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Aims: Patients suffering from chronic ischaemic heart failure with reduced left ventricular ejection fraction (HFrEF) have reduced quality-of-life, repetitive hospital admissions, and reduced life expectancy. Allogeneic cell therapy is currently investigated as a potential treatment option after initially encouraging results from clinical autologous and allogeneic trials in patients with HFrEF. We aimed to investigate the allogeneic Cardiology Stem Cell Centre Adipose tissue derived mesenchymal Stromal Cell product (CSCC_ASC) as an add-on therapy in patients with chronic HFrEF., Methods and Results: This is a Danish multi-centre double-blinded placebo-controlled phase II study with direct intra-myocardial injections of allogeneic CSCC_ASC. A total of 81 HFrEF patients were included and randomized 2:1 to CSCC_ASC or placebo injections. The inclusion criteria were reduced left ventricular ejection fraction (LVEF ≤ 45%), New York Heart Association (NYHA) class II-III despite optimal anti-congestive heart failure medication and no further revascularization options. Injections of 0.3 mL CSCC_ASC (total cell dose 100 × 10 6 ASCs) (n = 54) or isotonic saline (n = 27) were performed into the viable myocardium in the border zone of infarcted tissue using the NOGA Myostar® catheter (Biological Delivery System, Cordis, Johnson & Johnson, USA). The primary endpoint, left ventricular end systolic volume (LVESV), was evaluated at 6-month follow-up. The safety was measured during a 3-years follow-up period., Results: Mean age was 67.0 ± 9.0 years and 66.6 ± 8.1 years in the ASC and placebo groups, respectively. LVESV was unchanged from baseline to 6-month follow-up in the ASC (125.7 ± 68.8 mL and 126.3 ± 72.5 mL, P = 0.827) and placebo (134.6 ± 45.8 mL and 135.3 ± 49.6 mL, P = 0.855) group without any differences between the groups (0.0 mL (95% CI -9.1 to 9.0 mL, P = 0.992). Neither were there significant changes in left ventricular end diastolic volume or LVEF within the two groups or between groups -5.7 mL (95% CI -16.7 to 5.3 mL, P = 0.306) and -1.7% (95% CI -4.4. to 1.0, P = 0.212), respectively). NYHA classification and 6-min walk test did not alter significantly in the two groups (P > 0.05). The quality-of-life, total symptom, and overall summary score improved significantly only in the ASC group but not between groups. There were 24 serious adverse events (SAEs) in the ASC group and 11 SAEs in the placebo group without any significant differences between the two groups at 1-year follow-up. Kaplan-Meier plot using log-rank test of combined cardiac events showed an overall mean time to event of 30 ± 2 months in the ASC group and 29 ± 2 months in the placebo group without any differences between the groups during the 3 years follow-up period (P = 0.994)., Conclusions: Intramyocardial CSCC_ASC injections in patients with chronic HFrEF were safe but did not improve myocardial function or structure, nor clinical symptoms., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: The aim of the SCIENCE trial was to investigate whether a single treatment with direct intramyocardial injections of adipose tissue-derived mesenchymal stromal cells (CSCC&#95;ASCs) was safe and improved cardiac function in patients with chronic ischaemic heart failure with reduced ejection fraction (HFrEF)., Methods and Results: The study was a European multicentre, double-blind, placebo-controlled phase II trial using allogeneic CSCC&#95;ASCs from healthy donors or placebo (2:1 randomization). Main inclusion criteria were New York Heart Association (NYHA) class II-III, left ventricular ejection fraction (LVEF) <45%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels >300 pg/ml. CSCC&#95;ASCs or placebo (isotonic saline) were injected directly into viable myocardium. The primary endpoint was change in left ventricular end-systolic volume (LVESV) at 6-month follow-up measured by echocardiography. A total of 133 symptomatic HFrEF patients were included. The treatment was safe without any drug-related severe adverse events or difference in cardiac-related adverse events during a 3-year follow-up period. There were no significant differences between groups during follow-up in LVESV (0.3 ± 5.0 ml, p = 0.945), nor in secondary endpoints of left ventricular end-diastolic volume (-2.0 ± 6.0 ml, p = 0.736) and LVEF (-1.6 ± 1.0%, p = 0.119). The NYHA class improved slightly within the first year in both groups without any difference between groups. There were no changes in 6-min walk test, NT-proBNP, C-reactive protein or quality of life the first year in any groups., Conclusion: The SCIENCE trial demonstrated safety of intramyocardial allogeneic CSCC&#95;ASC therapy in patients with chronic HFrEF. However, it was not possible to improve the pre-defined endpoints and induce restoration of cardiac function or clinical symptoms., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: The study assessed 4-year outcomes of intramyocardial injections of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in patients with ischaemic heart failure., Methods and Results: The MSC-HF trial was a randomized, double-blind, placebo-controlled trial. Patients were randomized 2:1 to intramyocardial injections of MSCs or placebo. The primary endpoint was change in left ventricular end-systolic volume (LVESV), measured by magnetic resonance imaging or computed tomography. Sixty patients aged 30-80 years with ischaemic heart failure, New York Heart Association class II-III, left ventricular ejection fraction (LVEF) <45% and no further treatment options were randomized. Patients were followed clinically for 12 months and in addition 4-year data of hospitalizations and survival were retrieved. After 12 months, LVESV was significantly reduced in the MSC group and not in the placebo group, with difference between groups of 17.0 ± 16.2 mL (95% confidence interval 8.3-25.7, P = 0.0002). There were also significant improvements in LVEF of 6.2% (P < 0.0001), stroke volume of 16.1 mL (P < 0.0001) and myocardial mass (P = 0.009) between groups. A significant dose-response effect was also observed. Moreover, a significant reduction in the amount of scar tissue and quality of life score in the MSC group but not in the placebo group was observed. After 4 years, there were significantly fewer hospitalizations for angina in the MSC group and otherwise no differences in hospitalizations or survival. No side effects were identified., Conclusions: Intramyocardial injections of autologous bone marrow-derived MSCs improved myocardial function and myocardial mass in patients with ischaemic heart failure., (© 2019 European Society of Cardiology.)

The present first-in-human clinical trial evaluated the safety and feasibility of a newly developed and cryopreserved Cardiology Stem Cell Centre adipose-derived stromal cell (CSCC&#95;ASC) product from healthy donors for intramyocardial injection in ten patients with ischemic heart disease and ischemic heart failure (IHF). Batches of CSCC&#95;ASC were isolated from three healthy donors by liposuction from abdominal adipose tissue. Adipose mesenchymal stromal cells were culture expanded in bioreactors without the use of animal constituents, cryopreserved, and stored in vials in nitrogen dry-storage containers until use. Direct injection of CSCC&#95;ASC into the myocardium did not cause any complications or serious adverse events related to either treatment or cell administration in a 6-month follow-up period. Four out of ten heart failure patients developed donor-specific de novo human leukocyte antigen (HLA) class I antibodies, and two out of ten patients had donor-specific HLA antibodies already at baseline. There were no clinical symptoms or changes in inflammatory parameters in the follow-up period that indicated an ongoing immune response. There was a tendency toward improvement in cardiac function after CSCC&#95;ASC treatment at 6-month follow-up: left ventricular end systolic volume decreased and left ventricular ejection fraction increased. In addition, exercise capacity increased. These changes were independent of the presence or absence of HLA antibodies. It is concluded that the newly developed cryopreserved product CSCC&#95;ASC from healthy donors was a safe and feasible treatment. We observed a tendency toward efficacy in patients with IHF. These findings have to be confirmed in larger placebo controlled clinical trials. Stem Cells Translational Medicine 2017;6:1963-1971., (© 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Background: Approximately one third of patients with ST-segment elevation myocardial infarction (STEMI) have left ventricular hypertrophy (LVH), which is associated with impaired outcome. However, the causal association between LVH and outcome in STEMI is unknown. We evaluated the association between LVH and: myocardial infarct size, area at risk, myocardial salvage, microvascular obstruction, left ventricular (LV) function (all determined by cardiac magnetic resonance [CMR]), and all-cause mortality and readmission for heart failure in STEMI patients treated with primary percutaneous coronary intervention., Methods and Results: In this substudy of the DANAMI-3 trial, 764 patients underwent CMR. LVH was defined by CMR and considered present if LV mass exceeded 77 (men) and 67 g/m 2 (women). One hundred seventy-eight patients (24%) had LVH. LVH was associated with a larger final infarct size (15% [interquartile range {IQR}, 10-21] vs 9% [IQR, 3-17]; P<0.001) and smaller final myocardial salvage index (0.6 [IQR, 0.5-0.7] vs 0.7 [IQR, 0.5-0.9]; P<0.001). The LVH group had a higher incidence of microvascular obstruction (66% vs 45%; P<0.001) and lower final LV ejection fraction (LVEF; 53% [IQR, 47-60] vs 61% [IQR, 55-65]; P<0.001). In a Cox regression analysis, LVH was associated with a higher risk of all-cause mortality and readmission for heart failure (hazard ratio 2.59 [95% CI, 1.38-4.90], P=0.003). The results remained statistically significant in multivariable models., Conclusions: LVH is independently associated with larger infarct size, less myocardial salvage, higher incidence of microvascular obstruction, lower LVEF, and a higher risk of all-cause mortality and incidence of heart failure in STEMI patients treated with primary percutaneous coronary intervention., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01435408., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Aims: Regenerative treatment with mesenchymal stromal cells (MSCs) has been promising in patients with ischaemic heart failure but needs confirmation in larger randomized trials. We aimed to study effects of intra-myocardial autologous bone marrow-derived MSC treatment in patients with severe ischaemic heart failure., Methods and Results: The MSC-HF trial is a randomized, double-blind, placebo-controlled trial. Patients were randomized 2 : 1 to intra-myocardial injections of MSC or placebo, respectively. The primary endpoint was change in left ventricular end-systolic volume (LVESV), measured by magnetic resonance imaging or computed tomography at 6 months follow-up. Sixty patients aged 30-80 years with severe ischaemic heart failure, New York Heart Association (NYHA) classes II-III, left ventricular ejection fraction (LVEF) <45% and no further treatment options were randomized. Fifty-five patients completed the 6-month follow-up (37 MSCs vs. 18 placebo). At 6 months, LVESV was reduced in the MSC group: -7.6 (95% CI -11.8 to -3.4) mL (P = 0.001), and increased in the placebo group: 5.4 (95% CI -0.4 to 11.2) mL (P = 0.07). The difference between groups was 13.0 (95% CI 5.9-20.1) mL (P = 0.001). Compared with placebo, there were also significant improvements in LVEF of 6.2% (P<0.0001), stroke volume of 18.4 mL (P < 0.0001), and myocardial mass of 5.7 g (P = 0.001). No differences were found in NYHA class, 6-min walking test and Kansas City cardiomyopathy questionnaire. No side effects were identified., Conclusion: Intra-myocardial injections of autologous culture expanded MSCs were safe and improved myocardial function in patients with severe ischaemic heart failure., Study Registration Number: NCT00644410 (ClinicalTrials.gov)., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: To evaluate the clinical importance of the ST peak phenomenon during primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI)., Methods and Results: Continuous ST monitoring was performed in 942 STEMI patients from arrival until 90 minutes after revascularisation. ST peak was defined as ≥1 mm increase in the ST-segment during PCI compared with the ST elevation before intervention. ST peak was observed in 26.9% of patients. During median follow-up of 4.1 years, 20.7% of patients experienced a major adverse cardiac event (MACE). ST peak was associated with higher rates of mortality (13.4% versus 9.3%; p=0.044), admission for heart failure (10.6% versus 5.2%; p=0.002) and MACE (26.9% versus 18.2%; p=0.002), but not reinfarction (7.1% versus 5.2%; p=0.14). In two different Cox regression analyses, adjusting for predictors of MACE and ST peak including ST resolution and epicardial flow, ST peak remained significantly associated with MACE: adjusted hazard ratio (HR) 1.40 (95% confidence interval [CI] 1.01-1.95) and 1.41 (95% CI: 1.02-1.96)., Conclusions: In the largest study hitherto evaluating the ST peak phenomenon during primary PCI, we demonstrated that ST peak is a strong predictor of adverse long-term outcome and provides independent prognostic information beyond that provided by ST resolution and epicardial flow.

Aims Regenerative treatment with mesenchymal stromal cells (MSCs) has been promising in patients with ischaemic heart failure but needs confirmation in larger randomized trials. We aimed to study effects of intra-myocardial autologous bone marrow-derived MSC treatment in patients with severe ischaemic heart failure. Methods and results The MSC-HF trial is a randomized, double-blind, placebo-controlled trial. Patients were randomized 2 : 1 to intra-myocardial injections of MSC or placebo, respectively. The primary endpoint was change in left ventricular end-systolic volume (LVESV), measured by magnetic resonance imaging or computed tomography at 6 months follow-up. Sixty patients aged 30-80 years with severe ischaemic heart failure, New York Heart Association (NYHA) classes II-III, left ventricular ejection fraction (LVEF) <45% and no further treatment options were randomized. Fifty-five patients completed the 6-month follow-up (37 MSCs vs. 18 placebo). At 6 months, LVESV was reduced in the MSC group: -7.6 (95% CI -11.8 to -3.4) mL (P = 0.001), and increased in the placebo group: 5.4 (95% CI -0.4 to 11.2) mL (P = 0.07). The difference between groups was 13.0 (95% CI 5.9-20.1) mL (P = 0.001). Compared with placebo, there were also significant improvements in LVEF of 6.2% (P<0.0001), stroke volume of 18.4 mL (P < 0.0001), and myocardial mass of 5.7 g (P = 0.001). No differences were found in NYHA class, 6-min walking test and Kansas City cardiomyopathy questionnaire. No side effects were identified. Conclusion Intra-myocardial injections of autologous culture expanded MSCs were safe and improved myocardial function in patients with severe ischaemic heart failure. [ABSTRACT FROM AUTHOR]