Angiotensin AT(1) receptor inhibition in pacing induced heart failure: Effects on left ventricular myocardial collagen content and composition

The progression of left ventricular (LV) dilation with congestive heart fai lure (CHF) is associated with an increased incidence of morbidity and morta lity. The LV myocardial extracellular matrix has been implicated to play an important role in maintaining chamber shape and myocyte alignment. While a ngiotensin II AT(1) receptor (Ang AT(1)) receptor activation has been demon strated to contribute to increased vascular resistance with the CHF, whethe r activation of the myocardial Ang AT(1) receptor 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 AT(1) receptor inhibit ion on LV geometry and myocardial collagen content and structure with the d evelopment of pacing CHF. Pigs (25 kg) were instrumented in order to measur e LV function in the conscious state and were assigned to one of three grou ps: (1) Pacing CHF: rapid atrial pacing (240 bpm) for 3 weeks (n = 7): (2) Pacing CHF and Ang AT(1) Block: concomitant: Ang AT(1) receptor blockade (v alsartan, Novartis, Basel 60 mg/day) and rapid pacing (n=7); (3) sham contr ols (n=7). The Ang AT(1) receptor antagonist was delivered by osmotic minip ump and this dose has been demonstrated previously to significantly blunt t he Ang-II presser response. LV pump function and geometry was assessed by e chocardiography and LV myocardial collagen content by computer assisted his tomorphometry and biochemistry, In the pacing CI-IF group, LV fractional sh ortening was reduced (17+/-2 v 45 +/- 1%) and LV end-diastolic dimension in creased (5.91 +/- 0.09 v 3.75 +/- 0.07 cm) compared to controls (P<0.05). I n the pacing CHF and Ang AT(1) blockade group, LV pump function and dimensi ons were similar to untreated pacing CHF values. The relative content of LV myocardial fibrillar collagen was reduced with pacing CHF (7.6+/-0.4 v 11. 3+/-0.6%) compared to controls (P<0.05), and was similarly reduced in the p acing CHF and Ang AT(1) receptor blockade group (8.3+/-0.4%, P<0.05). LV my ocardial hydroxyproline was reduced with pacing CHF compared to controls (2 .35+/-0.21 v 2.89+/-0.42 mg/gdwt, P<0.05). While reduced with pacing CHF an d Ang AT(1) receptor blockade (2.54+/-0.25 mg/gdwt), this was not significa ntly different from controls (P=0.23). Ang AT(1) receptor inhibition in thi s model of CHF did not appear to favorably affect the degree of LV dilation and myocardial collagen structure. These results suggest that activation o f the myocardial Ang AT(1) receptor may not significantly contribute to LV remodelling with pacing CHF. (C) 1998 Academic Press.