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PURPOSE:: Exercise-induced dyspnea in patients with cardiopulmonary diseases may be related to sympathetic nervous system activation, with increased metabo- and/or chemosensitivities. Whether this mechanism plays a role in exercising normal subjects remains unclear. METHODS:: Muscle sympathetic nerve activity (MSNA), HR, ventilation (V E), O2 saturation (SpO2), and end-tidal PCO2 (PetCO2) were measured in 14 healthy young adults after 1 wk of beta1-receptor blockade with bisoprolol 5 mg.d[-1] versus placebo after a double-blind, placebo-controlled, randomized crossover design. The MSNA and the ventilatory responses to hyperoxic hypercapnia (7% CO2 in O2), DeltaV E/DeltaPetCO2, and isocapnic hypoxia (10% O2 in N2), DeltaV E/DeltaSpO2, and to an isometric muscle contraction followed by a local circulatory arrest (metaboreflex) were determined at rest followed by an incremental cardiopulmonary exercise test. RESULTS:: Bisoprolol did not change the V E and MSNA responses to hypercapnia, hyperoxia, or isometric muscle contraction or ischemia. Bisoprolol decreased maximum O2 uptake (P < 0.05), workload (P < 0.05), and HR (P < 0.0001) andboth V E/V O2 and V E/V CO2 slopes (P < 0.05). CONCLUSIONS:: These results suggest that decreased aerobic exercise capacity after intake ofbeta-blockers is accompanied by decreased ventilation at any metabolic rate. However, this occurs without detectable change in the sympathetic nervous system tone or in metabo- or chemosensitivity and is therefore probably of hemodynamic origin. [ABSTRACT FROM AUTHOR]

Background: Remote magnetic navigation-guided ablation with 3-dimensional (3D)-image integration could provide maximum benefit in patients with complex anatomy. We reviewed supraventricular tachycardia (SVT) ablation in adult patients with congenital heart disease to assess the contribution of these technologies., Methods and Results: One hundred fifty-four SVT ablation procedures (228 SVTs) using a 3D-electroanatomic mapping system in 116 adult patients with congenital heart disease (mean age, 41; 76 male) were classified into 3 groups: Group A, manual mapping/ablation (n=60 procedures); Group B, remote magnetic navigation-guided mapping/ablation with normal femoral vein access (49); and Group C, remote magnetic navigation-guided mapping/ablation with difficult access (45). Group A included simple anomalies with less SVTs. Group B comprised predominantly Fontan patients with more SVTs. Group C included more complex defects, such as intra-atrial baffle or interrupted inferior venous access, in which retrograde aortic and superior venous accesses were used exclusively with more frequent use of image integration (97.8%; P<0.001). Acute success was 91.5%, 83.7%, and 82.2%, respectively (P=0.370). In group C, fluoroscopy time was the shortest (median, 4.2 min; P<0.001) despite the longer procedure duration (median, 253 min; P<0.001). SVTs free rates were 80.4%, 82.4%, and 75.8%, respectively (P=0.787) during a mean 20-months follow-up period., Conclusions: The combination of remote magnetic navigation, 3D-image integration, and electroanatomic mapping system facilitated safe and feasible ablation with very low fluoroscopy exposure even in patients with complex anomalies.

Aims: We analysed the type and mechanism of supraventricular arrhythmias encountered in a series of symptomatic adults with atrial isomerism undergoing catheter ablation procedures., Methods and Results: The study population included consecutive adults with atrial isomerism who had previously undergone surgical repair or palliation of the associated anomalies. Patients underwent electrophysiological study for symptomatic arrhythmia in our institution between 2010 and 2012 using magnetic navigation in conjunction with CARTO RMT and three-dimensional (3D) image integration. Eight patients (five females) with a median age of 33 years [interquartile range (IQR) 24-39] were studied. Access to the cardiac chambers of interest was obtained retrogradely via the aorta using remotely navigated magnetic catheters in six patients. Radiofrequency ablation successfully targeted twin atrioventricular (AV) nodal reentrant tachycardia in two patients, atrial fibrillation (AF) in three, focal atrial tachycardia (AT) mainly originating in the left-sided atrium in four patients, and macro-reentrant AT dependent on a right-sided inferior isthmus in three patients. The median fluoroscopy time was 3.0 min (IQR 2-11). After a median follow-up of 10 months (IQR 6-21), five of the ablated patients are free from arrhythmia; two patients experienced episodes of self-terminated AF and AT, respectively, within one month post-ablation; the remaining patient had only non-sustained AT during the electrophysiological study and was managed medically., Conclusion: Various supraventricular tachycardia mechanisms are possible in adults with heterotaxy syndrome, all potentially amenable to radiofrequency ablation. The use of remote magnetic navigation along with 3D mapping facilitated the procedures and resulted in a short radiation time.

Background: The impact of recently introduced asymmetric bidirectional ablation catheters on procedural parameters and acute success rates of ablation procedures is unknown., Methods: We retrospectively analyzed data regarding ablations using a novel bidirectional catheter in a tertiary cardiac center and compared these in 1:5 ratio with a control group of procedures matched for age, gender, operator, and ablation type., Results: A total of 50 cases and 250 controls of median age 60 (50-68) years were studied. Structural heart disease was equally prevalent in both groups (39%) while history of previous ablations was more common in the study arm (54% vs 30%, P = 0.001). Most of the ablation cases were for atrial fibrillation (46%), followed by atrial tachycardia (28%), supraventricular tachycardia (12%), and ventricular tachycardia (14%). Median procedure duration was 128 (52-147) minutes with the bidirectional, versus 143 (105-200) minutes with the conventional catheter (P = 0.232), and median fluoroscopy time was 17 (10-34) minutes versus 23 (12-39) minutes, respectively (P = 0.988). There was a trend toward a lower procedure duration for the atrial tachycardia ablations, 89 (52-147) minutes versus 130 (100-210) minutes, P = 0.064. The procedure was successfully completed in 96% of the bidirectional versus 84% of the control cases (P = 0.151). A negative correlation was observed between the relative fluoroscopy duration and the case number (r = -0.312, P = 0.028), reflecting the learning curve for the bidirectional catheter., Conclusions: The introduction of the bidirectional catheter resulted in no prolongation of procedure parameters and similar success rates, while there was a trend toward a lower procedure duration for atrial tachycardia ablations., (©2013, The Authors. Journal compilation ©2013 Wiley Periodicals, Inc.)

In humans, assessment of the sympathetic component of the arterial baroreceptor reflex (sBRS) is usually based on microneurographic recordings of muscle sympathetic nerve activity (MSNA), while inducing reflex changes with intravenous administration of vasoactive drugs (modified Oxford method). This method has several limitations, among which its poor temporal resolution. Some studies have proposed alternative methods by using spontaneous changes in arterial pressure (AP) and MSNA, usually collected under baroreflex closed-loop conditions (AP alters MSNA while MSNA alters AP), which makes the results difficult to interpret. In rats, a method has been developed and validated (Kanbar et al., 2007 [1]), which uses oscillations of renal SNA at the frequency of the heart beat. At this frequency, the baroreflex operates under open-loop conditions because of the low-pass filter properties of the resistance vasculature. The goal of the present study was to examine whether this method is applicable in humans. Data were previously collected by Gujic et al. (2007) [2]. Briefly, MSNA and AP were recorded in 16 young healthy subjects during a 5-minute baseline resting period then during a modified Oxford test (sodium nitroprusside and phenylephrine administrations). Using the 5-minute baseline recordings, spontaneous sBRS was assessed through empirical mode decomposition over consecutive 20-second periods. Spontaneous sBRS was significantly related to pharmacological sBRS (R=0.67, n=16, P=0.004). During the 5-minute period, spontaneous sBRS exhibited variations (CV=21.7±1.7%) that were negatively correlated with AP in five subjects (R=-0.61±0.03, P<0.05) and positively correlated with MSNA in ten subjects (R=0.73±0.03, P<0.05). The new method is able to correctly estimate sBRS, and reveals the existence of previously unrecognized fast fluctuations of sBRS., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

1. Recently, we have demonstrated that cigarette smoke exposure proportionally increases plasma nicotine levels and arterial wave reflection to the aorta. However, the exact contribution of nicotine to the smoke-induced enhancement of wave reflection and the potential underlying mechanisms have not been fully investigated. 2. The present study was a prospective study in 15 healthy male non-smokers. All received a placebo and a 2 mg nicotine tablet, according to a randomized double-blind cross-over study design. Each subject underwent repeated measurements at baseline and for 1 h after nicotine or placebo intake, using carotid-femoral pulse wave velocity (PWV) to assess arterial compliance. Concurrently, aortic pressures and the augmentation index were evaluated using applanation tonometry. 3. Plasma nicotine concentrations achieved 1 h after intake of the nicotine tablet reached comparable levels to those achieved after 1 h exposure to passive smoke (3.6 +/- 0.4 vs 3.2 +/- 0.4 ng/mL, respectively; P = 0.4). 4. Nicotine enhanced arterial wave reflection to the aorta, as assessed by the augmentation index corrected for heart rate (4.2 +/- 1.3 vs-0.7 +/- 0.8% with placebo; P = 0.001). In addition, a progressive increase in carotid-femoral PWV was noted after nicotine administration (0.3 +/- 0.1 vs-0.02 +/- 0.1 m/s with placebo; P = 0.04). This remained significant even after adjustment for changes in mean blood pressure and heart rate (P = 0.01). 5. Plasma nicotine concentrations comparable to those achieved after exposure to passive smoke enhance arterial wave reflection to the aorta. This is accompanied by an increase in carotid-femoral PWV, denoting a deterioration of arterial compliance by nicotine.

Nicotine has been recognized for years as being pharmacologically responsible for the sympathoexcitatory effects of smoking. The effects of nicotine supplementation on myocardial blood flow as assessed by positron emission tomography are, however, unknown. We tested the hypothesis that nicotine substitution could interfere with myocardial blood flow autoregulation at rest in habitual smokers at risk of coronary artery disease. The short-term effect of a 4-mg nicotine tablet on myocardial blood flow was quantified with 13N ammonia positron emission tomography in 12 smokers with high cardiovascular risk (10 males and 2 females; mean age = 58+/-8 years; SCORE risk >5%). Nicotine increased systolic blood pressure from 129+/-7 to 134+/-7 mmHg (p = .03) and heart rate from 67+/-2 to 69+/-2 bpm (p = .04). As a result, nicotine raised the rate-pressure product from 8618+/-622 to 9285+/-627 bpm mmHg (p = .02). Nicotine tended to increase myocardial blood flow in the circumflex artery territory, but this effect failed to reach the level of statistical significance (from 0.56+/-0.06 to 0.63+/-0.03 ml/min/g; p>.15). This trend disappeared when myocardial blood flow was normalized for the rise in the rate-pressure product. Global myocardial perfusion, normalized for the changes in rate-pressure product, remained unchanged from 0.70+/-0.06 at baseline to 0.71+/-0.03 (ml/min/g)/(bpm mmHg) after nicotine. Nicotine supplementation in habitual smokers with high cardiovascular risk increased myocardial work without compromising resting myocardial blood flow autoregulation.

Environmental tobacco smoke (ETS) acutely affects peripheral and coronary vascular tone. Whether ETS exerts specific deleterious effects on aortic wave reflection through nicotine exposure, whether they persist after ETS cessation, and whether the smoke environment impairs microvascular function and increases asymmetrical dimethyl-arginine levels are not known. We tested these hypotheses in a randomized, crossover study design in 11 healthy male nonsmokers. The effects of 1 hour of exposure to ETS, as compared with a nontobacco smoke and normal air, on augmentation index corrected for heart rate and skin microvascular hyperemia to local heating were examined. Augmentation index increased both during (P=0.01) and after (P<0.01) the ETS session but remained unchanged in the nontobacco smoke session when compared with normal air. Nicotine levels after the exposure were related to the peak rise in augmentation index (r=0.84; P<0.01), denoting a predominant role of nicotine in ETS vascular effects. This was confirmed in a second set of experiments (n=14), where the sublingual administration of nicotine was associated with an acute impairment in wave reflection as compared with placebo (P=0.001). Both ETS and nontobacco smokes increased plasma asymmetrical dimethyl-arginine levels (P<0.001), but only ETS reduced the late rise in skin blood flow in response to heating (P=0.03). In conclusion, passive smoking specifically increases aortic wave reflection through a nicotine-dependent pathway and impairs microvascular function, even after the end of the exposure. However, both tobacco and nontobacco passive smoking inhalation increase plasma asymmetrical dimethyl-arginine levels.

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.

cAMP plays an important role in peripheral chemoreflex function in animals. We tested the hypothesis that the phosphodiesterase inhibitor and inotropic medication enoximone increases peripheral chemoreflex function in humans. In a single-blind, randomized, placebo-controlled crossover study of 15 men, we measured ventilatory, muscle sympathetic nerve activity, and hemodynamic responses to 5 min of isocapnic hypoxia, 5 min of hyperoxic hypercapnia, and 3 min of isometric handgrip exercise, separated by 1 wk, with enoximone and placebo administration. Enoximone increased cardiac output by 120 +/- 3.7% from baseline (P < 0.001); it also increased the ventilatory response to acute hypoxia [13.6 +/- 1 vs. 11.2 +/- 0.7 l/min at 5 min of hypoxia, P = 0.03 vs. placebo (by ANOVA)]. Despite a larger minute ventilation and a smaller decrease in O(2) desaturation (83 +/- 1 vs. 79 +/- 2%, P = 0.003), the muscle sympathetic nerve response to hypoxia was similar between enoximone and placebo (123 +/- 6 and 117 +/- 6%, respectively, P = 0.28). In multivariate regression analyses, enoximone enhanced the ventilatory (P < 0.001) and sympathetic responses to isocapnic hypoxia. Hyperoxic hypercapnia and isometric handgrip responses were not different between enoximone and placebo (P = 0.13). Enoximone increases modestly the chemoreflex responses to isocapnic hypoxia. Moreover, this effect is specific for the peripheral chemoreflex, inasmuch as central chemoreflex and isometric handgrip responses were not altered by enoximone.

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.

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.

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.

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.

Purpose of the Study: There is a controversy over whether or not routine comparative x-rays should be prescribed for young children with bone and joint trauma. We conducted a retrospective analysis to assess the contribution of such x-rays., Material and Methods: The series included 203 children aged less than fifteen years who had experienced bone and joint trauma. Two junior orthopedic surgeons, two senior orthopedic surgeons and two pediatric radiologists reread the x-rays to establish the diagnosis, using comparative x-rays to make any necessary correction of the diagnosis. The surgeons were asked to propose a therapeutic strategy for each diagnosis and the radiologists were asked to judge the value of the comparative x-rays., Results: The comparative x-rays were found to be reliable in only 87.5% of the cases, and were useful for diagnosis in only 8.8%. There were statistically significant differences depending on the localization, the patient's age, and the physician's experience., Discussion: Systematic use of comparative x-rays should be discouraged. Only trauma affecting the elbow in older children can, in particular cases, warrant prescription of comparative x-rays.