Myocardial gene transfer by selective pressure-regulated retroinfusion of coronary veins.

Catheter-based percutaneous transluminal gene delivery (PTGD) into the coronary artery still falls behind the expectations of an efficient myocardial gene delivery system. In this study gene delivery was applied by selective pressure-regulated retroinfusion through the coronary veins to prolong adhesion of replication defective adenovirus within the targeted myocardium. Adenoviral vectors consisted either of luciferase (Ad.rsv-Luc) or beta-galactosidase (Ad.rsv-betaGal) reporter gene under control of an unspecific promotor derived from the Rous sarcoma virus (RSV). In this pig model, selective retrograde gene delivery into the anterior cardiac vein during a brief period of ischemia substantially increased reporter gene expression in the targeted myocardium (LAD region) compared with antegrade delivery as a control. Repeated retrograde delivery during two periods of brief ischemia resulted in a more homogeneous transmural expression predominantly observed in cardiomyocytes (X-gal-staining). In the nontargeted myocardium (CX region) there was no evidence for adenoviral transfection. From our data we infer that selective pressure-regulated retroinfusion is a promising approach for efficient percutaneous transluminal gene delivery to the myocardium. Gene Therapy (2000) 7, 232-240.

Selective pressure-regulated retroinfusion of coronary veins as an alternative access of ischemic myocardium: implications for myocardial protection, myocardial gene transfer and angiogenesis.

There is renewed interest in the coronary venous system as an alternative access to ischemic myocardium. Selective pressure-regulated retroinfusion is a catheter-based approach which has been shown to increase the efficacy of retrograde oxygen delivery and drugs in experimental and clinical studies. Selective pressure-regulated retroinfusion may also target retrograde delivery of angiogenic growth factors and gene vectors to ischemic myocardium.

Comparison of Pura-Vario and Palmaz-Schatz stents following implantation using normal and high pressure in pigs: immediate and late results assessed by 3-dimensional IVUS.

INTRODUCTION: The Pura-Vario stent features 2 newly designed "bridging segments" for enhanced longitudinal flexibility, in order to allow easier and safer stent implantation. METHODS: The aim of the present experimental investigation was to analyze the expansion characteristics of the Pura-Vario stent (PV), and to compare it with the Palmaz-Schatz stent (PS). Furthermore, stent implantation using "high pressure" (18 atm) (HP) was compared with "normal pressure" (12 atm) (NP). Stents (n = 16) were implanted into the left anterior descending artery (LAD) and the circumflex artery (CX) of 8 pigs. Stent area, lumen area and stent asymmetry were measured by means of three-dimensional intravascular ultrasound (3D-IVUS): (1) immediately after implantation, and (2) at 14-days follow-up. RESULTS: Stent expansion was found not to be uniform: the "bridging segments" were significantly larger than the "diamond segments" in either stent model at day 0; this difference, however, disappeared at 14-days follow-up. Despite higher flexibility of the Pura-Vario stent, no difference in stent expansion was found between both stent models, neither immediately after implantation (mean lumen area: 9.75 +/- 0.28 mm2 (PV) vs. 9.82 +/- 0.34 mm2 (PS)), nor at 14-days follow-up (7.44 +/- 0.16 mm2 (PV) vs. 7.45 +/- 0.22 mm2 (PS)). Pura-Vario stents, however, were less asymmetric in the cross-sectional view. Implantation using "high pressure" resulted in larger and less asymmetric stent expansion only at day 0 (lumen area: 9.54 +/- 0.39 mm2 (HP) vs. 8.77 +/- 0.33 mm2 (NP) (p < 0.05)); this difference, however, disappeared after 14 days due to higher stent recoil in the "high pressure" group. CONCLUSION: Despite higher flexibility of the Pura-Vario stent, expansion characteristics of both stent models were comparable. "High pressure" implantation compared favorably with "normal pressure" implantation only at day 0, whereas no difference could be found between both techniques at 14-days follow-up.

Selective suction and pressure-regulated retroinfusion: an effective and safe approach to retrograde protection against myocardial ischemia in patients undergoing normal and high risk percutaneous transluminal coronary angioplasty.

OBJECTIVES: We sought to study the safety, feasibility and efficacy of selective suction and pressure-regulated retroinfusion to protect against myocardial ischemia in patients undergoing normal risk and high risk balloon angioplasty. BACKGROUND: In a pig model of acute myocardial ischemia it was previously shown that use of selective suction and pressure-regulated retroinfusion was able to substantially preserve regional myocardial function during ischemia with a higher efficacy than that obtained with unselective synchronized retroperfusion. METHODS: In 42 patients with normal risk (n = 27) or high risk (n = 15) percutaneous transluminal coronary angioplasty (PTCA), alternate balloon inflations of the left anterior descending coronary artery (60 s) were either supported or not supported by selective suction and pressure-regulated retroinfusion of the anterior interventricular vein. In an additional group of 10 patients with normal risk, retroinfusion was directly compared with autoperfusion during 10 min of ischemia. RESULTS: Balloon inflations without retroinfusion resulted in a decrease of regional myocardial function in the ischemic zone to 13% of baseline. In contrast, regional myocardial function was preserved at 76% of baseline (p < 0.05) during balloon inflation supported by retroinfusion. This preservation of regional myocardial function by retroinfusion was maintained during 10 min of ischemia with at least similar efficacy compared with autoperfusion. With retroinfusion, hemodynamic variables were stabilized in normal risk and high risk patients. No complications related to the catheterization of the anterior interventricular vein using a femoral approach (95% success rate) were observed, and clinical follow-up after 3 to 6 months was uneventful with regard to the coronary intervention. CONCLUSIONS: Use of selective suction and pressure-regulated retroinfusion was feasible and safe and had a high efficacy for preserving regional myocardial function and hemodynamic variables during PTCA in normal risk and selected high risk patients.

Targeting of dobutamine to ischemic myocardium without systemic effects by selective suction and pressure-regulated retroinfusion.

OBJECTIVE: To study the effects of low-dose dobutamine and/or glyceryl trinitrate in addition to selective suction and pressure-regulated retroinfusion with arterial blood on regional myocardial function of the ischemic myocardium and systemic hemodynamics. METHODS: Using a pig model of repeated brief (90 s) occlusions of the left anterior descending artery, selective suction and pressure-regulated retroinfusion was carried out either with arterial blood alone (SSRalone) or with arterial blood and simultaneous application of low-dose dobutamine (0.1 microgram/kg/min (SSRDOB), glyceryl trinitrate (0.03 mg/kg/min) (SSRNIT) or the combination of both drugs (SSRDOB + NIT). Regional myocardial function of the ischemic and non-ischemic myocardium was determined by sonomicrometry (segment shortening). RESULTS: Segment shortening in the ischemic area after 90 s of ischemia was preserved at 57.5 +/- 9.2% with SSRalone but at 78.0 +/- 22.3% of baseline with SSRDOB (P < 0.05). The addition of glyceryl trinitrate did not improve regional myocardial function further. No effects of locally applied dobutamine were observed with regard to non-ischemic myocardium or heart rate. Cardiac output and mean arterial blood pressures tended to be further stabilized with SSRDOB. CONCLUSIONS: Local application of low-dose dobutamine together with arterial blood by selective suction and pressure-regulated retroinfusion during brief myocardial ischemia resulted in improved regional myocardial function without undesired effects on non-ischemic myocardium or systemic hemodynamics.

Subchronic exposure of cardiomyocytes to low concentrations of tumor necrosis factor alpha attenuates the positive inotropic response not only to catecholamines but also to cardiac glycosides and high calcium concentrations.

The main purpose of this study was to determine the subchronic effects of low concentrations of tumor necrosis factor alpha (TNF alpha) on the inotropic response and on the cellular level of high energy phosphates of cardiomyocytes. Therefore, the inotropic response of cultured neonatal rat heart cells to 10(-5) M isoproterenol-, 10(-6) M ouabain-, 10(-5) M forskolin- and 2,4 mM calcium-perfusion was studied 24 h after exposure to TNF alpha (0.01/0.1/1/10/100 U/ml). In parallel experiments high energy phosphates (CP, ATP, ADP, AMP) were determined by high performance liquid chromatography. Furthermore, the reversibility of TNF alpha-induced changes was studied after washout of TNF alpha or after administration of anti-TNF alpha-antibody. Whereas control cells showed an increase of cell wall motion to 150 +/- 5% of baseline value during 10(-5) M isoproterenol-perfusion respectively 180 +/- 7% during 2,4 mM calcium-perfusion, 24 h exposure of the cells to 1 U/ml up to 100 U/ml TNF alpha resulted in an inhibition of the inotropic response. Almost complete inhibition was observed 12 h after exposure to TNF alpha and was reversible 12 h after administration of the anti-TNF alpha-antibody. If the cells were perfused with 10(-6) M ouabain or 10(-5) M forskolin, a similar inhibition of the inotropic response was observed 24 h after TNF alpha-exposure. Determination of high energy phosphates showed that 24 h TNF alpha-exposure resulted in a reversible decrease of ATP, ADP, AMP and CP by 30-40% (p < 0.05). However, a similar reduction of cellular high energy phosphate levels using a TNF alpha independent mechanism (2,5 mM 2-deoxy-D-glucose) did not inhibit the inotropic response of the cardiomyocytes. From our results we conclude that subchronic exposure to low concentrations of TNF alpha resulted in an almost complete but reversible inhibition of the response of cardiomyocytes to different inotropic agents suggesting that a common final step of the inotropic cascade might be altered by TNF alpha. Though energy metabolism of TNF alpha exposed cells was affected also, reduction of high energy phosphate levels alone did not explain the observed inhibition of the inotropic response of the cardiomyocytes.