Angiotensin-II Blockade in Mitral Regurgitation
Angiotensin-II Blockade in Mitral Regurgitation
Mitral regurgitation (MR) is common in the elderly and its prevalence is increasing with the
 aging of the population. Organic MR, due to primary valvular lesions, initiates a cascade of
 complications determined by its degree. MR of severe degree is associated with excess
 mortality and high cardiac morbidity (heart failure, atrial fibrillation). It also causes
 left ventricular remodeling which induces left ventricular dysfunction, which in turn leads
 to poor clinical outcome. Surgery can eliminate MR, but carries immediate and long-term
 risks, especially in the elderly. Therefore, chronically decreasing the degree of MR is a
 major goal of medical therapy but such an effect is yet unproved because of conflicting
 results of small and mostly non-randomized series. Our recent preliminary studies suggest
 that a sustained decrease of degree of MR and improvement of left ventricular remodeling can
 be achieved with powerful reduction of afterload, obtained in particular with angiotensin-II
 receptor blockade. Therefore, the present proposal seeks to address gaps of knowledge
 regarding vasoactive treatment of MR through the verification of the following hypothesis:
 Hypothesis: Vasoactive therapy using angiotensin-II receptor blocker (Candesartan Cilexetil)
 weighed against placebo produces a sustained reduction of the consequences of organic MR. The
 specific aims are that the treatment a) decreases the degree of MR (decreases the regurgitant
 volume, primary end-point) and b) improves left ventricular remodeling (decreases the
 end-diastolic volume index, secondary end-point), as compared to placebo.
Patients with MR organic (intrinsic valve disease), isolated (no other valve disease),
 moderate or more severe (regurgitant volume *30 mL/beat). A Clinical trial, randomized,
 placebo controlled, double-blind, without cross-over, of 1 year oral treatment with potent
 angiotensin-II receptor blockade using 32 mg Candesartan daily. The trial is preceded in all
 patients by an acute open-label study to determine tolerance and immediate response. The
 methods used to measure the end-points will be: a) Doppler-Echocardiography for quantitation
 of the degree of MR (measurement of regurgitant volume) using a combination of three
 simultaneous methods (quantitative Doppler, quantitative two-dimensional echocardiography,
 proximal flow convergence) and b) of left ventricular remodeling (end-diastolic volume index
 measured by echocardiography and by electron beam computed tomography). This single center
 study seeks to enroll a total of 90 patients. The analysis will be based on intention to
 treat and compare the regurgitant volume and left ventricular end-diastolic volume index
 measured after one year of treatment with the active drug or placebo. The results of the
 trial should provide strong evidence regarding medical treatment of patients with organic MR.
Inclusion Criteria:

 Patients:

 -  18 years old or older, with

 -  Mitral regurgitation on the basis of Color flow imaging

 -  Due to organic disease of the mitral valve on the basis of two-dimensional
 echocardiography

 -  Isolated (no valve disease other than functional tricuspid regurgitation on the basis
 of Doppler-Echocardiography)

 -  Pure (no mitral stenosis by Doppler echocardiography)

 -  Quantifiable by Doppler-Echocardiographic methods

 -  Of more than mild degree, defined as regurgitant volume * 30 mL/beat

 -  Occurring on native valves

 -  With Two-dimensional echocardiographic imaging allowing assessment of LV remodeling,
 and

 -  Asymptomatic (or mildly symptomatic but not considered as candidates for immediate
 surgery by their attending physician).

 Exclusion Criteria:

 -  Associated aortic valve disease (more than trace aortic regurgitation by color flow
 imaging or mean gradient *25 mmHg)

 -  Associated mitral stenosis (mean gradient* 5 mmHg, valve area < 1.5 cm2)

 -  Associated congenital or pericardial diseases on the basis of Doppler echocardiography

 -  Intolerance to either AII blockers or Angiotensin converting enzyme inhibitors

 -  Intolerance to iodine contrast material

 -  Intolerance to intravenous echographic contrast agents

 -  Renal failure with creatinine * 2 mg/dl

 -  Blood pressure below 100 mmHg

 -  Known renal artery stenosis

 -  Ongoing therapy with hydralazine, calcium-entry blocking drugs or angiotensin
 converting enzyme inhibitors

 -  Known severe comorbidity such as liver disease, malignancy

 -  Pregnancy (A negative pregnancy test and effective contraceptive methods are required
 prior to enrollment of females of childbearing potential (not post-menopausal or
 surgically sterilized)), and

 -  Patients considered as requiring mitral valve surgery by their attending physician or
 with previous valve repair or replacement.