Innate Immune Receptors, Key Actors in Cardiovascular Diseases

Cardiovascular diseases (CVDs) are the leading cause of death in the industrialized world. Most CVDs are associated with increased inflammation that arises mainly from innate immune system activation related to cardiac damage. Sustained activation of the innate immune system frequently results in maladaptive inflam- matory responses that promote cardiovascular dysfunction and remodeling. Much research has focused on determining whether some mediators of the innate immune system are potential targets for CVD therapy. The innate immune system has specific receptors—termed pattern recognition receptors (PRRs)—that not only recognize pathogen-associated molecular patterns, but also sense danger-associated molecular signals. Acti- vation of PRRs triggers the inflammatory response in different physiological systems, including the cardio- vascular system. The classic PRRs, toll-like receptors (TLRs), and the more recently discovered nucleotide- binding oligomerization domain-like receptors (NLRs), have been recently proposed as key partners in the progression of several CVDs (e.g., atherosclerosis and heart failure). The present review discusses the key findings related to the involvement of TLRs and NLRs in the progression of several vascular and cardiac diseases, with a focus on whether some NLR subtypes (nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing receptor 3 and nucleotide-binding oligomerization domain-containing protein 1) can be candidates for the development of new therapeutic strategies for several CVDs

Indicadores de calidad en cardiología. Principales indicadores para medir la calidad de los resultados (indicadores de resultados) y parámetros de calidad relacionados con mejores resultados en la práctica clínica (indicadores de práctica asistencial). INCARDIO (Indicadores de Calidad en Unidades Asistenciales del Área del Corazón): Declaración de posicionamiento de consenso de SEC/SECTCV

ResumenLa práctica clínica cardiológica requiere una organización compleja que influya en los resultados globales y puede diferir sustancialmente entre distintos hospitales y comunidades. El objetivo de este documento de consenso es definir indicadores de calidad en cardiología, incluidos los indicadores para medir la calidad de los resultados (indicadores de resultados) y los parámetros de calidad relacionados con mejores resultados en la práctica clínica (indicadores de práctica asistencial). El documento está destinado principalmente al sistema de asistencia sanitaria de España y puede servir de base para documentos similares en otros países.AbstractCardiology practice requires complex organization that impacts overall outcomes and may differ substantially among hospitals and communities. The aim of this consensus document is to define quality markers in cardiology, including markers to measure the quality of results (outcomes metrics) and quality measures related to better results in clinical practice (performance metrics). The document is mainly intended for the Spanish health care system and may serve as a basis for similar documents in othe rcountries

Innate immune receptors, key actors in cardiovascular diseases

Cardiovascular diseases (CVDs) are the leading cause of death in the industrialized world. Most CVDs are associated with increased inflammation that arises mainly from innate immune system activation related to cardiac damage. Sustained activation of the innate immune system frequently results in maladaptive inflammatory responses that promote cardiovascular dysfunction and remodeling. Much research has focused on determining whether some mediators of the innate immune system are potential targets for CVD therapy. The innate immune system has specific receptors—termed pattern recognition receptors (PRRs)—that not only recognize pathogen-associated molecular patterns, but also sense danger-associated molecular signals. Activation of PRRs triggers the inflammatory response in different physiological systems, including the cardiovascular system. The classic PRRs, toll-like receptors (TLRs), and the more recently discovered nucleotide-binding oligomerization domain-like receptors (NLRs), have been recently proposed as key partners in the progression of several CVDs (e.g., atherosclerosis and heart failure). The present review discusses the key findings related to the involvement of TLRs and NLRs in the progression of several vascular and cardiac diseases, with a focus on whether some NLR subtypes (nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing receptor 3 and nucleotide-binding oligomerization domain-containing protein 1) can be candidates for the development of new therapeutic strategies for several CVDs

CPEB alteration and aberrant transcriptome-polyadenylation lead to a treatable SLC19A3 deficiency in Huntington's disease

Huntington’s disease (HD) is a hereditary neurodegenerative disorder of the basal ganglia for which disease-modifying treatments are not yet available. Although gene-silencing therapies are currently being tested, further molecular mechanisms must be explored to identify druggable targets for HD. Cytoplasmic polyadenylation element binding proteins 1 to 4 (CPEB1 to CPEB4) are RNA binding proteins that repress or activate translation of CPE-containing transcripts by shortening or elongating their poly(A) tail. Here, we found increased CPEB1 and decreased CPEB4 protein in the striatum of patients and mouse models with HD. This correlated with a reprogramming of polyadenylation in 17.3% of the transcriptome, markedly affecting neurodegeneration-associated genes including PSEN1, MAPT, SNCA, LRRK2, PINK1, DJ1, SOD1, TARDBP, FUS, and HTT and suggesting a new molecular mechanism in neurodegenerative disease etiology. We found decreased protein content of top deadenylated transcripts, including striatal atrophy–linked genes not previously related to HD, such as KTN1 and the easily druggable SLC19A3 (the ThTr2 thiamine transporter). Mutations in SLC19A3 cause biotin-thiamine–responsive basal ganglia disease (BTBGD), a striatal disorder that can be treated with a combination of biotin and thiamine. Similar to patients with BTBGD, patients with HD demonstrated decreased thiamine in the cerebrospinal fluid. Furthermore, patients and mice with HD showed decreased striatal concentrations of thiamine pyrophosphate (TPP), the metabolically active form of thiamine. High-dose biotin and thiamine treatment prevented TPP deficiency in HD mice and attenuated the radiological, neuropathological, and motor HD-like phenotypes, revealing an easily implementable therapy that might benefit patients with HD

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

¿Revascularización completa en el infarto de miocardio con elevación del ST?: Sí, no lo dude

Primary angioplasty is now clearly established as the best reperfusion strategy for patients with ST-segment elevation myocardial infarction (STEMI), but the best strategy for significant stenosis at non-culprit vessels has not been adequately studied. Several randomized trials have been previously performed, but all of them with soft primary endpoints and consequently a low number of patients. The COMPLETE trial, for the first time, provides us with solid scientific evidence about what we should do in patients with STEMI and multi-vessel disease. This study included more than 4000 patients and has shown that complete revascularization reduces significantly the risk of cardiovascular death or myocardial infarction.La angioplastia primaria está reconocida como la mejor estrategia de reperfusión en el infarto de miocardio con elevación del segmento ST. No obstante, la mejor estrategia para el tratamiento de las lesiones coronarias significativas en arterias no relacionadas con el infarto no se había estudiado convenientemente. Hasta la fecha se habían realizado varios estudios aleatorizados pero con objetivos de beneficio clínico de gravedad menor o «blandos» y pocos pacientes. Por primera vez, el estudio COMPLETE proporciona evidencia científica sólida sobre la estrategia terapéutica en pacientes con infarto de miocardio con elevación del segmento ST y enfermedad multivaso. Este estudio, que incluyó a más de 4.000 pacientes, ha demostrado que la revascularización completa reduce significativamente el riesgo combinado de mortalidad o infarto de miocardio