eplerenone and Coronary-Restenosis

Aldosterone is known to have multiple adverse cardiovascular effects that are reminiscent of but independent from angiotensin II. These effects include endothelial dysfunction, heightened thrombogenicity, inflammation, and reparative fibrosis, and have been described in experimental and human models of aldosterone excess. Recently a number of clinical investigations have demonstrated that mineralocorticoid receptor (MR) antagonism, even in conditions not traditionally associated with systemic activation of the renin-angiotensin II-aldosterone pathway, may provide additional benefits above and beyond angiotensin-converting enzyme (ACE) inhibition and angiotensin receptor blockade. The Eplerenone Neurohormonal Efficacy and Survival Study (EPHESUS) with eplerenone in patients who were post-myocardial infarction underscores the additive benefit of such a strategy in post-infarction patients that typify an at-risk population for recurrent cardiovascular events. The mechanisms operative in acute coronary syndromes (ACS), including inflammation, altered hemostasis, and endothelial dysfunction, overlap significantly with those seen in the EPHESUS patient population. One may therefore hypothesize that MR antagonism with eplerenone may be beneficial in patients with ACS. Another advantage of using eplerenone is that it offers the advantages of MR antagonism without the side effects due to blockade of other nuclear receptors such as the androgen and progesterone receptors. If MR blockade is found to be beneficial in patients with ACS, the potential reduction in morbidity, mortality, and health care costs are profound.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Collagen; Coronary Restenosis; Eplerenone; Humans; Inflammation; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Syndrome; Thrombosis

Topics: Angioplasty, Balloon, Coronary; Animals; Collagen; Coronary Restenosis; Disease Models, Animal; Eplerenone; Humans; Hyperplasia; Mineralocorticoid Receptor Antagonists; Spironolactone; Stents; Swine; Tunica Intima

Enhanced extracellular matrix accumulation rather than cell proliferation contributes to later stages of in-stent restenosis. Aldosterone itself has been shown to increase cardiovascular fibrosis, therefore, we studied the suppressive effects of eplerenone, a new aldosterone receptor antagonist, on neointimal hyperplasia after coronary stent implantation in swine.. Palmatz-Shatz stents were implanted in the left anterior descending artery of 36 pigs. One hundred milligrams of Eplerenone was orally administered from 1 week before, to 4 weeks after stent implantation in Group E (n=18), and vehicle was given to Group C (n=18). Pigs were sacrificed 1 or 4 weeks after stent implantation. The number of infiltrating macrophages was calculated at 1 week. Morphometrical analysis was performed to measure the area of each layer, and %area of fibrosis and mRNA for collagen I, III and TGF-beta was analyzed by RT-PCR at 4 weeks.. The number of infiltrating macrophages was less in Group E than in Group C (p<0.01). The overall size of coronary arteries at 4 weeks was similar in both groups. However, the luminal area was larger in Group E than in Group C (p<0.05), and the intimal area was smaller in Group E than in Group C (p<0.05). The %area of fibrosis was significantly less in Group E than in Group C at 4 weeks (p<0.01). In Group E, the expression of mRNA for collagen I, III and TGF-beta was significantly reduced.. Orally administered eplerenone attenuated collagen accumulation within the neointima, thereby inhibiting neointimal hyperplasia after stent implantation.

Topics: Actins; Administration, Oral; Animals; Blood Vessel Prosthesis Implantation; Collagen Type I; Collagen Type III; Coronary Restenosis; Coronary Vessels; Disease Models, Animal; Eplerenone; Fibrosis; Hyperplasia; Immunohistochemistry; Macrophages; Male; Mineralocorticoid Receptor Antagonists; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spironolactone; Stents; Swine; Time Factors; Transforming Growth Factor beta; Tunica Intima