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- Generation of a human induced pluripotent stem cell line (UALGi001-A) from a patient with Left-Ventricular Noncompaction CardiomyopathyPublication . Calado, Sofia; Bento, Dina; Justino, David; Mendes-Silva, Leonardo; Marques, Nuno; Bragança, JoséLeft Ventricular Noncompaction Cardiomyopathy (LVNC) is characterized by excessive trabeculation of the left ventricle. To date, mutations in more than 40 genes have been associated with LVNC, however the exact mechanisms underlying the disease remain unknown. Here, we describe an induced pluripotent stem cell (iPSC) line (UALGi001-A) from a LVNC patient (LVNC-iPSC) that does not present mutations in the genes most commonly associated with the disease (van Waning et al., 2019). The LVNC-iPSC exhibited full pluripotency and differentiation potential, and retained a normal karyotype after reprogramming. This in vitro cellular model will be useful to study the molecular, genetic and functional aspects of LVNC.
- Generation and cardiac differentiation of a human induced pluripotent stem cell line UALGi002-A from a female patient with Left-Ventricular Noncompaction CardiomyopathyPublication . Calado, Sofia; Bento, Dina; Marques, Nuno; Bragança, JoséLeft Ventricular Noncompaction Cardiomyopathy (LVNC) is characterized by abnormal number and prominence of trabeculations of the left ventricle of the heart. Although LVNC has been associated with mutations in several genes encoding for transcriptional regulators, ion channels, sarcomeric and mitochondrial proteins, approximately 60% of LVNC patients do not present these genetic alterations. Here, we describe an induced pluripotent stem cell (hiPSC) line (UALGi002-A) originated from a LVNC female patient (LVNC-hiPSC) who does not present any previously known mutations associated to LVNC. The LVNC-hiPSC exhibited full pluripotency and differentiation potential and retained a normal karyotype after reprogramming. Moreover, the LVNC-hiPSC differentiated into contracting cardiomyocytes. This cellular model will be useful to study the molecular, genetic and functional aspects of LVNC in vitro.
- p.G360R is a pathogenic GLA gene mutation responsible for a classic phenotype of Fabry diseasePublication . Carvalho Silva, Daniela; Marques, Nuno; Azevedo, Olga; Miltenberger-Miltenyi, Gabriel; Bento, Dina; Guedes, Joao; Azevedo, Pedro; Bispo, Joao; Mota, Teresa; Fernandes, Raquel; Nzwalo, Hipólito; Cabrita, Ana; Ramos, André; de Jesus, IlidioThe authors report the case of a classic phenotype of Fabry disease in a 60-year-old male patient presenting with left ventricular hypertrophy and stroke. Genetic analysis revealed 2 GLA-gene variants, i.e., p.R356Q and p.G360R. This clinical case highlights that the finding of 2 or more GLA gene variants in a Fabry patient should lead to a careful evaluation in order to determine their exact role in the condition. This case also provides the first clinical evidence that the p.G360R mutation is pathogenic and responsible for a classic phenotype of Fabry disease. The clinical improvement following the initiation of enzyme replacement therapy reinforces the importance of Fabry disease awareness and diagnosis in patients exhibiting red flags, such as left ventricular hypertrophy and stroke.
- Specific therapy for transthyretin cardiac amyloidosis: a systematic literature review and evidence‐based recommendationsPublication . Marques, Nuno; Azevedo, Olga; Almeida, Ana Rita; Bento, Dina; Cruz, Inês; Correia, Emanuel; Lourenço, Carolina; Lopes, Luís RochaBackground The emergence of specific therapies for transthyretin cardiac amyloidosis (CA) warrants the need for a systematic review of the literature. Methods and Results A systematic review of the literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search was performed on MEDLINE, PubMed, and Embase databases on November 29, 2019. Studies were selected based on the following predefined eligibility criteria: English-language randomized controlled trials (RCTs), non-RCTs, or observational studies, which included adult patients with variant/wild-type transthyretin-CA, assessed specific therapies for transthyretin-CA, and reported cardiovascular outcomes. Relevant data were extracted to a predefined template. Quality assessment was based on National Institute for Health and Care Excellence recommendations (RCTs) or a checklist by Downs and Black (non-RCTs). From 1203 records, 24 publications were selected, describing 4 RCTs (6 publications) and 16 non-RCTs (18 publications). Tafamidis was shown to significantly improve all-cause mortality and cardiovascular hospitalizations and reduce worsening in 6-minute walk test, Kansas City Cardiomyopathy Questionnaire-Overall Summary score, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) in variant/wild-type transthyretin-CA. Patisiran showed promising results in a subgroup analysis of patients with variant transthyretin-CA, which have to be confirmed in RCTs. Inotersen showed conflicting results on cardiac imaging parameters. The one study on AG10 had only a 1-month duration and cardiovascular end points were exploratory and limited to cardiac biomarkers. Limited evidence from noncomparative single-arm small non-RCTs existed for diflunisal, epigallocatechin-3-gallate (green tea extract), and doxycycline+tauroursodeoxycholic acid/ursodeoxycholic acid. Conclusions This systematic review of the literature supports the use of tafamidis in wild-type and variant transthyretin-CA. Novel therapeutic targets including transthyretin gene silencers are currently under investigation.