Yin-Yang 1 transcription factor modulates ST2 expression during adverse cardiac remodeling post-myocardial infarction.

BACKGROUND: The cardioprotective effects of metformin remain poorly defined. Interleukin (IL)-33/ST2L signaling is a novel cardioprotective pathway, which is antagonized by the soluble isoform sST2. No data exist about the regulation of ST2 expression. This study aimed to evaluate the pathophysiological implication of Yin-Yang 1 (Yy1) transcription factor in cardiac remodeling and the expression of the soluble ST2 isoform. METHODS AND RESULTS: Myocardial infarction (MI) was induced in Wistar rats randomly receiving metformin or saline solution by permanent ligation of the left anterior coronary artery. In addition, a model of cardiomyocyte "biochemical strain" was used. Metformin administration improved post-MI cardiac remodeling, an effect that was associated with increased IL-33 and reduced sST2 levels in the myocardium. The anti-remodeling effects of metformin were also associated with a decrease in the transcription factor Yy1 intranuclear level and lower levels of phosphorylated HDAC4 within the cytoplasmic space. These effects were also observed in a cardiomyocyte biochemical strain model, where Yy1 silencing or HDAC4 inhibition blocked sST2 production in cardiomyocytes. Metformin blocked the HDAC4 phosphorylation induced by MI, preventing its export from the nucleus to the cytosol. The presence of dephosphorylated HDAC4 in the nucleus acted as a co-repressor of Yy1, repressing sST2 expression. CONCLUSION: The transcription factor Yy1 regulates sST2 expression, and repression of Yy1 by metformin results in lower levels of sST2 that are associated with favorable myocardial remodeling. The manipulation of YY1 or its co-repressor HDAC4 emerge as new targets to modulate ST2/IL33 signaling and prevent adverse cardiac remodeling.

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.

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.

Evaluation of the effects of a therapeutic renal diet to control proteinuria in proteinuric non-azotemic dogs treated with benazepril.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) are currently used to control proteinuria in dogs with chronic kidney disease. Renal diets (RDs) have beneficial effects in the management of azotemic dogs, but its role in proteinuric non-azotemic (PNAz) dogs has been poorly documented. HYPOTHESIS: Administration of a RD to PNAz dogs treated with benazepril (Be) improves proteinuria control compared with the administration of a maintenance diet (MD). ANIMALS: Twenty-two PNAz (urine protein/creatinine ratio [UPC] >1) dogs. METHODS: Randomized open label clinical trial design. Dogs were assigned to group-MD (5.5 g protein/100 kcal ME)/Be or to group-RD (3.7 g protein/100 kcal ME)/Be group during 60 days. Dogs with serum albumin (Alb) <2 g/dL received aspirin (1 mg/kg/12 hours). A physical examination, systolic blood pressure (SBP) measurement, complete blood count (CBC), biochemistry panel, urinalysis, and UPC were performed at day 0 (D0) and day 60 (D60). RESULTS: At D0, there were no significant differences between groups in the evaluated variables. During the study, logUPC (geometric mean (95% CI) and SBP (mean±SD mmHg) significantly decreased (paired t-test, P = 0.001) in Group-RD (logUPC(D0) = 3.16[1.9-5.25]; UPC(D60) = 1.20 [0.59-2.45]; SBP(D0) = 160 ± 17.2; SBP(D60) = 151 ± 15.8), but not in Group-MD (UPC(D0) = 3.63[2.69-4.9]; UPC(D60) = 2.14 [0.76-6.17]; SBP(D0) = 158 ± 14.7; SBP(D60) = 153 ± 11.5). However, RM-ANOVA test did not confirm that changes were consequence of dietary modification. Weight and Alb concentration did not change significantly in any group. CONCLUSION AND CLINICAL RELEVANCE: The administration of a RD to PNAz dogs treated with Be might help to control proteinuria and SBP compared with the administration of a MD, without inducing clinically detectable malnutrition, but more studies are warranted.

Effects of sedation with acepromazine maleate and buprenorphine hydrochloride on femoral artery blood flow in healthy dogs.

The purpose of this study was to qualify and quantify the femoral artery blood flow by duplex Doppler ultrasonography (DDU) in healthy dogs, before and after the administration of a combination of acepromazine maleate and buprenorphine hydrochloride (ACP-BPN). Seven healthy adult mongrel dogs and three adult beagles were used. Heart rate, arterial blood pressure and measurement of femoral artery blood flow by DDU were also recorded. The DDU measurements were: femoral artery diameter (FAD), peak systolic velocity (PSV), early retrograde (EDV) and end diastolic velocities (EnDV), mean velocity (BMV), pulsatility index (PI), flow velocity integral (FVI) and femoral blood flow (FBF). After 30 min, combination ACP-BPN was administered intramuscularly, and all the measurements were recorded again. The ACP-BPN protocol induced a significant decrease in systolic, mean, and diastolic arterial blood pressure, and heart rate. A significant increase in peak systolic velocity and integral flow velocity integral of the femoral blood were obtained. The Doppler spectra of the blood flow in the femoral artery revealed a spectral dispersion pattern after ACP-BPN administration in all the dogs. These results demonstrate that despite quantitative and qualitative changes, the overall femoral blood flow (FBF) is not significantly modified.

Calcium and phosphorus homeostasis in dogs with spontaneous chronic kidney disease at different stages of severity.

BACKGROUND: Studies in dogs with experimental chronic kidney disease (CKD) have demonstrated that abnormalities of calcium-phosphorus (Ca-P) homeostasis occur frequently and have a negative effect on kidney function and survival. However, the prevalence of these alterations in dogs with naturally occurring CKD at different stages of severity has not yet been investigated. HYPOTHESIS: Abnormalities of Ca-P metabolism occur early in the course of CKD with an increased prevalence in more severe stages. ANIMALS: Fifty-four dogs with CKD and 22 healthy dogs. METHODS: Blood and urine samples were obtained for a CBC, biochemistry, determination of parathyroid hormone (PTH), calcitriol, and ionized calcium concentrations and urinalysis. Based on urine protein/creatinine ratio and serum creatinine concentration, dogs were grouped according to the IRIS classification for CKD. RESULTS: Hyperparathyroidism (HPTH) (PTH > or = 48 pg/mL) was diagnosed in 41 (75.9%) dogs with CKD. Its prevalence increased from 36.4% (stage 1) to 100% (stage 4). Hyperphosphatemia (P > 5.5 mg/dL) was present in 37 (68.5%) dogs; increasing in prevalence from 18% (stage 1) to 100% (stage 4). Receiver-operating characteristic curve analysis showed that serum phosphorus concentration in the 4.5-5.5 mg/dL range correctly identified the presence of HPTH in most dogs. Calcitriol concentration progressively decreased in dogs with CKD and differences became statistically significant by stage 3. CONCLUSION AND CLINICAL RELEVANCE: HPTH and hyperphosphatemia occur frequently in dogs with naturally occurring CKD, even at early stages of CKD in some dogs. These findings highlight the importance of monitoring these parameters early in the course of CKD.

Serum phosphorus concentrations in dogs with leishmaniosis at different stages of chronic kidney disease.

Serum phosphorus concentrations were measured in 155 dogs with leishmaniosis at different stages of chronic kidney disease (CKD), and in 54 healthy dogs. CKD was classified into six stages, as follows: stage 0 (dogs with no evidence of CKD), serum creatinine (SCr) less than 125 micromol/l and urine protein:creatinine ratio (UPC) less than 0.2; stage 1A, SCr less than 125 micromol/l and UPC 0.2 to 0.5; stage 1B, SCr less than 125 micromol/l and UPC over 0.5; stage 2, SCr 125 micromol/l to 180 micromol/l; stage 3, SCr 181 micromol/l to 440 micromol/l; stage 4, SCr over 440 micromol/l. The dogs' serum phosphorus concentrations correlated significantly with the severity of CKD (P<0.001), and hyperphosphataemia (>1.8 mmol/l) affected 12 per cent, 11.8 per cent, 50 per cent, 76.9 per cent and 100 per cent of the dogs at stages 1A, 1B, 2, 3 and 4, respectively.

Glomerular filtration rate in dogs with leishmaniasis and chronic kidney disease.

BACKGROUND: Glomerular filtration rate (GFR) measurement is an indicator of kidney function. However, its usefulness in dogs at early stages of spontaneous chronic kidney disease (CKD) of glomerular origin, where routine laboratory techniques are not sufficiently sensitive, remains unproved. HYPOTHESIS: That GFR is reduced in proteinuric nonazotemic or mildly azotemic dogs with CKD secondary to leishmaniasis. ANIMALS: Twenty-six dogs with CKD secondary to leishmaniasis and 10 healthy dogs (control group). METHODS: CBC, serum biochemistry, and urinalysis (microalbuminuria and urine protein/creatinine ratio [UPC]) were performed in all dogs. GFR was calculated by measuring exogenous creatinine clearance. Based on degree of proteinuria and serum creatinine concentration (SCr), dogs were classified as group A (control; n = 10): UPC < 0.2, SCr < 1.4 mg/dL; group B (n = 8): UPC, 0.2-0.5, SCr < 1.4 mg/dL; group C (n = 10): UPC > 0.5, SCr < 1.4 mg/dL; group D (n = 5): SCr, 1.4-2 mg/dL; group E (n = 3): SCr > 2 mg/dL. RESULTS: GFR (mL/kg/min) was 3.9 +/- 0.29, 4.4 +/- 0.74, 4.5 +/- 1.44, 2.8 +/- 0.97, and 1.5 +/- 0.43 for groups A, B, C, D, and E, respectively. Eleven dogs (1 from group B, 3 from group C, 4 from group D, and all 3 dogs from group E) had an abnormally low GFR. Four dogs from group B and 5 dogs from group C had a GFR above the upper reference range (>4.5 mL/min/kg). CONCLUSION AND CLINICAL RELEVANCE: Some proteinuric nonazotemic or mildly azotemic dogs with leishmaniasis have low GFR, but glomerular hyperfiltration occurs in other dogs.

Unilateral renal agenesis associated with additional congenital abnormalities of the urinary tract in a Pekingese bitch.

An eight-month-old Pekingese bitch with urinary incontinence was found to have three congenital anomalies of the urinary tract: left renal agenesis, bilateral ectopic ureters with a left cranial blind-ending ureter, and urinary bladder hypoplasia. The diagnoses were made by retrograde vaginourethrography, excretory urography, ultrasonography and duplex Doppler ultrasonography. Although urological anomalies associated with renal agenesis have been frequently observed, a cranial blind-end ectopic ureter has not, to the authors' knowledge, been described in the bitch. The dog was managed medically with a restricted protein diet because of a compromised unilateral kidney with hydronephrosis and hydroureter.

Ocular complications of persistent hyperplastic primary vitreous in three dogs.

Persistent hyperplastic primary vitreous (PHPV) syndrome associated with either severe ocular complications or multiple ocular lesions was diagnosed in three young dogs, a Samoyed, a Spanish Pachon, and a mixed breed dog. Due to opacification of the anterior ocular structures, B-mode and color-flow Doppler ultrasonography were performed to aid diagnosis. The Samoyed presented with unilateral hyphema; the Spanish Pachon presented with unilateral secondary glaucoma associated with uveitis and hyphema OD and leucocoria OU; and the mixed breed presented with bilateral leucocoria. B-mode ultrasonography of the Samoyed revealed a subcapsular cataract and a hyperechoic tubular structure attached from the optic disk to the posterior lens capsule. In the Spanish Pachon B-mode ultrasonography of the right eye indicated microphakia, cataract formation, and a retrolental mass with a thin hyperechoic strand stretching from the optic disk to the posterior lens; and for the right eye cataract formation, PHPV, retinal detachment, and vitreous hemorrhage. In the mixed breed dog, B-mode ultrasonography of both eyes indicated microphthalmia, retrolental mass, and hyperechoic lenses. By color-flow Doppler imaging, blood flow was present in the retrolental mass of the right eye suggesting a persistent hyaloid artery.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy in a Siberian husky.

A seven-month-old male Siberian husky was presented with a recent history of anorexia, hindlimb weakness and syncope. Physical examination revealed severe tachycardia, tachypnoea and dyspnoea. Mucous membranes were pale and femoral pulses were weak. An electrocardiogram showed sustained ventricular tachycardia with a left bundle branch block configuration. Thoracic radiographs revealed slight right ventricular enlargement and two-dimensional echocardiography revealed mild right ventricular dilation at the cardiac apex and some hyperechogenic areas on the right side of the interventricular septum. Administration of intravenous lignocaine converted the ventricular tachycardia to sinus rhythm. The maintenance antiarrhythmic therapy consisted of oral procainamide and propranolol. Three weeks later the dog died suddenly. On postmortem examination, the right ventricular free wall was very thin at the apex, infundibulum and caudal aspect of the right ventricular parietal wall, similar to the 'triangle of dysplasia' of human patients. Histopathological examination revealed replacement of several areas of right ventricular free wall myocardium with connective tissue and fat. The right atrium and left ventricle were less severely affected by the same lesions. The clinical and pathological findings are similar to those reported in young people with arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Clinical and pathological findings of severe subvalvular aortic stenosis and mitral dysplasia in a rottweiler puppy.

Subvalvular aortic stenosis (SAS) and mitral dysplasia were diagnosed in an asymptomatic eight-week-old rottweiler. Clinical and pathological findings were compatible with a fixed and dynamic obstruction of the left ventricular outflow tract. Gross and microscopic pathological findings were consistent with the most severe form of SAS, described previously in Newfoundland dogs over six months of age. These observations demonstrate that very young asymptomatic puppies may suffer a severe complex form of SAS.

Persistent left cranial vena cava associated with multiple congenital anomalies in a six-week-old puppy.

A six-week-old male puppy was presented with a distended abdomen, dypsnoea and cyanosis. Auscultation revealed a grade II/VI systolic murmur. Thoracic radiographs showed gross cardiomegaly. An electrocardiogram revealed a narrow-complex tachycardia, deep S waves in leads I, II, III and aVF, and negative P waves in lead III. Two-dimensional echocardiography showed a high ventricular septal defect and marked dilation of the right-sided chambers. There was also an echolucent structure lateral to the left atrium at a site corresponding to the coronary sinus. Contrast echocardiography revealed right-to-left shunting through the septal defect. Necropsy confirmed the existence of a septal defect in the membranous part of the septum and a persistent left cranial vena cava with dilation of the coronary sinus. In addition, a small patent ductus arteriosus and tricuspid dysplasia were present.

Dilated coronary sinus in a dog with persistent left cranial vena cava.

This paper describes the electrocardiographic, echocardiographic (two-dimensional, M-mode, contrast and Doppler) and non-selective angiocardiographic features in a 3 year old female Beagle with dilated coronary sinus due to persistent left cranial vena cava. Negative P waves in leads III and aVR and a positive P wave in lead aVL were seen. Echocardiographically, a hypoechoic circular structure was seen between the left atrium and the pericardium in the area where the coronary sinus is located. A velocity pattern with two peaks was obtained, one systolic with velocity = 0.44 +/- 0.05 m/sec and the other diastolic with velocity = 0.27 +/- 0.01 m/sec. By M-mode echocardiography, at level of the aorta and the left atrium, a linear structure was identified between the left atrium and the pericardium; this structure was characterized by phasic movements of the anterior wall during the cardiac cycle. Following a left cephalic vein injection of saline, bubbles were seen within the coronary sinus; when saline was injected into the right cephalic vein, bubbles were also seen within the coronary sinus and right atrium and ventricle. Non-selective angiocardiography confirmed a dilated coronary sinus with persistent left cranial vena cava. The right cranial vena cava was absent. The dog was clinically normal and the unusual vessel was an incidental finding.

Electrocardiographic changes in the growing Mastín Español.

Serial electrocardiograms were recorded from 70 Mastín Español dogs in right lateral recumbency, aged between one day and three years, in order to observe the changes in the waveform and intervals, QRS morphology, cardiac rhythm and heart rate caused by their growth. Age and bodyweight caused a gradual increase in the duration and amplitude of the P wave, duration of the PR, QT and RR intervals, amplitude of the R wave and duration of the QRS complex and ST segment. Q wave was observed in nearly all the recordings with different amplitudes. The S wave was only significant in one-day-old animals and QRS morphology showed significant important changes from qrS and rS to qR and qRs morphologies during the first two weeks of life. The T wave increased its amplitude until the age of two months and changed its polarity (from negative to positive) from five months of age onwards. The heart rate decreased until the age of seven months, reaching stabilised values of 110 +/- 7.3 beats per minute. Sinus tachycardia was commonplace in animals under one month old and respiratory sinus arrhythmia was found from six months of age. Sex only influenced the duration and amplitude of the T wave. Males had higher mean values than females.