Testing the Efficacy of Pharmacological Agents in a Pericardial Target Delivery Model in the Swine

Summary

We have developed a swine model for the target delivery of pharmacological agents within the pericardial space/fluid. Using this approach, the relative benefits of administered agents on induced atrial fibrillation, relative refractory periods and/or ischemic protection can be investigated.

Abstract

To date, many pharmacological agents used to treat or prevent arrhythmias in open-heart cases create undesired systemic side effects. For example, antiarrhythmic drugs administered intravenously can produce drops in systemic pressure in the already compromised cardiac patient. While performing open-heart procedures, surgeons will often either create a small port or form a pericardial cradle to create suitable fields for operation. This access yields opportunities for target pharmacological delivery (antiarrhythmic or ischemic preconditioning agents) directly to the myocardial tissue without undesired side effects.

We have developed a swine model for testing pharmacological agents for target delivery within the pericardial fluid. While fully anesthetized, each animal was instrumented with a Swan-Ganz catheter as well as left and right ventricle pressure catheters, and pacing leads were placed in the right atrial appendage and the right ventricle. A medial sternotomy was then performed and a pericardial access cradle was created; a plunge pacing lead was placed in the left atrial appendage and a bipolar pacing lead was placed in the left ventricle. Utilizing a programmer and a cardiac mapping system, the refractory period of the atrioventricular node (AVN), atria and ventricles was determined. In addition, atrial fibrillation (AF) induction was produced utilizing a Grass stimulator and time in AF was observed. These measurements were performed prior to treatment, as well as 30 min and 60 min after pericardial treatment. Additional time points were added for selected studies. The heart was then cardiopleged and reanimated in a four chamber working mode. Pressure measurements and function were recorded for 1 hr after reanimation. This treatment strategy model allowed us to observe the effects of pharmacological agents that may decrease the incidence of cardiac arrhythmias and/or ischemic damage, during and after open-heart surgery.

Introduction

Currently in open-heart procedures, clinicians utilize antiarrhythmic and other treatment agents systemically. Yet, this can be problematic for many patients, especially those who are already clinically compromised. For example, intravenous treatments can result in systemic drops in blood pressure or renal dysfunction; further, they may create anesthesia management issues and/ or other long-term side effects.

Here we have created a model for testing the efficacy of administering pharmacological agents into the pericardial space. For example, this approach can be utilized for testing antiarrhythmic drugs, studying compounds that could increa....

Protocol

This protocol was approved by the University of Minnesota Institutional Animal Care and Use Committee.

Figure 1. Diagram of Study Paradigm Please click here to view a larger version of this figure.

Results

These results are characteristic of the data that can be collected utilizing this target delivery model of pharmacological agents in the swine. This data demonstrated notable increases in these ventricle effective refractory periods (VERP) following a DHA infusion in situ. In addition, the data establishes an increase in left ventricular pressure of DHA compared to control in vitro. The LV pressure in the DHA treated hearts were significantly higher compared to control at several time-points. This data .......

Discussion

Here, we have demonstrated a unique approach for testing the potential efficacy of target delivered compounds into the pericardial space. This study paradigm can be utilized to test current market released pharmaceutical products or experimental compounds, thus providing direct translational applications to various clinical settings. Within this treatment strategy there are two major clinical applications for delivering pharmaceuticals to the pericardial space: 1) open-heart or minimally invasive cardiac surgical procedu.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
SelectSecure 3830 lead	Medtronic		Pacing Lead
C304 Deflectable Catheter	Medtronic		Steerable catheter for placing leads
SelectSecure 3830 lead	Medtronic		active fixation pacing leads
Grass S48 Stimulator			Electrical Stimulator
Premium 6500 Unipolar Pacing			Plunge pacing lead for LAA
EnSite Cardiac Mapping			Electrophysiology mapping system
CareLink Programer 2092	Medtronic		programmer for pacing leads
GEM II pacemaker	Medtronic		pacemaker can
DLP Aortic Root Cannula	Medtronic		aortic root cannula for transplant
C-Arm Fluoroscopy	Ziehm		fluoroscopic imaging
Oscilliscope	Tektronix
11F Hemostasis introducer	SafeSheath		Hemostasis introducers
Swan-Ganz Catheter 8.0F	ICU Medical		thermal dilution catheter
Venogram balloon	Oscor		pressure monitoring
Ultraview SL	Spacelabs		EKG and blood pressure
s/5 Avance	General Electric		Anesthesia machine
Atrial 6492 – Unipolar Temporary Atrial Pacing Lead	Medtronic		temporary pacing lead
VIVID i	General Electric		2D electrocardiography unit