CEPARM: Four decades of dedication to advancing familial amyloidotic polyneuropathy research and patient care / CEPARM: Quatro décadas de dedicação ao avanço da pesquisa e cuidados com pacientes com polineuropatia amiloidótica familiar

This paper delves into the remarkable journey of the Centro de Paramiloidose Antônio Rodrigues de Mello (CEPARM), located at the Hospital Universitário Clementino Fraga Filho (HUCFF) of UFRJ, over the past four decades, from its establishment in 1984 to its emergence as a pioneering institution in the so called field of Familial Amyloidotic Polyneuropathy (FAP). Founded in response to the urgent need for specialized research and treatment of this rare genetic disorder prevalent among individuals of Portuguese descent mainly with expressive Polyneuropathy (Hereditary Transthyretin Amyloidosis with Polyneuropathy - hATTR-PN) or even Cardyomyopathy (Hereditary Transthyretin Amyloidosis with Cardyomyopathy hATTR-CM), CEPARM has played a crucial role in the evolution of this field. The paper offers a comprehensive overview of the center's development, emphasizing its major achievements, research contributions, and advancements in patient care. It highlights CEPARM's pivotal role in developing innovative treatment protocols, including the introduction of liver transplantation for FAP and groundbreaking therapies such as tafamidis, patisiran, inotersen, vutrisiran, and eplontersen. Additionally, the paper explores CEPARM's efforts to enhance patient quality of life through multidisciplinary care and support programs. By reflecting on the center's historical milestones, leadership transitions, and ongoing initiatives, this paper underscores CEPARM's unwavering commitment to advancing scientific knowledge and improving patient outcomes mainly in the realm of hATTR-PN.

Este artigo descreve a marcante trajetória do Centro de Paramiloidose Antônio Rodrigues de Mello (CEPARM), localizado no Hospital Universitário Clementino Fraga Filho (HUCFF) da UFRJ, ao longo das últimas quatro décadas, desde sua criação em 1984 até seu surgimento como instituição pioneira no chamado campo da Polineuropatia Amiloidótica Familiar (PAF). Fundado em resposta à necessidade urgente de investigação especializada e tratamento desta doença genética rara prevalente entre indivíduos de ascendência portuguesa, principalmente com Polineuropatia expressiva (Amiloidose Hereditária por Transtirretina com Polineuropatia - hATTR-PN) ou mesmo Cardiomiopatia (Amiloidose Hereditária pot Transtiretina com Cardiomiopatia - hATTR-CM), o CEPARM tem desempenhado um papel crucial na evolução deste campo. O artigo oferece uma visão abrangente do desenvolvimento do centro, enfatizando suas principais conquistas, contribuições de pesquisa, e avanços no atendimento ao paciente. Destaca o papel fundamental do CEPARM no desenvolvimento de protocolos de tratamento inovadores, incluindo a introdução do transplante de fígado para PAF e terapias inovadoras como tafamidis, patisiran, inotersen, vutrisiran e eplontersen. Além disso, o artigo explora os esforços do CEPARM para melhorar a qualidade de vida dos pacientes através de cuidados multidisciplinares e programas de apoio. Ao refletir sobre os marcos históricos do centro, as transições de liderança e as iniciativas em curso, este artigo sublinha o compromisso inabalável do CEPARM com o avanço do conhecimento científico e a melhoria dos resultados clínicos dos pacientes, principalmente no domínio da hATTR-PN.

Prevalencia de amiloidosis cardíaca por transtiretina en pacientes internados por insuficiencia cardíaca con fracción de eyección preservada y engrosamiento septal / Prevalence of transthyretin cardiac amyloidosis in pa tients hospitalized for heart failure with preserved ejection fraction and septal thickness

Resumen Introducción: La amiloidosis cardíaca por trans tiretina (TTR) se suele presentar como insuficiencia cardiaca (IC) con fracción de eyección preservada. Diagnosticarla tiene impacto clínico, ya que actual mente se dispone de tratamiento específico. El ob jetivo de este estudio fue evaluar la prevalencia en nuestro medio de TTR en pacientes hospitalizados por IC con función sistólica preservada e hipertrofia septal. Métodos: Estudio de corte transversal. Se incluyeron de forma prospectiva pacientes mayores a 18 años inter nados por IC con función sistólica conservada (fracción de eyección mayor a 50%) y espesor septal mayor o igual a 12 mm durante el periodo del 8/2019 a 1/2023. El com promiso cardiaco se evaluó mediante un centellograma óseo con pirofosfato (PYP) Se calculó la prevalencia de amiloidosis por TTR y su IC95%. Resultados: Se efectuó un centellograma en 59/82 pacientes. La edad fue de 85 [RIC 78-88] años, el 54% mujeres. Al ingreso, el 61% presentó ritmo de fibrilación/ aleteo auricular y una mediana de NT-Pro-Bnp de 3536 pg/ml [RIC 1700-7748 pg/nl]. La media de fracción de eyección fue de 57 (+/- 5) %. La prevalencia de amiloi dosis cardiaca por TTR diagnosticada por centellograma óseo con PYP fue del 19% (IC95% 9,7-30,1). No se detec taron diferencias con los 23 pacientes que no efectuaron centellograma. Conclusiones: En pacientes internados por IC con fracción de eyección preservada y engrosamiento sep tal el diagnóstico de amiloidosis cardiaca por TTR fue relativamente frecuente (1/5), por lo que consideramos que debería explorarse en forma rutinaria.

Abstract Introduction: Transthyretin cardiac amyloidosis (AT TR-CM) usually presents as heart failure with preserved ejection fraction. Its diagnosis has a significant clinical impact, as specific treatment is currently available. The aim of this study is to assess the prevalence of ATTR-CM in patients hospitalized for heart failure with preserved ejection fraction and septal thickness in our region. Methods: Cross-sectional study. Patients over 18 years old hospitalized for heart failure with preserved ejection fraction (greater than 50%) and septal thickness greater than or equal to 12 mm during the period from 8/2019 to 1/2023 were prospectively included. A pyrophosphate bone scintigraphy (PYP) was planned to assess cardiac involvement. The prevalence of ATTR-CM and its 95% confidence interval were calculated. Results: A PYP was performed in 59/82 patients. The median age was 85 [IQR 78-88] years old, 54% women. On admission, 61% had atrial fibrillation/flutter rhythm and the median NT-Pro-Bnp was 3536 [IQR 1700-7748] pg/nl. The mean ejection fraction was 57% (+/- 5). The prevalence of ATTR-CM diagnosed by bone scintigra phy with PYP was 19% (95%CI 9.7-30.1). No differences were found compared with those patients who did not perform a PYP. Conclusion: In patients admitted for heart failure with preserved ejection fraction and septal thickness, the diagnosis of ATTR-CM was relatively common (1/5). We believe that it should be routinely explored.

Amyloidosis of Bladder and Ureter – A Case Report

Introduction :Theamylodosis is a disorder of protein confirmation and metabolism in which insoulable fibrils are deposited extracellularly in body organs causing organ dysfunction and death. It is associated with inherited and inflammatory disorders. Primary amyloidosis of bladder and ureter is a rare disease and easily confused with neoplasm. Hematuria, irritative or obstructive lower urinary tract symptoms and cystitis-like manifestations are the common clinical presentation. History :Presenting a case of 61 year old male patient having gross heamturia and irritative urinary tract symptoms. Conclusion On radiology there is a wall thickening of bladder with calcification and wall thickening of right lower ureter. Biopsy was sent to histopathology department and histopathological examination demonstrated amyloidosis of bladder and ureter.

Infiltrative Cardiomyopathy Causing Heart Failure with Compromised Ejection Fraction (HFrEF) : An entity to look out for

Infiltrative cardiomyopathy is characterized by deposition of abnormal substances within the heart tissue resulting in diastolic dysfunction and less commonly systolic dysfunction late stage of the disease. The more common types of infiltrative cardiomyopathy are cardiac amyloidosis, sarcoidosis and hemochromatosis. We present the case of a 73 year old male with dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea and fainting episodes. Electrocardiogram (ECG) showed low-voltage QRS complexes, Right Bundle Branch Block (RBBB) with associated Left Anterior Fascicular Block (LAFB) and on echocardiogram demonstrated reduced systolic function. The Cardiac MRI demonstrated restrictive cardiomyopathy with both systolic and diastolic dysfunction concluding that there is infiltrative cardiomyopathy due to either sarcoidosis or amyloidosis. Caution must be exercised while using the guideline medical therapeutic drugs that form the pillar of comprehensive heart failure therapy as they have many untoward side effects.

Unveiling the complexity of cardiac amyloidosis: a comprehensive case report

This case report documents a woman in her sixties who initially presented with cardiac symptoms such as heart palpitations, shortness of breath, and fluctuating blood pressure. Following her hospital admission, she received a diagnosis of paroxysmal atrial fibrillation and underwent successful electrical cardioversion. Despite this intervention, her symptoms persisted, necessitating radiofrequency ablation of the Cavo-tricuspid isthmus, which proved to be highly effective. Subsequent diagnostic testing revealed the presence of coronary artery disease, atherosclerotic cardiosclerosis, and mitral valve abnormalities, all of which were managed appropriately. Upon discharge, the patient was prescribed a medication regimen comprising anticoagulants, hypotensive therapy, and statins, which she tolerated well. However, her symptoms deteriorated, leading to a referral to a specialized center where she was promptly diagnosed with cardiac amyloidosis (CA) and received appropriate treatment. Adjustments to her treatment plan were made based on this diagnosis, and a cardiac MRI confirmed the presence of amyloidosis. A biopsy of the buccal mucosa further confirmed the presence of AL-amyloidosis based on immunohistochemistry test results. The patient commenced chemotherapy, which unfortunately led to kidney damage but ultimately resulted in significant improvement in her condition. Recurrent atrial fibrillation episodes necessitated further interventions, which were performed swiftly and effectively. Multi-organ assessments revealed numerous abnormalities, guiding tailored management strategies. A multidisciplinary team comprising cardiology, hematology, and general practice specialists coordinated the patient's care, focusing on pharmacotherapy and lifestyle modifications, which were found to be highly effective. Emphasis was placed on continuous monitoring and adherence to treatment plans for long-term management, resulting in positive outcomes.

Antioxidantes en el tratamiento de las amiloidosis: una revisión bibliográfica / Antioxidants in the Treatment of Amyloidosis: a Literature Review

Introducción: el principal objetivo de la presente revisión es conocer la evidencia científica actual sobre el papel de los antioxidantes en relación con las amiloidosis. El estrés oxidativo ha sido estudiado en la amiloidosis y se realizó una revisión narrativa sobre artículos publicados en el uso de antioxidantes en el tratamiento de estas enfermedades. Estado del arte: se presentan artículos publicados desde el año 2010 hasta el año 2022, en relación con el empleo de carvedilol, epigalocatequina galato (EGCG), resveratrol y tetraciclinas en modelos y casos de amiloidosis. Discusión/Conclusión: la terapia antioxidante para la amiloidosis está en desarrollo temprano, por lo cual requiere más estudios clínicos para evaluar eficacia y seguridad a largo plazo. Los antioxidantes como el carvedilol y el EGCG muestran gran potencial en interferir con las fibrillas amiloides, pero se necesita más investigación para comprender su impacto completo y viabilidad como tratamiento a largo plazo. (AU)

Introduction: The primary objective of this review is to examine the current scientific evidence regarding the role of antioxidants in relation to amyloidosis. Oxidative stress has been studied in amyloidosis, and a narrative review of articles concerning the use of antioxidants in the treatment of these diseases was conducted. State of the Art: Articles published from 2010 to 2022 are presented, focusing on the use of carvedilol, epigallocatechin gallate (EGCG), resveratrol, and tetracyclines in amyloidosis models and cases. Discussion/Conclusion: Antioxidant therapy for amyloidosis is in its early stages of development, requiring further clinical studies to assess long-term effectiveness and safety. Antioxidants such as carvedilol and EGCG show significant potential in interfering with amyloid fibrils, but additional research is needed to fully comprehend their impact and viability as long-term treatments. (AU)

¿Qué hay de nuevo en el tratamiento de la amiloidosis? Parte 3: Polineuropatía amiloidótica familiar / Treatment of familial amyloid polyneuropathy

La amiloidosis por depósito de transtiretina es una enfermedad infrecuente y se debe al depósito de fibrillas de dicha proteína en diversos tejidos, aunque la afectación más frecuente es la cardíaca y la neurológica. Puede ser adquirida (antiguamente llamada "amiloidosis senil") o, menos frecuentemente, hereditaria debido a mutaciones en el gen que codifica para la transtiretina (TTR). Una manifestación habitual de la TTR mutada (de ahora en adelante ATTRv) es la polineuropatía amiloidótica familiar. En el Hospital Italiano de Buenos Aires, desde el año 2010 existe un grupo transdisciplinario de profesionales nucleados por el interés en optimizar la atención de personas con amiloidosis, formado por profesionales de distintas especialidades y de referencia a nivel nacional, con foco en la asistencia, la docencia y la investigación. En el año 2020, este grupo, denominado Grupo de Estudio de Amiloidosis (GEA), confeccionó guías de práctica clínica para el tratamiento de la polineuuropatía amiloidótica familiar. Desde entonces se han publicado múltiples ensayos clínicos que aportan contundencia al conocimiento disponible hasta el momento, mientras están en desarrollo nuevas líneas de investigación que robustecen y estimulan el estudio en el área. En esta revisión se realiza una actualización de las guías existentes en lo que respecta al tratamiento de la polineuropatía amiloidótica familiar por transtiretina y se explora el estado del arte. En el tratamiento de la polineuropatía amiloidótica familiar es conocido el uso del patisirán (un siRNA o small interfering RNA dirigido a interferir con la síntesis hepatocitaria de transtiretina). Actualmente está aprobado también para pacientes con trasplante hepático previo y progresión sintomática. Además de este medicamento, hoy se recomienda el vutrisirán, de la misma familia farmacológica pero con una posología de más fácil manejo y un perfil aceptable de efectos adversos. La edición génica in vivo también está en boga como nueva línea de investigación, siendo parte de múltiples ensayos clínicos actuales en curso. (AU)

Transthyretin amyloidosis is a rare disease caused by the deposition of fibrils of this protein in various tissues, with cardiac and neurological involvement being the most common. It can be acquired (formerly known as 'senile amyloidosis') or hereditary due to mutations in the gene encoding transthyretin (TTR), although this is less common. A common manifestation of mutated TTR (hereafter referred to as ATTRv) is familial amyloid polyneuropathy. At the Hospital Italiano de Buenos Aires, since 2010, there has been a transdisciplinary group of professionals united by the interest in optimizing the care of people with amyloidosis. This group is formed by professionals from different specialties, with a national reference, focusing on care, education, and research. In 2020, this team, known as the Amyloidosis Study Group (GEA), developed clinical practice guidelines for treating familial amyloid polyneuropathy. Since then, numerous clinical trials have been published that strengthen the available knowledge and new lines of research are being developed, enhancing and encouraging study in this area. This review provides an update of the existing guidelines regarding transthyretin familial amyloid polyneuropathy and explores the state of the art.In the treatment of familial amyloid polyneuropathy, the use of patisiran (a small interfering RNA or siRNA aimed at interfering with the hepatic synthesis of transthyretin) is well known. It is currently also approved for patients with a previous liver transplant and symptomatic progression. In addition to this medication, vutrisiran is currently recommended, from the same pharmacological family, but with an easier dosing regimen and an acceptable side effect profile. In vivo gene editing is also in vogue as a new line of research, being part of multiple ongoing clinical trials. (AU)

Reporte de un caso de amiloidosis sistémica al en un varón de 65 años con diarrea crónica y hemolacria / Report of case of systemic al amyloidosis in a 65-year-old man with chronic diarrhea and hemolacria

RESUMEN Se describe el caso de un varón de 65 años con diarrea crónica, equimosis palpebral y hemolacria. Se realizaron estudios de laboratorio, biopsia y análisis inmunohistoquímico para confirmar el diagnóstico. La variable dependiente fue el diagnóstico confirmado de amiloidosis AL, mientras que las variables independientes incluyeron los síntomas clínicos y los resultados de las pruebas diagnósticas. Se emplearon técnicas descriptivas para analizar los datos clínicos y de laboratorio. El paciente presentó diarrea crónica sin respuesta al tratamiento convencional, equimosis palpebral y hemolacria. Los estudios diagnósticos revelaron depósitos de amiloide en los tejidos. El análisis inmunohistoquímico confirmó amiloidosis sistémica de cadenas ligeras tipo AL. Se inició tratamiento específico, mejorando parcialmente los síntomas y estabilizando la condición del paciente. La amiloidosis sistémica de tipo AL requiere un alto índice de sospecha clínica para su diagnóstico oportuno. La combinación de estudios diagnósticos y tratamiento precoz puede mejorar el pronóstico de estos pacientes.

ABSTRACT The case of a 65-year-old male with chronic diarrhea, periorbital ecchymosis, and hemolacria is described. Laboratory studies, biopsy, and immunohistochemical analysis were performed to confirm the diagnosis. The dependent variable was the confirmed diagnosis of AL amyloidosis, while the independent variables included clinical symptoms and diagnostic test results. Descriptive techniques were used to analyze the clinical and laboratory data. The patient presented with chronic diarrhea unresponsive to conventional treatment, periorbital ecchymosis, and hemolacria. Diagnostic studies revealed amyloid deposits in the tissues. Immunohistochemical analysis confirmed systemic light chain AL amyloidosis. Specific treatment was initiated, partially improving the symptoms and stabilizing the patient's condition. Systemic AL amyloidosis requires a high index of clinical suspicion for timely diagnosis. The combination of diagnostic studies and early treatment can improve the prognosis of these patients.

Prevalencia de estenosis aórtica moderada-grave en pacientes con amiloidosis cardiaca en un centro de referencia / Prevalence of moderate-severe aortic stenosis in patients with cardiac amyloidosis in a referral center

Resumen Antecedentes: La estenosis aórtica (EA) es actualmente la enfermedad valvular más frecuente, con una prevalencia estimada de más del 4 % en octogenarios. Objetivo: Describir la prevalencia de estenosis aórtica (EA) moderada-grave en pacientes con amiloidosis por transtiretina wild type (ATTRwt). Además, describir las características clínicas, ecocardiográficas y la evolución en este grupo de pacientes. Método: Estudio de cohorte retrospectiva de pacientes con diagnóstico de ATTRwt, pertenecientes al Registro Institucional de Amiloidosis del Hospital Italiano de Buenos Aires, en el periodo del 30/11/2007 al 31/05/2021. El seguimiento de los pacientes se realizó a través de la historia clínica electrónica de la institución. Se estimó la prevalencia de EA moderada-grave, que se presenta como porcentaje con su intervalo de confianza del 95% (IC 95%). Se compararon las características por grupos según tuvieran o no EA moderada-grave. Resultados: Se incluyeron 104 pacientes con diagnóstico de ATTRwt. La mediana de seguimiento fue de 476 días [rango intercuartílico: 192-749]. La prevalencia de EA moderada-grave al momento del diagnóstico de ATTRwt fue del 10.5% (n = 11; IC95%: 5-18%). La mediana de edad de los pacientes con EA fue de 86 años [78-91] y predominó el sexo masculino (81.8%). La mayoría de los pacientes tenían el antecedente de insuficiencia cardiaca (n = 8) y fibrilación auricular (n = 8). Predominaron los pacientes con EA grave de bajo flujo y bajo gradiente (n = 7). Cuatro pacientes fueron sometidos a alguna intervención en la válvula aórtica. Durante el seguimiento, 5 pacientes (46%) tuvieron internaciones por insuficiencia cardiaca descompensada y 4 (36%) fallecieron. Conclusiones: En nuestra cohorte, la coexistencia de ambas patologías tuvo una prevalencia similar a la reportada en la literatura internacional. Se trató de una población añosa con alto porcentaje de fibrilación auricular y antecedente de insuficiencia cardiaca. La mayoría presentaron EA grave de bajo flujo y bajo gradiente.

Abstract Background: Aortic stenosis (AS) is currently the most common valvular disease, with an estimated prevalence of over 4% in octogenarians. Objective: To describe the prevalence of moderate-severe aortic stenosis (AS) in patients with wild type transthyretin amyloidosis (ATTRwt). Also, describe the clinical features, echocardiographic characteristics and clinical evolution. Method: Retrospective cohort of patients with diagnosis of ATTRwt, belonging to Hospital Italiano de Buenos Aires Institutional Amyloidosis Registry, from 30/11/2007 to 31/05/2021. Patients follow up was carried out through the institution clinical history. The prevalence of moderate-severe AE was estimated and presented as a percentage with its 95% confidence interval (95% CI). The characteristics were compared by groups according to whether or not they had moderate-severe AS. Results: 104 patients with ATTRwt were included. Median follow up was 476 days [interquartile range: 192-749]. Moderate-severe AS prevalence at the ATTRwt time of diagnosis was 10.5% (n = 11; 95% CI: 5-18%). The median age of patients with AS moderate-severe at the time of diagnosis of ATTRwt was 86 years [78-91] and the male sex predominated (82%). Most of the patients had a history of heart failure (n = 8) and atrial fibrillation (n = 8) prior to the diagnosis of ATTRwt. Most of the patients were subclassified as low flow low gradient severe AS group (n = 7). Four patients underwent some intervention on the aortic valve. During follow-up, 5 patients (46%) were hospitalized for decompensated heart failure and 4 (36%) died. Conclusions: In our cohort, the coexistence of both pathologies had a similar prevalence as reported in the international literature. It was an elderly population with a high percentage of atrial fibrillation and history of heart failure. Most of the patients presented with severe AS with low flow low gradient.

Acute cholecystitis with wild-type transthyretin systemic amyloidosis in the gallbladder: a case report

Amyloidosis is a rare disease involving the deposition of organised insoluble proteins in various body viscera, with the disease further classified into different subtypes. In exceedingly rare cases the literature has reported the presence of amyloid deposition in the gallbladder. We described the first documented case of wild-type transthyretin systemic amyloidosis involving the gallbladder, occurring in a 91-year-old female who presented with acute cholecystitis.

¿Qué hay de nuevo en el tratamiento de la amiloidosis? Parte 2: Cardiomiopatía por amiloidosis por transtiretina / What's new in the treatment of amyloidosis? Part 2: Cardiomyopathy due to transthyretin amyloidosis

La amiloidosis AL es una enfermedad debida al depósito, en órganos y tejidos, de fibrillas formadas por La amiloidosis por depósito de transtiretina es una enfermedad poco frecuente y se debe al depósito de fibrillas de dicha proteína en diversos tejidos, aunque la afectación más frecuente es la cardíaca y la neurológica. Puede ser adquirida (antiguamente llamada "amiloidosis senil") o hereditaria debido a mutaciones en el gen que codifica para la transtiretina. En 2020, el Grupo de Estudio de Amiloidosis confeccionó guías de práctica clínica para el tratamiento de la cardiomiopatía amiloidea por transtiretina. Desde entonces se han publicado múltiples trabajos que expanden el conocimiento disponible, y existen nuevas líneas de investigación. En esta revisión se actualizan las guías mencionadas explorando el estado del arte. En el caso de la cardiomiopatía por amiloidosis por transtiretina (TTR), las estrategias terapéuticas están orientadas predominantemente a disminuir la producción y agregación de TTR, además del tratamiento de sostén del daño orgánico. El tafamidis, un estabilizador de la TTR que impide su agregación y depósito, presenta cada vez más evidencia a favor de su uso para mejorar la sobrevida de pacientes con esta patología. Están en estudio terapias génicas como silenciadores de ARN mensajero o la edición génica in vivo para inhibir la expresión del gen que codifica para la TTR y generar efectos terapéuticos a largo plazo. Desde 2020 hay múltiples anticuerpos monoclonales que forman parte de ensayos clínicos en curso. (AU)

Transthyretin deposition amyloidosis is a rare disease caused by the deposition of fibrils of this protein in various tissues, although the most common manifestations are cardiac and neurological. It can be acquired (formerly known as "senile amyloidosis") or hereditary due to mutations in the gene encoding for transthyretin (TTR). In 2020, the Amyloidosis Study Group created clinical practice guidelines for treating transthyretin amyloidotic cardiomyopathy. Since then, published clinical trials have strengthened the available knowledge, and new lines of research have emerged. This review updates the mentioned guidelines by exploring the state of the art. In the case of transthyretin (TTR) amyloidosis cardiomyopathy, therapeutic strategies are predominantly aimed at reducing the production and aggregation of TTR apart from providing supportive treatment for organ damage. Tafamidis, a TTR stabilizer that prevents its aggregation and deposition, is increasingly supported by evidence for its use in improving the survival of patients with this condition. Gene therapies such as messenger RNA silencers or in vivo gene editing to inhibit the expression of the gene encoding for TTR and generate long-term therapeutic effects are under investigation. Multiple monoclonal antibodies have been part of ongoing clinical trials since 2020.

Fibrilación auricular en amiloidosis por transtirretina / Atrial fibrillation in transthyretin amyloidosis

Resumen La amiloidosis cardiaca es una enfermedad que se caracteriza por el depósito de material amiloide en la matriz extracelular del miocardio. Las arritmias son parte del amplio espectro de la enfermedad, de las cuales la fibrilación auricular (FA) es la más frecuente de todas. Debido a la heterogeneidad de la amiloidosis cardiaca, su incidencia real es desconocida, con lo que se denota un subdiagnóstico y en muchos casos estando oculta bajo la presentación de una enfermedad cardiaca habitual, lo que conlleva a una progresión silente de la misma y peores desenlaces. Se describe el caso clínico de un paciente con FA refractaria a cardioversión eléctrica y terapia ablativa en el contexto de amiloidosis cardiaca por transtirretina (ATTR) inicialmente inadvertida y descubierta como hallazgo incidental. El propósito de este reporte es revisar la asociación entre FA y ATTR, su epidemiología, fisiopatología, manifestación clínica, diagnóstico y tratamiento con el fin de ofrecer al personal médico herramientas para un diagnóstico oportuno de una enfermedad poco reconocida.

Abstract Cardiac amyloidosis is a disease characterized by the deposition of amyloid material in the extracellular matrix of the myocardium. Arrhythmias are part of the broad spectrum of the disease, with atrial fibrillation (AF) as the most common. Due to the heterogeneity of cardiac amyloidosis, its real incidence is unknown, denoting an underdiagnosis and in many cases being hidden under the presentation of a common heart disease, which leads to silent progression and worse outcomes. We describe the clinical case of a patient with AF refractory to electrical cardioversion and ablation therapy in the context of cardiac transthyretin amyloidosis (ATTR), initially unnoticed and found as an incidental diagnosis. The purpose of this report is to review the association between AF and ATTR, its epidemiology, pathophysiology, signs and symptoms, diagnosis and treatment in order to provide medical staff with tools for a timely diagnosis of a poorly recognized disease.

Localised sinonasal amyloidosis presenting with unilateral hearing loss: a case report and review of the literature

Localised sinonasal amyloidosis is a rare occurrence with only twenty-nine documented cases in literature. This report follows the case of a 79-year-old gentleman with an atypical presentation of headaches and unilateral (right-sided) hearing loss. The patient initially underwent magnetic resonance imaging of his internal auditory meatus which was normal. Flexible nasoendoscopy was performed which identified a right middle meatus discharging possible polypoidal lesion. A computed tomography scan of his sinuses was performed which identified a large soft tissue lesion projecting into the upper nasal airway arising from the nasal recess, with the appearance suspicious for a polyp. Subsequently, the patient underwent functional endoscopic sinus surgery to manage right maxillary sinusitis and further examine the right-sided polypoidal mass lesion that was obstructing the maxillary antrum. Maxillary sinus biopsy revealed a diagnosis of sinonasal amyloidosis while tests for systemic amyloidosis were negative.

Review and Progress in the Treatment of Renal Light Chain Amyloidosis / 罕见病研究

Renal light chain amyloidosis (AL amyloidosis) had poor prognosis before the 21st century. However, the treatment of AL amyloidosis has made great progress in the last decade. We reviewed traditional treatments of AL amyloidosis such as alkylating agents, proteasome inhibitors, and recent advances such as monoclonal antibodies. Bortezomib improved the hematological response and survival effectively of the patients, and the combination of Daratumumab brings faster and deeper hematological response, increasing the response rate of target organs such as the kidneys and heart. The renal response was significant higher in the patients with the therapy of Daratumumab, part of them could achieve very good partial response or better renal response. Autologous hematopoietic stem cell transplantation(auto-HSCT)improves hematological as well as organ response, and could be the first choice among eligible patients. Kidney transplantation is a feasible option for those with good hematological response.

Cardiac MR tissue tracking technique for quantitatively evaluating myocardial strain of cardiac amyloidosis patients / 中国介入影像与治疗学

Objective To observe the feasibility of cardiac MR tissue tracking(CMR-TT)technique for quantitatively evaluating myocardial strain of patients with myocardial amyloidosis(CA).Methods Cardiac MRI were collected from 20 patients of immunoglobulin amyloid light-chain CA(AL-CA,group A),20 cases of transthyretin CA(ATTR-CA,group B)and 20 healthy subjects(group C),and myocardial strain parameters were obtained using CMR-TT technique.Left ventricular cardiac function parameters were compared among 3 groups,so were strain parameters of each myocardial segment of left ventricle and global myocardium,including 3D longitudinal strain(LS),3D radial strain(RS)and 3D circumferential strain(CS).Results Compared with those in group C,significant differences of left ventricular cardiac function parameters were found in both group A and B(all P＜0.01),while no statistical difference was found between group A and B(all P＞0.05).Except for apical segment RS(P=0.81),strain parameters in group A and B were both lower than those in group C(all P＜0.01),while no significant difference was detected between group A and B(all P＞0.05).Conclusion CMR-TT technique could be used to quantitatively evaluate left ventricular myocardial strain of CA patients.

A Critical Review of Echocardiographic Findings for Diagnosing Cardiac Amyloidosis

Abstract This article provides a critical review of the diagnostic value of several echocardiographic findings in cardiac amyloidosis (CA). The importance of early and accurate detection of CA is emphasized, considering its challenging diagnosis and the need for a high index of suspicion by clinicians. Echocardiography is often the first choice for imaging assessment of cardiac structure and function when CA is suspected. The article encompasses several conventional echocardiographic features and speckle-tracking echocardiography-derived deformation parameters. Some of these indexes are grouped together to form scores, which can improve the accuracy of diagnosing CA. However, particularly in earlier stages, echocardiography has low specificity to distinguish amyloid from other hypertrophic phenotypes, highlighting the need for correlation with clinical red flags, laboratory tests, and additional cardiac imaging modalities.

Renal tubular acidosis in hereditary transthyretin amyloidosis (ATTRv) / Acidose tubular renal na amiloidose hereditária por transtirretina (ATTRv)

Abstract Introduction: Hereditary transthyretin amyloidosis (ATTRv) is a severe autosomal dominant systemic disease. It affects the peripheral and autonomic nervous systems, heart, kidneys, and eyes. Amyloid deposition has been demonstrated in the glomerular and tubulointerstitial compartments of the kidney. Therefore, urinary acidification disorders such as renal tubular acidosis (RTA) may be early manifestations of renal involvement in this population. Objective: To evaluate the prevalence of RTA in individuals with ATTRv. Methods: We included symptomatic and asymptomatic individuals with TTR mutation, older than 18 years, GFR >45 mL/min/1.73m2, without systemic metabolic acidosis. Urinary acidification protocol was performed with furosemide and fludrocortisone after 12 h of water deprivation (water deprivation test - WDT) and measurements of urine ammonium ( UNH 4 +) and titratable acidity (UTA). Proximal RTA (pRTA) was diagnosed when FEHCO3>10%. Incomplete form distal RTA (dRTA) was diagnosed if UpH>5.3. Results: We selected 49 individuals with a mean age of 40 (35.5-56.5) years, 63% of which were female, 84% were Caucasian, and mean GFR was 85.5 ± 20.5 mL/min/1.73m2. 94% had the genetic variant Val50Met and 57% were symptomatic. The prevalence of pRTA was 2% and of dRTA was 16.3%. In the subgroup with dRTA, there was no significant increase in excretion of UNH 4 + and UTA. We observed a good correlation between UpH by potentiometry and UpH dipstick. A UpH<5.5 on the dipstick had 100% sensitivity and negative predictive value to exclude dRTA. Conclusion: A high prevalence of RTA was found in individuals with TTR mutations. The UpH dipstick after WDT had good accuracy for screening for dRTA. Further studies are needed to evaluate the impact of early diagnosis and treatment of RTA in this population.

Resumo Introdução: A amiloidose hereditária por transtirretina (ATTRv) é uma doença sistêmica autossômica dominante grave. Afeta os sistemas nervoso periférico e autônomo, coração, rins e olhos. A deposição de amiloide foi demonstrada nos compartimentos glomerular e tubulointersticial do rim. Portanto, distúrbios de acidificação urinária, como acidose tubular renal (ATR), podem ser manifestações precoces de envolvimento renal nessa população. Objetivo: Avaliar a prevalência de ATR em indivíduos com ATTRv. Métodos: Incluímos indivíduos sintomáticos e assintomáticos com mutação na TTR, maiores de 18 anos, TFG >45 mL/min/1,73m2, sem acidose metabólica sistêmica. Realizou-se protocolo de acidificação urinária com furosemida e fludrocortisona após 12 horas de privação hídrica (teste de restrição hídrica - TRH) e medições de amônia urinária ( uNH 4 +) e acidez titulável (uTA) na urina. ATR proximal (ATRp) foi diagnosticada quando FEHCO3>10%. ATR distal (ATRd) de forma incompleta foi diagnosticada se pHu>5,3. Resultados: Selecionamos 49 indivíduos com idade média de 40 (35,5-56,5) anos, 63% mulheres, 84% caucasianos e TFG média de 85,5 ± 20,5 mL/min/1,73m2. 94% apresentaram a variante genética Val50Met; 57% eram sintomáticos. A prevalência de ATRp foi 2% e a de ATRd foi 16,3%. No subgrupo com ATRd, não houve aumento significativo na excreção de uNH 4 + e uTA. Observamos uma boa correlação entre pHU por potenciometria e pHU por fita reagente. Um pHU<5,5 na fita reagente apresentou 100% de sensibilidade e valor preditivo negativo para excluir a ATRd. ConclusÃO: Uma alta prevalência de ATR foi encontrada em indivíduos com mutações na TTR. O pHU por fita reagente após TRH teve boa precisão para triagem de ATRd. São necessários mais estudos para avaliar o impacto do diagnóstico e tratamento precoces da ATR nessa população.

SPECT/CT con 99mTc-pirofosfato en la evaluación de la amiloidosis cardíaca: estudio preliminar / SPECT/CT with 99mTc-pyrophosphate in the evaluation of cardiac amyloidosis: a preliminary study / SPECT/CT com pirofosfato de 99mTc na avaliação de amiloidose cardíaca: estudo preliminar

Introducción: la amiloidosis cardíaca (AC) es una miocardiopatía infiltrativa producida por depósito miocárdico extracelular de amiloide. Las variantes más frecuentes son debidas a cadenas ligeras de inmunoglobulinas o transtiretina (ATTR). El centellograma con 99mTc-pirofosfato (99mTc-PYP) es una técnica de imagen molecular que permite diferenciar los subtipos más frecuentes de AC. El presente estudio analizó el rol del 99mTc-PYP y el SPECT-CT en la evaluación de pacientes con sospecha clínica de AC. Materiales y métodos: se realizó 99mTc-PYP y SPECT-CT en 16 pacientes con sospecha clínica de AC, con edad promedio de 63 años. Se realizó análisis cualitativo de las imágenes planares y del SPECT-CT (Mediso, AnyScan), adquiridas 1-3 horas tras la inyección del radiotrazador. Para el análisis cuantitativo de las imágenes planares se calculó la relación H/CL (cuentas promedio obtenidas sobre las regiones de interés del corazón y el hemitórax contralateral). El estudio se consideró positivo para ATTR cuando la relación H/CL fue ≥1.5. Las imágenes de SPECT-CT fueron interpretadas para observar la distribución del trazador a nivel cardíaco y extracardíaco. Resultados: se identificó captación miocárdica de 99mTc-PYP en el ventrículo izquierdo en 6 pacientes y en el ventrículo derecho en 3 pacientes. En estos casos, la relación H/CL fue >1.5. En el resto se descartó la captación miocárdica, con relación H/CL<1.5. Se detectó actividad de pool vascular en las imágenes tomográficas de 7 pacientes y captación extracardíaca ósea anormal de causas traumáticas/degenerativas en 9 pacientes. Cinco pacientes presentaron captación hepática difusa, sin alteración estructural en el TC. Conclusiones: el 99mTc-PYP es una técnica clínicamente relevante en pacientes con sospecha de AC. Constituye una herramienta mínimamente invasiva, ampliamente disponible, de bajo costo y útil en el diagnóstico, pudiendo orientar al subtipo de AC. La información que aporta permite además orientar las opciones terapéuticas y brindar información pronóstica adicional.

Introduction: Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy caused by extracellular myocardial amyloid deposition. The most frequent variants are due to immunoglobulin light chains or transthyretin (ATTR). 99mTc-pyrophosphate (99mTc-PYP) scintigraphy is a molecular imaging technique that allows differentiation of the most common subtypes of AC. The present study analyzed the role of 99mTc-PYP and SPECT-CT in the evaluation of patients with clinical suspicion of CA. Materials and methods: 99mTc-PYP and SPECT-CT were performed in 16 patients with clinical suspicion of AC, with an average age of 63 years. Qualitative analysis was performed on the planar and SPECT-CT images (Mediso, AnyScan), acquired 1-3 hours after the injection of the radiotracer. For the quantitative analysis of the planar images, the H/CL ratio (average counts obtained over the regions of interest of the heart and the contralateral hemithorax) was calculated. The study was considered positive for ATTR when the H/CL ratio was ≥1.5. The SPECT-CT images were interpreted to observe the distribution of the tracer at the cardiac and extracardiac level. Results: Myocardial uptake of 99mTc-PYP was identified in the left ventricle in 6 patients and in the right ventricle in 3 patients. In these cases, the H/CL ratio was >1.5. In the rest, myocardial uptake was ruled out, with a H/CL ratio of 1.5. Vascular pool activity was detected in the tomographic images of 7 patients and abnormal extracardiac bone uptake of traumatic/degenerative causes in 9 patients. Five patients presented diffuse hepatic uptake, without structural alteration on CT. Conclusions: 99mTc-PYP is a clinically relevant technique in patients with suspected CA. It constitutes a minimally invasive tool, widely available, low cost and useful in diagnosis, and can guide the AC subtype. The information it provides also makes it possible to guide therapeutic options and provide additional prognostic information.

Introdução: a amiloidose cardíaca (AC) é uma cardiomiopatia infiltrativa causada pela deposição extracelular de amiloide no miocárdio. As variantes mais frequentes são devidas a cadeias leves de imunoglobulina ou transtirretina (ATTR). A cintilografia com 99mTc-pirofosfato (99mTc-PYP) é uma técnica de imagem molecular que permite a diferenciação dos subtipos mais comuns de QA. O presente estudo analisou o papel do 99mTc-PYP e do SPECT-CT na avaliação de pacientes com suspeita clínica de AC. Materiais e métodos: foram realizados 99mTc-PYP e SPECT-CT em 16 pacientes com suspeita clínica de QA, com idade média de 63 anos. A análise qualitativa foi realizada nas imagens planas e SPECT-CT (Mediso, AnyScan), adquiridas 1-3 horas após a injeção do radiotraçador. Para a análise quantitativa das imagens planas, foi calculada a relação H/CL (contagens médias obtidas nas regiões de interesse do coração e do hemitórax contralateral). O estudo foi considerado positivo para ATTR quando a relação H/CL era ≥1,5. As imagens SPECT-CT foram interpretadas para observar a distribuição do traçador em nível cardíaco e extracardíaco. Resultados: a captação miocárdica de 99mTc-PYP foi identificada no ventrículo esquerdo em 6 pacientes e no ventrículo direito em 3 pacientes. Nestes casos, a relação H/CL foi >1,5. Nos demais, foi descartada captação miocárdica, com relação H/CL de 1,5. Atividade do pool vascular foi detectada nas imagens tomográficas de 7 pacientes e captação óssea extracardíaca anormal de causas traumáticas/degenerativas em 9 pacientes. Cinco pacientes apresentaram captação hepática difusa, sem alteração estrutural na TC. Conclusões: o 99mTc-PYP é uma técnica clinicamente relevante em pacientes com suspeita de AC. Constitui uma ferramenta minimamente invasiva, amplamente disponível, de baixo custo e útil no diagnóstico, podendo orientar o subtipo AC. A informação que disponibiliza permite também orientar opções terapêuticas e fornecer informação prognóstica adicional.

Real-life experience with inotersen at CEPARM, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro / Experiência de vida-real com inotersena no CEPARM, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro

Abstract Background Hereditary transthyretin amyloidosis (ATTRv) is an inherited, progressive, and fatal disease still largely underdiagnosed. Mutations in the transthyretin (TTR) gene cause the TTR protein to destabilize, misfold, aggregate, and deposit in body tissues, which makes ATTRv a disease with heterogeneous clinical phenotype. Objective To describe the long-term efficacy and safety of inotersen therapy in patients with ATTRv peripheral neuropathy (ATTRv-PN). Methods Patients who completed the NEURO-TTR pivotal study and the NEURO-TTR OLE open-label extension study migrated to the present study and were followed-up for at least 18 more months to an average of 67 months and up to 76 months since day 1 of the inotersen therapy (D1-first dose of inotersen). Disease progression was evaluated by standard measures. Results Ten ATTRv-PN patients with Val30Met mutation were included. The mean disease duration on D1 was of 3 years, and the mean age of the patients was of 46.8 years. During an additional 18-month follow up, neurological function, based on the Neuropathy Impairment Score and the Polyneuropathy Disability Score, functionality aspects (Karnofsky Performance Status), and nutritional and cardiac aspects were maintained. No new safety signs have been noted. Conclusion The treatment with inotersen was effective and well tolerated for the average of 67 months and up to 76 months. Our results are consistent with those of larger phase-III trials.

Resumo Antecedentes Amiloidose hereditária por transtirretina (ATTRv) é uma doença hereditária, progressiva e fatal ainda largamente subdiagnosticada. Mutações no gene transtirretina (TTR) promovem desestabilização, desdobramento, agregação e depósito da proteína TTR em tecidos do corpo, o que faz da ATTRv uma doença de fenótipo clínico heterogêneo. Objetivo Descrever a eficácia e segurança da terapia com inotersena no longo prazo em pacientes com neuropatia periférica ATTRv (ATTRv-PN). Métodos Pacientes que completaram o estudo pivotal NEURO-TTR e o estudo de extensão aberta NEURO-TTR OLE migraram para este estudo e foram acompanhados por no mínimo 18 meses adicionais, em média por 67 meses, e por até 76 meses, desde o dia 1 da terapia com inotersena (D1-primeira dose de inotersena). A progressão da doença foi avaliada por medidas padronizadas. Resultados Dez pacientes com ATTRv-PN com mutação Val30Met foram incluídos. A duração média da doença no D1 era de 3 anos, e a média de idade dos pacientes era de 46,8 anos. Durante o período de acompanhamento adicional de 18 meses, a função neurológica, baseada no Neuropathy Impairment Score e no Polyneuropathy Disability Score, os aspectos de funcionalidade (Karnofsky Performance Status), nutricional e cardíacos estavam mantidos. Não se observou nenhum novo sinal de segurança. Conclusão O tratamento com inotersena foi eficaz e bem tolerado por 67 meses em média, e por até 76 meses. Nossos resultados são consistentes com os de estudos maiores de fase III.