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

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

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.

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