- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02560805
Role of Sympathetic Overactivity and Angiotensin II in PTSD and CV (ANG-P)
Post-Traumatic Stress Disorder and Cardiovascular Disease Risk: Role of Sympathetic Overactivity and Angiotensin II
Study Overview
Status
Conditions
Detailed Description
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.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Georgia
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Decatur, Georgia, United States, 30033
- Atlanta VA Medical Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Veterans
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.
|
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).
Subjects will watch a video clip of combat on a computer screen or wearing video goggles.
Subjects will squeeze a hand dynamometer intermittently.
Subjects' hand will be submerged in cold water (~0-1°C) up to the wrist for 1 minute.
Subjects will receive sodium nitroprusside 100 µg, which is bolused through an antecubital intravenous catheter.
Other Names:
Subjects will receive phenylephrine 150 µg, which is bolused through an antecubital intravenous catheter 60 seconds after the sodium nitroprusside bolus
Subjects will receive Losartan 25 mg once a day orally up to 12 weeks
Other Names:
Subjects will receive Atenolol 25 mg once a day orally up to 12 weeks
Other Names:
|
Experimental: Control
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.
|
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).
Subjects will watch a video clip of combat on a computer screen or wearing video goggles.
Subjects will squeeze a hand dynamometer intermittently.
Subjects' hand will be submerged in cold water (~0-1°C) up to the wrist for 1 minute.
Subjects will receive sodium nitroprusside 100 µg, which is bolused through an antecubital intravenous catheter.
Other Names:
Subjects will receive phenylephrine 150 µg, which is bolused through an antecubital intravenous catheter 60 seconds after the sodium nitroprusside bolus
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Muscle sympathetic nerve activity at rest and during mental stress
Time Frame: 12 weeks
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12 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Baroreflex sensitivity (BRS) at rest and during mental stress
Time Frame: 12 weeks
|
12 weeks
|
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Change in inflammatory biomarkers
Time Frame: 12 weeks
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Inflammatory biomarkers will be assessed using standard assays.
|
12 weeks
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Change in Blood Pressure
Time Frame: 12 weeks
|
12 weeks
|
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Change in PTSD symptoms
Time Frame: 12 weeks
|
12 weeks
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Jeanie Park, MD, Emory University
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Mental Disorders
- Trauma and Stressor Related Disorders
- Stress Disorders, Traumatic
- Stress Disorders, Post-Traumatic
- Physiological Effects of Drugs
- Adrenergic beta-Antagonists
- Adrenergic Antagonists
- Adrenergic Agents
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Anti-Arrhythmia Agents
- Antihypertensive Agents
- Vasodilator Agents
- Autonomic Agents
- Peripheral Nervous System Agents
- Protective Agents
- Adrenergic alpha-Agonists
- Adrenergic Agonists
- Cardiotonic Agents
- Respiratory System Agents
- Angiotensin II Type 1 Receptor Blockers
- Angiotensin Receptor Antagonists
- Sympathomimetics
- Sympatholytics
- Adrenergic beta-1 Receptor Antagonists
- Vasoconstrictor Agents
- Mydriatics
- Nitric Oxide Donors
- Nasal Decongestants
- Adrenergic alpha-1 Receptor Agonists
- Losartan
- Phenylephrine
- Oxymetazoline
- Atenolol
- Nitroprusside
Other Study ID Numbers
- IRB00082400
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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