BB Exposure Research Articles

Association of Early Beta-Blocker Exposure and Functional Outcomes in Critically Ill Patients With Moderate to Severe Traumatic Brain Injury: A Transforming Clinical Research and Knowledge in Traumatic Brain Injury Study.

We aimed to 1) describe patterns of beta-blocker utilization among critically ill patients following moderate-severe traumatic brain injury (TBI) and 2) examine the association of early beta-blocker exposure with functional and clinical outcomes following injury. Retrospective cohort study. ICUs at 18 level I, U.S. trauma centers in the Transforming Clinical Research and Knowledge in TBI (TRACK-TBI) study. Greater than or equal to 17 years enrolled in the TRACK-TBI study with moderate-severe TBI (Glasgow Coma Scale of <13) were admitted to the ICU after a blunt TBI. None. Primary exposure was a beta blocker during the first 7 days in the ICU, with a primary outcome of 6-month Glasgow Outcome Scale-Extended (GOSE). Secondary outcomes included: length of hospital stay, in-hospital mortality, 6-month and 12-month mortality, 12-month GOSE score, and 6-month and 12-month measures of disability, well-being, quality of life, and life satisfaction. Of the 450 eligible participants, 57 (13%) received early beta blockers (BB+ group). The BB+ group was on average older, more likely to be on a preinjury beta blocker, and more likely to have a history of hypertension. In the BB+ group, 34 participants (60%) received metoprolol only, 19 participants (33%) received propranolol only, 3 participants (5%) received both, and 1 participant (2%) received atenolol only. In multivariable regression, there was no difference in the odds of a higher GOSE score at 6 months between the BB+ group and BB- group (odds ratio = 0.86; 95% CI, 0.48-1.53). There was no association between BB exposure and secondary outcomes. About one-sixth of subjects in our study received early beta blockers, and within this group, dose, and timing of beta-blocker administration varied substantially. No significant differences in GOSE score at 6 months were demonstrated, although our ability to draw conclusions is limited by overall low total doses administered compared with prior studies.

Borrelia burgdorferi induces changes in the physical forces and immunity signaling pathways of endothelial cells early but not late during in vitro exposure

Borrelia burgdorferi (Bb) is the causative bacterial agent of Lyme disease which is on the rise in the USA and Europe. Once transmitted to the human host via an arthropod vector, Bb spreads through tissues by traveling along and through the vasculature, whose inner lumen is lined by a monolayer of endothelial cells (ECs). What are the precise mechanisms that Bb employs to achieve efficient dissemination through the vasculature is not well understood. Could extracellular Bb induce alterations in the EC force generation machinery, promoting its own spread by potentially weakening the EC barrier integrity? Using videomicroscopy coupled with traction force and monolayer stress microscopy, we monitored the response of ECs to Bb exposure and found a sharp, transient increase in EC traction and intercellular stresses, followed by a prolonged decrease in EC traction and monolayer stresses up to 15 hours post-exposure. After this point though all variables return to levels similar to those observed for never-exposed ECs. Using RNA-sequencing to better understand the underlying biochemical mechanisms involved, we discovered an upregulation of EC innate immune signaling pathways during early but not late exposure to Bb. In contrast to exposure of ECs to live Bb, when we exposed ECs to heat-inactivated Bb, we evidenced no sharp increase in traction forces at early exposure, neither reversal at late exposure, but found a sustained weakening of physical forces all throughout the exposure. Thus, we discovered a differential response of EC physical force generation and innate immune signaling to live versus heat-inactivated Bb. This indicates a tight interplay between the two and is suggestive of an active modulation of both processes that might be key in establishing infection.

Borrelia burgdorferi modulates the physical forces and immunity signaling in endothelial cells

SummaryBorrelia burgdorferi (Bb), a vector-borne bacterial pathogen and the causative agent of Lyme disease, can spread to distant tissues in the human host by traveling in and through monolayers of endothelial cells (ECs) lining the vasculature. To examine whether Bb alters the physical forces of ECs to promote its dissemination, we exposed ECs to Bb and observed a sharp and transient increase in EC traction and intercellular forces, followed by a prolonged decrease in EC motility and physical forces. All variables returned to baseline at 24 h after exposure. RNA sequencing analysis revealed an upregulation of innate immune signaling pathways during early but not late Bb exposure. Exposure of ECs to heat-inactivated Bb recapitulated only the early weakening of EC mechanotransduction. The differential responses to live versus heat-inactivated Bb indicate a tight interplay between innate immune signaling and physical forces in host ECs and suggest their active modulation by Bb.

Assessing knowledge, attitudes, and practices of Canadian veterinarians with regard to Lyme disease in dogs.

BackgroundThe blacklegged tick (BLT) is a vector for the bacterium Borrelia burgdorferi (Bb), which causes Lyme disease. Range expansion of the BLT in Canada is related to an increased risk of Lyme disease in many regions. Current literature, such as the 2018 American College of Veterinary Internal Medicine consensus statement, suggests that there may be differences in the approaches of veterinarians who encounter dogs exposed to Bb and dogs with Lyme disease.ObjectivesTo determine current knowledge, attitudes, and practices of Canadian veterinarians regarding Lyme disease in dogs.AnimalsNone.MethodsAn online survey was distributed to Canadian veterinarians through veterinary associations and industries. Survey responses were analyzed using descriptive statistics, spatial analysis, Fisher's exact tests, and univariable logistic regression.ResultsAt the completion of the survey, 192 responses were received from veterinarians practicing in all 10 Canadian provinces. Answers to short scenario and treatment questions reflected a wide variety of clinical approaches taken by veterinarians. Regional differences were seen in reported tick distribution and clinical approaches.Conclusions and Clinical ImportanceRegional differences and generalized differences were found in approaches used by responding Canadian veterinarians with regard to managing Bb exposure and Lyme disease in dogs. We identified areas for future research and knowledge mobilization for veterinarians.

Polygenic Score for β-Blocker Survival Benefit in European Ancestry Patients With Reduced Ejection Fraction Heart Failure.

β-Blockers (BBs) are mainstay therapy for heart failure with reduced ejection fraction. However, individual patient responses to BB vary, which may be partially due to genetic variation. The goal of this study was to derive and validate the first polygenic response predictor (PRP) for BB survival benefit in heart failure with reduced ejection fraction patients. Derivation and validation analyses were performed in n=1436 total HF patients of European descent and with ejection fraction <50%. The PRP was derived in a random subset of the Henry Ford Heart Failure Pharmacogenomic Registry (n=248) and then validated in a meta-analysis of the remaining patients from Henry Ford Heart Failure Pharmacogenomic Registry (n=247), the TIME-CHF (Trial of Intensified Versus Standard Medical Therapy in Elderly Patients With Congestive Heart Failure; n=431), and HF-ACTION trial (Heart Failure: a Controlled Trial Investigating Outcomes of Exercise Training; n=510). The PRP was constructed from a genome-wide analysis of BB×genotype interaction predicting time to all-cause mortality, adjusted for Meta-Analysis Global Group in Chronic Heart Failure score, genotype, level of BB exposure, and BB propensity score. Five-fold cross-validation summaries out to 1000 single-nucleotide polymorphisms identified optimal prediction with a 44 single-nucleotide polymorphism score and cutoff at the 30th percentile. In validation testing (n=1188), greater BB exposure was associated with reduced all-cause mortality in patients with low PRP score (n=251; hazard ratio, 0.19 [95% CI, 0.04-0.51]; P=0.0075) but not high PRP score (n=937; hazard ratio, 0.84 [95% CI, 0.53-1.3]; P=0.448)-a difference that was statistically significant (P interaction, 0.0235). Results were consistent regardless of atrial fibrillation, ejection fraction (≤40% versus 41%-50%), or when examining cardiovascular death. Among patients of European ancestry with heart failure with reduced ejection fraction, a PRP distinguished patients who derived substantial survival benefit from BB exposure from a larger group that did not. Additional work is needed to prospectively test clinical utility and to develop PRPs for other population groups and other medications.

Vitamin D Receptor Gene Polymorphism and the Risk of Multiple Sclerosis in the Azeri Population of Iran.

Multiple sclerosis (MS), a disease of the central nervous system (CNS), is associated with damage to the myelin sheath of neurons. It is demonstrated that vitamin D deficiency plays an important role in the development of the disease. Binding of vitamin D to its specific nuclear receptors is a way to exert its function. Possible correlation between the vitamin D receptor (VDR) gene and MS was evaluated in the Azeri population of Iran. Different genotypes of the Bsml site were determined by using the PCR-RFLP method in 148 MS patients and 220 non-relative healthy controls. In MS patients, genotype bb was significantly higher than the healthy controls (p<0.05). Additionally, most subjects of the MS group had been insufficiently exposed to sunlight before the age of 15 (p<0.001). Our findings indicated that the red meat intake in MS patients was significantly higher than the healthy controls (p<0.001). In addition, the healthy controls had appropriate dieting behaviors in comparison to MS patients (excessive intake of some foods) (p=0.0001). In conclusion, genotype BB and sufficient exposure to sunlight before the age of 15 were the protective factors against MS. Although, excessive consumption of red meat and inappropriate dieting behaviors were predisposing factors to MS disease.

Risk for Anaphylactic Reaction from Cardiac Catheterization in Patients Receiving β-Adrenergic Blockers or Angiotensin-Converting Enzyme-Inhibitors

β-Adrenergic blockers (BBs) have been associated with increased risk for severe anaphylactic reaction (AR) from contrast media; however, this was shown with intravenous contrast media, before widespread use of low osmolar contrast media, angiotensin-converting enzyme-inhibitors (ACE-Is), and cardioselective BBs. To assess the risk for AR during cardiac catheterization (CC) associated with BB or ACE-I exposure. Patients who experienced adverse reactions during CC from January 2004 to December 2013 were identified; 1 to 2 matched controls were assigned for each case. We analyzed AR rates in association with demographic variables, medication exposures (BBs, ACE-Is, angiotensin-receptor blockers, aspirin), and comorbidities: cardiovascular disorders, asthma, and atopy. We analyzed 71,782 CCs. Of these, severe 70 reactors were identified-46 (0.06%) fulfilled AR criteria. There were 35 cases of mild to moderate AR and 11 cases of severe AR (0.015%). There were no significant differences in age (61.3% vs 61.5%), sex (63% vs 64% males), cardiovascular disorder rate (78% vs 93%), and exposure to BBs (46% vs 51%; cardioselective: 77% vs 80%) and ACE-Is (37.0% vs 37.2%) in cases versus controls. Via multivariate logistic regression, BB exposure was not associated with greater AR frequency (P= .35) or severity (P= .40). Neither cardioselective BBs (P= 0.2) nor noncardioselective BBs (P= .5) influenced AR severity. ACE-Is had no effect on AR frequency (P= .35) or severity (P= .14). Lower AR frequency was associated with cardiovascular disorder (P= .01). In this case-control study, severe AR was rarely observed. Exposure to BBs or ACE-Is did not significantly influence AR frequency or severity; however, most BBs were cardioselective. Our findings imply that cardioselective BB or ACE-I suspension is not warranted in association with CC.

Repeated Exposure of Native African Adansonia Digitata (Baobab) and Moringa Oleifera (Moringa) Modifies Caco-2 Cell Differentiation but Not Carotenoid Absorption (P10-025-19)

ObjectivesThe inclusion of mineral rich African plants such as moringa (Moringa oleifera; MOR) and baobab (Adansonia Digitata; BB) into composite cereal porridges is a potentially sustainable strategy to providing key shortfall micronutrients including iron and zinc to at risk populations. However, only limited information is available on long term health effects of these materials including their potential to modify gut barrier function or their impact on absorption of other nutrients such as provitamin A carotenoids(pVAC). The present study investigated the impact of repeated exposure of MOR and BB to the human intestinal cell model (Caco-2) to assess changes in intestinal cell differentiation and subsequent pVAC uptake from model foods. MethodsTo study gut impacts from BB and MOR exposure at usage rate of 15% of a cereal porridge, Caco-2 cells were cultured and differentiated on 6 well plates for 10–14d with complete media containing digested BB (15%), moringa (15%) or saline (control) in a 1:8–12 ratio (v/v). Caco-2 cell differentiation was followed by 1H NMR and pVAC transporter by QRT-PCR and Western blotting. Cellular uptake of pVACs in differentiated monolayers was assessed for 4 h from a final acute dose of digested carrots (3590 mg/100 g total proVAC) estimated to deliver ∼30% of the RDA for VA. ResultsAlterations in select Caco-2 cell differentiation biomarkers were observed by NMR from repeated exposure to all treatments. Specifically, glycerophosphocholine and taurine were observed to significantly increase with repeated exposure to all treatments. Significant reduction (P < 0.05) in carotenoid uptake was observed following repeated exposure across all treatment groups. No significant differences between control and baobab or moringa treatment. Despite the reduction in carotenoid uptake, mRNA and protein levels of carotenoid transporters (CD-36, SR-B1 and FABP1) were not significantly altered by chronic exposure to BB or MOR suggesting reduced transport is a product of prolonged accumulation of background digesta matrix. ConclusionsOverall, at the levels explored in this study, mineral-rich BB or MOR do not appear to negatively impact differentiation of Caco-2 cells or their ability to accumulate pVAC carotenoids over prolonged exposure. Funding SourcesUSAID Food Processing & Post Harvest Innovation Lab. Sorghum & Millet Innovation Lab.

A rapid zebrafish embryo behavioral biosensor that is capable of detecting environmental β-blockers

β-Blockers (BB) are one of the most commonly prescribed pharmaceuticals used for treating cardiovascular and acute anxiety-related disorders. This class of drugs inhibit β-adrenoceptor signalling and given their growing, widespread use, BB are routinely detected in surface waters at nM concentrations. This is concerning as trace levels of BB impart developmental and reproductive dysfunction in non-target aquatic organisms, with potential for ecological risks. To date, environmental pharmaceutical risks to non-target animals are not part of the monitoring framework due to the lack of bioassays for assessing their biological effects. Behavioral endpoints have the advantage of a systems-level integration of multiple sensory signals and motor responses for toxicity screening; however, they are not currently used for risk assessment of environmental contaminants. The zebrafish (Danio rerio) embryo photomotor response (zfPMR) has been used in high-throughput behavioral screenings for neuroactive drug effects at high, therapeutic concentrations. Our objective here was to examine if we could utilize the zfPMR for screening environmental levels of BB. Embryos were placed into 96-well plates, exposed to chemicals and/or municipal wastewater effluent (MWWE), and their zfPMRs were measured with video-analysis. To specifically target BB, embryos were co-treated with isoproterenol, a β-adrenergic agonist that stimulates the zfPMR, and the inhibition of isoproterenol-induced response was used as a biomarker of BB exposure. Our results reveal that the inhibition of isoproterenol-stimulated zfPMRs can be used as a biosensor capable of detecting BB in the parts-per-billion to parts-per-trillion in water samples, including diluted MWWE. The method developed detects BB in spite of the presence of other neuroactive compounds in water samples. This systems level approach of rapid screening for BB effects provides the most promising evidence to date that behavioral neuromodulation can be potentially applied for environmental effects monitoring of pharmaceuticals.

Role of glutathione metabolism in host defense against Borrelia burgdorferi infection

Pathogen-induced changes in host cell metabolism are known to be important for the immune response. In this study, we investigated how infection with the Lyme disease-causing bacterium Borrelia burgdorferi (Bb) affects host metabolic pathways and how these metabolic pathways may impact host defense. First, metabolome analysis was performed on human primary monocytes from healthy volunteers, stimulated for 24 h with Bb at low multiplicity of infection (MOI). Pathway analysis indicated that glutathione (GSH) metabolism was the pathway most significantly affected by Bb Specifically, intracellular levels of GSH increased on average 10-fold in response to Bb exposure. Furthermore, these changes were found to be specific, as they were not seen during stimulation with other pathogens. Next, metabolome analysis was performed on serum samples from patients with early-onset Lyme disease in comparison with patients with other infections. Supporting the in vitro analysis, we identified a cluster of GSH-related metabolites, the γ-glutamyl amino acids, specifically altered in patients with Lyme disease, and not in other infections. Lastly, we performed in vitro experiments to validate the role for GSH metabolism in host response against Bb. We found that the GSH pathway is essential for Bb-induced cytokine production and identified glutathionylation as a potential mediating mechanism. Taken together, these data indicate a central role for the GSH pathway in the host response to Bb GSH metabolism and glutathionylation may therefore be important factors in the pathogenesis of Lyme disease and potentially other inflammatory diseases as well.

β-Blockers, Pneumonia, and Outcome After Ischemic Stroke

Increased sympathetic drive after stroke is involved in the pathophysiology of several complications including poststroke immunudepression. β-Blocker (BB) therapy has been suggested to have neuroprotective properties and to decrease infectious complications after stroke. We aimed to examine the effects of random pre- and on-stroke BB exposure on mortality, functional outcome, and occurrence of pneumonia after ischemic stroke. Data including standard demographic and clinical variables as well as prestroke and on-stroke antihypertensive medication, incidence of pneumonia, functional outcome defined using modified Rankin Scale and mortality at 3 months were extracted from the Virtual International Stroke Trials Archive. For statistical analysis multivariable Poisson regression was used. In total, 5212 patients were analyzed. A total of 1155 (22.2%) patients were treated with BB before stroke onset and 244 (4.7%) patients were newly started with BB in the acute phase of stroke. Mortality was 17.5%, favorable outcome (defined as modified Rankin Scale, 0-2) occurred in 58.2% and pneumonia in 8.2% of patients. Prestroke BB showed no association with mortality. On-stroke BB was associated with reduced mortality (adjusted risk ratio, 0.63; 95% confidence interval, 0.42-0.96). Neither prestroke BB nor on-stroke BB showed an association with functional outcome. Both prestroke and on-stroke BB were associated with reduced frequency of pneumonia (adjusted risk ratio, 0.77; 95% confidence interval, 0.6-0.98 and risk ratio, 0.49; 95% confidence interval, 0.25-0.95). In this large nonrandomized comparison, on-stroke BB was associated with reduced mortality. Prestroke and on-stroke BB were inversely associated with incidence of nosocomial pneumonia. Randomized trials investigating the potential of β-blockade in acute stroke may be warranted.

Borrelia burgdorferi Elicited-IL-10 Suppresses the Production of Inflammatory Mediators, Phagocytosis, and Expression of Co-Stimulatory Receptors by Murine Macrophages and/or Dendritic Cells

Borrelia burgdorferi (Bb) is a tick-borne spirochete that is the causative agent for Lyme disease. Our previous studies indicate that virulent Bb can potently enhance IL-10 production by macrophages (MØs) and that blocking IL-10 production significantly enhances bacterial clearance. We hypothesize that skin-associated APC types, such as MØs and dendritic cells (DCs) are potent producers of IL-10 in response to Bb, which may act in autocrine fashion to suppress APC responses critical for efficient Bb clearance. Our goal is to delineate which APC immune functions are dysregulated by Bb-elicited IL-10 using a murine model of Lyme disease. Our in vitro studies indicated that both APCs rapidly produce IL-10 upon exposure to Bb, that these levels inversely correlate with the production of many Lyme-relevant proinflammatory cytokines and chemokines, and that APCs derived from IL-10-/- mice produced greater amounts of these proinflammatory mediators than wild-type APCs. Phagocytosis assays determined that Bb-elicited IL-10 levels can diminish Bb uptake and trafficking by MØs, suppresses ROS production, but does not affect NO production; Bb-elicited IL-10 had little effect on phagocytosis, ROS, and NO production by DCs. In general, Bb exposure caused little-to-no upregulation of several critical surface co-stimulatory markers by MØs and DCs, however eliminating Bb-elicited IL-10 allowed a significant upregulation in many of these co-stimulatory receptors. These data indicate that IL-10 elicited from Bb-stimulated MØs and DCs results in decreased production of proinflammatory mediators and co-stimulatory molecules, and suppress phagocytosis-associated events that are important for mediating both innate and adaptive immune responses by APCs.

Exposure to ACEI/ARB and β-Blockers Is Associated with Improved Survival and Decreased Tumor Progression and Hospitalizations in Patients with Advanced Colon Cancer

BACKGROUND: Advanced colon cancer is associated with weight loss and decreased survival. Studies suggest that angiotensin and β-adrenergic blockade decrease colon cancer progression and ameliorate weight loss. This study aims to determine whether exposure to β-adrenoceptor blockers (BBs), angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin receptor blockers (ARBs) is associated with decreased mortality, tumor progression, number of hospitalizations, or weight loss in colorectal cancer. METHODS: Retrospective chart review included patients with advanced colorectal cancer. Survival, stage, hospitalization, cancer progression, cancer treatment, and body weight history were collected. RESULTS: Two hundred sixty-two of 425 new stage III to IV colorectal cancer cases reviewed met the study criteria. Those exposed to ACEI/ARB, BB, or both were more likely to have diabetes, hypertension, and stage III colorectal cancer. Adjusting for age, presence of hypertension and diabetes, and stage, ACEI/ARB + BB exposure was associated with decreased mortality compared to unexposed individuals [hazard ratio (HR) = 0.5, confidence interval (CI) = 0.29–0.85; Cox regression, P = .01]. Fewer total and cancer-related hospitalizations and decreased cancer progression in the ACEI/ARB + BB group versus the unexposed group (HR = 0.59, CI = 0.36–0.99, P = .047) were seen. Exposure did not affect weight changes; furthermore, body weight changes from both prediagnosis and at diagnosis to 6, 12, 18, and 24 months postdiagnosis predicted survival. CONCLUSIONS: We have observed an association between exposure to a combination of ACEI/ARB + BB and increased survival, decreased hospitalizations, and decreased tumor progression in advanced colorectal cancer. Future studies will be needed to replicate these results and generalize them to broader populations. Determination of causality will require a randomized controlled trial.

Maternal metabolic changes with dietary intake of blueberry during pregnancy and lactation predispose adult progeny to lower mammary tumor growth rate

We have shown the lower growth rates of tumors that developed from Wnt1‐transgenic (Tg) offspring of dams consuming whole blueberry powder (3% BB) during pregnancy and lactation, compared to those of control (Casein) dams. Dietary exposure at post‐weaning through lifetime did not mimic the effects of early BB exposure. The basis for maternal BB effects on mammary tumor growth was examined in dams exposed to BB or control diet as young adults (beginning at age 8 weeks) and throughout pregnancy and lactation. Dams at weaning were evaluated for growth and metabolic parameters. BB‐fed dams had lower abdominal and retroperitoneal fat pad weights than control‐fed dams, although their body weights did not differ. BB dams also displayed increased insulin sensitivity (lower blood glucose, serum insulin, HOMA) and higher serum glutathione and methionine levels. Isolated epithelial cells from pre‐neoplastic mammary tissues of Tg offspring exposed to maternal control and BB diets were analyzed for percentage of basal (CD29highCD24+) and luminal progenitor (CD29lowCD24+) populations. Maternal BB exposure (relative to control) resulted in lower percentage of the luminal subpopulation (6.4% vs 21%), which comprise the tumor bulk in Tg tissues. Results implicate the influence of the favorable metabolic and anti‐oxidative maternal environment with BB diet on developing mammary glands for the improved mammary tumor outcome.Grant Funding Source: USDA‐CRIS 6251–51000‐005–004S, Arkansas Biosciences Institute

Utilization of Hyperinsulinemia Euglycemia and Intravenous Fat Emulsion Following Poison Center Recommendations

Hyperinsulinemia euglycemia (HIE) and intravenous fat emulsion (IFE) may be beneficial in the treatment of calcium channel (CCB) and beta receptor (BB) antagonist toxicity. Many poison control centers (PCC) now recommend use. Healthcare providers may be unfamiliar with these treatments and may not institute them despite recommendations. We sought to determine how often HIE and IFE are recommended by a statewide PCC in CCB and BB toxicity, how often those recommendations are implemented, and whether a faxable information sheet increased adherence. All cases of CCB and BB exposure from January 2005-July 2011 where insulin or "other therapy" was coded were reviewed. Exclusion criteria included an incomplete PCC record, miscoding, and insulin administration as other than cardiovascular drug antidotal therapy. There were 215 CCB or BB exposures initially identified using the search criteria. HIE was recommended in 71 cases and started in one case prior to PCC recommendation. HIE was subsequently used in 30 cases after PCC recommendation (42 %). IFE was recommended by the PCC in 30 cases and implemented 10 times (33 %). In six cases, both HIE and IFE were implemented after recommendation. There was no statistical difference when recommendation was made via telephone or by faxable information sheet for HIE or IFE. HIE and IFE are two therapies that are potentially beneficial in the treatment of BB and CCB toxicity. Current national organization guidelines for use are limited. Exploration of reasons for not following recommendations and additional efforts to improve clinician education regarding HIE and IFE may be required to increase the utilization of these potentially lifesaving antidotes.

Abstract P104: β-Blocker Exposure and Systolic Heart Failure Outcomes by Race

Background: Beta adrenergic blocking agents (BB) are a mainstay of heart failure (HF) treatment yet there is inconclusive data regarding their efficacy in African Americans due to low racial diversity in the clinical trials of approved agents. Methods: This was a retrospective study of patients who received care from a large health system and had a primary hospital discharge diagnosis of heart failure between 1/2000 and 6/2008. Ejection fraction (EF) was abstracted from the medical record and only patients with EF&lt;50% were included. BB exposure (BBexp) was estimated over a six month rolling window using pharmacy claims; patients had to survive 6 months post-discharge to be included. Proportional hazards regression was used to test the association of this time-dependent BB exposure estimate with time to all-cause hospitalization or death, with adjustment for baseline covariates, as well as angiotensin converting enzyme/angiotensin receptor antagonist exposure. We performed analyses both stratified by race, and all-inclusive with an interaction term (BBexp*Race). Results: A total of 1094 patients met inclusion criteria; 476 whites and 618 African Americans. Median follow up was 2.1 years. In adjusted models, BBexp was independently associated with lower death or hospitalization in both groups, but appeared more protective in Whites (HR 0.41, 95%CI 0.27-0.61, p&lt;0.001) than African Americans (HR 0.67, 95%CI 0.48-0.94, p=0.024). The formal test for interaction also indicated a significant difference in the BBexp associated outcomes by race (p=0.04). This difference was driven mostly by hospitalizations (HR 0.40 vs. 0.67 in Whites vs. African Americans, respectively), while the association of BBexp with death appeared similar between groups (HR 0.30 vs. 0.24, respectively). Conclusion: In this observational data set, beta adrenergic blocker exposure appears less efficacious in preventing death or re-hospitalization among African Americans with heart failure compared to Whites. Further study is needed to better understand the risks and benefits of beta blockade in African Americans with heart failure.

The Risk Premium of Corporate Bonds

The expected risk premium of corporate bonds, defined as the non-default component of corporate bond spreads, is generally related non-monotonically to credit ratings. Over the course of a complete credit cycle, the risk premium is positive and higher than actual spreads for investment-grade bonds; it rises in absolute terms as ratings deteriorate, to reach a peak in the BB sector, and then starts falling and becomes negative for CCC-rated bonds. Explanations for such a peculiar shape of the expected risk premium curve range from inefficiencies due to market segmentation to the tendency of high-yield portfolio managers to overestimate their security selection skills. For investors concerned with generating the best risk-adjusted returns, the contour of the risk premium curve promotes investment-grade bonds, but for investors willing to tolerate more volatility to achieve higher absolute returns, crossing into speculative-grade territory to gain a BB exposure is the preferred structural strategy. Finally, corporate bonds rated B and below should be considered only by investors with superior (and rare) ability either to select outperforming individual securities or to time the market accurately. <b>TOPICS:</b>Portfolio construction, performance measurement, fixed income and structured finance