Soon-Chai Low, Nor Ashikin Md Sari, Cheng-Yin Tan, Azlina Ahmad-Annuar, Kum-Thong Wong, Wan-Chung Law, Rachel Siew-Hung Sim, Kon-Ping Lin, Nortina Shahrizaila, Khean-Jin Goh
We report the clinical and genetic characteristics of hereditary transthyretin amyloidosis in the multi-ethnic Malaysian population. Subjects with genetically confirmed transthyretin amyloidosis seen between 2001 till August 2020 were included. There were 30 patients and 14 asymptomatic carriers, of which 26 (59.1%) were men. The majority (86.7%) were ethnic Chinese while two (6.7%) each were Malay and Sri Lankan Tamil ethnicity respectively. Among patients, mean age of symptom-onset was 55.9 ± 9.8 years with mean duration from symptom-onset to diagnosis of 3...
March 27, 2021: Neuromuscular Disorders: NMD
Francesca Pastorelli, Gioele Fabbri, Claudio Rapezzi, Matteo Serenelli, Rosaria Plasmati, Veria Vacchiano, Alessandra Ferlini, Marco Manfrini, Fabrizio Salvi
BACKGROUND: Ile68Leu transthyretin-related amyloidosis (ATTR) is known as a mainly or exclusively cardiogenic variant. We hypothesized that an accurate specialized neurological evaluation could reveal a consistent frequency of mixed phenotypes. METHODS: Forty-six consecutive subjects with transthyretin (TTR) Ile68Leu (p.Ile88Leu) mutation (29 patients and 17 unaffected carriers) underwent an in-depth cardiac and neurologic evaluation at a single center. RESULTS: All 29 patients showed cardiac involvement...
May 28, 2021: Amyloid: the International Journal of Experimental and Clinical Investigation
Jennaire Lewars, Hersh Wazir, Brandon Gordon, Uyi Faluyi, Yousry Girgis
Amyloidoses are a family of inherited or acquired disorders characterized by the deposition of insoluble extracellular protein fibrils in various organs and tissues, thereby impairing their function. Amyloidoses are typically misfolded proteins, and on rare occasions, can deposit in the myocardium resulting in an infiltrative/restrictive cardiomyopathy. Restrictive cardiomyopathy is an underdiagnosed cause of congestive heart failure (CHF) with preserved ejection fraction, atrial and ventricular arrhythmias along with conduction defects...
April 21, 2021: Curēus
Roos J Leguit, Aryan Vink, Nicolaas de Jonge, Monique C Minnema, Marish I F Oerlemans
In about 4% of cases, amyloid light chain (AL) amyloidosis is due to an underlying lymphoplasmacytic lymphoma (LPL) or other monoclonal protein (M-protein) forming low-grade B-cell lymphoma, instead of a plasma cell neoplasm. We report an unusual case of a 55 year old male with co-localization of an IgG positive LPL and AL amyloidosis in his endomyocardial biopsy (EMB). The patient was diagnosed 4 years earlier with a low grade B-cell non Hodgkin lymphoma stage IV, at the time classified as marginal zone lymphoma...
May 23, 2021: Cardiovascular Pathology: the Official Journal of the Society for Cardiovascular Pathology
Aubin Michalon, Andreas Hagenbuch, Christian Huy, Evita Varela, Benoit Combaluzier, Thibaud Damy, Ole B Suhr, Maria J Saraiva, Christoph Hock, Roger M Nitsch, Jan Grimm
Transthyretin amyloid (ATTR) cardiomyopathy is a debilitating disease leading to heart failure and death. It is characterized by the deposition of extracellular ATTR fibrils in the myocardium. Reducing myocardial ATTR load is a therapeutic goal anticipated to translate into restored cardiac function and improved patient survival. For this purpose, we developed the selective anti-ATTR antibody NI301A, a recombinant human monoclonal immunoglobulin G1. NI301A was cloned following comprehensive analyses of memory B cell repertoires derived from healthy elderly subjects...
May 25, 2021: Nature Communications
V Löfbacka, O B Suhr, B Pilebro, J Wixner, T Sundström, K Lindmark, I Anan, P Lindqvist
AIMS/BACKGROUND: Transthyretin amyloid (ATTR) amyloidosis cardiomyopathy is an underdiagnosed, causatively treatable cause of heart failure. The aim of this study was to evaluate the efficacy of electrocardiography (ECG) and echocardiography on patients with increased interventricular septum diameter (IVSd) to identify ATTR cardiac amyloidosis (ATTR-CA) patients. METHODS: We investigated 58 patients with heart failure and an IVSd >14mm. Included were 33 ATTR-CA patients and 25 controls that consisted of non-amyloidosis heart failure (HF) patients with negative 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy...
May 25, 2021: Clinical Physiology and Functional Imaging
Cristina Chimenti, Maria Alfarano, Viviana Maestrini, Nicola Galea, Giuseppe De Vincentis, Romina Verardo, Francesco Fedele, Andrea Frustaci
A positive nuclear scintigraphy with hydroxy bisphosphonate bone tracer (99mTc-HPD) is believed to have high sensitivity (>99%) and specificity (91%) for the diagnosis of transthyretin amyloid cardiomyopathy. We report the case of an 85-year-old man with increased thickness of ventricular walls and a positive bone scintigraphy, who was unexpectedly found to have sarcomeric hypertrophic cardiomyopathy at left ventricular endomyocardial biopsy. Congo Red staining, immunohistochemistry, and transmission electronmicroscopy on six left ventricular samples scored negative for amyloidosis but were suggestive for sarcomeric hypertrophic cardiomyopathy...
May 25, 2021: ESC Heart Failure
Zhiyong Chen, Jasmine S Koh, Monica Saini, Karine S S Tay, Yi Jayne Tan, Josiah Y H Chai, Su Rong Fam, A R Juraidah, Peck Kee Lim, Adeline S L Ng, Kalpana Prasad, Chai Beng Tan, T Umapathi, Kamal K Verma, Ming Hui Yong, Chen Yu, Peng Soon Ng
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...
May 15, 2021: Journal of Neuromuscular Diseases
Divaya Bhutani, Samuel Pan, Farhana Latif, Rochelle L Goldsmith, Sunil E Saith, Markus Y Mapara, Rajshekhar Chakraborty, Suzanne Lentzsch, Mathew S Maurer
BACKGROUND: Cardiac involvement and dysfunction are common in patients presenting with AL and ATTR Amyloidosis. Cardiopulmonary exercise testing (CPET) performance is the gold standard to quantify functional capacity. PATIENTS AND METHODS: In this study, we evaluated CPET measurements in 41 patients with cardiac Amyloidosis and their correlation with current amyloid specific staging criteria. RESULTS: In both AL and ATTR cardiac Amyloidosis, percent predicted peak VO2 is significantly reduced and correlates with biomarker abnormalities...
April 23, 2021: Clinical Lymphoma, Myeloma & Leukemia
Daniel Otzen
Light chain amyloidosis (AL) is a fatal disorder wherein immunoglobulin light chain misfolds and aggregates, leading to amyloid plaques in various organs. Patient-specific mutations in the antibody VL domain are tightly linked to amyloidosis, but how these mutations drive AL is unknown. In recent work, Rottenaicher et al. analyze five mutations found in the variable (VL ) domain of a cardiac AL patient. Their data suggest that decreased VL stability and increased flexibility in the core of VL , caused by mutations outside of this core, could be key to aggregation, and highlight the delicate balancing act required for antibody maturation to enable antigen recognition while not altering protein biophysics...
May 18, 2021: Journal of Biological Chemistry
Kyle T Dittloff, Antonio Iezzi, Justin X Zhong, Priya Mohindra, Tejal A Desai, Brenda Russell
Age-related wild type transthyretin amyloidosis (wtATTR) is characterized by systemic deposition of amyloidogenic fibrils of misfolded transthyretin (TTR) in the connective tissue of many organs. In the heart this leads to cardiac dysfunction, which is a significant cause of age-related heart failure. The hypothesis tested is that TTR affects cardiac fibroblasts in ways that may contribute to fibrosis. When primary cardiac fibroblasts were cultured on TTR-deposited substrates, the F-actin cytoskeleton disorganized, focal adhesion formation decreased, and nuclear shape was flattened...
May 21, 2021: American Journal of Physiology. Heart and Circulatory Physiology
Ryan P Boyle, Josh Sharan, Gary Schwartz
Amyloidosis is a group of disorders that occurs due to the aggregation of insoluble and misfolded proteins in the extracellular space, eventually resulting in organ dysfunction. Type II amyloidosis is caused by the deposition of transthyretin (TTR), which will be the main focus of this article. Deposition of TTR in the myocardium results in a restrictive form of cardiomyopathy. TTR can also deposit in the flexor tenosynovium resulting in carpal tunnel syndrome (CTS). CTS develops five to ten years prior to cardiac amyloidosis (CA), and therefore, the temporal relationship allows CTS to be a diagnostic indicator for CA...
April 18, 2021: Curēus
Hidehiro Ishikawa, Atsushi Niwa, Shinya Kato, Yuichiro Ii, Akihiro Shindo, Keita Matsuura, Yamato Nishiguchi, Asako Tamura, Akira Taniguchi, Masayuki Maeda, Yoshio Hashizume, Hidekazu Tomimoto
Even with postmortem pathological examination, only limited information is provided of the foci of in vivo clinical information. Cerebral small vessel disease, which is associated with ageing, dementia and stroke, highlights the difficulty in arriving at a definitive diagnosis of the lesions detected on in vivo radiological examination. We performed a radiological-pathological comparative study using ex vivo MRI to examine small cerebral lesions. Four patients with small vessel disease lesions detected on in vivo MRI were studied...
2021: Brain communications
Ahsan Huda, Adam Castaño, Anindita Niyogi, Jennifer Schumacher, Michelle Stewart, Marianna Bruno, Mo Hu, Faraz S Ahmad, Rahul C Deo, Sanjiv J Shah
Transthyretin amyloid cardiomyopathy, an often unrecognized cause of heart failure, is now treatable with a transthyretin stabilizer. It is therefore important to identify at-risk patients who can undergo targeted testing for earlier diagnosis and treatment, prior to the development of irreversible heart failure. Here we show that a random forest machine learning model can identify potential wild-type transthyretin amyloid cardiomyopathy using medical claims data. We derive a machine learning model in 1071 cases and 1071 non-amyloid heart failure controls and validate the model in three nationally representative cohorts (9412 cases, 9412 matched controls), and a large, single-center electronic health record-based cohort (261 cases, 39393 controls)...
May 11, 2021: Nature Communications
Jin Chul Paeng, Joon Young Choi
Cardiac amyloidosis (CA) is a type of systemic amyloidosis, in which abnormal amyloid fibril is deposited in extracellular space of myocardium. Most common subtypes of CA are amyloidosis of immunoglobulin light chain (AL) and amyloidosis of transthyretin (ATTR). With increase in incidence of CA and development of new drugs, the needs of early and accurate diagnosis of CA are increasing. In CA, bone scan and SPECT/CT have long been used for diagnosis. Currently, bone scan is included in almost all practice guidelines as one of key diagnostic examinations for ATTR CA...
April 2021: Nuclear Medicine and Molecular Imaging
Xiaozhe Li, Beihui Huang, Junru Liu, Meilan Chen, Jingli Gu, Juan Li
PURPOSE: To assess the feasibility and prognostic value of minimal residual disease (MRD) evaluated by multiparameter flow cytometry (MFC) in newly diagnosed amyloid light chain (AL) amyloidosis. METHODS: Clinical data from 25 consecutive newly diagnosed AL amyloidosis patients with MRD data tested at 3 months after first-line therapy completion were retrospectively analysed in a single centre from 2012 to 2019. First-line therapy included 8 courses of VD or 4 courses of VD plus sequential autologous stem cell transplantation (ASCT), both without maintenance therapy...
May 8, 2021: Journal of Cancer Research and Clinical Oncology
Ana Devesa, Andrea Camblor Blasco, Ana María Pello Lázaro, Elham Askari, Gregoria Lapeña, Sandra Gómez Talavera, Mikel Taibo Urquía, Celia Rodríguez Olleros, José Tuñón, Borja Ibáñez, Álvaro Aceña
AIMS: As evidenced by scintigraphy imaging, the prevalence of transthyretin (TTR) cardiac amyloidosis in heart failure patients with preserved ejection fraction (HFpEF) and left ventricular hypertrophy (LVH) ranges between 13% and 19%. The natural evolution of cardiac amyloidosis begins with the deposition of amyloid material in the myocardium, with LVH ensuing at later stages. With current imaging modalities, it is possible to detect TTR cardiac amyloidosis before the hypertrophic stage...
May 8, 2021: ESC Heart Failure
David Zach, Klemens Ablasser, Ewald Kolesnik, Viktoria Hoeller, Friedrich Fruhwald, Florian Prüller, Clemens Reiter, Christine Beham-Schmid, Rainer Lipp, Peter P Rainer, Andreas Zirlik, Albert Wölfler, Nicolas Verheyen
Amyloid light chain (AL) cardiomyopathy is the most malignant specific cardiomyopathy. According to international recommendations, it should be ruled out non-invasively using the serum free light chain (FLC) ratio and immunofixation electrophoresis in both serum and urine. Here, we report on a 69-year-old female patient with new-onset heart failure with mid-range ejection fraction. Cardiac imaging was highly suggestive of cardiac amyloidosis. Amyloid scintigraphy showed faint myocardial tracer uptake according to Perugini Score 1, but immunofixation was negative and the FLC ratio was normal, despite a slight increase in lambda FLCs...
May 7, 2021: ESC Heart Failure
Ana L González-Cota, Carmen Santana-Calvo, Rocío Servín-Vences, Gerardo Orta, Enrique Balderas
The mitochondrial BKCa channel (mitoBKCa ) is a splice variant of plasma membrane BKCa (Maxi-K, BKCa , Slo1, KCa 1.1). While a high-resolution structure of mitoBKCa is not available yet, functional and structural studies of the plasma membrane BKCa have provided important clues on the gating of the channel by voltage and Ca2+ , as well as the interaction with auxiliary subunits. To date, we know that the control of expression of mitoBKCa , targeting and voltage-sensitivity strongly depends on its association with its regulatory β1-subunit, which overall participate in the control of mitochondrial Ca2+ -overload in cardiac myocytes...
December 2021: Channels
Martin Kaag Rasmussen, Humberto Mestre, Maiken Nedergaard
Brain harbors a unique ability to, figuratively speaking, shift its gears. During wakefulness, the brain is geared fully towards processing information and behaving, while homeostatic functions predominate during sleep. The blood-brain barrier establishes a stable environment that is optimal for neuronal function, yet the barrier imposes a physiological problem; transcapillary filtration that forms extracellular fluid in other organs is reduced to a minimum in brain. Consequently, the brain depends on a special fluid (the cerebrospinal fluid; CSF) that is flushed into brain along the unique perivascular spaces created by astrocytic vascular endfeet...
May 5, 2021: Physiological Reviews
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