Recombinant Human Vascular Endothelial Growth Factor
Recombinant Human Vascular Endothelial Growth Factor
Background. Patients with severe myocardial ischemia who are not candidates for percutaneous or surgical revascularization have few therapeutic options. Therapeutic angiogenesis in animal models with use of recombinant human vascular endothelial growth factor (rhVEGF) has resulted in successful revascularization of ischemic myocardium. This was a dose escalation trial designed to determine the safety and tolerability of intracoronary rhVEGF infusions.
Methods. and Results Patients were eligible if they had stable exertional angina, a significant reversible perfusion defect by stress myocardial perfusion study, and coronary anatomy that was suboptimal for percutaneous coronary intervention or coronary artery bypass grafting. rhVEGF was administered to a total of 15 patients by 2 sequential (eg, right and left) intracoronary infusions, each for 10 minutes, at rates of 0.005 (n = 4), 0.017 (n = 4), 0.050 (n = 4), and 0.167 mg/kg/min (n = 3). Pharmacokinetic sampling and hemodynamic monitoring were performed for 24 hours. Radionuclide myocardial perfusion imaging was performed before treatment and at 30 and 60 days after treatment. Follow-up angiograms were performed on selected patients at 60 days. The maximally tolerated intracardiac dose of rhVEGF was 0.050 mg/kg/min. Minimal hemodynamic changes were seen at 0.0050 mg/kg/min (2% ± 7% [SD] mean decrease in systolic blood pressure from baseline to nadir systolic blood pressure), whereas at 0.167 mg/kg/min there was a 28% ± 7% mean decrease from baseline to nadir (136 to 95 mm Hg systolic). Myocardial perfusion imaging was improved in 7 of 14 patients at 60 days. All 7 patients with follow-up angiograms had improvements in the collateral density score.
Conclusion. rhVEGF appears well tolerated by coronary infusion at rates up to 0.050 mg/kg/min. This study provides the basis for future clinical trials to assess the clinical benefit of therapeutic angiogenesis with rhVEGF.
Patients with severe myocardial ischemia who are not optimal candidates for percutaneous or surgical revascularization have few therapeutic options. In addition to symptoms that impair the quality of life, these patients are at risk for myocardial infarction and death. Mortality estimates for patients with reversible ischemia in 4 segments (in a 20-segment model) are between 2.3% and 4.6% per year. The natural process of collateral development, which can improve perfusion to jeopardized regions of myocardium, is inadequate in many patients. Despite advances in percutaneous and surgical revascularization techniques, the number of patients with significant myocardial ischemia not amenable to revascularization is likely to increase as the population ages and the mortality from coronary artery disease decreases.
This increasing clinical problem has stimulated interest in the use of angiogenic growth factors to promote the growth of collateral blood vessels in ischemic tissues. Successful therapeutic angiogenesis has been demonstrated in a variety of species with a number of angiogenic growth factors. In addition, initial clinical trials in patients with myocardial and critical limb ischemia have yielded promising initial results, but 2 exceptions have been small, with dose-escalation trials without control groups. Vascular endothelial growth factor (VEGF) is a protein responsible for the growth of new blood vessels during development in the healthy adult and in response to injury. It differs from other protein growth factors in its relative specificity for endothelial cells. It has now been produced in purified form by recombinant methods. This study investigated the safety and tolerability of intracoronary infusions of recombinant (r) human (h) VEGF in patients with areas of viable but underperfused myocardium who were not optimal candidates for standard revascularization procedures.
Background. Patients with severe myocardial ischemia who are not candidates for percutaneous or surgical revascularization have few therapeutic options. Therapeutic angiogenesis in animal models with use of recombinant human vascular endothelial growth factor (rhVEGF) has resulted in successful revascularization of ischemic myocardium. This was a dose escalation trial designed to determine the safety and tolerability of intracoronary rhVEGF infusions.
Methods. and Results Patients were eligible if they had stable exertional angina, a significant reversible perfusion defect by stress myocardial perfusion study, and coronary anatomy that was suboptimal for percutaneous coronary intervention or coronary artery bypass grafting. rhVEGF was administered to a total of 15 patients by 2 sequential (eg, right and left) intracoronary infusions, each for 10 minutes, at rates of 0.005 (n = 4), 0.017 (n = 4), 0.050 (n = 4), and 0.167 mg/kg/min (n = 3). Pharmacokinetic sampling and hemodynamic monitoring were performed for 24 hours. Radionuclide myocardial perfusion imaging was performed before treatment and at 30 and 60 days after treatment. Follow-up angiograms were performed on selected patients at 60 days. The maximally tolerated intracardiac dose of rhVEGF was 0.050 mg/kg/min. Minimal hemodynamic changes were seen at 0.0050 mg/kg/min (2% ± 7% [SD] mean decrease in systolic blood pressure from baseline to nadir systolic blood pressure), whereas at 0.167 mg/kg/min there was a 28% ± 7% mean decrease from baseline to nadir (136 to 95 mm Hg systolic). Myocardial perfusion imaging was improved in 7 of 14 patients at 60 days. All 7 patients with follow-up angiograms had improvements in the collateral density score.
Conclusion. rhVEGF appears well tolerated by coronary infusion at rates up to 0.050 mg/kg/min. This study provides the basis for future clinical trials to assess the clinical benefit of therapeutic angiogenesis with rhVEGF.
Patients with severe myocardial ischemia who are not optimal candidates for percutaneous or surgical revascularization have few therapeutic options. In addition to symptoms that impair the quality of life, these patients are at risk for myocardial infarction and death. Mortality estimates for patients with reversible ischemia in 4 segments (in a 20-segment model) are between 2.3% and 4.6% per year. The natural process of collateral development, which can improve perfusion to jeopardized regions of myocardium, is inadequate in many patients. Despite advances in percutaneous and surgical revascularization techniques, the number of patients with significant myocardial ischemia not amenable to revascularization is likely to increase as the population ages and the mortality from coronary artery disease decreases.
This increasing clinical problem has stimulated interest in the use of angiogenic growth factors to promote the growth of collateral blood vessels in ischemic tissues. Successful therapeutic angiogenesis has been demonstrated in a variety of species with a number of angiogenic growth factors. In addition, initial clinical trials in patients with myocardial and critical limb ischemia have yielded promising initial results, but 2 exceptions have been small, with dose-escalation trials without control groups. Vascular endothelial growth factor (VEGF) is a protein responsible for the growth of new blood vessels during development in the healthy adult and in response to injury. It differs from other protein growth factors in its relative specificity for endothelial cells. It has now been produced in purified form by recombinant methods. This study investigated the safety and tolerability of intracoronary infusions of recombinant (r) human (h) VEGF in patients with areas of viable but underperfused myocardium who were not optimal candidates for standard revascularization procedures.
