Abstract
The pathophysiology of cardiac failure involves activation of the renin-angiotensinaldosterone
system that contributes to adverse left ventricular remodelling. This is a
complex pathologic process that has been shown to be stimulated by haemodynamic
and humoral factors including aldosterone. The precise mechanisms by which
aldosterone contributes to this process are not known.
In a mouse animal model of pressure overload induced cardiac hypertrophy and
failure, the treatment with selective mineralocorticoid receptor, eplerenone, was
shown to attenuate adverse left ventricular remodelling. This was associated with
decreases in myocardial apoptosis, collagen turnover, oxidative stress and
inflammation, in the absence of a significant blood pressure change. Furthermore, we
administered aldosterone infusion and high salt diet to uninephrectomised mice
deficient in the gp91phox subunit of NADPH oxidase and to the wild type strain. It was
demonstrated that the increase in the blood pressure did not occur in the gp91phox
deficient mice and that both wild-type and knock-out strains developed cardiac
hypertrophy, but not interstitial fibrosis. Additionally, patients with chronic stable
heart failure were also studied. We found that plasma aldosterone level was
independently associated with levels of markers for oxidative stress (of 8-
isoprostaglandin F2α), inflammation (soluble intercellular adhesion molecule-1) and
matrix turnover (tissue inhibitor of metalloproteinase-1). High plasma osteopontin
levels were also noted.
Our experiments suggest that myocardial apoptosis, collagen turnover, oxidative
stress and inflammation may be involved in mediating the adverse effects of
mineralocorticoid receptor activation in pressure overload. In addition, the
development of cardiac hypertrophy may be a haemodynamically independent
process, but gp91phox subunit deficiency did not attenuate the hypertrophic response to
aldosterone infusion when administered in conjunction with high salt diet, suggesting
that there may be another mechanism that mediates aldosterone-induced hypertrophy.
The state of increased oxidative stress and inflammation, seen in animal models, may
also play an important role in chronic heart failure subjects. The importance of local
factors in the regulation of myocardial tissue remodelling has become increasingly
evident, but future investigations are required to clarify the role of aldosterone,
oxidative stress and inflammation in heart failure.