Might gene therapy offer symptomatic relief for patients with ‘no option’ angina?

June 1, 2005

December 14, 2005

Mohammed Hanif, Anish Patel, Cardiothoracic Registrar (Department of Cardiothoracic Surgery, Freeman Hospital and James Cook University Hospital, Middlesbrough)

Joel Dunning, Department of Cardiothoracic Surgery, Freeman Hospital and James Cook University Hospital, Middlesbrough

In [patients not amenable to conventional revascularisation] does [gene therapy] reduce the symptoms of [angina]?

There are a number of patients with poor left ventricular function being referred to the cardiac surgeon with angina who have had previous multiple revascularisation procedures and are on maximal medical therapy. They are clearly unsuitable for further surgical revascularisation either due to diffuse coronary artery disease with poor targets or have no useable conduits. Although some of these patients may be eligible for orthotopic heart transplantation, current waiting times for donor hearts and limitations in organ availability render this option unlikely to occur before the patient has become severely ill and reached status I priority level. Gene based modalities for ischaemic myocardium may eventually constitute a therapeutic option for these patients.

You wish to find out what current evidence exists in this area of research.

Medline 1990 to September 2005 using the OVID interface.

[exp vascular endothelial growth factor A/OR vascular endothelial growth factor.mp OR VEGF.mp OR exp Fibroblast Growth Factors/OR Fibroblast growth factor.mp OR FGF.mp] AND [Exp Thoracic surgery/OR Thoracic surgery.mp OR cardiac surgery.mp OR CABG.mp OR Coronary arter$ disease.mp OR myocardial.mp] limit to human.

Four hundred and sixty-four papers were found of which only 12 papers were clinically relevant. There were 7 cohort and 5 randomised trials.

Angiogenesis is a theoretically highly attractive strategy for patients for whom conventional revascularisation may not be an option. There are several agents that have been studied but Fibroblast Growth Factor (FGF) and Vascular Endothelial Growth Factor (VEGF) have been most studied in clinical trials. In addition, several methods of application have been studied, including intracoronary injection, percutaneous intramyocardial injection, intramyocardial injection via mini-thoracotomy and intramyocardial injection during coronary surgery.
We identified seven cohort studies that initially reported highly positive results. Using a minithoracotomy Losordo, Symes, Vale, and Fortuin all presented cohorts of patients followed up to 2 years post-injection. They found highly significant improvements in angina scoring, some improvements in exercise testing and even some angiographic or perfusion scanning benefits.

Rosengart reported initial findings on injection during coronary surgery and found some improvements in regional wall motion after injection.

While these studies were very positive, they suffered from a lack of control groups to compare their results with. We identified five randomised trials. Unfortunately their findings were less positive.

The AGENT trial recruited 79 patients and utilised Ad5-FGF4 delivered via intracoronary catheter. They failed to show improvement in angina or myocardial contractility at 4 and 12 weeks. However, they did show 20–30% improvement in exercise tolerance test at 4 and 12 weeks compared to baseline.

The VIVA trial recruited 178 patients and the primary outcome demonstrated significant improvement in angina class, frequency, QOL and ETT at 120 days post gene therapy using a dose of 50 ng.kg–1.min–1 of rhVEGF. There was no correlation between subjective improvement and objective measurement of myocardial perfusion and ventricular ejection fraction.

The FIRST Trial recruited 337 patients to receive rFGF2 via an intracoronary 20 min infusion or placebo, in a double blinded study. Despite the large size of the study, they failed to show any benefits in treadmill testing, angina scores or on nuclear perfusion scanning.

The Euroinject One Trial randomised 80 patients with 'no option' angina to VEGF injection or placebo. Both groups received 10 intramyocardial injections via a percutaneous route. No differences were found in symptoms, exercise testing, ejection fraction or myocardial perfusion scanning. A significant improvement was detected in local wall abnormalities, but this was the only positive finding.

The KAT Trialists randomised 103 patients already undergoing stenting to receiving placebo or VEGF via intracoronary infusion. They found a significant improvement in myocardial perfusion scanning, although they found no difference in angiographic findings, or clinical outcomes.

Gene therapy for ischaemic heart disease is in its infancy with evaluation trials of novel vectors, delivery methods and targeted patient population. The initial results from the randomised clinical trials using gene therapy for severe CHD are interesting but clear benefits are yet to be demonstrated. Longer term outcomes from the AGENT trial and VIVA trials are awaited.

1. Losordo DW, Vale PR, Symes JF, Dunnington CH, Esakof DD, Maysky M, Ashare AB, Lathi K, Isner JM.. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia.
2. Symes JF, Losordo DW, Vale PR, Lathi KG, Esakof DD, Mayskiy M, Isner JM.. Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease.
3. Vale PR, Losordo DW, Milliken CE, Maysky M, Esakof DD, Symes JF, Isner JM.. Left ventricular electromechanical mapping to assess efficacy of phVEGF(165) gene transfer for therapeutic angiogenesis in chronic myocardial ischemia.
4. Rosengart TK, Lee LY, Patel SR et al.. Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe CAD.
5. Hendel RC, Henry TD, Rocha-Singh K, Isner JM, Kereiakes DJ, Giordano FJ, Simons M, Bonow RO.. Effect of intracoronary recombinant human vascular endothelial growth factor on myocardial perfusion: evidence for a dose-dependent effect.
6. Grines CL, Watkins MW, Helmer G, Penny W, Brinker J, Marmur JD, West A, Rade JJ, Marrott P, Hammond HK, Engler RL.. Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris.
7. Henry TD, Annex BH, McKendall GR, Azrin MA, Lopez JJ, Giordano FJ, Shah PK, Willerson JT, Benza RL, Berman DS, Gibson CM, Bajamonde A, Rundle AC, Fine J, McCluskey ER.. Investigators VIVA. The VIVA trial: vascular endothelial growth factor in ischaemia for vascular angiogenesis.
8. Fortuin FD, Vale P, Losordo DW et al.. One-year follow-up of direct myocardial gene transfer of vascular endothelial growth factor-2 using naked plasmid deoxyribonucleic acid by way of thoracotomy in no-option patients.
9. Kastrup J, Jorgensen E, Ruck A, Tagil K, Glogar D, Ruzyllo W, Botker HE, Dudek D, Drvota V, Hesse B, Thuesen T, Blomberg P, Gyongyosi M, Sylven C.. Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable angina pectoris:a randomised double-blind placebo-controlled study:The Euroinject One Trial.
10. Reilly JP, Grise MA, Fortuin FD, Vale P, Schaer GL, Lopez JJ, Van Camp J, Henry T, Richenbacher W, Losordo DW, Schatz RA, Isner JM.. Long-term (2-year) clinical events following transthoracic intramyocardial gene transfer of VEGF-2 in no option patients.
11. Simons M, Annex BH, Laham RJ, Kleiman N, Henry T, Dauerman H, Udelson JE, Gervino EV, Pike M, Whitehouse MJ, Moon T, Chronos NA.. Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomised, controlled clinical trial.
12. Hedman M, Hartikainen J, Syvanne M et al.. Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty..phase II results of the Kuopio Angiogenesis Trial.