A meta-analysis of optimal medical therapy with or without percutaneous coronary intervention in patients with stable coronary artery disease.

BACKGROUND: Whether percutaneous coronary intervention (PCI) improves clinical outcomes in patients with chronic angina and stable coronary artery disease (CAD) has been a continuing area of investigation for more than two decades. The recently reported results of the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches, the largest prospective trial of optimal medical therapy (OMT) with or without myocardial revascularization, provides a unique opportunity to determine whether there is an incremental benefit of revascularization in stable CAD patients. METHODS: Scientific databases and websites were searched to find randomized clinical trials (RCTs). Pooled risk ratios were calculated using the random-effects model. RESULTS: Data from 10 RCTs comprising 12 125 patients showed that PCI, when added to OMT, were not associated with lower all-cause mortality (risk ratios, 0.96; 95% CI, 0.87-1.08), cardiovascular mortality (risk ratios, 0.91; 95% CI, 0.79-1.05) or myocardial infarction (MI) (risk ratios, 0.90; 95% CI, 0.78-1.04) as compared with OMT alone. However, OMT+PCI was associated with improved anginal symptoms and a lower risk for revascularization (risk ratios, 0.52; 95% CI, 0.37-0.75). CONCLUSIONS: In patient with chronic stable CAD (without left main disease or reduced ejection fraction), PCI in addition to OMT did not improve mortality or MI compared to OMT alone. However, this strategy is associated with a lower rate of revascularization and improved anginal symptoms.

Meta-Analysis of Optimal Revascularization Strategy for Patients With ST-Segment Elevation Myocardial Infarction and Multi-Vessel Coronary Artery Disease.

Several clinical trials have shown that complete revascularization (CR) lowers the risks of revascularization and nonfatal myocardial infarction (MI) in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease compared with infarct-related artery-only revascularization (IRA-OR). However, individual trials have been underpowered for hard outcomes such as cardiovascular (CV) mortality. Therefore, we conducted an updated meta-analysis representing the largest sample size to date inclusive of contemporary studies comparing CR versus IRA-OR. Pooled risk ratios (RRs) were calculated using random effects model. Data from 11 RCTs involving 7,343 patients showed that compared with IRA-OR, CR was associated with lower CV mortality (RR 0.75; 95% confidence interval [CI] 0.57 to 0.99; p = 0.04), MI (RR 0.70; 95% CI 0.53 to 0.93), and recurrent revascularization (RR 0.38; 95% CI 0.27 to 0.54), but similar all-cause mortality (RR 0.85; 95% CI 0.70 to 1.05). In conclusion, in patients with STEMI and multivessel coronary artery disease, compared with IRA-OR, CR was associated with lower risk for CV mortality, MI, and recurrent revascularization, suggesting that CR should be the standard of care for STEMI patients.

A functional module of yeast mediator that governs the dynamic range of heat-shock gene expression.

We report the results of a genetic screen designed to identify transcriptional coregulators of yeast heat-shock factor (HSF). This sequence-specific activator is required to stimulate both basal and induced transcription; however, the identity of factors that collaborate with HSF in governing noninduced heat-shock gene expression is unknown. In an effort to identify these factors, we isolated spontaneous extragenic suppressors of hsp82-deltaHSE1, an allele of HSP82 that bears a 32-bp deletion of its high-affinity HSF-binding site, yet retains its two low-affinity HSF sites. Nearly 200 suppressors of the null phenotype of hsp82-deltaHSE1 were isolated and characterized, and they sorted into six expression without heat-shock element (EWE) complementation groups. Strikingly, all six groups contain alleles of genes that encode subunits of Mediator. Three of the six subunits, Med7, Med10/Nut2, and Med21/Srb7, map to Mediator's middle domain; two subunits, Med14/Rgr1 and Med16/Sin4, to its tail domain; and one subunit, Med19/Rox3, to its head domain. Mutations in genes encoding these factors enhance not only the basal transcription of hsp82-deltaHSE1, but also that of wild-type heat-shock genes. In contrast to their effect on basal transcription, the more severe ewe mutations strongly reduce activated transcription, drastically diminishing the dynamic range of heat-shock gene expression. Notably, targeted deletion of other Mediator subunits, including the negative regulators Cdk8/Srb10, Med5/Nut1, and Med15/Gal11 fail to derepress hsp82-deltaHSE1. Taken together, our data suggest that the Ewe subunits constitute a distinct functional module within Mediator that modulates both basal and induced heat-shock gene transcription.

Alpha-synuclein targets the plasma membrane via the secretory pathway and induces toxicity in yeast.

A pathological feature of Parkinson's disease is the presence of Lewy bodies within selectively vulnerable neurons. These are ubiquitinated cytoplasmic inclusions containing alpha-synuclein, an abundant protein normally associated with presynaptic terminals. Point mutations in the alpha-synuclein gene (A30P and A53T), as well as triplication of the wild-type (WT) locus, have been linked to autosomal dominant Parkinson's. How these alterations might contribute to disease progression is unclear. Using the genetically tractable yeast Saccharomyces cerevisiae as a model system, we find that both the WT and the A53T isoforms of alpha-synuclein initially localize to the plasma membrane, to which they are delivered via the classical secretory pathway. In contrast, the A30P mutant protein disperses within the cytoplasm and does not associate with the plasma membrane, and its intracellular distribution is unaffected by mutations in the secretory pathway. When their expression is elevated, WT and A53T, but not A30P, are toxic to cells. At moderate levels of expression, WT and A53T induce the cellular stress (heat-shock) response and are toxic to cells bearing mutations in the 20S proteasome. Our results reveal a link between plasma membrane targeting of alpha-synuclein and its toxicity in yeast and suggest a role for the quality control (QC) system in the cell's effort to deal with this natively unfolded protein.