Monocyte modulation by liposomal alendronate improves cardiac function in a rat model of myocardial infarction

Acute myocardial infarction (AMI) is associated with high morbidity and mortality. The ischemic injury activates the innate immune response in two consecutive phases. Classical monocytes (CM, Ly6C^high and ED1^highCD43^low, mice and rats, respectively) accumulate in the inflammatory phase (first 3 days), and non-classical monocytes (NCM, Ly6C^low and ED1^highCD43^high, mice and rats, respectively) accumulate in the reparatory phase (4-7 days). Liposomal delivery systems of bisphosphonates shown to deplete circulating monocytes are now being examined in phase IIb clinical studies for the treatment of in-stent restenosis. Thus far, monocytes depletion during the 1^st (inflammatory) phase has failed to improve the prognosis following AMI. We hypothesized that inhibition of monocyte at the 2^nd phase post AMI, will lead to better healing and consequently improve heart function. In this study we examined the effect of monocyte modulation on cardiac healing following myocardial injury by nano-sized alendronate liposomes (LipAln) in a rat model of MI. Rats were treated with intravenous (IV) LipAln, on days 5, 7 and 9 post ligation of the left anterior descending artery (LAD). Two weeks post MI, circulating NCM and cardiac IL 10 expression in LipALN treated rats, were increased. Furthermore, cardiac function was better in LipAln treated rats post MI compared to saline treated rats (fractional shortening of 32.2%±1.9% and 26.0%±1.3%, LipAln and saline treated rats, respectively, p<0.05).

In conclusion, LipAln treatment, 5-9 days after MI, promotes better resolution of inflammation and improves cardiac healing. Increased circulating monocytes counts during the 2^nd phase, an increased ratio of NCM/CM subsets, and an increase of anti-inflammatory cytokines may all contribute to improve recovery.