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

Aims: We investigated the effects of CD34 + cell therapy in patients with heart failure with preserved ejection fraction (HFpEF)., Methods and Results: In a prospective pilot study, we enrolled 30 patients with HFpEF. In Phase 1, patients were treated with medical therapy for 6 months. Thereafter, all patients underwent CD34 + cell transplantation. Using electroanatomical mapping, we measured local mechanical diastolic delay and myocardial viability to guide the targeting of cell injections. Patients were followed for 6 months after cell transplantation (Phase 2), and the primary endpoint was the difference in change in E/e' between Phase 1 and Phase 2. In Phase 1, the decrease in E/e' was significantly less pronounced than in Phase 2 (-0.33 ± 1.72 vs. -3.77 ± 2.66, p = 0.001). During Phase 1, there was no significant change in global systolic strain (GLS; from -12.5 ± 2.4% to -12.8 ± 2.6%, p = 0.77), N-terminal pro-B-type natriuretic peptide (NT-proBNP; from 1463 ± 1247 pg/ml to 1298 ± 931 pg/ml, p = 0.31), or 6-min walk test (6MWT; from 391 ± 75 m to 402 ± 93 m, p = 0.42). In Phase 2, an improvement was noted in NT-proBNP (from 1298 ± 931 pg/ml to 887 ± 809 pg/ml, p = 0.02) and 6MWT (from 402 ± 93 m to 438 ± 72 m, p = 0.02). Although GLS did not change significantly in Phase 2 (from -12.8 ± 2.6% to -13.8 ± 2.7%, p = 0.36), we found improved local systolic strain at cell injection sites (-3.4 ± 6.8%, p = 0.005)., Conclusions: In this non-randomized trial, transendocardial CD34 + cell therapy in HFpEF was associated with an improvement in E/e', NT-proBNP, exercise capacity, and local myocardial strain at the cell injection sites., Clinical Trial Registration: ClinicalTrials.gov NCT02923609., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Purpose of Review: The purpose of this review is to discuss recent advances in the field of cell therapy in patients with heart failure with reduced ejection fraction (HFrEF) of ischemic (iCMP) and nonischemic (dCMP) etiology, heart failure with preserved ejection fraction (HFpEF), and in advanced heart failure patients undergoing mechanical circulatory support (LVAD)., Recent Findings: In HFrEF patients (iCMP and dCMP cohorts), autologous and/or allogeneic cell therapy was shown to improve myocardial performance, patients' functional capacity, and neurohumoral activation. In HFpEF patient population, the concept of cell therapy in novel and remains largely unexplored. However, initial data are very encouraging and suggest at least a similar benefit in improvements of myocardial performance (also diastolic function of the left ventricle), exercise capacity, and neurohumoral activation. Recently, cell therapy was explored in the sickest population of advanced heart failure patients undergoing LVAD support also showing a potential benefit in promoting myocardial reverse remodeling and recovery. In the past decade, several cell therapy-based clinical trials showed promising results in various chronic and advanced heart failure patient cohorts. Future cell treatment strategies should aim for more personalized therapeutic approaches by defining optimal stem cell type or their combination, dose, and delivery method for an individual patient adjusted for patient's age and stage/duration of heart failure.

Aims: Non-compaction cardiomyopathy (NCM) is a congenital heart disease characterized by an arrest of the myocardial compaction process. Although NCM patients have impaired formation of microvasculature, the functional impact of these changes remains undefined. We sought to analyse a potential correlation between myocardial ischemia and heart failure severity in NCM patients., Methods and Results: We enrolled 41 NCM patients (28 male and 13 female), aged 21-70 years. In all patients, we have determined left ventricular end-diastolic volume (LVEDV), left ventricular ejection fraction (LVEF), and global longitudinal strain (GLS) by echocardiography. At the same time, serum levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) have been measured, and myocardial single-photon emission computed tomography at rest and on stress was used to define significant myocardial ischemia defined as summed difference score ≥ 2. Myocardial ischemia has been demonstrated in 11 patients (27%, Group A), and 30 patients showed no significant ischemic changes (73%, Group B). The groups did not differ in sex, age, kidney, or liver function. When compared with Group B, Group A had significantly lower LVEF (35 ± 15% in Group A vs. 53 ± 11% in Group B, P < 0.001), higher LVEDV (188 ± 52 mL vs. 136 ± 52 mL, P = 0.007), lower GLS (-9.9 ± 5.2% vs. -14.5 ± 4.1%, P = 0.001), and higher NT-proBNP levels (1691 ± 1883 pg/mL vs. 422 ± 877 pg/mL, P = 0.006). Overall, higher summed difference score was associated with lower LVEF (r = -0.48, P = 0.001), higher LVEDV (r = 0.39, P = 0.012), lower GLS (r = 0.352, P = 0.024), and higher levels of NT-proBNP (r = 0.66, P < 0.001)., Conclusions: The presence of myocardial ischemia in patients with NCM is associated with worse left ventricular function, dilation of the left ventricle, and more pronounced neurohumoral activation., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Galectin-3 plasma levels (gal-3) were shown to correlate with the scar burden in chronic heart failure (CHF) setting. As scar burden predicts response to stem cell therapy, we sought to explore a correlation between gal-3 and response to CD34+ cell transplantation in patients with CHF., Methods: We performed a post hoc analysis of patients, enrolled in 2 prospective trials investigating the clinical effects of CD34+ cell therapy in patients with ischemic cardiomyopathy (ICMP) and nonischemic dilated cardiomyopathy (DCMP). CD34+ cells were mobilized by G-CSF, collected via apheresis, and injected transendocardially using NOGA system. Patients were followed for 3 months and demographic, echocardiographic, and biochemical parameters and gal-3 were analyzed at baseline and at follow-up. Response to cell therapy was defined as an LVEF increase of ≥5%., Results: 61 patients were included in the analysis. The mean age of patients was 52 years and 83% were male. DCMP and ICMP were present in 69% and 31% of patients, respectively. The average serum creatinine was 86 ± 23  μ mol/L, NT-proBNP 1132 (IQR 350-2279) pg/mL, and LVEF 30 ± 6%. Gal-3 at baseline and at 3 months did not differ significantly (13.4 ± 5.5 ng/mL vs. 13.1 ± 5.8 ng/mL; p = 0.72), and there were no differences in baseline gal-3 with respect to heart failure etiology (15.1 ± 7.2 ng/mL in ICMP vs. 12.7 ± 4.3 ng/mL in DCMP; p = 0.12). Comparing responders ( N = 49) to nonresponders ( N = 18), we found no differences in baseline gal-3 (13.6 ± 5.7 ng/mL vs. 13.2 ± 4.9 ng/mL; p = 0.80). However, responders had significantly lower gal-3 at 3-month follow-up (12.1 ± 4.0 ng/mL vs. 15.7 ± 8.4 ng/mL; p < 0.05). Also, responders demonstrated a significant decrease in gal-3 over 3 months, while in nonresponders, an increase in gal-3 occurred (-1.5 ± 5.4 ng/mL vs. +2.7 ± 4.3 ng/mL; p = 0.01)., Conclusions: In patients with chronic heart failure undergoing CD34+ cell therapy, a decrease in galectin-3 plasma levels is associated with beneficial response to this treatment modality. Further prospective data is warranted to confirm our findings and to deepen our understanding of the role of gal-3 in the field of stem cell therapy., Competing Interests: None of the authors has any conflicts of interest pertinent to this publication., (Copyright © 2019 Gregor Poglajen et al.)

Ventricular arrhythmias (VA) are of major concern in the field of cell therapy, potentially limiting its safety and efficacy. We sought to investigate the effects of CD34 + cell therapy on VA burden in patients with chronic heart failure (CHF). We performed registry data analysis of patients with CHF and implanted ICD/CRT devices treated with transendocardial CD 34 + cell therapy. Demographic, echocardiographic, and biochemical parameters were analyzed. Device records were reviewed and the number and type of VA 1 year prior to and 1 year after cell therapy were analyzed. All patients underwent electroanatomical mapping, and myocardial scar was defined as unipolar voltage (UV) <8.3 mV and linear local shortening (LLS) <6%. Of 209 patients screened, 48 met inclusion criteria. The mean age of the patients was 52 years and 88% were male. Nonischemic and ischemic cardiomyopathy were present in 55% and 45% of patients. The average serum creatinine was 91±26 µmol/L, serum bilirubin 18±9 µmol/L, NT-proBNP 1767 (468, 2446) pg/mL, LVEF 27±9% and 6' walk test 442±123 m. The average scar burden in patients with nonischemic and ischemic DCM was 58±15% and 51±25% (P=0.48). No significant difference in VA burden was observed before and after cell therapy (48% vs. 44%; P=0.68). ICD activation occurred in 19% and 27% of patients before and after cell therapy (P=0.33). According to our results, transendocardial CD34 + cell therapy does not appear to increase the risk of VA in chronic heart failure patients.

Background: We investigated a correlation between electromechanical properties of the myocardium and response to CD34+ cell therapy in patients with chronic heart failure., Methods and Results: We enrolled 40 patients with ischemic cardiomyopathy (ICM) and 40 with nonischemic dilated cardiomyopathy (DCM). All patients were in New York Heart Association functional class III and had a left ventricular ejection fraction (LVEF) <40%. CD34+ cells were mobilized by granulocyte colony-stimulating factor and collected via apheresis. Electroanatomic mapping was performed to define areas of myocardial scar and hibernation, and CD34+ cells were injected transendocardially in the hibernating areas. Patient were followed for 6 months; responders were defined as patients with LVEF increase of >5%. At baseline, the groups did not differ in sex, LVEF, creatinine, N-terminal pro-B-type natriuretic peptide or electroanatomic parameters (scar area: 53 ± 18% in ICM vs 55 ± 23% in DCM [P = .83]; hibernating area: 23 ± 13% vs 22 ± 12% [P = .56]). At 6 months we found similar rates of responders in both groups (60% in ICM vs 65% in DCM [P = .95]). When compared with nonresponders, responders had less myocardial scar (47 ± 17% vs 58 ± 15% [P = .003])., Conclusions: In patients with chronic heart failure due to ICM and DCM we observed similar electroanatomic properties of the myocardium. In both groups, lower myocardial scar burden was associated with better clinical response to CD34+ cell therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: T-wave amplitude variability (TAV) is a promising non-invasive predictor of arrhythmic events in patients with dilated cardiomyopathy. We aimed to evaluate the effect of cardiac resynchronization therapy (CRT) on native TAV, its relation with left ventricular (LV) reverse remodelling and the occurrence of ventricular tachyarrhythmias (VTs)., Methods and Results: In this prospective study, we included 40 heart failure patients with left bundle branch block in sinus rhythm (25 male; 16 with ischaemic aetiology; aged 62.7 ± 9.5 years; New York Heart Association class II-IV). Echocardiographic parameters and TAV were evaluated at baseline and 6 months after implantation of CRT device combined with an implantable cardioverter-defibrillator. T-wave amplitude variability was determined by a 20-min high-resolution electrocardiogram Holter recording during native conduction. After TAV assessment, patients were monitored for 15.7 ± 5.2 months for the occurrence of VTs. Decrease in median TAV [from 40.45 μV (24.75-56.00) to 28.15 μV (20.93-37.95), P = 0.004] was observed after 6 months of CRT. However, decrease of median TAV was only noticed in patients with LV reverse remodelling [46.9 μV (27.5-70.0) to 25.8 μV (20.2-32.4), P < 0.001] and in patients without VTs [40.5 μV (27.5-55.9) to 24.4 μV (17.1-31.5), P < 0.001]. Native median TAV > 35.4 µV after 6 months of CRT had an 83% sensitivity and 93% specificity for predicting the occurrence of VTs., Conclusions: Decrease of TAV after CRT is associated with LV reverse remodelling and indicates a reduction of the intrinsic arrhythmogenic substrate. Median TAV after CRT had a good predicting value for VT occurrence in long-term follow-up.

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. [ABSTRACT FROM AUTHOR]

Introduction: Previous studies have demonstrated that cell therapy may improve diastolic parameters in heart failure. Hypothesis: We sought to investigate the effects of transendocardial CD34+ cell therapy in patients with heart failure with preserved ejection fraction (HFpEF). Methods: In a pilot study we enrolled 14 patients with HFpEF (LVEF>50%, E/e'>15, NYHA III, NTproBNP levels >300 pg/ml). All patients received granulocyte-colony stimulating factor (G-CSF; 10 mcg/kg, 5 days); CD34+ cells were collected by apheresis. We performed electroanatomical mapping of the left ventricle and assessed local diastolic function by measuring local ventricular relaxation times at each of the sampling points. CD34+ cells were then injected transendocardially in the areas of diastolic dysfunction. Each patient received a dose of 80 million CD34+ cells divided into 20 injections. Results: Our study cohort included 9 male and 5 female patients aged 57±9 years, with LVEF of 56.9±6.6%, creatinine of 85±28 μmol/L, and bilirubin of 12.7±4.7 μmol/L. In all patients, electroanatomical mapping consisting of at least 150 sampling points was performed without any adverse events enabling us to adequately measure local diastolic function and identify target areas for cell delivery. At 1 year after cell delivery we found a significant improvement in left ventricular filling pressures as measured by E/e' (from 17.2±6.8 to 12.7±6.1, P=0.03), a decrease in NTproBNP (from 1137±792 pg/ml to 843±710 pg/ml, P=0.03), and a trend of improvement in global systolic strain (from -11.2±1.6% to -12.9±3.7%, P=0.16). Notably, we found a significant improvement of local systolic strain in myocardial segments that were targeted with stem cell injections (-3.4±4.2%, P=0.001). Conclusions: In patients with HFpEF, transendocardial CD34+ cell transplantation is feasible and safe, and appears to be associated with improved diastolic function and decrease in NTproBNP at 1 year after therapy. [ABSTRACT FROM AUTHOR]

Introduction: End-diastolic volume (EDV) between 200 and 370 mL has been associated with favorable clinical response to cell therapy in ischemic heart failure. Hypothesis: We sought to investigate the effects of EDV, a marker of disease severity, on the response to cell therapy in patients with nonischemic dilated cardiomyopathy (DCM). Methods: Five-year registry data from 134 consecutive patients with DCM (LVEF<40%, NHYA III) who underwent CD34+ cell transplantation was analyzed. All patients received granulocyte-colony stimulating factor (G-CSF; 10 mcg/kg, 5 days); CD34+ cells were collected by apheresis and delivered by transendocardial injection in areas of electromechanical missmatch. Patients with baseline EDV<200 mL were included in Group A (N=72), patients with EDV 200-370 mL were included in Group B (N=54); patients with EDV>370 mL were excluded (N=7). Favorable clinical response was defined by improved LVEF≥5% at 1 year post-cell therapy. Results: At baseline, Groups A and B did not differ in age (52±11 years in Group A vs. 53±10 years in Group B, P=0.95), sex (male: 79% vs. 83%, P=0.55), creatinine (1.07±0.28 mg/dL vs. 1.03±0.21 mg/dL, P=0.21), bilirubin (0.98±0.55 mg/dL vs. 1.00±0.51 mg/dL, P=0.58), or NTproBNP levels (1454±1658 pg/mL vs. 1589±1338 pg/mL, P=0.80). Baseline LVEF was higher in Group A (32.8±8.7%) than in Group B (30.2±8.7%, P=0.03). During follow-up, there were 4 deaths in Group A (6%), and 2 in Group B (4%, P=0.63); heart transplantation was performed in 4 patients from Group A (6%) and in 5 patients in Group B (9%, P=0.42). Favorable clinical response was found in 31/72 patients (43%) in Group A vs. 35/54 (65%) in Group B (P=0.016). Furthermore, EDV significantly decreased at 1 year in Group B (-56±30 mL, P=0.003), but not in Group A (+12±97 mL, P=0.13). On multivariate analysis, baseline EDV was an independent correlate of 1-year clinical outcome (P=0.02). Conclusions: EDV predicted clinical outcome following transendocardial CD34+ cell therapy in a nonischemic DCM patient population, informing target individuals with the highest likelihood of regenerative response. [ABSTRACT FROM AUTHOR]

Introduction: Although there is evidence of beneficial effects of CD34+ therapy in non-ischemic dilated cardiomyopathy (DCM), the individual patient response is highly variable. Hypothesis: We investigated the value of biomarkers of angiogenesis and endothelial dysfunction in predicting clinical response to transendocardial CD34+ cell transplantation in DCM patients. Methods: We enrolled 34 DCM patients (NYHA class III, LVEF<40%) in whom CD34+ cells were mobilized by G-CSF and collected via apheresis. Electromechanical mapping was performed to define areas of myocardial scar (unipolar voltage <8.3mV and local linear shortening <6%) and hibernation (unipolar voltage ≥8.3mV and local linear shortening <6%) and CD34+ cells were injected transendocardially in the hibernating areas. Patients were followed for 6 months and responders were defined as patients with LVEF increase of >5%. At the time of CD34+ cell transplantation we performed analysis of 27 biomarkers of angiogenesis and endothelial dysfunction. Results: Of 34 patients, 25 (74%) responded to CD34+ cell therapy (responders), and 9 (26%) were classified as non-responders. The groups did not differ in age (55±12 years in responders vs. 59±9 years in non-responders, P=0.43), gender (male: 88% vs. 78%, P=0.36) and baseline LVEF (31±9% vs. 33±7%, P=0.69). When compared to non-responders, responders had lower levels of NT-proBNP (1159±1043 ng/L in responders vs. 2667±2252 ng/L in non-responders, P=0.005), endocan (0.46±0.18 ng/mL vs. 0.62±0.21 ng/mL, P=0.04), thrombospondin-2 (13±5 ng/mL vs. 22±13 ng/mL, P=0.008), activin A (209±51 pg/mL vs. 299±62 pg/mL, P=0.002) and neuropilin-1 (175±35 ng/mL vs. 225±62 ng/mL, P=0.006). Interestingly, we found a significant correlation between these biomarkers and scar burden on electromechanical mapping (endocan: P=0.025, thrombospondin-2: P=0.01, activin A: P=0.015, neuropilin-1: P=0.018). Conclusion: Higher levels of endocan, thrombospondin-2, activin A and neuropilin-1 correlate with poor clinical response and higher scar burden in DCM patients undergoing transendocardial CD34+ cell transplantation. Thus, these biomarkers could represent a non-invasive tool for predicting response to CD34+ cell therapy. [ABSTRACT FROM AUTHOR]