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Aims: The DYNAMIC trial assessed the safety and explored the efficacy of multivessel intracoronary infusion of allogeneic cardiosphere-derived cells (CDCs) in patients with heart failure and reduced ejection fraction (HFrEF). Here we report the results of the DYNAMIC trial. Methods and results: We enrolled 14 patients with EF ≤35% and NYHA Class III-IV despite maximal medical and device-based therapy in this single-centre, open-label trial. Intracoronary catheterisation delivered four escalating doses (totalling 37.5-75 million cells) by sequential non-occlusive technique to all three major coronary arteries. The primary safety endpoint was a composite of post-infusion TIMI flow, ventricular tachycardia/fibrillation, sudden death, major adverse cardiac events or acute myocarditis within 72 hours. Twelve patients were male and EF averaged 23.0% (±4.5%). No primary safety endpoints were observed. Two patients died of HFrEF progression nine and 12 months following infusion. Compared to baseline, there was an improvement in EF (26.8% vs 22.9%, p=0.023) and left ventricular end-systolic volume (139.5 vs 177.8 cm3, p=0.03) at six months. Quality of life (QoL) scores and NYHA class (p=0.006) improved at six months. At 12 months, the improvement in EF and QoL remained significant. Conclusions: Global intracoronary infusion of allogeneic CDCs is safe and feasible. The efficacy of allogeneic CDCs in HFrEF needs to be tested in larger randomised trials. © Europa Digital & Publishing 2020. All rights reserved.

Aims Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial. Methods and We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) _15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients. Conclusion Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs. © 2020 Oxford University Press. All rights reserved.

Objective: We sought to understand the cellular and tissue-level changes underlying the attenuation of adverse remodeling by cardiosphere transplantation in acute myocardial infarction (MI). Background: Cardiospheres (CSps) are heart-derived multicellular clusters rich in stemness and capable of multilineage differentiation. Post-MI CSp transplantation improves left ventricular (LV) function and attenuates remodeling in both small and large animal studies. However, the mechanisms of benefit have not yet been fully elucidated. Methods: Four groups were studied: 1) "Sham" (Wistar Kyoto rats with thoracotomy and ligature without infarction); 2) "MI" (proximal LAD ligation with peri-infarct injection of vehicle); 3) "MI+CSp" (MI with cardiospheres injected in the peri-infarct area); 4) "Small MI" (mid-LAD ligation only). Results: In vivo 1 week after CSp transplantation, LV functional improvement was associated with an increase in cardiomyocyte proliferation. By 3 weeks, microvessel formation was enhanced, while cardiomyocyte hypertrophy and regional fibrosis were attenuated. Collagen deposition was reduced, collagen degradation was enhanced, and MMPs were upregulated. The beneficial effects of CSp transplantation were not observed in the Small MI group, indicating that the effects are not solely due to CSp-induced cardioprotection. In vitro, CSp-conditioned media reduced collagen production in coculture with fibroblasts and triggered neoangiogenesis in an ex vivo aortic ring assay. Conclusion: Cardiospheres enhance cardiomyocyte proliferation and angiogenesis, and attenuate hypertrophy and fibrosis, in the ischemic myocardium. These synergistic effects underlie the attenuation of adverse remodeling by cardiospheres. © 2014 Tseliou et al.

Self-assembling heart-derived stem cell clusters named cardiospheres (CSps) improve function and attenuate remodeling in rodent models of acute myocardial infarction. The effects of CSps in chronically remodeled myocardium post-MI, and the underlying mechanisms, remain unknown. One month after permanent coronary ligation, rats were randomly assigned to injection of vehicle (controls) or CSps in the peri-infarct area. One month post-injection, CSps increased left ventricular function, reduced scar mass and collagen density, and enhanced vascularity within the infarct zone compared to controls. Immunoblots revealed Tgfβ-1/smad cascade downregulation and an increase in soluble endoglin post-CSp injection. Six months post-transplantation, left ventricular function further improved and cardiomyocyte hypertrophy was attenuated in the CSp-treated group. In vitro, co-culture of CSps with fibroblasts recapitulated the suppression of the Tgf-β1/smad pathway changes, responses which were blunted by neutralizing antibody against endoglin. Thus, cardiosphere transplantation enhances angiogenesis and reduces fibrosis in chronically infarcted myocardium, leading to partial reversal of cardiac dysfunction. The underlying mechanism involves inhibition of Tgf-β1/smad signaling by CSp-secreted soluble endoglin. © 2014, Springer-Verlag Berlin Heidelberg.

Objectives: We sought to characterize the immunologic profile of allogeneic cardiospheres, which are 3-dimensional, self-assembling, cardiac-derived microtissues, and to evaluate their safety and efficacy in repairing ischemic heart tissue. Background: Intramyocardial injection of autologous cardiospheres ameliorates remodeling and improves global function in infarcted myocardium. It is as yet unknown whether allogeneic cardiospheres are similarly effective without eliciting deleterious immune reactions. Methods: We expanded cardiospheres from male Wistar Kyoto rat hearts and injected them surgically in the peri-infarct zone of Wistar Kyoto (syngeneic group, n = 28) and Brown Norway female rats (allogeneic group, n = 29). Female rats from both strains (n = 37) injected with normal saline served as controls. Results: In vitro, cardiospheres expressed a low immunogenic profile and inhibited proliferation of alloreactive T cells. In vivo, cell engraftment was similar in the syngeneic and allogeneic groups 1 week and 3 weeks after transplantation. Reductions in scar size and scar collagen content and increases in viable mass in the risk region were accompanied by improvements in left ventricular function and attenuation of left ventricle remodeling that were sustained during 6 months of follow up. Transplantation of allogeneic cardiospheres increased tissue expression of the regenerative growth factors vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor-1, stimulating angiogenesis. Syngeneic and allogeneic cardiospheres attenuated the inflammatory response observed histologically in the peri-infarct region. Conclusions: Allogeneic cardiospheres increase viable myocardium, decrease scar, improve function, and attenuate adverse remodeling in the infarcted rat heart, without deleterious immunological sequelae. These observations lay the groundwork for developing cardiospheres as a novel off-the-shelf microtissue product for myocardial regeneration. © 2013 American College of Cardiology Foundation.

Objetivo: determinar las razones clínicas de prescripción de hidromorfona OROS® a pacientes con dolor crónico no oncológico. Material y métodos: estudio observacional, retrospectivo y multicéntrico español, en pacientes con dolor crónico no oncológico tratados con hidromorfona OROS® entre 1 y 5 meses. Se registró información disponible en la historia clínica del paciente, a través de la práctica clínica habitual del investigador, así como tras la cumplimentación de cuestionarios dirigidos al paciente sobre su adherencia terapéutica (Morisky-Green) y calidad de vida (SF-36). Resultados: 53 investigadores incluyeron datos de las historias clínicas de 438 pacientes, de edad media 62 años, un 43,4% de ellos menores de 60 años. Las patologías predominantes fueron artrosis (50,5%) y lumbalgia (48,2%). Aunque la antigüedad del proceso doloroso fue de 6,4 años, un 23,3% de los pacientes llevaba padeciendo dolor más de 10 años. Previo inicio de tratamiento con hidromorfona OROS®, el 62% presentaba una puntuación EVA > 7 y el 33,5% una EVA 5-7. El tratamiento que recibían con mayor frecuencia era la combinación de AINE con un opioide menor, mientras que solo un 5% de los pacientes recibía como tratamiento único un opioide mayor. La principal razón de inicio con hidromorfona OROS® fue la falta de eficacia con el opioide previo (62,1%) seguida de un aumento en la intensidad de dolor (22,4%), y el primer criterio para su elección fue la eficacia (81,7%), seguido de la pauta posológica (60,3%) y perfil de tolerabilidad (47,7%). Un 93,4% de los pacientes afirmó tomar la medicación habitualmente a la hora indicada y un 57,8% consideró su salud mejor o igual que hacía un año. Conclusiones: el infratratamiento del dolor y la falta de utilización de opioides mayores en pacientes con dolor crónico no oncológico continúan siendo problemas de elevada magnitud. Hidromorfona OROS® se presenta como una válida opción terapéutica, destacando su eficacia, pauta posológica y perfil de tolerabilidad como criterios principales de elección.

Objectives: The goal of this study was to conduct a direct head-to-head comparison of different stem cell types in vitro for various assays of potency and in vivo for functional myocardial repair in the same mouse model of myocardial infarction. Background: Adult stem cells of diverse origins (e.g., bone marrow, fat, heart) and antigenic identity have been studied for repair of the damaged heart, but the relative utility of the various cell types remains unclear. Methods: Human cardiosphere-derived cells (CDCs), bone marrowderived mesenchymal stem cells, adipose tissuederived mesenchymal stem cells, and bone marrow mononuclear cells were compared. Results: CDCs revealed a distinctive phenotype with uniform expression of CD105, partial expression of c-kit and CD90, and negligible expression of hematopoietic markers. In vitro, CDCs showed the greatest myogenic differentiation potency, highest angiogenic potential, and relatively high production of various angiogenic and antiapoptotic-secreted factors. In vivo, injection of CDCs into the infarcted mouse hearts resulted in superior improvement of cardiac function, the highest cell engraftment and myogenic differentiation rates, and the least-abnormal heart morphology 3 weeks after treatment. CDC-treated hearts also exhibited the lowest number of apoptotic cells. The c-kit + subpopulation purified from CDCs produced lower levels of paracrine factors and inferior functional benefit when compared with unsorted CDCs. To validate the comparison of cells from various human donors, selected results were confirmed in cells of different types derived from individual rats. Conclusions: CDCs exhibited a balanced profile of paracrine factor production and, among various comparator cell types/subpopulations, provided the greatest functional benefit in experimental myocardial infarction. © 2012 American College of Cardiology Foundation.

Myocardial regeneration using stem and progenitor cell transplantation in the injured heart has recently become a major goal in the treatment of cardiac disease. Experimental studies and clinical applications have generally been encouraging, although the functional benefits that have been attained clinically are modest and inconsistent. Low cell retention and engraftment after myocardial delivery is a key factor limiting the successful application of cell therapy, irrespective of the type of cell or the delivery method. To improve engraftment, accurate methods for tracking cell fate and quantifying cell survival need to be applied. Several laboratory techniques (histological methods, real-time quantitative polymerase chain reaction, radiolabeling) have provided invaluable information about cell engraftment. In vivo imaging (nuclear medicine modalities, bioluminescence, and MRI) has the potential to provide quantitative information noninvasively, enabling longitudinal assessment of cell fate. In the present review, we present several available methods for assessing cell engraftment, and we critically discuss their strengths and limitations. In addition to providing insights about the mechanisms mediating cell loss after transplantation, these methods can evaluate techniques for augmenting engraftment, such as tissue engineering approaches, preconditioning, and genetic modification, allowing optimization of cell therapies. © 2010 American Heart Association, Inc.