Objectives To test the hypothesis that a small heart coupled with reduced blood volume contributes to the Postural Tachycardia Syndrome (POTS), while 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 MRI, and blood volume measurements. Twenty-five of them participated in a 3-mo specially designed exercise training program with 19 completing the program; these patients were reevaluated after training. Results were compared with those of 16 healthy controls. Results Upright heart rate and total peripheral resistance were greater, while stroke volume and cardiac output were smaller in patients than controls. Baroreflex function was similar between groups. Left ventricular mass (median [25%, 75%], 1.26 [1.12, 1.37] vs 1.45 [1.34, 1.57] g/kg; P<0.01) and blood volume (60 [54, 64] vs 71 [65, 78] ml/kg; P<0.01) were smaller in patients than controls. Exercise training increased left ventricular mass and blood volume by ~12% and ~7%, and decreased upright heart rate by 9 [1, 17] bpm. Ten out of 19 patients no longer met POTS criteria after training, while patients’ Quality of Life assessed by Short-Form 36 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 the majority of 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.”

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.

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 [69±1 (mean±SEM) years] and 31 women (68±1 years). Carotid artery stiffness (B-mode ultrasonography) and aortic stiffness (magnetic resonance imaging) were also determined. We found that elderly women had lower sympathetic baroreflex sensitivity than elderly men (–2.33±0.25 vs. –3.32±0.25 bursts·100 beats–1·mmHg–1; P=0.007). β-stiffness indices of the carotid artery and the aorta were greater in elderly women than in men (6.68±0.48 vs. 5.10±0.50 and 4.03±0.47 vs. 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), while this relation was shifted in parallel upward (towards a reduced sensitivity) in women with no changes in the slope (0.26 vs. 0.24 a.u.). 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.

We have recently found that exercise training is effective in the treatment of the Postural Orthostatic Tachycardia Syndrome (POTS). Whether this non-drug treatment is superior to “standard” drug therapies, such as β-blockade, is unknown. We tested the hypothesis that exercise training but not β-blockade treatment improves symptoms, hemodynamics, and renal-adrenal responses in POTS patients. Nineteen patients (18 women, 1 man) completed a double-blind drug trial (propranolol or placebo) for 4 weeks, followed by 3 months of exercise training. Fifteen age-matched healthy individuals (14 women, 1 man) served as controls. A 2-hour standing test was performed before and after drug treatment and training. Hemodynamics, catecholamines, plasma renin activity, and aldosterone were measured supine and during 2-hour standing. We found that both propranolol and training significantly lowered standing heart rate. Standing cardiac output was lowered after propranolol treatment (P=0.01), but was minimally changed after training. The aldosterone-to-renin ratio during 2-hour standing remained unchanged after propranolol treatment [4.1±1.7 (SD) pre vs. 3.9±2.0 post, P=0.46), but modestly increased after training (5.2±2.9 vs. 6.5±3.0, P=0.05). Plasma catecholamines were not affected by propranolol or training. Patient quality of life, assessed using the 36-item Short Form Health Survey, was improved after training (physical functioning score 33±10 pre vs. 50±9 post; social functioning score 37±9 vs. 48±6, both P<0.01), but not after propranolol treatment (34±10 vs. 36±11, P=0.63; 39±7 vs. 39±5, P=0.73). These results suggest that for patients with POTS, exercise training is superior to propranolol at restoring upright hemodynamics, normalizing renal-adrenal responsiveness, and improving quality of life.

Abstract-Approximately 500 000 American premenopausal women have the postural orthostatic tachycardia syndrome (POTS). We tested the hypothesis that in POTS women during orthostasis, activation of the renin-angiotensin-aldosterone system is greater, leading to better compensated hemodynamics in the midluteal phase (MLP) than in the early follicular phase of the menstrual cycle. Ten POTS women and 11 healthy women (controls) consumed a constant diet 3 days before testing. Hemodynamics and renal-adrenal hormones were measured while supine and during 2-hour standing. We found that blood pressure was similar, heart rate and total peripheral resistance were greater, and cardiac output and stroke volume were lower in POTS subjects than in controls during 2-hour standing. In controls, hemodynamic parameters were indistinguishable between menstrual phases. In POTS subjects, cardiac output and stroke volume were lower and total peripheral resistance was greater in the early follicular phase than MLP after 30 minutes of standing; however, blood pressure and heart rate were similar between phases. Plasma renin activity (9Ϯ6 [SD] versus 13Ϯ9 ng/mL per hour; Pϭ0.04) and aldosterone (43Ϯ22 versus 55Ϯ25 ng/dL; Pϭ0.02) were lower in the early follicular phase than MLP in POTS subjects after 2 hours of standing. Catecholamine responses were similar between phases. The percentage rate of subjects having presyncope was greater in the early follicular phase than MLP for both groups ( 2 PϽ0.01). These results suggest that the menstrual cycle modulates the renin-angiotensin-aldosterone system and affects hemodynamics during orthostasis in POTS. The high estrogen and progesterone in the MLP are associated with greater increases in renal-adrenal hormones and presumably more volume retention, which improve late-standing tolerance in these patients. (Hypertension. 2010;56:82-90.) Key Words: orthostatic intolerance Ⅲ renin-angiotensin-aldosterone system Ⅲ hemodynamics Ⅲ sex hormones P atients with the postural orthostatic tachycardia syndrome (POTS; also called chronic orthostatic intolerance) are unable to stand or remain upright for prolonged periods of time because of intolerable palpitations, light-headedness, weakness, or near-syncope. This disorder affects Ϸ500 000 Americans, 1 the majority of whom are young women. Severely affected patients are unable to work, attend school, or participate in recreational activities, resulting in substantial morbidity. However, the underlying pathophysiology remains unclear. It has been proposed that the mechanisms for POTS are heterogeneous. 2 We found recently that, as a group, patients with POTS have a small heart coupled with reduced blood and plasma volume, which contributes to a small stroke volume, ultimately resulting in reflex tachycardia during orthostasis. 3 The renin-angiotensin-aldosterone system (RAAS) plays an important role in the neurohumoral regulation of plasma volume and hemodynamic homeostasis in humans, especially during long-term orthostasis. 4 Despite its importance in ar...

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-tobeat 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.

Patients with the postural orthostatic tachycardia syndrome (POTS) are primarily premenopausal women, which may be attributed to female sex hormones. We tested the hypothesis that hormonal fluctuations of the menstrual cycle alter sympathetic neural activity and orthostatic tolerance in POTS women. Ten POTS women were studied during the early follicular (EF) and mid-luteal (ML) phases of the menstrual cycle. Haemodynamics and muscle sympathetic nerve activity (MSNA) were measured when supine, during 60 deg upright tilt for 45 min or until presyncope, and during the cold pressor test (CPT) and Valsalva manoeuvres. Blood pressure and total peripheral resistance were higher during rest and tilting in the ML than EF phase; however, heart rate, stroke volume and cardiac output were similar between phases. There were no mean ± SD differences in MSNA burst frequency (8 ± 8 EF phase vs. 10 ± 10 bursts min(-1) ML phase at rest; 34 ± 15 EF phase vs. 36 ± 16 bursts min(-1) ML phase at 5 min tilt), burst incidence or total activity, nor any differences in the cardiovagal and sympathetic baroreflex sensitivities between phases under any condition. The incidence of presyncope was also the same between phases. There were no differences in haemodynamic or sympathetic responses to CPT or Valsalva. These results suggest that the menstrual cycle does not affect sympathetic neural activity but modulates blood pressure and vasoconstriction in POTS women during tilting. Thus, factors other than sympathetic neural activity are probably responsible for the symptoms of orthostatic intolerance across the menstrual cycle in women with POTS.

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