Prognostic utility of novel biomarkers of cardiovascular stress in patients with aortic stenosis undergoing valve replacement.

OBJECTIVE: In heart failure populations without aortic stenosis (AS), the prognostic utility of multiple biomarkers in addition to clinical factors has been demonstrated. We aimed to determine whether multiple biomarkers of cardiovascular stress are associated with mortality in patients with AS undergoing aortic valve replacement (AVR) independent of clinical factors. METHODS: From a prospective registry of patients with AS, 345 participants who were referred for and treated with AVR (transcatheter (n=183) or surgical (n=162)) were included. Eight biomarkers were measured on blood samples obtained prior to AVR: growth differentiation factor 15 (GDF15), soluble ST2 (sST2), amino-terminal pro-B-type natriuretic peptide (NTproBNP), galectin-3, high-sensitivity cardiac troponin T, myeloperoxidase, high-sensitivity C reactive protein and monocyte chemotactic protein-1. Biomarkers were evaluated based on median value (high vs low) in a Cox proportional hazards model for all-cause mortality and a parsimonious group of biomarkers selected. Mean follow-up was 1.9±1.2 years; 91 patients died. RESULTS: Three biomarkers (GDF15, sST2 and NTproBNP) were retained in the model. One-year mortality was 5%, 12%, 18% and 33% for patients with 0 (n=79), 1 (n=96), 2 (n=87) and 3 (n=83) biomarkers elevated, respectively (p<0.001). After adjustment for the Society of Thoracic Surgeons (STS) risk score, a greater number of elevated biomarkers was associated with increased mortality (referent: 0 elevated): 1 elevated (HR 1.47, 95% CI 0.60 to 3.63, p=0.40), 2 elevated (HR 2.89, 95% CI 1.24 to 6.74, p=0.014) and 3 elevated (HR 4.59, 95% CI 1.97 to 10.71, p<0.001). Among patients at intermediate or high surgical risk (STS score ≥4), 1-year and 2-year mortality rates were 34% and 43% for patients with three biomarkers elevated versus 4% and 4% for patients with 0 biomarkers elevated. When added to the STS score, the number of biomarkers elevated provided a category-free net reclassification improvement of 64% at 1 year (p<0.001). The association between a greater number of elevated biomarkers and increased mortality after valve replacement was similar in the transcatheter and surgical AVR populations. CONCLUSIONS: These findings demonstrate the potential utility of multiple biomarkers to aid in risk stratification of patients with AS. Further studies are needed to evaluate their utility in clinical decision-making in specific AS populations.

Reactive oxygen species mediate microRNA-302 regulation of AT-rich interacting domain 4a and C-C motif ligand 5 expression during transitions between quiescence and proliferation.

Normal cell growth consists of two distinct phases, quiescence and proliferation. Quiescence, or G(0), is a reversible growth arrest in which cells retain the ability to reenter the proliferative cycle (G(1), S, G(2), and M). Although not actively dividing, quiescent cells are metabolically active and quiescence is actively maintained. Our results from microRNA PCR arrays and Taqman PCR assays showed a significant decrease (4-fold) in miR-302 levels during quiescence compared to proliferating normal human fibroblasts, suggesting that miR-302 could regulate cellular proliferation. Results from a Q-RT-PCR and dual-luciferase-3'-UTR reporter assays identified ARID4a (AT-rich interacting domain 4a, also known as RBP1) and CCL5 (C-C motif ligand 5) as targets for miR-302. Ionizing radiation decreased miR-302 levels, which was associated with an increase in its target mRNA levels, ARID4a and CCL5. Such an inverse correlation was also observed in cells treated with hydrogen peroxide as well as SOD2-overexpressing cells. Overexpression of miR-302 suppresses ARID4a and CCL5 mRNA levels, and increased the percentage of S-phase cells. These results identified miR-302 as an ROS-sensitive regulator of ARID4a and CCL5 mRNAs as well as demonstrate a regulatory role of miR-302 during quiescence and proliferation.

Overcoming adolescents' resistance to anti-inhalant appeals.

This research was concerned with factors that affect adolescents' evaluations of persuasive anti-inhalant messages and the association of these evaluations with usage intentions. Sixth and 7th graders (N=894) received anti-inhalant messages that varied as a result of the factorial combination of message source (doctor or peer), suggested harm (social or physical), and target (message was addressed directly or indirectly to receivers). Manipulated variables were crossed with inhalant-user status (resolute nonuser, vulnerable nonuser, and user). Significant (p<.01) target and status effects on message evaluation were found. Significant interactions of status with each of the manipulated variables also emerged. Users were resistant to threatened physical harms, but suggested harms did not differentially affect resolute nonusers or vulnerable nonusers. Users and vulnerable nonusers evaluated the message more positively when targeted indirectly (p<.05). Vulnerable nonusers were more receptive to peer sources, whereas users preferred adult sources. Message evaluation was significantly associated with inhalant usage intentions (r=-.22), and this association held even after the contributions of sex, sensation seeking, acculturation, prior use, familism, and assumed peer usage were accounted for in a multiple regression analysis (overall R(2)=.24).