ◽  
Vol 11 (1) ◽  
pp. 10-17
Author(s):  
Franco Iodice ◽  
Marco Di Mauro ◽  
Marco Giuseppe Migliaccio ◽  
Angela Iannuzzi ◽  
Roberta Pacileo ◽  
...  
Keyword(s):  
Heart Failure ◽  
Systematic Review ◽  
Cardiac Amyloidosis ◽  
Restrictive Cardiomyopathy ◽  
Novel Therapies ◽  
Preserved Ejection Fraction ◽  
Cardiac Damage ◽  
Transthyretin Amyloidosis ◽  
To Come ◽  
Almost All

Heart involvement in Cardiac Amyloidosis (CA) results in a worsening of the prognosis in almost all patients with both light-chain (AL) and transthyretin amyloidosis (ATTR). The mainstream CA is a restrictive cardiomyopathy with hypertrophic phenotype at cardiac imaging that clinically leads to heart failure with preserved ejection fraction (HFpEF). An early diagnosis is essential to reduce cardiac damage and to improve the prognosis. Many therapies are available, but most of them have late benefits to cardiac function; for this reason, novel therapies are going to come soon.

scholarly journals The Ultrastructure of Tissue Damage by Amyloid Fibrils

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4611
Author(s):  
Haruki Koike ◽  
Masahisa Katsuno
Keyword(s):  
Tissue Damage ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Prion Diseases ◽  
Nerve Biopsy ◽  
Al Amyloidosis ◽  
Amyloid Fibril Formation ◽  
Autopsy Specimens ◽  
Fibril Aggregates ◽  
Interfering Rna

Amyloidosis is a group of diseases that includes Alzheimer’s disease, prion diseases, transthyretin (ATTR) amyloidosis, and immunoglobulin light chain (AL) amyloidosis. The mechanism of organ dysfunction resulting from amyloidosis has been a topic of debate. This review focuses on the ultrastructure of tissue damage resulting from amyloid deposition and therapeutic insights based on the pathophysiology of amyloidosis. Studies of nerve biopsy or cardiac autopsy specimens from patients with ATTR and AL amyloidoses show atrophy of cells near amyloid fibril aggregates. In addition to the stress or toxicity attributable to amyloid fibrils themselves, the toxicity of non-fibrillar states of amyloidogenic proteins, particularly oligomers, may also participate in the mechanisms of tissue damage. The obscuration of the basement and cytoplasmic membranes of cells near amyloid fibrils attributable to an affinity of components constituting these membranes to those of amyloid fibrils may also play an important role in tissue damage. Possible major therapeutic strategies based on pathophysiology of amyloidosis consist of the following: 1) reducing or preventing the production of causative proteins; 2) preventing the causative proteins from participating in the process of amyloid fibril formation; and/or 3) eliminating already-deposited amyloid fibrils. As the development of novel disease-modifying therapies such as short interfering RNA, antisense oligonucleotide, and monoclonal antibodies is remarkable, early diagnosis and appropriate selection of treatment is becoming more and more important for patients with amyloidosis.

Transthyretin Amyloid Cardiomyopathy—Current and Future Therapies

2021 ◽  
pp. 106002802110003
Author(s):  
Jankhna D. Yadav ◽  
Harjot Othee ◽  
Kelly A. Chan ◽  
Damen C. Man ◽  
Paul P. Belliveau ◽  
...  
Keyword(s):  
Cardiac Amyloidosis ◽  
Complex Disease ◽  
Clinical Presentation ◽  
Target Therapy ◽  
Data Extraction ◽  
Organ Transplant ◽  
Standard Of Care ◽  
Transthyretin Amyloidosis ◽  
Treatment Benefits ◽  
Amyloid Cardiomyopathy

Objective: To describe the clinical presentation of transthyretin amyloid cardiomyopathy (ATTR-CM) and discuss current treatments and investigational products and their effect on patient outcomes. Data Sources: A literature search was performed in PubMed (September 2018 to December 2020) using the following keywords: transthyretin amyloidosis, cardiomyopathy, polyneuropathy and transthyretin amyloid cardiomyopathy, monoclonal light-chain, tafamidis, cardiac amyloidosis, ATTR cardiomyopathy, green tea and inhibition of cardiac amyloidosis, AG10, tolcapone, tolcapone and leptomeningeal ATTR, PRX004, NI006, patisiran, inotersen, vutrisiran, AKCEA-TTR-LRx, and NTLA-2001. Study Selection and Data Extraction: Clinical trials were evaluated for evidence supporting pharmacology, safety, efficacy, and measured outcomes. Data Synthesis: Until 2019, there were no approved treatments for ATTR-CM. Treatment consisted of symptom management and organ transplant. Nonpharmacological and pharmacological treatments focused on the symptoms of heart failure (HF) associated with ATTR-CM. However, there are several emerging therapies recently approved or in development to address the underlying pathophysiology. Treatment classes for ATTR-CM include transthyretin stabilizers, human monoclonal antibodies, gene silencers, and CRISPR/Cas9 gene editing. Relevance to Patient Care and Clinical Practice: ATTR-CM is a complex disease in which amyloidosis causes cardiomyopathy. Underdiagnosis is attributed to the clinical presentation being heterogeneous, indistinguishable from HF caused by other etiologies, and the need for invasive testing modalities, including endomyocardial biopsy. Improved diagnostic approaches along with targeted therapies can slow disease progression and enhance patient quality of life. Conclusion: Diagnostic modalities along with biomarker and genetic testing could detect disease earlier and target therapy more accurately. Novel therapies demonstrate potential treatment benefits and can help shape the standard of care for these patients.

Horner’s syndrome in dogs and cats – a review

2019 ◽  
Vol XXIV (138) ◽  
pp. 34-40
Author(s):  
Laís Limeira Rodrigues ◽  
Leonardo Pereira Mesquita ◽  
Denis Alberto Zanatto ◽  
Paulo César Maiorka
Keyword(s):  
Sympathetic Innervation ◽  
Clinical Signs ◽  
Physiological Characteristics ◽  
Diagnostic Tools ◽  
Horner’S Syndrome ◽  
Horner's Syndrome ◽  
The Third

In dogs and cats, Horner's syndrome is characterized by a group of clinical signs arising from an ipsilateral dysfunction of sympathetic innervation of the eye and its appendages. These signs include ptosis, miosis, anisocoria, prolapse of the third eyelid, and enophtalmos. Lesions that may affect directly or indirectly the sympathetic innervation of the eye, such as trauma, neoplasms, iatrogenic lesions, otitis, encephalitis, among others, can induce HS. The aim of the present study was to review the anatomical and physiological characteristics of sympathetic innervation for the ocular globe, with emphasis on the description of the peculiarities of HS, including its etiology, clinical signs, diagnostic tools, as well as its possible treatments and prognosis.

scholarly journals Endo-lysosomal Aβ concentration and pH enable formation of Aβ oligomers that potently induce Tau missorting

2020 ◽  
Author(s):  
Marie P. Schützmann ◽  
Filip Hasecke ◽  
Sarah Bachmann ◽  
Mara Zielinski ◽  
Sebastian Hänsch ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Tau Pathology ◽  
Aβ Oligomers ◽  
Lysosomal Ph ◽  
Amyloid Fibril Formation ◽  
Aβ Amyloid ◽  
Key Factor ◽  
Lysosomal System

AbstractAmyloid-β peptide (Aβ) forms metastable oligomers >50 kD, termed AβOs or protofibrils, that are more effective than Aβ amyloid fibrils at triggering Alzheimer’s disease-related processes such as synaptic dysfunction and Tau pathology, including Tau mislocalization. In neurons, Aβ accumulates in endo-lysosomal vesicles at low pH. Here, we show that the rate of AβO assembly is accelerated 8,000-fold upon pH reduction from extracellular to endo-lysosomal pH, at the expense of amyloid fibril formation. The pH-induced promotion of AβO formation and the high endo-lysosomal Aβ concentration together enable extensive AβO formation of Aβ42 under physiological conditions. Exploiting the enhanced AβO formation of the dimeric Aβ variant dimAβ we furthermore demonstrate targeting of AβOs to dendritic spines, potent induction of Tau missorting, a key factor in tauopathies, and impaired neuronal activity. The results suggest that the endosomal/lysosomal system is a major site for the assembly of pathomechanistically relevant AβOs.

scholarly journals The amphibian antimicrobial peptide uperin 3.5 is a cross-α/cross-β chameleon functional amyloid

2021 ◽  
Vol 118 (3) ◽  
pp. e2014442118
Author(s):  
Nir Salinas ◽  
Einav Tayeb-Fligelman ◽  
Massimo D. Sammito ◽  
Daniel Bloch ◽  
Raz Jelinek ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Membrane Damage ◽  
Fibril Formation ◽  
Regulation Mechanism ◽  
Bacterial Cells ◽  
Amyloid Fibril Formation ◽  
Β Amyloid ◽  
Β Sheets

Antimicrobial activity is being increasingly linked to amyloid fibril formation, suggesting physiological roles for some human amyloids, which have historically been viewed as strictly pathological agents. This work reports on formation of functional cross-α amyloid fibrils of the amphibian antimicrobial peptide uperin 3.5 at atomic resolution, an architecture initially discovered in the bacterial PSMα3 cytotoxin. The fibrils of uperin 3.5 and PSMα3 comprised antiparallel and parallel helical sheets, respectively, recapitulating properties of β-sheets. Uperin 3.5 demonstrated chameleon properties of a secondary structure switch, forming mostly cross-β fibrils in the absence of lipids. Uperin 3.5 helical fibril formation was largely induced by, and formed on, bacterial cells or membrane mimetics, and led to membrane damage and cell death. These findings suggest a regulation mechanism, which includes storage of inactive peptides as well as environmentally induced activation of uperin 3.5, via chameleon cross-α/β amyloid fibrils.

scholarly journals Ultrasonographic Diagnosis of Ileal Intussusception in Calf

2021 ◽  
Vol 49 ◽  
Author(s):  
Ana Clara Sarzedas Ribeiro ◽  
Rodolfo José Cavalcanti Souto ◽  
Tayrlla Polessa Rodrigues Silva ◽  
José Augusto Bastos Afonso ◽  
Carla Lopes Mendonça ◽  
...  
Keyword(s):  
Intestinal Obstruction ◽  
Low Cost ◽  
Clinical Signs ◽  
Chloride Content ◽  
Diagnostic Tools ◽  
Adjacent Segment ◽  
Ultrasound Images ◽  
Target Pattern ◽  
Non Invasive ◽  
Intestinal Obstructions

Background: Intussusception, characterized by invagination of an intestinal segment into the lumen of the adjacent segment, is one of the main causes of intestinal obstruction in cattle, and occurs more frequently in calves. The diagnosis of the disease is based on the history, clinical examination, and complementary exams, which are a challenge in this species, especially in calves, in which transrectal palpation is limited. As it is a non-invasive, effective, and low-cost test, ultrasonography could be an important tool in the diagnosis of intestinal obstructions, in which time is essential for the prognosis. Therefore, the objective was to report a case of intussusception in a calf diagnosed by ultrasound.Case: A 4-month-old calf, weaned at 3 months and raised intensively, was treated at the Clínica de Bovinos de Garanhuns, campus of the Universidade Federal Rural de Pernambuco (CBG/UFRPE), with a history of apathy, anorexia, and dyschezia for 3 days. On physical examination, fever, moderate dehydration, tachycardia, tachypnea with polypnea, bilaterally bulging abdomen, sound of fluid on ballottement, ruminal and intestinal hypomotility, and melena were observed. The hematological findings revealed leukocytosis due to neutrophilia (degenerate neutrophils), hypoproteinemia, and hyperfibrinogenemia. The analysis of the ruminal fluid showed compromised microbiota and increased chloride content. The transabdominal ultrasonography demonstrated, in the right ventral region, hypermotile and full small bowel loops and an increase in the volume of the peritoneal fluid. In addition, there was a segment of the small intestine which, in cross-section, showed multiple concentric rings (“onion rings”, “target pattern”, or “bull’s eye”) and adherence to adjacent loops, compatible with intestinal obstruction due to intussusception. Due to the seriousness of the clinical condition and the ultrasound findings, the animal was euthanized and the necropsy revealed focal fibrinous peritonitis and intestinal obstruction due to intussusception in ileum intestinal segments.Discussion: Intussusception has previously been reported in calves, however this is the first report of ultrasound diagnosis of the disease in Brazil. Although the etiology is rarely confirmed, the age group and recent changes in diet (weaning) were predisposing factors. The history, clinical signs, and laboratory tests were similar to those described in cattle with intussusception, however they may be present in other gastrointestinal illnesses. Other authors have also reported that the nonspecificity of the signs and the impossibility of performing transrectal palpation made it difficult to diagnose intestinal obstruction in calves without the use of other diagnostic tools. As it is a non-invasive and accurate technique, ultrasound has been used in ruminants for diagnostic purposes, including intestinal obstructions. In the present case, the main findings are described as the presence of a lesion with the appearance of multiple concentric rings, hypermotile, dilated, and full intestinal loops. The pathological findings were compatible with the ultrasound images and similar to those described by other authors, confirming the diagnosis. The use of ultrasonography as a diagnostic tool in cattle should be expanded, aiming at the early determination of diagnosis and prognosis, to reduce producer costs and animal discomfort. In cases of intussusception, late diagnosis makes treatment unfeasible.

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