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

Abstract

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 6 73 3 10 6 cells per liter) than in the no-IR group (54 6 35 3 10 6 cells per liter) or DM group (31 6 20 3 10 6 cells per liter; p = .005). Similarly, apheresis yielded the highest numbers of CD34 + cells in the IR group (IR group, 216 6 110 3 10 6 cells; no-IR group, 127 6 82 3 10 6 cells; DM group, 77 6 83 3 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 6.9%) and the no-IR group (+4.4% 6 7.2%) but not in the DM group (20.9% 6 5.4%; p = .035). The N-terminal probrain natriuretic peptide levels decreased in the IR and no-IR groups, but not in the DM group (2606 6 850 pg/ml; 2698 6 1,105 pg/ml; and +238 6 963 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. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:632-638 SIGNIFICANCEThe 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.

Concise Review: Perspectives and Clinical Implications of Bone Marrow and Circulating Stem Cell Defects in Diabetes

“…This would suggest that impaired homing is the most important defect of stem cell kinetic in the pathophysiology of diabetic vascular disease and that simply taking cells from the BM to the target tissue exerts therapeutic effects notwithstanding mobilopathy and impaired cellular function. More recently, a study reported that diabetes prevents the increase in ejection fraction after CD34 + cell therapy for nonischemic dilated cardiomyopathy , thereby lending support to the relevance of intrinsic cell dysfunction. A detailed analysis of whether diabetes limits the benefits of cell therapies for cardiovascular diseases would clarify how much the above‐described alterations in BM and stem cells impact on their therapeutic efficacy.…”

Clinical-based Cell Therapies for Heart Disease—Current and Future State

“…49 Importantly, a subset of patients with NIDCM and diabetes mellitus did not respond similarly to the non-diabetic population, which had an improvement in LVEF. 100 These studies demonstrate that specific subpopulations of patients respond to a greater or lesser extent to the same therapy, illustrating the importance of adequately assessing the profile of patients, the cell(s) to be delivered, and the route of delivery.…”

Can Stem Cells Improve Left Ventricular Ejection Fraction in Heart Failure? A Literature Review of Skeletal Myoblasts and Bone Marrow-Derived Cells

“…Another important point was that the diabetic patients had more advanced heart failure than their counterparts. Whether the diabetes, the more advanced heart failure, or the combination of both played a role in seeing no change in LVEF will have to be further studied [ 20 ].…”