Retroinfusion of NFkappaB decoy oligonucleotide extends cardioprotection achieved by CD18 inhibition in a preclinical study of myocardial ischemia and retroinfusion in pigs.

Myocardial reperfusion injury is partially mediated by postischemic inflammation. Beyond acute PMN recruitment, postischemic inflammation comprises subacute PMN adhesion, eg via NFkappaB activation. In a pig model of 60-min LAD occlusion by PTCA ballon inflation and 1 to 7 days of reperfusion, we investigated the impact of targeted NFkappaB decoy oligonucleotide (ODN) transfection in the area at risk (AAR) on infarct size and regional myocardial function. After 55 min of LAD occlusion, liposomes containing NFkappaB ODN were selectively retroinfused into the anterior interventricular vein for 5 min. Then, retroinfusion was stopped and reperfusion was initiated. Where indicated, CD18 antibody IB4 was infused systemically at 30 min of ischemia. Methylen blue and tetrazolium-red staining were used for quantification of the infarct size. Subendocardial segment shortening (SES) by sonomicrometric crystals in infarct area and AAR was assessed under pacing (expressed as % of control region). NFkappaB decoy ODN retroinfusion reduced infarct size (36 +/- 4% versus 49 +/- 5% in control hearts at day 7), whereas functional reserve of the AAR (SES 73 +/- 17% versus 46 +/- 18% at 180/min) tended to improve. Similar effects were observed after IB4 infusion (38 +/- 5% infarct size, 85 +/- 7% SES at 180/min). A combination of NFkappaB decoy ODN retroinfusion and IB4 infusion further decreased infarct size (26 +/- 2%) and improved functional reserve (SES 94 +/- 6% at 180/min). We conclude that NFkappaB decoy ODN transfection by retroinfusion is feasible in pig hearts and provides postischemic cardioprotection in addition to CD18 blockade.

Treatment of depression with methylphenidate in patients difficult to wean from mechanical ventilation in the intensive care unit.

BACKGROUND: Mechanical ventilation is often required to support patients in the intensive care unit (ICU) with life-threatening cardiovascular, respiratory, or neuromuscular disorders. Occasionally, difficulties related to weaning patients from this support occur owing to depression. The traditional and newer-generation antidepressant drugs have a relatively long latency of response that interferes with rehabilitation attempts in the ICU. Psychostimulants such as methylphenidate show a rapid onset of antidepressant activity and a benign side effect profile. METHOD: As consulting psychiatrists in the consultation-liaison service of a university hospital, we treated 7 patients with complex ICU courses presenting prolonged mechanical ventilation and psychomotor retardation associated with markedly depressed mood (DSM-IV criteria) by giving them methylphenidate. Methylphenidate was started on the first day at a dose of 2.5 mg p.o. in the morning and was increased by 2.5 mg each day with twice-a-day dosing in the morning and at noon until the patient responded or showed side effects. A maximum dose of 15 mg/day was not exceeded. Outcome evaluation was performed using the Clinical Global Impressions scale. RESULTS: Five (71 %) of 7 patients showed marked or moderate improvement in mood and activity within 3 to 4 days, and discontinuation of ventilator support was achieved within 8 to 14 days. Side effects with these 5 patients were not encountered. Of the remaining 2 patients (29%), 1 developed psychomotor agitation and anxiety within 4 days. Another patient showed only minimal improvement with regard to activity. CONCLUSION: Methylphenidate might be a rapidly effective and safe treatment for depression in difficult-to-wean patients hospitalized for life-threatening medical illness in the ICU. Implications for future research for this population of patients warrant formal randomized, prospective, clinical case-control evaluation.

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.

Preservation of regional myocardial function and myocardial oxygen tension during acute ischemia in pigs: comparison of selective synchronized suction and retroinfusion of coronary veins to synchronized coronary venous retroperfusion.

OBJECTIVES: The efficacy of selective synchronized suction and retroinfusion of coronary veins was compared with synchronized coronary venous retroperfusion in preventing ischemic reduction of regional myocardial function and myocardial oxygen tension. BACKGROUND: Because incomplete protection by synchronized coronary venous retroperfusion during ischemia might result from nonselective retroinfusion and only passive drainage of the veins, a suction device was added to a retroinfusion system. METHODS: Regional myocardial function (ultrasonic crystals) and myocardial oxygen tension (polarographic electrodes) were studied in 30 pigs during 10-min occlusion of the left anterior descending coronary artery (ischemia), followed by reperfusion. During ischemia, group A (n = 10) was supported by selective synchronized suction and retroinfusion; group B (n = 10) was supported by synchronized coronary venous retroperfusion, and group C (n = 10) was not supported by retroinfusion. RESULTS: In group A, subendocardial segment shortening decreased from 21 +/- 4% (mean +/- SD) before ischemia to 11 +/- 5% during ischemia. In contrast, systolic dyskinesia was observed in group B (-2 +/- 4%, p < 0.001) and group C (-2 +/- 5%, p < 0.001). During ischemia, the decrease in intramyocardial oxygen tension was less pronounced in group A (41 +/- 15 vs. 27 +/- 12 mm Hg) than in group B (40 +/- 10 vs. 19 +/- 10 mm Hg, p = 0.1) or group C (33 +/- 11 vs. 12 +/- 8 mm Hg, p = 0.002). During ischemia, myocardial surface oxygen tension was preserved > 0 mm Hg only in group A. CONCLUSIONS: Preservation of regional myocardial function and myocardial oxygen tension was substantially higher by selective synchronized suction and retroinfusion of coronary veins than by synchronized coronary venous retroperfusion in pigs.