Endothelial Dysfunction, Ischemia Reperfusion Injury
Conditions
Keywords
ischemia reperfusion injury, endothelial dysfunction, statins, rosuvastatin, atorvastatin, placebo, ecto-5'-nucleotidase, flow mediated dilation
Brief summary
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.
Interventions
DRUGplacebo
placebo for 3 days.
DRUGplacebo 7 days
placebo 7 days
DRUGrosuvastatin 7 days
rosuvastatin 20 mg/day for 7 days
DRUGatorvastatin 7 days
atorvastatin 80 mg/day for 7 days.
DRUGrosuvastatin
rosuvastatin 20 mg/day for 3 days.
DRUGatorvastatin 3 days
atorvastatin 80 mg/day for 3 days.
Sponsors
Radboud University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Difference in flow mediated dilation before and after 15 minutes ischemia | 30 minutes |
Secondary
| Measure | Time frame |
|---|---|
| Ecto-5'-nucleotidase activity and lipid profile after statin therapy | 3-7 days |
Countries
Netherlands
Outcome results
None listed