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Pathophysiology of Heart Failure-Role of Peripheral Circulatory Mechanisms on Effort Tolerance

Carlos Eduardo Negrão, PhD , Maria Janieire de Nazaré Nunes Alves, MD

Unity of Cardiovascular Rehabilitation and Exercise Physiology.
Heart Institute. School of Medicine.
University of São Paulo.
Brazil

Introduction
Exercise Intolerance in Heart Failure
Summary
References

Heart failure is a multifactorial disease with poor prognosis. Fifty percent of the heart failure patients die during the first five years since the diagnosis of the disease. Despite the improvement in the therapeutic approaches, heart failure is one of the main causes of death in the development countries.
From previous studies, we have learned that patients with heart failure have increased sympathetic nerve activity, which seems to be important to maintain the cardiac output and blood pressure during the first stage of the disease, but not during the chronic stage, when this increase in sympathetic activity worses the hemodynamic status. In addition, the increase in sympathetic activity is well related to severity of the heart failure (Fig. 1). The sympathetic nerve activity progressively increase from mild to severe heart failure. Some investigators have attributed this increase in sympathetic nerve activity to a cardiopulmonary and baroreflex dysfunction.

In the last decade, we have learned much about diagnosis and treatment of heart failure. However, we feel that we still need to better understand the exercise response in heart failure patients. In this presentation, we will discuss the possible explanations for the exercise intolerance in heart failure patients.

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Exercise Intolerance in Heart Failure

It is well know that patients with heart failure have dyspnea and exercise intolerance. However, the explanation for such responses are still under investigation. Some investigators have pointed out that the exercise intolerance is a consequence of central limitations, whereas others have suggested that it is due to peripheral limitations.

Central Limitations. It is well understood that exercise capacity depends upon the oxygen supply to the skeletal muscle, which, in turn, is a consequence of the increase in cardiac output and arterio-venous oxygen difference. In healthy subjects, the cardiac output increases proportionately to the exercise intensity. In heart failure patients, in whom the reduced cardiac output is the role, the inability of increasing adequately the cardiac output limits the exercise performance. In fact, previous studies have demonstrated that the attenuation in the increase of cardiac output during exercise is well related to the severity of the heart failure. In other words, the slope between cardiac output and oxygen uptake during progressive exercise is changed to the right, according with the increase in Functional Class from I to III. In addition, the maximal cardiac output reached during progressive exercise is significantly lower in Functional Class III than in Functional Class I heart failure patients. This reduced capacity to increase cardiac output during progressive exercise in heart failure patients can be explained by the lower cardiac contractility and the alteration in cardiac control. The cardiac insufficient causes a significant reduction in stroke volume or ejection fraction in heart failure patients. And the increased sympathetic overflow and the reduced vagal control in the heart may have important implications during exercise in heart failure patients. The chronic increase in sympathetic nerve activity to the heart provokes a decrease in b -adrenergic sensitivity in patients with heart failure, which may be one of the possible mechanisms to explain the limited tachycardiac response during exercise in these patients. Besides the augmented sympathetic nerve activity to the blood vessels may also limit the blood flow to the skeletal muscle during exercise in patients with heart failure, which is an additional hindrance to the increase in cardiac output. Therefore, the inability of increasing adequately cardiac output during exercise explains, in great proportion, the exercise intolerance in heart failure patients.

Peripheral Limitations. In order to meet an adequate energy supply during exercise, skeletal muscle undergoes to an intense vasodilatation. Today, we know that the vasodilatory responses during exercise is neurogenically and metabolically mediated. We have accumulated evidences that the increase in skeletal muscle in healthy subjects is cholinergically mediated and/or noradrenergically mediated. It has been described that handgrip exercise provokes vasodilatory response in the nonexercising forearm in healthy subjects. This vasodilatory response is cholinergically mediated, since intra-arterial administration of atropine blocks this vasodilatory response. Besides, the sympathetic blockade with phentolamine potentiates the vasodilatory responses during handgrip exercise in humans. These results point out that the sympathetic nerve activity restrains the muscle vasodilatory responses during exercise in healthy subjects. The increase in muscle flow during exercise is also metabolically mediated. The accumulation of metabolites, such as, extracellular potassium, adenosine, hydrogen ion, carbon dioxide and low oxygen tension are potent vasodilators.

In patients with heart failure, in whom the vasoconstriction is the role (Fig. 2), we could hypothesized that the vasodilatory response during exercise is decreased.

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Previous studies have demonstrated that the vasodilatation provoked by graded intra-arterial administration of metacholine is decreased in heart failure patients. These blood vessel alterations have been attributed to endothelium dysfunction. The decreased vasodilatory responses to acetylcholine in patients with heart failure may be due to the decreased production of nitric oxide, increased degradation of nitric oxide or even decreased vascular smooth muscle response to nitric oxide. Wang et al. 1994 have provided evidences that acethylcholine-stimulated release of nitric oxide in isolated coronary circulation and mRNA for the constitutive isoenzyme of nitric oxide synthase in aortic endothelial cells are decreased in experimental animals with heart failure. The increased degradation of nitric oxide may also explain the impaired endothelium dysfunction in heart failure. For instance, since the half-life of nitric oxide is very short, changes in histological structure of blood vessels that increase the distance between endothelial cells and underlying smooth muscle may be a hindrance for the diffusion of nitric oxide in heart failure.

We have demonstrated that during a defense reaction, provoked by mental stress in humans, patients with heart failure showed a blunted muscle vasodilatory response when compared with normal controls. In addition, more recently, we found that during isometric exercise the contralateral forearm vasodilatory response is diminished in patients with heart failure when compared with normal controls. These results suggest that the cholinergically mediated vasodilatation and/or endothelium function are impaired in heart failure patients during both mental stress or exercise. Interestingly, however, was the fact that in a recent study from our group, intra-arterially infusion of acetylcholine and L-arginine did not normalize the vasodilatory responses during mental stress in congestive heart failure patients. Then it is possible that the endothelium-dependent vasodilatory responses during mental stress or exercise are not the only mechanism underlying the blunted vasodilatory response in congestive heart failure patients. In fact, a Ph.D. dissertation performed in the Heart Institute, Scholl of Medicine, University of São Paulo showed that intra-arterial administration of ACE inhibitors normalized the vasodilatory responses to acetylcholine in heart failure patients. These results suggest that angiotensin II plays a role in the blunted vasodilatory response in heart failure patients.

The skeletal muscle disadaptation, in consequence of the reduced blood flow or prolonged inactivity, can also be important mechanism to explain the exercise intolerance in patients with heart failure. It has been described that the activity of oxidative enzymes in skeletal muscle is significantly reduced in patients with heart failure. This skeletal muscle disadaptation drastically limits exercise tolerance in heart failure patients. Therefore, low muscle blood flow, blood vessel alterations, and decreased oxidative capacity play important role in the exercise intolerance in patients with heart failure.

Reflex Limitations. It has been well documented that heart failure lead to baroreflex and cardiopulmonary dysfunction. Previous studies have shown that heart failure provokes decrease in baroreflex control of heart rate and muscle sympathetic nerve activity. In addition, this baroreflex impairment is more pronounced in severe heart failure than in mild heart failure. Since the cardiopulmonary and baroreflex controls restrain the sympathetic nerve activity to blood vessels, we can suggest that the increased vasoconstriction in heart failure may be, at least in part, due to the cardiopulmonary and baroreflex dysfunction. This impairment in baroreflex control may also have implications during exercise in heart failure. We have previously described that the baroreflex control restrains the increase in blood pressure during exercise in rats. Administration of phenylephrine i.v. provokes bradycardiac responses during exercise in rats. Besides, sinoaortic denervated rats have higher blood pressure response than normal controls rats. Then we could speculate that the diminishment of baroreflex control would facilitate the sympathetic overflow, which would retrain the vasodilatory compensatory mechanisms in skeletal muscle during exercise in heart failure.

It has been well established that during exercise the increase in sympathetic nerve activity, blood pressure and cardiac output are mediated by central command, mechanoreceptors, and metaboreceptors located in the skeletal muscle. The central command withdraws the cardiac vagal nerve activity, which results in increase in cardiac output. The mechanoreceptors stimulated by the muscle contraction also contributes to the increase in sympathetic nerve activity and heart rate in healthy humans. And the metaboreceptors, which depends on the intensity of exercise, seems to be the principal reflex system that maintains the increase in the sympathetic nerve activity during exercise. During isometric exercise when the central command, mechanoreceptors and metaboreceptors are activated, muscle sympathetic nerve activity increases similarly in heart failure patients and in normal controls. However, during postexercise regional circulatory arrest, when the metaboreceptor activation is isolated, muscle sympathetic nerve activity tends to return toward baseline in heart failure patients, but not in normal controls in whom muscle sympathetic nerve activity remains augmented. Piepoli et al. 1996, however, demonstrated an increased metaboreflex control of ventilation in heart failure patients. These results may have some implications during exercise. First, the decreased metaboreflex control of sympathetic nerve activity may be an additive explanation to the attenuated increase in cardiac output during exercise in heart failure patients. Second, whether the muscle vasodilatory response during exercise is also metaboreflex-mediated, we could speculated that the decreased metaboreflex in heart failure may have something to do with the blunted vasodilatory response during exercise in heart failure patients. Third, the augmented metaboreflex control of ventilation may explain the increased ventilatory response during exercise in heart failure patients (Fig. 3).

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Then it is possible that baroreflex and metaboreflex dysfunction in heart failure explain part of exercise intolerance in heart failure.

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Summary

Exercise intolerance in heart failure is a complex phenomenon that still needs to be better investigated. However, some mechanisms to explain such reduced exercise capacity are already available. First, the inability of increasing adequately cardiac output during exercise explain, in great proportion, the exercise intolerance in heart failure patients. Second, the reduced muscle blood flow, the blood vessel alterations, and the decreased muscle oxidative capacity contribute importantly to the exercise intolerance in patients with heart failure. Third, the baroreflex and metaboreflex dysfunction may explain part of exercise intolerance in heart failure.

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References

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