SUMMARYThe study was undertaken to determine whether the phenomenon of endothelium-dependent relaxation was impaired in the spontaneously diabetic BB Wistar rat. Endothelium-dependent relaxation in the aorta of overtly diabetic animals was compared with that in nondiabetic BB rats. The relaxative responses were elicited in vitro to acetylcholine (-8.0 to -5 . 5 log M) and histamine ( -7 . 0 to -3 . 0 log M) after precontraction with norepinephrine ( -6 . 0 log M). The maximum relaxations produced by both acetylcholine and histamine expressed as percentages of the contractions to norepinephrine were significantly lower in diabetic than in nondiabetic rats. Scanning electron microscopy revealed that in diabetic BB rats there was consistent evidence of swollen cells, raised nuclei, and sloughing of nuclei in endothelial cells of the aorta. In nondiabetic animals these features were not evident. These findings suggest the presence of a functional and morphological defect in endothelial cells in the aorta of the BB rat. Diabetes 36:978-81,1987 T he spontaneously diabetic BB Wistar rat is widely recognized as a model for type I diabetes (1). Although there are many investigations relating to various biochemical abnormalities in these animals, there is hardly any information available about the properties of their blood vessels.Recently there has been considerable interest in the function of endothelial cells in blood vessels, particularly with respect to the phenomenon of endothelium-dependent relaxation (2-4). This relaxative response is believed to be mediated by a metabolite of arachidonic acid derived from the lipoxygenase pathway (2). This property of blood vessels has been shown previously to be impaired in atherosclerosis (4,5). Such findings have resulted in speculation that loss of this property could play a part in the pathogenesis of vascular spasm.In view of the possible link between atherosclerosis and diabetes mellitus (6), this study was conducted to examine the endothelium-dependent relaxation in the aorta of the BB rat. In addition, morphologic appearances of endothelial cells were examined by scanning electron microscopy of the aortas. MATERIALS AND METHODSThe experimental animals were obtained from an inbred colony of BB Wistar rats in its 23rd generation, maintained at the University of Alberta (7). Endothelium-dependent relaxation was studied in two groups of animals (n = 7 in each). The experimental group consisted of insulin-dependent animals with overt evidence of diabetes mellitus. Animals were diagnosed as diabetic on the basis of random blood glucose levels in >13.9 mM on 2 successive days, glycosuria, and weight loss (7). These animals were maintained on insulin according to the Department of Health and Welfare (Canada) guidelines. The control group consisted of BB Wistar rats that had no overt evidence of diabetes. On alternate days, all animals were weighed and the glycosuria monitored. The blood glucose was measured at weekly intervals.The animals were anesthetized with an injection of p...

Pericarditis has been noted as a potential complication of pacemaker implantation. This study evaluated the risk of developing pericarditis following pacemaker implantation with active-fixation atrial leads. Included were 1,021 consecutive patients (mean age 73.4+/-0.4 years, range 16-101 years; 45.2% women) undergoing new pacemaker system implantation between 1991 and 1999 who were reviewed for the complication of pericarditis. The incidence and outcomes of postimplantation pericarditis in patients receiving active-fixation atrial leads were compared to those not receiving these leads. Of 79 patients who received active-fixation atrial leads, 4 (5%) developed pericarditis postpacemaker implantation. Of 942 patients with passive-fixation atrial leads or no atrial lead (i.e., a ventricular lead only), none developed pericarditis postoperatively (P < 0.001). Of patients receiving active-fixation ventricular leads only (n = 97), none developed pericarditis. No complications were apparent at the time of implantation in patients who developed pericarditis. Pleuritic chest pain developed between 1 and 28 hours postoperatively. Three patients had pericardial rubs without clinical or echocardiographic evidence of tamponade. They were treated conservatively with acetylsalicylic acid or ibuprofen and their symptoms resolved without sequelae in 1-8 days. One patient (without pericardial rub) died due to cardiac tamponade on postoperative day 6. Postmortem examination revealed hemorrhagic pericarditis with no gross evidence of lead perforation. Pericarditis complicates pacemaker implantation in significantly more patients who receive active-fixation atrial leads. It may be precipitated byperforation of the atrial lead screw through the thin atrial wall. Patients developing postoperative pericarditis should befollowed closely due to the risk of cardiac tamponade.

The effect of feeding a diet supplemented with lipids and containing 2% cholesterol on the endothelium-dependent relaxation of rabbit aorta to acetylcholine was assessed. The effect of feeding a standard rabbit diet after an initial period of 2% cholesterol feeding was assessed also. Age-matched male, New Zealand white rabbits were fed either a 2% cholesterol diet or a standard rabbit diet. The animals were-anesthetized with pentobarbitone sodium (25 mg/kg) and killed either at the beginning of the study (0 weeks) or at 4, 8, or 10 weeks. The animals in the reversal study were fed the 2% cholesterol diet for 6 weeks and killed after an additional 14 and 32 weeks on standard diet. The extent of atherosclerosis in the aorta was assessed by Sudan Red staining, estimation of tissue cholesterol, and light and electron microscopy. The relaxation response to acetylcholine was measured in rings of the thoracic aorta following precontraction with norepinephrine ( -6.0 log mol/1). The relaxation was significantly impaired in aortas from rabbits fed the 2% cholesteroldiet compared to aortas from animals fed the standard diet. The impairment of relaxation was apparent as early as 4 weeks after the start of the 2% cholesterol diet and remained impaired over the next 6 weeks. No improvement in endothelium-dependent relaxation was seen in rabbits on the reversal diet for 14 and 32 weeks. Thus, endothelium-dependent relaxation is attenuated in animals fed a 2% cholesterol diet, and the loss of relaxation persists for at least 32 weeks after the animals are returned to a standard diet.

BACKGROUND Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk. OBJECTIVES In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels. METHODS ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was <70 mg/dL (median 69.4 mg/dL; interquartile range: 64.3–74.0 mg/dL); in 14,573 patients (77.0%), both determinations were ≥70 mg/dL (median 94.0 mg/dL; interquartile range: 83.2–111.0 mg/dL). RESULTS In the lower LDL-C subgroup, MACE rates were 4.2 and 3.1 per 100 patient-years among placebo-treated patients with baseline lipoprotein(a) greater than or less than or equal to the median (13.7 mg/dL). Corresponding adjusted treatment hazard ratios were 0.68 (95% confidence interval [Cl]: 0.52–0.90) and 1.11 (95% Cl: 0.83–1.49), with treatment-lipoprotein(a) interaction on MACE ( P interaction = 0.017). In the higher LDL-C subgroup, MACE rates were 4.7 and 3.8 per 100 patient-years among placebo-treated patients with lipoprotein(a) >13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% Cl: 0.72–0.92) and 0.89 (95% Cl: 0.75–1.06), with P interaction = 0.43. CONCLUSIONS In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402 )

Experiments were designed to assess the effect of cholesterol feeding on the endothelium-mediated relaxation of the rabbit aorta to acetylcholine. Age-matched male New Zealand white rabbits were fed either a 2% cholesterol diet or standard rabbit chow. The animals were anaesthetized with sodium pentobarbitone and sacrificed after 4 and 8 weeks on these diets. Rings were prepared from the proximal thoracic aorta and examined in tissue baths. These rings were contracted first with norepinephrine (-6 log mol/L) and acetylcholine was added to demonstrate the endothelium-mediated relaxation. The endothelium-dependent relaxation was significantly less in aortas from rabbits fed the 2% cholesterol diet than in aortas from animals fed the conventional diet. This impairment of relaxation was apparent after both 4 and 8 weeks of cholesterol feeding. In both groups of animals no relaxation was seen in rings from which the endothelium was removed. These results show that cholesterol feeding leads to an impairment of endothelium-mediated relaxation of the rabbit aorta to acetylcholine.