Introduction

The diagnosis of heart failure is one of the areas in which biomarkers may be of value. There are many different types of marker that have been used to assist the management of human patients with cardiovascular disease. Interesting findings have also been generated in the application of similar tests to veterinary patients. The most promising markers in human patients have proved to be concentrations of cardiac troponins and concentrations of natriuretic peptides although a multitude of other markers have been evaluated including markers of myocardial remodelling and markers of inflammation.¹

The areas in which biomarkers may assist patient management can broadly be summarised in the following five areas; diagnosis, screening, risk stratification (or prognostication), monitoring (of disease progression or therapy) and therapeutic guidance. In veterinary studies the majority of emphasis has been on the use of biomarkers for diagnosis however there is some early promising data emerging from longitudinal studies which supports their use in risk stratification and monitoring response to therapy that are also worthy of mention.

Natriuretic peptides and cardiac troponins represent two very different types of marker. Natriuretic peptides are neurohumoral markers. They are peptides produced by the ventricular and atrial myocardium that are released in increased quantities when the myocardium is subjected to increased stress. This occurs when the pressure within cardiac chambers increases and when cardiac chambers dilate; thus they tend to increase as cardiac diseases progress and fluid is retained. Higher concentrations of the markers are associated with more severe forms of cardiac disease and peptide concentrations have been seen to be increased in dogs and cats with more advanced forms of common acquired cardiac diseases. By contrast troponins are "leakage" markers. They are released from myocardial cells that lose their integrity, such as would occur during significant myocardial cell death. The most common circumstance in which Troponin concentrations are elevated in human patients is during myocardial infarction when a significant number of myocardial cells die simultaneously. Infarction occurs much less frequently in veterinary patients. In diseases such as cardiomyopathies and primary valvular heart disease myocardial cell death would be expected to occur less frequently and in a less predictable manner and therefore this marker may be of less value for more common diseases of veterinary patients.

How Do We Validate Markers for Diagnosis of Heart Failure?

Validation of markers for the diagnosis of heart failure is usually undertaken in cross-sectional studies where concentrations of the marker are measured in patients with and without the diagnosis of interest. The "true" diagnosis is adjudicated in patients by comparison to a "gold standard". Various concentrations of the marker are then compared as potential "cut-off" values for the marker. In a circumstance where the concentration of the marker goes up with disease (as would be expected for both troponins and natriuretic peptides) if the patient's concentration is above the cut-off the result is considered positive and if the patient's concentration is below the cut-off it is considered negative. By comparing to the gold standard the number of "true" positive and negative results can be calculated. The proportion of truly affected patients that are picked up positive by the test is the "sensitivity" of the test and the proportion of truly unaffected patients that are negative on the test is the specificity of the test. Tests are often judged on their sensitivity and specificity. In Figure 1 a two by two table can be seen that illustrates a test that has a sensitivity of 90% and a specificity of 90%.

Figure 1. A two by two table for evaluating a diagnostic test.

Sometimes the sensitivity and specificity for every recorded concentration of the marker are calculated and then a curve plotted of "sensitivity" versus "1-specificity". This is called an ROC curve and the greater the area under the curve the more accurate the test is considered to be.

Several studies have been published that have evaluated the performance of natriuretic peptides and troponins in this way for cardiac diseases in dogs and cats. For the diagnosis of heart failure natriuretic peptides tend to perform better than troponins and the commercially available NTproBNP tests seem to be quite accurate in both dogs and cats.^2-6

The problem with this method of diagnosis is that it perpetuates what is called the "double dichotomy". It assumes that a patient either has, or does not have the outcome of interest and that a test result is either positive or negative. This is not always the case. A recent review article summarizing the use of natriuretic peptide concentrations in the diagnosis of heart failure in human patients concluded the following: "In most dyspneic patient populations, investigators have not been able to identify a single cut point to empirically rule in or rule out every patient with heart failure."⁷ Thus even in human patients these tests cannot be expected to right every time. "Positive" and "negative" results are of value and may well increase or decrease the likelihood of a patient having heart failure but tests should not be interpreted in isolation and concentrations of markers can be affected by confounding factors other than just the disease of interest.

Uses of Biomarkers for Purposes Other Than Diagnosis?

Longitudinal studies are required to demonstrate the utility of a test in the prediction of outcome. This can be referred to as "prognostication" or "risk stratification"; identifying patients at a greater risk of a particular outcome. In canine patients, studies have demonstrated that higher troponin concentrations⁸ and natriuretic peptide concentrations^9-10 are predictive of an increased risk of mortality in dogs with dilated cardiomyopathy and valvular heart disease respectively. The ability to identify patients with a greater risk of an adverse outcome might enhance clinical care by allowing greater efforts to be focused on those patients more likely to deteriorate. The value of multiple longitudinal assessments of patients' natriuretic peptide concentrations for the monitoring of disease status in patients has yet to be conclusively demonstrated but is an area of potential value that should be explored further.

In human patients serial monitoring of changed in natriuretic peptide concentration in response to heart failure therapy, and modifying therapy in light of the peptide concentrations has been shown to improve outcome with a reduced risk for mortality in patients treated in this way.¹¹ This potential use of biomarkers in veterinary patients has not been rigorously evaluated yet, although one study has shown a reduction in natriuretic peptide concentrations in dogs with advanced valvular heart disease in response to the introduction of pimobendan therapy.¹²

Conclusions

The use of biomarker concentrations as simple yes/no tests for the diagnosis of the presence of heart failure is one simple and potentially useful way to exploit these markers. When used in this way test results should never be interpreted in isolation. Potentially greater value of these markers may emerge as more is understood about their value in risk stratification of populations of diseased dogs and in the monitoring of the response to heart failure therapy; evidence of utility of the tests for the latter indication is as yet lacking in veterinary patients.

References

1.  Braunwald E. Biomarkers in heart failure. N Engl J Med 2008;358:2148-2159.

2.  Boswood A, Dukes-McEwan J, Loureiro J, et al. The diagnostic accuracy of different natriuretic peptides in the investigation of canine cardiac disease. J Small Anim Pract 2008;49:26-32.

3.  Connolly DJ, Soares Magalhaes RJ, Syme HM, et al. Circulating natriuretic peptides in cats with heart disease. J Vet Intern Med 2008;22:96-105.

4.  Fine DM, Declue AE, Reinero CR. Evaluation of circulating amino terminal-pro-B-type natriuretic peptide concentration in dogs with respiratory distress attributable to congestive heart failure or primary pulmonary disease. J Am Vet Med Assoc 2008;232:1674-1679.

5.  Fox PR, Oyama MA, Reynolds C, et al. Utility of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) to distinguish between congestive heart failure and non-cardiac causes of acute dyspnea in cats. J Vet Cardiol 2009;11 Suppl 1:S51-61.

6.  Oyama MA, Fox PR, Rush JE, et al. Clinical utility of serum N-terminal pro-B-type natriuretic peptide concentration for identifying cardiac disease in dogs and assessing disease severity. J Am Vet Med Assoc 2008;232:1496-1503.

7.  Chen WC, Tran KD, Maisel AS. Biomarkers in heart failure. Heart 2010;96:314-320.

8.  Oyama M, Solter P, Prosek R, et al. Cardiac Troponin-I levels in dogs and cats with cardiac disease. Journal of Veterinary Internal Medicine 2003;17:400.

9.  Moonarmart W, Boswood A, Fuentes VL, et al. N-terminal pro B-type natriuretic peptide and left ventricular diameter independently predict mortality in dogs with mitral valve disease. J Small Anim Pract 2010;51:84-96.

10. Serres F, Pouchelon JL, Poujol L, et al. Plasma N-terminal pro-B-type natriuretic peptide concentration helps to predict survival in dogs with symptomatic degenerative mitral valve disease regardless of and in combination with the initial clinical status at admission. J Vet Cardiol 2009;11:103-121.

11. Felker GM, Hasselblad V, Hernandez AF, et al. Biomarker-guided therapy in chronic heart failure: a meta-analysis of randomized controlled trials. Am Heart J 2009;158:422-430.

12. Atkinson KJ, Fine DM, Thombs LA, et al. Evaluation of pimobendan and N-terminal probrain natriuretic peptide in the treatment of pulmonary hypertension secondary to degenerative mitral valve disease in dogs. J Vet Intern Med 2009.