Rationale: Virtually all mesenchymal stem cell (MSC) studies assume therapeutic effects accrue from local myocardial effects of engrafted MSCs. Since few intravenously-administered MSCs engraft in the myocardium, studies have mainly utilized direct myocardial delivery. We adopted a different paradigm.

Objective: To test whether intravenously-administered MSCs reduce LV dysfunction both post-AMI and in ischemic cardiomyopathy, and that these effects are caused, at least partly, by systemic anti-inflammatory activities.

Methods and Results: Mice underwent 45min of left anterior descending artery occlusion. Human MSCs, grown chronically at 5% O2, were administered intravenously. LV function was assessed by serial echocardiography, TTC staining determined infarct size, and FACS assessed cell composition. Fluorescent and radiolabeled MSCs (1×106) were injected 24h post-MI and homed to regions of myocardial injury; however, the myocardium contained only a small proportion of total MSCs. Mice received 2×106 MSCs or saline intravenously 24h post-MI (n=16/group). At day 21, we harvested blood and spleens for FACS and hearts for TTC staining. Adverse LV remodeling and deteriorating LVEF occurred in control mice with large infarcts (≥25% LV). Intravenous MSCs eliminated the progressive deterioration in LVEF, LVEDV and LVESV. MSCs significantly decreased natural killer (NK) cells in the heart and spleen, and neutrophils in the heart. Specific NK cell depletion 24h pre-AMI significantly improved infarct size, LVEF, and adverse LV remodeling, changes associated with decreased neutrophils in the heart. In an ischemic cardiomyopathy model, mice 4 weeks post-MI were randomized to tail-vein injection of 2×106 MSCs, with injection repeated at week 3 (n=16) vs PBS control (n=16). MSCs significantly increased LVEF and decreased LVESV.

Conclusions: Intravenously-administered MSCs for AMI attenuate the progressive deterioration in LV function and adverse remodeling in mice with large infarcts, and in ischemic cardiomyopathy they improve LV function, effects apparently modulated in part by systemic anti-inflammatory activities.