Clinical trial NCT00987974: Short Term Statin Treatment and Endothelial Dysfunction Due to Ischemia and Reperfusion Injury
Official title: Short Term Statin Treatment and Endothelial Dysfunction Due to Ischemia and Reperfusion Injury
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Ischemia Reperfusion Injury
Endothelial Dysfunction
Keywords: ischemia reperfusion injury
endothelial dysfunction
statins
rosuvastatin
atorvastatin
placebo
ecto-5'-nucleotidase
flow mediated dilation
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2009-10-01
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.


Eligibility criteria: 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

Primary outcomes:
measure: Difference in flow mediated dilation before and after 15 minutes ischemia
timeFrame: 30 minutes
Secondary outcomes:
measure: Ecto-5'-nucleotidase activity and lipid profile after statin therapy
timeFrame: 3-7 days
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: RUNMC
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.