Supplement

Improving Cardiac Gene Therapy Efficacy Using Impella

Received:

Accepted:

Published online:

Support:The development of this supplement was funded by Abiomed.

Open Access:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Dr Ishikawa began by recalling that acute MI (AMI) was a deadly disease about 50 years ago, but advances in acute care, including early coronary revascularisation, have led to a significant decline in mortality.1,2 However, it has led to a parallel increase in the prevalence of heart failure (HF) and the subsequent increase in costs of care.3,4 In essence, the therapeutic advances in the management of AMI over the past few decades have led to a detour to the final destination of death that now goes through HF. He highlighted the research initiatives and publications by the Acute Cardiac Unloading and REcovery faculty in the past several years attempting to stem the development of HF following an AMI via mechanical unloading.5–10 This raises the question of what therapies can benefit patients who have already developed HF and prevent them from premature death. Dr Ishikawa’s team tested the idea of utilising mechanical left ventricular (LV) unloading to increase the efficacy of delivering cardiac gene therapy vectors in patients with established HF.

He highlighted the poor results of the phase IIb trial, Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID 2), which investigated the intracoronary administration of adeno-associated virus type 1 (AAV1)/SERCA2a gene in patients with Class III/IV HF.11 Possible reasons for the failure of the trial include insufficient myocardial uptake of the transduced gene, as the AAV concentration was very low. He then described the antegrade intracoronary injection of the gene therapy vector, which is advantageous given the relatively low invasiveness and homogeneous distribution. However, data on this approach demonstrate that the cardiac uptake of the vector is low and so requires a high vector dose to compensate.

Studies suggest that efficient cardiac gene transfer efficiency with AAV vectors can be achieved with high perfusion pressure, coronary flow, vector dose and longer exposure times. Dr Ishikawa presented his hypothesis of improving gene delivery by using the Impella device to enhance viral uptake. He proposed that Impella support could affect uptake in two ways. First, LV unloading with Impella will result in a decrease in LV wall stress and an increase in coronary flow and pressure. Second, Impella could be used to haemodynamically support the patient while the vector is delivered into the coronary system during temporary coronary balloon occlusion. This would allow for a longer dwell time by slowing the coronary perfusion rate and minimising the risk of haemodynamic collapse.

Dr Ishikawa tested the haemodynamic support approach with Impella in a pig model of subacute ischaemic HF. AMI is induced and the heart is allowed to remodel for 1 week. After 1 week, the AAV-6-Luc (5.0 × 1013) is delivered intracoronary, with or without Impella support (n=3 each), and the hearts were analysed for luciferase activity after 4 weeks. No clear benefit of unloading with Impella alone was observed when using antegrade intracoronary delivery of the AAV vector with a luciferase gene construct.

Next, he tested gene delivery via coronary occlusion, with or without Impella. All pigs tolerated temporary balloon occlusion in the infarcted left anterior descending artery with no change in the systolic aortic pressure, both with and without Impella. However, the systolic aortic pressure dropped to <60 mmHg in all pigs treated with balloon occlusion in the non-infarcted left circumflex artery without Impella, while this was maintained in pigs receiving Impella support. The delivery of the AAV vector via coronary artery (CA) balloon occlusion with Impella resulted in approximately a 20-fold increase in the expression of the transduced gene. Moreover, delivery of the AAV vector using a combination of CA and coronary sinus occlusion with Impella support resulted in an up to 800-fold increase in the transduced gene expression, comparable to intramyocardial exposure via surgical approach. All animals supported with Impella during simultaneous CA and sinus occlusion were haemodynamically stable throughout the procedure.

In conclusion, these results demonstrate that haemodynamic support with Impella allows for safe and efficacious AAV gene delivery to the heart. Future studies include testing the above model with a therapeutic gene and delineating the mechanisms leading to high gene transduction.

References

  1. Ezekowitz JA, Kaul P, Bakal JA, et al. Declining in-hospital mortality and increasing heart failure incidence in elderly patients with first myocardial infarction. J Am Coll Cardiol 2009;53:13–20.
    Crossref PubMed
  2. Rahimi K, Duncan M, Pitcher A, et al. Mortality from heart failure, acute myocardial infarction and other ischaemic heart disease in England and Oxford: a trend study of multiple-cause-coded death certification. J Epidemiol Community Health 2015;69:1000–5.
    Crossref PubMed
  3. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics – 2015 update: a report from the American Heart Association. Circulation 2015;131:e29–322.
    Crossref PubMed
  4. Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation 2011;123:933–44.
    Crossref PubMed
  5. Meyns B, Stolinski J, Leunens V, et al. Left ventricular support by catheter-mounted axial flow pump reduces infarct size. J Am Coll Cardiol 2003; 41:1087–95.
    Crossref PubMed
  6. Saku K, Kakino T, Arimura T, et al. Left ventricular mechanical unloading by total support of Impella in myocardial infarction reduces infarct size, preserves left ventricular function, and prevents subsequent heart failure in dogs. Circ Heart Fail 2018;11:e004397.
    Crossref PubMed
  7. Saku K, Kakino T, Arimura T, et al. Total mechanical unloading minimizes metabolic demand of left ventricle and dramatically reduces infarct size in myocardial infarction. PLoS One 2016;11:e0152911.
    Crossref PubMed
  8. Esposito ML, Zhang Y, Qiao X, et al. Left ventricular unloading before reperfusion promotes functional recovery after acute myocardial infarction. J Am Coll Cardiol 2018;72:501–14.
    Crossref PubMed
  9. Sunagawa G, Saku K, Arimura T, et al. Mechano-chronotropic unloading during the acute phase of myocardial infarction markedly reduces infarct size via the suppression of myocardial oxygen consumption. J Cardiovasc Transl Res 2019;12:124–34.
    Crossref PubMed
  10. Kapur NK, Qiao X, Paruchuri V, et al. Mechanical pre-conditioning with acute circulatory support before reperfusion limits infarct size in acute myocardial infarction. JACC Heart Fail 2015;3:873–82.
    Crossref PubMed
  11. Greenberg B, Butler J, Felker GM, et al. Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial. Lancet 2016;387:1178–86.
    Crossref PubMed