Mesenchymal stromal cells to treat patients with non-ischaemic heart failure: Results from SCIENCE II pilot study.

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_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_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_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_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.

Effect of allogeneic adipose tissue-derived mesenchymal stromal cell treatment in chronic ischaemic heart failure with reduced ejection fraction - the SCIENCE trial.

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.

Aortic valve leaflet and root dimensions in normal tricuspid aortic valves: A computed tomography study.

BACKGROUND AND AIM OF THE STUDY: The aim of this study was to use coronary computed tomography in patients with normal tricuspid aortic valves to perform detailed aortic root and aortic valve geometric analysis with a focus on the asymmetry of the three leaflets. METHODS: Retrospective analysis of anonymized coronary computed tomography angiograms was performed using dedicated software, where manual aortic root segmentation and marking of several points of interest were followed by automated measurements of aortic root and leaflets. Asymmetry of the three leaflets in individual patients was assessed by calculating absolute and relative differences between the largest and the smallest of the three leaflets. RESULTS: We analyzed 70 aortic valves, the mean patient age was 53 ± 11 years, and 50% (n = 35) of patients were female. All aortic valves were tricuspid, without calcifications and aortic roots were of normal dimensions. Some degree of asymmetry was present in all analyzed valves. Absolute and relative differences for free margin length were 3.2 ± 1.4 mm and 9.3 ± 3.8%, respectively. The largest relative difference was noted in the coaptation area (36.5 ± 16.5%) and the smallest in leaflet effective height (6.1 ± 4.8%). Using predefined cutoff criteria for absolute differences in leaflet dimensions, 86% of the valves were classified as asymmetric. CONCLUSIONS: Most normal tricuspid aortic valves show some degree of asymmetry. Equal free margin length of the three leaflets is not needed for normal tricuspid aortic valve function. Leaflet effective height showed the least amount of asymmetry confirming its importance in keeping the aortic valve competent.

Transendocardial CD34+ Cell Therapy Improves Local Mechanical Dyssynchrony in Patients With Nonischemic Dilated Cardiomyopathy.

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.

Larger End-Diastolic Volume Associates With Response to Cell Therapy in Patients With Nonischemic Dilated Cardiomyopathy.

OBJECTIVE: To investigate the association of left ventricular end-diastolic volume (LVEDV) and the response to cell therapy in patients with nonischemic dilated cardiomyopathy (NICM). PATIENTS AND METHODS: Five-year registry data from 133 consecutive patients with NICM who underwent CD34+ cell treatment were analyzed. All patients received granulocyte-colony stimulating factor; CD34+ cells were collected by apheresis and delivered by transendocardial injections. Patients with baseline LVEDV less than 200 mL (group A; n=72) and patients with LVEDV 200 to 370 mL (group B; n=54) were included. Patients with LVEDV greater than 370 mL were excluded (n=7). Favorable ejection fraction response was pre-defined by improvement in left ventricular ejection fraction (LVEF) greater than or equal to 5% at 1 y post-cell therapy. RESULTS: At baseline, groups A and B were comparable with regards to age (52±11 y in group A vs 53±10 y in group B; P=.95), sex (male: 79% vs 83%, respectively; P=.55), creatinine (1.07±0.28 mg/dL vs 1.03±0.21 mg/dL, respectively; P=.21), or N-terminal probrain natriuretic peptide (1454±1658 pg/mL vs 1589±1338 pg/mL, respectively; P=.80). Baseline LVEF was higher in group A (32.8±8.7%) than in group B (30.2±8.7%; P=.03). During follow-up, there were four deaths in group A (5.6%), and 2 in group B (3.7%, P=.63). At 1-year post-cell therapy, LVEDV decreased significantly in group B (-56±30 mL; P=.003), but not in group A (+12±97 mL; P=.13). On multivariate analysis, baseline LVEDV was an independent correlate of favorable response in LVEF to therapy (P=.02). CONCLUSION: Larger LVEDV was associated with more pronounced increase in LVEF after transendocardial CD34+ cell therapy in NICM patients, informing target individuals with the highest likelihood of regenerative response. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT02445534.

Favorable Response to CD34+ Cell Therapy Is Associated with a Decrease of Galectin-3 Levels in Patients with Chronic Heart Failure.

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.

Transendocardial CD34+ Cell Therapy does not Increase the Risk of Ventricular Arrhythmias in Patients with Chronic Heart Failure.

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.

Stem Cell and Left Ventricular Assist Device Combination Therapy.

Ventricular assist device (VAD) technology has evolved significantly over the past decades and currently represents one of the most important treatment strategies for patients with advanced chronic heart failure. There is increasing evidence that in selected patients undergoing long-term VAD support, improvement of myocardial structure and function may occur. However, there seems to be a significant discrepancy between structural and functional recovery of the failing myocardium, as only a small fraction of VAD-supported patients demonstrate reverse structural remodeling and eventually reach clinically significant and stable, functional improvement. More recently, cell therapy has gained a growing interest in the heart failure community because of its potential to augment reverse remodeling of the failing myocardium. Although theoretically the combination of long-term VAD support and cell therapy may offer significant advantages over using these therapeutic modalities separately, it remains largely unexplored. This review aims to summarize the current state of the art of the effects of VAD support and cell therapy on the reverse remodeling of the failing myocardium and to discuss the rationale for using a combined treatment strategy to further promote myocardial recovery in patients with advanced chronic heart failure.

Transendocardial CD34+ Cell Transplantation in Noncompaction Cardiomyopathy: First-in-Man Case Study.

Noncompaction cardiomyopathy is a rare congenital heart disorder characterized by an arrest of the myocardial compaction process. This results in the altered formation of coronary microvessels with a resulting decrease in myocardial perfusion. Transendocardial CD34+ cell transplantation has been shown to increase myocardial perfusion and function in patients with non-ischemic heart failure. In our first-in-man case study, we investigated the feasibility, safety and clinical effect of transendocardial CD34+ cell therapy in a patient with noncompaction cardiomyopathy.

Effects of Repetitive Transendocardial CD34+ Cell Transplantation in Patients With Nonischemic Dilated Cardiomyopathy.

RATIONALE: Preclinical data in heart failure models suggest that repetitive stem cell therapy may be superior to single-dose cell administration. OBJECTIVE: We investigated whether repetitive administration of CD34+ cells is superior to single-dose administration in patients with nonischemic dilated cardiomyopathy. METHODS AND RESULTS: Of 66 patients with dilated cardiomyopathy, New York Heart Association functional class III, and left ventricular ejection fraction (LVEF) <40% enrolled in the study, 60 were randomly allocated to repetitive cell therapy (group A, n=30) or single-cell therapy (group B, n=30). Patients received G-CSF (granulocyte colony-stimulating factor) for 5 days, and 80 million CD34+ cells were collected by apheresis and injected transendocardially. In group A, cell therapy was repeated at 6 months. All patients were followed for 1 year, and the primary end point was the difference in change in LVEF between the groups. At baseline, the groups did not differ in age, sex, LVEF, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or 6-minute walk test distance. When directly comparing groups A and B at 1 year, there was no significant difference in change in LVEF (from 32.2±9.3% to 41.2±6.5% in group A and from 30.0±7.0% to 37.9±5.3% in group B, P=0.40). From baseline to 6 months, both groups improved in LVEF (+6.9±3.3% in group A, P=0.001 and +7.1±3.5% in group B, P=0.001), NT-proBNP (-578±211 pg/mL, P=0.02 and -633±305 pg/mL, P=0.01), and 6-minute walk test (+87±21 m, P=0.03 and +92±25 m, P=0.02). In contrast, we observed no significant changes between 6 months and 1 year (LVEF: +2.1±2.3% in group A, P=0.19 and +0.8±3.1% in group B, P=0.56; NT-proBNP: -215±125 pg/mL, P=0.26 and -33±205 pg/mL, P=0.77; 6-minute walk test: +27±11 m, P=0.2 and +12±18 m, P=0.42). CONCLUSIONS: In patients with dilated cardiomyopathy, repetitive CD34+ cell administration does not seem to be associated with superior improvements in LVEF, NT-proBNP, or 6-minute walk test when compared with single-dose cell therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02248532.

CD34+ Cell Transplantation Improves Right Ventricular Function in Patients with Nonischemic Dilated Cardiomyopathy.

We investigated the effects of CD34+ cell therapy on right ventricular (RV) function in patients with nonischemic dilated cardiomyopathy (DCM). We enrolled 60 patients with DCM who were randomized to CD34+ cell therapy (Stem Cells (SC) Group n = 30), or no cell therapy (Controls, n = 30). The SC Group received granulocyte-colony stimulating factor, and CD34+ cells were collected by apheresis and injected transendocardially. Patients were followed for 6 months. At baseline, the groups did not differ in age, gender, left ventricular ejection fraction, N-terminal probrain natriuretic peptide, or parameters of RV function. At 6 months, we found a significant improvement in RV function in the SC Group (tricuspid annular plane systolic excursion [TAPSE]: +0.44 ± 0.64 cm, p = .001; peak systolic tissue Doppler velocity of tricuspid annulus [St]: +1.5 ± 2.1 cm/s; p = .001; percent of fractional area change [FAC]: +8.6% ± 5%, p = .01), but not in Controls (TAPSE: -0.07 ± 0.32 cm, p = .40; St: -0.1 ± 1.2 cm/s; p = .44; FAC: -1.2% ± 3.2%, p = .50). On repeat electroanatomical mapping, we found an improvement in interventricular septum viability in 19 of 30 patients from the SC Group; this correlated with the improvements in RV function (13/19 in the improved septum group versus 3/11 in the remaining cohort, p = .029). These results suggest that patients with DCM, changes in RV function correlate with changes of viability of interventricular septum. CD34+ cell therapy appears to be associated with improved right ventricular function in this patient cohort. (Clinical Trial Registration Information: www.clinicaltrials.gov; NCT02248532). Stem Cells Translational Medicine 2018;7:168-172.

Effects of Transendocardial CD34+ Cell Transplantation on Diastolic Parameters in Patients with Nonischemic Dilated Cardiomyopathy.

We sought to evaluate the physiological background and the effects of CD34+ cell transplantation on diastolic parameters in nonischemic dilated cardiomyopathy patients (DCM). We enrolled 38 DCM patients with NYHA class III and LVEF < 40% who underwent transendocardial CD34+ cell transplantation. Peripheral blood CD34+ cells were mobilized by G-CSF, collected via apheresis, and injected transendocardially in the areas of myocardial hibernation. Patients were followed for 1 year. At baseline, estimated filling pressures were significantly elevated (E/e' ≥ 15) in 18 patients (Group A), and moderately elevated (E/e '< 15) in 20 patients (Group B). The groups did not differ in age (54 ± 9 years vs. 52 ± 10 years; p = .62), gender (male: 85% vs. 78%; p = .57), or LVEF (31 ± 7% vs. 34 ± 6%; p = .37). When compared to Group B patients in Group A had more segments with myocardial scar (4.9 ± 2.7 vs. 2.7 ± 2.9; p = .03), myocardial hibernation (2.2 ± 1.6 vs. 0.9 ± 1.1; p = .02), and longer average local relaxation time on electroanatomical mapping (378 ± 41 ms vs. 333 ± 34 ms, p = .01). During follow-up there was an improvement in diastolic parameters in Group A (E/e': from 24.3 ± 12.1 to 16.3 ± 8.0; p = .005), but not in Group B (E/e': from 10.2 ± 3.7 to 13.2 ± 9.1; p = .19). Accordingly, in Group A, we found an increase in 6-minute walk distance (from 463 ± 83 m to 546 ± 91 m; p = .03), and a decrease in NT-proBNP (from 2140 ± 1743 pg/ml to 863 ± 836 pg/ml; p = .02). In nonischemic DCM, diastolic dysfunction appears to correlate with areas of myocardial scar and hibernation. Transendocardial CD34+ cell transplantation may improve diastolic parameters in this patient cohort. Stem Cells Translational Medicine 2017;6:1515-1521.

LVAD as a Bridge to Heart Transplantation in a Patient with Left Ventricular Noncompaction Cardiomyopathy and Advanced Heart Failure.

Left ventricular noncompaction cardiomyopathy (LVNC) is a rare hereditary cardiomyopathy characterized by the formation of an outer compacted and inner noncompacted layer of the myocardium. The latter is characterized by prominent trabeculations and deep intertrabecular recesses and is functionally inferior to the compacted myocardium. As there is no specific treatment for patients with LVNC who develop heart failure, the management of these patients is limited and many patients progress to advanced stages of the disease. For LVNC patients with advanced heart failure, the data regarding the use of mechanical circulatory support are scarce. We report a case of a 29-year-old patient with LVNC and advanced refractory heart failure, who was successfully bridged to heart transplantation using a long-term continuous-flow left ventricular assist device.

Imaging and 1-day kinetics of intracoronary stem cell transplantation in patients with idiopathic dilated cardiomyopathy.

BACKGROUND: Stem cell transplantation is an emerging method of treatment for patients with cardiovascular disease. There are few studies completed or ongoing on stem cell therapy in patients with idiopathic dilated cardiomyopathy (IDCM). Information on stem cell homing and distribution in the myocardium after transplantation might provide important insight into effectiveness of transplantation procedure. AIM: To assess early engraftment, retention and migration of intracoronarily transplanted stem cells in the myocardium of patients with advanced dilated cardiomyopathy of non-ischaemic origin using stem cell labeling with (99m)Tc-exametazime (HMPAO). MATERIALS, METHODS: Thirty-five patients with IDCM and advanced heart failure were included in the study. Autologous hematopoietic (CD34+) stem cells were harvested by peripheral blood apheresis after bone marrow stimulation, labeled with (99m)Tc-HMPAO, tested for viability and injected into coronary vessel supplying areas of myocardium selected by myocardial perfusion scintigraphy as dysfunctional yet viable. Imaging was performed 1h and 18h after transplantation. RESULTS: Myocardial stem cell retention ranged from 0 to 1.44% on early and 0-0.97% on delayed imaging. Significant efflux of stem cells occurred from site of delivery in this time period (p<0.001). Stem cell viability was not affected by labeling. CONCLUSION: Stem cell labeling with (99m)Tc-HMPAO is a feasible method for stem cell tracking after transplantation in patients with IDCM.

Efficacy of CD34+ Stem Cell Therapy in Nonischemic Dilated Cardiomyopathy Is Absent in Patients With Diabetes but Preserved in Patients With Insulin Resistance.

UNLABELLED: We evaluated the association of diabetes and insulin resistance with the response to cell therapy in patients with nonischemic dilated cardiomyopathy (DCM). A total of 45 outpatients with DCM received granulocyte colony-stimulating factor for 5 days. CD34(+) cells were then collected by apheresis and injected transendocardially. Twelve patients had diabetes mellitus (DM group), 17 had insulin resistance (IR group), and 16 displayed normal glucose metabolism (no-IR group). After stimulation, we found higher numbers of CD34(+) cells in the IR group (94 ± 73 × 10(6) cells per liter) than in the no-IR group (54 ± 35 × 10(6) cells per liter) or DM group (31 ± 20 × 10(6) cells per liter; p = .005). Similarly, apheresis yielded the highest numbers of CD34(+) cells in the IR group (IR group, 216 ± 110 × 10(6) cells; no-IR group, 127 ± 82 × 10(6) cells; DM group, 77 ± 83 × 10(6) cells; p = .002). Six months after cell therapy, we found an increase in left ventricular ejection fraction in the IR group (+5.6% ± 6.9%) and the no-IR group (+4.4% ± 7.2%) but not in the DM group (-0.9% ± 5.4%; p = .035). The N-terminal pro-brain natriuretic peptide levels decreased in the IR and no-IR groups, but not in the DM group (-606 ± 850 pg/ml; -698 ± 1,105 pg/ml; and +238 ± 963 pg/ml, respectively; p = .034). Transendocardial CD34(+) cell therapy appears to be ineffective in DCM patients with diabetes. IR was associated with improved CD34(+) stem cell mobilization and a preserved clinical response to cell therapy. SIGNIFICANCE: The present study is the first clinical study directly evaluating the effects of altered glucose metabolism on the efficacy of CD34(+) stem cell therapy in patients with nonischemic dilated cardiomyopathy. The results offer critical insights into the physiology of stem cell mobilization in heart failure and possibly an explanation for the often conflicting results obtained with stem cell therapy for heart failure. These results demonstrate that patients with dilated cardiomyopathy and diabetes do not benefit from autologous CD34(+) cell therapy. This finding could serve as a useful tool when selecting heart failure patients for future clinical studies in the field of stem cell therapy.

Increased red cell distribution width is associated with poor stem cell mobilization in patients with advanced chronic heart failure.

Parameters associated with poor CD34(+) stem cell mobilization in advanced chronic heart failure (CHF) patients were investigated. Forty-four CHF patients underwent bone marrow stimulation with granulocyte colony stimulating factor. Poor cell mobilization presents in 32% of patients. Poor and good mobilizers did not differ significantly regarding age, gender, left ventricular ejection fraction, kidney or liver function and exercise capacity. Significant differences were found regarding NT-proBNP levels and red cell distribution width (RDW). Increased RDW was the only independent predictor of poor CD34(+) stem cell mobilization on multivariable analysis and may serve as a biomarker of poor stem cell mobilization in CHF patients.

Immunologic Network and Response to Intramyocardial CD34+ Stem Cell Therapy in Patients With Dilated Cardiomyopathy.

BACKGROUND: Although stem cell therapy (SCT) is emerging as a potential treatment for patients with dilated cardiomyopathy (DCM), clinical response remains variable. Our objective was to determine whether baseline differences in circulating immunologic and nonimmunologic biomarkers may help to identify patients more likely to respond to intramyocardial injection of CD34(+)-based SCT. METHODS AND RESULTS: We enrolled from January 3, 2011 to March 5, 2012 37 patients with longstanding DCM (left ventricular ejection fraction [LVEF] <40%, New York Heart Association functional class III) who underwent peripheral CD34(+) stem cell mobilization with granulocyte colony-stimulating factor (G-CSF) and collection by means of apheresis. CD34(+) cells were labeled with (99m)Tc-hexamethylpropyleneamine oxime to allow assessment of stem cell retention at 18 hours. Response to SCT was predefined as an increase in LVEF of ≥5% at 3 months. The majority (84%) of patients were male with an overall mean LVEF of 27 ± 7% and a median N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of 2,774 pg/mL. Nineteen patients (51%) were responders to SCT. There was no significant difference between responders and nonresponders regarding to age, sex, baseline LVEF, NT-proBNP levels, or 6-minute walking distance. With the use of a partial least squares (PLS) predictive model, we identified 9 baseline factors that were associated with both stem cell response and stem cell retention (mechanistic validation). Among the baseline factors positively associated with both clinical response and stem cell retention were G-CSF, SDF-1, LIF, MCP-1, and MCP-3. Among baseline factors negatively associated with both clinical response and retention were IL-12p70, FASL, ICAM-1, and GGT. A decrease in G-CSF at 3-month follow-up was also observed in responders compared with nonresponders (P = .02). CONCLUSIONS: If further validated, baseline immunologic and nonimmunologic biomarkers may help to identify patients with DCM who are more likely to respond to CD34(+)-based SCT.

Stem cell therapy for chronic heart failure.

PURPOSE OF REVIEW: The aim of this review was to discuss recent advances in clinical aspects of stem cell therapy in heart failure with emphasis on patient selection, stem cell types and delivery methods. RECENT FINDINGS: Several stem cell types have been considered for the treatment of patients with heart failure. In nonischemic heart failure, transplantation of CD34 cells improved myocardial performance, functional capacity and neurohumoral activation. In ischemic heart failure, cardiosphere-derived cells were shown to reduce myocardial scar burden with concomitant increase in viable tissue and regional systolic wall thickening. Both autologous and allogeneic mesenchymal stem cells were shown to be effective in improving heart function in patients with ischemic heart failure; this may represent an important step toward the development of a standardized stem cell product for widespread clinical use. SUMMARY: Although trials of stem cell therapy in heart failure have shown promising results, the findings are not consistent. Given the wide spectrum of heart failure, it may be difficult to define a uniform stem cell therapy for all subsets of patients; instead, future stem cell therapeutic strategies should aim for a more personalized approach by establishing optimal stem cell type, dose and delivery method for an individual patient and disease state.

Intracoronary transplantation of CD34(+) cells is associated with improved myocardial perfusion in patients with nonischemic dilated cardiomyopathy.

BACKGROUND: We investigated the effects of intracoronary transplantation of CD34(+) cells on myocardial perfusion in patients with nonischemic dilated cardiomyopathy (DCM). METHODS AND RESULTS: We enrolled 21 patients with DCM (left ventricular ejection fraction [LVEF] <40%, New York Heart Association functional class III) who underwent peripheral stem cell mobilization with granulocyte-colony stimulating factor (G-CSF). CD34(+) cells were collected by means of apheresis. Patients underwent myocardial perfusion imaging, and CD34(+) cells were injected in the coronary artery supplying viable segments with reduced myocardial perfusion and regional dysfunction. Myocardial perfusion imaging was repeated 6 months later. Clinical response to stem cell therapy was predefined as a change in LVEF >5%. The majority of patients were men (81%) with an overall mean age 53 ± 9 years, LVEF 25 ± 5%, and 6-minute walking distance 354 ± 71 m. Myocardial perfusion defects at rest were observed in 86% of patients and were more common in the left anterior descending territory (50%). At 6 months' follow-up, there was a significant improvement in rest myocardial perfusion scores (6.3 ± 5.8 vs 3.1 ± 4.3; P < .001), LVEF (25 ± 7% vs 29 ± 8%; P = .005), and 6-minute walking distance (354 ± 71 m vs 404 ± 91 m; P < .001). Responders to stem cell therapy had lower summed rest perfusion score at both baseline (3.2 ± 3.0 vs 9.1 ± 6.3; P = .015) and follow-up (1.0 ± 1.5 vs 5.0 ± 5.1; P = .028). CONCLUSIONS: CD34(+) cell transplantation may lead to improved myocardial perfusion in patients with nonischemic DCM. Patients with less severe myocardial perfusion defects at baseline may have an increased likelihood to respond to intracoronary CD34(+) cell transplantation.

Effects of transendocardial CD34+ cell transplantation in patients with ischemic cardiomyopathy.

BACKGROUND: We investigated the effects of transendocardial CD34(+) cell transplantation in patients with ischemic cardiomyopathy. METHODS AND RESULTS: In a prospective crossover study, we enrolled 33 patients with ischemic cardiomyopathy with New York Heart Association class III and left ventricular ejection fraction <40%. In phase 1, patients were treated with medical therapy for 6 months. Thereafter, all patients underwent transendocardial CD34(+) cell transplantation. Peripheral blood CD34(+) cells were mobilized by granulocyte colony stimulating factor, collected via apheresis, and injected transendocardially in the areas of hibernating myocardium. Patients were followed up for 6 months after the procedure (phase 2). Two patients died during phase 1 and none during phase 2. The remaining 31 patients were 85% men, aged 57±6 years. In phase 1, we found no change in left ventricular ejection fraction (from 25.2±6.2% to 27.1±6.6%; P=0.23), N-terminal pro B-type natriuretic peptide (from 3322±3411 to 3672±5165 pg/mL; P=0.75) or 6-minute walk distance (from 373±68 to 411±116 m; P=0.17). In contrast, in phase 2 there was an improvement in left ventricular ejection fraction (from 27.1±6.6% to 34.9±10.9%; P=0.001), increase in 6-minute walk distance (from 411±116 to 496±113 m; P=0.001), and a decrease in N-terminal pro B-type natriuretic peptide (from 3672±5165 to 1488±1847 pg/mL; P=0.04). The average number of injected CD34(+) cells was 90.6±7.5×10(6). Higher doses of CD34(+) cells and a more diffuse distribution of transendocardial cell injections were associated with better clinical response. CONCLUSIONS: Transendocardial CD34(+) cell transplantation may be associated with improved left ventricular function, decreased N-terminal pro B-type natriuretic peptide levels, and better exercise capacity in patients with ischemic cardiomyopathy. These effects seem to be particularly pronounced in patients receiving diffusely distributed cell injections and high-dose cell therapy. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01350310.