Role of Sympathetic Overactivity and Angiotensin II in PTSD and CV
NCT ID: NCT02560805
Last Updated: 2025-03-05
Study Results
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Basic Information
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SUSPENDED
PHASE2
134 participants
INTERVENTIONAL
2015-10-31
2026-02-28
Brief Summary
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Detailed Description
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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
Conditions
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Study Design
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RANDOMIZED
PARALLEL
PREVENTION
DOUBLE
Study Groups
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Veterans with Post-traumatic Stress Disorder (PTSD)
For examining Objective 1 of this study, participants 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.
Microneurography
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).
Combat virtual reality video clip
Subjects will watch a video clip of combat on a computer screen or wearing video goggles.
Handgrip Exercise
Subjects will squeeze a hand dynamometer intermittently.
Cold Pressor Test (CPT)
Subjects' hand will be submerged in cold water (\~0-1°C) up to the wrist for 1 minute.
Sodium Nitroprusside (SNP)
Subjects will receive sodium nitroprusside 100 µg, which is bolused through an antecubital intravenous catheter.
Phenylephrine
Subjects will receive phenylephrine 150 µg, which is bolused through an antecubital intravenous catheter 60 seconds after the sodium nitroprusside bolus
Control
For examining Objective 1 of this study, 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.
Microneurography
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).
Combat virtual reality video clip
Subjects will watch a video clip of combat on a computer screen or wearing video goggles.
Handgrip Exercise
Subjects will squeeze a hand dynamometer intermittently.
Cold Pressor Test (CPT)
Subjects' hand will be submerged in cold water (\~0-1°C) up to the wrist for 1 minute.
Sodium Nitroprusside (SNP)
Subjects will receive sodium nitroprusside 100 µg, which is bolused through an antecubital intravenous catheter.
Phenylephrine
Subjects will receive phenylephrine 150 µg, which is bolused through an antecubital intravenous catheter 60 seconds after the sodium nitroprusside bolus
Losartan
Participants with PTSD randomized to receive losartan for 8 to 14 weeks.
Losartan
Losartan will be administered as 25 mg taken orally, once a day for to 8 to 14 weeks.
Atenolol
Participants with PTSD randomized to receive atenolol for 8 to 14 weeks.
Atenolol
Atenolol will be administered as 25 mg taken orally, once a day for to 8 to 14 weeks.
Transcutaneous Vagal Nerve Stimulation (tVNS)
Participants with PTSD randomized to receive treatment with tVNS for 8 to 14 weeks.
Transcutaneous Vagal Nerve Stimulation (tVNS)
Transcutaneous vagal nerve stimulation (tVNS) is administered using the gammaCore (ElectroCore) TENS device. The gammaCore device is a multi-use, hand-held, rechargeable portable device consisting of a rechargeable battery, signal generating and amplifying electronics, and two buttons to power on the device and for operator control of the stimulation intensity (range 0-40). A small amount of conductive gel is applied to the pair of stainless steel round discs on the device are placed vertically on the skin with the gel. The stimulation is increased until there is a strong vibration and slight muscle contraction in the lower face or neck (usual intensity 15-25). Then the dose is delivered for 2 minutes on the left side of the neck, and on the right side of the neck, for a total of 4 minutes of treatment. Participants will be instructed on the usage of the device and will self-administer up to 4 treatments twice per day.
Sham Transcutaneous Vagal Nerve Stimulation (tVNS)
Participants with PTSD randomized to receive treatment with sham-tVNS for 8 to 14 weeks.
Sham Transcutaneous Vagal Nerve Stimulation (tVNS)
A sham device that is identical to the gammaCore device will be provided to participants. Participants will be instructed on the usage of the device and will self-administer up to 4 treatments twice per day.
Interventions
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Microneurography
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).
Combat virtual reality video clip
Subjects will watch a video clip of combat on a computer screen or wearing video goggles.
Handgrip Exercise
Subjects will squeeze a hand dynamometer intermittently.
Cold Pressor Test (CPT)
Subjects' hand will be submerged in cold water (\~0-1°C) up to the wrist for 1 minute.
Sodium Nitroprusside (SNP)
Subjects will receive sodium nitroprusside 100 µg, which is bolused through an antecubital intravenous catheter.
Phenylephrine
Subjects will receive phenylephrine 150 µg, which is bolused through an antecubital intravenous catheter 60 seconds after the sodium nitroprusside bolus
Losartan
Losartan will be administered as 25 mg taken orally, once a day for to 8 to 14 weeks.
Atenolol
Atenolol will be administered as 25 mg taken orally, once a day for to 8 to 14 weeks.
Transcutaneous Vagal Nerve Stimulation (tVNS)
Transcutaneous vagal nerve stimulation (tVNS) is administered using the gammaCore (ElectroCore) TENS device. The gammaCore device is a multi-use, hand-held, rechargeable portable device consisting of a rechargeable battery, signal generating and amplifying electronics, and two buttons to power on the device and for operator control of the stimulation intensity (range 0-40). A small amount of conductive gel is applied to the pair of stainless steel round discs on the device are placed vertically on the skin with the gel. The stimulation is increased until there is a strong vibration and slight muscle contraction in the lower face or neck (usual intensity 15-25). Then the dose is delivered for 2 minutes on the left side of the neck, and on the right side of the neck, for a total of 4 minutes of treatment. Participants will be instructed on the usage of the device and will self-administer up to 4 treatments twice per day.
Sham Transcutaneous Vagal Nerve Stimulation (tVNS)
A sham device that is identical to the gammaCore device will be provided to participants. Participants will be instructed on the usage of the device and will self-administer up to 4 treatments twice per day.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
Exclusion Criteria
* 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
18 Years
65 Years
ALL
Yes
Sponsors
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American Heart Association
OTHER
Emory University
OTHER
Responsible Party
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Jeanie Park
Associate Professor
Principal Investigators
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Jeanie Park, MD
Role: PRINCIPAL_INVESTIGATOR
Emory University
Locations
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Atlanta VA Medical Center
Decatur, Georgia, United States
Countries
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Other Identifiers
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IRB00082400
Identifier Type: -
Identifier Source: org_study_id
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