Early diagnosis in ATTRv amyloidosis, how early is enough? How early is possible?

Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is a rare, progressive, and debilitating genetic disorder characterized by the deposition of abnormal transthyretin (TTR) protein aggregates in various tissues, leading to organ dysfunction. Early diagnosis of ATTRv amyloidosis is critical for starting timely interventions and improving patient outcomes. This review explores the concepts of "how early is enough" and "how early is possible" in the context of diagnosing ATTRv amyloidosis, highlighting the challenges and opportunities for early recognition.

Value of multi-modality small fiber assessments in a genotypically diverse cohort of transthyretin-related amyloidosis in the early stages of disease.

INTRODUCTION: Transthyretin-related amyloidosis (ATTRv) is a progressive multisystem disorder, predominantly involving the peripheral nerve system (PNS) and heart. Quantification of small fiber damage may help guide treatment decisions, as amyloid deposits frequently affect those fibers early in disease course. Corneal confocal microscopy (CCM) is a promising method to monitor patients with ATTRv, due to similarities between corneal nerves and PNS, as the cornea is innervated by Aδ and C fibers. METHODS: We compared CCM measures from ATTRv patients to a group of healthy individuals, matched by age and gender. We then investigated the correlations between small fiber tests (SFT): CCM, LDI-Flare and CDT, COMPASS-31 and disability scales (RODS and ONLS) in patients. RESULTS: Of 20 patients (6 with V30M), mean age 50.3±15.3Y, 7 female (35%), six (30%) had polyneuropathy and 10 (50%) carpal tunnel syndrome. CDT was abnormal in 9 and LDI-flare in 6 patients. CCM was abnormal in 19 tested patients and significantly reduced when compared to controls (CNFL: 6.31±0.31 vs. 15.21±1.02mm/mm2, p<0.001). Mean COMPASS-31-scores were 22.27±22.84; RODS and ONLS were 38.15±12.33 and 2.05±2.3, with no significant differences between sub-group scores. Disease duration was significantly correlated with ONLS (0.43, p=0.05) and RODS (0.46, p=0.03). There were no significant correlations between measures of disability and SFT. CONCLUSIONS: In a diverse cohort of ATTRv patients, CCM was the most frequent abnormal measurement. CCM can be a useful test to triage patients in the early disease stages and with few or equivocal symptoms.

Incidencia y causas de hospitalización en pacientes con amiloidosis cardiaca por transtiretina (AC-ATTR) y por cadenas ligeras (AC-AL) / Incidence and causes of hospitalization in patients with transthyretin (ATTR-CA) and light chain (AL-CA) cardiac amyloidosis

Introducción y objetivos: La amiloidosis cardiaca (AC) es una patología asociada a un elevado número de ingresos hospitalarios. Dada la escasa información disponible al respecto, planteamos un análisis de la incidencia y las causas de hospitalización en esta enfermedad.Material y métodosSe evaluaron 143 pacientes (128 por transtiretina [AC-ATTR] y 15 por cadenas ligeras [AC-AL]) incluidos en el Registro de Amiloidosis Cardiaca de Galicia (AMIGAL), recogiendo todas sus hospitalizaciones.ResultadosDurante un seguimiento mediano de 959 días se produjeron 179 hospitalizaciones no programadas (tasa de incidencia [TI] 512,6 ingresos hospitalarios por 1.000 pacientes-año), siendo las más habituales las de causa cardiovascular (n=109, TI 312,2). El motivo individual de ingreso hospitalario más frecuente fue la insuficiencia cardiaca (IC) (n=87, TI 249,2).La AC-AL se asoció con una TI de hospitalizaciones no programadas más elevada que la AC-ATTR (TI 781 vs. 483,2; HR 1,62; p=0,029) a expensas de las de causa no cardiovascular (TI 376 vs. 181,2; HR 2,07; p=0,027). La supervivencia libre de hospitalización no programada al año y a los tres años en la AC-AL fue menor que en la AC-ATTR (46,7 y 20,0% vs. 73,4 y 35,2%, respectivamente; p=0,021). (AU)

Introduction and objetives: Cardiac amyloidosis (CA) is a disorder associated with high number of hospital admissions. Given the scarce information available, we propose an analysis of the incidence and causes of hospitalization in this disease.Material and methodsOne hundred and forty-three patients [128 by transthyretin (ATTR-CA) and 15 by light chains (AL-CA)] included in Registro de Amiloidosis Cardiaca de Galicia (AMIGAL) were evaluated, including all hospitalizations.ResultsDuring a median follow-up of 959 days there were 179 unscheduled hospitalizations [incidence rate (IR) 512.6 admissions per 1000 patients-year], most common due to cardiovascular reasons (n=109, IR 312.2). Most frequent individual cause of hospitalization was heart failure (n=87, TI 249.2).AL-CA was associated with a higher IR of unscheduled hospitalizations than ATTR-CA (IR 781 vs. 483.2; HR 1.62; p=0,029) due to non-cardiovascular admissions (IR 376 vs. 181.2; HR 2.07; p=0.027). Unscheduled admission-free survival at 1 and 3 years in AL-CA was inferior than in ATTR-CA (46.7% and 20.0% vs. 73.4% and 35.2%, respectively; p=0.021). (AU)

[Incidence and causes of hospitalization in patients with transthyretin (ATTR-CA) and light chain (AL-CA) cardiac amyloidosis]. / Incidencia y causas de hospitalización en pacientes con amiloidosis cardiaca por transtiretina (AC-ATTR) y por cadenas ligeras (AC-AL).

INTRODUCTION AND OBJETIVES: Cardiac amyloidosis (CA) is a disorder associated with high number of hospital admissions. Given the scarce information available, we propose an analysis of the incidence and causes of hospitalization in this disease. MATERIAL AND METHODS: One hundred and forty-three patients [128 by transthyretin (ATTR-CA) and 15 by light chains (AL-CA)] included in Registro de Amiloidosis Cardiaca de Galicia (AMIGAL) were evaluated, including all hospitalizations. RESULTS: During a median follow-up of 959 days there were 179 unscheduled hospitalizations [incidence rate (IR) 512.6 admissions per 1000 patients-year], most common due to cardiovascular reasons (n=109, IR 312.2). Most frequent individual cause of hospitalization was heart failure (n=87, TI 249.2). AL-CA was associated with a higher IR of unscheduled hospitalizations than ATTR-CA (IR 781 vs. 483.2; HR 1.62; p=0,029) due to non-cardiovascular admissions (IR 376 vs. 181.2; HR 2.07; p=0.027). Unscheduled admission-free survival at 1 and 3 years in AL-CA was inferior than in ATTR-CA (46.7% and 20.0% vs. 73.4% and 35.2%, respectively; p=0.021). CONCLUSIONS: CA was associated with high incidence of hospitalizations, being heart failure the most frequent individual cause; unscheduled admission-free survival in AL-CA was lower than in ATTR-CA due mostly to non-cardiovascular admissions.

Relevancia del estudio genético de la amiloidosis cardíaca por transtiretina en el anciano / Importance of genetic study in elderly patients with transthyretin cardiac amyloidosis

Antecedentes y objetivo La amiloidosis cardiaca por transtiretina (AC-ATTR) es una enfermedad prevalente con la edad. Se recomienda realizar sistemáticamente un estudio genético incluso en los pacientes más añosos. Nuestro objetivo ha sido realizar un análisis de la prevalencia de amiloidosis por transtiretina hereditaria (ATTRv) en ancianos (≥75años) con AC-ATTR y sus implicaciones. Pacientes y método Estudio observacional retrospectivo de la cohorte de pacientes ancianos con AC-ATTR diagnosticados de acuerdo con el protocolo internacional. Analizamos los resultados de la secuenciación del gen TTR, las características diferenciales y sus implicaciones clínicas. Resultados Entre 2016 y 2022 se diagnosticaron 130 pacientes ancianos (89% cohorte) con AC-ATTR (85% varones). En 8 pacientes de los 123 con estudio genético se identificó una variante patogénica en TTR (6,5%), iniciándose tratamiento específico en 4 sujetos (50%). El estudio familiar identificó otro caso y 6 portadores asintomáticos. No hubo diferencias significativas entre características basales ni en los eventos clínicos. Conclusiones La prevalencia de ATTRv en ancianos con AC-ATTR fue del 6,5%, sin observarse características diferenciales que permitan guiar una indicación selectiva del análisis genético (AU)

Background and objective Cardiac transthyretin amyloidosis (CA-ATTR) is a prevalent disease with age. Genetic study is recommended, even in eldest patients. We aim to analyze the prevalence of hereditary transthyretin amyloidosis (ATTRv) in elderly patients (≥75years) with CA-ATTR and its implications. Patients and methodology Retrospective observational study of the cohort of elderly patients with CA-ATTR diagnosed according to the international recommended protocol. We analyze the results of sequencing TTR gene, the differential characteristics and their clinical implications. Results Between 2016 and 2022, 130 elderly patients (89% cohort) were diagnosed with CA-ATTR (85% male). In 8 of the 123 patients with a genetic study, a pathogenic variant in TTR was identified (6.5%), initiating specific treatment in 4 subjects (50%). The family study identified another case and 6 asymptomatic carriers. There were no significant differences between baseline characteristics or in clinical events. Conclusions The prevalence of ATTRv in elderly patients with CA-ATTR was 6.5% without observing differential characteristics that allow guiding a selective indication of genetic analysis (AU)

Cuantificación absoluta de la captación miocárdica de 99mTc-DPD en pacientes con amiloidosis cardiaca por depósitos de transtiretina (ATTR) / Absolute quantification of myocardial uptake of 99mTc-DPD in patients with cardiac amyloidosis due to transthyretin deposits (ATTR)

Objetivo Determinar la contribución diagnóstica de la cuantificación absoluta del depósito miocárdico de 99mTc-DPD en pacientes con amiloidosis cardiaca por depósitos de transtiretina (ATTR). Materiales y métodos Se realizó SPECT/TC a 41 pacientes con resultado gammagráfico positivo para amiloidosis cardiaca ATTR. Se dividió a los pacientes en dos grupos (grados2 y3 de Perugini) y se calcularon los SUVmax a nivel del hueso y de ambos ventrículos y el porcentaje de dosis calculado en estas áreas. Se empleó la prueba t de Student para comparar resultados y se calculó el área bajo la curva (AUC) para evaluar la eficacia diferencial y establecer unos puntos de corte discriminatorios entre ambos grupos de pacientes. Resultados Se observaron diferencias estadísticamente significativas en todas las variables a estudio, a excepción del SUVmax hueso. Las diferencias con mayor potencia estadística se observaron en las variables SUVmaxVD y el porcentaje de dosis en ambos ventrículos (p<0,001). El punto de corte obtenido para la variable SUVmaxVI fue de 8,620 (sensibilidad del 87,9% y especificidad del 100%; AUC: 0,966), mientras que el de la variable SUVmaxVD fue de 6,195 (sensibilidad del 81,8% y especificidad del 100%; AUC: 0,955). Conclusiones La cuantificación absoluta de la captación miocárdica de 99mTc-DPD en las imágenes SPECT/TC de pacientes con sospecha de amiloidosis cardiaca por depósitos de transtiretina supone una nueva herramienta diagnóstica que permite una adecuada clasificación de los pacientes, acorde a la escala de gradación visual de Perugini (AU)

Purpose To determine the diagnostic contribution of the absolute quantification of the myocardial deposit of 99mTc-DPD in patients with cardiac amyloidosis due to transthyretin deposits (ATTR). Materials and methods SPECT/CT was performed on 41 patients with positive scintigraphic results for ATTR cardiac amyloidosis. The patients were divided into two groups (Perugini grades2 and3) and the SUVmax at the level of the bone and both ventricles and the percentage of dose calculated in these areas were calculated. Student's t-test was used to compare results and the area under the curve (AUC) was calculated to assess differential efficacy and establish discriminatory cut-off points between both groups of patients. Results Statistically significant differences were observed in all the study variables, with the exception of SUVmax bone. The differences with the greatest statistical power were observed in the variables SUVmaxRV and the percentage of dose in both ventricles (P<.001). The cut-off point obtained for the variable SUVmaxLV was 8.620 (sensitivity 87.9% and specificity 100%; AUC: 0.966), while that of the variable SUVmaxRV was 6.195 (sensitivity 81.8% and specificity 100%; AUC: 0.955). Conclusions The absolute quantification of myocardial uptake of 99mTc-DPD in the SPECT/CT images of patients with suspected cardiac amyloidosis due to transthyretin deposits represents a new diagnostic tool that allows an adequate classification of patients, according to the visual grading scale of Perugini (AU)

Importance of genetic study in elderly patients with transthyretin cardiac amyloidosis. / Relevancia del estudio genético de la amiloidosis cardíaca por transtiretina en el anciano.

BACKGROUND AND OBJECTIVE: Cardiac transthyretin amyloidosis (CA-ATTR) is a prevalent disease with age. Genetic study is recommended, even in eldest patients. We aim to analyze the prevalence of hereditary transthyretin amyloidosis (ATTRv) in elderly patients (≥75years) with CA-ATTR and its implications. PATIENTS AND METHODOLOGY: Retrospective observational study of the cohort of elderly patients with CA-ATTR diagnosed according to the international recommended protocol. We analyze the results of sequencing TTR gene, the differential characteristics and their clinical implications. RESULTS: Between 2016 and 2022, 130 elderly patients (89% cohort) were diagnosed with CA-ATTR (85% male). In 8 of the 123 patients with a genetic study, a pathogenic variant in TTR was identified (6.5%), initiating specific treatment in 4 subjects (50%). The family study identified another case and 6 asymptomatic carriers. There were no significant differences between baseline characteristics or in clinical events. CONCLUSIONS: The prevalence of ATTRv in elderly patients with CA-ATTR was 6.5% without observing differential characteristics that allow guiding a selective indication of genetic analysis.

Absolute quantification of myocardial uptake of 99mTc-DPD in patients with cardiac amyloidosis due to transthyretin deposits (ATTR).

PURPOSE: To determine the diagnostic contribution of the absolute quantification of the myocardial deposit of 99mTc-DPD in patients with cardiac amyloidosis due to transthyretin deposits (ATTR). MATERIALS AND METHODS: SPECT/CT was performed in 41 patients with positive scintigraphic results for ATTR cardiac amyloidosis. The patients were divided into two groups (Perugini grades 2 and 3) and the SUVmax at the level of the bone and both ventricles and the percentage of dose calculated in these areas were calculated. The Student's t-test was used to compare results and the area under the curve (AUC) was calculated to assess differential efficacy and establish discriminatory cut-off points between both groups of patients. RESULTS: Statistically significant differences were observed in all the study variables, with the exception of bone SUVmax. The differences with the greatest statistical power were observed in the variables SUVmaxRV and the percentage of dose in both ventricles (p < 0.001). The cut-off point obtained for the variable SUVmaxLV was 8.620 (sensitivity 87.9% and specificity 100%; AUC 0.966), while that of the variable SUVmaxRV was 6.195 (sensitivity 81.8% and specificity 100%; AUC 0.955). CONCLUSIONS: The absolute quantification of myocardial uptake of 99mTc-DPD in the SPECT/CT images of patients with suspected cardiac amyloidosis due to transthyretin deposits represents a new diagnostic tool that allows adequate classification of patients according to the Perugini visual grading scale.

«Red flags» en pacientes con polineuropatía amiloidótica familiar relacionada con transtiretina (hATTR) en el momento del diagnóstico en un área no endémica de España / Red flags in patients with hereditary transthyretin amyloidosis at diagnosis in a non-endemic area of Spain

Introducción: La polineuropatía relacionada con el depósito de amiloide por transtiretina (hATTR, por sus siglas en inglés) es una enfermedad poco común, multisistémica, de inicio en la edad adulta con un pronóstico ominoso sin tratamiento. Para reconocer la enfermedad en la etapa más temprana posible, se ha propuesto un grupo de signos y síntomas, comúnmente conocidos como «red flags», y su presencia puede indicar la presencia de una hATTR subyacente en pacientes con polineuropatía sensitivo-motora progresiva.Materiales y métodosSe analizó la frecuencia de «red flags» en el momento del diagnóstico en 30 pacientes con hATTR de un área no endémica de España, con una mayoría de pacientes de inicio tardío.ResultadosLas frecuencias de «red flags» fueron las siguientes: síndrome del túnel carpiano bilateral 15/30 (50%); disautonomía temprana en 17/30 (56%); síntomas gastrointestinales en 14/30 (46,6%); pérdida inexplicable de peso en 8/30 (26,6%); enfermedad cardiaca en 12/30 (40%); hallazgos cardiacos asintomáticos en 13/30 (43,3%); enfermedad renal en 1/30 (3,3%); opacidades vítreas en 0/30 (0%); neuropatía familiar en 21/30 (70%); cardiopatía familiar en 15/30 (50%) y antecedentes familiares gastrointestinales en 3/30 (10%). Todos los pacientes presentaron al menos una «red flag» en el momento del diagnóstico, con una mediana de 4 «red flags».ConclusiónLas «red flags», incluso en los pacientes de inicio tardío, fueron hallazgos comunes en el momento del diagnóstico y su presencia en un paciente con polineuropatía sensitivo-motora simétrica debería alertarnos y conducir el diagnóstico a lo largo de la hATTR hasta excluirlo, independientemente de la edad de inicio o de la región endémica. (AU)

Introduction: Hereditary transthyretin (hATTR) amyloidosis with polyneuropathy is a rare multisystemic disease characterised by onset during adulthood and associated with poor prognosis if untreated. A set of signs and symptoms, commonly known as “red flags,” have been proposed to assist in early detection of the disease; presence of red flags may suggest underlying hATTR amyloidosis in patients with progressive sensorimotor polyneuropathy.Material and methodsWe analysed the frequency of red flags at the time of diagnosis in 30 patients with hATTR amyloidosis in a non-endemic area of Spain; onset was late in the majority of patients.ResultsThe frequencies of the red flags were as follows: bilateral carpal tunnel syndrome in 15 patients (50%), early autonomic dysfunction in 17 (56%), gastrointestinal problems in 14 (46.6%), unexplained weight loss in 8 (26.6%), heart disease in 12 (40%), asymptomatic cardiac findings in 13 (43.3%), kidney disease in one (3.3%), vitreous opacities in none, family history of neuropathy in 21 (70%), family history of heart disease in 15 (50%), and family history of gastrointestinal problems in 3 (10%). All patients presented at least one red flag at diagnosis, with a median of 4 red flags.ConclusionRed flags were common at the time of diagnosis, even in patients with late-onset hATTR amyloidosis. Presence of red flags in a patient with symmetrical sensorimotor polyneuropathy should serve as a warning sign, and lead to targeted diagnosis to rule out hATTR amyloidosis, independently of age of onset. (AU)

Papel actual de las técnicas de imagen en la amiloidosis cardíaca / Current role of imaging techniques in cardiac amyloidosis

La amiloidosis cardíaca (AC) es una enfermedad infradiagnosticada, y si no se trata es rápidamente fatal. Los nuevos tratamientos disponibles aumentan la necesidad de desarrollar métodos diagnósticos no invasivos para su detección precoz y para la monitorización de la respuesta terapéutica. Los hallazgos típicos de la AC en ecocardiografía y resonancia magnética, no son suficientemente específicos para distinguir la AC de cadenas ligeras (AL) de la amiloidosis por transtiretina (ATTR). La captación de un radiofármaco óseo por el miocardio es altamente específica para la AC-ATTR cuando se ha excluido la discrasia de células plasmáticas. Ahora, este método diagnóstico está reemplazando la necesidad de biopsia en muchos pacientes. La detección precoz de la AC, la cuantificación de su carga y la evaluación de la respuesta al tratamiento son los siguientes pasos importantes para que las imágenes avancen en la evaluación y el tratamiento de la AC. (AU)

Cardiac amyloidosis (CA) is an underdiagnosed disease and, if left untreated, rapidly fatal. Emerging therapies for CA increase the urgency of developing non-invasive diagnostic methods for its early detection and for monitoring therapeutic response. Classic imaging features on echocardiography and cardiac magnetic resonance, although typical for cardiac amyloidosis, are not specific enough to distinguish light chain amyloidosis from transthyretin. Myocardial bone-avid radiotracer uptake is highly specific for transthyretin cardiac amyloidosis when plasma cell dyscrasia has been excluded; it is now replacing the need for biopsy in many patients. Detection of early cardiac amyloidosis, quantitation of its burden, and assessment of response to therapy are important next steps for imaging to advance the evaluation and management of cardiac amyloidosis. (AU)

[Current role of imaging techniques in cardiac amyloidosis]. / Papel actual de las técnicas de imagen en la amiloidosis cardíaca.

Cardiac amyloidosis (CA) is an underdiagnosed disease and, if left untreated, rapidly fatal. Emerging therapies for CA increase the urgency of developing non-invasive diagnostic methods for its early detection and for monitoring therapeutic response. Classic imaging features on echocardiography and cardiac magnetic resonance, although typical for cardiac amyloidosis, are not specific enough to distinguish light chain amyloidosis from transthyretin. Myocardial bone-avid radiotracer uptake is highly specific for transthyretin cardiac amyloidosis when plasma cell dyscrasia has been excluded; it is now replacing the need for biopsy in many patients. Detection of early cardiac amyloidosis, quantitation of its burden, and assessment of response to therapy are important next steps for imaging to advance the evaluation and management of cardiac amyloidosis.

Diagnóstico de amiloidosis sistémica: bases hematológicas útiles para el cardiólogo clínico / Diagnosis in systemic amiloydosis: useful hematological bases for the clinical cardiologist / Diagnóstico de amiloidose sistémica: bases hematológicas úteis para o cardiologista clínico

Las amiloidosis son un grupo heterogéneo de patologías caracterizado por el depósito extracelular de proteínas fibrilares anormalmente plegadas que se depositan en los tejidos y ocasionan su disfunción. La calidad y expectativa de vida depende del órgano afectado y del grado de compromiso, la afectación cardíaca es la principal determinante de la sobrevida y calidad de vida. El diagnóstico requiere la biopsia tisular y tipificación de la proteína. Su detección tardía se asocia a inferior pronóstico y sobrevida. La forma más común de amiloidosis es la causada por depósito de cadenas livianas monoclonales (AL), para la cual nuevos agentes de inmuno y quimioterapia dirigidas a suprimir la clona de células plasmáticas han demostrado mejorar la sobrevida. Para la amiloidosis por transtiretina (ATTR), segunda en frecuencia, existen terapias estabilizadoras de la proteína y terapias dirigidas a detener su síntesis a través del silenciamiento genético. Esta revisión se dirige a describir las bases hematológicas útiles para el cardiólogo clínico.

The amyloidoses are a heterogeneous group of diseases caused by the extracellular deposition of abnormally folded fibrillar proteins in organs and tissues, causing their dysfunction. The quality and life expectancy depend on the affected organ, with cardiac involvement being the main determinant of survival and quality of life. Diagnosis requires tissue biopsy and protein typing. Its late detection is associated with a lower prognosis and survival. The most common form of amyloidosis is caused by monoclonal light chain (AL) deposition, for which new immunological agents and chemotherapy aimed at suppressing plasma cell cloning have been shown to improve survival. For transthyretin amyloidosis (ATTR), the second in frequency, there are protein-stabilizing therapies and therapies aimed at stopping its synthesis through genetic silencing. This review focuses on the hematological bases for the clinical cardiologist.

As amiloidoses são um grupo heterogêneo de patologias caracterizadas pela deposição extracelular de proteínas fibrilares anormalmente dobradas, que se depositam nos tecidos, causando sua disfunção. A qualidade e expectativa de vida dependem do órgão afetado e do grau de comprometimento, sendo o acometimento cardíaco o principal determinante da sobrevida e qualidade de vida. O diagnóstico requer biópsia tecidual e tipagem de proteínas. Sua detecção tardia está associada a um menor prognóstico e sobrevida. A forma mais comum de amiloidose é causada pela deposição monoclonal de cadeia leve (AL), para a qual novos agentes imuno e quimioterápicos destinados a suprimir a clonagem de plasmócitos demonstraram melhorar a sobrevida. Para a amiloidose por transtirretina (ATTR), segunda em frequência, existem terapias estabilizadoras de proteínas e terapias destinadas a interromper sua síntese por meio do silenciamento genético. Esta revisão enfoca a amiloidose sistêmica, com foco em bases hematológicas úteis para o cardiologista clínico.

Primer uso de tafamidis en amiloidosis cardíaca TTR en Uruguay / First use of tafamidis in cardiac amyloidosis TTR in Uruguay / Primeiro uso de tafamidis em amiloidose cardíaca TTR no Uruguai

La amiloidosis cardíaca es una entidad con creciente reconocimiento, la variedad por transtiretina es la que más se diagnostica en la tercera edad de la vida. Hay reciente disponibilidad de fármacos que mejoran el pronóstico y la calidad de vida de los pacientes. Presentamos un caso de amiloidosis por transtiretina donde se usó por primera vez en nuestro país el fármaco tafamidis aprobado para el tratamiento de esta enfermedad.

Cardiac amyloidosis is an entity on increasing recognition, transthyretin variety is the most diagnosed in the third age. There is a recent availability of drugs that can improve the prognosis and quality of life of these patients. We present a case of transthyretin amyloidosis and the first use of tafamidis in our country.

A amiloidose cardíaca é uma entidade em crescente reconhecimento, a variedade transtiretina é a mais diagnosticada em idosos. Há disponibilidade recente de medicamentos que melhoram o prognóstico e a qualidade de vida dos pacientes. Apresentamos um caso de amiloidosis transteretina onde o medicamento tafamidis aprovado para esta doença foi utilizado pela primeira vez em nosso país.

Estudio descriptivo de la amiloidosis por transtiretina en un hospital de tercer nivel sin unidad de referencia / A descriptive study of transthyretin amyloidosis in a tertiary hospital without a referral unit

Antecedentes y objetivo: La amiloidosis por transtiretina (ATTR) es una enfermedad rara que forma parte de las amiloidosis sistémicas, y es una enfermedad amenazante para la vida. Puede afectar a todos los órganos y sistemas, siendo la más frecuente la afectación neurológica y cardíaca. El objetivo de este estudio es detectar posibles casos de ATTR y realizar un estudio descriptivo de los mismos. Material y métodos: Estudio descriptivo unicéntrico realizado en un hospital de tercer nivel en el que se incluyen pacientes con sospecha de ATTR entre septiembre de 2016 y enero de 2020. Resultados: Se detectan 190 pacientes sospechosos de ATTR. En el estudio se incluyen 100 de ellos, así como 10 familiares de pacientes en los que se detecta ATTR en su variante genética. En total, se detecta ATTR variante genética en 7 individuos (3 con mutación presintomática de la enfermedad), 16 pacientes con ATTR asociada a la edad y 31 individuos con amiloidosis cardíaca no filiada con las pruebas realizadas, lo que confirma la presencia de esta enfermedad en áreas no endémicas. Conclusiones: La ATTR es una enfermedad que se ha de tener en cuenta en el diagnóstico diferencial de pacientes que presentan insuficiencia cardíaca con FEVI preservada, principalmente si se asocia a síntomas neurológicos (AU)

Background and objective: Transthyretin amyloidosis (ATTR) is a rare disease that is part of systemic amyloidosis and is life-threatening. It can affect all organs and systems, the most frequent being neurological and cardiac involvement. This study aims to detect possible ATTR cases and carry out a descriptive study of them. Material and methods: Descriptive single-centre study carried out in a tertiary hospital, which included patients with suspected ATTR between September 2016 and January 2020. Results: A total of 190 suspected ATTR patients were detected. The study includes 100 of these patients, as well as 10 relatives of patients in whom ATTR was detected in its genetic variant (ATTRv). In total, ATTRv was detected in 7 individuals (3 with a presymptomatic mutation of the disease), 16 patients with age-related ATTR and 31 individuals with unknown cardiac amyloidosis with the tests performed, which confirms the presence of this disease in non-endemic areas. Conclusions: ATTR is a disease that must be taken into account in the differential diagnosis of patients with heart failure with preserved LVEF, especially if associated with neurological symptoms (AU)

A descriptive study of transthyretin amyloidosis in a tertiary hospital without a referral unit.

BACKGROUND AND OBJECTIVE: Transthyretin amyloidosis (ATTR) is a rare disease that is part of systemic amyloidosis and is life-threatening. It can affect all organs and systems, the most frequent being neurological and cardiac involvement. This study aims to detect possible ATTR cases and carry out a descriptive study of them. MATERIAL AND METHODS: Descriptive single-centre study carried out in a tertiary hospital, which included patients with suspected ATTR between September 2016 and January 2020. RESULTS: A total of 190 suspected ATTR patients were detected. The study includes 100 of these patients, as well as 10 relatives of patients in whom ATTR was detected in its genetic variant (ATTRv). In total, ATTRv was detected in 7 individuals (3 with a presymptomatic mutation of the disease), 16 patients with age-related ATTR and 31 individuals with unknown cardiac amyloidosis with the tests performed, which confirms the presence of this disease in non-endemic areas. CONCLUSIONS: ATTR is a disease that must be taken into account in the differential diagnosis of patients with heart failure with preserved LVEF, especially if associated with neurological symptoms.

Cardiomiopatía amiloídea por transtiretina: diagnóstico y manejo en la actualidad / Transthyretin amyloid cardiomyopathy: a review

RESUMEN: La cardiomiopatía amiloide por transtiretina (CATTR) es una enfermedad caracterizada por depósito extracelular de fibrillas amiloides en el miocardio, a partir de transtiretina mal plegada, generando una miocardiopatía restrictiva. Esta proteína mal plegada puede tener origen hereditario o adquirido, siendo más frecuente en adultos mayores. La CA-TTR ha surgido como una causa subdiagnosticada de insuficiencia cardíaca con fracción de eyección preservada (IC FEp). El pilar fundamental para su diagnóstico es la alta sospecha clínica, basada en diversas banderas de alerta ya que la sintomatología que provoca suele ser inespecífica. Como veremos en esta revisión, el diagnóstico puede sustentarse con la cintigrafía ósea, reservando para situaciones particulares la toma de biopsia. Con el advenimiento de nuevas terapias que impactan en la sobrevida de esta enfermedad, el tiempo para realizar el diagnóstico certero y la diferenciación de otras causas de amiloidosis cardíaca como la de cadenas livianas, se ha tornado crucial.

ABSTRACT: Transthyretin amyloid cardiomyopathy (AT-TR-CM) is a disease characterized by extracellular deposition of amyloid fibrils in the myocardium, from misfolded transthyretin, generating a restrictive cardiomyopathy. This misfolded protein may be inherited or acquired, and is more prevalent in elderly patients. ATTR-CM has emerged as an underdiagnosed cause of heart failure with preserved ejection fraction (HF-PEF). The fundamental pillarfor its diagnosis is high clinical suspicion since the symptoms are usually nonspecific. The diagnosis can be made from bone scintigraphy, reserving myocardial biopsy for particular situations. With the advent of new therapies that affect the survival of these patients, a timely diagnosis has become crucial.

Aproximación diagnóstica a la amiloidosis cardiaca por transtiretina en un área no endémica. ¿Qué variables no invasivas orientan a su diagnóstico? / Diagnostic approach to transthyretin amyloidosis in a non-endemic area. Which non-invasive variables could guide the diagnosis?

Al editor: Clásicamente se ha considerado la amiloidosis cardiaca como una afección rara, con un amplio espectro de síntomas que requiere un alto índice de sospecha. Sin embargo, los estudios han demostrado que la amiloidosis cardiaca por transtiretina (TTR) es más común de lo que previamente se creía1,2. Las características clínicas que se han asociado a la amiloidosis cardiaca por TTR son el sexo masculino, la edad avanzada, la hipertrofia concéntrica y la función ventricular izquierda preservada1. Se realizó un análisis descriptivo retrospectivo de las gammagrafías solicitadas en nuestro centro para descartar amiloidosis cardiaca por TTR desde septiembre de 2016 hasta noviembre de 2019. En dicho periodo se realizaron 39 gammagrafías, con una tendencia al alza en los últimos meses. Los objetivos fueron evaluar las gammagrafías solicitadas y conocer el porcentaje de gammagrafías diagnósticas de amiloidosis por TTR, establecer qué características son más frecuentes en los pacientes con amiloidosis por TTR en nuestra población de referencia y analizar las características diferenciales de las distintas posibilidades diagnósticas. Del total de las pruebas, 22 (56.4% de la muestra) mostraron una captación de grado 2-3 de Perugini, diagnóstica de amiloidosis por TTR. De acuerdo con las recomendaciones de diagnóstico no invasivo de amiloidosis cardiaca por TTR3, se descartó la presencia de pico monoclonal. Únicamente se realizó estudio genético a 10 pacientes, en dos de los cuales se detectó una mutación patogénica (Val50Met y variante patogénica c.290C>A en heterocigosis); los ocho restantes no mostraron mutaciones en el estudio molecular del gen TTR.

Perfil clínico y evolución de la amiloidosis cardiaca en un centro español de referencia / Clinical profile and outcome of cardiac amyloidosis in a Spanish referral center

Introducción y objetivos La amiloidosis cardiaca (AC) se produce por depósito de fibras de amiloide en el miocardio. Las formas más frecuentes son la amiloidosis por cadenas ligeras (AL) y por transtiretina (ATTR). Nuestro objetivo es describir la experiencia en el diagnóstico, el tratamiento y el pronóstico en un centro especializado español. Métodos Se incluyó a todos los pacientes diagnosticados de AC en el Hospital Puerta de Hierro Majadahonda desde mayo de 2008 a septiembre de 2018 y se analizaron sus características clínicas, su evolución y su supervivencia. Resultados Se incluyó a 180 pacientes con AC, de los que 64 (36%) tenían AL (el 50% varones; edad, 65±11 años) y 116, ATTR (el 72% varones; edad, 79±11 años; 18 con ATTR hereditaria). La forma de presentación más frecuente fue la insuficiencia cardiaca en ambos grupos (el 81% con AL y el 45% con ATTR; p <0,01). Otras formas de presentación en pacientes con ATTR fueron arritmias auriculares (16%), trastornos de conducción (6%) e incidental (6%). Ya tenían otro diagnóstico establecido 70 pacientes (40%). Se pudo diagnosticar de manera no invasiva al 75% de los pacientes con ATTR. A pesar de que el retraso diagnóstico fue superior en la ATTR (2,8±4,3 frente a 0,6±0,7 años; p <0,001), la mortalidad fue mayor en los pacientes con AL (el 48 frente al 32%; p=0,028). El tipo de AL (HR=6,16; IC95%, 1,56-24,30; p=0,01), el sexo femenino (HR=2,35; IC95%, 1,24-4,46; p=0,01) y la clase funcional de la NYHA III-IV (HR=2,07; IC95%, 1,11-3,89; p=0,02) fueron predictores independientes de la mortalidad. Conclusiones La AC constituye un reto en la práctica clínica, con gran variabilidad en su presentación en función del subtipo y con un retraso diagnóstico y una mortalidad elevados. Son necesarias mejoras en el diagnóstico temprano y el tratamiento de estos pacientes. (AU)

Introduction and objectives Cardiac amyloidosis (CA) is produced by amyloid fiber deposition in the myocardium. The most frequent forms are those caused by light chains (AL) and transthyretin (ATTR). Our objective was to describe the diagnosis, treatment and outcomes of CA in a specialized Spanish center. Methods We included all patients diagnosed with CA in Hospital Universitario Puerta de Hierro Majadahonda from May 2008 to September 2018. We analyzed their clinical characteristics, outcomes, and survival. Results We included 180 patients with CA, of whom 64 (36%) had AL (50% men; mean age, 65±11 years) and 116 had ATTR (72% men; mean age 79±11 years; 18 with hereditary ATTR). The most common presentation was heart failure in both groups (81% in AL and 45% in ATTR, P <.01). Other forms of presentation in ATTR patients were atrial arrhythmias (16%), conduction disorders (6%), and incidental finding (6%); 70 patients (40%), had a previous alternative cardiac diagnosis. Diagnosis was noninvasive in 75% of ATTR patients. Diagnostic delay was higher in ATTR (2.8±4.3 vs 0.6±0.7 years, P <.001), but mortality was greater in AL patients (48% vs 32%, P=.028). Independent predictors of mortality were AL subtype (HR, 6.16; 95%CI, 1.56-24.30; P=.01), female sex (HR, 2.35; 95%CI,1.24-4.46; P=.01), and NYHA functional class III-IV (HR, 2.07; 95%CI, 1.11-3.89; P=.02). Conclusions CA is a clinical challenge, with wide variability in its presentation depending on the subtype, leading to diagnostic delay and high mortality. Improvements are needed in the early diagnosis and treatment of these patients. (AU)

Amiloidosis cardíaca por transtiretina / Transthyretin amyloid cardiomyopathy

La amiloidosis cardíaca por transtiretina (TTR) es una enfermedad infiltrativa, grave y progresiva, que se produce por el depósito de TTR en el corazón. Puede deberse a una alteración genética en su forma hereditaria (ATTRv) o a consecuencia de un proceso degenerativo asociado a la edad (ATTRwt). Gracias a los avances en técnicas de imagen y a la posibilidad de realizar un diagnóstico no invasivo hoy conocemos que la ATTR es una enfermedad más frecuente de lo tradicionalmente considerado y que es particularmente relevante en pacientes mayores de 65 años con insuficiencia cardíaca o con estenosis aórtica. Con la aparición de opciones de tratamiento capaces de modificar la historia natural de la ATTR se hace necesario que los clínicos estén familiarizados con el proceso diagnóstico y el tratamiento de esta enfermedad. En esta revisión se repasará el espectro clínico de presentación de la ATTR, su diagnóstico y su tratamiento. (AU)

Transthyretin (TTR) cardiac amyloidosis is a severe, progressive, infiltrative disease caused by the deposition of TTR at cardiac level. It may be due to a genetic alteration in its hereditary form (ATTRv) or as a consequence of an age-related degenerative process (ATTRwt). Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that ATTR is more frequent than traditionally considered and that it is particularly relevant in patients over 65 years with heart failure or with aortic stenosis. With the appearance of several treatment options capable of modifying the natural history of ATTR, it is necessary for clinicians to be familiar with the diagnostic process and treatment of this disease. This review will cover the clinical spectrum of presentation of ATTR, its diagnosis and treatment. (AU)

Clinical profile and outcome of cardiac amyloidosis in a Spanish referral center.

INTRODUCTION AND OBJECTIVES: Cardiac amyloidosis (CA) is produced by amyloid fiber deposition in the myocardium. The most frequent forms are those caused by light chains (AL) and transthyretin (ATTR). Our objective was to describe the diagnosis, treatment and outcomes of CA in a specialized Spanish center. METHODS: We included all patients diagnosed with CA in Hospital Universitario Puerta de Hierro Majadahonda from May 2008 to September 2018. We analyzed their clinical characteristics, outcomes, and survival. RESULTS: We included 180 patients with CA, of whom 64 (36%) had AL (50% men; mean age, 65±11 years) and 116 had ATTR (72% men; mean age 79±11 years; 18 with hereditary ATTR). The most common presentation was heart failure in both groups (81% in AL and 45% in ATTR, P <.01). Other forms of presentation in ATTR patients were atrial arrhythmias (16%), conduction disorders (6%), and incidental finding (6%); 70 patients (40%), had a previous alternative cardiac diagnosis. Diagnosis was noninvasive in 75% of ATTR patients. Diagnostic delay was higher in ATTR (2.8±4.3 vs 0.6±0.7 years, P <.001), but mortality was greater in AL patients (48% vs 32%, P=.028). Independent predictors of mortality were AL subtype (HR, 6.16; 95%CI, 1.56-24.30; P=.01), female sex (HR, 2.35; 95%CI, 1.24-4.46; P=.01), and NYHA functional class III-IV (HR, 2.07; 95%CI, 1.11-3.89; P=.02). CONCLUSIONS: CA is a clinical challenge, with wide variability in its presentation depending on the subtype, leading to diagnostic delay and high mortality. Improvements are needed in the early diagnosis and treatment of these patients.