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 ± 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.

Keywords: Diabetes; Dilated cardiomyopathy; Insulin resistance; Stem cells.

Figure 1.

Flowchart of the study design. After assessing the metabolic status, all patients received stimulation with granulocyte colony-stimulating factor (5 μg/kg b.i.d. for 5 days; phase 1). On the fifth day, we measured the peripheral blood CD34⁺ cell count, performed apheresis, and again measured the CD34⁺ cell numbers after apheresis. In phase 2, we performed electroanatomical mapping of the left ventricle and transendocardial injections of the CD34⁺ cell solution. The patients were followed up for 6 months after the procedure.

Figure 2.

Effects of insulin resistance and diabetes on CD34⁺ stem cell mobilization in patients with nonischemic dilated cardiomyopathy. (A): Concentration of CD34⁺ stem cells after 5 days of stimulation with granulocyte colony-stimulating factor in patients with nonischemic dilated cardiomyopathy with diabetes (right), nondiabetic patients with IR (middle), and nondiabetic patients without IR (left). We found a significantly increased CD34⁺ mobilization capacity in nondiabetic patients with IR. Abbreviation: IR, insulin resistance.

Figure 3.

The effect of metabolic status on changes in left ventricular function, NT-proBNP levels, and exercise capacity in patients with nonischemic dilated cardiomyopathy (DCM) undergoing transendocardial CD34⁺ cell therapy. The changes in left ventricular ejection fraction (A), NT-proBNP (B), and 6-MWK distance (C) after transendocardial CD34⁺ cell therapy in nonischemic DCM patients with diabetes, nondiabetic patients with IR, and nondiabetic patients without IR. We found a significant increase in LVEF and a significant decrease in NT-proBNP in nondiabetic patients with or without insulin resistance. In contrast, we found no significant effects of CD34⁺ cell therapy on LVEF and NT-proBNP in patients with diabetes. Exercise capacity, as measured by the 6-MWK distance, showed a trend for improvement in the IR group and no-IR group, but not in the DM group. Abbreviations: 6-MWK, 6-minute walk; DM, diabetes mellitus; IR, insulin resistance; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-brain natriuretic peptide.

Figure 4.

The CD34⁺ stem cell dose required for every 1% increase in LVEF at 6 months after stem cell therapy in patients with and without IR. In our patient population, we found cell therapy to have significantly greater relative efficacy in the no-IR group than in the IR group. Abbreviations: IR, insulin resistance; LVEF, left ventricular ejection fraction.