Local epicardial inotropic drug delivery allows targeted pharmacologic intervention with preservation of myocardial loading conditions

Heart, Lung and Circulation

Pezone

et al. 2014

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Background Most applications of pressure-volume conductance catheter measurements assess cardiovascular function at a single point in time after genetic, pharmacologic, infectious, nutritional, or toxicologic manipulation. Use of these catheters as a continuous monitor, however, is fraught with complexities and limitations. Methods Examples of the limitations and optimal use of conductance catheters as a continuous, real-time monitor of cardiovascular function are demonstrated during inotropic drug infusion in anesthetised rats. Results Inotropic drug infusion may alter ventricular dimensions causing relative movement of a well-positioned catheter, generating artifacts, including an abrupt pressure rise at end-systole that leads to over estimation of indices of contractility (max dP/dt) and loss of stroke volume signal. Simple rotation of the catheter, echocardiography-guided placement to the centre of the ventricle, or ventricular expansion through crystalloid infusion may correct for these artifacts. Fluid administration, however, alters left ventricular end-diastolic pressure and volume and therefore stroke volume, thereby obscuring continuous real-time haemodynamic measurements. Conclusions Pressure-volume artifacts during inotropic infusion are caused by physical contact of the catheter with endocardium. Repeated correction of catheter position may be required to use pressure volume catheters as a continuous real-time monitor during manipulations that alter ventricular dimensions, such as inotropic therapy.

Section: Introductionmentioning

confidence: 99%

Use of Pressure-volume Conductance Catheters in Real-time Cardiovascular Experimentation

Wei

Heart, Lung and Circulation

Pezone

et al. 2014

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“…Other studies have demonstrated favorable pharmacokinetics, with elevated myocardial drug levels and minimal peripheral concentration, when drug is given to the pericardial sac [23–28]. We have shown in small animals that local EC application of inotropic compounds leads to elevated myocardial drug and intracellular second messenger concentrations in target ventricular tissue, enhanced contractile response with lower systemic levels, and less atrial and peripheral vascular responses than IV infusion [29, 30]. EC epinephrine delivery in rats required only 1/3 rd of the IV dose rate to provide an equal contractile effect without raising plasma drug levels or deleterious systemic side effects such as tachycardia or peripheral vasodilation [30].…”

Section: Introductionmentioning

confidence: 83%

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

Journal of Controlled Release

Edelman

Pezone

et al. 2014

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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.

“…1a). This diffusion may be in equilibrium with clearance from capillaries and enzymatic degradation [13, 18] so that as long as the release continues, the gradient will persist. Local delivery may flood the tissue with drug; some small fraction binds to specific receptors and activates biological effect while the majority remains unbound.…”

Section: Discussionmentioning

confidence: 99%

“…A novel polymeric local epicardial (EC) drug releasing system designed to permit precise animal-weight based epinephrine release to the anterior wall of the beating rat heart was fabricated from calcium-cross-linked alginate hydrogels [18]. Briefly, 45 mcl of 2% alginate (#71238, Sigma-Aldrich) slurry in double distilled water (ddH20) was pipetted onto the upper side of the permeable membrane of a transwell support (#3472, 6.5mm, polyester, 3 micrometers pore size; Corning).…”

Section: Methodsmentioning

confidence: 99%

“…2b). This relationship, specific to these disks at the fixed volume and interval of applied drug solution, allows the release rate to be prescribed solely through adjustments in applied concentration [18]. This novel method of controlling epicardial drug release allows for precise animal-weight based dosing without any chemical modifications of the platform.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

High concentrations of drug in target tissues following local controlled release are utilized for both drug distribution and biologic effect: An example with epicardial inotropic drug delivery

Journal of Controlled Release

Edelman

Wei

et al. 2013

Self Cite

Local drug delivery preferentially loads target tissues with a concentration gradient from the surface or point of release that tapers down to more distant sites. Drug that diffuses down this gradient must be in unbound form, but such drug can only elicit a biologic effect through receptor interactions. Drug excess loads tissues, increasing gradients and driving penetration, but with limited added biological response. We examined the hypothesis that local application reduces dramatically systemic circulating drug levels but leads to significantly higher tissue drug concentration than might be needed with systemic infusion in a rat model of local epicardial inotropic therapy. Epinephrine was infused systemically or released locally to the anterior wall of the heart using a novel polymeric platform that provides steady, sustained release over a range of precise doses. Epinephrine tissue concentration, upregulation of cAMP, and global left ventricular response were measured at equivalent doses and at doses equally effective in raising indices of contractility. The contractile stimulation by epinephrine was linked to drug tissue levels and commensurate cAMP upregulation for IV systemic infusion, but not with local epicardial delivery. Though cAMP was a powerful predictor of contractility with local application, tissue epinephrine levels were high and variable - only a small fraction of the deposited epinephrine was utilized in second messenger signaling and biologic effect. The remainder of deposited drug was likely used in diffusive transport and distribution. Systemic side effects were far more profound with IV infusion which, though it increased contractility, also induced tachycardia and loss of systemic vascular resistance, which were not seen with local application. Local epicardial inotropic delivery illustrates then a paradigm of how target tissues differentially handle and utilize drug compared to systemic infusion.