Background Diet and exercise promote cardiovascular health but their relative contributions to atherosclerosis are not fully known. The transition from a sedentary to active lifestyle requires increased caloric intake to achieve energy balance. Using atherosclerosis-prone ApoE-null mice we sought to determine whether the benefits of exercise for arterial disease are dependent on the food source of the additional calories. Methods and Results Mice were fed a high-fat diet (HF) for 4.5 months to initiate atherosclerosis after which time half were continued on HF while the other half were switched to a high protein/fish oil diet (HP). Half of each group underwent voluntary running. Food intake, running distance, body weight, lipids, inflammation markers, and atherosclerotic plaque were quantified. Two-way ANOVA tests were used to assess differences and interactions between groups. Exercised mice ran approximately 6-km per day with no difference between groups. Both groups increased food intake during exercise and there was a significant main effect of exercise F((1,44) = 9.86, p<0.01) without interaction. Diet or exercise produced significant independent effects on body weight (diet: F(1,52) = 6.85, p = 0.012; exercise: F(1,52) = 9.52, p<0.01) with no significant interaction. The combination of HP diet and exercise produced a greater decrease in total cholesterol (F(1, 46) = 7.9, p<0.01) and LDL (F(1, 46) = 7.33, p<0.01) with a large effect on the size of the interaction. HP diet and exercise independently reduced TGL and VLDL (p<0.05 and 0.001 respectively). Interleukin 6 and C-reactive protein were highest in the HF-sedentary group and were significantly reduced by exercise only in this group. Plaque accumulation in the aortic arch, a marker of cardiovascular events was reduced by the HP diet and the effect was significantly potentiated by exercise only in this group resulting in significant plaque regression (F1, 49 = 4.77, p<0.05). Conclusion In this model exercise is beneficial to combat dyslipidemia and protect from atherosclerosis only when combined with diet.
Visceral adipose tissue (VAT) is a source of inflammatory cytokines that in obese subjects may contribute to low-level systemic inflammation and development of metabolic syndrome. Expansion of VAT involves adipocyte hyperplasia and hypertrophy and requires breakdown of the extracellular matrix and increased vascular outgrowth. To investigate changes of gene expression associated with VAT expansion and the role of combined genetics and diet, we implemented gene microarray analyses of VAT in NONcNZO10 (NZ10) and control SWR/J mice subjected to control chow (CD) or a diet of high protein and fish oil (HPO). NZ10 mice on CD showed increased body weight, hyperglycemia, and hyperinsulinemia at 25 weeks whereas those on HPO diet retained normal insulin levels and were normoglycemic. Two-way ANOVA revealed a significant interaction between diet and strain on blood glucose, serum insulin, and percent fat but not for body weight. Microarray heat maps revealed a remarkable combined effect of genetics and diet on genes that regulate extracellular matrix as well as angiogenic genes. Real time-PCR (RT-PCR) confirmed markedly increased expression of matrix metalloproteinases (MMPs) 2, 3, 11, and 12, vascular endothelial growth factor-A and C (VEGF-A and C), Von Willebrand Factor, and peroxisome proliferator-activated receptor-γ (PPAR-γ) selectively in the NZ10/CD group. MMP7 was significantly decreased. Protein levels of MMP2, 3, and 9 were significantly increased in the VA of NZ10 mice fed CD while those of MMP7 were downregulated. Microarrays also revealed diet-dependent two to fourfold increased expression of all four tissue inhibitor of metalloproteinases (TIMP) isoforms in NZ10 mice. Two-way ANOVA confirmed strongly interactive roles of diet and genetics on fat deposition and progression of type 2 diabetes in this polygenic mouse model.
Past clinical and experimental evidence suggests that cerebral aneurysms can be successfully excluded from the circulation solely by the endovascular placement of a flow diverting device across the aneurysm neck. These devices promote intraaneurysmal flow stasis and concomitant thrombosis by redirecting flow away from the aneurysm. To comprehensively test the efficacy of such flow divertors, we are implanting devices with three different porosities in a large cohort of elastase-induced aneurysms in rabbits. Treatment efficacy is quantified by a mathematical model that is fit to aneurysmal angiographic contrast washout curves. Results from three animals implanted with different device porosities are presented here. The model competently captures the behavior of the aneurysmal washout curves and provides reliable indices of device efficacy. Preliminary analysis indicates that immediately after implantation, the device with medium porosity performs better than the devices with lower and higher porosities.
Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Although treatment options for AF exist, many patients cannot be maintained in normal sinus rhythm. Amiodarone is an effective medication for AF but has limited clinical utility because of off-target tissue toxicity. Methods: Here, we use a pig model of AF to test the efficacy of an amiodarone-containing polyethylene glycol–based hydrogel. The gel is placed directly on the atrial epicardium through the pericardial space in a minimally invasive procedure using a specially designed catheter. RESULTS: Implantation of amiodarone-containing gel significantly reduced the duration of sustained AF at 21 and 28 days; inducibility of AF was reduced 14 and 21 days post-delivery. Off-target organ drug levels in the liver, lungs, thyroid, and fat were significantly reduced in animals treated with epicardial amiodarone gel compared with systemic controls in small-animal distribution studies. Conclusions: The pericardium is an underutilized therapeutic site and may be a new treatment strategy for AF and other cardiovascular diseases.
Past clinical and experimental evidence suggests that cerebral aneurysms can be successfully excluded from the circulation solely by the endovascular placement of a flow diverting device across the aneurysm neck. These devices promote intraaneurysmal flow stasis and concomitant thrombosis by redirecting flow away from the aneurysm. To comprehensively test the efficacy of such flow divertors, we are implanting devices with three different porosities in a large cohort of elastase-induced aneurysms in rabbits. Treatment efficacy is quantified by a mathematical model that is fit to aneurysmal angiographic contrast washout curves. Results from three animals implanted with different device porosities are presented here. The model competently captures the behavior of the aneurysmal washout curves and provides reliable indices of device efficacy. Preliminary analysis indicates that immediately after implantation, the device with medium porosity performs better than the devices with lower and higher porosities.
Our goal was to establish a contrast injection technique that uses the unique vascular anatomy of the rabbit ear to spare the valuable femoral artery access sites. The central artery of the left ear was cannulated. Contrast injected in a retrograde fashion opacified the right brachiocephalic artery and its branches. The technique can be used in rabbits with the usual bovine-type left common carotid artery origin.
Purpose: Angiographic contrast that is routinely injected into arteries is used not only to evaluate arterial geometry but also in many cases to assess perfusion. The authors conducted two experiments to examine the dispersion of angiographic contrast injected antegradely into an artery under conditions similar to those found in selective (carotid artery) or superselective (circle of Willis) angiography in order to determine the distance from the catheter tip at which the contrast can be considered fully mixed with the blood. A third experiment investigated whether the contrast once mixed with blood will separate from the mixture under the gravitational field due to a density mismatch. Methods: Experiment I—Under high‐speed angiographic acquisition, a bolus of contrast was injected through a catheter along the flow direction of a blood analog fluid flowing through a straight, long, cylindrical tube. The variation in grayscale intensity along the length of the tube was acquired and modeled as the step response to a second‐order system. The distance from the catheter tip at which the contrast mixes with the working fluid, the mixing length, was determined as the length along the tube after which the step response settles to within 3% of the steady state value. Experiment II—A bolus of angiographic contrast was injected at rates varying from 0.1 to 1 cc/s through three different catheter sizes in the left common carotid artery of three rabbits. The average cross‐sectional grayscale intensity over one cardiac cycle was calculated at four locations along the artery: Immediately distal to the catheter tip, at location of maximum grayscale intensity, and at 10 and 20 arterial diameters from the catheter tip. The status of mixing within 10 arterial diameters was assessed by differences between the grayscale value at this location and that at the maximum and 20 arterial diameter location. Experiment III—Angiographic contrast was premixed by agitation in three separate vials containing normal saline, canine blood, and glycerol/distilled‐water mixture. The vials were then stationed vertically and angiographic images obtained every 5 min for 1 h. The average intensity of contrast along the vertical length of each vial was obtained for every time point to record any changes in the distribution of contrast over time. Results: The first experiment shows that angiographic contrast completely mixes with steady flowing blood analog fluid within about eight tube diameters of the injection site. The second experiment shows that contrast completely mixes with blood within ten arterial diameters under appropriate injection parameters. The third experiment shows that angiographic contrast does not separate from, or settle out of, contrast‐carrying fluid mixtures for a period of 1 h. Conclusions: The results demonstrate that under typical injection conditions in the clinical setting, contrast issuing from the catheter completely mixes with the blood within ten artery diameters downstream of the catheter tip. Once mixed, it does not separate from the blood due to gravity.
In the past, various techniques such as indicator dilution, transit time, parametric imaging, or first-pass distribution have been used to estimate blood flow rates during angiographic contrast injections. We have previously employed the method of modeling contrast concentration curves to assess changes in flow exchange between parent cerebral vessels and cerebral aneurysms due to endovascular treatment by flow divertors [1]. There has been concern, however, that contrast injected under such situations may remain as a separate slug or stream flowing with blood or that contrast may settle from blood in the direction of gravity due to its higher density [2,3]. According to this argument, therefore, the analysis of the transport of angiographic contrast visualized under X-ray cannot be used to represent the transport of blood.
Despite many advances in the treatment of cerebral aneurysms in the last few decades, none of the available methods provide an unequivocal solution for all aneurysm sizes and morphologies. The feasibility of successfully treating aneurysms solely by the placement of an intravascular flow-diverting mesh across the aneurysm neck was established more than a decade ago [1]. Flow diverters disrupt the momentum exchange between the parent artery and aneurysm and significantly reduce intraaneurysmal hydrodynamic vorticity and kinetic energy. The resultant flow stasis promotes thrombus formation within the aneurysm sac, which eventually matures into fibrotic tissue, leading to exclusion of the aneurysm from the circulation. With the increased use of stents in the intracranial circulation, cases where coiling is not feasible, or is staged as a secondary procedure, are providing clinical evidence of the successful treatment of aneurysms with stents alone [2,3]. Methodological evidence of the performance of appropriately designed flow diverters in treating cerebral aneurysms has recently become available in the literature [4,5].
To characterize diet-dependent miRNA profiles and their targets in the visceral adipose of mice with polygenic susceptibility to type 2 diabetes.Six-week NONcNZO10/LtJ (NZ10) and control SWR/J mice were subjected to high protein-fish oil or control diets for 19 weeks and micro-RNA microarray analyses were implemented on visceral adipose RNA. We found that 27 miRNAs were significantly induced and 10 significantly repressed in the VA of obese NZ10 mice compared with controls. 12 selected regulated miRNAs were confirmed by RT-PCR based on the microarray data and we demonstrated that the expression of these miRNAs remained unaltered in the VA of control SWR mice. To assess the possible functional roles of miRNAs in adipogenesis, we also analyzed their expression in 3T3-L1 cells during growth and differentiation. This revealed that suppression of miRNA-205 alone correlated selectively with increased cell proliferation and lipid formation of adipocytes.Diet and genetics control the expression of obesity-regulated miRNAs in the visceral adipose of NZ10 mice.
