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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; BraganƧa, JosƩLeft 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; BraganƧa, JosƩLeft 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.
- Women vs. men in takotsubo cardiomyopathyPublication . Margarida Oliveira, M.; Bento, Dina; Santos, R.; Vieira, M. J.; Antunes, H.; Reis, L.; Ruivo, C.; Faria, R.; Marreiros, Ana; Almeida, A. R.Takotsubo cardiomyopathy (TCM) is a cardiac syndrome characterized by transient left ventricular dysfunction in the absence of coronary artery disease. It usually affects postmenopausal women but it can also affect men. Differences between genders regarding TCM are still not clearly defned.
- Sindrome coronĆ”ria aguda sem supradesnivelamento do segmento ST ā abordagem prĆ© hospitalarPublication . Fernandes, Raquel Menezes; Bento, Dina; Mimoso, Jorge; Jesus, IlĆdioO eletrocardiograma (ECG) de 12 derivaƧƵes Ć© o exame complementar de diagnĆ³stico inicial de maior relevĆ¢ncia num doente que se apresenta com dor torĆ”cica aguda e persistente. Se se documentar elevaĆ§Ć£o persistente do segmento-ST, cumprindo critĆ©rios diagnĆ³sticos de Enfarte Agudo do MiocĆ”rdio com supradesnivelamento do segmento-ST, estĆ” indicada a terapĆŖutica de reperfusĆ£o imediata. JĆ” o diagnĆ³stico de SĆndrome coronĆ”ria aguda sem supradesnivelamento do segmento-ST (SCA-SST) requer um elevado nĆvel de suspeiĆ§Ć£o, com base na apresentaĆ§Ć£o clĆnica do doente, na presenƧa de fatores de risco e de alteraƧƵes eletrocardiogrĆ”ficas. Se suspeita clĆnica de SCA-SST, deverĆ” administrar-se 300 mg de Ć”cido acetilsalicĆlico, iniciar terapĆŖutica antianginosa e transportar o doente monitorizado atĆ© ao ServiƧo de UrgĆŖncia para ser submetido a avaliaĆ§Ć£o adicional. NĆ£o estĆ” recomendada a administraĆ§Ć£o de inibidor P2Y12 ou de anticoagulaĆ§Ć£o em contexto prĆ©-hospitalar, devendo ser reservados para o momento do diagnĆ³stico definitivo de SCA-SST. Caso o doente mantenha dor torĆ”cica recorrente ou sinais de instabilidade clĆnica apesar da terapĆŖutica instituĆda, deverĆ” repetir-se ECG e, na presenƧa de alteraƧƵes dinĆ¢micas do segmento-ST, contactar-se o ServiƧo de Cardiologia da Ć”rea para internamento e eventual realizaĆ§Ć£o de coronariografia emergente.
- 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, HipĆ³lito; Cabrita, Ana; Ramos, AndrĆ©; 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.
- CRUSADE: Is it still a good score to predict bleeding inacute coronary syndrome?Publication . Bento, D.; Marques, N.; Guedes, J.; Azevedo, Pedro; Amado, JosƩ; Santos, W.; Bispo. J.; Mimoso, J.; Jesus, I.; Silva, D.Introduction: Major bleeding is a serious complication of acute coronary syndrome (ACS) andis associated with a worse prognosis. The CRUSADE bleeding score is used to stratify the risk ofmajor bleeding in ACS.Objective: To assess the predictive ability of the CRUSADE score in a contemporary ACS popu-lation.Methods: In a single-center retrospective study of 2818 patients admitted with ACS, the CRU-SADE score was calculated for each patient and its discrimination and goodness of fit wereassessed by the area under the receiver operating characteristic curve (AUC) and by the Hosmer-Lemeshow test, respectively. Predictors of in-hospital major bleeding (IHMB) were determined.Results: The IHMB rate was 1.8%, significantly lower than predicted by the CRUSADE score (7.1%,p<0.001). The incidence of IHMB was 0.5% in the very low risk category (rate predicted by thescore 3.1%), 1.5% in the low risk category (5.5%), 1.6% in the moderate risk category (8.6%),5.5% in the high risk category (11.9%), and 4.4% in the very high risk category (19.5%). Thepredictive ability of the CRUSADE score for IHMB was only moderate (AUC 0.73).The in-hospital mortality rate was 4.0%. Advanced age (p=0.027), femoral vascular access(p=0.004), higher heart rate (p=0.047) and ticagrelor use (p=0.027) were independent predictorsof IHMB.Conclusions: The CRUSADE score, although presenting some discriminatory power, significantlyoverestimated the IHMB rate, especially in patients at higher risk. These results questionwhether the CRUSADE score should continue to be used in the stratification of ACS.
- Screening of Lysosomal acid lipase deficiency in patients with severe dyslipidemia and premature coronaryheart diseasePublication . Azevedo, O.; Marques, N.; Antunes, H.; Azevedo, Pedro; Oliveira, M.; Bento, D.; Guedes, J.; Marmelo, B.; Faria, R.; Correia, E.Objectives: To determine the prevalence of Lysosomal Acid Lipase (LAL) deficiency in patients with severe dyslipidemia and premature coronary heart disease.
- Clinical features and natural history of PRKAG2 Variant Cardiac GlycogenosisPublication . Lopez-Sainz, Angela; Dominguez, Fernando; Rocha Lopes, Luis; Pablo Ochoa, Juan; Barriales-Villa, Roberto; Climent, Vicente; Linschoten, Marijke; Tiron, Coloma; Chiriatti, Chiara; Marques, Nuno; Rasmussen, Torsten B.; Angeles Espinosa, Maria; Beinart, Roy; Quarta, Giovanni; Cesar, Sergi; Field, Ella; Garcia-Pinilla, Jose M.; Bilinska, Zofia; Muir, Alison R.; Roberts, Angharad M.; Santas, Enrique; Zorio, Esther; Luisa Pena-Pena, Maria; Navarro, Marina; Fernandez, Adrian; Palomino-Doza, Julian; Azevedo, Olga; Lorenzini, Massimiliano; Garcia-Alvarez, Maria I.; Bento, Dina; Jensen, Morten K.; Mendez, Irene; Pezzoli, Laura; Sarquella-Brugada, Georgia; Campuzano, Oscar; Gonzalez-Lopez, Esther; Mogensen, Jens; Pablo Kaski, Juan; Arad, Michael; Brugada, Ramon; Asselbergs, Folkert W.; Monserrat, Lorenzo; Olivotto, Iacopo; Elliott, Perry M.; Garcia-Pavia, PabloBACKGROUND PRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood. OBJECTIVES The aim of this study was to describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort. METHODS Clinical, electrocardiographic, and echocardiographic data from 90 subjects with PRKAG2 variants (53% men; median age 33 years; interquartile range [IQR]: 15 to 50 years) recruited from 27 centers were retrospectively studied. RESULTS At first evaluation, 93% of patients were in New York Heart Association functional class I or II. Maximum left ventricular wall thickness was 18 +/- 8 mm, and left ventricular ejection fraction was 61 +/- 12%. Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline. Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation; 17 (19%) had pacemakers (median age at implantation 36 years; IQR: 27 to 46 years), and 16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years). After a median follow-up period of 6 years (IQR: 2.3 to 13.9 years), 71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers (median age at implantation 37 years; IQR: 29 to 48 years), 14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died. CONCLUSIONS PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life-threatening arrhythmias. Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age. (c) 2020 the American College of Cardiology Foundation. Published by Elsevier. All rights reserved.
- Specific therapy for transthyretin cardiac amyloidosis: a systematic literature review and evidenceābased recommendationsPublication . Marques, Nuno; Azevedo, Olga; Almeida, Ana Rita; Bento, Dina; Cruz, InĆŖs; Correia, Emanuel; LourenƧo, Carolina; Lopes, LuĆs 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.