Endometriosis: the consequence of uterine denervation-reinnervation.

Difficult intrapartum episodes and persistent straining during defecation cause injuries to uterine nerves and uterosacral ligaments. Injuries to uterine nerves (denervation) result in loss of fundocervical polarity, uterotubal dysmotility and retrograde menstruation. Ectopic endometrium, delivered by retrograde menstruation, adheres to injuries to uterosacral ligaments and peritoneal surfaces. Difficult vaginal deliveries result in laparoscopic appearances of asymmetry of uterosacral ligaments with, or without, ectopic endometrium. Straining during defaecation causes the "classic" appearances of nulliparous endometriosis including hypertrophy of the uterosacral ligaments often with large volumes of ectopic endometrium. Laparoscopic appearances depend on the site, nature, extent, and timing of tissue injury, as well as the presence of available endometrium. Tissue repair, including reinnervation in the uterine isthmus, cervix, vagina and uterosacral ligaments, contributes to chronic pelvic pain, dysmenorrhea, dyspareunia and subfertility some time after the primary injuries.

Early and sustained survival benefit associated with statin therapy at the time of percutaneous coronary intervention.

BACKGROUND: Long-term administration of statin therapy has been shown to reduce major coronary events and cardiac mortality within randomized clinical trials. In addition to lowering lipids, statins favorably affect platelet adhesion, thrombosis, endothelial function, inflammation, and plaque stability, which may potentially improve outcome after percutaneous coronary intervention (PCI). Therefore, we hypothesized that statin therapy has an early beneficial effect among patients undergoing PCI. METHODS AND RESULTS: Each year from 1993 to 1999, we prospectively collected data among the first 1000 patients undergoing PCI. Patients who presented with acute or recent myocardial infarction or cardiogenic shock were excluded from the analysis. Baseline, procedural, and 6-month data of statin-treated and non-statin-treated patients were compared. Propensity score and multivariate survival analysis were used to adjust for heterogeneity between the two groups. Of 5052 patients who completed follow-up, 26.5% were treated with statin at the time of the procedure. Statin therapy was associated with a mortality reduction at 30 days (0.8% versus 1.5%; hazard ratio, 0.53; P=0.048) and at 6 months (2.4% versus 3.6%; hazard ratio, 0.67; P=0.046). After adjusting for the propensity to receive statin therapy before the procedure and other confounders, statin therapy remained an independent predictor for survival at 6 months after coronary intervention (hazard ratio, 0.65; 95% CI, 0.42 to 0.99; P=0.045). CONCLUSIONS: In this large study cohort, statin therapy among PCI patients seems to be associated with a significant mortality advantage at early and intermediate-term follow-up.

Mortality benefit of beta-blockade after successful elective percutaneous coronary intervention.

OBJECTIVES: The goal of this study was to evaluate the mortality benefit of beta-blockers after successful percutaneous coronary intervention (PCI). BACKGROUND: Beta-blockers reduce mortality after myocardial infarction (MI), though limited data are available regarding their role after successful PCI. METHODS: Each year from 1993 through 1999, the first 1,000 consecutive patients undergoing PCI were systematically followed up. Patients presenting with acute or recent MI, shock, or unsuccessful revascularization procedures were excluded from the analysis. Clinical, procedural, and follow-up data of beta-blocker-treated and non-beta-blocker-treated patients were compared. A multivariate survival analysis model using propensity analysis was used to adjust for heterogeneity between the two groups. RESULTS: Of the 4,553 patients, 2,056 (45%) were treated with beta-blockers at the time of the procedure. Beta-blocker therapy was associated with a mortality reduction from 1.3% to 0.8% at 30 days (p = 0.13) and a reduction from 6.0% to 3.9% at one year (p = 0.0014). This survival benefit of beta-blockers was independent of left ventricular function, diabetic status, history of hypertension, or history of MI. Using propensity analysis, beta-blocker therapy remained an independent predictor for one-year survival after PCI (hazard ratio, 0.63; 95% confidence interval, 0.46 to 0.87; p = 0.0054). CONCLUSIONS: Within this large prospective registry, beta-blocker use was associated with a marked long-term survival benefit among patients undergoing successful elective percutaneous coronary revascularization.

Aspirin dose and six-month outcome after an acute coronary syndrome.

OBJECTIVES: This study was designed to compare the efficacy of low and intermediate aspirin doses in acute coronary syndromes. BACKGROUND: Little is known of the comparative efficacy of low and intermediate aspirin doses in this setting. METHODS: We compared six-month death, myocardial infarction (MI), and stroke in patients with unstable angina or acute MI discharged while receiving low (<150 mg) or intermediate (> or =150 mg) aspirin therapy in the GUSTO IIb and PURSUIT trials (n = 20,521). We used multivariable analysis and performed a propensity analysis in order to adjust for baseline imbalances between the groups. RESULTS: Aspirin doses <150 mg were prescribed to 29.9% (6,128) of patients. By six months, 6.4% of the patients (1,310 of 20,521) had a primary event, 6.2% of the patients receiving <150 mg and 6.6% of the patients receiving aspirin doses > or =150 mg (hazard ratio [HR] 1.06 [95% confidence interval (CI) 0.94 to 1.19], p = 0.35). After adjusting for baseline imbalances and the propensity score for discharge aspirin dose, there was no effect of aspirin dose on the composite end point at six months (HR 0.92 [95% CI 0.79 to 1.07], p = 0.28). However, the higher aspirin dose was associated with a reduction in six-month MI (HR 0.79 [95% CI 0.64 to 0.98], p = 0.03). The outcome was similar when patients were matched on the basis of the propensity score for aspirin dose (HR for death/MI/stroke 0.94 [95% CI 0.80 to 1.12], p = 0.51), although stroke occurred significantly more frequently among patients receiving the higher aspirin dose (HR 1.74 [95% CI 1.01 to 3.02] p = 0.05) and the effect on MI was no longer apparent. CONCLUSIONS: Although these data are non-randomized, they suggest that the aspirin dose upon discharge may influence the clinical course after unstable angina or acute MI.

Integrin alphaIIbbeta3 and its antagonism.

AlphaIIbbeta3, the major membrane protein on the surface of platelets, is a member of the integrin family of heterodimeric adhesion receptors. The alphaIIb and beta3 subunits are each composed of a short cytoplasmic tail, a single transmembrane domain, and a large, extracellular region that consists of a series of linked domains. Recent structural analyses have provided insights into the organization of this and other integrins and how a signal is initiated at its cytoplasmic tail to transform the extracellular domain of alphaIIbbeta3 into a functional receptor for fibrinogen or von Willebrand factor to support platelet aggregation and thrombus formation. These functions of alphaIIbbeta3 have been targeted for antithrombotic therapy, and intravenous alphaIIbbeta3 antagonists have been remarkably effective in the setting of percutaneous coronary interventions, showing both short-term and long-term mortality benefits. However, the development of oral antagonists has been abandoned on the basis of excess of mortality in clinical trials, and the extension of therapy with existing alphaIIbbeta3 antagonists to broadly treat acute coronary syndromes has not fully met expectations. An in-depth understanding of how antagonists engage and influence the function of alphaIIbbeta3 and platelets in the context of the new structural insights may explain its salutary and potential deleterious effects.

Characterization of a ligand-attenuated binding site on glycoprotein IIb/IIIa.

We describe an epitope on the platelet integrin, GPIIb/IIIa, identified by the monoclonal antibody, 4F8, which is attenuated by small-molecule GPIIb/IIIa ligands. 4F8 did not bind to the ligand binding pocket as it did not compete with a radiolabelled antagonist, (3)H-SC-52012. This indicates that the 4F8 epitope behaves as a ligand-attenuated binding site (LABS). Ligand-induced attenuation of 4F8 was an active process as it was prevented by pretreating platelets with cytochalasin D and reduced by prostaglandin E(1) or inhibition of protein kinase C. Disappearance of the epitope was required for full platelet activation as 4F8 prevented platelet aggregation without inhibiting fibrinogen binding. These results suggest a model where disappearance of the 4F8 epitope is a secondary event required for full "outside-in" signaling through GPIIb/IIIa.

Effect of clopidogrel pretreatment on inflammatory marker expression in patients undergoing percutaneous coronary intervention.

Platelets play an important role in the inflammatory response. In a nonrandomized comparison, we examined the effect of clopidogrel pretreatment on platelet inflammatory marker expression in patients undergoing percutaneous coronary intervention (PCI). Platelet expression of the inflammatory markers CD40 ligand (L) and CD62 P-selectin (P) and serum levels of interleukin-6 and CD40L were compared in patients pretreated (>24 hours before PCI) or not pretreated with clopidogrel. Blood samples were obtained before and after the procedure, and from 18 to 24 hours later. Marker expression in resting and adenosine diphosphate (ADP) (50 micromol/L) and thrombin receptor activating peptide (TRAP) (10 micromol/L) activated samples was quantified by flow cytometry. Serum CD40L and interleukin (IL)-6 levels were determined by enzyme-linked immunosorbent assay. Seventy-nine patients were recruited into the study. Forty-two percent were pretreated with clopidogrel for a median of 5 days (range 1 to 1,325). Clopidogrel pretreatment was associated with lower ADP-activated platelet CD40L expression in baseline and postprocedural samples. Similarly, platelet CD62P expression at all time points in ADP-activated and in baseline and postprocedural TRAP-activated samples was lower in patients pretreated with clopidogrel. These differences remained after multivariate adjustment between the groups. Serum CD40L levels increased from 2.13 +/- 2.37 ng/ml at baseline to 4.77 +/- 3.86 ng/ml at 18 to 24 hours after the procedure (p <0.0001). Similarly, serum IL-6 levels increased at 18 to 24 hours after the procedure (14.8 +/- 42.0 pg/ml before vs 25.5 +/- 36.0 pg/ml at 18 to 24 hours after the procedure, p <0.0001). Clopidogrel pretreatment did not affect serum IL-6 or CD40L levels. Thus, clopidogrel pretreatment reduces platelet inflammatory marker expression in patients undergoing PCI.

Relation between previous lipid-lowering therapy and infarct size (creatine kinase-MB level) in patients presenting with acute myocardial infarction.

Animal experimental data have shown that lipid-lowering agents reduce myocardial infarct size. This association has not been well studied in humans. We compared infarct size in 10,548 patients in the GUSTO IIb and PURSUIT trials who were (n = 1,028) or were not (n = 9,520) on lipid-lowering therapy before an enrolling myocardial infarction (MI). Patients using lipid-lowering agents before their index MI had smaller infarcts than those who were not using these agents (median peak creatine kinase [CK]-MB 4.2 vs 5.2 times the upper limit of normal [ULN]; p <0.0001). Similarly, in an unadjusted model, patients on previous lipid-lowering therapy were less likely to have a peak CK-MB >3 times the ULN (620 of 1,028 [60.3%] vs 6,486 of 9,520 patients [68.1%]; p <0.001; relative risk 0.88, 95% confidence interval 0.84 to 0.93, p <0.0001). In a covariate- and propensity-adjusted multivariable model, the association between pretreatment with lipid-lowering agents and smaller infarct size persisted (relative risk for CK-MB >3 times the ULN 0.94, 95% confidence interval 0.88 to 0.99, p = 0.04). In conclusion, patients on lipid-lowering agents before an MI had significantly smaller infarcts. These findings suggest that lipid-lowering therapy may exert additional salutary effects in the setting of acute coronary syndromes.

Early invasive strategies for acute coronary syndromes.

Early coronary angiography and percutaneous or operative revascularization is now the treatment of choice for both ST- and non-ST-segment elevation acute coronary syndromes (ACS). In non-ST-segment elevation ACS this strategy produces a 18% to 22% reduction in ischemic outcomes at 6 months and prevents 1.7 deaths, 2.0 nonfatal infarcts and 20 readmissions per 100 treated patients at 1-year follow-up. Early angiography allows definition of coronary anatomy and assessment of left ventricular function, both important predictors of long-term risk. Intracoronary stenting and intravenous glycoprotein IIb/IIIa antagonists have improved outcome in percutaneous revascularization and should be used in the majority of ACS patients undergoing PCI. Initial costs are higher with an early invasive strategy; however, these are offset by reductions in rehospitalizations and later ischemic complications.

Differences in uterine innervation at hysterectomy.

OBJECTIVE: Our purpose was to identify patterns of uterine innervation in normal uteri and selected clinical conditions including adenomyosis and chronic pelvic pain. STUDY DESIGN: A retrospective survey was performed of stored uteri removed at hysterectomy for a variety of clinical conditions, including 8 uteri from nulliparous subjects (group 1, mean age 40.0 years, range 30-52 years), 21 uteri with no reported histologic abnormality from multiparous subjects (group 2, mean age 43.4 years, range 32-53 years; mean parity 2.0, range 1-4), 31 uteri reported with adenomyosis (group 3, mean age 42.4 years, range 29-54 years; parity 2.0, range 0-4), and 17 uteri from subjects with pelvic pain (group 4, mean age 39.1 years, range 30-52 years; parity 2.5, range 1-7). Sections were cut from paraffin blocks of the isthmus of stored uteri (in the majority of cases) and stained with protein gene product 9.5 to identify nerves. Sections of pancreas provided positive controls. Each section was reviewed by two unblinded observers. RESULTS: Group 1 (n = 8, nulliparous uteri) showed significant nerve bundles at the endometrial-myometrial interface and in the subserosal layers, with nerve fibers noted in intervening neurovascular bundles supplying the myometrial stroma. Group 2 (n = 21, histologically normal uteri from parous subjects) showed patterns of innervation similar to those of group 1 with the exception that 6 uteri demonstrated areas of nerve fiber proliferation (see below, group 4). In group 3 (n = 31, uteri with adenomyosis), 30 uteri (30/31) showed large areas of myometrium without nerves and absence of nerves in the neurovascular bundles supplying these areas. Five uteri showed areas of nerve fiber proliferation at the margins of the adenomyosis. Subserosal nerves were present in the majority of these uteri. In group 4 (n = 17), uteri were removed for chronic pelvic pain. Eleven uteri demonstrated proliferation of small-diameter nerve fibers throughout the myometrium; in 6 uteri there was asymmetry of nerve fiber proliferation. CONCLUSIONS: Variations in uterine innervation were noted in the isthmic region of uteri stored after hysterectomy. Uteri with adenomyosis frequently demonstrated large areas with absence of nerve fibers; uteri from subjects with chronic pelvic pain showed proliferation of small-diameter nerve fibers throughout the myometrial stroma. Nerve fiber proliferation was asymmetric in some of these specimens.

Molecular and functional differences induced in thrombospondin-1 by the single nucleotide polymorphism associated with the risk of premature, familial myocardial infarction.

A serine (Ser-700) amino acid rather than an asparagine (Asn-700) at residue 700 of thrombospondin-1 has been linked to an increased risk for development of premature, familial heart attacks. We now have identified both functional and structural differences between the Ser-700 and Asn-700 thrombospondin-1 variants. The Ser-700 variant increased the rate and extent of platelet aggregation and showed increased surface expression on platelets compared with the Asn-700 variant. These differences could be ascribed to an enhanced interaction of the Ser-700 variant with fibrinogen on the platelet surface and are consistent with a prothrombotic phenotype in Ser-700 individuals. The Ser-700 variant thrombospondin-1 was conformationally more labile than the Asn-700 variant as demonstrated by increased susceptibility to proteolytic digestion and enhanced susceptibility to unfolding by denaturants. These data suggest a potential molecular and cellular basis for a genetic risk factor associated with early onset myocardial infarction.