TP508 (Chrysalin) reverses endothelial dysfunction and increases perfusion and myocardial function in hearts with chronic ischemia.

Endothelial dysfunction (ED) is characterized by impaired nitric oxide (NO) signaling, decreased NO-dependent vasodilatation, increased vascular inflammation, and diminished response to angiogenic factors. TP508 (Chrysalin), an angiogenic tissue repair peptide, was tested for potential effects on myocardial revascularization and ED using a porcine model of chronic myocardial ischemia. TP508 increased perfusion in ischemic regions up to16-fold (P < .02) and doubled myocardial wall thickening (P < .02) relative to placebo controls. Ischemic arterioles exhibited impaired NO-mediated vasodilation and diminished NO production. TP508 reversed ischemic effects, increasing NO-mediated vasodilation (P < .05), endothelial nitric oxide synthase (eNOS) expression, and NO production. In human endothelial cells, TP508 stimulated eNOS activation (1.84 +/- 0.2-fold; P < .02), increased NO production (85 +/- 18%; P < .02), and prevented hypoxia-induced eNOS downregulation (P < .01). Thus, TP508 reverses ED both in porcine ischemic hearts and cultured human endothelial cells. These results suggest potential therapeutic benefit of TP508 in myocardial revascularization and treatment of ED-related diseases.

Thoracic duct ligation and pericardectomy for treatment of idiopathic chylothorax.

Chylothorax is a devastating disease, and the success rates from either medical or surgical management are less than satisfactory. In some animals with chylothorax, a thickening of the pericardium occurs that is associated with chronic irritation induced by chyle. We hypothesized that pericardial thickening would lead to increased right-sided venous pressures and that abnormal venous pressures would act to impede the drainage of chyle via lymphaticovenous communications after thoracic duct (TD) ligation. We also hypothesized that serosanguineous effusions that occurred after TD ligation could effectively be treated or prevented by pericardectomy in affected animals. TD ligation plus pericardectomy was performed in 17 animals, and pericardectomy alone was performed in an additional 3 animals that presented during a 5.5-year period to the Texas A&M University (College Station, TX). Nineteen animals presented for an evaluation of idiopathic chylothorax (9 dogs and 10 cats), and 1 dog presented for serosanguineous pleural fluid after TD ligation that had been performed elsewhere. Echocardiography was normal in all animals, except for a subjectively thickened pericardium in 7 cats and 6 dogs. Clinical signs of pleural fluid accumulation resolved in 10 of 10 dogs and in 8 of 10 cats after surgery. The overall success rate for the surgical treatment of chylothorax (ie, the resolution of pleural fluid accumulation) in this study was 90% (100% in dogs and 80% in cats). These data suggest that TD ligation in conjunction with pericardectomy has a favorable outcome in animals with idiopathic chylothorax.

A novel aortic coarctation model for studying hypertension in the pig.

We have developed a reproducible renovascular model of hypertension via a controllable, suprarenal aortic coarctation in the pig. This model has many potential applications, including investigation of the effects of acute hypertension in the conscious animal; identification of cardiac and vascular adaptations to chronic hypertension and their reversal; determining the effect of pharmacologic agents or other interventions on hypertension; and furthering our understanding of the implications of chronic hypertension on neurologic function. A totally implantable system was devised by attaching a reinforced silicone vascular occluder to a vascular access port. The occluder was placed around the suprarenal aorta proximal to the diaphragm. Ten pigs were made hypertensive by sequentially inflating the occluder. In six pigs, telemetric monitoring of blood pressure was used to determine when the pigs had reached target pressures (mean arterial blood pressure >150 mm Hg). Four pigs did not have telemetry units placed and blood pressure and heart rate were monitored for 4 weeks by periodically restraining the pigs in a sling. Two pigs reversed their occlusion due to presumed technical errors; the remaining pigs were studied for 4 (n = 5) or 8 (n = 3) weeks and then euthanized. Advantages of this model of aortic coarctation are that the occlusions are performed in awake animals and excessive occlusion of the aorta resulting in neurologic dysfunction or other distress to the animal can be easily corrected by simply withdrawing a small amount of the fluid used for inflation of the occluder. Additionally, removal of the constriction does not require a second surgical procedure.