Natriuretic peptides are a family of structurally related hormones that include ANPs and BNPs. These hormones exert a variety of effects that maintain circulatory homeostasis in states of increased extracellular volume.1 In addition to promotion of natriuresis, these peptides also increase glomerular filtration rate, induce vasodilation, and act as antagonists of the renin-angiotensin system.2 Results of studies3–5 in dogs with experimental and naturally occurring heart disease have indicated that circulating BNP concentration increases proportionally with the severity of heart disease and clinical signs of heart failure.
B-type natriuretic peptide is primarily produced by ventricular myocytes, although the atria also contribute a small amount to their synthesis.6 B-type natriuretic peptide is synthesized as a preprohormone and processed to the prohormone form in ventricular myocytes. It is released into circulation in response to ventricular dysfunction, and a variety of disease states have been associated with high circulating concentrations of BNP including systolic dysfunction, diastolic dysfunction, volume overload, and pulmonary hypertension.7–10 During its release into the circulation, the prohormone is cleaved enzymatically into 2 fragments: the biologically active form BNP and the inactive fragment NT-proBNP. B-type natriuretic peptide and NT-proBNP are metabolized via separate pathways, resulting in a difference in the half-life between the 2 fragments. In humans, the half-lives of BNP and NT-proBNP are approximately 22 and 120 minutes, respectively.11 In dogs, the half-life of BNP is approximately 90 seconds,12 whereas the half-life of NT-proBNP is unknown; in sheep, an extended half-life of the inactive fragment has also been identified.13
In mammals, respiratory distress develops secondary to a myriad of causes and congestive heart failure and primary pulmonary disease are among the most common etiologies. However, distinguishing between these 2 disease states can be challenging. In humans, assessments of circulating BNP and NT-proBNP concentrations are both useful for making this diagnostic determination.14,15 In veterinary medicine, assessment of BNP concentration has also been shown to be a reliable tool for discriminating between congestive heart failure and primary pulmonary disease in dogs.16,17 Results of preliminary studiesa,b in dogs have suggested that assessment of circulating NT-proBNP concentration would be similarly useful. The purpose of the study reported here was to evaluate assessment of circulating NT-proBNP concentration as a means to discriminate between congestive heart failure and primary pulmonary disease in dogs with respiratory distress or cough.
Materials and Methods
This study was performed in compliance with the University of Missouri's animal care quality assurance policy on client-owned animals. Informed consent was obtained from all owners prior to participation in the study.
Dogs—All dogs that were evaluated at the University of Missouri Veterinary Medical Teaching Hospital from October 2006 to July 2007 because of coughing or respiratory distress were initially evaluated via complete physical examination and thoracic radiography. Dogs with evidence of cardiac disease received a complete echocardiographic evaluation (including assessment of left atrial-to-aortic diameter ratio and left ventricular end-diastolic diameter). Evidence of cardiac disease was defined as auscultation of a murmur or arrhythmia during physical examination or a radiographic vertebral heart score > 11. A vertebral heart score is derived from measurements of the short and long axes of the heart in relation to vertebral bodies.18 Left-sided heart failure was diagnosed radiographically by the presence of an interstitial to alveolar infiltrate that was most severe in the caudodorsal lung fields, pulmonary venous distension, and a large left atrium, in combination with echocardiographic evidence of left-sided heart disease. Right-sided heart failure was diagnosed by detection of jugular distension, hepatomegaly, and ascites via physical examination, in combination with radiographic and echocardiographic evidence of right-sided heart disease.
Dogs in which heart failure or cardiac disease was not detected via physical examination or thoracic radiography were included if they had radiographic evidence of airway or pulmonary parenchymal disease and underwent bronchoalveolar lavage with cytologic examination and bacterial culture of a lavage fluid sample. Dogs with evidence of concurrent cardiac and respiratory disease were excluded from the study.
The diagnosis of heart failure versus primary pulmonary disease was made initially by the investigator in charge of each case. Additionally, all radiographs were reviewed at completion of the study by a board-certified cardiologist (DMF).
Sample collection and processing—Blood samples for NT-proBNP assay were obtained from dogs within 12 hours of the initial diagnosis of heart failure. For dogs that were considered to have pulmonary disease, samples were collected prior to bronchoalveolar lavage procedures. Blood samples were collected in either additive-free evacuated tubes or tubes containing EDTA and centrifuged for 10 minutes at 1,720 X g; samples collected in additive-free evacuated tubes were allowed to clot for 20 to 30 minutes prior to centrifugation. Plasma or serum samples were harvested and frozen at −20°C within 60 minutes of blood sample collection. For each dog, only a plasma or serum sample was used in the subsequent analyses. The samples were batched for analysis and submitted frozen on dry ice to the testing laboratoryc for assay. The samples were identified by numeric code only; therefore, laboratory personnel were unaware of the patient's diagnosis. The test assay was a sandwich enzyme immunoassay that incorporated 2 purified sheep antibodies specific for canine NT-proBNP. The capture antibody (anti–NT-proBNP antibody) was bound to the wells of the microtiter plate, and the detection antibody (anti–NT-proBNP [tracer]) was conjugated to horseradish peroxidase. During incubation, volumes of standard or sample and conjugated detection antibody were added to the wells. In principle, NT-proBNP binds to the capture antibody coated in the wells and forms a sandwich with the detection antibody; bound NT-proBNP is quantified by an enzyme-catalyzed color change that is detectable on a standard microtiter plate reader. The amount of color developed is directly proportional to the amount of NT-proBNP immunoreactivity present in the standard or sample. For purposes of this study, a standard curve was plotted from the values measured and the concentration of NT-proBNP in the samples was calculated from that curve.
Statistical analysis—Data were not normally distributed; consequently, values are presented as median and IR (25% to 75%). To compare data from the congestive heart failure group and the primary pulmonary disease group, a Mann-Whitney U test was used. Linear regression was used to assess the strength of the relationship between serum or plasma NT-proBNP concentration and radiographic and echocardiographic measures of cardiac size. Statistical analyses were performed by use of commercial software.d A value of P < 0.05 was accepted as indicative of significance.
Results
Eighty-four dogs were evaluated for cough or respiratory distress during the study period. Of these, 21 dogs that had primary pulmonary disease were excluded because either bronchoalveolar lavage was medically contraindicated or the owners declined to permit the procedure. Seventeen dogs were also excluded because of concurrent cardiac and pulmonary disease, as indicated by auscultation of a murmur during physical examination or radiographic evidence of a large cardiac silhouette and additional radiographic changes indicative of a noncardiogenic pulmonary abnormality (eg, collapsing trachea, pulmonary mass, or bronchial pattern). Forty-six dogs met the inclusion criteria for participation in the study.
Twenty-five dogs were classified as having cardiac disease, and 21 dogs were classified as having pulmonary disease. The baseline characteristics of the 2 groups of dogs were compared. Dogs with cardiac disease were significantly (P = 0.007) older than dogs with pulmonary disease (median age, 10.9 years [IR, 0.3 to 15.4 years] vs 6.9 years [IR, 0.3 to 14.7 years]). There was no difference in weight (P = 0.749) or sex distribution (P = 0.080) between groups. Median weight of dogs with cardiac disease was 10.0 kg (22 lb; IR, 3.3 to 84.0 kg [7.3 to 184.8 lb]). Of these dogs, 3 were sexually intact males and 1 was a sexually intact female; 11 males and 10 females were neutered. Median weight of dogs with pulmonary disease was 19.3 kg (42.5 lb; IR, 1.9 to 68.1 kg [4.2 to 149.8 lb]). Of these dogs, 1 was a sexually intact male and 2 were sexually intact females; 6 males and 12 females were neutered. Dogs with cardiac disease had significantly (P < 0.001) higher radiographic vertebral heart scores than dogs with primary pulmonary disease (median score, 12.5 [IR, 10.5 to 15.5] vs 10.3 [IR, 8.5 to 10.5]).
Among the 25 dogs in which congestive heart failure was diagnosed as the underlying cause of respiratory distress or cough, chronic myxomatous degeneration of the mitral valve (with varying degrees of concurrent tricuspid valve degeneration) was detected in 18 dogs. Sixteen of those 18 dogs had signs of left-sided heart failure, whereas 2 dogs had signs of biventricular failure; 2 of the dogs also had atrial fibrillation. Dilated cardiomyopathy was diagnosed in 4 dogs; all of those dogs had atrial fibrillation and left-sided congestive heart failure. Two other dogs had myxomatous degeneration that primarily involved the tricuspid valve; both dogs had signs of right-sided heart failure, and 1 was syncopal. Patent ductus arteriosus and left-sided heart failure were diagnosed in the remaining dog.
Among the 21 dogs in which primary pulmonary disease was diagnosed as the underlying cause of the respiratory distress or cough, 11 had evidence of nonseptic inflammation (as determined from results of cytologic examination and bacterial cultures of bronchoalveolar lavage fluid samples). The inflammatory responses in these 11 dogs were classified as neutrophilic (n = 5), eosinophilic (3), and mixed (3). Bacterial infection was diagnosed in 7 dogs on the basis of results of cytologic examination and bacterial culture of bronchoalveolar lavage fluid samples. Organisms that were cultured included Escherichia coli (n = 3), Klebsiella pneumoniae (1), Streptococcus spp (1), Pseudomonas aeruginosa (1), and Peptostreptococcus sp (1). In 3 dogs, a neoplastic etiology of the respiratory signs was identified (lymphosarcoma in 2 dogs and carcinoma in 1 dog).
Serum or plasma samples from 46 dogs were analyzed for NT-proBNP concentration. Sera were obtained from some of the dogs that were examined initially, but plasma was obtained from most dogs. Concentrations of NT-proBNP in dogs are equivalent in serum and plasma samples.e However, in cats, assessment of NT-proBNP concentration is only valid in plasma samples. To avoid potential confusion at our institution in the future regarding which type of sample should be used for assessment of NT-proBNP concentration in these 2 species, canine blood samples were routinely collected into tubes containing EDTA in the latter part of the study. The distribution of NT-proBNP results obtained from the clinical subgroups was assessed by visual examination of a scatter plot because the number of dogs in each subgroup was too small to permit meaningful statistical analysis (Figure 1).
The median circulating NT-proBNP concentration in dogs with primary pulmonary disease was 357 pmol/L (IR, 192 to 565). That value was significantly (P < 0.001) less than the median NT-proBNP concentration in dogs with heart failure (2,544 pmol/L [IR, 1,652 to 3,476 pmol/L; Figure 2).
No statistical relationship between the NT-proBNP concentration and radiographic vertebral heart score was identified for either the primary pulmonary disease group (R2 = 0.003; P = 0.93) or the congestive heart failure group (R2 = 0.016; P = 0.55). Similarly, there was no relationship between the NT-proBNP concentration and the M-mode echocardiographically derived left atrial-to-aortic diameter ratio (R2 = 0.006; P = 0.74). There was a weak but significant relationship between circulating NT-proBNP concentration and the M-mode measurement of the left ventricular end-diastolic diameter (R2 = 0.2; P = 0.02; Figure 3).
Scatter plot to illustrate the distribution of plasma or serum concentrations of NT-proBNP among 46 dogs with respiratory distress or cough grouped according to disease classification. DCM = Dilated cardiomyopathy. CMMVD = Chronic myxomatous mitral valve degeneration. CMTVD = Chronic myxomatous tricuspid valve degeneration. PDA = Patent ductus arteriosus.
Citation: Journal of the American Veterinary Medical Association 232, 11; 10.2460/javma.232.11.1674
Scatter plot to illustrate the distribution of plasma or serum concentrations of NT-proBNP among 46 dogs with respiratory distress or cough grouped according to disease classification. DCM = Dilated cardiomyopathy. CMMVD = Chronic myxomatous mitral valve degeneration. CMTVD = Chronic myxomatous tricuspid valve degeneration. PDA = Patent ductus arteriosus.
Citation: Journal of the American Veterinary Medical Association 232, 11; 10.2460/javma.232.11.1674
Scatter plot to illustrate the distribution of plasma or serum concentrations of NT-proBNP among 46 dogs with respiratory distress or cough grouped according to disease classification. DCM = Dilated cardiomyopathy. CMMVD = Chronic myxomatous mitral valve degeneration. CMTVD = Chronic myxomatous tricuspid valve degeneration. PDA = Patent ductus arteriosus.
Citation: Journal of the American Veterinary Medical Association 232, 11; 10.2460/javma.232.11.1674
Box plots of serum or plasma NT-proBNP concentrations in dogs with respiratory distress or cough for which a diagnosis of congestive heart failure (n = 25) or primary pulmonary disease (21) was made. For each plot, the box represents the 25th and 75th percentiles, the line within the box represents the 50th percentile, and the whiskers represent the 10th and 90th percentiles. Black circles represent outliers. The median concentration for the dogs with cardiac disease was significantly (P < 0.001) greater than the median concentration for the dogs with pulmonary disease.
Citation: Journal of the American Veterinary Medical Association 232, 11; 10.2460/javma.232.11.1674
Box plots of serum or plasma NT-proBNP concentrations in dogs with respiratory distress or cough for which a diagnosis of congestive heart failure (n = 25) or primary pulmonary disease (21) was made. For each plot, the box represents the 25th and 75th percentiles, the line within the box represents the 50th percentile, and the whiskers represent the 10th and 90th percentiles. Black circles represent outliers. The median concentration for the dogs with cardiac disease was significantly (P < 0.001) greater than the median concentration for the dogs with pulmonary disease.
Citation: Journal of the American Veterinary Medical Association 232, 11; 10.2460/javma.232.11.1674
Box plots of serum or plasma NT-proBNP concentrations in dogs with respiratory distress or cough for which a diagnosis of congestive heart failure (n = 25) or primary pulmonary disease (21) was made. For each plot, the box represents the 25th and 75th percentiles, the line within the box represents the 50th percentile, and the whiskers represent the 10th and 90th percentiles. Black circles represent outliers. The median concentration for the dogs with cardiac disease was significantly (P < 0.001) greater than the median concentration for the dogs with pulmonary disease.
Citation: Journal of the American Veterinary Medical Association 232, 11; 10.2460/javma.232.11.1674
Scatter plots of serum or plasma NT-proBNP concentration versus echocardiographic and radiographic measures of cardiac size in dogs with respiratory distress or cough for which a diagnosis of congestive heart failure (n = 25) or primary pulmonary disease (21) was made. In all panels, the solid line represents the linear regression line. A—Circulating NT-proBNP concentration versus radiographic vertebral heart score (VHS) in dogs with cardiac disease. For this group, the relationship between the 2 variables was not significant (P > 0.05). B—Circulating NT-proBNP concentration versus radiographic VHS in dogs with pulmonary disease. For this group, the relationship between the 2 variables was not significant. C—Circulating NT-proBNP concentration versus left atrial-to-aortic diameter (LA:Ao) ratio in dogs with cardiac disease. There was no correlation between the 2 variables. D—Circulating NT-proBNP concentration versus left ventricular end-diastolic diameter (LVEDD) in dogs with cardiac disease. There was a weak correlation between the 2 variables.
Citation: Journal of the American Veterinary Medical Association 232, 11; 10.2460/javma.232.11.1674
Scatter plots of serum or plasma NT-proBNP concentration versus echocardiographic and radiographic measures of cardiac size in dogs with respiratory distress or cough for which a diagnosis of congestive heart failure (n = 25) or primary pulmonary disease (21) was made. In all panels, the solid line represents the linear regression line. A—Circulating NT-proBNP concentration versus radiographic vertebral heart score (VHS) in dogs with cardiac disease. For this group, the relationship between the 2 variables was not significant (P > 0.05). B—Circulating NT-proBNP concentration versus radiographic VHS in dogs with pulmonary disease. For this group, the relationship between the 2 variables was not significant. C—Circulating NT-proBNP concentration versus left atrial-to-aortic diameter (LA:Ao) ratio in dogs with cardiac disease. There was no correlation between the 2 variables. D—Circulating NT-proBNP concentration versus left ventricular end-diastolic diameter (LVEDD) in dogs with cardiac disease. There was a weak correlation between the 2 variables.
Citation: Journal of the American Veterinary Medical Association 232, 11; 10.2460/javma.232.11.1674
Scatter plots of serum or plasma NT-proBNP concentration versus echocardiographic and radiographic measures of cardiac size in dogs with respiratory distress or cough for which a diagnosis of congestive heart failure (n = 25) or primary pulmonary disease (21) was made. In all panels, the solid line represents the linear regression line. A—Circulating NT-proBNP concentration versus radiographic vertebral heart score (VHS) in dogs with cardiac disease. For this group, the relationship between the 2 variables was not significant (P > 0.05). B—Circulating NT-proBNP concentration versus radiographic VHS in dogs with pulmonary disease. For this group, the relationship between the 2 variables was not significant. C—Circulating NT-proBNP concentration versus left atrial-to-aortic diameter (LA:Ao) ratio in dogs with cardiac disease. There was no correlation between the 2 variables. D—Circulating NT-proBNP concentration versus left ventricular end-diastolic diameter (LVEDD) in dogs with cardiac disease. There was a weak correlation between the 2 variables.
Citation: Journal of the American Veterinary Medical Association 232, 11; 10.2460/javma.232.11.1674
Discussion
The results of the present study indicated that assessment of the concentration of circulating NT-proBNP has the potential to differentiate between primary pulmonary disease and congestive heart failure as a cause of respiratory distress or cough in dogs. It is known that assessment of circulating NT-proBNP can be used to identify humans with pulmonary disease and those with congestive heart failure.15,19 Although the lowest value among dogs with heart failure in our study and the highest value among dogs with pulmonary disease were similar, there was no overlap between the 2 groups. However, in a study20 of humans with acute dyspnea who attended an emergency room, there was a substantial degree of overlap in NT-proBNP concentrations between patients with heart failure and those with primary pulmonary disease, which decreased the diagnostic specificity of the test. The difference in degree of overlap of results from our study and those from the study in humans is likely because the sample size in the human study was larger and the selection criteria for the populations used in the 2 studies differed. In the present study, dogs were stratified into 2 distinct groups: one of dogs with congestive heart failure and the other of dogs with primary pulmonary disease and no evidence of heart disease. In the human study, no attempt was made to determine whether patients in which primary pulmonary disease was considered the cause of their respiratory distress also had concurrent cardiac abnormalities.
The aim of our study design was to delineate, as clearly as possible, circulating NT-proBNP concentrations in dogs with primary respiratory disease and to evaluate the overlap in the results for those dogs with results for dogs with cardiac failure. This approach, however, can also be considered a limitation of the study. Other studies4,16,21 of dogs with heart disease have revealed that circulating BNP concentration is increased even when heart failure is not present. Because NT-proBNP is coreleased with BNP, it is expected that dogs with nonclinical heart disease will have similar increases in circulating NT-proBNP concentration. Thus, dogs with respiratory signs that are of pulmonary origin are likely to have increased NT-proBNP concentrations if concurrent cardiac disease is present, compared with dogs that had pulmonary disease but no cardiac abnormalities. Therefore, circulating NT-proBNP concentration should be interpreted within the context of results of other diagnostic tests such as radiography, hematologic analyses, and echocardiography. Further studies in dogs are indicated to assess the discriminatory ability of NT-proBNP concentration assessment in dogs with concurrent pulmonary and heart diseases.
In the study of this report, a weak but predictable correlation was identified between the circulating NT-proBNP concentration and the echocardiographic left ventricular end-diastolic dimension. Surprisingly, there was no relationship between NT-proBNP concentration and left atrial-to-aortic diameter ratio. A study5 evaluating natriuretic peptides in dogs with mitral valve regurgitation revealed good correlation between the logarithmic circulating amino terminal-proANP concentration and left atrial-to-aortic diameter ratio and a modest correlation between the logarithmic circulating NT-proBNP concentration and left atrial-to-aortic diameter ratio. The positive correlation between the log amino terminal-proANP concentration and left atrial-to-aortic diameter ratio is expected given that ANP is primarily released in response to atrial distension. Although proBNP is primarily secreted in response to ventricular disease, a small amount is also released as a result of atrial enlargement. It was therefore expected that some correlation between the left atrial-to-aortic diameter ratio and circulating NT-proBNP concentration would be detected in the dogs of our study. However, in the aforementioned study5 of natriuretic peptides in dogs with mitral valve regurgitation, the sample size was larger, which may have increased the likelihood of detecting a relationship. It was also unexpected that no relationship between circulating NT-proBNP concentration and radiographic vertebral heart score was detected in either group. Although the lack of correlation may simply have been a reflection of the relatively small sample size in each group, it is as likely that NT-proBNP concentrations reflect a multitude of individual patient factors. The cardiac disease processes in the dogs of the present study were heterogeneous. Although most of the dogs had myxomatous mitral valve degeneration, several had varying degrees of concurrent tricuspid valve degeneration. Most dogs had signs of left-sided heart failure, but some had biventricular failure and rightsided heart failure signs predominated in others. Most dogs had a normal sinus rhythm, but several had atrial fibrillation. Additionally, samples were not collected at the same time point from all dogs with heart failure. Samples were collected from all dogs within 12 hours of the initial diagnosis, but the fact that treatment had been initiated in some and not in others at the time of sampling may have skewed the results of analysis. Finally, it is known that age, gender, and renal function all affect NT-proBNP concentration in humans.22–24 The study of this report was not designed to examine the effects of these confounding variables.
In the present study, assessment of circulating NT-proBNP concentration was useful in differentiation of dogs with heart disease and signs of congestive heart failure from those with primary pulmonary disease and no evidence of heart disease. In the heart failure group, only 1 dog had an NT-proBNP concentration < 1,000 pmol/L; 92% of dogs with heart failure had an NT-proBNP concentration > 1,400 pmol/L. Therefore, results of the study of this report suggest that dogs with respiratory distress or cough that have a circulating concentration of NT-proBNP > 1,400 pmol/L should be strongly suspected of having heart failure.
ABBREVIATIONS
| ANP | Atrial natriuretic peptide |
| BNP | B-type natriuretic peptide |
| IR | Interquartile range |
| NT-proBNP | Amino terminal pro-B-type natriuretic peptide |
Fine DM, DeClue AE, Reinero CR. NT-proBrain natriuretic peptide for discrimination of respiratory distress due to congestive heart failure or primary pulmonary disease. 25th Annual American College of Veterinary Internal Medicine Forum 2007 (abstr). J Vet Intern Med 2007;21:587–588.
Wess G, Timper N, Hirschberger J. The utility of NT-pro-BNP to differentiate cardiac and respiratory causes of coughing or dyspnea in dogs. 25th Annual American College of Veterinary Internal Medicine Forum 2007 (abstr). J Vet Intern Med 2007; 21:608.
Veterinary Diagnostic Institute, Irvine, Calif.
NCSS 2000, NCSS Inc, Kaysville, Utah.
Gauthiers S, Veterinary Diagnostics Institute, Irvine, Calif: Personal communication, 2007.
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