Left Ventricular Reverse Remodelling After Aortic Valve Replacement in Severe Valvular Aortic Stenosis - Effect of Blockade of the Angiotensin-II Receptor

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: