Gregor Zemljic

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±7.5×106. 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.

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

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 × 106 cells per liter) than in the no‐IR group (54 ± 35 × 106 cells per liter) or DM group (31 ± 20 × 106 cells per liter; p = .005). Similarly, apheresis yielded the highest numbers of CD34+ cells in the IR group (IR group, 216 ± 110 × 106 cells; no‐IR group, 127 ± 82 × 106 cells; DM group, 77 ± 83 × 106 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.

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′u2009≥u200915) in 18 patients (Group A), and moderately elevated (E/eu2009′<u200915) in 20 patients (Group B). The groups did not differ in age (54u2009±u20099 years vs. 52u2009±u200910 years; pu2009=u2009.62), gender (male: 85% vs. 78%; pu2009=u2009.57), or LVEF (31u2009±u20097% vs. 34u2009±u20096%; pu2009=u2009.37). When compared to Group B patients in Group A had more segments with myocardial scar (4.9u2009±u20092.7 vs. 2.7u2009±u20092.9; pu2009=u2009.03), myocardial hibernation (2.2u2009±u20091.6 vs. 0.9u2009±u20091.1; pu2009=u2009.02), and longer average local relaxation time on electroanatomical mapping (378u2009±u200941 ms vs. 333u2009±u200934 ms, pu2009=u2009.01). During follow‐up there was an improvement in diastolic parameters in Group A (E/e′: from 24.3u2009±u200912.1 to 16.3u2009±u20098.0; pu2009=u2009.005), but not in Group B (E/e′: from 10.2u2009±u20093.7 to 13.2u2009±u20099.1; pu2009=u2009.19). Accordingly, in Group A, we found an increase in 6‐minute walk distance (from 463u2009±u200983 m to 546u2009±u200991 m; pu2009=u2009.03), and a decrease in NT‐proBNP (from 2140u2009±u20091743 pg/ml to 863u2009±u2009836 pg/ml; pu2009=u2009.02). 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

Electroanatomic Properties of the Myocardium Predict Response to CD34+ Cell Therapy in Patients With Ischemic and Nonischemic Heart Failure

BACKGROUNDnWe investigated a correlation between electromechanical properties of the myocardium and response to CD34+ cell therapy in patients with chronic heart failure.nnnMETHODS AND RESULTSnWe 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: 53u2009±u200918% in ICM vs 55u2009±u200923% in DCM [Pu2009=u2009.83]; hibernating area: 23u2009±u200913% vs 22u2009±u200912% [Pu2009=u2009.56]). At 6 months we found similar rates of responders in both groups (60% in ICM vs 65% in DCM [Pu2009=u2009.95]). When compared with nonresponders, responders had less myocardial scar (47u2009±u200917% vs 58u2009±u200915% [Pu2009=u2009.003]).nnnCONCLUSIONSnIn 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.

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 nu2009=u200930), or no cell therapy (Controls, nu2009=u200930). 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]: +0.44u2009±u20090.64 cm, pu2009=u2009.001; peak systolic tissue Doppler velocity of tricuspid annulus [St]: +1.5u2009±u20092.1 cm/s; pu2009=u2009.001; percent of fractional area change [FAC]: +8.6%u2009±u20095%, pu2009=u2009.01), but not in Controls (TAPSE: −0.07u2009±u20090.32 cm, pu2009=u2009.40; St: −0.1u2009±u20091.2 cm/s; pu2009=u2009.44; FAC: −1.2%u2009±u20093.2%, pu2009=u2009.50). 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, pu2009=u2009.029). 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

Stem Cell Therapy in Patients with Chronic Nonischemic Heart Failure

Aim of the Review The aim of this review is to discuss recent advances in clinical aspects of stem cell therapy in chronic nonischemic heart failure (DCMP) with emphasis on patient selection, stem cell types, and delivery methods. Recent Findings Several stem cell types have been considered for the treatment of DCMP patients. Bone marrow-derived cells and CD34+ cells have been demonstrated to improve myocardial performance, functional capacity, and neurohumoral activation. Furthermore, allogeneic mesenchymal stem cells were also shown to be effective in improving heart function in this patient population; this may represent an important step towards the development of a standardized stem cell product for widespread clinical use in patients with DCMP. Summary The trials of stem cell therapy in DCMP patients have shown some promising results, thus making DCMP apparently more inviting target for stem cell therapy than chronic ischemic heart failure, where studies to date failed to demonstrate a consistent effect of stem cells on myocardial performance. Future stem cell strategies should aim for more personalized therapeutic approach by establishing the optimal stem cell type or their combination, dose, and delivery method for an individual patient adjusted for patients age and stage of the disease.

Effects of Repetitive Transendocardial CD34+ Cell Transplantation in Patients with Non-Ischemic 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.

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.