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INTRODUCTION: Repolarization dispersion in the right ventricular outflow tract (RVOT) contributes to the type-1 electrocardiographic (ECG) phenotype of Brugada syndrome (BrS), while data on the significance and feasibility of mapping repolarization dispersion in BrS patients are scarce. Moreover, the role of endocardial repolarization dispersion in BrS is poorly investigated. We aimed to assess endocardial repolarization patterns through an automated calculation of activation recovery interval (ARI) estimated on unipolar electrograms (UEGs) in spontaneous type-1 BrS patients and controls; we also investigated the relation between ARI and right ventricle activation time (RVAT), and T-wave peak-to-end interval (Tpe) in BrS patients. METHODS: Patients underwent endocardial high-density electroanatomical mapping (HDEAM); BrS showing an overt type-1 ECG were defined as OType1, while those without (latent type-1 ECG and LType1) received ajmaline infusion. BrS patients only underwent programmed ventricular stimulation (PVS). Data were elaborated to obtain ARI corrected with the Bazett formula (ARIc), while RVAT was derived from activation maps. RESULTS: 39 BrS subjects (24 OType1 and 15 LTtype1) and 4 controls were enrolled. OType1 and post-ajmaline LType1 showed longer mean ARIc than controls (306 ± 27.3 ms and 333.3 ± 16.3 ms vs. 281.7 ± 10.3 ms, p = .05 and p < .001, respectively). Ajmaline induced a significant prolongation of ARIc compared to pre-ajmaline LTtype1 (333.3 ± 16.3 vs. 303.4 ± 20.7 ms, p < .001) and OType1 (306 ± 27.3 ms, p < .001). In patients with type-1 ECG (OTtype1 and post-ajmaline LType1) ARIc correlated with RVAT (r = .34, p = .04) and Tpec (r = .60, p < .001), especially in OType1 subjects (r = .55, p = .008 and r = .65 p < .001, respectively). CONCLUSION: ARIc mapping demonstrates increased endocardial repolarization dispersion in RVOT in BrS. Endocardial ARIc positively correlates with RVAT and Tpec, especially in OType1.
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Potenciais de Ação , Algoritmos , Síndrome de Brugada , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Endocárdio , Frequência Cardíaca , Valor Preditivo dos Testes , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Síndrome de Brugada/fisiopatologia , Síndrome de Brugada/diagnóstico , Endocárdio/fisiopatologia , Adulto , Fatores de Tempo , Estudos de Casos e Controles , Ajmalina/administração & dosagem , Automação , Função Ventricular Direita , Estimulação Cardíaca Artificial , Idoso , Processamento de Sinais Assistido por ComputadorRESUMO
BACKGROUND: The endothelial nitric oxide synthase (eNOS) gene deficiency is known to cause impaired coronary vasodilating capability in animal models. In the general clinical population, the eNOS gene polymorphisms, able to affect eNOS activity, were associated with cardiometabolic risk features and prevalence of coronary artery disease (CAD). AIM: To investigate the association of eNOS Glu298Asp gene polymorphism, cardiometabolic profile, obstructive CAD and inducible myocardial ischemia in patients with suspected stable CAD. METHODS: A total of 506 patients (314 males; mean age 62 ± 9 years) referred for suspected CAD was enrolled. Among these, 325 patients underwent stress ECG or cardiac imaging to assess the presence of inducible myocardial ischemia and 436 patients underwent non-invasive computerized tomography or invasive coronary angiography to assess the presence of obstructive CAD. Clinical characteristics and blood samples were collected for each patient. RESULTS: In the whole population, 49.6% of patients were homozygous for the Glu298 genotype (Glu/Glu), 40.9% heterozygotes (Glu/Asp) and 9.5% homozygous for the 298Asp genotype (Asp/Asp). Obstructive CAD was documented in 178/436 (40.8%) patients undergoing coronary angiography while myocardial ischemia in 160/325 (49.2%) patients undergoing stress testing. Patients with eNOS Asp genotype (Glu/Asp + Asp/Asp) had no significant differences in clinical risk factors and in circulating markers. Independent predictors of obstructive CAD were age, gender, obesity, and low HDL-C. Independent predictors of myocardial ischemia were gender, obesity, low HDL-C and Asp genotype. In the subpopulation in which both stress tests and coronary angiography were performed, the Asp genotype remained associated with increased myocardial ischemia risk after adjustment for obstructive CAD. CONCLUSION: In this population, low-HDL cholesterol was the only cardiometabolic risk determinant of obstructive CAD. The eNOS Glu298Asp gene polymorphism was significantly associated with inducible myocardial ischemia independently of other risk factors and presence of obstructive CAD.
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Doença da Artéria Coronariana , Isquemia Miocárdica , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Artérias , HDL-Colesterol , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/genética , Genótipo , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/genética , Óxido Nítrico Sintase Tipo III/genética , Obesidade , Polimorfismo Genético , Fatores de RiscoRESUMO
We describe a unique case of skeletal and extraskeletal angiomatosis complicated by Kasabach-Merritt syndrome. The patient was a 3-year-old boy, who presented with involvement of both femurs and left tibia, as well as with soft tissue lesions of the left thigh. At birth, multiple hemangiomas of the soft tissues of the frontal and parietal scalp had been identified, together with a space-occupying lesion of the lung. Histologically, the skeletal and soft tissue lesions consisted of a proliferation of thin-walled, dilated blood vessels, with an endothelial lining devoid of atypia and exhibiting immunoreactivity for CD31 and CD34, while podoplanin and GLUT1 were negative. Whole exome sequencing performed on samples from the lesion of the femur, the tibia and the skin of the thigh, showed a GNAQ (c.286A>T:p.T96S) variant in all specimens, that was confirmed with digital droplet PCR. This case expands the clinical and pathologic spectrum of vascular proliferations showing similar molecular biology, characterized by GNAQ, GNA11 or GNA14 mutations.
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Angiomatose/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Síndrome de Kasabach-Merritt/genética , Angiomatose/patologia , Osso e Ossos/patologia , Pré-Escolar , Tecido Conjuntivo/patologia , Humanos , Síndrome de Kasabach-Merritt/patologia , Masculino , MutaçãoRESUMO
The mechanisms underlying motoneuron degeneration in amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder that affects the motor system with progressive paralysis, are complex and not yet fully understood. It is generally agreed that ALS is a multifactorial and multisystem disease due not only possibly to genetic causes but also to other factors like oxidative stress, mitochondrial dysfunction, protein aggregation, RNA dysmetabolism, autophagy, and excitotoxicity glutamate-mediate. Altered oxidative stress biomarker profile has been repeatedly reported in ALS patients, which may suggest that abnormal free radical production is relevant in the ALS pathogenesis. This review aims to investigate how oxidative stress can affect other proposed mechanisms of neurodegeneration in ALS.
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Esclerose Lateral Amiotrófica/fisiopatologia , Degeneração Neural/fisiopatologia , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologia , HumanosRESUMO
BACKGROUND: An intense fibrotic response after myocardial infarction (MI) may lead to scar expansion and left ventricular (LV) remodeling. We investigated the effects of the antifibrotic drug pirfenidone in this setting. METHODS: Male Wistar rats were randomized to: sham procedure (nâ=â13), reperfused MI-induced by ligating the left anterior descending artery (LAD) for 45âmin (nâ=â17), reperfused MI plus standard therapy (aspirin, angiotensin-converting enzyme inhibitor, beta blocker, and mineralocorticoid receptor antagonist) (nâ=â17), reperfused MI plus pirfenidone alone (nâ=â17), or reperfused MI plus standard therapy and pirfenidone (nâ=â17). Rats surviving MI induction underwent cardiac magnetic resonance scans after 72âh and 30âdays from MI, and were sacrificed on day 31. RESULTS: Rats completing the whole protocol numbered 11 in the sham group, 9 in the untreated MI group, 8 in the standard treatment group, 9 in the pirfenidone alone group, and 9 in the standard treatment plus pirfenidone group. No significant differences emerged between LV volumes, ejection fraction or mass at 30âdays or the differences from 72âh to 30âdays. Small, nonsignificant differences between rats on pirfenidone alone vs. those on standard therapy emerged. The total extent of LV fibrosis, quantified as area and percentage of the tissue sample, did not differ significantly between rats on pirfenidone alone vs. those on standard therapy alone. CONCLUSION: Pirfenidone does not have additional effects on LV remodeling or fibrosis compared with standard therapy, but its effects are similar to standard therapy alone.
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Cicatriz , Infarto do Miocárdio , Animais , Masculino , Ratos , Cicatriz/patologia , Fibrose , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/tratamento farmacológico , Ratos Wistar , Remodelação Ventricular , Distribuição Aleatória , Modelos Animais de DoençasRESUMO
Glioblastoma is one of the most common and lethal primary neoplasms of the brain. Patient survival has not improved significantly over the past three decades and the patient median survival is just over one year. Tumor heterogeneity is thought to be a major determinant of therapeutic failure and a major reason for poor overall survival. This work aims to comprehensively define intra- and inter-tumor heterogeneity by mapping the genomic and mutational landscape of multiple areas of three primary IDH wild-type (IDH-WT) glioblastomas. Using whole exome sequencing, we explored how copy number variation, chromosomal and single loci amplifications/deletions, and mutational burden are spatially distributed across nine different tumor regions. The results show that all tumors exhibit a different signature despite the same diagnosis. Above all, a high inter-tumor heterogeneity emerges. The evolutionary dynamics of all identified mutations within each region underline the questionable value of a single biopsy and thus the therapeutic approach for the patient. Multiregional collection and subsequent sequencing are essential to try to address the clinical challenge of precision medicine. Especially in glioblastoma, this approach could provide powerful support to pathologists and oncologists in evaluating the diagnosis and defining the best treatment option.
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Molecular autopsy is the process of investigating sudden death through genetic analysis. It is particularly useful in cases where traditional autopsy is negative or only shows non-diagnostic features, i.e., in sudden unexplained deaths (SUDs), which are often due to an underlying inherited arrhythmogenic cardiac disease. The final goal of molecular autopsy in SUD cases is to aid medico-legal inquiries and to guide cascade genetic screening of the victim's relatives. Early attempts of molecular autopsy relied on Sanger sequencing, which, despite being accurate and easy to use, has a low throughput and can only be employed to analyse a small panel of genes. Conversely, the recent adoption of next-generation sequencing (NGS) technologies has allowed exome/genome wide examination, providing an increase in detection of pathogenic variants and the discovery of newer genotype-phenotype associations. NGS has nonetheless brought new challenges to molecular autopsy, especially regarding the clinical interpretation of the large number of variants of unknown significance detected in each individual.
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BACKGROUND: Sudden unexplained death (SUD) refers to cases of sudden death where autopsy fails to identify any cardiac or extracardiac underlying cause. Guideline-directed standard genetic testing identifies a disease-causing mutation in less than one-third of cases of SUD. Conversely, whole exome sequencing (WES) may provide the key to solve most cases of SUD even after several years from the subject's death. METHODS: We report on a case of sudden unexpected death of a 37-year-old male, with inconclusive autopsy conducted 14 years ago. A recent reevaluation through WES was performed on DNA extracted from left ventricular samples. A multiple step process including several "in silico" tools was applied to identify potentially pathogenic variants. Data analysis was based on a 562 gene panel, including 234 candidate genes associated with sudden cardiac death or heart diseases, with the addition of 328 genes highly expressed in the heart. WebGestalt algorithms were used for association enrichment analysis of all genes with detected putative pathogenic variants. RESULTS: WES analysis identified four potentially pathogenic variants: RYR2:c.12168G>T, TTN:c.11821C>T (rs397517804), MYBPC3:c.1255C>T (rs368770848), and ACADVL:c.848T>C (rs113994167). WebGestalt algorithms indicated that their combination holds an unfavorable arrhythmic susceptibility which conceivably caused the occurrence of the events leading to our subject's sudden death. CONCLUSION: Associating WES technique with online prediction algorithms may allow the recognition of genetic mutations potentially responsible for otherwise unexplained deaths.
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Morte Súbita Cardíaca/etiologia , Sequenciamento do Exoma/métodos , Testes Genéticos/métodos , Mutação , Acil-CoA Desidrogenase de Cadeia Longa/genética , Adulto , Proteínas de Transporte/genética , Biologia Computacional/métodos , Conectina/genética , Frequência Cardíaca/genética , Humanos , Masculino , Canal de Liberação de Cálcio do Receptor de Rianodina/genéticaRESUMO
Myocardial infarction with nonobstructed coronary arteries (MINOCA) can be triggered by intense emotions. We report 5 cases of emotional stress-related death where forensic examination attributed myocardial infarction to a coronary spasm, with the ultimate cause of death being arrhythmias in 4 cases and cardiac rupture in the fifth. (Level of Difficulty: Beginner.).