Effects of intramyocardial pVEGF165 delivery on regional myocardial blood flow: evidence for a spatial 'delivery-efficacy' mismatch.

The aim of this study was to determine the effects of direct intramyocardial pVEGF165 gene transfer on regional myocardial blood flow in a porcine model of chronic myocardial ischaemia. Pigs underwent placement of an ameroid constrictor around the left circumflex coronary artery. After 3 weeks, animals received direct intramyocardial injections of pVEGF165 (20 x 50 microl at 1 microg/microl, n=11) or a plasmid vector encoding chloramphenicol acetyltransferase (20 x 50 microl at 1 microg/microl, n=11) into a specified target area (TA) of the left lateral wall. At 3 weeks after gene transfer, animals underwent final evaluation including a systematic assessment of regional myocardial blood flow (MBF) under resting and stress conditions. In all, 20 animals (10 per group) reached final studies. There was no change in mean arterial blood pressure or Rentrop collateral score from gene delivery to final studies in either group, nor were there differences between study groups. MBF was significantly higher in the areas adjacent to the TA in the VEGF group under resting (P<0.001) and stress conditions (P<0.05). In addition, pVEGF165 gene transfer abolished flow differences between the adjacent areas and the septum. MBF was not different between study groups in the TA, the anterior wall, or the septum. In conclusion, direct intramyocardial pVEGF165 gene transfer significantly improves myocardial blood flow. However, this effect is limited to the myocardial segments adjacent to the area of gene delivery. These data, therefore, demonstrate a spatial 'delivery-efficacy' mismatch with implications for myocardial gene delivery sites and detection of treatment effects in vivo.

Antioxidant and antiprotease status in peripheral blood and BAL fluid after cardiopulmonary bypass.

OBJECTIVE: Cardiopulmonary bypass (CPB) triggers systemic inflammation. Recent evidence suggests that metabolic and oxygenation management can affect the outcome of patients after cardiac surgery. We investigated the influence of oxidant/antioxidant and protease/antiprotease imbalance during the course of systemic and pulmonary inflammation. METHODS: In a study of 61 patients, we measured the intracellular thiol concentration, the intracellular activity of cathepsins and elastase, and the concentrations of secreted elastase, soluble alpha(1)-proteinase inhibitor (alpha(1)-PI), and secretory leukoprotease inhibitor (SLPI). Peripheral blood and BAL fluid (BALF) were obtained preoperatively and 2 h after CPB. RESULTS: A post-CPB depletion of thiol was found in blood granulocytes, lymphocytes, and monocytes, as well as BALF lymphocytes and macrophages. The degree of postoperative depletion correlated with PO(2) and blood glucose levels during CPB. Concomitant reduction of FEV(1) showed positive correlation with thiol depletion of blood monocytes and granulocytes. Elastase and cathepsin activities were increased in blood cells but not in lymphocytes or macrophages from BALF. The concentrations of secreted elastase were significantly increased in blood plasma but not in BALF. Enhanced antiprotease (alpha(1)-PI, SLPI) concentrations were measured in BALF but not in peripheral blood. CONCLUSIONS: The inflammatory response of the intra-alveolar compartment is clearly distinguishable from systemic inflammation. CPB causes a differentiated impairment of the antioxidant defense system as well as a protease/antiprotease imbalance in blood and BALF. Oxygenation under circumstances of CPB and concomitant pulmonary disease, as well as blood glucose metabolism, influence the antioxidative defense. Individual perioperative management of blood glucose and oxygenation could improve cellular defense systems in the peripheral blood and BALF and therefore result in a more favorable patient outcome.