Overview of the main subtypes of amyloidosis with the possibility of cardiac involvement.
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"9210",leadTitle:null,fullTitle:"Quantum Dots - Fundamental and Applications",title:"Quantum Dots",subtitle:"Fundamental and Applications",reviewType:"peer-reviewed",abstract:"Quantum dots (QDs) are luminescent semiconductor nanocrystals with unique chemical and physical properties due to their size and highly compact structure. QDs were first proposed for use in luminescent concentrators to replace organic dye molecules. In this book, the interest is in taking advantage of the emission properties of QDS, which can be tuned by their size, resulting from quantum confinement. In addition, the book discusses the potential of QDs as contrast and therapeutic agents in the field of medicine.",isbn:"978-1-83880-919-5",printIsbn:"978-1-83880-918-8",pdfIsbn:"978-1-83880-920-1",doi:"10.5772/intechopen.83206",price:100,priceEur:109,priceUsd:129,slug:"quantum-dots-fundamental-and-applications",numberOfPages:92,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"a4343b3c941808702febf1d6b5bda803",bookSignature:"Faten Divsar",publishedDate:"June 24th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/9210.jpg",numberOfDownloads:4654,numberOfWosCitations:7,numberOfCrossrefCitations:11,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:18,numberOfDimensionsCitationsByBook:2,hasAltmetrics:0,numberOfTotalCitations:36,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 29th 2019",dateEndSecondStepPublish:"September 20th 2019",dateEndThirdStepPublish:"November 19th 2019",dateEndFourthStepPublish:"February 7th 2020",dateEndFifthStepPublish:"April 7th 2020",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"293418",title:"Dr.",name:"Faten",middleName:null,surname:"Divsar",slug:"faten-divsar",fullName:"Faten Divsar",profilePictureURL:"https://mts.intechopen.com/storage/users/293418/images/system/293418.jpg",biography:"Faten Divsar received her PhD in analytical chemistry from Kharazmi University, Tehran in 2009. She conducted her postdoctoral training at Nanjing University (Nanjing, China) in 2011 and 2012, where her research was mainly devoted to the design of DNA biosensors by means of electrochemiluminescence spectrometry. Currently she is an Assistant Professor at the Chemistry Department of Payame Noor University, Iran. Her research focuses on two active programs, namely design of bioanalytical and electrochemical sensors, and development of innovative nanomaterials for pollution removal and water treatment.",institutionString:"Payame Noor University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Payame Noor University",institutionURL:null,country:{name:"Iran"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"208",title:"Material Science",slug:"nanotechnology-and-nanomaterials-material-science"}],chapters:[{id:"71780",title:"Introductory Chapter: Quantum Dots",doi:"10.5772/intechopen.92151",slug:"introductory-chapter-quantum-dots",totalDownloads:797,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Faten Divsar",downloadPdfUrl:"/chapter/pdf-download/71780",previewPdfUrl:"/chapter/pdf-preview/71780",authors:[{id:"293418",title:"Dr.",name:"Faten",surname:"Divsar",slug:"faten-divsar",fullName:"Faten Divsar"}],corrections:null},{id:"70534",title:"Quantum Confinement Effect of 2D Nanomaterials",doi:"10.5772/intechopen.90140",slug:"quantum-confinement-effect-of-2d-nanomaterials",totalDownloads:960,totalCrossrefCites:11,totalDimensionsCites:17,hasAltmetrics:0,abstract:"Quantum confinement is the spatial confinement of electron–hole pairs (excitons) in one or more dimensions within a material, and also electronic energy levels are discrete. It is due to the confinement of the electronic wave function to the physical dimensions of the particles. In this effect can be divided into three ways, 1D confinement (free carrier in a plane), quantum wells; 2D confinement (carriers are free to move down), quantum wire; and 3D confinement (carriers are confined in all directions), which are discussed in detail. In addition the formation mechanism of exciton and quantum confinement behavior of strong, moderate, and weak confinement have been discussed below.",signatures:"Gopal Ramalingam, Poopathy Kathirgamanathan, Ganesan Ravi, Thangavel Elangovan, Bojarajan Arjun kumar, Nadarajah Manivannan and Kaviyarasu Kasinathan",downloadPdfUrl:"/chapter/pdf-download/70534",previewPdfUrl:"/chapter/pdf-preview/70534",authors:[{id:"250055",title:"Dr.",name:"Elangovan",surname:"Thanagvel",slug:"elangovan-thanagvel",fullName:"Elangovan Thanagvel"},{id:"306901",title:"Dr.",name:"Ramalingam",surname:"Gopal",slug:"ramalingam-gopal",fullName:"Ramalingam Gopal"},{id:"307937",title:"Prof.",name:"Poopathy",surname:"Kathikamanagthan",slug:"poopathy-kathikamanagthan",fullName:"Poopathy Kathikamanagthan"},{id:"307938",title:"Prof.",name:"Ganasen",surname:"Ravi",slug:"ganasen-ravi",fullName:"Ganasen Ravi"},{id:"307939",title:"Mr.",name:"Bojarajan",surname:"Arjun Kumar",slug:"bojarajan-arjun-kumar",fullName:"Bojarajan Arjun Kumar"}],corrections:null},{id:"71659",title:"Temperature Effects in the Photoluminescence of Semiconductor Quantum Dots",doi:"10.5772/intechopen.91888",slug:"temperature-effects-in-the-photoluminescence-of-semiconductor-quantum-dots",totalDownloads:731,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Temperature effects in the exciton photoluminescence specific to semiconductor quantum dots (QDs) are reviewed using Si QDs as an example. The processes of direct and indirect optical excitation of spatially confined excitons in quantum dots embedded in dielectric matrix are analyzed. The temperature behavior of the quantum dots photoluminescence (PL) excited by various methods was described in detail by a generalized electronic transitions scheme using different exciton relaxation models. The different types of temperature dependences were analyzed. The analytical expressions were obtained for their description, which allow one to determine the energy and kinetic characteristics of QD photoluminescence. It was found that the shape of the temperature dependence makes it possible to understand whether the process of exciton relaxation contains several different thermally activated stages or this is a simple one-stage process. The applicability of the obtained expressions for the analysis of the luminescence properties of quantum dots is demonstrated by the example of crystalline and amorphous silicon nanoclusters in silica matrix. It has been established that the quantum confinement effect of excitons in quantum dots leads to a decrease in the frequency characteristics and thermal activation barriers for nonradiative transitions.",signatures:"Anatoly Zatsepin and Dmitry Biryukov",downloadPdfUrl:"/chapter/pdf-download/71659",previewPdfUrl:"/chapter/pdf-preview/71659",authors:[{id:"230919",title:"Dr.",name:"Anatoly",surname:"Zatsepin",slug:"anatoly-zatsepin",fullName:"Anatoly Zatsepin"},{id:"312874",title:"Dr.",name:"Dmitry",surname:"Biryukov",slug:"dmitry-biryukov",fullName:"Dmitry Biryukov"}],corrections:null},{id:"70028",title:"Quantum Dots CdSe/ZnS as a Source Array of Entangled States",doi:"10.5772/intechopen.88558",slug:"quantum-dots-cdse-zns-as-a-source-array-of-entangled-states",totalDownloads:699,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"A quantum dot is a quantum system in classical space with unique characteristics, as a result of a large quantum limitation. The experimental results of this chapter substantiate the ability of quantum dots to play a key role in purely quantum processes, for example, teleportation of quantum objects, and the generation of macroscopic quantum gravity force and, of course, are a qubit in quantum computing. A quantum dot has the ability to capture (capture) a photo-induced charge carrier by a surface defect of its crystal structure and, thereby, create a second stable long-lived quantum state, which is a necessary requirement for a qubit. This ability puts a quantum dot out of competition with respect to many other quantum objects, like qubits, in terms of the simplicity and cheapness of their continuous generation in standard laboratory conditions. Quantum dots have received wide recognition because of their unique exciton luminescence characteristics; this chapter substantiates a fundamentally new area to use quantum dots in the development and study of both fundamental and applied physics.",signatures:"Anatolii Isaev",downloadPdfUrl:"/chapter/pdf-download/70028",previewPdfUrl:"/chapter/pdf-preview/70028",authors:[{id:"308135",title:"M.D.",name:"Anatolii",surname:"Isaev",slug:"anatolii-isaev",fullName:"Anatolii Isaev"}],corrections:null},{id:"71347",title:"Quantum Dot Light-Emitting Diode: Structure, Mechanism, and Preparation",doi:"10.5772/intechopen.91162",slug:"quantum-dot-light-emitting-diode-structure-mechanism-and-preparation",totalDownloads:1151,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Quantum dot light-emitting diode (QLED) attracted much attention for the next generation of display due to its advantages in high color saturation, tunable color emission, and high stability. Compared with traditional LED display, QLED display has advantages in flexible and robust application, which makes wearable and stretchable display possible in the future. In addition, QLED display is a self-emissive display, in which light is generated by individual subpixel, each subpixel can be individually controlled. Each subpixel in LED display is constituted by liquid crystal and color filter, which make LED display have lower power efficiency and less enhanced functionality. This chapter introduces the QLED based on the QLED structure and light-emitting mechanism of QLED. Then, a novel method for fabricating QLEDs, which is based on the ZnO nanoparticles (NPs) incorporated into QD nanoparticles, will be introduced. The QLED device was fabricated by all-solution processes, which make the QLED fabrication process more flexible and more suitable for industrialization. What is more, as QLED devices were planned to integrate into a display, all-solution fabrication processes also make printing QLED display device possible in the near future.",signatures:"Ning Tu",downloadPdfUrl:"/chapter/pdf-download/71347",previewPdfUrl:"/chapter/pdf-preview/71347",authors:[{id:"311315",title:"Dr.",name:"Ning",surname:"Tu",slug:"ning-tu",fullName:"Ning Tu"}],corrections:null},{id:"71984",title:"Retracted: What Did We Attain with Luminescent Quantum Dots?",doi:"10.5772/intechopen.92209",slug:"retracted-what-did-we-attain-with-luminescent-quantum-dots-",totalDownloads:320,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Quantum dots (QDs) are practically nanoparticles, which are obtained by reducing sizes until they reach the order of nanometers. Their unique optical properties inspire scientists especially in medical sciences in applications such as tumor detection, cardiovascular imaging, and cancer targeting. Here, we first discuss scanning acoustic microscopy (SAM) results to evaluate the potential of SAM in the detection of lead-sulfide (PbS), graphene, and cadmium-telluride/cadmium sulfide (CdTe/CdS) quantum dot aggregates. The success of imaging quantum dots by SAM indicated the potential of SAM in monitoring the microenvironment of the disease and also the therapeutic effect of the drug-loaded QDs. Therefore, secondly we present confocal laser scanning microscopy results of graphene QDs engulfed in macrophages, which are in high numbers in the microenvironment of tumors, to evaluate the potential of graphene QDs in tumor targeting.",signatures:"Bukem Tanoren and Ali Eren Guzey",downloadPdfUrl:"/chapter/pdf-download/71984",previewPdfUrl:"/chapter/pdf-preview/71984",authors:[null],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:[{id:"65",label:"highly cited contributor"}]},relatedBooks:[{type:"book",id:"6408",title:"Novel Nanomaterials",subtitle:"Synthesis and Applications",isOpenForSubmission:!1,hash:"f3585d338d78e4d31c200d9991b03692",slug:"novel-nanomaterials-synthesis-and-applications",bookSignature:"George Z. Kyzas and Athanasios C. 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Amyloidosis is an infiltrative disease defined by extracellular accumulation of fibrillar proteins in the tissues, including the heart (cardiac amyloidosis (CA)). Lately, about 30 different types of amyloidosis have been described, each due to a specific misfolded protein [1]. Some types of amyloidosis are hereditary others are caused by abnormal organ or plasma cells producing a precursor protein. Additional causes involve long-term dialysis or inflammatory diseases. The disease is classified as “localized amyloidosis” and “systemic amyloidosis”.
The main subtypes of amyloidosis are summarized in the following:
CA is a leading cause of restrictive cardiomyopathy due to interstitial deposits of amyloid impairing the elasticity and contractility of the myocardium and leaving the muscle stiff. Early findings include abnormal myocardial relaxation, gradually advancing to restrictive filling pattern, with signs and symptoms of heart failure. As specified above, the most common types of CA are AL and ATTR-amyloidosis (Table 1). An early diagnosis is of paramount importance in order to start the adequate treatment according to the disease, which determines the patient’s prognosis.
Amyloid subtype | Precursor protein | Origin | Affected Organs | Clinical signs | Therapy |
---|---|---|---|---|---|
Mono-clonal light chain | Plasma cells in bone marrow | Heart, kidneys, liver, nerves, gastro-intestinal tract, liver, soft tissue | periorbital hematoma, macro-glossia, proteinuria, weight loss | Chemotherapy | |
Trans-thyretin mutation | Liver | Heart, kidneys, peripheral and autonomic nervous system, gastro-intestinal tract | Sudden cardiac death, arrhythmia, syncope, dysautonomia (orthostatic hypotension) peripheral sensory-motor neuropathy | Tafamidis, or 2-(3,5-dichloro-phenyl)-benzoxazole 6-carboxylic acid; Promising pharmacologic strategies to stabilize TTR | |
Abnormal Trans-thyretin | Liver | Heart and peripheral nervous system | Heart failure, spinal stenosis, bilateral carpal tunnel syndrome | ||
Serum amyloid A | Liver | Liver, kidneys, heart (rare) | Heart failure | Treatment of underlying inflammatory process | |
Mutation in Apolipo-protein A1 gene | Liver, kidneys, heart | Heart failure, proteinuria, hematuria, edema, hepato-splenomegaly | Liver transplantation | ||
Atrial natriuretic factor | Heart | Heart only | atrial fibrillation/arrhythmia | no specific therapy available |
Overview of the main subtypes of amyloidosis with the possibility of cardiac involvement.
Previously, the gold standard of CA diagnosis was a histological analysis of endomyocardial tissue. The invasive nature of an endomyocardial biopsy (EMB) limits its routine application. The following immediate or late complications are associated with EMB: pericardial effusion with or without tamponade, arrhythmias, tricuspid valve damage, pneumothorax, pulmonary embolism, nerve paralysis, bleeding complications, creation of an arteriovenous fistula, venous thromboembolism, and infections [17]. Major complications caused by EMB are described with a rate of 1% even when performed in large centers by experienced operators [18, 19, 20]. The cause of death is often perforation with tamponade.
Advances in imaging protocols have led to them being primarily used in daily clinical routine. The following chapter provides diagnostic steps for patients with CA including the most recent literature.
The diagnostic procedure starts with a simple electrocardiogram (ECG), which may already provide clues for the presence of CA. Historically, CA is a condition associated with low voltage in the ECG, which usually is defined as a peak-to-peak QRS amplitude of less than 5 millimeters in the limb leads and/or less than 10 millimeters in the precordial leads [21].
Rapezzi et al. analyzed ECG recordings of AL, ATTRm and ATTRwt-amyloidosis and found significant differences among the three groups for low QRS voltage and left bundle-branch block [22]. Left bundle-branch block was frequently present in ATTRwt (40%), while in AL low QRS voltage was more common (25% ATTR versus 60% in AL). Boldrini et al. assessed the prevalence of intraventricular and atrioventricular conduction delays in a cohort of 344 AL patients. Intraventricular conduction delay due to myocardial amyloid deposits was associated with worse systolic function, higher mortality, and higher levels of cardiac biomarker [23]. Further 276 patients with a diagnosis of systemic amyloidosis, admitted to the Beijing Union Medical College Hospital from January 2000 to December 2011, were evaluated by Cheng and colleagues [24]. The study reported atrial arrhythmia, low voltage on limb leads, AV-block, and pseudo-infarct pattern as the most present ECG pattern in CA than control groups. In summary, the study data suggests a high specificity and a positive predictive value of low voltage on limb leads and pseudo-infarct pattern for the diagnosis of CA. However, these features are only observed in some CA patients (50% AL and 30% ATTR) and often in a later stage of the disease [25].
The most frequent arrhythmias in CA are atrial fibrillation (45–65%), ventricular tachyarrhythmias (ventricular tachycardia 9.9% and ventricular fibrillation 0.7%) and AV conduction delays (3.5%) [26]. The risk of SCD is increased, especially in advanced disease. The Austrian hot spot mutation His108Arg is linked to an increased incidence of ventricular tachycardia [27]. The proarrhythmic substrate for ventricular arrhythmias in CA is left ventricular fibrosis leading to micro- and macro-reentrant circuits [28]. Therefore, Holter-ECG monitoring is recommended in CA at initial presentation and follow-up.
Although electrophysiological studies (EPS) do not serve as a diagnostic tool, research supports their prognostic relevance. For example, in a study by Reisinger et al., 92% had a prolonged His-ventricular (HV) interval (>55 ms), which was identified as an independent predictor of SCD on multivariate analysis among patients with AL [29]. In a recently published study by Orini et al., ventricular conduction and repolarization abnormalities were more pronounced in AL compared to ATTR-amyloidosis [30].
In conclusion, in patients with AL and ATTR-amyloidosis, ECG and Holter-monitor are important tools to diagnose AV conduction delays as well as atrial and ventricular arrhythmias. Implantation of a permanent pacemaker system is recommended in patients meeting the established criteria for device implantation [31]. EPS should be considered in the setting of unexplained syncope due to the fact of common HV prolongation in absence of AV-Block in the 12-lead ECG. Patients with AL-amyloidosis have a higher risk to develop arrhythmias and suffer from a poor prognosis. However, implantable cardioverter defibrillator (ICD) for primary prophylactic therapy did not show a survival benefit in AL-CA. Their use may be considered in patients with AL or ATTR associated CA complicated with ventricular arrhythmias causing hemodynamic instability, who are having a life expectancy of more than one year with good functional status [32, 33, 34].
In suspected CA further laboratory parameters are needed. Due to an underlying plasma cell dyscrasia in AL-amyloidosis, a monoclonal gammopathy is detected by electrophoresis and immunochemical measurements of specific isotypes or free light chains (FLC) pairs. The spike of light chains is referred as “Bence Jones protein”. For detection of even small amounts of FLC a serum fluorescence lifetime correlation spectroscopy and a serum FLC (sFLC) assay are of great additional value [35]. If monoclonal proteins are identified, the patient should be referred to a hematologist for further evaluation including a bone marrow biopsy. In case, an AL-amyloidosis can be ruled out, the next step should involve Technetium (Tc) -labeled cardiac scintigraphy (for further details see chapter 2.5).
Incorporation of sFLC differentiation into the current staging system for AL-amyloidosis improves risk stratification therapy optimization. Increased values of cardiac biomarkers such as brain natriuretic peptide (BNP), N-terminal brain natriuretic peptide (NT-proBNP), and Troponin (TnI, TnT) are used as screening parameters for cardiac involvement and clinical outcome. They might also assess the treatment response. In general, natriuretic peptides and Troponin levels are commonly elevated in CA, with a mild elevation seen in ATTR and higher levels in AL due to a cardiotoxic effect of light chains. The Mayo classification consists of TnT, NT-proBNP, and FLC-ratio (difference between light chain kappa and lambda) and helps estimating cardiac involvement and prognosis in AL patients [36].
Echocardiography is an essential screening tool for CA and speeds up diagnosis. The most important finding represents the ventricular hypertrophy associated with amyloid self-aggregation (Figure 1). However, left ventricular (LV) wall thickening may also be seen in other conditions, such as long-standing arterial hypertension, high-grade aortic stenosis, hypertrophic cardiomyopathy (HCM) or storage diseases such as Fabry’s disease. Therefore, further echocardiographic characteristics such as thickening of the atrial septum, valvular leaflets, as well as enlarged atria and pericardial effusion raise suspicion towards CA. Furthermore, assessment of diastolic function is a useful evaluation tool for CA. Diastolic dysfunction usually appears before pathologic measurements of left or right ventricular (RV) walls and it is the hallmark of amyloid heart disease [37]. A restrictive filling pattern is found in up to one-third of the CA population. According to the European classification of cardiomyopathies, CA may be regarded either as restrictive or hypertrophic cardiomyopathy based on the severity of diastolic filling impairment [38]. Based on hypertrophy and diastolic function parameters Aimo et al. developed a simple score named AMYLoidosis Index (AMYLI), as the product of relative wall thickness (RWT) and E/e’ ratio, for initial screening of CA patients (AMYLI <2.22 excludes the diagnosis in patients undergoing a diagnostic screening for CA) [39]. However, this score needs further validation and is currently not in use for clinical routine.
Echocardiographic imaging showing a parasternal long axis view of a left ventricular hypertrophy and an apical 4-chamber view demonstrating mitral regurgitation.
Historically, “sparkling myocardium” is associated with CA. Granular sparkling is seen in approximately 25% of CA patients, which is attributed to increased echogenicity of the amyloid protein [40]. However, scanning with tissue harmonic frequencies imparts increased echogenicity of myocardium in general and granular sparkling may be overdiagnosed. In general, “speckled appearance” alone is not diagnostic of CA, since HCM, end-stage renal disease, harmonic imaging, and glycogen storage disease produce similar appearance [41].
Speckle tracking as an advanced echocardiography technic is a useful tool to differentiate CA from other causes of LV hypertrophy including other storage diseases. Myocardial speckle tracking-based strain imaging of the LV can help in the differential diagnosis and the presence of relative apical sparing may indicate CA. While left ventricular ejection fraction (LVEF) is preserved at early stages of CA, the longitudinal systolic contraction is already impaired [40]. Typically, the longitudinal strain at the basal and the mid ventricular segments is reduced, while the longitudinal apical strain of the LV is preserved (apical sparing). Preserved apical strain can be visualized using the strain ratio or the bull’s eye plot (Figure 2) [42]. The pathophysiological basis of the apical sparing is not fully understood, but advanced imaging has shown evidence of amyloid deposition preferably in the basal and mid ventricular segments. In addition, a normal value of the global longitudinal strain (GLS) is known as a positive predictor for survival [43].
Automated strain imaging using speckle-tracking algorithm.
Although concomitant RV free wall hypertrophy is suggestive of infiltrative cardiomyopathy, an additional RV apical sparing pattern has been shown to distinguish CA from other storage diseases. Arvidsson et al. examined RV global and segmental strain of 42 subjects with ATTR amyloidosis. Patients with ATTR amyloidosis showed an apex-to-base RV strain gradient with relative apical sparing [44], RV involvement has been shown to occur most commonly after LV infiltration and has implications for prognosis [45].
To distinguish CA from other storage diseases, the following echocardiographic features may be helpful: presence of LV thickening, enlargement of the left atrium with wall thickening, lower E/e′, longer transmitral early filling wave deceleration time, reduced longitudinal strain in all myocardial segments with presence of relative apical sparing, additional RV hypertrophy with apical sparing pattern and mild pericardial and pleural effusion.
In summary, echocardiography using standard and speckle tracking imaging can provide many features suggesting amyloid heart disease though none of them are absolutely specific and further diagnostic tests are needed to accurately diagnose CA. Nevertheless, the presence of several echocardiographic findings increases the likelihood of the diagnosis, especially the combination of increased wall-thickness of the non-dilated LV with a restrictive filling pattern, biatrial enlargement, thickened valves, and pericardial effusion.
If echocardiographic findings hint at the presence of CA, cardiovascular magnetic resonance (CMR) is used to provide further support for the suspected diagnosis by evaluation of cardiac function and morphology using steady-state free precession (SSFP) sequences, tissue characterization via late gadolinium enhancement (LGE) and T1 mapping. CMR can characterize amyloid deposition in the extracellular tissue via LGE. In general, the phenomenon of LGE is explained by higher regional gadolinium concentration in the extracellular space and reduced distribution kinetics than in normal myocardium. In CA, the interstitium is substantially expanded by amyloid fiber accumulation, which is demonstrated by LGE in the myocardium with a dominant subendocardial distribution (Figure 3) [46, 47]. In a study by Pennell et al., a diffuse subendocardial LGE was observed in 69% [48]. Next to subendocardial different, other distribution patterns, ranging from the global transmural LGE to patchy focal LGE, have been described. The differences in the LGE pattern, especially the “patchy distribution” was explained by incorrect TI settings [49].
Cardiovascular magnetic resonance imaging of myocardial late gadolinium enhancement with pronounced septal and basal distribution.
Suboptimal “myocardial nulling” is characteristic of CA. It describes the impossibility of adjustment of inversion time to discriminate the blood pool from the myocardium. An inversion recovery pulse sequence is used to null the myocardial signal during delayed-enhanced imaging. Usually, the blood pool reaches the null point before normal myocardium. However, this relationship is reversed in CA. Phase-sensitive inversion recovery (PSIR) reconstruction is emerging as the most accurate method to overcome this problem and assess LGE in CA. This technique eliminated the difficulties of accurate TI selection, because tissue with the least gadolinium always appears nulled [50].
Krombach et al. described in 2007 another technic for the evaluation of CA using CMR [51]. The authors presented a measurement of myocardial T1 mapping values without application of LGE in identifying interstitial amyloid infiltration. Using this parameter, a sensitivity of 80% and a specificity of 94% was achieved in the study to diagnose CA. Determination of native and postcontrast (after application of the contrast agent) T1 mapping, allows for calculation of the extracellular volume (ECV), which correlates well with histological findings based on cardiac biopsies [52]. Meanwhile, several studies have demonstrated an increase in native T1 relaxation time as well as ECV of the myocardium in CA [53]. However, the diagnostic significance of ECV is limited due to overlap with other myocardial diseases associated with LV hypertrophy. Therefore, thresholds for native T1 relaxation time and ECV have not been established yet [54].
Due to the above-described comprehensive technical features, CMR represents an alternative to biopsy and has become an established part of the standard clinical pathway for CA diagnosis. In addition, it may provide prognostic information for patients with a confirmed diagnosis.
Tc-labeled cardiac scintigraphy provides incremental value to echocardiography and CMR, because of the ability to distinguish ATTR CA from other forms of LV hypertrophy [55]. Radionuclides have affinity towards myocardial amyloid deposits, especially towards myocardial ATTR. The binding of the radiotracer towards myocardial ATTR is supposed to be due to microcalcifications [56]. Three different technetium-labeled radiotracers are used for the diagnosis of ATTR-CA: 99mTc-PYP (99mTc-labeled pyrophosphate), 99mTc-DPD (99mTc-labeled 3,3- diphosphono-1,2-propanodicarboxylic acid), and 99mTc-HMDP (99mTc-labeled hydroxymethyl diphosphonate). Grading systems for the degree of uptake in the myocardium on planar imaging are quantitative and qualitative. Qualitative scores are based on the heart to contralateral lung uptake (H/CL) ratio with 99mTc-PYP or the heart to whole body ratio with 99mTc-DPD and 99mTc-HDMP (Figure 4) [57].
99mTc-HMDP bone scintigraphy for diagnosis of cardiac amyloidosis.
Gillmore et al. assessed the diagnostic accuracy of all three above-mentioned tracers in 1,217 patients with suspected CA. Any myocardial radiotracer uptake was >99% sensitive and 86% specific for detecting ATTR-CA, with the majority of false-positive results from patients with AL-amyloidosis. A higher amount of myocardial radiotracer uptake (grade 2 or 3) and the absence of monoclonal proteins in serum or urine had nearly 100% specificity and 100% positive predictive value for ATTR-CA [55]. Imaging differentiation between AL and ATTR-amyloidosis is based on the 99mTc-PYP H/CL uptake ratio; a ratio of <1.5 favors AL, whereas a ratio of ≥1.5 favors ATTR [58]. Semi-quantitative evaluation using 99mTc-PYP planar imaging, a H/CL ratio of >1.5 at 1 h accurately distinguished ATTR from AL-CA with 97% sensitivity and 100% specificity and a whole-body retention of 99mTc-DPD at 3 h is highly sensitive and specific for ATTR-CA [59].
In conclusion, Tc-labeled cardiac scintigraphy can reliably diagnose ATTR-amyloidosis in the absence of tissue biopsy, especially in cases of high myocardial radiotracer uptake and after laboratory exclusion of AL-amyloidosis.
Cardiac involvement in amyloidosis has a high mortality rate. For instance, patients with AL-amyloidosis have a 50% survival rate per year after the first episode of acute heart failure. Rapid diagnosis and initiation of chemotherapy are crucial in these patients. Besides, ATTR-amyloidosis may benefit from novel therapeutic options to improve symptoms and survival. The following features should raise the suspicion of CA: patients above 60 years of age with a low-flow low-gradient aortic stenosis, unexplained LV hypertrophy or peripheral sensory neuropathy, and patients with monoclonal gammopathy or elevated FLC levels. Non-invasive imaging technics are valuable in the assessment of CA and should be used widely. Cardiac imaging findings in echocardiography, CMR, or Tc-labeled bone or cardiac scintigraphy, are specific enough to diagnose CA in the setting of a positive non-cardiac biopsy (Figure 5). EMB with histological analysis of myocardial tissue is not essential anymore.
Typical imaging features to diagnose cardiac amyloidosis.
NA and DZ has received meeting support from Pfizer.
The other authors declare no conflict of interest.
AL | Light chain amyloidosis |
AMYLI | AMYLoidosis Index |
ANF | Atrial natriuretic factor |
ATTR | Amyloid transthyretin amyloidosis |
ATTRm | Mutant transthyretin amyloidosis |
ATTRwt | Transthyretin wild-type amyloidosis |
AV | atrioventricular |
BNP | Brain natriuretic peptide |
CA | Cardiac amyloidosis |
CMR | Cardiovacular magnetic resonance imaging |
ECG | Electrocardiography |
ECV | Extracellular volume |
EMB | Endomyocardial biopsy |
EPS | Electrophyisiology study |
ESC | European Society of Cardiology |
GLS | Global longitudinal strain |
HCM | Hypertrophic cardiomyopathy |
HV | His-ventricular |
ICD | Implantable cardioverter defibrillator |
LGE | Late gadolinium enhancement |
LVEF | Left ventricular ejection fraction |
NT-proBNP | N-terminal brain natriuretic peptide |
PSIR | Phase-sensitive inversion recovery |
RV | Right ventricular |
SAA | Serum amyloid A |
SCD | Sudden cardiac death |
sFLC | Serum free light chain |
SPECT | Single photon emission computed tomography |
SSFP | Steady-state free precession |
T4 | Thyroid hormone thyroxine |
TAVI | Transcatheter aortic valve implantation |
Tc | technicium |
TDI | Tissue Doppler imaging |
TnI | Troponin I |
TnT | Troponin T |
TTR | Transthyretin |
99mTc-PYP | 99mTc-labeled pyrophosphate |
99mTc-DPD | 99mTc-labeled 3,3- diphosphono-1,2-propanodicarboxylic acid |
99mTc-HMDP | 99mTc-labeled hydroxymethyl diphosphonate |
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\\n\\nWhen submitting their work, Authors are required to disclose the existence of any publicly available earlier drafts in a note to the Academic Editor. In cases where earlier drafts of the submitted version of the manuscript are publicly available, any overlap between the versions will generally not be considered an instance of self-plagiarism.
\\n\\n4. SOCIAL MEDIA, BLOG & MESSAGE BOARD POSTINGS
\\n\\nWe feel that social media, blogs and message boards are generally used with the same intention as grey literature, to formulate ideas for a manuscript and gather early feedback from like-minded researchers in order to improve a particular piece of work before submitting it for publication. Therefore, we do not consider such internet postings to be publication in the scholarly sense.
\\n\\nNevertheless, Authors are encouraged to disclose the existence of any internet postings in which they outline and describe their research or posted passages of their manuscripts in a note to the Academic Editor. Please note that we will not strictly enforce this request in the same way that we would instructions we consider to be part of our conditions of acceptance for publication. We understand that it may be difficult to keep track of all one’s internet postings in which the researcher´s current work might be mentioned.
\\n\\nIn cases where there is any overlap between the Author´s submitted manuscript and related internet postings, we will generally not consider it to be an instance of self-plagiarism. This also holds true for any co-Author as well.
\\n\\nFor more information on this policy please contact permissions@intechopen.com.
\\n\\nPolicy last updated: 2017-03-20
\\n"}]'},components:[{type:"htmlEditorComponent",content:'A significant number of working papers, early drafts, and similar work in progress are openly shared online between members of the scientific community. It has become common to announce one’s own research on a personal website or a blog to gather comments and suggestions from other researchers. Such works and online postings are, indeed, published in the sense that they are made publicly available. However, this does not mean that if submitted for publication by IntechOpen they are not original works. We differentiate between reviewed and non-reviewed works when determining whether a work is original and has been published in a scholarly sense or not.
\n\nThe significance of Peer Review cannot be overstated when it comes to defining, in our terms, what constitutes a published scientific work. Peer Review is widely considered to be the cornerstone of modern publishing processes and the key value-adding contribution to a scholarly manuscript that a publisher can make.
\n\nOther than the issue of originality, research misconduct is another major issue that all publishers have to address. IntechOpen’s Retraction & Correction Policy and various publication ethics guidelines identify both redundant publication and (self)plagiarism to fall within the definition of research misconduct, thus constituting grounds for rejection or the issue of a Retraction if the work has already been published.
\n\nIn order to facilitate the tracking of a manuscript’s publishing history and its development from its earliest draft to the manuscript submitted, we encourage Authors to disclose any instances of a manuscript’s prior publication, whether it be through a conference presentation, a newspaper article, a working paper publicly available in a repository or a blog post.
\n\nA note to the Academic Editor containing detailed information about a submitted manuscript’s previous public availability is the preferred means of reporting prior publication. This helps us determine if there are any earlier versions of a manuscript that should be disclosed to our readers or if any of those earlier versions should be cited and listed in a manuscript’s references.
\n\nSome basic information about the editorial treatment of different varieties of prior publication is laid out below:
\n\n1. CONFERENCE PAPERS & PRESENTATIONS
\n\nGiven that conference papers and presentations generally pass through some sort of peer or editorial review, we consider them to be published in the accepted scholarly sense, particularly if they are published as a part of conference proceedings.
\n\nAll submitted manuscripts originating from a previously published conference paper must contain at least 50% of new original content to be accepted for review and considered for publication.
\n\nAuthors are required to report any links their manuscript might have with their earlier conference papers and presentations in a note to the Academic Editor, as well as in the manuscript itself. Additionally, Authors should obtain any necessary permissions from the publisher of their conference paper if copyright transfer occurred during the publishing process. Failure to do so may prevent Us from publishing an otherwise worthy work.
\n\n2. NEWSPAPER & MAGAZINE ARTICLES
\n\nNewspaper and magazine articles usually do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense. Articles appearing in newspapers and magazines rarely possess the depth and structure characteristic of scholarly articles.
\n\nSubmitted manuscripts stemming from a previous newspaper or magazine article will be accepted for review and considered for publication. However, Authors are strongly advised to report any such publication in an accompanying note to the External Editor.
\n\nAs with the conference papers and presentations, Authors should obtain any necessary permissions from the newspaper or magazine that published the work, and indicate that they have done so in a note to the External Editor.
\n\n3. GREY LITERATURE
\n\nWhite papers, working papers, technical reports and all other forms of papers which fall within the scope of the ‘Luxembourg definition’ of grey literature do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense.
\n\nAlthough such papers are regularly made publicly available via personal websites and institutional repositories, their general purpose is to gather comments and feedback from Authors’ colleagues in order to further improve a manuscript intended for future publication.
\n\nWhen submitting their work, Authors are required to disclose the existence of any publicly available earlier drafts in a note to the Academic Editor. In cases where earlier drafts of the submitted version of the manuscript are publicly available, any overlap between the versions will generally not be considered an instance of self-plagiarism.
\n\n4. SOCIAL MEDIA, BLOG & MESSAGE BOARD POSTINGS
\n\nWe feel that social media, blogs and message boards are generally used with the same intention as grey literature, to formulate ideas for a manuscript and gather early feedback from like-minded researchers in order to improve a particular piece of work before submitting it for publication. Therefore, we do not consider such internet postings to be publication in the scholarly sense.
\n\nNevertheless, Authors are encouraged to disclose the existence of any internet postings in which they outline and describe their research or posted passages of their manuscripts in a note to the Academic Editor. Please note that we will not strictly enforce this request in the same way that we would instructions we consider to be part of our conditions of acceptance for publication. We understand that it may be difficult to keep track of all one’s internet postings in which the researcher´s current work might be mentioned.
\n\nIn cases where there is any overlap between the Author´s submitted manuscript and related internet postings, we will generally not consider it to be an instance of self-plagiarism. This also holds true for any co-Author as well.
\n\nFor more information on this policy please contact permissions@intechopen.com.
\n\nPolicy last updated: 2017-03-20
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