Gene Transfer for Ischemic Heart Failure in a Preclinical Model

Summary

A method of gene transfer for the treatment of ischemic heart failure is described using a swine model of myocardial infarction. Our simple and reproducible method enables us to readily evaluate the efficacy of various gene transfers with a very simple and reproducible way.

Abstract

Various emerging technologies are being developed for patients with heart failure. Well-established preclinical evaluations are necessary to determine their efficacy and safety.

Gene therapy using viral vectors is one of the most promising approaches for treating cardiac diseases. Viral delivery of various different genes by changing the carrier gene has immeasurable therapeutic potential.

In this video, the full process of an animal model of heart failure creation followed by gene transfer is presented using a swine model. First, myocardial infarction is created by occluding the proximal left anterior descending coronary artery. Heart remodeling results in chronic heart failure. Unique to our model is a fairly large scar which truly reflects patients with severe heart failure who require aggressive therapy for positive outcomes. After myocardial infarct creation and development of scar tissue, an intracoronary injection of virus is demonstrated with simultaneous nitroglycerine infusion. Our injection method provides simple and efficient gene transfer with enhanced gene expression. This combination of a myocardial infarct swine model with intracoronary virus delivery has proven to be a consistent and reproducible methodology, which helps not only to test the effect of individual gene, but also compare the efficacy of many genes as therapeutic candidates.

Protocol

1. Myocardial infarct creation

1. Female Yorkshire pigs (20kg) from Animal Biotech Industries (Doylestown, PA) are pre-medicated using Telazol (tiletamine/zolazepam) (8.0 mg/kg) and Buprenorphine (0.6 mg).
2. Animals are intubated and then ventilated with 100% oxygen. General anesthesia is maintained with Propofol (5-8mg/kg/hr) throughout the procedure.
3. The femoral site is prepared with 70% isopropyl alcohol followed by povidone iodine. A percutaneous puncture provides access to the artery and for sheath placement. After sheath insertion, 3000-5000 IU of heparin is administered IV to maintain an activated coagulation time of 250-300 seconds.<....

Discussion

Among the various causes of heart failure, ischemia is by far the most frequent in etiology. To overcome this serious disease, various therapeutic approaches are being developed. Careful evaluations of therapies are required before these promising therapies are can be applied to the clinics. Therefore, establishment of an ischemic heart failure model that represents the clinical conditions of patients is critical to development of heart failure therapies. Our swine myocardial infarct model meets these translational requ.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Telazol	Fort Dodge Animal Health	0856-9050-49
Propofol	APP Pharmaceuticals	63323-270-20
Heparin	APP Pharmaceuticals	63323-540-11
Amiodarone	APP Pharmaceuticals	63323-616-03
Atropin Sulfate	Med-Pharmex	54925-063-10
Potassium acetate	American Regent Inc.	2053-25
Nitroglycerine	American Regent Inc.	4810-25
Salix (Furosemide)	Intervet Inc.	710461
5 Fr Hockey stick catheter	Cordis	556-278-0L
7 Fr Hockey stick catheter	Cordis	778-278-00
Coronary wire	Abbott Laboratories	1044588
Coronary balloon	Abbott Laboratories	1009447-08
8Fr sheath	Terumo Medical Corp.	RSS801