Healthy Canines Research Articles

Sequential vapour ablation of adjacent segments in canine lung

Introduction: Vapour ablation is used to create lung volume reduction for emphysema patients to improve lung function and quality of life. This study characterises effects of vapour ablation treatment in lung segments within a lobe that are adjacent to lung segments previously treated with vapour in a healthy canine model. Because emphysema is a progressive disease, subsequent treatments could offer continued benefit to the patient. Method: Six healthy canines were treated with vapour at 8.5 cal/g in one upper lobe segment. After a 4-week healing period, the adjacent segment was treated. After a second 4-week healing period, necropsy was performed and the tissue inspected. Clinical effects were monitored during each healing period. Results: Each treatment was well tolerated and no significant abnormalities were observed during the healing phases, including death, pneumothorax, or major decline in health status. Animal health, oxygenation changes, pathology, and airway changes were monitored during the study. Analysis of these end points showed no difference in changes after treatment 2 as compared to changes after treatment 1. Conclusion: In this model, there was no evidence of increased or different clinical observations after a second adjacent vapour ablation. It was not possible to differentiate between the clinical effects of treatment 1 and the clinical effects of treatment 2. These results support investigation of sequential adjacent segmental vapour treatments in humans.

Valores de referencia de gases arteriales y de electrolitos en caninos de la sabana de Bogotá

Debido a la ausencia de valores de gasometría arterial que se ajusten a nuestras condiciones ambientales y a la amplia variedad de datos no actualizados en la literatura y utilizados en la práctica diaria, obtenidos con alturas, razas y equipos diferentes a los disponibles en nuestro medio, es necesario generar conocimiento propio ajustado a nuestra realidad. Se realizó una medición sistemática al azar de sangre arterial y venosa en 100 caninos sanos a la altura de la sabana de Bogotá (Chía: 2652 msnm; Cajicá: 2558 msnm; Sopó: 2650 msnm; La Calera: 2718 msnm y Bogotá: 2630 msnm), utilizando el analizador I-STAT® con cartucho EG7+. Se encontraron valores de referencia de gasometría, electrolitos, bases efectivas y pH. Los valores fueron comparados entre cuatro grupos por peso. Para cada parámetro se realizó estadística descriptiva basada en promedio, desviación estándar, error estándar, y se hallaron los límites de confianza (95 %) y los intervalos con desviación estándar (una y dos desviaciones). Se evidenció disminución de PCO2, PO2, SO2, bicarbonato, BE. El pH se encontró levemente aumentado, similar a lo reportado por autores a grandes alturas y diferentes (no corroborado estadísticamente) a reportes en literatura, en los que la altura no fue una variable. Aun así son usados frecuentemente como referencia en la práctica de pequeños animales; solo la PO2 presentó diferencias estadísticas por grupos de peso. Como conclusión, se evidenció una regulación del pH sanguíneo eficaz a 2600 msnm, con diferentes valores de bicarbonato, PCO2, PO2, BE, que indican la necesidad de obtener y utilizar valores de referencia acordes con condiciones locales.

Failure of Homeostatic Model Assessment of Insulin Resistance to Detect Marked Diet-Induced Insulin Resistance in Dogs

Accurate quantification of insulin resistance is essential for determining efficacy of treatments to reduce diabetes risk. Gold-standard methods to assess resistance are available (e.g., hyperinsulinemic clamp or minimal model), but surrogate indices based solely on fasting values have attractive simplicity. One such surrogate, the homeostatic model assessment of insulin resistance (HOMA-IR), is widely applied despite known inaccuracies in characterizing resistance across groups. Of greater significance is whether HOMA-IR can detect changes in insulin sensitivity induced by an intervention. We tested the ability of HOMA-IR to detect high-fat diet–induced insulin resistance in 36 healthy canines using clamp and minimal model analysis of the intravenous glucose tolerance test (IVGTT) to document progression of resistance. The influence of pancreatic function on HOMA-IR accuracy was assessed using the acute insulin response during the IVGTT (AIRG). Diet-induced resistance was confirmed by both clamp and minimal model (P < 0.0001), and measures were correlated with each other (P = 0.001). In striking contrast, HOMA-IR ([fasting insulin (μU/mL) × fasting glucose (mmol)]/22.5) did not detect reduced sensitivity induced by fat feeding (P = 0.22). In fact, 13 of 36 animals showed an artifactual decrease in HOMA-IR (i.e., increased sensitivity). The ability of HOMA-IR to detect diet-induced resistance was particularly limited under conditions when insulin secretory function (AIRG) is less than robust. In conclusion, HOMA-IR is of limited utility for detecting diet-induced deterioration of insulin sensitivity quantified by glucose clamp or minimal model. Caution should be exercised when using HOMA-IR to detect insulin resistance when pancreatic function is compromised. It is necessary to use other accurate indices to detect longitudinal changes in insulin resistance with any confidence.

Abdominal obesity is associated with heart disease in dogs.

BackgroundThe relationship between overall obesity and fat distribution in dogs and the development of heart disease is unclear. In the present study we evaluated the association between overall obesity and fat distribution and clinical heart disease by morphometric and computed tomography (CT)-based measurements. Body condition score (BCS), modified body mass index (MBMI, kg/m2), waist-to-hock-to-stifle distance ratio (WHSDR), waist-to-ilium wing distance ratio (WIWDR), and waist-to-truncal length ratio (WTLR) were compared between dogs with (n = 44) and without (n = 43) heart disease using receiver operating characteristic (ROC) analysis. Intra-abdominal fat (IAF) and subcutaneous fat (SQF) were measured in dogs with (n = 8) and without (n = 9) heart disease at the center of the fourth and fifth lumbar vertebrae by CT.ResultsBCS was similar between heart disease and healthy groups (3.6 ± 0.2 vs. 3.3 ± 0.1, P = 0.126). The following morphometric measurements were greater in the heart disease group compared with healthy canines: MBMI (65.0 ± 4.5 vs. 52.5 ± 3.7 kg/m2, respectively, P = 0.035); WIWDR (4.1 ± 0.1 vs. 3.1 ± 0.1, P < 0.01); and WTLR (1.25 ± 0.04 vs. 1.05 ± 0.04, P < 0.01). However, there was no significant difference in WHSDR (3.6 ± 0.1 vs. 3.7 ± 0.2, P = 0.875). Interestingly, IAF was significantly increased in dogs with heart disease compared with healthy dogs (23.5 ± 1.5% vs. 19.4 ± 1.2%, P = 0.039) whereas SQF was similar between two groups (35.5 ± 2.7% vs. 38.6 ± 3.5%, P = 0.496). Of the five morphometric indices studied, WIWDR and WTLR provided acceptable discrimination for diagnosing heart disease in dogs, with areas under the ROC curve of 0.778 (95% confidence interval [CI]:0.683-0.874) and 0.727 (95% CI:0.619-0.835), respectively.ConclusionsOur data indicate that abdominal obesity, rather than overall obesity, is associated with heart disease in dogs. Measurements of both WIWDR and WTLR are particular useful for detection of an abdominal obesity in dogs.

Analysis of microleakage of temporary restorative materials in primary teeth.

The aim of this study was to compare the coronal microleakage of restorative materials used between sessions of endodontic treatment in primary teeth. Forty healthy primary canines were chosen and randomly allocated to four groups: Group 1 - Cimpat Branco ® (n = 10), Group 2 - Bioplic ® (n = 10), Group 3 - Maxxion R ® glass ionomer cement (n = 10), and Group 4 (control) - Z350 ® composite resin (n = 10). Class V cavities were created and fillings carried out following the manufacturer's instructions. The teeth were submitted to thermocycling, sealed, and immersed in 0.5% basic fuchsin solution for 24 h. The teeth were split along their long axis in the vestibulolingual direction and the tooth-restorative material interface was photographed. The percentage of microleakage was calculated using the ImageJ program. Data were analyzed using the analysis of variance (ANOVA) F-test and Bonferroni's t-test, with a 5% level of significance. The following mean percentages of microleakage were found: Group 1 = 16.08%, Group 2 = 46.98%, Group 3 = 47.93%, and Group 4 = 11.03%. Statistically, significant differences were found in the comparison of Groups 1 and 4 to Groups 2 and 3. Cimpat Branco ® had a lower percentage of microleakage in comparison to Bioplic ® and Maxxion R ® glass ionomer cement.

&lt;i&gt;In Vitro&lt;/i&gt; Susceptibility of &lt;i&gt;Malassezia pachydermatis&lt;/i&gt; Isolates from Canine Skin with Atopic Dermatitis to Ketoconazole and Itraconazole in East Asia

ABSTRACTTopical or oral azole antifungals are commonly used in canine atopic dermatitis (AD), as the lipophilic yeast Malassezia pachydermatis exacerbates canine AD. To examine whether canine AD lesions harbor azole-resistant M. pachydermatis isolates in East Asia, we investigated the in vitro susceptibility of M. pachydermatis isolates to ketoconazole (KTZ) and itraconazole (ITZ) obtained from AD lesions of canines in Japan, Korea and Taiwan. The minimum inhibitory concentrations (MICs) of KTZ and ITZ were measured by the E-test using Sabouraud dextrose agar with 0.5% Tween 40. The MICs of KTZ and ITZ for isolates from canines with AD were significantly higher than the MICs for isolates from healthy canines. Our findings suggested that the clinical isolates from canine AD skin lesions were less susceptible to azoles than those from normal canine skin in East Asia.

Contour tracking in echocardiographic sequences via sparse representation and dictionary learning.

This paper presents a dynamical appearance model based on sparse representation and dictionary learning for tracking both endocardial and epicardial contours of the left ventricle in echocardiographic sequences. Instead of learning offline spatiotemporal priors from databases, we exploit the inherent spatiotemporal coherence of individual data to constraint cardiac contour estimation. The contour tracker is initialized with a manual tracing of the first frame. It employs multiscale sparse representation of local image appearance and learns online multiscale appearance dictionaries in a boosting framework as the image sequence is segmented frame-by-frame sequentially. The weights of multiscale appearance dictionaries are optimized automatically. Our region-based level set segmentation integrates a spectrum of complementary multilevel information including intensity, multiscale local appearance, and dynamical shape prediction. The approach is validated on twenty-six 4D canine echocardiographic images acquired from both healthy and post-infarct canines. The segmentation results agree well with expert manual tracings. The ejection fraction estimates also show good agreement with manual results. Advantages of our approach are demonstrated by comparisons with a conventional pure intensity model, a registration-based contour tracker, and a state-of-the-art database-dependent offline dynamical shape model. We also demonstrate the feasibility of clinical application by applying the method to four 4D human data sets.

GW24-e3929 Noninvasive renal sympathetic denervation by extracorporeal high-intensity focused ultrasound in a preclinical canine model

ObjectivesThe feasibility of noninvasive renal sympathetic denervation (RSD) using the novel approach of extracorporeal high-intensity focused ultrasound (HIFU) was investigated in this study.MethodsCatheter-based RSD has achieved promising clinical outcomes. Methods...

The altered expression profile of microRNAs in cardiopulmonary bypass canine models and the effects of mir-499 on myocardial ischemic reperfusion injury

BackgroundMicroRNAs were enrolled in various cardiovascular disease especially ischemic heart diseases, but the microRNA changes during myocardial ischemia reperfusion injury underwent cardiopulmonary bypass are still unknown. This study screens the microRNA differences in CPB canines and evaluates the relationship of microRNAs with myocardial ischemia reperfusion injury.Methods13 healthy canines received CPB with 60 minutes of aortic clamping and cardioplegic arrest, followed by 90 minutes reperfusion. Left ventricular myocardial samples, blood samples and hemodynamic data were taken at different time points. We performed microRNAs microarray experiments upon the left ventricle myocardium tissue of canines before CPB and after reperfusion for 90 minutes by pooling 3 tissue samples together and used qRT-PCR for confirmation.ResultsStatistically significant difference was found in mir-499 level before CPB and after reperfusion (T1 vs. T4, p = 0.041). We further examined the mir-499 levels by using qRT-PCR in all 13 canines at 4 different time points (T1 vs. T4, p = 0.029). Mir-499 expression was negatively correlated with cardiac troponin T (cTnT) and creatine kinase- MB (CK-MB) levels of canines in all time points samples (r = 0.469, p < 0.001 and r = 0.273, p = 0.050 respectively). Moreover, higher mir-499 expression level was associated with higher dP/dtmax at 25 minutes and 90 minutes after reperfusion.ConclusionMyocardial ischemic reperfusion injury with cardiopulmonary bypass results in declining level of mir-499 expression in left ventricle myocardium of canines, suggesting mir-499 would be a potential therapeutic target in cardiac protection during open heart surgery.

Age determination of adult individuals by three-dimensional modelling of canines

Accurate age determination is fundamental in both forensic medicine and anthropology. Many methods that relate dental characteristics to adult age have been proposed, but there is still no simple and reliable method that does not damage the study material. The aim of this work was to propose a relevant and practical technique for determining age in adults that could be used in both living and deceased individuals. The sample was composed of 210 CT scans from individuals aged from 15 to 85years old, with four healthy canines present in the mouth. The 840 canines were modelled using Mimics® 10.01 software. The pulp volume/total volume ratio ×100 was determined for each tooth. Seven mathematical models, corresponding to all possible real situations, were determined by the weighted least squares method and ranked in order of relative performance. The adequacy of the seven models to the data was very high with the regressions proposed (0.915 < R (2) adjusted < 0.964). Ranked in order of performance, the maxillary model was the most powerful of the seven models for age determination, followed by the 4 canines model, the 13 model and the 23 model.

Evaluación Del Índice Tei En Diversos Protocolos De Tranquilización Preanestésica En Caninos Sanos

Evaluación Del Índice Tei En Diversos Protocolos De Tranquilización Preanestésica En Caninos Sanos

Noninvasive Renal Sympathetic Denervation by Extracorporeal High-Intensity Focused Ultrasound in a Pre-Clinical Canine Model

This study investigated the feasibility of noninvasive renal sympathetic denervation (RSD) by using the novel approach of extracorporeal high-intensity focused ultrasound (HIFU). Catheter-based RSD has achieved promising clinical outcomes. Under the guidance of Doppler flow imaging, therapeutic ablations (250 W × 2 s) were performed by using extracorporeal HIFU on the bilateral renal nerves (36.3 ± 2.8 HIFU emissions in each animal) in a mean 27.4-min procedure in 18 healthy canines of the ablation group. Similar procedures without acoustic energy treatment were conducted in 5 canines of the sham group. The animals were killed on day 6 or 28. Blood pressure (BP), plasma noradrenaline (NA) level, and renal function were determined on days 0, 6, and 28. Pathological examinations were performed on all retrieved samples. All of the animals survived the treatment. After ablation, BP and NA significantly decreased compared with the baseline values (BP changed -15.9/-13.6 mmHg, NA changed -55.4% [p < 0.001] 28 days after ablation]) and compared with the sham group on days 6 and 28. Ablation lesions around the renal artery adventitia were observed on day 6. A histological examination revealed the disruption of nerve fibers, necrosis of Schwann cells and neurons, and apparent denervation on day 28. No procedure-related complications were observed. Effective RSD was successfully achieved by using the extracorporeal HIFU method in canines. Thus, noninvasive HIFU may be further explored as an important and novel strategy for RSD.

Effect of mechanical ventilation with different tidal volumes on pulmonary surfactant in dogs during cardiopulmonary resuscitation

Objective To observe the effects of mechanical ventilation with different tidal volumes (Vt) on the pulmonary surfactant in dogs during cardiopulmonary resuscitation (CPR) and discuss the strategy of mechanical ventilation for CPR.Methods A total of 24 healthy,adult and mongrel canines were randomly (random number) divided into three groups,namely control group (A),low Vt group (B) and high Vt group (C).Canines without ventricular fibrillation in group A were not supported with mechanical ventilation,while canines in group B and group C were induced to get ventricular fibrillation (VF) with pacing catheter inserted through right external carotid vein into the right ventricle.CPR was initiated with mechanical ventilation with different Vt for 6 hours after ventricular fibrillation.The Vt set in group B was 6 ml/kg body weight and Vt set in group C was 20 ml/kg body weight.The arterial blood gas analyses were tested in different intervals.The levels of phosphatidylchline in bronchia alveolus lavage fluid (BALF) was assayed with high performance liquid chromatography (HPLC).The ratio of wet and dry weight and the morphological change scores of lung tissue were calculated.Results After ventricular fibrillation,pH,PaO2 in both groups B and C decreased and PaCO2 increased in comparison with those before VF (P ＜ 0.05),while pH,PaO2 and PaCO2 were improved after mechanical ventilation.These was statistical difference in PaCO2 between group B and group C 2 h after mechanical ventilation (P ＜ 0.05).There was difference in HCO3-between group B and group C 6 h after ROSC.The rate of successful restoration of spontaneous circulation (ROSC) and the 72 h survival rate were 75％ and 50％ respectively in group B,and 62.5％ and 40％ respectively in group C.There were no statistically different between two groups (P ＞ 0.05).The levels of phosphatidylchline in BALF of group B and C greatly decreased compared with the group A (All P ＜0.01),while phosphatidylcholine detected in the group C decreased much more than that in the group B (P ＜0.01).The W/D ratio and morphological change scores in the group C were higher than those in the group B (P ＜ 0.01).Conclusion Low tidal volume ventilation can reduce the loss of pulmonary surfactant and mitigate pulmonary injury.Therefore it may be a protective ventilation strategy after resuscitation. Key words: Cardiopulmonary resuscitation; Mechanical ventilation ; Tidal volumes ; Lung injury ; Pulmonary surfactant

Effects of pretreatment with etomidate on the contents of alanine transaminase, aspartate transaminase, malondialdehyde and superoxide dismutase in dogs with hepatic ischemia/reperfusion injury

Objective To investigate the effects of pretreatment with etomidate on hepatic injury and the contents of alanine transaminase (ALT),aspartate transaminase (AST) in plasma and malondialdehyde (MDA),superoxide dismutase (SOD) in hepatic tissue during hepatic ischemia/repeffusion injury(HI/RI) in dogs.Methods 20 adult healthy hybrid canines were randomly divided into 4 groups(n=5): Sham group(group S),ischemia/reperfusion group (group I/R),low dosage of Etomidate group(group El,0.6 mg/kg) and high dosage of Etomidate group (group E2,1.5 mg/kg).Canines in all groups were injected Etomidate or NS except group S.The porta hepatis of canines in group S was separated without ligation.The model of HI/RI were established by ligating porta hepatis.The biochemical indicators of ALT and AST in plasma were measured at 4 time points: before blocked,30 min after ischemis,l,2 h after repeffusion.The contents of MDA and activity of SOD in hepatic tissue were also measured.Hepatic tissue was observed with light microscope after operation.Results Compared with group S,group I/R,group E1 and group E2 increased the level of ALT and AST in plasma (P＜0.01).Compared with group I/R,the level of ALT,AST in group E1 and group E2 decreased significantly(P＜0.01),moreover,group E2 decreased more obviously.Reperfusion 2 h: ALT: (2911±89) U/L(group I/R),(863±95) U/L(group E2); AST: (2722±103) U/L(group I/R),(1056±115) U/L(group E2)].Compared with group S,group I/R,group E1 and group E2 increased the level of MDA and group I/R decreased the expression level of SOD,group E1 and group E2 increased the level of SOD in hepatic tissue (P＜0.01).Compared with group I/R,group E1 and group E2 decreased significantly the level of MDA and increased significantly the level of SOD in hepatic tissue (P＜0.01),and group E2 more obviously[MDA:(21.70±-2.01) nmol·mg-1·prot-1 (group I/R),(12.69±1.02) nmol·mg-1·prot-1 (group E2),SOD: (191±12) nmol·mg-1 ·prot-1(group I/R),(634±26) nmol· mg-1·prot-1 (group E2)].Light microscope showed evidently that the pathological changes of hepatic tissue were more slight in group E1 and group E2 than that in group I/R,and group E2 more slight than group El.Conclusions Pretreatment with etomidate has protective effects on hepatic ischemia reperfusion injury,and it is related to the control lipid peroxidation of etomidate.And the protective effects of high dosage of etomidate (1.5 mg/kg) was more reliable. Key words: Etomidate ; Pretreatment ; Hepatic ischemia/reperfusion ; Alanine transaminase ; Aspartate transaminase; Malondialdehyde; Superoxide dismutase

Safety of Acute Vagus Nerve Stimulation Therapy With Chronic Ivabradine Therapy

Safety of Acute Vagus Nerve Stimulation Therapy With Chronic Ivabradine Therapy

Differential routes of carboplatin administration influence lymphocyte apoptosis in retroperitoneal lymph nodes

We aimed to investigate carboplatin distribution in retroperitoneal lymph nodes and its effect on lymphocyte apoptosis following intravenous (IV), intra-arterial (IA), and retroperitoneal (RP) administration. Sixty-three healthy female canines were randomly assigned as IV, IA, or RP administration of carboplatin. At 0.5, 1, 2, 4, 8, 24, and 72 h after carboplatin treatment, retroperitoneal lymph nodes (n = 6 at each time point) were collected and high-performance liquid chromatography was employed to measure the carboplatin content. The differences in carboplatin pharmacokinetics of the three administration routes were compared. Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) was carried out to measure the lymphocyte apoptosis of the retroperitoneal lymphocytes. The peak concentration of carboplatin in plasma following IV administration was the highest among all approaches; as to the peak time, RP administration was longer than the other two administrations. Concentration for carboplatin in the retroperitoneal lymph node was highest following IA administration at early time points, but at higher time points, concentration was significantly higher following RP administration. Penetration of carboplatin into the retroperitoneal space was higher following RP administration. Following RP administration, the level of apoptotic lymphocytes in the retroperitoneal lymph nodes was significantly greater than either IV or IA. Following RP administration of carboplatin, the concentration, area under the curve of carboplatin and the number of apoptotic lymphocytes were significantly higher than those following IV and IA administration. This suggests that RP administration of carboplatin is beneficial for the treatment of retroperitoneal lymph node metastasis.

Controlled oxygen reperfusion protects the lung against early ischemia-reperfusion injury in cardiopulmonary bypasses by downregulating high mobility group box 1

ABSTRACTRestricting oxygen delivery during the reperfusion phase of cardiopulmonary bypass (CPB) protects the heart, but effects on lung ischemia reperfusion (IR) in CPB are unknown. We examined whether extracellular high mobility group box 1 (HMGB1) mediated inflammation during early lung IR injury in CPB. Fourteen healthy canines received CPB with 60 minutes of aortic clamping and cardioplegic arrest, followed by 90 minutes reperfusion. Following surgery, the animals were randomized into control (n = 7) or test (n = 7) groups. Control animals received a constant level of 80% FiO2 during the entire procedure, and the test group received a gradual increase in FiO2 during the first 25 minutes of reperfusion. In the test group, the FiO2 was initiated at 40% and increased by 10% every 5 minutes, to 80%. Histology, lung injury variables, HMGB1 expression, and inflammatory responses were assessed at baseline (T1) and at 25 minutes (T2) and 90 minutes (T3) after starting reperfusion. Treatment with controlled oxygen significantly suppressed lung pathologies, lung injury variables, and inflammatory responses (all P < .001). After lung IR injury, HMGB1 mRNA and protein expressions were significantly decreased in the controlled oxygen group (all P < .001). Controlled oxygen reperfusion is protective in the early stages of lung IR injury in a canine CPB model, and this protection is linked to HMGB1 downregulation.

Effect of plasma-rich in platelet-derived growth factors on peri-implant bone healing: An experimental study in canines

Background:Tissue engineering principles can be exploited to enhance alveolar and peri-implant bone reconstruction by applying such biological factors as platelet-derived growth factors. The objective of the present study is to investigate the effect of autologous plasma-rich in growth factors (on the healing of peri-implant bone in canine mandible).Materials and Methods:In this prospective experimental animal study, two healthy canines of the Iranian mix breed were selected. Three months after removing their premolar teeth on both sides of the mandible, 12 implants of the Osteo Implant Corporationsystem, 5 mm in diameter and 10 mm in length, were selected to be implanted. Plasma rich in growth factors (PRGF) were applied on six implants while the other six were used as plain implants without the plasma. The implants were installed in osteotomy sites on both sides of the mandible to be removed after 4 weeks with the surrounding bones using a trephine bur. Mesio-distal sections and implant blocks, 50 μ in diameter containing the peri-implant bone, were prepared By basic fuchin toluidine-bluefor histological and histomorphometric evaluation by optical microscope. The data were analyzed using Mann-Whitney Test (P<0.05).Results:The bone trabeculae and the type of bone generation in PRGF and control groups had no statistically significant differences (P=0.261, P=0.2) although the parameters showed higher measured values in the PRGF group. However, compared to the control, application of PRGF had significantly increased bone-to-implant contact (P=0.028)Conclusion:Based on the results, it may be concluded that application of PRGF on the surface of implant may enhance bone-to-implant contact.

Cardiorenal Actions of TRV120027, a Novel ß-Arrestin–Biased Ligand at the Angiotensin II Type I Receptor, in Healthy and Heart Failure Canines

Background— The angiotensin II type 1 receptor (AT1R) plays a key role in regulating cardiorenal function. Classic “unbiased” AT1R antagonists block receptor coupling to both G αq and ß-arrestin–mediated signals, which desensitize G-protein signaling as well as transduce G-protein–independent signals. TRV120027 is a novel ß-arrestin–biased AT1R ligand, which engages ß-arrestins while blocking G-protein signaling. At the AT1R, TRV120027 can inhibit angiotensin II–mediated vasoconstriction, whereas, through ß-arrestin coupling, increase cardiomyocyte contractility. We defined for the first time the acute cardiorenal actions of TRV120027 in healthy and heart failure (HF) canines. Methods and Results— Healthy and HF canines (induced by tachypacing) were anesthetized. After instrumentation and equilibration, a 30-minute baseline clearance was performed, followed by further clearance with escalating doses of intravenous TRV120027 (0.01, 0.1, 1, 10, and 100 μg/kg per minute) and a 30-minute washout. In healthy canines, TRV120027 decreased pulmonary capillary wedge pressure and systemic and renal vascular resistances, while increasing cardiac output, renal blood flow, glomerular filtration rate, and urinary sodium excretion. In HF canines, TRV120027 decreased mean arterial pressure, right atrial pressure, and pulmonary capillary wedge pressure, systemic and renal vascular resistances and increased cardiac output and renal blood flow. Glomerular filtration rate and urinary sodium excretion were maintained. Conclusions— We report for the first time the cardiorenal actions of the novel ß-arrestin–biased AT1R ligand TRV120027. In both normal and HF canines, TRV120027 demonstrated cardiac unloading actions while preserving renal function. With this beneficial pharmacological profile, TRV120027 represents a novel strategy for the treatment of HF.

Noninvasive reconstruction of the three-dimensional ventricular activation sequence during pacing and ventricular tachycardia in the canine heart

Single-beat imaging of myocardial activation promises to aid in both cardiovascular research and clinical medicine. In the present study we validate a three-dimensional (3D) cardiac electrical imaging (3DCEI) technique with the aid of simultaneous 3D intracardiac mapping to assess its capability to localize endocardial and epicardial initiation sites and image global activation sequences during pacing and ventricular tachycardia (VT) in the canine heart. Body surface potentials were measured simultaneously with bipolar electrical recordings in a closed-chest condition in healthy canines. Computed tomography images were obtained after the mapping study to construct realistic geometry models. Data analysis was performed on paced rhythms and VTs induced by norepinephrine (NE). The noninvasively reconstructed activation sequence was in good agreement with the simultaneous measurements from 3D cardiac mapping with a correlation coefficient of 0.74 ± 0.06, a relative error of 0.29 ± 0.05, and a root mean square error of 9 ± 3 ms averaged over 460 paced beats and 96 ectopic beats including premature ventricular complexes, couplets, and nonsustained monomorphic VTs and polymorphic VTs. Endocardial and epicardial origins of paced beats were successfully predicted in 72% and 86% of cases, respectively, during left ventricular pacing. The NE-induced ectopic beats initiated in the subendocardium by a focal mechanism. Sites of initial activation were estimated to be ∼7 mm from the measured initiation sites for both the paced beats and ectopic beats. For the polymorphic VTs, beat-to-beat dynamic shifts of initiation site and activation pattern were characterized by the reconstruction. The present results suggest that 3DCEI can noninvasively image the 3D activation sequence and localize the origin of activation of paced beats and NE-induced VTs in the canine heart with good accuracy. This 3DCEI technique offers the potential to aid interventional therapeutic procedures for treating ventricular arrhythmias arising from epicardial or endocardial sites and to noninvasively assess the mechanisms of these arrhythmias.