Hybrid Interventions in Congenital Heart Disease: A Review of Current Practice and Rationale for Use.

BACKGROUND: Hybrid interventions have become a common option in the management for a variety of patients with congenital heart disease. In this review, we discuss the data that have driven decision making about hybrid interventions to date. METHODS: The existing literature on various hybrid approaches was reviewed and summarized. In addition, the key tenants to creating a successful hybrid program within a congenital heart center are elucidated. RESULTS: Hybrid strategies for single-ventricle patients, pulmonary atresia with intact ventricular septum, branch pulmonary artery stenosis, and muscular ventricular septal defect closure have important benefits and limitations compared with traditional approaches. CONCLUSION: A growing body of evidence supports the use of hybrid interventions in congenital heart disease. But important questions remain regarding improved survival and other long-term outcomes, such as neurocognition, that might impact widespread adoption as a primary treatment strategy.

Aortic valve repair using geometric ring annuloplasty in pediatric and congenital heart disease patients.

OBJECTIVE: Existing replacement options for the aortic valve have significant drawbacks, especially in children. A geometric annuloplasty ring can help to achieve consistently successful aortic valve repair, but only limited experience with use of this device has been reported in pediatric and congenital heart disease patients. METHODS: All pediatric and adult congenital patients at our institution who underwent aortic valve repair with placement of a geometric annuloplasty ring were reviewed. The study period spanned from July 2018 to April 2022. Hemodynamic outcomes were evaluated using transthoracic echocardiography. RESULTS: The study included 36 subjects. The median age was 17.4 years (range, 8-30 years). Twenty-one subjects were younger than age 18 years. The most common primary diagnoses were neoaortic valve insufficiency or neoaortic root dilation, and congenital aortic stenosis with bicuspid or functionally unicuspid aortic valve. Of the 34 subjects with procedural success, 31 (91%) had use of additional valve repair techniques and 26 (76%) had an additional concomitant procedure performed. Operative mortality was 0% (0/33), and major complication rate was 6% (2/33). The median follow-up time was 1.9 years (maximum, 3.8 years). The mean grade of aortic insufficiency was signific antly reduced after repair, with no change in mean gradients. Freedom from reoperation over the follow-up period was 97% (33/34), and freedom from ≥3+ recurrent aortic insufficiency was 94% (32/34). CONCLUSIONS: A geometric annuloplasty ring can be used to help achieve consistently successful aortic valve repair with excellent perioperative and follow-up outcomes, even in pediatric and complex congenital heart disease patients.

Midterm outcomes of the Potts shunt for pediatric pulmonary hypertension, with comparison to lung transplant.

OBJECTIVE: For children with severe pulmonary hypertension, addition of Potts shunt to a comprehensive palliation strategy might improve the outcomes afforded by medications and delay lung transplantation. METHODS: A prospective analysis was conducted of all children undergoing Potts shunt (first performed in 2013) or bilateral lung transplant for pulmonary hypertension from 1995 to present. RESULTS: A total of 23 children underwent Potts shunt (20 surgical, 3 transcatheter), and 31 children underwent lung transplant. All children with Potts shunt had suprasystemic right ventricle pressures despite maximal medical treatment. In the majority of patients, the Potts shunt was performed through a left thoracotomy approach (90%, 18/20), by direct anastomosis (65%, 13/20), and without the use of extracorporeal support (65%, 13/20). Perioperative outcomes after Potts shunt were superior to lung transplant including mechanical ventilation time (1.3 vs 10.2 days, P = .019), median hospital length of stay (9.8 vs 34 days, P = .012), and overall complication rate (35% [7/20] vs 81% [25/31], P = .003). Risk factors for operative mortality after Potts shunt (20%, 4/20; compared with 6%, 2/31 for lung transplant, P = .195) included preoperative extracorporeal membrane oxygenation and significant right ventricle dysfunction. In midterm follow-up (median 1.8, maximum 6.1 years), patients with Potts shunt had durable equalization of right ventricle/left ventricle pressures and improved functional status. There was no significant survival difference in patients with Potts shunt and patients with lung transplant (P = .258). CONCLUSIONS: Potts shunt is an effective palliation for children with suprasystemic pulmonary hypertension that may become part of a strategy to maximize longevity and functional status for these challenging patients.

Pericardial Mitochondrial DNA Levels Are Associated With Atrial Fibrillation After Cardiac Surgery.

BACKGROUND: Postoperative atrial fibrillation (POAF) is the most common complication after cardiac surgery, and is associated with increased morbidity and mortality. Inflammation has been implicated as an etiology of POAF. Mitochondrial DNA (mtDNA) has been shown to initiate inflammation. This study analyzed inflammatory mechanisms of POAF by evaluating mtDNA, neutrophils, and cytokines/chemokines in the pericardial fluid and blood after cardiac surgery. METHODS: Blood and pericardial fluid from patients who underwent coronary artery bypass or heart valve surgery, or both, were collected intraoperatively and at 4, 12, 24, and 48 hours postoperatively. Real-time polymerase chain reaction was used to quantify mtDNA in the pericardial fluid and blood. A Luminex (Luminex Corp, Austin, TX) assay was used to study cytokine and chemokine levels. Flow cytometry was used to analyze neutrophil infiltration and activation in the pericardial fluid. RESULTS: Samples from 100 patients were available for analysis. Postoperatively, mtDNA and multiple cytokine levels were higher in the pericardial fluid versus blood. Patients who had POAF had significantly higher levels of mtDNA in the pericardial fluid compared with patients who did not (P < .001, area under the curve 0.74). There was no difference in the mtDNA concentration in the blood between the POAF group and non-POAF group (P = .897). Neutrophil concentration increased in the pericardial fluid over time from a baseline of 0.8% to 56% at 48 hours (P < .01). CONCLUSIONS: The pericardial space has a high concentration of inflammatory mediators postoperatively. Mitochondrial DNA in the pericardial fluid was strongly associated with the development of POAF. This finding provides insight into a possible mechanism of inflammation that may contribute to POAF, and may offer novel therapeutic targets.

The hemodynamic and atrial electrophysiologic consequences of chronic left atrial volume overload in a controllable canine model.

OBJECTIVE: The purpose of this study was to determine the effects of chronic left atrial volume overload on atrial anatomy, hemodynamics, and electrophysiology using a titratable left ventriculoatrial shunt in a canine model. METHODS: Canines (n = 16) underwent implantation of a shunt between the left ventricle and the left atrium. Sham animals (n = 8) underwent a median sternotomy without a shunt. Atrial activation times and effective refractory periods were determined using 250-bipolar epicardial electrodes. Biatrial pressures, systemic pressures, left atrial and left ventricle diameters and volumes, atrial fibrillation inducibility, and durations were recorded at the initial and at 6-month terminal study. RESULTS: Baseline shunt fraction was 46% ± 8%. The left atrial pressure increased from 9.7 ± 3.5 mm Hg to 13.8 ± 4 mm Hg (P < .001). At the terminal study, the left atrial diameter increased from a baseline of 2.9 ± 0.05 cm to 4.1 ± 0.6 cm (P < .001) and left ventricular ejection fraction decreased from 64% ± 1.5% to 54% ± 2.7% (P < .001). Induced atrial fibrillation duration (median, range) was 95 seconds (0-7200) compared with 0 seconds (0-40) in the sham group (P = .02). The total activation time was longer in the shunt group compared with the sham group (72 ± 11 ms vs 62 ± 3 ms, P = .003). The right atrial and not left atrial effective refractory periods were shorter in the shunt compared with the sham group (right atrial effective refractory period: 156 ± 11 ms vs 141 ± 11 ms, P = .005; left atrial effective refractory period: 142 ± 23 ms vs 133 ± 11 ms, P = .35). CONCLUSIONS: This canine model of mitral regurgitation reproduced the mechanical and electrical remodeling seen in clinical mitral regurgitation. Left atrial size increased, with a corresponding decrease in left ventricle systolic function, and an increased atrial activation times, lower effective refractory periods, and increased atrial fibrillation inducibility. This model provides a means to understand the remodeling by which mitral regurgitation causes atrial fibrillation.

State of the Art in Pediatric Lung Transplantation.

Pediatric lung transplantation is a highly specialized therapy for end-stage pulmonary disease in children, and is performed in only a handful of transplant centers around the world. Advancement in the field has been made on many fronts in recent years, including in public policy and organ allocation strategies, donor selection and management, emerging technologies for donor lung rehabilitation and bridge-to-transplant support of listed candidates, and ongoing refinement of surgical techniques. Despite this progress, children continue to suffer discrepant waitlist mortality and longer waiting times than their adult counterparts, and face special challenges of donor availability and size matching. Here, we assess the current state of the art in pediatric lung transplantation, reviewing progress made to date and further opportunities to improve care for this unique group of patients.

Anomalous Systemic Artery to the Left Lower Lobe: Literature Review and a New Surgical Technique.

Anomalous systemic arterial supply to the basal segments of the left lower lobe without coexisting pulmonary artery connection is a rare anomaly. Most feel treatment is necessary; however, the ideal strategy is unclear. Treatments described include embolization, pulmonary resection, or anastomosis to the native pulmonary artery. We recently encountered an infant with this anomaly and present a literature review summarizing all recent reports. Additionally, we describe a novel surgical technique to create a tension-free anastomosis utilizing segmental aortic translocation that we employed in our patient due to a large distance between the anomalous vessel and native left pulmonary artery.

Long-Term Survival Prediction for Coronary Artery Bypass Grafting: Validation of the ASCERT Model Compared With The Society of Thoracic Surgeons Predicted Risk of Mortality.

BACKGROUND: The recently developed American College of Cardiology Foundation-Society of Thoracic Surgeons (STS) Collaboration on the Comparative Effectiveness of Revascularization Strategy (ASCERT) Long-Term Survival Probability Calculator is a valuable addition to existing short-term risk-prediction tools for cardiac surgical procedures but has yet to be externally validated. METHODS: Institutional data of 654 patients aged 65 years or older undergoing isolated coronary artery bypass grafting between 2005 and 2010 were reviewed. Predicted survival probabilities were calculated using the ASCERT model. Survival data were collected using the Social Security Death Index and institutional medical records. Model calibration and discrimination were assessed for the overall sample and for risk-stratified subgroups based on (1) ASCERT 7-year survival probability and (2) the predicted risk of mortality (PROM) from the STS Short-Term Risk Calculator. Logistic regression analysis was performed to evaluate additional perioperative variables contributing to death. RESULTS: Overall survival was 92.1% (569 of 597) at 1 year and 50.5% (164 of 325) at 7 years. Calibration assessment found no significant differences between predicted and actual survival curves for the overall sample or for the risk-stratified subgroups, whether stratified by predicted 7-year survival or by PROM. Discriminative performance was comparable between the ASCERT and PROM models for 7-year survival prediction (p < 0.001 for both; C-statistic = 0.815 for ASCERT and 0.781 for PROM). Prolonged ventilation, stroke, and hospital length of stay were also predictive of long-term death. CONCLUSIONS: The ASCERT survival probability calculator was externally validated for prediction of long-term survival after coronary artery bypass grafting in all risk groups. The widely used STS PROM performed comparably as a predictor of long-term survival. Both tools provide important information for preoperative decision making and patient counseling about potential outcomes after coronary artery bypass grafting.

A Minimally Invasive Stand-alone Cox-Maze Procedure Is as Effective as Median Sternotomy Approach.

OBJECTIVE: The Cox-Maze IV procedure has been shown to be an effective treatment for atrial fibrillation when performed concomitantly with other operations either via median sternotomy or right minithoracotomy. Few studies have compared these approaches in patients with lone atrial fibrillation. This study examined outcomes with sternotomy versus minithoracotomy in stand-alone Cox-Maze IV procedures at our institution. METHODS: Between 2002 and 2015, 195 patients underwent stand-alone biatrial Cox-Maze IV. Minithoracotomy was used in 75 patients, sternotomy in 120. Freedom from atrial tachyarrhythmias was ascertained using electrocardiography, Holter, or pacemaker interrogation at 3 to 60 months. Predictors of recurrence were determined using logistic regression. RESULTS: Of 23 preoperative variables, the only differences between groups were that minithoracotomy patients had a higher rate of New York Heart Association 3/4 symptoms and a lower rate of previous stroke. Minithoracotomy and sternotomy patients had similar atrial fibrillation duration and type. Minithoracotomy patients had a smaller left atrial diameter (4.5 vs 4.8 cm, P = 0.03). More minithoracotomy patients received a box lesion (73/75 vs 100/120, P = 0.002). Minithoracotomy patients had a shorter hospital stay (7 vs 8 days, P = 0.009) and a similar rate of major complications (3/75 (4%) vs 7/120 (6%), P = 0.74). There were no differences in mortality or freedom from atrial tachyarrhythmias. Predictors of atrial fibrillation recurrence included a preoperative pacemaker, omission of the left atrial roof line, and New York Heart Association 3/4 symptoms. CONCLUSIONS: Stand-alone Cox-Maze IV via minithoracotomy was as effective as via sternotomy with a shorter hospital stay. A minimally invasive approach is our procedure of choice.

Postoperative atrial fibrillation following cardiac surgery: a persistent complication.

Postoperative atrial fibrillation (POAF) is a common, expensive and potentially morbid complication following cardiac surgery. POAF occurs in around 35% of cardiac surgery cases and has a peak incidence on postoperative day 2. Patients who develop POAF incur on average $10 000-$20 000 in additional hospital treatment costs, 12-24 h of prolonged ICU time, and an additional 2 to 5 days in the hospital. POAF has been identified as an independent predictor of numerous adverse outcomes, including a 2- to 4-fold increased risk of stroke, reoperation for bleeding, infection, renal or respiratory failure, cardiac arrest, cerebral complications, need for permanent pacemaker placement, and a 2-fold increase in all-cause 30-day and 6-month mortality. The pathogenesis of POAF is incompletely understood but likely involves interplay between pre-existing physiological components and local and systemic inflammation. POAF is associated with numerous risk factors including advanced age, pre-existing conditions that cause cardiac remodelling and certain non-cardiovascular conditions. Clinical management of POAF includes both prophylactic and therapeutic measures, although the efficacy of many interventions remains in question. This review provides a comprehensive and up-to-date summary of the pathogenesis of POAF, outlines current clinical guidelines for POAF prophylaxis and management, and discusses new avenues for further investigation.

Topographic mapping of left ventricular regional contractile injury in ischemic mitral regurgitation.

OBJECTIVE: Restrictive leaflet tethering resulting from regional left ventricular (LV) contractile injury causes ischemic mitral regurgitation (MR). We hypothesized that 3-dimensional LV topographic mapping by MRI-based multiparametric strain analysis could characterize the regional contractile injury patterns that differentiate ischemic coronary artery disease patients who have ischemic MR from those who do not. METHODS: Magnetic resonance imaging-based multiparametric strain data were calculated for 15,300 LV grid points in 100 normal volunteers. Strain parameters from ischemic MR (n = 10) and ischemic no-MR (n = 36) patients were then normalized to this normal human strain database with z score quantification of standard deviation from the normal mean. Mean multiparametric strain z scores were calculated for 18 LV subregions (basilar/mid/apical levels; 6 LV regions). Mean strain z scores for papillary muscle-related (basilar/mid levels of anterolateral, posterolateral, and posterior) and nonpapillary muscle-related (all other) subregions were compared between ischemic MR and ischemic no-MR groups. RESULTS: Across all patients, contractile injury was greater in the papillary muscle-related regions compared with the nonpapillary regions (P = .007). In the papillary regions, contractile injury was greater in the ischemic MR group compared with the no-MR group (z scores, 1.91 ± 1.13 vs 1.20 ± 1.01, respectively; P < .001). Strain values in the nonpapillary muscle-related subregions were not different between the 2 groups (1.31 ± 1.04 vs 1.20 ± 1.03; P = .301). CONCLUSIONS: Multiparametric strain analysis demonstrated severe normalized contractile injury in the papillary muscle-related LV subregions in patients with ischemic MR. The mean degree of normalized injury approached 2 standard deviations and was significantly worse than the levels seen in ischemic no-MR patients.

Potassium and Magnesium Supplementation Do Not Protect Against Atrial Fibrillation After Cardiac Operation: A Time-Matched Analysis.

BACKGROUND: Despite a lack of demonstrated efficacy, potassium and magnesium supplementation are commonly thought to prevent postoperative atrial fibrillation (POAF) after cardiac operation. Our aim was to evaluate the natural time course of electrolyte level changes after cardiac operation and their relation to POAF occurrence. METHODS: Data were reviewed from 2,041 adult patients without preoperative AF who underwent coronary artery bypass grafting, valve operation, or both between 2009 and 2013. In patients with POAF, the plasma potassium and magnesium levels nearest to the first AF onset time were compared with time-matched electrolyte levels in patients without AF. RESULTS: POAF occurred in 752 patients (36.8%). At the time of AF onset or the matched time point, patients with POAF had higher potassium (4.30 versus 4.21 mmol/L, p < 0.001) and magnesium (2.33 versus 2.16 mg/dL, p < 0.001) levels than controls. A stepwise increase in AF risk occurred with increasing potassium or magnesium quintile (p < 0.001). On multivariate logistic regression analysis, magnesium level was an independent predictor of POAF (odds ratio 4.26, p < 0.001), in addition to age, Caucasian race, preoperative ß-blocker use, valve operation, and postoperative pneumonia. Prophylactic potassium supplementation did not reduce the POAF rate (37% versus 37%, p = 0.813), whereas magnesium supplementation was associated with increased POAF (47% versus 36%, p = 0.005). CONCLUSIONS: Higher serum potassium and magnesium levels were associated with increased risk of POAF after cardiac operation. Potassium supplementation was not protective against POAF, and magnesium supplementation was even associated with increased POAF risk. These findings help explain the poor efficacy of electrolyte supplementation in POAF prophylaxis.

Pulmonary Valve Replacement With Small Intestine Submucosa-Extracellular Matrix in a Porcine Model.

BACKGROUND: Prosthetic materials available for pediatric pulmonary valve replacement (PVR) lack growth potential, inevitably leading to a size mismatch. Small intestine submucosa-derived extracellular matrix (SIS-ECM) has been suggested to possess regenerative properties. We aimed to investigate its function and potential to increase in size as a PVR in a piglet. METHODS: An SIS-ECM trileaflet valved conduit was designed. Hanford minipigs, n = 6 (10-34 kg), underwent PVR with an intended survival of six months, with monthly echocardiograms evaluating valve size and function. The conduit was excised for histologic analysis. RESULTS: Of the six, one was sacrificed at three months for midterm analysis, and one at month 3 due to endocarditis. The remaining four constituted the study cohort. The piglet weight increased by 186% (19.56 ± 10.22 kg to 56.00 ± 7.87 kg). Conduit size increased by 30% (1.42 ± 0.14 cm to 1.84 ± 0.14 cm; P < .01). The native right ventricular outflow tract increased by 43% and the native pulmonary artery by 84%, resulting in a peak gradient increase from 10.08 ± 2.47 mm Hg to 36.25 ± 18.80 mm Hg (P = .03). Additionally, all valves developed at least moderate regurgitation. Conduit histology showed advanced remodeling with myofibroblast infiltration, neovascularization, and endothelialization. The leaflets remodeled beginning at the base with the leaflet edge being less cellular. In addition to the known endocarditis, bacterial colonies were discovered within a leaflet in another. CONCLUSIONS: The SIS-ECM valved conduit implanted into a piglet demonstrated cellular infiltration with vascular remodeling and an increase in diameter. Conduit stenosis was a result of slower rates of size increase than native tissue. Suboptimal leaflet performance requires design modifications.

Tracheal Resection With Carinal Reconstruction for Squamous Cell Carcinoma.

Surgical resection is the treatment of choice for primary malignancies of the trachea. We present here the rare case of a lifelong nonsmoker with primary squamous cell carcinoma of the trachea, requiring tracheal resection and anterior carinal reconstruction. Patient preparation, surgical technique, and considerations to avoid airway anastomotic complications are discussed.

Minimally invasive surgery for atrial fibrillation.

The surgical treatment of atrial fibrillation (AF) has been revolutionized over the past two decades through surgical innovation and improvements in endoscopic imaging, ablation technology, and surgical instrumentation. These advances have prompted the development of the less complex and less morbid Cox-Maze IV procedure, and have allowed its adaptation to a minimally invasive right mini-thoracotomy approach that can be used in stand-alone AF ablation and in patients undergoing concomitant mitral and tricuspid valve surgery. Other minimally invasive ablation techniques have been developed for stand-alone AF ablation, including video-assisted pulmonary vein isolation, extended left atrial lesion sets, and a hybrid approach. This review will discuss the tools, techniques, and outcomes of minimally invasive surgical procedures currently being practiced for AF ablation.

Expanded Polytetrafluoroethylene for Chordal Replacement: Preventing Knot Failure.

PURPOSE: Expanded polytetrafluoroethylene suture is commonly used for chordal replacement in mitral valve repair, but due to material characteristics, knots can unravel. Our aim was to determine the knot security, including how many throws are necessary to prevent knot failure, with Gore-Tex (W.L. Gore and Associates, Elkton, MD) and the newly available Chord-X (On-X Life Technologies Inc, Austin, TX). DESCRIPTION: Knots were evaluated for maximal load based on: number of throws (6, 8, 10, and 12), tension to secure each throw (10%, 50%, and 85%) and suture type (Gore-Tex CV-5 and Chord-X 3-0). A physiologic force of 2 N was used for comparison. EVALUATION: We evaluated 240 knots. For all knots, the mean load to failure was 11.1 ± 5.8 N. Failure occurred due to unraveling in 141 knots (59%) at 7.1 ± 4.1 N and to breaking in 99 (41%) at 16.7 ± 2.0 N (p < 0.01). Gore-Tex failed at higher loads (12.6 ± 6.0 N vs 9.5 ± 5.2 N, p < 0.01); however, an equivalent number, 6 Gore-Tex and 6 Chord-X, unraveled at 2 N, all with fewer than 10 throws. CONCLUSIONS: Expanded polytetrafluoroethylene has adequate strength to prevent breakage; however, a risk of knot unraveling at physiologic conditions exists when fewer than 10 throws are performed.

Late outcomes after the Cox maze IV procedure for atrial fibrillation.

OBJECTIVE: The Cox maze IV procedure (CMPIV) has been established as the gold standard for surgical ablation; however, late outcomes using current consensus definitions of treatment failure have not been well described. To compare to reported outcomes of catheter-based ablation, we report our institutional outcomes of patients who underwent a left-sided or biatrial CMPIV at 5 years of follow-up. METHODS: Between January 2002 and September 2014, data were collected prospectively on 576 patients with AF who underwent a CMPIV (n = 532) or left-sided CMPIV (n = 44). Perioperative variables and long-term freedom from AF, with and without AADs, were compared in multiple subgroups. RESULTS: Follow-up at any time point was 89%. At 5 years, overall freedom from AF was 93 of 119 (78%), and freedom from AF off AADs was 77 of 177 (66%). No differences were found in freedom from AF, with or without AADs, at 1, 2, 3, 4, and 5 years for patients with paroxysmal AF (n = 204) versus with persistent/longstanding persistent AF (n = 305), or for those who underwent standalone versus a concomitant CMP. Duration of preoperative AF and hospital length of stay were the best predictors of failure at 5 years. CONCLUSIONS: The outcomes of the CMPIV remain good at late follow-up. The type of preoperative AF or the addition of a concomitant procedure did not affect late success. The results of the CMPIV remain superior to those reported for catheter ablation and other forms of surgical AF ablation, especially for patients with persistent or longstanding AF.

Age-related differences in cardiac ischemia-reperfusion injury: effects of estrogen deficiency.

Despite conflicting evidence for the efficacy of hormone replacement therapy in cardioprotection of postmenopausal women, numerous studies have demonstrated reductions in ischemia/reperfusion (I/R) injury following chronic or acute exogenous estradiol (E2) administration in adult male and female, gonad-intact and gonadectomized animals. It has become clear that ovariectomized adult animals may not accurately represent the combined effects of age and E2 deficiency on reductions in ischemic tolerance seen in the postmenopausal female. E2 is known to regulate the transcription of several cardioprotective genes. Acute, non-genomic E2 signaling can also activate many of the same signaling pathways recruited in cardioprotection. Alterations in cardioprotective gene expression or cardioprotective signal transduction are therefore likely to result within the context of aging and E2 deficiency and may help explain the reduced ischemic tolerance and loss of cardioprotection in the senescent female heart. Quantification of the mitochondrial proteome as it adapts to advancing age and E2 deficiency may also represent a key experimental approach to uncover proteins associated with disruptions in cardiac signaling contributing to age-associated declines in ischemic tolerance. These alterations have important ramifications for understanding the increased morbidity and mortality due to ischemic cardiovascular disease seen in postmenopausal females. Functional perturbations that occur in mitochondrial respiration and Ca(2+) sensitivity with age-associated E2 deficiency may also allow for the identification of alternative therapeutic targets for reducing I/R injury and treatment of the leading cause of death in postmenopausal women.

Increased estrogen receptor ß in adipose tissue is associated with increased intracellular and reduced circulating adiponectin protein levels in aged female rats.

BACKGROUND: Obesity and associated metabolic and cardiovascular disease risk are correlated with reduced circulating adiponectin (APN) levels. Metabolic and cardiovascular disease risk is also increased after menopause and may be linked to disturbances in estrogen receptor (ER) signaling in adipose. OBJECTIVE: We hypothesized that age-associated estrogen (E(2))-deficiency alters the ERα/ß ratio in adipose tissue and increases risk for metabolic disease via APN-ac activated mechanisms. METHODS: Visceral adipose was isolated from adult (6 months) and aged (24 months) female Fisher 344 rats (n = 5-6/group) with ovaries intact or removed by surgical ovariectomy (OVX) and subjected to western blotting. RESULTS: Notably, weight was greatest in aged OVX rats (P < 0.01) and associated with a 2-fold increase in ERß protein versus adult intact rats (P < 0.001). ER levels were increased in aged OVX versus adult OVX rats. Intra-adipocyte APN was also increased in aged OVX rats versus all groups (P < 0.01), whereas circulating APN levels decreased in aged OVX versus adult OVX rats (P < 0.05). Endoplasmic reticulum protein of 44 kDa (Erp44) levels remained the same (P = 0.09). Adiponectin receptor-1 (AdipoR1) and peroxisome proliferator-activated receptor-α (PPAR-α) were also unchanged. AdipoR2, PPAR-γ, and phosphorylated adenosine monophosphate-dependant kinase (pAMPK) to total AMPK ratio all decreased with age (P < 0.05). CONCLUSIONS: Collectively, these data suggested that age-associated increases in ERß paired with decreased PPAR-γ levels might predispose E(2)-deficient postmenopausal women for increased adiposity and associated metabolic and cardiovascular disease risk. Reduced circulating APN and AdipoR2 levels might contribute to age and E(2)-deficiency linked disease progression.