DCM Support: cell therapy and circulatory support for dilated cardiomyopathy patients with severe ventricular impairment.

AIMS: The DCM Support trial (NCT03572660) uses a percutaneous circulatory support device (Impella CP, Abiomed, Danvers, MA, USA) to improve the safety of an intracoronary cell infusion procedure in patients with dilated cardiomyopathy (DCM) and a severely reduced left ventricular ejection fraction (LVEF). METHODS AND RESULTS: DCM Support is a single-site, single-arm Phase II trial enrolling 20 symptomatic DCM patients with an LVEF ≤ 35% despite optimal medical and device therapy. After 5 days of granulocyte colony-stimulating factor therapy and a subsequent bone marrow aspiration, patients undergo an intracoronary infusion of autologous bone-marrow-derived mononuclear cells. The Impella CP device is used to provide haemodynamic support during the infusion procedure. The trial's primary endpoint is change in LVEF from baseline at 3 months. Secondary efficacy endpoints are change in LVEF from baseline at 12 months, and change in exercise capacity, New York Heart Association class, quality of life, and N-terminal pro-B-type natriuretic peptide levels from baseline at 3 and 12 months. Safety endpoints include procedural safety and major adverse cardiac events at 3 and 12 months. CONCLUSIONS: This is the first trial to assess the safety and efficacy of cytokine and autologous intracoronary cell therapy with a procedural circulatory support device for patients with severe left ventricular impairment. This novel combination may allow us to target a patient population most at need of this therapy.

Cell administration routes for heart failure: a comparative re-evaluation of the REGENERATE-DCM and REGENERATE-IHD trials.

Aims: Given the logistical issues surrounding intramyocardial cell delivery, we sought to address the efficacy of the simpler, more accessible intracoronary route by re-evaluating REGENERATE-DCM and REGENERATE-IHD (autologous cell therapy trials for heart failure; n = 150). Methods: A retrospective statistical analysis was performed on the trials' combined data. The following end points were evaluated: left ventricular ejection fraction (LVEF), N-terminal pro brain natriuretic peptide concentration (NT-proBNP), New York Heart Association class (NYHA) and quality of life. Results: This demonstrated a new efficacy signal for intracoronary delivery, with significant benefits to: LVEF (3.7%; p = 0.01), NT-proBNP (median -76 pg/ml; p = 0.04), NYHA class (48% patients; p = 0.01) and quality of life (12 ± 19; p = 0.006). The improvements in LVEF, NYHA and quality of life scores remained significant compared to the control group. Conclusion: The efficacy and logistical simplicity of intracoronary delivery should be taken into consideration for future trials.

Trials of cell therapy for heart failure have not clearly identified the best method to deliver the cells to the heart. A small proportion of these studies have used the intracoronary method (which infuses the cells into the heart's arteries) as it was thought to be less effective. However, this is the simplest method and uses widely accessible techniques and equipment. By combining data from two previous heart failure trials, we sought to look for an efficacy signal for the intracoronary method in a larger sample size. We found that the intracoronary route demonstrated improvements in patients' heart function and symptoms. Although it may require a larger number of patients to show efficacy, this signal, alongside the intracoronary route's relative simplicity, should be taken into consideration when future trials of cell therapy for heart failure are planned.

Five-year follow-up of intracoronary autologous cell therapy in acute myocardial infarction: the REGENERATE-AMI trial.

AIMS: The long-term outcomes of the intracoronary delivery of autologous bone marrow-derived cells (BMCs) after acute myocardial infarction are not well established. Following the promising 1 year results of the REGENERATE-AMI trial (despite it not achieving its primary endpoint), this paper presents the analysis of the 5 year clinical outcomes of these acute myocardial infarction patients who were treated with an early intracoronary autologous BMC infusion or placebo. METHODS AND RESULTS: A 5 year follow-up of major adverse cardiac events (defined as the composite of all-cause death, recurrent myocardial infarction, and all coronary revascularization) and of rehospitalization for heart failure was completed in 85 patients (BMC n = 46 and placebo n = 39). The incidence of major adverse cardiac events was similar between the BMC-treated patients and the placebo group (26.1% vs. 18.0%, P = 0.41). There were no cases of cardiac death in either group, but an increase in non-cardiac death was seen in the BMC group (6.5% vs. 0%, P = 0.11). The rates of recurrent myocardial infarction and repeat revascularization were similar between the two groups. There were no cases of rehospitalization for heart failure in either group. CONCLUSION: This 5 year follow-up analysis of the REGENERATE-AMI trial did not show an improvement in clinical outcomes for patients treated with cell therapy. This contrasts with the 1 year results which showed improvements in the surrogate outcome measures of ejection fraction and myocardial salvage index.

Exploration of the views and experiences of research healthcare professionals during their redeployment to clinical roles during the COVID-19 pandemic.

AIM: This study aimed to explore the views and experiences of research healthcare professionals towards their redeployment to frontline clinical roles during the COVID-19 pandemic. BACKGROUND: Healthcare professionals working in research were redeployed during the COVID-19 pandemic to support the delivery of clinical services across the National Health Service. They are experienced clinicians with research knowledge and skills, and specific working patterns. It is important to understand how these professionals were used and supported during their transition to clinical roles during the pandemic. METHOD: Between July and September 2020, 15 research healthcare professionals were recruited into this qualitative study. Each participant completed a single semi-structured interview lasting approximately 30-60 min, conducted remotely using a teleconferencing platform. Interviews were transcribed verbatim, and data analysed by the process of inductive thematic analysis with the assistance of NVivo 12.06 (Nov, 2019). FINDINGS: Four main themes were identified from analysis of the transcripts: (a) initial personal response to the pandemic (subthemes: of anxieties due to unknown disease impact and concern for others); (b) mobilization for clinical redeployment (subthemes: motivations for voluntary redeployment, the professional challenges, personal fears and the organization and preparedness for redeployment); (c) adaptive deployment to clinical roles (subthemes: adapting to new roles and responsibilities, challenges faced and coping mechanisms), (d) reflections and learnings (subthemes: reintegration to original roles and sense of achievement). CONCLUSION: Research healthcare professionals are highly adaptable professionals equipped with core transferable skills. With the appropriate support, re-familiarization and induction they are a valuable resource during the pandemic response. IMPLICATIONS TO PRACTICE: Research healthcare professionals are experienced practitioners with transferrable skills and strong sense of duty and resilience. Induction programmes to promote recalibration to clinical settings would improve their adaptability, foster confidence and emotional well-being. Careful consideration is required prior to mass redeployment to ensure research continuity in both COVID-19 and other health conditions.

Umbilical cord-derived mesenchymal stromal cells in cardiovascular disease: review of preclinical and clinical data.

The human umbilical cord has recently emerged as an attractive potential source of mesenchymal stromal cells (MSCs) to be adopted for use in regenerative medicine. Umbilical cord MSCs (UC-MSCs) not only share the same features of all MSCs such as multi-lineage differentiation, paracrine functions and immunomodulatory properties, they also have additional advantages, such as no need for bone marrow aspiration and higher self-renewal capacities. They can be isolated from various compartments of the umbilical cord (UC) and can be used for autologous or allogeneic purposes. In the past decade, they have been adopted in cardiovascular disease and have shown promising results mainly due to their pro-angiogenic and anti-inflammatory properties. This review offers an overview of the biological properties of UC-MSCs describing available pre-clinical and clinical data with respect to their potential therapeutic use in cardiovascular regeneration, with current challenges and future directions discussed.

Circulatory support and stem cell therapy in the management of advanced heart failure: a concise review of available evidence.

Stem cell therapy utilizing bone marrow mononuclear cells (BMC's) is a potential strategy to treat heart failure patients with improvement in symptom profile and cardiac function. We describe a rationale for concurrent BMC and left ventricular assist device therapy in selected heart failure patients. This combination therapy has demonstrated improved myocardial perfusion and cardiac function in patients with advanced ischemic cardiomyopathy. Moreover, preclinical data support improved cell retention with left ventricular unloading. The beneficial effects of BMC's are likely through a paracrine mechanism initiating a 'cardiac-repair' process. Combination therapy of BMC's and a left ventricular assist device may exhibit a synergistic effect with improved engraftment of BMC's through left ventricular unloading.

A randomized double-blind control study of early intra-coronary autologous bone marrow cell infusion in acute myocardial infarction: the REGENERATE-AMI clinical trial†.

AIMS: Clinical trials suggest that intracoronary delivery of autologous bone marrow-derived cells (BMCs) 1-7 days post-acute myocardial infarction (AMI) may improve left ventricular (LV) function. Earlier time points have not been evaluated. We sought to determine the effect of intracoronary autologous BMC on LV function when delivered within 24 h of successful reperfusion therapy. METHODS AND RESULTS: A multi-centre phase II randomized, double-blind, and placebo-controlled trial. One hundred patients with anterior AMI and significant regional wall motion abnormality were randomized to receive either intracoronary infusion of BMC or placebo (1:1) within 24 h of successful primary percutaneous intervention (PPCI). The primary endpoint was the change in left ventricular ejection fraction (LVEF) between baseline and 1 year as determined by advanced cardiac imaging. At 1 year, although LVEF increased compared with baseline in both groups, the between-group difference favouring BMC was small (2.2%; 95% confidence interval, CI: -0.5 to 5.0; P = 0.10). However, there was a significantly greater myocardial salvage index in the BMC-treated group compared with placebo (0.1%; 95% CI: 0.0-0.20; P = 0.048). Major adverse events were rare in both treatment groups. CONCLUSION: The early infusion of intracoronary BMC following PPCI for patients with AMI and regional wall motion abnormality leads to a small non-significant improvement in LVEF when compared with placebo; however, it may play an important role in infarct remodelling and myocardial salvage.