M.A. Oyama

School of Veterinary Medicine, University of Pennsylvania, Philadelphia PA, USA.

Assessment of heart function suffers from lack of blood-based assays, such as the quantification of BUN, creatinine, ALT, bile acids, and so forth achieves for other organ systems. However, the heart is more than just a muscular pump. In fact, it is also an endocrine organ that elaborates a set of peptides with natriuretic and diuretic actions. These "neurohormones" are produced in response to stress or disease and can be found in circulation using species-specific assays. In addition to producing cardiac neurohormones, the injured heart "leaks" marker substances associated with disrupted muscle filaments and damaged cell membranes. Cardiac troponin-I and cardiac troponin-T are components of the actin-myosin complex and are released from ischemic or necrotic cardiac myocytes. In humans, measurement of cardiac troponin is the gold standard for detection of myocardial infarction. While major cardiac infarctions are relatively rare in companion animals, common diseases such as mitral valve degeneration and cardiomyopathy also damage heart muscle and produce elevated cardiac troponin concentrations. Feline cardiomyopathy is also associated with elevated troponin. Other markers of disease that are commonly used in human medicine, such as C-reactive protein, have been measured in dogs with heart disease. Commercially available tests are now available for many cardiac-specific markers. Thus, blood-based cardiac tests are becoming increasingly feasible in veterinary species. The potential clinical utility of cardiac biomarkers involves 1) diagnosis of heart disease in asymptomatic and symptomatic patients, 2) monitoring response to treatment, and 3) prognostication. This article discusses the clinical use of atrial natriuretic peptide, B-type natriuretic peptide, and cardiac troponin in dogs and cats with heart disease. Future directions involving additional blood and urine-based substances will also be discussed.

CARDIAC TROPONIN

Troponin is an essential component of cardiac and striated muscle. Three types of troponin exist, I, T, and C. Together, these molecules form a tripartite complex that regulates binding of cytosolic calcium and interaction of the sarcomeric actin and myosin filaments. The cardiac isoforms of troponin-I (cTnI) and troponin-T (cTnT) are antigenically distinct from the skeletal muscle forms and consequently, are sensitive and specific markers of myocardial ischemia, cellular injury, and necrosis. In humans, cardiac troponin is used to diagnosis acute myocardial infarction. In veterinary patients, where major infarctions are relatively rare, cTnI and cTnT may still have clinical use in detecting low-level myocardial injury due to a variety of conditions such as dilated and hypertrophic cardiomyopathy, subaortic stenosis, myocarditis, and mitral valve disease. It appears that canine, feline, and equine cardiac troponin can be reliably measured using a variety of human assays, however, the results from different machines can show considerable variation, and direct comparison between different assay platforms is problematic. Table 1 summarizes studies that sought to establish normal reference values for cTnI or cTnT in veterinary species. Table 2 summarizes reports of elevated cardiac troponins in species of veterinary interest.

GDV, gastic dilation and volvulus; BCT, blunt chest trauma; MVD, mitral valve disease; DCM, dilated cardiomyopathy; PE, pericardial effusion; SAS, subaortic stenosis; HCM, hypertrophic cardiomyopathy; VT, ventricular tachycardia; CHF, congestive heart failure; DXR, doxorubicin treatment.

As a marker of cardiac injury, cTnI and cTnT may have prognostic value. In a small group of dogs with cardiomyopathy, dogs with cTnI >0.2 ng/mL had shorter survival times than dogs with lower concentrations (112 vs 357 days, Ρ = 0.006) [1]. More studies are needed to confirm this preliminary finding. In dogs with GDV, cTnI and cTnT correlated to severity of cardiac arrhythmias and outcome [12]. Dogs that died had higher cTnI (24.9 ng/mL) and cTnT (0.18 ng/mL) than dogs that survived. In cats with HCM, those with higher cTnI had more severe disease and congestive heart failure vs. affected but asymptomatic cats [10]. Furthermore, troponin elevations are weakly correlated to the extent of left ventricular hypertrophy in cats with HCM [6,10]. In dogs, troponin levels correlated to the extent of gross and histologic cardiac damage found on necropsy in dogs with myocardial necrosis due to experimental infarction or babesiosus [8,13]. Collectively, these data suggest that elevated troponin is correlated to the magnitude of cardiac injury and that high levels likely indicate a poor prognosis.

Little is known about the use of troponin as a guide to medical therapy. To the author’s knowledge, no reports of serial cTnI or cTnT measurements in animals with spontaneous disease exist. Studies should be performed to determine if troponin levels change after treatment for heart failure, and if so, how might these assays be used to help tailor therapy of individual patients.

It is unlikely that troponin can be used as a screening tool for asymptomatic disease or determining cause of respiratory distress. Despite the finding that cats with asymptomatic HCM have elevated cTnI, the overlap between this group and healthy cats is substantial. In dogs with dyspnea, cTnI was not useful in distinguishing between cardiac (eg, CHF) and non-cardiac (eg,. primary respiratory) etiologies [14], nor was cTnI useful in detecting occult canine cardiomyopathy in a population of high-risk patients [15].

ATRIAL NATRIURETIC PEPTIDE

Atrial natriuretic peptide (ANP) is produced by atrial myocytes and is released by atrial stretch. Atrial stretch occurs secondary to high left atrial pressures that result from cardiomyopathy or valvular disease. The biologic action of ANP is counter to the actions of the renin-angiotensin-aldosterone system, that is, ANP induces vasodilation and diuresis. ANP is secreted as a prohormone, which is rapidly cleaved to form the mature and biologically active C-terminal ANP and an N-terminal pro-ANP (NT-proANP) fragment. The longer half-life of NT-proANP makes it the more useful diagnostic target. Canine NT-proANP can be measured with a commercially available ELISA system (Vetsign Canine Cardioscreen, Guidhay Ltd, UK). The primary indication for the assay is to distinguish cardiac vs. non-cardiac causes of respiratory distress in dogs. Levels >1700 fmol/mL are highly suggestive of congestive heart failure as the cause of dyspnea (92% probability), while levels 1351 - 1700fmol/ml are suggestive of heart failure. The normal reference value is <1350>

B-TYPE NATRIURETIC PEPTIDE

B-type natriuretic peptide (BNP) shares many similar characteristics to ANP insofar as its secretion from the heart in a prohormone form, its diuretic action, and short half-life of the mature C-terminal fragment. Recently, a canine-specific NT-proBNP ELISA has become available in Europe and the US (Canine CardioSCREEN proBNP, Guildhay Ltd, UK and Veterinary Diagnostics Institute, Irvine, CA). It is generally thought that BNP has wider application and clinical utility than ANP. Similar to ANP, in dogs presenting with respiratory difficulty, NT-proBNP can distinguish etiology of respiratory distress. NTproBNP >1000 pmol/L is associated with a 95% probability of a cardiac cause of dyspnea (eg, CHF). Moderate elevations of BNP (NT-proBNP >210pmol/L) are suggestive of underlying heart disease, but not necessarily CHF in asymptomatic animals. The normal reference range is <210>

In humans, BNP levels carry prognostic significance. Patients with high or persistently elevated levels fare worse than individuals with low levels (17,18]. The author hopes that NT-proBNP assay can be used for a variety of similar clinical applications, including detection of occult disease in cats and dogs, prognostication, and monitoring of therapy. Large-scale studies investigating these specific indications are needed before more concrete recommendations can be made.