Abnormalities of angiotensin regulation in postural tachycardia syndrome

Abstract

Background: Postural tachycardia syndrome (POTS) is a disorder characterized by excessive orthostatic tachycardia and significant functional disability. We previously reported that POTS patients have low blood volume and inappropriately low plasma renin activity (PRA) and aldosterone. In this study, we sought to more fully characterize the renin-angiotensin-aldosterone system (RAAS) to gain a better understanding of the pathophysiology of POTS.

Objective: The purpose of this study was to prospectively assess the plasma levels of angiotensin (Ang) peptides and their relationship to other RAAS components in patients with POTS compared with healthy controls.

Methods: Heart rate, PRA, Ang I, Ang II, Ang (1-7), and aldosterone were measured in POTS patients (n = 38) and healthy controls (n = 13) while they were consuming a sodium-controlled diet.

Results: POTS patients had larger orthostatic increases in heart rate than did controls (52 ± 3 [mean ± SEM] bpm vs 27 ± 6 bpm, P = .001). Plasma Ang II was significantly higher in POTS patients (43 ± 3 pg/mL vs 28 ± 3 pg/mL, P = .006), whereas plasma Ang I and angiotensin 1-7 [Ang-(1-7)] were similar between groups. Despite the twofold increase of Ang II, POTS patients trended to lower PRA levels than did controls (0.9 ± 0.1 ng/mL/h vs 1.6 ± 0.5 ng/mL/h, P = .268) and lower aldosterone levels (4.6 ± 0.8 pg/mL vs 10.0 ± 3.0 pg/mL, P = .111). Estimated angiotensin-converting enzyme-2 (ACE2) activity was significantly lower in POTS patients than in controls (0.25 ± 0.02 vs 0.33 ± 0.03, P = .038).

Conclusion: Some patients with POTS have inappropriately high plasma Ang II levels, with low estimated ACE2 activity. We propose that these abnormalities in Ang regulation may play a key role in the pathophysiology of POTS in some patients.

Trial registration: ClinicalTrials.gov NCT00608725.

Figure 1

Plasma levels of angiotensin (Ang) peptides (pg/ml) including Ang I (Panel A), Ang II (Panel B), Ang-(1–7) (Panel C) and angiotensin converting enzyme 2 (ACE2; Panel D) activity for patients with POTS and healthy control subjects. ACE2 activity was estimated as the Ang-(1–7):Ang II ratio. Note that estimated ACE2 activity is reduced in POTS, which may explain the elevated Ang II levels.

Figure 2

Schematic diagram of the renin-angiotensin-aldosterone (RAAS) system profile in healthy individuals (TOP) and the proposed RAAS profile in patients with POTS (Bottom). Vertical arrows indicate up- or down-regulation of RAAS components. Patients with POTS have high levels of Ang II despite low levels of PRA. The high Ang II might be due to low ACE2 activity with decreased clearance. Despite the high Ang II levels, however, this aldosterone levels are low in the patients with POTS. AGT = angiotensinogen; PRA = plasma renin activity; ACE = angiotensin converting enzyme; ACE2 = angiotensin converting enzyme 2; Ang = angiotensin; AT1R = angiotensin receptor type 1.