Abstract Therapeutics that inhibit enzymes, receptors, ion channels, and cotransporters have long been the mainstay of cardiovascular medicine. Now, oligonucleotide therapeutics offer a modern variation on this paradigm of protein inhibition. Rather than target a protein, however, small interfering ribonucleic acids and antisense oligonucleotides target the messenger RNA (mRNA) from which a protein is translated. Endogenous, cellular mechanisms enable the oligonucleotides to bind a selected sequence on a target mRNA, leading to its degradation. The catalytic nature of the process confers an advantage over the stoichiometric binding of traditional small molecule therapeutics to their respective protein targets. Advances in nucleic acid chemistry and delivery have enabled development of oligonucleotide therapeutics against a wide range of diseases, including hyperlipidemias and hereditary transthyretin-mediated amyloidosis with polyneuropathy. While most of these therapeutics were initially designed for rare diseases, recent clinical trials highlight the potential impact of oligonucleotides on more common forms of cardiovascular disease.

RESUMO Antecedentes: Amiloidose hereditária por transtirretina (hATTR) com polineuropatia é uma doença rara, hereditária, multissistêmica, frequentemente fatal, causada por mutação no gene da transtirretina (TTR). Características dos pacientes ao diagnóstico, especialmente dados antropométricos, são raros na literatura, e são relevantes para definir estratégias terapêuticas eficazes. Objetivo: Este estudo objetivou descrever características demográficas, antropométricas, e da doença, numa coorte de pacientes de um centro de referência no Brasil. Métodos: Pacientes sintomáticos, não incluídos previamente em ensaios clínicos e elegíveis para tratamento foram recrutados. Etnia, estado de residência, idade, sexo, peso, altura, índice de massa corporal (IMC), mutação TTR e Polyneuropathy Disability Score (PND) ao diagnóstico foram analisados. Resultados: Foram incluídos 108 pacientes, sendo 58,33% do sexo masculino e 60,19% caucasianos. Na região sudeste residem 83,33%. A idade média foi 51,61 (±16,37) anos. O peso médio foi 65,76 (±15,16) Kg, a altura média foi 168,33 (±10,26) cm e o IMC médio foi 23,11 (±4,45) Kg/m2. A mutação mais prevalente foi V30M (86,11%). Pacientes com escore PND 0 apresentando neuropatia autonômica foram 14,81%. Pacientes PND I-II e PND III-IV totalizaram 52,78% e 32,41%, respectivamente. Peso e IMC médios foram significativamente menores em pacientes com manifestações sensitivo-motoras. Conclusões: Esta é a maior coorte de pacientes do Brasil que teve dados antropométricos descritos. Dados basais demográficos, antropométricos e das manifestações da doença indicam que o atraso no diagnóstico ainda é um problema, e esforços precisam ser feitos para acelerá-lo a fim de maximizar as oportunidades com os novos medicamentos que alteram o curso da doença.

ABSTRACT Background: Hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy is a rare, inherited, multisystem, and often fatal disease caused by a variant in transthyretin (TTR) gene. Baseline characteristics of patients, especially anthropometric data, are scarce in the literature, and they are relevant to define effective treatment strategies. Objective: This study aimed to describe baseline demographic, anthropometric, and disease characteristics in a cohort of patients from a reference center in Brazil. Methods: Symptomatic patients not previously included in clinical trials and eligible for treatment were enrolled. Ethnicity, state of residence, age, sex, weight, height, body mass index (BMI), TTR variant, and Polyneuropathy Disability Score (PND) at diagnosis were analyzed. Results: Among the 108 patients enrolled, 58.33% were male, 60.19% were Caucasian, and 83.33% lived in the Southeast region. Mean age was 51.61 (±16.37) years, mean weight was 65.76 (±15.16) kg, mean height was 168.33 (±10.26) cm, and mean BMI was 23.11 (±4.45) kg/m2. The most prevalent variant was V30M (86.11%). Patients with PND score 0 presenting autonomic neuropathy were 14.81%. Patients with PND score I-II and III-IV were 52.78 and 32.41%, respectively. Mean weight and BMI were significantly lower in patients with sensory-motor manifestations. Conclusions: This is the largest cohort of patients in Brazil for whom anthropometric characteristics have been described. Baseline demographic, anthropometric, and disease data indicate that delay in diagnosis of hATTR amyloidosis with polyneuropathy is still a problem and that efforts must be made to expedite diagnosis and maximize opportunities for new disease-modifying treatments.