Last updated on February 2019

Anxiety-mediated Impairments in Large Elastic Artery Function and the Autonomic Nervous System

Brief description of study

The goal of this study is to evaluate the effectiveness of a short-term (4 weeks) pharmacological blockade of sympathetic nerve activity (clonidine) on anxiety symptoms, vascular function, inflammation, muscle sympathetic nerve activity, and oxidant stress in individuals with moderate-to-high anxiety. Individuals who are interested in the study will be identified by an online screening survey and will be contacted by the research team; advertisements, flyers and mass emails will direct individuals to the online screening survey. Those deemed eligible to participate will be randomized to either the clonidine intervention or hydrochlorothiazide as a blood-pressure lowering control condition. If eligible participants are currently being treated with blood pressure-lowering medications, they will be asked to go off these medications for 2 weeks prior to and during the course of the study. During the 2 week washout of blood pressure-lowering medications, participants will have safety visits (2 additional visits) that include measurements of blood pressure at 4 days and 7 days after the beginning of the washout period before the intervention. Assessments of anxiety symptoms via various surveys, vascular function (via non-invasive, well-established techniques), inflammation, muscle sympathetic nerve activity, and oxidant stress will be performed at baseline and at the post intervention session. Similar baseline measurements will be performed in control subjects with low or no anxiety for comparison, but these individuals will not undergo the intervention.

Participants with moderate-to-high anxiety will have a total of 6 visits to the laboratory, which includes the screening and consent (visit 1). Visit 2 (baseline measurements) and visit 6 (post-intervention measurements) will be more extensive (~4.5 hours) compared to the other visits (~30 min). Participants completing the washout will have an additional 2 visits (~30 min each) before "visit 2." Control subjects with low or no anxiety will only participate in visit 1 (screening and consent ) and visit 2 (baseline measurements).

Detailed Study Description

Anxiety disorders are the most common mental health problems in the United States, occurring in about 18% of adults per year, and a lifetime prevalence of approximately 28% (25). Importantly, anxiety disorders are associated with increased risk for sudden cardiac death and non-fatal myocardial infarction (27, 46) independent of other mood disorders (13, 15). However, establishing a clear consensus on the mechanism(s) by which chronic anxiety confers cardiovascular disease (CVD) risk has proven difficult. Previous studies examining the potential role of vascular dysfunction in subjects with anxiety have been confounded by co-morbidities (e.g., hypertension, smoking, obesity) (31, 38) and added psychiatric disorders (63). Additionally, studies focusing on the relation between anxiety and robust predictors of CVD mortality, such as large elastic artery (e.g., aortic, carotid) stiffness, have been lacking.

Anxiety is experienced as negative feelings of threat, restlessness, tension and irritability, and somatic symptoms, such as palpitations, sweating, trembling, and dry mouth (57). Patients with clinically diagnosed anxiety disorder demonstrate more than 2-fold increase in future CVD events (23). Despite the strong association between anxiety and CVD risk, there is currently a gap in knowledge describing potential mechanisms by which anxiety leads to CVD. Evidence suggests that chronically high levels of anxiety may be associated with the progression of subclinical atherosclerosis such as carotid artery intima-media thickness (38) and elevated inflammation (5, 44). Symptoms of anxiety may also lead to impairment in resistance vessel dilator function (53). However, few studies have examined large elastic artery stiffness in subjects with high levels of anxiety. This is clinically important because large elastic artery stiffness (i.e., carotid and aortic) is a robust independent risk factor for CVD events such as stroke and myocardial infarction (6, 19, 59, 61). Interestingly, greater large elastic artery stiffness (aortic) is observed with higher resting muscle sympathetic nerve activity (MSNA) in healthy individuals even after adjusting for BP (9, 55). In this regard, numerous studies have shown that high MSNA independent of any increase in blood pressure can have deleterious vascular (7, 17, 32), metabolic (2, 20), cardiac (50, 52), and renal effects (1, 14, 54). Higher tonic MSNA is an independent determinant of aortic artery stiffness as assessed by the gold standard carotid-femoral pulse wave velocity (PWV) in healthy humans (55). Even acute increases in MSNA, such as during mental stress which is a potent stimulus for increases in MSNA (3), can lead to transiently greater large elastic artery stiffness (40). Furthermore, in healthy humans, acute mental stress induces transient endothelial dysfunction (16), an important modulator of arterial stiffness. Given findings from previous studies (22) showing that anxiety symptoms are associated with indices of elevated sympathetic nerve activity (e.g., elevated circulating norepinephrine), lead us to our overall hypothesis that anxiety-induced sympathetic overactivity leads to increased large elastic artery (carotid and aortic) stiffness in subjects with chronic anxiety.

The purpose of this study is to 1) determine the extent to which measures of vascular and autonomic function (large elastic artery stiffness, vascular inflammation and baroreflex function) is impaired in subjects with moderate-to-high anxiety, and 2) test the magnitude by which short-term (4 weeks) sympathetic nerve activity blockade (clonidine) improves large elastic artery stiffness, vascular inflammation and baroreflex function in subjects with moderate-to-high levels of anxiety.

In healthy subjects, chronic anxiety has been associated with increased risk of cardiac events (13, 15, 23). Interestingly, evidence suggests baroreflex function is reduced in subjects with anxiety (48, 60), thus adding additional cardiac risk burden to this population. Consistent with this, impairment in cardiac baroreflex sensivity (BRS) is a significant predictor of cardiac arrhythmias and myocardial infarction mortality (29, 56). Moreover, reduced cardiac BRS is a sensitive predictor of mortality after myocardial infarction (28, 30), particularly in subjects with anxiety (47). Reduced baroreflex activation can be attributed, in part, to reduced distensibility of baroreceptor regions within the elastic carotid and aortic arteries as a result of increased arterial stiffness (8). Given the associated risk of cardiac BRS impairment with anxiety, and the increase in large elastic artery stiffness in this population, there is a critical need to examine whether reductions in SNA and large elastic artery stiffness ameliorates cardiac BRS impairment in subjects with anxiety, thus providing experimental support for the novel idea that anxiety leads to increased CVD risk at least in part through elevated large artery stiffness.

Clinical Study Identifier: NCT03109795

Recruitment Status: Closed

Brief Description Eligibility Contact Research Team

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