Vascular alterations during the development and progression of experimental heart failure

Background: Congestive heart failure (HF) is a multifactorial and progressi ve condition associated with multiple systemic and vascular alterations. Th e onset and progression of these alterations and the cause of the condition remain undefined. The main purpose of the present study was to help unders tand the temporal evolution of vascular alterations and their contribution to the pathogenesis of HF. Vascular reactivity to angiotensin II (Ang II) a nd norepinephrine (NE), as well as circulating and local angiotensin-conver ting enzyme (ACE) activity, were assessed in the Syrian cardiomyopathic ham ster (SCH) model. Methods and Results: We have shown previously that in 2-month-old SCH anima ls that had not yet developed the clinical manifestations of HF, the contra ctile response of aortic rings to Ang II was markedly enhanced compared wit h normal animals. In addition, SCHs showed increased ACE activity in aortic tissue. To assess the relevance of these findings to the development and p rogression of HF, the temporal evolution of the contractile response of aor tic rings to Ang II and NE was evaluated in hamsters at 2, 6, and 11 months of age. Age-matched normal hamsters were used as controls. Within the SCH group, the maximal contraction induced to 10 mu moI/L of NE in 2- and 11-mo nth-old animals was similar, but significantly greater than in the age-matc hed controls (for 2-month-old animals; 1.43 +/- 0.21 g in SCHs v 1.04 +/- 0 .15 g in controls; P < .05 and for Ii-month-old animals; 1.41 +/- 0.14 g in SCHs v 1.06 +/- 0.07 g in controls; P < .05). The drug concentrations nece ssary to obtain 50% of the maximal response from the NE concentration-respo nse curves were similar for SCHs and controls at all ages tested. In contra st, the contractility induced by 0.1 mu mol/L of Ang II increased progressi vely in cardiomyopathic animals from 2 to 11 months of age (from 1.3 +/- 0. 1 to 1.8 +/- 0.2 g; n = 9; P < .05). In age-matched normal hamsters, the co ntractile response to Ang II (0.9 +/- 0.1 g) did not vary with age. These f indings were observed concomitantly with an increased ACE activity in plasm a (18.65 +/- 1.77 nmol/mg x min in controls v 26.5 +/- 1.79 nmol/mg x min i n SCHs; P (.05; n = 7) and in heart tissue (0.244 +/- 0.016 nmol/mg x min i n controls v 0.563 +/- 0.027 nmol/mg x min in SCHs; P < .05; n = 20) of 11- month-old SCHs. Conclusions: These results suggest that, in young animals, increased vascul ar response to elevated levels of NE and hyperreactivity to Ang II could be critical factors in the development and progression of HF. Indeed, Ang II- induced contractility, as well as plasma and heart ACE activity, are good p redictors of the progression and severity of HF.