Activation of Peroxisome Proliferator-Activated Receptor-δ as Novel Therapeutic Strategy to Prevent In-Stent Restenosis and Stent Thrombosis.

OBJECTIVE: Drug-eluting coronary stents reduce restenosis rate and late lumen loss compared with bare-metal stents; however, drug-eluting coronary stents may delay vascular healing and increase late stent thrombosis. The peroxisome proliferator-activated receptor-delta (PPARδ) exhibits actions that could favorably influence outcomes after drug-eluting coronary stents placement. APPROACH AND RESULTS: Here, we report that PPARδ ligand-coated stents strongly reduce the development of neointima and luminal narrowing in a rabbit model of experimental atherosclerosis. Inhibition of inflammatory gene expression and vascular smooth muscle cell (VSMC) proliferation and migration, prevention of thrombocyte activation and aggregation, and proproliferative effects on endothelial cells were identified as key mechanisms for the prevention of restenosis. Using normal and PPARδ-depleted VSMCs, we show that the observed effects of PPARδ ligand GW0742 on VSMCs and thrombocytes are PPARδ receptor dependent. PPARδ ligand treatment induces expression of pyruvate dehydrogenase kinase isozyme 4 and downregulates the glucose transporter 1 in VSMCs, thus impairing the ability of VSMCs to provide the increased energy demands required for growth factor-stimulated proliferation and migration. CONCLUSIONS: In contrast to commonly used drugs for stent coating, PPARδ ligands not only inhibit inflammatory response and proliferation of VSMCs but also prevent thrombocyte activation and support vessel re-endothelialization. Thus, pharmacological PPARδ activation could be a promising novel strategy to improve drug-eluting coronary stents outcomes.

Influence of ventricular pacing on myocardial oxygen tension.

INTRODUCTION: The influence of heart rate on cardiac output, oxygen consumption, and myocardial activity has been widely investigated. However, the influence of heart rate on myocardial oxygen tension (pO2) remains unclear. Since the introduction of flexible pO2 micro catheters to measure partial oxygen tension in a working muscle, it is possible to investigate the influence of heart rate on myocardial oxygen tension. METHODS: Intraoperatively, a flexible pO2 micro catheter was positioned in the mid-myocardium of 8 male farm pigs. The heart rate was varied via an external pacer from base rate up to fibrillation and the corresponding myocardial pO2 was measured. RESULTS: Within 2 min, the myocardial pO2 adjusted to a change in heart rate. In this animal model, an optimal myocardial pO2 was observed at 109 bpm. A further increase in heart rate led to a decrease in myocardial pO2. When the heart rate was reaching the level of a fibrillation, pO2 dropped to zero. CONCLUSION: In young healthy pigs--with a normal blood vessel regulation and the pharmacologic and experimental conditions used in this study--a significant relation between myocardial pO2 and heart rate was observed. Myocardial oxygen tension increased during cardiac pacing until a heart rate of 109 bpm. Thereafter a decline of pO2 occurred. Each change in heart rate resulted in a corresponding change of pO2 within roughly 2 min.

Interaction between a perfluorocarbon emulsion and radiographic contrast media.

This study evaluated specially designed perfluorocarbon (PFC) emulsions as blood substitutes in case of induced ischemia of the left heart ventricle in healthy farm pigs. Two hundred ml of perfluorocarbon emulsion were infused while 200 ml of blood were simultaneously drawn. Radiographic contrast media were given to aid placement of balloon catheters in the left coronary artery. Histopathological analysis showed that right heart failure caused the deaths of both pigs. Particles (up to>3 micro) of foreign body materials obstructed capillaries of all organs analyzed (heart, lung, liver, kidneys and spleen). Laboratory investigation showed severe interference between the PFC emulsion and radiographic contrast media, resulting in the deterioration of the PFC emulsion. The strongest interference occurred when PFC emulsion and Accupaque interacted; particle size started at an initial 311 nm and went up to >3 micro within seconds. Great care must be taken when PFC emulsions are used in combination with x-ray contrast media. None of the described radiographic contrast media should be used within 48 hours prior to the use of this PFC emulsion. Also, the use of these contrast media should be avoided for a certain period of time after using PFC emulsion. The mechanisms of elimination of PFC emulsions from the circulation are not completely understood and has yet to be evaluated.