Sympathoexcitation increases the QT/RR slope in healthy men: differential effects of hypoxia, dobutamine, and phenylephrine.

INTRODUCTION: Dynamic ventricular repolarization assessed by QT/RR slopes studies the effects of modifications in cardiac repolarization independently of variations in RR interval (RR). The effects of changes in sympathetic and vagal activity on the QT/RR slope are controversial. We tested the hypothesis that sympathoexcitation is an important determinant of the QT/RR slope. METHODS AND RESULTS: We compared the effects of a reflex sympathetic activation in response to hypoxia, to the direct effects of the infusion of the beta-adrenergic agent dobutamine, on the QTa (apex) and QTe (end)/RR slopes. Dobutamine was titrated to obtain similar increases in cardiac output than with hypoxia. Cardiac vagal activity was estimated by rMSSD and pNN50. In a second group of healthy subjects, we assessed the effect of a reflex cardiac vagal activation in response to phenylephrine infusion on the same variables. We observed a similar increase in QTa and QTe slopes during hypoxia and dobutamine (both P < 0.017 vs. normoxia), despite divergent changes in cardiac vagal activity, as rMSSD and pNN50 decreased with hypoxia compared to normoxia (P < 0.001) but increased during dobutamine infusion compared to hypoxia (P < 0.017). In contrast, these slopes did not change during the rises in rMSSD and pNN50 elicited by phenylephrine (P > 0.7). CONCLUSION: Beta-adrenergic stimulation induces comparable increases in the QT/RR slopes than hypoxia, but in the presence of a larger cardiac vagal activity. Vagal cardiac activation by phenylephrine does not change the QT slopes. This reveals that the sympathetic system is an important determinant of QT/RR dynamicity in healthy men.

Increased metaboreflex activity is related to exercise intolerance in heart transplant patients.

Heart transplantation does not normalize exercise capacity or the ventilatory response to exercise. We hypothesized that excessive muscle reflex activity, as assessed by the muscle sympathetic nerve activity (MSNA) response to handgrip exercise, persists after cardiac transplantation and that this mechanism is related to exercise hyperpnea in heart transplant recipients (HTRs). We determined the MSNA, ventilatory, and cardiovascular responses to isometric and dynamic handgrips in 11 HTRs and 10 matched control subjects. Handgrips were followed by a post-handgrip ischemia to isolate the metaboreflex contribution to exercise responses. HTRs and control subjects also underwent recordings during isocapnic hypoxia and a maximal, symptom-limited, cycle ergometer exercise test. HTRs had higher resting MSNA (P < 0.01) and heart rate (P < 0.01) than the control subjects. Isometric handgrip increased MSNA in HTRs more than in the controls (P = 0.003). Dynamic handgrip increased MSNA only in HTRs. During post-handgrip ischemia, MSNA and ventilation remained more elevated in HTRs (P < 0.05). The MSNA and ventilatory responses to hypoxia were also higher in HTRs (both P < 0.04). In HTRs, metaboreflex overactivity was related to the ventilatory response to exercise, characterized by the regression slope relating ventilation to CO(2) output (r = +0.8; P < 0.05) and a lower peak ventilation (r = +0.81; P < 0.05) during cycle ergometer exercise tests. However, increased chemoreflex sensitivity (r = +0.91; P < 0.005), but not metaboreflex activity, accounted for the lower peak ventilation during exercise in a stepwise regression analysis. In conclusion, heart transplantation does not normalize muscle metaboreceptor activity; both increased metaboreflex and chemoreflex control are related to exercise intolerance in HTRs.

Differential effects of metaboreceptor and chemoreceptor activation on sympathetic and cardiac baroreflex control following exercise in hypoxia in human.

Muscle metaboreceptors and peripheral chemoreceptors exert differential effects on the cardiorespiratory and autonomic responses following hypoxic exercise. Whether these effects are accompanied by specific changes in sympathetic and cardiac baroreflex control is not known. Sympathetic and cardiac baroreflex functions were assessed by intravenous nitroprusside and phenylephrine boluses in 15 young male subjects. Recordings were performed in random order, under locally circulatory arrested conditions, during: (1) rest and normoxia (no metaboreflex and no chemoreflex activation); (2) normoxic post-handgrip exercise at 30% of maximum voluntary contraction (metaboreflex activation without chemoreflex activation); (3) hypoxia without handgrip (10% O2 in N2, chemoreflex activation without metaboreflex activation); and (4) post-handgrip exercise in hypoxia (chemoreflex and metaboreflex activation). When compared with normoxic rest (-42 +/- 7% muscle sympathetic nerve activity (MSNA) mmHg(-1)), sympathetic baroreflex sensitivity did not change during normoxic post-exercise ischaemia (PEI; -53 +/- 9% MSNA mmHg(-1), P = 0.5) and increased during resting hypoxia (-68 +/- 5% MSNA mmHg(-1), P < 0.01). Sympathetic baroreflex sensitivity decreased during PEI in hypoxia (-35 +/- 6% MSNA mmHg(-1), P < 0.001 versus hypoxia without exercise; P = 0.16 versus normoxic PEI). Conversely, when compared with normoxic rest (11.1 +/- 1.7 ms mmHg(-1)), cardiac baroreflex sensitivity did not change during normoxic PEI (8.3 +/- 1.3 ms mmHg(-1), P = 0.09), but decreased during resting hypoxia (7.3 +/- 0.8 ms mmHg(-1), P < 0.05). Cardiac baroreflex sensitivity was lowest during PEI in hypoxia (4.3 +/- 1 ms mmHg(-1), P < 0.01 versus hypoxia without exercise; P < 0.001 versus normoxic exercise). The metaboreceptors and chemoreceptors exert differential effects on sympathetic and cardiac baroreflex function. Metaboreceptor activation is the major determinant of sympathetic baroreflex sensitivity, when these receptors are stimulated in the presence of hypoxia.

Does endothelin play a role in chemoreception during acute hypoxia in normal men?

BACKGROUND: The peripheral chemoreceptors are the dominant reflex mechanism responsible for the rise in ventilation and muscle sympathetic nerve activity (MSNA) in response to hypoxia. Animal studies have suggested that endothelin (ET) plays an important role in chemosensitivity. Moreover, several human clinical conditions in which circulating ET levels are increased are accompanied by enhanced chemoreflex sensitivity. Whether ET plays a role in normal human chemosensitivity is unknown. METHODS: We determined whether bosentan, a nonspecific ET receptor antagonist, would decrease chemoreflex sensitivity in 14 healthy subjects. We assessed the effects of bosentan on the response to isocapnic hypoxia, using a randomized, crossover, double-blinded study design. RESULTS: Bosentan increased mean (+/- SEM) plasma ET levels from 1.97 +/- 0.28 to 2.53 +/- 0.23 pg/mL (p = 0.01). Hypoxia increased mean minute ventilation from 6.7 +/- 0.3 to 8+/0.4 L/min (p < 0.01), mean MSNA from 100 to 111 +/- 5% (p < 0.01), mean heart rate from 67 +/- 3 to 86 +/- 3 beats/min (p < 0.01), and mean systolic BP from 116 +/- 3 to 122 +/- 3 mm Hg (p < 0.01). However, none of these responses differed between therapy with bosentan and therapy with placebo (p = 0.26). Bosentan did not affect the mean MSNA responses to the apneas, during normoxia (change from baseline: placebo, 259 +/- 58%; bosentan, 201 +/- 28%; p = 0.17) or during hypoxia (change from baseline: placebo, 469 +/- 139%; bosentan, 329 +/- 46%; p = 0.24). The durations of the voluntary end-expiratory apneas in normoxia and hypoxia, and the subsequent reductions in oxygen saturation, were also similar with therapy using bosentan and placebo (p = 0.42). CONCLUSION: In healthy men, ET does not play an important role in peripheral chemoreceptor activation by acute hypoxia.

Atrial septostomy decreases sympathetic overactivity in pulmonary arterial hypertension.

BACKGROUND: We have reported previously that the sympathetic nervous system is activated in patients with pulmonary arterial hypertension (PAH), and that this is only partly explained by a decrease in arterial oxygenation. Possible causes for increased muscle sympathetic nerve activity (MSNA) in patients with PAH include right atrial distension and decreased cardiac output. Both may be improved by atrial septostomy, but this intervention also further decreases arterial oxygenation. In the present study, we wanted to investigate the effect of atrial septostomy on MSNA in patients with PAH. METHODS: We recorded BP, heart rate (HR), arterial O2 saturation (SaO2), and MSNA before and after atrial septostomy in PAH patients (mean [+/- SE] age, 48 +/- 5 years) and in closely matched control subjects. Measurements were also performed after septostomy, while SaO2 was brought to the preprocedure level by supplemental O2 therapy. RESULTS: Compared to the control subjects (n = 10), the PAH patients (n = 11) had a lower mean BP (75 +/- 2 vs 96 +/- 3 mm Hg, respectively; p < 0.001), lower mean SaO2 (92 +/- 1% vs 97 +/- 0%, respectively; p < 0.001), increased mean HR (84 +/- 4 vs 68 +/- 3 beats/min; p < 0.01), and markedly increased mean MSNA (76 +/- 5 vs 29 +/- 2 bursts per minute; p < 0.001). Atrial septostomy decreased mean SaO2 (to 85 +/- 2%; p < 0.001) and mean MSNA (to 69 +/- 4 bursts per minute; p < 0.01), but did not affect HR or BP. Therapy with supplemental O2 did not affect MSNA, BP, or HR. The decrease in MSNA was correlated to the decrease in right atrial pressure (r = 0.62; p < 0.05). CONCLUSIONS: Atrial septostomy in PAH patients decreases sympathetic hyperactivity despite an associated decrease in arterial oxygenation, and this appears to be related to decreased right atrial distension.

Sympathetic control after cardiac resynchronization therapy: responders versus nonresponders.

Cardiac resynchronization therapy (CRT) decreases muscle sympathetic nerve activity (MSNA) in patients with severe congestive heart failure (CHF) and cardiac asynchrony. Whether this affects equally patients who clinically respond or not to CRT is unknown. We tested the hypothesis that the favorable effects of CRT on MSNA disappear on CRT interruption only in those who respond to CRT. Twenty-three consecutive CHF patients participated in the study, among whom 16 presented a symptomatic improvement by one or more New York Heart Association (NYHA) functional classes 15 +/- 5 mo after CRT (responders), and seven had not improved after 12 +/- 4 mo of CRT (nonresponders). MSNA and echocardiographic recordings were obtained in random order during atrio-right ventricular pacing (ARV), without stimulation in patients who were not pacemaker dependent (OFF, n = 17), and during atrio-biventricular pacing (BIV). Responders had a longer 6-min walking distance, a lower NYHA class and brain natriuretic peptide levels, and a better quality of life than did nonresponders (all P < 0.05). MSNA increased by 25 +/- 7% in the responders, whereas it remained unchanged in the nonresponders, when shifting from the BIV mode to a nonsynchronous condition (ARV and OFF modes) (P < 0.01). Cardiac output decreased by 0.7 +/- 0.2 l/min in the responders but did not change when shifting from the BIV mode to the nonsynchronous pacing mode in the nonresponders (P < 0.01). In conclusion, reversible sympathoinhibition is a marker of the clinical response to CRT.

Hyperoxia enhances metaboreflex sensitivity during static exercise in humans.

Peripheral chemoreflex inhibition with hyperoxia decreases sympathetic nerve traffic to muscle circulation [muscle sympathetic nerve activity (MSNA)]. Hyperoxia also decreases lactate production during exercise. However, hyperoxia markedly increases the activation of sensory endings in skeletal muscle in animal studies. We tested the hypothesis that hyperoxia increases the MSNA and mean blood pressure (MBP) responses to isometric exercise. The effects of breathing 21% and 100% oxygen at rest and during isometric handgrip at 30% of maximal voluntary contraction on MSNA, heart rate (HR), MBP, blood lactate (BL), and arterial O2 saturation (SaO2) were determined in 12 healthy men. The isometric handgrips were followed by 3 min of postexercise circulatory arrest (PE-CA) to allow metaboreflex activation in the absence of other reflex mechanisms. Hyperoxia lowered resting MSNA, HR, MBP, and BL but increased Sa(O2) compared with normoxia (all P < 0.05). MSNA and MBP increased more when exercise was performed in hyperoxia than in normoxia (MSNA: hyperoxic exercise, 255 +/- 100% vs. normoxic exercise, 211 +/- 80%, P = 0.04; and MBP: hyperoxic exercise, 33 +/- 9 mmHg vs. normoxic exercise, 26 +/- 10 mmHg, P = 0.03). During PE-CA, MSNA and MBP remained elevated (both P < 0.05) and to a larger extent during hyperoxia than normoxia (P < 0.05). Hyperoxia enhances the sympathetic and blood pressure (BP) reactivity to metaboreflex activation. This is due to an increase in metaboreflex sensitivity by hyperoxia that overrules the sympathoinhibitory and BP lowering effects of chemoreflex inhibition. This occurs despite a reduced lactic acid production.

Acute cardiovascular and sympathetic effects of nicotine replacement therapy.

Sympathetic overactivity is implicated in the increased cardiovascular risk of cigarette smokers. Excitatory nicotinic receptors are present on peripheral chemoreceptor cells. Chemoreceptors located in the carotid and aortic bodies increase ventilation (Ve), blood pressure (BP), heart rate (HR), and sympathetic nerve activity to muscle circulation (MSNA) in response to hypoxia. We tested the hypothesis that nicotine replacement therapy (NRT) increases MSNA and chemoreceptor sensitivity to hypoxia. Sixteen young healthy smokers were included in the study (8 women). After a randomized and blinded sublingual administration of a 4-mg tablet of nicotine or placebo, we measured minute Ve, HR, mean BP, and MSNA during normoxia and 5 minutes of isocapnic hypoxia. Maximal voluntary end-expiratory apneas were performed at baseline and at the end of the fifth minute of hypoxia. Nicotine increased HR by 7+/-3 bpm, mean BP by 5+/-2 mm Hg, and MSNA by 4+/-1 bursts/min, whereas subjects breathed room air (all P<0.05). During hypoxia, nicotine also raised HR by 8+/-2 bpm, mean BP by 2+/-1 mm Hg, and MSNA by 7+/-2 bursts/min (all P<0.05). Nicotine increased MSNA during the apneas performed in normoxia and hypoxia (P<0.05). Nicotine also raised the product of systolic BP and HR, a marker of cardiac oxygen consumption, during normoxia, hypoxia, and the apneas (P<0.05). Ve, apnea duration, and O2 saturation during hypoxia and the apneas remained unaffected. In conclusion, sympathoexcitatory effects of NRT are not because of an increased chemoreflex sensitivity to hypoxia. NRT increases myocardial oxygen consumption in periods of reduced oxygen availability.

Chemoreflex and metaboreflex responses to static hypoxic exercise in aging humans.

PURPOSE: We tested the hypothesis that aging decreases the contribution of metaboreceptors to sympathetic responses during exercise in hypoxia. METHODS: We recorded sympathetic nerve traffic to muscle circulation (MSNA), heart rate (HR), blood pressure (BP), minute ventilation (VE), and blood lactate (BL) in 12 older (55 +/- 10 yr) and 12 younger (22 +/- 2 yr) normal subjects during three randomized interventions: isocapnic hypoxia (chemoreflex activation), isometric handgrip exercise (HG) in normoxia (metaboreflex activation), and HG during isocapnic hypoxia (concomitant metaboreflex and chemoreflex activation). All interventions were followed by a forearm circulatory arrest period to allow metaboreflex activation in the absence of exercise and chemoreflex activation. RESULTS: Older subjects had higher resting MSNA (38 +/- 12 vs 23 +/- 9 bursts per minute; P < 0.01) and BP (P < 0.001). Heart rate, minute ventilation, and blood lactate did not differ (all P > 0.5). MSNA responses to HG in normoxia (P < 0.05) and in hypoxia (P < 0.05) were smaller in the older subjects, but were similar during hypoxia alone. The increase in HR was smaller in the older subjects for all interventions (all P < 0.05). In contrast, the increase in systolic and diastolic BP, VE, and BL were similar in both groups (P > 0.05). During the local circulatory arrest, MSNA and BP remained elevated in both groups after HG in normoxia (P < 0.01) and in hypoxia (P < 0.01), but MSNA changes were smaller in the older subjects (P < 0.05). CONCLUSION: Aging reduces sympathetic reactivity to isometric handgrip, but does not prevent the metaboreceptors to remain the main determinant of sympathetic activation during exercise in hypoxia.

Sympathetic nerve activity after thoracoscopic cardiac resynchronization therapy in congestive heart failure.

BACKGROUND: Sympathetic benefits of thoracoscopic cardiac resynchronization therapy (TCRT) in congestive heart failure (CHF) are unknown. We determined cardiac hemodynamics, functional status, and muscle sympathetic nerve activity (MSNA) in a group of TCRT patients. We aimed to compare these patients with CHF patients with cardiac asynchrony (ASY) to substantiate the beneficial effects of TCRT. METHODS AND RESULTS: Eleven patients resynchronized by TCRT 6 +/- 1 months before study inclusion (SYN) and 10 matched ASY patients underwent blood pressure, heart rate, and MSNA recordings. All underwent functional status, cardiac index, and left ventricular ejection fraction (LVEF) assessments. SYN patients had shorter QRS duration and interventricular mechanical delays, longer 6 minute walking distance and lower New York Heart Association class (all P < .05) than ASY patients. MSNA of 56 +/- 2 bursts/min in ASY patients was higher than in SYN patients (48 +/- 3 bursts/min, P < .05). Cardiac index was higher in SYN patients than in ASY patients (2.8 +/- 0.2 versus 1.9 +/- 0.2 L.min.m2, P < .05, respectively). MSNA was highest in the patients with the lowest LVEF (r = -0.49, P < .05), cardiac index (r = -0.48, P < .05) and 6-minute walking distance (r = -0.50, P < .05). CONCLUSION: Lower sympathetic nerve activities in TCRT patients are related to more favorable cardiac indexes and six minute walking distances suggesting a sympathetic, hemodynamic, and functional improvement by TCRT.

Chemoreflex and metaboreflex control during static hypoxic exercise.

To investigate the effects of muscle metaboreceptor activation during hypoxic static exercise, we recorded muscle sympathetic nerve activity (MSNA), heart rate, blood pressure, ventilation, and blood lactate in 13 healthy subjects (22 +/- 2 yr) during 3 min of three randomized interventions: isocapnic hypoxia (10% O(2)) (chemoreflex activation), isometric handgrip exercise in normoxia (metaboreflex activation), and isometric handgrip exercise during isocapnic hypoxia (concomitant metaboreflex and chemoreflex activation). Each intervention was followed by a forearm circulatory arrest to allow persistent metaboreflex activation in the absence of exercise and chemoreflex activation. Handgrip increased blood pressure, MSNA, heart rate, ventilation, and lactate (all P < 0.001). Hypoxia without handgrip increased MSNA, heart rate, and ventilation (all P < 0.001), but it did not change blood pressure and lactate. Handgrip enhanced blood pressure, heart rate, MSNA, and ventilation responses to hypoxia (all P < 0.05). During circulatory arrest after handgrip in hypoxia, heart rate returned promptly to baseline values, whereas ventilation decreased but remained elevated (P < 0.05). In contrast, MSNA, blood pressure, and lactate returned to baseline values during circulatory arrest after hypoxia without exercise but remained markedly increased after handgrip in hypoxia (P < 0.05). We conclude that metaboreceptors and chemoreceptors exert differential effects on the cardiorespiratory and sympathetic responses during exercise in hypoxia.