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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. [ABSTRACT FROM AUTHOR]

We investigated the effects of cell therapy on local mechanical dyssynchrony (LMD) in patients with nonischemic dilated cardiomyopathy (NICM). We analyzed electromechanical data of 30 NICM patients undergoing CD34+ cell transplantation. All patients underwent bone marrow stimulation; CD34+ cells were collected by apheresis and injected transendocardially. At baseline and at 6 months after therapy, we performed electromechanical mapping and measured unipolar voltage (UV) and LMD at cell injection sites. LMD was defined as a temporal difference between global and segmental peak systolic displacement normalized to the average duration of the RR interval. Favorable clinical response was defined as increase in the left ventricular ejection fraction (LVEF) ≥5% between baseline and 6 months. Using paired electromechanical point-by-point analysis, we were able to identify 233 sites of CD34+ cell injections in 30 patients. We found no overall differences in local UV between baseline and 6 months (10.7 ± 4.1 mV vs 10.0 ± 3.6 mV, P = 0.42). In contrast, LMD decreased significantly (17 ± 17% at baseline vs 13 ± 12% at 6 months, P = 0.00007). Favorable clinical response at 6 months was found in 19 (63%) patients (group A), and 11 (37%) patients did not respond to cell therapy (group B). At baseline, the two groups did not differ in age, gender, LVEF, or N terminal-pro brain natriuretic peptide (NT-proBNP) levels. Similarly, we found no differences in baseline UV (9.5 ± 2.9 mV in group A vs 8.6 ± 2.4 mV in group B, P = 0.41) or LMD at cell injection sites (17 ± 19% vs 16 ± 14%, P = 0.64). In contrast, at 6 months, we found higher UV in group A (10.0 ± 3.1 mV vs 7.4 ± 1.9 mV in group B, P = 0.04). Furthermore, when compared with group B, patients in group A displayed a significantly lower LMD (11 ± 12% vs 16 ± 10%, P = 0.002). Thus, it appears that favorable clinical effects of cell therapy in NICM patients may be associated with a decrease of LMD at cell injection sites. [ABSTRACT FROM AUTHOR]

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 μmol/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. [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]

Background: Data from preclinial models suggest that cell therapy may be associated with antiarrythmic effects due to improved cell-to-cell coupling. Hypothesis: We sought to investigate potential anti-arrhythmogenic effects of transendocardial CD34+ cell therapy in patients with chronic heart failure (CHF). Metods: We performed registry data analysis of 48 patients with CHF and implanted ICD/CRT devices treated with transendocardial CD 34+ cell therapy. Patients demonstrating ventricular arrhythmias (VA) in 12 months prior to cell therapy were included in the analysis. All patients were followed for 12 months after cell therapy. Demographic, echocardiographic and biochemical parameters were analysed. All patients uderwent electroanatomical mapping and myocardial scar was defined as unipolar voltage (UV)<8.3mV and linear local shortening (LLS)<6%. Areas of slow conduction were defined as areas with fragmented QRS signal. QRS fragmentation was defined as a multicomponent QRS signal and the cut-off value for normal QRS fragmentation was ≤ 4 positive peak deflections. Results: Of 20 patients included, 6 (30%, Group A) did not experience VA and 14 (70%, Group B) continued to have VA in 12 months after cell therapy. The two groups did not differ in gender (male; 67% in Group A vs. 93% in Group B; P=0.14), age (57±10 years vs. 53±8 years; P=0.31), chronic kidney disease (17% vs. 21%; P=0.82), NT-proBNP levels (1375±958 pg/mL vs. 1679±1629 pg/mL; P=0.69), left ventricular ejection fraction (31±6% vs. 29±8%; P=0.55), LV end-diastolic volume (221±126 mL vs. 229±85 mL; P=0.89) and amiodarone therapy (16% vs. 14%; P=0.89). In Group A significantly higher percentage of cell injections was performed in areas of slow conduction when compared to Group B (47±11% vs. 29±16%; P=0.03). Additionally, in Group B, the number ob ICD activations after cell therapy was reduced (3.6±2.7 ICD activations before cell therapy vs. 2.1±2.0 ICD activations after cell therapy; P=0.14). Conclusions: Transendocardial CD34+ cell therapy may reduce the VA burden in CHF when applied to the areas of slow conduction of the left ventricle. Prospective data are needed to confirm the anti-arrhythmic potential of cell therapy in chronic heart failure patients. [ABSTRACT FROM AUTHOR]