Search

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.

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. StemCellsTranslationalMedicine2017;6:1515–1521

The association of diabetes and insulin resistance (IR) with the cell therapy response in patients with nonischemic dilated cardiomyopathy (DCM) was evaluated. Outpatients with DCM received granulocyte colony‐stimulating factor for 5 days. CD34+cells were collected by apheresis and injected transendocardially. However, transendocardial CD34+cell therapy appeared ineffective in DCM patients with diabetes. IR was associated with improved CD34+stem cell mobilization and a preserved clinical response to cell therapy. 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 × 106cells per liter) than in the no‐IR group (54 ± 35 × 106cells per liter) or DM group (31 ± 20 × 106cells per liter; p= .005). Similarly, apheresis yielded the highest numbers of CD34+cells in the IR group (IR group, 216 ± 110 × 106cells; no‐IR group, 127 ± 82 × 106cells; DM group, 77 ± 83 × 106cells; 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. 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.

Introduction:The underlying mechanisms of coronary allograft vasculopathy (CAV) after heart transplantation remain incompletely understood.Hypothesis:As CD34+cells represent one of the key determinants of coronary vascular homeostasis we investigated the potential association between CAV and CD34+cell count in heart transplant recipients.Methods:In a single-center prospective pilot cohort study we included 59 adult heart transplant recipients without history of congenital heart disease, multi-organ transplantation or oncologic therapy. All patients underwent coronary CT angiography and the presence of CAV was defined in accordance with the ISHT criteria. At the time of CT angiography, we collected blood samples and measured CD34+cell count using Beckman-Coulter Navios EX flow cytometry with standard antibodies according to ISAGE protocol as well as biomarkers of angiogenesis using Luminex assay kit.Results:CAV was present in 15 patients (25%; Group A) and absent in 42 patients (75%; Group B). The two groups did not differ in age (62±11 years in Group A vs. 60±11 years in Group B, P=0.56), gender (male: 100% vs. 80% in Group B, P=0.07), heart failure etiology (ischemic: 53% vs. 43%, P=0.50), presence of hypertension (60% vs. 63%, P=0.80), diabetes (33% vs. 25%, P=0.54) or renal insufficiency (53% vs. 43%, P=0.50). Also, donor age (44±14 years in Group A vs. 43±12 years in Group B, P=0.66), allograft ischemic time (202±72 min vs. 190±68 min, P=0.57), tacrolimus trough levels (8.8±3.8 μg/L vs. 7.4±1.9 μg/L, P=0.14), MMF dose (2067±442 mg vs. 2178±606 mg; P=0.52) and statin therapy (86% vs. 75%; P=0.36) were comparable. While total leukocyte count was similar in both groups (7.7±2.1x109/L in Group A vs. 6.8±2.2x109/L in Group B, P=0.60), we found significantly lower CD34+cell count in Group A compared to Group B (1.33±0.45x106/L vs. 2.23±1.45x106/L, P=0.02). Conversely, VEGF serum levels were significantly lower in Group A than in Group B (0.09±0.06 ng/L vs. 0.14±0.09 ng/L; P=0.03).Conclusions:Decreased CD34+cell count and increased VEGF serum levels appear to be associated with CAV in heart transplant recipients. Further studies are warranted to investigate the potential of CD34+cells in prevention and treatment of CAV in this patient cohort.