Danish phase II trial using adipose tissue derived mesenchymal stromal cells for patients with ischaemic heart failure

Abstract

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 dif...

Stem cell therapy for heart failure in the clinics: new perspectives in the era of precision medicine and artificial intelligence

“…A considerable number of recent clinical trials in stem cell therapy for HF have demonstrated its promise and substantially increased our understanding of the behaviors and working mechanisms of stem/progenitor cells in patients ( Table 1 ). ( Hamshere et al, 2015 ; Martino et al, 2015 ; Perin et al, 2015 ; Choudry et al, 2016 ; Noiseux et al, 2016 ; Patel et al, 2016 ; Bartolucci et al, 2017 ; Butler et al, 2017 ; Choudhury et al, 2017 ; Florea et al, 2017 ; Gwizdala et al, 2017 ; Hare et al, 2017 ; Steinhoff et al, 2017 ; Teerlink et al, 2017 ; Xiao et al, 2017 ; Bassetti et al, 2018 ; Vrtovec et al, 2018 ; Yau et al, 2019 ; Bolli et al, 2020 ; He et al, 2020 ; Makkar et al, 2020 ; Mathiasen et al, 2020 ; Ulus et al, 2020 ; Bolli et al, 2021 ; Qayyum et al, 2023a ; Qayyum et al, 2023b ; Perin et al, 2023 ) In the next phase of clinical stem cell research, it is critical to address the outcome discrepancy between preclinical and clinical studies and expand the scope of stem cell-based therapy to other forms of cardiomyopathy, such as chemotherapy- or arrhythmia-induced cardiomyopathy. Exploiting the power of AI/ML and computational tools will facilitate our understanding of the benefits and limitations of stem cell therapy and provide a systems perspective for properly applying stem cell therapeutics in the context of precision and personalized medicine.…”

“…In contrast, human clinical trials using adipose-derived MSCs for HF treatment failed to show any significant beneficial outcomes ( Qayyum et al, 2023a ; Qayyum et al, 2023b ). Yau et al reported that intramyocardially injecting allogenic BM-derived MSCs during LVAD implantation did not improve the successful weaning from LVAD, 1-year mortality, or the rate of serious adverse events ( Yau et al, 2019 ).…”

Standardisation is the key to the sustained, rapid and healthy development of stem cell‐based therapy

“…Unlike the MyoCath catheter's stainless‐steel needle, the MyoStar catheter has a nitinol needle. Such two catheter systems have been used in the field of cardiac regeneration and repair 70–72 . Unlike the previous two catheter systems, the Helix catheter is a non‐integrated system that also allows safe transplantation of stem cells to improve myocardial contractility 73 .…”

“…Such two catheter systems have been used in the field of cardiac regeneration and repair. 70 , 71 , 72 Unlike the previous two catheter systems, the Helix catheter is a non‐integrated system that also allows safe transplantation of stem cells to improve myocardial contractility. 73 The C‐Cath catheter is made of nickel‐titanium alloy, which improves stem cell retention in the myocardium and ensures infusion safety and ease of use.…”

Efficacy of Mesenchymal Stem Cell Transplantation on Major Cardiovascular Events and Paraclinical Parameters in Ischemic and Non-Ischemic Heart Failure Patients and the Factors Influencing these Effects: A Meta‑Analysis of Randomized Controlled Trials

“…HF worsening was reported in ten trials (19,22,24,25,27,29,(31)(32)(33)(34) including 700 participants in the treatment group and 635 participants in the control group. However, one trial dominated (34) the results of this outcome, and with that trial removed, the lower risk of HF worsening in the treatment group became signi cant (RR = 0.65; 95% CI: 0.45 to 0.93, p = 0.019) (Fig.…”