Biochemical Markers of Cardiac Dysfunction
WSAVA 2002 Congress
David Sisson, DVM, DACVIM-Cardiology
College of Veterinary Medicine, University of Illinois

Introduction

Biochemical screening for heart disease in certain defined pet populations using natriuretic peptide, endothelin, or troponin assays is an attractive hypothesis. The prospect of identifying dogs (and cats) with asymptomatic heart disease via biochemical testing is exciting from several perspectives. First, it would likely permit individuals without extensive training in cardiology to identify animals with heart disease more accurately and at an earlier point in time. Such testing could facilitate the delivery of medical treatment at an earlier stage of the disease process than is currently accomplished while avoiding unnecessary treatment of unaffected or mildly affected animals. Biochemical testing might also help clarify the status of dogs with equivocal results when evaluated by other diagnostic modalities, e.g., dogs with "cardiomegaly" on thoracic radiographs or large breed dogs with mildly reduced contractile indices on an echocardiogram. Some obvious applications might include screening the breeding populations of cats for hypertrophic cardiomyopathy and asymptomatic Doberman pinschers for dilated cardiomyopathy. For screening purposes, a test must have very high sensitivity; i.e., it should detect at least 90 per cent of the target group(s). It must also have a reasonable level of specificity, as this population of animals will subsequently require additional evaluation, such as echocardiography, at substantial cost to the owner to confirm the diagnosis. The required level of specificity is debatable, but it is reasonable to assume that a useful test would have a specificity exceeding 70 percent.

Pathophysiology

The clinical syndrome of congestive heart failure (CHF) is characterized by increased peripheral resistance, reduced cardiac output, and elevated venous filling pressures. Increased peripheral vascular resistance is due to increased sympathetic tone and increased plasma concentrations of norepinephrine, angiotensin II, arginine vasopressin, and endothelin. Plasma concentrations of the natriuretic peptides, ANP and BNP, also increase in patients with chronic heart failure, in response to atrial distension and ventricular wall stress, respectively. Recent studies in human patients with heart disease suggest that plasma ANP and BNP concentrations can be used to predict disease severity, to predict mortality, to monitor therapy, and to identify patients with asymptomatic left ventricular dysfunction. A similar role has been proposed in regard to plasma endothelin concentrations. Recent studies indicate that either acute or chronic cardiac injury induces release of troponin complex subunits into the circulation, where their levels tend to be proportional to the severity of cardiac damage.

Natriuretic Peptides

ANP is a 28 amino acid peptide secreted from the atria in response to atrial stretch. On secretion, proANP is cleaved to the biologically active 28-amino-acid C-terminal ANP and the 98-amino acid N-terminal (NT)-proANP. The two peptides are secreted into the circulation in equimolar quantities. NT-proANP differs from ANP in that its half-life in circulation is longer and it is more stable and more easily measured in the laboratory. BNP, which is primarily secreted from the ventricle, is a 32-amino acid peptide that shares structural and biological similarities to ANP. The biologically active peptide sequence of BNP lies in the carboxyterminal of the pro-BNP peptide. Processing of pro-BNP after an arg-x-x-arg sequence results in the formation of a 32 amino acid peptide (BNP-32) containing a 17 amino acid ring structure similar to that found in ANP. ANP and BNP bind to the natriuretic peptide-A receptor (NPR-A) which, via 3',5'- cyclic guanosine monophosphate (cGMP), mediates natriuresis, vasodilatation, renin inhibition, antimitogenesis, and lusitropic effects on the heart. Both peptides are cleared by the natriuretic peptide-C receptor and degraded by the ectoenzyme neutral endopeptidase (24.11).

Circulating ANP and BNP have emerged as important diagnostic and prognostic markers of congestive heart failure in human patients. Gottlieb et al. reported that (C-terminal) ANP provides prognostic data on survival, ventricular ectopy, and hemodynamic abnormalities. Davis et al. identified ANP as a specific and sensitive test for predicting CHF in elderly subjects. Lerman et al. reported that NT-ANP, which is cleared more slowly and is more stable than the biologically active C-terminal ANP, was superior to C-terminal ANP as a marker of asymptomatic left ventricular dysfunction. Davis et al. reported that elevated BNP was an excellent discriminator of cardiac and non-cardiac dyspnea. Recently, Richards et al. reported that N-terminal BNP measured 2 to 4 days after myocardial infraction independently predicted left ventricular function and 2-year survival. In studies by Yamato et al., BNP emerged as superior to either N-terminal or C-terminal ANP as a marker for ventricular systolic or diastolic dysfunction and ventricular hypertrophy in patients with, or at risk for, cardiac disease. In November 2000, the FDA approved the first clinical BNP assay for use at the time of hospital admission for the express purpose of identifying those human patients having a high likelihood of underlying heart disease. In a recent study of human patients with congestive heart failure, a predetermined plasma concentration of brain natriuretic peptide was used as a target for the titration of medical therapy. There were fewer adverse clinical events in those patients treated with BNP guidance than in patients where therapy was guided by clinical assessment alone.

More limited studies have been performed in companion animals. Natriuretic peptide levels have been shown to correlate with class of heart failure in dogsand their measurement may allow veterinarians to offer pet owners a more accurate long-term prognosis. Natriuretic peptide assays might also prove useful for monitoring the efficacy of a therapeutic intervention. ANP concentrations are known to increase in dogs with mitral regurgitation, heartworm disease, and congestive heart failure. Haggstrom et al. has suggested that BNP levels in Cavalier King Charles spaniels with mitral regurgitation do not rise as dramatically as in humans with ischemic or other types of myocardial disease, and that NT-ANP better reflects the severity of mitral regurgitation.

Endothelin

Endothelin (ET-1) is a potent 21 amino acid vasoconstricting peptide produced by the vascular endothelium and the heart where it is converted from a 38-39 amino acid peptide (big ET-1) by the action of endothelin converting enzyme (ECE). Two endothelin receptor subtypes, ETA-R and ETB-R mediate the actions of ET-1. The type A receptor (ETA-R) mediates smooth muscle vasoconstriction and proliferation, while the more complex type B receptor (ETB-R) appears to antagonize these effects. Chronic elevations of ET-1 in heart failure patients increase systemic vascular resistance, induce hypertrophy of vascular smooth muscle, and stimulate myocardial hypertrophy.

Cardiac Troponins

The cardiac troponin complex is comprised of three subunits (I, T, and C), regulating the excitation-contraction coupling of the sarcomeric proteins. Acute and/or chronic cardiac injury induces release of these subunits into the circulation, where their levels are proportional to the severity of myocardial damage. Markers such as cTnI and cTnT demonstrate greater specificity for myocardial damage than previously used enzymatic markers such as lactate dehydrogenase and creatine-kinase-MB. In human cases of suspected acute myocardial infarction or trauma, the measurement of serum cTnT and/or cTnI levels is regarded as the diagnostic standard of evaluation. Circulating cardiac troponin concentrations have also been used to detect chronic myocardial damage in humans with DCM, HCM, trauma, myocarditis, arrhythmias and systemic hypertension.

The value of measuring circulating troponin concentrations in dogs with naturally occurring heart disease is not well established. O'Brien et al. have performed several studies establishing the specificity of cardiac troponin I and troponin T (cTnI and cTnT) versus skeletal muscle troponins in dogs. Sleeper et al. recently published normal values for circulating plasma troponin I concentrations in dogs and cats. Schober et al. found elevated troponin concentrations in cats with cardiomyopathy and in dogs with dilated cardiomyopathy or suspected myocardial contusion. A recent study by Lobetti et al indicated that cTnI reflected the severity of myocardial damage in canine Babesiasis.

Summary

The prospect of being able to differentiate dogs with heart disease from those with primary respiratory disease or some other disorder via an inexpensive blood-based assay is an exciting one with obvious clinical application. We anticipate that, in the near future, veterinarians will be using one of these assays or a combination to confirm a clinical diagnosis of heart failure, to help differentiate dogs with primary respiratory disease from those with heart disease, or to assess the need for further cardiac diagnostics. Moreover, it is feasible that these goals could be accomplished using a simple bedside test, similar to the same way we currently test for heartworms in dogs or FELV/ FIV infection in cats.

References

1.  Chen HH and Burnett JC. The natriuretic peptides in heart failure: diagnostic and therapeutic potentials. Proc Am Assoc of Am Phys 1999; 111:406-16.

2.  Davis M, et al. Plasma brain natriuretic peptide in assessment of acute dyspnea. Lancet 1994,343:440-444.

3.  Muders F, et al. Evaluation of plasma natriuretic peptides as markers for left ventricular dysfunction. Am Heart J 1997; 134:442-49.

4.  McDonagh TA, et al. Biochemical detection of left ventricular systolic dysfunction. Lancet 1998; 351:9-13.

5.  Hasegawa K, et al. Ventricular expression of brain natriuretic peptide in hypertrophic cardiomyopathy. Circulation 1993; 88:372-80.

6.  Yamamoto K, et al. Superiority of brain natriuretic peptide as a hormonal marker of ventricular systolic and diastolic dysfunction and left ventricular hypertrophy. Hypertension 1996; 28:988-94.

7.  Gottlieb SS, et al. Prognostic importance of atrial natriuretic peptide in patients with chronic heart failure. J Am Coll Cardiol 1989; 13:1534-39.

8.  H@ggstr`m J, et al. Plasma concentration of atrial natriuretic peptide in relation to severity of mitral regurgitation in Cavalier King Charles Spaniels. Am J Vet Res 1994; 55:698-703.

9.  H@ggstr`m J, et al. Effects of naturally acquired decompensated mitral valve regurgitation on the RAA system and ANP concentration in dogs. Am J Vet Res 1997; 58:77-82.

10. Troughton RW, et al. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet 2000; 355:1126-30.

11. Murdoch DR, et al. Brain natriuretic peptide is stable in whole blood and can be measured using a simple rapid assay: implications for clinical practice. 1997 Heart 78:594-97.

12. Buckley MG, et al. Cardiac peptide stability, aprotinin and room temperature: importance for assessing cardiac function in clinical practice. Clin Sci 1999; 97:689-95

13. Zolk O, et al. Expression of endothelin-1, endothelin-converting enzyme, and endothelin receptors in chronic heart failure. Circulation 1999; 99(16): 2118-23.

14. Ricchiuti V, et al. Cardiac troponin I and T alterations in dog hearts with myocardial infarction: correlation with infarct size. Am J Clin Pathol 1998; 110:241-247.

15. Siciliano M, et al. Troponin I serum concentration: a new marker of left ventricular hypertrophy in patients with essential hypertension. Ital Heart J 2000; 1:532-535.

16. Sato Y, et al. Persistently increased serum concentrations of cardiac troponin t in patients with idiopathic dilated cardiomyopathy are predictive of adverse outcomes. Circulation 2001; 103:369-373.

17. O'Brien PJ, et al. Differential reactivity of cardiac and skeletal muscle from various species in a cardiac troponin I immunoassay. Clin Chem 1997; 43:2333-2338.

18. Sleeper MM, et al. Cardiac troponin I in the normal dog and cat. J Vet Intern Med 2001 Sep-Oct; 15(5): 501-3

19. Lobetti R, et al. Cardiac troponins in canine babesiosis. J Vet Intern Med 2002 Jan-Feb; 16(1): 63-8

20. Shober KE et al. Circulating cardiac troponins in small animals. 19th Annual ACVIM Proceedings, 2001. pp 91-92.

Speaker Information
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David Sisson, DVM, DACVIM-Cardiology
College of Veterinary Medicine, University of Illinois


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