Objective-To evaluate whether a p38␣/ mitogen-activated protein kinase inhibitor, SB-681323, would limit the elevation of an inflammatory marker, high-sensitivity C-reactive protein (hsCRP), after a percutaneous coronary intervention (PCI). Methods and Results-Coronary artery stents provide benefit by maintaining lumen patency but may incur vascular trauma and inflammation, leading to myocardial damage. A key mediator for such stress signaling is p38 mitogen-activated protein kinase. Patients with angiographically documented coronary artery disease receiving stable statin therapy and about to undergo PCI were randomly selected to receive SB-681323, 7.5 mg (nϭ46), or placebo (nϭ46) Key Words: angina pectoris Ⅲ atherosclerosis Ⅲ ischemia Ⅲ stent Ⅲ vascular biology Ⅲ inflammation P ercutaneous coronary intervention (PCI) has become the predominant form of coronary artery revascularization. 1 The benefits for resolution of chronic angina and/or salvation of ischemic myocardium during acute coronary syndromes are well documented. 2 However, PCI procedures can also injure the vessel wall, generating a considerable inflammatory response and smooth muscle cell proliferation, 3,4 culminating in restenosis at the lesion site (observed in 5% to 10% of subjects during the first year after PCI). 5,6
Epidemiological data suggest that estrogen deficiency in post menopausal women may contribute to the severity of AMD. We discovered that 17β-estradiol (E 2 ) was a crucial regulator of the severity of extracelllular matrix turnover (ECM) dysregulation both in vivo and in vitro. We also found in vitro that the presence of estrogen receptor (ER)β regulates MMP-2 activity. Therefore in an attempt to delineate the role of the ER subtypes, female estrogen receptor knockout (ERKO) mice were fed a high-fat diet, and the eyes were exposed to seven 5-second doses of nonphototoxic levels of bluegreen light over 2 weeks. Three months after cessation of blue light treatment, transmission electron microscopy was performed to assess severity of deposits, Bruchs membrane changes, and choriocapillaris endothelial morphology. We found that changes in the trimolecular complex of proMMP-2, MMP-14 and TIMP-2 correlated with increased Bruch's membrane thickening or sub retinal deposit formation (basal laminar deposits) in ERKOβ mice. In addition RPE isolated from ERKO β mice had an increase in expression of total collagen and a decrease in MMP-2 activity. Finally we found that ERK an intermediate signaling molecule in the MMP pathway was activated in RPE isolated from ERKOβ mice. These data suggest that mice which lack ERβ are more susceptible to in vivo injury associated with environmental light and high fat diet.
Eyes with age-related macular degeneration (AMD) demonstrate accumulation of specific deposits and extracellular matrix (ECM) molecules under the retinal pigment epithelium (RPE). AMD is about two times more prevalent in aging postmenopausal women. Therefore we studied whether 17β-estradiol (E 2 ) modulates the expression and activity of the trimolecular complex (MMP-2, TIMP-2 and MMP-14), molecules which are of major importance for ECM turnover in RPE. We used cell lines isolated from estrogen receptor knockout mice (ERKO) to determine which ER (estrogen receptor) subtype was important for ECM regulation in RPE cells.We found that mouse RPE sheets had higher baseline MMP-2 activity in the presence of ERβ. This correlated with higher MMP-2 activity in RPE cell lines isolated from ERKOα mice. Exposure to E 2 increased MMP-2 activity in mouse RPE cell lines. In addition E 2 increased transcriptional activation of the MMP-2 promoter through a functional Sp1 site which required the presence of ERβ, but not ERα. E 2 also maintained levels of pro MMP-2, and MMP-14 and TIMP-2 activity after oxidant injury. Since the direct effects of E 2 on MMP-2 transcriptional activation and the regulation of the trimolecular complex after oxidant induced injury requires ERβ, this receptor subtype may have a role as a potential therapeutic target to prevent changes in activation of MMP-2.
The relation between time to first shock and clinical outcome was studied in 60 patients who received an automatic implantable cardioverter-defibrillator (AICD) from August 1983 through May 1988. The mean (+/- SD) patient age was 64 +/- 10 years, 82% were men and the mean ejection fraction was 33 +/- 13%. During follow-up, 38 patients (63%) had one or more shocks; there were no differences in age, gender distribution or ejection fraction at entry between the shock and no shock groups. Among 51 patients with coronary artery disease, 31 (61%) had one or more shocks, whereas all seven patients with cardiomyopathy had one or more shocks (p less than 0.05). Neither of the two patients with idiopathic ventricular fibrillation had shocks. Of the 13 deaths, 12 occurred during post-hospital follow-up and 1 during the index hospitalization. Of the four sudden post-hospital deaths, only one was due to tachyarrhythmia in the absence of acute myocardial infarction. All four sudden deaths and five of eight post-hospital nonsudden deaths occurred in patients who had had one or more appropriate shocks during follow-up. Eight of the nine first appropriate shocks among patients who subsequently died occurred within the first 3 months of follow-up, but the actual deaths were delayed to a mean of 14.1 +/- 13.9 months (p less than 0.05). The mean time to all deaths was 14.8 +/- 13.1 months. The ejection fraction was significantly lower among patients who died than among patients who survived (25 +/- 7% versus 35 +/- 14%, p less than 0.02), but it did not distinguish risk of first shocks.(ABSTRACT TRUNCATED AT 250 WORDS)
The use of membrane-active antiarrhythmic agents may be complicated by aggravation of existing arrhythmias or development of new drug-induced arrhythmias. Four patients, referred because of out-of-hospital cardiac arrest or symptomatic sustained ventricular tachycardia, were receiving class IC antiarrhythmic agents in an attempt to prevent inducibility of sustained ventricular tachycardia. New or worsening spontaneous arrhythmias developed while they were on flecainide acetate (n=3) or encainide hydrochloride (n=l) therapy. Spontaneous runs of rapid nonsustained and sustained ventricular tachycardia developed in two. Increased frequency of premature ventricular contractions and repetitive forms of ventricular ectopic activity developed in one, despite the fact that inducibility of sustained ventricular tachycardia had been prevented. Salvos and nonsustained ventricular tachycardia developed in the fourth patient. Propranolol had failed to prevent inducibility of sustained ventricular tachycardia during previous programmed stimulation studies in three of the four patients, but it reproducibly suppressed drug-induced arrhythmias that appeared only after administration of the IC agents in each patient. Suppression of the proarrhythmic effects by ,-adrenergic blockade suggests a possible interaction of these drugs with autonomic function in the genesis of the observed proarrhythmic effects. Direct pharmacologic control of proarrhythmic drug effects has not previously been reported. (Circulation 1989;80:1571-1579
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