The Impact of Patient Sex on the Response to Intramyocardial Mesenchymal Stem Cell Administration in Patients with Non-Ischemic Dilated Cardiomyopathy.

AIMS: Sex differences impact the occurrence, presentation, prognosis, and response to therapy in heart disease. Particularly, the phenotypic presentation of patients with non-ischemic dilated cardiomyopathy (NIDCM) differs between men and women. However, whether the response to mesenchymal stem cell (MSC) therapy is influenced by sex remains unknown. We hypothesize that males and females with NIDCM respond similarly to MSC therapy. METHODS AND RESULTS: Male (n = 24) and female (n = 10) patients from the POSEIDON-DCM trial who received MSCs via transendocardial injections were evaluated over 12 months. Endothelial function was measured at baseline and 3 months post-TESI. At baseline, EF was lower (p = 0.004) and end diastolic volume (EDV; p = 0.0002) and end systolic volume (ESV; p = 0.0002) were higher in males vs. females. In contrast, baseline demographic characteristics, Minnesota Living with Heart Failure Questionnaire (MLHFQ), and 6-minute walk test (6MWT) were similar between groups. EF improved in males by 6.2 units (p = 0.04) and in females by 8.6 units (p = 0.04; males vs. females, p = 0.57). EDV and ESV were unchanged over time. The MLHFQ score, New York Heart Association (NYHA) class, endothelial progenitor cell-colony forming units (EPC-CFUs), and serum TNF-alpha improved similarly in both groups. CONCLUSIONS: Despite major differences in phenotypic presentation of NIDCM in males and females, this study is the first of its kind to demonstrate that MSC therapy improves a variety of parameters in NIDCM irrespective of patient sex. These findings have important clinical and pathophysiologic implications regarding the impact of sex on responses to cell-based therapy for NIDCM. TRANSLATIONAL PERSPECTIVE: Important patient sex differences exist in NIDCM clinical phenotype and gene expression profiles. The effectiveness of pharmacological treatment relative to patient sex requires evaluation due to the paucity of sex-specific data in clinical trials. Herein, we report that despite baseline phenotypic differences in left ventricular remodeling, MSC treatment improves the NIDCM phenotype irrespective of patient sex. Importantly, MSC administration to female patients may lead to an increased rate of heart failure with recovered EF, which carries an improved mortality, transplant rate, and hospitalization rate. This hypothesis-generating study encourages the design of future trials that evaluate patient sex differences in response to cell-based therapy.