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We read with great interest the excellent review article on drug therapy in chronic heart failure (CHF) by McKenzie and Cowley.1 The authors discuss the haemodynamic, neurohormonal, and sympathetic nervous system mechanisms contributing to heart failure, but maintain a cardiocentric view in explaining how these three mechanisms together lead to the deterioration of the failing heart and its haemodynamics. The cardiocentric view holds that the exercise intolerance and dyspnoea are direct consequences of insufficient adaptation of the cardiac output to the increased demands during physical exertion. In the early 1980s, this view was challenged by Franciosa and others, who documented a complete lack of correlation between the left ventricular ejection fraction and exercise capacity as determined by ergometry.2
Initially neurohormonal and sympathetic influences were recognised to adversely influence cardiac function and even increase mortality, as discussed in the article.
After years of extensive research, we now know that CHF causes a peripheral hypoperfusion due to impaired endothelium-dependent vasodilation and leads to profound morphological, metabolic, and functional alterations in the skeletal muscles. These changes represent intrinsic alterations induced by the systemic neurohumoral and inflammatory response in CHF and not just a consequence of “deconditioning”.
Coats et al first proposed the “muscle hypothesis” which emphasised the key role of the skeletal muscle in the pathophysiology of exercise intolerance in CHF.3 In this model, left ventricular dysfunction initiates a systemic inflammatory process accompanied by an imbalance between anabolic and catabolic factors. Together, these processes induce muscle catabolism leading to a peripheral and respiratory myopathy contributing to early muscular fatigue and dyspnoea respectively. In recent years, the molecular mechanisms involved in the development of this “CHF-induced myopathy” have been extensively investigated. Hambrecht and others confirmed raised levels of proinflammatory cytokines (especially interleukin-1α and interferon-α) in skeletal muscle biopsies of CHF patients; these cytokines stimulate the expression of inducible nitric oxide synthase which produces intracellular levels of nitric oxide high enough to inhibit key enzymes of the mitochondrial oxidative phosphorylation.
Exercise training has been shown to interrupt the vicious circle described in the muscle hypothesis. Signs of local inflammation (local cytokine levels, iNOS expression, etc) are reduced and mitochondrial volume density raised. Together, these beneficial effects lead to delayed muscular fatigue and improved exercise capacity. Braith and colleagues recently confirmed that endurance training in patients with CHF reduces resting levels of neurohormones (angiotensin, −26%; aldosterone, −32%; vasopressin, −30%; atrial natriuretic peptide, −27%) in addition to the effects of optimal medical therapy.4 Interestingly, peak exercise levels of neurohormones remained unchanged after training intervention. Exercise training in CHF can improve basal nitric oxide production and enhance endothelium-dependent peripheral vasodilation.5
In conclusion it is important to understand that fatigue and dyspnoea in CHF are related to the activity and strength of the peripheral and respiratory muscles and not just on reduced peripheral blood flow, pulmonary vascular congestion as suggested in the article.
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