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

• Status: Active, not recruiting
• Trial end date: 2023-12-31
• Target enrollment: 0
• Participant gender: All

Summary

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).

• Phase: Phase 4
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Seth Holwerda; University of Iowa
• Treatments: Clonidine; Hydrochlorothiazide

Criteria

Inclusion Criteria for participants with moderate-to-high anxiety to undergo drug intervention:

• Willing and able to provide written, signed consent after the nature of the study has been explained, and prior to any research-related procedures.

Age is > or = 18 and < or = 79 years

No history of cardiovascular disease (e.g., heart attack, stroke, heart failure, valvular heart disease, cardiomyopathy), or peripheral arterial disease.

Non-smokers, defined as no history of smoking or no smoking for at least the past 3 months.

Normal resting 12-lead ECG (no evidence of myocardial infarction, left ventricular hypertrophy, left-bundle branch block, 2nd or 3rd degree AV block, atrial fibrillation/flutter, atherosclerosis).

Blood chemistries indicative of normal renal (creatinine <2.0mg/dl), liver (<3 times upper limit for ALT, AST), and thyroid function (TSH between 0.4 - 5.0 mU/L) or on stable thyroid medication with no dose change for 3 months.

Exclusion Criteria:

• Current use of clonidine or beta-blockers

Current use of antihypertensive medications for reasons other than hypertension (e.g., hydrochlorothiazide for leg edema or kidney stone prevention, beta-blockers for tremor)

Difficult to control hypertension (e.g., on 2 or 3 antihypertensive medications)

Low blood pressure (e.g., systolic BP < 110 mmHg)

Hypertensive and have not been stable on their current antihypertensive medication regimen for at least 6 months

Blood pressure not controlled either on or off antihypertensive medications (e.g., BP > 150/100)

Current diagnosis or history of cancer, liver disease, HIV/AIDS

History of brain tumor, aneurysm or injury

Clinical diagnosis of mental health disorders such as bipolar disorder or schizophrenia

History of cardiovascular disease such as heart angioplasty/stent or bypass surgery, myocardial infarction, stroke, heart failure with or without LV ejection fraction <40%, cardiomyopathy, valvular heart disease, cardiomyopathy, heart transplantation, atherosclerosis.

Current tobacco user or history of tobacco use within the past 3 months (cigarettes, cigars, chewing tobacco, Hookah).

History of lung emphysema, chronic bronchitis or chronic obstructive pulmonary disease (COPD).

Abnormal resting 12-lead ECG (e.g., evidence of myocardial infarction, left ventricular hypertrophy, left-bundle branch block, 2nd or 3rd degree AV block, atrial fibrillation/flutter, atherosclerosis).

Serious neurologic disorders including seizures.

History of renal failure, dialysis or kidney transplant.

Use of any investigational products or investigational medical devices within 30 days prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.

Recent flu-like symptoms within the past 2 weeks.

Pregnant or breastfeeding at screening, or planning to become pregnant (self or partner) at any time during the study. A urinary pregnancy test will be done on all females. If test is positive, the subject will be excluded.

History of rheumatoid arthritis, Grave's disease, systemic lupus erythamatosis, and Wegener's granulomatosis.

Taking anticoagulation, anti-seizure, or antipsychotic agents.

Start of or dose change to an antidepressant or anti-anxiety medication within the past 3 months (if no change in medication or dose in past 3 month, then subject will be eligible).

Immunodeficiency or systemic autoimmune disease.

History of bleeding disorders or conditions of the microcirculation (i.e. von Willebrand disease, Raynaud's disease).

History of co-morbid condition that would limit life expectancy to <1 year.

Taking chronic non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin, naproxen, acetaminophen (Tylenol®), ibuprofen (Advil®, Motrin®) and not able or willing to go off of for 2 weeks prior to each study visit.

Taking cox-2 inhibitors (Celebrex®, Vioxx®, etc) or allopurinol (Zyloprim®, Lopurin®, Aloprim®).

Taking steroids or biologics: corticosteroids (prednisone); methotrexate, infliximib (Remicade®), etaneracept (Enbrel®); anakinra (Kineret®).

Those who are currently donating blood, platelets, or plasma at the time of screening.

Vulnerable populations (prisoners, etc.) will not be eligible to participate in this study.

On weight loss drugs (i.e. orilistat (Xenical®), sibutramine (Meridia®), phenylpropanol-amine (Acutrim®)), or similar over-the-counter medications within 3 months of screening.

Any surgery within 30 days of screening

Those who currently donate blood, platelets, or plasma

Any condition that, in the view of the PI or Co-I, places the subject at high risk or poor treatment and study compliance.

We will also enroll 36 participants ages 18-79 years (50% men, 50% women) with low or no anxiety as control subjects to participate in only baseline testing (not participate in the drug intervention).

Inclusion criteria:

Willing and able to provide written, signed consent after the nature of the study has been explained, and prior to any research-related procedures.

Age is > or = 18 and < or = 79 years

No history of cardiovascular disease (e.g., heart attack, stroke, heart failure, valvular heart disease, cardiomyopathy), or peripheral arterial disease.

Non-smokers, defined as no history of smoking or no smoking for at least the past 3 months.

Normal resting 12-lead ECG (no evidence of myocardial infarction, left ventricular hypertrophy, left-bundle branch block, 2nd or 3rd degree AV block, atrial fibrillation/flutter, atherosclerosis).

Blood chemistries indicative of normal renal (creatinine <2.0mg/dl), liver (<3 times upper limit for ALT, AST), and thyroid function (TSH between 0.4 - 5.0 mU/L) or on stable thyroid medication with no dose change for 3 months.

Exclusion Criteria:

Current use of clonidine or beta-blockers

Current use of antihypertensive medications for reasons other than hypertension (e.g., hydrochlorothiazide for leg edema or kidney stone prevention, beta-blockers for tremor)

Difficult to control hypertension (e.g., on 2 or 3 antihypertensive medications)

Low blood pressure (e.g., systolic BP < 110 mmHg)

Hypertensive and have not been stable on their current antihypertensive medication regimen for at least 6 months

Blood pressure not controlled either on or off antihypertensive medications (e.g., BP > 150/100)

Current diagnosis or history of cancer, liver disease, HIV/AIDS

History of brain tumor, aneurysm or injury

Clinical diagnosis of mental health disorders such as bipolar disorder or schizophrenia

History of cardiovascular disease such as heart angioplasty/stent or bypass surgery, myocardial infarction, stroke, heart failure with or without LV ejection fraction <40%, cardiomyopathy, valvular heart disease, cardiomyopathy, heart transplantation, atherosclerosis.

Current tobacco user or history of tobacco use within the past 3 months (cigarettes, cigars, chewing tobacco, Hookah).

History of lung emphysema, chronic bronchitis or chronic obstructive pulmonary disease (COPD).

Abnormal resting 12-lead ECG (e.g., evidence of myocardial infarction, left ventricular hypertrophy, left-bundle branch block, 2nd or 3rd degree AV block, atrial fibrillation/flutter, atherosclerosis).

Serious neurologic disorders including seizures.

History of renal failure, dialysis or kidney transplant.

Use of any investigational products or investigational medical devices within 30 days prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.

Recent flu-like symptoms within the past 2 weeks.

Pregnant or breastfeeding at screening, or planning to become pregnant (self or partner) at any time during the study. A urinary pregnancy test will be done on all females. If test is positive, the subject will be excluded.

History of rheumatoid arthritis, Grave's disease, systemic lupus erythamatosis, and Wegener's granulomatosis.

Taking anticoagulation, anti-seizure, or antipsychotic agents.

Start of or dose change to an antidepressant or anti-anxiety medication within the past 3 months (if no change in medication or dose in past 3 month, then subject will be eligible).

Immunodeficiency or systemic autoimmune disease.

History of bleeding disorders or conditions of the microcirculation (i.e. von Willebrand disease, Raynaud's disease).

History of co-morbid condition that would limit life expectancy to <1 year.

Taking chronic non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin, naproxen, acetaminophen (Tylenol®), ibuprofen (Advil®, Motrin®) and not able or willing to go off of for 2 weeks prior to each study visit.

Taking cox-2 inhibitors (Celebrex®, Vioxx®, etc) or allopurinol (Zyloprim®, Lopurin®, Aloprim®).

Taking steroids or biologics: corticosteroids (prednisone); methotrexate, infliximib (Remicade®), etaneracept (Enbrel®); anakinra (Kineret®).

Those who are currently donating blood, platelets, or plasma at the time of screening.

Vulnerable populations (prisoners, etc.) will not be eligible to participate in this study.

On weight loss drugs (i.e. orilistat (Xenical®), sibutramine (Meridia®), phenylpropanol-amine (Acutrim®)), or similar over-the-counter medications within 3 months of screening.

Any surgery within 30 days of screening

Those who currently donate blood, platelets, or plasma

Any condition that, in the view of the PI or Co-I, places the subject at high risk or poor treatment and study compliance.

We will also enroll 36 participants ages 18-79 years (50% men, 50% women) with low or no anxiety as control subjects to participate in only baseline testing (not participate in the drug intervention). These subjects will be either lean (body mass index < 25) or on the obesity spectrum (body mass index > 30).

Because obesity is linked with hypertension and type 2 diabetes, enrollment of subjects may include those with pre-hypertension or hypertension (systolic blood pressure >/= 120 - <180 mmHg- average of at least 3 measurements 2 min apart after 10 min seated resting position), and/or pre-diabetes (defined as fasting blood glucose between 100-126 mg/dl, fasting blood glucose of 140-199 mg/dl at 120 min of an oral glucose tolerance test, or HbA1C of 6-6.5%) or type 2 diabetes (defined as fasting blood glucose between >126 mg/dl, fasting blood glucose of >199 mg/dl at 120 min of an oral glucose tolerance test, or HbA1C > 6.5%). These subjects may be taking anti-hypertensive and/or diabetes (anti-hyperglycemic) medications. Subjects will be asked to refrain from medications the morning of the study visit, and to bring their medications with them to take immediately following their study visit.

Inclusion criteria:

Willing and able to provide written, signed consent after the nature of the study has been explained, and prior to any research-related procedures.

Age is > or = 18 and < or = 79 years

No history of cardiovascular disease (e.g., heart attack, stroke, heart failure, valvular heart disease, cardiomyopathy), or peripheral arterial disease.

Non-smokers, defined as no history of smoking or no smoking for at least the past 3 months.

Normal resting 12-lead ECG (no evidence of myocardial infarction, left ventricular hypertrophy, left-bundle branch block, 2nd or 3rd degree AV block, atrial fibrillation/flutter, atherosclerosis).

Blood chemistries indicative of normal renal (creatinine <2.0mg/dl), liver (<3 times upper limit for ALT, AST), and thyroid function (TSH between 0.4 - 5.0 mU/L) or on stable thyroid medication with no dose change for 3 months.

Exclusion Criteria:

Current diagnosis or history of cancer, liver disease, HIV/AIDS

History of brain tumor, aneurysm or injury

Clinical diagnosis of mental health disorders such as bipolar disorder or schizophrenia

History of cardiovascular disease such as heart angioplasty/stent or bypass surgery, myocardial infarction, stroke, heart failure with or without LV ejection fraction <40%, cardiomyopathy, valvular heart disease, cardiomyopathy, heart transplantation, atherosclerosis.

Current tobacco user or history of tobacco use within the past 3 months (cigarettes, cigars, chewing tobacco, Hookah).

History of lung emphysema, chronic bronchitis or chronic obstructive pulmonary disease (COPD).

Abnormal resting 12-lead ECG (e.g., evidence of myocardial infarction, left ventricular hypertrophy, left-bundle branch block, 2nd or 3rd degree AV block, atrial fibrillation/flutter, atherosclerosis).

Serious neurologic disorders including seizures.

History of renal failure, dialysis or kidney transplant.

Use of any investigational products or investigational medical devices within 30 days prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.

Recent flu-like symptoms within the past 2 weeks.

Pregnant or breastfeeding at screening, or planning to become pregnant (self or partner) at any time during the study. A urinary pregnancy test will be done on all females. If test is positive, the subject will be excluded.

History of rheumatoid arthritis, Grave's disease, systemic lupus erythamatosis, and Wegener's granulomatosis.

Taking anticoagulation, anti-seizure, or antipsychotic agents.

Start of or dose change to an antidepressant or anti-anxiety medication within the past 3 months (if no change in medication or dose in past 3 month, then subject will be eligible).

Immunodeficiency or systemic autoimmune disease.

History of bleeding disorders or conditions of the microcirculation (i.e. von Willebrand disease, Raynaud's disease).

History of co-morbid condition that would limit life expectancy to <1 year.

Taking chronic non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin, naproxen, acetaminophen (Tylenol®), ibuprofen (Advil®, Motrin®) and not able or willing to go off of for 2 weeks prior to each study visit.

Taking cox-2 inhibitors (Celebrex®, Vioxx®, etc) or allopurinol (Zyloprim®, Lopurin®, Aloprim®).

Taking steroids or biologics: corticosteroids (prednisone); methotrexate, infliximib (Remicade®), etaneracept (Enbrel®); anakinra (Kineret®).

Those who are currently donating blood, platelets, or plasma at the time of screening.

Vulnerable populations (prisoners, etc.) will not be eligible to participate in this study.

On weight loss drugs (i.e. orilistat (Xenical®), sibutramine (Meridia®), phenylpropanol-amine (Acutrim®)), or similar over-the-counter medications within 3 months of screening.

Any surgery within 30 days of screening

Those who currently donate blood, platelets, or plasma

Any condition that, in the view of the PI or Co-I, places the subject at high risk or poor treatment and study compliance.