Heart rate variability decreases after 3 months of sustained treatment with fingolimod.

The objective is to prospectively investigate short- and mid-term changes of heart rate variability (HRV) in patients with relapsing-remitting multiple sclerosis (RRMS), being started on fingolimod. In this prospective clinical trial, patient (n = 33) with RRMS starting treatment with fingolimod underwent a time-domain-based analysis of HRV (breathing at rest, deep breath, and in response to the Valsalva maneuver) shortly before, 4.5 h and 3 months after first intake. Blood pressure changes after the Valsalva maneuver were used as a marker of the sympathetic noradrenergic system. We used a non-invasive continuous beat-to-beat heart rate and blood pressure monitoring. In addition, the Fatigue Severity Scale and the refined and abbreviated Composite Autonomic Symptom Score were applied. Significant changes in HRV in RRMS patients, following treatment with fingolimod, were detected. After an initial increase in HRV, measured 4.5 h after the first intake of fingolimod, a substantial decrease in HRV occurred within 3 months on continuous treatment. There is a growing body of evidence for short-term cardiovascular side effects in continuous treatment with fingolimod, driven by the ANS. The mechanisms and the clinical relevance of the observed changes in HRV need further evaluation, especially in longer and larger prospective studies.

Influence of sex, menstrual cycle, and oral contraceptives on cerebrovascular resistance and cardiorespiratory function during Valsalva or standing.

Women experience orthostatic intolerance more than men, and they experience faintness more in the early follicular [i.e., low-hormone (LH)] than luteal [i.e., high-hormone (HH)] phase of the menstrual cycle. Men (n = 13, 25.8 ± 1.8 yr old) and women in the LH (days 2-5; placebo) and HH (days 18-24; high dose) phases of the menstrual cycle with (OC; n = 14, 22.0 ± 0.8 yr old) or without (NOC; n = 12, 21.8 ± 0.5 yr old) oral contraceptive (OC) use underwent the Valsalva maneuver and a supine-sit-stand protocol. Blood pressure, normalized stroke volume [stroke volume index (SVi)], cardiac output index, heart rate, end-tidal CO2, and middle cerebral artery (MCA) blood flow velocity were measured. When subjected to the Valsalva maneuver, all women had a greater increase in diastolic and mean MCA blood flow velocity than men (P ≤ 0.065), with no significant effect of menstrual cycle phase or OC use. When subjected to the supine-sit-stand protocol, men had lower MCA blood flow velocity (P < 0.038) than all women, and SVi was higher in men than in the NOC group in all postures (P < 0.011) and in the OC group in the LH phase of the menstrual cycle during standing (P = 0.010). Only men experienced higher resistance index (P < 0.001) and pulsatility index (P < 0.001) with standing. The OC group had lower end-tidal CO2 (P = 0.002) than the NOC group (P = 0.030) and men (P ≤ 0.067). SVi (P = 0.004) and cardiac output index (P = 0.008) were higher in the OC than NOC group. A tendency toward a lower mean MCA blood flow velocity (P = 0.058) and higher SVi (P = 0.059) and pulsatility index (P = 0.058) was noted in the HH than LH phase. Mean arterial pressure was higher in the OC than NOC group in the LH phase (P = 0.049) and lower in the HH than LH phase (P = 0.014). Our results indicate that cycling estrogens/progestins can influence ventilatory, cardiovascular, and/or cerebrovascular physiology.NEW & NOTEWORTHY We have found sex differences in the cerebrovascular response to the Valsalva maneuver and standing. Men have greater cerebral vasoconstriction (or women have greater cerebral vasodilation) during late phase II of the Valsalva maneuver, and the cerebrovascular resistance index increases in men, but not in women, during standing. Furthermore, our findings indicate that both the menstrual cycle phase and oral contraceptive use can influence cardiovascular function both at rest and during active standing.

Evaluation of augmented pulse pressure variation using the Valsalva manoeuvre as a predictor of fluid responsiveness under open-chest conditions: A prospective observational study.

BACKGROUND: Pulse pressure variation (PPV) is a well known dynamic preload indicator of fluid responsiveness. However, its usefulness in open-chest conditions remains controversial. OBJECTIVE: We evaluated whether augmented PPV during a Valsalva manoeuvre can predict fluid responsiveness after sternotomy. DESIGN: A prospective, observational study. SETTING: Single-centre trial, study period from October 2014 to June 2015. PATIENTS: Forty-nine adult patients who underwent off-pump coronary arterial bypass grafting. INTERVENTION: After midline sternotomy, haemodynamic parameters were measured before and after volume expansion (6 ml kg of crystalloids). PPV was calculated both automatically (PPVauto) and manually (PPVmanual). For PPV augmentation, we performed Valsalva manoeuvres with manual holding of the rebreathing bag and constant airway pressure of 30 cmH2O for 10 s before fluid loading and calculated PPV during the Valsalva manoeuvre (PPVVM). MAIN OUTCOME MEASURES: The predictive ability of PPVVM for fluid responsiveness using receiver-operating characteristic curve analysis. Responders were identified when an increase in cardiac index of at least 12% occurred after fluid loading. RESULTS: Twenty-one patients were responders and 28 were nonresponders. PPVVM successfully predicted fluid responsiveness with an area under the curve (AUC) of 0.88 [95% confidence interval (95% CI) 0.75 to 0.95; sensitivity 91%, specificity 79%, P < 0.0001] and a threshold value of 55%. Baseline PPVauto and PPVmanual also predicted fluid responsiveness [AUC 0.75 (0.62 to 0.88); sensitivity 79%, specificity 75%; and 0.76 (0.61 to 0.87]; sensitivity 71%, specificity 71%, respectively). However, only PPVVM showed a significant AUC-difference from that of central venous pressure (P = 0.008) and correlated with the change of cardiac index induced by volume expansion (r = 0.6, P < 0.001). CONCLUSION: Augmented PPV using a Valsalva manoeuvre can be used as a clinically reliable predictor of fluid responsiveness under open-chest condition. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02457572.

The impact of rotigotine on cardiovascular autonomic function in early Parkinson's disease.

Dysautonomia can occur in early stages of Parkinson's disease (PD) influencing tolerance to dopaminergic therapies. Rotigotine, a non-ergot dopamine agonist, has recently been developed as an effective alternative antiparkinsonian drug, but its influence on the autonomic nervous system was not investigated. Twenty subjects out of 34 consecutive de novo PD patients were submitted to full assessment of cardiovascular autonomic function before and after reaching a stable rotigotine regimen [6 mg/24 h (n = 3) or 8 mg/24 h (n = 17)]. Patients reached significant clinical improvement (-27% on the Unified Parkinson's Disease Rating Scale part III) and did not show significant differences in cardiovascular tests compared to baseline data. However, an unexpected trend towards increasing systolic blood pressure after head-up tilt test was detected. Our study demonstrates that rotigotine does not influence cardiovascular autonomic responses in early de novo PD patients. Consequently, it may represent a well-tolerated and efficacious therapeutic option in newly diagnosed PD subjects.

Autonomic function following acute organophosphorus poisoning: a cohort study.

Autonomic dysfunction after chronic low level exposure to organophosphorus (OP) pesticides has been consistently reported in the literature, but not following a single acute overdose. In order to study autonomic function after an acute OP overdose, sixty-six overdose patients were compared to 70 matched controls. Assessment of autonomic function was done by heart rate response to standing, deep breathing (HR-DB) and Valsalva manoeuvre; blood pressure (BP) response to standing and sustained hand grip; amplitude and latency of sympathetic skin response (SSR); pupil size and post-void urine volume. The patients were assessed one and six weeks after the exposure. The number of patients who showed abnormal autonomic function compared to standard cut-off values did not show statistically significantly difference from that of controls by Chi-Square test. When compared to the controls at one week the only significant differences consistent with autonomic dysfunction were change of diastolic BP 3 min after standing, HR-DB, SSR-Amplitude, SSR-Latency, post-void urine volume and size of the pupil. At 6 weeks significant recovery of autonomic function was observed and only HR-DB was decreased to a minor degree, -5 beats/min [95%CI 2-8]. This study provides good evidence for the lack of long term autonomic dysfunction following acute exposure to OP pesticides.

Effect of low-dose amitriptyline on autonomic functions and peripheral blood flow in fibromyalgia: a pilot study.

OBJECTIVE: Amitriptyline (10-50mg) is the most common drug prescribed for the treatment of fibromyalgia. Amitriptyline influences the autonomic nervous system, as is well known; fibromyalgia is also associated with dysautonomia. The present preliminary study was designed to observe the effects of amitriptyline prescribed in a low dose (10mg) on the autonomic function tests and blood flow measurements in well-diagnosed patients with fibromyalgia. METHODOLOGY: Amitriptyline (10mg) was prescribed for 3 months to 21 female patients with fibromyalgia. A standard battery of noninvasive autonomic function tests comprising of lying to standing test, hand grip test, cold pressor test, deep breathing test, and Valsalva maneuver was performed both before and after amitriptyline therapy to study the autonomic reactivity of the patients with fibromyalgia. Heart rate variability analysis was done to quantify autonomic tone (activity). Blood flow measurement around the knee joint was performed using impedance plethysmography technique. The patients were also assessed for 10 major clinical symptoms of primary fibromyalgia and state and trait anxiety (state and trait anxiety inventory) at both instances. RESULTS: No significant changes in autonomic activity (tone) and reactivity were observed after amitriptyline therapy. Clinical symptom score and anxiety scores (both state and trait) decreased significantly from the pretreatment values. Blood flow measurement showed significant improvement in blood flow index values at the affected sites after amitriptyline therapy. CONCLUSION: Amitriptyline therapy (10mg for 3 months) increases blood flow to the affected sites. It does not affect autonomic tone and reactivity in the patients with fibromyalgia.

Effects of a dual L/N-type calcium channel blocker cilnidipine on blood pressure, pulse rate, and autonomic functions in patients with mild to moderate hypertension.

The current study was conducted to examine the effects of cilnidipine, a dual L/N-type calcium channel blocker, on blood pressure, pulse rate, and autonomic functions in patients with mild-to-moderate hypertension. Sixteen patients with mild-to-moderate hypertension (8 males and 8 females; 44-72 years of age) were treated with cilnidipine (10 mg/day) for 3 months. Before and after the treatment, the following measurements were conducted; beat-to-beat blood pressure during late phase II and overshoot phase of the Valsalva maneuver, the Valsalva ratio, heart rate response to deep breathing, systolic and diastolic blood pressure, and pulse rate. The head-up tilt test was also performed before and after the treatment. Cilnidipine significantly decreased either the systolic or diastolic blood pressure from 151 +/- 15 mmHg to 129 +/- 14 mmHg or 84 +/- 11 mmHg to 71 +/- 9 mmHg, respectively. For pulse rate, there were no significant changes during therapy. Beat-to-beat blood pressure during late phase II and overshoot phase of the Valsalva maneuver indicated significant improvements in both figures. The heart rate response to deep breathing and the Valsalva ratio indicated no significant differences during therapy. Before and after the treatment, no orthostatic hypotension was observed during the head-up tilt test. The current study revealed that cilnidipine significantly decreases blood pressure with improving autonomic functions while having no adverse effects on heart rate response and pulse rate.

Sympathetic cardiac influence and arterial blood pressure instability.

Previous studies have suggested that sympathetic cardiac blockade enhances baroreflex function, whereas parasympathetic blockade diminishes baroreflex sensitivity and elicits arterial blood pressure (ABP) instability. The aim of this project was to test the hypothesis that sympathetic cardiac blockade was beneficial in maintaining ABP stability during orthostatic challenge. In 8 young healthy subjects, measurements were taken before and after sympathetic cardiac blockade (beta1-adrenoceptor blockade via metoprolol) in combination with or without parasympathetic blockade (atropine) at rest and during lower body negative pressure (LBNP). Arterial blood samples were obtained to evaluate plasma renin activity (PRA) and norepinephrine (NE). Power spectral analyses were performed on heart rate (HR) and ABP variability. LBNP -50 Torr significantly decreased systolic blood pressure (SBP, -6+/-3 mm Hg) and increased PRA (from 0.72+/-0.23 to 1.75+/-0.24 ng ml(-1) h(-1)) and NE (from 1.02+/-0.11 to 2.13+/-0.32 pg ml(-1)). Low frequency (LF, 0.04-0.12 Hz) SBP and diastolic blood pressure (DBP) variability were significantly augmented by LBNP (4.1+/-1.6 vs. 10.8+/-3.0 mm Hg2, and 3.1+/-1.0 vs. 7.9+/-1.9 mm Hg2, respectively). Following metoprolol, arterial baroreflex sensitivity (assessed by the slope of HR interval to SBP during injection with 1 mug kg(-1) phenylephrine) increased significantly (9.9+/-2.2 to 19.6+/-4.1 ms mm Hg(-1)). With beta1-adrenoceptor blockade, LBNP still decreased SBP (-10+/-2 mm Hg) and increased NE, but did not significantly augment PRA (0.59+/-0.22 vs. 1.03+/-0.18 ng ml(-1) h(-1)), or LF SBP and DBP variability (3.3+/-0.6 vs. 5.7+/-1.3 mm Hg2, and 3.1+/-0.7 vs. 5.4+/-1.1 mm Hg2, respectively). The increased PRA during LBNP remained non-significant following metoprolol combined with atropine, whereas the augmented LF SBP (2.6+/-0.7 vs. 9.9+/-2.8 mm Hg2) and DBP (2.5+/-0.7 vs. 11.1+/-3.0 mm Hg2) variability were significantly accentuated compared to both metoprolol alone and control conditions, accompanied by a greater delta SBP (-17+/-7 mm Hg) and significantly diminished baroreflex gain (0.91+/-0.05 ms/mm Hg). These data suggested that removal of sympathetic cardiac influence improved cardiovascular stability as indicated by a diminished LF ABP variability, which was related to an enhanced cardiac responsiveness.

Alpha-lipoic acid in the treatment of autonomic diabetic neuropathy (controlled, randomized, open-label study).

AIM: to evaluate the effect of alpha-lipoic acid in autonomic diabetic neuropathy in a controlled, randomized, open-label study. MATERIAL AND METHODS: 46 patients with type 1 diabetes and different forms of autonomic neuropathy, of mean age 38.1 +/- 12.5 years and mean duration of diabetes 16.8 +/- 8.9 years were treated with alpha-lipoic acid for 10 days 600mg daily iv, thereafter one film tablet of 600mg daily for 50 days. 29 type 1 diabetic patients with autonomic diabetic neuropathy, of mean age 40.2 +/- 9.3 years and mean duration of diabetes 15.4 +/- 7.9 years served as a control group. We have followed-up patients' complaints, Ewing's tests, laboratory parameters of oxidative stress. RESULTS: There was a significant improvement after treatment in the score for severity of cardiovascular autonomic neuropathy--from 6.43 +/- 0.9 to 4.24 +/- 1.8 (p<0.001), while in the control group it worsened from 6.18 +/- 1.3 to 6.52 +/- 0.9 (p>0.1). We found improvement in the Valsalva manoeuvre after treatment - from 1.05 +/- 0.04 to 1.13 +/- 0.08 (p<0.001); in the deep-breathing test -from 3.4 +/- 2.8 to 10.4 +/- 5.7 (p<0.001); and in the lying-to-standing test--from 0.99 +/- 0.01 to 1.01 +/- 0.02 (p>0.1), while in the control group there was no improvement. There was a beneficial effect of treatment on the change of systolic blood pressure at the lying-to-standing test--from 22.7 +/- 11.5 to 9.8 +/- 7.9 (p<0.001), while in the control group the change was 20.5 +/- 11.1 mmHg and 19.7 +/- 12.9 mmHg (p>0.1), respectively. We found improvement in diabetic enteropathy in six patients; in the complaints of dizziness, instability upon standing in six patients; in neuropathic edema of the lower extremities in four patients and in erectile dysfunction in four patients after treatment, while in the control group no change was reported in the symptoms and signs of autonomic neuropathy by the end of the follow-up period. There were changes in the laboratory parameters of oxidative stress after therapy--total serum antioxidant capacity increased from 20.42 +/- 1.8 to 22.96 +/- 2.3 microgH2O2/ml/min (p<0.05), serum SOD activity - from 269.8 +/- 31.1 to 319.8 +/- 29.IU/l (p=0.02) and erythrocyte SOD--from 0.89 +/- 0.10 to 1.11 +/- 0.09 U/gHb (p=0.04). CONCLUSION: Our results demonstrate that alpha-lipoic acid (Thiogamma) appears to be an effective drug in the treatment of the different forms of autonomic diabetic neuropathy.

Contrast transcranial Doppler ultrasound in the detection of right-to-left shunts: comparison of Echovist-200 and Echovist-300, timing of the Valsalva maneuver, and general recommendations for the performance of the test.

BACKGROUND AND PURPOSE: Cardiac right-to-left shunts (RLS) can be identified by transesophageal echocardiography (TEE) as well as by transcranial Doppler ultrasound (TCD) using contrast agents, such as Echovist-200 or Echovist-300 in conjunction with a Valsalva maneuver (VM) as provocation procedure. Both Echovist preparations are in use. Currently, the appropriate timing of the VM is still under debate. METHODS: Sixty-four patients were investigated by both TEE and bilateral TCD of the middle cerebral arteries. The following protocol was applied in a randomized way: (1) no VM, (2) VM for 5 s starting with the beginning of Echovist-300 injection, (3) VM for 5 s starting 5 s after the beginning of Echovist-300 injection, (4) VM for 5 s starting 10 s after the beginning of Echovist-300 injection, and (5) VM for 5 s starting 5 s after the beginning of Echovist-200 injection. RESULTS: In 27 patients, an RLS was demonstrated by both TEE and contrast TCD (shunt-positive). Twenty-two patients were negative in both investigations, no patient was positive on TEE but negative on TCD, 15 patients were only positive on at least one TCD investigation but negative on TEE. Tests 3 and 5 were the most appropriate ones; test 3 was slightly superior to test 5. CONCLUSIONS: TCD using Echovist-300 or Echovist-200 is a sensitive method to identify TEE-proven cardiac RLS. To achieve the best diagnostic accuracy, the VM should be performed for a duration of 5 s starting at 5 s following the beginning of contrast injection.

The effect of catechol-O-methyltransferase inhibition with entacapone on cardiovascular autonomic responses in L-Dopa-treated patients with Parkinson's disease.

We have compared the effects of entacapone, a peripherally acting catechol-O-methyltransferase (COMT) inhibitor, and placebo on cardiovascular autonomic responses in L-Dopa/dopa decarboxylase inhibitor-treated patients with Parkinson's disease (PD). In a double-blind, randomized, crossover study with two consecutive 1-week treatment periods, a battery of cardiovascular reflex tests (orthostatic, Valsalva, deep breathing, and isometric hand grip tests) was performed in a group of 15 patients with idiopathic PD. The first set of tests was performed after withholding L-Dopa overnight (control, "off" stage). The second and third sets of tests were performed in "on" stage after 1-week treatment with either entacapone 200 mg or placebo administered with each dose of L-Dopa/dopa decarboxylase (DDC) inhibitor. Valsalva, deep breathing, and orthostatic tests demonstrated no statistically significant differences in the ratio of the longest and shortest electrocardiographic R-to-R wave (R-R) intervals between entacapone and placebo or between study treatments and control. Blood pressure responses to both orthostatic challenge and prolonged isometric work (hand grip test) were similar between treatments. Systolic orthostatic hypotension was observed in only one patient during the control test, but it occurred more frequently after L-Dopa/DDC inhibitor, regardless of concomitant administration of either entacapone (n = 3) or placebo (n = 4). Peripheral COMT inhibition with entacapone does not significantly alter cardiovascular autonomic responses in L-Dopa-treated patients with PD.

Autonomic consequences of brainstem infarction.

OBJECTIVE: It is well known that patients with brainstem infarctions sometimes experience dizziness, vertigo and falls, although the exact mechanism is not clear. Therefore, we designed a study to quantify autonomic function in patients with brainstem infarction. PATIENTS AND METHODS: We examined autonomic function in 15 patients with brainstem infarctions, who had a history of vertigo, nausea, floating sensation and/or general fatigue during standing, and 31 age-matched controls using the composite autonomic scoring scale (CASS), which was used to grade autonomic function. The patients underwent initial autonomic assessment and then were subjected to aniracetam therapy. The drug was given orally (dose of 600 mg/day) for a duration of 56 days. Upon completion of aniracetam administration, the CASS was again tested. RESULTS: Upon initial assessment, the patients had mild reductions in mean blood pressure (MBP) and lack of an increasing heart rate (HR) within 5 min of head up-tilt, an impairment in BP correction during late phase II and reduced phase IV beat-to-beat BP response to the Valsalva maneuver, and reduced heart rate response to deep breathing (HRdb). CASS indicated mild autonomic dysfunction. After 8 weeks of treatment with aniracetam, the patients' symptoms improved and the autonomic tests showed improvement in autonomic function. CONCLUSION: Part of the pathogenesis of recurrent vertigo or dizziness with brainstem infarction might be due to mild autonomic dysfunction. Aniracetam, which activates the cholinergic system in brain, might correct the cardiovagal system in these patients. The CASS may be a sensitive tool for assessing mild autonomic dysfunction in patients with brainstem infarction.

Dynamic cerebral autoregulation testing as a diagnostic tool in patients with carotid artery stenosis.

Evaluation of dynamic cerebral autoregulation might yield a physiologically more adequate measure of cerebral hemodynamic impairment in carotid artery stenosis than CO2-reactivity. This study re-evaluates and compares the Valsalva maneuver (VM) and phase shift during deep breathing. Nineteen patients with severe carotid artery stenosis and 17 age-matched controls were examined using transcranial Doppler sonography and non-invasive blood pressure recordings (Finapres). Phase shift was determined by cross-spectral analysis, responses to VM were graded by the formerly-introduced autoregulation slope index (ASI) and the new Valsalva time index (VTI). Phase shift and autoregulatory indices were significantly reduced on the affected side (p < 0.001). Correlations with CO2-reactivity were significant when pooling values of controls and patients (r from 0.54 to 0.78; p < 0.001). Correlations except for the VTI (r = -0.65; p = 0.002) were not significant considering only the affected side in patients. Correlations of pooled values between phase shift and VM-derived indices were significant (VTI r = -0.62; p < 0.001; ASI r = 0.49; p < 0.001), within patients only when comparing side-to-side differences (VTI r = -0.58; p = 0.009; ASI r = 0.52; p = 0.023). In conclusion, detection of impaired cerebral autoregulation is possible both by deep breathing and VM. The new VTI seems to be more suitable than the conventional ASI. Inter-method agreement concerning the extent of impairment is only acceptable for intra-individual side-to-side differences. Since absolute values of one autoregulation testing method or CO2-reactivity alone might fail, various tests should be combined for comprehensive assessment of cerebral hemodynamic impairment.

Mechanisms of blood pressure alterations in response to the Valsalva maneuver in postural tachycardia syndrome.

The postural tachycardia syndrome (POTS) is characterized clinically by orthostatic lightheadedness and tachycardia. When these patients perform a Valsalva maneuver, there is an excessive blood pressure increment after cessation of the maneuver (phase IV) that is sometimes associated with headaches. It is not known whether excessive phase IV is due to excessive peripheral vascular tone (an alpha-adrenergic mechanism) or is a manifestation of increased beta-adrenergic tone (hyperadrenergic state). The authors undertook a pharmacologic study evaluating the effect of intravenous phentolamine (alpha-adrenergic antagonist) and propranolol (beta-adrenergic antagonist) on the different phases of the Valsalva maneuver in a group of patients with POTS and age-matched normal control subjects. Patients with POTS had mean phases, when compared with controls, that were characterized by more negative II_E (p = 0.07), smaller II_L (p = 0.04), and significantly larger phase IV (p = 0.001). The effect of phentolamine was qualitatively and quantitatively different in POTS when compared with controls. Ten mg phentolamine in controls resulted in a significant accentuation of phase II_E (p = 0.001), attenuation of phase II_L (p = 0.002), and increase of phase IV (57.6 vs 30.7 mm Hg; p = 0.025). These changes resembled those of patients with POTS at baseline. In patients with POTS, the phase II abnormalities, already present, were further accentuated (p <0.001), and phase IV became smaller (50.6 vs 73.8 mm Hg; p = 0.09). Propranolol had no significant effect on phases II_E and II_L, but significantly reduced phase IV in both controls (p <0.05) and in patients with POTS (p <0.001) and improved the headache symptoms, when present, during and after phase IV. The authors conclude that phase IV is mainly under beta-adrenergic regulation and that the exaggerated phase IV in POTS is a result of a hyperadrenergic state.

Climacteric vasomotor symptoms do not imply autonomic dysfunction.

OBJECTIVE: To study whether oestrogen replacement therapy has an effect on autonomic haemodynamic control in postmenopausal women. DESIGN: A placebo-controlled, prospective, randomised, double-blind cross-over trial. POPULATION: Fourteen healthy postmenopausal women who had had a hysterectomy, of whom 12 were double-blind. METHODS: At the end of each treatment period we conducted autonomic nervous system tests: the Valsalva manoeuvre, the deep breathing test, study at rest and the active orthostatic test. Baroreflex sensitivity was evaluated non-invasively from the Valsalva manoeuvre. Heart rate variability was assessed in time and frequency domains during supine rest and standing. Serum oestradiol was also measured and the previous two weeks' symptoms were assessed. RESULTS: Autonomic nervous function was mostly normal for age and unchanged by oestrogen. Vasomotor symptoms were not associated with autonomic dysfunction. Baroreflex sensitivity was 13.3 ms/mmHg (SD 7.4 ms/mmHg) with placebo and 10.5 ms/mmHg (SD 5.4 ms/mmHg) with oestrogen (P = 0.052). This was mostly due to a fall in three of the highest indices. In the orthostatic test the 30 s blood pressure overshoot in two women exceeded the normal 90% confidence interval upper limit, making the mean response strong, especially in the symptomatic group (n = 7). Oestrogen attenuated this overshoot. CONCLUSIONS: Oestrogen did not have a consistent effect on the autonomic nervous system. Oestrogen attenuated a highly sensitive baroreflex and a strong 30 s blood pressure rise in the orthostatic test. This minor effect of oestrogen could be due to the fact that, in general, women with menopausal symptoms do not have impaired autonomic haemodynamic control. The effect of oestrogen in women with autonomic nervous system dysfunction remains to be studied.

Cardiovascular autonomic reactivity in schizophrenics under neuroleptic treatment: A potential predictor of short-term outcome?

In schizophrenics cardiovascular autonomic reactivity (CAR) can be used as an indicator of autonomic arousal. Using a standardized autonomic test battery (modified according to Ewing and Clarke) we prospectively compared the CAR between 46 actually ill schizophrenics (diagnosis according to DSM-III-R) treated with either haloperidol (n = 26) or clozapine (n = 20) and 30 well-matched healthy volunteers. Multivariate analysis demonstrated a significant effect of neuroleptic medication (haloperidol vs. clozapine) on heart rate and diastolic blood pressure under resting conditions as well as on the heart rate variance (30:15 ratio, deep-breathing, Valsalva) and blood pressure tests (sustained handgrip, Schellong). In addition a positive treatment response (using predefined outcome criteria of the Brief Psychiatric Rating Scale) was independently associated with lower resting heart rates and less impaired 30:15 ratios under neuroleptic medication. Our data indicate that clozapine treatment was associated with a substantial impairment of CAR, which can be explained by the drug's anticholinergic properties in combination with an increase in norepinephrine outflow. The greater heart rate variability in responders might be due to an early neuroleptic-induced decrease of sympathetic activity in the autonomic nervous system, which may precede clinical improvement. Our findings are discussed in relation to neuroleptic-induced changes in plasma catecholamine levels suggested to be useful biological markers in predicting treatment outcome.