CCR5 Expression is Lower in Women, and Mediates Sex-Based Differences in Post-LVAD Right Ventricular Failure

Abstract

Purpose Women have increased risk of right ventricular failure (RVF) after LVAD implant, however the underlying pathophysiology is unknown. Chemokines are inflammatory signaling molecules, and fundamental to cardiac homeostasis and stress adaptation. Prior studies have demonstrated a cardio-protective role for chemokine receptor-5 (CCR5) in viral myocarditis and severe Chagas cardiomyopathy, and that sex hormones modulate CCR5 gene expression. We have previously shown that CCR 3-8 down-regulation is predictive of RVF and 1-year survival after implant. We hypothesized that CCR5 expression mediates sex-based differences in post-LVAD RVF. Methods CCR expression was examined in patient's peripheral blood 24 hours pre-LVAD. RNA was isolated using PAXgene protocol. Gene expression was assessed using a targeted microarray (RT2 Profiler PCR array, Qiagen). Results were expressed as PCR cycles to threshold (CT). ΔCT was calculated as (CCR gene CT) - (HPRT1 control gene CT), and log2 transformed for analysis. Log-fold differences in expression were reported using 2−ΔΔCT method. RVF was defined as both planned and unplanned RVAD requirement. Multivariable logistic regression was used to determine the association of sex with RVF, adjusting for significantly different covariates (p Results We analyzed 111 LVAD patients (mean age: 53.57 ± 13 years, 18% female, 17.1% black). The criteria for RVF was met in 35 (31.5%) patients. Women had increased incidence of RVF (50% vs. 27.5%, p=0.047), and under-expressed CCR5 (1.41 fold decrease, p=0.012) compared to men. After controlling for age, heart failure etiology, albumin, BUN, creatinine and cardiac output, women had a higher risk of RVF (HR: 3.18, 95% CI: 1.04-9.8, p=0.043). Addition of CCR5 as a covariate to the model attenuated the association of female sex with RVF (HR: 2.86, 95% CI: 0.91-8.97, p=0.071). Conclusion Pre-implant CCR5 expression is lower in women than in men and may mediate sex disparities in post-LVAD RVF.