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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT02445534.

Keywords: Diastolic dysfunction cardiomyopathy; Heart failure; Stem cell.

Figure 1

Flow chart of the study design. At baseline, we analyzed parameters of diastolic function in all patients and classified them in two groups according to the presence of diastolic dysfunction, defined by elevated estimated filling pressures (E/e′ ≥ 15). In all patients, peripheral blood CD34⁺ cells were mobilized by G‐CSF, collected via apheresis, and injected transendocardially in the areas of electromechanical mismatch on electro‐anatomical mapping. Patients were followed for 1 year.

Figure 2

Analysis of local diastolic function. Exemplary postprocessing analysis of local diastolic function by measuring radial deformation (relative to heart axis) of each mapping point in 10 ms intervals. The 3D color‐coded map displays the timing of diastole (red areas represent early diastole, purple areas represent late diastole).

Figure 3

Analysis of scar and hibernation. Exemplary 3D (A, C) and corresponding 2D (B, D) quantitative polar maps of a patient with nonischemic DCM, showing unipolar voltage and linear shortening. Segments with predominance of high unipolar voltage and high LLS (purple, blue, or green color on both panels) are defined as normal myocardium (N); segments with predominance of low unipolar voltage and low LLS (red and yellow color on both panels) are defined as scarred myocardium (S); and segments with a predominance of high unipolar voltage (purple, blue, or green on left panel) and low LLS (red or yellow on right panel) are defined as hibernating myocardium (H). Abbreviation: LLS, linear shortening.

Figure 4

The effects of CD34⁺ cell therapy on estimated left ventricular filling pressures in patients with nonischemic DCM. Within 1 year, we have found a significant improvement in estimated left ventricular filling pressures (measured by E/e′) only in patients who displayed elevated filling pressures at baseline (E/e′ ≥ 15). In the remaining cohort, no significant change in E/e' was found.

Figure 5

Differences in local diastolic function in patients in with higher (Group A) and lower (Group B) E/e'. The average local relaxation time measured by electro‐anatomical mapping was significantly higher in patients with higher E/e'. This difference was even more pronounced when analyzing local relaxation time at the sites of cell injections.