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Angiotensin-(1-7) Cardiovascular Effects in Aging

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ClinicalTrials.gov Identifier: NCT05301192
Recruitment Status : Not yet recruiting
First Posted : March 29, 2022
Last Update Posted : July 14, 2022
Sponsor:
Information provided by (Responsible Party):
Amy Arnold, Milton S. Hershey Medical Center

Tracking Information
First Submitted Date  ICMJE March 17, 2022
First Posted Date  ICMJE March 29, 2022
Last Update Posted Date July 14, 2022
Estimated Study Start Date  ICMJE October 1, 2022
Estimated Primary Completion Date May 31, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 18, 2022)
Change in Muscle Sympathetic Nerve Burst Rate [ Time Frame: 110 minutes ]
Muscle sympathetic nerve burst rate will be measured continuously using peroneal nerve microneurography during angiotensin-(1-7) versus saline infusion.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 18, 2022)
  • Change in Muscle Sympathetic Nerve Burst Incidence [ Time Frame: 110 minutes ]
    Muscle sympathetic nerve burst incidence will be measured continuously using peroneal nerve microneurography during angiotensin-(1-7) versus saline infusion.
  • Change in Muscle Sympathetic Nerve Amplitude [ Time Frame: 110 minutes ]
    Muscle sympathetic nerve amplitude will be measured continuously using peroneal nerve microneurography during angiotensin-(1-7) versus saline infusion.
  • Change in Muscle Sympathetic Nerve Total Activity [ Time Frame: 110 minutes ]
    Muscle sympathetic nerve total activity will be measured continuously using peroneal nerve microneurography during angiotensin-(1-7) versus saline infusion.
  • Change in Brachial Artery Diameter [ Time Frame: 110 minutes ]
    A blood pressure cuff will be inflated to a suprasystolic pressure for 5 minutes then deflated. Brachial artery diameter will be measured continuously before, during, and after cuff inflation using duplex ultrasound at baseline and at the end of angiotensin-(1-7) versus saline infusion.
  • Change in Systolic and Diastolic Blood Pressure [ Time Frame: 110 minutes ]
    Blood pressure will be measured continuously with a finger and arm cuff during angiotensin-(1-7) versus saline infusion.
  • Change in Heart Rate [ Time Frame: 110 minutes ]
    Heart rate will be measured continuously by electrocardiogram during angiotensin-(1-7) versus saline infusion.
  • Change in Heart Rate Variability [ Time Frame: 110 minutes ]
    Heart rate variability will be calculated from the continuous electrocardiogram recordings obtained during angiotensin-(1-7) versus saline infusion.
  • Change in Plasma Catecholamines [ Time Frame: 110 minutes ]
    Circulating catecholamine levels will be measured in blood samples obtained at baseline and at the end of angiotensin-(1-7) versus saline infusion.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: March 18, 2022)
  • Change in Angiotensin II [ Time Frame: 110 minutes ]
    Plasma angiotensin II levels will be measured in blood samples obtained at baseline and at the end of angiotensin-(1-7) versus saline infusion.
  • Change in Angiotensin-(1-7) [ Time Frame: 110 minutes ]
    Plasma angiotensin-(1-7) levels will be measured in blood samples obtained at baseline and at the end of angiotensin-(1-7) versus saline infusion.
  • Change in Renin Activity [ Time Frame: 110 minutes ]
    Plasma renin activity will be measured in blood samples obtained at baseline and at the end of angiotensin-(1-7) versus saline infusion.
  • Change in Aldosterone [ Time Frame: 110 minutes ]
    Plasma or serum aldosterone levels will be measured in blood samples obtained at baseline and at the end of angiotensin-(1-7) versus saline infusion.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Angiotensin-(1-7) Cardiovascular Effects in Aging
Official Title  ICMJE Angiotensin-(1-7) Cardiovascular Effects in Aging
Brief Summary Aging is an independent risk factor for developing hypertension and cardiovascular disease; however, the mechanisms underlying age-related cardiovascular disease remain poorly understood. One hallmark of aging is an increase in sympathetic nervous system activity, which can decrease the number and/or sensitivity of β2 adrenergic receptors to reduce dilation of blood vessels and increase blood pressure. Identifying new targets to restore vascular β2 adrenergic receptor signaling may help reduce cardiovascular risk in aging. This study will test the hypothesis that angiotensin-(1-7), a protective hormone of the renin-angiotensin system, can reduce cardiovascular sympathetic outflow and blood pressure and improve endothelial function in older healthy humans.
Detailed Description A randomized, double blind, placebo-controlled, crossover study will be conducted to determine if acute intravenous angiotensin-(1-7) infusion can reduce cardiovascular sympathetic tone and blood pressure and improve the function of blood vessels in older healthy individuals. This is an outpatient study that requires a screening visit, and if eligible, two study visits separated by at least one week in the Clinical Research Center within the Penn State Milton S. Hershey Medical Center. The study visits will include intravenous infusion of angiotensin-(1-7) or saline for approximately two hours, starting with increasing doses and holding at a steady-state dose. Endothelial function will be measured and blood samples and endothelial cells collected at baseline and at the end of infusions. Blood pressure, heart rate, and muscle sympathetic nerve activity via microneurography will be measured throughout the study. Each study visit will last approximately 4 hours.
Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Condition  ICMJE Aging
Intervention  ICMJE
  • Drug: Angiotensin-(1-7)
    This is a biologically active endogenous angiotensin peptide that may play an important role in regulation of blood pressure.
    Other Name: Angiotensin I/II (1-7) Acetate
  • Drug: Saline
    Saline will be used as the placebo comparator.
    Other Names:
    • Normal saline
    • 0.9% sodium chloride
Study Arms  ICMJE
  • Experimental: Angiotensin-(1-7)
    Participants will receive intravenous angiotensin-(1-7) at one study visit for 110 minutes. Angiotensin-(1-7) will be given in escalating doses of 2 ng/kg/min, 4 ng/kg/min, and 8 ng/kg/min. Each of these doses will be infused for 10 minutes. Following the dose escalation, angiotensin-(1-7) will be given at 8 ng/kg/min for an additional 80 minutes. Infusion rates will be calculated for each participant based on body mass.
    Intervention: Drug: Angiotensin-(1-7)
  • Placebo Comparator: Saline
    Participants will receive intravenous saline at one study visit for 110 minutes total. The volume of saline will match the volume of angiotensin-(1-7) infused. Infusion rates will be calculated for each participant based on body mass.
    Intervention: Drug: Saline
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: March 18, 2022)
26
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 31, 2024
Estimated Primary Completion Date May 31, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Men and women of all races and ethnicities
  • Capable of giving informed consent
  • Fluent in written and spoken English
  • Age 65-80 years
  • Body mass index (BMI) between 18.5 and 30 kg/m2
  • Normotensive defined as seated blood pressure <130/80 mmHg and without hypertensive medications
  • Satisfactory history and physical exam

Exclusion Criteria:

  • Age < 65 or > 80 years
  • Women who are pregnant, nursing, or taking hormone replacement therapy
  • Decisional impairment
  • Prisoners
  • Current or recent (less than 6 months) recreational drug history or excessive alcohol abuse history (greater than 14 drinks per week)
  • Current smokers
  • Highly trained athletes
  • Evidence of type I or type II diabetes (fasting glucose > 126 mg/dL or use of anti-diabetic medications)
  • Hypertension or history of serious cardiovascular disease (e.g., myocardial infarction within 6 months, symptomatic coronary artery disease, presence of angina pectoris, significant arrhythmia, congestive heart failure, deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis, hypertrophic cardiomyopathy) or cerebrovascular disease (e.g., cerebral hemorrhage, stroke, transient ischemic attack).
  • History or presence of immunological or hematological disorders
  • Impaired hepatic function [aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels >2 times upper limit of normal range]
  • Impaired renal function (serum creatinine >2.0 mg/dl)
  • Anemia
  • Taking drugs known to influence sympathetic activity (e.g. serotonin-norepinephrine reuptake inhibitors, norepinephrine transporter inhibitors, stimulants).
  • Treatment with anticoagulants (e.g. warfarin)
  • Treatment with chronic systemic glucocorticoid therapy (>7 consecutive days in 1 month in the 1-month preceding the study)
  • Treatment with any investigational drug in the 1-month preceding the study
  • Known allergy or contraindication to angiotensin converting enzyme inhibitors or angiotensin receptor blockers, both of which increase endogenous angiotensin-(1-7) levels as part of their mechanism of action
  • Inability to give, or withdraw, informed consent
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 65 Years to 80 Years   (Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Aimee Cauffman, RN 717-531-1617 acauffman@pennstatehealth.psu.edu
Contact: Amanda Miller, PhD 717-531-7676 aross1@pennstatehealth.psu.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05301192
Other Study ID Numbers  ICMJE STUDY 17401
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party Amy Arnold, Milton S. Hershey Medical Center
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Milton S. Hershey Medical Center
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Amy C Arnold, PhD Penn State Medical Center
PRS Account Milton S. Hershey Medical Center
Verification Date July 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP