Minimally Invasive Delivery of Hydrogel-Encapsulated Amiodarone to the Epicardium Reduces Atrial Fibrillation.

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.

Toward Non-Invasive and Automatic Intravenous Infiltration Detection: Evaluation of Bioimpedance and Skin Strain in a Pig Model.

Intravenous (IV) therapy is prevalent in hospital settings, where fluids are typically delivered with an IV into a peripheral vein of the patient. IV infiltration is the inadvertent delivery of fluids into the extravascular space rather than into the vein (and requires urgent treatment to avoid scarring and severe tissue damage), for which medical staff currently needs to check patients periodically. In this paper, the performance of two non-invasive sensing modalities, electrical bioimpedance (EBI), and skin strain sensing, for the automatic detection of IV infiltration was investigated in an animal model. Infiltrations were physically simulated on the hind limb of anesthetized pigs, where the sensors for EBI and skin strain sensing were co-located. The obtained data were used to examine the ability to distinguish between infusion into the vein and an infiltration event using bioresistance and bioreactance (derived from EBI), as well as skin strain. Skin strain and bioresistance sensing could achieve detection rates greater than 0.9 for infiltration fluid volumes of 2 and 10 mL, respectively, for a given false positive, i.e., false alarm rate of 0.05. Furthermore, the fusion of multiple sensing modalities could achieve a detection rate of 0.97 with a false alarm rate of 0.096 for 5mL fluid volume of infiltration. EBI and skin strain sensing can enable non-invasive and real-time IV infiltration detection systems. Fusion of multiple sensing modalities can help to detect expanded range of leaking fluid volumes. The provided performance results and comparisons in this paper are an important step towards clinical translation of sensing technologies for detecting IV infiltration.

A Minimally Invasive, Translational Method to Deliver Hydrogels to the Heart Through the Pericardial Space.

Biomaterials are a new treatment strategy for cardiovascular diseases but are difficult to deliver to the heart in a safe, precise, and translatable way. We developed a method to deliver hydrogels to the epicardium through the pericardial space. Our device creates a temporary compartment for hydrogel delivery and gelation using anatomic structures. The method minimizes risk to patients from embolization, thrombotic occlusion, and arrhythmia. In pigs there were no clinically relevant acute or subacute adverse effects from pericardial hydrogel delivery, making this a translatable strategy to deliver biomaterials to the heart.

Role of Micro RNA-205 in Promoting Visceral Adiposity of NZ10 Mice with Polygenic Susceptibility for Type 2 Diabetes.

SCOPE: To characterize diet-dependent miRNA profiles and their targets in the visceral adipose of mice with polygenic susceptibility to type 2 diabetes. METHODS AND RESULTS: 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. CONCLUSION: Diet and genetics control the expression of obesity-regulated miRNAs in the visceral adipose of NZ10 mice.

Direct continuous measurement of draining vein pressure during Onyx embolization in a swine arteriovenous malformation model.

OBJECTIVE: Periprocedural intracranial hemorrhage secondary to intranidal flow redirection may develop after arteriovenous malformation (AVM) embolization. We hypothesized that continuous draining vein pressure monitoring may identify clinically relevant hemodynamic changes during devascularization. Our goal was to characterize the draining vein pressures in a swine rete mirabile AVM model during embolization with Onyx. METHODS: An acute swine AVM model was constructed in six animals. Baseline, transoperative and final AVM area measurements were used to determine the degree of AVM embolization. Continuous video recordings were captured at 10 s intervals of active embolization. Draining vein pressure, arterial feeder pressure and heart rate were continuously monitored. RESULTS: The baseline and post-embolization mean draining vein pressures were 49.8±17.2 and 33.0±11.7 mm Hg (p=0.01), mean arterial pressures were 79.8±19.4 and 79.6±25.2 mm Hg (p=0.94), mean transnidal pressures were 35.8±19.7 and 45.4±33.7 mm Hg (p=0.37) and mean heart rates were 81.1±11.9 and 83.1±12.8 bpm (p=0.38), respectively. The draining vein pressure was averaged according to the degree of AVM embolization and represented as a relative change compared with the baseline draining vein pressure, and the slopes were found to decrease in all cases (p=0.02). In half of the animals the draining vein pressure decreased progressively as the AVM was embolized. In the remaining animals the venous pressure only started to decline after the AVM had been devascularized by > 50%. CONCLUSIONS: The draining vein pressure response during Onyx embolization in the swine AVM model is heterogeneous. Continuous draining vein pressure monitoring is feasible and may potentially identify clinically relevant hemodynamic changes during AVM embolization.

Influence of diet on visceral adipose remodeling in NONcNZO10 mice with polygenic susceptibility for type 2 diabetes.

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.

An essential role for diet in exercise-mediated protection against dyslipidemia, inflammation and atherosclerosis in ApoE⁻/⁻ mice.

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.

The mixability of angiographic contrast with arterial blood.

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.

Treatment of rabbit elastase-induced aneurysm models by flow diverters: development of quantifiable indexes of device performance using digital subtraction angiography.

It has been known for more than a decade that intracranial aneurysms can be successfully treated by deploying a porous meshed tube in the parent vessel of the aneurysm. Such devices are currently called flow diverters because they promote intraneurysmal flow stasis and thrombosis by diverting blood flow away from the aneurysm sac. The objective of this study was to use angiographic data to quantify and compare the performance of flow diverters of original design in successfully occluding an experimental aneurysm model. Three different configurations of a novel flow diverter with varying porosities and pore densities were implanted in 30 rabbit elastase-induced aneurysms. Temporal variations in angiographic contrast intensity within the aneurysms were fit to a mathematical model. Optimized model parameters were supplemented by the angiographic percentage aneurysm occlusion and an angiographic measure of device flexibility to derive composite scores of performance. Angiographic quantification further suggested a parameter, which could be employed to estimate long-term aneurysm occlusion probabilities immediately after treatment. Performance scores showed that the device with a porosity of 70% and pore density of 18 pores/mm (2) performed better than devices with 65% porosity, 14 pores/mm (2), and 70% porosity, 12 pores/mm (2) with relative efficacies of 100%, 84%, and 76%, respectively. The pore density of flow diverters, rather than porosity, may thus be a critical factor modulating device efficacy. A value of the prognostic parameter of less than 30 predicted greater than 97% angiographic aneurysm occlusion over six months with a sensitivity of 73% and specificity of 82%.

An original flow diversion device for the treatment of intracranial aneurysms: evaluation in the rabbit elastase-induced model.

BACKGROUND AND PURPOSE: The potential for successful treatment of intracranial aneurysms by flow diversion is gradually being recognized in the clinical setting; however, the devices currently available (stents) are not designed for flow diversion. We evaluate the long-term response of an appropriately designed flow diversion device in producing thrombotic occlusion of experimental aneurysms. METHODS: Three different configurations of an original flow diversion device were implanted across thirty elastase-induced aneurysm models in rabbits. Ten animals per device configuration were followed-up for 3 weeks (n=3), 3 months (n=3), or 6 months (n=4), and tissue explanted postsacrifice was sent for histology. The temporal variation in angiographic contrast intensity within each aneurysm was fitted with a mathematical model to quantify the alteration in local hemodynamics caused by the implanted device. A predictive index, called the washout coefficient, was constructed to estimate long-term aneurysm occlusion probabilities immediately after treatment with any flow diversion device. RESULTS: The device with a porosity of 70% and pore density of 18 pores/mm(2) performed better at occluding aneurysms than devices with 70% porosity, 12 pores/mm(2) and 65% porosity, 14 pores/mm(2). A value of the washout coefficient less than 30 predicted greater than 97% angiographic aneurysm occlusion over a period of 6 months with a sensitivity of 73% and specificity of 82%. CONCLUSIONS: The flow diversion devices effected successful and stable aneurysm occlusion. Pore density, rather than porosity, may be the critical factor modulating efficacy of such devices.

Neurological deficits associated with the elastase-induced aneurysm model in rabbits.

OBJECTIVE: Although the rabbit elastase-induced aneurysm model is currently used widely for endovascular research and device testing, procedural causes leading to animal morbidity and mortality have not yet been clearly described. We conducted a retrospective study to analyse factors contributing to neurological deficits in rabbits that underwent the elastase-induced aneurysm creation procedure at our research center from 2002 to 2005 in order to improve the technique and reduce procedure-related morbidity and mortality. METHODS: A total sample of 38 animals that underwent the procedure under the same conditions was analysed in two groups: animals that presented neurological deficits (ND, n=15) and animals that were neurological deficit free (NDF, n=23). Data were collected by reviewing the animal records and radiographic images from the procedures. Statistical analyses using the Mann-Whitney test, unpaired t-test with Welch correction and Fisher's exact tests were performed to compare the two groups based on variables associated with endothelial injury and activation of the coagulation cascade. RESULTS: The variables of animal weight (signifying state of health of the animal), total procedure time, total balloon occlusion time and clot formation were found to be significantly and/or very significantly correlated to ND presentation. DISCUSSION: Successful creation of the rabbit elastase-induced aneurysm model depends on careful control over several technical details. Important variables governing outcome have been identified here. A specific, improved endovascular arrangement that facilitates maneuvering of the devices and reduces the risk of air emboli is presented.

Angiographic assessment of the performance of flow divertors to treat cerebral aneurysms.

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.

Contrast injection via the central artery of the left ear in rabbits: a new technique to simplify follow-up studies.

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.