Isabel Rodríguez

Mutaciones en el gen de la cadena pesada de la betamiosina en pacientes con miocardiopatía hipertrófica

Introduction and objectives. To determine the frequency of mutations in the beta-myosin heavy-chain gene (MYH7) in a cohort of patients with hypertrophic cardiomyopathy (HCM) and their families, and to investigate correlations between genotype and phenotype. Methods. Single-strand conformation polymorphism analysis and sequencing of fragments with abnormal MYH7 gene mobility were carried out in 128 consecutive index patients with HCM. The phenotypes of patients with and without mutations were compared and the phenotypes of identified families were recorded. Results. A total of 11 mutations were found in 13 families (10%); 7/11 had been previously described. The I736T mutation was found in 3 families and the A797T in 2. One patient had 2 mutations (i.e., I736T and R787H). Mutations were more frequent in patients with a family history of sudden death (31%) and in those with severe hypertrophy (39% had a thickness ≥30 mm). Mutations were found in 29 of 42 members of the 13 families, including 6 family members (20%) who were healthy carriers and aged ≤36 years. Sudden death had occurred in 8 members of 4 families: four in 2 families with the I736T mutation, 1 in a family with A797T, 1 in a family with R870H, and 2 in a family with A901P. Conclusions. MYH7 mutations were present in 10% of our families. Mutations were more frequent in patients with a family history of sudden death and in those with severe hypertrophy. Most mutations had been described previously. Some appeared in several families. For some mutations, the correlation between genotype and phenotype was stable, while for others, there were marked differences between the phenotypes of the index

Mitochondrial DNA and TFAM gene variation in early-onset myocardial infarction: Evidence for an association to haplogroup H

The main objective of this research was to define the association between common mitochondrial DNA (mtDNA) polymorphisms and mitochondrial transcription A gene (TFAM) variants and myocardial infarction (MI) in patients with atherosclerotic diseased vessels. Ten mitochondrial polymorphisms that defined the nine common European haplogroups were genotyped in 500 male patients with early onset MI (<55 years) and at least one atherosclerotic coronary vessel (angiographically confirmed), and 500 healthy controls. In addition, we searched for DNA variants in the coding region of the TFAM gene and compared patients and controls for the allele and genotype frequencies. Early onset MI was strongly associated with male gender and tobacco smoking in our population. MtDNA haplogroup H (defined by allele 7028 °C) was significantly more frequent in a first group of patients (n = 250) compared to controls (n = 300), and the association was confirmed in a second group of only smokers (250 patients and 200 controls). For total patients and controls, we obtained a p = 0.002 (OR = 1.50; 95% CI = 1.17-1.92) for H vs. the other haplogroups. We found four common TFAM polymorphisms, with allele/genotype frequencies that did not differ between patients and controls. In conclusion, mitochondrial haplogroup H was associated with early onset MI in male smokers. Our work supported a role for the mtDNA variation in the risk for atherosclerosis and ischemic associated events, likely due to differences in mitochondrial function and reactive oxygen production between the different haplogroups.

Gremlin Activates the Smad Pathway Linked to Epithelial Mesenchymal Transdifferentiation in Cultured Tubular Epithelial Cells

Gremlin is a developmental gene upregulated in human chronic kidney disease and in renal cells in response to transforming growth factor-β (TGF-β). Epithelial mesenchymal transition (EMT) is one process involved in renal fibrosis. In tubular epithelial cells we have recently described that Gremlin induces EMT and acts as a downstream TGF-β mediator. Our aim was to investigate whether Gremlin participates in EMT by the regulation of the Smad pathway. Stimulation of human tubular epithelial cells (HK2) with Gremlin caused an early activation of the Smad signaling pathway (Smad 2/3 phosphorylation, nuclear translocation, and Smad-dependent gene transcription). The blockade of TGF-β, by a neutralizing antibody against active TGF-β, did not modify Gremlin-induced early Smad activation. These data show that Gremlin directly, by a TGF-β independent process, activates the Smad pathway. In tubular epithelial cells long-term incubation with Gremlin increased TGF-β production and caused a sustained Smad activation and a phenotype conversion into myofibroblasts-like cells. Smad 7 overexpression, which blocks Smad 2/3 activation, diminished EMT changes observed in Gremlin-transfected tubuloepithelial cells. TGF-β neutralization also diminished Gremlin-induced EMT changes. In conclusion, we propose that Gremlin could participate in renal fibrosis by inducing EMT in tubular epithelial cells through activation of Smad pathway and induction of TGF-β.

Regulation of miR-29b and miR-30c by vitamin D receptor activators contributes to attenuate uraemia-induced cardiac fibrosis

Background Uraemic cardiomyopathy, a process mainly associated with increased myocardial fibrosis, is the leading cause of death in chronic kidney disease patients and can be prevented by vitamin D receptor activators (VDRAs). Since some microRNAs (miRNAs) have emerged as regulators of the fibrotic process, we aimed to analyse the role of specific miRNAs in VDRA prevention of myocardial fibrosis as well as their potential use as biomarkers. Methods Wistar rats were nephrectomized and treated intraperitoneally with equivalent doses of two VDRAs: calcitriol and paricalcitol. Biochemical parameters, cardiac fibrosis, miRNA (miR-29b, miR-30c and miR-133b) levels in the heart and serum and expression of their target genes collagen I (COL1A1), matrix metalloproteinase 2 (MMP-2) and connective tissue growth factor (CTGF) in the heart were evaluated. Results Both VDRAs attenuated cardiac fibrosis, achieving a statistically significant difference in the paricalcitol-treated group. Increases in RNA and protein levels of COL1A1, MMP-2 and CTGF and reduced expression of miR-29b and miR-30c, known regulators of these pro-fibrotic genes, were observed in the heart of chronic renal failure (CRF) rats and were attenuated by both VDRAs. In serum, significant increases in miR-29b, miR-30c and miR-133b levels were observed in CRF rats, which were prevented by VDRA use. Moreover, vitamin D response elements were identified in the three miRNA promoters. Conclusions VDRAs, particularly paricalcitol, attenuated cardiac fibrosis acting on COL1A1, MMP-2 and CTGF expression, partly through regulation of miR-29b and miR-30c. These miRNAs and miR-133b could be useful serum biomarkers for cardiac fibrosis and also potential new therapeutic targets.

TGFBR2 Gene Mutational Spectrum in Aortic Pathology

We have read with great interest the excellent paper recently published in the Journal by Siu and Silversides about bicuspid aortic valves ([1][1]). As mentioned, bicuspid aortic valve (BAV) is a congenital anomaly of great importance, not only because of its prevalence (affecting 0.5% to 2% of the

Bicuspid aortic valve syndrome: a multidisciplinary approach for a complex entity

Bicuspid aortic valve (BAV) or bicuspid aortopathy is the most common congenital heart disease. It can be clinically silent and it is often identified as an incidental finding in otherwise healthy, asymptomatic patients. However, it can be dysfunctioning at birth, even requiring neonatal intervention, or, in time, lead to aortic stenosis, aortic insufficiency, and endocarditis, and also be associated with aortic aneurysm and aortic dissection. Given its prevalence and significant complications, it is estimated that BAV is responsible for more deaths and morbidity than the combined effects of all the other congenital heart defects. Pathology of BAV is still not well known and many questions are unresolved. In this manuscript we review some aspects on bicuspid aortopathy, a heterogeneous and frequent disease in which like some authors have previously described, complex gene environment are present. Further investigations and, what is more, multidisciplinary teams are needed to improve our knowledge on this really fascinating disease.

Nonsyndromic thoracic aortic aneurysm and dissection: Finally answers.

a Area del Corazón del Hospital Universitario Central de Asturias, Avda Roma s/n, Oviedo, Spain b Bone andMineral ResearchUnit, IRSIN, Hospital Universitario Central de Asturias, REDinREN from ISCIII, Area del CorazónHospital Universitario Central de Asturias, AvdaRoma s/n, Oviedo, Spain c Cardiac Surgery, Hospital Universitario Central de Asturias, Area del Corazón Hospital Universitario Central de Asturias, Avda Roma s/n, Oviedo, Spain

Bicuspid Aortic Valve Aortopathy Syndrome: A Potentially Familiar Disease

We read with great interest the editorial by Sorrell et al on bicuspid aortic valves and aortic disorders, which was recently published in the Journal. It is important to highight the relevance of this congenital disease, prevalent mong 0.5% to 2% of the population, and its association ith other congenital defects, ascending aortic aneurysm, nd the risk of aortic dissection, as well as its probable hereditary or familial pattern present in 10% to 30% of bicuspid aortic valve cases. Studies in patients with bicuspid aortic valves have shown a decrease in the elasticity and distension ability of the aortic wall related to a reduced content in fibrillin 1 in the vascular wall, leading to increased production of matrix metalloproteases and alterations of the endogenous inhibitors capable of weakening the extracellular matrix. In patients with bicuspid aortic valves, genetic mutations of matrix metalloprotease-2 have been found that are correlated with high matrix metalloprotease-2 plasma concentrations. Furthermore, several polymorphisms have been found in the matrix metalloprotease-1 promoter that affect protein levels. These studies and the desire to discover the genetic bases for patients with bicuspid aortic valves and the increase in matrix metalloprotease expression in the aortic wall have led our group to study 90 patients with bicuspid aortic valves and 76 controls with tricuspid aortic valves, analyzing the differences and incidences of diverse polymorphisms ( 1607 1G/2G, 519 A/G, and 340 T/C) of he matrix metalloprotease-1 promoter region related to the oncentrations of the protein. Of patients with bicuspid ortic valves, 48% presented with aortic stenosis, 50% preented with insufficiency, 46% presented with ascending ortic aneurysm, and 8% presented with aortic coarctation. nother 11% have a family history of this disorder, which

Biscuspid aortic valve syndrome: diversity and controversy.

We have read with great interest the manuscript recently published in your journal by Allen et al. [1] about the influence of beta-blocker therapy in aortic blood flow in patients with bicuspid aortic valve (BAV). The initiative of this study is really welcome and, considering that BAV is the most frequent congenital disease, it would be interesting to design a prospective and multicentre study about this matter, although still some questions remain in the air. As we all know, BAV is a heterogeneous disease and it can present as an isolated valvulopathy or in association with other congenital diseases and aortic diseases such as dilatation of the ascending aorta and aortic coarctation. A recent publication by Disha et al. opens an interesting debate about the follow-up of patients with BAV and normal aortic size at the moment of valvular surgery. As authors said, there is a lack of data regarding the risk of aortic events in this subgroup of patients and here is a new issue of concern: bicuspid aortopathy represents a spectrum of different proximal aortic phenotypes which are the manifestation of a genetic complexity still unsolved [2]. As it is known, alterations in the aortic media and differences in aortic elastic properties and wall stress are also present in the aortopathy associated to BAV, but further studies are still needed in order to identify not only genes responsible for BAV but also the different phenotypes associated with this entity or syndrome. In this scenario of heterogeneity, diversity and controversy we think that of course, preoperative evaluation of aortic root is mandatory and, until more clear evidence exists, a periodically follow-up after aortic valve surgery should be carried out. About this last issue and, in order to answer questions, prospective and multicentre studies would also be welcome.