Pathophysiology and Neuroendocrine Response to Acquired Heart Disease in Dogs
Department of Small Animal Clinical Sciences, Faculty of Veterinary Medicine and Animal Science
The medical treatment of chronic heart failure (CHF) has evolved over the last 40 years, from the primary use of digitalis and diuretics in the 1950s and 1960s to the use of inotropic agent and vasodilators in the 1970s. These treatments for heart failure were primarily directed toward the relief of clinical signs by unloading the heart, inotropic support and decreasing the increased venous and capillary pressures. The syndrome of heart failure was explained in terms of heamodynamics, the so-called haemodynamic pump model. However, during the 1980s and 1990s it gradually became clear that the syndrome of heart failure was far more complicated than what could be explained only in terms of heamodynamics. A new view of heart failure emerged, the so-called neuroendocrine model. Because the effects of many of the factors identified as being of importance for the development and progression of CHF can be blunted, there has been an opening and high expectations for potential new cardiac drugs in the human and in the veterinary field. However, some of the recently presented clinical trails have been disappointing, raising concern that we have come close to exhausting any additional effect that can be achieved by pharmacological impact drawing on current neuroendocrine concepts.1
The fundamental difference between the pump and the neuroendocrine models may not be obvious without more detailed knowledge in the pathophysiology of heart failure. Congestive heart failure (CHF) is defined as an inability of the left ventricle to provide adequate perfusion to metabolising tissues under widely ranging physiologic conditions. This condition is characterised by clinical signs that arises from underperfused and congested organs. The more advanced the impairment in pump function, the less the heart is able to provide adequate perfusion of the kidneys and skeletal muscle during levels of physical activity associated with even minimal increases in metabolic requirements. The pathophysiologic cycle that links the failing heart function with the appearance of clinical signs is not fully understood in heart disease. Nevertheless, it is clear that an activation of several neurohumoral systems and the interplay between kidneys, adrenal glands, heart, and the blood vessels contribute to the abnormal sodium and water homeostasis and reapportionment of systemic blood flow that occur in CHF.2
The failing cardiac function is met largely by compensatory responses of cardiac, renal, central nervous and peripheral vascular systems. These systems operate under the influence of neurohumoral and endocrine factors.2 Activation of these humoral systems apparently serves as a compensatory mechanism for the failing circulation. However, overshoot of such mechanisms may further depress cardiac function by increasing afterload, resulting in a vicious cycle of reflex neuroendocrine activation. Corollary decreases in renal function activate the renin-angiotensin-aldosterone system as well, which further contributes to the cycle of downward-spiraling cardiac function. Many hormonal factors are increased in congestive heart failure and the net effect is marked vasoconstriction. The level of activation of some of these neurohormonal systems apparently corresponds to the severity of heart failure. Furthermore, elevated levels of the vaso-constrictive hormones, including norepinephrine, various components of the renin angiotensin-aldosterone system (RAAS), endothelins and arginine vasopressin,3,4 may play a more direct role in worsening heart failure. In fact, elevated catecholamine levels are directly related to prognosis in people.3 Catecholamines increase myocardial oxygen demand and are also arrhythmogenic.5 Actions of these systems are counteracted by vasodilator, diuretic, and natriuretic factors such as the natriuretic peptides6 and nitric oxide (NO).4 Accordingly, increased plasma concentrations of atrial natriuretic peptide (ANP) are reported in many cardiac disorders, including asymptomatic dogs,6 and it has been suggested that this increased circulating activity of ANP may be an important mechanism for limiting the actions of RAAS in these patients.6 Mortality rates are reduced in symptomatic dogs treated with angiotensin-converting enzyme (ACE) inhibitors in addition to standard therapy.7,8 Thus, it is clear that changes in the neuroendocrine profile are not only markers of the severity of heart failure, but also directly worsen it. Interventions that antagonize or diminish these neuroendocrine changes apparently benefit patients with heart failure.
The recognition of the importance of these neuroendocrine factors for long-term outcome in heart failure patients has led to the concept of "cardioprotection", e.g., to protect the heart from long-term exposure to neuroendocrine overexposure leading, among other things, to myocardial remodeling.2 This deepened understanding of the neuroendocrine factors on myocardial cell function led to a hope that the progression of the disease could be slowed or stopped in early intervention in asymptomatic individuals with low degree heart disease. Indeed, recent clinical trials in people have shown that monotherapy with ACE-inhibitors improves quality of life and survival not only in asymptomatic patients with left ventricular dysfunction9 but also in those without heart disease but belonging to a risk group for developing it.10 Therefore, two large placebo-controlled multicenter trials, the SVEP and the VetProof trials,11,12 were undertaken to study the effect of ACE-inhibitor monotherapy on the progression of clinical signs in asymptomatic mitral regurgitation in dogs. Both failed to show a significant difference between the placebo and the treatment groups in time from onset of therapy to confirmed decompensated HF,11,12 in dogs with or without cardiomegaly. Furthermore, the remodeling process in dogs with heart disease appears to be more complicated than previously thought; it has recently been suggested that this process, as such, is an example of tissue activation that is difficult to stop or slow by current pharmacological means without changing the fundamental pathophysiology, i.e., increased heart rate and loading conditions.13
Thus it is apparent that although some aspects of the change in neuroendocrine profile that occur in heart failure are comparably clear, the overall scenario is not. Many neurohormones other than the ones mentioned above are in play and most interact in different ways with each other and have different receptor subtypes and have important effects on other organs than the heart (vessels, blood cells, kidney, brain) and have auto/paracrine effects as well as endocrine effects and finally, important differences exist between different heart diseases and different dog breeds. For instance, dogs with dilated cardiomyopathy appears to have a more pronounced activation of circulating RAAS activity and catecholamines than do dogs with mitral regurgitation.14-16 Therefore, a certain caution must be exercised when trying to interpret what a given change in a given neurohormone level might mean in terms of disease progression and/or treatment. In conclusion, the area neuroendocrine hormones is expanding and it is likely that new drugs aimed at blocking certain of these factors will emerge in the future. The usefulness of measuring most of the neuroendocrine hormones today is to study the pathophysiology of heart disease/ failure and, to some extent, evaluate therapeutic success (aldosterone). The exceptions are the natriuretic peptides that are likely to emerge as both diagnostic indicators of heart disease (BNP) and severity of heart failure (ANP).
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