Epicardial reservoir-enabled multidose delivery of exogenous FSTL1 leads to improved cardiac function, healing, and angiogenesis.

Epicardial delivery of human follistatin-like 1 protein (FSTL1) induces significant cardiac benefit following a myocardial infarction (MI). However, the optimal dosing regimen for maximal therapeutic benefit has not yet been elucidated. To investigate the impact of multiple FSTL1 doses, without the confounding effects of multiple surgical procedures for multidose delivery, alternative delivery strategies are needed. Here, we use an epicardial reservoir that allows non-invasive delivery of additional doses after implantation to investigate the impact of single, double, and triple FSTL1 dose regimens in a rat model of MI. Multidose delivery of FSTL1 improves ejection fraction (3 doses), fractional shortening (1, 2 and 3 doses), and chamber stiffness (2 doses) 28 days after MI. Histologically, multiple FSTL1 doses increase ventricular wall thickness (2 and 3 doses) and reduce infarct size (1, 2, and 3 doses). We also demonstrate a dose-dependent increase in blood vessel number and density in the infarct zone, with three FSTL1 doses leading to the highest improvements. This study shows that multidose delivery of FSTL1 improves cardiac function, healing, and angiogenesis following MI. The epicardial delivery platform used here may be essential in optimizing dosing regimens of various bioagent combinations for a range of clinical indications.