Myocardial gene therapy and gene expression in angina pectoris

• Background: Angiogenesis does not fully counteract myocardial ischemia in stable angina pectoris. Refractory angina pectoris, with remaining symptoms despite medication and no possibility for bypass surgery or angioplasty, is rather common. Angiogenic gene therapy is a novel treatment strategy for these patients. Methods and results: In study I, six patients with refractory angina received intramyocardial injections of 0.25-1 mg plasmid encoding Vascular Endothelial Growth Factor (phVEGF-A165) via thoracotomy. The peak systolic velocity improved in all six patients but perioperative myocardial infarction occurred in two patients. Study II was a double-blind randomised controlled trial of the same plasmid or placebo plasmid (0.5 mg), delivered via a percutaneous catheter system in 80 patients with refractory angina. Reversible perfusion defects and wall motion improved in the phVEGF-A165-treated area compared to placebo. Nitroglycerin use tended to decrease with active treatment while symptom class and exercise capacity showed no effect beyond placebo. Five catheter-related adverse events occurred but no adverse effects were related to the plasmid. In study III, the prognosis of refractory angina was assessed in all 225 patients screened for study II. The mortality was 10.6% at three years. The baseline screening angiogram found revascularisation options in 10% of patients, although previous examinations had ruled out such possibilities. After twelve months, 36% of the trial patients had improved by at least two symptom classes and 37% had increased their exercise time by at least 60 seconds, with no difference between placebo and active groups. In study IV-V, the gene expression pattern in a reversibly ischemic myocardial area was compared to a normal area in eight patients with stable angina pectoris. Real-time polymerase chain reaction showed increased expression of ANP and BNP but not of VEGF and VEGF receptor 1 and 2 in reversibly ischemic myocardium. In microarray measurements, 15 additional known angiogenesis stimulators lacked differential expression. Instead, we found increased expression of several other genes with potential angiogenic, angiogenesis inhibiting, anti-apoptotic and muscle-related function but with yet unknown role in the myocardium. Conclusions: Intramyocardial phVEGF-A165 is safe and increases myocardial perfusion in patients with stable angina pectoris. The effect on symptoms should be tested in a larger trial. Patients with refractory angina pectoris have a rather low mortality and symptomatic improvement is common. Overexpressing VEGF (or other angiogenic factors) seems a rational strategy, as most angiogenesis stimulators not are overexpressed in ischemic myocardium in stable angina. The ischemia-related overexpression of ANP, BNP and other genes with a probable anti-angiogenic function might be a limiting factor in angiogenesis.

Nyckelord

Angina pectoris, gene therapy, vascular endothelial growth factor, plasmid, prognosis, collaterals, angiogenesis, gene expression, microarray, natriuretic peptides.

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