Baroreflex dysfunction and augmented sympathetic nerve responses during mental stress in veterans with post-traumatic stress disorder

Abstract

Key points: Patients with post-traumatic stress disorder (PTSD) are at a significantly higher risk of developing hypertension and cardiovascular disease. The mechanisms underlying this increased risk are not known. Studies have suggested that PTSD patients have an overactive sympathetic nervous system (SNS) that could contribute to cardiovascular risk; however, sympathetic function has not previously been rigorously evaluated in PTSD patients. Using direct measurements of sympathetic nerve activity and pharmacological manipulation of blood pressure, we show that veterans with PTSD have augmented SNS and haemodynamic reactivity during both combat-related and non-combat related mental stress, impaired sympathetic and cardiovagal baroreflex sensitivity, and increased inflammation. Identifying the mechanisms contributing to increased cardiovascular (CV) risk in PTSD will pave the way for developing interventions to improve sympathetic function and reduce CV risk in these patients.

Abstract: Post-traumatic stress disorder (PTSD) is associated with increased cardiovascular (CV) risk. We tested the hypothesis that PTSD patients have augmented sympathetic nervous system (SNS) and haemodynamic reactivity during mental stress, as well as impaired arterial baroreflex sensitivity (BRS). Fourteen otherwise healthy Veterans with combat-related PTSD were compared with 14 matched Controls without PTSD. Muscle sympathetic nerve activity (MSNA), continuous blood pressure (BP) and electrocardiography were measured at baseline, as well as during two types of mental stress: combat-related mental stress using virtual reality combat exposure (VRCE) and non-combat related stress using mental arithmetic (MA). A cold pressor test (CPT) was administered for comparison. BRS was tested using pharmacological manipulation of BP via the Modified Oxford technique at rest and during VRCE. Blood samples were analysed for inflammatory biomarkers. Baseline characteristics, MSNA and haemodynamics were similar between the groups. In PTSD vs. Controls, MSNA (+8.2 ± 1.0 vs. +1.2 ± 1.3 bursts min-1 , P < 0.001) and heart rate responses (+3.2 ± 1.1 vs. -2.3 ± 1.0 beats min-1 , P = 0.003) were significantly augmented during VRCE. Similarly, in PTSD vs. Controls, MSNA (+21.0 ± 2.6 vs. +6.7 ± 1.5 bursts min-1 , P < 0.001) and diastolic BP responses (+6.3 ± 1.0 vs. +3.5 ± 1.0 mmHg, P = 0.011) were significantly augmented during MA but not during CPT (P = not significant). In the PTSD group, sympathetic BRS (-1.2 ± 0.2 vs. -2.0 ± 0.3 burst incidence mmHg-1 , P = 0.026) and cardiovagal BRS (9.5 ± 1.4 vs. 23.6 ± 4.3 ms mmHg-1 , P = 0.008) were significantly blunted at rest. PTSD patients had significantly higher highly sensitive-C-reactive protein levels compared to Controls (2.1 ± 0.4 vs. 1.0 ± 0.3 mg L-1 , P = 0.047). Augmented SNS and haemodynamic responses to mental stress, blunted BRS and inflammation may contribute to an increased CV risk in PTSD.

Keywords: arterial baroreflex; blood pressure; inflammation; stress; sympathetic activity.

© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Figures

Figure 1. Hemodynamic and sympathetic reactivity during virtual reality combat exposure

Change in SBP (A), DBP (B), mean arterial pressure (MAP) (c), heart rate (HR) (D), muscle sympathetic nerve activity (MSNA) quantified as burst frequency (bursts/min) (E) and total activity (AU/min) (F) during 3 min of virtual reality combat exposure in PTSD patients (filled circles) and Controls (open circles). *P < 0.05 between PTSD and Control groups.

Figure 2. Hemodynamic and sympathetic reactivity during mental arithmetic

Change in SBP (A), DBP (B), MAP (C), HR (D), MSNA quantified as burst frequency (bursts min–1) (E) and total activity (AU min–1) (F) during 3 min of mental arithmetic in PTSD patients (filled circles) and Controls (open circles). *P < 0.05 between PTSD and Control groups.

Figure 3. Hemodynamic and sympathetic reactivity during the cold pressor test

Change in MSNA quantified as burst frequency (bursts min–1) (A) and total activity (AU min–1) (B), MAP (C) and HR (D) during 1 min of CPT in PTSD patients vs. Controls.

Figure 4. Sympathetic and cardiovagal baroreflex sensitivity at rest

The linear relationships between diastolic blood pressure and MSNA burst incidence (A) and between SBP and R‐R interval (RRI) (C) are shown at rest and were derived from the mean slope values from individual linear regressions performed during baroreflex testing in PTSD (continuous line) vs. Controls (dashed line). The mean slope of the individual linear regressions between DBP and MSNA represents mean sympathetic BRS and was significantly less steep in PTSD [−1.2 ± 0.2 bursts (100 heart beats)–1 mmHg–1; R2 = 0.77 ± 0.02] vs. Controls [−2.0 ± 0.3 bursts (100 heart beats)–1 mmHg–1; R2 = 0.85 ± 0.02; P = 0.026] (A and B). The mean slope of the individual linear regressions between systolic blood pressure and RRI represents mean cardiovagal BRS and was significantly less steep in PTSD (9.5 ± 1.4 ms mmHg–1; R2 = 0.74 ± 0.02) vs. Controls (23.6 ± 4.3 ms mmHg−1; R2 = 0.75 ± 0.02; P = 0.008) (C and D). The operating point around which the baroreflex operates is derived from baseline measures and signified by the closed circles (PTSD) and open circles (Controls). *P < 0.05 between PTSD and Control groups.

Figure 5. Sympathetic and cardiovagal baroreflex sensitivity during virtual reality combat exposure

The linear relationship between diastolic blood pressure (DSB) and MSNA burst incidence (A) and between systolic blood pressure and R‐R interval (RRI) (C) are shown during concomitant VRCE, and were derived from the mean slope values from individual linear regressions performed during baroreflex testing in PTSD (continuous line) vs. Controls (dashed line). There was no significant difference between the groups in the mean slope of the individual linear regressions between DBP and MSNA that represents mean sympathetic BRS (A and B). The mean slope of the individual linear regressions between systolic blood pressure and RRI represents cardiovagal BRS and was significantly less steep in PTSD (9.3 ± 1.9 ms mmHg–1; R2 = 0.75 ± 0.02) vs. Controls (22.4 ± 4.3 ms mmHg–1; R2 = 0.75 ± 0.03; P = 0.014) (C and D). The operating point around which the baroreflex operates is signified by the closed circles (PTSD) and open circles (Controls). *P < 0.05 between PTSD and Control groups.

Figure 6. Inflammatory biomarkers

Highly sensitivity hsCRP (A), interleukin 2 (IL‐2) (B) and interleukin 6 (IL‐6) and (C) levels in PTSD patients vs. Controls. *P < 0.05 between PTSD and Control groups.