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 F2??), 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.
| Identifer | oai:union.ndltd.org:ADTP/257225 |
| Date | January 2006 |
| Creators | Kotlyar, Eugene, St Vincents Hospital Clinical School, UNSW |
| Publisher | Awarded by:University of New South Wales. St Vincents Hospital Clinical School |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Eugene Kotlyar, http://unsworks.unsw.edu.au/copyright |
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