Phillip F. Heller

Paclitaxel Stent Coating Inhibits Neointimal Hyperplasia at 4 Weeks in a Porcine Model of Coronary Restenosis

BackgroundDespite limiting elastic recoil and late vascular remodeling after angioplasty, coronary stents remain vulnerable to restenosis, caused primarily by neointimal hyperplasia. Paclitaxel, a microtubule-stabilizing drug, has been shown to inhibit vascular smooth muscle cell migration and proliferation contributing to neointimal hyperplasia. We tested whether paclitaxel-coated coronary stents are effective at preventing neointimal proliferation in a porcine model of restenosis. Methods and ResultsPalmaz-Schatz stents were dip-coated with paclitaxel (0, 0.2, 15, or 187 &mgr;g/stent) by immersion in ethanolic paclitaxel and evaporation of the solvent. Stents were deployed with mild oversizing in the left anterior descending coronary artery (LAD) of 41 minipigs. The treatment effect was assessed 4 weeks after stent implantation. The angiographic late loss index (mean luminal diameter) decreased with increasing paclitaxel dose (P <0.0028 by ANOVA), declining by 84.3% (from 0.352 to 0.055, P <0.05) at the highest level tested (187 &mgr;g/stent versus control). Accompanying this change, the neointimal area decreased (by 39.5%, high-dose versus control;P <0.05) with increasing dose (P <0.040 by ANOVA), whereas the luminal area increased (by 90.4%, high-dose versus control;P <0.05) with escalating dose (P <0.0004 by ANOVA). Inflammatory cells were seen infrequently, and there were no cases of aneurysm or thrombosis. ConclusionsPaclitaxel-coated coronary stents produced a significant dose-dependent inhibition of neointimal hyperplasia and luminal encroachment in the pig LAD 28 days after implantation; later effects require further study. These results demonstrate the potential therapeutic benefit of paclitaxel-coated coronary stents in the prevention and treatment of human coronary restenosis.

Beneficial Effects of Chronic Pharmacological Manipulation of β-Adrenoreceptor Subtype Signaling in Rodent Dilated Ischemic Cardiomyopathy

Background—Studies in isolated cardiac myocytes have demonstrated that signaling via specific &bgr;1-adrenergic receptor subtypes (&bgr;1ARs) promotes but that signaling via &bgr;2ARs protects from cell death. We hypothesized that prolonged &bgr;2AR stimulation or &bgr;1AR blockade would each protect myocytes from death and thereby ameliorate cardiac remodeling in chronic heart failure. Methods and Results—A large myocardial infarction (MI) induced in rats by coronary artery ligation resulted in a dilated cardiomyopathy (DCM) characterized by infarct expansion and a progressive increase in left ventricular (LV) end-diastolic volume, accompanied by a reduction in ejection fraction (EF), as assessed by repeated echocardiography. Pressure-volume analysis at 8 weeks after ligation showed that diastolic stiffness (Eed) and arterial elastance (Ea) were increased, end-systolic elastance (Ees) was decreased, and arterioventricular (AV) coupling (Ea/Ees) had deteriorated. Apoptosis was present in both peri-infarct and remote myocardium. Chronic (6-week) administration of the &bgr;2AR agonists fenoterol or zinterol, starting at 2 weeks after MI, reduced the extent of LV dilation, infarct expansion, and EF decline. The &bgr;1AR blocker metoprolol did not affect the former and preserved EF to a lesser extent than did the &bgr;2AR agonists. At 8 weeks after ligation, apoptosis was reduced by all drugs but to a greater extent by &bgr;2AR agonists than by the &bgr;1AR blocker. Both &bgr;2AR agonists and the &bgr;1AR blocker improved AV coupling, the former mainly by reducing Ea and the latter mainly by increasing Ees. Only the &bgr;2AR agonists reduced the Eed and the MI size by reducing infarct expansion. Conclusions—These results provide proof of concept for the efficacy of chronic &bgr;2AR stimulation in this DCM model.

Na + /H + exchanger: proton modifier site regulation of activity

The Na+/H+ exchangers (NHE1-6) are integral plasma membrane proteins that catalyze the exchange of extracellular Na+ for intracellular H+. In addition to Na+ and H+ transport sites, NHE has an intracellular allosteric H+ modifier site that increases exchange activity when occupied by H+. NHE activity is also subject to control by a variety of extrinsic factors including hormones, growth factors, cytokines, and pharmacological agents. Many of these factors, working through second messenger pathways acting directly or indirectly on NHE, regulate NHE activity by shifting the apparent affinity of the H+ modifier site to more alkaline or more acid pH. The underlying molecular mechanisms involved in the activation of NHE by the H+ modifier site are poorly understood at this time, but likely involve slow protein conformational changes within a NHE oligomer. In this paper, we present initial experiments measuring intracellular pH-dependent transition rates between active and inactive oligomeric conformations and describe how these transition rates may be important for overall regulation of NHE activity.

Paclitaxel and Arterial Smooth Muscle Cell Proliferation

To the Editor: I have recently completed reading “Paclitaxel Inhibits Arterial Smooth Muscle Cell Proliferation and Migration In Vitro and In Vivo Using Local Drug Delivery,” published in the July 15, 1997, issue of Circulation. My questions concerning this study are related to the claimed statistical significance of the in vivo data. According to the published methodology, the data were …

Modulation of CCAAT/Enhancer-Binding Protein-α Gene Expression by Metabolic Signals in Rodent Adipocytes

The transcription factor CCAAT/enhancer-binding protein-α (C/EBPα) is a positive modulator of transcription for several adipocyte-specific genes that play a role in energy metabolism. However, there is little information available regarding the regulation of its expression by metabolic signals. Exposure to insulin for 5–24 h attenuated C/EBPα expression when 3T3-L1 adipocytes were incubated in 24 mm glucose, but not in 5.7 mm glucose. Nuclear run-on transcription assays indicated a transcriptional repression of C/EBPα gene, but not that of C/EBPβ. Glucosamine, a product of the hexosamine pathway, in the presence of low glucose mimicked high glucose’s ability to reduce C/EBPα messenger RNA expression in insulin-treated cells. Similar results were obtained with xylitol, an activator of the pentose phosphate pathway. There was no correlation between the accumulation of hexosamine pathway metabolites (e.g. UDP-N-acetylhexosamines) and/or changes in intracellular protein glycosylation with the ability of high ...

The Sustained Release of Galardin and Taxol from Gelatin Chondroitin Sulfate Coacervate Films

Coronary artery atherosclerosis is the leading cause of death in the United States. Restenosis following percutaneous transluminal balloon angioplasty (PTCA) remains the limiting factor in the use of this treatment for coronary artery disease. Restenosis occurs in 30% of patients within 6 months. The restenotic lesion is a fibroproliferative response with resulting smooth muscle cell migration, proliferation and extracellular matrix production. Despite a decade of research there is no effective strategy for preventing restenosis in man.

KINETICS OF ACCUMULATION OF THE ADP-SENSITIVE AND ADP-INSENSITIVE PHOSPHOENZYMES AND THEIR RELATIONSHIP TO Ca2+ TRANSLOCATION IN SARCOPLASMIC RETICULUM

Publisher Summary The decomposition of the phosphoenzyme resulting from the addition of adenosine diphosphate (ADP) can be resolved into rapid and slow phases corresponding to the ADP-sensitive (EP) and ADP insensitive (E*P) phosphoenzymes, respectively. The distribution of ADP-sensitive and ADP-insensitive phosphoenzymes is approximately 1:1 in the steady state. This ratio is rapidly achieved following phosphorylation with ATP. The decomposition of the ADP-insensitive phosphoenzyme liberates a less-than-stoichiometric amount of Pi. This discrepancy is observed in ionophore-treated vesicles at short reaction times and becomes more pronounced when the external Ca2+ concentration is raised during dephosphorylation. The simultaneous addition of ADP and high (millimolar) Ca2+ activates the breakdown of the ADP-insensitive phosphoenzyme in the direction of the ADP-sensitive form. The site involved in this effect faces the extra-vesicular surface and has a low affinity for Ca2+ and has a Hill coefficient greater than 1 (n = 1.73). The accumulation of intra-vesicular Ca2+ in the presteady state occurs at a slower rate than the formation of the Ca2+ jump-sensitive, ADP-insensitive phosphoenzyme.