Pheochromocytoma, Fulminant Heart Failure, and a Phenylephrine Challenge. the Perioperative Management of Adrenalectomy in a Jehovah's Witness Patient: a Case Report.

Perioperative management of pheochromocytoma in the setting of catecholamine-induced heart failure requires careful consideration of hemodynamic optimization and possible mechanical circulatory support. A Jehovah's Witness patient with catecholamine-induced acutely decompensated heart failure required dependable afterload reduction for a cardio-protective strategy. This was emphasized due to the relative contraindication to perioperative anticoagulation required for mechanical circulatory support. A phenylephrine challenge clearly demonstrated adequate alpha blockade after only 24 hours of phenoxybenzamine treatment. This resulted in advancement of the surgery date. This case also highlights management of beta blockade, volume and salt loading, autologous blood transfusion, and profound post-operative vasoplegia in the setting of cardiogenic shock. Careful attention to hemodynamic optimization and cardio-protective strategies ultimately resulted in positive outcome for this challenging clinical scenario.

New-Onset Atrial Fibrillation in Adult Patients After Cardiac Surgery.

PURPOSE OF REVIEW: An overview of recent literature regarding pathophysiology, risk factors, prophylaxis, and treatment of new-onset atrial fibrillation (AF) in post-cardiac surgical patients. RECENT FINDINGS: AF is the most frequent adverse event after cardiac surgery with significant associated morbidity, mortality, and financial cost. Its causes are multifactorial, and models to stratify patients into risk categories are progressing but a consistent, evidence-based system has not yet been developed. Pharmacologic and surgical interventions to prevent and treat this complication have been an area of ongoing research and recent societal guidelines reflect this. SUMMARY: Inconsistencies remain surrounding how to best identify higher-risk AF patients, which interventions should be used to prevent and treat AF, and which patient groups should receive these interventions. The evidence for these available strategies and their place in contemporary guidelines are summarized.

Society of Cardiovascular Anesthesiologists/European Association of Cardiothoracic Anaesthetists Practice Advisory for the Management of Perioperative Atrial Fibrillation in Patients Undergoing Cardiac Surgery.

Postoperative atrial fibrillation (poAF) is the most common adverse event after cardiac surgery and is associated with increased morbidity, mortality, and hospital and intensive care unit length of stay. Despite progressive improvements in overall cardiac surgical operative mortality and postoperative morbidity, the incidence of poAF has remained unchanged at 30%-50%. A number of evidence-based recommendations regarding the perioperative management of atrial fibrillation (AF) have been released from leading cardiovascular societies in recent years; however, it is unknown how closely these guidelines are being followed by medical practitioners. In addition, many of these society recommendations are based on patient stratification into "normal" and "elevated" risk groups for AF, but criteria for that stratification have not been clearly defined. In an effort to improve the perioperative management of AF, the Society of Cardiovascular Anesthesiologists (SCA) Clinical Practice Improvement Committee developed a multidisciplinary Atrial Fibrillation Working Group that created a summary of current best practice based on a distillation of recent guidelines from professional societies involved in the care of cardiac surgical patients. An evidence-based set of survey questions was then generated to describe the current practice of perioperative AF management. Through collaboration with the European Association of Cardiothoracic Anaesthetists (EACTA), that survey was distributed to the combined memberships of both the SCA and EACTA, yielding 641 responses and resulting in the most comprehensive understanding to date of perioperative AF management in North America, Europe, and beyond. The survey data demonstrated the broad range of therapies utilized for the prevention and treatment of poAF, as well as a spectrum of adherence to published guidelines. With the goal of improving adherence, a graphical advisory tool was created with an easily accessible format that could be utilized for bedside management. Finally, given that no evidence-based threshold currently exists to differentiate patients at normal risk to develop poAF from those at elevated risk, the SCA/EACTA AF working group created a list of poAF risk factors using expert opinion and based on published risk score models for poAF. This approach allows stratification of patients into risk groups and facilitates adherence to the evidence-based recommendations summarized in the graphical advisory tool. It is our hope that these new additions to the clinical toolkit for the management of perioperative AF will improve the evidence-based care and outcomes of cardiac surgical patients worldwide.

Society of Cardiovascular Anesthesiologists/European Association of Cardiothoracic Anaesthetists Practice Advisory for the Management of Perioperative Atrial Fibrillation in Patients Undergoing Cardiac Surgery.

Postoperative atrial fibrillation (poAF) is the most common adverse event after cardiac surgery and is associated with increased morbidity, mortality, and increased hospital and intensive care unit length of stay. Despite progressive improvements in overall cardiac surgical operative mortality and postoperative morbidity, the incidence of poAF has remained unchanged at 30% to 50%. A number of evidence-based recommendations regarding the perioperative management of atrial fibrillation (AF) have been released from leading cardiovascular societies in recent years; however, it is unknown how closely these guidelines are being followed by medical practitioners. In addition, many of these society recommendations are based on patient stratification into "normal" and "elevated" risk groups for AF, but criteria for that stratification have not been defined clearly. In an effort to improve the perioperative management of AF, the Society of Cardiovascular Anesthesiologists (SCA) Clinical Practice Improvement Committee developed a multidisciplinary Atrial Fibrillation Working Group that created a summary of current best practices based on distillation of recent guidelines from professional societies involved in the care of cardiac surgical patients. An evidence-based set of survey questions then was generated to describe the current practice of perioperative AF management. Through a collaboration with the European Association of Cardiothoracic Anaesthetists (EACTA), that survey was distributed to the combined memberships of both the SCA and the EACTA, yielding 641 responses and resulting in the most comprehensive understanding to date of perioperative AF management in North America and Europe and beyond. The survey data demonstrated the broad range of therapies used for prevention and treatment of poAF, as well as a spectrum of adherence to published guidelines. With the goal of improving adherence, a graphical advisory tool was created with an easily accessible format that could be used for bedside management. Finally, given that no evidence-based threshold currently exists to differentiate patients at normal risk of developing poAF from those at elevated risk, the SCA/EACTA AF working group created a list of poAF risk factors using expert opinion, based on published risk score models for poAF. This allows stratification of patients into risk groups and facilitates adherence to the evidence-based recommendations summarized in the graphical advisory tool. It is the working group's hope that these new additions to the clinical toolkit for management of perioperative AF will improve the evidence-based care and outcomes of cardiac surgical patients worldwide.

Rescue transoesophageal echocardiography for refractory haemodynamic instability during transvenous lead extraction.

AIMS: The rising number of cardiovascular implantable electronic devices has led to a steep increase in transvenous lead extractions (TLEs). Procedure-related, haemodynamically significant adverse events are uncommon during TLE yet remain an inevitable risk. While the use of transoesophageal echocardiography (TEE) as a guide to clinical decision-making during refractory circulatory instability has been well established, the specific utility of rescue TEE during TLE has not been comprehensively studied. METHODS AND RESULTS: Twenty-six patients who required emergent TEE to determine the aetiology of intractable haemodynamic instability during TLE were evaluated. Pericardial effusion requiring urgent pericardiocentesis and/or cardiac surgical intervention was diagnosed by TEE in 10 patients, and progressed to cardiac arrest in 4 patients. Haemorrhagic shock developed in two patients suffering from femoral vein laceration and right haemothorax, respectively. One additional patient developed acute respiratory compromise and right ventricular dysfunction diagnosed by TEE, which necessitated prolonged post-operative intubation and inotropic therapy. In 14 patients, TEE excluded life-threatening cardiovascular injuries and enabled the pursuit of continued medical management. Two patients with reassuring TEE findings underwent intra-operative placement of chest tubes for pneumothorax. All the 26 patients were discharged from the hospital. CONCLUSION: While TLE is a relatively safe procedure, life-threatening cardiovascular injuries remain a rare risk. In this study, the use of rescue TEE ruled out significant cardiovascular injuries in the majority of patients. Furthermore, rescue TEE had a substantial impact on the efficiency of determining the aetiology of refractory haemodynamic instability during TLE and thereby facilitated the timely initiation of definitive intervention.

Matrix metalloproteinase and G protein coupled receptors: co-conspirators in the pathogenesis of autoimmune disease and cancer.

Similarities in the pathologies of autoimmune diseases and cancer have been noted for at least 30 years. Inflammatory cytokines and growth factors mediate cell proliferation, and proteinases, especially the collagenase, Matrix Metalloproteinase-1 (MMP-1), contribute to disease progression by remodeling the extracellular matrix and modulating the microenvironment. This review focuses on two cancers (melanoma and breast) and on the autoimmune disorder, rheumatoid arthritis (RA), and discusses the activated stromal cells found in these diseases. MMP-1 was originally thought to function only to degrade interstitial collagens, but recent studies have revealed novel roles for MMP-1 involving the G protein-coupled receptors: the chemokine receptor, CXCR-4, and Protease Activated Receptor-1 (PAR-1). Cooperativity between MMP-1 and CXCR4/SDF-1 signaling influences the behavior of activated fibroblasts in both RA and cancer. Further, MMP-1 is a vital part of an autocrine/paracrine MMP-1/PAR-1 signal transduction axis, a function that amplifies its potential to remodel the matrix and to modify cell behavior. Finally, new therapeutic agents directed at MMP-1 and G protein-coupled receptors are emerging. Even though these agents are more specific in their targets than past therapies, these targets are often shared between RA and cancer, underscoring fundamental similarities between autoimmune disorders and some cancers.

Retinoid X receptor and peroxisome proliferator-activated receptor-gamma agonists cooperate to inhibit matrix metalloproteinase gene expression.

INTRODUCTION: We recently described the ability of retinoid X receptor (RXR) ligand LG100268 (LG268) to inhibit interleukin-1-beta (IL-1-beta)-driven matrix metalloproteinase-1 (MMP-1) and MMP-13 gene expression in SW-1353 chondrosarcoma cells. Other investigators have demonstrated similar effects in chondrocytes treated with rosiglitazone, a ligand for peroxisome proliferator-activated receptor-gamma (PPARgamma), for which RXR is an obligate dimerization partner. The goals of this study were to evaluate the inhibition of IL-1-beta-induced expression of MMP-1 and MMP-13 by combinatorial treatment with RXR and PPARgamma ligands and to investigate the molecular mechanisms of this inhibition. METHODS: We used real-time reverse transcription-polymerase chain reaction to measure LG268- and rosiglitazone-mediated inhibition of MMP gene transcription in IL-1-beta-treated SW-1353 chondrosarcoma cells. An in vitro collagen destruction assay was a functional readout of MMP collagenolytic activity. Luciferase reporter assays tested the function of a putative regulatory element in the promoters of MMP-1 and MMP-13, and chromatin immunoprecipitation (ChIP) assays detected PPARgamma and changes in histone acetylation at this site. Post-translational modification of RXR and PPARgamma by small ubiquitin-like modifier (SUMO) was assayed with immunoprecipitation and Western blot. RESULTS: Rosiglitazone inhibited MMP-1 and MMP-13 expression in IL-1-beta-treated SW-1353 cells at the mRNA and heterogeneous nuclear RNA levels and blunted IL-1-beta-induced collagen destruction in vitro. Combining LG268 and rosiglitazone had an additive inhibitory effect on MMP-1 and MMP-13 transcription and collagenolysis. IL-1-beta inhibited luciferase expression in the MMP reporter assay, but rosiglitazone and LG268 had no effect. ChIP indicated that treatment with IL-1-beta, but not LG268 and rosiglitazone, increased PPARgamma at the proximal promoters of both MMPs. Finally, rosiglitazone or LG268 induced 'cross-SUMOylation' of both the target receptor and its binding partner, and IL-1-beta-alone had no effect on SUMOylation of RXR and PPARgamma but antagonized the ligand-induced SUMOylation of both receptors. CONCLUSIONS: The PPARgamma and RXR ligands rosiglitazone and LG268 may act through similar mechanisms, inhibiting MMP-1 and MMP-13 transcription. Combinatorial treatment activates each partner of the RXR:PPARgamma heterodimer and inhibits IL-1-beta-induced expression of MMP-1 and MMP-13 more effectively than either compound alone. We conclude that the efficacy of combined treatment with lower doses of each drug may minimize potential side effects of treatment with these compounds.

Regulation of matrix metalloproteinase gene expression by a retinoid X receptor-specific ligand.

OBJECTIVE: To evaluate the effects of LG100268 (LG268), a synthetic ligand for the nuclear hormone receptor retinoid X receptor, on the expression of matrix metalloproteinase 1 (MMP-1) and MMP-13 induced by proinflammatory cytokines in a chondrocyte model. METHODS: SW-1353 human chondrosarcoma cells were used to study the effects of LG268 on interleukin-1beta (IL-1beta)-stimulated MMP production and collagen degradation. Gene expression was determined by quantitative real-time reverse transcription-polymerase chain reaction, and protein levels were determined by Western blot analysis. Collagen degradation was determined by an in vitro matrix destruction assay. The effects of LG268 on nuclear protein binding and histone acetylation were determined by electrophoretic mobility shift assay and chromatin immunoprecipitation assay, respectively. RESULTS: LG268 treatment specifically antagonized the IL-1beta-mediated induction of MMP-1 and MMP-13 heterogeneous nuclear RNA, messenger RNA, and protein. The inhibitory effect of LG268 was found to be due to a decrease in the rate of MMP-1 and MMP-13 transcription. LG268 treatment also prevented the in vitro degradation of a type I collagen matrix by IL-1beta-treated SW-1353 cells. The inhibitory effect of LG268 on MMP-1 and MMP-13 transcription appears to be mediated, at least in part, through modulation of histone modification in regions of the MMP-1 and MMP-13 promoters that contain binding sites for activator protein 1 transcription factors. CONCLUSION: These data indicate that LG268 treatment selectively inhibits inflammatory cytokine-induced production of MMP-1 and MMP-13 at the level of gene transcription and blocks collagen destruction by proinflammatory cytokine-stimulated chondrocytic cells. This study is among the first to describe how rexinoids affect gene expression, and the findings suggest that the rexinoid class of compounds may have a future role in preventing the irreversible collagen destruction seen in the arthritides.

Matrix metalloproteinases: role in arthritis.

The irreversible destruction of the cartilage, tendon, and bone that comprise synovial joints is the hallmark of both rheumatoid arthritis (RA) and osteoarthritis (OA). While cartilage is made up of proteoglycans and type II collagen, tendon and bone are composed primarily of type I collagen. RA is an autoimmune disease afflicting numerous joints throughout the body; in contrast, OA develops in a small number of joints, usually resulting from chronic overuse or injury. In both diseases, inflammatory cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) stimulate the production of matrix metalloproteinases (MMPs), enzymes that can degrade all components of the extracellular matrix. The collagenases, MMP-1 and MMP-13, have predominant roles in RA and OA because they are rate limiting in the process of collagen degradation. MMP-1 is produced primarily by the synovial cells that line the joints, and MMP-13 is a product of the chondrocytes that reside in the cartilage. In addition to collagen, MMP-13 also degrades the proteoglycan molecule, aggrecan, giving it a dual role in matrix destruction. Expression of other MMPs such as MMP-2, MMP-3 and MMP-9, is also elevated in arthritis and these enzymes degrade non-collagen matrix components of the joints. Significant effort has been expended in attempts to design effective inhibitors of MMP activity and/or synthesis with the goal of curbing connective tissues destruction within the joints. To date, however, no effective clinical inhibitors exist. Increasing our knowledge of the crystal structures of these enzymes and of the signal transduction pathways and molecular mechanisms that control MMP gene expression may provide new opportunities for the development of therapeutics to prevent the joint destruction seen in arthritis.

A model system for increased meiotic nondisjunction in older oocytes.

For at least 5% of all clinically recognized human pregnancies, meiotic segregation errors give rise to zygotes with the wrong number of chromosomes. Although most aneuploid fetuses perish in utero, trisomy in liveborns is the leading cause of mental retardation. A large percentage of human trisomies originate from segregation errors during female meiosis I; such errors increase in frequency with maternal age. Despite the clinical importance of age-dependent nondisjunction in humans, the underlying mechanisms remain largely unexplained. Efforts to recapitulate age-dependent nondisjunction in a mammalian experimental system have so far been unsuccessful. Here we provide evidence that Drosophila is an excellent model organism for investigating how oocyte aging contributes to meiotic nondisjunction. As in human oocytes, nonexchange homologs and bivalents with a single distal crossover in Drosophila oocytes are most susceptible to spontaneous nondisjunction during meiosis I. We show that in a sensitized genetic background in which sister chromatid cohesion is compromised, nonrecombinant X chromosomes become vulnerable to meiotic nondisjunction as Drosophila oocytes age. Our data indicate that the backup pathway that normally ensures proper segregation of achiasmate chromosomes deteriorates as Drosophila oocytes age and provide an intriguing paradigm for certain classes of age-dependent meiotic nondisjunction in humans.