Angiotension AT1Receptor Inhibition in Pacing Induced Heart Failure: Effects on Left Ventricular Myocardial Collagen Content and Composition

Abstract

The progression of left ventricular (LV) dilation with congestive heart failure (CHF) is associated with an increased incidence of morbidity and mortality. The LV myocardial extracellular matrix has been implicated to play an important role in maintaining chamber shape and myocyte alignment. While angiotensin II AT1receptor (Ang AT1) receptor activation has been demonstrated to contribute to increased vascular resistance with the CHF, whether activation of the myocardial Ang AT1receptor system contributes to LV dilation and myocardial collagen remodelling with CHF remains unclear. The goal of this study was to examine the effects of Ang AT1receptor inhibition on LV geometry and myocardial collagen content and structure with the development of pacing CHF. Pigs (25 kg) were instrumented in order to measure LV function in the conscious state and were assigned to one of three groups: (1) Pacing CHF: rapid atrial pacing (240 bpm) for 3 weeks (n=7); (2) Pacing CHF and Ang AT1Block: concomitant Ang AT1receptor blockade (valsartan, Novartis, Basel 60 mg/day) and rapid pacing (n=7); (3) sham controls (n=7). The Ang AT1receptor antagonist was delivered by osmotic minipump and this dose has been demonstrated previously to significantly blunt the Ang-II pressor response. LV pump function and geometry was assessed by echocardiography and LV myocardial collagen content by computer assisted histomorphometry and biochemistry. In the pacing CHF group, LV fractional shortening was reduced (17±2v45±1%) and LV end-diastolic dimension increased (5.91±0.09v3.75±0.07 cm) compared to controls (P<0.05). In the pacing CHF and Ang AT1blockade group, LV pump function and dimensions were similar to untreated pacing CHF values. The relative content of LV myocardial fibrillar collagen was reduced with pacing CHF (7.6±0.4v11.3±0.6%) compared to controls (P<0.05), and was similarly reduced in the pacing CHF and Ang AT1receptor blockade group (8.3±0.4%,P<0.05). LV myocardial hydroxyproline was reduced with pacing CHF compared to controls (2.35±0.21v2.89±0.42 mg/gdwt,P<0.05). While reduced with pacing CHF and Ang AT1receptor blockade (2.54±0.25 mg/gdwt), this was not significantly different from controls (P=0.23). Ang AT1receptor inhibition in this model of CHF did not appear to favorably affect the degree of LV dilation and myocardial collagen structure. These results suggest that activation of the myocardial Ang AT1receptor may not significantly contribute to LV remodelling with pacing CHF.