Outcomes of transcatheter aortic valve implantation compared with surgical aortic valve replacement in geriatric patients with chronic kidney disease
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BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a less invasive treatment modality for patients with severe aortic valve stenosis (AS) who are at a higher risk if they have surgery. Preoperative chronic kidney disease (CKD) influences outcomes of cardiac surgery and is associated with a higher mortality and more complicated hospital course. The aims of our study were to evaluate the comparative outcomes of TAVI versus surgical aortic valve replacement (SAVR) in geriatric patients with preoperative CKD. MATERIALS AND METHODS: We prospectively collected data on patients > 75 years of age who underwent either SAVR or TAVI at Shaare Zedek Medical Center, Jerusalem, Israel. The outcomes studied were postoperative acute kidney injury (AKI), in-hospital and long-term mortality, and major neurologic and infectious morbidity. RESULTS: A total of 318 patients were analyzed, of those, 199 and 119 underwent SAVR and TAVI, respectively. In patients with CKD, there was no statistically significant difference in postoperative AKI. SAVR patients had significantly higher in-hospital mortality (OR 5.9; 95% CI 1.6 - 29.6, p = 0.02), postoperative infection (OR 4.2; 95% CI 1.6 - 12.4, p = 0.005), and longer duration of hospital stay. Mortality at 1 and 2 years was lower in the SAVR group, although the difference was not statistically significant (p = 0.059). CONCLUSION: For elderly patients with CKD who are at a higher risk if they have surgery. TAVI offers a good alternative with lower procedural risk.
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Hyponatremia Predicts Poor Outcomes in Patients With Chronic Kidney Disease Undergoing Heart Operation.

BACKGROUND: Preoperative hyponatremia adversely affects outcomes of cardiothoracic operation. However, in patients with chronic kidney disease, the association of sodium levels on postoperative events has never been evaluated. We investigated the impact of preoperative hyponatremia on outcomes after cardiac operation in patients with non-dialysis-dependent chronic kidney disease. Primary end points were operative mortality and acute kidney injury that required dialysis. Secondary end points were major infection and long-term survival. METHODS: The study is observational and includes all patients with stage III to IV chronic kidney disease (non-dialysis) undergoing cardiac operation between February 2000 and January 2016. Patients were stratified into two groups by preoperative sodium levels: sodium less than 135 mEq/L and sodium of 135 mEq/L or more. RESULTS: There were 1,008 patients (mean estimated glomerular filtration rate [GFR]: 43 ± 14 mL • min-1 • 1.73 m-2) with 92 patients (9%) in the low-sodium group. Patients with low sodium had higher operative mortality (p = 0.0004), need for new dialysis (p = 0.0008), and infection (p = 0.002). Predictors of operative mortality were European System for Cardiac Operative Risk Evaluation (EuroSCORE) (hazard ratio [HR] 1.03. 95% confidence interval [CI]: 1.02 to 1.05, p < 0.0001), decreasing values of sodium (HR 1.14. 95% CI: 1.07 to 1.2, p = 0.0002), and decreasing values of GFR (HR 1.01, 95% CI: 1.003 to 1.03, p = 0.007). Sodium less than 135 mEq/L was independently associated with increased need for dialysis (HR 1.3, 95% CI: 1.1 to 1.7, p = 0.0008). By linear regression, decreasing values of preoperative sodium were proportionate to the incidence of operative mortality (p < 0.0001) and need for dialysis (p < 0.0001). CONCLUSIONS: Preoperative hyponatremia is a predictor of increased mortality and other adverse events in patients with non-dialysis-dependent chronic kidney disease undergoing cardiac operation. These findings are similar to those in hyponatremic patients without kidney disease.

Preoperative aldosterone receptor blockade and outcomes of cardiac surgery in patients with chronic kidney disease
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BACKGROUND AND AIMS: Recent clinical evidence demonstrates that chronic low-dose mineralocorticoid receptor antagonists (MRA), when added to optimal treatment, result in reductions in cardiovascular mortality. However, continuation of MRAs before cardiac surgery in patients with CKD has never been evaluated and its potential benefit or harm in this specific clinical setting is largely unknown. MATERIALS AND METHODS: This is an observational study that included adult CKD patients undergoing cardiac surgery. Patients were divided into two groups according to preoperative use of spironolactone (SPL). The studied outcomes were postoperative acute kidney injury (AKI) requiring dialysis, mortality, and major morbidities (cardiovascular, neurologic, and infectious). RESULTS: Data on 698 patients with preoperative CKD stage III and IV were analyzed: 99 received SPL preoperatively and 599 did not. At baseline, patients on SPL had higher EuroScore and had more complicated surgery. No significant differences in the incidence of postoperative AKI, myocardial infarction (MI), cardiovascular accident (CVA), sepsis, and mortality were detected between groups in both univariate and multivariate analyses. However, incidence of postoperative low cardiac output state (p < 0.008) was significantly higher in the SPL group. Propensity score matching analyses yielded similar results. CONCLUSIONS: Although SPL is usually administered to significantly sicker patients, its use is not associated with increased major postoperative complications. However, the modulating effect of SPL in this clinical study remains to be elucidated in a prospective randomized trial.
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Neutrophil-Lymphocyte Ratio: Prognostic Impact in Heart Surgery. Early Outcomes and Late Survival.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) is a recognized marker of inflammation associated with poor outcomes in various clinical situations. We analyzed the prognostic significance of preoperative elevated NLR in patients undergoing cardiac surgery. METHODS: We performed a retrospective review of 3,027 consecutive patients undergoing cardiac surgery. Receiver-operating-characteristic was used to determine the cutoff value for elevated NLR. Multivariate regression was used to determine the predictive value of preoperative NLR on clinical outcomes. Cox proportional hazards functions were used to determine predictors of late events. Late survival data to 16 years was obtained from the Ministry of Interior. RESULTS: The cutoff value for elevated NLR was 2.6. Patients with elevated NLR were older (p < 0.0001), had a higher incidence of cardiac comorbidity (p < 0.0001), and higher European System for Cardiac Operative Risk Evaluation score (p < 0.0001). An elevated NLR emerged as an independent predictor of operative mortality (hazard ratio [HR] 2.15, 95% confidence interval [CI]: 1.51 to 3.08, p < 0.0001); pleural effusion (HR 1.42, 95% CI: 1.13 to 1.80, p = 0.003); low output syndrome (HR 1.54, 95% CI: 1.23 to 1.93, p = 0.0002); prolonged ventilation (HR 1.49, 95% CI: 1.23 to 1.82, p = 0.0001); or composite outcomes (HR 1.61, 95% CI: 1.36 to 1.91, p < 0.0001). The NLR emerged as an independent predictor of late mortality (HR 1.19, 95% CI: 1.11 to 1.28; p < 0.0001). CONCLUSIONS: Elevated NLR is associated with a higher incidence of adverse outcomes after cardiac surgery. It is a predictor of operative as well as late mortality. Further studies are warranted to determine whether prophylactic treatment with antiinflammatory agents can prevent such outcomes. It may be warranted to include the baseline NLR as another variable in risk stratification of patients about to undergo cardiac surgery.

Preoperative hemoglobin and outcomes in patients with CKD undergoing cardiac surgery.

BACKGROUND AND OBJECTIVES: Preoperative anemia adversely affects outcomes of cardiothoracic surgery. However, in patients with CKD, treating anemia to a target of normal hemoglobin has been associated with increased risk of adverse cardiac and cerebrovascular events. We investigated the association between preoperative hemoglobin and outcomes of cardiac surgery in patients with CKD and assessed whether there was a level of preoperative hemoglobin below which the incidence of adverse surgical outcomes increases. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This prospective observational study included adult patients with CKD stages 3-5 (eGFR<60 ml/min per 1.73 m(2)) undergoing cardiac surgery from February 2000 to January 2010. Patients were classified into four groups stratified by preoperative hemoglobin level: <10, 10-11.9, 12-13.9, and ≥ 14 g/dl. The outcomes were postoperative AKI requiring dialysis, sepsis, cerebrovascular accident, and mortality. RESULTS: In total, 788 patients with a mean eGFR of 43.5 ± 3.7 ml/min per 1.73 m(2) were evaluated, of whom 22.5% had preoperative hemoglobin within the normal range (men: 14-18 g/dl; women: 12-16 g/dl). Univariate analysis revealed an inverse relationship between the incidence of all adverse postoperative outcomes and hemoglobin level. Using hemoglobin as a continuous variable, multivariate logistic regression analysis showed a proportionally greater frequency of all adverse postoperative outcomes per 1-g/dl decrement of preoperative hemoglobin (mortality: odds ratio, 1.38; 95% confidence interval, 1.23 to 1.57; P<0.001; sepsis: odds ratio, 1.31; 95% confidence interval, 1.14 to 1.49; P<0.001; cerebrovascular accident: odds ratio, 1.31; 95% confidence interval, 1.00 to 1.67; P=0.03; postoperative hemodialysis: odds ratio, 1.38; 95% confidence interval, 1.11 to 1.75; P<0.01). Moreover, preoperative hemoglobin<12 g/dl was an independent risk factor for postoperative mortality (odds ratio, 2.6; 95% confidence interval, 1.1 to 7.3; P=0.04). CONCLUSIONS: Similar to the general population, preoperative anemia is associated with adverse postoperative outcomes in patients with CKD. Whether outcomes could be improved by therapeutically targeting higher preoperative hemoglobin levels before cardiac surgery in patients with underlying CKD remains to be determined.

[Does mitral valve annuloplasty improve long-term survival in patients having moderate ischemic mitral regurgitation undergoing CABG?].

BACKGROUND: The best surgical approach for patients with moderate ischemic mitral regurgitation (IMR) is still undetermined. We examined long term outcomes in patients with moderate IMR undergoing coronary bypass (CABG), and compared outcomes between those undergoing isolated CABG to those undergoing concomitant restrictive annuloplasty. METHODS: Between the years 1993-2011, 231 patients with moderate IMR underwent CABG: group 1 (n = 186) underwent isolated CABG, group 2 (n = 15) underwent CABG with concomitant mitral valve annuloplasty. Univariate analysis was used to compare baseline parameters. Kaplan-Meier estimates were used to compare survival. Cox multivariate regression was used to determine predictors for late survival. Survival data up to 20 years is 97% complete. RESULTS: The groups were similar with respect to age, prior MI, LV function, and incidence of atrial fibrillation. Patients undergoing mitral repair had a higher incidence of congestive heart failure (CHF) (p < 0.0001). After surgery more repair patients required use of inotropes (p = 0.0005). Overall operative mortality was 7% and similar between groups. Ten year survival was 55% and 52% for groups 1 and 2 respectively (p = 0.2). Predictors of late mortality included age, CHF, LV dimensions and LV dysfunction. Neither the addition of a mitral procedure and type of ring implanted nor residual MR after surgery, emerged as predictors of survival. CONCLUSIONS: In patients with moderate ischemic MR, neither operative mortality nor long term survival are affected by the performance of a restrictive annuloplasty. For patients with CHF, mitral repair may be beneficial in terms of survival.

Comparison between transcatheter and surgical aortic valve replacement: a single-center experience.

BACKGROUND AND AIM OF THE STUDY: A comparison was made of the outcomes after transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (AVR) in high-risk patients. METHODS: All patients aged > 75 years that underwent a procedure for severe aortic stenosis with or without coronary revascularization at the authors' institution were included in the study; thus, 64 patients underwent TAVI and 188 underwent AVR. Patients in the TAVI group were older (mean age 84 +/- 5 versus 80 +/- 4 years; p < 0.0001) and had a higher logistic EuroSCORE (p = 0.004). RESULTS: Six patients (9%) died during the procedure in the TAVI group, and 23 (12%) died in the AVR group (p = 0.5). Predictors for mortality were: age (p < 0.0001), female gender (p = 0.02), and surgical valve replacement (p = 0.01). Gradients across the implanted valves at one to three months postoperatively were lower in the TAVI group (p < 0.0001). Actuarial survival at one, two and three years was 78%, 64% and 64%, respectively, for TAVI, and 83%, 78% and 75%, respectively, for AVR (p = 0.4). Age was the only predictor for late mortality (p < 0.0001). CONCLUSION: TAVI patients were older and posed a higher predicted surgical risk. Procedural mortality was lower in the TAVI group, but mid-term survival was similar to that in patients undergoing surgical AVR. Age was the only predictor for late survival. These data support the referral of high-risk patients for TAVI.

Diagnosis and treatment of early bioprosthetic malfunction in the mitral valve position due to thrombus formation.

Bioprosthetic valve thrombosis is uncommon and the diagnosis is often elusive and may be confused with valve degeneration. We report our experience with mitral bioprosthetic valve thrombosis and suggest a therapeutic approach. From 2002 to 2011, 149 consecutive patients who underwent mitral valve replacement with a bioprosthesis at a single center were retrospectively screened for clinical or echocardiographic evidence of valve malfunction. Nine were found to have valve thrombus. All 9 patients had their native valve preserved, representing 24% of those with preserved native valves. Five patients (group 1) presented with symptoms of congestive heart failure at 16.4 ± 12.4 months after surgery. Echocardiogram revealed homogenous echo-dense film on the ventricular surface of the bioprosthesis with elevated transvalvular gradient, resembling early degeneration. The first 2 patients underwent reoperation: valve thrombus was found and confirmed by histologic examination. Based on these, the subsequent 3 patients received anticoagulation treatment with complete thrombus resolution: mean mitral gradient decreased from 23 ± 4 to 6 ± 1 mm Hg and tricuspid regurgitation gradient decreased from 83 ± 20 to 49 ± 5 mm Hg. Four patients (group 2) were asymptomatic, but routine echocardiogram showed a discrete mass on the ventricular aspect of the valve: 1 underwent reoperation to replace the valve and 3 received anticoagulation with complete resolution of the echocardiographic findings. In conclusion, bioprosthetic mitral thrombosis occurs in about 6% of cases. In our experience, onset is early, before anticipated valve degeneration. Clinical awareness followed by an initial trial with anticoagulation is warranted. Surgery should be reserved for those who are not responsive or patients in whom the hemodynamic status does not allow delay. Nonresection of the native valve at the initial operation may play a role in the origin of this entity.

Very prolonged stay in the intensive care unit after cardiac operations: early results and late survival.

BACKGROUND: Prolonged intensive care unit (ICU) stay is a surrogate for advanced morbidity or perioperative complications, and resource utilization may become an issue. It is our policy to continue full life support in the ICU, even for patients with a seemingly grim outlook. We examined the effect of duration of ICU stay on early outcomes and late survival. METHODS: Between 1993 and 2011, 6,385 patients were admitted to the ICU after cardiac surgery. Patients were grouped according to length of stay in the ICU: group 1, 2 days or less (n = 4,631; 73%); group 2, 3 to 14 days (n = 1,423; 22%); group 3, more than 14 days (n = 331; 5%). Length of stay in ICU for group 3 patients was 38 ± 24 days (range, 15 to 160; median 31). Clinical profile and outcomes were compared between groups. RESULTS: Patients requiring prolonged ICU stay were older, underwent more complex surgery, had greater comorbidity, and a higher predicted operative mortality (p < 0.0001). They had a higher incidence of adverse events and increased mortality (p < 0.0001). Of the 331 group 3 patients, 60% were discharged: survival of these patients at 1, 3, and 5 years was 78%, 65%, and 52%, respectively. Operative mortality as well as late survival of discharged patients was proportional to duration of ICU stay. CONCLUSIONS: Current technology enables keeping sick patients alive for extended periods of time. Nearly two thirds of patients requiring prolonged ICU leave hospital, and of these, 50% attain 5-year survival. These data support offering full and continued support even for patients requiring very prolonged ICU stay.

Preoperative renal dysfunction and clinical outcomes of cardiac surgery in octogenarians.

BACKGROUND: The proportion of elderly individuals is growing and the prevalence of chronic kidney disease (CKD) among elderly people undergoing cardiac surgery is increasing constantly. The aim of this study was to determine the influence of different degrees of preoperative renal dysfunction on postoperative outcomes in patients older than 80years of age. METHODS: This is an observational study that included adult patients undergoing cardiac surgery in which data were collected prospectively. Patients were divided into groups according to their preoperative plasma creatinine and eGFR levels. RESULTS: From February 1997 to January 2010, 318 octogenarians underwent cardiac surgery. Of these, 140 patients (44%) had abnormal preoperative creatinine levels. A significantly higher incidence of postoperative sepsis (4% vs. 17%, p 0.03), CVA (1% vs. 6%, p 0.03), and prolonged hospital stay (16±13 vs. 20±16days, p 0.04) were detected in patients with preoperative kidney dysfunction. Subgroup analysis revealed that preoperative CKD stage IV (eGFR 15-30ml/min/1.73m(2)) but not CKD stage III (eGFR 30-60ml/min/1.73m(2)) and preoperative creatinine >1.8mg/dl were independently associated with increased incidence of postoperative CVA (OR 4; 95% CI 0.07-0. 8, p=0.05 for eGFR, and OR 7.8; 95% CI 1.2-60, p=0.003 for creatinine). However, no significant increment in postoperative mortality with decreasing eGFR or increasing preoperative creatinine was demonstrated. CONCLUSIONS: A substantial increase in the risk of postoperative CVA and sepsis, but not mortality, was demonstrated in octogenarians with advanced but not mild degrees of preoperative CKD. Compared to younger patients, a high burden of comorbidities in octogenarians may have a greater influence on outcomes post cardiac surgery than impaired renal function. Our data may provide a rationale for modified risk stratification in octogenarian candidates for cardiac surgery.

Influence of minimal changes in preoperative renal function on outcomes of cardiac surgery.

BACKGROUND/AIMS: Cardiovascular morbidity and mortality are high in patients with chronic kidney disease. We evaluated the influence of small differences in preoperative kidney function on mortality and complications following cardiac surgery. METHODS: This is an observational study that included adult patients undergoing cardiac surgery. Preoperative estimated glomerular filtration rate (eGFR) was estimated by the 4-component Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations based on preoperative creatinine levels. For analysis, patients were divided into groups according to their preoperative creatinine (0.2 mg/dl increments) and eGFR levels (15-30 ml/min/1.73 m(2) decrements). RESULTS: Data on 5,340 patients were analyzed. A significant increase in postoperative mortality was demonstrated with preoperative creatinine at high-normal versus low-normal values (OR 1.7, 95% CI: 1-2.5; p = 0.02). For preoperative creatinine >1.2 mg/dl, adjusted OR for in-hospital mortality increased stepwise with every 0.2-mg/dl increment of creatinine. In addition, a statistically significant increment of mortality was detected with every 15-ml/min/1.73 m(2) decrement in preoperative eGFR. CONCLUSIONS: Minimal changes of preoperative kidney function are associated with a substantial increase in the risk of mortality and morbidity following cardiac surgery. Even within the 'normal' range, minimal increases in serum creatinine levels are associated with increased risk of adverse events postoperatively.

Surgery for ischemic mitral regurgitation: should the valve be repaired?

BACKGROUND AND AIM OF THE STUDY: Patients with ischemic cardiomyopathy undergoing coronary artery bypass grafting (CABG) often have concomitant mitral regurgitation (MR). Repairing the valve at the time of surgery is not universally accepted. The results of CABG with or without mitral valve annuloplasty (MVA) were compared in patients with reduced left ventricular (LV) function and ischemic MR. METHODS: Among a total of 195 patients, 108 underwent isolated CABG, and 87 underwent CABG with MVA. The study end-points included survival, degree of MR, and NYHA functional class. RESULTS: Patients in the MVA group were younger (mean age 63 +/- 10 versus 68 +/- 9 years; p <0.001), but had a more severe cardiac pathology, with severe LV dysfunction in 45% versus 26% (p = 0.006) and severe MR in 82% versus 14% (p < 0.001). The operative mortality was 9%, and similar in both groups. The follow up was complete, with a mean survival period of 87 +/- 50 months. Although, overall, no improvement was seen in LV function, symptomatic improvement was more pronounced in the MVA group (p = 0.006). At follow up, residual MR was present in 2% of the MVA group and in 47% of the CABG-only group (p < 0.0001). For the MVA and CABG-only groups, respectively, survival at five and 10 years was 68% and 46% versus 77% and 52% (p = NS). By multivariate analysis, neither degree of MR nor LV function at follow up had any impact on survival. CONCLUSION: In patients with a reduced LV function undergoing CABG, the addition of a mitral annuloplasty does not increase the operative risk. Although patients in the MVA group were more ill, there was a better symptomatic improvement in this group, and they attained a similar survival. It is recommended that MVA be performed at the time of CABG in patients having moderate or greater MR associated with a reduced LV function.

The possible risk for strokes complicating cardiac surgery in patients with intraoperative hypothermia.

BACKGROUND: The effect of hypothermia as a possible neuroprotective tool on the outcome of cardiac surgery is still controversial. METHODS: We retrospectively assessed all patients who underwent cardiac surgery within a 14-year period and compared patients with and without postoperative stroke. RESULTS: Stroke occurred more frequently in patients who underwent valve repair/replacement combined with coronary artery bypass grafting (CABG) than in patients who had CABG alone (p = 0.0002). All strokes (1.4%) were ischemic and mostly of large-vessel etiology. All patients with stroke had intraoperative minimal temperature <34°C. More patients in this group than in the group without stroke had an intraoperative minimal temperature <30°C (p = 0.01). Stepwise multivariate analysis of all pre- and intraoperative parameters identified significant risk factors for stroke: hypertension, diabetes mellitus and previous stroke as preoperative risk factors, but only lower minimal temperature as a significant intraoperative risk factor (p = 0.03; odds ratio 1.080/1°C, 95% confidence interval 1.004-1.152). The mean intraoperative temperature was 28 ± 4°C in patients who developed stroke and 30 ± 3°C in patients without stroke. CONCLUSIONS: Intraoperative hypothermia around 28°C might be harmful and associated with increased risk for postsurgical stroke.

Repair of ischemic mitral regurgitation: comparison between flexible and rigid annuloplasty rings.

BACKGROUND: The surgical treatment of ischemic mitral regurgitation (MR) usually involves implantation of an annuloplasty ring. We compared results of mitral valve repair using a flexible or a rigid annuloplasty ring in patients with ischemic MR undergoing coronary artery bypass graft surgery. METHODS: There were 169 patients. A flexible ring was implanted in 117 and a rigid ring in 52. Age and clinical profile, degree of left ventricular dysfunction, and degree of MR (mean 3.2) were similar between groups. RESULTS: Operative mortality was 9% in each group. Follow-up (58 +/- 30 months for flexible group and 14 +/- 7 months for rigid group) was available for 91%. For the flexible and rigid ring groups, respectively, mean New York Heart Association functional class was 1.9 and 1.6, with 33% and 14% in classes III to IV (p = 0.03); mean MR grade was 1.25 and 0.7 (p = 0.006). There was no difference in left ventricle function or dimensions. At follow-up, 29 patients (34%) in the flexible group had residual MR of moderate degree or greater compared with 6 (15%) in the rigid group (p = 0.03). Mean tricuspid incompetence gradient was 39 and 34 mm Hg (p = nonsignificant); however, the degree of reduction was greater in the rigid group (p = 0.001). Late mortality was observed in 32 patients, all in the flexible group. CONCLUSIONS: Clinical and hemodynamic results are better with rigid mitral annuloplasty rings compared with flexible rings. That result may be due to ring design, which dictates not only the annular diameter but also annular configuration. Longer follow-up is needed to determine differences in survival.

Activation of estrogen receptor-beta regulates hippocampal synaptic plasticity and improves memory.

Estrogens have long been implicated in influencing cognitive processes, yet the molecular mechanisms underlying these effects and the roles of the estrogen receptors alpha (ERalpha) and beta (ERbeta) remain unclear. Using pharmacological, biochemical and behavioral techniques, we demonstrate that the effects of estrogen on hippocampal synaptic plasticity and memory are mediated through ERbeta. Selective ERbeta agonists increased key synaptic proteins in vivo, including PSD-95, synaptophysin and the AMPA-receptor subunit GluR1. These effects were absent in ERbeta knockout mice. In hippocampal slices, ERbeta activation enhanced long-term potentiation, an effect that was absent in slices from ERbeta knockout mice. ERbeta activation induced morphological changes in hippocampal neurons in vivo, including increased dendritic branching and increased density of mushroom-type spines. An ERbeta agonist, but not an ERalpha agonist, also improved performance in hippocampus-dependent memory tasks. Our data suggest that activation of ERbeta can regulate hippocampal synaptic plasticity and improve hippocampus-dependent cognition.

Termination of pseudopregnancy in the rat alters the response to progesterone, chlordiazepoxide, and MK-801 in the elevated plus-maze.

RATIONALE: Allopregnanolone, a neurosteroid-reduced metabolite of progesterone, is a well-documented positive modulator of the gamma-aminobutyric type A (GABA(A)) receptor. As has been reported for other positive modulators of the GABA(A) receptor, chronic exposure to neurosteroids is hypothesized to decrease GABA(A) receptor function. Drawing from the literature on chronic exposure to benzodiazepines or alcohol, putative changes in N-methyl-D-aspartate (NMDA) receptor function are also expected after chronic neurosteroid exposure. OBJECTIVES: To assess the sensitivity of the GABA(A) and NMDA receptors after chronic elevation of neurosteroid produced by termination of pseudopregnancy in behavioral tests of anxiety and sensorimotor coordination. METHODS: Female rats ovariectomized on day 10 of pseudopregnancy were tested in the elevated plus-maze and on the rotor rod after an acute injection of progesterone (4 mg/0.2 ml, s.c.), chlordiazepoxide (5 or 15 mg/kg, i.p.), or MK-801 (0.025, 0.05, or 0.1 mg/kg, i.p.). RESULTS: Pseudopregnancy termination produced an anxiogenic-like response in the plus-maze; an acute injection of progesterone restored baseline levels of behavior in this test. Pseudopregnancy termination eliminated the anxiolytic-like, sedative, and ataxic effects of chlordiazepoxide. In contrast, pseudopregnancy termination produced an increased sensitivity to the anxiolytic-like and ataxic effects of MK-801. CONCLUSIONS: The effects of pseudopregnancy termination on the behavioral response to positive modulators of the GABA(A) receptor are consistent with results from studies in which chronic exposure to neurosteroids decreases the response to acute neurosteroid and benzodiazepine administration. However, unlike the enhanced glutamatergic tone resulting from discontinuation of chronic benzodiazepine or alcohol exposure, the termination of pseudopregnancy apparently decreases NMDA receptor function.

Termination of pseudopregnancy in the rat produces an anxiogenic-like response that is associated with an increase in benzodiazepine receptor binding density and a decrease in GABA-stimulated chloride influx in the hippocampus.

The neurosteroid, 3alpha-OH-5alpha-pregnan-20-one (allopregnanolone) is a potent positive modulator of the GABA(A) receptor complex. Its pharmacological spectrum of action is shared by the benzodiazepines and alcohol, and includes anxiolytic, anticonvulsant, ataxic, and hypnotic effects. Discontinuation from chronic exposure to allopregnanolone or other neuroactive steroids has been shown to elicit behavioral effects that are typically seen in benzodiazepine or alcohol withdrawal. In this series of experiments, the effects of an endogenous elevation of ovarian steroids on brain GABA(A) receptor function was examined by inducing pseudopregnancy. In female rats, pseudopregnancy did not affect behavior in the elevated plus-maze, despite a persistent increase in circulating levels of allopregnanolone. Pseudopregnancy was associated with a decrease in the maximal binding density of 3H-flunitrazepam in the cerebral cortex and cerebellum; however, GABA-stimulated chloride influx in cerebral cortical, hippocampal, and cerebellar synaptoneurosomes remained unaffected during pseudopregnancy. Termination of pseudopregnancy by ovariectomy precipitated an anxiogenic-like effect in the elevated plus-maze. The withdrawal from elevated ovarian steroid levels also increased the number of benzodiazepine receptors and decreased GABA-stimulated chloride influx in the hippocampus.

The preclinical biology of a new potent and selective progestin: trimegestone.

Trimegestone (TMG) is a 19-norpregnane progestin being developed, in combination with an estrogen, for the treatment of postmenopausal symptoms. TMG binds to the human progesterone receptor with an affinity greater than medroxyprogesterone acetate (MPA), norethindrone (NET), and levonorgestrel (LNG). In contrast, TMG binds with low affinity to the androgen, glucocorticoid and mineralocorticoid receptor and has no measurable affinity for the estrogen receptor. Compared to other progestins, TMG demonstrates an improved separation of its PR affinity from its affinity to other classical steroid hormone receptors. In vivo, TMG has potent progestin activity. For example, TMG produces glandular differentiation of the uterine endometrium in rabbits and is about 30 and 60 times more potent than MPA and NET, respectively. In the rat, TMG maintains pregnancy, induces deciduoma formation, inhibits ovulation and has uterine anti-estrogenic activity. With respect to these endpoints, TMG appears to be more potent and selective on uterine epithelial responses than other classical progestin responses. In vivo, TMG does not have significant androgenic, glucocorticoid, anti-glucocorticoid or mineralocorticoid activity but does have anti-mineralocorticoid activity and modest anti-androgenic effects. This overall profile is qualitatively similar to progesterone. When TMG is administered chronically, it antagonizes the effect of estradiol on the uterus but does not antagonize the beneficial bone sparing activity of estradiol. In rat studies evaluating CNS GABAA receptor modulatory activity, TMG is less active on this likely undesirable endpoint than progesterone and norethindrone acetate, which may translate into fewer mood-related side effects. The results indicate that TMG is a potent and selective progestin with a preclinical profile well suited for hormone replacement therapy.