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

Abstract

Local myocardial application of inotropes may allow the study of pharmacologically augmented central myocardial contraction in the absence of confounding peripheral vasodilating effects and alterations in heart loading conditions. Novel alginate epicardial (EC) drug releasing platforms were used to deliver dobutamine to the left ventricle of rats. Pressure-volume analyses indicated that although both local and systemic intravenous (i.v.) use of inotropic drugs increase stroke volume and contractility, systemic infusion does so through heart unloading. Conversely, EC application preserves heart load and systemic blood pressure. EC dobutamine increased indices of contractility with minimal rise in heart rate and lower reduction in systemic vascular resistance than i.v. infusion. Drug sampling showed that dobutamine concentration was 650-fold higher in the anterior wall than in the inferior wall. The plasma dobutamine concentration with local delivery was about half as much as with systemic infusion. These data suggest that inotropic EC delivery has a localized effect and augments myocardial contraction by different mechanisms than systemic infusion, with far fewer side effects. These studies demonstrate a pharmacologic paradigm that may improve heart function without interference from effects on the vasculature, alterations in heart loading, and may ultimately improve the health of heart failure patients.

Fig. 1. In vitro characterization of novel epicardial (EC) alginate drug release platforms to precisely control delivered dose rate

A) dobutamine (5 μl) is applied to the upper side of 6.5 mm diameter alginate discs in varying concentrations (1.39, 2.08, 3.13, 4.69, 6.25, 9.38 and 12.5 mg/ml) and the released drug into the lower receiving chamber is shown as a function of time (N=8 ±SD). Linear correlation of these data yielded a release rate for each applied concentration. B) The applied dobutamine concentration is shown as a function of release rate. Linear regression of these data allow the estimation of the appropriate concentration of drug in 5 μl aliquots (C_ec) to be applied to the alginate discs in vivo to achieve a desired epicardial dobutamine release rate (r_ec).

Fig. 2. Sample pressure-volume loops before and after EC and IV dobutamine (0.5 μg/kg/min) treatment

In this example, the LV pressure to volume ratio at end systole (P_es/V_es, circular markers), an index of contractility, increases similarly for EC (16%) and IV (14%) administration. The stroke volume (maximum less the minimum ventricular volume) is increased with both treatments from the pre-teatment baseline (BL), 27% for EC and 39% for IV. With EC application, left ventricular end diastolic volume (LVEDV) is mostly preserved, falling by less than 2%, while the pressure in the ventricle during systolic ejection is increased by 6%, indicating preserved preload and increased arterial pressures. With IV application, the LVEDV falls by 8% indicating decreased preload and the ventricular pressure during systolic ejection falls by 9% lower, indicating a loss of afterload and systolic arterial pressures. These pressure-volume loops suggest that the mechanism of action of inotropic agents depends on the method of application to the heart.

Fig. 3. Dose response of dobutamine for IV and EC application in terms of A) max dP/dt, B) Heart rate (HR), C) systemic vascular resistance (SVR), D) Mean Arterial Preasure (MAP) and E) Stroke Volume (SV) over a wide range of applied doses

Data are fit to sigmoidal curves (Prism 5.04, Graph Pad). Peak increase in max dP/dt was 49% for IV and 62% for EC delivery. The ED50 for max dP/dt was 1.1 and 1.7 μg/kg/min for EC and IV, respectively. Peak increase in HR was 28% for IV and 10% for EC delivery. The ED50 for HR was 0.5 and 1.8 μg/kg/min, for EC and IV respectively. Peak decrease in SVR was 82% for IV and 39% for EC delivery. The ED50 for SVR was 1.0 and 1.9 μg/kg/min, for EC and IV respectively. Peak increase in MAP was 12% and the ED50 was 1.7 μg/kg/min for EC application. The MAP data for IV infusion did not fit a sigmoidal profile, however, most of the data show a reduction with dosing. Peak increase in SV was 158% for IV and 61% for EC delivery. The ED50 for SV was 1.6 and 3.2 μg/kg/min, for EC and IV respectively.

Fig. 4. Change in A) max dP/dt, B) Heart rate (HR), C) systemic vascular resistance (SVR), D) Mean Arterial Preasure (MAP) and E) Stroke Volume (SV) at low

(0.5 μg/kg/min) and high (5 μg/kg/min) dose for EC and IV administration. At low dose the rise in contractility is significantly greater for EC over IV infusion, while at the higher dose both EC application and IV infusion increases contractility to a similar extent. HR increases more so for IV than EC application at the high dose and SVR falls to a greater extent with IV infusion than EC application at either dose. At low dose, MAP is higher for EC application than IV infusion, however, at higher doses MAP decreases similarly for both forms of delivery. Stroke volume increases in a dose dependent manner but the differences between EC and IV delivery were not statistically different at either dose (N=7, * P < 0.05).

Fig 5. Scatter plots of contractility as a function of distant cardiovascular effects

A) Heart rate (HR) response as a function of contractility response (Max dP/dt) for each data point in multidose per animal (dose response) protocol. For the same increase in contractility, IV infusion causes a greater increase in HR than EC application. B) Systemic vascular resistance (SVR) response as a function of contractility response (Max dP/dt) for each data point in multidose per animal protocol. For the same increase in contractility, IV infusion causes a greater loss of SVR than EC application.

Fig 6. Pharmacokinetic data

Dobutamine deposition in the A) anterior wall of the left ventricle, B) Plasma, C) Inferior wall of the left ventricle and D) right atrium. Tissue levels are normalized to mass of protein (g). The right atrium was sampled for dobutamine levels as a proxy for the concentration in the sinoatrial node that paces the heart. Some of the samples were below the detection limit (12.5 ng/g for tissue, 1 ng/ml for plasma, horizontal grey shading) of the liquid chromatography/mass spectroscopy technique (N=7, average ± SD, * P < 0.05).

Fig. 7. Hemodynamic response as a function of plasma dobutamine concentration for A) max dP/dt, B) Heart rate (HR), C) systemic vascular resistance (SVR), D) Mean Arterial Preasure (MAP) and E) Stroke Volume (SV) for low

(0.5 μg/kg/min) and high (5 μg/kg/min) dose given either by EC or IV routes. Data are fit to sigmoidal curves (Prism 5.04, Graph Pad). Hemodynamic responses correlate to blood levels for IV infusion. Max dP/dt, HR and SV do not correlate with blood concentrations with local EC application, as they are dependent on drug levels within the myocardium. SVR and MAP, which can be considered peripheral effects correlate with plasma drug levels even with local application (N=7, note that some of the plasma samples were below detection limits and these data are omitted from this analysis.)