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Summary: Disparities relating to postpartum recovery outcomes in different socio‐economic and racial ethnic groups are underexplored. We conducted a planned analysis of a large prospective caesarean delivery cohort to explore the relationship between ethnicity, socio‐economic status and postpartum recovery. Eligible patients were enrolled and baseline demographic, obstetric and medical history data were collected 18 h and 30 h following delivery. Patients completed postpartum quality of life and recovery measures in person on day 1 (EuroQoL EQ‐5D‐5L, including global health visual analogue scale; Obstetric Quality of Recovery‐10 item score; and pain scores) and by telephone between day 28 and day 32 postpartum (EQ‐5D‐5L and pain scores). Socio‐economic group was determined according to the Index of Multiple Deprivation quintile of each patient's usual place of residence. Data from 1000 patients who underwent caesarean delivery were included. There were more patients of Asian, Black and mixed ethnicity in the more deprived quintiles. Patients of White ethnicities had shorter postpartum duration of hospital stay compared with patients of Asian and Black ethnicities (35 (28–56 [18–513]) h vs. 44 (31–71 [19–465]) h vs. 49 (33–75 [23–189]) h, respectively. In adjusted models at day 30, patients of Asian ethnicity had a significantly greater risk of moderate to severe pain (numerical rating scale ≥ 4) at rest and on movement (odds ratio (95%CI) 2.42 (1.24–4.74) and 2.32 (1.40–3.87)), respectively). There were no differences in readmission rates or incidence of complications between groups. Patients from White ethnic backgrounds experience shorter postpartum duration of stay compared with patients from Asian and Black ethnic groups. Ethnic background impacts pain scores and recovery at day 1 postpartum and following hospital discharge, even after adjusting for socio‐economic group. Further work is required to understand the underlying factors driving differences in pain and recovery and to develop strategies to reduce disparities in obstetric patients. [ABSTRACT FROM AUTHOR]

Summary: To better understand outcomes in postpartum patients who receive peripartum anaesthetic interventions, we aimed to assess quality of recovery metrics following childbirth in a UK‐based multicentre cohort study. This study was performed during a 2‐week period in October 2021 to assess in‐ and outpatient post‐delivery recovery at 1 and 30 days postpartum. The following outcomes were reported: obstetric quality of recovery 10‐item measure (ObsQoR‐10); EuroQoL (EQ‐5D‐5L) survey; global health visual analogue scale; postpartum pain scores at rest and movement; length of hospital stay; readmission rates; and self‐reported complications. In total, 1638 patients were recruited and responses analysed from 1631 (99.6%) and 1282 patients (80%) at one and 30 days postpartum, respectively. Median (IQR [range]) length of stay postpartum was 39.3 (28.5–61.0 [17.7–513.4]), 40.3 (28.5–59.1 [17.8–220.9]), and 35.9 (27.1–54.1 [17.9–188.4]) h following caesarean, instrumental and vaginal deliveries, respectively. Median (IQR [range]) ObsQoR‐10 score was 75 ([62–86] 4–100) on day 1, with the lowest ObsQoR‐10 scores (worst recovery) reported by patients undergoing caesarean delivery. Of the 1282 patients, complications within the first 30 days postpartum were reported by 252 (19.7%) of all patients. Readmission to hospital within 30 days of discharge occurred in 69 patients (5.4%), with 49 (3%) for maternal reasons. These data can be used to inform patients regarding expected recovery trajectories; facilitate optimal discharge planning; and identify populations that may benefit most from targeted interventions to improve postpartum recovery experience. [ABSTRACT FROM AUTHOR]

Summary: Sevoflurane and desflurane are the most commonly used volatile anaesthetics for maintenance of anaesthesia. In this study, we aimed to evaluate the relationship between choice of volatile anaesthetic and early postoperative respiratory complications, and to address a critical knowledge gap in safety outcomes between these two commonly used agents. We performed a retrospective analysis of adult (non‐cardiac surgery) patients who received sevoflurane or desflurane for the maintenance of general anaesthesia at our institution between 2005 and 2018. We evaluated the association between desflurane exposure (when compared with sevoflurane) and the primary outcome of postoperative respiratory complications, defined by early post‐extubation desaturation (SpO2 < 90%) or re‐intubation within 7 days postoperatively. Multivariable regression analyses were performed and adjusted for confounding factors, including patient, anaesthetic and surgical factors. Propensity matched, interaction and sub‐group analyses were performed to assess outcomes in high‐risk groups: morbidly obese (BMI > 35 kg.m−2); elderly (age > 65 years); and high risk of respiratory complications as well as the primary outcome at 24 h. Desflurane was used for 23,830 patients and sevoflurane for 84,608 patients. Patients exposed to desflurane did not demonstrate a reduced risk of postoperative respiratory complications when compared with sevoflurane (adjusted odds ratio 0.99, 95%CI 0.94–1.04, p = 0.598). These findings were consistent across all sub‐groups of high‐risk patients and in the propensity score matched cohort. In summary, desflurane use was not associated with reduced postoperative respiratory complications when compared with sevoflurane. In the context of environmental and cost concerns with volatile anaesthetic agents, our study provides important data to support organisational decisions regarding the use of desflurane. [ABSTRACT FROM AUTHOR]

Background Variability in obstetric anaesthetia practice and care delivered within the UK is under-explored. The ObsQoR study explored structures, processes, and outcomes of obstetric anaesthesia in 107 hospitals within the UK's National Health Service, and the results of the hospital-level survey are reported here. Methods Hospitals were surveyed to assess obstetric anaesthesia provision, practice, and care delivery. Questions explored staffing, service provision and training, facilities present, clinical practices, outcome measurement, and key indicators of quality in obstetric anaesthesia. Results We received responses from 106 participating hospitals, representing 69% of all UK obstetric units. One hundred (94%) hospitals had a dedicated consultant obstetric anaesthetist within working hours, with 27 (25%) of hospitals' duty anaesthetists having additional clinical responsibilities outside the care of obstetric patients outside of working hours. Around 102 hospitals (98%) offer multidisciplinary team training, of which 95 (93%) use a simulation-based method. Dedicated high-risk antenatal clinics were present in 50 (47%) hospitals. The majority of hospitals provide written patient information in multiple languages for discussing obstetric anaesthesia options (77, 82%). Seventy-three hospitals (69%) use point-of-care testing to estimate haemoglobin concentration. Labour epidural analgesia is most commonly delivered via patient-controlled epidural analgesia in 80 (76%) hospitals, and the incidence of post-dural puncture headaches was recorded by 80 (76%) hospitals. Conclusions These results demonstrate variation in the provision of staffing, facilities, clinical practices, and outcome measurements across the UK. To deliver safe and equitable care across the UK, there needs to be standardisation of anaesthetic peripartum care based on national recommendations and the benchmarking and measurement of appropriate markers of quality., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. UK National Research Ethics Service (South Central - Berkshire B REC) issued approval 19/SC/0333. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, O'Carroll et al.)

Introduction: Routine workflows were redesigned during the first surge of the COVID-19 pandemic to standardize perioperative management of patients and minimize the risk of viral exposure and transmission to staff members. Just-in-time (JIT), in situ simulation training was adopted to implement urgent change, the value of which in a public health crisis has not previously been explored., Methods: Implementation of workflow changes in the setting of the COVID-19 pandemic was accomplished through JIT, in situ simulation training, delivered over a period of 3 weeks to participants from anesthesia, nursing, and surgery, within our healthcare network. The perceived value of this training method was assessed using a postsimulation training survey, composed of Likert scale assessments and free-text responses. The impact on change in practice was assessed by measuring compliance with new COVID-19 workflows for cases of confirmed or suspected COVID-19 managed in the operating room, between March and August 2020., Results: Postsimulation survey responses collected from 110 of 428 participants (25.7%) demonstrated significant positive shifts along the Likert scale on perceived knowledge of new workflow processes, comfort in adopting them in practice and probability that training would have an impact on future practice (all P s < 0.001). Free-text responses reflected appreciation for the training being timely, hands-on, and interprofessional. Compliance with new COVID workflows protocols in practice was 95% (121 of 127 cases) and was associated with lower than expected healthcare worker test positive rates (<1%) within the network during this same period., Conclusions: These findings support JIT, in situ simulation training as a preparedness measure for the perioperative care of COVID-19 patients and demonstrate the value of this approach during public health crises., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society for Simulation in Healthcare.)

Background: The management of obstetric patients with coronavirus disease 2019 (COVID-19) due to human-to-human transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires unique considerations. Many aspects of labour and delivery practice required adaptation in response to the global pandemic and were supported by guidelines from the Royal College of Obstetrics and Gynaecologists. The adoption and adherence to these guidelines is unknown., Methods: Participating centres in "Quality of Recovery in Obstetric Anaesthesia study-a multicentre study" (ObsQoR) completed an electronic survey based on the provision of services and care related to COVID-19 in October 2021. The survey was designed against the Royal College of Obstetricians and Gynaecologists COVID-19 guidelines., Results: One hundred and five of the 107 participating centres completed the survey (98% response rate representing 54% of all UK obstetric units). The median [IQR] annual number of deliveries among the included sites was 4389 [3000-5325]. Ninety-nine of the 103 (94.3%) sites had guidelines for the management of peripartum women with COVID-19. Sixty-one of 105 (58.1%) sites had specific guidance for venous thromboembolism (VTE) prophylaxis. Thirty-seven of 104 (35.6%) centres restricted parturient birthing plans if a positive diagnosis of COVID-19 was made. A COVID-19 vaccination referral pathway encouraging full vaccination for all pregnant women was present in 63/103 centres (61.2%)., Conclusion: We found variability in care delivered and adherence to guidelines related to COVID-19. The clinical implications for this related to quality of peripartum care is unclear, however there remains scope to improve pathways for immunisation, birth plans and VTE prophylaxis., (Copyright © 2022 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

Study Objective: To evaluate the effectiveness of preoperative gabapentinoid administration., Design: Retrospective hospital registry study., Setting: Tertiary referral center (Boston, MA)., Patients: 111,008 adult non-emergency, non-cardiac surgical patients between 2014 and 2018., Interventions: Preoperative administration of gabapentinoids (gabapentin or pregabalin)., Measurements: We tested the primary hypothesis that preoperative gabapentinoid use was associated with lower odds of hospital readmission within 30 days. Contingent on this hypothesis, we examined whether lower intraoperative opioid utilization mediated this effect. Secondary outcome was postoperative respiratory complications., Main Results: Gabapentinoid administration was associated with lower odds of readmission (adjusted odds ratio [OR adj ] 0.80 [95% CI, 0.75-0.85]; p < 0.001). This effect was in part mediated by lower intraoperative opioid utilization in patients receiving gabapentinoids (8.2% [2.4-11.5%]; p = 0.012). Readmissions for gastrointestinal disorders (OR adj 0.74 [0.60-0.90]; p = 0.003), neuro-psychiatric complications (OR adj 0.66 [0.49-0.87]; p = 0.004), non-surgical site infections (OR adj 0.68 [0.52-0.88; p = 0.004) and trauma or poisoning (OR adj 0.25 [0.16-0.41]; p < 0.001) occurred less frequently in patients receiving gabapentinoids. The risk of postoperative respiratory complications was lower in patients receiving gabapentinoids (OR adj 0.77 [0.70-0.85]; p < 0.001). Lower doses of pregabalin (< 75 mg) and gabapentin (< 300 mg) compared to both, no and high-dose administration of gabapentinoids, were associated with a lower risk of postoperative respiratory complications (OR adj 0.61 [0.50-0.75]; p < 0.001 and OR adj 0.70 [0.53-0.92]; p = 0.012, respectively). These lower gabapentinoid doses prevented 30-day readmission (OR adj 0.74 [0.65-0.85]; p < 0.001). The results were robust in several sensitivity analyses including surgical procedure defined subgroups and patients undergoing ambulatory surgery., Conclusions: The preoperative use of pregabalin and gabapentin, up to doses of 75 and 300 mg respectively, mitigates the risks of hospital readmission and postoperative respiratory complications which can in part be explained by lower intraoperative opioid use. Further research is warranted to elucidate mechanisms of the preventive action., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Preparedness efforts for a COVID-19 outbreak required redesign and implementation of a perioperative workflow for the management of obstetric patients. In this report we describe factors which influenced rapid cycle implementation of a novel comprehensive checklist for the perioperative care of the COVID-19 parturient., Methods: Within our labour and delivery unit, implementation of a novel checklist for the COVID-19 parturient requiring perioperative care was accomplished through rapid cycling, debriefing and on-site walkthroughs. Post-implementation, consistent use of the checklist was reported for all obstetric COVID-19 perioperative cases (100% workflow checklist utilization). Retrospective analysis of the factors influencing implementation was performed using a group deliberation approach, mapped against the Consolidated Framework for Implementation Research (CFIR)., Results: Analysis of factors influencing implementation using CFIR revealed domains of process implementation and innovation characteristics as overwhelming facilitators for success. Constructs within the outer setting, inner setting, and characteristic of individuals (external pressures, baseline culture, and personal attributes) were perceived to act as early barriers. Constructs such as communication culture and learning climate, shifted in influence over time., Conclusion: We describe the influential factors of implementing a novel comprehensive obstetric workflow for care of the COVID-19 perioperative parturient during the first surge of the pandemic using the CFIR framework. Early workflow adoption was facilitated primarily by two domains, namely thoughtful innovation design and careful implementation planning in the setting of a long-standing culture of improvement. Factors initially assessed as barriers such as communication, culture and learning climate, transitioned into facilitators once a perceived benefit was experienced by healthcare teams. These results provide important information for the implementation of rapid change during a time of crisis., (© 2021. The Author(s).)

Background: In this study, we explored the utility of intravenous opioid rescue analgesia in the post anesthesia care unit (PACU-OpResc) as a single marker of thoracic epidural analgesia (TEA) failure and evaluated the resource implications and quality improvement applications of this measure., Methods: We performed a retrospective analysis of all TEA placements over a three-year period at a single academic medical center in Boston, Massachusetts. The study exposure was PACU-OpResc. Primary outcome was PACU length of stay (LOS). Secondary outcomes included reasons for delayed PACU discharge and intraoperative hypotension. The analyses were adjusted for confounding variables including patient comorbidities, surgical complexity, intraoperative intravenous opioids, chronic opioid use and local anesthetic bolus through TEA catheter. Post analysis chart review was conducted to determine the positive predictive value (PPV) of PACU-OpResc for inadequate TEA. As a first Plan-Do-Study-Act cycle, we then introduced a checkbox for documentation of a sensory level check after TEA placement. Post implementation data was collected for 7 months., Results: PACU-OpResc was required by 211 (22.1%) patients who received preoperative TEA, was associated with longer PACU LOS (incidence rate ratio 1.20, 95% CI:1.07-1.34, p = 0.001) and delayed discharge due to inadequate pain control (odds ratio 5.15, 95% CI 3.51-7.57, p <  0.001). PACU-OpResc had a PPV of 76.3 and 60.4% for re-evaluation and manipulation of the TEA catheter in PACU, respectively. Following implementation of a checkbox, average monthly compliance with documented sensory level check after TEA placement was noted to be 39.7%. During this time, a reduction of 8.2% in the rate of PACU-OpResc was observed., Conclusions: This study demonstrates that PACU-OpResc can be used as a quality assurance measure or surrogate for TEA efficacy, to track performance and monitor innovation efforts aimed at improving analgesia, such as our intervention to facilitate sensory level checks and reduced PACU-OpResc., Trial Registration: not applicable.

Health care workers performing aerosolizing procedures on patients with transmissible infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are at high-risk for disease acquisition. Current guidelines designed to protect health care workers during aerosolizing procedures prioritize personal protective equipment and enhanced infection control techniques, in particular during procedures such as intubation. To date, little emphasis has been placed on risk mitigation in the setting of bronchoscopy, a procedure that has significant aerosolization potential. Herein, we present an innovative closed bronchoscopy system designed to reduce aerosolization during bronchoscopy., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

Background: Care of the pregnant patient during the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic presents many challenges, including creating parallel workflows for infected and noninfected patients, minimizing waste of materials, and ensuring that clinicians can seamlessly transition between types of anesthesia. The exponential community spread of disease limited the time for development and training., Methods: The goals of our workflow and process development were to maximize safety for staff and patients, minimize the risk of contamination, and reduce the waste of unused supplies and materials. We used a cyclical improvement system and the plus/delta debriefing method to rapidly develop workflows consisting of sequential checklists and procedure-specific packs., Results: We designed independent workflows for labor analgesia, neuraxial anesthesia for cesarean delivery, conversion of labor analgesia to cesarean anesthesia, and general anesthesia. In addition, we created procedure-specific material packs to optimize supplies and prevent wastage. Finally, we generated sequential checklists to allow staff to perform standard operating procedures without extensive training., Conclusions: Collectively, these workflows and tools allowed our staff to urgently care for patients in high-risk situations without prior experience. Over time, we refined the workflows using a cyclical improvement system. We present our checklists and workflows as well as the system we used for their development, so that others may use them to their benefit.

Preparedness measures for the anticipated surge of coronavirus disease 2019 (COVID-19) cases within eastern Massachusetts included the establishment of alternate care sites (field hospitals). Boston Hope hospital was set up within the Boston Convention and Exhibition Center to provide low-acuity care for COVID-19 patients and to support local healthcare systems. However, early recognition of the need to provide higher levels of care, or critical care for the potential deterioration of patients recovering from COVID-19, prompted the development of a hybrid acute care-intensive care unit. We describe our experience of implementing rapid response capabilities of this innovative ad hoc unit. Combining quality improvement tools for hazards detection and testing through in situ simulation successfully identified several operational hurdles. Through rapid continuous analysis and iterative change, we implemented appropriate mitigation strategies and established rapid response and rescue capabilities. This study provides a framework for future planning of high-acuity services within a unique field hospital setting., (Copyright © 2020, the American Society of Anesthesiologists, Inc. All Rights Reserved.)

Idiopathic pulmonary arterial hypertension (IPAH) is a rare and devastating condition. There is no known cure for IPAH, and current treatment options are not always effective. Autologous myeloid angiogenic cells (MACs) have been explored as a novel therapy for IPAH, but preliminary data from clinical trials show limited beneficial effects. A complete understanding of IPAH MAC function remains elusive. This study was designed to comprehensively compare cell function between IPAH MACs and healthy control MACs. MACs were procured through the culture of peripheral blood mononuclear cells in endothelial selective medium for 7 days. Compared with healthy MACs, IPAH MACs exhibited (1) significantly lower levels of endothelial markers as shown by fluorescence microscopy; (2) a markedly higher rate of apoptosis under both normal culture condition and serum starvation as shown by the TUNEL assay; (3) significantly decreased migration towards vascular endothelial growth factor as shown by a modified Boyden chamber migration assay; and (4) similar vascular endothelial growth factor and endothelial nitric oxide synthase mRNA levels as shown by reverse transcription quantitative PCR. In conclusion, various aspects of IPAH MAC function are impaired. To achieve greater therapeutic benefits, pharmacologic and (or) genetic manipulations to improve IPAH MAC function, particularly to promote cell survival and migration, are warranted.

Following the daily review of patients on the general intensive care unit (GICU), ongoing issues are addressed and a management plan formulated. Within our unit, the documentation of this daily review is freehand and should include all items covered within the local GICU daily review checklist. However, an initial audit of the daily review demonstrated an average completion rate of only 57%, with several aspects of care consistently missed, most notably: eye and mouth care in ventilated patients (44% and 40%, respectively), glucose control (33%), stress ulcer prophylaxis (54%), and inspection and need for peripheral and central lines (24%). The current system relied on doctors learning the requirements for the clerking and remembering to document them all. It is known that there is a low level of reliability in successfully applying proven medical evidence; this is partly explained by dependence on vigilance and hard work by the clinician, and absence of checklists and protocols to reduce the impact of human factors on results. The majority of doctors on the unit believe they consistently record all items of this checklist, highlighting the gap between the ideal that clinicians strive towards and the outcome. An abbreviated daily review checklist was therefore implemented in the form of a laminated bookmark into the medical notes, to act as a reminder of the items that should be considered in the daily review and prompt subsequent documentation. Bookmarks were implemented over two PDSA cycles and medical notes re-audited. Post-intervention, the documentation of the daily review improved to an overall completion rate of >77%, with notable improvements in eye and mouth care in ventilated patients (89%, 95% respectively), glucose control (67%), stress ulcer prophylaxis (100%), and inspection and need for peripheral and central lines (43%). The daily review checklist concisely summarised onto bookmarks were cheap and simple to create, durable and easy to use, and improved the overall documentation of the daily review. The effect of this outcome remains untested.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder. Circulating angiogenic cells (CACs) play an important role in vascular repair and regeneration. This study was designed to examine the function of CACs derived from patients with HHT. Peripheral blood mononuclear cells (PBMNCs) isolated from patients with HHT and age- and gender-matched healthy volunteers were assessed for expression of CD34, CD133 and VEGF receptor 2 by flow cytometry. PBMNCs were cultured to procure early outgrowth CACs. Development of endothelial cell (EC) phenotype in CACs was analyzed by fluorescence microscopy. CAC apoptosis was assayed with Annexin V staining, and CAC migration assessed by a modified Boyden chamber assay. mRNA expression of endoglin (ENG), activin receptor-like kinase-1 (ACVLR1 or ALK1) and endothelial nitric oxide synthase (eNOS) in CACs was measured by real time RT-PCR. The percentage of CD34+ cells in PBMNCs from HHT patients was significantly higher than in PBMNCs of healthy controls. CACs derived from patients with HHT not only showed a significant reduction in EC-selective surface markers following 7-day culture, but also a significant increase in the rate of basal apoptosis and blunted migration in response to vascular endothelial growth factor and stromal cell-derived factor-1. CACs from HHT patients expressed significantly lower levels of ENG, ALK1 and eNOS mRNAs. In conclusion, CACs from patients with HHT exhibited various functional impairments, suggesting a reduced regenerative capacity of CACs to repair the vascular lesions seen in HHT patients.

Patients admitted to hospital are immediately overloaded with information from staff in A&E, to subsequent acute medical and inpatient wards. Essential details are conveyed to patients at each step, including diagnosis, management and identification of various team members involved in their care. An initial audit within our South London hospital revealed only one third of patients admitted onto a single medical ward could recall the name of a single member of their treating team, and less than 10% retained that information over 5 days. Identification (ID) cards were devised to facilitate clear transfer of information detailing the patient's treating team. These ID cards were piloted through a series of PDSA cycles on one inpatient medical ward following a consultant led ward round. Post intervention, 67% managed to recall a single member of the treating team, with 67% retaining this information 5 days later, a dramatic improvement. ID cards were then trialed on one surgical ward, demonstrating equally impressive results with over 87% of patients recalling their named consultant following ID card implementation, up from 54% initially. Similar trends were demonstrated for recalling other treating team members. This simple measure improved patients ability to recall and retain names of a least a single member of their treating team, encouraged communication between patients and medical team and ultimately improved patient satisfaction and quality of care. ID cards were quick and easy to implement and have been approved by the hospital patient safety committee to implement throughout the Trust.

Endothelial progenitor cells (EPCs) participate in angiogenesis and the response to chronic ischemia. Risk factors and cardiovascular disease attenuate EPC number, function, and survival. Continuous therapy with nitroglycerin (glyceryl trinitrate; GTN) is associated with increased vascular oxidative stress, leading to nitrate tolerance and endothelial dysfunction. Thus, GTN therapy may also affect EPCs. The purpose of this study was to determine whether continuous exposure to GTN in vivo or during ex vivo expansion affects the circulating number and functional characteristics of human EPCs. To determine the effects of continuous in vivo GTN exposure, EPCs isolated from 28 healthy males before and after receiving 0.6 mg/h GTN (n=17) or no treatment (n=11) for 1 week were expanded for 6 days and compared. To determine the effects of continuous ex vivo GTN exposure, EPCs isolated before randomization were expanded for 6 days in medium supplemented with 100 nM, 300 nM, or 1 microM GTN. EPCs expanded without GTN served as controls (n=10). In vivo, GTN exposure significantly increased the percentage of circulating cells expressing the EPC marker CD34 and increased the susceptibility of expanded EPCs to apoptosis but had no impact on the phenotypic differentiation or migration of EPCs. Ex vivo, GTN exposure increased apoptosis while decreasing phenotypic differentiation, migration, and mitochondrial dehydrogenase activity of EPCs, compared with EPCs expanded in the absence of GTN. Taken together, these results suggest that continuous GTN therapy might impair EPC-mediated processes, an effect that could be detrimental in the setting of ischemic cardiovascular disease.

Mutations in the bone morphogenetic protein (BMP) receptor-2 (BMPR2) have been found in patients with idiopathic pulmonary arterial hypertension (IPAH); however, the mechanistic link between loss of BMPR2 signaling and the development of pulmonary arterial hypertension is unclear. We hypothesized that, contrary to smooth muscle cells, this pathway promotes survival in pulmonary artery endothelial cells (ECs) and loss of BMPR2 signaling will predispose to EC apoptosis. ECs were treated with BMP-2 or BMP-7 (200 ng/mL) for 24 hours in regular or serum-free (SF) medium, with and without addition of tumor necrosis factor alpha, and apoptosis was assessed by flow cytometry (Annexin V), TUNEL, or caspase-3 activity. Treatment for 24 hours in SF medium increased apoptosis, and both BMP-2 and BMP-7 significantly reduced apoptosis in response to serum deprivation to levels not different from serum controls. Transfection with 5 microg of small interfering RNAs for BMPR2 produced specific gene silencing assessed by RT-PCR and Western blot analysis. BMPR2 gene silencing increased apoptosis almost 3-fold (P=0.0027), even in the presence of serum. Circulating endothelial progenitor cells (EPCs) isolated from normal subjects or patients with IPAH were differentiated in culture for 7 days and apoptosis was determined in the presence and absence of BMPs. BMP-2 reduced apoptosis induced by serum withdrawal in EPCs from normal subjects but not in EPCs isolated from patients with IPAH. These results support the hypothesis that loss-of-function mutations in BMPR2 could lead to increased pulmonary EC apoptosis, representing a possible initiating mechanism in the pathogenesis of pulmonary arterial hypertension.