Search

Atrial fibrillation (AF) and heart failure are common overlapping cardiovascular disorders. Despite important therapeutic advances over the past several decades, controversy persists about whether a rate control or rhythm control approach constitutes the best option in this population. There is also considerable debate about whether antiarrhythmic drug therapy or ablation is the best approach when rhythm control is pursued.  A brief historical examination of the literature addressing this issue will be performed. An analysis of several important clinical outcomes observed in the prospective, randomized studies, which have compared AF ablation to non-ablation treatment options, will be discussed. This review will conclude with recommendations to guide clinicians on the status of AF ablation as a treatment option when considering management options in heart failure patients with atrial fibrillation., (© 2023 Wiley Periodicals LLC.)

Clinical trials have shown that electric stimulation (ELSM) using either cardiac resynchronization therapy (CRT) or cardiac contractility modulation (CCM) approaches is an effective treatment for patients with moderate to severe heart failure, but the mechanisms are incompletely understood. Extracellular vesicles (EV) produced by cardiac mesenchymal stem cells (C-MSC) have been reported to be cardioprotective through cell-to-cell communication. In this study, we investigated the effects of ELSM stimulation on EV secretion from C-MSCs (C-MSC ELSM ). We observed enhanced EV-dependent cardioprotection conferred by conditioned medium (CM) from C-MSC ELSM compared to that from non-stimulated control C-MSC (C-MSC Ctrl ). To investigate the mechanisms of ELSM-stimulated EV secretion, we examined the protein levels of neutral sphingomyelinase 2 (nSMase2), a key enzyme of the endosomal sorting complex required for EV biosynthesis. We detected a time-dependent increase in nSMase2 protein levels in C-MSC ELSM compared to C-MSC Ctrl . Knockdown of nSMase2 in C-MSC by siRNA significantly reduced EV secretion in C-MSC ELSM and attenuated the cardioprotective effect of CM from C-MSC ELSM in HL-1 cells. Taken together, our results suggest that ELSM-mediated increases in EV secretion from C-MSC enhance the cardioprotective effects of C-MSC through an EV-dependent mechanism involving nSMase2.

Background The increasing use of cardiac implantable electronic devices (CIEDs) in a growing patient population has led to an even greater increase in CIED infection rates. Antibacterial CIED envelopes are often used as part of an infection risk-reduction strategy. However, best practices for when to use an envelope and which envelope to choose remain to be elucidated. Methods In this retrospective study, the records of 455 patients undergoing CIED implantation by a single surgeon were reviewed to identify trends in envelope use and outcomes after implantation through 12 months of follow-up. Of these patients, 165 were managed with a biologic antibacterial CIED envelope (CanGaroo®, Aziyo Biologics, Inc., Silver Spring, MD), 219 with a non-biologic envelope (Tyrx®, Medtronic Inc., Monmouth Junction, NJ), and 71 with no envelope. Results Most patients had two or more infection risk factors (77.9% with any envelope vs. 52.1% with no envelope; P < 0.001). Factors significantly associated with the use of an envelope included the history of heart failure, systemic anticoagulant use, the use of high-power or more complex devices, and reoperations. The overall rate of adverse events was 9.2% (n = 42). Rates of infection and hematoma were 1.8% and 2.6%, respectively. A decision tree is proposed that may aid clinical decision-making when considering CIED envelope usage. Conclusions There were no significant differences between groups in overall or individual adverse event rates. These data provide insight into real-world clinical decisions regarding the use of CIED envelopes and support the use of antibiotic-eluting CIED envelopes to limit infection risk in high-risk patients., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2022, Woodard et al.)

Background: Cardiovascular implantable electronic devices (CIEDs) are implanted in an increasing number of patients each year, which has led to an increase in the risk of CIED infection. Antibacterial CIED envelopes locally deliver antibiotics to the implant site over a short-term period and have been shown to reduce the risk of implant site infection. These envelopes are derived from either biologic or non-biologic materials. There is a paucity of data examining patient risk profiles and outcomes from using these envelope materials in the clinical setting and comparing these results to patients receiving no envelope with their CIED implantation., Aim: To evaluate risk profiles and outcomes of patients who underwent CIED procedures with an antibacterial envelope or no envelope., Methods: After obtaining Internal Review Board approval, the records of consecutive patients who underwent a CIED implantation procedure by a single physician between March 2017 and December 2019 were retrospectively collected from our hospital. A total of 248 patients within this period were identified and reviewed through 12 mo of follow up. The CIED procedures used either no envelope ( n = 57), a biologic envelope (CanGaroo ® , Aziyo Biologics) that was pre-hydrated by the physician with vancomycin and gentamicin ( n = 89), or a non-biologic envelope (Tyrx™, Medtronic) that was coated with a resorbable polymer containing the drug substances rifampin and minocycline by the manufacturer ( n = 102). Patient selection for receiving either no envelope or an envelope (and which envelope to use) was determined by the treating physician. Statistical analyses were performed between the 3 groups (CanGaroo, Tyrx, and no envelope), and also between the No Envelope and Any Envelope groups by an independent, experienced biostatistician., Results: On average, patients who received any envelope (biologic or non-biologic) were younger (70.7 ± 14.0 vs 74.9 ± 10.6, P = 0.017), had a greater number of infection risk factors (81.2% vs 49.1%, P < 0.001), received more high-powered devices (37.2% vs 5.8%, P = 0.004), and were undergoing more reoperative procedures (47.1% vs 0.0%, P < 0.001) than patients who received no envelope. Between the two envelopes, biologic envelopes tended to be used more often in higher risk patients (84.3% vs 78.4%) and reoperative procedures (62.9% vs 33.3%) than non-biologic envelopes. The rate of CIED implant site pocket infection was low (any envelope 0.5% vs no envelope 0.0%) and was statistically equivalent between the two envelope groups. Other reported adverse events (lead dislodgement, lead or pocket revision, device migration or erosion, twiddler's syndrome, and erythema/fever) were low and statistically equivalent between groups (biologic 2.2%, non-biologic 3.9%, no envelope 1.8%)., Conclusion: CIED infection rates for biologic and non-biologic antibacterial envelopes are similar. Antibacterial envelopes may benefit patients who are higher risk for infection, however additional studies are warranted to confirm this., Competing Interests: Conflict-of-interest statement: Woodard D is a consultant for Aziyo Biologics, Inc. The other authors have no relevant financial relationships to disclose., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

High-definition (HD) mapping with the Advisor HD Grid and HD Wave Solution software offers unparalleled resolution in mapping complex arrhythmias. The unique shape of a HD Grid (16 electrodes in a 4 × 4 pattern) allows for the mapping of orthogonal electrograms (EGMs). In so doing, the HD Grid catheter virtually eliminates the issue of 'bipolar blindness', a phenomenon seen when a wavefront of propagation is traveling perpendicular to a bipole pair. By improving the accuracy of the 3D electroanatomical map, HD Grid offers the potential of shorter procedure times, safer ablations and higher success rates. The following article explores the role of HD Grid in mapping a variety of arrhythmias including supraventricular tachycardias, atrial fibrillation and ventricular tachycardia. In addition, the authors explore the role of HD Grid in more recently described substrate-based advanced mapping techniques.

Rationale: Supervised treadmill exercise for claudication in peripheral arterial disease is effective but poorly tolerated because of ischemic leg pain. Near infrared spectroscopy allows non-invasive detection of muscle ischemia during exercise, allowing for characterization of tissue perfusion and oxygen utilization during training., Objective: We evaluated walking time, muscle blood flow, and muscle mitochondrial capacity in patients with peripheral artery disease after a traditional pain-based walking program and after a muscle oxygen-guided walking program., Method and Results: Patients with peripheral artery disease trained thrice weekly in 40-minute-long sessions for 12 weeks, randomized to oxygen-guided training ( n = 8, age 72 ± 9.7 years, 25% female) versus traditional pain-based training ( n = 10, age 71.6 ± 8.8 years, 20% female). Oxygen-guided training intensity was determined by maintaining a 15% reduction in skeletal muscle oxygenation by near infrared spectroscopy rather than relying on symptoms of pain to determine exercise effort. Pain free and maximal walking times were measured with a 12-minute Gardner treadmill test. Gastrocnemius mitochondrial capacity and blood flow were measured using near infrared spectroscopy. Baseline pain-free walking time was similar on a Gardner treadmill test (2.5 ± 0.9 vs. 3.6 ± 1.0 min, p = 0.5). After training, oxygen-guided cohorts improved similar to pain-guided cohorts (pain-free walking time 6.7 ± 0.9 vs. 6.9 ± 1.1 min, p < 0.01 for change from baseline and p = 0.97 between cohorts). Mitochondrial capacity improved in both groups but more so in the pain-guided cohort than in the oxygen-guided cohort (38.8 ± 8.3 vs. 14.0 ± 9.3, p = 0.018). Resting muscle blood flow did not improve significantly in either group with training., Conclusions: Oxygen-guided exercise training improves claudication comparable to pain-based training regimens. Adaptations in mitochondrial function rather than increases in limb perfusion may account for functional improvement. Increases in mitochondrial oxidative capacity may be proportional to the degree of tissue hypoxia during exercise.

Sarcoidosis is a systemic granulomatous disease that frequently involves the myocardium. Unfortunately, the sentinel manifestations of cardiac sarcoidosis are often potentially fatal bradyarrhythmia and tachyarrhythmia. Advanced imaging modalities such as cardiac magnetic resonance have allowed for increased diagnosis of cardiac involvement. The current review article explores diagnosis and treatment strategies for arrhythmias in patients with cardiac sarcoidosis., Competing Interests: The authors report no conflicts of interest for the published content., (Copyright: © 2019 Innovations in Cardiac Rhythm Management.)

Objective : Non-valvular atrial fibrillation (NVAF), a common cardiac arrhythmia, is associated with high morbidity and carries a substantial economic burden. Historically, vitamin K antagonists (VKAs; e.g. warfarin) have been used for therapy of NVAF, but recently several direct oral anticoagulants (DOACs) have been approved for prevention of stroke in patients with NVAF. This review summarizes the real-world evidence (RWE) for healthcare resource utilization (HRU) in patients receiving oral anticoagulants (VKAs and/or DOACs) for therapy of NVAF. Methods : A PRISMA-compliant literature search assessed Medline ® and Embase ® databases from 1 January 2011 to 4 May 2017, and the National Health Service Economic Evaluation Database from 1 January 2011 to 31 December 2015. Publications were included if they reported observational data from real-world use of one or more anticoagulant therapies. Outcomes of interest included hospitalizations, length of stay (LOS), mortality and costs. Results : Twenty-eight publications were included. Apixaban and dabigatran were associated with fewer bleed-related hospitalizations than warfarin. Bleed-related LOS were generally longer for warfarin than for DOACs. Bleed-related treatment costs were lower for patients receiving apixaban or receiving dabigatran than patients receiving rivaroxaban or receiving warfarin. Bleed-related mortality in patients receiving oral anticoagulation for treatment of NVAF were low across all DOACs and warfarin. Conclusions : The limited available evidence for HRU burden among patients receiving oral anticoagulation for NVAF suggests that DOACs (particularly apixaban and dabigatran) offer some degree of benefit in terms of HRU outcomes, compared with warfarin. Further work is required to understand HRU outcomes in patients receiving DOACs.

Systolic heart failure (HF) is associated with exercise intolerance that has been attributed, in part, to skeletal muscle dysfunction. The purpose of this study was to compare skeletal muscle oxidative capacity and training-induced changes in oxidative capacity in participants with and without HF. Participants with HF (n = 16, 65 ± 6.6 years) were compared with control participants without HF (n = 23, 61 ± 5.0 years). A subset of participants (HF: n = 7, controls: n = 5) performed 4 weeks of wrist-flexor exercise training. Skeletal muscle oxidative capacity was determined from the recovery kinetics of muscle oxygen consumption measured by near-infrared spectroscopy (NIRS) following a brief bout of wrist-flexor exercise. Oxidative capacity, prior to exercise training, was significantly lower in the HF participants in both the dominant (1.31 ± 0.30 min(-1) vs. 1.59 ± 0.25 min(-1), P = 0.002; HF and control groups, respectively) and nondominant arms (1.29 ± 0.24 min(-1) vs. 1.46 ± 0.23 min(-1), P = 0.04; HF and control groups, respectively). Following 4 weeks of endurance training, there was a significant difference in the training response between HF and controls, as the difference in oxidative training adaptations was 0.69 ± 0.12 min(-1) (P < 0.001, 95% CI 0.43, 0.96). The wrist-flexor training induced a ~50% improvement in oxidative capacity in participants without HF (mean difference from baseline = 0.66 ± 0.09 min(-1), P < 0.001, 95% CI 0.33, 0.98), whereas participants with HF showed no improvement in oxidative capacity (mean difference from baseline = -0.04 ± 0.08 min(-1), P = 0.66, 95% CI -0.24, 0.31), suggesting impairments in mitochondrial biogenesis. In conclusion, participants with HF had reduced oxidative capacity and impaired oxidative adaptations to endurance exercise compared to controls., (© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Atrial fibrillation frequently complicates myocardial infarction. Patients with atrial fibrillation complicating acute coronary syndrome have increased morbidity and mortality relative to patients that remain in normal sinus rhythm. No studies have identified a mortality benefit to rhythm control compared with rate control in the setting of acute coronary syndrome. Stroke prevention should be pursued with oral anticoagulation therapy, although the majority of patients with atrial fibrillation associated with acute coronary syndrome receive only antiplatelet therapy. There are several novel oral anticoagulant therapies now available, but these agents have not been well studied in combination with dual antiplatelet therapy. Therefore, warfarin as part of triple therapy is the most conservative approach until additional data becomes available.

A 41-year-old man underwent implantation of a right-sided implantable cardioverter defibrillator after removal of an infected left-sided system. Defibrillation threshold (DFT) testing on the right-sided system failed to convert ventricular fibrillation at maximum device output (35 J) compared with a DFT of less than 15 J on the previous left-sided system. A single-coil lead was selectively placed into the hemiazygous vein, which courses leftward of the spine in a posterior-anterior projection, resulting in an improved shocking vector and reduction in DFTs to less than 25 J., (©2010, The Authors. Journal compilation ©2010 Wiley Periodicals, Inc.)

Background: Risk-stratifying heart failure patients for primary prevention implantable cardioverter-defibrillators (ICDs) remains a challenge, especially for blacks, who have an increased incidence of sudden cardiac death but have been underrepresented in clinical trials. We hypothesized that the S1103Y cardiac sodium channel SCN5A variant influences the propensity for ventricular arrhythmias in black patients with heart failure and reduced ejection fraction., Methods and Results: Blacks (n=112) with ejection fractions <35% receiving primary prevention ICDs were identified from the Duke Electrophysiology Genetic and Genomic Studies (EPGEN) biorepository and followed for appropriate ICD therapy (either anti tachycardia pacing or shock) for documented sustained ventricular tachycardia or fibrillation. The S1103Y variant was overrepresented in patients receiving appropriate ICD therapy compared with subjects who did not (35% versus 13%, P=0.03). Controlling for baseline characteristics, the adjusted hazard ratio using a Cox proportional hazard model for ICD therapy in Y1103 allele carriers was 4.33 (95% confidence interval, 1.60 to 11.73, P=<0.01). There was no difference in mortality between carriers and noncarriers., Conclusions: This is the first report that the S1103Y variant is associated with a higher incidence of ventricular arrhythmias in blacks with heart failure and reduced ejection fraction.

Objective: The management of patients with atrial fibrillation (AF) following a myocardial infarction (MI) remains uncertain. This study compared a rate control strategy to an anti-arrhythmic-based rhythm control strategy for the treatment of AF following myocardial infarction., Design, Setting and Patients: We studied 1131 patients with AF after MI who were enrolled in the Valsartan in Acute Myocardial Infarction Trial (VALIANT). We classified patients into those treated with a rhythm control strategy (n=371) and those treated with a rate control strategy (n=760)., Main Outcomes Measures: Using Cox models, we compared the two groups with respect to both death and stroke during two different time periods after randomisation for which data collection had been pre-specified: 0-45 days and 45-1096 days., Results: After adjustment, a rhythm control strategy was found to be associated with increased early mortality (0-45 days: HR: 1.9, 95% CI 1.2 to 3.0, p=0.004) but not late mortality (45-1096 days: HR 1.1, 95% CI 0.9 to 1.4, p=0.45). No difference was observed in the incidence of stroke (0-45 days: HR 1.2, 95% CI 0.4 to 3.7, p=0.73; 45-1096 days: HR 0.6, 95% CI 0.3 to 1.3, p=0.21)., Conclusions: In patients with AF after an MI, an anti-arrhythmic drug-based rhythm control strategy is associated with excess 45-day mortality compared with a rate control strategy, but is not associated with increased mortality outside of the immediate peri-infarct period. These results potentially identify a patient population in whom the use of anti-arrhythmic drug therapy may portend an increased risk of death.

Parasympathetic stimulation of pancreatic islets augments glucose-stimulated insulin secretion by inducing inositol trisphosphate receptor (IP(3)R)-mediated calcium ion (Ca2+) release. Ankyrin-B binds to the IP(3)R and is enriched in pancreatic beta cells. We found that ankyrin-B-deficient islets displayed impaired potentiation of insulin secretion by the muscarinic agonist carbachol, blunted carbachol-mediated intracellular Ca2+ release, and reduced the abundance of IP3R. Ankyrin-B-haploinsufficient mice exhibited hyperglycemia after oral ingestion but not after intraperitoneal injection of glucose, consistent with impaired parasympathetic potentiation of glucose-stimulated insulin secretion. The R1788W mutation of ankyrin-B impaired its function in pancreatic islets and is associated with type 2 diabetes in Caucasians and Hispanics. Thus, defective glycemic regulation through loss of ankyrin-B-dependent stabilization of IP3R is a potential risk factor for type 2 diabetes.

The organization of membrane-spanning proteins within discrete microdomains is critical for their physiologic function. This is especially important in the heart, where ion transporter and force-transducing microdomains are responsible for excitation-contraction coupling, anisotropic depolarization, and mechanotransduction. The following review will discuss recent advances in our understanding of the patterning of ion channel and force-transmitting membrane microdomains in cardiomyocytes, focusing on the T-tubule and intercalated disc.

Background: Medical errors have been increasingly identified as a major source of morbidity and mortality in both outpatient and acute care settings. Central to the evaluation of many medical problems, the 12-lead electrocardiogram (ECG) is susceptible to both technical and interpretative errors. Proper interpretation, however, is dependent on the quality and accuracy of the acquired ECG., Methods: We evaluated the impact of both a newly designed electrocardiograph and a newly developed automated computer algorithm on the incidence and detection of electrode cable reversals (lead reversals). The study tested the association of the incidence of electrode cable reversals and the design of the connection terminal. The study was performed during a 7-month period preceding (53,875 ECGs) and after (53,344 ECGs) the implementation of the new system. Electrode cable reversals occurring in various sites of the medical center were tabulated and compared. We then sought to determine if computer detection algorithms could increase point-of-care detection of electrode cable reversals and, thereby, offset the influence of cardiograph design changes. Two commercially available automated detection algorithms were compared for their abilities to identify electrode cable reversals in our study population., Results: During the 7-month postimplementation period, there was a significant increase in the incidence in electrode cable reversals (0.5% vs 0.1%, P < .001). The incidence of reversals for ECGs obtained in the emergency department was twice that of those obtained within the hospital (0.79% vs 0.38%, P < .01). Automated detection of electrode cable reversals from the 7-month study period increased from 38% to 71% (P < or = .0001), using a recently released automated algorithm supplied by the manufacturer., Conclusions: Electrode cable reversals are a prevalent source of medical errors that receives very little attention by the clinical community. The association of an increase in electrode cable reversals with an altered electrode cable connection terminal, coupled with an increased ability to detect electrode cable reversals using the manufacturer's recently developed algorithms, emphasizes the importance of ongoing research efforts to identify technical errors in electrocardiography.

Heart failure represents a major source of morbidity and mortality in industrialized nations. As the leading hospital discharge diagnosis in the United States in patients over the age of 65, it is also associated with substantial economic costs. While the acute symptoms of volume overload frequently precipitate inpatient admission, it is the symptoms of chronic heart failure, including fatigue, exercise intolerance and exertional dyspnea, that impact quality of life. Over the last two decades, research into the enzymatic, histologic and neurohumoral alterations seen with heart failure have revealed that hemodynamic derangements do not necessarily correlate with symptoms. This "hemodynamic paradox" is explained by alterations in the skeletal musculature that occur in response to hemodynamic derangements. Importantly, gender specific effects appear to modify both disease pathophysiology and response to therapy. The following review will discuss our current understanding of the systemic effects of heart failure before examining how exercise training and cardiac resynchronization therapy may impact disease course.

Hypothesis: Perioperative allogeneic blood product transfusion would be associated with venous thromboembolic complications in surgical patients., Design: Observational study using a state discharge database., Setting: Nonfederal acute care hospitals in Maryland performing colorectal cancer resections between January 1, 1994, and December 31, 2000., Patients: We obtained data on 14 014 adult patients having a primary diagnosis code for colorectal cancer and a primary procedure code for colorectal resection., Main Outcome Measures: The primary outcome variable was a discharge diagnosis of venous thromboembolism (VTE)., Results: Venous thromboembolism occurred in 1% of patients and was associated with an adjusted 3.8-fold increase in mortality (odds ratio, 3.8; 95% confidence interval, 2.1-6.8), a 61% increase in mean hospital length of stay, and a 72% increase in mean total hospital charges. Risk factors for VTE after adjustment included transfusion, female sex, age 80 years or older, moderate to severe liver disease vs no liver disease, admission through the emergency department, and low annual surgeon case volume. Transfusion was associated with an increase in the odds of developing VTE in women (odds ratio, 1.8; 95% confidence interval, 1.2-2.6) but not in men (odds ratio, 0.9; 95% confidence interval, 0.5-1.9). In the absence of transfusion, female compared with male sex was not associated with an increased risk of VTE (odds ratio, 1.2; 95% confidence interval, 0.8-1.7)., Conclusions: In this large observational study of patients undergoing colorectal cancer resection, perioperative allogeneic blood transfusion was associated with an increased risk of VTE in women but not in men. Given the substantial morbidity and mortality associated with VTE and the implication that this finding has for postoperative management in women, this association must be confirmed in independent studies.

T-type Ca(2+) channels are believed to play an important role in pain perception, and anesthetic steroids such as alphaxalone and allopregnanolone, which have a 5alpha-configuration at the steroid A, B ring fusion, are known to inhibit T-type Ca(2+) channels and cause analgesia in a thermal nociceptive model (Soc Neurosci Abstr 29:657.9, 2003). To define further the structure-activity relationships for steroid analgesia, we synthesized and examined a series of 5beta-reduced steroids for their ability to induce thermal antinociception in rats when injected locally into the peripheral receptive fields of the nociceptors and studied their effects on T-type Ca(2+) channel function in vitro. We found that most of the steroids completely blocked T-type Ca(2+) currents in vitro with IC(50) values at a holding potential of -90 mV ranging from 2.8 to 40 microM. T current blockade exhibited mild voltage-dependence, suggesting that 5beta-reduced neuroactive steroids stabilize inactive states of the channel. For the most potent steroids, we found that other voltage-gated currents were not significantly affected at concentrations that produce nearly maximal blockade of T currents. All tested compounds induced dose-dependent analgesia in thermal nociceptive testing; the most potent effect (ED(50), 30 ng/100 microl) obtained with a compound [(3beta,5beta,17beta)-3-hydroxyandrostane-17-carbonitrile] that was also the most effective blocker of T currents. Compared with previously studied 5alpha-reduced steroids, these 5beta-reduced steroids are more efficacious blockers of neuronal T-type Ca(2+) channels and are potentially useful as new experimental reagents for understanding the role of neuronal T-type Ca(2+) channels in peripheral pain pathways.

Transfusion is associated with multiple risks and morbidities. Little is known, however, about preoperative predictors of transfusion in gastrointestinal surgery patients. To identify factors that influence transfusion practices, we analyzed hospital discharge data from colorectal cancer surgery patients in Maryland between 1994 and 2000 (n = 14,052). The primary outcome variable was whether or not patients received a blood product ("Any Transfusion"). Characteristics independently associated with an increased risk of receiving Any Transfusion included: advanced age (>80 yr: OR 2.3; 95% CI 1.9-2.9; 70-79 yr: OR 1.6; 95% CI 1.4-2.0 vs. <60 yr), moderate to severe liver disease (OR 2.5; 95% CI 1.5-4.2), mild liver disease (OR 2.1; 95% CI 1.5-2.9), diabetes with complications (OR 2.1; 95% CI 1.6-2.6), chronic renal disease (OR 2.1; 95% CI 1.4-3.0), female gender (OR 1.3; 95% CI 1.2-1.5), chronic pulmonary disease (COPD) (OR 1.3; 95% CI 1.1-1.4), and metastatic disease (OR 1.2; 95% CI 1.1-1.4). Patients at hospitals with an annual case volume in the highest quartile were at an increased risk for receiving Any Transfusion (OR 2.1; 95% CI 1.3-3.4) and those with surgeons in the highest volume quartile (>12 cases/yr) were at a decreased risk (OR 0.8; 95% CI 0.6-0.99). The association between greater surgeon case volume and low transfusion rates was seen in all but the very high volume hospitals (>74 cases/yr). Blood product transfusion was associated with a 2.5-fold (95% CI 2.1-3.1) increased mortality, 3.7 day (95% CI 2.1-3.1) increase in hospital length of stay, and a 7120 dollars (95% CI 6472 dollars-7769 dollars) increase in total charges compared to patients that did not receive Any Transfusion. This data can be used by providers in discussions with patients regarding the risks for transfusion and in identifying patients in whom strategies to reduce transfusions should be evaluated.

Estrogens are potent neuroprotective compounds in a variety of animal and cell culture models, and data indicate that estrogen receptor (ER)-mediated gene transcription is not required for some of these effects. To further address the requirement for an ER in estrogen enhancement of neuronal survival, we assessed the enantiomer of 17beta-estradiol (ENT-E(2)), which has identical chemical properties but interacts only weakly with known ERs, for neuroprotective efficacy. ENT-E(2) was both as potent and efficacious as 17beta-estradiol in attenuating oxidative stress-induced death in HT-22 cells, a murine hippocampal cell line. Further, ENT-E(2) completely attenuated H(2)O(2) toxicity in human SK-N-SH neuroblastoma cells at a 10 nM concentration. In a rodent model of focal ischemia, 17beta-estradiol (100 microgram/kg) or ENT-E(2) (100 microgram/kg), injected 2 h before middle cerebral artery occlusion, resulted in a 60 and 61% reduction in lesion volume, respectively. ENT-E(2), at the doses effective in this study, did not stimulate uterine growth or vaginal opening in juvenile female rats when administered daily for 3 days. These data indicate that the neuroprotective effects of estrogens, both in vitro and in vivo, can be disassociated from the peripheral estrogenic actions.

This study reports the actions of enantiomer pairs of anesthetic steroids 3alpha5alphaP/ent-3alpha5alphaP and 3alpha5betaP/ent-3alpha5betaP as modulators of gamma-aminobutyric acid (GABA)(A) receptors and as anesthetics. The enantiomers of structurally related 17-carbonitrile analogs also are examined. These studies were aimed at 1) determining whether the steroid recognition site could distinguish between molecules differing in shape, but not other physical properties (enantioselectivity); 2) providing further insight into the structure-activity relationships of anesthetic steroids; and 3) determining whether modulation of GABA(A) receptor function correlates with anesthetic potency for anesthetic steroid enantiomers. Stereoselective actions of the compounds were evaluated in four different bioassays: 1) noncompetitive displacement of [(35)S]t-butylbicyclophosphorothionate from the picrotoxin site of GABA(A) receptors present in rat brain membrane preparations; 2) modulation of GABA currents in cultured rat hippocampal neurons; 3) loss of righting reflex in tadpoles; and 4) loss of righting reflex in mice. The data indicate that 5alpha-reduced steroids, but not 5beta-reduced steroids, show a high degree of enantioselectivity/enantiospecificity in their actions as modulators of GABA(A) receptors and as anesthetics. For all compounds studied, the effects on GABA(A) receptor function closely tracked with anesthetic effects. These data show that the anesthetic steroid recognition site is capable of distinguishing enantiomers, suggesting a protein-binding site of specific dimensions and shape. The results are compatible either with a structural model of the binding site that can accommodate 3alpha5alphaP, 3alpha5betaP, and ent-3alpha5betaP, but not ent-3alpha5alphaP, or with two different binding sites for steroid anesthetics.

Class I P-glycoproteins (Pgp) confer multidrug resistance in tumors, but the physiologic function of Pgp in normal tissues remains uncertain. In cells derived from tissues that normally express Pgp, recent data suggest a possible role for Pgp in cholesterol trafficking from the plasma membrane to the endoplasmic reticulum. We investigated the esterification of plasma membrane cholesterol under basal conditions and in response to sphingomyelinase treatment in transfected and drug-selected cell lines expressing differing amounts of functional class I Pgp. Compared with parental NIH 3T3 fibroblasts, cells transfected with human multidrug resistance (MDR1) Pgp esterified more cholesterol both without and with sphingomyelinase. Esterification also was greater in drug-selected Dox 6 myeloma cells than parental 8226 cells, which express low and non-immunodetectable amounts of Pgp, respectively. However, no differences in total plasma membrane cholesterol were detected. Transfection of fibroblasts with the multidrug resistance-associated protein (MRP) did not alter esterification, showing that cholesterol trafficking was not generally affected by ATP-binding cassette transporters. Steroidal (progesterone, dehydroepiandrosterone) and non-steroidal antagonists (verapamil, PSC 833, LY335979, and GF120918) were evaluated for effects on both cholesterol trafficking and the net content of 99mTc-Sestamibi, a reporter of drug transport activity mediated by Pgp. In Pgp-expressing cells treated with nonselective and selective inhibitors, both the kinetics and efficacy of inhibition of cholesterol esterification differed from the antagonism of drug transport mediated by Pgp. Thus, although the data show that greater expression of class I Pgp within a given cell type is associated with enhanced esterification of plasma membrane cholesterol in support of a physiologic function for Pgp in facilitating cholesterol trafficking, the molecular mechanism is dissociated from the conventional drug transport activity of Pgp.

A number of steroids seem to have anesthetic effects resulting primarily from their ability to potentiate currents gated by gamma-aminobutyric acidA (GABAA) receptor activation. One such compound is (3alpha,5alpha, 17beta)-3-hydroxyandrostane-17-carbonitrile [(+)-ACN]. We were interested in whether carbonitrile substitution at other ring positions might result in other pharmacological consequences. Here we examine effects of (3beta,5alpha, 17beta)-17-hydroxyestrane-3-carbonitrile [(+)-ECN] on GABAA receptors and Ca2+ channels. In contrast to (+)-ACN, (+)-ECN does not potentiate GABAA-receptor activated currents, nor does it directly gate GABAA-receptor mediated currents. However, both steroids produce an enantioselective reduction of T-type current. (+)-ECN blocked T current with an IC50 value of 0.3 microM with a maximal block of 41%. (+)-ACN produced a partial block of T current (44% maximal block) with an IC50 value of 0.4 microM. Block of T current showed mild use- and voltage-dependence. The (-)-ECN enantiomer was about 33 times less potent than (+)-ECN, with an IC50 value of 10 microM and an amount of maximal block comparable to (+)-ECN. (+)-ECN was less effective at blocking high-voltage-activated Ca2+ current in DRG neurons (IC50 value of 9. 3 microM with maximal block of about 27%) and hippocampal neurons. (+)-ECN (10 microM) had minimal effects on voltage-gated sodium and potassium currents in rat chromaffin cells. The results identify a steroid with no effects on GABAA receptors that produces a partial inhibition of T-type Ca2+ current with reasonably high affinity and selectivity. Further study of steroid actions on T currents may lead to even more selective and potent agents.

The unnatural enantiomers of dehydroepiandrosterone sulfate (1), pregnenolone sulfate (2), and (3alpha,5beta)-3-hydroxypregnan-20-one sulfate (3), compounds 4-6, respectively, were prepared by total steroid synthesis. The enantioselectivity of the compounds as negative modulators of the GABAA receptors present in cultured rat hippocampal neurons was examined using electrophysiological methods. Enantioselectivity was found for the inhibitory actions of the dehydroepiandrosterone enantiomers. The IC50s for compounds 1 and 4 were 11 +/- 1 and 80 +/- 14 microM, respectively. Little, if any, enantioselectivity was found for the other two pairs of steroid sulfate inhibitors. The IC50s for compounds 2 and 5 were 82 +/- 12 and 76 +/- 27 microM, respectively. The IC50s for compounds 3 and 6 were 39 +/- 7 and 46 +/- 2 microM, respectively. The results suggest that the sites of action for the androstane and pregnane series of steroid sulfate blockers of GABA-mediated current are different. The observed enantioselectivity for the actions of dehydroepiandrosterone sulfate indicates that its inhibitory actions are mediated via a chiral recognition site and provides new evidence in support of the earlier hypothesis that there is a binding site for this compound on GABAA receptors. Conversely, the failure to observe enantioselectivity for the actions of pregnenolone sulfate and steroid sulfate 3 indicates that a chiral recognition site for these steroids does not exist on GABAA receptors and suggests that the effects of these compounds on this receptor's function may arise indirectly as a consequence of steroid-induced membrane perturbation.