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.

ischemia reperfusion injury, endothelial dysfunction, statins, rosuvastatin, atorvastatin, placebo, ecto-5'-nucleotidase, flow mediated dilation

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

Meijer P, Oyen WJ, Dekker D, van den Broek PH, Wouters CW, Boerman OC, Scheffer GJ, Smits P, Rongen GA. Rosuvastatin increases extracellular adenosine formation in humans in vivo: a new perspective on cardiovascular protection. Arterioscler Thromb Vasc Biol. 2009 Jun;29(6):963-8. doi: 10.1161/ATVBAHA.108.179622. Epub 2009 Apr 9.

Kharbanda RK, Peters M, Walton B, Kattenhorn M, Mullen M, Klein N, Vallance P, Deanfield J, MacAllister R. Ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia-reperfusion in humans in vivo. Circulation. 2001 Mar 27;103(12):1624-30. doi: 10.1161/01.cir.103.12.1624.

Wouters CW, Wever KE, Bronckers I, Hopman MT, Smits P, Thijssen DH, Rongen GA. Short-term statin treatment does not prevent ischemia and reperfusion-induced endothelial dysfunction in humans. J Cardiovasc Pharmacol. 2012 Jan;59(1):22-8. doi: 10.1097/FJC.0b013e318232b1a4.