Journal of Veterinary Cardiology, Vol. 2, No. 2, December 2000
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Neuroendocrine variables in cardiac stress testing as indicators of disease severity
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he clinical syndrome of heart failure has been investigated so extensively during the last 20 years that it may now almost be regarded as a metabolic disorder. No longer a simple hemodynamic paradigm of pump dysfunction, heart failure is now characterized as a complex clinical syndrome with release of many neurohormones and cytokines, which are believed to contribute to the progression of disease.1,2 Examples of factors that are now well known for having a role in the development of heart failure are the renin-angiotensin-aldosterone system (RAAS), catecholamines, endothelin, the natriuretic peptides and vasopressin.1,2 The practical importance of the increased understanding of the neuroendocrine systems is development of new drugs. As our understanding of the neuroendocrine response to diminished cardiac performance improves, novel and even more imaginative neurohormonal and cytokine antagonists are likely to emerge as important new treatments for heart failure. However, these neuroendocrine variables may, in some instances, also give some indication of disease severity and prognosis. Generally, increasing concentrations found in the circulation are associated with increasing severity of cardiac dysfunction and, thereby, a poorer prognosis. Unfortunately, the individual variation for many of these vasoactive substances is high, often too high to allow any clear diagnostic information for an individual, possibly with the exception of the natriuretic peptides. The situation is even further complicated by the fact that many of the vasoactive substances have local counterparts, such as the RAAS,3,4 or act locally in a paracrine manner, such as the endothelins.5 There are several indications that circulating activity may not necessarily reflect local activities. There are many problems involved in working with naturally occurring heart disease in dogs. These problems often involve the owners, ethics and the work to accumulate sufficient number of cases. Furthermore, a clinical material is invariably tainted by variations in breed, age, severity of disease and by the presence of disease other than cardiac etc. These problems and the need for animal models to study diseases occurring in people and have led to standardized experiments conducted on experimental animals. Experimental models of heart failure often involve a procedure where heart failure is induced acutely, although more reports involving experimental models of chronic heart failure are available in recent years.6,7 What is to be considered a “chronic experimental model� may be argued, but this issue is beyond this brief presentation. The study by McEntee et al. in this issue involved right rapid ventricular pacing (RRVP), a reliable and frequently used method to induce heart failure by introducing a rate overload.8,9 One of the benefits of this method is that the severity of heart failure may be varied depending on how high the heart rate is set. However, it is well known that heart failure experimentally induced on experimental dogs (often young and healthy before the experiment) may not be equivalent to what occurs in dogs with naturally occurring heart disease (often old and diseased at the onset of heart failure). During the progress of naturally occurring heart disease, several morphologic and endocrinologic changes ensue that may differ from those that develop during acute experiments. Furthermore, it likely that most cases of heart failure in dogs that occurs naturally is the end of a process that spans over a comparably long time. This is well known in myxomatous mitral valve disease, but there are more evidence that also dilated cardiomyopathy (DCM) also has a true "occult" phase where the disease is present but it is undiscovered because of limitations in our diagnostic capability. 10,11 Two-dimensional and doppler echocardiography has become the major diagnostic tool of evaluation of heart disease because of its ability to provide valuable information accurately and non-invasively. Stress testing and stress-echocardiography may prove to be ways to improve our diagnostic capabilities further. Stress testing has been used in human medicine for many years to evaluate the consequences of a heart condition,12 but in later years it is also used to evaluate abnormalities in myocardial motion and performance that may not be evident at rest. 13,14 Classical stress testing in dogs using an exercise test, such as treadmill exercise, involves many problems, especially in case of obtaining a stress-echocardiogram. In recent years pharmacological stress testing has more frequently been applied, most commonly dobutamine stress testing.11 There are several obvious advantages with this type of stress testing. Nevertheless dobutamine infusion should not be considered equivalent to physical exercise. The increase in heart rate is usually lower than with exercise and useful clinical information such as duration of exercise, exercise capacity, and reproduction of clinical signs may not be obtained. 15 Measurements of different neuroendocrine factors is still involves many methodological problems. The method most commonly used to determine factor concentrations in plasma and tissue is radioimmunoassay. This method is very tedious to perform, especially for measurements of tissue levels, and is not suitable for routine clinical
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practice. Much work remains for developing more rapid and simpler methods. Furthermore, there are often special requirements concerning sample collection and storage. For example, blood samples intended for angiotensin II assays are recommended be collected in tubes with a peptidase inhibitor to stop the chemical reaction where angiotensin I is converted into angiotensin II. This reaction may continue in the tubes after the samples have been collected. The trend is that new substances are often considered to be very unstable. With time, the assays become more robust and more knowledge about that specific factor is available. This leads to that the requirements for sample collection and sample storage tend to become less strict. At present, most information about neuroendocrine factors derives from studies involving experimental animals. For reasons mentioned above, there are only a few studies available that involves naturally occurring heart disease in dogs and cats.16-19 Most of these studies involve either myxomatous mitral valve disease or DCM, These studies indicate that different types of heart disease may result in different neuroendocrine profile but this needs to be further evaluated. There is also very little information available on the state of local mechanisms in different naturally occurring heart disease. The blood samples in the studies involving naturally occurring heart disease were generally obtained during resting or semi-resting conditions. It is likely that diseased individuals have a different neuroendocrine response than normal individuals to stress testing, as indicated in the study by McEntee et al in this issue. Future studies involving dobutamine stress testing in naturally occurring heart disease may show that neuroendocrine testing may provide with valuable diagnostic and prognostic information in asymptomatic dogs. Jens Häggström, DVM, PhD, DECVIM-CA (Cardiology)
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