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 past decade 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 Gulf War 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. With these extensive and ongoing conflicts, and the tremendous deleterious mental health and socioeconomic impact of PTSD, research to understand and treat all aspects of PTSD is vitally important. One less recognized but highly significant consequence of PTSD is an increased risk of hypertension, cardiovascular (CV) disease, and its risk factors. One mechanism likely underlying increased CV risk in PTSD is chronic overactivation of the sympathetic nervous system (SNS). SNS overactivity leads to increased CV risk by increasing blood pressure (BP), and also via BP-independent effects including vascular inflammation, insulin resistance, and myocardial fibrosis. Chronic inflammation is likely a key culprit contributing to SNS overactivation and blunted baroreflex sensitivity (BRS) in PTSD. In Objective 1 of this study, the researchers will ascertain that humans with PTSD have chronic overactivation of muscle sympathetic nerve activity (MSNA), blunted BRS, and elevated inflammation both at rest and during mental stress. In addition to chronic inflammation, trauma-related stress is known to activate the renin-angiotensin system (RAS) leading to higher brain angiotensin II (ATII) that is an important mediator of brain inflammation and has a direct sympathoexcitatory effect. Previous studies in both animals and humans with a variety of chronic diseases such as obesity, heart failure, and chronic kidney disease, have shown that blockade of the ATII receptor using angiotensin receptor blockers (ARBs) reduces SNS activity and improves BRS. The extent to which ARB treatment influences SNS activation, BRS, and inflammation in PTSD patients remains unknown. Currently, peripheral sympatholytics such as β-blockers and α-blockers are often prescribed for PTSD symptoms; however, treatment is often complicated by adverse effects including hypotension, orthostasis, fatigue, and erectile dysfunction. In addition, these peripheral sympatholytics cause a reflex increase in central sympathetic output as evidenced by increased MSNA; therefore, these medications may actually contribute to increased CV risk in PTSD. As opposed to peripheral sympatholytics, losartan is well tolerated, without metabolic side effects, and reduces central SNS activation which has potential to impact future CV risk. Vagal nerve stimulation has been shown in both animal and human studies to safely and effectively reduce sympathetic activity and inflammation. tVNS is a noninvasive method that involves placing a device over the skin overlying the vagus nerve on the neck. The device delivers mild electrical stimulation, using transcutaneous electrical nerve stimulation (TENS) unit. Prior studies have shown that transcutaneous vagal nerve stimulation safely and effectively reduced muscle sympathetic nerve activity in healthy humans and improved heart rate variability, indicating a decrease in sympathetic nervous system (SNS) activity, and a shift in cardiac autonomic function toward parasympathetic (PNS) predominance. Another study, found that tVNS acutely improved cardiac baroreflex sensitivity. Since PTSD patients have high SNS, low PNS activity and impaired baroreflex sensitivity, tVNS may be one safe and noninvasive method of improving autonomic function in this patient population. The researchers will test whether tVNS leads to both an acute and sustained improvement in SNS function in PTSD. Study Objective 2 evaluates the clinical utility of losartan treatment on autonomic control in humans with PTSD. Participants with PTSD will be randomized to treatment with the ARB losartan (25 mg daily) versus the comparison drug atenolol (25 mg daily) for 8-14 weeks. Alternatively, participants with PTSD may be randomized to treatment with tVNS versus sham-tVNS for 8-14 weeks