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Abstract Background In the absence of echocardiography, identification of cardiomegaly via thoracic radiography is a necessary criterion for classification of disease severity in dogs with myxomatous mitral valve disease (MMVD). Objective Modified-vertebral left atrial size (M-VLAS) facilitates objective radiographic assessment of the left atrium (LA) in 2 dimensions and identifies LA enlargement more accurately than existing methods. Animals Sixty-four dogs with various stages of MMVD and 6 control healthy dogs. Methods Retrospective case–control study. Medical records were searched for dogs with varying severity of MMVD. Modified-vertebral left atrial size, vertebral left atrial size (VLAS), vertebral heart size (VHS), and radiographic left atrial dimension (RLAD) were measured from thoracic radiographs and compared with echocardiographically derived measurements. Results Positive correlation to LA/Ao was identified for M-VLAS (r = 0.77, P < .001), VLAS (r = 0.76, P < .001), RLAD (r = 0.75, P < .001), and VHS (r = 0.67, P < .001). Receiver operating characteristic analyzes provided an area under the curve of 0.97 (95% CI, 0.94-1.00) for M-VLAS, which was superior to VHS (0.90, 95% CI, 0.94-1.00, P = .03) in identifying dogs with LA/Ao ≥1.6. A cut-off value of ≥3.4 vertebrae using M-VLAS provided 92.7% sensitivity and 93.1% specificity in predicting LA enlargement. Conclusions and clinical importance M-VLAS, which is superior to VHS, offers an accurate and repeatable way to radiographically identify LA enlargement in dogs with MMVD.

Objective: The treatment of syncope depends largely on its possible etiology. Therefore, identifying the cause of syncope is very important in treatment planning. Herein, we report an etiology of syncope caused by pulmonary hypertension (PH) associated with canine filariasis, followed by syncope due to bradyarrhythmia 1 year later. Materials and Methods: An 8-year-old male English Cocker Spaniel was referred to our hospital for a second opinion regarding syncope that the dog had started experiencing approximately 2 months prior. Based on the examination findings, we diagnosed that the fainting was due to heartworm disease and associated PH. After increasing the dose of pimobendan (0.50 mg/kg, q12h), the syncope subsided. However, syncope recurred on the 215th day of the first episode. Results: The findings that differed from those during the initial examination were that car¬diac arrest was observed for approximately 5 sec during auscultation, along with sinus arrest. Therefore, to further investigate for syncope, a Holter electrocardiograph was obtained for 3 days. Consequently, sinus arrest was identified as the etiology of the recurrent syncope, and the patient was diagnosed with sick sinus syndrome, Rubenstein classification type II. Following cilostazol (10 mg/kg, q12h) administration, the syncope subsided. Conclusion: This case reports syncope in a dog, which typically occurs due to different etiologies. When a dog has PH, it may be important to think about the possibility of arrhythmias caused by a bigger right heart.

Myxomatous mitral valve disease (MMVD) is the most common cardiovascular disease in small-breed dogs, and some affected dogs develop congestive heart failure (CHF). Although pimobendan is recommended to delay the onset of CHF, its effect on survival following CHF onset development remains unclear. This retrospective study evaluated the survival prognosis of 143 small-breed dogs diagnosed with first-time CHF due to MMVD, comparing pretreated (n = 54) and untreated (n = 89) groups. Pretreated dogs received cardiac medications including pimobendan for at least five weeks before CHF onset. Pretreated dogs had a significantly larger normalized left ventricular internal diameter (LVIDDN; p = 0.002) and higher left atrium-to-aortic root ratio (LA/Ao; p = 0.044) at CHF onset than untreated dogs. The median survival time after CHF onset was significantly longer in untreated dogs (481 days, 95% confidence interval (CI) 393-569 days) than in pretreated dogs (212 days, 95% CI 73-351 days; p = 0.028). Univariable Cox proportional hazards analysis identified pretreatment (p = 0.031), chordae tendineae rupture (p = 0.011), and the LA/Ao (p < 0.001) as significant predictors of survival. Our findings suggest that the administration of cardiac medications, including pimobendan, prior to the onset of CHF was not independently associated with improved survival following CHF.

Solubility and permeability are key parameters for establishing in vitro-in vivo correlation for poorly water-soluble active pharmaceutical ingredients (APIs). Recent studies demonstrate that not only solubility, but also effective permeability of the API may change due to the addition of solubilizing agents, and there is a certain mathematical relation between these physicochemical parameters. The aim of this study was to show the importance of early screening of solubility and permeability in presence of additives in order to achieve the expected bioavailability of the API. In this work, the effect of surfactants and microenvironmental pH modifiers were in focus, and pimobendan was chosen as model drug.In the case of pH modifiers, the equilibrium solubility of the API increased, while the permeability decreased significantly. No negative effect was observed for two surfactants at low additive levels, but these two additives also exhibited a slightly negative effect on permeability when used at higher concentrations. In the simultaneous dissolution-permeation studies the surfactants-containing formulation was found to have slightly higher flux than the pH-modifier-containing one. It can be due to the phenomenon that the dissolution of the active substance can be enhanced by these surfactants without any significant permeability reducing effect.The results obtained from the present study clearly demonstrate the importance of studying drug-additive interactions in every step of formulation development and based on these, the selection of the appropriate quality and quantity of additives. In addition, the results also underline the significance of performing simultaneous dissolution-permeation studies to predict bioavailability.

Background: Some dogs with severe mitral valve regurgitation can have chronic cough, but its cause is unclear. Many of these dogs exhibit left principal (synonym mainstem) bronchial collapse or compression. Some clinicians believe that an enlarged heart, particularly the dilated left atrium, compresses the left principal bronchus, while others argue that a healthy bronchus cannot be compressed and that the cough is due to concurrent airway disease, such as bronchomalacia. In this study, we aimed to investigate the correlation between chronic cough and radiographic signs of bronchial narrowing in dogs with cardiomegaly secondary to primary mitral valve regurgitation. Methods: Four radiologists independently evaluated 51 sets of thoracic radiographs from client-owned dogs with cardiomegaly due to severe mitral valve regurgitation, including 26 sets of radiographs belonging to dogs with chronic (>8 weeks) cough and 25 without cough. The presence or absence of bronchial narrowing was assessed while the radiologists were blinded to patient characteristics and each other’s findings. Results: Interobserver variability was high, and the radiologists could not reliably predict which dogs had a chronic cough. Dogs with left atrial enlargement and airway narrowing sometimes coughed and sometimes did not. Likewise, some dogs with left atrial enlargement but no signs of airway compression or collapse coughed, and some did not. It was impossible to distinguish the groups based on these features. Conclusions: Bronchial compression by an enlarged heart and left atrium is an unlikely cause of chronic cough in dogs with severe primary mitral valve regurgitation.

Current anti-HBV therapeutic strategy relies on interferon and nucleos(t)ide-type drugs with the limitation of functional cure, inducing hepatitis B surface antigen (HBsAg) loss in very few patients. Notably, the level of HBsAg has been established as an accurate indicator to evaluate the drug efficacy and predict the disease prognosis, thus exploring a novel drug targeting HBsAg will be of great significance. Herein, by screening 978 compounds from an FDA-approved drug library and determining the inhibitory function of each drug on HBsAg level in HepG2.2.15 cells supernatant, we identified that pimobendan (Pim) has a powerful antiviral activity with relatively low cytotoxicity. The inhibitory effect of Pim on HBsAg as well as other HBV markers was validated in HBV-infected cell models and HBV-transgenic mice. Mechanistically, real-time PCR and dual-luciferase reporter assay were applied to identify the partial correlation of transcription factor CAAT enhancer-binding protein α (C/EBPα) with the cccDNA transcription regulated by Pim. This indicates Pim is an inhibitor of HBV transcription through suppressing HBV promoters to reduce HBV RNAs levels and HBsAg production. In conclusion, Pim was identified to be a transcription inhibitor of cccDNA, thereby inhibiting HBsAg and other HBV replicative intermediates both in vitro and in vivo . This report may provide a promising lead for the development of new anti-HBV agent.

Background Pimobendan has been proven to delay the onset of congestive heart failure (CHF) in dogs with mitral regurgitation (MR); however, molecular underlying mechanisms have not been fully elucidated. This study aimed to investigate (1) the effects of pimobendan on cardiac function, cardiac mitochondrial quality and morphology, and cardiac ultrastructure in a rat model of chronic MR and (2) the direct effect of pimobendan on intracellular reactive oxygen species (ROS) production in cardiac cells. MR was surgically induced in 20 Sprague-Dawley rats, and sham procedures were performed on 10 rats. Eight weeks post-surgery, the MR rats were randomly divided into two groups: the MR group and the MR + pimobendan group. Pimobendan (0.15 mg/kg) was administered twice a day via oral gavage for 4 weeks, whereas the sham and MR groups received equivalent volumes of drinking water. Echocardiography was performed at baseline (8 weeks post-surgery) and at the end of the study (4 weeks after treatment). At the end of the study protocol, all rats were euthanized, and their hearts were immediately collected, weighed, and used for transmission electron microscopy and mitochondrial quality assessments. To evaluate the role of pimobendan on intracellular ROS production, preventive or scavenging properties were tested with H 2 O 2 -induced ROS generation in rat cardiac myoblasts (H9c2). Results Pimobendan preserved cardiac functions and structure in MR rats. In addition, pimobendan significantly improved mitochondrial quality by attenuating ROS production and depolarization ( P  < 0.05). The cardiac ultrastructure and mitochondrial morphology were significantly preserved in the MR + pimobendan group. In addition, pimobendan appeared to play as a ROS scavenger, but not as a ROS preventer, in H 2 O 2 -induced ROS production in H9c2 cells. Conclusions Pimobendan demonstrated cardioprotective effects on cardiac function and ultrastructure by preserving mitochondrial quality and acted as an ROS scavenger in a rat model of MR.

Background: Myxomatous mitral valve degeneration is the most common canine heart disease. Several clinical trials have investigated various treatments. The latest recommendations are published in the ACVIM consensus guidelines (2019). Our study aimed to investigate how closely veterinary practitioners apply the treatment recommendations of these guidelines and the latest clinical trials. Methods: An online survey was sent to Dutch and Belgian veterinary practices via digital channels. Results: The data from 363 fully completed surveys were analyzed. For stage B1 disease, 93% recommended, correctly, no treatment. For stage B2 disease, 67% of the respondents recommended starting pimobendan as monotherapy. For chronic treatment of stage C disease, 16 different drug combinations were mentioned, but nobody recommended surgery. Only 48% of the respondents recommended the only evidence-based drug combination: a loop diuretic with pimobendan. A concerning finding was the simultaneous prescription of two loop diuretics, by 19% of the respondents. Conclusions: Treatment recommendations showed an increasing variation with more advanced disease stages from B1 through B2 to C. This reflects the increasing disagreement among the panelists who prepared the ACVIM consensus guidelines. Practitioners of our study seem to practice more evidence-based medicine than veterinary cardiologists, as it was reported in a recent survey-based study.

Background Pimobendan, diuretics, and an angiotensin-converting enzyme inhibitor (ACEi) are widely used for the management of chronic valvular heart disease in dogs; however, the effects of that combination on heart rate variability (HRV) are unknown. The purpose of this study was to assess the HRV of symptomatic myxomatous mitral valve degeneration (MMVD) dogs in response to therapy with a combination of pimobendan, diuretics, and ACEi. Results MMVD stage C (n = 17) dogs were enrolled and a 1-hour Holter recording together with echocardiography, blood pressure measurement, and blood chemistry profiles were obtained before and 1, 3, and 6 months after oral treatment with pimobendan (0.25 mg/kg), enalapril (0.5 mg/kg), and furosemide (2 mg/kg) twice daily. The results revealed that MMVD stage C dogs at the baseline had lower values of time-domain indices, low frequency (LF), high frequency (HF), and total power, as well as higher value of LF/HF. Triple therapy significantly increases these parameters in MMVD stage C dogs (P < 0.05). A positive moderate correlation was observed between time domain parameters and a left ventricular internal diastole diameter normalized to body weight (P < 0.05). Conclusions It can be concluded that MMVD stage C dogs possess low HRV due to either the withdrawal of parasympathetic tone or enhanced sympathetic activation, and a combination therapy was shown to enhance cardiac autonomic modulation inferred from the increased heart rate variability. Therefore, a combination therapy may be useful for restoring normal autonomic nervous system activity in dogs with MMVD stage C.

Background Intracardiac heartworm (IH) disease is a serious condition that can become life threatening if the patient develops caval syndrome. We aim to describe the management and outcome of IH in dogs evaluated by Medvet’s New Orleans cardiology service from November 2015 to December 2021. Methods Records of 27 dogs with IH were examined retrospectively. Follow-up information was obtained from phone conversations with referring veterinarians and owners. Results Nine of 27 dogs had a previous diagnosis of heartworm disease and were undergoing “slow kill” treatment; 12/27 dogs' heartworm disease was a new diagnosis, and 6/27 had either scheduled or started adulticide therapy. Nine dogs had heartworm extraction. No dogs died during the heartworm extraction procedure. Four of 9 dogs have died (survival time 1; 676; 1815 and 2184 days). One dog died the day after the procedure secondary to continued respiratory distress; the other three died of non-cardiac causes. Five of nine are alive (median follow-up 1062 (range 648–1831) days. Eleven dogs had IH resolution. In 7/11 this occurred while undergoing stabilization for heartworm extraction. In 4/11 heartworm extraction was not recommended because of low IH burden. All dogs with IH resolution were discharged from the hospital. Four of 11 have died (survival time 6; 22, 58 and 835 days), and 6/11 are alive (median follow-up 523 (range 268–2081) days. One was lost to follow-up after 18 days. Five dogs were medically managed. In one of five dogs, extraction was not recommended because of low IH burden. In four of five extraction was recommended but declined. One of five has died (survival 26 days), and four of five are alive (follow-up 155, 371, 935 and 947 days). Two dogs were killed at the time of diagnosis. Fifteen of 27 dogs were considered to have caval syndrome. Conclusion The results suggest that patients with IH resolution have a good long-term prognosis. Most often IH resolution occurred while the dog was undergoing stabilization for heartworm extraction. When IHs are present, heartworm extraction should still be considered the treatment of choice and recommended as first-line therapy whenever possible. Graphical Abstract