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Aims: Allogeneic stem cell therapy is more logistically suitable compared with autologous cell therapy for large-scale patient treatment. We aim to investigate the clinical safety and efficacy profile of the allogeneic adipose tissue derived mesenchymal stromal cell product (CSCC&#95;ASC) as an add-on therapy in patients with chronic non-ischaemic heart failure with reduced left ventricular ejection fraction (HFrEF) < 40%., Methods and Results: This is a single-centre investigator-initiated randomized phase I/II study with direct intra-myocardial injections of 100 million allogeneic CSCC&#95;ASC. A total of 30 HFrEF patients with New York Heart Association (NYHA) class ≥II despite optimal anticongestive heart failure medication and plasma NT-proBNP > 300 pg/mL (>35 pmol/L) were included and randomized 2:1 to CSCC&#95;ASC or standard care. The primary endpoint left ventricular end systolic volume (LVESV) and other echo related parameters were analysed by an investigator blinded for treatment allocation. No difference in serious adverse events was observed between groups. LVESV decreased significantly from baseline to 6 months follow-up in the ASC group (153.7 ± 53.2 mL and 128.7 ± 45.6 mL, P < 0.001) and remained unchanged in the standard care group (180.4 ± 39.4 mL and 186.7 ± 48.9 mL, P = 0.652). There was a significant difference between the groups in LVESV change (31.3 ± 11.0 mL, P = 0.009). The difference from baseline to follow-up between the two groups in left ventricular end diastolic volume (LVEDV) was 18.7 ± 12.4 mL, P = 0.146 and in left ventricular ejection fraction (LVEF) -7.8 ± 2.1%, P = 0.001. Considering the baseline values of LVESV, LVEDV and LVEF as covariates, the difference between groups for change from baseline to follow-up resulted in a P-value of 0.056, 0.076, and 0.738, respectively. NYHA class and self-reported health did also improve significantly in the ASC group compared with the standard care group (0.7 ± 0.2, P = 0.001 and -12.8 ± 5.3, P = 0.025; respectively). There was no difference in NT-proBNP (-371 ± 455 pmol/L, P = 0.422) or in 6 min walk test (12 ± 31 m, P = 0.695) between groups., Conclusions: Intramyocardial injections of allogeneic CSCC&#95;ASC in patients with chronic non-ischaemic HFrEF was safe and improved LVESV, LVEF, NYHA class, and self-reported health compared with standard care group., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Despite tremendous therapeutic advancements, a significant proportion of coronary artery disease patients suffer from refractory angina pectoris, that is, quality-of-life-compromising angina that is non-manageable with established pharmacological and interventional treatment options. Adenoviral vascular endothelial growth factor-D ΔNΔC (AdVEGF-D)-encoding gene therapy (GT) holds promise for the treatment of refractory angina., Methods: ReGenHeart is an investigator-initiated, multicentre, randomised, placebo-controlled and double-blinded phase 2 clinical trial that aims to study the safety and efficacy of intramyocardially administered angiogenic AdVEGF-D GT for refractory angina. Patients will be randomised in a 2:1 ratio and blocks of six to receive either AdVEGF-D or placebo. Primary endpoints are improvements in functional capacity assessed with the 6 min walking test and angina symptoms with Canadian Cardiovascular Society class after 6 month follow-up. Secondary endpoints are improvements in myocardial perfusion assessed with either positron emission tomography or single-photon emission CT after 6 month follow-up and functional capacity and angina symptoms after 12 months. In addition, changes in the quality of life, the use of angina medication and the incidence of major adverse cardiac and cerebrovascular events will be evaluated., Conclusions: The phase 2 ReGenHeart trial will provide knowledge of the safety and efficacy of AdVEGF-D GT to ameliorate symptoms in refractory angina patients, extending and further testing positive results from the preceding phase 1/2a trial., Competing Interests: Competing interests: JEKH received consultancy fees from Novo Nordisk and speaker fees from the BMS-Pfizer alliance. JK received consultancy fees from GE Healthcare and Synektik and speaker fees from GE Healthcare, Bayer, Lundbeck, Boehringer-Ingelheim, Pfizer, Siemens Healthineers and Merck, outside of the submitted work. AS received consultancy fees from Amgen, Astra Zeneca, Boehringer Ingelheim and Pfizer, and speaker fees from Abbott, Astra Zeneca and Bayer. Other authors declare that they have no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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&#95;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&#95;ASC. A total of 81 HFrEF patients were included and randomized 2:1 to CSCC&#95;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&#95;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&#95;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.)

Introduction: Peripartum cardiomyopathy (PPCM) is a rare but potentially lifethreatening disease, defined as idiopathic cardiomyopathy occurring towards the end of pregnancy or in the months following delivery, abortion or miscarriage. We aim to raise awareness of this condition and give an overview of current knowledge as well as an insight and comparison of clinical trials focusing on randomized controlled trials., Material and Methods: Systematic literature searches were conducted using PubMed up to December 2021. Studies published involving clinical trials and interventions in women with PPCM after 1970 were selected., Results: Randomized controlled trials have shown that the addition of Bromocriptine to standardized heart failure therapy improves outcome in terms of recovery of Left Ventricular Ejection Fraction (LVEF), symptoms and death. Bromocriptine 2.5 mg twice daily for two weeks followed by 2.5 mg once daily for six weeks had the best trend and outcome. The addition of Levosimendan to standardized heart failure therapy had no effect, whereas the addition of Selenium improved heart failure symptoms but did not reduce risk in terms of unrecovered LVEF or death. One prospective study showed potential usage of TNF-alfa inhibitors, but was never tried in a randomized clinical trial., Conclusion: PPCM is a rare and potentially fatal disease. New insights on pathophysiology, genetics and clinical studies, particularly randomized controlled trials, have shown that the addition of Bromocriptine has a beneficial effect in terms of improved LVEF and death. However, some clinical studies have shown promising results using anti-inflammatory pharmacological agents with an improvement in LVEF. We suggest that targeting an anti-inflammatory route may prove beneficial in patients with PPCM. However, further research is highly warranted., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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., (© 2019 European Society of Cardiology.)

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.

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 registered with ClinicalTrials.gov NCT03651791., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Anders Bruun Mathiasen et al.)

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.

Aim: To compare the efficacy of computed tomography (CT) texture analysis and conventional evaluation by radiologists for differentiation between large adrenal adenomas and carcinomas., Materials and Methods: Quantitative CT texture analysis was used to evaluate 54 histopathologically proven adrenal masses (mean size=5.9 cm; range=4.1-10 cm) from 54 patients referred to Anderson Cancer Center from January 2002 through April 2014. The patient group included 32 women (mean age at mass evaluation=59 years) and 22 men (mean age at mass evaluation=61 years). Adrenal lesions seen on precontrast and venous-phase CT images were labelled by three different readers, and the labels were used to generate intensity- and geometry-based textural features. The textural features and the attenuation values were considered as input values for a random forest-based classifier. Similarly, the adrenal lesions were classified by two different radiologists based on morphological criteria. Prediction accuracy and interobserver agreement were compared., Results: The textural predictive model achieved a mean accuracy of 82%, whereas the mean accuracy for the radiologists was 68.5% (p<0.0001). The interobserver agreements between the predictive model and radiologists 1 and 2 were 0.44 (p<0.0005; 95% confidence interval [CI]: 0.25-0.62) and 0.47 (p<0.0005; 95% CI: 0.28-0.66), respectively. The Dice similarity coefficient between the readers' image labels was 0.875±0.04., Conclusion: CT texture analysis of large adrenal adenomas and carcinomas is likely to improve CT evaluation of adrenal cortical tumours., (Copyright © 2019. Published by Elsevier Ltd.)

Purpose: Large adrenal masses pose a diagnostic dilemma. The purpose of this study was twofold: first, to assess the degree of interobserver agreement in evaluating the morphology of pathologically proven adrenal adenomas and adrenocortical carcinomas larger than 4 cm in diameter; and second, to identify morphologic characteristics that correlated with the pathologic diagnosis., Materials and Methods: For this blinded, retrospective study, we collected cases of 25 adrenal adenomas and 33 adrenocortical carcinomas measuring larger than 4 cm. Two radiologists evaluated morphologic characteristics of the lesions on CT. Interobserver agreement was evaluated using kappa statistics, and the correlation of imaging characteristics with the diagnosis was evaluated using a logistic regression model., Results: We found the highest interobserver agreement in the assessment of precontrast attenuation (Κ = 0.81) as well as substantial agreement in determining the shape and the presence of calcifications (Κ = 0.69 and 0.74, respectively). Readers agreed less often regarding the presence of fat (Κ = 0.48), as well as regarding the presence of necrosis, heterogeneity, and the overall impression (Κ = 0.15, 0.24, and 0.26, respectively). CT characteristics correlated with benignity included round shape (p = 0.02), an overall radiologic impression of a benign lesion (p < 0.0001), the presence of fat (p = 0.01), and a precontrast attenuation of less than 10 Hounsfield units (p < 0.0001). The latter two of these characteristics were highly specific for benign pathology (93% and 100%, respectively)., Conclusion: Our study suggests that CT has the ability to consistently identify characteristics significantly correlated with benign vs. malignant adrenal tumors.

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 × 10 6 vs. 39.1 ± 23.6 × 10 6 , p = .020 and 62.0 ± 55.0 × 10 6 vs. 29.0 ± 19.3 × 10 6 , 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 × 10 6 vs. 22.6 ± 13.3 × 10 6 , p < .001) and in males compared to females (56.4 ± 61.5 × 10 6 vs. 30.9 ± 27.9 × 10 6 , 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.

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., (© 2015 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

We aimed to evaluate the effect of intramyocardial injections of autologous VEGF-A 165 -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-A 165 . 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, and P = 0.720 for time duration, watt, and METs, resp.). Intramyocardial delivered VEGF-A 165 -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.

The aim was to compare absolute quantified myocardial perfusion (MP) to semi-quantitative measurements of MP using MRI for detection of ischemia. Twenty-nine patients underwent rest and stress MP imaging obtained by 1.5T MRI and analyzed using own developed software and by commercial available software. Linear regression analysis demonstrated that absolute quantitative data correlated stronger to maxSI (rest: r=0.296, p=.193; stress: r=0.583, p=0.011; myocardial perfusion reserve (MPR): r=0.789, p<0.001; and Δ myocardial blood flow (Δ MBF: r=0.683, p=0.004) than to upslope (rest: r=0.420, p=0.058; stress: r=0.096, p=0.704; MPR: r=0.682, p=0.004; and Δ MBF: r=0.055, p=0.804). Absolute quantified MP was able to distinguish between ischemic and non-ischemic territories at rest (left anterior descending artery (LAD): 103.1±11.3mL/100g/min vs. 206.3±98.5mL/100g/min; p=0.001, right coronary artery (RCA): 124.1±45.2mL/100g/min vs. 241.3±81.7mL/100g/min; p<0.001, and left circumflex artery (LCX): 132.8±53.8mL/100g/min vs. 181.2±56.6mL/100g/min; p=0.060) and at stress (LAD: 148.1±47.2mL/100g/min vs. 296.6±111.6mL/100g/min; p=0.012, RCA: 173.4±63.7mL/100g/min vs. 290.2±100.6mL/100g/min; p=0.008, and LCX: 206.6±105.1mL/100g/min vs. 273.8±78.0mL/100g/min; p=0.186). The correlation between global maxSI and positron emission tomography data was non-significant at rest and borderline significant at stress (r=0.265, p=0.382 and r=0.601, p=0.050, respectively). Quantified MP may be useful in patients for detection of ischemia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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&#95;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&#95;ASC in patients with chronic IHF. A total of 81 patients will be randomised at 2 : 1 to CSCC&#95;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&#95;ASC product from healthy donors in a double-blind, placebo-controlled, multicentre study in patients with IHF.

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 ischemia induced by coronary microvascular disease does not elicit myocardial fibrosis in this population. The examined parameters seem to provide independent information about myocardial and coronary disease.

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).

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.

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.)

Recently, focus has changed from anatomical assessment of coronary arteries towards functional testing to evaluate the effect of stenosis on the myocardium before intervention. Besides positron-emission tomography (PET), cardiac MRI (CMR), and cardiac CT are able to measure myocardial perfusion. Myocardial perfusion abnormalities are the first sign of the ischaemic cascade in the development of coronary artery disease (CAD). PET is considered the non-invasive clinical reference standard for absolute quantification of myocardial perfusion. The diagnostic and prognostic value of PET is well-known and is used in routine clinical practice. However, PET uses radioactive tracers and has a lower spatial resolution compared to CMR and CT. CMR and CT are emerging techniques in the field of myocardial perfusion imaging. CMR uses magnetic resonance to obtain images, whereas CT uses x-rays during first-pass of non-ionic and ionic contrast agents, respectively. Absolute quantification with CMR has yet to be established in routine clinical practice, while CT has yet to prove its diagnostic and prognostic value. The upcoming years may change the way we diagnose and treat patients suspected of having CAD with more precise methods for measuring myocardial perfusion. The aim of this comprehensive review is to discuss current and emerging imaging techniques used for myocardial perfusion imaging., (Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

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.

Diabetes mellitus is a well-known risk factor for coronary artery disease (CAD), which can lead to acute myocardial infarction, chronic myocardial ischaemia and heart failure. Despite the advantages in medical treatment, percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG), morbidity and mortality is still high in patients with CAD. Along with PCI and CABG or in patients without options for revascularization, stem cell regenerative therapy in controlled trials is a possibility. Stem cells are believed to exert their actions by angiogenesis and regeneration of cardiomyocytes. Recently published clinical trials and meta-analysis of stem cell studies have shown encouraging results with increased left ventricle ejection fraction and reduced symptoms in patients with CAD and heart failure. There is some evidence of mesenchymal stem cell being more effective compared to other cell types and cell therapy may be more effective in patients with known diabetes mellitus. However, further investigations are warranted.

Introduction: Aim was to compare absolute myocardial perfusion using cardiac magnetic resonance imaging (CMRI) based on Tikhonov's procedure of deconvolution and rubidium-82 positron emission tomography (Rb-82 PET)., Materials and Methods: Fourteen patients with coronary artery stenosis underwent rest and adenosine stress imaging by 1.5-Tesla MR Scanner and a mCT/PET 64-slice Scanner. CMRI were analyzed based on Tikhonov's procedure of deconvolution without specifying an explicit compartment model using our own software. PET images were analyzed using standard clinical software. CMRI and PET data was compared with Spearman's rho and Bland-Altman analysis., Results: CMRI results were strongly and significantly correlated with PET results for the absolute global myocardial perfusion differences (r=0.805, p=0.001) and for global myocardial perfusion reserve (MPR) (r=0.886, p<0.001). At vessel territorial level, CMRI results were also significantly correlated with absolute PET myocardial perfusion differences (r=0.737, p<0.001) and MPR (r=0.818, p<0.001). Each vessel territory had similar strong correlation for absolute myocardial perfusion differences (right coronary artery (RCA): r=0.787, p=0.001; left anterior descending artery (LAD): r=0.796, p=0.001; left circumflex artery (LCX): r=0.880, p<0.001) and for MPR (RCA: r=0.895, p<0.001; LAD: r=0.886, p<0.001; LCX: r=0.886, p<0.001)., Conclusion: On a global and vessel territorial basis, CMRI-measured absolute myocardial perfusion differences and MPR were strongly and significantly correlated with the Rb-82 PET findings., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The challenge for therapies targeting perfusion abnormalities is to identify and evaluate the region of interest. The aim of this study was to compare rest and stress myocardial perfusion measured by cardiac multi-detector computed tomography (MDCT) and cardiac magnetic resonance (CMR) imaging in patients with invasive coronary angiography demonstrated occluded vessels. Twenty-four patients with refractory angina due to occluded coronary arteries underwent perfusion imaging obtained by 320-MDCT scanner and 1.5 T MR scanner. Rest and adenosine stress images were obtained and interpreted using the modified 17-segment American Heart Association model. For the qualitative analysis, each segment was graded according to the following scoring system: 0 = no defect, 1 = hypoperfusion transmural extent <1/3, 2 = 1/3-1/2, 3 = >1/2, and 4 = infarct stigmata. In the semiquantitative analysis the perfusion was either scored 0 (normal) or 1 (abnormal). The summed rest and stress scores were calculated. MDCT and CMR had a high probability to identify perfusion defects. An excellent correlation between MDCT and CMR summed rest (r = 0.916) and stress scores (r = 0.915) was found. The interobserver reproducibility was high for MDCT and CMR images. The qualitative and semiquantitative MDCT against CMR analysis of rest and stress images showed high concordance to detect perfusion defects per vascular territory and on a per myocardial segment basis. 320-MDCT and CMR perfusion imaging can be used clinically to identify myocardial perfusion defects and potentially evaluate the effect of therapy targeting perfusion abnormalities.

Since the introduction of percutaneous coronary intervention for coronary artery disease, thousands of patients have been treated with the implantation of coronary stents. Moreover, several of the patients with coronary stent undergo cardiac magnetic resonance (CMR) imaging every year. This case report is of a 77-year-old man who was previously treated with the implantation of a coronary stent in the left circumflex artery. He underwent CMR imaging, which revealed a process 14×21 mm in the left atrium. Cardiac contrast computed tomography did not demonstrate any cardiac pathology. While the signal loss on MRI associated with implanted metallic devices is known, we report a case where an implanted coronary stent in the left circumflex artery led to an intracardiac signal loss mimicking intracardiac thrombus/tumor., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Adipose tissue represents an abundant, accessible source of multipotent adipose-derived stromal cells (ADSCs). Animal studies have suggested that ADSCs have the potential to differentiate in vivo into endothelial cells and cardiomyocytes. This makes ADSCs a promising new cell source for regenerative therapy to replace injured tissue by creating new blood vessels and cardiomyocytes in patients with chronic ischemic heart disease. The aim of this special report is to review the present preclinical data leading to clinical stem cell therapy using ADSCs in patients with ischemic heart disease. In addition, we give an introduction to the first-in-man clinical trial, MyStromalCell Trial, which is a prospective, randomized, double-blind, placebo-controlled study using culture-expanded ADSCs obtained from adipose-derived cells from abdominal adipose tissue and stimulated with VEGF-A(165) the week before treatment.

Background: Epidemiologically, high-density lipoprotein (HDL) cholesterol levels associate inversely with risk of ischemic cardiovascular disease. Whether this is a causal relation is unclear., Methods: We studied 10,281 participants in the Copenhagen City Heart Study (CCHS) and 50,523 participants in the Copenhagen General Population Study (CGPS), of which 991 and 1,693 participants, respectively, had developed myocardial infarction (MI) by August 2010. Participants in the CCHS were genotyped for all six variants identified by resequencing lecithin-cholesterol acyltransferase in 380 individuals. One variant, S208T (rs4986970, allele frequency 4%), associated with HDL cholesterol levels in both the CCHS and the CGPS was used to study causality of HDL cholesterol using instrumental variable analysis., Results: Epidemiologically, in the CCHS, a 13% (0.21 mmol/liter) decrease in plasma HDL cholesterol levels was associated with an 18% increase in risk of MI. S208T associated with a 13% (0.21 mmol/liter) decrease in HDL cholesterol levels but not with increased risk of MI or other ischemic end points. The causal odds ratio for MI for a 50% reduction in plasma HDL cholesterol due to S208T genotype in both studies combined was 0.49 (0.11-2.16), whereas the hazard ratio for MI for a 50% reduction in plasma HDL cholesterol in the CCHS was 2.11 (1.70-2.62) (P(comparison) = 0.03)., Conclusion: Low plasma HDL cholesterol levels robustly associated with increased risk of MI but genetically decreased HDL cholesterol did not. This may suggest that low HDL cholesterol levels per se do not cause MI.

Objective: To evaluate the effect of diabetes self-management education (DSME) on glycaemic control (HbA1c) in Pakistani children suffering from type-1 diabetes mellitus., Study Design: Quasi-experimental study., Place and Duration of Study: This study was conducted at the Diabetic OPD of National Institute of Child Health, Karachi, from April to September 2009., Methodology: Sixty children with a mean age of 9.94 years with type-1 Diabetes mellitus (T1DM) were selected conveniently from the diabetic OPD. The patients along with their parents/caregivers attended a modular series of diabetes self-management education program consisting of 2 sessions. Customized program was designed to educate children regarding general information about the disease, basic insulin therapy, planning for hypoglycaemia, hyperglycaemia, activity, traveling and basic nutritional management. It was conducted by a multidisciplinary paediatric diabetes team including an endocrinologist, general paediatrician, nutritionist and diabetic nurse. The educational sessions were followed by monthly revision exercises. HbA1c levels were measured at baseline and after 3 months and compared using paired sample t-test., Results: Out of a total of 60 patients, 50 completed the trial. There was a significant decrease in the HbA1c levels after the DSME program. The mean pre- and postintervention HbA1c levels were 9.67±0.65 and 8.49±0.53 respectively with a p-value < 0.001., Conclusion: In the studied group, DSME programs helped to improve glycaemic control. It should be an integral part of patient treatment in diabetic care setups.