Background: Gene therapy is a promising option for heart failure patients, but there remains a lack of effective delivery mechanisms. The Impella device is a heart pump that can increase coronary flow and pressure, an important factor in gene transduction efficiency when using intracoronary delivery. Because it also lends haemodynamic support, the Impella can be coupled with balloon coronary occlusion to increase exposure time and allow for higher vector concentrations.
Hypothesis: We hypothesised that use of the Impella offers stable haemodynamics during coronary occlusion delivery of adeno-associated viral vector (AAV)-6 encoding luciferase and results in higher gene transduction efficiency than delivery without the Impella
Methods: Two weeks after MI induction in Yorkshire pigs, intracoronary delivery of AAV-6-luciferase was performed: delivery with Impella + coronary artery occlusion (CA; n=3), Impella + coronary artery and coronary sinus occlusion (CA + CS; n=2) and viral injection without Impella unloading (n=3). Four weeks later, tissues were harvested from various heart regions and other organs to assess luciferase expression and viral uptake.
Results: Impella support offered safe vector delivery during 1–2 minutes of CA and CS. Impella + coronary artery block enhanced luciferase expression globally in the heart, but not in non-heart tissue, such as the liver, compared to injection without coronary artery block. Impella with CA + CS block even further increased luciferase expression by increasing viral uptake, as evidenced by increased vector genome in the tissues, detected by polymerase chain reaction. At the infarct border zone, an important area for cardiac gene therapy, CA + CS led to a >300-fold increase in luciferase (p=0.005) compared to viral injection alone.
Conclusion: Impella unloading with CA + CS dramatically improves AAV gene expression in the heart while minimising off-target expression, thus it is a promising method for the clinical application of cardiac gene therapy.