Assessment of NTproBNP Concentration in Dogs - IDEXX ...

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SMALL ANIMALS/EXOTICN-terminal pro-B-type natriuretic peptide is a cardiacbiomarker that is increased in the blood of dogswith heart disease. 1,2 N-terminal pro-B-type natriureticpeptide is formed when its parent pro-hormone, pro-B-type natriuretic peptide, is cleaved into 2 molecules,NT-proBNP and C-BNP. The pro-B-type natriuretic peptideis produced in response to an increase in intracardiachydrostatic pressure, increased cardiac wall stress,angiotensin II, myocardial hypoxia, and heightenedsympathetic tone. 3 As such, both serum NT-proBNPand C-BNP concentrations represent potential diagnostictools to help diagnose congestive heart failure. 4,5 Inhumans, C-BNP 6–8 and NT-proBNP 9–11 assays possesshigh sensitivity and specificity in differentiating betweencardiac and pulmonary causes of respiratory distress.In circulation, C-BNP is rapidly degraded, 12 makinglaboratory testing difficult. Commercially availabletests in dogs and cats exclusively detect NT-proBNP,which is thought to possess a longer half-life.Results of a previous study 1 indicate that dogs withrespiratory signs resulting from congestive heart failurehave significantly higher serum NT-proBNP concentrationsthan dogs with primary respiratory tract disease.The magnitude of difference between the 2 populationswas such that the serum NT-proBNP concentration provideda clinically useful test with an adequate sensitivityand specificity for differentiating between the 2 populations.However, all dogs did not undergo the sameset of diagnostic tests, and a substantial proportion ofthe study population lacked both evaluation of thoracicradiographs and an echocardiographic examination.Thus, the usefulness of this peptide as an adjunct diagnostictest merits closer evaluation. We hypothesizedthat serum NT-proBNP concentration would be higherin dogs with congestive heart failure than in dogswith primary respiratory tract disease and that serumNT-proBNP concentration would help to differentiatebetween cardiac and noncardiac causes of respiratorysigns in dogs. The purpose of the multicenter studyreported here was to assess the clinical sensitivity andspecificity of a serum NT-proBNP assay to differentiatebetween cardiac versus noncardiac (ie, primary respiratorytract disease) causes of respiratory signs, and todetermine an optimal cutoff value that would facilitatethis assessment.Materials and MethodsAnimals—Study procedures were approved by theinstitutional animal use and care committees of eachqualifying participating institution. Owner consent wasobtained for all dogs included in the study. Fourteenveterinary cardiology practices prospectively recruiteddogs between September 2006 and November 2007.Dogs were eligible for inclusion if the owner reported acomplaint of respiratory signs that were severe enoughto affect the dog’s quality of life. Qualifying signs includedcoughing, stertor, stridor, excessive panting,increased respiratory effort, tachypnea, or overt respiratorydistress. Dogs were excluded if respiratory signswere caused by obvious trauma (eg, vehicular trauma).Assessment of disease—All dogs underwentthoracic radiography and M-mode, 2-D, and Dopplerechocardiography. Vertebral heart size was measuredon the left or right lateral radiographic projection ofthe thorax by the attending cardiologist as previouslydescribed. 13,14 Additional diagnostic testing to help determinethe underlying cause of the respiratory signs(eg, fluoroscopy, tracheal wash, and bronchoscopy)was performed at the discretion of the attending clinician.The LVIDd, LVIDs, and LA:Ao were measured bymeans of standard echocardiographic techniques. 15,16Detection of tricuspid regurgitation by use of echocardiographywas recorded. Pulmonary hypertension wasarbitrarily defined as a velocity of tricuspid regurgitation> 3.25 m/s (pressure gradient > 42.3 mm Hg). Inthe absence of tricuspid regurgitation, a presumptiveechocardiographic diagnosis of pulmonary hypertensionwas made in dogs with a combination of severeright ventricular hypertrophy or dilation, flattenedinterventricular septum, and an enlarged main pulmonaryartery, in the absence of increased right ventricularto pulmonary artery outflow velocity.A standardized patient datasheet was used to recordpatient signalment, clinical signs, and diagnosticfindings. On the basis of this workup, and withoutknowledge of the NT-proBNP assay results, a boardcertifiedveterinary cardiologist assigned the dog to 1of 4 groups as follows: group 1 included dogs with congestiveheart failure (findings of severe cardiac disease,perihilar or caudodorsal pulmonary interstitial pattern,cardiomegaly, enlarged pulmonary veins, pleural effusion,and ascites) and without primary respiratory tractdisease; group 2 included dogs with primary respiratorytract disease (parenchymal lung disease [findingsof cranioventral or lobar alveolar pattern, lung lobe torsion,and bullae] or upper airway disease [findings oflaryngeal paralysis, brachycephalic syndrome, collapsingtrachea, and moderate or severe bronchiolar pulmonarypattern]) and without underlying cardiac disease(no heart murmur and no evidence of clinically relevantleft-sided cardiac disease on echocardiography); group3 included dogs with primary respiratory tract disease(as described for group 2 dogs) that also had heart diseasethat was not congestive heart failure (detection ofheart murmur or cardiac disease on echocardiographywithout evidence of congestive heart failure on thoracicradiography, physical examination, or other diagnostictests); and group 4 included dogs for which the etiologyof respiratory signs could not be reliably ascribedto either respiratory tract disease or congestive heartfailure.Measurement of serum NT-proBNP concentration—Venousblood samples were collected at the timeof admission. Blood was drawn into plain evacuatedglass tubes that did not contain any additives. Sampleswere centrifuged within 60 minutes after collection,and serum was stored at –20°C prior to batched overnightshipment for analysis. Samples were shipped withcold packs and packing materials provided by the assaymanufacturer. Serum NT-proBNP concentration wasdetermined with a commercially available canine-specificNT-proBNP assay a as previously described. 2Statistical analysis—Data were summarized asmedian (IQR [ie, 25th to 75th percentile]) or mean ±1320 Scientific Reports JAVMA, Vol 235, No. 11, December 1, 2009
SD. Multiple group comparisons of radiographic, echocardiographic,and NT-proBNP data were performed viaKruskal-Wallis analysis and the Dunn multiple comparisontests. The Spearman method was used to test forcorrelations between serum NT-proBNP concentrationand body weight, age, and radiographic and echocardiographicheart size. Multivariate linear regression wasperformed to identify whether these variables were associatedwith serum NT-proBNP concentration; cutoffP values for entry into and removal from the multivariatemodel were < 0.05 and > 0.10, respectively. Receiver-operatingcharacteristic curves were constructed todetermine the sensitivity, specificity, positive and negativepredictive values, accuracy (defined as the sum ofthe concordant results divided by the sum of all resultsin a 2 X 2 table), and AUC ROCof NT-proBNP results,compared with the cardiologist’s diagnosis. All analyseswere performed with standard software. b,c Values of P
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