Transplantation of Mesenchymal Stem Cells for Prevention of Acute Myocardial Infarction Induced Heart Failure: Study Protocol of a Phase III Randomized Clinical Trial (Prevent-TAHA8)

BackgroundResults from recent clinical trials on bone marrow mononuclear cell (BM-MNC) transplantation show that this intervention can help reduce the incidence of heart failure (HF) after acute myocardial infarction (AMI). However, no study has evaluated the effect of the transplantation of mesenchymal stem cells (MSCs) on a clinical endpoint such as HF.MethodsThis single-blinded, randomized, multicenter trial aims to establish whether the intracoronary infusion of umbilical cord-derived Wharton’s jelly MSCs (WJ-MSCs) helps prevent HF development after AMI. The study will enroll 360 patients 3 to 7 days following AMI. Only patients aged below 65 years with impaired LV function (LVEF < 40%) will be included. They will be randomized (2:1 ratio) to either receive standard care or a single intracoronary infusion of 107 WJ-MSCs. The primary outcome of this study is the assessment of HF development during long-term follow-up (3 years).DiscussionData will be collected until Nov 2024. Thereafter, the analysis will be conducted. Results are expected to be ready by Dec 2024. We will prepare and submit the related manuscript in accordance with the SPIRIT guidelines. This study will help determine whether or not the infusion of intracoronary WJ-MSCs in patients with AMI will reduce the incidence of AMI-induced HF.Trial RegistrationClinicalTrials.gov, NCT05043610, Registered 14 September 2021 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05043610

Transplantation of mesenchymal stem cells for prevention of acute myocardial infarction induced heart failure: Study protocol of a phase III randomized clinical trial

Background: Results from recent clinical trials on bone marrow mononuclear cell (BM-MNC) transplantation show that this intervention can help reduce the incidence of heart failure (HF) after acute myocardial infarction (AMI). However, no study has evaluated the effect of the transplantation of mesenchymal stem cells (MSCs) on a clinical endpoint such as HF.Methods: This single-blinded, randomized, multicenter trial aims to establish whether the intracoronary infusion of umbilical cord-derived Wharton’s jelly MSCs (WJ-MSCs) helps prevent HF development after AMI. The study will enroll 360 patients 3 to 7 days following AMI. Only patients aged below 65 years with impaired LV function (LVEF < 40%) will be included. They will be randomized (2:1 ratio) to either receive standard care or a single intracoronary infusion of 107 WJ-MSCs. The primary outcome of this study is the assessment of HF development during long-term follow-up (3 years).Results: Data will be collected until Nov 2024. Thereafter, the analysis will be conducted. Results are expected to be ready by Dec 2024. We will prepare and submit the related manuscript in accordance with the SPIRIT guidelines. Conclusions: This study will help determine whether or not the infusion of intracoronary WJ-MSCs in patients with AMI will reduce the incidence of AMI-induced HF.Trial Registration: ClinicalTrials.gov, NCT05043610, Registered 14 September 2021 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05043610

Single vs. Double Intracoronary Injection of Mesenchymal Stromal Cell after Acute Myocardial Infarction: The Study Protocol from a Randomized Clinical Trial. BOOSTER-TAHA7 trial

BackgroundMeta-analysis from previous studies have shown that treatment with Mesenchymal stromal cell (MCSs) may increase the left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI) by 3.84% and the effect is greater in those who are not aged and have developed a reduced LVEF. However, it seems that MSC transplantation does its effect through an indirect paracrine effect and direct differentiation to the cardiomyocytes does not occur. Therefore, it can be hypothesized that this paracrine effect would be augmented if repeated doses of MSC are transplanted. This study is conducted to compare single vs. double injection of MSCs.MethodsThis is a single-blind, randomized, multicenter trial aiming to determine whether intracoronary infusion of double doses of umbilical cord-derived Wharton’s jelly MSCs (WJ-MSCs) improves LVEF more after AMI compared to single administration. The study will enroll 60 AMI 3 to 7 days after AMI. The patients should be under 65 years old and have a severe impairment in LV function (LVEF < 40%). They will be randomized to three arms receiving single or double doses of intracoronary infusion of WJ-MSCs or placebo. Primary endpoint of this study is assessment of improvement in LVEF at 6-month post intervention as compared to the baseline. DiscussionThis investigation will help to determine whether infusion of booster (second) dose of intracoronary WJ-MSCs in patients with AMI will contribute to increasing its effect on the improvement of myocardial function.Trial registrationIRCT20201116049408N1. (www.IRCT.ir)

Rational Route of Delivery Mesenchymal Stem Cell Therapy for Acute Myocardial Infarction (AMI) and Chronic Ischemic Cardiomyopathy (ICM): a Systematic Review and Meta-analysis

Background: Recent studies suggest that mesenchymal stem cells (MSCs) may have therapeutic potential for both acute myocardial infarction (AMI) and chronic ischemic cardiomyopathy (ICM). However, the rational route of delivery MSC therapy has not reached consensus. We performed a systematic review of clinical trials evaluating the rational route of delivery MSCs for AMI or ICM.Methods: Databases including Embase, PubMed, and Cochrane Central Register of Controlled Trials were searched from inception to February 2021. Studies that examined the use of MSCs in adults with AMI or ICM were eligible. Bias of included studies were assessed by the Cochrane risk of bias tool. The primary outcome was cardiac function assessed by left ventricular ejection fraction (LVEF) and the secondary outcome was cardiac remodeling which was assessed by left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV), we also explored the safety between different routes. Results: 18 studies fulfilled eligibility criteria, which consist of 11 studies evaluated AMI and 7 studies evaluated ICM. In AMI group, only when patients received intracoronary infusion(IC) can improve LVEF (SMD 0.88, 95% CI 0.64-1.12), and there was a decrease in LVEDV&LVESV when administered IC or intravenous infusion (IV). While in ICM group, no significant difference in LVEF was noted no matter administered which route, and transendocardial stem cell injection(TESI) seems to be effective in decreasing LVEDV&LVESV. Safety appeared no difference between different routes. Conclusions: Results from our systematic review suggest that intracoronary infusion seems more effective for MSC’s delivery in AMI group, while in ICM group, TESI better.

Primary angioplasty after distal intracoronary infusion of nicorandil solution mixed with contrast media

A 50-year-old woman presented with history of intermittent angina for 2 days and signs of extensive anterior wall myocardial infarction. An urgent coronary angiogram showed a large proximally occluded left anterior descending (LAD) artery with no distal vessel opacification. After one attempt of thrombus aspiration, there was no improvement in Thrombolysis in Myocardial Infarction (TIMI) flow. The aspiration catheter was then parked in the distal vessel beyond the thrombotic lesion and 2 mg of intravenous nicorandil drug mixed with 10 mL of 50% dilute iodinated contrast media was infused slowly. A comparison was made to proximal vessel angiogram and the angioplasty procedure was then completed with a right size stent, restoring TIMI 3 flow in the LAD. This method minimises clot manipulations by avoiding repeated balloon predilatations or thrombus aspiration attempts and thus prevents the occurrence of no-reflow in lesions with large thrombus burden.

The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: the BAMI trial

Aims Bone marrow-derived mononuclear cell (BM-MNC) therapy may improve myocardial recovery in patients following acute myocardial infarction (AMI), though existing trial results are inconsistent. Methods and results Originally an open-label, multicentre Phase III trial, BAMI was designed to demonstrate the safety and efficacy of intracoronary infusion of BM-MNCs in reducing the time to all-cause mortality in patients with reduced left ventricular ejection fraction (LVEF, ≤45%) after primary angioplasty (PPCI) for ST-elevation AMI. Unexpectedly low recruitment means the trial no longer qualifies as a hypothesis-testing trial, but is instead an observational study with no definitive conclusions possible from statistical analysis. In total, 375 patients were recruited: 185 patients were randomized to the treatment arm (intracoronary infusion of BM-MNCs 2–8 days after PPCI) and 190 patients to the control arm (optimal medical therapy). All-cause mortality at 2 years was 3.26% [6 deaths; 95% confidence interval (CI): 1.48–7.12%] in the BM-MNC group and 3.82% (7 deaths; 95% CI: 1.84–7.84%) in the control group. Five patients (2.7%, 95% CI: 1.0–5.9%) in the BM-MNC group and 15 patients (8.1%, CI : 4.7–12.5%) in the control group were hospitalized for heart failure during 2 years of follow-up. Neither adverse events nor serious adverse events differed between the two groups. There were no patients hospitalized for stroke in the control group and 4 (2.2%) patients hospitalized for stroke in the BM-MNC group. Conclusions Although BAMI is the largest trial of autologous cell-based therapy in the treatment of AMI, unexpectedly low recruitment and event rates preclude any meaningful group comparisons and interpretation of the observed results.

Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial

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 results We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥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. Trial registration Clinicaltrials.gov identifier: NCT01458405.