414
Exp Physiol 99.2 (2014) pp 414–426
Research Paper
Influence of locomotor muscle afferent inhibition on the ventilatory response to exercise in heart failure Thomas P. Olson1 , Michael J. Joyner2 , John H. Eisenach2 , Timothy B. Curry2 and Bruce D. Johnson1
Experimental Physiology
Departments of 1 Internal Medicine, Division of Cardiovascular Diseases and 2 Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA
New Findings r What is the central question of this study? Patients with heart failure often develop ventilatory abnormalities at rest and during exercise, but the mechanisms underlying these abnormalities remain unclear. This study investigated the influence of inhibiting afferent neural feedback from locomotor muscles on the ventilatory response during exercise in heart failure patients. r What is the main finding and its importance? Our results suggest that inhibiting afferent feedback from locomotor muscle via intrathecal opioid administration significantly reduces the ventilatory response to exercise in heart failure patients.
Patients with heart failure (HF) develop ventilatory abnormalities at rest and during exercise, but the mechanism(s) underlying these abnormalities remain unclear. We examined whether the inhibition of afferent neural feedback from locomotor muscles during exercise reduces exercise ventilation in HF patients. In a randomized, placebo-controlled design, nine HF patients (age, 60 ± 2 years; ejection fraction, 27 ± 2%; New York Heart Association class 2 ± 1) and nine control subjects (age, 63 ± 2 years) underwent constant-work submaximal cycling (65% peak power) with intrathecal fentanyl (impairing the cephalad projection of opioid receptor-sensitive afferents) or sham injection. The hypercapnic ventilatory response was measured to determine whether cephalad migration of fentanyl occurred. There were no differences in hypercapnic ventilatory response within or between groups in either condition. Despite a lack of change in ventilation, tidal volume or respiratory rate, HF patients had a mild increase in arterial carbon dioxide (P aCO2 ) and a decrease in oxygen (P aO2 ; P < 0.05 for both) at rest. The control subjects demonstrated no change in P aCO2 , P aO2 , ventilation, tidal volume or respiratory rate at rest. In response to fentanyl during exercise, HF patients had a reduction in ventilation (63 ± 6 versus 44 ± 3 l min−1 , P < 0.05) due to a lower respiratory rate (30 ± 1 versus 26 ± 2 breaths min−1 , P < 0.05). The reduced ventilation resulted in lower P aO2 (97.6 ± 2.5 versus 79.5 ± 3.0 mmHg, P < 0.05) and increased P aCO2 (37.3 ± 0.9 versus 43.5 ± 1.1 mmHg, P < 0.05), with significant improvement in ventilatory efficiency (reduction in the ventilatory equivalent for carbon dioxide; P < 0.05 for all). The control subjects had no change in ventilation or measures of arterial blood gases. These data suggest that inhibition of afferent feedback from locomotor muscle significantly reduces the ventilatory response to exercise in HF patients. (Received 20 August 2013; accepted after revision 21 October 2013; first published online 25 October 2013) Corresponding author T. P. Olson: Mayo Clinic, Division of Cardiovascular Diseases, 200 First Street SW, Rochester, MN 55905, USA. Email: [email protected]
DOI: 10.1113/expphysiol.2013.075937
C 2013 The Authors. Experimental Physiology C 2013 The Physiological Society
Exp Physiol 99.2 (2014) pp 414–426
Ventilatory response to exercise in heart failure
Introduction Patients with heart failure (HF) develop a number of pulmonary abnormalities that influence ventilatory control and contribute to limitations in the activities of daily living. Poor ventilatory efficiency, often measured as the ventilatory equivalent for carbon dioxide (V˙ E /V˙ CO2 slope), is an important predictor of morbidity and mortality, independent of exercise capacity and central haemodynamics (Kleber et al. 2000; Guazzi et al. 2005). As a result, recent attention has been given to the mechanisms leading to altered ventilatory control in HF (Woods et al. 2010). Along these lines, several neurally mediated mechanisms are known to alter ventilation, breathing pattern, pulmonary function and pulmonary haemodynamics, such as pulmonary J receptors associated with lung fluid balance, atrial stretch receptors linked with central haemodynamic overload, and traditional central and peripheral chemoreceptors (Roberts et al. 1986; Olson et al. 2006, 2007). In addition to these mechanisms, afferent feedback linked to receptors in skeletal muscle is thought to contribute to the cardiovascular and ventilatory response to exercise in HF (Piepoli, 1998; Schmidt et al. 2005). In this scheme, afferent feedback originating from group III and IV (myelinated and unmyelinated, respectively) unencapsulated afferent nerve endings in and around the skeletal muscle contributes to altered ventilatory control during exercise. Evidence in support of this theory in healthy humans dates to the mid-1930s; however, this concept has not been definitively tested in humans with HF (Alam & Smirk, 1937; Middlekauff & Sinoway, 2007; Piepoli & Coats, 2007). Along these lines, researchers in our laboratory, among others, have shown that reflex feedback from metabolically sensitive locomotor muscle afferents during postexercise circulatory occlusion contributes to the increased ventilatory response in HF (Olson et al. 2010b). Additionally, researchers in our laboratory and others have shown that increased respiratory muscle work in the setting of HF with limited cardiac reserve results in blood flow redistribution away from the locomotor muscle towards the respiratory muscle, further highlighting the important need for a better understanding of locomotor muscle afferent feedback as it relates to ventilatory control in HF (Borghi-Silva et al. 2008; Olson et al. 2010a). A number of investigators have previously attempted to block/inhibit afferent neurological feedback from skeletal muscle in both animal and human models (Tibes, 1977; Fernandes et al. 1990; Friedman et al. 1993; Amann et al. 2008). However, it is apparent that the method used to modulate afferent feedback in these studies may have influenced efferent neuromuscular control and resulted in altered central command. Recently, Amann et al. (2008) examined the impact of inhibiting somatosensory C 2013 The Authors. Experimental Physiology C 2013 The Physiological Society
415
feedback from the locomotor muscles on cardiovascular control during exercise in healthy trained humans using 0.5% lidocaine. These authors showed that the use of lidocaine as a spinal anaesthetic led to impaired motor unit recruitment and, subsequently, increased central motor drive for a given work rate. Importantly, in a follow-up study by the same group, intrathecal injection of fentanyl (a selective μ-opioid receptor agonist) was used to examine the influence of muscle afferents on the ventilatory and cardiovascular response to exercise in healthy humans (Amann et al. 2010). With the use of fentanyl as the mode for afferent neural blockade, these authors demonstrated significant attenuation of the cardiovascular and ventilatory responses to highintensity, constant-workload cycling, with no impact on measures of efferent neuromuscular control. These results confirm previous findings in an animal model, which demonstrated that subarachnoid injection of an opioid receptor agonist greatly attenuated the reflex pressor and ventilatory responses to static contraction of the triceps surae muscles, without influencing sympathetic neural outflow (Hill & Kaufman, 1990). In this light, the purpose of this study was to determine whether the ventilatory response to exercise in HF can be reduced by inhibition of locomotor muscle afferent feedback via lumbar intrathecal fentanyl injection. We hypothesized that inhibition of this afferent feedback would reduce the ventilatory response to exercise to a greater extent in patients with HF than in healthy ageand sex-matched control subjects.
Methods Study population
Nine patients from the Mayo Clinic Heart Failure Service and the Cardiovascular Health Clinic (a preventive and rehabilitative centre) were recruited (Table 1). Inclusion criteria for HF patients included the following: diagnosis of ischaemic or dilated cardiomyopathy with duration of HF symptoms >1 year; stable HF symptoms (>3 months); left ventricular ejection fraction ≤35% (from clinical records within 3 months); body mass index
Exp Physiol 99.2 (2014) pp 414–426
Research Paper
Influence of locomotor muscle afferent inhibition on the ventilatory response to exercise in heart failure Thomas P. Olson1 , Michael J. Joyner2 , John H. Eisenach2 , Timothy B. Curry2 and Bruce D. Johnson1
Experimental Physiology
Departments of 1 Internal Medicine, Division of Cardiovascular Diseases and 2 Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA
New Findings r What is the central question of this study? Patients with heart failure often develop ventilatory abnormalities at rest and during exercise, but the mechanisms underlying these abnormalities remain unclear. This study investigated the influence of inhibiting afferent neural feedback from locomotor muscles on the ventilatory response during exercise in heart failure patients. r What is the main finding and its importance? Our results suggest that inhibiting afferent feedback from locomotor muscle via intrathecal opioid administration significantly reduces the ventilatory response to exercise in heart failure patients.
Patients with heart failure (HF) develop ventilatory abnormalities at rest and during exercise, but the mechanism(s) underlying these abnormalities remain unclear. We examined whether the inhibition of afferent neural feedback from locomotor muscles during exercise reduces exercise ventilation in HF patients. In a randomized, placebo-controlled design, nine HF patients (age, 60 ± 2 years; ejection fraction, 27 ± 2%; New York Heart Association class 2 ± 1) and nine control subjects (age, 63 ± 2 years) underwent constant-work submaximal cycling (65% peak power) with intrathecal fentanyl (impairing the cephalad projection of opioid receptor-sensitive afferents) or sham injection. The hypercapnic ventilatory response was measured to determine whether cephalad migration of fentanyl occurred. There were no differences in hypercapnic ventilatory response within or between groups in either condition. Despite a lack of change in ventilation, tidal volume or respiratory rate, HF patients had a mild increase in arterial carbon dioxide (P aCO2 ) and a decrease in oxygen (P aO2 ; P < 0.05 for both) at rest. The control subjects demonstrated no change in P aCO2 , P aO2 , ventilation, tidal volume or respiratory rate at rest. In response to fentanyl during exercise, HF patients had a reduction in ventilation (63 ± 6 versus 44 ± 3 l min−1 , P < 0.05) due to a lower respiratory rate (30 ± 1 versus 26 ± 2 breaths min−1 , P < 0.05). The reduced ventilation resulted in lower P aO2 (97.6 ± 2.5 versus 79.5 ± 3.0 mmHg, P < 0.05) and increased P aCO2 (37.3 ± 0.9 versus 43.5 ± 1.1 mmHg, P < 0.05), with significant improvement in ventilatory efficiency (reduction in the ventilatory equivalent for carbon dioxide; P < 0.05 for all). The control subjects had no change in ventilation or measures of arterial blood gases. These data suggest that inhibition of afferent feedback from locomotor muscle significantly reduces the ventilatory response to exercise in HF patients. (Received 20 August 2013; accepted after revision 21 October 2013; first published online 25 October 2013) Corresponding author T. P. Olson: Mayo Clinic, Division of Cardiovascular Diseases, 200 First Street SW, Rochester, MN 55905, USA. Email: [email protected]
DOI: 10.1113/expphysiol.2013.075937
C 2013 The Authors. Experimental Physiology C 2013 The Physiological Society
Exp Physiol 99.2 (2014) pp 414–426
Ventilatory response to exercise in heart failure
Introduction Patients with heart failure (HF) develop a number of pulmonary abnormalities that influence ventilatory control and contribute to limitations in the activities of daily living. Poor ventilatory efficiency, often measured as the ventilatory equivalent for carbon dioxide (V˙ E /V˙ CO2 slope), is an important predictor of morbidity and mortality, independent of exercise capacity and central haemodynamics (Kleber et al. 2000; Guazzi et al. 2005). As a result, recent attention has been given to the mechanisms leading to altered ventilatory control in HF (Woods et al. 2010). Along these lines, several neurally mediated mechanisms are known to alter ventilation, breathing pattern, pulmonary function and pulmonary haemodynamics, such as pulmonary J receptors associated with lung fluid balance, atrial stretch receptors linked with central haemodynamic overload, and traditional central and peripheral chemoreceptors (Roberts et al. 1986; Olson et al. 2006, 2007). In addition to these mechanisms, afferent feedback linked to receptors in skeletal muscle is thought to contribute to the cardiovascular and ventilatory response to exercise in HF (Piepoli, 1998; Schmidt et al. 2005). In this scheme, afferent feedback originating from group III and IV (myelinated and unmyelinated, respectively) unencapsulated afferent nerve endings in and around the skeletal muscle contributes to altered ventilatory control during exercise. Evidence in support of this theory in healthy humans dates to the mid-1930s; however, this concept has not been definitively tested in humans with HF (Alam & Smirk, 1937; Middlekauff & Sinoway, 2007; Piepoli & Coats, 2007). Along these lines, researchers in our laboratory, among others, have shown that reflex feedback from metabolically sensitive locomotor muscle afferents during postexercise circulatory occlusion contributes to the increased ventilatory response in HF (Olson et al. 2010b). Additionally, researchers in our laboratory and others have shown that increased respiratory muscle work in the setting of HF with limited cardiac reserve results in blood flow redistribution away from the locomotor muscle towards the respiratory muscle, further highlighting the important need for a better understanding of locomotor muscle afferent feedback as it relates to ventilatory control in HF (Borghi-Silva et al. 2008; Olson et al. 2010a). A number of investigators have previously attempted to block/inhibit afferent neurological feedback from skeletal muscle in both animal and human models (Tibes, 1977; Fernandes et al. 1990; Friedman et al. 1993; Amann et al. 2008). However, it is apparent that the method used to modulate afferent feedback in these studies may have influenced efferent neuromuscular control and resulted in altered central command. Recently, Amann et al. (2008) examined the impact of inhibiting somatosensory C 2013 The Authors. Experimental Physiology C 2013 The Physiological Society
415
feedback from the locomotor muscles on cardiovascular control during exercise in healthy trained humans using 0.5% lidocaine. These authors showed that the use of lidocaine as a spinal anaesthetic led to impaired motor unit recruitment and, subsequently, increased central motor drive for a given work rate. Importantly, in a follow-up study by the same group, intrathecal injection of fentanyl (a selective μ-opioid receptor agonist) was used to examine the influence of muscle afferents on the ventilatory and cardiovascular response to exercise in healthy humans (Amann et al. 2010). With the use of fentanyl as the mode for afferent neural blockade, these authors demonstrated significant attenuation of the cardiovascular and ventilatory responses to highintensity, constant-workload cycling, with no impact on measures of efferent neuromuscular control. These results confirm previous findings in an animal model, which demonstrated that subarachnoid injection of an opioid receptor agonist greatly attenuated the reflex pressor and ventilatory responses to static contraction of the triceps surae muscles, without influencing sympathetic neural outflow (Hill & Kaufman, 1990). In this light, the purpose of this study was to determine whether the ventilatory response to exercise in HF can be reduced by inhibition of locomotor muscle afferent feedback via lumbar intrathecal fentanyl injection. We hypothesized that inhibition of this afferent feedback would reduce the ventilatory response to exercise to a greater extent in patients with HF than in healthy ageand sex-matched control subjects.
Methods Study population
Nine patients from the Mayo Clinic Heart Failure Service and the Cardiovascular Health Clinic (a preventive and rehabilitative centre) were recruited (Table 1). Inclusion criteria for HF patients included the following: diagnosis of ischaemic or dilated cardiomyopathy with duration of HF symptoms >1 year; stable HF symptoms (>3 months); left ventricular ejection fraction ≤35% (from clinical records within 3 months); body mass index
