Sandra P. Tou

Canine Models of Duchenne Muscular Dystrophy and Their Use in Therapeutic Strategies

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder in which the loss of dystrophin causes progressive degeneration of skeletal and cardiac muscle. Potential therapies that carry substantial risk, such as gene- and cell-based approaches, must first be tested in animal models, notably the mdx mouse and several dystrophin-deficient breeds of dogs, including golden retriever muscular dystrophy (GRMD). Affected dogs have a more severe phenotype, in keeping with that of DMD, so may better predict disease pathogenesis and treatment efficacy. Various phenotypic tests have been developed to characterize disease progression in the GRMD model. These biomarkers range from measures of strength and joint contractures to magnetic resonance imaging. Some of these tests are routinely used in clinical veterinary practice, while others require specialized equipment and expertise. By comparing serial measurements from treated and untreated groups, one can document improvement or delayed progression of disease. Potential treatments for DMD may be broadly categorized as molecular, cellular, or pharmacologic. The GRMD model has increasingly been used to assess efficacy of a range of these therapies. A number of these studies have provided largely general proof-of-concept for the treatment under study. Others have demonstrated efficacy using the biomarkers discussed. Importantly, just as symptoms in DMD vary among patients, GRMD dogs display remarkable phenotypic variation. Though confounding statistical analysis in preclinical trials, this variation offers insight regarding the role that modifier genes play in disease pathogenesis. By correlating functional and mRNA profiling results, gene targets for therapy development can be identified.

Association of Dilated Cardiomyopathy with the Striatin Mutation Genotype in Boxer Dogs

BACKGROUND Myocardial disease in the Boxer dog is characterized by 1 of 2 clinical presentations, dilated cardiomyopathy (DCM) characterized by ventricular systolic dysfunction, dilatation and tachyarrhythmias, and arrhythmogenic right ventricular cardiomyopathy (ARVC) characterized by ventricular tachyarrhythmias, syncope, and sudden death. Boxer ARVC has been associated with a deletion in the striatin gene in some families. HYPOTHESIS/OBJECTIVES We hypothesized that both presentations represent a single disease, and the development of DCM in the Boxer is associated with the striatin deletion. ANIMALS Thirty-three adult Boxer dogs with DCM, 29 adult Boxer dogs with the striatin deletion and ARVC, and 16 Boxers without cardiac disease. METHODS DNA samples were evaluated for the striatin deletion. Association of the deletion with the DCM phenotype was tested by a Fishers exact test. T-tests were used to evaluate potential differences between the positive heterozygous and positive homozygous groups with DCM with regard to age, LVIDD, LVIDS, and FS%. RESULTS Thirty of 33 dogs with DCM were positive for the striatin deletion. The striatin mutation and the homozygous genotype were strongly associated with the DCM phenotype (P < .001 and P = .005). There was no statistical difference between the heterozygous and homozygous groups with regard to age and echocardiographic measurements. CONCLUSIONS AND CLINICAL IMPORTANCE This study demonstrates an association between DCM in the Boxer dog and the striatin mutation, particularly with the homozygous genotype. The observation that 3/33 dogs developed DCM and lacked the striatin mutation suggests that there is at least 1 other cause of DCM in the Boxer dog.

Cutting balloon catheterization for interventional treatment of cor triatriatum dexter: 2 cases.

Cutting balloon dilatation was performed successfully in two dogs with cor triatriatum dexter and clinical signs of ascites. The cutting balloon catheter uses incisional microtomes embedded in a balloon catheter. During balloon expansion, these microtomes incise the adjacent tissue, decreasing circumferential wall stress. This theoretically reduces both the likelihood of fracturing the adjacent tissues in an uncontrolled manner and the potential neoproliferative response to standard balloon dilatation and the subsequent incidence of re-stenosis. In both cases described, clinical signs resolved completely following cutting balloon dilatation of the anomalous membrane. Based on the outcome of these 2 cases, cutting balloon dilatation appears to be a viable treatment option for dogs affected with cor triatriatum dexter.

Case-control study of the effects of pimobendan on survival time in cats with hypertrophic cardiomyopathy and congestive heart failure

OBJECTIVE To assess survival time and adverse events related to the administration of pimobendan to cats with congestive heart failure (CHF) secondary to hypertrophic cardiomyopathy (HCM) or hypertrophic obstructive cardiomyopathy (HOCM). DESIGN Retrospective case-control study. ANIMALS 27 cats receiving treatment with pimobendan and 27 cats receiving treatment without pimobendan. PROCEDURES Medical records between 2003 and 2013 were reviewed. All cats with HCM or HOCM treated with a regimen that included pimobendan (case cats) were identified. Control cats (cats with CHF treated during the same period with a regimen that did not include pimobendan) were selected by matching to case cats on the basis of age, sex, body weight, type of cardiomyopathy, and manifestation of CHF. Data collected included signalment, physical examination findings, echocardiographic data, serum biochemical values, and survival time from initial diagnosis of CHF. Kaplan-Meier survival curves were constructed and compared by means of a log rank test. RESULTS Cats receiving pimobendan had a significant benefit in survival time. Median survival time of case cats receiving pimobendan was 626 days, whereas median survival time for control cats not receiving pimobendan was 103 days. No significant differences were detected for any other variable. CONCLUSIONS AND CLINICAL RELEVANCE The addition of pimobendan to traditional treatment for CHF may provide a substantial clinical benefit in survival time for HCM-affected cats with CHF and possibly HOCM-affected cats with CHF.

Hybrid cutting balloon dilatation for treatment of cor triatriatum sinister in a cat

A hybrid surgical approach and balloon dilatation were performed successfully in a cat with cor triatriatum sinister and clinical signs of congestive heart failure. Left lateral thoracotomy was used to access the heart and cutting balloon followed by standard balloon dilatation were utilized to dilate the perforation in the anomalous left atrial membrane. Clinical signs resolved completely after dilation of the anomalous left atrial membrane. Based upon the outcome of this case, balloon dilatation appears to be a viable treatment option for cats affected with cor triatriatum sinister.

Intracoronary allogeneic cardiosphere-derived stem cells are safe for use in dogs with dilated cardiomyopathy

Cardiosphere‐derived cells (CDCs) have been shown to reduce scar size and increase viable myocardium in human patients with mild/moderate myocardial infarction. Studies in rodent models suggest that CDC therapy may confer therapeutic benefits in patients with non‐ischaemic dilated cardiomyopathy (DCM). We sought to determine the safety and efficacy of allogeneic CDC in a large animal (canine) model of spontaneous DCM. Canine CDCs (cCDCs) were grown from a donor dog heart. Similar to human CDCs, cCDCs express CD105 and are slightly positive for c‐kit and CD90. Thirty million of allogeneic cCDCs was infused into the coronary vessels of Doberman pinscher dogs with spontaneous DCM. Adverse events were closely monitored, and cardiac functions were measured by echocardiography. No adverse events occurred during and after cell infusion. Histology on dog hearts (after natural death) revealed no sign of immune rejection from the transplanted cells.

Accuracy of point-of-care lung ultrasonography for the diagnosis of cardiogenic pulmonary edema in dogs and cats with acute dyspnea

OBJECTIVE To determine the accuracy of a point-of-care lung ultrasonography (LUS) protocol designed to diagnose cardiogenic pulmonary edema (CPE) in dyspneic dogs and cats. DESIGN Diagnostic test evaluation. ANIMALS 76 dogs and 24 cats evaluated for dyspnea. PROCEDURES Dogs and cats were evaluated by LUS; B lines were counted at 4 anatomic sites on each hemithorax. A site was scored as positive when > 3 B lines were identified. Animals with ≥ 2 positive sites identified on each hemithorax were considered positive for CPE. Medical records were evaluated to obtain a final diagnosis (reference standard) for calculation of the sensitivity and specificity of LUS and thoracic radiography for the diagnosis of CPE. RESULTS Dogs and cats with a final diagnosis of CPE had a higher number of positive LUS sites than did those with noncardiac causes of dyspnea. Overall sensitivity and specificity of LUS for the diagnosis of CPE were 84% and 74%, respectively, and these values were similar to those of thoracic radiography (85% and 87%, respectively). Use of LUS generally led to the misdiagnosis of CPE (ie, a false-positive result) in animals with diffuse interstitial or alveolar disease. Interobserver agreement on LUS results was high (κ > 0.85). CONCLUSIONS AND CLINICAL RELEVANCE LUS was useful for predicting CPE as the cause of dyspnea in dogs and cats, although this technique could not be used to differentiate CPE from other causes of diffuse interstitial or alveolar disease. Point-of-care LUS has promise as a diagnostic tool for dyspneic dogs and cats.

Pulmonary atresia and ventricular septal defect with aortopulmonary collaterals in an adult dog.

Pulmonary atresia and ventricular septal defect (PA-VSD) was diagnosed in a 2-year-old castrated male Terrier mix. Transthoracic echocardiography identified a large ventricular septal defect, overriding aorta and severe right ventricular hypertrophy. A main pulmonary artery could not be identified, consistent with pulmonary atresia or persistent truncus arteriosus. Transesophageal echocardiography and angiography confirmed PA-VSD with aortopulmonary collateral circulation arising from the descending thoracic aorta. This case report describes the antemortem diagnosis of the rare congenital defect PA-VSD in an adult dog.

Complication rates associated with transvenous pacemaker implantation in dogs with high-grade atrioventricular block performed during versus after normal business hours.

Background Transvenous pacemaker implantation in dogs is associated with a relatively high complication rate. At our institution, pacemaker implantation in dogs with high‐grade atrioventricular block (HG‐AVB) frequently is performed as an after‐hours emergency. Hypothesis Among dogs with HG‐AVB, the rate of major complications is higher when pacemakers are implanted after hours (AH) compared to during business hours (BH). Animals Client‐owned dogs with HG‐AVB that underwent transvenous pacemaker implantation between January 2002 and December 2012 at the North Carolina State University Veterinary Teaching Hospital. Methods Retrospective medical record review. Two‐year follow‐up was required for complications analysis. Results Major complications occurred in 14/79 dogs (18%) and included lead dislodgement, lead or generator infection, lead or generator migration, and pacing failure. Incidence of major complications was significantly higher AH (10/36, 28%) compared to BH (4/43, 9%; P = .041), and all infectious complications occurred AH. Median survival time for all dogs was 27 months and did not differ between AH and BH groups for either all‐cause (P = .70) or cardiac (P = .40) mortality. AH dogs were younger than BH dogs (P = .010), but there were no other clinically relevant differences between BH and AH groups in terms of demographic, clinical, or procedural variables. Conclusions and Clinical Importance At our institution, AH transvenous pacemaker placement is associated with a higher rate of major complications (especially infections) compared to BH placement. This difference may be because of a variety of human factor differences AH versus BH.

Suspected acute myocardial infarction in a dystrophin-deficient dog.

Golden retriever muscular dystrophy (GRMD) is a model for the genetically homologous human disease, Duchenne muscular dystrophy (DMD). Unlike the mildly affected mdx mouse, GRMD recapitulates the severe DMD phenotype. In addition to skeletal muscle involvement, DMD boys develop cardiomyopathy. While the cardiomyopathy of DMD is typically slowly progressive, rare early episodes of acute cardiac decompensation, compatible with myocardial infarction, have been described. We report here a 7-month-old GRMD dog with an apparent analogous episode of myocardial infarction. The dog presented with acute signs of cardiac disease, including tachyarrhythmia, supraventricular premature complexes, and femoral pulse deficits. Serum cardiac biomarkers, cardiac-specific troponin I (cTnI) and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), were markedly increased. Echocardiography showed areas of hyperechoic myocardial enhancement, typical of GRMD cardiomyopathy. Left ventricular dyskinesis and elevated cTnI were suggestive of acute myocardial damage/infarction. Over a 3-year period, progression to a severe dilated phenotype was observed.