As heart failure worsens, one of the mechanisms responsible for reducing exercise tolerance is peripheral dysfunction. At a certain point in the disease course, reduced cardiac reserve, and hence a reduced peripheral blood supply, cannot alone account for the decreased exercise tolerance and clinical deterioration. We now know that central hemodynamics at rest do not reflect functional capacity in chronic heart failure. Peripheral dysfunction becomes established and then progresses, constituting an additional aggravating factor in its own right. We still cannot predict which patients will be affected, when, and at what rate.
The putative pathophysiologic mechanisms involved in peripheral dysfunction form a vicious circle of inducers and aggravators. There is unlikely to be a single triggering factor; it is also unlikely that the same factors are involved in different patients. The post on peripheral dysfunction in chronic heart failure constitutes a container full of (too many) causes and confusing consequences, and almost empty of remedies. As the disease progresses, the muscle response becomes established in ways and phases that differ with individual biologic predisposition and susceptibility to the inductive stimuli. These stimuli may themselves coexist and be expressed with differing intensities. The relationship between stimulus and effect is the focus of intensive pathophysiologic and clinical research: is muscle only a passive target organ, and does its involvement result only in decreased exercise tolerance? Or is muscle an organ that responds to aggression by a defensive counter-reaction (saving energy through symptoms that prompt a reduction in physical activity) or counter-attack (adrenergic activation, acceleration of cachexia, active disuse)? The answer, which may well be valid only for the individual patient, will inform the correct treatment of peripheral dysfunction in each case. The main mechanisms responsible for peripheral dysfunction are:
Vascular: reduced muscle flow causing reduced muscle oxygenation, endothelial dysfunction, and structural changes in the peripheral vasculature
Decreased exercise capacity due to disuse and reduced muscle mass
Cachexia due to malnutrition and a hypercatabolic state comprising excessive adrenergic stimulation, elevated cortisol and adrenocorticotrophic hormone (ACTH) levels, and multiple cytokines
Impaired skeletal myocyte metabolism with detectable histologic changes.
Reduced peripheral blood flow
Reduced peripheral flow is an important inducer of peripheral dysfunction. Its causes are an increase in peripheral resistance due to sympathetic activation and baroreflex downregulation, hyperactivation of the plasma and tissue renin-angiotensin systems, and increased vascular rigidity. However, muscle hypoperfusion alone is not the full explanation. There are groups of heart failure patients with abnormal muscle metabolism in regions with a normal blood supply. Nor does aerobic capacity always increase in parallel with increasing peripheral blood flow. Heart transplantation is a case in point, as is the interval between the hemodynamic and functional capacity responses to angiotensin-converting enzyme (ACE) inhibitor therapy.
In chronic heart failure, basal endothelial vasodilator release is normal, but endothelium-dependent vasodilatation does not respond consensually to inhibitory or stimulatory stimuli. The nitric oxide synthesis inhibitor (L-arginine, or L-NMMA) decreases the endothelium-mediated vasodilator response to exercise (handgrip) in normal subjects, but not in heart failure patients. There is a significant correlation between depression of endothelial-dependent vasodilatation and aerobic capacity, confirming the relationship between the two. Endothelial dysfunction could be due to reduced shear stress from circulating blood, which decreases the gene expression of the enzymes that synthesize endothelial nitric oxide. Disuse could be responsible for such reduced shear stress. There may also be mechanisms that enhance nitric oxide degradation (eg, increased oxidative stress, circulating cytokines). Insulin resistance is another factor that promotes endothelial dysfunction, and is found in patients with heart failure. Inhibition of endothelial nitric oxide production triggers a protracted process of increased vascular resistance. Nitric oxide also depresses smooth muscle proliferation; its inhibition can result in plasma endothelin-1 levels 10 times higher than in controls. Thus, endothelial cells in heart failure patients probably release endothelin-1 much faster than in normal subjects. Such repeated vasoconstrictor stimuli are likely to have both central and peripheral effects, notably with further increases in peripheral resistance.
Structural changes in the peripheral vasculature
Biopsy studies of structural changes in the peripheral vasculature (eg, increased sodium content causing endothelial edema) have failed to show differences between heart failure patients and controls in terms of luminal and endothelial cell dimensions, although the capillary basement membrane is slightly thicker in heart failure patients. In particular, repeated experiments have shown a normal capillary/fiber ratio.
Myocyte atrophy and histological changes
Different studies have found, vs controls, fewer oxidative slow fibers (type I), more type II fibers and intermediate fast fibers (between types Ila and lib: type Ilab), fewer aerobic chains towards the fast glycolytic type lib fibers, and smaller fibers overall. Small fibers mean reduced muscle mass, or atrophy, as found in 68% of heart failure patients. Muscle atrophy is associated with other causes of peripheral dysfunction, eg, muscle deconditioning, increased adrenergic stimulation, and increases in cortisol and/or cytokines. It decreases exercise tolerance and daily activity. Cardiac cachexia involves a similar degree of muscle atrophy in the arms and legs, and significantly exceeds the atrophy observed in noncachectic heart failure patients and controls. This suggests that disuse (less probable in the arms than in the legs) is only one cause of atrophy; it also emphasizes the specificity of cachexia. Myocyte characteristics in heart failure patients also include decreases in mitochondrial density and in the surface area of mitochondrial cristae that show good correlation with peak oxygen uptake. This finding confirms the oxidative deficit in muscle.
Altered skeletal myocyte metabolism
Biopsy studies in heart failure patients have shown that all energy-producing metabolic paths are compromised, with lactic acidosis and increased amino acid utilization, suggesting proteolysis. The electron transport chain becomes dysfunctional, with decreased cytochrome c activity. Decreased citrate synthase and succinate dehydrogenase activities reflect tricarboxylic acid cycle dysfunction, while decreased 3-hydroxyacyl-CoA dehydrogenase activity reveals a decrease in fatty acid [3-oxidation. Substrate availability is also decreased, in particular glycogen, adenosine triphosphate, and phosphocrea-tine. Other features include a decrease in mitochondrial creatine kinase (essential for the transfer of high-energy phosphates resulting from mitochondrial oxidative phosphorylation to myosin filaments in the cytosol), an increase in the expression of inducible nitric oxide synthase (responsible for increasing intracellular nitric oxide), inhibition of the respiratory chain enzymes, and an altered energy production/utilization ratio. Not only is energy production decreased, but utilization is increased, probably because the cell has to work harder to maintain homeostasis and/or to combat the catabolism resulting from hyperstimulation by elevated levels of catecholamines, cortisol, ACTH, and cytokines, and possible insulin resistance.
Systemic mechanisms Malnutrition
Decreased calorie and protein intake is an obvious cause of atrophy and cachexia. It may be due to anorexia, itself caused by congestive hepatomegaly constricting gastric volume and prompting early satiety. Contributory factors are a tasteless (low-fat, low-salt) diet and certain drugs (eg, digitalis and diuretics). Also involved are increased energy consumption and reduced nutrient utilization (fat and protein malabsorption due to decreased enzyme synthesis, mucous membrane edema, and increased portal pressure). Malnutrition can sometimes usefully be differentiated into its calorie, protein, vitamin, and mineral variants.
Cachexia consists of severe muscle wasting, anorexia, changes in hematology and clinical chemistry typical of malnutrition (anemia, hypoalbuminemia, leukopenia, hypercholesterolemia), and inflammatory changes (increases in erythrocyte sedimentation rate and fibrinogen). It results from interaction between hemodynamic factors, malnutrition, muscle deconditioning, and neurohumoral hypercatabolism (increased circulating catecholamines and tumor necrosis factor [TNF]/soluble TNF receptors, and altered growth factor levels). Once initiated, cachexia aggravates the cytokine activation, anorexia, malnutrition, and protein breakdown in a vicious circle. Cachexia is present in some 16% of patients with severe heart failure. It is a potent independent risk factor, which, when combined with a peak oxygen uptake <14 mL/kg/min, predicts high mortality (73% at 18 months). Cytokines Proinflammatory cytokines (TNF-a, its soluble antigens and receptors, interleukin-1, interleukin-6 and their soluble receptors) are elevated in advanced heart failure, and even, in the case of interleukin-6, in less severe heart failure of whatever cause, with or without cachexia. They induce cachexia by inhibiting protein synthesis and accelerating protein catabolism, resulting in anorexia and hyponutrition. TNF-a also impairs endothelial-mediated vasodilatation by increasing free radical production by vascular smooth muscle cells, which both inhibits the production of nitric oxide and increases its elimination. Oxidative stress induced by cytokines causes endothelial apoptosis, most notably when the cell’s antioxidant reserves are decreased, as in heart failure. Disuse In normal subjects, disuse causes muscle tissue loss and atrophy, oxidative enzyme depletion, and activation of the sympathetic nervous system and renin-angiotensin system. Heart failure patients commonly decrease their daily activity even below the limits imposed by cardiac and peripheral dysfunction. Lack of adequate daily physical activity may therefore be one cause of the muscle atrophy and metabolic changes often found in these patients. Loss of stimulation by repeated increases in blood flow lowers the expression of nitric oxide synthase, causing reduced nitric oxide synthesis and endothelial dysfunction. However, studies in heart failure patients have shown that disuse does not alter muscle fiber distribution. This underlines the point already made: no one factor suffices to initiate and maintain peripheral dysfunction; instead, all play a role, reinforcing each other. Their effects are complementary. Further confirmation is provided by respiratory muscle dysfunction, which is similar to that in peripheral muscle. There is a significant correlation between the reductions in airways resistance and maximum inspiratory and expiratory force, and reduced strength in the quadriceps and forearm muscles. There are also histologic parallels between the two muscle groups. Yet, the respiratory muscles of heart failure patients are certainly not exposed to disuse. Reversibility of muscle dysfunction Muscle reconditioning Patientsfunctional capacity and autonomy respond to physical training therapy, whether of the whole body or a particular muscle group, using conventional workloads in mild-to-moderate heart failure, and a low workload in advanced disease. Reconditioning has the opposite effects to disuse, on all the same mechanisms. It improves peripheral vasodilatation (reduced peripheral resistance, increased peripheral peak oxygen uptake, and arteriovenous difference at maximal effort) and endothelial function, both locally and systemically. It also reduces muscle atrophy, causes a shift towards type I fibers, and increases both capillary density and muscle strength. It enhances peripheral aerobic metabolism (increased oxidative enzyme activity and decreased lactate accumulation), even in the absence of improved blood flow, and increases mitochondrial volume density by nearly 20%. In particular, there are increases in the volume density of cytochrome c oxidase-positive mitochondria and in the surface density of the mitochondrial cristae and inner membrane. Physical training may also decrease sympathetic nervous system activation, increase vagal activity, and reduce ergoreflex activation (stimulation of muscle ergoreceptors sensitive to metabolic changes). In summary, reconditioning improves metabolic status, and decreases acidosis, ergoreceptor stimulation, and sympathetic vasoconstriction. However, all the effects obtained after months of exercise training reverse immediately when training stops, as shown in studies using a training-detraining protocol. This raises the organizational problem of how to achieve patient adherence to available health facilities. Drug treatment Long-term ACE inhibitor treatment can improve myocyte metabolism and histology. Lactic dehydrogenase activity increases, as does the area of muscle fiber types I, II and Ila. Endothelial dysfunction also improves, due to inhibition of bradykinin breakdown by the ACE inhibitor; the increased tissue levels of bradykinin stimulate the release of nitric oxide and vasodilatory prostaglandins. Given that most patients are already receiving ACE-inhibitor therapy, these benefits are already being delivered. Transplant Muscle function recovery is very slow and often incomplete after heart transplantation. Dysfunction has been documented 1 year post-transplant. Fiber type abnormalities persist, and although fiber area increases, it does not revert to normal. The capillary/fiber ratio and capillary density remain unchanged. Oxidative enzyme activity increases. At a later stage (1.5 years posttransplant), a reduced phosphocreatine/(phosphocreatine + organic phosphate) ratio suggests that peripheral abnormalities persist (notably a reduced oxidative capacity and increased reliance on glycolysis). The most plausible explanation may be a side effect of cyclosporine, causing structural and functional changes in the endothelium. Persistent peripheral dysfunction accounts for the subnormal functional capacity and reduced muscle strength found after heart transplant. [gallery ids=""]