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Cell-and gene-based therapies form one of the pillars of regenerative medicine. This chapter reviews the recent progress in applying advanced therapy medicinal products (ATMPs) with a focus on mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs), besides an emphasis on covering in-depth the administration routes for cell and gene therapy medicinal products. The authors will provide a practical overview of the two cell types in myocardial regeneration, drug development, and cardiac disease modeling, besides the administration routes for ATMPs in patients with cardiovascular diseases, including refractory angina and chronic heart failure. Remarkably, the three-dimensional NOGA-XP cardiac mapping system allows for electromechanical assessment of the myocardial viability delineating target zones for cells or gene constructs delivery. This chapter will also focus on clinical aspects and current strategies for ATMPs therapies in recent and prospective clinical trials.

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 × 106 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, 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 × 106 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 with

Background and 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_ASCs) was safe and improved cardiac function in patients with chronic ischemic heart failure with reduced ejection fraction (HFrEF). Methods The study was a European multi-centre double-blinded placebo-controlled phase II trial using allogeneic CSCC_ASCs from healthy donors or placebo (2:1 randomization). Main inclusion criteria were NYHA II-III, left ventricular ejection fraction (LVEF) < 45%, and NT-ProBNP levels>300 pg/mL. CSCC_ASCs or placebo (isotonic saline) were injected directly into viable myocardium. Primary endpoint was change in left ventricular end-systolic volume (LVESV) at 6 months follow up measured by echocardiography. Results 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-years follow-up period. There were no significant differences between the groups during follow up in LVESV (0.3 ± 5.0 ml, P = 0.945), nor in secondary endpoints left ventricular end-diastolic volume (−2.0 ± 6.0 ml, P = 0.736) and LVEF (−1.6 ± 1.0%, P = 0.119). The NYHA classification improved slightly within the first year in both groups without any difference between groups. There were no changes in 6-Minute Walk Test, NT-ProBNP, CRP or quality-of-life the first year in any of the two groups. Conclusion The SCIENCE trial demonstrated safety of intramyocardial allogeneic CSCC_ASC therapy in patients with chronic HFrEF. However, it was not possible to improve the predefined endpoints and induce restoration of cardiac function or clinical symptoms, 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_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_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_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_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.

Non-ischemic dilated cardiomyopathy (NIDCM) constitutes one of the most common causes to non-ischemic heart failure. Despite treatment, the disease often progresses, causing severe morbidity and mortality, making novel treatment strategies necessary. Due to the regenerative actions of mesenchymal stem cells (MSCs), they have been proposed as a treatment for NIDCM. This systematic review aims to evaluate efficacy and mode of action (MoA) of MSC-based therapies in NIDCM. A systematic literature search was conducted in Medline (Pubmed) and Embase. A total of 27 studies were included (3 clinical trials and 24 preclinical studies). MSCs from different tissues and routes of delivery were reported, with bone marrow-derived MSCs and direct intramyocardial injections being the most frequent. All included clinical trials and 22 preclinical trials reported an improvement in cardiac function following MSC treatment. Furthermore, preclinical studies demonstrated alterations in tissue structure, gene, and protein expression patterns, primarily related to fibrosis and angiogenesis. Consequently, MSC treatment can improve cardiac function in NIDCM patients. The MoA underlying this effect involves anti-fibrosis, angiogenesis, immunomodulation, and anti-apoptosis, though these processes seem to be interdependent. These encouraging results calls for larger confirmatory clinical studies, as well as preclinical studies utilizing unbiased investigation of the potential MoA.

Atherosclerosis of coronary arteries can result in a hypoxic state where myocardial cells may become dysfunctional or die. The oxygen sensing transcription factor hypoxia inducible factor 1 responds to low oxygen levels by elevating the production of angiogenic growth factors, such as vascular endothelial growth factor (VEGF). Despite this, endogenous processes and conventional therapies are inefficient in some patients. To stimulate angiogenesis, VEGF has been injected into the myocardium. As stated in this review, this therapy has so far been proven safe and studies are conducted in several countries, including Denmark.

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.

Background: Stem cell therapy is investigated as a treatment option for patients with ischemic heart disease. In this study, long-term safety and efficacy of autologous intra-myocardial injections of adipose-derived stromal cells (ASCs) was studied in patients with refractory angina. Methods: Sixty patients with coronary artery stenosis and preserved left ventricular ejection fraction were 2:1 randomised to intramyocardial injections of ASCs or saline and followed for 3 years. Results: For patients in the ASC group, the bicycle exercise time and the exercise performance in watt were un-changed (383 ± 30 s to 370 ± 44 s, P = 0.052 and 81 ± 6 to 78 ± 10, P = 0.123, respectively), but the performance in METs was reduced significantly (4.2 ± 0.3 to 4.0 ± 0.4, P = 0.027) during the follow-up period. However, in the same period, there was in the placebo group a significant decline in bicycle exercise time (437 ± 53 s to 383 ± 58 s, P = 0.001), the exercise performance measured in watt (87 ± 12 W to 80 ± 12 W, P = 0.019) and in METs (4.5 ± 0.4 to 4.1 ± 0.4, P = 0.002). Moreover, angina measured as CCS class was significantly reduced in the ASC group but not in the placebo group (2.5 ± 0.9 to 1.8 ± 1.2, P = 0.002 and 2.5 ± 0.8 to 2.1 ± 1.3, P = 0.186, respectively). However, no significant change was observed between the two groups. Conclusions: Patients receiving ASCs had improved cardiac symptoms and unchanged exercise capacity, in opposition to deterioration in the placebo group. Trial registration ClinicalTrials.gov Identifier: NCT01449032. Registered 7 October 2011-Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT01449032 term=jens+kastrup&rank=7.

Background. While regenerative stem cell therapy for ischemic heart disease has moved into phase 3 studies, little is still known about retention and migration of cell posttransplantation. In human studies, the ability to track transplanted cells has been limited to labeling with radioisotopes and tracking using nuclear imaging. This method is limited by low resolution and short half-lives of available radioisotopes. Longitudinal tracking using magnetic resonance imaging (MRI) of myocardial injected cells labeled with iron oxide nanoparticles has shown promising results in numerous preclinical studies but has yet to be evaluated in human studies. We aimed to evaluate MRI tracking of mesenchymal stromal cells (MSCs) labeled with ultrasmall paramagnetic iron oxide (USPIO) nanoparticles after intramyocardial transplantation in patients with ischemic heart disease (IHD). Methods. Five no-option patients with chronic symptomatic IHD underwent NOGA-guided intramyocardial transplantation of USPIO-labeled MSCs. Serial MRI scans were performed to track labeled cells both visually and using semiautomated T2∗ relaxation time analysis. For safety, we followed symptoms, quality of life, and myocardial function for 6 months. Results. USPIO-labeled MSCs were tracked for up to 14 days after transplantation at injection sites both visually and using semiautomated regional T2∗ relaxation time analysis. Labeling of MSCs did not impair long-term safety of treatment. Conclusion. This was a first-in-man clinical experience aimed at evaluating the utility of MRI tracking of USPIO-labeled bone marrow-derived autologous MSCs after intramyocardial injection in patients with chronic IHD. The treatment was safe, and cells were detectable at injection sites up to 14 days after transplantation. Further studies are needed to clarify if MSCs migrate out of the injection area into other areas of the myocardium or if injected cells are washed out into the peripheral circulation. The trial is regi

Adipose-derived stromal cell (ASC) therapy is currently investigated as a new treatment option for patients with ischemic heart disease (IHD). The aim of this study was to evaluate the effect of ASC therapy in patients with chronic IHD measuring myocardial perfusion and cardiac function using cardiac magnetic resonance imaging (CMRI). Patients were included in MyStromalCell trial, a phase II, randomized, double-blinded, placebo-controlled study investigated the effect of ASCs in patients with chronic IHD with preserved left ventricular ejection fraction (LVEF). In total, 41 of 60 patients underwent cine, late enhancement, rest and stress imaging with CMRI. There was a non-significant difference between stress and rest values in maximal signal intensity, a measure of myocardial perfusion, from baseline to follow-up comparing placebo with ASC group (–52.52 ± 88.61 and 3.05 ± 63.17, p = 0.061, respectively). LVEF, myocardial mass, stroke volume, left ventricle end-diastolic volume and end-systolic volume changed non-significantly (–0.5 ± 4.7%, –3.5 ± 13.1 g, –0.7 ± 8.6 mL, 1.9 ± 25.1 mL and 2.6 ± 16.5 mL, respectively) in the placebo group and in the ASC group (0.7 ± 8.6%, 0.9 ± 10.8 g, –0.3 ± 26.1 mL, –3.0 ± 31.5 mL and –2.7 ± 20.4 mL, respectively) from baseline to 6 months follow-up. The amount of scar tissue was unchanged in the placebo group by 0.0 ± 1.6 g, p = 1.0 and in the ASC group with –0.3 ± 2.3 g, p = 0.540. There was no difference between the groups. There was a non-significant trend toward increased myocardial perfusion but no significant changes in functional parameters or amount of scar tissue in patients treated with ASCs compared with patients allocated into the placebo group.

Coronary microvascular dysfunction (CMD) is associated with a poor prognosis even in absence of obstructive coronary artery disease. CMD can be assessed as a myocardial blood flow reserve by positron emission tomography (PETMBFR) and as coronary flow velocity reserve by transthoracic Doppler echocardiography (TTDECFVR). Impaired first-pass perfusion assessed by cardiac magnetic resonance (CMR) is an early sign of ischemia. We aimed to investigate the association between CMD and CMR first-pass perfusion. Women (n = 66) with angina pectoris and an invasive coronary angiogram (<50% stenosis) were assessed by TTDECFVR and in a subgroup of these (n = 54) also by PETMBFR. Semi-quantitative evaluation of first-pass perfusion at rest and adenosine stress was assessed by gadolinium CMR in all 66 women. Four measures of CMR perfusion reserve were calculated using contrast upslope, maximal signal intensity and both indexed to arterial input. Mean (standard deviation) age was 62 (8) years. Median (interquartile range) TTDECFVR was 2.3 (1.8;2.7) and PETMBFR was 2.7 (2.2;3.1). Using a cut-off of 2.0 for TTDECFVR and 2.5 for PETMBFR, 25 (38%) and 21 (39%) had CMD, respectively. CMR myocardial perfusion reserve from contrast upslope (CMR_MPRupslope) showed moderate but significant correlation with PETMBFR (R = .46, p < .001) while none of the other CMR variables were associated with CMD. A CMR_MPRupslope cut-off of 0.78 identified CMD, area under the curve 0.73 (p = .001). The results indicate that CMR_MPRupslope may be associated to PETMBFR; a measure of CMD. Further research is needed to validate and implement the use of CMR first pass perfusion in this population.

BACKGROUND: Number of stromal cells injected in patients with ischaemic heart disease (IHD) may be of importance for the treatment efficacy, which in turn may be influenced by various patient-related factors. In this study, we investigate whether patient-related factors influence the number of autologous stromal cells reached after in vitro culture expansion for clinical therapy.METHODS: Culture expansion data from 111 patients with IHD treated with autologous stromal cells in three clinical trials were used. We correlated the final cell count after two passages of cultivation with different patient factors.RESULTS: There was a significant relation between body mass index (BMI) and the number of adipose derived stromal cells (ASCs) reached after culture expansion and for all patients included into the three studies (r = 0.375, p = .019 and r = 0.200, p = .036, respectively). Moreover, there was a significantly higher number of ASCs reached in patients with hypertension compared to those without hypertension and for all patients overall (68.8 ± 39.6 × 106 vs. 39.1 ± 23.6 × 106, p = .020 and 62.0 ± 55.0 × 106 vs. 29.0 ± 19.3 × 106, p < .001, respectively). The same tendency was seen with bone marrow derived mesenchymal stromal cells (MSCs) in patients with hypertension compared to those without hypertension (58.4 ± 61.8 × 106 vs. 22.6 ± 13.3 × 106, p < .001) and in males compared to females (56.4 ± 61.5 × 106 vs. 30.9 ± 27.9 × 106, p = .041). Moreover, a significant negative correlation between left ventricular ejection fraction and number of MSCs was found (r = -0.287, p = .017).CONCLUSIONS: Patient related factors such as BMI, hypertension and gender may influence the number of MSCs reached after in vitro culture expansion.

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_ASC) product from healthy donors for intramyocardial injection in ten patients with ischemic heart disease and ischemic heart failure (IHF). Batches of CSCC_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_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_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_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.

BACKGROUND: Ischemic heart failure (IHF) has a poor prognosis in spite of optimal therapy. We have established a new allogeneic Cardiology Stem Cell Centre adipose-derived stromal cell (CSCC_ASC) product from healthy donors. It is produced without animal products, in closed bioreactor systems and cryopreserved as an off-the-shelf product ready to use.STUDY DESIGN: A multicentre, double-blind, placebo-controlled phase II study with direct intramyocardial injections of allogeneic CSCC_ASC in patients with chronic IHF. A total of 81 patients will be randomised at 2 : 1 to CSCC_ASC or placebo. There is no HLA tissue type matching needed between the patients and the donors.METHODS: The treatment will be delivered by direct injections into the myocardium. The primary endpoint is change in the left ventricle endsystolic volume at 6-month follow-up. Secondary endpoints are safety and changes in left ventricle ejection fraction, myocardial mass, stroke volume, and cardiac output. Other secondary endpoints are change in clinical symptoms, 6-minute walking test, and the quality of life after 6 and 12 months.CONCLUSION: The aim of the present study is to demonstrate safety and the regenerative efficacy of the allogeneic CSCC_ASC product from healthy donors in a double-blind, placebo-controlled, multicentre study in patients with IHF.

We aimed to evaluate the effect of intramyocardial injections of autologous VEGF-A165-stimulated adipose-derived stromal cells (ASCs) in patients with refractory angina. MyStromalCell trial is a randomized double-blind placebo-controlled study including sixty patients with CCS/NYHA class II-III, left ventricular ejection fraction > 40%, and at least one significant coronary artery stenosis. Patients were treated with ASC or placebo in a 2 : 1 ratio. ASCs from the abdomen were culture expanded and stimulated with VEGF-A165. At 6 months follow-up, bicycle exercise tolerance increased significantly in time duration 22 s (95%CI -164 to 208 s) (P= 0.034), in watt 4 (95%CI -33 to 41, 0.048), and in METs 0.2 (95%CI -1.4 to 1.8) (P= 0.048) in the ASC group while there was a nonsignificant increase in the placebo group in time duration 9 s (95%CI -203 to 221 s) (P= 0.053), in watt 7 (95%CI -40 to 54) (P= 0.41), and in METs 0.1 (95%CI -1.7 to 1.9) (P= 0.757). The difference between the groups was not significant (P= 0.680,P= 0.608, andP= 0.720 for time duration, watt, and METs, resp.). Intramyocardial delivered VEGF-A165-stimulated ASC treatment was safe but did not improve exercise capacity compared to placebo. However, exercise capacity increased in the ASC but not in the placebo group. This trial is registered with ClinicalTrials.gov NCT01449032.

INTRODUCTION: Computed tomography (CT) is a novel method for assessment of myocardial perfusion and has not yet been compared to rubidium-82 positron emission tomography (PET). We aimed to compare CT measured semi-quantitative myocardial perfusion with absolute quantified myocardial perfusion using PET and to detect stenotic territories in patients with severe coronary artery disease.MATERIALS AND METHODS: Eighteen patients with stenosis narrowing coronary arteries ≥70% demonstrated on invasive coronary angiography underwent rest and adenosine stress imaging obtained by 320-multidetector CT scanner and CT/PET 64-slice scanner. CT measured myocardial attenuation density (AD) and perfusion index (PI) were correlated to absolute PET myocardial perfusion values.RESULTS: Rest AD, rest and stress PI did not correlate to PET findings (r = 0·412, P = 0·113; r = 0·300, P = 0·259; and r = 0·508, P = 0·064, respectively). However, there was a significant correlation between stress AD and stress PET values (r = 0·670, P = 0·009) and between stress and rest differences for AD and PI with PET differences (r = 0·620, P = 0·006; and r = 0·639, P = 0·004, respectively). Furthermore, significant differences were observed between remote and stenotic territories for rest and stress AD (48 ± 14HU and 37 ± 16HU, P = 0·002; 76 ± 19HU and 58 ± 13HU, P<0·001, respectively), PI (9·6 ± 2·9 and 7·5 ± 3·1, P = 0·002; 21·6 ± 4·1 and 16·9 ± 3·9, P<0·001, respectively) and PET (0·96 ± 0·37 ml g(-1) min(-1) and 0·86 ± 0·26 ml g(-1) min(-1) , P = 0·036; 2·07 ± 0·76 ml g(-1) min(-1) and 1·61 ± 0·76 ml g(-1) min(-1) , P = 0·006, respectively).CONCLUSIONS: Semi-quantitative CT parameters may be useful in the detection of myocardium subtended by stenotic coronary arteries.

Ischemic heart disease (IHD) is one of the leading causes of death worldwide and is characterized by the formation of atherosclerotic plaques in the coronary arteries reducing the blood supply to the heart muscle causing ischemia. IHD can result in ST-elevation myocardial infarction (STEMI), chronic IHD and heart failure. The patients suffer from chest pain (angina), dyspnea and a reduced quality of life. Common for all these conditions is loss of functional cardiomyocytes and endothelial cells. Stem cell therapy to regenerate injured myocardium is a new treatment option which has gained much interest in the last 10-15 years especially after STEMI. Many preclinical and clinical studies have shown encouraging results but also very diverse clinical outcomes after stem cell treatment. This diversity in results may be explained by different factors, such as cell isolation technique, infarct location, timing and route of delivery, cell dosage, cell type etc. The present review will try to elaborate and clarify the present status for stem cell therapy in STEMI.

Although, treatment of ischemic heart disease (IHD) has improved considerably within the last decades, it is still the main cause of death worldwide. Despite maximum treatment, many IHD patients suffer from refractory angina and heart failure, which severely limits their daily lives. Moreover, IHD is very costly for the health care system. Therefore, new treatment options and strategies are being researched intensely. Stem cell therapy to improve myocardial perfusion and stimulate growth of new cardiomyocytes could be a new way to go. Nevertheless, the results from clinical studies have varied considerably, probably due to the use of many different cell lines obtained from different tissues and the different patient populations. The present review will focus on treatment with the mesenchymal stromal cell from bone marrow and adipose tissue in animal and patients with acute and chronic IHD (CIHD).

BACKGROUND: Even in absence of obstructive coronary artery disease women with angina pectoris have a poor prognosis possibly due to coronary microvascular disease. Coronary microvascular disease can be assessed by transthoracic Doppler echocardiography measuring coronary flow velocity reserve (CFVR) and by positron emission tomography measuring myocardial blood flow reserve (MBFR). Diffuse myocardial fibrosis can be assessed by cardiovascular magnetic resonance (CMR) T1 mapping. We hypothesized that coronary microvascular disease is associated with diffuse myocardial fibrosis.METHODS: Women with angina, a clinically indicated coronary angiogram with <50 % stenosis and no diabetes were included. CFVR was measured using dipyridamole (0.84 mg/kg) and MBFR using adenosine (0.84 mg/kg). Focal fibrosis was assessed by 1.5 T CMR late gadolinium enhancement (0.1 mmol/kg) and diffuse myocardial fibrosis by T1 mapping using a modified Look-Locker pulse sequence measuring T1 and extracellular volume fraction (ECV).RESULTS: CFVR and CMR were performed in 64 women, mean (SD) age 62.5 (8.3) years. MBFR was performed in a subgroup of 54 (84 %) of these women. Mean native T1 was 1023 (86) and ECV (%) was 33.7 (3.5); none had focal fibrosis. Median (IQR) CFVR was 2.3 (1.9; 2.7), 23 (36 %) had CFVR < 2 indicating coronary microvascular disease, and median MBFR was 2.7 (2.2; 3.0) and 19 (35 %) had a MBFR value below 2.5. No significant correlations were found between CFVR and ECV or native T1 (R (2) = 0.02; p = 0.27 and R (2) = 0.004; p = 0.61, respectively). There were also no correlations between MBFR and ECV or native T1 (R (2) = 0.1; p = 0.13 and R (2) = 0.004, p = 0.64, respectively). CFVR and MBFR were correlated to hypertension and heart rate.CONCLUSION: In women with angina and no obstructive coronary artery disease we found no association between measures of coronary microvascular disease and myocardial fibrosis, suggesting that myocardial is

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., 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).

The present Cochrane review included 23 studies randomized placebo-controlled clinical trials with a total of 1,255 patients. The effect of autologous cell therapy versus placebo was examined on left ventricular ejection fraction (LVEF), adverse effects and mortality in patients with chronic ischaemic heart disease. Patients treated with cell therapy had improved LVEF and functional status compared to patients who received placebo. There were no cell-related and only few procedure-related side effects. A positive effect of cell therapy on long-term survival was also demonstrated.