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Purpose: Isocitrate dehydrogenase 1 (IDH1) mutations occur in 5% to 10% of patients with acute myeloid leukemia (AML). Ivosidenib is an IDH1 inhibitor, approved for use in patients with IDH1-mutated AML. Patients and Methods: We conducted a multicenter, phase I trial of maintenance ivosidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH1-mutated AML. Ivosidenib was initiated between days 30 and 90 following HCT and continued for up to 12 28-day cycles. The first dose level was 500 mg daily, with level reduction to 250 mg daily, if needed, in a 3 × 3 de-escalation design. Ten additional patients would then receive the MTD or recommended phase 2 dose (RP2D). The primary endpoint was establishing the MTD or RP2D of ivosidenib. Results: Eighteen patients were enrolled, of whom 16 initiated post-HCT ivosidenib. One dose-limiting toxicity, grade(g) 3 QTc prolongation, was observed. The RP2D was established at 500 mg daily. Attributable g≥3 adverse events were uncommon, with the most common being QTc prolongation in 2 patients. Eight patients discontinued maintenance, with only one due to adverse event. Six-month cumulative incidence (CI) of gII-IV aGVHD was 6.3%, and 2-year CI of all cGVHD was 63%. Two-year CI of relapse and nonrelapse mortality (NRM) were 19% and 0%, respectively. Two-year progression-free (PFS) was 81%, and 2-year overall survival (OS) was 88%. Conclusions: Ivosidenib is safe and well-tolerated as maintenance therapy following HCT. Cumulative incidence of relapse and NRM, as well as estimations of PFS and OS, were promising in this phase I study.

Representativeness of Study Participants

Supplemental Figure 2: Overall and progression-free survival for patients according to NPM1 mutational status

Purpose:Isocitrate dehydrogenase 1 (IDH1) mutations occur in 5% to 10% of patients with acute myeloid leukemia (AML). Ivosidenib is an IDH1 inhibitor, approved for use in patients with IDH1-mutated AML.Methods:We conducted a multicenter, phase I trial of maintenance ivosidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH1-mutated AML. Ivosidenib was initiated between days 30 and 90 following HCT and continued for up to 12 28-day cycles. The first dose level was 500 mg daily, with level reduction to 250 mg daily, if needed, in a 3 × 3 de-escalation design. Ten additional patients would then receive the MTD or recommended phase 2 dose (RP2D). The primary endpoint was establishing the MTD or RP2D of ivosidenib.Results:Eighteen patients were enrolled, of whom 16 initiated post-HCT ivosidenib. One dose-limiting toxicity, grade(g) 3 QTc prolongation, was observed. The RP2D was established at 500 mg daily. Attributable g≥3 adverse events were uncommon, with the most common being QTc prolongation in 2 patients. Eight patients discontinued maintenance, with only one due to adverse event. Six-month cumulative incidence (CI) of gII-IV aGVHD was 6.3%, and 2-year CI of all cGVHD was 63%. Two-year CI of relapse and nonrelapse mortality (NRM) were 19% and 0%, respectively. Two-year progression-free (PFS) was 81%, and 2-year overall survival (OS) was 88%.Conclusions:Ivosidenib is safe and well-tolerated as maintenance therapy following HCT. Cumulative incidence of relapse and NRM, as well as estimations of PFS and OS, were promising in this phase I study.

Supplemental Figure 1: Overall and progression-free survival for patients, according to whether the transplant followed first line or second line treatment.

IDH2 (isocitrate dehydrogenase 2) mutations occur in approximately 15% of patients with acute myeloid leukemia (AML). The IDH2 inhibitor enasidenib was recently approved for IDH2-mutated relapsed or refractory AML. We conducted a multi-center, phase I trial of maintenance enasidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH2-mutated myeloid malignancies. Two dose levels, 50mg and 100mg daily were studied in a 3 × 3 dose-escalation design, with 10 additional patients treated at the recommended phase 2 dose (RP2D). Enasidenib was initiated between days 30 and 90 following HCT and continued for twelve 28-day cycles. Twenty-three patients were enrolled, of whom 19 initiated post-HCT maintenance. Two had myelodysplastic syndrome, and 17 had AML. All but 3 were in first complete remission. No dose limiting toxicities were observed, and the RP2D was established at 100mg daily. Attributable grade ≥3 toxicities were rare, with the most common being cytopenias. Eight patients stopped maintenance before completing 12 cycles, due to adverse events (n=3), pursuing treatment for graft-vs-host disease (GVHD) (n=2), clinician choice (n=1), relapse (n=1), and COVID infection (n=1). No cases of grade ≥3 acute GVHD were seen, and 12-month cumulative incidence of moderate/severe chronic GVHD was 42% (20-63%). Cumulative incidence of relapse was 16% (95% CI: 3.7-36%); 1 subject relapsed while receiving maintenance. Two-year progression-free and overall survival were 69% (95% CI: 39-86%) and 74% (95% CI, 44-90%), respectively. Enasidenib is safe, well-tolerated, with preliminary activity as maintenance therapy following HCT, and merits additional study. The study was registered at www.clinicaltrials.gov (#NCT03515512).

The xanthine oxidase (XO) system is a significant source of vascular oxidative stress, which is believed to impair endothelial function, an important contributor to atherosclerotic disease. We tested whether febuxostat, a potent XO inhibitor, improves coronary endothelial function (CEF) in patients with stable coronary artery disease (CAD) in a single-center, randomized, placebo-controlled, double-blind crossover trial.CEF was measured using noninvasive magnetic resonance imaging (MRI) assessment of changes in 30 patients with stable CAD and baseline impaired CEF. Patients received either febuxostat or placebo for 6 weeks and then were crossed over to the alternative for an additional 6 weeks. MRI-detected changes in coronary flow and in coronary cross-sectional area from rest to isometric handgrip exercise, a known endothelial-dependent stressor, were measured at the end of each 6 week period.Mean serum urate levels were lower at the end of the 6-week febuxostat period (2.9±0.8mg/dL) than at the end of the 6-week placebo period (5.9±0.04, P.001). However, there were no significant differences in any of the CEF parameters measured at the end of the febuxostat and placebo periods.In summary, although XO inhibition with febuxostat was well tolerated and lowered serum urate, it did not improve the primary end point of the study, CEF measured using MRI after 6 weeks of treatment. In conclusion, these findings suggest that short-term inhibition of XO does not significantly improve impaired CEF in patients with stable CAD.

Characterization of molecular alterations in acute myeloid leukemia (AML) has led to development of targeted therapies, including FLT3 and IDH1/2 inhibitors. Maintenance therapy following hematopoietic cell transplantation (HCT) has shown substantial promise. Enasidenib (ENA), a selective IDH2 inhibitor, was associated with impressive rates of response in relapsed/refractory (R/R) AML and is now FDA-approved for this indication. We sought to assess the tolerability and define the maximum tolerated dose (MTD) of ENA as maintenance following HCT for IDH2-mutated myeloid malignancy. HCT-eligible patients (pts) ≥ 18 years with AML in remission, or myelodysplastic syndrome (MDS) with 1000/µL and platelets > 50000/µL). Those with prior HCT, active disease, QTc ≥450ms, and active infections were excluded. ENA was initiated between day 30 and 90 after HCT, at which time the following were required: chimerism ≥70% of donor origin among blood/marrow cells, no acute graft versus host disease (aGVHD) requiring ≥0.5mg/kg/day prednisone or equivalent, and no relapse. ENA was taken orally (po) daily (qd) in 28-day cycles. The period for dose-limiting toxicity (DLT) evaluation was the first cycle, escalation to successive levels was guided by DLT incidence, and 2 levels (50mg,100mg) were studied. Following establishment of MTD or recommended phase 2 dose (RP2D), 10 pts would be enrolled in an expansion cohort. Pts were monitored for relapse and toxicity and continued until disease progression, intolerable toxicity, or receipt of 12 cycles. Nineteen pts have been registered prior to HCT at 3 sites, Massachusetts General Hospital, Dana Farber Cancer Institute, and Johns Hopkins Hospital. Three pts could not initiate ENA following HCT; 2 due to logistic challenges of the COVID pandemic and 1 due to relapse. The remaining 16 pts initiated ENA treatment. The median age was 61 years (range 31-76); 12 (75%) were male, and 13 (81%) were Caucasian. Fourteen (88%) had AML, of which 6 were AML with MDS related changes and 2 had antecedent myeloproliferative neoplasm. Two pts (13%) had MDS. Among these 16 pts, 9 (56%) had IDH2 R140, and 5 (25%) had IDH2 R172 mutations. IDH2 subtype data was unavailable for 2 pts. Of 15 pts with available data from time of diagnosis, 11 (73%) had intermediate-risk and 4 (27%) had adverse-risk cytogenetics. Among these 15 pts, common concurrent mutations were DNMT3A (47%), SRSF2 (33%), and RUNX1 (33%). Eleven AML pts (85%) received intensive versus non-intensive therapies (15%) prior to HCT, and among all pts, 7 (44%) had received ENA prior to HCT. HCT data was available for all 16 pts; 4 pts (25%) received myeloablative, and 12 (75%) received reduced-intensity conditioning. Nine pts (56%) had a matched unrelated, 6 (38%) had haploidentical, and 1 (6%) had a matched related donor HCT. Three pts were enrolled at the 50mg dose level, 6 pts at 100mg, and after no DLTs were detected, the remaining were enrolled in an expansion cohort at 100mg qd. Median follow-up (F/U) for surviving patients is currently 11.7 months (range 1.5-18.9). 2 pts (13%) have relapsed during F/U, at 96 and 364 days post HCT. Additional ≥grade (G) 3 toxicities detected during treatment, possibly or probably related to ENA, included neutropenia, anemia, and bilirubinemia. Six pts (38%) required dose interruptions lasting a median 19 days (range 7-25), 4 required a dose reduction to 50mg, and 1 stopped treatment due to G3 bilirubinemia. In total, 3 pts (18%) discontinued study treatment, 1 for aforementioned G3 bilirubinemia, 1 to pursue a GVHD trial, and 1 for relapse. Six pts have completed the 12-month f/u without relapse, and 7 remain on study. 15 of 16 pts remain alive. Thus far, 3 pts have experienced ≥ G2 aGVHD, and 4 had moderate chronic GVHD. Serial measurement of 2HG is being conducted on samples, and these will be reported. Enasidenib is well-tolerated as post-HCT maintenance therapy for myeloid malignancy at the RP2D of 100mg qd. No DLTs have been detected, and a low rate of post-HCT relapse has been identified to date, although longer f/u is needed. Larger, randomized studies of ENA in the post-SCT setting would determine the true efficacy of this agent as maintenance therapy. Disclosures Fathi: Blueprint: Consultancy; Jazz: Consultancy; Amgen: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Takeda: Consultancy, Research Funding; Boston Biomedical: Consultancy; Amphivena: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Forty Seven: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy. Soiffer:Gilead: Consultancy; Novartis: Consultancy; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; VOR Biopharma: Consultancy; alexion: Consultancy; Rheos Therapeutics: Consultancy; Cugene: Consultancy; Precision Bioscience: Consultancy; Be the Match/ National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Consultancy. Levis:Menarini: Honoraria; Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria. Mims:Novartis: Speakers Bureau; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Agios: Consultancy; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Abbvie: Membership on an entity's Board of Directors or advisory committees. Devine:Magenta Therapeutics: Consultancy. Defilipp:Incyte: Research Funding; Regimmune: Research Funding; Syndax Pharmaceuticals: Consultancy. Spitzer:Jazz Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees. Frigault:Celgene: Consultancy; Arcellx: Consultancy; Novartis: Consultancy, Research Funding; Gilead/Kite: Consultancy, Research Funding. Amrein:Amgen: Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Research Funding. Hobbs:Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding; Constellation: Honoraria, Research Funding; Jazz: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria. Brunner:Janssen: Research Funding; Acceleron Pharma Inc.: Consultancy; GSK: Research Funding; Xcenda: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz Pharma: Consultancy; Forty Seven, Inc: Consultancy; Celgene/BMS: Consultancy, Research Funding; Biogen: Consultancy; Astra Zeneca: Research Funding. Narayan:Genentech: Other: Prior Spouse employment within 24 months and prior spouse equity divested within past 24 months; Takeda: Other: Prior Spouse employment within 24 months; Sanofi-Genzyme: Other: Current Spouse employment . Chen:AbbVie: Other: Data and Safety Monitoring Board Member; Incyte Corporation: Consultancy; Takeda: Consultancy; Actinium: Other: Data and Safety Monitoring Board Member; Equillium: Other: Data and Safety Monitoring Board Member; Magenta: Consultancy; Kiadis: Consultancy. OffLabel Disclosure: Enasidenib as post-transplant maintenance therapy

Background Among various cardiac autoantibodies (AAbs), those recognizing the β 1 -adrenergic receptor (β 1 AR) demonstrate agonist-like effects and induce myocardial damage that can be reversed by β-blockers and immunoglobulin G3 (IgG3) immunoadsorption. Objectives The goal of this study was to investigate the role of β 1 AR-AAbs belonging to the IgG3 subclass in patients with recent-onset cardiomyopathy. Methods Peripheral blood samples were drawn at enrollment in patients with recent-onset cardiomyopathy (left ventricular ejection fraction [LVEF] ≤0.40; 1 AR-AAb was determined, and echocardiograms were assessed, at baseline and 6 months. Patients were followed up for ≤48 months. Results Among the 353 patients who had blood samples adequate for the analysis, 62 (18%) were positive for IgG3-β 1 AR-AAbs (IgG3 group), 58 (16%) were positive for IgG but not IgG3 (non-IgG3 group), and the remaining were negative. There were no significant differences in baseline systolic blood pressure, heart rate, or LVEF among the groups at baseline. Left ventricular end-diastolic and end-systolic diameters were significantly larger in the non-IgG3 group compared with the other groups (left ventricular end-diastolic diameter, p 1 AR-AAb was an independent predictor of LVEF at 6 months and change in LVEF over 6 months, even after multivariable adjustment (LVEF at 6 months, β = 0.20, p = 0.01; change in LVEF, β = 0.20, p = 0.008). In patients with high New York Heart Association functional class (III or IV) at baseline, the IgG3 group had a lower incidence of the composite endpoint of all-cause death, cardiac transplantation, and hospitalization due to heart failure, whereas the non-IgG3 group had the highest incidence of the composite endpoint. Conclusions IgG3-β 1 AR-AAbs were associated with more favorable myocardial recovery in patients with recent-onset cardiomyopathy.

Background Giant cell myocarditis is a rapidly progressive and often fatal condition without a clear etiology or treatment. A better understanding of giant cell myocarditis pathogenesis is critical to developing treatments to prevent progression and reverse damage. We compared the gene expression of giant cell myocarditis with that of nonfailing hearts. Methods Left ventricular samples from two giant cell myocarditis patients harvested during ventricular assist device placement and six unused donor hearts were examined using Affymetrix U133A microarrays. Differential gene expression was defined with a Bonferroni-adjusted p value ≤0.05 from a Student's t -test and an absolute fold change ≥2.0. Select gene expression was confirmed with quantitative PCR. Results Of 115 differentially expressed genes, most were upregulated in giant cell myocarditis and involved in immune response, transcriptional regulation, and metabolism. T-cell activation genes included chemokine receptor 4; chemokine ligands 5, 9, 13, and 18; interleukin-10 receptor alpha; and beta-2 integrin. Conclusions Gene expression analysis of giant cell myocarditis offers novel insights into its pathogenesis, namely the role of T-cell activators of the Th1 subset and immune response genes previously implicated in heart failure. This forms the basis for future work aimed at defining novel therapeutic targets for giant cell myocarditis.

Cardiomyopathy can be initiated by many factors, but the pathways from unique inciting mechanisms to the common end point of ventricular dilation and reduced cardiac output are unclear. We previously described a microarray-based prediction algorithm differentiating nonischemic (NICM) from ischemic cardiomyopathy (ICM) using nearest shrunken centroids. Accordingly, we tested the hypothesis that NICM and ICM would have both shared and distinct differentially expressed genes relative to normal hearts and compared gene expression of 21 NICM and 10 ICM samples with that of 6 nonfailing (NF) hearts using Affymetrix U133A GeneChips and significance analysis of microarrays. Compared with NF, 257 genes were differentially expressed in NICM and 72 genes in ICM. Only 41 genes were shared between the two comparisons, mainly involved in cell growth and signal transduction. Those uniquely expressed in NICM were frequently involved in metabolism, and those in ICM more often had catalytic activity. Novel genes included angiotensin-converting enzyme-2 (ACE2), which was upregulated in NICM but not ICM, suggesting that ACE2 may offer differential therapeutic efficacy in NICM and ICM. In addition, a tumor necrosis factor receptor was downregulated in both NICM and ICM, demonstrating the different signaling pathways involved in heart failure pathophysiology. These results offer novel insight into unique disease-specific gene expression that exists between end-stage cardiomyopathy of different etiologies. This analysis demonstrates that transcriptome analysis offers insight into pathogenesis-based therapies in heart failure management and complements studies using expression-based profiling to diagnose heart failure of different etiologies.

Rationale: Transendocardial stem cell injection (TESI) with mesenchymal stem cells improves remodeling in chronic ischemic cardiomyopathy, but the effect of the injection site remains unknown. Objective: To address whether TESI exerts its effects at the site of injection only or also in remote areas, we hypothesized that segmental myocardial scar and segmental ejection fraction improve to a greater extent in injected than in noninjected segments. Methods and Results: Biplane ventriculographic and endocardial tracings were recorded. TESI was guided to 10 sites in infarct-border zones. Sites were mapped according to the 17-myocardial segment model. As a result, 510 segments were analyzed in 30 patients before and 13 months after TESI. Segmental early enhancement defect (a measure of scar size) was reduced by TESI in both injected (−43.7±4.4%; n=95; P P P P =0.003) but not in noninjected scar segments (21.3±2.6–23.5±3.2%; P =0.20; between-group comparison P P =0.003), versus P =0.33, between-group comparison P Conclusions: These findings illustrate a dichotomy in regional responses to TESI. Although scar size reduction was evident in all scar segments, scar size reduction and ventricular functional responses preferentially occurred at the sites of TESI versus non-TESI sites. Furthermore, improvement was greatest when segmental left ventricular dysfunction was severe.

Aims We sought to test the hypothesis that inherent biological factors contribute to gender differences in disease pathophysiology of new-onset heart failure (HF), which can be detected from the transcriptome of a single endomyocardial biopsy (EMB). Methods and results We analysed samples from male ( n = 29) and female patients ( n = 14) with idiopathic dilated cardiomyopathy (IDCM) and new-onset HF with U133 Plus 2.0 microarrays (Affymetrix) and significance analysis of microarrays (SAM). There were 35 overexpressed and 16 downregulated transcripts in men vs. women [ q 1.2]. In addition to overexpression of Y-chromosome-related transcripts ( n = 18), such as USP9Y (FC > 13.1), DDX3Y (FC > 11.3), RPS4Y1 (FC > 9.9), and EIF1AY (FC > 11.8) in males, there was overexpression of CD24 (FC > 5.6) and KCNK1 (FC > 1.5). In females, XIST was highly overexpressed (FC > 28.9), together with X-linked zinc finger proteins (FC > 1.9) and autosomal genes GATAD1 (FC > 1.6), SLC2A12 (FC > 2.9), and PDE6B (FC > 1.5). Analysis of a public data set of end-stage IDCM ( n = 15) resulted in ∼85% overlap with our findings. Conclusion This is the first study that identified gender-specific transcriptomic differences in new-onset HF. Our findings may offer novel insights into fundamental biological differences in the pathophysiology of HF between sexes and provide a platform for personalized medicine.

Background— Prediction of prognosis remains a major unmet need in new-onset heart failure (HF). Although several clinical tests are in use, none accurately distinguish between patients with poor versus excellent survival. We hypothesized that a transcriptomic signature, generated from a single endomyocardial biopsy, could serve as a novel prognostic biomarker in HF. Methods and Results— Endomyocardial biopsy samples and clinical data were collected from all patients presenting with new-onset HF from 1997 to 2006. Among a total of 350 endomyocardial biopsy samples, 180 were identified as idiopathic dilated cardiomyopathy. Patients with phenotypic extremes in survival were selected: good prognosis (event-free survival for at least 5 years; n=25) and poor prognosis (events [death, requirement for left ventricular assist device, or cardiac transplant] within the first 2 years of presentation with HF symptoms; n=18). We used human U133 Plus 2.0 microarrays (Affymetrix) and analyzed the data with significance analysis of microarrays and prediction analysis of microarrays. We identified 46 overexpressed genes in patients with good versus poor prognosis, of which 45 genes were selected by prediction analysis of microarrays for prediction of prognosis in a train set (n=29) with subsequent validation in test sets (n=14 each). The biomarker performed with 74% sensitivity (95% CI 69% to 79%) and 90% specificity (95% CI 87% to 93%) after 50 random partitions. Conclusions— These findings suggest the potential of transcriptomic biomarkers to predict prognosis in patients with new-onset HF from a single endomyocardial biopsy sample. In addition, our findings offer potential novel therapeutic targets for HF and cardiomyopathy.

Context Pulmonary artery catheters (PACs) have been used to guide therapy in multiple settings, but recent studies have raised concerns that PACs may lead to increased mortality in hospitalized patients. Objective To determine whether PAC use is safe and improves clinical outcomes in patients hospitalized with severe symptomatic and recurrent heart failure. Design, setting, and participants The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) was a randomized controlled trial of 433 patients at 26 sites conducted from January 18, 2000, to November 17, 2003. Patients were assigned to receive therapy guided by clinical assessment and a PAC or clinical assessment alone. The target in both groups was resolution of clinical congestion, with additional PAC targets of a pulmonary capillary wedge pressure of 15 mm Hg and a right atrial pressure of 8 mm Hg. Medications were not specified, but inotrope use was explicitly discouraged. Main outcome measures The primary end point was days alive out of the hospital during the first 6 months, with secondary end points of exercise, quality of life, biochemical, and echocardiographic changes. Results Severity of illness was reflected by the following values: average left ventricular ejection fraction, 19%; systolic blood pressure, 106 mm Hg; sodium level, 137 mEq/L; urea nitrogen, 35 mg/dL (12.40 mmol/L); and creatinine, 1.5 mg/dL (132.6 micromol/L). Therapy in both groups led to substantial reduction in symptoms, jugular venous pressure, and edema. Use of the PAC did not significantly affect the primary end point of days alive and out of the hospital during the first 6 months (133 days vs 135 days; hazard ratio [HR], 1.00 [95% confidence interval {CI}, 0.82-1.21]; P = .99), mortality (43 patients [10%] vs 38 patients [9%]; odds ratio [OR], 1.26 [95% CI, 0.78-2.03]; P = .35), or the number of days hospitalized (8.7 vs 8.3; HR, 1.04 [95% CI, 0.86-1.27]; P = .67). In-hospital adverse events were more common among patients in the PAC group (47 [21.9%] vs 25 [11.5%]; P = .04). There were no deaths related to PAC use, and no difference for in-hospital plus 30-day mortality (10 [4.7%] vs 11 [5.0%]; OR, 0.97 [95% CI, 0.38-2.22]; P = .97). Exercise and quality of life end points improved in both groups with a trend toward greater improvement with the PAC, which reached significance for the time trade-off at all time points after randomization. Conclusions Therapy to reduce volume overload during hospitalization for heart failure led to marked improvement in signs and symptoms of elevated filling pressures with or without the PAC. Addition of the PAC to careful clinical assessment increased anticipated adverse events, but did not affect overall mortality and hospitalization. Future trials should test noninvasive assessments with specific treatment strategies that could be used to better tailor therapy for both survival time and survival quality as valued by patients.

Transendocardial Stem Cell Injection (TESI) with mesenchymal stem cells improves left ventricular (LV) geometry in chronic ischemic cardiomyopathy, by reducing myocardial scar, LV volumes, and sphericity index. To address whether TESI exerts its effects at the site of injection only or also in

Mesenchymal stem cells (MSCs) are under evaluation as a therapy for ischemic cardiomyopathy (ICM). Both autologous and allogeneic MSC therapies are possible; however, their safety and efficacy have not been compared.To test whether allogeneic MSCs are as safe and effective as autologous MSCs in patients with left ventricular (LV) dysfunction due to ICM.A phase 1/2 randomized comparison (POSEIDON study) in a US tertiary-care referral hospital of allogeneic and autologous MSCs in 30 patients with LV dysfunction due to ICM between April 2, 2010, and September 14, 2011, with 13-month follow-up.Twenty million, 100 million, or 200 million cells (5 patients in each cell type per dose level) were delivered by transendocardial stem cell injection into 10 LV sites.Thirty-day postcatheterization incidence of predefined treatment-emergent serious adverse events (SAEs). Efficacy assessments included 6-minute walk test, exercise peak VO2, Minnesota Living with Heart Failure Questionnaire (MLHFQ), New York Heart Association class, LV volumes, ejection fraction (EF), early enhancement defect (EED; infarct size), and sphericity index.Within 30 days, 1 patient in each group (treatment-emergent SAE rate, 6.7%) was hospitalized for heart failure, less than the prespecified stopping event rate of 25%. The 1-year incidence of SAEs was 33.3% (n = 5) in the allogeneic group and 53.3% (n = 8) in the autologous group (P = .46). At 1 year, there were no ventricular arrhythmia SAEs observed among allogeneic recipients compared with 4 patients (26.7%) in the autologous group (P = .10). Relative to baseline, autologous but not allogeneic MSC therapy was associated with an improvement in the 6-minute walk test and the MLHFQ score, but neither improved exercise VO2 max. Allogeneic and autologous MSCs reduced mean EED by −33.21% (95% CI, −43.61% to −22.81%; P.001) and sphericity index but did not increase EF. Allogeneic MSCs reduced LV end-diastolic volumes. Low-dose concentration MSCs (20 million cells) produced greatest reductions in LV volumes and increased EF. Allogeneic MSCs did not stimulate significant donor-specific alloimmune reactions.In this early-stage study of patients with ICM, transendocardial injection of allogeneic and autologous MSCs without a placebo control were both associated with low rates of treatment-emergent SAEs, including immunologic reactions. In aggregate, MSC injection favorably affected patient functional capacity, quality of life, and ventricular remodeling.clinicaltrials.gov Identifier: NCT01087996.