Ischemic heart disease is the leading cause of morbidity and mortality in the US and is often caused by myocardial infarction (MI). The inflammatory response associated with MI leads to an increase in circulating bone marrow cells, particularly monocytes and macrophages. This response is crucial for removing dead tissue and initiating the healing process. However, exacerbated inflammation following MI can be detrimental and is associated with infarct expansion, poor cardiac remodeling and adverse clinical outcomes. Currently, there are no therapies to treat the inflammation that occurs after MI. Modulating inflammation represents a paradigm shift in the treatment of MI, but clinical translation has not been realized. Therapeutic transition of macrophages to a reparative phenotype, known as alternative macrophage polarization, represents a promising strategy in reducing scarring and heart failure after MI. To address this, we have prepared a formulation containing azithromycin (AZM), a clinically approved antibiotic that has been shown to induce alternative macrophage polarization. The lipid composition of the formulation enables 30 mol% AZM to be packaged in the lipid bilayer and a resulting formulation diameter of 203 ± 1 nm. Intravenous administration of liposomal azithromycin (L-AZM) to mice after MI indicates rapid uptake by macrophages and monocytes with significant accumulation in the cardiac lesion after injury. Notably, less than 1% of liposomes are present in cardiomyocytes. Using in vitro and in vivo assays, L-AZM is found to reduce the pro-inflammatory cytokine milieu (e.g. TNFα and IL-1β), while increasing the anti-inflammatory cytokine profiles (e.g. IL-10, TGF-β). Finally, L-AZM is shown to preserve cardiac function, reduce lesion volume post MI, and improve overall survival. These data indicate that L-AZM is a promising candidate for continued pre-clinical evaluation and translation to treat patients experiencing a myocardial infarction.

Liposomal azithromycin reduces post-ischemic cardiac inflammation

ACS Fall 2020 Virtual Meeting

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