Short Term Statin Treatment and Endothelial Dysfunction Due to Ischemia and Reperfusion Injury

Study Overview
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Brief Summary
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Rationale: Apart from their cholesterol lowering effects, statins have cholesterol-independent pleiotropic actions, such as upregulation of 5'-ectonucleotidase and up-regulation of NO-synthase that may increase tolerance against ischemia-reperfusion injury (IR-injury). Several animal studies have shown reduction of IR-injury as a result of statin treatment in both the heart and the kidney. Recently the investigators have shown, using Annexin A5 targeting after voluntary ischemic exercise to assess IR-injury, a protective effect of a 7 day oral rosuvastatin treatment. A three day treatment with atorvastatin however failed to reduce annexin targeting. Assessment of the flow mediated dilation of the brachial artery as measure of endothelial (dys)function, is a validated model to research effects of possible protective strategies and perform mechanistic experiments on IR-injury in humans in vivo. The investigators hypothesize that pretreatment with statins can increase endothelial tolerance against ischemia and reperfusion injury. Objective: To study the protective effect of pretreatment (both 3 day and 7 day) with rosuvastatin and atorvastatin on flow mediated dilation after 15 minutes ischemia and 15 minutes reperfusion. Study design: placebo-controlled randomised double-blind trial Study population: Healthy volunteers, age 18-50 Intervention: Treatment with either rosuvastatin 20 mg, atorvastatin 80mg or placebo during either 3 or 7 days Main study parameters: Difference in flow mediated dilation before and after 15 minutes ischemia. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Treatment with rosuvastatin or atorvastatin is not expected to harm the volunteers. Most reported side effects of rosuvastatin and atorvastatin are gastro-intestinal complains and myalgia. The volunteers will not benefit directly from participating in this study.

Official Title
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Short Term Statin Treatment and Endothelial Dysfunction Due to Ischemia and Reperfusion Injury

Conditions
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Ischemia Reperfusion Injury, Endothelial Dysfunction

Intervention / Treatment
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* Drug: rosuvastatin
* Drug: atorvastatin 3 days
* Drug: placebo
* Drug: rosuvastatin 7 days
* Drug: atorvastatin 7 days
* Drug: placebo 7 days


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-50 Written informed consent Exclusion Criteria: Smoking History of any cardiovascular disease Hypertension (in supine position: systole >140 mmHg, diastole >90 mmHg) Diabetes Mellitus (fasting glucose >7.0 mmol/L or random glucose >11.0 mmol/L) Hyperlipidaemia (fasting total cholesterol >5.5 mmol/L or random cholesterol >6.5 mmol/L) Alanine amino transferase >90 U/L Creatine kinase >440 U/L Raised rhabdomyolysis risk GFR <60 ml/min Overt clinical signs of hypothyroidism Myopathy in family history Alcohol abuse Concomitant chronic use of medication Participation to any drug-investigation during the previous 60 days as checked with VIP check. Professional athletes

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rosuvastatin 3days<br>8 Subjects will use rosuvastatin 20 mg/day for 3 days | Drug: rosuvastatin<br>* rosuvastatin 20 mg/day for 3 days.<br>* Other names: crestor;|
| Active Comparator: atorvastatin 3 days<br>8 Subjects will use atorvastatin 80 mg/day for 3 days.pj | Drug: atorvastatin 3 days<br>* atorvastatin 80 mg/day for 3 days.<br>* Other names: lipitor;|
| Placebo Comparator: placebo 3days<br>8 Subjects will use placebo for 3 days. | Drug: placebo<br>* placebo for 3 days.<br>|
| Experimental: rosuvastatin 7 days<br>8 Subjects will use rosuvastatin 20 mg/day for 7 days. | Drug: rosuvastatin 7 days<br>* rosuvastatin 20 mg/day for 7 days<br>* Other names: crestor;|
| Active Comparator: atorvastatin 7 days<br>8 Subjects will use atorvastatin 80 mg/day for 7 days. | Drug: atorvastatin 7 days<br>* atorvastatin 80 mg/day for 7 days.<br>* Other names: lipitor;|
| Placebo Comparator: placebo 7 days<br>8 Subjects will use placebo for 7 days. | Drug: placebo 7 days<br>* placebo 7 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in flow mediated dilation before and after 15 minutes ischemia |  | 30 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ecto-5'-nucleotidase activity and lipid profile after statin therapy |  | 3-7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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statins, ischemia reperfusion injury, endothelial dysfunction, rosuvastatin, atorvastatin, placebo, ecto-5'-nucleotidase, flow mediated dilation