Effects of pimobendan in cats with hypertrophic cardiomyopathy and recent congestive heart failure: Results of a prospective, double-blind, randomized, nonpivotal, exploratory field study.

BACKGROUND: The benefits of pimobendan in the treatment of congestive heart failure (CHF) in cats with hypertrophic cardiomyopathy (HCM) have not been evaluated prospectively. HYPOTHESIS/OBJECTIVES: To investigate the effects of pimobendan in cats with HCM and recent CHF and to identify possible endpoints for a pivotal study. We hypothesized that pimobendan would be well-tolerated and associated with improved outcome. ANIMALS: Eighty-three cats with HCM and recently controlled CHF: 30 with and 53 without left ventricular outflow tract obstruction. METHODS: Prospective randomized placebo-controlled double-blind multicenter nonpivotal field study. Cats received either pimobendan (0.30 mg/kg q12h, n = 43), placebo (n = 39), or no medication (n = 1) together with furosemide (<10 mg/kg/d) with or without clopidogrel. The primary endpoint was a successful outcome (ie, completing the 180-day study period without a dose escalation of furosemide). RESULTS: The proportion of cats in the full analysis set population with a successful outcome was not different between treatment groups (P = .75). For nonobstructive cats, the success rate was 32% in pimobendan-treated cats versus 18.2% in the placebo group (odds ratio [OR], 2.12; 95% confidence interval [CI], 0.54-8.34). For obstructive cats, the success rate was 28.6% and 60% in the pimobendan and placebo groups, respectively (OR, 0.27; 95% CI, 0.06-1.26). No difference was found between treatments for the secondary endpoints of time to furosemide dose escalation or death (P = .89). Results were similar in the per-protocol sets. Adverse events in both treatment groups were similar. CONCLUSIONS AND CLINICAL IMPORTANCE: In this study of cats with HCM and recent CHF, no benefit of pimobendan on 180-day outcome was identified.

Effect of atenolol on heart rate, arrhythmias, blood pressure, and dynamic left ventricular outflow tract obstruction in cats with subclinical hypertrophic cardiomyopathy.

OBJECTIVE: To investigate the negative chronotropic, antiarrhythmic, and obstruction-relieving effects of atenolol in cats with subclinical hypertrophic cardiomyopathy (HCM). ANIMALS: Seventeen cats with HCM. METHODS: Results for echocardiography, electrocardiography, Doppler blood pressure, and 24 h Holter monitoring were compared in cats before and 2-4 weeks after atenolol therapy (6.25-12.5 mg PO q 12 h). RESULTS: The left ventricular outflow tract maximum velocity (LVOT Vmax) decreased after atenolol administration (mean Vmax pre-treatment 3.3 m/s ± 1.8 m/s; post-treatment 1.6 m/s ± 1.0 m/s, p < 0.0001). Heart rate (HR) decreased after atenolol for all HR modalities. The total number of ventricular origin complexes (TotVent) and ventricular premature complexes (VPCs) decreased after atenolol. The VPCs decreased from a geometric mean of 61 complexes/24 h (range, 11-620 complexes/24 h) to 15 complexes/24 h (range, 1-1625 complexes/24 h) (p < 0.0001). Murmur grade decreased after atenolol from a median grade of 3/6 to 2/6 (p < 0.0001). The systolic blood pressure did not change (mean pre-treatment 130 mmHg ± 16 mmHg, mean post-treatment 123 mmHg ± 20 mmHg, p = 0.2). CONCLUSION: Atenolol decreases HR, murmur grade, and LVOT obstruction, and to a lesser degree, frequency of ventricular ectopy, in cats with subclinical HCM. Further studies are needed to determine if sudden cardiac death or long-term outcome is influenced by atenolol administration.

Heart rate and arrhythmia frequency of normal cats compared to cats with asymptomatic hypertrophic cardiomyopathy.

OBJECTIVES: To compare heart rate and arrhythmia frequency and complexity in a normal population of cats to a population of cats with hypertrophic cardiomyopathy (HCM). ANIMALS: 17 cats with HCM and 15 cats with normal echocardiograms. METHODS: Results for echocardiography, electrocardiography, Doppler blood pressure, and 24-h Holter monitoring were compared between groups. RESULTS: There was no difference in heart rate between HCM cats and normal cats regardless of modality used. All (17/17) HCM cats had ventricular arrhythmias (geometric mean 124 complexes/24 h) with 82% (14/17) exhibiting complex arrhythmias (couplets, triplets, or ventricular tachycardia). Most (14/15) normal cats had ventricular arrhythmias (geometric mean 4 complexes/24 h), but only 20% (3/15) exhibited complexity. HCM cats had significantly more total ventricular complexes, ventricular premature complexes and accelerated idioventricular rhythm than normal cats (P < 0.0001, P < 0.0001, and P = 0.01, respectively). Eighty eight percent (15/17) of HCM cats had supraventricular arrhythmias (geometric mean 9 complexes/24 h) with 23% (4/17) exhibiting complexity. Sixty percent (9/15) of normal cats had supraventricular arrhythmias (geometric mean 1 complex/24 h) with 13% (2/15) exhibiting complexity. Cats with hypertrophic cardiomyopathy had significantly more supraventricular complexes than normal cats (P = 0.0148). CONCLUSION: Cats with asymptomatic HCM have more frequent and complex ventricular and supraventricular arrhythmias than normal cats but do not have different overall heart rates compared to normal cats. Further studies are needed to determine if these arrhythmias are associated with an increased risk of sudden cardiac death or influence long-term survival.

A single codon insertion in PICALM is associated with development of familial subvalvular aortic stenosis in Newfoundland dogs.

Familial subvalvular aortic stenosis (SAS) is one of the most common congenital heart defects in dogs and is an inherited defect of Newfoundlands, golden retrievers and human children. Although SAS is known to be inherited, specific genes involved in Newfoundlands with SAS have not been defined. We hypothesized that SAS in Newfoundlands is inherited in an autosomal dominant pattern and caused by a single genetic variant. We studied 93 prospectively recruited Newfoundland dogs, and 180 control dogs of 30 breeds. By providing cardiac screening evaluations for Newfoundlands we conducted a pedigree evaluation, genome-wide association study and RNA sequence analysis to identify a proposed pattern of inheritance and genetic loci associated with the development of SAS. We identified a three-nucleotide exonic insertion in phosphatidylinositol-binding clathrin assembly protein (PICALM) that is associated with the development of SAS in Newfoundlands. Pedigree evaluation best supported an autosomal dominant pattern of inheritance and provided evidence that equivocally affected individuals may pass on SAS in their progeny. Immunohistochemistry demonstrated the presence of PICALM in the canine myocardium and area of the subvalvular ridge. Additionally, small molecule inhibition of clathrin-mediated endocytosis resulted in developmental abnormalities within the outflow tract (OFT) of Xenopus laevis embryos. The ability to test for presence of this PICALM insertion may impact dog-breeding decisions and facilitate reduction of SAS disease prevalence in Newfoundland dogs. Understanding the role of PICALM in OFT development may aid in future molecular and genetic investigations into other congenital heart defects of various species.

Prediction of first onset of congestive heart failure in dogs with degenerative mitral valve disease: the PREDICT cohort study.

OBJECTIVE: To identify risk factors for first-onset congestive heart failure (CHF) in dogs with degenerative mitral valve disease (DMVD). ANIMALS: Eighty-two dogs with and without CHF secondary to DMVD were retrospectively assigned to a derivation cohort. Sixty-five dogs with asymptomatic DMVD were recruited into a prospective validation cohort. METHODS: Variables associated with risk of CHF in dogs were identified in a derivation cohort and used to construct a predictive model, which was then prospectively tested through longitudinal examination of a validation cohort. RESULTS: Logistic regression analysis of the derivation cohort yielded a predictive model that included the left atrial to aortic root dimension ratio (LA:Ao) and plasma concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP). When this model was prospectively applied to the validation cohort, it correctly predicted first-onset of CHF in 69.2% of cases. Analysis of the validation cohort revealed that plasma NT-proBNP concentration and indexed left ventricular end-diastolic diameter (LVIDd:Ao) were independent risk factors for development of first-onset CHF in dogs with DMVD (NT-proBNP ≥ 1500 pmol/L, odds ratio (OR), 5.76, 95% confidence interval (CI), 1.37-24.28, P = 0.017; LVIDd:Ao ≥ 3, OR, 6.11, 95% CI, 1.09-34.05, P = 0.039). CONCLUSIONS: Measures of left heart size and plasma NT-proBNP concentration independently estimate risk of first-onset of CHF in dogs with DMVD. These parameters can contribute to the management of dogs with DMVD.

Assessment of serum N-terminal pro-B-type natriuretic peptide concentration for differentiation of congestive heart failure from primary respiratory tract disease as the cause of respiratory signs in dogs.

OBJECTIVE: To determine whether serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration is useful in discriminating between cardiac and noncardiac (ie, primary respiratory tract disease) causes of respiratory signs (ie, coughing, stertor, stridor, excessive panting, increased respiratory effort, tachypnea, or overt respiratory distress) in dogs. DESIGN: Multicenter cross-sectional study. ANIMALS: P 115 dogs with respiratory signs. PROCEDURES: Dogs with respiratory signs were solicited for study. Physical examination, thoracic radiography, and echocardiography were used to determine whether respiratory signs were the result of cardiac (ie, congestive heart failure) or noncardiac (ie, primary respiratory tract disease) causes. Serum samples for NT-proBNP assay were obtained at time of admission for each dog. Receiver-operating characteristic curves were constructed to determine the ability of serum NT-proBNP concentration to discriminate between cardiac and noncardiac causes of respiratory signs. RESULTS: Serum NT-proBNP concentration was significantly higher in dogs with cardiac versus noncardiac causes of respiratory signs. In dogs with primary respiratory tract disease, serum NT-proBNP concentration was significantly higher in those with concurrent pulmonary hypertension than in those without. A serum NT-proBNP cutoff concentration > 1,158 pmol/L discriminated between dogs with congestive heart failure and dogs with primary respiratory tract disease with a sensitivity of 85.5% and a specificity of 81.3%. CONCLUSIONS AND CLINICAL RELEVANCE: Measuring serum NT-proBNP concentration in dogs with respiratory signs helps to differentiate between congestive heart failure and primary respiratory tract disease as an underlying cause.

Utility of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) to distinguish between congestive heart failure and non-cardiac causes of acute dyspnea in cats.

BACKGROUND: Circulating plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration facilitates emergency diagnosis of congestive heart failure (CHF) in people. Its utility to discriminate between dyspneic cats with CHF vs. primary respiratory disease requires further assessment. Our objectives were to determine if NT-proBNP (1) differentiates dyspneic cats with CHF vs. primary respiratory disease; (2) increases with renal insufficiency; (3) correlates with left atrial dimension, radiographic cardiomegaly, and estimated left ventricular filling pressure (E/E(a)). METHODS: NT-proBNP was measured in 167 dyspneic cats (66 primary respiratory disease, 101 CHF) to evaluate (1) relationship with clinical parameters; (2) ability to distinguish CHF from primary respiratory disease; (3) optimal cut-off values using receiver operating characteristic (ROC) curve analysis. RESULTS: NT-proBNP (1) was higher (median and inter-quartile [25th-75th] percentile) in CHF (754 pmol/L; 437, 1035 pmol/L) vs. primary respiratory disease (76.5 pmol/L; 24, 180 pmol/L) cohorts (P<0.001); (2) positively correlated in CHF cats with increased inter-ventricular septal end-diastolic thickness (rho=0.266; P=0.007) and LV free wall thickness (rho=0.218; P=0.027), but not with radiographic heart size, left atrial size, left ventricular dimensions, E/E(a) ratio, BUN, creatinine, or thyroxine; (3) distinguished dyspneic CHF cats from primary respiratory disease at 265 pmol/L cut-off value with 90.2% sensitivity, 87.9% specificity, 92% positive predictive value, and 85.3% negative predictive value (area under ROC curve, 0.94). CONCLUSIONS: NT-proBNP accurately discriminated CHF from respiratory disease causes of dyspnea.

Results of the veterinary enalapril trial to prove reduction in onset of heart failure in dogs chronically treated with enalapril alone for compensated, naturally occurring mitral valve insufficiency.

OBJECTIVE: To determine the efficacy of long-term enalapril administration in delaying the onset of congestive heart failure (CHF). DESIGN: Placebo-controlled, double-blind, multicenter, randomized trial. ANIMALS: 124 dogs with compensated mitral valve regurgitation (MR). PROCEDURES: Dogs randomly assigned to receive enalapril or placebo were monitored for the primary endpoint of onset of CHF for < or = 58 months. Secondary endpoints included time from study entry to the combined endpoint of CHF-all-cause death; number of dogs free of CHF at 500, 1,000, and 1,500 days; and mean number of CHF-free days. RESULTS: Kaplan-Meier estimates of the effect of enalapril on the primary endpoint did not reveal a significant treatment benefit. Chronic enalapril administration did have a significant benefit on the combined endpoint of CHF-all-cause death (benefit was 317 days [10.6 months]). Dogs receiving enalapril remained free of CHF for a significantly longer time than those receiving placebo and were significantly more likely to be free of CHF at day 500 and at study end. CONCLUSIONS AND CLINICAL RELEVANCE: Chronic enalapril treatment of dogs with naturally occurring, moderate to severe MR significantly delayed onset of CHF, compared with placebo, on the basis of number of CHF-free days, number of dogs free of CHF at days 500 and study end, and increased time to a combined secondary endpoint of CHF-all-cause death. Improvement in the primary endpoint, CHF-free survival, was not significant. Results suggest that enalapril modestly delays the onset of CHF in dogs with moderate to severe MR.

Angiographic classification of patent ductus arteriosus morphology in the dog.

OBJECTIVES: To characterize angiographic morphology and minimum internal transverse diameter of left-to-right shunting patent ductus arteriosus (PDA) in a large series of dogs. BACKGROUND: PDA is the most common congenital cardiac malformation in the dog. Transarterial ductal occlusion is increasingly performed to close this defect. While accurate assessment of ductal morphology and luminal diameter is important to assure optimal occlusion using catheter-delivered devices, such information is currently limited. ANIMALS, MATERIALS AND METHODS: In 246 dogs representing 31 breeds with left-to-right shunting PDA, right lateral selective aortic angiograms were recorded and reviewed. RESULTS: PDA morphology conformed to four general phenotypes (types I, IIA, IIB, and III) which varied according to degree of ductal tapering, and the presence, absence, or location of abrupt ductal narrowing. Minimum internal ductal diameter for all dogs averaged 2.9mm (median, 2.5mm; range, 1.0-9.5mm) and was not correlated to age or body weight. There was no significant difference in minimum internal diameters between types I, IIA or IIB PDA, whereas, type III PDA was significantly wider (p=0.024) than other phenotypes. The most frequently-encountered variant (type IIA) was identified in 54.4% of cases (average minimum internal diameter, 2.3mm [median, 2.2mm; range, 1.0-5.5mm]). CONCLUSIONS: PDA angiographic morphology was categorized based upon the degree, presence, or absence of ductal narrowing, and the location of ductal attenuation. When planning PDA repair, this information should assist planning, selection and deployment of transcatheter occluding devices.

Survival times in dogs with severe subvalvular aortic stenosis treated with balloon valvuloplasty or atenolol.

OBJECTIVE: To determine survival times in dogs with severe subvalvular aortic stenosis (SAS) treated by means of balloon valvuloplasty or with atenolol, a beta-adrenoceptor blocking drug. DESIGN: Prospective study. ANIMALS: 38 dogs < 24 months old with severe SAS (peak systolic pressure gradient > or = 80 mm Hg). PROCEDURE: 10 dogs underwent balloon valvuloplasty and were reexamined 6 weeks later to determine the feasibility of the procedure. The remaining 28 dogs were randomly assigned to undergo balloon valvuloplasty (n = 15) or to be treated with atenolol long term (13) and were reexamined annually for 9 years or until the time of death. RESULTS: For the first 10 dogs, mean pressure gradient 6 weeks after balloon valvuloplasty (mean +/- SD, 119 +/- 32.6 mm Hg) was significantly decreased, compared with mean baseline pressure gradient (167 +/- 40.1 mm Hg). Median survival time for dogs that underwent balloon valvuloplasty (55 months) was not significantly different from median survival time for dogs treated with atenolol (56 months). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that balloon valvuloplasty can result in a significant decrease in the peak systolic pressure gradient in dogs with severe SAS, at least for the short term. No clear benefit in survival times was seen for dogs that underwent balloon valvuloplasty versus dogs that were treated with atenolol.

Effects of long-term administration of enalapril on clinical indicators of renal function in dogs with compensated mitral regurgitation.

OBJECTIVE: To determine the effect of long-term administration of enalapril on renal function in dogs with severe, compensated mitral regurgitation. DESIGN: Randomized controlled trial. ANIMALS: 139 dogs with mitral regurgitation but without overt signs of heart failure. PROCEDURE: Dogs were randomly assigned to be treated with enalapril (0.5 mg/kg [0.23 mg/lb], PO, q 24 h) or placebo, and serum creatinine and urea nitrogen concentrations were measured at regular intervals for up to 26 months. RESULTS: Adequate information on renal function was obtained from 132 dogs; follow-up time ranged from 0.5 to 26 months (median, 12 months). Mean serum creatinine and urea nitrogen concentrations were not significantly different between dogs receiving enalapril and dogs receiving the placebo at any time, nor were concentrations significantly different from baseline concentrations. Proportions of dogs that developed azotemia or that had a +/- 35% increase in serum creatinine or urea nitrogen concentration were also not significantly different between groups. CONCLUSIONS: And Clinical Relevance: Results suggest that administration of enalapril for up to 2 years did not have any demonstrable adverse effects on renal function in dogs with severe, compensated mitral regurgitation.