N.S. Moïse

Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: The EPIC Study—A Randomized Clinical Trial

Background Pimobendan is effective in treatment of dogs with congestive heart failure (CHF) secondary to myxomatous mitral valve disease (MMVD). Its effect on dogs before the onset of CHF is unknown. Hypothesis/Objectives Administration of pimobendan (0.4–0.6 mg/kg/d in divided doses) to dogs with increased heart size secondary to preclinical MMVD, not receiving other cardiovascular medications, will delay the onset of signs of CHF, cardiac‐related death, or euthanasia. Animals 360 client‐owned dogs with MMVD with left atrial‐to‐aortic ratio ≥1.6, normalized left ventricular internal diameter in diastole ≥1.7, and vertebral heart sum >10.5. Methods Prospective, randomized, placebo‐controlled, blinded, multicenter clinical trial. Primary outcome variable was time to a composite of the onset of CHF, cardiac‐related death, or euthanasia. Results Median time to primary endpoint was 1228 days (95% CI: 856–NA) in the pimobendan group and 766 days (95% CI: 667–875) in the placebo group (P = .0038). Hazard ratio for the pimobendan group was 0.64 (95% CI: 0.47–0.87) compared with the placebo group. The benefit persisted after adjustment for other variables. Adverse events were not different between treatment groups. Dogs in the pimobendan group lived longer (median survival time was 1059 days (95% CI: 952–NA) in the pimobendan group and 902 days (95% CI: 747–1061) in the placebo group) (P = .012). Conclusions and Clinical Importance Administration of pimobendan to dogs with MMVD and echocardiographic and radiographic evidence of cardiomegaly results in prolongation of preclinical period and is safe and well tolerated. Prolongation of preclinical period by approximately 15 months represents substantial clinical benefit.

Combination Therapy with Digoxin and Diltiazem Controls Ventricular Rate in Chronic Atrial Fibrillation in Dogs Better than Digoxin or Diltiazem Monotherapy: A Randomized Crossover Study in 18 Dogs

BACKGROUND Atrial fibrillation (AF) with excessively high ventricular rates (VR) occurs in dogs with advanced heart disease. Rate control improves clinical signs in these patients. Optimal drug therapy and target VR remain poorly defined. HYPOTHESIS Digoxin-diltiazem combination therapy reduces VR more than either drug alone in dogs with high VR AF. ANIMALS Eighteen client-owned dogs (>15 kg) with advanced heart disease, AF, and average VR on 24-hour Holter > 140 beats per minute (bpm). METHODS After baseline Holter recording, dogs were randomized to digoxin or diltiazem monotherapy, or combination therapy. Repeat Holter evaluation was obtained after 2 weeks; dogs were then crossed over to the other arm (monotherapy or combination therapy) for 2 weeks and a third Holter was acquired. Twenty-four hour average VR, absolute and relative VR changes from baseline, and percent time spent within prespecified VR ranges (>140, 100-140, and <100 bpm) were compared. Correlations between serum drug concentrations and VR were examined. RESULTS Digoxin (median, 164 bpm) and diltiazem (median, 158 bpm) decreased VR from baseline (median, 194 bpm) less than the digoxin-diltiazem combination (median, 126 bpm) (P < .008 for each comparison). With digoxin-diltiazem, VR remained <140 bpm for 85% of the recording period, but remained >140 bpm for 88% of the recording period with either monotherapy. Serum drug concentrations did not correlate with VR. CONCLUSIONS AND CLINICAL IMPORTANCE At the dosages used in this study, digoxin-diltiazem combination therapy provided a greater rate control than either drug alone in dogs with AF.

Effect of transvenous electrical cardioversion on plasma cardiac troponin I concentrations in horses with atrial fibrillation.

BACKGROUND Whether electrical cardioversion of cardiac arrhythmias results in cardiomyocyte damage is unknown. OBJECTIVE To describe effect of transvenous electrical cardioversion (TVEC) on plasma cardiac troponin I (cTnI) concentration in horses. ANIMALS All horses presented to the Cornell University Hospital for Animals for cardioversion of atrial fibrillation between May 2006 and October 2008 were eligible for inclusion in the study. Owners of 14 horses elected for TVEC and each horse was then enrolled (16 procedures). METHODS Prospective observational study measuring concentrations of plasma cTnI before and after TVEC. RESULTS Median cTnI concentration increased from 0.045 ng/mL at baseline (range 0.0-0.20 ng/mL) to 0.11 ng/mL after TVEC (range 0.0-3.73 ng/mL) (P= .036). This increase was not associated with the number of shocks delivered, maximal energy delivered, cumulative energy delivered, chronicity of atrial fibrillation before cardioversion, or positioning of the pulmonary artery catheter. CONCLUSIONS The increase in cTnI is unlikely to be clinically important. The increase might be correlated with persistent atrial dysfunction after TVEC, suggesting that a longer convalescent period after the procedure could be warranted.

Transesophageal Echocardiography as the Sole Guidance for Occlusion of Patent Ductus Arteriosus using a Canine Ductal Occluder in Dogs

Background Transcatheter occlusion of patent ductus arteriosus (PDA) is usually performed by fluoroscopy alone or together with transesophageal echocardiography (TEE). Transthoracic echocardiography (TTE) guidance has been used for deployment of Amplatz Canine Ductal Occluder (ACDO), but sometimes is limited by suboptimal acoustic windows. Transesophageal echocardiography can overcome such issues and provides higher image resolution at the level of the great vessels. Objectives To determine if TEE without fluoroscopy could be used to successfully perform ductal occlusion for the treatment of PDA in dogs. Animals Twenty client‐owned dogs with PDA. Methods A prospective consecutive case series of PDA occlusion was performed using only TEE guidance. Dogs were positioned in right lateral recumbency and the TEE probe was positioned to visualize the descending aorta, PDA, and pulmonary artery. The guide wire, long introducer sheath, and ACDO were imaged by TEE to direct deployment. Results Ductal occlusion was performed successfully without need for fluoroscopy and without complications in 19 dogs. One dog required a second larger ACDO because of embolization of the first device 18 hours after positioning. Conclusions and Clinical Importance We have demonstrated that TEE monitoring without concurrent fluoroscopy can guide each step of transcatheter ACDO embolization thereby providing an alternate method of visualization for this procedure. Use of TEE alone can reduce radiation exposure or is an option when fluoroscopy is not available, and, therefore, should be evaluated in a larger case series to better assess procedural failure rates.

Combination therapy with mexiletine and sotalol suppresses inherited ventricular arrhythmias in German shepherd dogs better than mexiletine or sotalol monotherapy: a randomized cross-over study.

OBJECTIVES To determine the spontaneous variability of ventricular arrhythmias (VA) and evaluate anti-arrhythmic efficacy of mexiletine, sotalol, and a mexiletine-sotalol combination in German shepherd dogs (GSD) with inherited arrhythmias. ANIMALS, MATERIALS AND METHODS 12 affected GSD, median age 20 weeks, received mexiletine (8 mg/kg PO q8 h), sotalol (2.5 mg/kg PO q12 h), and combination therapy for 6 days in random order. Pre- and post-treatment 24 h Holter recordings were acquired, allowing determination of VA variability and reduction in 24 h VA for each treatment. Drug concentrations during each arm were measured. RESULTS An anti-arrhythmic effect could be inferred if ventricular premature complexes (VPC), ventricular couplets (V(cpl)), ventricular tachycardia runs (VT(runs)) and total ventricular ectopy (VE(tot)) frequency were reduced by 61%, 97%, 98%, and 63% (1 control Holter model), by 53%, 94%, 95%, and 54% (4 control Holter model) and by 54%, 95%, 96% and 56% (3 control Holter model). Combination therapy reduced VPC and VE(tot) in more dogs (5/12 and 6/12) than mexiletine (1/11 and 2/11) or sotalol (2/9 and 1/9) (p < 0.05). The combination therapy reduced the mean number of VPC, V(cpl), and VE(tot). Sotalol monotherapy produced an increase in VT(runs). Plasma mexiletine concentration was higher during combination therapy than with monotherapy. CONCLUSIONS Combination therapy reduced VPC in affected GSD. Sotalol monotherapy increased VT(runs). Combination therapy increased plasma mexiletine concentrations.

Change in β‐Catenin Localization Suggests Involvement of the Canonical Wnt Pathway in Boxer Dogs with Arrhythmogenic Right Ventricular Cardiomyopathy

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease with high prevalence in the Boxer dog population. It is characterized by replacement of the myocardium with fatty or fibro‐fatty tissue. Several mechanisms for the development of ARVC have been suggested, including dysfunction of the canonical Wnt pathway, which is linked to many cellular functions, including growth and differentiation of adipocytes. Hypothesis Wnt pathway dysfunction is involved in the development of ARVC in the Boxer as evidenced by mislocalization of β‐catenin, an integral Wnt pathway modulator, and striatin, a known Wnt pathway component. Animals Five dogs without ARVC and 15 Boxers with ARVC were identified by 24‐hour Holter monitoring and histopathologic examination of the heart. Methods Right ventricular samples were collected and examined using confocal microscopy, Western blots, and quantitative (q) PCR. Results Confocal microscopy indicated that β‐catenin localized at sites of cell‐to‐cell apposition, and striatin localized in a diffuse intracellular pattern in hearts without ARVC. In hearts affected with ARVC, both β‐catenin and striatin were colocalized with the endoplasmic reticulum (ER) marker calreticulin. Western blots indentified a 50% increase in the amount of β‐catenin in ARVC samples. No change in β catenin mRNA was detected using qPCR. Conclusions Our data suggest that trafficking of Wnt pathway proteins from the ER to their proper location within the cell is inhibited in Boxers with ARVC. These results suggest that disturbances in the Wnt pathway may play a role in the development of ARVC in the Boxer.

Lidocaine Converts Acute Vagally Associated Atrial Fibrillation to Sinus Rhythm in German Shepherd Dogs with Inherited Arrhythmias

BACKGROUND Lidocaine is most frequently used to treat ventricular arrhythmias. However, lidocaine may have an antiarrhythmic effect for certain supraventricular arrhythmias. HYPOTHESIS We hypothesized that lidocaine would be effective in converting experimentally induced atrial fibrillation (AF) to sinus rhythm and that a decrease in the dominant frequency (DF) and an increase in the organization as judged by the spectral entropy (SE) would occur over the course of the conversion. ANIMALS Seven German Shepherd (GS) Dogs. METHODS Dogs were anesthetized with fentanyl and pentobarbital. AF was induced with standard pacing protocols while left and right atrial monophasic action potentials (MAP) were recorded. The power spectra from the MAP recordings were analyzed to determine DF and SE during treatment with boluses of 2 mg/kg lidocaine. RESULTS Lidocaine converted AF to sinus rhythm in all dogs and all episodes (n = 19). Conversion time was 27-87 seconds. After atropine, sustained AF was not induced; however, 5 episodes of atrial tachycardia resulted, and 3 were converted with lidocaine. Frequency domain analysis of 12 conversion sequences showed that left and right DF of the MAP signals decreased from the time of injection to conversion to sinus rhythm (P < .001). Mean SE indicated a gradient between the left and right atria (P = .003) that did not change during conversion. CONCLUSIONS AND CLINICAL IMPORTANCE Vagally associated AF in GS dogs is terminated with lidocaine. Lidocaine is likely an effective treatment in clinical dogs with vagally associated AF.

Atrial-Based Pacing for Sinus Node Dysfunction in Dogs: Initial Results

BACKGROUND An important consideration for the treatment of sick sinus syndrome (SSS) lies in the function of the atrioventricular (AV) node because most patients with SSS retain the ability to conduct atrial impulses. HYPOTHESIS/OBJECTIVES This retrospective study examined the feasibility of atrial pacing (AAI) in dogs with sinus node dysfunction (SND). ANIMALS Sixteen dogs with SND and AAI pacing were identified. METHODS Retrospective review of medical records. RESULTS Follow-up time ranged from 45 to 1,227 days (mean: 292 days). Only 1 dog developed AV block 3 days postoperatively. Complete lead dislodgment occurred in 3/16 dogs 1, 19, and 27 days postoperatively. Lead perforation into the pericardial space occurred in 2/16 dogs. Rising thresholds for pacing with possible lead microdislodgment or fibrosis were suspected in another 3/16 dogs 57, 192, and 1,016 days after implantation. None of these dogs had complete loss of capture but all required higher thresholds for pacing. CONCLUSIONS AND CLINICAL IMPORTANCE Based on this small group of dogs, clinically important AV block does not appear to occur in the long-term for dogs with SND. Risks of lead perforation, complete dislodgment, and rising thresholds for pacing, possibly because of microdislodgment, may be related to the initial skill level of the operator or the leads that were used. Use of leads with reduced torque at the lead tip, higher flexibility, increased lead-tip surface of contact with the endocardium or, more likely, use of alternate locations for pacing in the small right atrium of dogs with SND may decrease the frequency of these complications.

Genetic analysis of ventricular arrhythmia in young German Shepherd Dogs.

BACKGROUND Ventricular arrhythmias (VA) and sudden death are inherited in German Shepherd Dogs (GSDs). OBJECTIVES To estimate the genetic parameters (heritabilities and correlations) of 3 traits of VA (single premature ventricular complexes (PVCs), 2 consecutive PVCs (couplets), and 3 or more consecutive PVCs-ventricular tachycardia [VT]). ANIMALS Three hundred and ninety-eight GSDs. METHODS Prospective, observational, case control study. Dogs were phenotyped by 24-hour ambulatory ECG from 6 to 45 weeks of age. Edited ECG records included the number of incidents of (1) single PVCs, (2) couplets, and (3) VT. RESULTS A data set of 1,239 Holter records from 398 GSDs was used to estimate genetic variables. Phenotypic correlations for affectedness (binarily coded 0/1) of the 3 traits ranged from 0.55 to 0.74, whereas correlations for severity (continuous values of 24-hour VA counts) ranged from 0.26 to 0.39. Estimates of genetic correlation among the severity traits were 0.06 to 0.27. Estimated heritabilities were 0.54, 0.54, and 0.46 for affectedness and 0.33, 0.69, and 0.69 for severity of PVCs, couplets, and VT, respectively. Month and year of birth and age at ECG recording had significant effects on all 3 traits. Season of ECG recording had a significant effect on the number of single PVCs, but not couplets or incidents of VT. Age of onset differed, with single PVCs appearing an average of 4 days earlier than couplets and VT. CONCLUSION These results imply a strong genetic component for this disease but suggest that differences in the 3 traits should be taken into consideration in studies to identify the underlying genes.

Longitudinal Analysis of Quality of Life, Clinical, Radiographic, Echocardiographic, and Laboratory Variables in Dogs with Preclinical Myxomatous Mitral Valve Disease Receiving Pimobendan or Placebo : The EPIC Study

Background Changes in clinical variables associated with the administration of pimobendan to dogs with preclinical myxomatous mitral valve disease (MMVD) and cardiomegaly have not been described. Objectives To investigate the effect of pimobendan on clinical variables and the relationship between a change in heart size and the time to congestive heart failure (CHF) or cardiac‐related death (CRD) in dogs with MMVD and cardiomegaly. To determine whether pimobendan‐treated dogs differ from dogs receiving placebo at onset of CHF. Animals Three hundred and fifty‐four dogs with MMVD and cardiomegaly. Materials and Methods Prospective, blinded study with dogs randomized (ratio 1:1) to pimobendan (0.4–0.6 mg/kg/d) or placebo. Clinical, laboratory, and heart‐size variables in both groups were measured and compared at different time points (day 35 and onset of CHF) and over the study duration. Relationships between short‐term changes in echocardiographic variables and time to CHF or CRD were explored. Results At day 35, heart size had reduced in the pimobendan group: median change in (Δ) LVIDDN −0.06 (IQR: −0.15 to +0.02), P < 0.0001, and LA:Ao −0.08 (IQR: −0.23 to +0.03), P < 0.0001. Reduction in heart size was associated with increased time to CHF or CRD. Hazard ratio for a 0.1 increase in ΔLVIDDN was 1.26, P = 0.0003. Hazard ratio for a 0.1 increase in ΔLA:Ao was 1.14, P = 0.0002. At onset of CHF, groups were similar. Conclusions and Clinical Importance Pimobendan treatment reduces heart size. Reduced heart size is associated with improved outcome. At the onset of CHF, dogs treated with pimobendan were indistinguishable from those receiving placebo.