Primary Hyperaldosteronism and Ischemia-reperfusion Injury (PHA-FMD)

Primary Hyperaldosteronism and Endothelial Ischemia-reperfusion Injury

Patients with primary hyperaldosteronism experience more cardiovascular events compared to patients with primary hypertension, independent of the blood pressure level.

In this research we hypothesize that patients with primary hyperaldosteronism are more susceptible to ischemia-reperfusion injury.

Study Overview

• Status: Completed
• Conditions: Primary Hyperaldosteronism
• Intervention / Treatment: Procedure: forearm ischemia and reperfusion

Detailed Description

Patients with PHA have an increased risk of cardiovascular events, independent of blood pressure level. Also in patients suffering a myocardial infarction, circulating aldosterone levels are associated with increased mortality. In animal models of myocardial infarction, the administration of exogenous aldosterone increased infarct size, although other studies did not report this effect. In similar models, antagonists of the mineralocorticoid receptor (MR) reduced infarct size, which was completely abolished in ecto-5'-nucleotidase (CD73, the enzyme that catalyses extracellular formation of the endogenous nucleoside adenosine) and adenosine receptor knock-out mice. Therefore, we hypothesize that patients with PHA have an increased susceptibility for ischemia-reperfusion (IR)-injury due to down-regulation of the enzyme CD73. We will use the reduction in brachial flow-mediated dilation (FMD) by forearm IR as a well-validated endpoint for (endothelial) IR-injury.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525EZ
      • Radboud University Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria patients with primary hyperaldosteronism:

• Age 18-75 years
• Confirmed primary hyperaldosteronism (aldosterone >0.28 nmol/l after salt loading)
• Serum potassium ≥ 3.5 mmol/L (with or without potassium supplementation)
• Written informed consent

Inclusion Criteria patients with primary hypertension:

• Age 18-75 years
• Primary hypertension
• Baseline aldosterone <0.30 nmol/l and aldosterone-renin-ratio<0.09
• Serum potassium ≥ 3.5 mmol/L
• Written informed consent

Exclusion Criteria for both arms (patients with primary hyperaldosteronism and patients with primary hypertension:

• Smoking
• History of atherosclerotic disease (myocardial infarction (MI), stroke, or peripheral vascular disease)
• Not possible to change the antihypertensive medication into only diltiazem with or without hydralazine, according to the treating physician.
• Not possible to temporarily interrupt statin treatment, if the patient use statins, according to the treating physician.
• Severe renal dysfunction (MDRD < 30 ml/min)
• Second/third degree AV-block on electrocardiography
• Cardiac failure
• Diabetes Mellitus
• Use of acetylsalicylic acid and NSAID's theophylline, and dipyridamole

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Primary hyperaldosteronism; patients with primary hyperaldosteronism will be subjected to the intervention forearm ischemia and reperfusion (20 minutes of forearm ischemia and 20 minutes of reperfusion). Primary endpoint is the reduction in brachial FMD by forearm ischemia-reperfusion, as a measure of endothelial ischemia-reperfusion injury	Procedure: forearm ischemia and reperfusion; both arms will be subjected to 20 minutes of forearm ischemia and 20 minutes of reperfusion.
PLACEBO_COMPARATOR: Primary hypertension; Patients with primary hypertension (PHA excluded)will be subjected to 20 minutes of forearm ischemia and 20 minutes of reperfusion. Primary endpoint is the reduction in brachial FMD by forearm ischemia-reperfusion, as a measure of endothelial ischemia-reperfusion injury	Procedure: forearm ischemia and reperfusion; both arms will be subjected to 20 minutes of forearm ischemia and 20 minutes of reperfusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
brachial FMD	primary outcome measure is the reduction in brachial artery FMD after 20 minutes of forearm ischemia and 20 minutes of reperfusion in patients with primary hyperaldosteronism (compared to patients with primary hypertension)	1 day morning

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CD73 and adenosine	Blood will be drawn to determine circulating adenosine concentration and the CD73 activity on mononuclear cells	one day morning (just before FMD experiment)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
aldosterone and renin	Just before the FMD experiment, blood will be drawn for aldosterone and renin levels. These levels will not be determined, unless the brachial artery FMD after ischemia and reperfusion is significantly reduced in patients with primary hyperaldosteronism. We will store the plasma and serum at -20 C. If applicable, the aldosterone and aldosterone-to-renin ratio will be determined to correlate the primary outcome measure to the aldosterone and ARR levels.	1 day
leukocyte telomere length (LTL)	We will measure LTL in 12 patients with PHA and 12 patients with EHT to assess wether aldosterone excess increases telomere shortening in patients with PHA	1 day

Collaborators and Investigators

• Sponsor: Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (ACTUAL): May 1, 2017
• Study Completion (ACTUAL): July 1, 2017

Study Registration Dates

• First Submitted: October 31, 2013
• First Submitted That Met QC Criteria: November 6, 2013
• First Posted (ESTIMATE): November 7, 2013

Study Record Updates

• Last Update Posted (ACTUAL): October 12, 2017
• Last Update Submitted That Met QC Criteria: October 11, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: primary hyperaldosteronism; primary hypertension; forearm ischemia-reperfusion; (reduction) in brachial artery FMD; endothelial ischemia-reperfusion injury
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Endocrine System Diseases; Adrenocortical Hyperfunction; Adrenal Gland Diseases; Ischemia; Reperfusion Injury; Hyperaldosteronism
• Other Study ID Numbers: NL45381.091.13