Reduced carboxylesterase 1 is associated with endothelial injury in methamphetamine-induced pulmonary arterial hypertension.

Pulmonary arterial hypertension is a complication of methamphetamine use (METH-PAH), but the pathogenic mechanisms are unknown. Given that cytochrome P450 2D6 (CYP2D6) and carboxylesterase 1 (CES1) are involved in metabolism of METH and other amphetamine-like compounds, we postulated that loss of function variants could contribute to METH-PAH. Although no difference in CYP2D6 expression was seen by lung immunofluorescence, CES1 expression was significantly reduced in endothelium of METH-PAH microvessels. Mass spectrometry analysis showed that healthy pulmonary microvascular endothelial cells (PMVECs) have the capacity to both internalize and metabolize METH. Furthermore, whole exome sequencing data from 18 METH-PAH patients revealed that 94.4% of METH-PAH patients were heterozygous carriers of a single nucleotide variant (SNV; rs115629050) predicted to reduce CES1 activity. PMVECs transfected with this CES1 variant demonstrated significantly higher rates of METH-induced apoptosis. METH exposure results in increased formation of reactive oxygen species (ROS) and a compensatory autophagy response. Compared with healthy cells, CES1-deficient PMVECs lack a robust autophagy response despite higher ROS, which correlates with increased apoptosis. We propose that reduced CES1 expression/activity could promote development of METH-PAH by increasing PMVEC apoptosis and small vessel loss.

Perioperative outcomes in male patients undergoing cystectomy, radical colorectal procedure or total pelvic exenteration.

Background: Total pelvic exenteration (TPE) in men is a surgical procedure to treat genitourinary and colorectal malignancies. Despite improvement in multimodal strategies and technology, mortality is still high and literature is limited about perioperative outcomes comparison to other radical procedures. Methods: We analyzed National Surgical Quality Improvement Program (NSQIP) baseline database of all male patients undergoing cystectomy, low anterior resection/abdominoperineal resection (LAR/APR) or TPE from January 1, 2005 to December 31, 2016. Postoperative complications within 30 days after surgery were measured including: Wound infection, septic complications, deep vein thrombosis, cardiovascular events, and return to the operating room or mortality, etc. Differences between groups were analyzed using analysis of variance (ANOVA) tests. Results: A total of 7,375 patients underwent radical cystectomy, 49,762 underwent LAR/APR and 792 underwent TPE. Cystectomy patients were on average older compared to TPE or LAR/APR patients (P<0.001). In univariable and multivariable analysis, patients undergoing TPE had greater infectious and septic complications compared to cystectomy (odds ratio =1.09; 95% confidence interval (CI): 1.06-1.12) and LAR/APR (odds ratio =1.08; 95% CI: 1.05-1.11). Moreover, TPE had a slightly higher mortality within the 30-day postoperatively than those who underwent LAR/APR (odds ratio =1.01; 95% CI: 1.00-1.02) and cystectomy (odds ratio =1.01; 95% CI: 1.00-1.01). Conclusions: Men undergoing TPE had greater rates of infections and postoperative complications compared to those undergoing radical cystectomy and LAR/APR. From a clinical standpoint, TPE has high morbidity that could provide opportunity for quality improvement projects with the goal of mitigating high complication rates.