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POINT-COUNTERPOINT
1Heart Failure Unit
Cardiology Department
G. da Saliceto Hospital
Piacenza, Italy
e-mail: m.piepoli{at}imperial.ac.uk
2University of Sydney, Australia
The diagnosis of chronic heart failure (CHF) depends on both cardiac dysfunction and symptoms. Traditionally, these symptoms were attributed solely to the effects of altered central hemodynamics, dyspnea being due to pressure and volume overload causing pulmonary congestion and reduced cardiac output causing muscular fatigue. The trouble was that as simple and as popular as this explanation was, it just did not fit the facts. The majority of heart failure patients we see in the 21st Century are treated, not congested, do not develop pulmonary edema on exercise, and their cardiac output is rarely the limiting factor when they exercise. Nevertheless, they are very symptomatic (28).
Investigator after investigator has found little or no correlation between indexes of central hemodynamic status or pulmonary function and exercise tolerance (27). What was missing was the realization that in treated euvolemic CHF, symptoms arose from the periphery and not the heart or lungs (3). During exercise, patients demonstrate exaggerated ventilation and tachycardia and stop without reaching a maximal cardiac output because of intolerable symptoms and the inability of skeletal muscle to receive and use oxygen and nutrients (4,8).
Skeletal Muscle Hypothesis. Heart failure affects every step in the oxygen transport system, from the center (heart, lung, central neural control) to the periphery (circulation, neurohumoral status, reflexes, muscle metabolism). The peripheral changes become the weakest link in the exercise chain and become the cause of exercise-limiting symptoms (9).
The past 20 years have witnessed the development of an initially controversial but now widely accepted and elegantly simple idea: the "muscle hypothesis" (Fig. 2). Damage to the heart and disturbance of central hemodynamics trigger compensatory mechanisms, including neurohumoral and sympathetic activation, with initially peripheral vasoconstrictor and tachycardic effects. However, in the longer term, these compensatory mechanisms also trigger harmful changes in multiple organ systems, including skeletal muscle structure, function, metabolism, peripheral vascular and endothelial responses, including apoptosis, necrosis, and inflammatory activation. These are responsible for substantial tissue loss, altered fiber type patterns, decreased oxidative enzyme number and function, mitochondrial destruction, metabolic disturbance, and hormonal resistance syndromes, including both insulin and growth hormone resistance (6).
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Muscle Reflexes in Heart Failure. The Evidence
Experimental studies. In animal models of heart failure, abnormal responses to both mechanoreflex and metaboreflex stimulations have been documented. The heightened metaboreflex activation, when confronted with an inability to increase myocardial contractility causes an exaggerated vasoconstriction during exercise (7, 15). In response to mechanical stimuli, an overactivity of finely myelinated group III afferents (mechanoreflex) was evident in a postinfarct rat heart failure model starting at the beginning of the contraction and contributing to the pressure response (11). Therefore even mild physical activity would lead a state of almost constant activation of the renin-angiotensin system and the related renal responses. Selective abolition of exaggerated mechanoreflex is associated with improved physiological hemodynamic and chronotropic responses to exercise (26). Activation of the muscle reflex is reversible: in dog model, recovery from pacing-induced heart failure was associated with a fast return to normal cardiac function but a slow reduction of the muscle reflex activation, consistent with a different rate of recovery of the controlling system. (2)
Human studies. Overactivation of muscle metaboreflexes in human CHF has been shown to cause exaggerated ventilatory, hemodynamic, and vasoconstrictor responses (16). Unlike central hemodynamics, these muscle reflex responses powerfully predict exercise intolerance and symptom generation (5, 14). Deterioration of the syndrome is characterized by further increased metaboreflex activation (19) with a consequent further impairment of exercise tolerance, ventilatory abnormalities, higher risk of arrhythmias, and increased mortality (20).
CHF patients have an exaggerated metaboreflex response to both forearm (21,22) and lower limb muscular exercise (23): the strong correlation between metaboreflex activation assessed in different limbs has suggested that a unique mechanism is responsible for overactivation of the metaboreflex system.
Biochemical studies. Exaggerated metaboreceptor firing in human heart failure is dependent on systemic acidosis and prostaglandin and bradykinin release within the muscle. Modulation of these metabolite concentrations acutely reduces the muscle reflex activity, which suggests a causative role in triggering and/or mediating the ergoreflex response. The increased prostaglandin and bradykinin productions both at rest and during exercise in CHF were attenuated after ketoprofen infusion, associated with ergoreflex reduction (24). A reversal of hyperactive metaboreflex during exercise obtained by buffering the increased acidotic response has further supported the contribution of muscle catabolism in symptom generation for both fatigue and dyspnea (25).
Body composition studies. Clinical deterioration is accompanied by peripheral muscle wasting and altered autonomic reflex control. A strong relationship between more advanced cardiac cachexia and heightened muscle reflex overactivity supports the crucial role played by maladaptive changes in the muscles (18).
Intervention studies to reverse muscle reflex activation. The evidence of the beneficial effect of exercise training in CHF, in terms of symptoms, survival, and hospitalization reduction, further supports the muscle hypothesis (17). Training improves skeletal muscle alterations, demonstrating that peripheral abnormalities are not irreversible (1): it enhances mitochondrial density and oxidative enzyme activity, increases capillary density and shift toward aerobic metabolism (6, 10), and reduces metaboreflex overactivation (16). All of these effects are seen despite little if any central hemodynamic change and even at subhemodynamically effective training workloads.
The muscle hypothesis adds another vicious cycle of deterioration that affects CHF sufferers: damaged muscle causes exaggerated reflex responses, which limit exercise, cause symptoms, and further augment harmful neurohormonal overactivity. Like other vicious cycles in heart failure, initially useful physiological responses turn maladaptive over time. The importance of this should not be lost on us: it tells us that muscles and fitness might determine how symptomatic a patients is and it opens opportunities for prevention (metabolically targeted therapies) treatment (muscle therapies including training) and novel targets for therapeutic intervention over the whole exercise process, from metabolism, ventilatory and circulatory control, muscle growth and death, and reflex modulation. Yes, the muscles are important and they talk to the brain through the metaboreflexes.
REFERENCES
This article has been cited by other articles:
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  A. Crisafulli, E. Salis, F. Tocco, F. Melis, R. Milia, G. Pittau, M. A. Caria, R. Solinas, L. Meloni, P. Pagliaro, et al. Impaired central hemodynamic response and exaggerated vasoconstriction during muscle metaboreflex activation in heart failure patients Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2988 - H2996. [Abstract] [Full Text] [PDF]
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 C. F. Notarius and J. S. Floras Increased mechanoreceptor/metaboreceptor stimulation explains the exaggerated exercise pressor reflex seen in heart failure J Appl Physiol, February 1, 2007; 102(2): 824 - 824. [Full Text] [PDF]
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