Mechanisms of Sympathetic Overactivity in Post-traumatic Stress Disorder

创伤后应激障碍（PTSD）是一种非常普遍且使人衰弱的心理健康疾病

Post-traumatic stress disorder (PTSD) is a highly prevalent and debilitating mental health disorder that is independently associated with an increased risk of cardiovascular (CV) disease and hypertension. Given the large numbers of post-9/11 Veterans afflicted with PTSD, addressing this under-recognized but highly significant consequence of PTSD is of paramount importance to protect the future health of these young Veterans. We have shown that post-9/11 Veterans with PTSD have overactivation of the sympathetic nervous system (SNS) during mental stress and impaired arterial baroreflex sensitivity (BRS) that could contribute to the pathogenesis of hypertension and CV disease in these patients. While we have now established that central sympathetic output is augmented in PTSD, the downstream effects of SNS output on blood pressure (BP) regulation in PTSD remain unknown and is a major goal of this proposal. We hypothesize that augmented sympathetic nerve activity in PTSD leads to augmented SNS-mediated vasoconstriction within the kidney, an organ with a critical role in BP regulation. Exaggerated increases in sympathetically mediated renal vasoconstriction could perpetuate sustained increases in BP over time via renal sodium reabsorption and activation of the renin-angiotensin system (RAS). To test this hypothesis, we will measure renal blood flow velocity using Doppler ultrasound, continuous hemodynamics, muscle sympathetic nerve activity (MSNA) using microneurography, plasma renin activity and inflammatory biomarkers at rest and during mental stress in post 9/11 Veterans and matched controls. We further hypothesize that SNS activation leads to an exaggerated vasoconstrictive response (i.e. heightened neurovascular transduction of SNS activity) mediated by abnormal vascular adrenergic receptor sensitivity in PTSD. To test this hypothesis, we will determine vascular alpha-1 adrenergic receptor (α1AR) sensitivity by measuring vasoconstriction in response to exponentially increasing doses of the selective α1AR agonist phenylephrine using a linear variable differential transformer in PTSD and controls. Finally, prior studies have shown that transcutaneous vagus nerve stimulation (tVNS) reduces SNS activity, improves BRS, and lowers inflammation in healthy humans and a number of chronic diseases; however, the potential benefits of tVNS on SNS function and regulation in PTSD have never previously been investigated. We hypothesize that tVNS acutely lowers SNS activity and improves sympathetic and cardiovagal BRS in PTSD. To test this hypothesis, we will measure MSNA, EKG, hemodynamics, inflammation, and BRS using pharmacologic manipulation of BP at rest and during tVNS (versus sham stimulation) in PTSD patients. tVNS could be a novel nonpharmacologic approach to reducing SNS activity and restoring BRS in these patients. Improving SNS overactivity and BRS may have long term benefits on reducing CV risk in PTSD patients.