The novel antiarrhythmic drug dronedarone: comparison with amiodarone

Dronedarone is a noniodinated benzofuran derivative that has been developed to overcome the limiting iodine-associated adverse effects of the commonly used antiarrhythmic drug, amiodarone. It displays a wide cellular electrophysiological spectrum largely similar to amiodarone, inhibiting the potassium currents I(Kr), I(Ks), I(KI), I(KACh), and I(sus), as well as sodium currents and L-type calcium currents in isolated cardiomyocytes. In addition, dronedarone exhibits antiadrenergic properties. In vivo, dronedarone has been shown to be more effective than amiodarone in several arrhythmia models, particularly in preventing ischemia- and reperfusion-induced ventricular fibrillation and in reducing mortality. However, an increased incidence of torsades de pointes with dronedarone in dogs shows that possible proarrhythmic effects of dronedarone require further evaluation. The clinical trails DAFNE, EURIDIS, and ADONIS indicated safety, antiarrhythmic efficacy and low proarrhythmic potential of the drug in low-risk patients. In contrast, the increased incidence of death in the dronedarone group of the discontinued ANDROMEDA trial raises safety concerns for patients with congestive heart failure and moderate to severe left ventricular dysfunction. Dronedarone appears to be effective in preventing relapses of atrial fibrillation and atrial flutter. Torsades de pointes, the most severe adverse effect associated with amiodarone, has not yet been reported in humans with dronedarone. Unlike amiodarone, dronedarone had little effect on thyroid function and hormone levels in animal models and had no significant effects on human thyroid function in clinical trials. In conclusion, dronedarone could be a useful drug for prevention of atrial fibrillation and atrial flutter relapses in low-risk patients. However, further experimental studies and long-term clinical trials are required to provide additional evidence of efficacy and safety of dronedarone.     

Glycated collagen I induces premature senescence-like phenotypic changes in endothelial cells

Diabetic vasculopathy is central to the development of diverse cardiovascular, renal, retinal, and neurological complications of diabetes. We previously demonstrated that growth of endothelial cells on glycated extracellular matrix proteins (collagen and matrigel) results in a significant decrease in cell proliferation. In the present study, we show that early-passage human umbilical vein endothelial cells (HUVECs) grown on glycated collagen (GC) express hallmarks of premature cell senescence, ie, increase in the proportion of cells expressing senescence-associated beta-galactosidase activity, apoptotic rate, and p53 and p14(AFR) expression, but in contrast to replicative senescence, display neither attrition of telomeres nor decrease in telomerase activity. An increased frequency of prematurely senescent cells was similarly observed in vivo in aortae of young Zucker diabetic rats, compared with lean controls. NO production by HUVECs grown on GC was decreased, despite a 3-fold increase in eNOS expression and was associated with the increased nitrotyrosine-modified proteins. Development of premature senescence of HUVECs on GC could be prevented and reversed by treatments with the peroxynitrite scavenger, ebselen, eNOS intermediate N(omega)-hydroxy-L-arginine (NOHA), or superoxide dismutase mimetic Mn-TBAP. Concomitant with the reversal of senescence, ebselen, and NOHA each restored NO production to levels observed with HUVECs grown on unmodified collagen. Our findings indicate that diabetes mellitus in vivo and GC exposure in vitro elicit premature senescence of the vascular endothelium, a process with distinct pathogenetic mechanisms. Premature senescence of the vascular endothelium is hypothesized to be an important contributor to diabetic vasculopathy and a consequence of reduced NO availability, peroxynitrite, and/or superoxide excess.     

Psychosomatic interrelations following liver transplantation

It is well described that quality of life (QoL) improved after liver transplantation. The aim of the present study was to investigate how psychosocial parameters develop after liver transplantation (LTX) and whether post-operative complaints are the result of osteoporosis or patient somatization. The prospective study looks into biomedical and psychosocial parameters of 82 LTX patients before, 1 and 3 yrs after transplantation. Osteoporosis was measured by bone mineral density (BMD) and psychosocial parameters were assessed with validated questionnaires measuring complaints, mood and overall QoL. Overall QoL and mood improved after liver transplantation, while back and limb pain increased continuously. Back and limb pain were highly correlated with reduced bone density and high values for tiredness and depressive anxiety. Back and limb pain of patients following liver transplantation may indicate the development of a post-operative depression in some cases. The treatment offered by an essentially biologically based medicine may promote the manifestation of this depression as a somatization disorder.     

PPAR alpha activator fenofibrate inhibits myocardial inflammation and fibrosis in angiotensin II-infused rats

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)alpha is highly expressed in the heart. PPAR alpha may play a role in cardiac hypertrophy, but effects on cardiac function, inflammation, and fibrosis are unknown. We tested the hypothesis that the PPAR alpha activator fenofibrate prevents myocardial inflammation and fibrosis in angiotensin (Ang) II-infused rats. METHODS AND RESULTS: Sprague Dawley rats received Ang II (120 ng/kg/min subcutaneously), fenofibrate (100 mg/kg/d p.o.), or Ang II + fenofibrate. After 7 d, systolic blood pressure (mmHg) was elevated (P < 0.01) in Ang II-infused rats (173 +/- 4) vs. controls (115 +/- 2) and reduced by fenofibrate (137 +/- 5). Electrophoretic mobility shift assay demonstrated that Ang II upregulated cardiac nuclear factor kappa B activity by 50%. Ang II significantly increased cardiac expression of vascular-cell adhesion molecule-1, platelet endothelial cell adhesion molecule, and intercellular adhesion molecule-1. Increases in expression of these inflammatory mediators were normalized by fenofibrate. Ang II-induced expression of transforming growth factor-beta 1, collagen deposition, and macrophage infiltration were partially prevented by fenofibrate. CONCLUSIONS: The PPAR alpha activator fenofibrate prevented development of hypertension, and improved myocardial inflammation and collagen deposition in Ang II-infused rats. The hypolipidemic drug fenofibrate may be useful in prevention and treatment of myocardial disease associated with hypertension and hyperlipidemia.     

Single and tandem stents in sheep iliac arteries: Is there a difference in patency?

Purpose: To compare patency and neointima formation of single and tandem arterial stents. Methods: In each of six sheep, two Memotherm nitinol stents (tandem stents) were inserted into the external iliac artery on one side and a single stent into the artery on the opposite side. The size of the iliac lumen was assessed in the proximal, middle, and distal segments of the stents by intravascular ultrasound (IVUS) before, immediately after, and 1 month after implantation when the sheep were killed. Neointimal thickness was determined in the proximal, middle, and distal segments of each stent by light microscopy. Results: All stents remained patent. There was no significant difference in lumen and neointimal thickness between single and tandem stents. Cranial tandem stents showed a significantly wider lumen and smaller neointimal thickness than caudal tandem stents. In the proximal and distal segments, the lumen of the stents was significantly smaller and the neointimal thickness greater than in the middle segment; differences in neointimal thickness were significant only between the proximal and the middle segment. Conclusion: In an experimental setting, tandem stents did not interfere with one another with regard to patency and neointima formation when compared with a single contralateral stent. Neointimal thickening after stent insertion seems to be inversely related to the original arterial diameter.     

Percutaneous fragmentation of pulmonary emboli in dogs with the impeller-basket catheter

A new catheter system for rapid percutaneous fragmentation of pulmonary emboli was tested in nine dogs. The system consisted of a high-speed rotating impeller, placed within the center of a self-expandable basket. Preformed radiopaque emboli were introduced via the right external jugular vein. In nine tests in five dogs, a single embolus was launched after the right pulmonary artery had been balloon occluded and the impeller-basket catheter had been positioned into the left pulmonary artery, Seven of nine emboli were completely fragmented, each within less than 10 s. In two tests, performed in two different dogs, the catheter was positioned after complete embolization of the left pulmonary artery. In both cases, the central pulmonary arteries could be fully, and the segmental arteries partly, recanalized. Mobility of the system within the pulmonary arteries was limited. There was no evidence of wall damage at the rotation site of the impeller. Free serum hemoglobin did not increase after treatment. We conclude that the device can be safely operated in the left pulmonary artery system of dogs. It causes no significant hemolysis, and is able to accomplish rapid recanalization of the central arteries. Due to limited steerability, occluded side branches cannot be treated consistently.     

Iliocaval stenosis and iliac venous thrombosis in retroperitoneal fibrosis: Percutaneous treatment by use of hydrodynamic thrombectomy and stenting

A case of bilateral iliac stenosis and caval stenosis due to retroperitoneal fibrosis was treated by caval stenting and iliac balloon angioplasty, but was complicated by subsequent iliac thrombosis. Venous thrombectomy was successfully achieved by hydrodynamic thrombectomy, and iliac patency was stabilized by bilateral stent insertion.