RESUMEN
Daratumumab-based regimens are the new standard of care for newly diagnosed patients with AL amyloidosis based on the results of the ANDROMEDA study. However, real-world data on daratumumab efficacy in upfront therapy in unselected patients are scanty. In the framework of a prospective observational study, we investigated the efficacy and safety of daratumumab in 88 newly diagnosed patients, including subjects with IIIb cardiac stage (26%) or myeloma defining events (29%). Daratumumab was administered with bortezomib in 50 (56%) patients, lenalidomide in 31 (35%), and monotherapy in 7 (8%). The rate of serious adverse events was low (16%). The overall hematologic response rate was 75% with 52 (59%) patients attaining at least a very good partial response (VGPR) at six months. Amongst patients evaluable for organ response, the rate of cardiac and renal responses at 6 months was 31% and 21%, respectively. Comparing stage IIIb patients with the remaining ones, the rate of profound hematologic response was not significantly different (≥VGPR 57% vs. 59%, p 0.955) likewise the rate of cardiac (33% vs. 30%, p 0.340) and renal (40% vs. 16%, p 0.908) responses. Daratumumab-based regimens demonstrated to be safe and effective in treatment-naïve AL amyloidosis even in advanced stage disease.
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Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Humanos , Masculino , Femenino , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Anciano , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano de 80 o más Años , Estudios Prospectivos , Lenalidomida/administración & dosificación , Lenalidomida/uso terapéutico , Lenalidomida/efectos adversos , Bortezomib/administración & dosificación , Bortezomib/uso terapéutico , Bortezomib/efectos adversos , Adulto , Resultado del TratamientoRESUMEN
BACKGROUND: Hereditary transthyretin (ATTRv, v for variant) amyloidosis with polyneuropathy is a rare disease caused by mutations in the transthyretin gene. In ATTRv amyloidosis, multisystem extracellular deposits of amyloid cause tissue and organ dysfunction. Patisiran is a small interfering RNA molecule drug that reduces circulating levels of mutant and wild-type TTR proteins. Prior to its regulatory approval, patisiran was available in Italy through a compassionate use programme (CUP). The aim of this study was to analyse the long-term outcomes of patients who entered into the CUP. METHODS: This was a multicentre, observational, retrospective study of patients with ATTRv amyloidosis treated with patisiran. The analysis included change from baseline to 12, 24, 36 and 48 months in familial amyloid polyneuropathy (FAP) stage, polyneuropathy disability (PND) class, neuropathy impairment score (NIS), modified body mass index (mBMI), Compound Autonomic Dysfunction Test (CADT), Karnofsky Performance Status (KPS) scale and Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) questionnaire. Safety data were also analysed. RESULTS: Forty patients from 11 Italian centres were enrolled: 23 in FAP 1 (6 in PND 1 and 17 in PND 2) and 17 in FAP 2 (8 in PND 3a and 9 in PND 3b) stage. In this population, the mean NIS at baseline was 71.4 (± 27.8); mBMI, 917.1 (± 207) kg/m2; KPS, 67.1 (± 14.0); Norfolk QoL-DN, 62.2 (± 25.2); and CADT, 13.2 (± 3.3). Statistical analysis showed few significant differences from baseline denoting disease stability. No new safety signals emerged. CONCLUSIONS: Patisiran largely stabilised disease in patients with ATTRv amyloidosis.
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Neuropatías Amiloides Familiares , Humanos , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/complicaciones , Italia , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Resultado del Tratamiento , ARN Interferente Pequeño/uso terapéutico , Calidad de VidaRESUMEN
BACKGROUND AND PURPOSE: Hereditary transthyretin (TTR) amyloidosis (ATTRv) is a dominantly inherited, adult-onset, progressive, and fatal disease caused by mutations in the transthyretin gene. Therapeutic agents approved for this disease include the TTR stabilizer tafamidis and the gene-silencing drugs patisiran and inotersen. Inotersen is an antisense oligonucleotide that suppresses the hepatic production of transthyretin. After European Medical Agency approval in 2018, an early-access program was opened in Italy, and in this article, we present the long-term outcome of a cohort of Italian ATTRv patients who received inotersen within this program. METHODS: This is a multicenter, observational, retrospective study of patients affected by ATTRv that started inotersen during the early-access program. The primary end point was safety. Secondary end points included change from baseline in familial amyloid polyneuropathy (FAP) stage, Polyneuropathy Disability, Neuropathy Impairment Scale, Compound Autonomic Dysfunction Test, Norfolk Quality of Life-Diabetic Neuropathy, troponin, N-terminal pro-brain natriuretic peptide, interventricular septum thickness, and body mass index. RESULTS: In total, 23 patients were enrolled. No patient permanently discontinued the treatment because of thrombocytopenia, and no cases of severe thrombocytopenia were observed. Five patients discontinued the treatment permanently because of voluntary withdrawal (two patients), renal failure after infective pyelonephritis, not related to inotersen, drug-related hypotension, and amyloid-negative crescentic glomerulonephritis. In seven patients, dosing frequency was reduced to every 2 weeks due to recurrent thrombocytopenia. Considering the FAP stage, only two patients worsened, whereas the other 21 patients remained stable until the last follow-up available. CONCLUSIONS: The long-term safety profile of inotersen is favorable. Neurologic disease severity at baseline is the main factor associated with progression.
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Neuropatías Amiloides Familiares , Trombocitopenia , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/genética , Humanos , Italia , Oligonucleótidos , Fenotipo , Prealbúmina/genética , Calidad de Vida , Estudios Retrospectivos , Trombocitopenia/complicacionesRESUMEN
Immunoglobulin light chain amyloidosis (AL amyloidosis) is caused by misfolded light chains that form soluble toxic aggregates that deposit in tissues and organs, leading to organ dysfunction. The leading determinant of survival is cardiac involvement. Current staging systems use N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponins T and I (TnT and TnI) for prognostication, but many centers do not offer NT-proBNP. We sought to derive a new staging system using brain natriuretic peptide (BNP) that would correlate with the Mayo 2004 staging system and be predictive for survival in AL amyloidosis. Two cohorts of patients were created: a derivation cohort of 249 consecutive patients who had BNP, NT-proBNP, and TnI drawn simultaneously to create the staging system and a complementary cohort of 592 patients with 10 years of follow-up to determine survival. In the derivation cohort, we found that a BNP threshold of more than 81 pg/mL best associated with Mayo 2004 stage and also best identified cardiac involvement. Three stages were developed based on a BNP higher than 81 pg/mL and a TnI higher than 0.1 ng/mL and compared with Mayo 2004 with high concordance (κ = 0.854). In the complementary cohort, 25% of patients had stage I, 44% had stage II, 15% had stage III, and 16% had stage IIIb disease with a median survival not reached in stage I, 9.4 years in stage II, 4.3 years in stage III, and 1 year in stage IIIb. This new Boston University biomarker scoring system will allow centers without access to NT-proBNP the ability to appropriately stage patients with AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT00898235.
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Biomarcadores de Tumor/sangre , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/patología , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Troponina T/sangre , Anciano , Femenino , Estudios de Seguimiento , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/sangre , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/clasificación , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an underappreciated cause of heart failure that results from misfolded TTR (prealbumin) protein. Diflunisal is an approved non-steroidal anti-inflammatory drug that stabilizes TTR, with limited data available regarding effects on cardiac structure and function. METHODS AND RESULTS: ATTR-CM patients (n=81, 41% treated with 250 mg twice-daily diflunisal by clinical practice) were retrospectively identified with baseline and follow-up (median interval 1 year) serum biomarker and echocardiographic data compared, including global longitudinal strain (GLS). Chi-squared and Wilcoxon tests assessed differences between subjects, divided by treatment group, and univariable and multivariable linear regression was performed. At baseline, patients treated with diflunisal were younger (68 vs 77 years, P = .0001), with lower B-type natriuretic peptide (BNP; 249 vs 545 pg/mL, Pâ¯=â¯.009) and serum creatinine (1.1 vs 1.2 mg/dL, Pâ¯=â¯.04), but similar TTR concentration (Pâ¯=â¯.31), cardiac troponin I (Pâ¯=â¯.06), and GLS (Pâ¯=â¯.67). At follow-up, diflunisal untreated versus treated patients showed differences in TTR concentration (19 vs 33 mg/dL, Pâ¯=â¯.01) and favorable differences in left atrial volume index (+4.6 vs -1.4 mL/m2, Pâ¯=â¯.002) and cardiac troponin I (+0.03 vs -0.01 ng/mL, Pâ¯=â¯.01) for the entire cohort. Among the subset with wild-type ATTR (n=53), diflunisal treatment was associated with differences in GLS (+1.2% untreated vs +0.1% treated, Pâ¯=â¯.03). Changes in wall thickness (Pâ¯=â¯.2), left ventricular ejection fraction (Pâ¯=â¯.71), and BNP (Pâ¯=â¯.42) were similar between groups. CONCLUSIONS: In ATTR-CM, diflunisal treatment resulted in measurable differences in some parameters of cardiac structure and function after only 1 year of administration. Further longer-term analysis is warranted.
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Neuropatías Amiloides Familiares , Cardiomiopatías , Diflunisal , Insuficiencia Cardíaca , Anciano , Anciano de 80 o más Años , Diflunisal/administración & dosificación , Femenino , Humanos , Masculino , Prealbúmina , Estudios Retrospectivos , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
V122I is one of more than 130 mutations in transthyretin gene associated with hereditary TTR (ATTRv) amyloidosis. Main clinical expression is an infiltrative pseudohypertrophic cardiomyopathy with mild or no neurological symptoms. It is particularly common among African-Americans (prevalence: 3%-4%). We report 12 subjects from seven unrelated Caucasian families hailing from Sicily and carrying the V122I mutation. One patient was homozygous for V122I and in another family two subjects also carried the E89Q variant in compound heterozygosity. All the subjects underwent neurologic/neurophysiologic evaluation and cardiologic baseline tests; in five of them, cardiac magnetic resonance and/or (99 m) Tc-DPD scintigraphy were performed. Three of 12 subjects were asymptomatic carriers. Of the remaining nine subjects, in four of nine patients, the nerve conduction studies revealed a polyneuropathy; in one of them, this represents the only sign of disease after 5 years of follow-up. In eight of nine subjects, we found a hypertrophic restrictive cardiomyopathy and cardiac failure, associated with a carpal tunnel syndrome. Although in non-Afro-American individuals V122I prevalence is low, subjects carrying this mutation have been identified in the United Kingdom, Italy, and France. Our report describes a large cohort of V122I Caucasian patients from a non-endemic area, confirming the possible underestimation of this mutation in the non-African population. Moreover, it highlights the heterogeneity in the genotype-phenotype correlation of ATTRv mutations, suggesting that the presence of a polyneuropathy has to be identified as soon as possible, since available treatments are, in Europe, so far authorized only for ATTRv amyloid peripheral neuropathy.
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Neuropatías Amiloides Familiares , Cardiopatías , Polineuropatías , Prealbúmina/genética , Población Blanca , Adulto , Anciano , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/etnología , Neuropatías Amiloides Familiares/genética , Estudios de Seguimiento , Cardiopatías/diagnóstico , Cardiopatías/etnología , Cardiopatías/etiología , Cardiopatías/genética , Humanos , Masculino , Persona de Mediana Edad , Polineuropatías/diagnóstico , Polineuropatías/etnología , Polineuropatías/etiología , Polineuropatías/genética , Sicilia/etnología , Población Blanca/etnología , Población Blanca/genéticaRESUMEN
Systemic amyloidoses are rare and proteiform diseases, caused by extracellular accumulation of insoluble misfolded fibrillar proteins. Prognosis is dictated by cardiac involvement, which is especially frequent in light chain (AL) and in transthyretin variants (ATTR, both mutated, (ATTRm), and wild-type, (ATTRwt)). Recently, ATTRwt has emerged as a potentially relevant cause of a heart failure with preserved ejection fraction (HFpEF). Cardiac amyloidosis is an archetypal example of restrictive cardiomyopathy, with signs and symptoms of global heart failure and diastolic dysfunction. Independent of the aetiology, cardiac amyloidosis is associated with left ventricular concentric "hypertrophy" (i.e. increased wall thickness), preserved (or mildly depressed) ejection fraction, reduced midwall fractional shortening and global longitudinal function, as well as evident diastolic dysfunction, up to an overly restrictive pattern of the left ventricular filling. Cardiac biomarkers such as troponins and natriuretic peptides are very robust and widely accepted diagnostic as well as prognostic tools. Owing to its dismal prognosis, accurate and early diagnosis is mandatory and potentially life-saving. Although pathogenesis is still not completely understood, direct cardiomyocyte toxicity of the amyloidogenic precursor proteins and/or oligomer aggregates adds on tissue architecture disruption caused by amyloid deposition. The clarification of mechanisms of cardiac damage is offering new potential therapeutic targets, and several treatment options with a relevant impact on prognosis are now available.
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Amiloidosis/terapia , Cardiomiopatías/terapia , Amiloidosis/sangre , Amiloidosis/complicaciones , Amiloidosis/diagnóstico , Cardiomiopatías/sangre , Cardiomiopatías/complicaciones , Cardiomiopatías/diagnóstico , Insuficiencia Cardíaca/etiología , Humanos , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/patología , Péptidos Natriuréticos/sangre , Prealbúmina/genética , Pronóstico , Volumen Sistólico , Troponina/sangreRESUMEN
BACKGROUND: Early identification of immunoglobulin light-chain amyloidosis (AL) is crucial due to its rapid progression. Monoclonal light-chain (M-LC) testing is the first step in the diagnostic workup for patients with suspected cardiac amyloidosis (CA). We aimed to determine whether the time interval between the first CA suspicion and M-LC testing can be related to AL amyloidosis survival outcomes. METHODS: All patients (n = 94) with isolated cardiac AL amyloidosis diagnosed at our center between 2016 and 2020 were included. Those with pre-existing known monoclonal protein (monoclonal gammopathy of undetermined significance or smoldering multiple myeloma) were excluded. Time intervals to diagnostic tests and diagnosis were calculated and assessed for their survival prediction ability. RESULTS: The time interval between first CA suspicion (on echocardiography) and M-LC testing correlated with early mortality, and the best cutoff predicting survival, was 6 weeks. The 26 patients (â¼28% of entire cohort) who underwent M-LC-studies >6 weeks after first suspicion more frequently presented Mayo stage IIIb (65% vs. 35%, p = .008), showing poorer overall survival than those (n = 68, 72%) referred for early M-LC studies (median 3 vs. 14 months, p = .039). CONCLUSIONS: Monoclonal protein testing should be the first-step in the diagnostic workup for patients with echocardiographic/other instrumental red flags raising CA suspicion.
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Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Humanos , Masculino , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/patología , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/metabolismo , Femenino , Anciano , Persona de Mediana Edad , Ecocardiografía , Cadenas Ligeras de Inmunoglobulina/sangre , Cadenas Ligeras de Inmunoglobulina/metabolismo , Estudios Retrospectivos , Cardiomiopatías/mortalidad , Cardiomiopatías/diagnóstico , Cardiomiopatías/patología , Cardiomiopatías/metabolismo , Anciano de 80 o más AñosRESUMEN
BACKGROUND AND PURPOSE: To evaluate the prevalence and the prognostic implications of conduction delays in a large cohort of cardiac AL patients. METHODS: Echo Doppler and 12-lead ECG were collected in 344 consecutive patients in whom diagnosis of AL amyloidosis was concluded between 2008 and 2010. Patients were subdivided according to the presence (n = 240) or absence (n = 104) of cardiac involvement. RESULTS: When compared with patients without myocardial involvement, cardiac AL was associated with prolonged PQ, QRS, QT and QTc intervals (P < 0.05), and with higher prevalence of intraventricular blocks (27.5% vs. 16.5%, P < 0.05), that was associated with higher wall thickness, worse diastolic and regional systolic function, higher NT-proBNP values (all P < 0.05), and higher mortality (P = 0.0001; median follow-up: 402 days). CONCLUSION: Intraventricular conduction delays have a negative prognostic impact in patients with cardiac AL amyloidosis. Their presence should not be overlooked in the diagnostic workup, prompting a more accurate cardiological support.
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Amiloidosis/epidemiología , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/epidemiología , Cardiomiopatías/epidemiología , Ecocardiografía Doppler/métodos , Electrocardiografía/métodos , Sistema de Conducción Cardíaco/anomalías , Distribución por Edad , Anciano , Amiloidosis/diagnóstico , Amiloidosis/fisiopatología , Análisis de Varianza , Biomarcadores/análisis , Síndrome de Brugada , Trastorno del Sistema de Conducción Cardíaco , Cardiomiopatías/diagnóstico , Cardiomiopatías/fisiopatología , Estudios de Cohortes , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Péptido Natriurético Encefálico/análisis , Fragmentos de Péptidos/análisis , Prevalencia , Pronóstico , Modelos de Riesgos Proporcionales , Valores de Referencia , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Distribución por Sexo , Estadísticas no Paramétricas , Tasa de SupervivenciaRESUMEN
BACKGROUND: In cardiac AL amyloidosis, myocardial infiltration is typically associated with "low QRS voltages" at the 12-lead electrocardiogram (ECG). Although considered as one of the hallmarks of the disease, its reported prevalence varies from 45% to 70%, mainly because of nonhomogeneous definitions. METHODS: To identify the "low QRS voltage" parameter having the best diagnostic value in identifying cardiac amyloidosis, and to assess its possible prognostic role, ECG and echocardiographic data were collected at diagnosis in 337 consecutive never-treated AL patients (233 with, 104 without cardiac involvement). Prognosis was assessed after a median follow-up of 14.5 months. RESULTS: "Low QRS voltage" prevalence varied from 84.12% when using Sokolow-Lyon index ≤15 mm to 27.04% with the definition of low total voltages (QRS amplitude ≤5 mm in each peripheral and ≤10 mm in each precordial lead), the widely used definition of low peripheral voltages (≤5 mm in each peripheral lead) being able to identify 66.52% cardiac AL patients. The presence of "low peripheral voltages" was associated with a more severe cardiac involvement, and was able to differentiate Mayo stage II patients' survival (i.e., AL patients with intermediate prognosis). According to receiver operator characteristic (ROC) curve analysis, sensitivity and specificity were 58.72% and 80.00%, for a peripheral QRS amplitude ≤24.5 mm (the sum of QRS in all the 6 peripheral leads), and 76.26% and 65.00% for a Sokolow-Lyon index ≤11 mm. CONCLUSIONS: In cardiac AL amyloidosis the prevalence of low QRS voltages is highly dependent on the method used for defining this ECG alteration.
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Amiloidosis/diagnóstico , Cardiomiopatías/diagnóstico , Electrocardiografía/métodos , Anciano , Amiloidosis/fisiopatología , Cardiomiopatías/fisiopatología , Ecocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy caused by extracellular deposition of amyloid fibrils, mainly derived from transthyretin, either wild-type or hereditary variants, or immunoglobulin light chains misfolding. It is characterized by an increased left ventricular (LV) mass and diastolic dysfunction, which can lead to heart failure with preserved ejection fraction and/or conduction disturbances. The diagnosis is based on invasive pathology demonstration of amyloid deposits, or non-invasive criteria using advanced cardiovascular imaging techniques. Nevertheless, 12-lead electrocardiogram (ECG) remains of crucial importance in the assessment of patients with CA, since they can manifest peculiar features such as low QRS voltages, in discordance with the LV hypertrophy, but also pseudo-infarction patterns, sinus node dysfunction, atrioventricular blocks, premature supraventricular and ventricular beats, which support the presence of a myocardial disease. Great awareness of these common ECG characteristics of CA is needed to increase diagnostic performance and improve patient's outcome. In the present review, we discuss the current role of the ECG in the diagnosis and management of CA, focusing on the most common ECG abnormalities and rhythm disorders.
RESUMEN
BACKGROUND: The development of reproducible and sensitive outcome measures has been challenging in hereditary transthyretin (ATTRv) amyloidosis. Recently, quantification of intramuscular fat by magnetic resonance imaging (MRI) has proven as a sensitive marker in patients with other genetic neuropathies. The aim of this study was to investigate the role of muscle quantitative MRI (qMRI) as an outcome measure in ATTRv. METHODS: Calf- and thigh-centered multi-echo T2-weighted spin-echo and gradient-echo sequences were obtained in patients with ATTRv amyloidosis with polyneuropathy (n = 24) and healthy controls (n = 12). Water T2 (wT2) and fat fraction (FF) were calculated. Neurological assessment was performed in all ATTRv subjects. Quantitative MRI parameters were correlated with clinical and neurophysiological measures of disease severity. RESULTS: Quantitative imaging revealed significantly higher FF in lower limb muscles in patients with ATTRv amyloidosis compared to controls. In addition, wT2 was significantly higher in ATTRv patients. There was prominent involvement of the posterior compartment of the thighs. Noticeably, FF and wT2 did not exhibit a length-dependent pattern in ATTRv patients. MRI biomarkers correlated with previously validated clinical outcome measures, Polyneuropathy Disability scoring system, Neuropathy Impairment Score (NIS) and NIS-lower limb, and neurophysiological parameters of axonal damage regardless of age, sex, treatment and TTR mutation. CONCLUSIONS: Muscle qMRI revealed significant difference between ATTRv and healthy controls. MRI biomarkers showed high correlation with clinical and neurophysiological measures of disease severity making qMRI as a promising tool to be further investigated in longitudinal studies to assess its role at monitoring onset, progression, and therapy efficacy for future clinical trials on this treatable condition.
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Neuropatías Amiloides Familiares , Polineuropatías , Humanos , Estudios Transversales , Neuropatías Amiloides Familiares/diagnóstico por imagen , Músculos , Polineuropatías/diagnóstico por imagen , Polineuropatías/etiología , Imagen por Resonancia Magnética , Biomarcadores , PrealbúminaRESUMEN
BACKGROUND: Very small case series of patients with apolipoprotein A1 (ApoA1) amyloidosis are available. METHODS: We described the clinical and echocardiographic characteristics of individuals with the pathogenic APOA1 variant Leu75Pro (p. Leu99Pro), referred for cardiac screening. RESULTS: We enrolled 189 subjects, 54% men, median age 55 years (interquartile range 42-67), 39% with concomitant renal disease and 31% with liver disease. Median left ventricular ejection fraction was 60% (55-66). Overall, these subjects did not show overt diastolic dysfunction nor left ventricular (LV) hypertrophy. Age correlated with interventricular septal (IVS) thickness (r = 0.484), LV mass index (r = 0.459), E/e' (r = 0.501), and right ventricular free wall thickness (r = 0.594) (all p < 0.001). Some individuals displayed red flags for cardiac amyloidosis (CA), and 14% met non-invasive criteria for CA. Twenty-nine subjects died over 5.8 years (4.1-8.0), with 10 deaths for cardiovascular causes. Individuals meeting echocardiographic criteria for CA had a much higher risk of all-cause death (p = 0.009), cardiovascular death (p = 0.001), cardiovascular death or heart failure (HF) hospitalisation (p < 0.001). Subjects with both renal and liver involvement had a more prominent cardiac involvement, and shortest survival. CONCLUSIONS: Subjects with the APOA1 Leu75Pro variant displayed minor echocardiographic signs of cardiac involvement, but 14% met echocardiographic criteria for CA. Subjects with suspected CA had a worse outcome.
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Amiloidosis , Apolipoproteína A-I , Masculino , Humanos , Persona de Mediana Edad , Femenino , Volumen Sistólico , Apolipoproteína A-I/genética , Función Ventricular Izquierda , Ecocardiografía , Hipertrofia Ventricular Izquierda/complicaciones , Amiloidosis/patologíaRESUMEN
AIM: Epidemiology of wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) remains poorly defined. A better characterization of pathways leading to ATTRwt-CA diagnosis is of key importance, and potentially informative of disease course and prognosis. The aim of this study was to describe the characteristics of contemporary pathways leading to ATTRwt-CA diagnosis, and their potential association with survival. METHODS AND RESULTS: This was a retrospective study of patients diagnosed with ATTRwt-CA at 17 Italian referral centres for CA. Patients were categorized into different 'pathways' according to the medical reason that triggered the diagnosis of ATTRwt-CA (hypertrophic cardiomyopathy [HCM] pathway, heart failure [HF] pathway, incidental imaging or incidental clinical pathway). Prognosis was investigated with all-cause mortality as endpoint. Overall, 1281 ATTRwt-CA patients were included in the study. The diagnostic pathway leading to ATTRwt-CA diagnosis was HCM in 7% of patients, HF in 51%, incidental imaging in 23%, incidental clinical in 19%. Patients in the HF pathway, as compared to the others, were older and had a greater prevalence of New York Heart Association (NYHA) class III-IV and chronic kidney disease. Survival was significantly worse in the HF versus other pathways, but similar among the three others. In multivariate model, older age at diagnosis, NYHA class III-IV and some comorbidities but not the HF pathway were independently associated with worse survival. CONCLUSIONS: Half of contemporary ATTRwt-CA diagnoses occur in a HF setting. These patients had worse clinical profile and outcome than those diagnosed either due to suspected HCM or incidentally, although prognosis remained primarily related to age, NYHA functional class and comorbidities rather than the diagnostic pathway itself.
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Neuropatías Amiloides Familiares , Cardiomiopatías , Insuficiencia Cardíaca , Humanos , Prealbúmina/genética , Prealbúmina/metabolismo , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/epidemiología , Neuropatías Amiloides Familiares/complicaciones , Estudios Retrospectivos , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/complicaciones , Cardiomiopatías/diagnóstico , Cardiomiopatías/epidemiología , Cardiomiopatías/complicacionesRESUMEN
Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly recognized as a treatable cause of heart failure (HF). Advances in diagnosis and therapy have increased the number of patients diagnosed at early stages, but prognostic data on patients without HF symptoms are lacking. Moreover, it is unknown whether asymptomatic patients benefit from early initiation of transthyretin (TTR) stabilizers. Objectives: The aim of this study was to describe the natural history and prognosis of ATTR-CM in patients without HF symptoms. Methods: Clinical characteristics and outcomes of patients with ATTR-CM without HF symptoms were retrospectively collected at 6 international amyloidosis centers. Results: A total of 118 patients (78.8% men, median age 66 years [IQR: 53.8-75 years], 68 [57.6%] with variant transthyretin amyloidosis, mean left ventricular ejection fraction 60.5% ± 9.9%, mean left ventricular wall thickness 15.4 ± 3.1 mm, and 53 [45%] treated with TTR stabilizers at baseline or during follow-up) were included. During a median follow-up period of 3.7 years (IQR: 1-6 years), 38 patients developed HF symptoms (23 New York Heart Association functional class II and 14 functional class III or IV), 32 died, and 2 required cardiac transplantation. Additionally, 20 patients received pacemakers, 13 developed AF, and 1 had a stroke. Overall survival was 96.5% (95% CI: 91%-99%), 90.4% (95% CI: 82%-95%), and 82% (95% CI: 71%-89%) at 1, 3, and 5 years, respectively. Treatment with TTR stabilizers was associated with improved survival (HR: 0.31; 95% CI: 0.12-0.82; P = 0.019) and remained significant after adjusting for sex, age, ATTR-CM type, and estimated glomerular filtration rate (HR: 0.18; 95% CI: 0.06-0.55; P = 0.002). Conclusions: After a median follow-up period of 3.7 years, 1 in 3 patients with asymptomatic ATTR-CM developed HF symptoms, and nearly as many died or required cardiac transplantation. Treatment with TTR stabilizers was associated with improved prognosis.
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The past few years have witnessed an unprecedented acceleration in the clinical development of novel therapeutic options for hereditary transthyretin amyloidosis. Recently approved agents and drugs currently under investigation not only represent a major breakthrough in this field but also provide validation of the therapeutic potential of innovative approaches, like RNA interference and CRISPR-Cas9-mediated gene editing, in rare inherited disorders. In this review, we describe the evolving therapeutic landscape for hereditary transthyretin amyloidosis and discuss how this highly disabling and fatal condition is turning into a treatable disease. We also provide an overview of the molecular mechanisms involved in transthyretin (TTR) amyloid formation and regression, to highlight how a deeper understanding of these processes has contributed to the identification of novel treatment targets. Finally, we focus on major areas of uncertainty and unmet needs that deserve further efforts to improve long-term patients' outcomes and allow for a brighter future.
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Neuropatías Amiloides Familiares , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/terapia , Edición Génica , Humanos , Prealbúmina/genética , Prealbúmina/uso terapéutico , Interferencia de ARNRESUMEN
Introduction: Hereditary transthyretin-mediated amyloidosis (ATTRv; v for variant) is a rare, progressive, fatal multi-systemic disease, autosomal dominantly inherited with heterogeneous clinical phenotype caused by mutations in the TTR gene. Mutations promoting proteolytic remodeling and tetramer dissociation result in fragmented and full-length TTR monomers that misfold, aggregate and deposit at multiple sites (mainly nerves and heart) causing peripheral neuropathy and/or cardiomyopathy.Areas covered: The authors discuss patisiran, the first approved RNA interference-based therapeutic agent that suppresses the circulating levels of the amyloidogenic protein TTR both wild-type and mutant. This compound demonstrated a safe clinical profile in phase I and II studies and showed a significant clinical effect in a phase III (APOLLO) trial in ATTRv patients. An open-label-extension study is still underway but, based on the positive results, the regulatory agencies granted approval for the treatment of ATTRv with polyneuropathy in Stage I and II.Expert opinion: The patisiran program has demonstrated that substantial TTR concentration reduction is associated with significant and sustained improvement in polyneuropathy scores, quality-of-life profile and several outcome measures that capture the systemic burden of the disease. The drug resulted safe also in long term follow-up studies while its efficacy for ATTR with cardiomyopathy is under investigation.