Effect of Angiotensin II Receptor Blockers (ARB) on Left Ventricular Reverse Remodelling After Aortic Valve Replacement in Severe Valvular Aortic Stenosis
Effect of Angiotensin II Receptor Blockers (ARB) on Left Ventricular Reverse Remodelling After Aortic Valve Replacement in Severe Valvular Aortic Stenosis
The consequence of aortic valve stenosis (AVS) is increased pressure load on the left
 ventricle which causes left ventricular (LV) hypertrophy, and myocardial stretch will cause
 activation of cardiac peptides and activation of the renin angiotensin aldosterone system
 (RAAS). The consequence of LV hypertrophy is increased chamber-stiffness and delayed active
 LV relaxation which initially will cause diastolic and later systolic dysfunction. In heart
 failure (HF) and ischemic heart disease the degree of diastolic dysfunction has been
 demonstrated to correlate with functional class, neurohormonal activation and prognosis which
 also recently have been suggested for AVS.

 With longstanding elevated filling pressures the left atrium (LA) will dilate. Only limited
 data are available on the degree and importance of LA dilatation in AVS.

 When apparent, symptoms of HF in AVS are associated with high mortality rates. If LV systolic
 dysfunction also is present prognosis will deteriorate further. In these cases aorta valve
 replacement (AVR) is recommended. AVR will normalize pressure overload and thereby decreases
 LV hypertrophy. Previously it was believed that in time LV hypertrophy regressed towards
 normal and even normalized. Recent studies however have demonstrated that LV hypertrophy
 regression mainly happens during the first year after AVR, and little subsequent changes are
 seen during the remaining 10 years. Furthermore, patients that experience most regression of
 hypertrophy have more favourable outcome and better functional class than patients with less
 regression of hypertrophy. Thus absence of reverse remodelling is associated with poor
 outcome after AVR. Importantly the regression of LV hypertrophy is closely paralleled by
 decreasing RAAS hyperactivity.

 RAAS hyperactivity may be attenuated pharmacologically with angiotensin II receptor blockers
 (ARB) which in systemic hypertension with LV hypertrophy has been associated with reverse
 remodelling.

 The hypothesis is that in patients undergoing AVR for symptomatic AVS, 12 months post
 operative blockade of the angiotensin II receptor will accelerate LV and LA reverse
 remodelling, reduce filling pressures and suppress neurohormonal activation compared with
 conventional therapy. This will lead to improved exercise tolerance and due to improved left
 atrial function reducing the risk of atrial arrythmias.
1. Background:

 Aortic valve stenosis (AVS) is the most common valvular disease in the western world.
 The prevalence increases with age where "degenerative" changes of the aortic valve with
 thickening, accumulation of calcium and progressive dysfunction of the valve usually
 becomes apparent in patients older than 60 years. Although the development of AVS
 generally is believed to be a degenerative process more recent studies have demonstrated
 AVS is caused by a complex process of increased cellularity, lipid accumulation,
 extracellular matrix deposition, and with disease progression calcification of lesions.
 Although mild and moderate AVS generally is well tolerated severe AVS is associated with
 considerable morbidity and mortality, and valve replacement is generally required.

 The consequence of AVS is increased pressure load on the left ventricle which causes
 changes in the ventricular structure. Pressure overload causes replication of the
 sarcomeres leading to left ventricular (LV) hypertrophy, and myocardial stretch will
 cause activation of cardiac peptides and activation of the renin angiotensin aldosterone
 system (RAAS). With progression of disease, RAAS activation will, through stimulation of
 the angiotensin-II receptor mediate fibroblast proliferation, promote fibrosis and
 directly affect the extracellular matrix. The consequence of LV hypertrophy and
 interstitial fibrosis is increased chamber-stiffness and delayed active LV relaxation
 which initially will cause diastolic (increased LV end-diastolic pressure) and later in
 the disease progression also systolic dysfunction. In congestive heart failure and
 ischemic heart disease the degree of diastolic dysfunction has been demonstrated to
 correlate with functional class, neurohormonal activation and prognosis which also
 recently has been suggested for AVS. Thus, although not fully elucidated the transition
 from well compensated hypertrophy caused by pressure overload to symptomatic heart
 failure may be related to evolving diastolic dysfunction. With longstanding elevated
 filling pressures the left atrium will dilate due to chronically increased atrial
 afterload. Only limited data are available on the degree and importance of LA dilatation
 in AVS.

 When apparent, symptoms of heart failure in AVS is associated with high mortality rates.
 If LV systolic dysfunction also is present prognosis will deteriorate further. In these
 cases aorta valve replacement (AVR) is recommended. AVR will normalize pressure overload
 and thereby decreases LV hypertrophy. Previously it was believed that in time LV
 hypertrophy regressed towards normal and even normalized. More recent studies however
 have demonstrated that LV hypertrophy regression mainly happens during the first 12-18
 months after AVR, and little subsequent changes are seen during the remaining 10 years.
 Furthermore, patients that experience most regression of hypertrophy has more favourable
 outcome and better functional class than patients with less regression of hypertrophy.
 Thus absence of reverse remodelling is associated with poor outcome after AVR.
 Importantly the regression of LV hypertrophy is closely paralleled by decreasing RAAS
 hyperactivity.

 RAAS hyperactivity may be attenuated pharmacologically using angiotensin converting
 enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) which in systemic
 hypertension with LV hypertrophy has been associated with reverse remodelling. This may
 at least partly be associated with increased collagenase activity and depressed collagen
 synthesis. Thus attenuation of RAAS hyperactivity may in theory lead to decreased
 myocardial fibrosis and improving the diastolic function of the LV. The effect of ARB
 treatment in patients with AVS that have undergone AVR is not known.

 2. Hypothesis:

 In patients undergoing AVR for symptomatic valvular aortic stenosis, 12 months post
 operative blockade of the angiotensin II receptor will accelerate LV and LA reverse
 remodelling, reduce filling pressures and suppress neurohormonal activation compared
 with conventional therapy. This will lead to improved exercise tolerance and due to
 improved left atrial function reducing the risk of atrial arrythmias.

 3. Specific Objectives:

 3.1 Primary Objectives

 -  In a consecutive population undergoing AVR for symptomatic AVS to compare

 1. LV mass index

 2. LA volume index

 3. Plasma nt-pro BNP concentration after 12 months treatment with candesartan
 compared with conventional treatment

 3.2 Secondary Objectives

 -  In a consecutive population undergoing AVR for symptomatic AVS to compare

 1. Diastolic E/e' ratio

 2. Overall LV function assessed by the Doppler echocardiographic Tei Index

 3. Regional LV function assessed with tissue Doppler imaging

 4. LV end systolic and end diastolic volume index after 12 months treatment with
 candesartan compared with conventional treatment.

 3.3 Tertiary Objectives

 -  In a consecutive population undergoing AVR for symptomatic AVS to compare the
 occurrence and atrial arrhythmias assessed with 48h Holter after 12 months
 treatment with candesartan compared with conventional management.

 -  In a consecutive population undergoing AVR for symptomatic AVS to compare exercise
 capacity after 12 months treatment with candesartan compared with conventional
 management.

 -  In a consecutive population undergoing AVR for symptomatic AVS to assess serial
 changes in LV diastolic, overall LV function and regional LV systolic function 12
 months after valve replacement

 -  In a consecutive population undergoing AVR for symptomatic AVS to assess serial
 changes in plasma nt-pro BNP, ANP, and renin 12 months after valve replacement.

 4. Methods:

 4.1 Design

 The study is a prospective single center randomized study (PROBE design). Eligible patients
 will be randomized to either conventional management or conventional management and 12 months
 treatment with candesartan. Treatment with candesartan will be unblinded but all
 neurohormonal analyses and analyses of LV and LA size and function will be performed blinded
 for treatment allocation and clinical data.

 4.4 Study Procedures

 Patients scheduled for elective aortic valve replacement for severe AVS at Odense University
 Hospital will consecutively be offered participation in the study at hospital admission (2
 days prior to surgery). If patient consent is obtained patients will undergo the study
 program. Baseline echocardiography, neurohormonal analyses, and 6 min walk test will be
 performed the day before surgery. After surgery and when the patient is transferred from
 cardiac intensive care unit to step down unit treatment with candesartan (Atacand®) 8 mg
 daily is initiated, and during hospitalization patients are titrated to 32 mg. After hospital
 discharge patients will be followed in the heart failure clinic at Odense University
 Hospital. Study medication will be handed to the patient at each visit.

 Enrollment is planned to start February 2006 and continue for 18 months or until 140 patients
 have been enrolled.

 4.4.1 Echocardiography

 Doppler echocardiography will be performed prior to valve replacement, and repeated 3, 6, and
 12 months after surgery. Examinations will be performed on a GE medical Vivid 5 ultrasound
 machine. Images will be obtained from the parasternal and apical windows. M-mode recordings
 will be done in the parasternal long-axis view. Pulsed Doppler measurements of mitral inflow
 will be obtained with the transducer in the apical four-chamber view, with a 1-2 mm Doppler
 sample volume placed between the tips of mitral leaflets during diastole. Tissue Doppler
 imaging of the mitral annulus will be obtained from the apical 4-chamber view with a 1.5-mm
 sample volume placed at the medial mitral annulus. All Doppler echocardiographic examinations
 are done with horizontal sweep set to 100 mm/s. At least 3-5 cardiac cycles will be measured.
 Finally color coded real time tissue Doppler images will be acquired in the apical windows.

 -  End-systolic, end-diastolic volume and ejection fraction will be calculated according to
 the Simpson modified biplane method.

 -  LV mass will be estimated using the recommendations of the American Society of
 Echocardiography.

 -  Maximal left atrial volume will be measured at end-systole with the use of two
 orthogonal apical views.

 -  From the pulsed wave mitral inflow signal, peak E wave velocity, peak A wave velocity,
 and mitral E-wave deceleration time will be measured. From pulsed wave Doppler recording
 of LV outflow ejection time will be recorded. From these recordings Tei index will be
 assessed.

 -  From peak tricuspid regurgitant velocity and size of inferior v. cava pulmonary arterial
 systolic pressure will be estimated.

 -  From the tissue Doppler assessment of the medial mitral annulus early (E') diastolic
 velocity will be recorded. Diastolic function will be graded in grades 0-3 and diastolic
 E/e' ratio calculated.

 -  From color coded tissue Doppler images systolic longitudinal fibre shortening will be
 assessed using tissue tracking, and systolic strain will be assessed on a regional
 basis.

 4.4.2 Neurohormonal Analyses

 Prior to surgery and at each follow-up visit venous blood samples will be drawn for analysis
 of plasma N-terminal proBNP, and of plasma N-terminal ANP concentrations. In addition prior
 to surgery and after 6 and 12 months treatment with candesartan RAAS activity will be
 assessed using plasma-renin activity, plasma-aldosterone, and plasma-noradrenalin. In
 addition plasma will be frozen at each visit for possible later analysis.

 4.4.3 Six Minutes Walk Test

 A 6 min. walk test will be performed at baseline and at each outpatient visit (3, 6, 9 and 12
 month).

 4.4.3 Holter Monitoring

 At the 12 months visit a 2-channel 48 hours Holter monitoring will be performed and analyzed
 for occurrence of atrial arrhythmias.

 4.4.4 Blood Pressure

 Measurement of blood pressure will be done standardized after 30 min of rest at each visit.
 Target blood pressure will be 140/80 mmHg or less and treatment instituted when appropriate.

 4.4.5 Study Events

 During the study period hospitalizations for worsening of heart failure, fatal / nonfatal
 stroke, fatal/nonfatal acute coronary syndrome, hospitalization for atrial arrhythmias, and
 death from all causes will be recorded.
Inclusion Criteria:

 1. Symptomatic severe AVS referred for valve replacement (mechanic prosthesis or
 bioprosthesis) at Odense University Hospital

 2. Signed informed consent

 Exclusion Criteria:

 1. Severe renal failure (s-creatinine >300 mmole/l)

 2. Moderate or severe hepatic failure

 3. Moderate or severe LV systolic dysfunction (LVEF<40%)

 4. Patients already treated with ACE-I or ARB

 5. Known intolerance for ARB

 6. Unwilling to participate in the study

 7. Poor echocardiographic window

 8. Pregnant women