70 research outputs found
Does any therapy really work for neurocardiogenic syncope?
Get PDFEffectiveness of a treatment for neurocardiogenic syncope can be defined in terms of symptom response, quality-of-life, healthcare utilization, treatment side effects and cost-effectiveness. Most trials have focused on syncope recurrence or burden, without assessing quality-of-life formally. Drug and device interventions are characterized by a dearth of randomized controlled trials, with those few of robust design demonstrating little impact on recurrence of syncope. General advice includes hydration, trigger recognition and counter pressure maneuvers to attenuate episodes. Lifestyle recommendations have limited comparative effectiveness evidence, but are favored due to lack of side effects and low cost. The frequency of syncope improves in many patients regardless of the intervention, although ultimate recurrence of syncope remains high. In the minority of patients seeking treatment due to recurrence, midodrine has reasonable supporting evidence for effectiveness with some evidence for beta-blockers in older age patients. Emerging evidence favors pacing in patients with asystole during spontaneous (as opposed to provoked) syncope. Combining long-term implantable cardiac monitoring, tilt and adenosine triphosphate testing may yet accurately define the optimal minority who benefit from pacing. In the remaining majority, pharmacologic and device interventions should be used sparingly until clear benefits are established. Better understanding of patient fears, beliefs and behaviors may help develop cognitive therapies and improve quality-of-life alongside the focus on physical symptoms
Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome.
Get PDFEukaryotic gene transcription is accompanied by acetylation and methylation of nucleosomes near promoters, but the locations and roles of histone modifications elsewhere in the genome remain unclear. We determined the chromatin modification states in high resolution along 30 Mb of the human genome and found that active promoters are marked by trimethylation of Lys4 of histone H3 (H3K4), whereas enhancers are marked by monomethylation, but not trimethylation, of H3K4. We developed computational algorithms using these distinct chromatin signatures to identify new regulatory elements, predicting over 200 promoters and 400 enhancers within the 30-Mb region. This approach accurately predicted the location and function of independently identified regulatory elements with high sensitivity and specificity and uncovered a novel functional enhancer for the carnitine transporter SLC22A5 (OCTN2). Our results give insight into the connections between chromatin modifications and transcriptional regulatory activity and provide a new tool for the functional annotation of the human genome. Activation of eukaryotic gene transcription involves the coordination of a multitude of transcription factors and cofactors on regulatory DNA sequences such as promoters and enhancers and on the chromatin structure containing these elements 1-3 . Promoters are located at the 5¢ ends of genes immediately surrounding the transcriptional start site (TSS) and serve as the point of assembly of the transcriptional machinery and initiation of transcription 4 . Enhancers contribute to the activation of their target genes from positions upstream, downstream or within a target or neighboring gene Recent investigations using chromatin immunoprecipitation (ChIP) and microarray (ChIP-chip) experiments have described the chromatin architecture of transcriptional promoters in yeast, fly and mammalian systems 9 . In a manner largely conserved across species, active promoters are marked by acetylation of various residues of histones H3 and H4 and methylation of H3K4, particularly trimethylation of this residue. Nucleosome depletion is also a general characteristic of active promoters in yeast and flies, although this feature remains to be thoroughly examined in mammalian systems. Although some studies suggest that distal regulatory elements like enhancers may be marked by similar histone modification patterns 10-13 , the distinguishing chromatin features of promoters and enhancers have yet to be determined, hindering our understanding of a predictive histone code for different classes of regulatory elements. Here, we present high-resolution maps of multiple histone modifications and transcriptional regulators in 30 Mb of the human genome, demonstrating that active promoters and enhancers are associated with distinct chromatin signatures that can be used to predict these regulatory elements in the human genome. RESULTS Chromatin architecture and transcription factor localization We performed ChIP-chip analysis 14 to determine the chromatin architecture along 44 human loci selected by the ENCODE consortium as common targets for genomic analysis 15 , totaling 30 Mb
Histone Modifications at Human Enhancers Reflect Global Cell-Type-Specific Gene Expression
Get PDFThe human body is composed of diverse cell types with distinct functions. Although it is known that lineage specification depends on cell-specific gene expression, which in turn is driven by promoters, enhancers, insulators and other cis-regulatory DNA sequences for each gene1, 2, 3, the relative roles of these regulatory elements in this process are not clear. We have previously developed a chromatin-immunoprecipitation-based microarray method (ChIP-chip) to locate promoters, enhancers and insulators in the human genome4, 5, 6. Here we use the same approach to identify these elements in multiple cell types and investigate their roles in cell-type-specific gene expression. We observed that the chromatin state at promoters and CTCF-binding at insulators is largely invariant across diverse cell types. In contrast, enhancers are marked with highly cell-type-specific histone modification patterns, strongly correlate to cell-type-specific gene expression programs on a global scale, and are functionally active in a cell-type-specific manner. Our results define over 55,000 potential transcriptional enhancers in the human genome, significantly expanding the current catalogue of human enhancers and highlighting the role of these elements in cell-type-specific gene expression
Clinical characteristics and outcomes of patients with heart failure with reduced ejection fraction and chronic obstructive pulmonary disease: insights from PARADIGM-HF
Get PDFBackground:
Chronic obstructive pulmonary disease (COPD) is a common comorbidity in heart failure with reduced ejection fraction, associated with undertreatment and worse outcomes. New treatments for heart failure with reduced ejection fraction may be particularly important in patients with concomitant COPD.
Methods and Results:
We examined outcomes in 8399 patients with heart failure with reduced ejection fraction, according to COPD status, in the PARADIGMâHF (Prospective Comparison of Angiotensin Receptor BlockerâNeprilysin Inhibitor With AngiotensinâConverting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. Cox regression models were used to compare COPD versus nonâCOPD subgroups and the effects of sacubitril/valsartan versus enalapril. Patients with COPD (n=1080, 12.9%) were older than patients without COPD (mean 67 versus 63 years; P<0.001), with similar left ventricular ejection fraction (29.9% versus 29.4%), but higher NTâproBNP (Nâterminal proâBâtype natriuretic peptide; median, 1741 pg/mL versus 1591 pg/mL; P=0.01), worse functional class (New York Heart Association III/IV 37% versus 23%; P<0.001) and Kansas City Cardiomyopathy QuestionnaireâClinical Summary Score (73 versus 81; P<0.001), and more congestion and comorbidity. Medical therapy was similar in patients with and without COPD except for betaâblockade (87% versus 94%; P<0.001) and diuretics (85% versus 80%; P<0.001). After multivariable adjustment, COPD was associated with higher risks of heart failure hospitalization (hazard ratio [HR], 1.32; 95% CI, 1.13â1.54), and the composite of cardiovascular death or heart failure hospitalization (HR, 1.18; 95% CI, 1.05â1.34), but not cardiovascular death (HR, 1.10; 95% CI, 0.94â1.30), or allâcause mortality (HR, 1.14; 95% CI, 0.99â1.31). COPD was also associated with higher risk of all cardiovascular hospitalization (HR, 1.17; 95% CI, 1.05â1.31) and noncardiovascular hospitalization (HR, 1.45; 95% CI, 1.29â1.64). The benefit of sacubitril/valsartan over enalapril was consistent in patients with and without COPD for all end points.
Conclusions:
In PARADIGMâHF, COPD was associated with lower use of betaâblockers and worse health status and was an independent predictor of cardiovascular and noncardiovascular hospitalization. Sacubitril/valsartan was beneficial in this highârisk subgroup.
Registration:
URL: https://www.clinicaltrials.gov; Unique identifier: NCT01035255
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