Myocardial drug distribution generated from local epicardial application: Potential impact of cardiac capillary perfusion in a swine model using epinephrine

Abstract

Prior studies in small mammals have shown that local epicardial application of inotropic compounds drives myocardial contractility without systemic side effects. Myocardial capillary blood flow, however, may be more significant in larger species than in small animals. We hypothesized that bulk perfusion in capillary beds of the large mammalian heart enhances drug distribution after local release, but also clears more drug from the tissue target than in small animals. Epicardial (EC) drug releasing systems were used to apply epinephrine to the anterior surface of the left heart of swine in either point-sourced or distributed configurations. Following local application or intravenous (IV) infusion at the same dose rates, hemodynamic responses, epinephrine levels in the coronary sinus and systemic circulation, and drug deposition across the ventricular wall, around the circumference and down the axis, were measured. EC delivery via point-source release generated transmural epinephrine gradients directly beneath the site of application extending into the middle third of the myocardial thickness. Gradients in drug deposition were also observed down the length of the heart and around the circumference toward the lateral wall, but not the interventricular septum. These gradients extended further than might be predicted from simple diffusion. The circumferential distribution following local epinephrine delivery from a distributed source to the entire anterior wall drove drug toward the inferior wall, further than with point-source release, but again, not to the septum. This augmented drug distribution away from the release source, down the axis of the left ventricle, and selectively towards the left heart follows the direction of capillary perfusion away from the anterior descending and circumflex arteries, suggesting a role for the coronary circulation in determining local drug deposition and clearance. The dominant role of the coronary vasculature is further suggested by the elevated drug levels in the coronary sinus effluent. Indeed, plasma levels, hemodynamic responses, and myocardial deposition remote from the point of release were similar following local EC or IV delivery. Therefore, the coronary vasculature shapes the pharmacokinetics of local myocardial delivery of small catecholamine drugs in large animal models. Optimal design of epicardial drug delivery systems must consider the underlying bulk capillary perfusion currents within the tissue to deliver drug to tissue targets and may favor therapeutic molecules with better potential retention in myocardial tissue.

A four-compartment PBPK heart model accounting for cardiac metabolism - model development and application

“…The disposition within the cardiac wall follows the assumed pattern after a postmortem study by Garcia et al 175859. Therefore, investigating the disposition between cardiac mural layers requires more mechanistic insight, most likely with a permeability-limited kinetics assumption.…”

Multiscale Experimental and Computational Modeling Approaches to Characterize Therapy Delivery to the Heart from an Implantable Epicardial Biomaterial Reservoir

“…However, larger increases in the surface area had a more pronounced effect on increasing the concentration of drug analog along the transmural thickness at shorter time scales. Factors such as the size and thickness [5] of the heart tissue and the size of the infarct may need to be considered when determining the surface area of the device, and when scaling up.…”

“…In one exemplary configuration of this strategy, a biomaterial loaded with therapeutic agents acts as a reservoir on the surface of the heart, providing sustained release to a localized region, thereby preventing adverse systemic affects and increasing myocardial uptake [1] . A wide variety of therapeutics ranging from small molecules such as amiodarone [4] , epinephrine [5] , dobutamine [6] to larger biomolecules such as peptides [7] , growth factors [3] , exosomes [8] , cells [9], [10], [11], [12], [13] , and gene therapies [14] preloaded onto biomaterials and implanted on the epicardial surface have been investigated in animal models of a range cardiovascular conditions. Enhanced therapeutic benefit relative to the more standard methods of delivery has been shown in these studies, demonstrating that the epicardial strategy may accelerate clinical translation of these strategies.…”

Immune-modulatory alginate protects mesenchymal stem cells for sustained delivery of reparative factors to ischemic myocardium

“…Lovich and colleagues demonstrated that epicardial delivery leads to rapid diffusion of drugs throughout the myocardium, with 500x increase in potency compared to systemic delivery. 39,40 Whyte and colleagues recently reported the utility of pericardial MSC delivery to improve cardiac function over a 4 week period. 13 This innovative strategy, however, required weekly cellular injection into the epicardial reservoir to achieve efficacy.…”