Background-Patients with Gilbert syndrome have mild unconjugated hyperbilirubinemia. It has been shown that bilirubin is an endogenous antioxidant. We evaluated the role of oxidative stress in endothelial function in patients with Gilbert syndrome under normal conditions without cardiovascular risk factors. Methods and Results-A total of 108 young men with Gilbert syndrome without cardiovascular risk factors and 108 age-matched healthy men (normal controls) were enrolled in this study. Serum concentrations of bilirubin were higher in patients with Gilbert syndrome than in control subjects (29.2 +/- 11.6 versus 9.4 +/- 2.7 mu mol/L; P<0.001). Serum concentrations of malondialdehyde-modified low-density lipoprotein and urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG), as indices of oxidative stress, were lower in patients with Gilbert syndrome than in control subjects (61.8 +/- 24.5 versus 72.5 +/- 21.8 U/L, P=0.034; 7.8 +/- 2.4 versus 10.4 +/- 3.2 ng/mg creatinine, P=0.001, respectively). Flow-mediated vasodilation was greater in patients with Gilbert syndrome than in normal control subjects (7.2 +/- 2.2% versus 5.9 +/- 1.7%; P<0.001). Vascular responses to nitroglycerine were not significantly different between the 2 groups. Flow-mediated vasodilation correlated with serum concentration of bilirubin (r=0.44, P<0.001), malondialdehyde-modified low-density lipoprotein (r=-0.25, P=0.01), and urinary excretion of 8-OHdG (r=-0.27, P=0.004) in patients with Gilbert syndrome but not in control subjects. In addition, serum concentration of bilirubin correlated with malondialdehyde-modified low-density lipoprotein (r=-0.20, P=0.04) and 8-OHdG (r=-0.21, P=0.02) in patients with Gilbert syndrome but not in control subjects. Conclusions-Patients with Gilbert syndrome had low levels of oxidative stress associated with hyperbilirubinemia and enhancement of endothelium-dependent vasodilation.

Background-After myocardial ischemia, extracellular matrix (ECM) deposition occurs at the site of the focal injury and at the border region. Methods and Results-We have applied a novel proteomic method for the analysis of ECM in cardiovascular tissues to a porcine model of ischemia/reperfusion injury. ECM proteins were sequentially extracted and identified by liquid chromatography tandem mass spectrometry. For the first time, ECM proteins such as cartilage intermediate layer protein 1, matrilin-4, extracellular adipocyte enhancer binding protein 1, collagen alpha-1(XIV), and several members of the small leucine-rich proteoglycan family, including asporin and prolargin, were shown to contribute to cardiac remodeling. A comparison in 2 distinct cardiac regions (the focal injury in the left ventricle and the border region close to the occluded coronary artery) revealed a discordant regulation of protein and mRNA levels; although gene expression for selected ECM proteins was similar in both regions, the corresponding protein levels were much higher in the focal lesion. Further analysis based on > 100 ECM proteins delineated a signature of early-and late-stage cardiac remodeling with transforming growth factor-beta 1 signaling at the center of the interaction network. Finally, novel cardiac ECM proteins identified by proteomics were validated in human left ventricular tissue acquired from ischemic cardiomyopathy patients at cardiac transplantation. Conclusion-Our findings reveal a biosignature of early-and late-stage ECM remodeling after myocardial ischemia/reperfusion injury, which may have clinical utility as a prognostic marker and modifiable target for drug discovery. (Circulation. 2012; 125: 789-802.)

Background-Although coronary artery bypass grafting is generally preferred in symptomatic patients with severe, complex multivessel, or left main disease, some patients present with clinical features that make coronary artery bypass grafting clinically unattractive. Percutaneous coronary intervention with hemodynamic support may be feasible for these patients. Currently, there is no systematic comparative evaluation of hemodynamic support devices for this indication. Methods and Results-We randomly assigned 452 symptomatic patients with complex 3-vessel disease or unprotected left main coronary artery disease and severely depressed left ventricular function to intra-aortic balloon pump (IABP) (n=226) or Impella 2.5 (n=226) support during nonemergent high-risk percutaneous coronary intervention. The primary end point was the 30-day incidence of major adverse events. A 90-day follow-up was required, as well, by protocol. Impella 2.5 provided superior hemodynamic support in comparison with IABP, with maximal decrease in cardiac power output from baseline of -0.04 +/- 0.24 W in comparison with -0.14 +/- 0.27 W for IABP (P=0.001). The primary end point (30-day major adverse events) was not statistically different between groups: 35.1% for Impella 2.5 versus 40.1% for IABP, P=0.227 in the intent-to-treat population and 34.3% versus 42.2%, P=0.092 in the per protocol population. At 90 days, a strong trend toward decreased major adverse events was observed in Impella 2.5-supported patients in comparison with IABP: 40.6% versus 49.3%, P=0.066 in the intent-to-treat population and 40.0% versus 51.0%, P=0.023 in the per protocol population, respectively. Conclusions-The 30-day incidence of major adverse events was not different for patients with IABP or Impella 2.5 hemodynamic support. However, trends for improved outcomes were observed for Impella 2.5-supported patients at 90 days.

Background-Historically, sub-Saharan Africa has had the highest prevalence rates of clinically detected rheumatic heart disease (RHD). Echocardiography-based screening improves detection of RHD in endemic regions. The newest screening guidelines (2006 World Health Organization/National Institutes of Health) have been tested across India and the Pacific Islands, but application in sub-Saharan Africa has, thus far, been limited to Mozambique. We used these guidelines to determine RHD prevalence in a large cohort of Ugandan school children, to identify risk factors for occult disease, and to assess the value of laboratory testing. Methods and Results-Auscultation and portable echocardiography were used to screen randomly selected schoolchildren, 5 to 16 years of age, in Kampala, Uganda. Disease likelihood was defined as definite, probable, or possible in accordance with the 2006 National Institutes of Health/World Health Organization guidelines. Ninety-seven percent of eligible students received screening (4869 of 5006). Among them, 130 children (2.7%) had abnormal screening echocardiograms. Of those 130, secondary evaluation showed 72 (55.4%) with possible, probable, or definite RHD; 18 (13.8%) with congenital heart disease; and 40 (30.8%) with no disease. Echocardiography detected 3 times as many cases of RHD as auscultation: 72 (1.5%) versus 23 (0.5%; P < 0.001). Children with RHD were older (10.1 versus 9.3 years; P = 0.002). Most cases (98%) involved only the mitral valve. Lower socioeconomic groups had more RHD (2.7% versus 1.4%; P = 0.036) and more advanced disease (64% versus 26%; P < 0.001). Antistreptolysin O titers were elevated in children with definite RHD. Conclusions-This is one of the largest single-country childhood RHD prevalence studies and the first to be conducted in sub-Saharan Africa. Our data support inclusion of echocardiography in screening protocols, even in the most resource-constrained settings, and identify lower socioeconomic groups as most vulnerable. Longitudinal follow-up of children with echocardiographically diagnosed subclinical RHD is needed. (Circulation. 2012;125:3127-3132.)

Background-Eplerenone is known to reduce time to first hospitalization for heart failure or cardiovascular death in patients with heart failure and mild symptoms. In chronic diseases such as heart failure, characterized by repeat hospitalizations, analyzing all heart failure hospitalizations, not just the first, should give a more complete picture of treatment benefits. Methods and Results-The Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure (EMPHASIS-HF) trial compared eplerenone with placebo in 2737 patients with mild heart failure, followed for a median 2.08 years (interquartile range, 1.08-3.10 years). Data were collected on all hospitalizations, with a focus on those due to heart failure. Heart failure hospitalization rates in the eplerenone and placebo groups were 10.70 and 16.99 per 100 patient-years, respectively. Allowing for skewness in the frequency of hospitalizations by using the negative binomial generalized linear model, the rate ratio (eplerenone versus placebo) was 0.53 (95% confidence interval, 0.42-0.66; P<0.0001). A plot of cumulative hospitalization rates over time revealed that most of the reduced risk on eplerenone occurred in the first year of follow-up. Several baseline variables strongly predicted the risk of hospitalization. More complex statistical methods, adjusting for mortality (as informative censoring), made a negligible difference in these findings. Conclusions-Eplerenone markedly reduces the risk of heart failure hospitalizations in patients with heart failure and mild symptoms to a greater extent than is captured by only studying the time to first hospitalization. Future clinical trials in heart failure would gain from incorporating repeat hospitalizations into their primary evaluation of treatment effects. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00232180. (Circulation. 2012; 126: 2317-2323.)