Reporting Standards in Clinical Studies Evaluating Bone Marrow Aspirate Concentrate: A Systematic Review.

PURPOSE: To perform a systematic review of clinical studies evaluating bone marrow aspirate concentrate (BMAC) in the treatment of musculoskeletal pathology to compare levels of reporting with recently published minimum standards. METHODS: A systematic review of the clinical literature from August 2002 to August 2017 was performed. Human clinical studies published in English and involving the administration of BMAC for musculoskeletal applications were included. Studies evaluating non-concentrated preparations of bone marrow aspirate or preparations of laboratory cultured cells were excluded. Studies evaluating the treatment of dental or maxillofacial conditions were excluded. Similarly, in vitro studies, editorials, letters to the editor, and reviews were excluded. Levels of reporting were compared with previously published minimum standards agreed on through an international Delphi consensus process. RESULTS: Of 1,580 studies identified on the initial search, 46 satisfied the criteria for inclusion. Considerable deficiencies in reporting of key variables including the details of BMAC preparation and composition were noted. Studies reported information on only 42% (range, 25%-60%) of the variables included within established minimum reporting standards. No study provided adequate information to enable the precise replication of preparation protocols and accurate characterization of the BMAC formulation delivered. CONCLUSIONS: We found that all existing clinical studies in the literature evaluating BMAC for orthopaedic or sports medicine applications are limited by inadequate reporting of both preparation protocols and composition. Deficient reporting of the variables that may critically influence outcomes precludes interpretation, prevents other researchers from reproducing experimental conditions, and makes comparisons across studies difficult. We encourage the adoption of emerging minimum reporting standards for clinical studies evaluating the use of mesenchymal stem cells in orthopaedics. LEVEL OF EVIDENCE: Level IV, systematic review of Level I through IV studies.

Changing trends in total knee replacement.

INTRODUCTION: This study evaluates a possible change in the demographics and surgical practice observed in a large cohort of patients undergoing total knee replacement (TKR). PATIENTS AND METHODS: We performed a retrospective analysis of a prospectively collected data on two groups of consecutive patients undergoing primary TKR. Group one consisted of patients who underwent surgery between 1994 and 1998. Group two consisted of patients who had surgery between 2009 and 2012. RESULTS: The mean age of group two was significantly greater than that of group one: 68.9 years (68.1-69.7 years) for group one versus 70.1 years (69.6-70.6 years) for group two (p = 0.009). The mean BMI of group two was significantly greater than that of group one: 29.5 kg/m2 (29.0-29.9 kg/m2) for group one versus 32.0 kg/m2 (31.7-32.3 kg/m2) for group two (p < 0.001). The mean pain component of the AKSS was significantly worse in group one than in group two: 28.6 (27.2-30.0) for group one versus 35.5 (34.6-36.4) for group two (p < 0.001). The mean function component of the AKSS was significantly worse in group one than in group two: 48.6 (47.3-49.9) for group one versus 51.5 (50.7-52.3) for group two (p < 0.001). CONCLUSION: This study describes the change in demographics of patients undergoing TKR in our institution over the last two decades.

Multimodal therapy as an algorithm to limb salvage in diabetic patients with large heel ulcers.

In many series of diabetic foot ulcer care, heel ulcers greater than 4 cm across have been identified as an independent predictor of limb loss. Therefore, we set out to pursue the most aggressive limb salvage algorithm in patients with heel ulcers greater than 4 cm in diameter. Over 5 years, we identified 21 patients, 39-84 years of age, all with diabetes mellitus, with heel ulcers greater than 4 cm in diameter and had magnetic resonance imaging or bone scan evidence of osteomyelitis. Seven of the 21 patients had end-stage renal disease defined as being haemodialysis dependent. All patients had ankle brachial indices <0·4 or monophasic pulse volume recordings. All patients underwent distal bypass surgery with vein. After adequate perfusion was obtained, all patients underwent partial calcanectomy and intra-operative negative pressure wound therapy (NPWT) placement. This was followed by treatment with recombinant platelet-derived growth factor (PDGF). One patient underwent amputation during the healing process secondary to ongoing sepsis. Twenty of 21 patients healed acutely (within 6 months). Three of 20 patients went on to subsequent below knee amputation within 12 months of healing primarily. At 2 years, 12 of 21 (57%) were ambulating independently, 1 of 21 was dead, 4 of 21 had undergone amputation, 4 (19%) had limbs that were intact but were not ambulating. A total limb salvage rate of 76% at 2 years mirrored the secondary patency rates, with 100% follow up. Heel ulcers require multimodality therapy if they are going to have any chance to heal. We believe the algorithm presented allows for the required revascularisation and a modulation of the heel ulcer microenvironment by augmenting the microcirculation through NPWT, and improving the proliferative capacity with PDGF.

Functional Outcome After Nonoperative Treatment of a Proximal Humeral Fracture in Adults.

BACKGROUND: The functional outcome following nonoperative treatment of a proximal humeral fracture and the factors that influence it are poorly defined. We aimed to prospectively assess patient-reported outcome measures (PROMs) in a patient cohort at 1 year after the injury. METHODS: In this study, 774 adult patients sustaining a proximal humeral fracture completed PROM assessments, including the Oxford Shoulder Score (OSS), the EuroQol-5 Dimensions-3 Levels (EQ-5D-3L), and visual analog scale (VAS) assessments of pain, health, and overall treatment satisfaction at 1 year. The mean patient age was 65.6 years, and 73.8% of patients were female. The influences of demographic and fracture measurements and complications on the OSS and EQ-5D-3L were assessed. RESULTS: The 1-year mean scores were 33.2 points (95% confidence interval [CI], 32.1 to 34.2 points) for the OSS and 0.58 (95% CI, 0.55 to 0.61) for the EQ-5D-3L. There was considerable heterogeneity in the reported scores, and the 3 demographic variables of higher levels of dependency, higher levels of social deprivation, and a history of affective (mood) disorder were most consistently associated with poorer outcomes, accounting for between 37% and 43% of the score variation. The initial fracture translation potentially leading to nonunion accounted for 9% to 15% of the variation, and a displaced tuberosity fracture was also predictive of 1% to 4% of the outcome variation. There was evidence of a ceiling effect for the OSS, with 238 patients (30.8%) having a score of ≥47 points but a mean outcome satisfaction of only 72.9 points, and this effect was more pronounced in younger, active individuals. At the other end of the spectrum, 239 patients (30.9%) reported an OSS of ≤24 points, and 120 patients (15.5%) had a "worse-than-death" EQ-5D-3L score. CONCLUSIONS: Nonoperative treatment of proximal humeral fractures produces considerable variation in shoulder-specific and general health outcomes at 1 year, and a substantial proportion of patients have poor perceived functional outcomes. The outcome for the majority of less-displaced fractures is mainly influenced by preexisting patient-related psychosocial factors, although the fracture-related factors of displacement, nonunion, and tuberosity displacement account for a small but measurable proportion of the variation and the poorer outcomes in the minority with more severe injuries. LEVEL OF EVIDENCE: Prognostic Level I. See Instructions for Authors for a complete description of levels of evidence.

Outcomes associated with secondary implant removal and arthrolysis in patients with a painful stiff shoulder after proximal humeral fracture fixation.

AIMS: Open reduction and plate fixation (ORPF) for displaced proximal humerus fractures can achieve reliably good long-term outcomes. However, a minority of patients have persistent pain and stiffness after surgery and may benefit from open arthrolysis, subacromial decompression, and removal of metalwork (ADROM). The long-term results of ADROM remain unknown; we aimed to assess outcomes of patients undergoing this procedure for stiffness following ORPF, and assess predictors of poor outcome. METHODS: Between 1998 and 2018, 424 consecutive patients were treated with primary ORPF for proximal humerus fracture. ADROM was offered to symptomatic patients with a healed fracture at six months postoperatively. Patients were followed up retrospectively with demographic data, fracture characteristics, and complications recorded. Active range of motion (aROM), Oxford Shoulder Score (OSS), and EuroQol five-dimension three-level questionnaire (EQ-5D-3L) were recorded preoperatively and postoperatively. RESULTS: A total of 138 patients underwent ADROM; 111 patients were available for long-term follow-up at a mean of 10.9 years (range 1 to 20). Mean age was 50.8 years (18 to 75);79 (57.2%) were female. Mean time from primary ORPF to ADROM was 11.9 months (6 to 19). Five patients developed superficial wound infection; ten developed symptomatic osteonecrosis/post-traumatic arthrosis (ON/PTA); four underwent revision arthrolysis. Median OSS improved from 17 (interquartile range (IQR) 12.0 to 22.0) preoperatively to 40.0 (IQR 31.5 to 48.0) postoperatively, and 39.0 (IQR 31.5 to 46.5) at long-term follow-up (p < 0.001). Median EQ-5D-3L improved from 0.079 (IQR -0.057 to 0.215) to 0.691 (IQR 0.441 to 0.941) postoperatively, and 0.701 (IQR 0.570 to 0.832) at long-term follow-up (p < 0.001). We found that aROM improved in all planes (p < 0.001). Among the variables assessed on multivariable analysis, a manual occupation, worsening Charlson Comorbidity Index and increasing socioeconomic deprivation were most consistently predictive of worse patient-reported outcome scores. Patients who subsequently developed ON/PTA reported significantly worse one-year and late OSS. CONCLUSION: ADROM in patients with persistent symptomatic stiffness following ORPF can achieve excellent short- and long-term outcomes. More deprived patients, those in a manual occupation, and those with worsening comorbidities have worse outcomes following ADROM. Cite this article: Bone Joint J 2022;104-B(1):157-167.

Prediction of Nonunion After Nonoperative Treatment of a Proximal Humeral Fracture.

BACKGROUND: The prevalence of nonunion after a proximal humeral fracture (PHF) and the risk factors for its occurrence are poorly defined. We aimed to estimate the rate of nonunion in nonoperatively treated patients and to produce a clinical model for its prediction. METHODS: Two thousand two hundred and thirty adult patients (median age, 72 years [range, 18 to 103 years]; 75.5% were female) with a PHF underwent assessment of fracture union using standard clinical evaluation and conventional radiographs. We assessed the prevalence of nonunion and measured the effect of 19 parameters on healing. Best statistical practices were used to construct a multivariate logistic regression model. The PHF assessment of risk of nonunion model (PHARON) was externally validated in a subsequent prospectively collected population of 735 patients, treated by the same protocol in our institution. RESULTS: Overall, 231 (10.4%) of 2,230 patients developed nonunion. Only 3 (0.8%) of 395 patients with a head-shaft angle (HSA) of >140° developed nonunion; in this cohort, none of the measured candidate variables were independently predictive of nonunion on multivariate logistic regression analysis. In the larger cohort of 1,835 patients with an HSA of ≤140°, 228 (12.4%) developed nonunion. Decreasing HSA, increasing head-shaft translation (HST), and smoking were independently predictive of nonunion on multivariate analysis. The prevalence of nonunion was very low (1%) in the majority with both an HSA of >90° and HST of <50%, whereas the risk was much higher (83.7%) in the 8.3% with an HSA of ≤90° and HST of ≥50%. In both groups, the prevalence of nonunion was much higher in smokers. CONCLUSIONS: The prevalence of nonunion after PHF is higher than previously reported. Most patients have favorable risk-factor estimates and a very low risk of this complication, but a smaller subgroup is at much higher risk. The risk can be accurately estimated with PHARON, using standard clinical assessment tools. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Open Reduction and Long Locking Plate Fixation of Complex Proximal Humeral Metadiaphyseal Fractures.

BACKGROUND: A minority of proximal humeral fractures extend into the diaphysis and their optimal treatment remains controversial. We evaluated the outcomes and risk of complications in patients with these injuries, treated by a protocol of open reduction and long locking plate fixation (LPF). METHODS: Between 2007 and 2014, all locally resident patients with a proximal humeral fracture extending into the diaphysis were referred to a specialist shoulder clinic. Operative treatment using a protocol of open reduction and LPF was offered to medically fit patients. Those with 2-year radiographic follow-up were included in the study, and standardized assessments of clinical and radiographic outcomes were performed during the first 2 years postoperatively. At a mean of 8.8 years (range, 5 to 12 years) after LPF, the functional outcomes and satisfaction of surviving, cognitively intact patients were assessed with a questionnaire study. RESULTS: One hundred and two patients met the inclusion criteria; the majority were older women who had incurred the injury during a simple fall. Fractures were divided into 2 types depending on the pattern of diaphyseal extension. The pain levels, functional scores, and satisfaction with treatment were satisfactory both at the 2-year follow-up and at the longer-term follow-up at a mean of 8.8 years postsurgery. Complications were predominantly due to postsurgical stiffness (in 7 patients, with 3 undergoing additional surgery) and nonunion or fixation failure (in 7 patients, with 6 undergoing additional surgery). CONCLUSIONS: Proximal humeral fractures with diaphyseal extension are rare. The results of our study support the use of LPF in medically stable patients in centers with the expertise to perform these procedures. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Complications and Long-Term Outcomes of Open Reduction and Plate Fixation of Proximal Humeral Fractures.

BACKGROUND: The optimal treatment of complex proximal humeral fractures in adults remains controversial. We evaluated the risk of complications and the long-term outcomes in patients with a severely displaced fracture or a fracture-dislocation of the proximal part of the humerus treated with open reduction and plate fixation (ORIF). METHODS: Between 1995 and 2012, 5,897 consecutive patients with a proximal humeral fracture were referred to a specialist shoulder clinic for surgical assessment. Indications for surgery included anterior or posterior fracture-dislocation, substantial tuberosity involvement with >1 cm of displacement in a Neer 3 or 4-part fracture configuration, disengagement of the head from the shaft, or severe varus or valgus deformity of the head. All patients who met the surgical criteria and had been followed for 2 years were included, and standardized clinical and radiographic assessments of outcomes were performed. At a median of 10.8 years (range, 5 to 22 years) after ORIF, all surviving cognitively intact patients completed a patient-reported questionnaire assessing functional outcomes and satisfaction. RESULTS: Three hundred and sixty-eight patients (6.2%) met the inclusion criteria and had the appropriate follow-up. The study population had a high rate of complex fracture configurations; 77.2% had tuberosity involvement, 54.1% had complete head-shaft disengagement, and 44.0% had a dislocated head. Eighty-seven patients (23.6%) had postoperative stiffness, 25 (6.8%) had fixation failure/nonunion, and 16 (4.3%) had late osteonecrosis/posttraumatic osteoarthritis; these complications were the reason for the majority of the reoperations in the cohort. The survivorship until any reoperation was 74% at 10 years, but when reoperations for stiffness were excluded, the survivorship was 90% during the same time period. The patients' mean levels of pain, function, and satisfaction with treatment were good to excellent. CONCLUSIONS: Our results support the use of primary ORIF in medically fit patients with a severely displaced fracture or a fracture-dislocation of the proximal part of the humerus in centers where the expertise to carry out such treatment exists. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Reporting of Mesenchymal Stem Cell Preparation Protocols and Composition: A Systematic Review of the Clinical Orthopaedic Literature.

BACKGROUND: Mesenchymal stem cells (MSCs) are increasingly being used in the treatment of a wide variety of sports-related conditions. Despite this enthusiasm, the biological properties of MSCs and their effects on musculoskeletal tissue healing remain poorly understood. MSC-based strategies encompass cell populations with heterogeneous phenotypes isolated from multiple tissues and using different methods. Therefore, comprehensive reporting of the source, preparation methods, and characteristics of MSC strategies is essential to enable interpretation of results. PURPOSE: To perform a systematic review of levels of reporting of key variables in MSC preparation and composition for clinical studies evaluating MSC-based therapies in the treatment of musculoskeletal conditions. STUDY DESIGN: Systematic review. METHODS: A systematic review of the clinical orthopaedic and sports medicine literature from 2002 to 2017 was performed. The following inclusion criteria were used: human clinical trials, published in the English language, involving the administration of MSC-based therapies for orthopaedic or sports medicine applications. In vitro or ex vivo studies, editorials, letters to the editor, and studies relating to cosmetic, neurological, or dental applications were excluded. RESULTS: Of the 1259 studies identified on the initial search, 36 studies were found to satisfy the inclusion criteria for analysis on comprehensive review. Fifty-seven percent of studies evaluated bone marrow-derived MSCs, 41% evaluated adipose-derived MSCs, and 2% evaluated synovium-derived MSCs. Considerable deficiencies in the reporting of key variables, including the details of stem cell processing, culture conditions, and the characteristics of cell populations delivered, were noted. Overall, studies reported only 52% (range, 30%-80%) of variables that may critically influence outcome. No study provided adequate information relating to all of these variables. CONCLUSION: All existing clinical studies evaluating MSCs for orthopaedic or sports medicine applications are limited by inadequate reporting of both preparation protocols and composition. Deficient reporting of the variables that may critically influence outcome precludes interpretation, prevents others from reproducing experimental conditions, and makes comparisons across studies difficult. We encourage the adoption of emerging minimum reporting standards for clinical studies evaluating the use of MSCs in orthopaedics.

Open Reduction and Tunneled Suspensory Device Fixation Compared with Nonoperative Treatment for Type-III and Type-IV Acromioclavicular Joint Dislocations: The ACORN Prospective, Randomized Controlled Trial.

BACKGROUND: Nonoperative management of complete acromioclavicular (AC) joint dislocation has yielded reasonable results, although patients may report dissatisfaction with the outcome. The purpose of this prospective, randomized, controlled trial was to compare patient outcome following nonoperative care versus operative treatment with open reduction and tunneled suspension device (ORTSD) fixation for acute, type-III or IV disruptions of the AC joint. METHODS: Sixty patients aged 16 to 35 years with an acute type-III or IV disruption of the AC joint were randomized to receive ORTSD fixation or nonoperative treatment, following a power analysis to determine sample size. Functional outcomes were assessed with use of the Disabilities of the Arm, Shoulder and Hand (DASH) as the primary outcome measure and the Oxford Shoulder Scores (OSS) and Short Form (SF-12) as secondary outcome measures at 6 weeks, 3 months, 6 months, and 1 year after treatment. Reduction was evaluated with use of radiographs. Any complications were noted at each assessment. The economic implication of each treatment was evaluated. RESULTS: ORTSD and nonoperative groups were similar with regard to demographics at baseline. The mean degree of radiographic displacement was significantly less in patients following ORTSD fixation (1.75 mm) compared with patients who received nonoperative treatment (10.61 mm, p < 0.0001). At 1 year postoperatively, the mean DASH score was 4.67 in the nonoperative treatment group and 5.63 in the ORTSD group, and the mean OSS was 45.72 and 45.63, respectively. Patients managed with ORTSD fixation had inferior DASH scores at 6 weeks (p < 0.01). There were 5 patients who experienced failed nonoperative treatment and subsequently underwent a surgical procedure. ORTSD fixation (£3,359.73) was associated with significantly higher costs than nonoperative treatment (£796.22, p < 0.0001). CONCLUSIONS: ORTSD fixation confers no functional benefit over nonoperative treatment at 1 year following type-III or IV disruptions of the AC joint. Although patients managed nonoperatively generally recovered faster, a substantial group of patients remained dissatisfied following nonoperative treatment and required delayed surgical reconstruction. We were unable to identify any demographic or injury-related factors that predicted a poorer outcome in these patients. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Minimum Information for Studies Evaluating Biologics in Orthopaedics (MIBO): Platelet-Rich Plasma and Mesenchymal Stem Cells.

BACKGROUND: A comprehensive approach to the evaluation of biologic therapies for musculoskeletal conditions is required to guide appropriate future use. Clinical studies evaluating platelet-rich plasma (PRP) and mesenchymal stem cells (MSCs) are limited by inadequate reporting of scientific details critical to outcome. We developed minimum reporting requirements for clinical studies evaluating PRP and MSCs using Delphi consensus methods. METHODS: The need for consensus on the minimum reporting requirements for studies evaluating biologics was identified at the American Academy of Orthopaedic Surgeons/Orthopaedic Research Society (AAOS/ORS) Biologic Treatments for Orthopaedic Injuries Symposium in 2015 and the American Orthopaedic Society for Sports Medicine (AOSSM) Biologic Treatments for Sports Injuries II Think Tank in 2015. A working group facilitated the development of 2 expert consensus statements for PRP and MSCs using Delphi techniques. Exhaustive lists of items that could be reported on by clinical studies evaluating PRP or MSCs were generated by searching the published literature and protocols. PRP and MSC expert groups, each made up of 24 invited speakers at the AAOS and AOSSM symposia, were surveyed on 3 occasions to establish consensus on the inclusion of each item within minimum reporting guidelines. In addition to rating their agreement, the experts were encouraged to propose further items or modifications. Predefined criteria were used to refine item lists after each survey. Final lists were compiled into checklist statements by the working group. RESULTS: For PRP, the working group identified 93 experimental information items from the literature. Twenty-three experts (96%) completed 3 rounds of surveys. After 3 rounds, 58 items generated consensus with >75% agreement and <5% disagreement. These items were compiled into a 23-statement checklist. For MSCs, 103 items were identified from the published literature. Twenty-three experts (96%) completed 3 rounds of surveys. After 3 rounds, the 61 items for which consensus was reached were compiled into a 25-statement checklist. CONCLUSIONS: This study has established expert consensus on the minimum reporting requirements for clinical studies evaluating PRP and MSCs. CLINICAL RELEVANCE: These checklists provide specifications for the minimum information that should be reported by clinical studies evaluating PRP or MSCs.

Resurfacing hip replacement and cemented total hip replacement have equivalent outcome at one year in a disease matched population: a case-control study of patient reported outcome measures.

Resurfacing hip replacement has demonstrated good survival and outcomes for cohorts of younger male patients, but few controlled studies exist. In this study we compared patient reported outcome measures and satisfaction scores at one year following resurfacing hip replacement in 69 male patients with two control groups of equal numbers undergoing cemented total hip replacement: aged-matched patients and disease matched patients. At one year we found no difference in improvement in patient reported outcome measures between patients undergoing resurfacing hip replacement and disease matched patients, whereas patients undergoing resurfacing hip replacement had a statistically significant improvement in Oxford Hip Score compared to the age-matched controls (p<0.047) although this was below the minimally clinically detectable difference. Resurfacing hip replacement and total hip replacement both confer increase in patient reported outcome scores and high patient satisfaction at one year. The results of this study will allow better counselling of patients and help inform treatment decisions.

Functional anatomy and biomechanics of shoulder stability in the athlete.

Glenohumeral joint motion results from a complex interplay between static and dynamic stabilizers that require intricate balance and synchronicity. Instability of the shoulder is a commonly encountered problem in active populations, especially young athletes. The underlying pathoanatomy predisposing to further episodes and the needs of individual athletes must be considered in determining the most appropriate treatment.

Debonding of the acetabular porous coating of a hip resurfacing arthroplasty: a case report.

We report an unusual case of loosening of the acetabular component of a hip resurfacing arthroplasty due to debonding of the titanium surface coating from the acetabular shell. A 41-year-old male scaffolder had bilateral hip resurfacings in 2006. These initially functioned well. At 54 months he was found to have migration of the acetabular component on the right side. This was subsequently revised to a cemented total hip arthroplasty. Debonding of the surface coating was suspected on radiographs prior to the revision procedure, and was confirmed intraoperatively.

Vascular effects of apelin in vivo in man.

OBJECTIVES: This study was designed to establish the direct vascular effects of apelin in vivo in man. BACKGROUND: Apelin is the endogenous ligand for the previously orphaned G-protein-coupled receptor, APJ. This novel pathway is widely expressed in the cardiovascular system and is emerging as an important mediator of cardiovascular homeostasis. In pre-clinical models, apelin causes venous and arterial vasodilation. METHODS: Vascular effects of apelin were assessed in 24 healthy volunteers. Dorsal hand vein diameter was measured by the Aellig technique during local intravenous infusions (0.1 to 3 nmol/min) of apelin-36, (Pyr(1))apelin-13, and sodium nitroprusside (0.6 nmol/min). Forearm blood flow was measured by venous occlusion plethysmography during intrabrachial infusions of apelin-36 and (Pyr(1))apelin-13 (0.1 to 30 nmol/min) and subsequently in the presence or absence of a "nitric oxide clamp" (nitric oxide synthase inhibitor, L-N(G)-monomethylarginine [8 mumol/min], coinfused with nitric oxide donor, sodium nitroprusside [90 to 900 ng/min]), or a single oral dose of aspirin (600 mg) or matched placebo. RESULTS: Although sodium nitroprusside caused venodilation (p < 0.0001), apelin-36 and (Pyr(1))apelin-13 had no effect on dorsal hand vein diameter (p = 0.2). Both apelin isoforms caused reproducible vasodilation in forearm resistance vessels (p < 0.0001). (Pyr(1))apelin-13-mediated vasodilation was attenuated by the nitric oxide clamp (p = 0.004) but unaffected by aspirin (p = 0.7). CONCLUSIONS: Although having no apparent effect on venous tone, apelin causes nitric oxide-dependent arterial vasodilation in vivo in man. The apelin-APJ system merits further clinical investigation to determine its role in cardiovascular homeostasis.