Role of Sympathetic Overactivity and Angiotensin II in PTSD and CV

Study Overview
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Brief Summary
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The purpose of this study is to find out why patients with post-traumatic stress disorder (PTSD) have an increased risk for heart disease and high blood pressure later in life. A second purpose is to find out what causes PTSD patients to have high adrenaline levels during stress. This study will also test if a medicine called losartan improves high adrenaline levels in patients with PTSD and if a certain gene that has to do with high blood pressure might be associated with high adrenaline levels.

Detailed Description
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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. Study Objective 2 evaluates the clinical utility of losartan treatment on autonomic control in humans with PTSD. 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 showb 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.

Official Title
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Post-Traumatic Stress Disorder and Cardiovascular Disease Risk: Role of Sympathetic Overactivity and Angiotensin II

Conditions
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Stress Disorders, Post-Traumatic

Intervention / Treatment
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* Procedure: Microneurography
* Behavioral: Combat virtual reality video clip
* Procedure: Handgrip Exercise
* Procedure: Cold Pressor Test (CPT)
* Drug: Sodium Nitroprusside (SNP)
* Drug: Phenylephrine
* Drug: Losartan
* Drug: Atenolol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: veterans ages 18-65 years old with PTSD and without PTSD (controls) matched for age, gender, and race. Exclusion Criteria: pregnancy hypertension diabetes heart or vascular disease illicit drug use excessive alcohol use (>2 drinks per day) hyperlipidemia autonomic dysfunction current treatment with clonidine, beta blockers, angiotensin-converting-enzyme (ACE) inhibitors, or angiotensin II receptor blockers (ARBs) treatment with monoamine oxidase (MAO) inhibitors within the last 14 days any serious systemic disease chronic kidney disease defined as estimated glomerular filtration rate (GFR) < 60 cc/min hyperkalemia (serum potassium > 5 meq/dL) systolic blood pressure < 100 mm Hg diastolic blood pressure < 60 mm Hg heart rate < 50 beats/min known hypersensitivity to ARBs or beta blockers

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Veterans<br>Subjects with post-traumatic stress disorder (PTSD) will be evaluated using microneurography, static handgrip exercise, cold pressor test, combat virtual reality video clip, and baroreflex sensitivity using sodium nitroprusside and phenylephrine. For the second phase, they will be randomized to either losartan or atenolol. | Procedure: Microneurography<br>* Skin will be stimulated with a pencil-shaped electrode to find a certain nerve. Once the nerve is found, two tiny sterile wire needles (about the size of acupuncture needles) will be put in the skin. One needle is put just under the skin at a short distance away from the nerve, and the other one into the nerve. The needles are attached to a computer recorder to record the nerve activity. It may take up to one hour to get the needles in the right place. After the tiny needle is in the right place, investigators record nerve activity at rest for about 10 minutes. Then, it will be recorded throughout the rest of the visit (up to 4 hours).<br>Behavioral: Combat virtual reality video clip<br>* Subjects will watch a video clip of combat on a computer screen or wearing video goggles.<br>Procedure: Handgrip Exercise<br>* Subjects will squeeze a hand dynamometer intermittently.<br>Procedure: Cold Pressor Test (CPT)<br>* Subjects' hand will be submerged in cold water ( 0-1°C) up to the wrist for 1 minute.<br>Drug: Sodium Nitroprusside (SNP)<br>* Subjects will receive sodium nitroprusside 100 µg, which is bolused through an antecubital intravenous catheter.<br>* Other names: Nitropress;Drug: Phenylephrine<br>* Subjects will receive phenylephrine 150 µg, which is bolused through an antecubital intravenous catheter 60 seconds after the sodium nitroprusside bolus<br>Drug: Losartan<br>* Subjects will receive Losartan 25 mg once a day orally up to 12 weeks<br>* Other names: Cozaar;Drug: Atenolol<br>* Subjects will receive Atenolol 25 mg once a day orally up to 12 weeks<br>* Other names: Tenormin;|
| Experimental: Control<br>Healthy controls will be evaluated using microneurography, static handgrip exercise, cold pressor test, combat virtual reality video clip, and baroreflex sensitivity using sodium nitroprusside and phenylephrine. | Procedure: Microneurography<br>* Skin will be stimulated with a pencil-shaped electrode to find a certain nerve. Once the nerve is found, two tiny sterile wire needles (about the size of acupuncture needles) will be put in the skin. One needle is put just under the skin at a short distance away from the nerve, and the other one into the nerve. The needles are attached to a computer recorder to record the nerve activity. It may take up to one hour to get the needles in the right place. After the tiny needle is in the right place, investigators record nerve activity at rest for about 10 minutes. Then, it will be recorded throughout the rest of the visit (up to 4 hours).<br>Behavioral: Combat virtual reality video clip<br>* Subjects will watch a video clip of combat on a computer screen or wearing video goggles.<br>Procedure: Handgrip Exercise<br>* Subjects will squeeze a hand dynamometer intermittently.<br>Procedure: Cold Pressor Test (CPT)<br>* Subjects' hand will be submerged in cold water ( 0-1°C) up to the wrist for 1 minute.<br>Drug: Sodium Nitroprusside (SNP)<br>* Subjects will receive sodium nitroprusside 100 µg, which is bolused through an antecubital intravenous catheter.<br>* Other names: Nitropress;Drug: Phenylephrine<br>* Subjects will receive phenylephrine 150 µg, which is bolused through an antecubital intravenous catheter 60 seconds after the sodium nitroprusside bolus<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Muscle sympathetic nerve activity at rest and during mental stress |  | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Baroreflex sensitivity (BRS) at rest and during mental stress |  | 12 weeks | 
| Change in inflammatory biomarkers | Inflammatory biomarkers will be assessed using standard assays. | 12 weeks | 
| Change in Blood Pressure |  | 12 weeks | 
| Change in PTSD symptoms |  | 12 weeks |