Role of Sympathetic Overactivity and Angiotensin II in PTSD and CV

More than 2,000,000 soldiers have been deployed to Iraq and Afghanistan in the pastdecade as part of Operation Enduring Freedom/ Operation Iraqi Freedom/ Operation New Dawn(OEF/OIF/OND), and are returning with high rates of post‐traumatic stress disorder(PTSD). The prevalence of PTSD in OEF/OIF/OND veterans is estimated at around 11.5‐19.9%post deployment, with prevalence rates of 12.1% and 30.9% in older veterans from the GulfWar and Vietnam era, respectively. PTSD is also common in the general population, as 7%of the US population will meet the diagnostic criteria for PTSD in their lifetime. Withthese extensive and ongoing conflicts, and the tremendous deleterious mental health andsocioeconomic impact of PTSD, research to understand and treat all aspects of PTSD isvitally important.One less recognized but highly significant consequence of PTSD is an increased risk ofhypertension, cardiovascular (CV) disease, and its risk factors. One mechanism likelyunderlying increased CV risk in PTSD is chronic overactivation of the sympathetic nervoussystem (SNS). SNS overactivity leads to increased CV risk by increasing blood pressure(BP), and also via BP‐independent effects including vascular inflammation, insulinresistance, and myocardial fibrosis.Chronic inflammation is likely a key culprit contributing to SNS overactivation andblunted baroreflex sensitivity (BRS) in PTSD. In Objective 1 of this study, theresearchers will ascertain that humans with PTSD have chronic overactivation of musclesympathetic nerve activity (MSNA), blunted BRS, and elevated inflammation both at restand during mental stress.In addition to chronic inflammation, trauma‐related stress is known to activate therenin‐angiotensin system (RAS) leading to higher brain angiotensin II (ATII) that is animportant mediator of brain inflammation and has a direct sympathoexcitatory effect.Previous studies in both animals and humans with a variety of chronic diseases such asobesity, heart failure, and chronic kidney disease, have shown that blockade of the ATIIreceptor using angiotensin receptor blockers (ARBs) reduces SNS activity and improvesBRS. The extent to which ARB treatment influences SNS activation, BRS, and inflammationin PTSD patients remains unknown. Currently, peripheral sympatholytics such as β‐blockersand α‐blockers are often prescribed for PTSD symptoms; however, treatment is oftencomplicated by adverse effects including hypotension, orthostasis, fatigue, and erectiledysfunction. In addition, these peripheral sympatholytics cause a reflex increase incentral sympathetic output as evidenced by increased MSNA; therefore, these medicationsmay actually contribute to increased CV risk in PTSD. As opposed to peripheralsympatholytics, losartan is well tolerated, without metabolic side effects, and reducescentral SNS activation which has potential to impact future CV risk.Vagal nerve stimulation has been shown in both animal and human studies to safely andeffectively reduce sympathetic activity and inflammation. tVNS is a noninvasive methodthat involves placing a device over the skin overlying the vagus nerve on the neck. Thedevice delivers mild electrical stimulation, using transcutaneous electrical nervestimulation (TENS) unit. Prior studies have shown that transcutaneous vagal nervestimulation safely and effectively reduced muscle sympathetic nerve activity in healthyhumans and improved heart rate variability, indicating a decrease in sympathetic nervoussystem (SNS) activity, and a shift in cardiac autonomic function toward parasympathetic(PNS) predominance. Another study, found that tVNS acutely improved cardiac baroreflexsensitivity. Since PTSD patients have high SNS, low PNS activity and impaired baroreflexsensitivity, tVNS may be one safe and noninvasive method of improving autonomic functionin this patient population. The researchers will test whether tVNS leads to both an acuteand sustained improvement in SNS function in PTSD.Study Objective 2 evaluates the clinical utility of losartan treatment on autonomiccontrol in humans with PTSD. Participants with PTSD will be randomized to treatment withthe ARB losartan (25 mg daily) versus the comparison drug atenolol (25 mg daily) for 8‐14weeks. Alternatively, participants with PTSD may be randomized to treatment with tVNSversus sham‐tVNS for 8‐14 weeks