NATRIURETIC PEPTIDES

ANP and BNP, released from the myocardium primarily in response to elevated wall stress, elicit vasodilation, diuresis, and natriuresis. In this respect the biological activity of ANP and BNP counters that of the renin-angiotensin-aldosterone system, which also is activated in cats with heart disease and heart failure. Production of ANP occurs primarily within the atrial myocardium, whereas in cats with heart disease, both the atrial and ventricular myocardium secrete BNP.^3–5 Both hormones are produced initially as prohormones, and upon secretion are cleaved subsequently by serum proteases to form the active hormone (C-terminal ANP and C-terminal BNP), as well as an inactive N-terminal portion (NT-proANP and NT-proBNP). Detection of the circulating N-terminal fragments is facilitated by their longer half-life and greater stability as compared with the C-terminal molecules. Thus the commercially available feline ANP and BNP tests detect the N-terminal molecules specifically.

In human beings ANP and BNP assays are used to (1) detect asymptomatic disease in high-risk populations, (2) assess severity of disease, (3) confirm or exclude a diagnosis of heart failure in emergent patients, (4) provide prognosis, and (5) guide treatment through use of sequential measurements.^2,6,7

DETECTION OF UNDERLYING HEART DISEASE

Circulating concentrations of C-ANP and C-BNP are elevated in cats with heart disease,⁸ and plasma C-ANP concentrations correlate strongly with left atrial pressure in cats.⁹ NT-proANP and NT-proBNP are similarly elevated in affected cats.¹⁰ Median (95% CI) concentration of NT-proANP in healthy control cats, cats with heart disease without heart failure, and cats with heart disease and heart failure was 682 (530 to 834) pmol/L, 1176 (810 to 1543) pmol/L, and 1865 (1499 to 2231) pmol/L, respectively.¹⁰ Using a cutoff value of 960 pmol/L, NT-proANP assay possessed a sensitivity of 84 per cent and specificity of 82 per cent in distinguishing healthy controls from cats with heart disease or heart failure. Overall, NT-proANP assay classified 83 per cent of the 78 cats correctly in the study. In the same study¹⁰ median (95% CI) concentration of NT-proBNP in healthy control cats, cats with heart disease without heart failure, and cats with heart disease and heart failure was 34 (11 to 56) pmol/L, 184 (111 to 257) pmol/L, and 525 (437 to 612) pmol/L, respectively. Using a cutoff value of 49 pmol/L, NT-proBNP assay possessed 100 per cent sensitivity and 89 per cent specificity, and 96 per cent of all cats were classified correctly. Thus every cat with heart disease or heart failure (n = 50) was detected by NT-proBNP assay. The detection of heart disease in cats using NT-proBNP assay is further supported by a study of 80 healthy control cats and 86 cats with asymptomatic heart disease.¹¹ In this population an NT-proBNP cutoff value of 40 pmol/L yielded 90 per cent sensitivity and 85 per cent specificity for detecting cats with asymptomatic heart disease. These results indicate that detection of asymptomatic or occult cardiomyopathy is possible using natriuretic peptide assay, and in particular NT-proBNP assay. Cats with preclinical cardiomyopathy are a particularly important subpopulation, because by definition they demonstrate no clinical signs referable to their underlying disease. Cats with preclinical disease frequently escape detection until overt sequelae (i.e., pulmonary edema, pleural effusion, systemic thromboembolism) develop, at which time prognosis is very poor.

In general, screening tests are most useful when the assay in use is highly sensitive and is applied to a high-risk population with a relatively high prevalence of disease.¹² In a feline population this may include breeds at high risk (e.g., Maine Coon), older cats, or cats with heart murmurs or gallop rhythms. This combination of high sensitivity and relatively high prevalence maximizes the predictive power of the test by reducing the number of false-positive and false-negative results.

ASSESSMENT OF DISEASE SEVERITY

In cats with cardiomyopathy, circulating NT-proANP and NT-proBNP concentrations correlate with traditional indices of disease severity, such as vertebral heart size, left ventricular wall thickness, and left atrial size.^10,13 These results agree with findings in human beings with hypertrophic cardiomyopathy (HCM).^14,15 It should be noted, however, that the precise clinical utility of circulating BNP concentrations for quantification of disease severity in any individual patient is still a subject of great debate.^16,17 Importantly NT-proBNP may not detect very early and mild disease (i.e., a false-negative result). More studies in this specific population are needed. The importance of detecting very early disease can be viewed in different ways. On the one hand, a false-negative result would allow a cat with mild disease to remain undetected, and this may negatively impact breeding decisions made for animals young enough to still be bred. In this regard identification and screening for specific causative genetic mutations remains the gold standard (see Chapter 39). On the other hand, proponents of cardiac blood testing argue that the impact of a false-negative result on any individual animal outside of breeding considerations is relatively low, such that very mild disease is not typically associated with clinical signs, nor are there proven medical interventions that alter the course of disease at this early stage. Thus no practical intervention other than rechecking disease at a later date is typically performed in cats with very mild disease. Based on previous studies indicating a high degree of sensitivity and specificity in cats with moderate to severe disease,^10,11,13 one could reasonably expect that serial NT-proBNP assay in these cats could be used to detect progressive disease.

DETECTING HEART FAILURE IN THE CAT WITH RESPIRATORY SIGNS

In cats with respiratory signs BNP assay helps to differentiate causes of dyspnea. In a study of 137 cats who presented with respiratory signs, plasma NT-proBNP higher than 265 pmol/L yielded a sensitivity of 91 per cent and specificity of 85 per cent in detecting those cats with heart failure (n = 84) versus those with primary respiratory diseases such as asthma, pneumonia, or neoplasia (n = 53).¹³ Similarly, Connolly et al¹⁰ reported that NT-proBNP higher than 220 pmol/L possessed 94 per cent sensitivity and 88 per cent specificity, whereas NT-proANP higher than 986 pmol/L possessed 94 per cent sensitivity and 80 per cent specificity, in 41 cats with respiratory disease and 33 cats with heart failure. Finally Wess et al¹⁸ reported that NT-proBNP higher than 277 pmol/L achieved 95 per cent sensitivity and 85 per cent specificity in 21 cats with respiratory disease and 20 cats with heart failure. Thus the cumulative results of these studies suggest that NT-proANP, and in particular, NT-proBNP, are useful as part of the diagnostic evaluation of cats who present with respiratory signs. Those cats with elevated NT-proBNP concentrations likely suffer from congestive heart failure, whereas those with lower values are more likely to have primary respiratory disease. The value of such testing is especially pertinent to patients who are not stable enough for routine diagnostic tests (e.g., thoracic radiography, echocardiography, transtracheal wash). The development of rapid pet-side assays is needed to fulfill the potential of these tests maximally for use in the emergent patient.