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1
Ablasser, Klemens, Nicolas Verheyen, Theresa Glantschnig, Giulio Agnetti, and Peter P. Rainer. "Unfolding Cardiac Amyloidosis –From Pathophysiology to Cure." Current Medicinal Chemistry 26, no. 16 (August 26, 2019): 2865–78. http://dx.doi.org/10.2174/0929867325666180104153338.
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Deposition of amyloidogenic proteins leading to the formation of amyloid fibrils in the myocardium causes cardiac amyloidosis. Although any form of systemic amyloidosis can affect the heart, light-chain (AL) or transthyretin amyloidosis (ATTR) account for the majority of diagnosed cardiac amyloid deposition. The extent of cardiac disease independently predicts mortality. Thus, the reversal of arrest of adverse cardiac remodeling is the target of current therapies. Here, we provide a condensed overview on the pathophysiology of AL and ATTR cardiac amyloidoses and describe treatments that are currently used or investigated in clinical or preclinical trials. We also briefly discuss acquired amyloid deposition in cardiovascular disease other than AL or ATTR.
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Musetti, Veronica, Francesco Greco, Vincenzo Castiglione, Alberto Aimo, Cataldo Palmieri, Dario Genovesi, Assuero Giorgetti, et al. "Tissue Characterization in Cardiac Amyloidosis." Biomedicines 10, no. 12 (November 28, 2022): 3054. http://dx.doi.org/10.3390/biomedicines10123054.
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Cardiac amyloidosis (CA) has long been considered a rare disease, but recent advancements in diagnostic tools have led to a reconsideration of the epidemiology of CA. Amyloid light-chain (AL) and transthyretin (ATTR) amyloidoses are the most common forms of cardiac amyloidosis. Due to the distinct treatments and the different prognoses, amyloid typing is crucial. Although a non-biopsy diagnosis can be obtained in ATTR amyloidosis when certain diagnostic criteria are fulfilled, tissue characterization still represents the gold standard for the diagnosis and typing of CA, particularly in AL amyloidosis. The present review focuses on the status of tissue characterization in cardiac amyloidosis, from histochemistry to immunohistochemistry and mass spectrometry, as well as on its future directions.
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Hund, Ernst, Arnt Kristen, Michaela Auer-Grumbach, Christian Geber, Frank Birklein, Wilhelm Schulte-Mattler, Claudia Sommer, Hartmut Schmidt, and Christoph Röcken. "Transthyretin-Amyloidose (ATTR-Amyloidose): Empfehlungen zum Management in Deutschland und Österreich." Aktuelle Neurologie 45, no. 08 (September 14, 2018): 605–16. http://dx.doi.org/10.1055/a-0649-0724.
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ZusammenfassungDie Transthyretin-Amyloidose (ATTR-Amyloidose) ist eine seltene, rasch verlaufende neurodegenerative Erkrankung, verursacht durch Mutationen im Transthyretin-Gen. Aufgrund der Seltenheit ist sie wenig bekannt mit der Folge, dass die Diagnose in vielen Fällen nicht oder für eine effektive Therapie zu spät gestellt wird. Therapeutisch steht seit Anfang der 1990er-Jahre die Lebertransplantation zur Verfügung, seit 2011 der oral einzunehmende Transthyretinstabilisator Tafamidis. Weitere Substanzen sind in der klinischen Prüfung oder stehen vor der Zulassung. Hierzu zählen die gentherapeutischen Substanzen Inotersen und Patisiran, die auf dem Boden der RNA-Interferenz wirken, für die Behandlung der Polyneuropathie und Tafamidis zur Behandlung der Kardiomyopathie bei ATTR-Amyloidosen. Die vorliegende Arbeit deutschsprachiger Experten gibt Empfehlungen zu Diagnostik, Management und Therapie von ATTR-Amyloidosen und soll helfen, diese erbliche, heute aber gut behandelbare, Erkrankung einem weiteren Kreis von Ärzten bekannt zu machen.
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Park, Gil Yong, Angelo Jamerlan, Kyu Hwan Shim, and Seong Soo A. An. "Diagnostic and Treatment Approaches Involving Transthyretin in Amyloidogenic Diseases." International Journal of Molecular Sciences 20, no. 12 (June 18, 2019): 2982. http://dx.doi.org/10.3390/ijms20122982.
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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.
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Ferreira, Nelson, Maria Saraiva, and Maria Almeida. "Uncovering the Neuroprotective Mechanisms of Curcumin on Transthyretin Amyloidosis." International Journal of Molecular Sciences 20, no. 6 (March 14, 2019): 1287. http://dx.doi.org/10.3390/ijms20061287.
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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.
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D'Souza, Anita, Keren Osman, Cristiana Costa Chase, Azah Borham, and Marianna Bruno. "The Hematologist's Role in Amyloidosis Management: Disease Awareness, Diagnostic Workup, and Practice Patterns." Blood 136, Supplement 1 (November 5, 2020): 28–29. http://dx.doi.org/10.1182/blood-2020-137740.
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Introduction: Systemic amyloidoses are progressive, life-threatening diseases characterized by the deposition of amyloid protein fibrils of varying origin in different tissues/organ systems (Merlini G, et al. N Engl J Med 2003;349:583-96). The precursor amyloidogenic protein influences the disease's clinical course, and identification of the specific protein is essential because treatment varies substantially by subtype. While there are 36 known proteins that can aggregate as amyloid in humans (Benson MD, et al. Amyloid 2018;25:215-9), the two most prevalent protein subtypes causing cardiac amyloidosis are derived from immunoglobulin light chains (AL) and transthyretin (ATTR) (Kittleson MM, et al. Circulation 2020;141:e7-22). Both AL and ATTR subtypes often infiltrate the heart, resulting in a restrictive cardiomyopathy along with other multiorgan involvement. Appropriate classification, early identification, and prompt treatment may substantially improve clinical outcomes. Because AL disease occurs in the context of plasma cell dyscrasia, hematologists can play an important role in amyloidosis suspicion, diagnostic workup, and management. However, differentiation of AL and ATTR amyloidoses in patients with signs of cardiac dysfunction is often challenging, and a multidisciplinary approach, including referral to cardiologists, is recommended early in the patient diagnostic workup. To gain insights into hematologists' disease awareness and practices, we interviewed hematologists involved in amyloidosis patient care across the US. Methods: A qualitative double-blind telephone survey was conducted between November 2019 and February 2020 of US hematologists who had diagnosed and/or treated at least 2 patients with AL amyloidosis over the past 2 years. The participants differed based on their experience in various clinical practice settings, including community hospital and private practices, academic institutions, and amyloidosis centers. Results: A total of 16 hematologists participated in the survey (community hospital, n=3; community private practice, n=5; academic institution, n=3; amyloidosis center, n=5). Hematologists at amyloidosis/academic centers (AAC) reported that the AL amyloidosis patient's journey typically involved visits to multiple primary care physicians and specialists in the community over a prolonged period (approximately 1 to 1.5 years) before the patient received a diagnosis (Figure [A]). Community specialists' referrals to academic physicians within the same specialty, due to lack of familiarity with amyloidosis centers, contributed in part to the delay. Several differences were found between hematologists in the community and those at AAC in level of disease awareness and referral/testing practices (Table; Figure [B]). Hematologists in community practice were less likely to be aware of ATTR amyloidosis, refer patients with suspected amyloid to cardiologists, or conduct recommended screening/diagnostic testing. In contrast, hematologists at AAC were highly aware of ATTR amyloidosis, collaborated closely with cardiologists, and used recommended amyloidosis tests. Across practice settings, hematologists consistently conducted biopsies of bone marrow and fat pad in patients with suspected AL amyloidosis to confirm the presence of amyloid. After amyloid was confirmed with Congo red staining, 75% of community hematologists discontinued testing, without establishing the amyloid protein subtype; hematologists at AAC consistently assessed amyloid protein subtype using immunohistochemistry and/or mass spectrometry to differentiate AL and ATTR prior to initiating treatment. Diagnostic algorithms supporting AL and ATTR differentiation were consistently in place and followed at AAC but not in community-based practices. Conclusions: Disease awareness, referral practices, and screening/testing procedures can differ between hematologists in the community setting and those in AAC. Community hematologists may benefit from additional education and wider use of diagnostic algorithms on AL/ATTR amyloidosis. Reinforcing the importance of cardiology referral and guidance on best practices for screening/biopsies/subtyping in patients with suspected amyloidosis who have cardiac symptoms should be prioritized. Disclosures D'Souza: Amgen, Merck, TenoBio: Research Funding; Akcea, Imbrium, Janssen, Pfizer: Consultancy. Costa Chase:Celgene: Speakers Bureau. Borham:Pfizer: Current Employment, Current equity holder in publicly-traded company. Bruno:Pfizer: Current Employment, Current equity holder in publicly-traded company.
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Staron, Andrew, Lawreen H. Connors, Frederick L. Ruberg, John L. Berk, Lisa M. Mendelson, and Vaishali Sanchorawala. "The Changing Face of Amyloidosis Referrals at a Tertiary Center over the Past 3 Decades." Blood 132, Supplement 1 (November 29, 2018): 5536. http://dx.doi.org/10.1182/blood-2018-99-112193.
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Abstract Amyloidosis is an increasingly recognized group of disorders, characterized by the deposition of misfolded protein aggregates in various tissues and organs. For over 50 years, the Amyloidosis Center at Boston University Medical Center (BUMC) has taken lead in the comprehensive evaluation and treatment of patients with this disease. The center serves as a tertiary referral site both nationally and globally, with patients visiting from 18 countries in recent years. Historically, immunoglobulin light chain (AL) amyloidosis associated with a plasma cell dyscrasia has had the greatest prevalence at our center. Other forms of amyloidosis, such as the hereditary mutant transthyretin (ATTRm) and age-related wild type transthyretin (ATTRwt) amyloidoses, have been seen less commonly due in part to underdiagnosis and a perceived paucity of effective treatments. We report here the spectrum of referrals at the Amyloidosis Center at BUMC from 1990 to 2017. We used data from a prospectively maintained database of consented patients. Of the 3084 patients seen for an initial evaluation at our center during this period, patients with AL amyloidosis decreased from 86% to 79% to 65% in the first, second and third decade, respectively. In the same time intervals, ATTRm amyloidosis cases increased from 12% to 14% to 19% of the total patients; an even steeper increase, from 2% to 7% to 16%, was seen in patients with ATTRwt amyloidosis. There is a marked trend towards more referrals of ATTR amyloidosis at BUMC. We believe this reflects increasing awareness and advancements in the diagnostic and therapeutic landscape of ATTR amyloidosis. In the early 2000s, the potential for misdiagnosis of hereditary ATTR as AL amyloidosis was recognized (Lachmann, et al. N Engl J Med. 2002). Accordingly, biochemical analysis by immunogold electron microscopy or laser capture tandem mass spectrometry has become a standard for more accurate typing of amyloid protein. Availability and utilization of these specific pathological modalities may in part explain the growing proportion of ATTR amyloidosis seen at our center. Perhaps an even more significant factor is the development of nuclear cardiac imaging techniques, which accurately diagnose ATTR cardiac amyloidosis without the need for endomyocardial biopsy. In the last decade, technetium associated bone-avid tracers, such as pyrophosphate (PYP), have been found to be highly sensitive and specific in identifying ATTR cardiac amyloidosis among patients with heart failure (Gillmore, et al. Circulation. 2016). Ease of performance and interpretation, availability and standardization have spurred widespread adaptation of this imaging modality, thereby allowing for recognition of ATTR cases that were undiagnosed in prior decades. A recent surge in diagnosis of ATTR amyloidosis is coincident with an evolving therapeutic landscape. There have been a number of clinical trials for ATTR amyloidosis, investigating transthyretin protein suppression and stabilization, as well as fibril clearance. Three therapies have completed phase III trials and are pending US regulatory review and registration. Publicity surrounding these trials has led physicians and patients to seek referral to tertiary centers for evaluation for novel treatments. The rise in new ATTR referrals at BUMC is countered by a decline in AL amyloidosis referrals, from a former average of 102 new cases per year to 91 per year in the last decade. We believe this to be largely owed to increasing experience with and adoption by community hematologists of the therapeutic options for AL amyloidosis, which are derived from treatments for multiple myeloma. In conclusion, once thought to be exceedingly rare, ATTR is becoming an increasingly prevalent form of amyloidosis at tertiary centers, comprising nearly 1 of every 3 new referrals at BUMC in the past decade. We anticipate that this proportion will rise further as PYP nuclear imaging becomes incorporated into screening algorithms for heart failure and awareness spreads about the anticipated approval of new pharmaceuticals for ATTR amyloidosis. Disclosures Berk: Ionis: Honoraria, Other: Investigator; Alnylam: Honoraria, Other: Investigator; Pfizer: Other: Investigator.
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Khoor, Andras, and Thomas V. Colby. "Amyloidosis of the Lung." Archives of Pathology & Laboratory Medicine 141, no. 2 (February 1, 2017): 247–54. http://dx.doi.org/10.5858/arpa.2016-0102-ra.
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Context.—Amyloidosis is a heterogeneous group of diseases characterized by the deposition of congophilic amyloid fibrils in the extracellular matrix of tissues and organs. To date, 31 fibril proteins have been identified in humans, and it is now recommended that amyloidoses be named after these fibril proteins. Based on this classification scheme, the most common forms of amyloidosis include systemic AL (formerly primary), systemic AA (formerly secondary), systemic wild-type ATTR (formerly age-related or senile systemic), and systemic hereditary ATTR amyloidosis (formerly familial amyloid polyneuropathy). Three different clinicopathologic forms of amyloidosis can be seen in the lungs: diffuse alveolar-septal amyloidosis, nodular pulmonary amyloidosis, and tracheobronchial amyloidosis. Objective.—To clarify the relationship between the fibril protein–based amyloidosis classification system and the clinicopathologic forms of pulmonary amyloidosis and to provide a useful guide for diagnosing these entities for the practicing pathologist. Data Sources.—This is a narrative review based on PubMed searches and the authors' own experiences. Conclusions.—Diffuse alveolar-septal amyloidosis is usually caused by systemic AL amyloidosis, whereas nodular pulmonary amyloidosis and tracheobronchial amyloidosis usually represent localized AL amyloidosis. However, these generalized scenarios cannot always be applied to individual cases. Because the treatment options for amyloidosis are dependent on the fibril protein–based classifications and whether the process is systemic or localized, the workup of new clinically relevant cases should include amyloid subtyping (preferably with mass spectrometry–based proteomic analysis) and further clinical investigation.
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Koike, Haruki, and Masahisa Katsuno. "The Ultrastructure of Tissue Damage by Amyloid Fibrils." Molecules 26, no. 15 (July 29, 2021): 4611. http://dx.doi.org/10.3390/molecules26154611.
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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.
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Yilmaz, A., J. Bauersachs, F. Bengel, R. Büchel, I. Kindermann, K. Klingel, F. Knebel, et al. "Diagnosis and treatment of cardiac amyloidosis: position statement of the German Cardiac Society (DGK)." Clinical Research in Cardiology 110, no. 4 (January 18, 2021): 479–506. http://dx.doi.org/10.1007/s00392-020-01799-3.
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AbstractSystemic forms of amyloidosis affecting the heart are mostly light-chain (AL) and transthyretin (ATTR) amyloidoses. The latter is caused by deposition of misfolded transthyretin, either in wild-type (ATTRwt) or mutant (ATTRv) conformation. For diagnostics, specific serum biomarkers and modern non-invasive imaging techniques, such as cardiovascular magnetic resonance imaging (CMR) and scintigraphic methods, are available today. These imaging techniques do not only complement conventional echocardiography, but also allow for accurate assessment of the extent of cardiac involvement, in addition to diagnosing cardiac amyloidosis. Endomyocardial biopsy still plays a major role in the histopathological diagnosis and subtyping of cardiac amyloidosis. The main objective of the diagnostic algorithm outlined in this position statement is to detect cardiac amyloidosis as reliably and early as possible, to accurately determine its extent, and to reliably identify the underlying subtype of amyloidosis, thereby enabling subsequent targeted treatment.
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Tschöpe, Carsten, Ahmed Elsanhoury, Sonja Diekmann, and Uwe Kühl. "Hypertrophe Kardiomyopathien und die kardiale ATTR-Amyloidose – eine aktuelle Übersicht für den klinischen Alltag." DMW - Deutsche Medizinische Wochenschrift 147, no. 17 (August 28, 2022): 1127–34. http://dx.doi.org/10.1055/a-1744-3126.
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Was ist neu? Hypertrophe obstruktive Kardiomyopathie Mavacamten, der erste Myosin-Aktivator, konnte erfolgreich in dem EXPLORER-HCM-Studienprogramm getestet werden. Lebensqualität und linksventrikuläre Druckgradienten-Abnahme wurden optimiert. Ob damit jedoch auch die Überlebensrate und Prognose der betroffenen Patienten verbessert wird, kann bis heute noch nicht gesagt werden. Die europäischen Zulassungsbehörden sehen allerdings bisher die Ergebnisse als so bedeutsam an, dass mit einer Führung der Substanzklasse vielleicht schon in den nächsten 6–8 Monaten zu rechnen ist. In den USA ist die Substanz bereits seit April 2022 zugelassen. Der Einsatz der Substanz bei HCM-Patienten ohne Obstruktion wird ebenfalls zurzeit untersucht. Kardiale Transthyretin-Amyloidosen Kardiale Amyloidosen haben meist eine gute Ejektionsfraktion, jedoch sind auch EF mit 40 oder < 30 % möglich. Das Auftreten einer kardialen Amyloidose bei Patienten mit der Symptomatik einer Herzinsuffizienz mit erhaltener Ejektionsfraktion (HFpEF) ist in bis zu 15 % der Fälle nachzuweisen. Tafamidis ist die einzige zurzeit zugelassene erfolgreiche Therapiemöglichkeit bei Patienten mit kardialer ATTR-Amyloidose. Dies wurde auch durch weitere Beobachtungsregister der ATTR-ACT-Studie gezeigt. Für die Klinik ist zusätzlich wichtig, dass die Amyloidose auch die Aortenklappe befällt. Zahlreiche Patienten entwickeln somit auch eine Aortenstenose, die erkannt und meist interventionell zu behandeln ist.
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Gonzalez-Duarte, Alejandra, and Alfredo Ulloa-Aguirre. "A Brief Journey through Protein Misfolding in Transthyretin Amyloidosis (ATTR Amyloidosis)." International Journal of Molecular Sciences 22, no. 23 (December 6, 2021): 13158. http://dx.doi.org/10.3390/ijms222313158.
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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.
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Anikonova, L. I., O. A. Vorobyeva, and N. V. Bakulina. "ATTR-amyloidosis - a systemic disease involving the kidneys." Nephrology and Dialysis 24, no. 3 (2022): 441–56. http://dx.doi.org/10.28996/2618-9801-2022-3-441-456.
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ATTR amyloidosis (transthyretin amyloidosis) is a progressive, fatal disease characterized by the accumulation of transthyretin amyloid mainly in the peripheral nervous system (somatic and autonomic) and heart, as well as in the kidneys, gastrointestinal tract, eyeballs, and ligaments, which impairs the normal function of organs and systems. The hereditary form of ATTR amyloidosis, or ATTRv amyloidosis, is found all over the world and is characterized by broad genetic and phenotypic heterogeneity, resulting in late diagnosis. The kidneys are a potential target organ in ATTRv amyloidosis. Clinically, nephropathy is manifested by albuminuria, proteinuria, nephrotic syndrome, or decreased renal function. A nephrologist may be involved in the diagnosis of amyloid nephropathy/ATTRv amyloidosis in a patient with symptoms of renal damage in an endemic region or with a family history of ATTRv amyloidosis, or, more difficult, in the diagnosis of a sporadic case of ATTRv amyloidosis when symptoms of nephropathy were detected in a patient in a non-endemic region without a known family history of amyloidosis. The diagnosis of amyloidosis, especially is sporadic cases, requires the nephrologist to know the specific symptoms, the so-called "red flags" of ATTR amyloidosis that allow suspecting amyloidosis, and methods to confirm the diagnosis. Kidney biopsy in the presence of nephropathy is the gold standard in the diagnosis of amyloidosis. Congo-red staining of biopsy specimens with subsequent visualization of the apple-green birefringence of congophilic masses with polarized light is crucial for histological confirmation of the diagnosis. Immunohistochemistry is used for amyloid typing. The less available method for typing is mass spectrometry of affected tissue. Detection of "red flags" of amyloidosis in a patient with nephropathy makes it possible to diagnose ATTR amyloidosis in some cases without a biopsy, by TTR gene sequencing or myocardial scintigraphy with 99mTc-pyrophosphate. After amyloidosis is diagnosed, it is necessary to conduct a detailed examination for assessing the damage to potential target organs, which requires an interdisciplinary approach. Early diagnosis and disease-modifying therapies can slow the progression of neuropathy and cardiomyopathy, and presumably nephropathy.
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Frangolho, Ana, Bruno E. Correia, Daniela C. Vaz, Zaida L. Almeida, and Rui M. M. Brito. "Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity." Molecules 25, no. 23 (December 3, 2020): 5698. http://dx.doi.org/10.3390/molecules25235698.
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One of the molecular hallmarks of amyloidoses is ordered protein aggregation involving the initial formation of soluble protein oligomers that eventually grow into insoluble fibrils. The identification and characterization of molecular species critical for amyloid fibril formation and disease development have been the focus of intense analysis in the literature. Here, using photo-induced cross-linking of unmodified proteins (PICUP), we studied the early stages of oligomerization of human transthyretin (TTR), a plasma protein involved in amyloid diseases (ATTR amyloidosis) with multiple clinical manifestations. Upon comparison, the oligomerization processes of wild-type TTR (TTRwt) and several TTR variants (TTRV30M, TTRL55P, and TTRT119M) clearly show distinct oligomerization kinetics for the amyloidogenic variants but a similar oligomerization mechanism. The oligomerization kinetics of the TTR amyloidogenic variants under analysis showed a good correlation with their amyloidogenic potential, with the most amyloidogenic variants aggregating faster (TTRL55P > TTRV30M > TTRwt). Moreover, the early stage oligomerization mechanism for these variants involves stepwise addition of monomeric units to the growing oligomer. A completely different behavior was observed for the nonamyloidogenic TTRT119M variant, which does not form oligomers in the same acidic conditions and even for longer incubation times. Thorough characterization of the initial steps of TTR oligomerization is critical for better understanding the origin of ATTR cytotoxicity and developing novel therapeutic strategies for the treatment of ATTR amyloidosis.
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Chen, Zhiyong, Jasmine S. Koh, Monica Saini, Karine S. S. Tay, Yi Jayne Tan, Josiah Y. H. Chai, Su Rong Fam, et al. "Hereditary Transthyretin Amyloidosis- Clinical and Genetic Characteristics of a Multiracial South-East Asian Cohort in Singapore." Journal of Neuromuscular Diseases 8, no. 4 (July 30, 2021): 723–33. http://dx.doi.org/10.3233/jnd-210656.
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Background and aims: Studies of hereditary transthyretin amyloidosis (ATTRv amyloidosis) in South-East Asia are underrepresented in the literature. We report the unique phenotypic and genetic characteristics of this disorder in a multiracial South-East Asian cohort. Methods: Patients with genetically proven ATTRv amyloidosis were identified over a 13-year period (2007–2020) at the National Neuroscience Institute, Singapore. Clinical, laboratory, genotypic and electrophysiological features were retrospectively reviewed. Results: 29 patients comprising Chinese, Malay, Burmese, Vietnamese and Indonesians with ATTRv amyloidosis were identified. Somatic neuropathy was the most common initial presentation, followed by carpal tunnel syndrome, autonomic dysfunction and cardiac dysfunction. ATTR-A97S (p.Ala117Ser) was the most common variant found in 14 patients, constituting 66.7%of ethnic Chinese patients and 48.3%of the entire cohort. Five patients had early-onset disease (age < 50 years) with the following variants: ATTR-V30M (p.Val50Met), ATTR-G47A (p.Gly67Ala), ATTR-S50I (p.Ser70Ile) and ATTR-A97S (p.Ala117Ser); one patient with ATTR-A97S (p.Ala117Ser) had isolated unilateral carpal tunnel syndrome with amyloid deposits identified on histological examination of the transverse carpal ligament. All early-onset patients had a positive parental history; two patients, with ATTR-S50I (p.Ser70Ile) and ATTR-Ala97Ser (p.Ala117Ser) respectively, demonstrated anticipation with mother-to-daughter inheritance. Amongst the 24 patients with late-onset disease (age≥50 years), two patients had novel variants, ATTR-G66D (p.Glu86Asp) and ATTR-A81V (p.Ala101Val) that were confirmed to be pathogenic based on the histological identification of transthyretin amyloid. Other identified variants included ATTR-V30M (p.Val50Met), ATTR-R34T (p.Arg54Thr), ATTR-S50I (p.Ser70Ile), ATTR-H88R (p.His108Arg) and ATTR-A97S (p.Ala117Ser). Conclusion: Our study further expands the genotypic and phenotypic knowledge regarding ATTRv amyloidosis.
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Nikitin, S. S., S. N. Bardakov, N. A. Suponeva, I. V. Zhirov, T. A. Adyan, D. A. Grishina, and R. V. Deev. "Phenotypic heterogeneity and diagnostic features of transthyretin amyloidosis with polyneuropathy." Neuromuscular Diseases 11, no. 3 (December 13, 2021): 12–36. http://dx.doi.org/10.17650/2222-8721-2021-11-3-12-36.
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Transthyretin amyloidosis (ATTR-amyloidosis) is a systemic progressive fatal disease, for which a modifying therapy has recently been proposed that delays the progression of the disease and improves the patient’s quality of life. The delay in the diagnosis of ATTR-amyloidosis is associated with the heterogeneity of the manifestations of the disease, as well as insufficient awareness of doctors of different specialties about the disease. A review of recent studies on the symptomatology, diagnosis, molecular genetic characteristics of ATTR-amyloidosis and the most common forms of the disease with the predominant involvement of peripheral nerves and the heart, as well as the kidneys, gastrointestinal tract, and eyes is presented. The international consensus recommendations for the diagnosis of suspected ATTR-amyloidosis using modern methods that facilitate early and accurate diagnosis are discussed. The reasons and the most frequent misdiagnoses of ATTR-amyloidosis, which also lead to a delay in the timely appointment of therapy, are considered. Molecular genetic testing should be considered early in the evaluation of a patient with unexplained peripheral neuropathy and cardiomyopathy. A diagnostic algorithm based on the initial symptoms and manifestations of the cardiovascular and nervous systems facilitates the identification of a patient with clinical suspicion of ATTR-amyloidosis by the general practitioner. Early diagnosis is critically important for patients with ATTR polyneuropathy, since the early prescription of Vindakel (tafamidis), registered in the Russian Federation in 2017, allows a significant clinical effect to be obtained. Timely administration of Vindakel significantly slows down the progression of the disease, improves the prognosis and quali ty of life in patients with ATTR polyneuropathy.
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Nasonova, S. N., I. V. Zhirov, M. M. Magomedov, M. A. Saidova, Yu F. Osmolovskaya, and S. N. Tereschenko. "Experience with tafamidis in a patient with transthyretin amyloidosis." Kardiologiia 60, no. 3 (May 3, 2020): 155–60. http://dx.doi.org/10.18087/cardio.2020.3.n824.
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Transthyretin amyloidosis (ATTR) is a threatening and severe genetic disease characterized by damages to organs and systems caused by a pathological protein transthyretin produced in the liver. Clinical manifestations of this disease vary from injuries of the nervous system to injuries of the cardiovascular system. Prognosis for ATTR-amyloidosis remains unfavorable. The absence of pathognomonic symptoms complicates diagnostics of this disease, which tends to simulate other conditions. At present, medicines exist, which are pathogenetic in the treatment of ATTR-amyloidosis. The article describes a clinical case of ATTR-amyloidosis with primary heart injury complicated with functional class III chronic heart failure during the tafamidis treatment.
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Nativi-Nicolau, Jose, Nitasha Sarswat, Johana Fajardo, Muriel Finkel, Younos Abdulsattar, Adam Castaño, Lori Klein, and Alexandra Haddad-Angulo. "Best Practices in Specialized Amyloidosis Centers in the United States: A Survey of Cardiologists, Nurses, Patients, and Patient Advocates." Clinical Medicine Insights: Cardiology 15 (January 2021): 117954682110152. http://dx.doi.org/10.1177/11795468211015230.
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Background: Because transthyretin amyloid cardiomyopathy (ATTR-CM) poses unique diagnostic and therapeutic challenges, referral of patients with known or suspected disease to specialized amyloidosis centers is recommended. These centers have developed strategic practices to provide multidisciplinary comprehensive care, but their best practices have not yet been well studied as a group. Methods: A qualitative survey was conducted by telephone/email from October 2019 to February 2020 among eligible healthcare providers with experience in the management of ATTR-CM at US amyloidosis centers, patients with ATTR-CM treated at amyloidosis centers, and patient advocates from amyloidosis patient support groups. Results: Fifteen cardiologists and 9 nurse practitioners/nurses from 15 selected amyloidosis centers participated in the survey, with 16 patients and 4 patient advocates. Among participating healthcare providers, the most frequently cited center best practices were diagnostic capability, multidisciplinary care, and time spent on patient care; the greatest challenges involved coordination of patient care. Patients described the “ideal” amyloidosis program as one that provides physicians with expertise in ATTR-CM, sufficient time with patients, comprehensive patient care, and opportunities to participate in research/clinical trials. The majority of centers host patient support group meetings, and patient advocacy groups provide support for centers with physician/patient education and research. Conclusions: Amyloidosis centers offer comprehensive care based on staff expertise in ATTR-CM, a multidisciplinary approach, advanced diagnostics, and time dedicated to patient care and education. Raising awareness of amyloidosis centers’ best practices among healthcare providers can reinforce the benefits of early referral and comprehensive care for patients with ATTR-CM.
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Gibbs, Simon DJ, Caroline Wong, James Hare, Hendrik Zimmet, Jay Hocking, Anthony P. Schwarer, and Stephen B. Ting. "99m Technetium-Hydroxy-Diphosphate Tracer (99mTcHDP) Bone Scintigraphy: An Easily Accessible, Rapid, Non-Invasive Diagnostic Tool for Cardiac Amyloidosis." Blood 128, no. 22 (December 2, 2016): 3557. http://dx.doi.org/10.1182/blood.v128.22.3557.3557.
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Abstract Aim: Cardiac amyloidosis is a protein deposition disease that can be difficult to diagnose and has a poor prognosis if diagnosis or treatment are delayed. The two major subtypes are AL and transthyretin (ATTR). Both have vastly different treatments so confirming the correct amyloid subtype is crucial. A tissue biopsy is usually required for the diagnosis of amyloidosis and to distinguish between the subtypes. No blood test, echocardiography or cardiac MRI can reliably distinguish between AL and ATTR. With a cardiac biopsy, distinguishing AL from ATTR can be challenging with immunohistochemistry, and time consuming with mass spectrometry. Recently, Gillmore et al demonstrated bone scintigraphy with 99mTc-DPD tracer can reliably diagnose ATTR, avoiding endomyocardial biopsies to confirm the subtype in most cases. [1] 99mTc-HDP is a tracer similar to 99mTc-DPD and is more readily available in Australian and the USA. We sought to examine the use of 99mTcHDP bone scintigraphy in Australia and determine the accuracy of this tracer to diagnose cardiac amyloidosis and distinguish between the AL and ATTR subtypes. Methods: All patients with confirmed ATTR or AL who had 99mTcHDP bone scintigraphy were analysed. Results were correlated with histology, NT ProBNP, Troponin-T, free light chains, cardiac MRI and echocardiography. Grading was conducted with Perugini scoring.[1] Results: 25 patients with amyloidosis diagnosed by cardiac MRI and/or biopsy, had 99mTcHDP bone scintigraphy. 18 were confirmed ATTR, 7 AL. Two ATTR patients had hereditary disease (Thy60Ala and Gly109Lys), the remainder were wildtype. 17 (94%) patients with ATTR and 2 (29%) AL had positive scans. The negative ATTR patient had localized bladder disease only with a normal echocardiogram and cardiac biomarkers. All ATTR patients with positive scans had Perugini scores of 2 or 3, including the 2 patients with hereditary mutations, while the two positive AL only had scores of 1. All 11 patients with amyloid features on cardiac MRI had positive scans. Mean NTproBNP values for ATTR and AL were 530pmol/L and 1396pmol/L respectively. The two AL amyloidosis patients with positive bone scans had higher NTproBNP values. No ATTR patient had a detectable plasma cell dyscrasia. Conclusion: Bone scintigraphy with 99mTcHDP tracer is an easily accessible, rapid and non-invasive method of diagnosing cardiac amyloidosis. In our small series, all patients with Perugini scores 2 or 3 had ATTR, while those with negative or Perugini score 1 scan either had AL or no cardiac amyloidosis. There was a suggestion that AL patients with higher NTproBNP scores were more likely to have positive scans. This suggests that the 99mTcHDP tracer can be used like 99mTc-DPD to aid in the diagnosis of cardiac amyloidosis, and, as suggested by Gillmore et al, can confirm the ATTR subtype in those with no detectable plasma cell dyscrasia and Perugini score 2 or 3 scans, thus hastening accurate diagnosis and avoiding cardiac biopsies. Reference: Gillmore JD, Maurer MS, Falk RH, Merlini M, Damy T, Dispenzieri A, et al. Non-biopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016 Jun 14;133(24):2404-12 Disclosures No relevant conflicts of interest to declare.
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Cowan, Andrew J., Martha Skinner, J. Mark Sloan, John L. Berk, Carl J. O'Hara, David C. Seldin, and Vaishali Sanchorawala. "Macroglossia – Not Always AL Amyloidosis." Blood 116, no. 21 (November 19, 2010): 5007. http://dx.doi.org/10.1182/blood.v116.21.5007.5007.
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Abstract Abstract 5007 Introduction: Amyloidosis is characterized by extracellular deposition of abnormal insoluble fibrillar proteins. The two most frequent systemic amyloidoses are the light-chain (AL amyloidosis) and familial transthyretin (ATTR) forms. Clinical presentations often vary between the two types. Macroglossia is viewed as pathognomic of AL amyloidosis, and has not previously been described in patients with hereditary TTR amyloidosis. Here, we describe two cases of systemic amyloidosis with macroglossia in which immuno-electron microscopy diagnosed ATTR in one and AL in the other. Case Presentations: A 61 year old woman presented initially to her general internist with weight loss, difficulty swallowing, and tongue numbness. Her clinical exam revealed macroglossia and peripheral neuropathy. Tongue and axillary lymph node biopsies demonstrated amyloid deposits by Congo red staining. There was no evidence of renal, cardiac or other vital organ involvement. She had no evidence of a plasma cell dyscrasia with negative serum and urine immunofixation electrophoresis, normal serum free light chain concentration and ratio as well as polytypic plasma cells in the bone marrow. Immuno-electron microscopy using gold-labeled antibodies was performed on the tongue biopsy. The fibrils were immunoreactive with anti-TTR but not anti-kappa, anti-lambda, or anti-AA antibodies. DNA sequencing identified a known amyloidogenic T60A TTR mutation in exon 3 of chromosome 18, confirming the diagnosis of ATTR with amyloidotic polyneuropathy and macroglossia. The second case involved a 59 year old man with renal insufficiency. He complained of fatigue, weight loss, and tongue swelling. Physical examination was significant for macroglossia and submandibular gland enlargement. Tongue biopsy demonstrated amyloid deposits by Congo red staining. As in the previous case, markers of plasma cell dyscrasia with clonal plasma cells in the bone marrow, blood, and urine were absent. Immuno-electron microscopy of the tongue biopsy documented antibody reactivity to lambda light chain and not TTR, kappa light chain or AA proteins, confirming the diagnosis of AL amyloidosis. He subsequently underwent treatment with high dose intravenous melphalan followed by stem cell transplantation achieving a good clinical response sustained for 2 years to date. Discussion: While macroglossia is thought to be pathognomonic of AL amyloidosis, we report a case of macroglossia with fibrillar ATTR amyloid deposits diagnosed by immuno-electron microscopy. This is contrasted with a clinical presentation consistent with AL in which routine laboratory testing failed to identify evidence of a plasma cell dyscrasia. In both cases, electron microscopy demonstrated immunoreactivity for the fibrils of a single pathogenic protein. The first case was confirmed by DNA sequencing, and the second had a typical response to anti-plasma cell chemotherapy, in spite of the lack of identifiable markers of disease. Disclosures: No relevant conflicts of interest to declare.
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Javidiparsijani, Sara, and Maria M. Picken. "Should the Reporting of Bone Marrow Positivity for Amyloid Be Revised?: A Critical Assessment Based on 66 Biopsies From a Single Institution." Archives of Pathology & Laboratory Medicine 144, no. 8 (January 16, 2020): 967–73. http://dx.doi.org/10.5858/arpa.2019-0324-oa.
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Context.— Amyloidoses are rare but heterogeneous disorders for which diagnosis is contingent upon the detection of deposits by Congo red stain and amyloid protein typing determines the treatment options. Objective.— To address the reporting of bone marrow (BM) involvement by amyloid in relation to the spatial distribution of deposits and to explore whether the location of deposits may have clinical relevance. Design.— We examined 66 BM biopsies positive for amyloid with regard to the location and type of amyloid, the percentage and clonality of plasma cells, other organ involvement, and relevant clinical information. Results.— In 21 cases, amyloid deposits involved BM stroma, whereas 45 cases were nonstromal. All cases of stromal involvement were typed as amyloid light chain (AL) amyloidosis (or presumed AL), whereas nonstromal involvement was associated with at least 3 types of amyloidosis: AL, amyloid transthyretin (ATTR), and amyloid A (AA). The initial diagnosis of amyloidosis was made in a BM specimen in 21 of 66 cases (31.8%). Plasma cells ranged from 1% to 80% (mean, 13.4%; median, 8%; <10% in 44 of 66 specimens [66.6%]) and were monoclonal in 58 of 66 cases (87.8%), and in 54 of 66 cases (81.8%) amyloid deposits were documented in at least one other organ. Conclusions.— This study demonstrates that there is significant heterogeneity in the spatial distribution of amyloid in BM biopsy specimens with medullary, extramedullary, purely vascular, or combined involvement. Whereas stromal deposits were associated exclusively with AL, nonstromal and purely vascular deposits were seen in at least 3 types of systemic amyloidosis (AL, AA, and ATTR). We discuss the reporting of BM biopsy tissue positivity for amyloid deposits.
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Henein, Michael Y., and Per Lindqvist. "Myocardial Work Does Not Have Additional Diagnostic Value in the Assessment of ATTR Cardiac Amyloidosis." Journal of Clinical Medicine 10, no. 19 (September 30, 2021): 4555. http://dx.doi.org/10.3390/jcm10194555.
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Background: Reduced LV longitudinal strain (GLS) and increased relative apical sparing (RELAPS) and increased wall thickness have been proposed as features for transthyretin cardiac amyloidosis (ATTR-CA). Myocardial work (MW) has recently been shown as useful afterload independent disease marker, hence we aimed to investigate its use in differentiating ATTR-CA from heart failure with increased septal thickness but no cardiac amyloidosis (CA) (HFnCA). Methods: This study included patients with HF and increased septal thickness ≥ 14 mm. We included 59 patients with hereditary (ATTRv) and 27 wild type transthyretin amyloidosis (ATTRwt) described as ATTR-CA based on DPD scintigraphy. We also enrolled 30 non-amyloidosis heart failure patients with negative DPD scintigraphy, as a control group. Myocardial work (MW) was used to assess the index (GWI), constructive (GCW) and wasted (GWW) work. Relative wall thickness (RWT) and relative apical sparing (RELAPS) were tested as conventional measures. Results: The RWT and RELAPS were higher in ATTR-CA (p < 0.001) and predicted ATTR-CA (RWT; AUC = 0.84, p < 0.001) and RELAPS (AUC = 0.81, p < 0.001). MW; GWI (p = 0.04), GCW (p = 0.03), GWW (p = 0.001) were all lower in ATTR-CA compared with HFnCA but only GWW predicted ATTR-CA, (AUC = 0.75, p < 0.001). Binary logistic univariate regression analysis showed RWT (p = 0.003, β = 16.2) and RELAPS (p = 0.003, β = 2.3) to be associated with ATTR-CA but not MW. GWI and GCW correlated with NT-proBNP (p < 0.05) and Troponin (p < 0.01), but not RWT or RELAPS. Conclusion: Myocardial work had lower accuracy, compared to RWT or RELAPS, in identifying ATTR-CA but was better related to biomarkers. Thus, MW assessment is unlikely to have additional value in improving the diagnosis of heart failure due to ATTR-CA.
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Dasari, S., A. Chiu, J. Theis, J. A. Vrana, P. J. Kurtin, K. L. Rech, L. N. Dao, et al. "Bone marrow involvement by ATTR amyloid is common in cardiac amyloidosis patients and may signal advanced-stage disease." American Journal of Clinical Pathology 156, Supplement_1 (October 1, 2021): S94. http://dx.doi.org/10.1093/ajcp/aqab191.200.
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Abstract Introduction/Objective Amyloidosis encompasses a heterogeneous group of disorders characterized by abnormal deposition of misfolded proteins leading to progressive organ failure. Accurate amyloid typing is essential for proper patient management, as treatment regimens vary dramatically across different types. Bone marrow (BM) biopsy, in conjunction with fat pad aspiration/biopsy, is often the first step in patients with suspected amyloidosis. Although BM involvement by AL amyloid has been previously characterized, little is known about the incidence, morphology and clinical phenotype of non-AL amyloid in BM. Methods/Case Report We retrospectively identified 1469 BM biopsies by querying our reference laboratory database of 19,298 specimens from myriad anatomic sites typed by mass spectrometry-based proteomics (LC-MS/MS). These were reviewed for frequency of amyloid types (N=1469), distribution of amyloid deposits (N=139), and clinical phenotypes (N=345), with particular emphases on cardiac involvement. Results (if a Case Study enter NA) We identified the following amyloid types: AL (N=1172; 79.8%), ATTR (transthyretin) (N=240; 16.3%), AH (immunoglobulin heavy chain) (N=38; 2.6%), AA (serum amyloid A) (N=17; 1.2%), and Aβ2M (β2-microglobulin) (N=2; 0.1%). ATTR deposits showed striking predilection for periosteal soft tissue and/or periosteal vessels, and rarely involved BM stroma and/or interstitial vessels, while AL variably involved these compartments. AA primarily involved interstitial vessels. Both AL and ATTR cases commonly had a monoclonal gammopathy (AL: 92.9%; ATTR: 62.5%) with concomitant cardiac amyloidosis (AL: 91.6%; ATTR: 100%). Compared to AL, ATTR patients had higher stage cardiac amyloidosis and lower overall survival. Conclusion ATTR is common in BM, constituting16.3% of cases in our cohort. Rarer amyloid types, such as AA, AH and AB2M can also occur in BM. ATTR was frequently identified in patients with concomitant monoclonal gammopathy, in whom AL may have been suspected. Although ATTR deposits have distinctive morphologic distribution, primarily involving periosteal soft tissue and/or periosteal vessels and rarely involving BM stroma and/or interstitial vessels, there is considerable morphologic overlap with AL. Therefore, it is imperative to type BM amyloidosis, preferably by LC-MS/MS, to ensure proper patient management. Furthermore, BM involvement by ATTR may be a marker for advanced stage of disease.
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Khayambashi, S., C. Hahn, N. Fine, E. Mahe, and K. Elzinga. "P.045 Biopsies of the transverse carpal ligament and tenosynovium for tissue confirmation of transthyretin amyloidosis." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 49, s1 (June 2022): S19. http://dx.doi.org/10.1017/cjn.2022.146.
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Background: Transthyretin Amyloidosis (ATTR) is a common cause of both cardiomyopathy and carpal tunnel syndrome, with many patients needing carpal tunnel release (CTR). Although tafamidis is now an approved treatment of ATTR cardiomyopathy, insurers in most provinces require biopsy confirmation of amyloidosis. Endomyocardial biopsy is often the chosen approach due to optimal sensitivity, albeit with risk of serious adverse events such as stroke, cardiac tamponade, and arrhythmias. CTR may present an ideal opportunity for obtaining amyloidosis biopsy confirmation. Methods: ATTR patients undergoing CTR had biopsy of their transverse carpal ligament (TCL) and/or flexor tenosynovium to assess the sensitivity of both sites for biopsy confirmation of amyloidosis. Results: Twelve patients consecutively underwent biopsies during CTR, with 4 (33%) having bilateral CTR and biopsy. Among 16 TCL biopsies and 14 tenosynovium biopsies, 100% demonstrated amyloid deposition. Another patient had isolated tenosynovium biopsy without CTR and also demonstrated amyloidosis. There were no serious adverse events, and 1/13 (8%) had wound dehiscence requiring repeat suturing. Conclusions: Biopsy of the TCL and/or tenosynovium during CTR is safe, cost-effective, and sensitive, and may represent an alternative to endomyocardial biopsy in patients requiring tissue confirmation for tafamidis approval. ATTR patients eligible for tafamidis may benefit from early neurology assessment.
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Mori, Atsushi, Yukihiro Saito, Kazufumi Nakamura, Toshihiro Iida, Satoshi Akagi, Masashi Yoshida, Makiko Taniyama, Toru Miyoshi, and Hiroshi Ito. "Microcalcification and 99mTc-Pyrophosphate Uptake without Increased Bone Metabolism in Cardiac Tissue from Patients with Transthyretin Cardiac Amyloidosis." International Journal of Molecular Sciences 24, no. 3 (January 18, 2023): 1921. http://dx.doi.org/10.3390/ijms24031921.
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Transthyretin cardiac amyloidosis (ATTR-CA) is characterized by high 99mTc-labeled bone tracer uptake in the heart. However, the mechanism of bone tracer uptake into the heart remains controversial. Since bone tracer uptake into metastatic bone tumors is thought to be associated with increased bone metabolism, we examined 99mTc-pyrophosphate (PYP) scintigraphy findings, endomyocardial biopsy (EMB) tissue findings, and the expression of bone metabolism-related genes in the EMB tissues in patients with ATTR-CA, amyloid light-chain cardiac amyloidosis (AL-CA), and noncardiac amyloidosis (non-CA) in this study. The uptake of 99mTc-PYP in the heart was significantly higher in the ATTR-CA patients than in the AL-CA and non-CA patients. A higher percentage of ATTR-CA EMB tissue showed von Kossa-positive microparticles: ATTR-CA, 62%; AL-CA, 33%; and non-CA, 0%. Calcified microparticles were identified using transmission electron microscopy. However, none of the osteogenic marker genes, osteoclastic marker genes, or phosphate/pyrophosphate-related genes were upregulated in the EMB samples from ATTR-CA patients compared to those from AL-CA and non-CA patients. These results suggest that active calcification-promoting mechanisms are not involved in the microcalcification observed in the heart in ATTR-CA. The mechanisms explaining bone tracer uptake in the heart, which is stronger than that in the ribs, require further investigation.
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Ando, Y. "Therapy of ATTR amyloidosis: perspective." Amyloid 18, sup1 (June 2011): 182–84. http://dx.doi.org/10.3109/13506129.2011.574354068.
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Benson, Merrill D. "Inotersen treatment for ATTR amyloidosis." Amyloid 26, sup1 (March 29, 2019): 27–28. http://dx.doi.org/10.1080/13506129.2019.1582497.
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Castaño, Adam, Stephen Helmke, Julissa Alvarez, Susan Delisle, and Mathew S. Maurer. "Diflunisal for ATTR Cardiac Amyloidosis." Congestive Heart Failure 18, no. 6 (July 2, 2012): 315–19. http://dx.doi.org/10.1111/j.1751-7133.2012.00303.x.
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Dungu, Jason N. "Cardiac Amyloid — An Update." European Cardiology Review 10, no. 2 (2015): 113. http://dx.doi.org/10.15420/ecr.2015.10.2.113.
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Cardiac amyloidosis is a condition characterised by rapidly progressive heart failure and poor prognosis. The two main subtypes, immunoglobulin light chains (AL) and transthyretin (ATTR), have been investigated extensively in recent years. Cardiac imaging has advanced with the widespread use of cardiac MRI with late gadolinium enhancement imaging and newer techniques including T1 mapping to quantify amyloid burden. Nuclear imaging has developed as a highly accurate method to confirm cardiac amyloid deposits non-invasively with very high sensitivity in ATTR amyloidosis. Despite advances in imaging, cardiac biopsy remains the gold standard diagnostic test to confirm and type amyloidosis. Hereditary ATTR amyloidosis of V122I type has been the focus of important studies in the past year, due to the high prevalence of the amyloidogenic allele in patients of African descent. Recent research concluded a significant number of Afro-Caribbean heart failure patients are likely to have undiagnosed cardiac amyloidosis. Misdiagnosis may lead to inappropriate treatment with potentially harmful ‘standard’ heart failure medications with no evidence base in amyloidosis. Treatment options have, until recently, been limited but cardiac amyloidosis is the focus of novel therapeutic regimes. New insights into the pathophysiological mechanisms resulting in disease have suggested exciting targets for drug therapy.
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Nemshah, Yaser, Alex Clavijo, and Gyanendra Sharma. "Amyloid Heart Disease." US Cardiology Review 12, no. 2 (2018): 113. http://dx.doi.org/10.15420/usc.2018.5.1.
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Cardiac amyloidosis is a group of disorders that develop secondary to the deposition of misfolded proteins in the heart. It can occur in isolation or as part of a systemic disease and can be inherited or acquired. Amyloid light chain (AL) and amyloid transthyretin (ATTR) are the two main forms of amyloid proteins that can infiltrate the heart. With the increased use of advanced imaging techniques and protocols, the recognition and diagnosis of cardiac amyloidosis, especially ATTR, has become easier. New therapies intended to improve survival and quality of life in patients with cardiac amyloidosis are emerging. This article provides an up-to-date review of cardiac amyloidosis.
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Hahn, Katharina, Peter Urban, Rolf Rüdiger Meliß, Hans-Detlef Axmann, Frank Siebert, and Christoph Röcken. "Karpaltunnelsyndrom und ATTR-Amyloidose." Handchirurgie · Mikrochirurgie · Plastische Chirurgie 50, no. 05 (September 2018): 329–34. http://dx.doi.org/10.1055/a-0747-6096.
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Zusammenfassung Hintergrund Das Karpaltunnelsyndrom ist das häufigste Kompressionssyndrom eines peripheren Nervs. Unter anderem wird es durch Transthyretin-Amyloid verursacht, das sich in Karpaltunnelgeweben ablagert. Die meisten Betroffenen sind älter als 50 Jahre. Das Karpaltunnelsyndrom stellt häufig das erste Symptom einer Transthyretin-Amyloidose dar, die im schlimmsten Fall zur Amyloid-Kardiomyopathie mit den Symptomen einer Herzinsuffizienz führt und die Lebensqualität und Lebenszeit einschränkt. Für diesen Artikel wurden alle histologischen Gewebeproben von Karpaltunnelgewebe aus den Jahren 2010 bis 2018 nach den klinischen Patienteneigenschaften Alter und Geschlecht ausgewertet. Durch die gezielte Auswertung des Transthyretin-Amyloidgehalts in verschiedenen Regionen des Karpaltunnels konnte eine Empfehlung zur Resektion für die optimale histologische Diagnostik herausgearbeitet werden. Material und Methoden Im Amyloidregister Kiel werden alle Fälle unter anderem nach Amyloidart und vorliegendem Gewebe archiviert. Für die Auswertung lagen 582 Resektate von Patientinnen und Patienten mit Transthyretin-Amyloid im Karpaltunnelgewebe aus den Jahren 2010 bis Anfang 2018 vor. Ergänzend wurde der Transthyretin-Amyloidgehalt aus zwei verschiedenen Regionen des Karpaltunnels (Synovialisgewebe und Retinaculum flexorum) miteinander verglichen. Ergebnisse Es lagen mehrheitlich Resektate von Frauen vor (53 %). Das mediane Alter betrug 78 Jahre für das gesamte Kollektiv, 77 Jahre für Männer und 79 Jahre für Frauen. Die Resektate des Retinaculum flexorum enthielten signifikant mehr Amyloid (9,66 % Amyloid) als die Resektate aus dem Synovialisgewebe des Karpaltunnels (2,10 % Amyloid). Die Prävalenz der durch ATTR-Amyloid-bedingten Karpaltunnelsyndrome beträgt 11,66 %. Schlussfolgerungen Sowohl Männer als auch Frauen erkranken an einem Karpaltunnelsyndrom, das durch Transthyretin-Amyloid verursacht wird. Insbesondere im Alter von über 50 Jahren sollte im Rahmen der ätiologischen Abklärung des Karpaltunnelsyndroms an Amyloidablagerungen als Auslöser gedacht werden. Die frühzeitige histologische Diagnostik ist in Hinblick auf das Risiko einer kardialen Amyloidose von hoher Relevanz. Für eine frühzeitige und korrekte Diagnose der Transthyretin-Amyloidose im Karpaltunnelgewebe eignet sich vor allem die histologische Untersuchung des Retinaculum flexorum, so dass von diesem immer eine Probe-Exzision entnommen und histologisch untersucht werden sollte.
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Mahrholdt, Heiko, Karin Klingel, and Udo Sechtem. "Die kardiale Amyloidose – ein Krankheitsbild im Wandel." DMW - Deutsche Medizinische Wochenschrift 143, no. 18 (September 2018): 1335–43. http://dx.doi.org/10.1055/s-0043-109420.
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AbstractA fast and reliable diagnosis of cardiac amyloidosis requires a significant amount of clinical awareness. It is especially important to come to an early diagnosis in patients with cardiac AL amyloidosis in order to improve the otherwise unfavourable clinical course in these patients. There is a significant increase in the number of patients with cardiac amyloidosis of the ATTR wild-type variety. These patients are often elderly males presenting with predominantly right sided heart failure. We present a diagnostic pathway enabling a structured approach to these patients using multimodality cardiac imaging and endomyocardial biopsy. Early chemotherapy is the key to improving symptoms in patients with AL amyloidosis. In contrast, pharmacologic approaches for treating cardiac ATTR amyloidosis need further research and clinical trials.
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Li, Weijia, Dipan Uppal, Yu Chiang Wang, Xiaobo Xu, Damianos G. Kokkinidis, Mark I. Travin, and James M. Tauras. "Nuclear Imaging for the Diagnosis of Cardiac Amyloidosis in 2021." Diagnostics 11, no. 6 (May 30, 2021): 996. http://dx.doi.org/10.3390/diagnostics11060996.
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Cardiac amyloidosis is caused by the deposition of misfolded protein fibrils into the extracellular space of the heart. The diagnosis of cardiac amyloidosis remains challenging because of the heterogeneous manifestations of the disease. There are many different types of amyloidosis with light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis being the most common types of cardiac amyloidosis. Endomyocardial biopsy is considered the gold standard for diagnosing cardiac amyloidosis and differentiating amyloid subtypes, but its use is limited because of the invasive nature of the procedure, with risks for complications and the need for specialized training and centers to perform the procedure. Radionuclide cardiac imaging has recently become the most commonly performed test for the diagnosis of ATTR amyloidosis but is of limited value for the diagnosis of AL amyloidosis. Positron emission tomography has been increasingly used for the diagnosis of cardiac amyloidosis and its applications are expected to expand in the future. Imaging protocols are under refinement to achieve better quantification of the disease burden and prediction of prognosis.
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Nakov, Radislav, Stayko Sarafov, Ventsislav Nakov, Mariana Gospodinova, Tihomir Todorov, Andrey Kirov, Albena Todorova, and Ivailo Tournev. "Transthyretin Amyloidosis with Gastrointestinal Manifestation: a Case Report." Journal of Gastrointestinal and Liver Diseases 28, no. 3 (September 1, 2019): 359–61. http://dx.doi.org/10.15403/jgld-422.
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Transthyretin amyloidosis (ATTR) is a rare, progressive, life-threatening, hereditary disorder caused by mutations in the transthyretin gene. Due to the phenotypic heterogeneity, ATTR is difficult to recognize and it is often diagnosed very late. In ATTR gastrointestinal (GI) disorders play an important role in the patients’ morbidity and mortality. In some cases, GI symptoms are present even before the onset of the peripheral polyneuropathy. However, the complaints are various and it is really difficult to differentiate them from other GI disorders. We present a 61-year old male referred for diarrhea, unintentional weight loss and early satiety. He had hypotension after longstanding hypertension, numbness and tingling in the feet. We considered a broad differential diagnosis spectrum of chronic diarrhea syndrome and performed numerous laboratory, biochemical, imaging, endoscopic, histological and genetic tests. Transthyretin amyloidosis with a Glu89Gln mutation was diagnosed. Transthyretin amyloidosis is frequently misdiagnosed, representing a diagnostic challenge in GI practice. The presence of certain clinical combinations could help gastroenterologists to include ATTR in their diagnostic work-up.
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Fujita, Teppei, Takayuki Inomata, Toyoji Kaida, Yuichirou Iida, Yuki Ikeda, Takeru Nabeta, Shunsuke Ishii, et al. "Tafamidis for the Treatment of Hereditary Transthyretin Amyloid Cardiomyopathy: A Case Report." Cardiology 137, no. 2 (2017): 74–77. http://dx.doi.org/10.1159/000455089.
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Tafamidis meglumine is a novel medicine that has been shown to slow the progression of peripheral neurological impairment in patients with hereditary transthyretin amyloidosis (ATTR). However, the efficacy of tafamidis against ATTR-related cardiac amyloidosis remains unclear. A 72-year-old woman had cardiac hypertrophy and axonopathy in her lower legs. Endomyocardial biopsy revealed an infiltrative cardiomyopathy consistent with amyloidosis. Immunostaining and genetic studies confirmed the diagnosis of ATTR, and tafamidis was started subsequently. Two years after the initiation of tafamidis treatment, electromyography demonstrated no change in the axonopathy in her lower legs; however, electrocardiography displayed QRS prolongation, and echocardiography disclosed an increase in interventricular septal thickness. Endomyocardial biopsy indicated that transthyretin amyloid infiltration of the myocardium was not reduced. In this case, there was no apparent progression of axonopathy, although there were signs of worsening amyloid cardiomyopathy during the treatment with tafamidis.
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Rameev, V. V., R. P. Myasnikov, P. P. Vinogradov, L. V. Kozlovskaya, S. V. Moiseev, E. I. Fomicheva, S. A. Beregovskaya, et al. "Systemic ATTR-amyloidosis, a Rare Form of Internal Organ Damage." Rational Pharmacotherapy in Cardiology 15, no. 3 (July 6, 2019): 349–58. http://dx.doi.org/10.20996/1819-6446-2019-15-3-349-358.
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The article presents the case report of a rare hereditary form of systemic ATTR-amyloidosis in Russian patient with a discussion of approaches to the diagnosis and treatment of this form, also based on the own experience in the management of such patients. Modern ideas about the pathogenesis of the disease as well as detailed information about the clinical manifestations of amyloid cardiopathy and of other organs are presented. The nature of structural and hemodynamic changes in the heart is discussed on the basis of experience, including own, ultrasound examination of the heart in patients with amyloidosis, especially the article focuses the reader's attention on the true infiltrative nature of transtiretin amyloid cardiopathy in contrast to AL-amyloidosis, in which there is a significant inflammatory component that determines a more unfavorable natural course of AL-amyloidosis of the heart. The article discusses the differential diagnosis of different types of amyloidosis, the diagnostic difficulties associated with weak congophilia of transtiretin amyloidosis and at the same time substantiates the need for morphological verification of the diagnosis. Modern methods of treatment of ATTR-amyloidosis are discussed.
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Saleem, Mariam, Besher Sadat, Meredith Van Harn, and Karthikeyan Ananthasubramaniam. "Towards a Diagnosis of Cardiac Amyloidosis: Single Center Experience with 99m Technetium Pyrophosphate Planar Imaging and Opportunities for Standardization of Diagnostic Workflow." Medicina 59, no. 2 (February 16, 2023): 378. http://dx.doi.org/10.3390/medicina59020378.
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Background and Objectives: Cardiac amyloidosis is a disorder caused by amyloid fibril deposition in the extracellular space of the heart. Almost all forms of clinical cardiac amyloidosis are transthyretin amyloidosis (ATTR) or light chain amyloidosis. 99m technetium pyrophosphate (99mTc PYP scan) has changed the landscape of the non-biopsy diagnosis of ATTR cardiac amyloidosis (ATTR-CA) by providing remarkably high diagnostic accuracy. We examined our experience with PYP scans in patients undergoing workup for ATTR-CA and evaluated the diagnostic workflow in patients with intermediate PYP scan results. Materials and Methods: Retrospective chart review study in which we analyzed data of 84 patients who underwent c-99m pyrophosphate (PYP) SPECT scan for the diagnosis of ATTR-CA from 2017 till 2021 at our institution. We identified three groups: Low uptake (PYPL uptake ratio < 1.2 + visual grade 1/0), n = 30, Intermediate uptake (PYPI uptake ratio 1.2–1.49, visual grade 2/3), n = 25 and High uptake (PYPH uptake ratio ≥ 1.5 + visual grade 2/3), n = 29. We reviewed patients’ demographics, medical histories, echo parameters and diagnostic testing including light chain analysis, cardiac magnetic resonance results, and biopsies. Results: Mean patients’ age was 73, male-to=female ratio 3:1, 59% of patients were African American. Cardiovascular comorbidities, cardiac biomarkers (BNP and Troponin) and amyloid-related neuropathy were similar in all groups. A statistically significant difference in septal thickness/posterior wall thickness and final diagnosis were found between the groups. The distribution of overall diagnostic testing ratios for the PYPI group included serum protein electrophoresis 92%, urine protein electrophoresis 65%, free light chain 80%, CMR 32%, tissue biopsy done in 20% and BM biopsy in 16%, which are similar to the ratios of other groups. Overall, 25% (n = 5, 4 TTR-CA and 1 AL Amyloid) of patients in the PYPI group had a final diagnosis of CA established with additional testing (p = 0.001 vs. other groups). Conclusions: The 99mPYP scan is an accurate noninvasive test for cardiac ATTR-CA. Importantly, 25% of the PYPI group had a final diagnosis of ATTR-CA reiterating that diagnosis needs to be pursued in PYPI cases based on clinical suspicion. Routine evaluation and exclusion of light chain disease and establishing a consistent workflow for amyloid diagnosis and continued education for technologists and readers of PYP scans is key to a successful amyloidosis workup.
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Fonseca, Daniel, Samuel Gilberto, Cristina Ribeiro-Silva, Raquel Ribeiro, Inês Batista Guinote, Susana Saraiva, Ricardo A. Gomes, et al. "The role of fibrinogen glycation in ATTR: evidence for chaperone activity loss in disease." Biochemical Journal 473, no. 14 (July 12, 2016): 2225–37. http://dx.doi.org/10.1042/bcj20160290.
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Transthyretin amyloidosis (ATTR) belongs to a class of disorders caused by protein misfolding and aggregation. ATTR is a disabling disorder of autosomal dominant trait, where transthyretin (TTR) forms amyloid deposits in different organs, causing dysfunction of the peripheral nervous system. We previously discovered that amyloid fibrils from ATTR patients are glycated by methylglyoxal. Even though no consensus has been reached about the actual role of methylglyoxal-derived advanced glycation end-products in amyloid diseases, evidence collected so far points to a role for protein glycation in conformational abnormalities, being ubiquitously found in amyloid deposits in Alzheimer's disease, dialysis-related amyloidosis and Parkinson's diseases. Human fibrinogen, an extracellular chaperone, was reported to specifically interact with a wide spectrum of stressed proteins and suppress their aggregation, being an interacting protein with TTR. Fibrinogen is differentially glycated in ATTR, leading to its chaperone activity loss. Here we show the existence of a proteostasis imbalance in ATTR linked to fibrinogen glycation by methylglyoxal.
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Gospodinova, Mariana, Elena Kinova, Iana Simova, Yoto Yotov, Marina Garcheva, Galina Kirova, Kamelia Genova, et al. "Diagnostic algorithm in transthyretin amyloidosis with cardiomyopathy." Bulgarian Cardiology 26, no. 2 (July 6, 2020): 5–20. http://dx.doi.org/10.3897/bgcardio.26.e53407.
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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.
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Rubin, Jonah, and Mathew S. Maurer. "Cardiac Amyloidosis: Overlooked, Underappreciated, and Treatable." Annual Review of Medicine 71, no. 1 (January 27, 2020): 203–19. http://dx.doi.org/10.1146/annurev-med-052918-020140.
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Cardiac amyloidosis (CA) is an infiltrative and restrictive cardiomyopathy that leads to heart failure, reduced quality of life, and death. The disease has two main subtypes, transthyretin cardiac amyloidosis (ATTR-CA) and immunoglobulin light chain cardiac amyloidosis (AL-CA), characterized by the nature of the infiltrating protein. ATTR-CA is further subdivided into wild-type (ATTRwt-CA) and variant (ATTRv-CA) based on the presence or absence of a mutation in the transthyretin gene. CA is significantly underdiagnosed and increasingly recognized as a cause of heart failure with preserved ejection fraction. Advances in diagnosis that employ nuclear scintigraphy to diagnose ATTR-CA without a biopsy and the emergence of effective treatments, including transthyretin stabilizers and silencers, have changed the landscape of this field and render early and accurate diagnosis critical. This review summarizes the epidemiology, pathophysiology, diagnosis, prognosis, and management of CA with an emphasis on the significance of recent developments and suggested future directions.
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Shehab, Abdullah, Albena Todorova, Aysha Ahmed, Esther Gonzalez-Lopez, Fabian Knebel, Haluk Alibazoglu, Hani Sabbour, et al. "Pearls from the First Gulf Cardiac Amyloidosis Summit 2021." New Emirates Medical Journal 3, no. 1 (April 2022): 1–11. http://dx.doi.org/10.2174/03666220117152535.
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Abstract: These proceedings from the First Gulf Cardiac Amyloidosis Summit held in June 2021 aimed to increase awareness of cardiac amyloidosis among the wider medical community in the region. Although the clinical presentation of cardiac amyloidosis is highly variable, a number of ‘red flags’ have been identified to raise suspicion of the disease and prompt further investigation. Accurate diagnosis of cardiac amyloidosis is challenging and relies on the integration of clinical, imaging and laboratory investigations. Recent imaging techniques, including bone scintigraphy together with a complete serum and urine workup, allow, in the majority of patients, accurate non-invasive diagnosis without the need for confirmatory endomyocardial biopsies. Early differential diagnosis between light-chain (AL) amyloidosis and amyloid transthyretin amyloidosis (ATTR) is critical for timely delivery of appropriate therapy. AL amyloidosis is a medical emergency requiring chemotherapy and supportive care. Treatment for ATTR-amyloidosis is most effective when administered early, before development of significant symptoms or cardiac dysfunction. Optimal management of patients involves close collaboration between multidisciplinary specialists, which may include hematologists, cardiologists, and other subspecialists, ideally at a designated specialty center with interest and expertise in amyloidosis.
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Riley, Mark, Ammoura Ibrahim, Maria Kofman, and Ruben Peredo-Wende. "Transthyretin amyloidosis and herpes zoster infection: a mimic of temporal arteritis." BMJ Case Reports 14, no. 6 (June 2021): e241505. http://dx.doi.org/10.1136/bcr-2020-241505.
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We describe the case of a patient who presented with symptoms of persistent headaches, left-sided facial pain and blurry vision of the left eye. The patient had recovered from a herpes zoster infection of the V1 division of the trigeminal nerve 1 month prior. Serum inflammatory markers were elevated, raising concern for temporal arteritis. Empiric high-dose prednisone was initiated. Bilateral temporal artery biopsies were performed but did not show evidence of vasculitis or multinucleated giant cells. Instead, extracellular material deposits were present within the vessel walls. Congo red staining was diagnostic for amyloidosis. Liquid chromatography and mass spectrometry identified the amyloid fibrils to be transthyretin-type (ATTR) consistent with age-related amyloidosis. Temporal artery involvement of amyloidosis is rare but when present is most often due to light chain amyloidosis. Based on our review of the literature, only a few cases of temporal artery ATTR amyloidosis have been reported.
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Nativi-Nicolau, Jose, Nowell M. Fine, José Thomás Ortiz-Pérez, Duncan Brown, Montserrat Vera-Llonch, Sheila R. Reddy, Eunice Chang, and Marian H. Tarbox. "Clinical manifestations and healthcare utilization before diagnosis of transthyretin amyloidosis." Journal of Comparative Effectiveness Research 11, no. 14 (October 2022): 1031–44. http://dx.doi.org/10.2217/cer-2022-0074.
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Introduction: Initial clinical manifestations of transthyretin amyloidosis (ATTR) are not well understood, making timely diagnosis challenging. Methods: Patients aged ≥68 years newly diagnosed with ATTR were identified using Medicare Research Identifiable Files. Symptom manifestation and healthcare utilization were measured during 3 years pre-diagnosis; demographics and comorbidity index during 1-year pre-diagnosis. Controls (ATTR-free) were matched 1:1 to patients with ATTR based on age, sex and region; same index date and enrollment as match. Results: We identified 552 matched ATTR-control pairs: mean age 78.3 (standard deviation 6.3) and 64.5% male. Among patients with ATTR (vs controls), cardiovascular conditions (92.9 vs 75.9%) and hospitalization (54.0 vs 35.5%) were frequent during 3 years pre-diagnosis. Conclusion: Patients with ATTR have multiple symptoms and hospitalizations pre-diagnosis, recognition of which may facilitate earlier diagnosis and treatment.
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Verheyen, Nicolas, Maria Ungericht, Lisa Paar, Kathrin Danninger, Stefanie Schneiderbauer-Porod, Franz Duca, Bernhard Cherouny, et al. "Diagnostic Accuracy of Bone Scintigraphy for the Histopathological Diagnosis of Cardiac Transthyretin Amyloidosis—A Retrospective Austrian Multicenter Study." Biomedicines 10, no. 12 (November 28, 2022): 3052. http://dx.doi.org/10.3390/biomedicines10123052.
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We aimed to ascertain the real-world diagnostic accuracy of bone scintigraphy in combination with free light chain (FLC) assessment for transthyretin (ATTR) cardiac amyloidosis (CA) using the histopathological diagnosis derived from endomyocardial biopsy (EMB) as a reference standard. We retrospectively analyzed 102 patients (22% women) with suspected CA from seven Austrian amyloidosis referral centers. The inclusion criteria comprised the available results of bone scintigraphy, FLC assessment, and EMB with histopathological analysis. ATTR and AL were diagnosed in 60 and 21 patients (59%, 21%), respectively, and concomitant AL and ATTR was identified in one patient. The specificity and positive predictive value (PPV) of Perugini score ≥ 2 for ATTR CA were 95% and 96%. AL was diagnosed in three out of 31 patients (10%) who had evidence of monoclonal proteins and a Perugini score ≥ 2. When excluding all patients with detectable monoclonal proteins (n = 62) from analyses, the PPV of Perugini score ≥ 2 for ATTR CA was 100% and the NPV of Perugini score < 2 for ATTR CA was 79%. Conclusively, ATTR CA can be diagnosed non-invasively in the case of a Perugini score ≥ 2 and an unremarkable FLC assessment. However, tissue biopsy is mandatory in suspected CA in any other constellation of non-invasive diagnostic work-up.
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Stan, Claudiu, Raluca Mititelu, Robert Daniel Adam, and Ruxandra Jurcuţ. "Awareness of Nuclear Medicine Physicians in Romania Regarding the Diagnostic of Cardiac Amyloidosis—A Survey-Based Study." Diagnostics 12, no. 2 (February 21, 2022): 556. http://dx.doi.org/10.3390/diagnostics12020556.
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Amyloidosis is a heterogeneous group of diseases caused by the extracellular deposition of amyloid insoluble fibrils in multiple organs, resulting in various clinical manifestations. Cardiac amyloidosis (CA) occurs mainly in primary light-chain (AL) amyloidosis, hereditary transthyretin (ATTRv) amyloidosis and senile or wild-type transthyretin (ATTRwt) amyloidosis. Knowing that myocardial uptake at bone scintigraphy is an essential step in the ATTR-CA diagnostic algorithm, the level of awareness among nuclear medicine physicians (NMPs) using bone tracer scintigraphy is of great importance. The objective of the study was to evaluate NMPs’ awareness of scintigraphy with bisphosphonates for the detection of CA. We conducted an online survey among NMPs from Romania to assess their current awareness and state of knowledge of nuclear techniques used in CA. Among the total 65 Romanian NMPs, 35 (53%) responded to this questionnaire. Approximately three-quarters of participants (74%) found a diffuse accumulation of bisphosphonates in the heart on scintigraphy performed for bone pathology as an incidental discovery. Detection of myocardial uptake of 99mTc-labeled bisphosphonates on scintigraphy suggests CA-AL for 3% of participants and for 9% of respondents, the appearance is of uncertain cardiac amyloidosis, while 5% of participants observed cardiac uptake but did not report it as CA. Even if more than half of those who responded to this survey (54%) found abnormal cardiac uptake and interpreted it as CA-ATTR, only 14% contacted the referring physician to draw attention to the incidental discovery to refer the patient to a specialist in rare genetic cardiomyopathy. Regarding the knowledge about the categories of bisphosphonates recommended in the diagnosis of CA-ATTR, 54% answered inadequately that methylene diphosphonate (MDP) could be used. Romanian nuclear physicians are partially familiar with CA diagnosis by scintigraphy, but its diagnostic potential and standardization, recommended radiotracers and acquisition times and interpretation algorithms are known in varying proportions. Therefore, there is a need to enhance knowledge through continuing medical education programs in order to standardize the protocols for the acquisition, processing and interpretation of bisphosphonate scintigraphy for the detection of cardiac ATTR amyloidosis.
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Thelander, Ulrika, Gunilla T. Westermark, Gunnar Antoni, Sergio Estrada, Alice Zancanaro, Elisabet Ihse, and Per Westermark. "Cardiac microcalcifications in transthyretin (ATTR) amyloidosis." International Journal of Cardiology 352 (April 2022): 84–91. http://dx.doi.org/10.1016/j.ijcard.2022.01.036.
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Hawkins, P. "Therapeutic advances in hereditary ATTR amyloidosis." Neuromuscular Disorders 28 (April 2018): S1. http://dx.doi.org/10.1016/s0960-8966(18)30292-x.
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Marzuki, Hadi, Erwin A. Soeriadi, Astri Astuti, Hendra Budiawan, and Achmad Hussein S. Kartamihardja. "Difference Uptake of 99mTc-Pyrophosphate vs 99mTc- Methylenediphosphate in Detecting Cardiac Amyloidosis; First Experience in Hasan Sadikin General Hospital." Journal of Medicine and Health 4, no. 1 (February 22, 2022): 10. http://dx.doi.org/10.28932/jmh.v4i1.3640.
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Cardiac amyloidosis (CA) is a disorder caused by deposits of insoluble fibrils in the myocardium and an underdiagnosed cause of heart failure. Immunoglobulin Light Chain-Associated Amyloid (AL) and Amyloidosis Transthyretin-related (ATTR) are the two protein precursors that most commonly cause cardiac amyloidosis. It is important to distinguish between these two types of amyloidosis because the treatment and prognosis of each types is different. Recent advances in cardiac radionuclide imaging, in particular using bone-seeking agents such as 99mTc-Pyrophosphate (PYP) and 99mTc-Methylenediphosphate (MDP), can differentiate AL from ATTR. This study aimed was to investigate the uptake characteristic of both tracers in CA. Three patients with suspected of having cardiac amyloidosis underwent two cardiac radionuclide imaging examinations using those two different radiopharmaceuticals. The cardiac images were analyzed quantitatively and semi-quantitatively based on ASNC (American Society of Nuclear Medicine) criteria. Cardiac radioactivity uptake of 99mTc-PYP was better from those of 99mTc-MDP based on quantitative as well as semi-quantitative (visual assessment).
Keywords: cardiac amyloidosis; cardiac imaging; 99mTc-PYP; 99mTc-MDP
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Arnberg, Elsa, Per Eldhagen, Viktor Löfbacka, Ashwin Venkateshvaran, Björn Pilebro, and Per Lindqvist. "RWT/SaVR—A Simple and Highly Accurate Measure Screening for Transthyretin Cardiac Amyloidosis." Journal of Clinical Medicine 11, no. 14 (July 15, 2022): 4120. http://dx.doi.org/10.3390/jcm11144120.
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Background: Cardiac amyloidosis is an underdiagnosed condition and simple methods for accurate diagnosis are warranted. We aimed to validate a novel, dual-modality approach to identify transthyretin cardiac amyloidosis (ATTR-CA), employing echocardiographic relative wall thickness (RWT), and ECG S-wave from aVR (SaVR), and compare its accuracy with conventional echocardiographic approaches. Material and methods: We investigated 102 patients with ATTR-CA and 65 patients with left ventricular hypertrophy (LVH), all with septal thickness > 14 mm. We validated the accuracy of echocardiographic measures, including RWT, RWT/SaVR, posterior wall thickness (PWT), LV mass index (LVMI), left atrial volume index (LAVI), global longitudinal strain (GLS), and relative apical sparing (RELAPS) to identify ATTR-CA diagnosed using DPD-scintigraphy or abdominal fat biopsy. Results: PWT, RWT, RELAPS, troponin, and RWT/SaVR were significantly higher in ATTR-CA compared to LVH. RWT/SaVR > 0.7 was the most accurate parameter to identify ATTR-CA (sensitivity 97%, specificity 90% and accuracy 91%). RELAPS was found to have much less accuracy (sensitivity 74%, specificity 76% and accuracy 73%). Conclusion: We can confirm the very strong diagnostic accuracy of RWT/SaVR to identify ATTR-CA in patients with septal thickness > 14 mm. Given its high sensitivity and specificity, RWT/SaVR > 0.7 has the potential to implement as a non-invasive, simple, and widely available diagnostic tool when screening for ATTR-CA.
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Rasmussen, Torsten B., Bertil T. Ladefoged, Anne M. Dybro, Tor S. Clemmensen, Rikke H. Sørensen, Astrid J. Terkelsen, Henning Mølgaard, Henrik Vase, and Steen H. Poulsen. "Transthyretin Gene Variants and Associated Phenotypes in Danish Patients with Amyloid Cardiomyopathy." Cardiogenetics 12, no. 1 (January 4, 2022): 1–11. http://dx.doi.org/10.3390/cardiogenetics12010001.
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Genotyping divides transthyretin cardiac amyloidosis (ATTR-CA) in hereditary (ATTRv) and wild type (ATTRwt) forms. This study investigated the prevalence and clinical presentation of ATTRv in a contemporary cohort of consecutive ATTR-CA patients diagnosed at a tertiary Danish amyloidosis center. Age at diagnosis, clinical- and echocardiographic data, and transthyretin (TTR) genotype were recorded. Relatives of ATTRv patients underwent clinical phenotyping and predictive gene testing. Genetic testing in 102 patients identified four TTR variant carriers: p.Pro63Ser, p.Ala65Ser (n = 2) and p.Val142Ile. The mean age of ATTRv index patients was significantly lower compared to ATTRwt patients: 70.2 ± 1.2 versus 80.0 ± 6.2, p-value: 0.005. Evaluation of ATTRv families identified seven TTR variant carriers with a median age of 65 years (range 48–76) and three were diagnosed with ATTR-CA by DPD-scintigraphy. Family members with ATTR-CA were all asymptomatic and had normal levels of cardiac biomarkers. In conclusion, the prevalence of ATTRv in a contemporary Danish ATTR-CA cohort is 4%. ATTRv index patients were significantly younger age at diagnosis than ATTRwt patients. Non-p.Leu131Met TTR variants have reduced penetrance at the age of 65 years in which approximately half of variant carriers have asymptomatic ATTR-CA with normal LV systolic function and cardiac biomarker analyses.