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The present study aimed to compare pulmonary vein (PV) diameters between Cavalier King Charles Spaniels (CKCSs) with myxomatous mitral valve disease (MMVD) and healthy CKCSs, assess correlations between PV diameters and echocardiographic parameters, and identify the optimal PV diameter cut-off value that distinguishes stage C from stage B2. CKCSs were recruited both retrospectively and prospectively and classified according to the ACVIM guidelines (stages A, B1, B2, and C). From a left apical view, the diameters of three PVs (PV1, PV2, and PV3) were measured with high reproducibility. In healthy dogs, the PV2 diameter showed no correlation with body weight. The PV2 diameter was significantly higher in stage B2 compared to B1 and in stage C compared to B2, while no difference was found between stages A and B1. The median (IQR) PV2 diameters were 4.9 mm (3.9–5.2) in stage A, 5.1 mm (4.0–6.0) in stage B1, 9.3 mm (7.3–11.1) in stage B2, and 13.7 mm (9.9–15.1) in stage C. Positive correlations were observed between the PV2 diameter and the left ventricular internal diameter normalized for body weight, the left atrium-to-aorta ratio, mitral E wave peak velocity, tricuspid regurgitation pressure gradient, and regurgitant fraction. A PV2 diameter cut-off value of 12.8 mm discriminated stage C from stage B2 with 57% sensitivity and 93% specificity. The PV2 diameter is a reproducible echocardiographic measure that increases with MMVD severity and could assist in the early detection of congestive heart failure. However, the modest sensitivity observed reflects the overlap of PV2 measurements between stages B2 and C. Therefore, PV2 should be interpreted with caution and considered a supportive, rather than exclusive, tool in disease staging and therapeutic decision-making.

Abstract Background Restrictive cardiomyopathy (RCM) is a common primary cardiomyopathy of cats. However, little information is available regarding prognostic variables in large populations of cats with RCM. Objectives To characterize the epidemiological, clinical, and echocardiographic features of cats with RCM and to document their survival times and risk factors for cardiac death (CD). Animals Ninety-two cats with RCM. Methods Retrospective study. Diagnosis of RCM was based on echocardiographic and Doppler criteria. Median survival time to CD and adjusted hazard ratios (HR) were estimated by the Kaplan-Meier method and multivariate Cox models, respectively. Results The feline population (median age [interquartile range], 8.6 years [4.1-12.4]; body weight, 4.0 kg [3.3-4.7]) included 83 cats (90%) with the myocardial RCM form and 9 (10%) with the endomyocardial fibrosis RCM form. Most RCM cats (64/92, 70%) were symptomatic at the time of diagnosis, with dyspnea related to congestive heart failure in 57 of 64 cats (89%). The median survival time of the 69 cats with the myocardial RCM form and available follow-up was 667 days (range, 2-3710 days) considering CD. Independent of age, biatrial enlargement, and arrhythmias, increase of the left atrium (LA)-to-aorta (Ao) ratio (hazard ration [HR], 2.5 per 0.5-unit increase; 95% confidence interval [CI], 1.5-4.2; P < .001) and presence of severe LA enlargement (end-diastolic LA : Ao ≥2; HR, 3.4; 95% CI, 1.3-8.7; P = .01) were significantly associated with shorter time to CD. Conclusions and Clinical Importance Cardiac death is common in RCM cats, and LA enlargement seems independently associated with decreased survival time in these cats.

The domestic dog represents an ideal model for identifying susceptibility genes, many of which are shared with humans. In this study, we investigated the genetic contribution to individual differences in 40 clinically important measurements by a genome-wide association study (GWAS) in a multinational cohort of 472 healthy dogs from eight breeds. Meta-analysis using the binary effects model after breed-specific GWAS, identified 13 genome-wide significant associations, three of them showed experimental-wide significant associations. We detected a signal at chromosome 13 for the serum concentration of alanine aminotransferase (ALT) in which we detected four breed-specific signals. A large proportion of the variance of ALT (18.1–47.7%) was explained by this locus. Similarly, a single SNP was also responsible for a large proportion of the variance (6.8–78.4%) for other measurements such as fructosamine, stress during physical exam, glucose, and morphometric measurements. The genetic contribution of single variant was much larger than in humans. These findings illustrate the importance of performing meta-analysis after breed-specific GWAS to reveal the genetic contribution to individual differences in clinically important measurements, which would lead to improvement of veterinary medicine.

Serum triglyceride concentrations increase in dogs with obesity, which is typically assessed by body condition score (BCS), however little is known about changes that take place in non-obese dogs in overweight condition. Further, the associations of triglyceride levels with other markers of energy homeostasis are poorly characterised in healthy animals. The present study aimed to evaluate associations between both BCS and triglyceride concentrations with other markers of lipid and glucose metabolism in healthy, non-obese dogs, as well as to assess whether these markers change significantly in non-obese dogs with overweight as compared to their lean counterparts. Serum concentrations of cholesterol, free fatty acids, triglycerides, insulin, glucose and fructosamine were measured in 532 healthy, client-owned dogs, assigned either to ‘lean’ (BCS: 3–5) or ‘overweight’ (BCS: 6–7) categories. Generalised linear mixed models were used to assess associations between BCS categories, triglyceride concentrations and other variables, correcting for the effect of breed. Compared with lean dogs, overweight dogs had a greater serum cholesterol concentration (95% CI, 5.3–6.2 mmol/L or 205–237 mg/dL versus 5.1–5.4 mmol/L or 198–210 mg/dL, p  = 0.0032), insulin concentration (95% CI, 17.5–22.1 μU/ml versus 16.7–18.0 μU/ml, p  = 0.0374) and were older (95% CI, 4.0–5.3 versus 3.4–3.7 years, p  = 0.0005). Triglyceride concentrations were positively associated with fructosamine ( r 2  = 0.31, p  = 0.0012), cholesterol ( r 2  = 0.25, p  < 0.0001), insulin ( r 2  = 0.14, p  = 0.0030) and glucose ( r 2  = 0.10, p  = 0.0014) concentrations, and negatively associated with free fatty acid concentrations ( r 2  = 0.11, p  < 0.0001). However, there was no association between triglyceride concentrations and age. In conclusion, both BCS and triglyceride concentrations were associated with other markers of glucose and lipid metabolism in non-obese healthy dogs, amongst which those with overweight showed metabolic changes as compared to their lean counterparts. Triglyceride concentrations were associated with an increase in insulin and fructosamine concentrations that might reflect an early-phase impairment in glucose tolerance which, surprisingly, was concurrent with lower basal free fatty acid concentrations.

Diabetes mellitus is a serious health problem in both dogs and humans. Certain dog breeds show high prevalence of the disease, whereas other breeds are at low risk. Fructosamine and glycated haemoglobin (HbA1c) are two major biomarkers of glycaemia, where serum concentrations reflect glucose turnover over the past few weeks to months. In this study, we searched for genetic factors influencing variation in serum fructosamine concentration in healthy dogs using data from nine dog breeds. Considering all breeds together, we did not find any genome-wide significant associations to fructosamine serum concentration. However, by performing breed-specific analyses we revealed an association on chromosome 3 (pcorrected ≈ 1:68 × 10-6) in Belgian shepherd dogs of the Malinois subtype. The associated region and its close neighbourhood harbours interesting candidate genes such as LETM1 and GAPDH that are important in glucose metabolism and have previously been implicated in the aetiology of diabetes mellitus. To further explore the genetics of this breed specificity, we screened the genome for reduced heterozygosity stretches private to the Belgian shepherd breed. This revealed a region with reduced heterozygosity that shows a statistically significant interaction (p = 0.025) with the association region on chromosome 3. This region also harbours some interesting candidate genes and regulatory regions but the exact mechanisms underlying the interaction are still unknown. Nevertheless, this finding provides a plausible explanation for breed-specific genetic effects for complex traits in dogs. Shepherd breeds are at low risk of developing diabetes mellitus. The findings in Belgian shepherds could be connected to a protective mechanism against the disease. Further insight into the regulation of glucose metabolism could improve diagnostic and therapeutic methods for diabetes mellitus.

Diagnosis of pulmonary arterial hypertension (PAH) relies on Doppler measurement of pulmonic and tricuspid regurgitation (TR). However, these are not always detectable.BACKGROUNDDiagnosis of pulmonary arterial hypertension (PAH) relies on Doppler measurement of pulmonic and tricuspid regurgitation (TR). However, these are not always detectable.Tissue Doppler imaging (TDI), a novel noninvasive ultrasound technique, provides indirect but sensitive and specific assessment of elevated systolic pulmonary artery pressure (SPAP) in dogs.HYPOTHESISTissue Doppler imaging (TDI), a novel noninvasive ultrasound technique, provides indirect but sensitive and specific assessment of elevated systolic pulmonary artery pressure (SPAP) in dogs.One hundred and five dogs with TR.ANIMALSOne hundred and five dogs with TR.Prospective observational study. Dogs were categorized as presenting normal (group 1, n = 45), mildly increased (group 2, n = 19), or moderately to severely increased (group 3, n = 41) SPAP, based on TR peak velocities (< 2.5, 2.5-3.0, and > 3.0 m/s, respectively). Ten quantitative echo-Doppler- and TDI-derived variables were assessed, including the main pulmonary arterial diameter to aortic diameter ratio, pulmonary flow acceleration time, and acceleration-to-ejection time ratio, the Tei index of right ventricular function, and 6 longitudinal basal right ventricular TDI variables.METHODSProspective observational study. Dogs were categorized as presenting normal (group 1, n = 45), mildly increased (group 2, n = 19), or moderately to severely increased (group 3, n = 41) SPAP, based on TR peak velocities (< 2.5, 2.5-3.0, and > 3.0 m/s, respectively). Ten quantitative echo-Doppler- and TDI-derived variables were assessed, including the main pulmonary arterial diameter to aortic diameter ratio, pulmonary flow acceleration time, and acceleration-to-ejection time ratio, the Tei index of right ventricular function, and 6 longitudinal basal right ventricular TDI variables.A significant correlation was observed between SPAP and each of the 10 tested variables (P < .05). Conventional echo-Doppler variables were less discriminating than the TDI for predicting increased SPAP. The combined systolic and diastolic right TDI index had the highest sensitivity and specificity (89% and 93% respectively, for a cutoff of 11.8 cm/s) and could discriminate between dogs in group 1 from dogs in group 2.RESULTSA significant correlation was observed between SPAP and each of the 10 tested variables (P < .05). Conventional echo-Doppler variables were less discriminating than the TDI for predicting increased SPAP. The combined systolic and diastolic right TDI index had the highest sensitivity and specificity (89% and 93% respectively, for a cutoff of 11.8 cm/s) and could discriminate between dogs in group 1 from dogs in group 2.TDI provided effective predictors of systolic PAH and demonstrated that both alterations in right-sided systolic and diastolic myocardial function can occur with mild increases in SPAP.CONCLUSIONS AND CLINICAL IMPORTANCETDI provided effective predictors of systolic PAH and demonstrated that both alterations in right-sided systolic and diastolic myocardial function can occur with mild increases in SPAP.

BACKGROUND: There are breed differences in several blood variables in healthy dogs. OBJECTIVE: Investigate breed variation in plasma endothelin‐1 (ET‐1) concentration, plasma renin activity, and serum cortisol concentration. ANIMALS: Five‐hundred and thirty‐one healthy dogs of 9 breeds examined at 5 centers (2–4 breeds/center). METHODS: Prospective observational study. Circulating concentrations of ET‐1 and cortisol, and renin activity, were measured using commercially available assays. Absence of organ‐related or systemic disease was ensured by thorough clinical investigations, including blood pressure measurement, echocardiography, ECG, blood and urine analysis. RESULTS: Median ET‐1 concentration was 1.29 (interquartile range [IQR], 0.97–1.82) pg/mL, median cortisol concentration 46.0 (IQR, 29.0–80.8) nmol/L, and median renin activity 0.73 (IQR, 0.48–1.10) ng/mL/h in all dogs. Overall, breed differences were found in ET‐1 and cortisol concentrations, and renin activity (P < .0001 for all). Pair‐wise comparisons between breeds differed in 67% of comparisons for ET‐1, 22% for cortisol, and 19% for renin activity, respectively. Within centers, breed differences were found at 5/5 centers for ET‐1, 4/5 centers for cortisol, and 2/5 centers for renin activity. Newfoundlands had highest median ET‐1 concentration, 3 times higher than Cavalier King Charles Spaniels, Doberman Pinschers, and Dachshunds. Median renin activity was highest in Dachshunds, twice the median value in Newfoundlands and Boxers. Median cortisol concentration was highest in Finnish Lapphunds, almost 3 times higher than in Boxers. CONCLUSIONS AND CLINICAL IMPORTANCE: Breed variation might be important to take into consideration when interpreting test results in clinical studies.

Hypertrophic cardiomyopathy (HCM) and chronic systemic hypertension (SHT) can both lead to left-ventricular hypertrophy (LVH) in cats. Assessment of LVH-associated myocardial dysfunction could provide new insights in the understanding of the pathophysiology of these diseases.BACKGROUNDHypertrophic cardiomyopathy (HCM) and chronic systemic hypertension (SHT) can both lead to left-ventricular hypertrophy (LVH) in cats. Assessment of LVH-associated myocardial dysfunction could provide new insights in the understanding of the pathophysiology of these diseases.Quantification of left-ventricular free-wall (LVFW) motion using tissue Doppler imaging (TDI) could permit differentiation of feline HCM from SHT-related LVH (LVH-SHT).HYPOTHESISQuantification of left-ventricular free-wall (LVFW) motion using tissue Doppler imaging (TDI) could permit differentiation of feline HCM from SHT-related LVH (LVH-SHT).A total of 108 cats of different breeds were enrolled in this study: 35 cats with HCM, 17 with concentric LVH and SHT, and 56 healthy cats as a control group.ANIMALSA total of 108 cats of different breeds were enrolled in this study: 35 cats with HCM, 17 with concentric LVH and SHT, and 56 healthy cats as a control group.All cats were examined by conventional echocardiography and 2-dimensional color TDI.METHODSAll cats were examined by conventional echocardiography and 2-dimensional color TDI.Radial and longitudinal diastolic LVFW velocities were similarly altered in cats with HCM and LVH-SHT, compared to controls. Systolic velocities were also lower in the groups with hypertrophy than in the controls, for longitudinal but not radial motion. To determine whether these diastolic and systolic alterations could also be observed in cats without LVFW hypertrophy, we performed a subgroup analysis in cats with a normal M-mode examination, that is, with only a localized subaortic interventricular septum hypertrophy. A significant radial and longitudinal diastolic dysfunction was still observed in both the HCM and LVH-SHT groups compared to controls, and systolic dysfunction was detected in the longitudinal motion.RESULTSRadial and longitudinal diastolic LVFW velocities were similarly altered in cats with HCM and LVH-SHT, compared to controls. Systolic velocities were also lower in the groups with hypertrophy than in the controls, for longitudinal but not radial motion. To determine whether these diastolic and systolic alterations could also be observed in cats without LVFW hypertrophy, we performed a subgroup analysis in cats with a normal M-mode examination, that is, with only a localized subaortic interventricular septum hypertrophy. A significant radial and longitudinal diastolic dysfunction was still observed in both the HCM and LVH-SHT groups compared to controls, and systolic dysfunction was detected in the longitudinal motion.LVFW motion is similarly altered in cats with HCM and LVH-SHT. This dysfunction occurs independently of the presence of myocardial hypertrophy, demonstrating that TDI is capable of detecting systolic and diastolic segmental functional changes in nonhypertrophied wall segments in cats with HCM and SHT.CONCLUSIONSLVFW motion is similarly altered in cats with HCM and LVH-SHT. This dysfunction occurs independently of the presence of myocardial hypertrophy, demonstrating that TDI is capable of detecting systolic and diastolic segmental functional changes in nonhypertrophied wall segments in cats with HCM and SHT.

Little is known about the vascular function and expression of endothelial and neuronal nitric oxide synthases (eNOS and nNOS) in Duchenne muscular dystrophy (DMD). Bradykinin is involved in the regulation of eNOS expression induced by angiotensin-converting enzyme inhibitors. We characterized the vascular function and eNOS and nNOS expression in a canine model of DMD and evaluated the effects of chronic bradykinin treatment. Vascular function was examined in conscious golden retriever muscular dystrophy (GRMD) dogs with left ventricular dysfunction (measured by echocardiography) and in isolated coronary arteries. eNOS and nNOS proteins in carotid arteries were measured by western blot and cyclic guanosine monophosphate (cGMP) content was analyzed by radioimmunoassay. Compared with controls, GRMD dogs had an impaired vasodilator response to acetylcholine. In isolated coronary artery, acetylcholine-elicited relaxation was nearly absent in placebo-treated GRMD dogs. This was explained by reduced nNOS and eNOS proteins and cGMP content in arterial tissues. Chronic bradykinin infusion (1 μg/min, 4 weeks) restored in vivo and in vitro vascular response to acetylcholine to the level of control dogs. This effect was NO-mediated through upregulation of eNOS and nNOS expression. In conclusion, this study is the first to demonstrate that DMD is associated with NO-mediated vascular endothelial dysfunction linked to an altered expression of eNOS and nNOS, which can be overcome by bradykinin.

Little information is available about the prevalence of renal dysfunction in dogs with chronic valvular heart disease (CVD).BACKGROUNDLittle information is available about the prevalence of renal dysfunction in dogs with chronic valvular heart disease (CVD).Azotemia and a decrease in glomerular filtration rate (GFR) are more severe with increased severity of CVD.HYPOTHESISAzotemia and a decrease in glomerular filtration rate (GFR) are more severe with increased severity of CVD.124 (study No. 1) and 24 (study No. 2) client-owned dogs with CVD.ANIMALS124 (study No. 1) and 24 (study No. 2) client-owned dogs with CVD.A retrospective study (study No. 1) was performed to assess the prevalence of azotemia in the New York Heart Association (NYHA) classes of heart failure in dogs with CVD. A prospective study (study No. 2) was then designed to determine GFR in dogs with different degrees of CVD severity. Complete physical examination, electrocardiography, blood pressure measurement, thoracic radiographs, echocardiography, and plasma and urine analyses were also performed.METHODSA retrospective study (study No. 1) was performed to assess the prevalence of azotemia in the New York Heart Association (NYHA) classes of heart failure in dogs with CVD. A prospective study (study No. 2) was then designed to determine GFR in dogs with different degrees of CVD severity. Complete physical examination, electrocardiography, blood pressure measurement, thoracic radiographs, echocardiography, and plasma and urine analyses were also performed.In study No. 1, 50% of the dogs were azotemic and the percentage of azotemic dogs increased with functional class (up to 70% in NYHA class IV patients). In study No. 2, 8/24 dogs were azotemic. Plasma urea and creatinine were higher in NYHA class III-IV dogs compared with class I-II dogs. The GFR was lower (P < .001) in NYHA class III-IV dogs (1.7 +/- 0.7 mL/min/kg) than in class I to II dogs (3.1 +/- 0.8 mL/min/kg). Only 1 dog in class I-II had a GFR below 2 mL/min/kg and only 2/9 class III-IV dogs had a GFR above 2 mL/min/kg.RESULTSIn study No. 1, 50% of the dogs were azotemic and the percentage of azotemic dogs increased with functional class (up to 70% in NYHA class IV patients). In study No. 2, 8/24 dogs were azotemic. Plasma urea and creatinine were higher in NYHA class III-IV dogs compared with class I-II dogs. The GFR was lower (P < .001) in NYHA class III-IV dogs (1.7 +/- 0.7 mL/min/kg) than in class I to II dogs (3.1 +/- 0.8 mL/min/kg). Only 1 dog in class I-II had a GFR below 2 mL/min/kg and only 2/9 class III-IV dogs had a GFR above 2 mL/min/kg.Azotemia and renal impairment increase with the severity of congestive heart failure and are frequent findings in dogs with CVD. It remains to be shown if deterioration of renal function is a direct result of progression of the heart disease.CONCLUSION AND CLINICAL RELEVANCEAzotemia and renal impairment increase with the severity of congestive heart failure and are frequent findings in dogs with CVD. It remains to be shown if deterioration of renal function is a direct result of progression of the heart disease.