Post-Traumatic Stress Disorder and Cardiovascular Disease Risk: Role of Sympathetic Overactivity and Angiotensin II
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 134
- 试验地点
- 2
- 主要终点
- Change in Muscle Sympathetic Nerve Activity (MSNA)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •veterans ages 18-65 years old with PTSD and without PTSD (controls) matched for age, gender, and race.
排除标准
- •pregnancy
- •hypertension
- •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
研究组 & 干预措施
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.
干预措施: Combat virtual reality video clip (Behavioral)
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.
干预措施: Combat virtual reality video clip (Behavioral)
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.
干预措施: Microneurography (Procedure)
Sham Transcutaneous Vagal Nerve Stimulation (tVNS)
Participants with PTSD randomized to receive treatment with sham-tVNS for 8 to 14 weeks.
干预措施: Sham Transcutaneous Vagal Nerve Stimulation (tVNS) (Device)
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.
干预措施: Handgrip Exercise (Procedure)
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.
干预措施: Cold Pressor Test (CPT) (Procedure)
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.
干预措施: Microneurography (Procedure)
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.
干预措施: Handgrip Exercise (Procedure)
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.
干预措施: Cold Pressor Test (CPT) (Procedure)
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.
干预措施: Sodium Nitroprusside (SNP) (Drug)
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.
干预措施: Phenylephrine (Drug)
Transcutaneous Vagal Nerve Stimulation (tVNS)
Participants with PTSD randomized to receive treatment with tVNS for 8 to 14 weeks.
干预措施: Transcutaneous Vagal Nerve Stimulation (tVNS) (Device)
Losartan
Participants with PTSD randomized to receive losartan for 8 to 14 weeks.
干预措施: Losartan (Drug)
Atenolol
Participants with PTSD randomized to receive atenolol for 8 to 14 weeks.
干预措施: Atenolol (Drug)
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.
干预措施: Sodium Nitroprusside (SNP) (Drug)
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.
干预措施: Phenylephrine (Drug)
结局指标
主要结局
Change in Muscle Sympathetic Nerve Activity (MSNA)
时间窗: Baseline, after study intervention (up to 14 weeks)
Multiunit postganglionic sympathetic nerve activity is recorded from a tungsten microelectrode inserted into the peroneal nerve with a reference microelectrode inserted in close proximity. Efferent nerve signals are amplified, filtered, rectified and integrated (time constant 0.1 s) to obtain a mean voltage display of MSNA. MSNA bursts are automatically detected using the following criteria: burst-to-noise ratio of 3:1 within a 0.5-s search window, with an average latency of 1.2-1.3 s in burst occurrence from the previous R-wave. MSNA is expressed as burst frequency measured a bursts per minute. MSNA will be examined at rest and during mental stress.
次要结局
- C-reactive protein (CRP)(Baseline, after study intervention (up to 14 weeks))
- Change in Baroreflex Sensitivity (BRS)(Baseline, after study intervention (up to 14 weeks))
- Interleukin 2 (IL-2)(Baseline, after study intervention (up to 14 weeks))
- Interleukin 6 (IL-6)(Baseline, after study intervention (up to 14 weeks))
- Angiotensin II (ATII)(Baseline, after study intervention (up to 14 weeks))
- Lipoprotein-associated Phospholipase A2 Mass (Lp-PLA2)(Baseline, after study intervention (up to 14 weeks))
研究者
Jeanie Park
Associate Professor
Emory University