Borgeat K, Connolly DJ, Luis Fuentes V. Cardiac biomarkers in cats. J Vet Cardiol 2015;17:574-86.
Accurate diagnosis of cardiac disease in cats poses a number of conundrums for the clinician. Cats may have serious cardiac disease (subclinical or occult cardiomyopathy) with no clinical signs whatsoever, and then perianesthetic death or sudden death at home may occur without warning. When a heart murmur is ausculted, especially a soft to moderate one (grades I-III/VI), it may or may not be associated with clinically significant heart disease, and there are no clear criteria to identify such murmurs as pathologic or non-pathologic. Cats who present in respiratory distress may have cardiac disease or respiratory disease, or both, and it is often challenging to distinguish these in a fragile patient in crisis.
The ability to use relatively inexpensive, easily accessible laboratory tests to identify clinically significant heart disease in feline patients can facilitate faster and more targeted diagnosis and treatment of these patients. This review article discusses the role of cardiac biomarkers in clinical decision-making in feline cardiorespiratory medicine, including N-terminal pro-brain natriuretic peptide (NT-proBNP), N-terminal pro-atrial natriuretic peptide (NT-proANP), cardiac troponin I (cTnI), and cardiac troponin T (cTnT).
The natriuretic peptides are synthesized by the cardiac myocytes, and are sent into the systemic circulation in significant amounts when there is excessive stretch on the atria (ANP), ventricles (BNP), ischemia, hypoxia, sympathetic activation, or production of angiotensin II. Normal amounts of these peptides are useful in maintaining homeostasis in healthy individuals, because they help regulate blood pressure and bodily fluid balance. Troponins are proteins that are involved in contraction of the myocardium. They play a role in facilitating actin-myosin binding, which is fundamental to cardiac muscle contraction. If the myocardium is injured, troponin subunits are released into the systemic circulation, so when they are detected in significant levels in the blood, damage of and leakage from cardiac myocytes are occurring.
In animal patients, the two most commonly used biomarkers are NT-proBNP and cTnI. Relevant studies regarding the use of cardiac biomarkers were summarized with respect to several areas of concern: distinguishing cardiac from non-cardiac causes of respiratory distress, pleural fluid and urinary NT-proBNP measurement, identification of cats with occult cardiomyopathy, effects of systemic non-cardiac disease on cardiac biomarkers, point-of-care tests, prognostic utility of cardiac biomarkers, and limitations of cardiac biomarkers.
Eight studies of the use of cardiac biomarkers in distinguishing cardiac from non-cardiac causes of respiratory distress were reviewed. Three of the four studies evaluating cTnI reported a higher median concentration of this biomarker in the group with cardiac disease, and one (the smallest study) did not identify a statistically significant difference between the group with cardiac disease and the group with non-cardiac disease. In all of the studies involving cTnI, there was a lot of overlap in cTnI values between groups with cardiac and non-cardiac disease.
Four other studies demonstrated that NT-proBNP has greater accuracy than cTnI in distinguishing cardiac from non-cardiac causes of respiratory distress. Those groups that had respiratory distress of cardiac etiology had higher median NT-proBNP values than groups of cats with non-cardiogenic respiratory distress. One study also included NT-proANP, and this biomarker was less accurate in identifying cardiac disease than NT-proBNP, but NT-proANP was still found to be useful in detecting cardiogenic respiratory distress.
NT-proBNP levels can be accurately measured in the pleural fluid and urine of humans. In one study of cats presented to an emergency hospital, measurement of NT-proBNP in pleural fluid and urine was considered to be adequate and reliable. In these cats, NT-proBNP levels in pleural fluid were higher than in plasma, and the urine NT-proBNP/creatinine ratio was higher in cats with cardiogenic pleural effusion than in those with pleural effusion of non-cardiac etiology. Although useful cut-off values to distinguish patients with cardiac disease from those with non-cardiac disease using urine NT proBNP measurements could not be determined, possibly due to issues with urine sample handling or processing, NT-proBNP levels in pleural fluid obtained via thoracocentesis are a reliable substitute for blood NT-proBNP assays. This in turn may eliminate the need for additional restraint and blood sample collection in a compromised and fragile patient who has already undergone thoracocentesis.
Due to the expense and lack of universal accessibility to echocardiography, the use of cardiac biomarkers in identifying occult cardiomyopathy was assessed in eleven studies, the two largest of which were expressly designed to identify occult cardiomyopathy in a screened population of cats using cardiac biomarkers. Ten of the eleven studies reviewed determined that cardiac biomarkers were significantly higher in groups of cats with echocardiographic evidence of cardiomyopathy than in groups of healthy controls. In five studies comparing the levels of NT-proBNP in cats with heart disease versus healthy cats, NT-proBNP was found to be significantly higher in the groups with cardiac disease.
However, in the studies which evaluated the use of NT-proBNP to distinguish different grades of severity of cardiomyopathy, the NT-proBNP assay was less accurate in identifying mild grades of cardiac disease. Therefore, echocardiography is still the modality of choice for diagnosing cats with mild or early stage cardiomyopathy. Although two studies also reviewed the use of cTnI as a diagnostic biomarker in cats with heart disease but not in heart failure, and found that cTnI levels were significantly higher in cats with heart disease, the authors conclude, based on all the studies they reviewed, that NT-proBNP is the superior cardiac biomarker for identifying occult cardiomyopathy in cats.
The effects of body weight/condition, age, and sex on cardiac biomarkers in cats has not been thoroughly investigated, although it is known that levels of circulating cardiac biomarkers are influenced by age, sex, renal and thyroid function, body condition, and presence of anemia in humans. The studies of the influence of other conditions on circulating cardiac biomarker levels in cats include hyperthyroidism (3 studies), chronic kidney disease (CKD) +/-hypertension (2 studies), and anemia (one reporting preliminary data). In hyperthyroid cats, NT-proANP, NT-proBNP, and cTnI are increased, and will go back to levels comparable in non-hyperthyroid cats once the cat is rendered euthyroid by radioactive iodine therapy. However, neither NT-proBNP nor cTnI can differentiate between cats with hyperthyroidism and primary cardiomyopathy.
One study determined that cats with azotemic CKD often had higher cTnI levels than healthy cats. None of the cats investigated, however, had echocardiography performed, and no control group was used. Other studies have investigated the natriuretic peptides in cats with CKD. The studies of cats with CKD were inconsistent in their standardization and use of echocardiography, so further, prospective, standardized studies in cats with CKD +/- hypertension were recommended by the authors, in which all subjects are screened with echocardiography to rule in or rule out occult cardiac disease, and in which a healthy age- and sex-matched control group of cats without CKD is included. The single study of cats with anemia demonstrated that anemic cats had higher circulating levels of cTnI than a control population of unwell, nonanemic cats. In this study, echocardiography was also not performed on all study patients.
Accurate point-of-care (or "cage-side") tests for cardiac biomarkers would be very useful in evaluating cats who present with respiratory distress, especially in primary or emergency care settings. A patient-side NT-proBNP colorimetric ELISA has been developed that appears useful in identifying cats with moderate and severe grades of occult heart disease. In a study of 146 cats referred for cardiac evaluation, this test was found to have a 94% negative predictive value (NPV) and a positive predictive value (PPV) of 64%, which means the test is better at ruling out moderate to severe cardiac disease in a patient that does not have it, than in identifying cardiac disease in a patient that does have it. The population in which these results were obtained had a high prevalence (24%) of moderate to severe cardiac disease. In another, healthier population of cats, such as shelter cats, with a lower prevalence of moderate to severe cardiac disease, this test could be useful as a screening measure, because its NPV would be even higher, although the PPV would be much lower. No studies regarding the use of this test to determine if respiratory distress is cardiogenic or noncardiogenic in origin have been published, but the authors suggest that if a negative colorimetric NT-proBNP assay is obtained on a cat in respiratory distress, it is likely that the respiratory signs are noncardiogenic in origin.
Studies have also been published regarding the prognostic use of cardiac biomarkers in cats. In humans, NT-proBNP, cTnI, and cTnT are all used to help determine prognosis in people with hypertrophic cardiomyopathy (HCM). In cats, the cardiac troponins may be more useful than the natriuretic peptides in providing prognostic information. In one study of 36 cats with HCM, cTnI and cTnT were higher in cats who died of cardiac causes than survivors, and cTnT was the better prognostic marker of the two. Another study of 41 cats with HCM demonstrated that those HCM cats with circulating concentrations of cTnI > 0.7 ng/mL at the time of diagnosis had a shorter time to cardiac death. Serial cTnT monitoring could be clinically useful in such patients, although no published studies have reported how cardiac biomarkers may change over time in cats with cardiomyopathy.
The major limitations in comparing and compiling results from multiple studies of cardiac biomarkers in cats in various situations related to cardiac and respiratory diseases involve non-standardized treatment protocols, lack of consensus in how to grade severity of feline cardiomyopathy, lack of echocardiographic studies on all subjects, and inconsistent exclusion of animals with concurrent hyperthyroidism or hypertension from some of the studies. Future studies on the value of the urinary NTproBNP/creatinine ratio as a diagnostic test are recommended by the authors; more information is also needed regarding urine sample preparation and handling and its influence on the results of this test. [PJS]
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