Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease

doi:10.1016/S0003-4975(99)00807-3

The Annals of Thoracic Surgery

Volume 68, Issue 3, September 1999, Pages 830-836

Presented at the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25–27, 1999.

https://doi.org/10.1016/S0003-4975(99)00807-3 Get rights and content

Abstract

Background. Patients presenting with medically intractable angina who have undergone previous coronary bypass (CABG) and/or percutaneous revascularization procedures are frequently deemed “inoperable” based on angiographic findings of diffuse distal disease or a lack of available conduits. We initiated a phase I clinical trial to assess the safety and bioactivity of intramyocardial transfection of plasmid DNA encoding for the angiogenic mitogen vascular endothelial growth factor (phVEGF165) in such patients.

Methods. phVEGF165 (125 μg, n = 10; 250 μg, n = 10) was injected directly into the myocardium through a mini left anterior thoracotomy as sole therapy in 20 patients (15 male, 5 female, age 48 to 74 years) with class III or IV angina, reversible ischemia on stress sestamibi scans, and “inoperable” coronary artery disease.

Results. All patients tolerated surgery uneventfully and were extubated on the table. No perioperative myocardial infarction, hemodynamic instability, or change in ventricular function occurred. Mean hospital stay was 3.9 days. There was one late death (4 months). Plasma VEGF protein level increased from 30.6 ± 4.1 pg/mL pretreatment to 73.7 ± 10.1 pg/mL 14 days posttreatment (p = 0.0002) and returned to baseline by day 90. All 16 patients followed to day 90 reported a reduction in angina (nitroglycerin use/week = 60.2 ± 4.9 preop vs 3.5 ± 1.6 at 90 days; p < 0.0001). Seventy percent (7 of 10) patients were completely angina free at 6 months. A reduction in ischemic defects on single photon emission computerized tomography sestamibi scans was observed in 13 of 17 patients at 60 days (7 of 8 in the 250-μg group). Stress perfusion score decreased from 19.4 ± 3.7 at baseline to 15.9 ± 3.4 at 60 days (p = 0.025). Angiographic evidence of improved collateral filling of at least one occluded vessel was observed in all patients evaluated at day 60.

Conclusions. Direct myocardial gene transfer with phVEGF165 via a mini-thoracotomy can be performed safely and may result in significant symptomatic improvement in patients with “inoperable” coronary artery disease.

Section snippets

Patients and methods

The protocol for this phase I, nonrandomized, dose-escalating clinical trial was approved by the Institutional Review Board of St. Elizabeth’s Medical Center (January 1998), the Recombinant Advisory Committee of the National Institutes of Health, and the Food and Drug Administration.

Patients were considered eligible for intramyocardial gene therapy if they presented with Canadian Cardiovascular Society functional class III or IV angina refractory to maximum medical therapy and had demonstrable

Patient characteristics

The demographic and pretreatment clinical data for the 20 patients thus far treated with phVEGF165 are shown in Table 1, subdivided into two groups of 10 patients based on the total dose of DNA administered. The average age of the 15 men and 5 women in the study group was 62.7 years, ranging from 48 to 74 years. All patients had multiple risk factors for coronary artery disease, including a history of tobacco use in 13 (65%), hypertension in 19 (95%), diabetes in 9 (45%), hyperlipidemia in 18

Comment

Collateral circulation in the heart develops as a compensatory mechanism to supply oxygenated blood to myocardium jeopardized by coronary occlusive lesions. Studies have demonstrated that this occurs at least in part because myocardial hypoxia induces augmentation of expression of endothelial mitogens such as VEGF and other angiogenic growth factors along with their specific receptors [7]. Why the collateral circulation is adequate in some circumstances but inadequate in others remains a

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Original Articles: CardiovascularGene therapy with vascular endothelial growth factor for inoperable coronary artery disease

Abstract

Section snippets

Patients and methods

Patient characteristics

Comment

Biochem Biophys Res Commun

J Vasc Surg

J Biol Chem

Lancet

J Surg Res

J Thorac Cardiovasc Surg

Direct intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor augments collateral development and tissue perfusion

Circulation

Evidence of collateral development following intramyocardial gene therapy with vascular endothelial growth factor

Surg Forum

Constitutive expression of phVEGF165 following intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia

Circulation

Automatic quantification of ejection fraction from gated myocardial perfusion SPECT

J Nucl Med

Original Articles: Cardiovascular
Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease