Magalì Giordano

Gas-loaded nanocarriers (G-LN) show promise in improving heart transplantation (HTx) outcomes. Given their success in reducing cell death during normothermic hypoxia/reoxygenation (H/R) in vitro, we tested their integration into cardioplegic solutions and static cold storage (SCS) during simulated HTx. Wistar rat hearts underwent four hours of SCS with four G-LN variants: O₂- or N₂-cyclic-nigerosyl-nigerose-nanomonomers (CNN), and O₂- or N₂-cyclic-nigerosyl-nigerose-nanosponges (CNN-NS). We monitored physiological-hemodynamic parameters and molecular markers during reperfusion to assess cell damage/protection. Hearts treated with nanomonomers (N₂-CNN or O₂-CNN) showed improvements in left ventricular developed pressure (LVDP) and a trend towards faster recovery of the rate pressure product (RPP) compared to controls. However, nanosponges (N₂-CNN-NS or O₂-CNN-NS) did not show similar improvements. None of the groups exhibited an increase in diastolic left ventricular pressure (contracture index) during reperfusion. Redox markers and apoptosis/autophagy pathways indicated an increase in Beclin 1 for O₂-CNN and in p22phox for N₂-CNN, suggesting alterations in autophagy and the redox environment during late reperfusion, which might explain the gradual decline in heart performance. The study highlights the potential of nanomonomers to improve early cardiac performance and mitigate cold/H/R-induced stunning in HTx. These early improvements suggest a promising avenue for increasing HTx success. Nevertheless, further research and optimization are needed before clinical application.

Despite the development of cutting-edge treatments, coronary artery disease (CAD) morbidity and mortality rates remain present at high levels. Therefore, new cardioprotective approaches are crucial to improve the health of patients. To date, experimental investigations of acute ischemia-reperfusion injury (IRI) have generally demonstrated the efficacy of local ischemic preconditioning and postconditioning cardioprotection techniques as well as of remote conditioning. However, application in clinical settings is still highly controversial and debated. Currently, remote ischemic conditioning (RIC) seems to be the most promising method for heart repair. Protective factors are released into the bloodstream, and protection can be transferred within and across species. For a long time, the cross-function and cross-transmission mechanisms of cardioprotection were largely unknown. Recently, it has been shown that small, anuclear, bilayered lipid membrane particles, known as extracellular vesicles (EVs), are the drivers of signal transduction in cardiac IRI and RIC. EVs are related to the pathophysiological processes of cardiovascular diseases (CVDs), according to compelling evidence. In this review, we will first review the current state of knowledge on myocardial IRI and cardioprotective strategies explored over the past 37 years. Second, we will briefly discuss the role of EVs in CVD and the most recent improvements on EVs as prognostic biomarkers, diagnostic, and therapeutic agents. We will discuss how EVs can be used as a new drug delivery mechanism and how they can be employed in cardiac treatment, also from a perspective of overcoming the impasse that results from neglecting confounding factors.