NOGA-guided analysis of regional myocardial perfusion abnormalities treated with intramyocardial injections of plasmid encoding vascular endothelial growth factor A-165 in patients with chronic myocardial ischemia: subanalysis of the EUROINJECT-ONE multicenter double-blind randomized study.

BACKGROUND: The aim of this substudy of the EUROINJECT-ONE double-blind randomized trial was to analyze changes in myocardial perfusion in NOGA-defined regions with intramyocardial injections of plasmid encoding plasmid human (ph)VEGF-A(165) using an elaborated transformation algorithm. METHODS AND RESULTS: After randomization, 80 no-option patients received either active, phVEGF-A165 (n=40), or placebo plasmid (n=40) percutaneously via NOGA-Myostar injections. The injected area (region of interest, ROI) was delineated as a best polygon by connecting of the injection points marked on NOGA polar maps. The ROI was projected onto the baseline and follow-up rest and stress polar maps of the 99m-Tc-sestamibi/tetrofosmin single-photon emission computed tomography scintigraphy calculating the extent and severity (expressed as the mean normalized tracer uptake) of the ROI automatically. The extents of the ROI were similar in the VEGF and placebo groups (19.4+/-4.2% versus 21.5+/-5.4% of entire myocardium). No differences were found between VEGF and placebo groups at baseline with regard to the perfusion defect severity (rest: 69+/-11.7% versus 68.7+/-13.3%; stress: 63+/-13.3% versus 62.6+/-13.6%; and reversibility: 6.0+/-7.7% versus 6.7+/-9.0%). At follow-up, a trend toward improvement in perfusion defect severity at stress was observed in VEGF group as compared with placebo (68.5+/-11.9% versus 62.5+/-13.5%, P=0.072) without reaching normal values. The reversibility of the ROI decreased significantly at follow-up in VEGF group as compared with the placebo group (1.2+/-9.0% versus 7.1+/-9.0%, P=0.016). Twenty-one patients in VEGF and 8 patients in placebo group (P<0.01) exhibited an improvement in tracer uptake during stress, defined as a >or =5% increase in the normalized tracer uptake of the ROI. CONCLUSIONS: Projection of the NOGA-guided injection area onto the single-photon emission computed tomography polar maps permits quantitative evaluation of myocardial perfusion in regions treated with angiogenic substances. Injections of phVEGF A165 plasmid improve, but do not normalize, the stress-induced perfusion abnormalities.

Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris A randomized double-blind placebo-controlled study: the Euroinject One trial.

OBJECTIVES: In the Euroinject One phase II randomized double-blind trial, therapeutic angiogenesis of percutaneous intramyocardial plasmid gene transfer of vascular endothelial growth factor (phVEGF-A(165)) on myocardial perfusion, left ventricular function, and clinical symptoms was assessed. BACKGROUND: Evidence for safety and treatment efficacy have been presented in phase I therapeutic angiogenesis trials. METHODS: Eighty "no-option" patients with severe stable ischemic heart disease, Canadian Cardiovascular Society functional class 3 to 4, were assigned randomly to receive, via the NOGA-MyoStar system (Cordis Corp., Miami Lakes, Florida), either 0.5 mg of phVEGF-A(165) (n = 40) or placebo plasmid (n = 40) in the myocardial region showing stress-induced myocardial perfusion defects on (99m)Tc sestamibi/tetrofosmin single-photon emission computed tomography. RESULTS: No differences among the groups were recorded at baseline with respect to clinical, perfusion, and wall motion characteristics. After three months, myocardial stress perfusion defects did not differ significantly between the VEGF gene transfer and placebo groups (38 +/- 3% and 44 +/- 2%, respectively). Similarly, semiquantitative analysis of the change in perfusion in the treated region of interest did not differ significantly between the two groups. Compared with placebo, VEGF gene transfer improved the local wall motion disturbances, assessed both by NOGA (p = 0.04) and contrast ventriculography (p = 0.03). Canadian Cardiovascular Society functional class classification of angina pectoris improved significantly in both groups but without difference between the groups. No phVEGF-A(165)-related adverse events were observed; however, NOGA procedure-related adverse events occurred in five patients. CONCLUSIONS: The VEGF gene transfer did not significantly improve stress-induced myocardial perfusion abnormalities compared with placebo; however, improved regional wall motion, as assessed both by NOGA and by ventriculography, may indicate a favorable anti-ischemic effect. This result should encourage more studies within the field. Transient VEGF overexpression seems to be safe.

Serial changes in the high-frequency ECG during the first year following acute myocardial infarction.

BACKGROUND: Previous studies have shown reduced high-frequency QRS components (HF-QRS) after acute myocardial infarction (MI). The purpose of this study was to investigate serial changes in HF-QRS during the first year following acute MI. METHODS: A total of 75 patients were included. Standard- and high-frequency ECGs were recorded on five occasions during the year following the MI (a few days after the MI, after 6 weeks, and after 3, 6 and 12 months). RESULTS: There was a statistically significant increase in HF-QRS during the follow-up year (P = 0.002). There were no significant differences in HF-QRS when comparing either the infarct location or the presence or absence of reperfusive therapy. Large differences in HF-QRS were observed, both intra-individually and inter-individually, during the year. CONCLUSIONS: There was a statistically significant increase in HF-QRS during the year following acute MI.

Patient gender and radiopharmaceutical tracer is of minor importance for the interpretation of myocardial perfusion images using an artificial neural network.

The purpose of this study was to assess the influence of patient gender and choice of perfusion tracer on computer-based interpretation of myocardial perfusion images. For the image interpretation, an automated method was used based on image processing and artificial neural network techniques. A total of 1000 patients were studied, all referred to the Royal Brompton Hospital in London for myocardial perfusion scintigraphy over a period of 1 year. The patients were randomized to receive either thallium or one of the two technetium tracers, methoxyisobutylisonitrile or tetrofosmin. Artificial neural networks were trained with either mixed gender or gender-specific and mixed tracer or tracer-specific training sets of different sizes. The performance of the networks was assessed in separate test sets, with the interpretation of experienced physicians regarding the presence or absence of fixed or reversible defects in the images as the gold standard. The neural networks trained with large mixed gender training sets were as good as the networks trained with gender-specific data sets. In addition, the neural networks trained with large mixed tracer training sets were as good as or better than the networks trained with tracer-specific data sets. Our results indicate that the influence of patient gender and perfusion tracer are of minor importance for the computer-based interpretation of the myocardial perfusion images. The differences that occur can be compensated for by larger training sets.

Effect of mobilization of bone marrow stem cells by granulocyte colony stimulating factor on clinical symptoms, left ventricular perfusion and function in patients with severe chronic ischemic heart disease.

OBJECTIVES: A phase I safety and efficacy study with granulocyte colony stimulating factor (G-CSF) mobilization of bone marrow stem cells to induce vasculogenesis in patients with severe ischemic heart disease (IHD) was conducted. DESIGN, PATIENTS AND RESULTS: 29 patients with IHD participated in the study. Thirteen patients were treated with G-CSF for 6 days and 16 patients served as controls. G-CSF treatment was without any serious adverse events. Four patients were "poor mobilizers" with a maximal increase in CD34+ cells to 5,000+/-700/mL blood (mean+/-S.D.) compared to 28,900+/-5,100/mL blood in "mobilizers". At the follow-up, G-CSF treated had improved in CCS classification, NTG consumption and angina attacks, but the controls only in CCS classification. No difference was seen between the two groups. The decline in NTG consumption tended to be significant in "mobilizers" compared to controls. Myocardial perfusion was unchanged at adenosine stress single photon emission computerized tomography (SPECT) or magnetic resonance images (MRI). Left ventricular ejection fraction decreased from 57% to 52% (p<0.01, MRI) and from 48% to 44% (p=0.07, SPECT) in G-CSF treated, but was unchanged measured with echocardiography. CONCLUSIONS: Treatment by G-CSF improved symptoms but not signs of myocardial ischemia in patients with severe IHD. The effects seemed related to mobilization of stem cells. An adverse effect on ejection fraction could not be excluded.

Circulating angiogenic cytokines and stem cells in patients with severe chronic ischemic heart disease--indicators of myocardial ischemic burden?

BACKGROUND: Angiogenic growth factors and stem cell therapies have demonstrated varying results in patients with chronic coronary artery disease. A reason could be that these mechanisms are already up-regulated due to reduced blood supply to the myocardium. The objective of this study was to examine if plasma concentrations of circulating stem cells and angiogenic cytokines in patients with severe stable chronic coronary artery disease were correlated to the clinical severity of the disease. METHODS: Fifty-four patients with severe coronary artery disease and reversible ischemia at stress myocardial perfusion scintigraphy were prospectively included. The severity of the disease was quantified by an exercise tolerance test, Canadian Cardiovascular Society angina classification, and Seattle Angina Pectoris Questionnaire. Fifteen persons without coronary artery disease served as control subjects. RESULTS: Plasma concentration of VEGF-A, FGF-2, SDF-1, and circulating CD34+ and CD34-/CD45- cells were similar in the two groups, but early stem cell markers (CD105, CD73, CD166) and endothelial markers (CD31, CD144, VEGFR2) were significantly different between patients and control subjects (p<0.005-0.001). Diabetic patients had higher concentration of SDF-1 (2528 vs. 2150 pg/ml, p=0.004). We found significant correlations between both VEGF-A, FGF-2, and CD34+ to disease severity, including degree of reversible ischemia, angina stability score, and exertional dyspnoea. CONCLUSIONS: Plasma concentrations of circulating stem cells and angiogenic cytokines have large inter-individual variations, which probably exclude them from being useful as indicators of myocardial ischemic burden.