Prognostic significance of sympathetic nervous system activation in pulmonary arterial hypertension.

RATIONALE: The sympathetic nervous system has been reported to be activated in pulmonary arterial hypertension (PAH). OBJECTIVES: We investigated the prognostic significance of muscle sympathetic nervous system activity (MSNA) in PAH. METHODS: Thirty-two patients with PAH were included in the study and underwent a measurement of MSNA over a 6-year period of time. They had undergone a concomitant evaluation of New York Heart Association (NYHA) functional class, a 6-minute walk distance (6MWD), an echocardiographic examination, and a right heart catheterization for diagnostic or reevaluation purposes. The median follow-up time was 20.6 months (interquartile range, 45.8 mo). Clinical deterioration was defined by listing for transplantation or death. MEASUREMENTS AND MAIN RESULTS: Seventeen patients presented with clinical deterioration. As compared with the 15 others, they had an increased MSNA (80 +/- 12 vs. 52 +/- 18 bursts/min; P < 0.001) and heart rate (88 +/- 17 vs. 74 +/- 12 bpm; P = 0.01), a lower 6MWD (324 +/- 119 vs. 434 +/- 88 m; P < 0.01) and a deteriorated NYHA functional class (3.6 +/- 0.5 vs. 2.9 +/- 0.8; P < 0.001). The hemodynamic variables were not different. MSNA was directly related to heart rate and inversely to 6MWD. A univariate analysis revealed that increased MSNA and heart rate, NYHA class IV, lower 6MWD, and pericardial effusion were associated with subsequent clinical deterioration. A multivariate analysis showed that MSNA was an independent predictor of clinical deterioration. For every increase of 1 burst/minute, the risk of clinical deterioration during follow-up increased by 6%. CONCLUSIONS: Sympathetic nervous system activation is an independent predictor of clinical deterioration in pulmonary arterial hypertension.

Effects of eythropoietin administration on mitral regurgitation and left ventricular remodeling in heart failure patients.

The effects of erythropoietin administration on mitral regurgitation in patients with congestive heart failure have not yet been examined. After 2 months, erythropoietin treatment results in a significant reduction in left ventricular volumes and mitral regurgitation severity and improves hemodynamics.

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.

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.

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.

Regression of left ventricular hypertrophy after arteriovenous fistula closure in renal transplant recipients: a long-term follow-up.

The long-term effects of hemodialysis arteriovenous fistula (AVF) closure on left ventricular (LV) morphology are unknown. Using echocardiography, we prospectively studied 17 kidney transplant recipients before, 1, and, 21 months after AVF closure (mean fistula flow 1371 +/- 727 mL/min). Eight kidney transplant recipients with a patent AVF, matched for age, time after AVF creation, and time after transplantation, served as controls. LV mass index (LVMI) decreased from 139 +/- 44 g/m2 before AVF closure to 127 +/- 45 g/m2 and 117 +/- 40 g/m2 at 1 and 21 months post-closure, respectively (p < 0.001), but remained unchanged in controls. LV hypertrophy prevalence (LVMI > 125 g/m2) decreased from 65% before, to 41% early, and 18%, late, after surgery (p = 0.008), mostly from a decrease in LV end-diastolic diameter. Consequently, the prevalence of LV concentric remodeling (relative wall thickness > 0.45 without hypertrophy) increased from 12% before, to 35% early, and 65% late, after surgery (p = 0.003). Diastolic arterial blood pressure increased from 78 +/- 15 mmHg before, to 85 +/- 13 mmHg early, and 85 +/- 10 mmHg late, after surgery (p < 0.015). In conclusion, closure of large and/or symptomatic AVF induces long-term regression of LV hypertrophy. However, residual concentric remodeling geometry as well as diastolic blood pressure increase may blunt the expected beneficial cardiac effects of the procedure.

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.

Acute arterio-venous fistula occlusion decreases sympathetic activity and improves baroreflex control in kidney transplanted patients.

BACKGROUND: The acute bradycardia induced by the occlusion of an arteriovenous fistula (AVF), known as the Nicoladoni-Branham sign, is considerably larger than that which occurs during carotid sinus massage. This suggests increased arterial baroreflex sensitivity during acute AVF occlusion. Moreover, the influence of acute AVF occlusion on muscle sympathetic nerve traffic (MSNA, by microneurography) is unknown. We therefore assessed the effects of acute AVF occlusion on baroreflex sensitivity and on MSNA in patients with stable functional kidney grafts and patent AVF. METHODS: We measured blood pressure (BP), MSNA (n = 11), heart rate (HR), cardiac output (CO) and arterial baroreflex sensitivity (n = 18) at baseline and during acute, 30-s pneumatic AVF occlusions in 23 renal transplanted recipients. RESULTS: During the first 5 s of the AVF occlusion, mean BP increased from 98+/-4 to 112+/-4 mmHg (P<0.0001) while MSNA decreased to 28+/-5% of baseline values (P<0.0001) and HR decreased from 71+/-3 to 61+/-3 b.p.m. (P<0.0001). The largest increases in BP were accompanied by the most marked decreases in MSNA (r = -0.79, P = 0.003) and HR (r = -0.49; P = 0.01) during the first 5 s of the AVF occlusion. During AVF occlusion baseline CO of 6.9+/-0.3 decreased to 5.6+/-0.3 l/min (P<0.0001) while baroreflex sensitivity increased from 10+/-1 to 17+/-2 ms/mm Hg (P<0.001). CONCLUSIONS: Arterial baroreceptor activation and increased arterial baroreflex sensitivity decrease heart rate during AVF occlusion. In addition, our study is the first to demonstrate that arterial baroreflex activation decreases sympathetic nerve traffic during the Nicoladoni-Branham sign.

Peripheral sympathetic control during dobutamine infusion: effects of aging and heart failure.

OBJECTIVES: We assessed the effects of beta-adrenergic agonism on muscle sympathetic nerve activity (MSNA) in patients with congestive heart failure (CHF) and young and matched controls. BACKGROUND: Myocardial response to beta-adrenergic stimulation decreases with aging and with CHF. METHODS: In CHF patients, we measured cardiac hemodynamics and MSNA (microneurography) before, with short-term (n = 5), and after 48-h (n = 9) of dobutamine infusion (10 microg/kg/min). In eight young controls and nine controls matched to the CHF patients, we measured cardiac hemodynamics and MSNA during randomized short-term dobutamine (10 microg/kg/min) and placebo infusions. RESULTS: In CHF patients, short-term dobutamine infusion did not modify mean blood pressure (MBP), MSNA, or heart rate (HR). Moreover, 48-h dobutamine infusion increased cardiac index (3.1 +/- 0.2 vs. 2.2 +/- 0.2 l/min/m(2), p = 0.006), decreased mean pulmonary pressure (28 +/- 7 vs. 38 +/- 7 mm Hg, p = 0.0001) and peripheral resistance (1,099 +/- 112 vs. 1,759 +/- 263, p = 0.03), but did not change MBP, HR, or MSNA in the patients. In matched controls, dobutamine increased HR (87 +/- 5 vs. 65 +/- 2 beats/min, p = 0.0009) but did not change MBP or MSNA. In young controls, dobutamine increased MBP (102 +/- 2 vs. 90 +/- 2 mm Hg, p = 0.0003) and decreased MSNA (28 +/- 5 vs. 35 +/- 3 bursts/min, p = 0.03) but did not change HR (p = 0.054). In the controls, the largest increases in MBP with dobutamine were associated with the most marked reductions in MSNA (r = -0.49, p = 0.04) and the smallest increases in HR (r = -0.70, p = 0.001). CONCLUSIONS: Arterial baroreceptor activation during increases in MBP inhibits MSNA and limits the HR response to dobutamine in controls. This mechanism, together with peripheral vasodilation, probably contributes to the absence of peripheral sympathetic withdrawal despite substantial hemodynamic improvements in CHF patients.

Dobutamine potentiates the peripheral chemoreflex in patients with congestive heart failure.

BACKGROUND: beta-Adrenergic agonists may increase chemoreflex sensitivity to hypoxia in normal humans. Chemoreflex function is important in the pathophysiology of heart failure. Whether the beta-1 agonist dobutamine, which is frequently administered to patients with heart failure, alters their chemoreflex sensitivity is not known. METHODS: We tested the hypothesis that dobutamine increases chemoreflex sensitivity in patients with congestive heart failure (CHF) using a randomized, double-blinded, placebo-controlled study design. We assessed the influence of dobutamine on minute ventilation and hemodynamics during normoxic breathing and during peripheral chemoreflex deactivation by hyperoxia (100% O(2)) in 9 patients with CHF. RESULTS: Dobutamine increased minute ventilation in patients with CHF (9.4+/-0.9 versus 8.4+/-0.7 L/min, P=.005) during normoxia. Peripheral chemoreflex deactivation by hyperoxia suppressed the ventilatory effects of dobutamine (10.4+/-1.4 L/min for dobutamine versus 10.0+/-1.2 L/min for placebo, P=.34). CONCLUSIONS: Dobutamine increases ventilation during normoxia, but not during hyperoxia in patients with CHF. We conclude that dobutamine enhances peripheral chemoreflex sensitivity in patients with congestive heart failure.

Dobutamine potentiates arterial chemoreflex sensitivity in healthy normal humans.

beta-Adrenergic agonists may increase chemosensitivity in humans. We tested the hypothesis that the beta1-agonist dobutamine increases peripheral chemosensitivity in a double-blind placebo-controlled randomized and crossover study. In 15 healthy subjects, we examined the effects of dobutamine on breathing, hemodynamics, and sympathetic nerve activity (measured using microneurography) during normoxia, isocapnic hypoxia (10% O2), posthypoxic maximal voluntary end-expiratory apnea, hyperoxic hypercapnia, and cold pressor test (CPT). Dobutamine increased ventilation (7.5 +/- 0.3 vs. 6.7 +/- 0.2 l/min, P = 0.0004) during normoxia, markedly enhanced the ventilatory (16.1 +/- 1.6 vs. 11.4 +/- 0.7 l/min, P < 0.0001) and sympathetic (+403 +/- 94 vs. +222 +/- 5%, P < 0.03) responses at the fifth minute of isocapnic hypoxia, and enhanced the sympathetic response to the apnea performed after hypoxia (+501 +/- 107% vs. +291 +/- 38%, P < 0.05). No differences were observed between dobutamine and placebo on the responses to hyperoxic hypercapnia and CPT. Dobutamine increases ventilation during normoxia and potentiates the ventilatory and sympathetic responses to hypoxia in healthy subjects. Dobutamine does not affect the responses to hyperoxic hypercapnia and CPT. We conclude that dobutamine enhances peripheral chemosensitivity.