Primary Hyperaldosteronism and Ischemia-reperfusion Injury

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Primary Hyperaldosteronism and Endothelial Ischemia-reperfusion Injury

Conditions
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Primary Hyperaldosteronism

Intervention / Treatment
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* Procedure: forearm ischemia and reperfusion


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Primary hyperaldosteronism<br>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<br>* both arms will be subjected to 20 minutes of forearm ischemia and 20 minutes of reperfusion.<br>|
| Placebo Comparator: Primary hypertension<br>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<br>* both arms will be subjected to 20 minutes of forearm ischemia and 20 minutes of reperfusion.<br>|

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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primary hyperaldosteronism, primary hypertension, forearm ischemia-reperfusion, (reduction) in brachial artery FMD, endothelial ischemia-reperfusion injury