Anxiety is the most common psychiatric disorder. Anxiety is associated with increased risk of cardiovascular events, independent of conventional risk factors. However, the mechanisms underiying this link are unknown, and it has never been proved that treating anxiety reduces cardiovascular risk. This project will address these important issues. We have gathered compelling data demonstrating that even modest anxiety symptoms are associated with sympathetic nerve activation, inflammation, and profound impairment of resistance vessel function in humans. Using a multidisciplinary approach, we will address three speciflc aims: 1) Does anxietv produce vascular dvsfunction through increased inflammation or oxidant stress? We will measure ex vivo endothelial cell proteins reflecting inflammation and oxidant stress in subjects with anxiety symptom scores in the highest and lowest quartiles. We will then test whether anti-inflammatory (salsalate) and anti-oxidant (ascorbic acid) interventions reverse vascular dysfunction in high compared to low anxiety subjects.
This aim will additionally examine whether peripheral resistance vessel dysfunction is also present in the brain using functional MRI to measure cerebral blood flow, and whether this is improved by salsalate. 2) Does anxietv produce vascular dysfunction through svmpathetic activation? We will test whether sympathetic inhibition with clonidine for 4 weeks improves inflammation, oxidant stress and vascular dysfunction to a greater degree in high than low anxiety subjects. 3) Does treatment of anxietv improve svmpathetic activation, inflammation, oxidant stress and Vascular dvsfunction? We will randomly assign subjects with high anxiety to a novel mindfulness-based acceptance and commitment therapy (ACT) or time control. This therapy has been shown in our hands and others to have substantial and durable effects on anxiety symptoms. We will test whether ACT produces signiflcantly greater improvements in microneurographic sympathetic nerve activity, endothelial cell proteins reflecting inflammation and oxidant stress, and forearm resistance vessel function. This project should: A) Provide compelling evidence that anxiety causes vascular damage. B) Elucidate mechanisms involved in the effects of anxiety on the vasculature. C) Help develop novel phenotypes for future research on anxiety classiflcation, severity and treatment. D) Suggest new strategies for cardiovascular risk stratiflcation and prevention. We will achieve these goals through a distinctive multidisciplinary collaboration between investigators expert in cardiovascular biology, psychiatry, behavioral psychology and neuroimaging.

Public Health Relevance

Anxiety is a psychiatric condition found in about 20% ofthe US population, which has been linked to increased risk for heart attack and stroke. We propose to examine the reasons for this association, and test agents that block inflammation and the sympathetic nervous system in patients with low and high levels of anxiety. We will also examine whether treating anxiety reduces sympathetic activation and vascular damage. This project will help develop new ways to identify and treat people at high cardiovascular risk.

National Institute of Health (NIH)
Research Program Projects (P01)
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Heart, Lung, and Blood Program Project Review Committee (HLBP)
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University of Iowa
Iowa City
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Santana-Filho, Valter J; Davis, Greg J; Castania, Jaci A et al. (2014) Autocrine/paracrine modulation of baroreceptor activity after antidromic stimulation of aortic depressor nerve in vivo. Auton Neurosci 180:24-31
Coble, Jeffrey P; Johnson, Ralph F; Cassell, Martin D et al. (2014) Activity of protein kinase C-? within the subfornical organ is necessary for fluid intake in response to brain angiotensin. Hypertension 64:141-8
Raven, Peter B; Chapleau, Mark W (2014) Blood pressure regulation XI: overview and future research directions. Eur J Appl Physiol 114:579-86
Thunhorst, Robert L; Beltz, Terry; Johnson, Alan Kim (2014) Age-related declines in thirst and salt appetite responses in male Fischer 344√óBrown Norway rats. Physiol Behav 135:180-8
Hay, Meredith; Xue, Baojian; Johnson, Alan Kim (2014) Yes! Sex matters: sex, the brain and blood pressure. Curr Hypertens Rep 16:458
Harlan, Shannon M; Rahmouni, Kamal (2013) Neuroanatomical determinants of the sympathetic nerve responses evoked by leptin. Clin Auton Res 23:1-7
Xue, Baojian; Zhang, Zhongming; Beltz, Terry G et al. (2013) Estrogen receptor-* in the paraventricular nucleus and rostroventrolateral medulla plays an essential protective role in aldosterone/salt-induced hypertension in female rats. Hypertension 61:1255-62
Harlan, Shannon M; Guo, Deng-Fu; Morgan, Donald A et al. (2013) Hypothalamic mTORC1 signaling controls sympathetic nerve activity and arterial pressure and mediates leptin effects. Cell Metab 17:599-606
Schiller, Crystal Edler; O'Hara, Michael W; Rubinow, David R et al. (2013) Estradiol modulates anhedonia and behavioral despair in rats and negative affect in a subgroup of women at high risk for postpartum depression. Physiol Behav 119:137-44
Lamkin, Donald M; Lutgendorf, Susan K; Lubaroff, David et al. (2011) Cancer induces inflammation and depressive-like behavior in the mouse: modulation by social housing. Brain Behav Immun 25:555-64

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