Ovariectomy increases vascular calcification via the OPG/RANKL cytokine signalling pathway.

BACKGROUND: Observational studies suggest a strong relationship between menopause and vascular calcification. Receptor activator of nuclear factor-kappaBeta ligand (RANKL) and osteoprotegerin (OPG) are critical regulators of bone remodelling and modulate vascular calcification. We assessed the hypothesis that ovariectomy increases vascular calcification via the OPG/RANKL axis. MATERIALS AND METHODS: Age-matched sexually mature rabbits were randomized to ovariectomy (OVX, n = 12) or sham procedure (SHAM, n = 12). One month post-procedure, atherosclerosis was induced by 15 months 0.2%-cholesterol diet and endothelial balloon denudations (at months 1 and 3). Aortic atherosclerosis was assessed in vivo by magnetic resonance imaging (MRI) at months 9 and 15. At sacrifice, aortas were harvested for ex vivo microcomputed tomography (microCT) and molecular analysis of the vascular tissue. RESULTS: Vascular calcification density and calcific particle number were significantly greater in OVX than SHAM (8.4 +/- 2.8 vs. 1.9 +/- 0.6 mg cm(-3), P = 0.042, and 94 +/- 26 vs. 33 +/- 7 particles cm(-3), P = 0.046, respectively). Calcification morphology, as assessed by the arc angle subtended by the largest calcific particle, showed no difference between groups (OVX 33 +/- 7 degrees vs. SHAM 33 +/- 5 degrees , P = 0.99). By Western blot analysis, OVX increased the vascular OPG:RANKL ratio by 66%, P = 0.029, primarily by decreasing RANKL (P = 0.019). At month 9, MRI demonstrated no difference in atheroma volume between OVX and SHAM, and no significant change was seen by the end of the study. CONCLUSIONS: In contrast to bone, vascular OPG:RANKL ratio increased in response to ovariectomy with a corresponding fourfold increase in arterial calcification. This diametrical organ-specific response may explain the comorbid association of osteoporosis with calcifying atherosclerosis in post-menopausal women.

The role of high-density lipoprotein cholesterol in the prevention and possible treatment of cardiovascular diseases.

Despite significant progress in the management of atherosclerosis and its resultant complications, cardiovascular disease remains the principal cause of death in the world. The National Cholesterol Education Project Adult Treatment Panel III (NCEP ATP III) recognizes low levels of high-density lipoprotein cholesterol (HDL) as a risk factor for coronary heart disease (CHD) and high levels of HDL as a risk-reducing factor; however, the elevation of HDL as a specific therapeutic target for the prevention and treatment of CHD has yet to be accepted on the same level as low-density lipoprotein (LDL)-reducing therapies. Current HDL elevators including nicotinic acid, fibric acid derivatives, peroxisome proliferator activated receptor (PPAR) agonists and statins also affect other lipid constituents which make interpretation of the clinical trials of these drugs difficult in teasing out the independent effect of HDL elevation. Ample laboratory investigation suggests that HDL elevation would reduce atherosclerotic burden through multiple independent mechanisms. In this review, we explore HDL biology, its potential mechanisms in the treatment of atherosclerotic disease, and promising new drugs with HDL-raising activity.

Excimer laser (308 nm) recanalisation of in-stent restenosis: thermal considerations.

Excimer laser recanalisation of in-stent restenosis may be a viable modality for improving coronary patency. However, the presence of arterial stents modifies the thermal properties of the irradiated area and may alter temperature patterns generated during ablation. The goal of this study was to evaluate, in vitro, temperature changes during excimer laser ablation of stented vessels and compare them with those obtained from unstented (control) vessels. Six different stent types (AVE Microstent-II, AVE-GFX, ACS Multi-link, JJ Palmaz-Schatz, JJ Crown, and NIR) were deployed in freshly excised porcine coronary vessels. Three control unstented samples were also measured. Blood or saline was infused through the vessels, while the tissue environment was kept at approximately 37 degrees C. A 308 nm excimer laser (Spectranetics, CVX300) with an eccentric 2.0 mm laser catheter (Spectranetics, EII) delivered two trains of 200 pulses each, 10 s apart, at 60 mJ/mm2, and 40 Hz, simulating maximum clinical exposure. The catheter was positioned midway in the stent, first coaxially parallel to the vessel wall, and then at an angle against the stent and vessel wall. Temperature measurements (n= 168 for blood, n=96 for saline) were performed with a approximately 210 microm diameter, fast-response thermocouple with 0.1 degrees C resolution. The probe was positioned to within approximately 250 microm from the inner surface of the vessels. Tissue temperature was measured at the catheter tip and at the distal and proximal edges of the stents. Maximum recorded temperatures for coaxial and angular alignment, did not exceed 42.2 degrees C (approximately 6 degrees C above baseline) and 54.2 degrees C (approximately 18.1 degrees C above baseline) respectively, for all stents types tested, controls, and all probe locations. Both stented and unstented vessels exhibited comparable temperature gradients. The observed maximum temperatures, obtained under extreme lasing conditions, indicated that 308 nm ablation, in the presence of stents under blood or saline infusion, produces clinically acceptable temperatures.