Publications

The early sequence of events leading to the development of the acute respiratory distress syndrome (ARDS) in patients with sepsis remains inadequately understood. The purpose of this study was to identify changes in gene expression early in the course of illness, when mechanisms of injury may provide the most relevant treatment and prognostic targets. We collected whole blood RNA in critically ill patients admitted from the Emergency Department to the intensive care unit within 24 h of admission at a tertiary care center. Whole genome expression was compared in patients with sepsis and ARDS to patients with sepsis alone. We selected genes with >1 log2 fold change and false discovery rate <0.25, determined their significance in the literature, and performed pathway analysis. Several genes were upregulated in 29 patients with sepsis with ARDS compared with 28 patients with sepsis alone. The most differentially expressed genes included key mediators of the initial neutrophil response to infection: olfactomedin 4, lipocalin 2, CD24, and bactericidal/permeability-increasing protein. These gene expression differences withstood adjustment for age, sex, study batch, white blood cell count, and presence of pneumonia or aspiration. Pathway analysis demonstrated overrepresentation of genes involved in known respiratory and infection pathways. These data indicate that several neutrophil-related pathways may be involved in the early pathogenesis of sepsis-related ARDS. In addition, identifiable gene expression differences occurring early in the course of sepsis-related ARDS may further elucidate understanding of the neutrophil-related mechanisms in progression to ARDS.

CYBA (p22(phox)) is an integral constituent of the NADPH oxidases and is consequently a main component of oxidative stress, which is strongly associated with hypertension. This study investigates the contribution of CYBA polymorphisms toward the complex etiology of hypertension in two ethnically different populations, one located at a high altitude and the other at a low altitude. The significance of CYBA single nucleotide polymorphisms and their correlation with clinical and biochemical phenotypes were investigated in age- and ethnicity-matched unrelated permanent high-altitude residents (>3500 m) comprising 245 controls and 241 patients. The results were replicated in a second population comprising 935 controls and 545 patients who lived at a low altitude (<200 m). The analysis of covariance revealed that CYBA risk alleles and their haplotypes, rs8854A/rs9932581G/rs4873C and rs8854G/rs9932581G/rs4873C, were positively correlated with clinical parameters, for example, systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP), and biochemical parameters, for example, 8-isoPGF2α level, and inversely correlated with catalase activity in patients compared with controls (P⩽0.01, each). Conversely, the protective alleles and their haplotype, rs8854G/rs9932581A/rs4873T, were inversely correlated with SBP, DBP, MAP and 8-isoPGF2α level, and positively correlated with catalase activity (P⩽0.001, each). Furthermore, correlation analysis between the clinical and biochemical parameters revealed a positive correlation of SBP, DBP and MAP with 8-isoPGF2α levels and a negative correlation with catalase activity in both populations (P<0.0001, each). CYBA (p22(phox)) variants influence the markers of oxidative stress and are associated with hypertension.

OBJECTIVE

To define the long term outcomes of Fractional Flow Reserve (FFR) guided revascularization of ambiguous left main coronary artery (LMCA) lesions by performing a pooled meta-analysis of all available studies.

BACKGROUND

Prospective studies evaluating the use of fractional flow reserve (FFR) for clinical decision-making in ambiguous unprotected left main coronary artery (LMCA) stenosis suggest the relative safety of that approach, but any final conclusions are limited by small sample size. We performed a pooled meta-analysis of studies to define the long-term outcomes in these patients.

METHODS

Six prospective cohort studies involving 525 patients met the inclusion criteria. Patients underwent revascularization (revascularization group) or medical therapy (deferred group) based on FFR. The primary outcome was defined as rate of major cardiovascular events (a composite of death from all causes, nonfatal myocardial infarctions and subsequent revascularizations). The secondary outcomes included individual components of the primary end point. Pooled effect sizes were calculated using a fixed effects model.

RESULTS

Based on the FFR results, 217 patients (41%) underwent revascularization. There was no statistically significant difference between the groups in the rates of primary end point (P = 0.15), all-cause mortality (P = 0.06) or nonfatal myocardial infarctions (P = 0.76). However, there was a significant increase in the rate of subsequent revascularizations in the deferred patients (P = 0.002).

CONCLUSION

The long term clinical outcomes in patients with ambiguous LMCA stenosis for whom revascularization is deferred based on FFR are favorable and similar to the revascularized group in terms of overall mortality and subsequent myocardial infarctions.