© 2003 European Society of Cardiology
Reproducibility of the measurement of the muscle ergoreflex activity in chronic heart failure
National Heart and Lung Institute, and Royal Brompton Hospital, Imperial College School of Science Technology and Medicine, London, UK
* Corresponding author. Heart Failure Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. Tel.: +44-207-352-8121x2708; fax: +44-207-351-8510 E-mail addres: m.piepoli{at}ic.ac.uk
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. Discussion5. ConclusionReferences |
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Background: A causative role for symptom generation in heart failure has been attributed to overactive muscle afferents, metaboreflex and mechanoreflex. We examined the reproducibility of the methods commonly used to assess these reflexes.
Material and methods: Twelve stable heart failure patients (62.8±2.4 years) and 18 normals were studied. The metaboreflex was evaluated on both leg and arm exercises, by performing two runs of 5-min submaximal handgrip and leg exercises. On one run the subjects recovered normally (control recovery), while on the other a post-exercise regional circulatory occlusion (PE-RCO) was induced in the exercising limb, to isolate the stimulation of the metaboreceptor after exercise. The metaboreflex was quantified as the difference in ventilation between the PE-RCO and the control recovery periods with respect to rest. The existence of a mechanoreflex was sought by comparing the ventilatory increment per unit of active work (dVE/dVO2 ratio) between leg passive movement and active low level exercise. The coefficients of variation (CV) were computed to express the reproducibility of these reflexes in heart failure. Results: The metaboreflex was overactive in patients vs. normals during both arm (7.2±2.8 l/min vs. 0.06±0.3 l/min) and leg (5.6±1.2 l/min vs. 0.5±0.2 l/min) tests. The mechanoreflex was not different between patients and normals: dVE/dVO2 during passive movement 48.9±18.3 and 22.4±26.5; active exercise 42.3±18.4 and 31.9±18.7 (P=NS). In patients, the CV for the metaboreflex was 23.4% in the arm and 35.3% in the leg, while for the mechanoreflex test CV was 38.1% during passive movement and 21.1% during active exercise.
Conclusion: The described method of measuring the muscle reflex activity shows an adequate reproducibility in heart failure patients.
Key Words: Exercise • Ventilation • Skeletal muscle • Autonomic nervous system • Ergoreceptor
Received October 28, 2002; Revised December 6, 2002; Accepted December 15, 2002
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionReferences |
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In chronic heart failure (CHF), muscle fatigue and breathlessness are major symptoms and relate to a poor prognosis. Objectively, patients show reduced exercise tolerance and an increased ventilatory response to exercise, of which the mechanisms are still not completely understood. Recently interest has been focused on peripheral skeletal muscle changes as determinant factors in the pathogenesis of these limiting symptoms in CHF. In particular, decreased muscular metabolic capacity has been described, due to structural and functional changes within the muscles such as changes in fibre type and decreased activity of oxidative enzymes in CHF patients [1]. These muscle metabolic abnormalities and/or circulatory insufficiency might cause local overproduction and accumulation of muscle metabolic products, which may be responsible for an enhanced stimulation of group III and IV neural afferents located in the skeletal muscle. An overactivation of the muscle afferent response during exercise is closely related to patient symptoms and to the ventilatory response to exercise: thus a putative role of this reflex in the origin of dyspnoea and exercise intolerance in CHF was proposed [2,3].
These group III and IV muscle afferents, conventionally called ergoreceptors, have two subtypes: metaboreceptors (chemical afferents sensitive to the metabolic products of muscle work) and mechanoreceptors (afferents activated by deformational changes in the joints and limbs, occurring also during passive movements). These receptors may play an important role in symptom generation in CHF [4]. Although techniques have been developed to assess the reflex response from these receptors, their reproducibility has not been assessed in detail. Thus we set out to determine the reproducibility of these methods for evaluation of metaboreflex and mechanoreflex activity in patients with CHF and healthy controls.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionReferences |
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2.1. Study population
Twelve patients with stable CHF due to ischaemic heart disease or idiopathic dilated cardiomyopathy and 18 age, sex and weight-matched healthy subjects were studied. All patients were consecutively recruited from the out-patient Heart Failure Clinic at our Institution, while normal subjects were recruited from ‘The 316 Club’ comprised of ex-members of the executive of British Aerospace at Stevenage (England, UK) and colleagues and relatives. Baseline characteristics are shown in Table 1.
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Inclusion criteria for patient population were the presence of clinical stability and no change of medication in the 3 months prior to the study, no involvement in any exercise-training program. The patients were all symptomatic on exercise and limited by breathlessness or muscle fatigue.
No subject from the normal group had clinical signs or past history of heart or pulmonary diseases.
The study was approved by the local ethics committee and conformed to the Declaration of Helsinki. All subjects gave written informed consent.
2.2. Protocol and data
All experimental sessions were carried out in a temperature-controlled, air-conditioned room. The subjects were asked to avoid strenuous physical activity for 24 h before each test and to refrain from eating and smoking or consuming caffeine for 3 h prior to the study. The tests were preceded by 30 min in a quiet environment.
After an initial clinical screening, all subjects performed a routine cardiopulmonary exercise test to determine their exercise capacity and to familiarize themselves with the laboratory environment, using a maximal symptom-limited, modified Bruce protocol (commencing at stage 0: 1.0 mph at 5.0% gradient) on a Marquette Case 15 treadmill (Milwaukee, USA).
Ventilatory data were recorded throughout the cardiopulmonary exercise and all the metaboreflex and mechanoreflex tests. Subjects breathed air through a mouthpiece and wore a nose clip. Minute ventilation (VE) and respiratory rate (RR) were measured continuously on-line using a calibrated heated pneumotachograph, while oxygen consumption (VO2) and carbon dioxide production (VCO2) breath-by-breath using a respiratory mass spectrometer (Amis 2000, Innovision, Denmark).
2.3. Metaboreceptor tests during arm exercise
The reproducibility of the method for the evaluation of the metaboreflex on arm exercise was assessed by two sessions of arm metaboreceptor tests performed 5 days apart, using a protocol which has been shown to fix the metabolic state of the muscle and to maintain activation of the metaboreceptors in the arm [2].
Preliminary evaluation of maximal capacity was computed by three maximal efforts of squeezing the balloon of a calibrated handgrip device (a modified sphygmomanometer bulb) (Jewel Movement Sphygmomanometer, Tycos, USA).
Each session of arm metaboreflex test included the execution of two handgrip exercises performed in a random order after a 5-min resting period: (i) a 5 min repetition of rhythmic handgrip achieved by squeezing the balloon of a sphygmomanometer (30 squeezes/min) at 50% of the predetermined maximal capacity followed by 3 min control recovery; (ii) the same exercise protocol followed, immediately from the cessation of exercise, by 3 min of blood flow stasis (post-handgrip regional circulatory occlusion, PH-RCO) on the exercising arm by inflation of an upper arm biceps tourniquet to 30 mmHg above systolic pressure at the beginning of recovery. Sixty minutes separated each repetition of arm exercise. The metaboreflex was quantified as the difference in ventilation variables (VE, RR, VO2 and VCO2) between the PH-RCO and the control recovery periods [2].
Subgroups of 7 patients (age 62.9±3.0 years, peakVO2 16.5±1.2 ml/min/kg) and 7 normal subjects (age 62.0±5.1 years, peakVO2 33.2±1.1 ml/min/kg) were enrolled, whose clinical characteristics were not significantly different from the whole study population.
2.4. Metaboreceptor tests during leg exercise
The reproducibility of the method for the evaluation of the metaboreflex on leg exercise was assessed by two sessions of leg metaboreceptor tests performed on separate days, 5 days apart, by using a protocol shown to fix the metabolic state of the muscle and to maintain activation of the metaboreceptors in the leg [4].
Each session included two leg exercises performed in a random order after a 5-min resting period: (i) a 5 min bout of cycling on a cycle ergometer (ERG 601, Bosch, Germany) at 60–70% of the previously determined peakVO2 followed by 3 min of control recovery; (ii) the same exercise protocol followed by, immediately from the cessation of exercise, 3 min of blood flow stasis (post-leg exercise regional circulatory occlusion, PLE-RCO) by inflation of bilateral upper thigh tourniquets to 30 mmHg above peak exercise arm systolic pressure. Sixty minutes separated each bout of leg exercise. As above, the metaboreflex was quantified as the difference in ventilation variables (VE, RR, VO2 and VCO2) between the PLE-RCO and the control recovery periods [4].
Subgroups of 7 patients (age 67.4±2.9 years, peakVO2 15.5±1.4 ml/min/kg) and 7 normal subjects (age 59.3±4.2 years, P<0.05 vs. CHF patients, peakVO2 34.9±3.9 ml/min/kg), whose clinical characteristics were not significantly different from the whole patient population, were enrolled.
2.5. Mechanoreceptor tests
The reproducibility of the method for the evaluation of the mechanoreflex on leg exercise was assessed by two sessions of leg mechanoreceptor tests performed on separate days, 5 days apart, by using an established protocol shown to isolate this reflex [4].
Each session involved the subject resting for 3 min then having 3 min of passive leg movement followed by 3 min of active exercise.
The passive leg movement was performed by attaching a rope around each pedal via toe clips, to allow the pedals to be rotated by an investigator at a rate of 45 rpm, without effort from the experimental subject. Each subject was instructed to relax and not to contract any muscles while their legs were being revolved: during the active exercise, the patient cycled at 45 rpm at a workload of 10 W for 3 min: this load was applied during the active exercise to prevent over-rotation of the pedals which can lead to a change in posture that could complicate interpretation of the data. A 3-min resting period separated the passive and active exercises.
The ventilation variables were measured during passive movement and active exercise. The increase in VE per unit increase in oxygen input (dVE/dVO2 ratio) resulting from active exercise was compared to the dVE/dVO2 ratio arising from passive movement. It would not be possible to eliminate the metaboreflex response, since some work would always be done by the leg muscles even when the pedals were moved by external forces (because of spontaneous muscle tone). However, if a significant mechanoreflex contribution to ventilation existed, then passive exercise would give a higher dVE/dVO2 ratio above that seen in active exercise [4].
Subgroup of 7 patients (age 64.3±3.3 years, peakVO2 15.3±1.3 ml/min/kg) and 7 normal subjects (age 59.7±3.7 years, peakVO2 30.4±3.6 ml/min/kg), whose clinical characteristics were not significantly different from the whole patient population, was enrolled.
2.6. Statistical analysis
Data are presented as mean±standard error of the means. A P value <0.05 was considered significant. The reproducibility was evaluated using the method recommended by Bland and Altman [5]. The results were expressed as standard deviations of differences (S.D.D.) between the repeat measurements. The coefficient of variation (CV) quantifies the variability of the test values in proportion to their mean values. The CV was defined as the S.D.D. between paired measurements divided by the average value of the means for each set of consecutive measurements: this coefficient represents S.D.D. in percentage relative to the mean of the sample. The CV was not calculated for controls or VO2 and VCO2 measurements because the mean value, being the differences between two very similar values, was close to zero.
The metaboreflex contribution to ventilatory variables was computed as the difference of the changes in each ventilatory variable (VE, RR, VO2, VCO2) between the mean resting values and the average of the 2nd and 3rd min recoveries with and without PH-RCO for arm exercise (or PLE-RCO for leg exercise) (Fig. 1) [3].
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For the mechanoreflex the reproducibility of the dVE/dVO2 ratios during both passive movements and active exercise was assessed [4].
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionReferences |
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The normal control group in the total population and in the single subgroups matched the patient groups in age, sex and weight. Compared with controls, patients had a lower peakVO2 and a higher VE/VCO2 (Table 1). Each subject completed the applicable test with no complication.
3.1. Metaboreceptor tests in the arm
During arm exercise patients showed enhanced metaboreflex activity with respect to controls. There was no statistically significant difference between the 2 days in any of the ventilatory values measured during the metaboreflex tests performed in the two sessions in either group of subjects (P=NS) (Table 2). Also the S.D.D. were below or proximal to the unity for all ventilation variables, with the exemption of the RR in the control group (Table 2).
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The CV for metaboreceptor activity in patients for VE was 23.4% while for the RR was 52.1%. The reproducibility of the metaboreflex test during arm exercise for VE in patients and normals is shown in Fig. 2 (top).
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3.2. Metaboreceptor tests in the leg
For leg exercise too, patients showed enhanced metaboreflex activity with respect to controls. Again there was no statistical difference between the two episodes in any of the ventilatory values measured in the two different days for both groups of subjects (P=NS) (Table 3), with the exception of the RR in the patient group. Also the S.D.D. were below or proximal to the unity for all ventilation variables, with the exemption of the RR in the control and patient groups (Table 3).
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The CV for metaboreceptor activity in patients for VE was 35.3%, while for the RR was 85.4%. The reproducibility of the metaboreceptor activity test during leg exercise for VE in patients and normals is shown in Fig. 2 (bottom).
3.3. Mechanoreceptor tests
There were no differences in dVE/dVO2 ratios between passive movement and active exercise in both CHF patients and control subjects, implying no significant role of mechanoreflex activity in either group. The values of VE and VO2 were comparable between the two sessions for all phases of the tests (resting, passive movement, active exercise) in both study populations: the mean differences were not significantly different. The S.D.D. were below or proximal to the unity for all ventilation variables. Also the mean values of dVE and dVO2 and their ratios (dVE/dVO2) during both passive movement and active exercise did not significantly change in both study populations in the two session days (Table 4).
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The mean difference in leg mechanoreceptor activity (dVE/dVO2 ratio) during passive movement in patients was 4.3, with S.D.D. 17.8 (CV 38.1%) and in control subjects was –3.7, and the S.D.D. 27.0. The mean difference in leg mechanoreceptor (dVE/dVO2 ratio) during active exercise in patients was 0.4 l/min, and the S.D.D. 8.9 l/min (CV 21.1%) and in control subjects was 3.1 l/min, and the S.D.D. 24.0 l/min (Table 4).
The reproducibility of values of dVE/dVO2 ratios during passive movement and during active exercise for all subjects is shown in Fig. 3.
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionReferences |
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4.1. Background
Previous studies have been performed looking at the ventilatory activity of skeletal muscle ergoreceptors (metaboreceptors and mechanoreceptors), highlighting the important role of muscle afferents on exercise hyperventilation in CHF. An overactivity of the metaboreflex has been hypothesised to play a key role not only in the genesis of symptoms but also on the progress of the disease. Several studies have been focussed on the investigation of these reflexes recently, using non-invasive methodology, such as post-exercise circulatory occlusion [2–4,6]. However, no evidence has been shown on the reproducibility of this methodology to compute the muscle reflexes. Here we aimed to investigate this issue in both arm and leg exercises. We also evaluated the reproducibility of the methodology to evaluate the activity of the mechanoreflex to the ventilatory response to leg exercise: recently, a putative role of an increased activity of these receptors sensitive to passive movements in patho-physiology of CHF syndrome was hypothesised [4].
4.2. Present study
In agreement with previous reports [2,4] we found a significantly higher activity of the metaboreflex in the ventilatory drive during both the arm and leg exercise in CHF population vs. controls, but a limited contribution from the mechanoreceptors in the leg.
The methods for evaluating the metaboreceptors during both the arm and leg tests showed an adequate level of reproducibility in both patients and normal controls. Also the methods for evaluating the mechanoreceptor showed reasonable reproducibility in both populations.
However, intrinsic limitations in the methodology itself made difficult to fully assess the contribution of these receptors with respect to the metaboreflex. Further investigations are required to assess the most accurate method for testing mechanoreceptor activity.
4.2.1. Reproducibility of the methodology of the metaboreflex activity
A previous study [3] has shown the importance of the metaboreflex contribution to the responses to exercise in both the arm and the leg in CHF patients. The present study demonstrates that the responses shown in the arm and the leg are reproducible in a CHF population. With that degree of reproducibility in the arm the changes that have been previously described in CHF and normals can be accepted to be physiologically relevant and the differences observed are not derived from day to day changes of metaboreflex activity assessment.
The reproducibility of the methodology for assessing the metaboreflex during the leg exercise was seen to be not so good as during the arm exercise. Therefore, this suggests that for the characterisation of the metaboreflex activity and the comparison of different groups of subjects the methodology of metaboreflex testing during arm handgrip exercise should be considered the method of choice. The higher reproducibility of the metaboreflex when the tests were performed during arm exercise compared to the leg could be related to the methodology used itself. When exercise is performed in the arm, there is a rapid inflation of the cuff after exercise ensuring an almost complete occlusion of blood flow due to the smaller size of the muscles in the arm and the ability to cuff them. In the leg, the artery runs deep in the upper thigh and is surrounded by four large muscle groups, which offer resistance to the cuff occlusion. Leakage of metabolites into the systemic circulation may have an affect on the ventilatory drive, reducing the measured metaboreflex response, and consequently its reproducibility.
Still the methods of the assessment of this reflex during leg exercise shows reasonable reproducible results. Thus, metaboreflex activity assessed during leg exercise may still offer significant information and may be considered the choice method when physiological parameters obtained during routine clinical exercise tests (bicycle or treadmill) are requested. Moreover, leg exercises are more clinically relevant for symptoms generation and quality of life in CHF patients.
Healthy controls did not show similar high relative degree of reproducibility such as patient population. This was because the value being measured, the metaboreflex response, was the difference between two very similar measures of ventilation. Since the result is close to zero the variability, although no greater in absolute terms, appears much larger in CV terms.
4.2.2. Reproducibility of the methodology of the mechanoreceptor activity
Previous studies performed on mechanoreceptor activity have conflicting results. Mitchell [7] found that the group III muscle fibres appeared to be activated by deformational changes occurring in the contracting muscle and termed them mechanoreceptors. Another study [8] concluded that passive limb movement was shown to cause an increase in VO2 of almost 90% of the size of the increase produced by active unloaded exercise. Previous studies from our lab [4] have shown that changes in VE, VO2 and VCO2 do occur during passive movement, however, this increase in ventilation during passive movement was proportional to the increase in VO2 (dVE/dVO2 slope) in both controls and CHF patients. This suggests that there is no significant role of the muscle mechanoreflex in either group or, more probably, a lack of sensitivity of the test used to ascertain the activity of the mechanoreflex in skeletal muscle. In fact the role played by the mechanoreflex in the ventilatory response is obscured by the concomitant activation of the metaboreflex also during passive exercise. The same deformational changes in the muscle which are supposed to selectively stimulate muscle mechanoreceptors constitute also a powerful stimulus for the activation of the metaboreflex. Therefore, both receptors are activated during all forms of movement, whether active or passive. Further investigation to identify a more appropriate methodology is warranted in this aspect.
The methodology of the mechanoreflex test showed high reproducibility during both the passive movement phase and the active exercise phase in CHF patients. In normal controls the test did not prove to be as reproducible (Table 4). It is possible to hypothesise that in normal population, with preserved skeletal fibre morphology and function, the limitation of the here used methodology is even more evident, and, therefore, with more important lack of sensitivity of the test.
The general autonomic control, or the activity of other reflex activities was not investigated here. However, we know from previous experiences that activation of muscle reflex is associated with and predicts autonomic alterations, reduced baroreflex sensitivity and increased chemoreflex activation [9]. A central damping of peripheral traffic cannot be advocated as primary explanation of this overactivation, since we have shown the role of peripheral metabolic abnormalities (mainly increased idrogenion concentration) being causative involved: the buffering of the pH reduction in the blood draining from exercising limb abolished the increased ergoreceptor activity in heart failure [10].
The limited number of enrolled subject could be considered a shortcoming for this study: however, the reproducibility values observed are in the range on physiological variability and are compatible with the research purpose.
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5. Conclusion |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionReferences |
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We have shown that the methodology for the evaluation of the metaboreflex during leg and arm exercises display good reproducibility in CHF populations. The method used to assess the mechanoreflex activity during leg movements also shows good reproducibility in CHF patients; however, the current techniques employed to analyse the contribution of the mechanoreflex needs to be refined to rule out the activity of the metaboreflex.
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Acknowledgements |
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A.S. and M.P. are supported by The Wellcome Trust, A.C. is supported by the Viscount Royston Trust.
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References |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionReferences |
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- Ponikowski P.P., Chua T.P., Francis D.P., Coats A.J.S., Piepoli M. Muscle ergoreceptor overactivity reflects deterioration in clinical status and cardiorespiratory reflex in chronic heart failure. Circulation (2001) 104(19):2324–2330.
[Abstract/Free Full Text] - Scott A.C., Wensel R., Davos C.H. Skeletal muscle reflex in heart failure patients: role of hydrogen. Circulation (2003) 107(2):300–306.
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