Genome-wide analysis of mitral valve disease in Cavalier King Charles Spaniels

The Cavalier King Charles Spaniel (CKCS) is prone to severe early onset mitral valve disease. In this study, 36 purebred CKCS dogs were evaluated for mitral valve murmur and divided into early and late onset groups. A genome-wide genetic approach was used to assess whether the condition is determined by a small number of genetic factors. There were no regions of highly discrepant homo/heterozygosity in the two groups. Similarly, there was no evidence for loci associated with mitral valve murmur in a genome-wide association study. This analysis suggests that familial occurrence of mitral valve murmur in the CKCS breed is not due to a single major gene effect, indicating that breeding strategies to eliminate the disease cannot be based on genotype information at this time.     

Assessment of changes in hemostatic markers in Cavalier King Charles Spaniels with myxomatous mitral valve disease

OBJECTIVE: To evaluate markers of hemostasis and their relationship to the degree of mitral regurgitation (MR) and platelet function in Cavalier King Charles Spaniels (CKCSs) with myxomatous mitral valve disease. ANIMALS: 76 clinically healthy CKCSs and 24 control dogs. PROCEDURE: All dogs underwent echocardiographic examination; various hemostatic, hematologic, and biochemical variables were evaluated in blood. The CKCSs were allocated to 1 of 3 groups on the basis of MR severity. In 8 control dogs and 8 CKCSs, plasma von Willebrand factor (vWF) multimer analysis was performed. RESULTS: Compared with control dogs, plasma fibrinogen concentration was higher in all CKCSs and related to left ventricular end diastolic diameter and left atrial-to-aortic root ratio among all CKCSs. The activated partial thromboplastin times and plasma D-dimer concentration were similar among the 4 groups. Plasma vWF concentration was lower in CKCSs with moderate to severe MR, compared with that of CKCSs with no MR and control dogs. There was a relationship between plasma vWF concentration and platelet function in CKCSs but not in control dogs. In 4 CKCSs with moderate to severe MR and low plasma vWF concentration, amounts of vWF high-molecular-weight multimers (HMWMs) were low. CONCLUSIONS AND CLINICAL RELEVANCE: In CKCSs, MR appeared to be associated with a low plasma vWF concentration and likely a loss of vWF HMWMs (possibly through their destruction via shear stress to the blood). The importance of the changes in plasma fibrinogen concentration and the thromboembolic risk in dogs with MR remain to be investigated.     

Echocardiographic measurement of the mitral valve in normal Cavalier King Charles spaniels: repeatability,optimal future study methods,and preliminary reference intervals

Introduction/ObjectivesCavalier King Charles spaniels (CKCS) are ideal candidates for longitudinal study of myxomatous mitral valve (MV) disease and stage B1 clinical trials; however, the optimization of MV measurement acquisition and repeatability must be better defined to realize this potential. Additionally, breed-specific reference ranges for CKCS MV measurements are lacking. Study objectives were to assess measurement repeatability and define optimal methods for the longitudinal study of echocardiographic MV anatomy and to define preliminary, two-dimensional echocardiographic reference ranges for MV measurements in CKCS.AnimalsForty CKCS between 10 and 24 months old.Materials and methodsPre- and post-sedation two-dimensional echocardiographic images optimized for the MV were obtained. The length, width, and area of the anterior and posterior leaflets and the diameter of the MV annulus at end-diastole and end-systole were measured. Measurement repeatability was assessed using % coefficient of variation and repeatability coefficients.ResultsIntraoperator repeatability was best for the operator with previous MV measurement experience, with comparable results for the experienced operator measuring the second operator's images, mimicking a core echocardiography laboratory setting. Except for MV annulus diameter at end-systole, sedation had no significant effect on any MV measurements, nor did it impact measurement repeatability. Preliminary, breed-specific reference ranges were defined for the population, with CKCS often noted to have a larger annular diameter at end-systole than end-diastole.ConclusionsOptimal methods for longitudinal study of the MV in CKCS have been proposed, as have two-dimensional preliminary echocardiographic reference ranges for CKCS MV measurements. The MV annulus in CKCS may differ from other breeds.     

Heart rate variability in relation to severity of mitral regurgitation in Cavalier King Charles spaniels

Heart rate variability was measured in 81 Cavalier King Charles spaniels to investigate if it could be used to evaluate the severity of mitral regurgitation and to predict decompensation. Heart rate variability was assessed by the natural logarithm of the variance of the R-R intervals for 20 consecutive beats obtained from electrocardiographic recordings. Twenty-two of the dogs were clinically normal and 59 had mitral regurgitation caused by chronic valvular disease. The severity of mitral regurgitation was evaluated by echocardiography and thoracic radiography. Heart rate variability was found to be reduced (P < 0.001) among dogs with severe left atrial and ventricular dilatation and clinical signs of congestion. No significant differences in heart rate variability were found among normal dogs, dogs with only cardiac murmur, and dogs with echocardiographic evidence of slight to moderate left atrial and ventricular dilatation. Overall, an association was found between heart rate variability and left atrial to aortic root ratio and left ventricular end diastolic diameters (r = 0.72 and 0.64, respectively, P < 0.001), as well as heart and respiratory rate (r = 0.80 and 0.69, respectively, P < 0.001). Multiregression analysis showed that, in order of importance, heart rate, left atrial diameter and respiratory rate had significant effects on heart rate variability. Among these parameters, heart rate variability and left atrial diameter were found to be most efficient in separating decompensated dogs from compensated. It is concluded that heart rate variability may provide the clinician with valuable information when assessing the severity of mitral regurgitation caused by chronic valvular disease.     

Primary secretory otitis media in the Cavalier King Charles spaniel: a review of 61 cases

Sixty-one episodes of primary secretory otitis media (PSOM) were diagnosed in 43 Cavalier King Charles spaniels over a 10-year period. The principal findings were signs of moderate to severe pain localised to the head or cervical area, and/or neurological signs. Diagnosis was made by examination of the tympanic membrane and middle ear with the aid of an operating microscope under general anaesthesia. A bulging, but intact, tympanic membrane was found in most cases. Following myringotomy, a highly viscous mucus plug was found filling the middle ear. Treatment, consisting of removal of the mucus plug, flushing of the middle ear, and local and systemic medical therapy, had to be repeated between one and five times. The prognosis was good in all cases. PSOM is an important differential diagnosis in Cavalier King Charles spaniels with signs of pain involving the head and neck, and/or neurological signs.     

Increased NT-proANP predicts risk of congestive heart failure in Cavalier King Charles spaniels with mitral regurgitation caused by myxomatous valve disease

ObjectivesTo evaluate the predictive value of plasma N-terminal pro-atrial natriuretic peptide (NT-proANP) and nitric oxide end-products (NOx) as markers for progression of mitral regurgitation caused by myxomatous mitral valve disease.AnimalsSeventy-eight privately owned Cavalier King Charles spaniels with naturally occurring myxomatous mitral valve disease.MethodsProspective longitudinal study comprising 312 measurements over a 4.5 year period. Clinical values were recorded, NT-proANP concentrations were measured by radioimmunoassay, and NOx were analyzed colorimetrically. To predict congestive heart failure (CHF), Cox proportional hazards models with time-varying covariates were constructed.ResultsThe hazard ratio for NT-proANP (per 1000 pmol/l increase) to predict future CHF was 6.7 (95% confidence interval, 3.6–12.5; p < 0.001). The median time to CHF for dogs with NT-proANP levels >1000 pmol/l was 11 months (95% confidence interval, 5.6–12.6 months), compared to 54 months (46 – infinity) for dogs with concentrations ≤1000 pmol/l (p < 0.001). Due to intra- and inter-individual variability, most corresponding analyses for NOx were insignificant but dogs reaching CHF had a lower mean NOx concentration than dogs not reaching CHF (23 vs. 28 μmol/l, p = 0.016). Risk of CHF increased with increase in heart rate (>130 beats per minute) and grade of murmur (≥3/6).ConclusionsThe risk of CHF due to mitral regurgitation is increased in dogs with blood NT-proANP concentrations above 1000 pmol/l. Measurement of NT-proANP can be a valuable tool to identify dogs that may develop CHF within months.     

Inheritance of occipital bone hypoplasia (Chiari type I malformation) in Cavalier King Charles Spaniels

Occipital bone hypoplasia with foramen magnum obstruction and secondary syringomyelia (SM) is a common condition in the Cavalier King Charles Spaniel (CKCS) that is similar to human Chiari type I malformation. A worldwide family tree of more than 5,500 CKCSs spanning a maximum of 24 generations was established by obtaining pedigree information from 120 dogs diagnosed with SM secondary to occipital bone hypoplasia. The ongoing study showed 6 of 8 great grandparents of all affected dogs could be traced back to 2 female ancestors so that all 8 were descended from one or the other or both. The disease appears to be more severe and have an earlier onset with increased inbreeding, especially when breeding from affected dogs. The family tree of idiopathic epilepsy (IE) appears to be a different subset of the CKCS population, although some overlap was observed. Idiopathic epilepsy is more frequent in lines originating from whole-color dogs. Selection for coat color is believed to have influenced the development of both occipital hypoplasia with secondary SM and IE. In addition, breeding guidelines to reduce the incidence of mitral valve disease have placed further pressures on the gene pool.     

Pregabalin alleviates clinical signs of syringomyelia-related central neuropathic pain in Cavalier King Charles Spaniel dogs: a randomized controlled trial

ObjectiveWe aimed to assess the efficacy and benefit-risk profile of pregabalin (PGN) to reduce the clinical signs of central neuropathic pain (CNeP) as reflected by scratching episodes in dogs with symptomatic syringomyelia (SM).Study designRandomized, double-blind, placebo-controlled crossover study.AnimalsA total of 12 client-owned Cavalier King Charles Spaniels (age, 1.1–7.4 years, bodyweight, 8.2–10.8 kg) with magnetic resonance imaging-confirmed SM and clinical signs of CNeP.MethodsDogs were randomized to either PGN 150 mg or placebo for 25 days, followed by 48 hour washout period before crossover to the alternate phase of 25 days. The primary outcome was defined as number of scratching events during 10 minutes of video-recorded physical activity. Treatment effect was estimated using a generalized estimation equation model. Benefit-risk and quality of life assessments were obtained through owner interviews focusing on potential adverse events.ResultsThe treatment effect estimate was an 84% (95% confidence interval = 75–89%) reduction in mean number of scratching events relative to baseline compared with placebo (p < 0.0001). Owner-assessed satisfactory quality of life was status quo and rated as ‘good’ or ‘could not be better’ in six/11 dogs and improved in four/11 dogs. The most prevalent adverse events were increased appetite in nine/12 dogs and transient ataxia in nine/12 dogs. There was one dog withdrawn by the owner 7 days after crossover to PGN owing to persistent ataxia. No dogs needed rescue analgesia during the trial.Conclusions and clinical relevancePGN is superior to placebo in the reduction of clinical signs of SM-related CNeP in dogs. At a dose range of 13–19 mg kg^–1 orally twice daily, the encountered adverse events were acceptable to all but one owner.     

Feline cutaneous hemangiosarcoma: a retrospective study of 18 cases (1998-2003)

Cutaneous hemangiosarcoma (HSA) has been infrequently reported in dogs and cats. Medical records of 18 cats diagnosed with cutaneous HSA were reviewed. Age at the time of diagnosis, breed, sex, tumor location, tumor size, treatment type, survival time, disease-free interval, and cause of death were evaluated. Aggressive surgical excision of the tumor was attempted in 10 cats. A complete surgical excision was achieved in five of the 10 cats. Median survival times were statistically longer in cats that underwent surgery versus cats that did not. Cats with cutaneous HSA treated with aggressive surgical excision of their tumors may have a good long-term prognosis.     

Hepatic microvascular dysplasia in dogs: a retrospective study of 24 cases (1987-1995)

Hepatic microvascular dysplasia (HMD) is a disease involving a microscopic shunting of blood through the liver without the presence of a macroscopic portosystemic shunt (PSS). Data was collected from medical records and telephone conversations with referring veterinarians and owners of 24 dogs diagnosed with HMD. Criteria for diagnosis included histopathological evidence of microvascular dysplasia on hepatic biopsy as well as surgical exploration and a normal mesenteric portogram to rule out a macroscopic PSS. Dogs with HMD frequently have less severe clinical signs and a better long-term prognosis than do those with a PSS that are managed medically.     

Suspected contact scrotal dermatitis in the dog: a retrospective study of 13 cases (1987 to 2003)

Objectives : The aim of this study was to assess the clinical and aetiological aspects of contact dermatitis of the scrotum in dogs. Methods : The medical records of 13 dogs with suspected scrotal contact dermatitis were retrospectively included in the study. For each case, historical findings, results of physical and dermatological examination and of avoidance tests as well as follow‐up were included. Results of re‐exposure tests and patch tests were also included when available. Results : Avoidance tests to various suspected substances such as floor detergents, bleach, cement, laundry detergent and plastic fabric were performed and led to clinical improvement in all patients. Provocative re‐exposure was performed in six cases, with five positive responses. Patch tests were undertaken in three of the five re‐exposed cases, with two responding positively. Clinical Significance : Scrotal skin is thin and with few hair follicles, and is therefore very susceptible to contact dermatitis. A range of substances can induce contact dermatitis. The diagnosis of contact dermatitis is made by results of avoidance and/or provocation tests and/or patch tests. Once an aetiological agent has been identified, treatment is straightforward consisting of avoidance of this agent.     

Congenital keratoconjunctivitis sicca and ichthyosiform dermatosis in 25 Cavalier King Charles spaniel dogs. Part I: clinical signs, histopathology, and inheritance

The clinical presentation and progression (over 9 months to 13 years) of congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (CKCSID) in the Cavalier King Charles spaniel dog are described for six new cases and six previously described cases. Cases presented with a congenitally abnormal (rough/curly) coat and signs of KCS from eyelid opening. Persistent scale along the dorsal spine and flanks with a harsh frizzy and alopecic coat was evident in the first few months of life. Ventral abdominal skin was hyperpigmented and hyperkeratinized in adulthood. Footpads were hyperkeratinized from young adulthood with nail growth abnormalities and intermittent sloughing. Long-term follow-up of cases (13/25) is described. Immunomodulatory/lacrimostimulant treatment had no statistically significant effect on Schirmer tear test results, although subjectively, this treatment reduced progression of the keratitis. Histopathological analysis of samples (skin/footpads/lacrimal glands/salivary glands) for three new cases was consistent with an ichthyosiform dermatosis, with no pathology of the salivary or lacrimal glands identified histologically. Pedigree analysis suggests the syndrome is inherited by an autosomal recessive mode.     

Immunohistochemical characterization of the extracellular matrix in normal mitral valves and in chronic valve disease (endocardiosis) in dogs

This study aimed to characterize the composition and distribution of the extracellular matrix (ECM) components in normal canine mitral valves (MV) and in chronic heart valve disease (CVD).MV of 50 dogs (normal (n = 9), mild (n = 13), moderate (n = 17), severe (n = 11) CVD) were investigated macroscopically, histologically (H.-E., picrosirius red) and immunohistochemically (collagen I, III, IV, V, VI, elastin, laminin, fibronectin, heparan sulphate).In normal MV, ECM components were expressed in a typical layered pattern. In mild CVD, basement membrane components (laminin, collagen IV, fibronectin) were increased. Advanced CVD was characterized by myxomatous nodular lesions displaying a marginal and a central region comprised mainly of collagen I, VI and fibronectin in the former and collagen I and III in the latter. Collagen IV and laminin appeared multifocally in marked CVD.In conclusion, not only an accumulation of proteoglycans, but also a distinctly altered expression of basement membrane components, and collagens characterizes CVD.     

Heart Sounds and Murmurs: Changes Related to Severity of Chronic Valvular Disease in the Cavalier King Charles Spaniel

Auscultatory, phonocardiographic (PCG), radiographic, and echocardiographic evidence of chronic valvular disease (CVD) were studied in 79 Cavalier King Charles Spaniels with a mean age of 7.6 years (SD 2.6). Cardiac murmurs were present in 59 of the dogs and the intensity of the systolic cardiac murmur, assessed by auscultation (grade 1–6), was correlated (P < .001) to the severity of CVD (heart failure class) and to the echocardiographical dimensions of the heart (left atrial ratio, La/Ao-d, and left ventricular end diastolic diameter, LVEDD) (both P < .001). The heart sounds and duration of electromechanical systole (Q-S2) were investigated in all dogs using measurements obtained from PCG recordings. Normal regression equations describing the relation between heart rate and systolic intervals (Q-S1, Q-S2 and S1-S2) were established based on observations in 11 normal control Cavalier King Charles Spaniels. The total electromechanical systole (Q-S2), Q-S1, and S1-S2 intervals in the 59 dogs were related to the corresponding normal regression equation. A shortening of Q-S2 and S1-S2 intervals were found in dogs belonging to heart failure class I (Q-S2; P < .01 and S1 -S2; P < .05), class II, and classes III and IV (both P < .001). The ratio of the amplitudes of the first (S1) and second heart sounds (S2) measured on the PCG recordings was found to be increased in dogs belonging to class I (P < .01), class II, and classes III and IV (both P < .001). The relationship between cardiac dimensions (LVEDD and La/Ao-d) and S1a/S2a ratio was described by quadratic regression and found to be significant for both parameters (LVEDD; P < .001, R²= .54 and La/Ao-d; P < .001, R²= .63). The presence of a third heart sound (S3) was detected, using PCG, in 21 of the 68 dogs. The proportion of dogs exhibiting S3 increased with heart failure class (and increasing cardiac dimensions) (P < .001). These findings were confirmed by observations in 13 Cavalier King Charles Spaniels with cardiac failure progressing from heart failure class I to class II (Mean LVEDD from 30.2 to 35.2 mm and mean La/Ao-d from 1.09 to 1.43). An increase in intensity of the heart murmur, assessed by auscultation, increase in the ratio of the amplitudes of S1 and S2, as well as a shortening in Q-S2 and S1-S2 intervals (all P < .01) were found in these dogs. None of these dogs showed an S3 in heart failure class I, but 7 of the 13 dogs developed an S3 in class II.     

Radiographic detection of thoracic lesions in adult cows: a retrospective study of 42 cases (1995-2002)

Medical records of 42 cows that underwent both thoracic radiographic and postmortem examinations within a period of 7 days were reviewed to develop an evaluation grid to interpret bovine thoracic radiographs and to determine the sensitivity and the specificity of thoracic radiographs for detection of thoracic lesions, based on postmortem examination. Most cows (64%) had clinical signs of respiratory disease, whereas 19% showed signs of cardiac problems. The sensitivity and specificity of radiographs for identifying cows with thoracic lesions were 94% and 50%, respectively. In this study, with a prevalence of thoracic lesions of 86%, the positive- and negative-predictive values were 92% and 57%, respectively. This study provides an evaluation grid that allows standardization of the reading of bovine thoracic radiographs and the identification of most thoracic lesions. Bovine thoracic radiographs are useful in detecting thoracic lesions in cows.