Study of variations in inpatient opioid consumption after total shoulder arthroplasty: influence of patient- and surgeon-related factors.

BACKGROUND: The aims of this study were to examine variances in inpatient opioid consumption after total shoulder arthroplasty (TSA) and to determine factors influencing inpatient opioid utilization. METHODS: The sample included patients undergoing elective TSA at a tertiary-level institution between January 2016 and April 2018. Opioid consumption during the inpatient stay was converted into morphine milligram equivalents (MMEs), accounting for dosage and route of administration. The MMEs were calculated per patient encounter and used to calculate mean opioid consumption. Bivariate linear regression analysis was performed to assess the impact of patient-related factors and surgery-related factors on inpatient opioid consumption. RESULTS: Altogether 20 surgeons performed 622 TSAs. The average opioid dose per encounter was 47.4 ± 65.7 MME/d. MMEs prescribed varied significantly among surgeon providers (P < .01). Pre-existing psychiatric disorders (P = .00012), preoperative opioid use (P = .0013), highest quartile of median household income (P = .048), current-smoker status (P < .001), age < 60 years (P < .01), and general anesthesia (vs. regional anesthesia, P = .005) were associated with significant inpatient opioid consumption after TSA. Sex, race, American Society of Anesthesiologists status, replacement type (anatomic TSA vs. reverse TSA), and prior shoulder surgery did not show any significant differences. CONCLUSION: There is considerable variation in inpatient opioid consumption after TSA at the same institution. Knowledge of modifiable and nonmodifiable risk factors that increase inpatient opioid consumption will help to optimize multimodal analgesia protocols for TSA.

Effects of Sagittal Spinal Alignment on Postural Pelvic Mobility in Total Hip Arthroplasty Candidates.

BACKGROUND: Recent research has demonstrated that patients with reduced pelvic mobility from standing to sitting have higher rates of dislocation after total hip arthroplasty (THA). This study evaluates the effect of sagittal spinal deformity, defined by pelvic incidence-lumbar lordosis mismatch (PI-LL), on postural changes in pelvic tilt (PT). METHODS: A multicenter database of 1100 preoperative THA patients was queried. Anterior-pelvic-plane tilt (APPt), spinopelvic tilt (SPT), and LL were measured from radiographs of patients in supine, standing, flexed-seated, and stepping-up postures; PI was measured from computed tomography. Patients were separated into 3 groups based on PI-LL (<-10°, -10° to 10°, >10°) and propensity-score matched by PI. Lumbar flatback-deformity was defined as PI-LL > 10°, hyperlordosis: PI-LL < -10°. SPT/APPt, including changes between each posture were compared across PI-LL groups using analysis of variance, with post-hoc Tukey tests. Pearson correlations were reported when testing associations between SPT/APPt change and PI-LL. RESULTS: After propensity-score matching, 288 patients were analyzed (mean 65 y; 49% F). SPT and APPt change differed across all PI-LL categories from standing to seated, supine, and stepping-up with less SPT/APPt recruitment among hyperlordotic vs flatback patients (all P < .001). Greater PI-LL correlated with greater SPT recruitment from standing to seated (R = 0.294), supine (R = 0.292), and stepping-up (R = 0.207) (all P < .001). Smaller LL changes from standing to seated were associated with greater SPT recruitment (R = 0.372, P < .001). CONCLUSIONS: Postural changes in SPT/APPt are associated with spinopelvic measures in THA candidates. Hyperlordotic patients tend to utilize their spines more compared with flatback patients who were more likely to recruit PT. Increased focus on patients with lumbar flatback and hyperlordosis may help in reducing prosthetic dislocation prevalence following THA.

Emerging Strategies on Adjuvant Therapies for Nerve Recovery.

Current strategies for promoting faster and more effective peripheral nerve healing have utilized a wide variety of techniques and approaches. Nerve grafts, conduits, and stem cell therapy all have their respective advantages. However, there are still some difficulties in attaining complete functional recovery with a single treatment modality. The utilization of adjuvant treatments, in combination with current standard-of-care methods, offers the potential to improve patient outcomes. This paper highlights the current landscape of adjuvant treatments for enhancing peripheral nerve repair and regeneration.

The Use of Bone Morphogenetic Protein 2 (BMP-2) in Spine Surgery Is It Valuable?

BACKGROUND: Bone morphogenetic protein 2 (BMP-2) is one of the most widely used biologics in spine surgery. Its osteoinductive properties have been shown since its inception to improve fusion rates. Despite the positive effects on promoting fusion, there remains concerns regarding the significant costs associated with its use. The goal of this review was to investigate the value of BMP-2 in spine surgery. METHODS: A literature search was performed on various studies that report on the cost effectiveness and the value of BMP-2 in spine surgery. The value of BMP-2 was analyzed in two distinct settings: comparison to the gold standard iliac crest autograft and demineralized bone matrix. The value of BMP-2 was further analyzed in the setting of spinal deformity surgery. RESULTS: The findings of our review determined that BMP-2 offers significant improvement in outcomes related to improvement of fusion rates and minimization of pseudoarthrosis and reoperations related to pseudoarthrosis and donor site morbidity from harvesting iliac crest bone graft. However, BMP-2 has been found to be significantly more expensive in comparison to iliac crest bone graft and other bone graft substitutes, which detracts from its positive value. In deformity surgery, BMP-2 is associated with improvement in fusion rates as well as reducing the rate of reoperations and pseudoarthrosis. These positive outcomes, however, are associated with an expensive upfront cost for BMP-2. CONCLUSIONS: In terms of value, BMP-2 is associated with improvement in quality outcomes related to a reduction in pseudoarthrosis and reoperations. It also leads to improved outcomes with a reduction in donor site morbidity associated with iliac crest bone graft harvest. However, the value of BMP-2 is negatively affected because of its significant costs. As a result, higher expense thresholds are needed to increase quality adjusted life years in patients who receive BMP-2. Further research investigating ways to minimize the costs associated with BMP-2 use can further improve its value in spine surgery.

Bariatric Surgery Lowers Rates of Spinal Symptoms and Spinal Surgery in a Morbidly Obese Population.

STUDY DESIGN: Retrospective analysis of New York State Inpatient Database years 2004-2013. OBJECTIVE: Assess rates of spinal diagnoses and procedures before and after bariatric surgery (BS). SUMMARY OF BACKGROUND DATA: BS for morbid obesity helps address common comorbidity burdens and improves quality of life for patients. The effects of BS on spinal disorders and surgical intervention have yet to be investigated. MATERIALS AND METHODS: Patients included in analysis if they underwent BS and were seen at the hospital before and after this intervention. Spinal conditions and rates of surgery assessed before and after BS using χ 2 tests for categorical variables. Multivariable logistic regression analysis used to compare rates in BS patients to control group of nonoperative morbidly obese patients. Logistic testing controlled for comorbidities, age, biological sex. RESULTS: A total of 73,046 BS patients included (age 67.88±17.66 y, 56.1% female). For regression analysis, 299,504 nonbariatric, morbidly obese patients included (age 53.45±16.52 y, 65.6% female). Overall, rates of spinal symptoms decreased following BS (7.40%-5.14%, P <0.001). Cervical, thoracic, lumbar spine diagnoses rates dropped from 3.28% to 2.99%, 2.91% to 2.57%, and 5.39% to 3.92% (all P <0.001), respectively. Most marked reductions seen in cervical spontaneous compression fractures, cervical disc herniation, thoracic radicular pain, spontaneous lumbar compression fractures, lumbar spinal stenosis, lumbar spondylosis. Controlling for comorbidities, age and sex, obese nonbariatric patients more likely to have encounters associated with several cervical, thoracic or lumbar spinal diagnoses and procedures, especially for cervical spontaneous compression fracture, radicular pain, lumbar spondylosis, lumbar spinal stenosis, posterior procedures. BS significantly lowered comorbidity burden for many specific factors. CONCLUSIONS: BS lowered rates of documented spinal disorders and procedures in a morbidly obese population. These findings provide evidence of additional health benefits following BS, including reduction in health care encounters for spinal disorders and rates of surgical intervention.

Assessment of Postoperative Outcomes of Spine Fusion Patients With History of Cardiac Disease.

INTRODUCTION: There is paucity on the effect of different cardiac diagnoses on outcomes in elective spine fusion patients. METHODS: Patients undergoing elective spine fusion surgery were isolated in the PearlDiver database. Patients were stratified by having a previous history of coronary artery disease (CAD), congestive heart failure (CHF), valve disorder (valve), dysrhythmia, and no heart disease (control). Means comparison tests (chi-squared and independent samples t-tests, as appropriate) compared differences in demographics, diagnoses, comorbidities, procedural characteristics, length of stay, complication outcomes, and total hospital charges among the cohort. RESULTS: In total, 537,252 elective spine fusion patients were stratified into five groups: CAD, CHF, valve, dysrhythmia, and control. Among the cohort, patients with CHF had significantly higher rates of morbid obesity, peripheral vascular disease, and chronic kidney disease (P < 0.001 for all). Patients with CAD had significantly higher rates of chronic obstructive pulmonary disease, diabetes, hypertension, and hyperlipidemia (all P < 0.001). Comparing postoperative outcomes for CAD and control subjects, CAD was associated with higher odds of myocardial infarction (odds ratio [OR]: 1.64 [1.27 to 2.11]) (P < 0.05). Assessing postoperative outcomes for CHF versus control subjects, patients with CHF had higher rates of pneumonia, cerebrovascular accident (CVA), myocardial infarction, sepsis, and death (P < 0.001). Compared with control subjects, CHF was a significant predictor of death in spine fusion patients (OR: 2.0 [1.1 to 3.5], P = 0.022). Patients with valve disorder compared with control displayed significantly higher rates of 30-day readmission (P < 0.05) and 1.38× greater odds of CVA by 90 days postoperatively (OR: 1.4 [1.1 to 1.7], P = 0.007). Patients with dysrhythmia were associated with significantly higher odds of CVA (OR: 1.8 [1.4 to 2.3], P < 0.001) by 30 days postoperatively. CONCLUSION: Heart disease presents an additional challenge to spine fusion patients who are undergoing a challenging and risky procedure. Before surgical intervention, a proper understanding of cardiac diagnoses could give insight into the potential risks for each patient based on their heart condition and preventive measures showing benefit in minimizing perioperative complications after elective spine fusion.

Fusing to the Sacrum/Pelvis: Does the Risk of Reoperation in Thoracolumbar Fusions Depend on Upper Instrumented Vertebrae (UIV) Selection?

BACKGROUND: There is controversy as to whether fusions should have the upper instrumented vertebrae (UIV) end in the upper lumbar spine or cross the thoracolumbar junction. This study compares outcomes and reoperation rates for thoracolumbar fusions to the sacrum or pelvis with UIV in the lower thoracic versus lumbar spine to determine if there is an increased reoperation rate depending on UIV selection. METHODS: A retrospective review of prospectively collected data was conducted from a single-center database on adult patients with degeneration and deformity who underwent primary and revision fusions with a caudal level of S1 or ilium between 2012 and 2018. Fusions were classified as anterior, posterior, or combination approach. Revision fusions included patients who had spinal surgery at another institution prior to their revision surgery at the center. Patients were categorized into 1 of 3 groups based on UIV: T9-T11, upper lumbar region (L1-L2), and lower lumbar region (L3-L5). Inclusion criteria were age 18 years or older and at least 1 year of clinical follow-up. Patients were excluded from analysis if they had tumors, infections, or less than 1 year of follow-up after the index procedure. RESULTS: The reoperation rates for the UIV groups in the thoracic (28%) and upper lumbar (27%) spine were nearly equal in magnitude and were both significantly higher than the reoperation rate in the lower lumbar group (18%, P = .046). Reoperation for the diagnosis of adjacent segment disease was 8.3% in the upper lumbar spine and statistically significantly higher than the reoperation rates for adjacent segment disease in the thoracic (1%) or lower lumbar (4.5%, P = .042) spine. Reoperations for pseudoarthrosis and proximal junctional kyphosis were 13% and 4%, respectively, in the thoracic spine, both of which were statistically significantly different (pseudoarthrosis, P = .035; proximal junctional kyphosis, P = .002) from the reoperation rates for the same diagnoses in the upper lumbar spine (4.6% and 1%) or lower lumbar spine (6.2% and 0%). A multivariate logistical regression model at 2-year follow up did not show a statistically significant difference between reoperation rates between the thoracic and upper lumbar spine UIV groups. CONCLUSION: Constructs with UIV in the thoracic spine suffer from higher rates of proximal junctional kyphosis and pseudoarthrosis, whereas those with UIV in the upper lumbar spine have higher rates of adjacent segment disease. Given this tradeoff, there is no certain recommendation on what UIV will result in a lower reoperation rate in thoracolumbar fusion constructs to the sacrum or pelvis. Surgeons must evaluate patient characteristics and risks to make the optimal decision.

Enhanced Recovery After Surgery Trends in Adult Spine Surgery: A Systematic Review.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) is a multimodal, multidisciplinary approach to optimizing the postsurgical recovery process through preoperative, perioperative, and postoperative interventions. ERAS protocols are emerging quickly within orthopedic spine surgery, yet there is a lack of consensus on optimal ERAS practices. OBJECTIVE: The aim of this systematic review is to identify and discuss the trends in spine ERAS protocols and the associated outcomes. METHODS: A literature search on PubMed was conducted to identify clinical studies that implemented ERAS protocols for various spine procedures in the adult population. The search included English-language literature published through December 2019. Additional sources were retrieved from the reference lists of key studies. Studies that met inclusion criteria were identified manually. Data regarding the study population, study design, spine procedures, ERAS interventions, and associated outcome metrics were extracted from each study that met inclusion criteria. RESULTS: Of the 106 studies identified from the literature search, 22 studies met inclusion criteria. From the ERAS protocols in these studies, common preoperative elements include patient education and modified preoperative nutrition regimens. Perioperative elements include multimodal analgesia and minimally invasive surgery. Postoperative elements include multimodal pain management and early mobilization/rehabilitation/nutrition regimens. Outcomes from ERAS implementation include significant reductions in length of stay, cost, and opioid consumption. Although these trends were observed, there remained great variability among the ERAS protocols, as well as in the reported outcomes. CONCLUSIONS: ERAS may improve cost-effectiveness to varying degrees for spinal procedures. Specifically, the use of multimodal analgesia may reduce overall opioid consumption. However, the benefits of ERAS likely will vary based on the specific procedure. CLINICAL RELEVANCE: This review contributes to the assessment of ERAS protocol implementation in the field of adult spine surgery.

Evaluation of Health-related Quality of Life Improvement in Patients Undergoing Spine Versus Adult Reconstructive Surgery.

STUDY DESIGN: Retrospective analysis of outcomes in single-level spine and primary hip and knee arthroplasty patients. OBJECTIVE: The aim of this study was to compare baseline and postoperative outcomes in patients undergoing spine surgery procedures with total hip arthroplasty (THA) and total knee arthroplasty (TKA) to further define outcomes in orthopedic surgery. SUMMARY OF BACKGROUND DATA: Computer-adaptive Patient Reported Outcome Information System (PROMIS) allows for standardized assessment of the health-related quality of life across different disease states. METHODS: Patients who underwent spine surgery (anterior cervical discectomy and fusion, cervical disc replacement, lumbar laminectomy, microscopic lumbar discectomy, transforaminal lumbar interbody fusion or adult reconstruction surgery [THA, TKA]) were grouped. Mean Charlson Comorbidity Index (CCI), Baseline (BL), and 6-month PROMIS scores of physical function, pain interference, and pain intensity were determined. Paired t tests compared differences in CCI, BL, 6 months, and change in PROMIS scores for spine and adult reconstruction procedures. RESULTS: A total of 304 spine surgery patients (age = 58.1 ±â€Š15.6; 42.9% female) and 347 adult reconstruction patients (age = 62.9 ±â€Š11.8; 54.1% Female) were compared. Spine surgery groups had more disability and pain at baseline than adult reconstruction patients according to physical function ([21.0, 22.2, 9.07, 12.6, 10.4] vs. [35.8, 35.0], respectively, P < 0.01), pain interference ([80.1, 74.1, 89.6, 92.5, 90.6] vs. [64.0, 63.9], respectively, P < 0.01), and pain intensity ([53.0, 53.1, 58.3, 58.5, 56.1] vs. [53.4, 53.8], respectively, P < 0.01). At 6 months, spine surgery patients remained more disabled and had more pain compared to adult reconstruction patients. Over the 6-month timespan, spine patients experienced greater improvements than adult reconstruction patients in terms of physical function ([+8.7, +22.2, +9.7, +12.9, +12.1] vs. [+5.3, +3.9], respectively, P < 0.01) and pain interference scores ([-15.4,-28.1, -14.7, -13.1, -12.3] vs. [-8.3, -6.0], respectively, P < 0.01). CONCLUSION: Spinal surgery patients had lower BL and 6-month PROMIS scores, but greater relative improvement in PROMIS scores compared to adult reconstruction patients. LEVEL OF EVIDENCE: 3.

The Optimal Location to Measure Scapholunate Diastasis on Screening Radiographs.

BACKGROUND: Lack of a universally accepted location and normal value limits the utility of measuring scapholunate diastasis. The primary purpose of this study was to define the optimal location to measure the scapholunate gap throughout sequential ligament transections. Secondary purposes were to compare plain radiographs with fluoroscopy and to evaluate interrater reliability in measuring scapholunate diastasis. METHODS: Five cadaver forearms were imaged with intact carpal ligaments and after sequentially transecting the scapholunate, radioscaphocapitate, and scaphotrapezium-trapezoid ligaments. Plain radiographs and static fluoroscopic images were obtained with wrists in neutral and 30° ulnar deviation for each stage. Multiple reviewers performed measurements of the scapholunate interval at 3 separate locations. Mean distances were calculated and pairwise comparisons between groups were made. Intraclass correlation was calculated to determine interrater reliability. RESULTS: Overall, measurements made in the middle of the scapholunate joint had the smallest margins of error for all imaging modalities, ligament disruptions, and wrist positions. For normal wrists, the mean scapholunate measurements were all less than 2.0 mm at the middle of the joint, regardless of imaging modality or wrist position. Fluoroscopy detected significance between more stages of instability than plain radiographs at the middle of the joint. CONCLUSIONS: Measurements in the middle of the scapholunate joint in neutral and 30° of ulnar deviation under fluoroscopic imaging best capture all stages of ligamentous disruptions. Measurements less than 2.0 mm at the middle of the scapholunate interval may be considered within normal range.

Novel Spiked-Washer Repair Is Biomechanically Superior to Suture and Bone Tunnels for Arcuate Fracture Repair.

OBJECTIVES: Injuries to the posterolateral corner of the knee can lead to chronic degenerative changes, external rotation instability, and varus instability if not repaired adequately. A proximal fibula avulsion fracture, referred to as an arcuate fracture, has been described in the literature, but a definitive repair technique has yet to be described. The objective of this study was to present a novel arcuate fracture repair technique, using a spiked-washer with an intramedullary screw, and to compare its biomechanical integrity to a previously described suture and bone tunnel method. METHODS: Ten fresh-frozen cadaveric knees underwent a proximal fibula osteotomy to simulate a proximal fibula avulsion fracture. The lateral knee capsule and posterior cruciate ligament were also sectioned to create maximal varus instability. Five fibulas were repaired using a novel spiked-washer technique and the other 5 were repaired using the suture and bone tunnel method. The repaired knees were subjected to a monotonic varus load using a mechanical testing system instrument until failure of the repair or associated posterolateral corner structures. RESULTS: Compared with the suture repair group, the spiked-washer repair group demonstrated a 100% increase in stiffness, 100% increase in yield, 110% increase in failure force, and 108% increase in energy to failure. CONCLUSIONS: The spiked-washer technique offers superior quasi-static biomechanical performance compared with suture repair with bone tunnels for arcuate fractures of the proximal fibula. Further clinical investigation of this technique is warranted and the results of this testing may lead to improved outcomes and patient satisfaction for proximal fibula avulsion fractures.

Transcriptional Landscape of Cardiomyocyte Maturation.

Decades of progress in developmental cardiology has advanced our understanding of the early aspects of heart development, including cardiomyocyte (CM) differentiation. However, control of the CM maturation that is subsequently required to generate adult myocytes remains elusive. Here, we analyzed over 200 microarray datasets from early embryonic to adult hearts and identified a large number of genes whose expression shifts gradually and continuously during maturation. We generated an atlas of integrated gene expression, biological pathways, transcriptional regulators, and gene regulatory networks (GRNs), which show discrete sets of key transcriptional regulators and pathways activated or suppressed during CM maturation. We developed a GRN-based program named MatStat(CM) that indexes CM maturation status. MatStat(CM) reveals that pluripotent-stem-cell-derived CMs mature early in culture but are arrested at the late embryonic stage with aberrant regulation of key transcription factors. Our study provides a foundation for understanding CM maturation.

Regenerative medicine for the heart: perspectives on stem-cell therapy.

SIGNIFICANCE: Despite decades of progress in cardiovascular biology and medicine, heart disease remains the leading cause of death, and there is no cure for the failing heart. Since heart failure is mostly caused by loss or dysfunction of cardiomyocytes (CMs), replacing dead or damaged CMs with new CMs might be an ideal way to reverse the disease. However, the adult heart is composed mainly of terminally differentiated CMs that have no significant self-regeneration capacity. RECENT ADVANCES: Stem cells have tremendous regenerative potential and, thus, current cardiac regenerative research has focused on developing stem cell sources to repair damaged myocardium. CRITICAL ISSUES: In this review, we examine the potential sources of cells that could be used for heart therapies, including embryonic stem cells and induced pluripotent stem cells, as well as alternative methods for activating the endogenous regenerative mechanisms of the heart via transdifferentiation and cell reprogramming. We also discuss the current state of knowledge of cell purification, delivery, and retention. FUTURE DIRECTIONS: Efforts are underway to improve the current stem cell strategies and methodologies, which will accelerate the development of innovative stem-cell therapies for heart regeneration.

Precardiac deletion of Numb and Numblike reveals renewal of cardiac progenitors.

Cardiac progenitor cells (CPCs) must control their number and fate to sustain the rapid heart growth during development, yet the intrinsic factors and environment governing these processes remain unclear. Here, we show that deletion of the ancient cell-fate regulator Numb (Nb) and its homologue Numblike (Nbl) depletes CPCs in second pharyngeal arches (PA2s) and is associated with an atrophic heart. With histological, flow cytometric and functional analyses, we find that CPCs remain undifferentiated and expansive in the PA2, but differentiate into cardiac cells as they exit the arch. Tracing of Nb- and Nbl-deficient CPCs by lineage-specific mosaicism reveals that the CPCs normally populate in the PA2, but lose their expansion potential in the PA2. These findings demonstrate that Nb and Nbl are intrinsic factors crucial for the renewal of CPCs in the PA2 and that the PA2 serves as a microenvironment for their expansion.DOI: http://dx.doi.org/10.7554/eLife.02164.001.

Mutations in Alström protein impair terminal differentiation of cardiomyocytes.

Cardiomyocyte cell division and replication in mammals proceed through embryonic development and abruptly decline soon after birth. The process governing cardiomyocyte cell cycle arrest is poorly understood. Here we carry out whole-exome sequencing in an infant with evidence of persistent postnatal cardiomyocyte replication to determine the genetic risk factors. We identify compound heterozygous ALMS1 mutations in the proband, and confirm their presence in her affected sibling, one copy inherited from each heterozygous parent. Next, we recognize homozygous or compound heterozygous truncating mutations in ALMS1 in four other children with high levels of postnatal cardiomyocyte proliferation. Alms1 mRNA knockdown increases multiple markers of proliferation in cardiomyocytes, the percentage of cardiomyocytes in G2/M phases, and the number of cardiomyocytes by 10% in cultured cells. Homozygous Alms1-mutant mice have increased cardiomyocyte proliferation at 2 weeks postnatal compared with wild-type littermates. We conclude that deficiency of Alström protein impairs postnatal cardiomyocyte cell cycle arrest.

Direct contact with endoderm-like cells efficiently induces cardiac progenitors from mouse and human pluripotent stem cells.

RATIONALE: Pluripotent stem cell-derived cardiac progenitor cells (CPCs) have emerged as a powerful tool to study cardiogenesis in vitro and a potential cell source for cardiac regenerative medicine. However, available methods to induce CPCs are not efficient or require high-cost cytokines with extensive optimization due to cell line variations. OBJECTIVE: Based on our in-vivo observation that early endodermal cells maintain contact with nascent pre-cardiac mesoderm, we hypothesized that direct physical contact with endoderm promotes induction of CPCs from pluripotent cells. METHOD AND RESULT: To test the hypothesis, we cocultured mouse embryonic stem (ES) cells with the endodermal cell line End2 by co-aggregation or End2-conditioned medium. Co-aggregation resulted in strong induction of Flk1(+) PDGFRa(+) CPCs in a dose-dependent manner, but the conditioned medium did not, indicating that direct contact is necessary for this process. To determine if direct contact with End2 cells also promotes the induction of committed cardiac progenitors, we utilized several mouse ES and induced pluripotent (iPS) cell lines expressing fluorescent proteins under regulation of the CPC lineage markers Nkx2.5 or Isl1. In agreement with earlier data, co-aggregation with End2 cells potently induces both Nkx2.5(+) and Isl1(+) CPCs, leading to a sheet of beating cardiomyocytes. Furthermore, co-aggregation with End2 cells greatly promotes the induction of KDR(+) PDGFRa(+) CPCs from human ES cells. CONCLUSIONS: Our co-aggregation method provides an efficient, simple and cost-effective way to induce CPCs from mouse and human pluripotent cells.