Study clarifies exercise intolerance
Neural link may explain muscle hypothesis’
Why are CHF patients unable to perform as they did before they developed the disease? Why do they experience extreme muscle fatigue and shortness of breath? The exercise limitation syndrome and abnormal responses to effort in these patients is common, but their causes are unknown. It is known that an exaggerated ventilatory response to exercise is a good predictor of exercise limitation in this syndrome, but the exact causes of the excessive ventilation and vasoconstriction are unclear. A group of Italian and British investigators recently looked at the link between muscle changes in these patients and their abnormal ventilatory and hemodynamic responses to exercise.1
Their goal was to explain the "muscle hypothesis" — the concept that an overactivated muscle signal in heart failure causes the increased ventilatory drive and hence an increase in the ventilation to carbon dioxide output ratio.
The researchers proposed at the outset of their study that ergoreceptors, muscle afferents sensitive to exercise metabolites, may be a neural link between the muscular abnormalities that patients have and the fact that they are able to exercise only in a limited fashion. Ergoreceptors modulate the hemodynamic, ventilatory, and autonomic responses during exercise to optimize the muscle work. They are overactive during exercise with CHF.
For their study, the investigators followed 92 stable patients with heart failure — one-third in NYHA class I, one-third in class II, and one-third in class III — and 28 age-matched healthy controls. All were clinically stable, in sinus rhythm, and had not changed medication for at least three months before the study. None of the patients were participating in an exercise training program, and none had chronic lung disease, diabetes, or neuromuscular disorder. Two-thirds of the patients had undergone bypass surgery for coronary revascularization.
The patients were assessed for exercise tolerance using a maximal upright bicycle and for ergoreflex activity using dynamic handgrips. Blood pressure and ventilatory responses during both leg and arm exercises were compared in controls and CHF patients. The investigators also compared both group’s ergoreflex contribution to the hemodynamic and ventilatory responses to exercise. During both leg and handgrip exercises, they observed a progressive decline in exercise tolerance in CHF patients. The activity of the ergoreflex in the ventilatory response correlated with the severity of the symptoms; the class I patients had significantly lower ergoreflex activity compared with those in class II or III.
The study authors wrote, "Major abnormalities have been described in skeletal muscle structure, function, and metabolism. Physical training has been shown in chronic heart failure to reverse partially the peripheral abnormalities of the muscles and improve exercise tolerance, ventilation, and general well-being without a significant change in central hemodynamics. Thus it has been proposed [the muscle hypothesis] that an overactivated muscle signal in heart failure resulting from abnormalities in exercising muscle causes the increased ventilatory drive and hence an increase in the ventilation to carbon dioxide output ratio. This hypothesis could also explain the frequent coincidence of fatigue and breathlessness on exercise in chronic heart failure because both may have their genesis in abnormal skeletal muscle."
Robert Hilkert, MD, has another definition of muscle hypotheses: Abnormal receptors within the skeletal muscles are afferent links to exercise metabolites, and as such, they lead to increased ventilatory drive and the muscle fatigue CHF patients suffer. Hilkert is the director of the CHF program at Robert Wood Johnson University Hospital in New Brunswick, NJ.
The investigators concluded that in CHF, the overactivity of the ergoreflex is related to a degree of functional limitation and appears, through direct ventilatory and cardiovascular responses, to contribute to the abnormal responses to exercise, explaining the "muscle hypothesis."
Their published conclusion: "A missing link relating exercise limitation to the peripheral abnormalities of chronic heart failure may be neural, based on a muscle work-sensitive reflex, the ergoreflex, that is overactive in chronic heart failure. The overactivity of the ergoreceptors is related to a degree of functional limitation, and appears, through direct ventilatory and hemodynamic responses, to contribute to the abnormal responses to exercise."
Their study confirmed that the symptoms of CHF patients such as dyspnea and fatigue are associated with reduced indexes of exercise tolerance and, in particular, abnormal control of respiration during exercise with elevated ventilatory response. Findings confirmed that the ventilatory response to exercise is not closely linked to cardiac dysfunction as originally thought. Weak correlation between left ventricular ejection fraction and indexes of exercise limitation was observed.
"This finding," the study authors wrote, "is in agreement with the most recent studies that reported that leg blood flow in patients with exertional fatigue is actually normal and that some candidates for heart transplantation exhibit reduced peak VO2 [exercise oxygen consumption] but relatively preserved hemodynamic function. Instead, highly significant correlations were found between indexes of exercise limitation and the activity of muscle reflex, confirming the hypothesis of the ergoreceptors as neural link between peripheral metabolic abnormalities and exaggerated exercise response."
Observers comment
Hilkert says that there’s a lot more to CHF than just the underlying heart function and that the key to CHF lies in the periphery. "Some patients, even if their heart function is bad, often can do very well. They might walk around with an ejection fraction of 10% and be able to do mild to moderate activities and have a fairly active lifestyle. They seem to adapt to their condition. Others with an ejection fraction of 30% may be in and out of the hospital with CHF. Their bodies don’t adapt as well."
He says that the study tells us how muscles sense abnormal blood flow, reduced function, and other components of the muscle hypothesis. "If we can figure out what’s going on in muscle biochemically and neurochemically — why muscles sense things differently and then send different feedback to the brain to increase the ventilatory drive — that puts us one step further toward something we can do to help our CHF patients."
Sharon L. Merritt, RN, MSN, EdD, director of the center for narcolepsy research at the University of Illinois College of Nursing in Chicago, says the authors have proposed a theory that needs to undergo much further testing before it is ready to be acted upon. "The hypothesis is interesting, but one study doesn’t make something fact."
Scot Irwin, DPT, professor of physical therapy at North Georgia College in Dahlonega, GA, says his concern about this study is that the authors fail to give any alternative causes for the dyspnea associated with exercise and heart failure. "They also do not know the subjects’ pulmonary artery pressures or left-ventricular end-diastolic pressures which may give a stronger clue as to the cause of the symptoms."
Another problem, he says, is that they are proposing that there are ergoreceptors. "I have not been able to find a description of such an anatomical site, so I would question whether this was a theoretical paper or an experimental one as they propose."
Finally, Irwin says, this whole concept could be a "chicken and the egg" phenomenon. "The chronic failure causes increased sensitivity of the muscles to lack of blood flow, hypoxia, and a need for anaerobic metabolism, thus the increased ergoreceptor activity.’ I believe the authors have gone a little too far with their conclusions until an anatomical site can be discovered for these ergoreceptors,’ and then they should be able to actually study the receptor site activity directly — not indirectly and theoretically as they have done here."
"The study results are quite impressive," says Lawrence P. Cahalin, MA, PT, CCS, a physical therapy professor at Sargent College of Health and Rehabilitation Services at Boston University. "The study authors have furthered our understanding of CHF and some of the mechanisms underlying its clinical presentation. They have identified several very important relationships that will advance the understanding and hopefully the treatment of CHF by highlighting the important role of physical exercise."
He says another important area that may also be related to the authors’ findings is the role of the ventilatory muscles in the muscle hypothesis. "The strength, endurance, and pattern of activation of the breathing muscles as well as the neural control of breathing in CHF [and their relationship to the dyspnea of CHF] is poorly understood, but several studies suggest that ventilatory muscle training may decrease the dyspnea and disablement of CHF. Further research is needed to better understand the clinical manifestations of CHF which are likely multifaceted and interrelated."
Reference
1. Piepoli M, Ponikowski P, Clark AL, et al. A neural link to explain the muscle hypothesis’ of exercise intolerance in chronic heart failure. Am Heart J 1999; 137(6):1,050-1,056.
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