IL-15 and IL15RA in Osteoarthritis: Association With Symptoms and Protease Production, but Not Structural Severity.

Objective: Interleukin-15 (IL-15) is a pro-inflammatory cytokine that is increased in joint fluids of early-stage osteoarthritis (OA) patients, and has been associated with expression of proteases that can damage cartilage, and the development of neuropathic pain-like symptoms (NP) after nerve injury. The objective of this study was to further explore the role of IL-15 in the pathogenesis of OA cartilage degeneration and test genetic variation in the IL-15 receptor α gene (IL15RA) for an association with OA with radiographic severity and symptoms. Methods: Cartilage samples from donors (n = 10) were analyzed for expression of the IL15 receptor α-chain using immunohistochemistry, and for responses to IL-15 in vitro using explant cultures. Data from two independent Nottinghamshire-based studies (n = 795 and n = 613) were used to test genetic variants in the IL15RA gene (rs2228059 and rs7097780) for an association with radiographic severity, symptomatic vs. asymptomatic OA and NP. Results: IL-15Rα was expressed in chondrocytes from cartilage obtained from normal and degenerative knees. IL-15 significantly increased the release of matrix metalloproteinase-1 and -3 (MMP-1 and -3), but did not affect loss of proteoglycan from the articular matrix. Genetic variants in the IL15RA gene are associated with risk of symptomatic vs. asymptomatic OA (rs7097780 OR = 1.48 95% 1.10-1.98 p < 0.01) and with the risk of NP post-total joint replacement (rs2228059 OR = 0.76 95% 0.63-0.92 p < 0.01) but not with radiographic severity. Conclusions: In two different cohorts of patients, we show an association between genetic variation at the IL15 receptor and pain. Although ex vivo cartilage explants could respond to IL-15 with increased protease production, we found no effect of IL-15 on cartilage matrix loss and no association between IL15RA variants and radiographic severity. Together, these results suggest that IL-15 signaling may be a target for pain, but may not impact structural progression, in OA.

Left ventricular global longitudinal strain predicts mortality and heart failure admissions in African American patients.

BACKGROUND: Several studies have demonstrated the importance of left ventricular (LV) global longitudinal strain (GLS) as a reliable prognostic indicator in patients with heart failure (HF). These studies have included few African American (AA) patients, despite the growing prevalence and severity of HF in this patient population. HYPOTHESIS: LV GLS predicts long-term HF admission and all-cause mortality in AA patients with chronic HF on optimal guideline-directed medical therapy (GDMT). METHODS: We enrolled 207 AA adults, age 56 ± 14.5 years, with New York Heart Association (NYHA) class I through III HF on optimal GDMT from the University of Illinois HF clinic between November 2001 and February 2014. LV GLS was assessed by velocity vector imaging using 2-, 3-, and 4-chamber views. Patients were followed for HF admissions and death for 3 ± 3.0 years. LV GLS value of -7.95 was used as the optimal cutoff point that maximizes sensitivity and specificity RESULTS: LV GLS < -7.95% was significantly associated with higher all-cause mortality and HF admissions in Kaplan-Meier survival curves (log-rank P < 0.001). After incorporation in multivariate Cox proportional hazard models, GLS < -7.95% was found to be an independent predictor of all-cause mortality (hazard ratio [HR] = 4.04; 95% confidence interval [CI]: 1.07-15.32; P = 0.04] and HF admissions (HR = 3.86; 95% CI: 1.38-10.77; P = 0.010). CONCLUSIONS: In AA patients with chronic stable HF on GDMT, more impaired LV GLS (< -7.95%) is a strong and independent predictor of long-term all-cause mortality and HF admissions.