Arteriovenous fistula closure after renal transplantation: a prospective study with 24-hour ambulatory blood pressure monitoring.

We prospectively evaluated the effects of arteriovenous fistula closure on 24-hour ambulatory blood pressure measurements and on left ventricular geometry assessed by echocardiography. Sixteen kidney transplant recipients were studied before and 1 month after surgical fistula closure. The mean of 24-hour diastolic blood pressure increased from 77+/-7 mmHg to 82+/-8 mmHg (P=0.003) without systolic changes. The diastolic blood pressure increase correlated with the reduction in left ventricular mass (P=0.0034). In multivariate analysis, the diastolic blood pressure increase best correlated with preoperative cardiac index (P=0.01). After a similar time delay between two studies, blood pressure remained unchanged in 14 kidney transplant controls with a patent fistula not scheduled for closure. Because the increase in diastolic blood pressure after arteriovenous fistula closure occurred regardless of the preoperative level of diastolic pressure, we suggest that blood pressure should be monitored after fistula closure, particularly when preoperative diastolic blood pressure is borderline or elevated.

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.

Dose-dependent effect of dobutamine on chemoreflex activity in healthy volunteers.

AIMS: beta-adrenergic agonists increase peripheral chemoreceptor sensitivity in humans. We tested the hypothesis that beta(1)-agonist-related increase in peripheral chemoreflex sensitivity is selective and dose-dependent. METHODS: Using a double-blind, placebo-controlled, randomized, crossover study, we examined the effects of dobutamine (n = 17 healthy subjects) at perfusion rates of 2.5 microg kg(-1) min(-1) (D2.5) and 7.5 microg kg(-1) min(-1) (D7.5) on ventilation, haemodynamics and sympathetic nerve activity during normoxia, isocapnic hypoxia, posthypoxic maximal voluntary end-expiratory apnoea, hyperoxic hypercapnia and cold pressor test (CPT). We analysed the effect of pretreatment with atenolol on dobutamine-evoked chemosensitivity. RESULTS: Dobutamine dose-dependently increased ventilation (placebo 6.7 +/- 0.5 vs. D2.5 7.8 +/- 0.4 vs. D7.5 8.7 +/- 0.4 l min(-1), P < 0.005) during normoxia, enhanced the ventilatory (placebo 14.4 +/- 0.6 vs. D2.5 17.3 +/- 0.8 vs. D7.5 22.5 +/- 1.9 l min(-1), P < 0.0001) and sympathetic (placebo + 215 +/- 31 vs. D2.5 + 285 +/- 19 vs. D7.5 + 395 +/- 50% of baseline, P < 0.03) responses at the fifth minute of isocapnic hypoxia and enhanced the sympathetic response to apnoea performed after hypoxia (increase after 5 min of hypoxia: + 290 +/- 43% for placebo vs.+ 360 +/- 21% for D2.5 vs. 537 +/- 69% for D7.5, P < 0.05). No differences were observed between dobutamine and placebo in the responses to hyperoxic hypercapnia and CPT. Atenolol inhibited the dobutamine-related hyperventilation and apnoea shortening during normoxia and hypoxia. CONCLUSION: Dobutamine enhances peripheral chemosensitivity at low infusion rates selectively and in a dose-dependent manner. There is a beta(1) adrenoceptor component in dobutamine-evoked increase in peripheral chemosensititivity; however, a contribution of additional adrenoceptor subtypes cannot be excluded.

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.

Effects of peripheral chemoreceptors deactivation on sympathetic activity in heart transplant recipients.

Heart transplantation initially normalizes sympathetic hyperactivity directed at the muscle circulation. However, sympathetic activity increases with time after transplantation and the exact mechanisms responsible for sympathetic control in heart transplant recipients remain unclear. We examined the effects of peripheral chemoreflex deactivation caused by breathing 100% oxygen on muscle sympathetic nerve activity (expressed as number of burst per minute and mean burst amplitude), heart rate, and mean blood pressure in 13 heart transplant recipients, 13 patients with essential hypertension, and 10 controls. Heart transplant recipients disclosed the highest sympathetic activity, whereas it did not differ between controls and patients with essential hypertension (51+/-16 versus 37+/-14 versus 39+/-12 burst/min, respectively; P<0.05). Breathing 100% oxygen, in comparison with 21% oxygen, reduced sympathetic activity (-4+/-4 versus -1+/-2 burst/min, P<0.01; 85+/-9 versus 101+/-8% of amplitude at baseline, P<0.001) and mean blood pressure (-4+/-5 versus +3+/-6 mm Hg; P<0.05) in heart transplant recipients, decreased sympathetic activity (-4+/-4 versus 0+/-3 burst/min, P<0.05; 90+/-16 versus 101+/-9% of amplitude at baseline, P<0.05) in patients with essential hypertension, but did not reduce sympathetic activity (2+/-4 versus 3+/-3 burst/min, P=NS; 95+/-11 versus 95+/-13% of amplitude at baseline, P=NS) in control subjects. The sympathetic response to hyperoxia was more marked in heart transplant recipients than in controls (85+/-9 versus 95+/-11% of baseline amplitude; P<0.05). The decrease in sympathetic activity was most evident in patients with the longest time after heart transplantation (r=-0.75, P<0.01). In conclusion, tonic chemoreflex activation increases resting muscle sympathetic nerve activity and favors blood pressure elevation after heart transplantation.

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.

Arterial stiffness and wave reflections in patients with sickle cell disease.

We tested the hypothesis that lower blood pressure and increased vasodilatation reported in sickle cell disease (SCD) patients with hemoglobin SS genotype (SS) are translated by lower arterial stiffness determined by pulse wave velocity (PWV) and wave reflections assessed by augmentation index (AI). We enrolled 20 SS (8 females; 12 male) patients closely matched for age, gender, height, and body mass index to 20 subjects with hemoglobin AA genotype (AA). Carotid-femoral PWV (PWV(CF)) and carotid-radial PWV (PWV(CR)) were recorded with the Complior device. Aortic AI was derived from pressure wave analysis (SphygmocoR). PWV(CF) and PWV(CR) were lower in SS than in AA (4.5+/-0.7 m/s versus 6.9+/-0.9 m/s, P<0.0001 and 6.6+/-1.2 m/s versus 9.5+/-1.4 m/s, P<0.0001, respectively). AI was lower in SS than in AA (2+/-14% versus 11+/-8%, P=0.02). Multivariate analysis revealed that both PWV(CF) and PWV(CR) were negatively associated with hemoglobin SS type and positively related to mean arterial pressure (MAP), whereas AI was positively associated with MAP and total cholesterol (all P<0.0001). Multivariate analysis restricted to SS indicated a positive association between PWV(CF) and PWV(CR) with age but a negative association with MAP (R2=0.57 and 0.51, respectively, both P<0.001), whereas MAP and heart rate were independently associated with AI (R2=0.65, P<0.001). This study provides the first evidence that SCD is associated with both lower arterial stiffness and wave reflections. SS patients have a paradoxical negative association between PWV and MAP, suggesting that low MAP does not protect them against arterial stiffness impairment.

Increased sympathetic nerve activity in pulmonary artery hypertension.

BACKGROUND: This study tested the hypothesis that sympathetic nerve activity is increased in pulmonary artery hypertension (PAH), a rare disease of poor prognosis and incompletely understood pathophysiology. We subsequently explored whether chemoreflex activation contributes to sympathoexcitation in PAH. METHODS AND RESULTS: We measured muscle sympathetic nerve activity (MSNA) by microneurography, heart rate (HR), and arterial oxygen saturation (Sao(2)) in 17 patients with PAH and 12 control subjects. The patients also underwent cardiac echography, right heart catheterization, and a 6-minute walk test with dyspnea scoring. Circulating catecholamines were determined in 8 of the patients. Chemoreflex deactivation by 100% O(2) was assessed in 14 patients with the use of a randomized, double-blind, placebo-controlled, crossover study design. Compared with the controls, the PAH patients had increased MSNA (67+/-4 versus 40+/-3 bursts per minute; P<0.0001) and HR (82+/-4 versus 68+/-3 bpm; P=0.02). MSNA in the PAH patients was correlated with HR (r=0.64, P=0.006), Sao(2) (r=-0.53, P=0.03), the presence of pericardial effusion (r=0.51, P=0.046), and NYHA class (r=0.52, P=0.033). The PAH patients treated with prostacyclin derivatives had higher MSNA (P=0.009), lower Sao(2) (P=0.01), faster HR (P=0.003), and worse NYHA class (P=0.04). Plasma catecholamines were normal. Peripheral chemoreflex deactivation with hyperoxia increased Sao(2) (91.7+/-1% to 98.4+/-0.2%; P<0.0001) and decreased MSNA (67+/-5 to 60+/-4 bursts per minute; P=0.0015), thereby correcting approximately one fourth of the difference between PAH patients and controls. CONCLUSIONS: We report for the first time direct evidence of increased sympathetic nerve traffic in advanced PAH. Sympathetic hyperactivity in PAH is partially chemoreflex mediated and may be related to disease severity.