Broader adaptive range of sympathetic burst size in response to blood pressure change in older women with greater arterial stiffness.

KEY POINTS: In this study, we focused on muscle sympathetic nerve activity (MSNA) burst size and occurrence separately as subcomponents of the sympathetic baroreflex in older adults, and we found that the distribution (variation) of burst size against burst occurrence was greater in women than men. Older women had greater carotid artery stiffness compared with older men, while blood pressure (BP) distribution (variation) was comparable between sexes. Sympathetic baroreflex sensitivity assessed with burst incidence was less sensitive as the carotid artery became stiffer in older men and women, while that assessed with burst area was more sensitive as the carotid artery became stiffer in older women but not in older men. These results help us understand the mechanisms underlying the compensation for the impaired response of MSNA burst occurrence in older women with greater carotid artery stiffness to regulate BP similar to that in older men. ABSTRACT: There are sex differences in arterial stiffness and neural control of blood pressure (BP) among older adults. We examined whether the sympathetic response to BP is greater in older women than men in burst size but not burst occurrence. Burst occurrence and size were assessed with burst interval and area of muscle sympathetic nerve activity, respectively, and the distributions of these indices were evaluated by range during supine rest in 61 healthy older subjects (30 men (69 ± 6 years) and 31 women (68 ± 6 years); means ± SD). Also, we analysed sympathetic baroreflex sensitivity (BRS) with burst occurrence and area simultaneously. Carotid ß-stiffness was measured with B-mode ultrasonic image and carotid BP. The range of burst interval was smaller in older women than men (P = 0.002), while there was no difference in the range of burst area. Carotid ß-stiffness was greater in older women than men (6.7 ± 2.7 vs. 5.1 ± 2.7, P = 0.027). Sympathetic BRS assessed with burst incidence was lower in older women than men (-2.3 ± 1.4 vs. -3.3 ± 1.4 bursts·100 beats-1  mmHg-1 , P = 0.007), while this sex difference was observed when assessed with burst area after adjusting for carotid ß-stiffness (-116.1 ± 135.0 vs. -185.9 ± 148.2 a.u. burst-1  mmHg-1 , P = 0.040), but not before. Sympathetic BRS assessed with burst area was negatively (more sensitive) correlated with carotid ß-stiffness in older women (r = -0.53, P = 0.002) but not men. These data suggest that the response of burst size within each burst is augmented for the baroreflex BP control despite the impaired response of burst occurrence in older women with greater carotid stiffness.

The international POTS registry: Evaluating the efficacy of an exercise training intervention in a community setting.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) affects primarily young women and impairs quality of life. We found that in a research setting, exercise training along with lifestyle intervention is effective as a nondrug therapy for POTS. OBJECTIVE: To evaluate the efficacy of our exercise training/lifestyle intervention in POTS patients in a community environment. METHODS: We established a POTS registry and enrolled 251 patients (86% women, aged 26 ± 11 [SD] years) through their physicians. A 3-month program involving mild- to moderate-intensity endurance training (progressing from semirecumbent to upright, 3-5 times/wk, 30-45 min/session) plus strength training was implemented along with increasing salt/water intake. The program was delivered to the physicians, who oversaw training in their patients. A 10-minute stand test was performed at the physician's office and patient quality of life was assessed using the 36-Item Short Form Health Survey. RESULTS: One hundred and three patients completed the program. Of those that completed, 71% no longer qualified for POTS and were thus in remission. The increase in heart rate from supine to 10-minute stand was markedly lower (23 ± 14 vs. 46 ± 17 beats/min before intervention; P < .001), while patient quality of life was improved dramatically after intervention (P < .001). Of those who were followed for 6-12 months (n = 31), the effect was persistent. CONCLUSIONS: A training/lifestyle intervention program can be implemented in a community setting with physician supervision and is effective in the treatment of POTS. It remains to be determined whether exercise can be an effective long-term treatment strategy for this condition, though patients are encouraged to maintain an active lifestyle indefinitely.

Age and sex differences in muscle sympathetic nerve activity in relation to haemodynamics, blood volume and left ventricular size.

We compared the effect of age- and sex-related differences in haemodynamics, blood volume (BV) and left ventricular (LV) size and mass on resting muscle sympathetic nerve activity (MSNA) in healthy, normotensive adults. Twenty young men (19-47 years old) and 20 young women (21-46 years old) as well as 15 older men (62-80 years old) and 15 older women (60-82 years old) were studied. Cardiac output (acetylene rebreathing), total peripheral resistance, forearm vascular resistance (FVR; venous occlusion plethysmography) and MSNA were measured during supine rest. Blood volume was calculated (CO rebreathing), and LV mass, end-diastolic (LVEDV) and end-systolic volumes (LVESV) were measured using magnetic resonance imaging. Cardiac index (P < 0.001 and P = 0.016), BV (both P < 0.001), LV mass (P < 0.001 and P = 0.002), LVEDV (P < 0.001 and P = 0.002) and LVESV (both P < 0.001) were lower in the older and female groups, respectively. Total peripheral resistance was significantly higher in the older (P < 0.001) and female groups (P = 0.014), but FVR was increased in the female groups (P = 0.048) only (age, P = 0.089). The MSNA was greater in the older groups (P < 0.001) only (sex, P = 0.228). Increased MSNA was shown to correlate with a decrease in BV (P = 0.004) in men only when adjusted for age (women, P = 0.133). There was a positive relation between MSNA and FVR (P = 0.020) in men but not women (P = 0.422). There were no significant relations between MSNA and LV mass, LVEDV or LVESV. The findings suggest that the increase in resting MSNA with age may be related to the decline in BV in men only, but it is unknown whether sex differences in sympathetic adrenergic vasoconstriction occur independently of these changes.

Morning blood pressure surge is associated with arterial stiffness and sympathetic baroreflex sensitivity in hypertensive seniors.

Morning blood pressure (BP) surge is considered to be an independent risk factor for cardiovascular diseases. We tested the hypothesis that increased large-artery stiffness and impaired sympathetic baroreflex sensitivity (BRS) contribute to augmented morning surge in elderly hypertensive subjects. Morning surge was assessed as morning systolic BP averaged for 2 h just after waking up minus minimal sleeping systolic BP by using ambulatory BP monitoring (ABPM) in 40 untreated hypertensive [68 ± 1 (SE) yr] and 30 normotensive (68 ± 1 yr) subjects. Beat-by-beat finger BP and muscle sympathetic nerve activity (MSNA) were recorded in the supine position and at 60° upright tilt. We assessed arterial stiffness with carotid-to-femoral pulse wave velocity (cfPWV) and sympathetic BRS during spontaneous breathing. Awake and asleep ABPM-BPs and morning surge were higher in hypertensive than normotensive subjects (all P < 0.001). cfPWV was higher (P = 0.002) and sympathetic BRS was lower (P = 0.096) in hypertensive than normotensive subjects. Hypertensive subjects with morning surge ≥35 mmHg (median value) had higher cfPWV (11.9 ± 0.5 vs. 9.9 ± 0.4 m/s, P = 0.002) and lower sympathetic BRS (supine: -2.71 ± 0.25 vs. -3.73 ± 0.29, P = 0.011; upright: -2.62 ± 0.22 vs. -3.51 ± 0.35 bursts·100 beats(-1)·mmHg(-1), P = 0.052) than those with morning surge <35 mmHg. MSNA indices were similar between groups (all P > 0.05), while upright total peripheral resistance was higher in hypertensive subjects with greater morning surge than those with lesser morning surge (P = 0.050). Morning surge was correlated positively with cfPWV (r = 0.59, P < 0.001) and negatively with sympathetic BRS (r = 0.51, P < 0.001) in hypertensive subjects only. Thus, morning BP surge is associated with arterial stiffness and sympathetic BRS, as well as vasoreactivity during orthostasis in hypertensive seniors.

Elderly blacks have a blunted sympathetic neural responsiveness but greater pressor response to orthostasis than elderly whites.

Neural control of blood pressure (BP) has been reported to differ between young blacks and whites. We hypothesized that elderly blacks have enhanced sympathetic neural responses during orthostasis compared with elderly whites. Muscle sympathetic nerve activity, arm-cuff BP, and heart rate were recorded continuously, and cardiac output, stroke volume, and total peripheral resistance were measured intermittently during supine and 5-minute 60° upright tilt in 10 blacks (65 [SD, 4] years; 4 women) and 20 whites (68 [6] years; 8 women). We found that muscle sympathetic nerve activity burst frequency was similar between blacks and whites in the supine position (44 [10] versus 42 [7] bursts per minute) and during upright tilt (59 [11] versus 60 [9] bursts per minute; P=0.846 for race, P<0.001 for posture, and P=0.622 for interaction). However, upright total muscle sympathetic nerve activity was smaller in blacks than in whites (162 [39] versus 243 [112]%; P=0.003). Systolic BP, heart rate, cardiac output, and stroke volume were not different between groups. Diastolic BP was similar in the supine position, increased in all of the subjects during tilting; upright diastolic BP was greater in blacks than in whites (80 [10] versus 71 [7] mmHg; P=0.008). Total peripheral resistance did not differ between blacks and whites in the supine position or during upright tilt (P=0.354 for race, P<0.001 for posture, P=0.825 for interaction). Thus, elderly blacks have a blunted sympathetic neural responsiveness but enhanced pressor response to orthostasis compared with elderly whites, which may be attributable to an augmented sympathetic vascular transduction and/or nonadrenergic vasoconstrictor mechanisms (ie, angiotensin II or the venoarteriolar response).

Relationship between sympathetic baroreflex sensitivity and arterial stiffness in elderly men and women.

Previous human studies have shown that large-artery stiffness contributes to an age-related decrease in cardiovagal baroreflex sensitivity. Whether this is also true with sympathetic baroreflex sensitivity is unknown. We tested the hypothesis that sympathetic baroreflex sensitivity is associated with the stiffness of baroreceptor segments (the carotid artery and the aorta) in elderly individuals and that sex affects this relationship. Sympathetic baroreflex sensitivity was assessed from the spontaneous changes in beat-by-beat diastolic pressure and corresponding muscle sympathetic nerve activity (microneurography) during supine rest in 30 men (mean±SEM: 69±1 years) and 31 women (68±1 years). Carotid artery stiffness (B-mode ultrasonography) and aortic stiffness (MRI) were also determined. We found that elderly women had lower sympathetic baroreflex sensitivity than elderly men (-2.33±0.25 versus -3.32±0.25 bursts · 100 beats(-1) · mm Hg(-1); P=0.007). ß-Stiffness indices of the carotid artery and the aorta were greater in elderly women than in men (6.68±0.48 versus 5.10±0.50 and 4.03±0.47 versus 2.68±0.42; both P<0.050). Sympathetic baroreflex sensitivity was inversely correlated with carotid artery stiffness in both men and women (r=0.49 and 0.50; both P<0.05), whereas this relation was shifted in parallel upward (toward a reduced sensitivity) in women with no changes in the slope (0.26 versus 0.24 arbitrary units). Sympathetic baroreflex sensitivity and aortic stiffness showed similar trends. Thus, barosensory artery stiffness seems to be one independent determinant of sympathetic baroreflex sensitivity in elderly men and women. The lower sympathetic baroreflex sensitivity in elderly women may predispose them to an increased prevalence of hypertension.

Sex differences in the modulation of vasomotor sympathetic outflow during static handgrip exercise in healthy young humans.

Sex differences in sympathetic neural control during static exercise in humans are few and the findings are inconsistent. We hypothesized women would have an attenuated vasomotor sympathetic response to static exercise, which would be further reduced during the high sex hormone [midluteal (ML)] vs. the low hormone phase [early follicular (EF)]. We measured heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) in 11 women and 10 men during a cold pressor test (CPT) and static handgrip to fatigue with 2 min of postexercise circulatory arrest (PECA). HR increased during handgrip, reached its peak at fatigue, and was comparable between sexes. BP increased during handgrip and PECA where men had larger increases from baseline. Mean ± SD MSNA burst frequency (BF) during handgrip and PECA was lower in women (EF, P < 0.05), as was ΔMSNA-BF smaller (main effect, both P < 0.01). ΔTotal activity was higher in men at fatigue (EF: 632 ± 418 vs. ML: 598 ± 342 vs. men: 1,025 ± 416 a.u./min, P < 0.001 for EF and ML vs. men) and during PECA (EF: 354 ± 321 vs. ML: 341 ± 199 vs. men: 599 ± 327 a.u./min, P < 0.05 for EF and ML vs. men). During CPT, HR and MSNA responses were similar between sexes and hormone phases, confirming that central integration and the sympathetic efferent pathway was comparable between the sexes and across hormone phases. Women demonstrated a blunted metaboreflex, unaffected by sex hormones, which may be due to differences in muscle mass or fiber type and, therefore, metabolic stimulation of group IV afferents.

Effects of exercise training on arterial-cardiac baroreflex function in POTS.

PURPOSE: Postural orthostatic tachycardia syndrome (POTS) is characterized by excessive tachycardia in the upright position. To test the hypothesis that patients with POTS have impaired arterial-cardiac baroreflex function, while exercise training normalizes the baroreflex function in these patients. METHODS: Seventeen POTS patients aged 27 ± 9 (mean ± SD) years underwent an exercise training program for 3 months. Arterial-cardiac baroreflex function was assessed by spectral and transfer function analysis of beat-to-beat R-R interval (RRI) and systolic blood pressure (SBP) variability in the supine position and at 60° upright tilt during spontaneous breathing before and after training. Data were compared with 17 healthy sedentary controls. RESULTS: Even though upright heart rate (HR) was greater in patients than controls, indexes of RRI variability did not differ between groups. Transfer function gain (SBP to RRI), used as an index of arterial-cardiac baroreflex sensitivity was similar between patients and controls in both low- (LF, P = 0.470) and high-frequency (HF, P = 0.663) ranges. Short-term exercise training decreased upright HR and increased RRI variability in POTS patients. LF baroreflex gain increased significantly in the supine position and during upright tilt [analysis of variance (ANOVA), P = 0.04 for training], while HF gain increased modestly after training (ANOVA, P = 0.105 for training) in these patients; however, the baroreflex gains remained within the normal ranges when compared with healthy controls. CONCLUSIONS: These data suggest that patients with POTS have normal arterial-cardiac baroreflex function in both supine and upright postures. Short-term exercise training increases the baroreflex sensitivity in these patients, associated with a decrease in upright heart rate.

Cardiac origins of the postural orthostatic tachycardia syndrome.

OBJECTIVES: The purpose of this study was to test the hypothesis that a small heart coupled with reduced blood volume contributes to the postural orthostatic tachycardia syndrome (POTS) and that exercise training improves this syndrome. BACKGROUND: Patients with POTS have marked increases in heart rate during orthostasis. However, the underlying mechanisms are unknown and the effective therapy is uncertain. METHODS: Twenty-seven POTS patients underwent autonomic function tests, cardiac magnetic resonance imaging, and blood volume measurements. Twenty-five of them participated in a 3-month specially designed exercise training program with 19 completing the program; these patients were re-evaluated after training. Results were compared with those of 16 healthy controls. RESULTS: Upright heart rate and total peripheral resistance were greater, whereas stroke volume and cardiac output were smaller in patients than in controls. Baroreflex function was similar between groups. Left ventricular mass (median [25th, 75th percentiles], 1.26 g/kg [1.12, 1.37 g/kg] vs. 1.45 g/kg [1.34, 1.57 g/kg]; p < 0.01) and blood volume (60 ml/kg [54, 64 ml/kg] vs. 71 ml/kg [65, 78 ml/kg]; p < 0.01) were smaller in patients than in controls. Exercise training increased left ventricular mass and blood volume by approximately 12% and approximately 7% and decreased upright heart rate by 9 beats/min [1, 17 beats/min]. Ten of 19 patients no longer met POTS criteria after training, whereas patient quality of life assessed by the 36-item Short-Form Health Survey was improved in all patients after training. CONCLUSIONS: Autonomic function was intact in POTS patients. The marked tachycardia during orthostasis was attributable to a small heart coupled with reduced blood volume. Exercise training improved or even cured this syndrome in most patients. It seems reasonable to offer POTS a new name based on its underlying pathophysiology, the "Grinch syndrome," because in this famous children's book by Dr. Seuss, the main character had a heart that was "two sizes too small."

Menstrual cycle effects on sympathetic neural responses to upright tilt.

Young women are more susceptible to orthostatic intolerance than men, though the sex-specific pathophysiology remains unknown. As blood pressure (BP) is regulated through the baroreflex mechanism, we tested the hypothesis that baroreflex control of muscle sympathetic nerve activity (MSNA) during orthostasis is impaired in women and can be affected by the menstrual cycle. MSNA and haemodynamics were measured supine and during a graded upright tilt (30 deg for 6 min, 60 deg for 45 min or till presyncope) in 11 young men and 11 women during the early follicular (EFP) and mid-luteal phase (MLP) of the menstrual cycle. Sympathetic baroreflex sensitivity was quantified using the slope of the linear correlation between total activity and diastolic BP during spontaneous breathing. Baroreflex function was further assessed during a Valsalva manoeuvre (VM). Although MSNA burst frequency responses during tilting were similar between sexes and menstrual phases, increases in total activity were lower in women during EFP than MLP (P = 0.030), while total peripheral resistance and plasma noradrenaline were not similarly lower; upright total activity tended to be lower in women during EFP than men (P = 0.102). Sympathetic baroreflex sensitivity did not differ between sexes (P = 0.676) supine (-281 +/- 46 (S.E.M.) units beat(-1) mmHg(-1) in men vs -252 +/- 52 in EFP and -272 +/- 40 in MLP in women), at 30 deg tilt (-648 +/- 129 vs -611 +/- 79 and -487 +/- 94), and at 60 deg tilt (-792 +/- 135 vs -831 +/- 92 and -814 +/- 142); this sensitivity was not affected by the menstrual cycle (P = 0.747). Similar sympathetic baroreflex sensitivity between sexes and phases was also observed during the VM. Cardiovagal baroreflex sensitivity assessed during decreasing BP (i.e. early phase II of the VM) was comparable between sexes, but it was greater in men than women during increasing BP (i.e. phase IV); the menstrual cycle had no influences on cardiovagal baroreflex sensitivity. We conclude that the menstrual cycle affects sympathetic neural responses but not sympathetic baroreflex sensitivity during orthostasis, though upright vasomotor sympathetic activity is not clearly different between men and women. Not only sympathetic but also cardiovagal baroreflex sensitivity is similar between sexes and menstrual phases during a hypotensive stimulus. However, cardiovagal baroreflex-mediated bradycardia during a hypertensive stimulus is different between sexes but not affected by the menstrual cycle. Thus, other factors rather than sympathetic baroreflex control mechanisms contribute to sex differences in orthostatic tolerance in young humans.