Browsing by Subject "Cardiomyopathy"
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- PublicationRestrictedA Novel Founder Mutation in MYBPC3: Phenotypic Comparison With the Most Prevalent MYBPC3 Mutation in Spain.(Elsevier, 2016-10-28) Sabater Molina, María; Saura, Daniel; García Molina Sáez, Esperanza; González Carrillo, Josefa; Polo, Luis; Pérez Sánchez, Inmaculada; Olmo, María Carmen; Oliva Sandoval, María José; Barriales Villa, Roberto; Carbonell, Pablo; Pascual Figal, Domingo A.; Gimeno, Juan Ramón; Ciencias SociosanitariasIntroducción y objetivos: Las mutaciones en MYBPC3 son causa de miocardiopatía hipertrófica (MCH). A pesar de que la mayorı´a de ellas producen una proteína truncada, la gravedad del fenotipo es diversa. Se describe el fenotipo clínico de una nueva mutación en MYBPC3, p.Pro108Alafs*9, presente en 13 familias del sur de España, y se compara con la mutación de MYBPC3 con mayor prevalencia en dicha región (c.2308 + 1 G > A). Métodos: Se estudió a 107 familiares de 13 casos índice que tenían diagnóstico de MCH y portaban la mutación p.Pro108Alafs*9. Se realizó un anélisis del árbol genealógico, junto con una evaluación clínica y determinación del genotipo. Resultados: Se identificó en total a 54 portadores de la mutación p.Pro108Alafs*9, de los que 39 tenían MCH. Hubo 5 casos de muerte súbita en las 13 familias. La penetrancia de la enfermedad aumentaba a medida que se incrementaba la edad, y los pacientes con MCH fueron con más frecuencia varones, y estos contrajeron la enfermedad más precozmente que las mujeres. El fenotipo fue similar en la p.Pro108Alafs*9 y la c.2308 + 1 G > A, pero se observaron diferencias en varios factores de riesgo y en la supervivencia. Hubo tendencia a mayor masa ventricular izquierda en la p.Pro108Alafs*9 que en la c.2308 + 1G > A. La resonancia magnética cardiaca reveló una extensión y un patrón de fibrosis similares en ambas. Conclusiones: La mutación p.Pro108Alafs*9 se asoció a MCH, alta penetrancia y aparición de la enfermedad a mediana edad.
- PublicationOpen AccessAge-related changes of the ultrastructure in the cardiomyopathic hamster (UM-X7.1 Syrian hamster) parathyroid gland(Murcia : F. Hernández, 2004) Utsumi, M.; Moriguchi, K.; Takahashi, H.; Kinoshita, C.; Togari, A.; Mizutani, M.; Ohno, N.We qualitatively and quantitatively investigated parathyroid glands of the UM-X7.1 cardiomyopathic hamster at 1, 2, 6 and 12 months of age to compare them with those of the normal hamster. We found that at 1 month of age in the UM-X7.1 hamster, the Golgi apparatus, lipid droplets and secretory granules decreased. There were no significant differences between the UM-X7.1 hamster and the control hamster at 2 months of age. At 6 months of age, the Golgi apparatus, rER and the secretory granules significantly increased in the UM-X7.1 hamster. At 12 months of age, the Golgi apparatus and lysosomes increased, while the secretory granules decreased. Ultrastructurally, we consider that in the UM-X7.1 hamster, the synthesis and release of the parathyroid at 6 months of age may be activated by an excessive amount of circulating catecholamine, and the functional activity of the parathyroid glands at 12 months of age may be depressed by the increased plasma calcium level. These findings suggest that the activities of the synthesis and release of the parathyroid hormone were the highest at 6 months of age in the UM-X7.1 hamster.
- PublicationRestrictedCharacteristics of sudden death in inherited heart disease(Elsevier, 2009-09-17) Gimeno, Juan Ramón; Oliva, María José; Lacunza, Javier; García Alberola, Arcadio; Sabater Molina, María; Martínez Sánchez, Juan José; Saura, Daniel; Romero, Antonio; Valdés, Mariano; Ciencias SociosanitariasIntroduction and objectives Cardiomyopathy and channelopathy are major causes of sudden death (SD). The little information available on the context in which SD occurs has come from only a few referral centers. The objective was to investigate the circumstances surrounding SD in families with inherited heart disease.. Methods. The study included 152 SD patients (mean age, 43[19] years) from 103 families. The reasons for inclusion were resuscitated SD in 7%, recent SD in 8%, and a diagnosis of cardiomyopathy or channelopathy in a living relative in 72%. Also, 13% were athletes. Family trees were constructed and each death’s circumstances were recorded. Autopsy and medical records were reviewed. Results. Overall, 18% of SDs occurred during physical exercise, 32% during normal daily activities, and 37% during rest or sleep. There was a significant association between male sex and SD: 111 males (73.0%) versus 41 females (27.0%; P=.03). Exercise-related SD was associated with young age (P=.01). The percentage of SDs associated with exercise, stress, or normal daily activities was significantly greater with cardiomyopathy than channelopathy (61% vs 41%, P=.057). All athletes were male and the majority died during exercise (50% vs 11% of non-athletes; P=.0002). Patients with Brugada syndrome had the highest percentage of SDs during rest or sleep (ie, 47%). No clear trigger could be identified in 33%. Conclusions. SD was common in inherited heart disease, which accounted for a significant number of cases. Males clearly predominated over females (ratio, 3:1) among SD cases (irrespective of pathological type). Most SDs occurred during exercise or normal daily activities in cardiomyopathies and during rest or sleep in channelopathies. The percentage of exercise-related SDs (i.e. 18%) was higher than expected.
- PublicationOpen AccessGenetics of hypertrophic cardiomyopathy: A review of current state.(Wiley, 2017-03-21) Sabater Molina, María; Pérez Sánchez, Inmaculada; Gimeno, Juan Ramón; Hernández del Rincón, Juan Pedro; Ciencias SociosanitariasHypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease. HCM is a highly complex and heterogeneous disease regarding not only the number of associated mutations but also the severity of phenotype, symptom burden, and the risk of complications, such as heart failure and sudden death. The penetrance is incomplete and it is age and gender dependent. It is accepted as a disease of the sarcomere. Sixty percent of HCM cases carry mutations in 1 of 8 sarcomere protein genes, mainly non-sense MYBPC3 and missense MYH7 variants. Young patients with severe phenotype and other clinical features are included in proposed scores for prediction of high positive genetic result. The number of genes reported as disease-causing has increased in the last few years, in some cases without robust evidence. Currently available in silico tools are not always useful for differentiation between benign and deleterious variants. There is enough information on genotypephenotype correlations to start understanding the mechanisms of the disease. Genetic and environmental modifiers have been explored with some interesting insights from miRNA studies with potential as biomarkers and therapeutic agents. There is an additional value of genetic testing in HCM for prognosis. Knowledge about genetics and functional studies are the basis of near future therapies.
- PublicationOpen AccessMicrovascular pathology in Friedreich cardiomyopathy.(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Koeppen, Arnulf H.; Qian, Jiang; Travis, Alicia M.; Sossei, Alyssa B.; Feustel, Paul J.; Mazurkiewic, Joseph E.Heart disease is an integral part of Friedreich ataxia (FA). In addition to cardiomyocyte hypertrophy, fiber necrosis, and inflammatory infiltration, sections show fibrosis and disorganized capillaries. We examined the left ventricular wall (LVW) of 41 homozygous and 2 compound heterozygous FA patients aged 10-87 and 21 controls aged 2-69. Immunohistochemistry with an antibody to CD34 allowed quantitative counts of capillary profiles for a comparison with cardiomyocyte counts in the same field. Capillary counts (mean±standard deviation [SD]) in normal controls were 1926±341/mm2, while mean cardiomyocyte counts were 2003±686/mm 2 . The median ratio of capillaries to cardiomyocytes was 1.0 (interquartile range [IQR]: 0.9- 1.2). In FA, the number of cardiomyocytes/mm 2 was significantly less (704±361; p<0.001), and the median ratio of capillaries to heart fibers was 2.0 (IQR:1.4-2.4). There was a significant correlation of the expanded guanine-adenine-adenine trinucleotides (shorter allele, GAA1) with a younger age of onset, shorter disease duration, and lower cardiomyocyte counts. The ratio of capillaries to heart fibers was higher in patients with long GAA1 repeat expansions (e.g., 3.31 in GAA1 of 1200). Double-label immunofluorescence for CD34 and the fibroblast marker S100A4 revealed co-expression in endothelial cells, supporting endothelial-to- mesenchymal transition in the pathogenesis of cardiac fibrosis in FA. We propose that the pathogenesis of FA heart disease includes primary fibrosis.
- PublicationRestrictedThe EP300/TP53 pathway, a suppressor of the Hippo and canonical WNT pathways, is activated in human hearts with arrhythmogenic cardiomyopathy in the absence of overt heart failure(Oxford University Press [University Publisher], 2021-06-14) Rouhi, Leila; Fan, Siyang; Cheedipudi, Sirisha M.; Braza Boils, Aitana; Sabater Molina, María; Yao, Yan; Robertson, Matthew J.; Coarfa, Cristian; Gimeno, Juan Ramón; Molina, Pilar; Gurha, Priyatansh; Zorio, Esther; Marian, Ali J.; Ciencias SociosanitariasAims Arrhythmogenic cardiomyopathy (ACM) is a primary myocardial disease that typically manifests with cardiacarrhythmias, progressive heart failure, and sudden cardiac death (SCD). ACM is mainly caused by mutations ingenes encoding desmosome proteins. Desmosomes are cell–cell adhesion structures and hubs for mechanosensing and mechanotransduction. The objective was to identify the dysregulated molecular and biological pathways in human ACM in the absence of overt heart failure. Methods and results Transcriptomes in the right ventricular endomyocardial biopsy samples from three independent individuals carrying truncating mutations in the DSP gene and five control samples were analysed by RNA-Seq (discovery group). These cases presented with cardiac arrhythmias and had a normal right ventricular function. The RNA-Seq analysis identified 5000 differentially expressed genes (DEGs), which predicted suppression of the Hippo and canonical WNT pathways, among others. Dysregulated genes and pathways, identified by RNA-Seq, were tested for validation in the right and left ventricular tissues from five independent autopsy-confirmed ACM cases with defined mutations (validation group), who were victims of SCD and had no history of heart failure. Protein levels and nuclear localization of the cWNT and Hippo pathway transcriptional regulators were reduced in the right and left ventricular validation samples. In contrast, levels of acetyltransferase EP300, known to suppress the Hippo and canonical WNT pathways, were increased and its bona fide target TP53 was acetylated. RNA-Seq data identified apical junction, reflective of cell–cell attachment, as the most disrupted biological pathway, which were corroborated by disrupted desmosomes and intermediate filament structures. Moreover, the DEGs also predicted dysregulation of over a dozen canonical signal transduction pathways, including the Tec kinase and integrin signalling pathways. The changes were associated with increased apoptosis and fibro-adipogenesis in the ACM hearts.
- PublicationOpen AccessTrabeculated myocardium in hypertrophic cardiomyopathy: clinical consequences(MDPI, 2020-09-27) Casanova, José David; González Carrillo, Josefa; Martín Jiménez, Jesús; Cuenca Muñoz, Antonio Javier; Muñoz Esparza, Carmen; Siguero Alvárez, Marcos; Escribá, Rubén; Burillo Milla , Esther; Pompa, José Luis de la; Raya, Ángel; Gimeno, Juan Ramón; Sabater Molina, María; Bernabé García, Gregorio; Ingeniería y Tecnología de ComputadoresHypertrophic cardiomyopathy (HCM) is often accompanied by increased trabeculated myocardium (TM)—which clinical relevance is unknown. We aim to measure the left ventricular (LV) mass and proportion of trabeculation in an HCM population and to analyze its clinical implication. Methods and Results: We evaluated 211 patients with HCM (mean age 47.8 ± 16.3 years, 73.0% males) with cardiac magnetic resonance (CMR) studies. LV trabecular and compacted mass were measured using dedicated software for automatic delineation of borders. Mean compacted myocardium (CM) was 160.0 ± 62.0 g and trabecular myocardium (TM) 55.5 ± 18.7 g. The percentage of trabeculated myocardium (TM%) was 26.7% ± 6.4%. Females had significantly increased TM% compared to males (29.7 ± 7.2 vs. 25.6 ± 5.8, p < 0.0001). Patients with LVEF < 50% had significantly higher values of TM% (30.2% ± 6.0% vs. 26.6% ± 6.4%, p = 0.02). Multivariable analysis showed that female gender and neutral pattern of hypertrophy were directly associated with TM%, while dynamic obstruction, maximal wall thickness and LVEF% were inversely associated with TM%. There was no association between TM% with arterial hypertension, physical activity, or symptoms. Atrial fibrillation and severity of hypertrophy were the only variables associated with cardiovascular death. Multivariable analysis failed to demonstrate any correlation between TM% and arrhythmias. Conclusions: Approximately 25% of myocardium appears noncompacted and can automatically be measured in HCM series. Proportion of non-compacted myocardium is increased in female, non-obstructives, and in those with lower contractility. The amount of trabeculation might help to identify HCM patients prone to systolic heart failure.
- PublicationRestrictedUnclassifiable arrhythmic cardiomyopathy associated with Emery–Dreifuss caused by a mutation in FHL1(Wiley, 2016-02-09) San Román, I.; Martínez, F.; Albert, L.; Polo, L.; Guardiola, J.; García-Molina, E.; Muñoz-Esparza, C.; López-Ayala, J.M.; Sabater Molina, María; Gimeno Blanes, Juan Ramón; Medicina; Facultad de MedicinaEmery–Dreifuss muscular dystrophy (EDMD) is a heterogeneous genetic disorder characterized by peripheral muscular weakness often associated with dilated cardiomyopathy. We characterize clinically a large family with a mutation in FHL1 gene (p.Cys255Ser). Penetrance was 44%, 100% for males and 18% for females. The heart was the main organ involved. Affected adult males had mild hypertrophy, systolic dysfunction and restriction with non-dilated ventricles. Carriers had significant QTc prolongation. The proband presented with resuscitated cardiac arrest. There were two transplants. Pathological study of explanted heart showed fibrofatty replacement and scarring consistent with arrhythmogenic cardiomyopathy and prominent left ventricular trabeculations. Myopathic involvement was evident in all males. Females had no significant neuromuscular disease. Mutations in FHL1 cause unclassifiable cardiomyopathy with coexisting EDMD. Prognosis is poor and systolic impairment and arrhythmias are frequent. Thrombopenia and raised creatine phosphokinase should raise suspicion of an FHL-1 disorder in X-linked cardiomyopathy.