The Potential of Candesartan to Retard the Progression of Aortic Stenosis
The Potential of Candesartan to Retard the Progression of Aortic Stenosis
The present study defines a blinded, randomized, placebo-controlled, prospective study, the
 aim of which is to determine the influence of effective treatment with Type 1 angiotensin II
 (Ang II) receptor (AT-1R) antagonist, using candesartan (target dose 16 mg) on stenotic
 aortic valves. The investigators will specifically quantify whether candesartan attenuates
 the key pathogenic mechanisms of aortic valve stenosis, namely inflammation, fibrosis,
 elastin degradation, calcification, and neovascularization.
We will include in the study 120 consecutive patients with clinically significant,
 symptomatic aortic stenosis referred to the Helsinki University Central Hospital for
 consideration of valve replacement surgery. Patients who can be put on the hospital's normal
 waiting list for elective angiography (i.e who do not need urgent surgery) and who give their
 informed consent, will be randomized into two groups to start therapy with candesartan (8
 mg/d for 2 weeks, and then 16 mg/d until surgery) or placebo. On average, the overall
 duration of the drug intervention will be 3 months, i.e., the average time in our institution
 from referral to surgery. In addition, patients (n=50) undergoing aortic valve replacement
 surgery due to aortic regurgitation caused by dilation of the aortic root will be included.
 This population consists of both patients with early sclerotic, i.e., pre-stenotic, changes
 in their aortic valves (n=30) and of patients without any sclerotic or stenotic changes in
 their aortic valves (n=20). The group with sclerotic changes in their aortic valves (n=30)
 will be divided into two groups to receive candesartan (8 mg/d 2 wk, and then 16 mg/d until
 surgery) (n=15) or placebo (n=15). The removed aortic valves will be examined utilizing
 real-time PCR, autoradiography, fluorometry, immunohistochemistry, double immunofluorescence,
 confocal microscopy, and enzyme immunoassays. With these techniques, several markers of
 inflammation, calcification, fibrosis, and the amount of lipid accumulation and oxidation of
 LDL in the valves will be examined.
Inclusion Criteria:

 -  120 consecutive patients with clinically significant, symptomatic aortic stenosis
 referred to the Helsinki University Central Hospital for consideration of valve
 replacement surgery.

 Exclusion Criteria:

 -  Individuals with past myocardial infarction, more than mild mitral valve disease, or
 previous cardiac surgery will be excluded.

 -  Patients with heart failure who need urgent surgery or those with hypotension
 (systolic blood pressure below 110 mm Hg) will be excluded.

 -  Patients already taking ACE inhibitors or AT-1R antagonists will be excluded from the
 study population.

 -  Other exclusion criteria include the following:

 -  Complicated diabetes

 -  Primary cardiomyopathy

 -  Pregnant women, women who are breast feeding, and women of childbearing potential
 who are not using chemical or mechanical contraception or have a positive serum
 pregnancy test

 -  History of malignancy (unless a documented disease free period exceeding 5-years
 is present) with the exception of basal cell or squamous cell carcinoma of the
 skin. Women with a history of cervical dysplasia would be permitted to enter the
 study provided they had 3 consecutive clear Papanicolaou (Pap) smears

 -  Hypothyroidism (TSH 1.5xULN)

 -  History of alcohol or drug abuse within the last 5 years (this may affect
 compliance)

 -  Unexplained creatine kinase (CK 3xULN) (To protect patient safety)

 -  Serum creatinine >176 umol/L (2.0mg/dL)

 -  Participation in another investigational drug study less than 4 weeks before
 enrolment in the study, or according to subjects local ethics committee
 requirements where a larger period is stipulated (to avoid potential
 misinterpretation of overlapping adverse events)