Myxomatous mitral valve disease in Miniature Schnauzers and Yorkshire Terriers: 134 cases (2007-2016).

OBJECTIVE: To characterize features of myxomatous mitral valve disease (MMVD) in Miniature Schnauzers and Yorkshire Terriers. ANIMALS: 69 Miniature Schnauzers and 65 Yorkshire Terriers, each with MMVD. PROCEDURES: Medical record data for each dog were collected; the study period was January 2007 through December 2016. If available, radiographic data were evaluated, and a vertebral heart scale score was assigned for each dog. Statistical analysis was performed with Student t and Fisher exact tests. RESULTS: Compared with Yorkshire Terriers, the prevalence of MMVD was significantly higher in Miniature Schnauzers and affected dogs were significantly younger at the time of diagnosis. Miniature Schnauzers were significantly more likely to have mitral valve prolapse and syncope, compared with Yorkshire Terriers. Yorkshire Terriers were significantly more likely to have coughing and have had previous or current treatment with cardiac medications, compared with Miniature Schnauzers. There was no statistical difference between breeds with regard to abnormally high vertebral heart scale scores or radiographic evidence of congestive heart failure. CONCLUSIONS AND CLINICAL RELEVANCE: With regard to MMVD, features of the disease among Miniature Schnauzers and Yorkshire Terriers were similar, but there were also a few discernable differences between these 2 breeds and from historical findings for dogs with MMVD of other breeds. Clinical signs at the time of diagnosis differed between the 2 breeds, which may have reflected concurrent breed-specific conditions (sick sinus syndrome or airway disease [eg, tracheal collapse]). Future work should include prospective studies to provide additional information regarding the natural progression of MMVD in these dog breeds.

A deleterious mutation in the ALMS1 gene in a naturally occurring model of hypertrophic cardiomyopathy in the Sphynx cat.

BACKGROUND: Familial hypertrophic cardiomyopathy is a common inherited cardiovascular disorder in people. Many causal mutations have been identified, but about 40% of cases do not have a known causative mutation. Mutations in the ALMS1 gene are associated with the development of Alstrom syndrome, a multisystem familial disease that can include cardiomyopathy (dilated, restrictive). Hypertrophic cardiomyopathy has not been described. The ALMS1 gene is a large gene that encodes for a ubiquitously expressed protein. The function of the protein is not well understood although it is believed to be associated with energy metabolism and homeostasis, cell differentiation and cell cycle control. The ALMS1 protein has also been shown to be involved in the regulation of cell cycle proliferation in perinatal cardiomyocytes. Although cardiomyocyte cell division and replication in mammals generally declines soon after birth, inhibition of ALMS1 expression in mice lead to increased cardiomyocyte proliferation, and deficiency of Alstrom protein has been suggested to impair post-natal cardiomyocyte cell cycle arrest. Here we describe the association of familial hypertrophic cardiomyopathy in Sphynx cats with a novel ALMS1 mutation. RESULTS: A G/C variant was identified in exon 12 (human exon 13) of the ALMS1 gene in affected cats and was positively associated with the presence of hypertrophic cardiomyopathy in the feline population (p < 0.0001). The variant was predicted to change a highly conserved nonpolar Glycine to a positively charged Arginine. This was predicted to be a deleterious change by three in silico programs. Protein prediction programs indicated that the variant changed the protein structure in this region from a coil to a helix. Light microscopy findings included myofiber disarray with interstitial fibrosis with significantly more nuclear proliferative activity in the affected cats than controls (p < 0.0001). CONCLUSION: This study demonstrates a novel form of cardiomyopathy associated with ALMS1 in the cat. Familial hypertrophic cardiomyopathy is a disease of genetic heterogeneity; many of the known causative genes encoding for sarcomeric proteins. Our findings suggest that variants in genes involved with cardiac development and cell regulation, like the ALMS1 gene, may deserve further consideration for association with familial hypertrophic cardiomyopathy.

Assessment of PDK4 and TTN gene variants in 48 Doberman Pinschers with dilated cardiomyopathy.

OBJECTIVE: To evaluate the frequency of variants in the pyruvate kinase dehydrogenase 4 (PDK4) and titin (TTN) genes in a group of Doberman Pinschers with dilated cardiomyopathy (DCM) and to determine whether there were unique clinical attributes to each variant. ANIMALS: 48 Doberman Pinschers with DCM. PROCEDURES: Doberman Pinschers with recently diagnosed DCM were identified, and genomic DNA from each was genotyped with a PCR assay for detection of PDK4 and TTN genetic variants. Dogs were grouped on the basis of whether they had the TTN variant alone, PDK4 variant alone, both variants, or neither variant. Descriptive statistics were compiled for dog age, body weight, and left ventricular dimensions and fractional shortening and for the presence of ventricular and supraventricular arrhythmias and heart failure. Results were compared across groups. RESULTS: Of the 48 dogs, 28 had the TTN variant alone, 10 had both variants, 6 had neither variant, and 4 had the PDK4 variant alone. The mean age was younger for dogs with the PDK4 variant alone, compared with other dogs. However, the number of dogs with the PDK4 variant alone was very small, and there was an overlap in age across groups. No other meaningful differences were detected across groups, and independent genotype-phenotype relationships were not identified. CONCLUSIONS AND CLINICAL RELEVANCE: Although findings indicated that the TTN variant was most common, 6 dogs had neither variant, and this fact supported the concept of ≥ 1 other genetic contributor to DCM in Doberman Pinschers. Future studies are warranted to evaluate genotype-phenotype relationships in Doberman Pinschers with DCM.

Retrospective evaluation of the safety and tolerability of pimobendan in cats with obstructive vs nonobstructive cardiomyopathy.

BACKGROUND: Pimobendan is frequently used off-label for treatments of cats with congestive heart failure (CHF). Concern exists regarding the safety of pimobendan in cats with outflow tract obstruction (OTO). OBJECTIVES: In cats treated with pimobendan, incidence of adverse effects will not differ between cats with OTO vs cats with nonobstructive cardiomyopathy. ANIMALS: Two-hundred sixty cats with CHF (57 with OTO, 203 with nonobstructive disease). METHODS: Retrospective medical record review. Groups were compared using 2-sample t-tests, Wilcoxon rank-sum tests, and Fisher exact tests. RESULTS: Compared to cats with nonobstructive cardiomyopathy, cats with OTO were younger (8.9 [interquartile range (IQR) 6.6] vs 10.8 [6.3] years, P = .0036), more likely to have a heart murmur (51/57 [90%] vs 76/203 [37.8%] cats, P < .0001), more likely to manifest CHF as pulmonary edema (53/57 [83%] vs 144/203 [70.9%] cats, P = .0004), and less likely to have pleural effusion (19/57 [33%] vs 122/203 [60.1%] cats, P = .0005). Adverse effects suspected to be related to pimobendan administration occurred in 12/260 cats (4.6%), including 11/203 cats (5.4%) with nonobstructive cardiomyopathy and 1/57 cat (2%) with OTO (P = .7). Pimobendan was discontinued due to adverse effects in 4/260 cats (1.5%), 3 with nonobstructive disease and 1 with OTO (P = 1.0). Acute adverse hemodynamic effects after pimobendan administration were not detected in any cats. CONCLUSIONS AND CLINICAL IMPORTANCE: Pimobendan is well tolerated in cats with cardiomyopathy and CHF, regardless of the presence of OTO.

Renin-angiotensin aldosterone profile before and after angiotensin-converting enzyme-inhibitor administration in dogs with angiotensin-converting enzyme gene polymorphism.

BACKGROUND: An angiotensin-converting enzyme (ACE) gene polymorphism occurs in dogs; however, functional importance is not well studied. HYPOTHESIS: We hypothesized that dogs with the polymorphism would show alternative renin-angiotensin aldosterone system (RAAS) pathway activation and classical RAAS pathway suppression before and after ACE-inhibitor administration, as compared to dogs without the polymorphism that would show this pattern only after ACE-inhibitor administration. ANIMALS: Twenty-one dogs with mitral valve disease that were genotyped for the ACE gene polymorphism. METHODS: This retrospective study utilized stored samples from 8 ACE gene polymorphism-negative (PN) dogs and 13 ACE gene polymorphism-positive (PP) dogs before and after enalapril administration. Equilibrium analysis was performed to evaluate serum RAAS metabolites and enzyme activities. Results were compared before and after enalapril, and between groups. RESULTS: The classical RAAS pathway was suppressed and the alternative RAAS pathway was enhanced for both genotypes after administration of enalapril, with no differences before enalapril administration. Aldosterone breakthrough occurred in both PN (38%) and PP (54%) dogs despite angiotensin II suppression. Aldosterone was significantly higher (P = .02) in ACE gene PP dogs (median, 92.17 pM; IQR, 21.85-184.70) compared to ACE gene PN dogs (median, 15.91 pM; IQR, <15.00-33.92) after enalapril. CONCLUSIONS AND CLINICAL IMPORTANCE: The ACE gene polymorphism did not alter baseline RAAS activity. Aldosterone breatkthrough in some dogs suggests nonangiotensin mediated aldosterone production that might be negatively influenced by genotype. These results support the use of aldosterone receptor antagonists with ACE-inhibitors when RAAS inhibition is indicated for dogs, especially those positive for the ACE gene polymorphism.

Echocardiographic phenotype of canine dilated cardiomyopathy differs based on diet type.

INTRODUCTION: Canine dilated cardiomyopathy (DCM) can result from numerous etiologies including genetic mutations, infections, toxins, and nutritional imbalances. This study sought to characterize differences in echocardiographic findings between dogs with DCM fed grain-free (GF) diets and grain-based (GB) diets. ANIMALS: Forty-eight dogs with DCM and known diet history. METHODS: This was a retrospective analysis of dogs with DCM from January 1, 2015 to May 1, 2018 with a known diet history. Dogs were grouped by diet (GF and GB), and the GF group was further divided into dogs eating the most common grain-free diet (GF-1) and other grain-free diets (GF-o). Demographics, diet history, echocardiographic parameters, taurine concentrations, and vertebral heart scale were compared between GB, all GF, GF-1, and GF-o groups at diagnosis and recheck. RESULTS: Dogs eating GF-1 weighed less than GB and GF-o dogs, but age and sex were not different between groups. Left ventricular size in diastole and systole was greater, and sphericity index was less for GF-1 compared with GB dogs. Diastolic left ventricular size was greater for all GF compared with that of GB dogs. Fractional shortening, left atrial size, and vertebral heart scale were not different between groups. Taurine deficiency was not identified in GF dogs, and presence of congestive heart failure was not different between groups. Seven dogs that were reevaluated after diet change (6 received taurine supplementation) had clinical and echocardiographic improvement. CONCLUSIONS: Dietary-associated DCM occurs with some GF diets and can improve with nutritional management, including diet change. The role of taurine supplementation, even without deficiency, is uncertain.

A missense variant in the titin gene in Doberman pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death.

The dog provides a large animal model of familial dilated cardiomyopathy for the study of important aspects of this common familial cardiovascular disease. We have previously demonstrated a form of canine dilated cardiomyopathy in the Doberman pinscher breed that is inherited as an autosomal dominant trait and is associated with a splice site variant in the pyruvate dehydrogenase kinase 4 (PDK4) gene, however, genetic heterogeneity exists in this species as well and not all affected dogs have the PDK4 variant. Whole genome sequencing of a family of Doberman pinchers with dilated cardiomyopathy and sudden cardiac death without the PDK4 variant was performed. A pathologic missense variant in the titin gene located in an immunoglobulin-like domain in the I-band spanning region of the molecule was identified and was highly associated with the disease (p < 0.0001). We demonstrate here the identification of a variant in the titin gene highly associated with the disease in this spontaneous canine model of dilated cardiomyopathy. This large animal model of familial dilated cardiomyopathy shares many similarities with the human disease including mode of inheritance, clinical presentation, genetic heterogeneity and a pathologic variant in the titin gene. The dog is an excellent model to improve our understanding of the genotypic phenotypic relationships, penetrance, expression and the pathophysiology of variants in the titin gene.

Angiotensin-converting enzyme activity in Cavalier King Charles Spaniels with an ACE gene polymorphism and myxomatous mitral valve disease.

OBJECTIVES: Myxomatous mitral valve disease (MMVD) is the most common heart disease in the dog. It is particularly common in the Cavalier King Charles Spaniel (CKCS) breed and affected dogs are frequently managed with angiotensin-converting enzyme inhibitors (ACE-I). We have previously identified a canine ACE gene polymorphism associated with a decrease in angiotensin-converting enzyme (ACE) activity. The aim of this study was to evaluate for the prevalence of the ACE polymorphism in CKCS with mitral valve disease and to determine whether the presence of the polymorphism is associated with alterations in ACE activity at different stages of cardiac disease. METHODS: Seventy-three dogs with a diagnosis of mitral valve disease were evaluated and a blood sample was drawn for ACE polymorphism genotyping and ACE activity measurement. RESULTS: Forty-three dogs were homozygous for the ACE polymorphism; five were heterozygous and 25 were homozygous wild type. The mean age and the median severity of disease were not different for dogs with the polymorphism and dogs with the wild-type sequence. The median baseline ACE activity was significantly lower for the ACE polymorphism (27.0 U/l) than the wild-type sequence dogs (31.0 U/l) (P=0.02). Dogs with more severe disease and the ACE polymorphism had significantly lower levels of ACE activity than dogs with the wild-type sequence (P=0.03). CONCLUSION: The CKCS appears to have a high prevalence of the ACE variant. Dogs with the ACE variant had lower levels of ACE activity even in more advanced mitral valve disease than dogs without the variant. The clinical significance of this finding and its impact on the need for ACE-I in dogs with the polymorphism and heart disease deserves further study.

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.

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.

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.

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.

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.

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.

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.

Echocardiographic estimation of systemic systolic blood pressure in dogs with mild mitral regurgitation.

BACKGROUND: Systemic hypertension is likely underdiagnosed in veterinary medicine because systemic blood pressure is rarely measured. Systemic blood pressure can theoretically be estimated by echocardiography. According to the modified Bernoulli equation (PG = 4v(2)), mitral regurgitation (MR) velocity should approximate systolic left ventricular pressure (sLVP), and therefore systolic systemic blood pressure (sSBP) in the presence of a normal left atrial pressure (LAP) and the absence of aortic stenosis. The aim of this study was to evaluate the use of echocardiography to estimate sSBP by means of the Bernoulli equation. HYPOTHESIS: Systemic blood pressure can be estimated by echocardiography. ANIMAL: Seventeen dogs with mild MR. No dogs had aortic or subaortic stenosis, and all had MR with a clear continuous-wave Doppler signal and a left atrial to aorta ratio of < or = 1.6. METHODS: Five simultaneous, blinded continuous-wave measurements of maximum MR velocity (Vmax) and indirect sSBP measurements (by Park's Doppler) were obtained for each dog. Pressure gradient was calculated from Vmax by means of the Bernoulli equation, averaged, and added to an assumed LAP of 8 mm Hg to calculate sLVP. RESULTS: Calculated sLVP was significantly correlated with indirectly measured sSBP within a range of 121 to 218 mm Hg (P = .0002, r = .78). Mean +/- SD bias was 0.1 +/- 15.3 mm Hg with limits of agreement of -29.9 to 30.1 mm Hg. CONCLUSION: Despite the significant correlation, the wide limits of agreement between the methods hinder the clinical utility of echocardiographic estimation of blood pressure.