A neural link to explain the “muscle hypothesis” of exercise intolerance in chronic heart failure
Massimo Piepoli, MD, PhD,a,b Piotr Ponikowski,MD,a Andrew L. Clark,a Waldemar Banasiak, MD,a Alessandro Capucci, MD,b and Andrew J.S. Coats, DM a London, United Kingdom, and Piacenza, Italy
Background In chronic heart failure the cause of exercise limitation is still unclear: ergoreceptors, muscle afferents
sensitive to exercise metabolites, are proposed as a neural link between muscular abnormalities and the limited exercise responses in this syndrome.
Methods In 92 stable patients with heart failure (34 in New York Heart Association class I, 27 in class II, and 31 in
class III) and 28 age-matched normal controls, we assessed exercise tolerance (maximal upright bicycle) and ergoreflex activity (2 dynamic handgrips: one control and one followed by 3 minutes of local circulatory occlusion to isolate the ergore-flex component by metabolite trapping).
Results Patients, with respect to the controls, showed reduced exercise tolerance (peak V .
O 2:20 vs 33 mL/kg/min),
increased ergoreflex effects on ventilation (9 vs 4 L/min), systolic pressure (37 vs 13 mm Hg), and leg vascular resistance (45 vs 22 units) (all P < .005); with the progression of the symptoms, a progressive increase in ergoreflex contribution to the ventilatory response to exercise was observed. The indexes of exercise limitation during arm and leg exercise (ie, peak V .O 2,V ./V .
CO 2slope) correlated highly with the ergoreflex contribution to ventilatory response during handgrip test (r ≤0.7, P < .0001) but weakly with left ventricular ejection fraction (r ≤0.5).
Conclusion In chronic heart failure, 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.” (Am Heart J 1999;137:1050-6.)
Exercise limitation and abnormal responses to effort are important for both the quality of life and the prognosis of patients with chronic heart failure:the exaggerated ventila-tory response to exercise is a good predictor of exercise limitation in this syndrome.1Severe exercise limitation has been associate
d with poor outcome in patients with coro-nary artery disease.2However,the exact causes of the excessive ventilation and vasoconstriction are still unclear.Intuitively cardiovascular and pulmonary factors were considered central to symptom generation,but published data are not consistent with this hypothesis:poor correla-tion is present between exercise limitation and central hemodynamic indexes such as left ventricular ejection fraction,left ventricular end-diastolic dimension,3cardiac index,4or pulmonary capillary wedge pressure,5suggest-ing that other factors may play an important role.
It is well known that patients with chronic heart fail-ure have a variety of peripheral abnormalities develop
(eg,muscle atrophy,reduced peripheral blood flow,
reduced oxidative capacity) that limit exercise tolerance in their own right.6,7Mancini et al,8assessing muscle mass in relation to exercise performance in patients with chronic heart failure,found positive linear correla-tions between peak oxygen uptake (peak ·VO 2
) and mus-cle circumference,area,and mass,suggesting that mus-cle alteration itself could contribute to effort
intolerance.9The link between the muscle changes and the abnormal ventilatory and hemodynamic responses to exercise remains,however,unclear.
Ergoreceptors are afferents arising from skeletal muscle that are sensitive to the metabolic products of muscular exercise:they modulate the hemodynamic,ventilatory,and autonomic responses during exercise to optimize the mus-cle work.10,11These receptors are overactive during exer-cise in chronic heart failure.12In this study we aimed to investigate whether the ergoreflex could correlate with indexes of exercise limitation,thus forming a neural link between the exaggerated ventilatory responses to exercise and the abnormal skeletal muscles in this syndrome.
Methods
Subjects
We studied 92 subjects with various grades of left ventricular impairment caused by ischemic heart disease (34 in New
York
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Piepoli et al 1051
Heart Association (NYHA) functional class I,27 class II,and 31class III) and 28 age-matched normal controls (Table I).All patients were clinically stable,in sinus rhythm,and had not changed medication for at least 3 months before the study.
None was participating in any exercise training program or had any significant chronic lung or valvular heart disease,diabetes,or neuromuscular disorder.None showed evidence of residual myocardial ischemia,and 61 of 92 patients had undergone bypass surgery for coronary revascularization.Left ventricular ejection fraction was assessed by radionuclide ventriculogra-phy.Exercise capacity,expressed as exercise duration and peak ·VO 2
,was tested by upright bicycle ergometer (Tunturi,Profes-sional Model,Finland) in 5 minute/25 W incremental stages to exhaustion:the tests were repeated at least twice in the labora-tory until reproducible exercise performance was achieved.
Ergoreflex assessment protocol
The subjects were asked to avoid strenuous physical activity for at least 24 hours before each assessment test and to refrain from eating and smoking for 3 hours before.All exercise tests were performed with the patient in the supine position with the arm extended.First a maximal voluntary ha
ndgrip contrac-tion was measured as the greatest of the peak forces produced by 3 brief maximal handgrip contractions.The evaluation of the ergoreflex activity included 2 exercises performed in a ran-dom order 11,12:(1) a control handgrip exercise with repetitive finger flexion by pulling a lever of a dynamometer at 50% of the predetermined maximal contraction (this was done with the nondominant arm at the rate of 40 pulls/min until exhaus-tion);(2) the same protocol followed by,from 10 seconds before the end of exercise,3 minutes circulatory (venous and arterial) occlusion by forearm tourniquet inflation to +30 mm Hg above systolic pressure (post-handgrip regional circulatory occlusion).After the cuff was inflated,the subject was
instructed to relax.Thus the contribution of the muscle ergore-ceptors was evaluated by trapping the metabolites in the exer-cising muscle after exercise.This protocol has been shown to fix the metabolic state of the muscle and to prolong the activa-tion of the ergoreceptors.11,12Thirty minutes separated each bout of handgrip exercise.Handgrip tests were performed on a conventional handgrip dynamometer (Jamar,Tokyo,Japan)modified and connected to a display positioned in front of the subject to show the amount of effort of each contraction (in watts) to help the subjects maintain the same level of exercise.
Measurements
Hemodynamic data.Blood pressure was recorded beat to
beat with the noninvasive Ohmeda 2300 Finapres device (Ohmeda monitoring System,Englewood,Colo),which has been shown to provide a reliable index of blood pressure changes over a short period.13Right leg (nonexercising limb)blood flow was measured by standard techniques 14with a mercury-in-Silastic strain gauge plethysmograph (Hokanson,Washington),and expressed in milliliters per 100 mL of tissue per minute.The corresponding leg vascular resistance
(expressed in arbitrary units) was computed from these data.Ventilatory data.Subjects breathed air through a mouth-piece with a nose clip in place and continuous on-line ventila-tion and expiratory gas data were measured:(·VO 2,CO 2
pro-duction [·VCO 2
],and ventilation [·V]) with a respiratory mass spectrometer (Innovision,Odense,Denmark).
Statistical analysis
The exercise capacity and the ventilatory responses during both leg and arm exercises were compared between control subjects and patients with class I,II,and III heart failure.Between
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Piepoli et al
1052the groups we also compared the ergoreflex contribution to the hemodynamic and ventilatory responses to exercise,estimated in absolute values (ie,difference between the 3-minute post-handgrip regional circulatory occlusion and the 3-minute recov-ery run without cuff occlusion) and in percentage values (ie,dif-ference of the percentage values of the peak exercise responses still persisting at 3 minutes after handgrip regional circulatory occlusion compared with 3 minutes recovery run without cuff occlusion).Analysis of variance for repeated measures was used.Unpaired t test or nonparametric tests,depending on the normal-ity of the distributions,corrected when appropriate by Scheffe’s procedure for multiple comparisons,were used in the post-hoc comparison between different groups.
To evaluate the relative contribution of cardiac and periph-eral muscle factors to the abnormal responses to exercise we correlated (by simple regression analysis) measurements of
exercise limitation of arm and leg exercise (peak ·VO 2,·V/·VCO 2
slope,and exercise duration) with an index of cardiac func-tion (left ventricular ejection fraction) and with the strength of the ergoreflex (ergoreflex contribution to the ventilatory responses to exercise).Results are given as mean ±SD.
Results
During both leg and handgrip exercises,control normals
showed higher peak ·VO 2
,longer exercise durations,lower ·V/·VCO 2
slopes,and higher arm strength compared with patients with heart failure (all P < .05).Among patients with heart failure from different NYHA classes,a progres-sive decline in exercise tolerance was observed:thus class
I patients showed higher peak ·VO 2
,longer exercise dura-tions,lower ·V/·VCO 2
slopes,and higher arm strength com-pared with more symptomatic patients (Table I).
In all patients and controls,the isolation of the ergore-flex after handgrip prolonged the increases in systolic
and diastolic blood pressure,·V
,respiratory rate,and leg vascular resistance:the ergoreflex activity was evident both in absolute and in percentage values (Table II).However the strength of this reflex was higher in class II and III patients with respect to class I patients or nor-mal subjects (Table II).
The activity of the ergoreflex in the ventilatory
response correlated with the severity of the symptoms,as described by the NYHA classification:the class I patients had significantly lower ergoreflex activity (6 ±2 L/min) compared with those in class II (9 ±2 L/min)or in class III (12 ±3 L/min) (P < .0001) (Figure 1).Highly significant correlations were observed
between the ergoreflex contribution to the respiratory responses to handgrip and ventilatory indexes of exer-cise limitation (peak ·VO 2,·V/·VCO 2) assessed during
handgrip exercise.Strong correlations were also observed between the ergoreflex activity evaluated during handgrip and indexes of exercise limitation
assessed during a different mode of exercise,that is,leg exercises (Figure 2).Significant correlations
were also present between ergoreflex activity and exercise dura-tion during arm and leg exercise (r = 0.7,P < .0001).Instead the indexes of exercise limitation during arm and leg efforts correlated weakly (r = 0.5) with the left ventricular ejection fraction (Figure 3).
Discussion
Background
The exact causes of the symptoms of exercise limita-tion are still poorly understood in stable patients with chronic heart failure who are well hydrated.The thesis
American Heart Journal
Volume 137, Number 6Piepoli et al1053 of backward heart failure causing dyspnea by conges-
tion of the lungs and poor cardiac output explaining
muscle fatigue have been disputed.15
Chronic heart failure is a multiorgan disorder,which
although initiated by a reduction in left ventricular func-
tion,is characterized by biochemical,neurohormonal,
metabolic,and functional alterations in the periphery.
Therefore noncardiac factors frequently become the
major determinants for both symptom generation and
limitation of exercise tolerance.Major abnormalities
have been described in skeletal muscle structure,func-
tion,and metabolism,including early depletion of phos-
phocreatinine,early acidification and accumulation of
inorganic phosphate and adenosine diphosphate,and a
reduction in the rate of resynthesis of phosphocreati-
nine.7Physical training has been shown in chronic heart
failure to reverse partially the peripheral abnormalities
of the muscles16and improve exercise tolerance,ventila-
tion,and general well-being without a significant change
in central hemodynamics.17,18
Thus it has been proposed (the “muscle hypothesis”)
that an overactivated muscle signal in heart failure
resulting from abnormalities in exercising muscle
modulatecauses 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.
Anatomy and physiology of the ergoreflex
The anatomic basis of this muscle signal has been identified in the ergoreceptors,small myelinated and unmyelinated afferents of the skeletal muscle (group III and group IV afferents).The endings of these fine fibers are termed “free”or “naked”nerve terminals and are associated with collagen structure in the skeletal mus-cle or with blood and lymphatic vessels.19They play the role of a feedback control mechanism to maintain the homeostasis between muscle work and energy supply to perform it.Stimulated by the metabolic state of the muscle,the ergoreceptors monitor the effectiveness of the blood flow20,21and adjust the cardiocirculatory, ventilatory,and autonomic responses to meet the increased metabolic needs of the contracting muscle.11 Their fibers are traveling in the lateral spinothalamic tract of the spinal cord;the integration areas of the cen-tral nervous system necessary for the expression of the reflex mechanism have been identified in the ventrolat-eral medulla,which includes the lateral reticular nucleus.22Recordings from cell bodies in the ventrolat-eral medulla demonstrate discharge characteristics that are the same as those seen fro
m either a group III or group IV muscle afferent during muscle contraction;the electrical activity in this area can be correlated with efferent sympathetic nerve activity to the heart.23
Much work has been done to identify the stimulus that activates these receptors.Some of the possible metabolic products of a discrepancy between blood flow and metabolism in the contracting muscle that have been shown to activate the muscle afferents are potassium,24a decrease in pH,25,26prostaglandins,27 and blood flow itself.28
This reflex might be sensitized by the muscle acidosis seen in chronic heart failure during exercise,inducing abnormally elevated ventilatory drive,with vasocon-striction and sympathoactivation.12Therefore the bene-ficial effect of physical conditioning may be mediated by a reduction of the activity of the muscle ergoreflex, either directly or through reduction of the metabolic signal activating the ergoreceptors.
This study
This study confirms that the symptoms of patients with heart failure,such as dyspnea and fatigue,are associated with reduced indexes of exercise tolerance (peak ·VO2, exercise duration) and,in particular,abnormal control of respiration during exercise with elevated ventilatory response (·V/·VCO
2).1Moreover our study findings con-firm that the ventilatory response to exercise is not closely linked to cardiac dysfunction as originally thought: weak correlation between left ventricular ejection frac-tion and indexes of exercise limitation was observed.This finding is in agreement with the most recent studies that reported that leg blood flow in patients with exertional There is progressive increase in muscle ergoreflex activity with increasing severity of symptoms, as described by the NYHA, in heart failure with respect to normal controls (mean ±SD; *P< 0.05, °P< .005, •P< .0005 vs control; #P< .05, †P< .005 vs class I; $P< .05 vs class II).
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Piepoli et al
1054fatigue is actually normal 29and that some candidates for
heart transplantation exhibit reduced peak exercise ·VO 2
but relatively preserved hemodynamic function.5
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 meta-bolic abnormalities and exaggerated exercise response.Interesting was the finding of significant correlation of ergoreflex activity to arm exercise with indexes of exer-cise limitation during a different form of strain,such as leg exercise (Fig 2).This suggests the presence of an overactive muscle reflex that may not be restricted to a single body district,but representative of a generalized abnormality of the skeletal muscles.
In fact the metabolic alterations of skeletal muscle in chronic heart failure are probably caused by several fac-tors,such as muscle atrophy,impaired muscle activation,reduced blood flow,intrinsic changes of the muscle,and deconditioning effects;the actions of these (and maybe other) factors have been investigated as responsible for the metabolic abnormalities of the skeletal muscle
described.30That dysfunction occurs in muscle districts not expected to be deconditioned 31or where the blood flow was found to be normal 32provides evidence that multiple concomitant factors are involved in a general-ized ergoreflex overactivation.Therefore it is not surpris-ing that the finding of an exaggerated ventilatory
response to leg exercise (·V/·VCO 2slope),which itself
has been shown to correlate well with exercise limita-tion,was best correlated with measures of ergoreflex overactivity during a different form of exercise.
Recently it has been suggested that other factors are at least as important as the ergoreflex in the generation of abnormal responses to exercise in heart failure.One of these factors is an overactivity of peripheral and cen-tral chemoreceptors.33The mechanisms causing altered chemosensitivity are obscure:an interaction between ergoreflex and central chemoreflex could be involved.Signals from muscle ergoreceptors may feed directly in the respiratory control centers causing central augmen-tation of both medullary and carotid chemoreceptor input.Alternatively muscle ergoreceptors may induce changes in central hypercapnic chemosensitivity.It is evident that the 4 groups,including the control group and patients with heart failure and class I to III
disease show progressively lower measured peak ·VO 2
values.It is also evident from Figure 1 that ergoreflex
High significant correlations between ergoreflex contribution to ventilatory response to exercise (·VL/min) and
·
VO 2and ·V/·VCO 2slope during handgrip and leg exercise in patients with heart failure and normal controls.

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