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The ISCHEMIA trial found that patients with chronic coronary disease randomized to invasive strategy had better health status than those randomized to conservative strategy. It is unclear how best to translate these population-level results to individual patients. The authors sought to identify patient characteristics associated with health status from invasive and conservative strategies, and develop a prediction algorithm for shared decision-making. One-year disease-specific health status was assessed in ISCHEMIA with the Seattle Angina Questionnaire (SAQ) Summary Score (SAQ SS) and Angina Frequency, Physical Limitations (PL), and Quality of Life (QL) domains (range 0-100, higher = less angina/better health status). Among 4,617 patients from 320 sites in 37 countries, mean SAQ SS was 74.1 ± 18.9 at baseline and 85.7 ± 15.6 at 1 year. Lower baseline SAQ SS and younger age were associated with better 1-year health status with invasive strategy (P interaction = 0.009 and P interaction = 0.004, respectively). For the individual domains, there were significant treatment interactions for baseline SAQ score (Angina Frequency, PL), age (PL, QL), anterior ischemia (PL), and number of baseline antianginal medications (QL), with more benefit of invasive in patients with worse baseline health status, younger age, anterior ischemia, and on more antianginal medications. Parsimonious prediction models were developed for 1-year SAQ domains with invasive or conservative strategies to support shared decision-making. In the management of chronic coronary disease, individual patient characteristics are associated with 1-year health status, with younger age and poorer angina-related health status showing greater benefit from invasive management. This prediction algorithm can support the translation of the ISCHEMIA trial results to individual patients. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522) [Display omitted] [ABSTRACT FROM AUTHOR]

The impact of complete revascularization (CR) on angina-related health status (symptoms, function, quality of life) in chronic coronary disease (CCD) has not been well studied. Among patients with CCD randomized to invasive (INV) vs conservative (CON) management in ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), we compared the following: 1) the impact of anatomic and functional CR on health status compared with incomplete revascularization (ICR); and 2) the predicted impact of achieving CR in all INV patients compared with CON. Multivariable regression adjusting for patient characteristics was used to compare 12-month health status after independent core laboratory-defined CR vs ICR in INV patients who underwent revascularization. Propensity-weighted modeling was then performed to estimate the treatment effect had CR or ICR been achieved in all INV patients, compared with CON. Anatomic and functional CR were achieved in 43.3% and 57.8% of 1,641 INV patients, respectively. Among revascularized patients, CR was associated with improved Seattle Angina Questionnaire Angina Frequency compared with ICR after adjustment for baseline differences. After modeling CR and ICR in all INV patients, patients with CR and ICR each had greater improvements in health status than CON, with better health status with CR than ICR. The projected benefits of CR were most pronounced in patients with baseline daily/weekly angina and not seen in those with no angina. Among patients with CCD in ISCHEMIA, health status improved more with CR compared with ICR or CON, particularly in those with frequent angina. Anatomic and functional CR provided comparable improvements in quality of life. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522) [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Chronic stress in patients with cardiovascular disease (CVD), including peripheral artery disease (PAD), is independently associated worse outcomes. A model that can reliably identify factors associated with risk of chronic stress in patients with CVD is needed. Methods: In a prospective myocardial infarction (MI) registry (TRIUMPH), we constructed a logistic regression model using 27 patient demographic, socioeconomic, and clinical factors, adjusting for site, to identify predictors of chronic stress over 1 year. Stress at baseline and at 1-, 6- and 12-month follow-up was measured using the 4-item Perceived Stress Scale (PSS-4) [range 0–16, scores ≥6 depicting high stress]. Chronic stress was defined as at least 2 follow-up PSS-4 scores ≥6. We identified and validated this final model in another prospective registry of patients with symptomatic PAD, the PORTRAIT study. Results: Our derivation cohort consisted of 4,340 patients with MI (mean age 59.1 ± 12.3 years, 33% females, 30% non-white), of whom 30% had chronic stress at follow-up. Of the 27 factors examined, female sex, current smoking, socioeconomic status, and economic burden due to medical care were positively associated with chronic stress, and ENRICHD Social Support Instrument (ESSI) score and age were inversely related to chronic stress. In the validation cohort of 797 PAD patients (mean age 68.6±9.7 years, 42% females, 28% non-white, 18% chronic stress) the c-statistic for the model was 0.77 and calibration was excellent. Conclusions: We can reliably identify factors that are independently associated with risk of chronic stress in patients with CVD. As chronic stress is associated with worse outcomes in this population, our work identifies potential targets for interventions to as well as the patients that could benefit from these. [ABSTRACT FROM AUTHOR]

Background: Heart failure is a common and devastating complication of type 2 diabetes (T2D). Prompt recognition of heart failure may avert hospitalization, facilitate use of guideline-directed therapies, and impact choice of T2D medications. We sought to determine the rate and factors associated with heart failure documentation in T2D patients with evidence of volume overload requiring loop diuretics. Methods: DCR is an on-going, prospective US registry of outpatient T2D patients from > 5000 cardiology, endocrinology, and primary care clinicians (current analysis used data from 2013–2019). Among T2D patients receiving loop diuretics, we examined the rate of chart documentation of heart failure. We used a 3-level hierarchical logistic regression model (patients nested within physician within practice) to examine factors associated with heart failure diagnosis. Results: Among 1,322,640 adults with T2D, 225,125 (17.0%) were receiving a loop diuretic, of whom 91,969 (40.9%) had documentation of heart failure. Male sex, lower body mass index, atrial fibrillation, chronic kidney disease, and coronary artery disease were associated with greater odds of heart failure diagnosis. After accounting for patient factors, patients seen by cardiologists were the most likely to have HF documented followed by PCPs and then endocrinologists. Conclusions: Among US outpatients with T2D, 17% of patients had evidence of volume overload—defined by loop diuretic prescription—of whom fewer than half had a clinical diagnosis of heart failure. While there may be non-heart failure indications for loop diuretics, our data suggest that a substantial proportion of T2D patients may have unrecognized heart failure and therefore could be missing opportunities for targeted therapies that could alter the clinical course of heart failure. [ABSTRACT FROM AUTHOR]

To improve the patient-centeredness of care, patient-reported outcomes have been increasingly used to quantify patients' symptoms, function, and quality of life. In heart failure, the Kansas City Cardiomyopathy Questionnaire (KCCQ) has been qualified by the U.S. Food and Drug Administration as a Clinical Outcome Assessment and recommended as a performance measure for quantifying the quality of care. By systematically asking the same questions reproducibly over time, the KCCQ can validly and sensitively capture the impact of heart failure on patients' lives and is strongly associated with clinical events over time. This review describes how to interpret the KCCQ, how it should be analyzed in clinical trials to maximize the interpretability of results, and how it can be used in clinical practice and population health. By providing a deeper understanding of the KCCQ, it is hoped that its use can further improve the patient-centeredness of heart failure care. [ABSTRACT FROM AUTHOR]

Background: In the ISCHEMIA-CKD trial, the primary analysis showed no significant difference in the risk of death or myocardial infarction with initial angiography and revascularization plus guideline-based medical therapy (invasive strategy) as compared with guideline-based medical therapy alone (conservative strategy) in participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease (an estimated glomerular filtration rate of <30 ml per minute per 1.73 m2 or receipt of dialysis). A secondary objective of the trial was to assess angina-related health status.Methods: We assessed health status with the Seattle Angina Questionnaire (SAQ) before randomization and at 1.5, 3, and 6 months and every 6 months thereafter. The primary outcome of this analysis was the SAQ Summary score (ranging from 0 to 100, with higher scores indicating less frequent angina and better function and quality of life). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate the treatment effect with the invasive strategy.Results: Health status was assessed in 705 of 777 participants. Nearly half the participants (49%) had had no angina during the month before randomization. At 3 months, the estimated mean difference between the invasive-strategy group and the conservative-strategy group in the SAQ Summary score was 2.1 points (95% credible interval, -0.4 to 4.6), a result that favored the invasive strategy. The mean difference in score at 3 months was largest among participants with daily or weekly angina at baseline (10.1 points; 95% credible interval, 0.0 to 19.9), smaller among those with monthly angina at baseline (2.2 points; 95% credible interval, -2.0 to 6.2), and nearly absent among those without angina at baseline (0.6 points; 95% credible interval, -1.9 to 3.3). By 6 months, the between-group difference in the overall trial population was attenuated (0.5 points; 95% credible interval, -2.2 to 3.4).Conclusions: Participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease did not have substantial or sustained benefits with regard to angina-related health status with an initially invasive strategy as compared with a conservative strategy. (Funded by the National Heart, Lung, and Blood Institute; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.). [ABSTRACT FROM AUTHOR]

Background: In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients.Methods: We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency.Results: At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina).Conclusions: In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.). [ABSTRACT FROM AUTHOR]

In medical and epidemiologic studies, relative risk is usually the parameter of interest. However, calculating relative risk using standard log-Binomial regression approach often encounters non-convergence. A modified Poisson regression, which uses robust variance, was proposed by Zou in 2004. Although the modified Poisson regression with sandwich variance estimator is valid for the estimation of relative risk, the predicted probability of the outcome may be greater than the natural boundary 1 for the unobserved but plausible covariate combinations. Moreover, the lower and upper bounds of confidence intervals for predicted probabilities could fall out of (0, 1). Chu and Cole, in 2010, proposed a Bayesian approach to overcome this issue. Posterior median was used to get the parameter estimation. However, the Bayesian approach may provide biased estimation, especially when the probability of outcome is high. In this article, we propose an alternative constraint optimization approach for estimating relative risk. Our approach can reach similar or better performance than Bayesian approach in terms of bias, root mean square error, coverage rate, and predictive probabilities. Simulation studies are conducted to demonstrate the usefulness of this approach. Our method is also illustrated by Prospective Registry Evaluating Myocardial Infarction: Event and Recovery data. [ABSTRACT FROM AUTHOR]

Background: Implementation of medical emergency teams has been identified as a potential strategy to reduce hospital deaths, because these teams respond to patients with acute physiological decline in an effort to prevent in-hospital cardiac arrest. However, prior studies of the association between medical emergency teams and hospital mortality have been limited and typically have not accounted for preimplementation mortality trends.Methods: Within the Pediatric Health Information System for freestanding pediatric hospitals, annual risk-adjusted mortality rates were calculated for sites between 2000 and 2015. A random slopes interrupted time series analysis then examined whether implementation of a medical emergency team was associated with lower-than-expected mortality rates based on preimplementation trends.Results: Across 38 pediatric hospitals, mean annual hospital admission volume was 15 854 (range, 6684-33 024), and there were a total of 1 659 059 hospitalizations preimplementation and 4 392 392 hospitalizations postimplementation. Before medical emergency team implementation, hospital mortality decreased by 6.0% annually (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.92-0.96) across all hospitals. After medical emergency team implementation, hospital mortality continued to decrease by 6% annually (OR, 0.94; 95% CI, 0.93-0.95), with no deepening of the mortality slope (ie, not lower OR) in comparison with the preimplementation trend, for the overall cohort (P=0.98) or when analyzed separately within each of the 38 study hospitals. Five years after medical emergency team implementation across study sites, there was no difference between predicted (hospital mean of 6.18 deaths per 1000 admissions based on preimplementation trends) and actual mortality rates (hospital mean of 6.48 deaths per 1000 admissions; P=0.57).Conclusions: Implementation of medical emergency teams in a large sample of pediatric hospitals in the United States was not associated with a reduction in hospital mortality beyond existing preimplementation trends. [ABSTRACT FROM AUTHOR]

In this study, we report the pharmacological effects of a novel PDE10A inhibitor, SEP-39. SEP-39 is a potent (1.0 nM) inhibitor of human PDE10A in vitro , with good selectivity (> 16000-fold) against other PDEs. In an in vivo occupancy study, the RO 50 value was determined to be 0.7 mg/kg (p.o.), corresponding to plasma and brain exposures of 28 ng/mL and 43 ng/g, respectively. Using microdialysis, we show that 3 mg/kg (p.o.) SEP-39 significantly increased rat striatal cGMP concentrations. Furthermore, SEP-39 inhibits PCP-induced hyperlocomotion at doses of 1 and 3 mg/kg (p.o.) corresponding to 59–86% occupancy. At similar doses in a catalepsy study, the time on the bar was increased but the maximal effect was less than that seen with haloperidol. In an EEG study, 3 and 10 mg/kg (p.o.) SEP-39 suppressed REM intensity and increased the latency to REM sleep. We also demonstrate the procognitive effects of SEP-39 in the rat novel object recognition assay. These effects appear to require less PDE10A inhibition than the reversal of PCP-induced hyperlocomotion or EEG effects, as improvements in recognition index were seen at doses of 0.3 mg/kg and above. Our data demonstrate that SEP-39 is a potent, orally active PDE10A inhibitor with therapeutic potential in a number of psychiatric indications. [ABSTRACT FROM AUTHOR]

Background Prior studies have demonstrated that patients with high-risk acute myocardial infarction (AMI) are less likely to receive guideline-directed medications during hospitalisation. It is unknown if this paradox persists following discharge. We aimed to assess if persistence with guideline-directed medications post discharge varies by patients' risk following AMI. Methods Data were analysed from two prospective, multicentre US AMI registries. The primary outcome was persistence with all prescribed guideline-directed medications (aspirin, ß-blockers, statins, angiotensinantagonists) at 1, 6 and 12 months post discharge. The association between risk and medication persistence post discharge was assessed using multivariable mixed-effect models. Results Among 6434 patients with AMI discharged home, 2824 were considered low-risk, 2014 intermediate-risk and 1596 high-risk for death based upon their Global Registry of Acute Coronary Event (GRACE) 6-month risk score. High-risk was associated with a lower likelihood of receiving all appropriate therapies at discharge compared with low-risk patients (relative risk (RR) 0.90; 95% CI 0.87 to 0.94). At 12 months, the rate of persistence with all prescribed therapies was 61.5%, 57.9% and 45.9% among lowrisk, intermediate-risk and high-risk patients, respectively. After multivariable adjustment, high-risk was associated with lower persistence with all prescribed medications (RR 0.87; 95% CI 0.82 to 0.92) over follow-up. Similar associations were seen for individual medications. Over the 5 years of the study, persistence with prescribed therapies post discharge improved modestly among highrisk patients (RR 1.05; 95% CI 1.03 to 1.08 per year). Conclusions High-risk patients with AMI have a lower likelihood of persistently taking prescribed medications post discharge as compared with low-risk patients. Continued efforts are needed to improve the use of guideline-directed medications in high-risk patients. [ABSTRACT FROM AUTHOR]

Background: Achieving 'personalized medicine' requires enrolling representative cohorts into genetic studies, but patient self-selection may introduce bias. We sought to identify characteristics associated with genetic consent in a myocardial infarction (MI) registry. Methods: We assessed correlates of participation in the genetic sub-study of TRIUMPH, a prospective MI registry (n = 4,340) from 24 US hospitals between April 2005 and December 2008. Factors examined included extensive sociodemographics factors, clinical variables, and study site. Predictors of consent were identified using hierarchical modified Poisson regression, adjusting for study site. Variation in consent rates across hospitals were quantified by the median rate ratio (MRR). Results: Most subjects consented to donation of their genetic material (n = 3,484; 80%). Participation rates varied greatly between sites, from 40% to 100%. After adjustment for confounding factors, the MRR for hospital was 1.22 (95% confidence interval (CI) 1.11 to 1.29). The only patient-level factors associated with consent were race (RR 0.93 for African Americans versus whites, 95% CI 0.88 to 0.99) and body mass index (RR 1.03 for BMI ≥ 25, 95% CI 1.01 to 1.06). Conclusion: Among patients with an MI there were notable differences in genetic consent by study site, but little association with patient-level factors. This suggests that variation in the way information is presented during recruitment, or other site factors, strongly influence patients' decision to participate in genetic studies. B [ABSTRACT FROM AUTHOR]

Background: Little information is available about factors associated with racial differences across a broad spectrum of post-myocardial infarction outcomes, including patients' symptoms and quality of life. Objective: To determine racial differences in mortality, rehospitalization, angina, and quality of life after myocardial infarction and identify the factors associated with these differences. Design: Prospective cohort study. Setting: 10 hospitals in the United States. Patients: 1849 patients who had myocardial infarction, 28% of whom were black. Measurements: Demographic, economic, clinical, psychosocial, and treatment characteristics and outcomes were prospectively collected. Outcomes included time to 2-year all-cause mortality, 1-year rehospitalization, and Seattle Angina Questionnaire-assessed angina and quality of life. Results: Black patients had higher unadjusted mortality (19.9% vs. 9.3%; P < 0.001) and rehospitalization rates (45.4% vs. 40.4%; P = 0.130), more angina (28.0% vs. 17.8%; P = 0.001), and worse mean quality of life (80.6 [SD, 22.5] vs. 85.9 [SD, 17.2]; P < 0.001). After adjustment for patient characteristics, black patients trended toward greater mortality (hazard ratio, 1.29 [95% CI, 0.92 to 1.81]; P = 0.142), fewer rehospitalizations (hazard ratio, 0.82 [CI, 0.66 to 1.02]; P = 0.071), and higher likelihood of angina at 1 year (odds ratio, 1.41 [CI, 1.03 to 1.94]; P = 0.032) but similar quality of life (mean difference, -0.6 [CI, -3.4 to 2.2]). Adjustment for site of care further attenuated mortality differences (hazard ratio, 1.04 [CI, 0.71 to 1.52]; P = 0.84). Adjustment for treatments had minimal effect on any association. Limitation: Residual confounding and missing data may have introduced bias. Conclusion: Although black patients with myocardial infarction have worse outcomes than white patients, these differences did not persist after adjustment for patient factors and site of care. Further adjustment for treatments received minimally influenced observed differences. Strategies that focus on improving baseline cardiac risk and hospital factors may do more than treatment-focused strategies to attenuate racial differences in myocardial infarction outcomes. Funding: The National Heart, Lung, and Blood Institute Specialized Center of Clinically Oriented Research in Cardiac Dysfunction and Disease, CV Therapeutics, and Cardiovascular Outcomes. [ABSTRACT FROM AUTHOR]

While generic health status measures quantify the impact of all patients’ diseases on their health-related quality of life, disease specific measures focus on only one of the many conditions that a patient may have. If a patient has two diseases with similar clinical manifestations, they may respond differently to a disease-specific instrument if one of their conditions improves while the other worsens or remains stable, thus undermining the instruments in that patient population. We sought empirical evidence of the reliability and validity (including responsiveness) of the Kansas City Cardiomyopathy Questionnaire (KCCQ), a disease-specific measure for heart failure (HF), among HF patients with and without anemia, a condition that has similar symptoms to HF. This work used a prospective cohort study of 811 HF outpatients from 58 U.S. centers with a baseline assessment of anemia of whom 698 were followed for 3 months with serial health status measures. Among participants, 268 (33%) were anemic. The construct validity of the KCCQ was supported by showing similar correlations with the New York Heart Association (NYHA) classification in patients with and without anemia ( P value for interaction = 0.38). The internal consistency (Cronbach’s alpha = 0.92 and 0.93 for anemic and non-anemic patients, respectively) and test–retest reliability (mean 3-month change scores in stable patients = −2.8 [SD = 1.4] and −0.5 [SD = 0.8], P = 0.14) were similar. Estimates of responsiveness were also similar. This study provides empirical evidence that the psychometric properties of the KCCQ are similar in patients with or without anemia, a potentially confounding clinical condition in patients with heart failure. [ABSTRACT FROM AUTHOR]

Abstract: Acetylcholine mediates its effects through both the nicotinic acetylcholine receptors (ligand-gated ion channels) and the G protein-coupled muscarinic receptors. It plays pivotal roles in a diverse array of physiological processes and its activity is controlled through enzymatic degradation by acetylcholinesterase. The effects of receptor agonists and enzyme inhibitors, collectively termed cholinomimetics, in antinociception/analgesia are well established. These compounds successfully inhibit pain signaling in both humans and animals and are efficacious in a number of different preclinical and clinical pain models, suggesting a broad therapeutic potential. In this review we examine and discuss the evidence for the therapeutic exploitation of the cholinergic system as an approach to treat pain. [Copyright &y& Elsevier]

Abstract: GPR26 and GPR78 are orphan GPCRs (oGPCRs) that share 51% amino acid sequence identity and are widely expressed in selected tissues of the human brain as well as the developing and adult mouse brain. Investigation of the functional activity of GPR26 and GPR78 via expression in HEK293 cells showed that both proteins are constitutively active and coupled to elevated cAMP production. Accordingly, in yeast, GPR26 demonstrated apparent agonist-independent coupling to a chimeric Gpa1 protein in which the 5 C-terminal amino acids were from Gαs. A comparison of the proteins revealed an atypical glutamine residue in GPR78 in place of the conserved arginine residue (R3.50) in the so-called DRY box. Site-directed mutants R3.50 in GPR26 were constructed and retained their constitutive activity suggesting that these 2 receptors activate G proteins in a manner that is distinct from other group 1 GPCRs. [Copyright &y& Elsevier]

Context Previous data support an association between polymorphisms of the β1- and β2-adrenergic receptors (ADRB1 and ADRB2) and surrogate end points of response to β-adrenergic blocker therapy. However, no associations between these polymorphisms and mortality have been demonstrated. Objective To evaluate the effect of ADRB1 Arg389Gly (1165 CG), Ser49Gly (145 AG), and ADRB2 Gly16Arg (46 GA), Gln27Glu (79 CG) genotypes on survival among patients discharged with prescribed β-blockers after an acute coronary syndrome (ACS). Design, Setting, and Patients Prospective cohort study of 735 ACS patients admitted to 2 Kansas City, Mo, medical centers between March 2001 and October 2002; 597 patients were discharged with β-blocker therapy. Main Outcome Measure Multivariable-adjusted time to all-cause 3-year mortality. Results There were 84 deaths during follow-up. There was a significant association between ADRB2 genotype and 3-year mortality among patients prescribed β-blocker therapy. For the 79 CG polymorphism, Kaplan-Meier 3-year mortality rates were 16% (35 deaths), 11% (27 deaths), and 6% (4 deaths) for the CC, CG, and GG genotypes, respectively (P = .03; adjusted hazard ratios [AHRs], 0.51 [95% confidence interval {CI}, 0.30-0.87] for CG vs CC and 0.24 (95% CI, 0.09-0.68) for GG vs CC, P = .004). For the ADRB2 46 GA polymorphism, 3-year Kaplan-Meier mortality estimates were 10% (17 deaths), 10% (28 deaths), and 20% (20 deaths) for the GG, GA, and AA genotypes, respectively (P = .005; AHRs, 0.48 [95% CI, 0.27-0.86] for GA vs AA and 0.44 [95% CI, 0.22-0.85] for GG vs AA, P = .02). No mortality difference between genotypes was found among patients not discharged with β-blocker therapy for either the 79 CG or 46 GA polymorphisms (P = .98 and P = .49, respectively). The ADRB2 diplotype and compound genotypes were predictive of survival in patients treated with β-blockers (P = .04 and P = .002; AHRs, 5.36 [95% CI, 1.83-15.69] and 2.41 [95% CI, 0.86-6.74] for 46 A homozygous and composite heterozygous vs 79 G homozygous, respectively). No association of the ADRB1 variants with mortality was observed in either the β-blocker or no β-blocker groups. Conclusions Patients prescribed β-blocker therapy after an ACS have differential survival associated with their ADRB2 genotypes. Further assessment of the benefits of β-blocker therapy in high-risk genotype groups may be warranted. [ABSTRACT FROM AUTHOR]

Objectives: We sought to investigate the role of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in preventing the new onset of type 2 diabetes mellitus. Background: Diabetes is a public health problem of epidemic proportions and its prevalence is on the rise. The typical American born today has a one in three chance of developing type 2 diabetes. This diagnosis is associated with an adverse cardiovascular prognosis and is considered the risk equivalent of established coronary disease. Even in high-risk individuals, diabetes is a preventable disease. Several studies have shown that ACE inhibitors and ARBs decrease the incidence of new-onset type 2 diabetes. However, the exact role of these agents in diabetes prevention has not yet been fully elucidated. Methods: We conducted a meta-analysis of 12 randomized controlled clinical trials of ACE inhibitors or ARBs, identified through a MEDLINE search and a review of reports from scientific meetings, to study the efficacy of these medications in diabetes prevention. Results: This showed that ACE inhibitors and ARBs were associated with reductions in the incidence of newly diagnosed diabetes by 27% and 23%, respectively, and by 25% in the pooled analysis. Conclusions: The use of an ACE inhibitor or ARB should be considered in patients with pre-diabetic conditions such as metabolic syndrome, hypertension, impaired fasting glucose, family history of diabetes, obesity, congestive heart failure, or coronary heart disease. [Copyright &y& Elsevier]

OBJECTIVE: To assess the effect of antenatal and postnatal corticosteroids on head circumference growth and weight gain from birth to discharge.METHODS: We conducted a retrospective analysis of nonanomalous newborns admitted to the neonatal intensive care unit from 23 to 34 6/7 weeks of gestation. Independent variables included maternal age, race, nulliparity, poor prenatal care, multiple gestation, obstetric complications, alcohol, tocolytic drugs, smoking, illicit drugs, gestational age at birth, presentation, method of delivery, 5-minute Apgar score < 7, surfactant use, severe intracranial hemorrhage, and length of stay.RESULTS: Antenatal and postnatal corticosteroids were given in 62% and 14% of the newborns, respectively, and 10% of newborns received both. The mean (±SD) weight gain and head circumference growth in the nursery was 440 ± 582 g (n = 14,217) and 2.54 ± 3.42 cm (n = 12,808), respectively. After multivariable analysis, use of antenatal corticosteroids did not affect weight gain (3.6 ± 4.6 g) and head circumference growth (0.05 ± 0.04 cm) compared with no exposure to perinatal corticosteroids, but postnatal corticosteroids were associated with significant reductions in weight gain and head circumference growth (−120 ± 12.2 g and −0.53 ± 0.11 cm, respectively).CONCLUSIONS: Antenatal corticosteroid therapy did not affect weight gain or head circumference growth in the nursery, even when used in conjunction with postnatal corticosteroid therapy. [Copyright &y& Elsevier]

OBJECTIVE: To determine whether antenatal corticosteroid use is associated with weight and head circumference at birth.METHODS: We conducted a retrospective analysis of nonanomalous newborns admitted to 100 neonatal intensive care units from 23 to 34 6/7 weeks of gestation using multivariable analysis of variance that controlled for several potentially confounding variables.RESULTS: There were 14,338 cases of birth weight and 13,670 for head circumference available for analysis. Independent variables included maternal age, race, nulliparity, poor prenatal care, multiple gestation, obstetric complications, alcohol, smoking, illicit drugs, presentation, gestational age at birth, and method of delivery. The mean (±SD) birth weight was 1671 ± 574 g and head circumference was 289 ± 33 mm. The multivariable effect of antenatal corticosteroid on birth weight (mean ± SE) was −63 ± 5.7 g and on head circumference was −3.1 ± 0.4 mm. Even after controlling for birth weight, a significant reduction in head circumference (−1.2 ± 0.3 mm; 95% CI = −1.8, −0.6) was associated with antenatal corticosteroid use. This suggested that antenatal corticosteroids were associated with a greater reduction in brain growth than somatic growth.CONCLUSION: Antenatal corticosteroid may be associated with a reduction in birth weight and head circumference, independent of other major predictive factors. The reduction in head circumference persists even after controlling for the reduction in birth weight. The clinical significance of these findings is unknown. [Copyright &y& Elsevier]

Abstract: The cell bodies of ascending noradrenergic neurons in the brain are located predominantly in the locus coeruleus. An in vitro model of locus coeruleus neurons could prove to be a useful tool in the investigation of noradrenergic neural networks and their associated pathophysiologies. The CATH.a cell line demonstrates some of the properties expected of locus coeruleus neurons, and the present study investigated the neurotransmitter uptake and release properties of the CATH.a cells. It was surprising that the CATH.a cells failed to accumulate [3H]noradrenaline ([3H]NA), suggesting the lack of a functional NA transporter. RT-PCR supported this finding by demonstrating the absence of NA transporter mRNA. Treatment of CATH.a cells with various differentiating agents failed to increase the [3H]NA uptake. Endogenous NA release was studied using HPLC detection, which revealed a lack of depolarisation-induced increases in endogenous NA release. A human NA transporter-transfected CATH.a cell line was generated (termed RUNT), and a study of the [3H]NA uptake revealed that the RUNT cells displayed significant uptake that could be blocked by cocaine (10 μM). Furthermore, the uptake capacity could be dramatically increased by differentiation of the cells with dibutyryl cyclic AMP (1 mM) for 24 h. Using dibutyryl cyclic AMP-differentiated RUNT cells, high K+ concentrations (50 mM) significantly increased [3H]NA release above basal levels. [ABSTRACT FROM AUTHOR]

Introduction: Patients with critical limb ischemia (CLI) can undergo endovascular peripheral vascular intervention (PVI) to restore blood flow and decrease risk of amputation. As a potential indicator of quality for CLI care, we sought to describe 30-day major amputation rates following PVI. We also examined rate variability, and patient-level and sitelevel factors predicting amputations, using a national electronic health record (EHR) database. Methods: Using the Cerner Health Facts de-identified EHR database, patients with CLI diagnosis codes undergoing PVI were identified. The rate of amputation within 30 days of PVI was calculated. Risk ratios predicting amputation were derived using a mixed effects Poisson regression model adjusting for 16 patient and clinical factors. Median risk ratios (MRRs) were calculated to quantify site-level variability in amputations. Results: A total of 20,204 PVI procedures for CLI from 179 healthcare sites were identified. Mean age at procedure was 69.0 ± 12.6 years, 58.0% were male, and 29.6% were persons of color. Amputation within 30 days of PVI occurred after 570 (2.8%) procedures. Malnutrition, previous amputation, diabetes, and being of Black race were predictors of amputation. Amputation rates across sites ranged from 0.0% to 10.0%. The unadjusted MRR was 1.40 (95% CI 1.35-1.46), which was attenuated after adjusting for patient-level factors (MRR 1.30, 95% CI 1.26-1.34) and site characteristics (MRR 1.11, 95% CI 1.09-1.13). Conclusions: Among PVI procedures for CLI treatment, 30-day amputation rates varied across institutions. Although patient-level factors explained some variability, site-level factors explained most variation in the rates of these outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: There is limited literature on sample adequacy for molecular testing and genomic sequencing for pancreatic ductal adenocarcinoma obtained via EUS fine-needle aspiration (FNA) versus EUS fine-needle biopsy (FNB). Thus, we aimed to compare these two modalities regarding sample adequacy for molecular testing and genomic sequencing. In this retrospective chart review study, we analyzed all patients with pancreatic ductal adenocarcinoma who underwent EUS at Saint Luke's Hospital, Kansas City, MO, from 1 January 2018, to 31 December 2021. A rapid on-site evaluation was performed for all cases by cytotechnologists. We found that out of 1417 EUS procedures, 132 patients underwent EUS-guided biopsies. The mean number of passes required for FNB and FNA was similar. However, EUS-FNB, under rapid on-site specimen evaluation guidance, was superior to FNA in obtaining adequate samples for molecular testing. In addition, tumor surface area and tumor cellularity are essential parameters in determining sample adequacy for molecular testing, regardless of the tissue acquisition modality. Background and Aims: There is limited literature on sample adequacy for molecular testing in pancreatic ductal adenocarcinoma obtained via endoscopic ultrasound (EUS) fine-needle aspiration (FNA) versus EUS fine-needle biopsy (FNB). We aimed to compare these two modalities regarding sample adequacy for molecular and genomic sequencing. Methods: We reviewed all patients with pancreatic ductal adenocarcinoma who underwent EUS at Saint Luke's Hospital from 2018 to 2021. The patients were categorized based on the method of EUS tissue acquisition, specifically FNA or FNB. A comprehensive evaluation was conducted for all cases by cytotechnologists. Results: Out of 132 patients who underwent EUS-guided biopsies, 76 opted for FNA, 48 opted for FNB, and 8 opted for a combination of both. The average number of passes required for FNB and FNA was 2.58 ± 1.06 and 2.49 ± 1.07, respectively (p = 0.704), indicating no significant difference. Interestingly, 71.4% (35) of FNB-obtained samples were deemed adequate for molecular testing, surpassing the 32.1% (26) adequacy observed with FNA (p < 0.001). Additionally, 46.4% (26) of FNB-obtained samples were considered adequate for genomic testing, a notable improvement over the 23.8% (20) adequacy observed with FNA (p = 0.005). Conclusion: Although the number of passes required for cytologic diagnosis did not differ significantly between EUS-FNB and EUS-FNA, the former demonstrated superiority in obtaining samples adequate for molecular testing. Tumor surface area and cellularity were crucial parameters in determining sample adequacy for molecular testing, irrespective of the chosen tissue acquisition modality. [ABSTRACT FROM AUTHOR]

Whether initial invasive management in older vs younger adults with chronic coronary disease and moderate or severe ischemia improves health status or clinical outcomes is unknown. The goal of this study was to examine the impact of age on health status and clinical outcomes with invasive vs conservative management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. One-year angina-specific health status was assessed with the 7-item Seattle Angina Questionnaire (SAQ) (score range 0-100; higher scores indicate better health status). Cox proportional hazards models estimated the treatment effect of invasive vs conservative management as a function of age on the composite clinical outcome of cardiovascular death, myocardial infarction, or hospitalization for resuscitated cardiac arrest, unstable angina, or heart failure. Among 4,617 participants, 2,239 (48.5%) were aged <65 years, 1,713 (37.1%) were aged 65 to 74 years, and 665 (14.4%) were aged ≥75 years. Baseline SAQ summary scores were lower in participants aged <65 years. Fully adjusted differences in 1-year SAQ summary scores (invasive minus conservative) were 4.90 (95% CI: 3.56-6.24) at age 55 years, 3.48 (95% CI: 2.40-4.57) at age 65 years, and 2.13 (95% CI: 0.75-3.51) at age 75 years (P interaction = 0.008). Improvement in SAQ Angina Frequency was less dependent on age (P interaction = 0.08). There were no age differences between invasive vs conservative management on the composite clinical outcome (P interaction = 0.29). Older patients with chronic coronary disease and moderate or severe ischemia had consistent improvement in angina frequency but less improvement in angina-related health status with invasive management compared with younger patients. Invasive management was not associated with improved clinical outcomes in older or younger patients. (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches [ISCHEMIA]; NCT01471522) [Display omitted] [ABSTRACT FROM AUTHOR]

Background: In patients with coronary artery disease (CAD), low diastolic blood pressure (DBP) is associated with increased risk of myocardial infarction, but its association with angina is unknown.Objectives: The goal of this study was to examine the association of low DBP and angina in patients with CAD.Methods: The study assessed the frequency of angina (measured by using the Seattle Angina Questionnaire-Angina Frequency score) according to DBP in patients with known CAD from 25 U.S. cardiology clinics. Hierarchical logistic regression was used to test the association between DBP and angina, with a spline term for DBP to assess nonlinearity.Results: Among 1,259 outpatients with CAD, 411 (33%) reported angina in the prior month, with higher rates in the lowest DBP quartile (40 to 64 mm Hg: 37%). In the unadjusted model, DBP was associated with angina with a J-shaped relationship (p = 0.017, p for nonlinearity = 0.027), with a progressive increase in odds of angina as DBP decreased below ∼70 to 80 mm Hg. This association remained significant after sequential adjustment for demographic characteristics (p = 0.002), comorbidities (p = 0.002), heart rate (p = 0.002), systolic blood pressure (p = 0.046), and antihypertensive antianginal medications (p = 0.045).Conclusions: In patients with chronic CAD, there seemed to be an association between lower DBP and increased odds of angina. If validated, these findings suggest that clinicians should consider less aggressive blood pressure control in patients with CAD and angina. [ABSTRACT FROM AUTHOR]

Highlights • EPHX2 p.Lys55Arg genotype and prognosis were evaluated in ischemic CVD patients. • Arg55 carriers exhibited higher 5-year mortality than Lys/Lys in a discovery cohort. • Higher mortality risk in Arg55 carriers was not replicated in an independent cohort. • Higher risk of cardiovascular death was observed in Caucasian Arg55 homozygotes. Abstract Inhibition of soluble epoxide hydrolase (sEH, EPHX2) elicits potent cardiovascular protective effects in preclinical models of ischemic cardiovascular disease (CVD), and genetic polymorphisms in EPHX2 have been associated with developing ischemic CVD in humans. However, it remains unknown whether EPHX2 variants are associated with prognosis following an ischemic CVD event. We evaluated the association between EPHX2 p.Lys55Arg and p.Arg287Gln genotype with survival in 667 acute coronary syndrome (ACS) patients. No association with p.Arg287Gln genotype was observed (P = 0.598). Caucasian EPHX2 Arg55 carriers (Lys/Arg or Arg/Arg) had a significantly higher risk of 5-year mortality (adjusted hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.01–2.55, P = 0.045). In an independent population of 2712 ACS patients, this association was not replicated (adjusted HR 0.92, 95% CI 0.70–1.21, P = 0.559). In a secondary analysis, Caucasian homozygous Arg55 allele carriers (Arg/Arg) appeared to exhibit a higher risk of cardiovascular mortality (adjusted HR 2.60, 95% CI 1.09–6.17). These results demonstrate that EPHX2 p.Lys55Arg and p.Arg287Gln polymorphisms do not significantly modify survival after an ACS event. Investigation of other sEH metabolism biomarkers in ischemic CVD appears warranted. [ABSTRACT FROM AUTHOR]

Background Quantifying quality of life (QoL) after left ventricular assist device (LVAD) remains challenging. Heart failure (HF)-specific health status measures are ideal for assessing symptoms of HF; however, if patients’ QoL is limited by other factors, they may experience improved HF-specific QoL but no concurrent improvement in generic QoL. We sought to examine and predict discrepancies between disease-specific and generic QoL measures after LVAD. Methods We examined HF-specific and generic QoL with the Kansas City Cardiomyopathy Questionnaire (KCCQ) and EuroQol-5D Visual Analog Scale (VAS), respectively, among 1,888 patients with advanced heart failure who underwent LVAD implantation from 2012 to 2014 as part of the INTERMACS registry. Results Both measures showed substantial improvement, on average, at 6 months after LVAD, with mean changes of 32.7 ± 25.0 and 27.6 ± 27.4, respectively. Among the 1,539 patients (81.5%) with moderate/large improvement in KCCQ, 334 (21.7%) had discordant changes in generic QoL (i.e., VAS did not substantially increase despite improvement in KCCQ). In a multivariable logistic regression model, baseline VAS score was the strongest predictor of KCCQ-VAS discordance, whereas post-LVAD complications were not significant predictors of discordance. Conclusions Most patients have major improvements in both HF-specific and generic QoL after LVAD implantation, and discordance in these measures after LVAD is uncommon. When it did occur, discordance was primarily observed in patients who reported good generic QoL on the VAS before LVAD (despite substantial impairment due to congestive HF). These results support the continued use of HF-specific health status measures to monitor QoL before and after LVAD implantation. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the variation in the perception of patients about elective percutaneous coronary intervention in stable coronary artery disease. The study was conducted to 1,004 patients with stable coronary artery disease who were undergoing elective percutaneous coronary intervention across 10 academic and community hospitals in the U.S. between 2009 and 2011. The study showed that 20% of the patients classified the procedure as emergent.

Background: The ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) trial randomized participants with chronic coronary disease (CCD) to guideline-directed medical therapy with or without angiography and revascularization. The study examined the association of nonadherence with health status outcomes.Objectives: The study sought to compare 12-month health status outcomes of adherent and nonadherent participants with CCD with an a priori hypothesis that nonadherent patients would have better health status if randomized to invasive management.Methods: Self-reported medication-taking behavior was assessed at randomization with a modified 4-item Morisky-Green-Levine Adherence Scale, and participants were classified as adherent or nonadherent. Twelve-month health status was assessed with the 7-item Seattle Angina Questionnaire (SAQ-7) summary score (SS), which ranges from 0 to 100 (higher score = better). The association of adherence with outcomes was evaluated using Bayesian proportional odds models, including an interaction by study arm (conservative vs invasive).Results: Among 4,480 randomized participants, 1,245 (27.8%) were nonadherent at baseline. Nonadherent participants had worse baseline SAQ-7 SS in both conservative (72.9 ± 19.3 vs 75.6 ± 18.4) and invasive (71.0 ± 19.8 vs 74.2 ± 18.7) arms. In adjusted analyses, adherence was associated with higher 12-month SAQ-7 SS in both treatment groups (mean difference in SAQ-7 SS with conservative treatment = 1.6 [95% credible interval: 0.3-2.9] vs with invasive management = 1.9 [95% credible interval: 0.8-3.1]), with no interaction by treatment.Conclusions: More than 1 in 4 participants reported medication nonadherence, which was associated with worse health status in both conservative and invasive treatment strategies at baseline and 12 months. Strategies to improve medication adherence are needed to improve health status outcomes in CCD, regardless of treatment strategy. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522). [ABSTRACT FROM AUTHOR]

Objective: Medicare Advantage (MA), Medicare's managed care program, is quickly expanding, yet little is known about diabetes care quality delivered under MA compared with traditional fee-for-service (FFS) Medicare.Research Design and Methods: This was a retrospective cohort study of Medicare beneficiaries ≥65 years old enrolled in the Diabetes Collaborative Registry from 2014 to 2019 with type 2 diabetes treated with one or more antihyperglycemic therapies. Quality measures, cardiometabolic risk factor control, and antihyperglycemic prescription patterns were compared between Medicare plan groups, adjusted for sociodemographic and clinical factors.Results: Among 345,911 Medicare beneficiaries, 229,598 (66%) were enrolled in FFS and 116,313 (34%) in MA plans (for ≥1 month). MA beneficiaries were more likely to receive ACE inhibitors/angiotensin receptor blockers for coronary artery disease, tobacco cessation counseling, and screening for retinopathy, foot care, and kidney disease (adjusted P ≤ 0.001 for all). MA beneficiaries had modestly but significantly higher systolic blood pressure (+0.2 mmHg), LDL cholesterol (+2.6 mg/dL), and HbA1c (+0.1%) (adjusted P < 0.01 for all). MA beneficiaries were independently less likely to receive glucagon-like peptide 1 receptor agonists (6.9% vs. 9.0%; adjusted odds ratio 0.80, 95% CI 0.77-0.84) and sodium-glucose cotransporter 2 inhibitors (5.4% vs. 6.7%; adjusted odds ratio 0.91, 95% CI 0.87-0.95). When integrating Centers for Medicare and Medicaid Services-linked data from 2014 to 2017 and more recent unlinked data from the Diabetes Collaborative Registry through 2019 (total N = 411,465), these therapeutic differences persisted, including among subgroups with established cardiovascular and kidney disease.Conclusions: While MA plans enable greater access to preventive care, this may not translate to improved intermediate health outcomes. MA beneficiaries are also less likely to receive newer antihyperglycemic therapies with proven outcome benefits in high-risk individuals. Long-term health outcomes under various Medicare plans requires surveillance. [ABSTRACT FROM AUTHOR]

Background: Patients with ST-elevation myocardial infarction (STEMI) complicated by an out-of-hospital-cardiac-arrest (OHCA) may vary widely in their probability of dying. Large variation in mortality may have implications for current national efforts to benchmark operator and hospital mortality rates for coronary angiography. We aimed to build a risk-adjustment model of in-hospital mortality among OHCA survivors with concurrent STEMI.Methods: Within the Cardiac Arrest Registry to Enhance Survival (CARES), we included adults with OHCA and STEMI who underwent emergent angiography within 2 hours of hospital arrival between January 2013 and December 2019. Using multivariable logistic regression to adjust for patient and cardiac arrest factors, we developed a risk-adjustment model for in-hospital mortality and examined variation in patients' predicted mortality.Results: Of 2,999 patients (mean age 61.2 ± 12.0, 23.1% female, 64.6% white), 996 (33.2%) died during their hospitalization. The final risk-adjustment model included higher age (OR per 10-year increase, 1.50 [95% CI: 1.39-1.63]), unwitnessed OHCA (OR, 2.51 [1.99-3.16]), initial non-shockable rhythm [OR, 5.66 [4.52-7.13]), lack of sustained pulse for > 20 minutes (OR, 2.52 [1.88-3.36]), and longer resuscitation time (increased with each 10-minute interval) (c-statistic = 0.804 with excellent calibration). There was large variability in predicted mortality: median, 25.2%, inter-quartile-range: 14.0% to 47.8%, 10th-90th percentile: 8.2 % to 74.1%.Conclusions: In a large national registry, we identified 5 key predictors for mortality in patients with STEMI and OHCA and found wide variability in mortality risk. Our findings suggest that current national benchmarking efforts for coronary angiography, which simply adjusts for the presence of OHCA, may not adequately capture patient case-mix severity. [ABSTRACT FROM AUTHOR]

The TOPCAT database was obtained and queried for cumulative events for the primary outcome of heart failure hospitalization, aborted cardiac arrest, and death from cardiovascular causes. To be enrolled in the trial, patients needed to have symptoms of heart failure, a left ventricular ejection fraction >=45%, and either a hospitalization for heart failure within the previous 12 months or an elevated natriuretic peptide level. For example, TOPCAT evaluated the effect of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction using a composite of death from cardiovascular causes, aborted cardiac arrest, and heart failure hospitalization.1 This TOPCAT analysis demonstrated that spironolactone did not significantly reduce the time-to-first composite events. [Extracted from the article]

Objectives: Overcoming racial differences in acute coronary syndrome (ACS) outcomes is a strategic goal for U.S. health care. Genetic polymorphisms in the adrenergic pathway seem to explain some outcome differences by race in other cardiovascular diseases treated with β-adrenergic receptor blockade (BB). Whether these genetic variants are associated with survival among ACS patients treated with BB, and if this differs by race, is unknown. Background: β-adrenergic receptor blockade after ACS is a measure of quality care, but the effectiveness across racial groups is less clear. Methods: A prospective cohort of 2,673 ACS patients (2,072 Caucasian; 601 African-American) discharged on BB from 22 U.S. hospitals were followed for 2 years. Subjects were genotyped for polymorphisms in ADRB1, ADRB2, ADRA2C, and GRK5. We used proportional hazards regression to model the effect of genotype on mortality, stratified by race and adjusted for baseline factors. Results: The overall 2-year mortality rate was 7.5% for Caucasians and 16.7% for African Americans. The prognosis associated with different genotypes in these BB-treated patients differed by race. In Caucasians, ADRA2C 322-325 deletion carriers had significantly lower mortality as compared with homozygous individuals lacking the deletion (hazard ratio: 0.46; confidence interval [CI]: 0.21 to 0.99; p = 0.047; race × genotype interaction p = 0.053). In African Americans, the ADRB2 16R allele was associated with significantly increased mortality (hazard ratio for RG vs. GG: 2.10; CI: 1.14 to 3.86; RR vs. GG: 2.65; CI: 1.38 to 5.08; p = 0.013; race × genotype interaction p = 0.096). Conclusions: Adrenergic pathway polymorphisms are associated with mortality in ACS patients receiving BB in a race-specific manner. Understanding the mechanism by which different genes impact post-ACS mortality differently in Caucasians and African Americans might illuminate opportunities to improve BB therapy in these groups. [Copyright &y& Elsevier]

In this study, we investigated the activation of the serum response element (SRE) by the D2 dopamine receptor (D2R) agonist quinpirole. Stimulation of CHO cells expressing the D2R by quinpirol evoked a dose-dependent SRE activation, which was completely blocked by overnight treatment of pertussis toxin or by co-expression of the β-adrenergic receptor kinase C-terminus, implicating the involvement of Gαi and Gβγ in the signal transduction. Furthermore, using MEK inhibitors and dominant negative mutants of RhoA, Rac1, and Cdc42, we showed that the Gβγ-mediated activation of the SRE in CHO cells utilizes both MAPK and Rho pathways. Expression of either regulator of G protein signaling 2 or 4 (RGS2 or RGS4) proteins significantly attenuated the quinpirole-induced SRE activation. These results delineate the signaling pathways which couple D2 receptor to the transcriptional activation of SRE and demonstrate a modulatory role for RGS proteins in these processes. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

This editorial outlines the data supporting aggressive lipid goals and options for treating low-density lipoprotein (LDL) cholesterol to a range of approximately 30 to 70 mg/dl. The physiologically normal cholesterol range is approximately 30 to 70 mg/dl for native hunter-gatherers, healthy human neonates, free-living primates, and virtually all wild mammals. Randomized statin trials in patients with recent acute coronary syndromes and stable coronary artery disease have demonstrated that cardiovascular events are reduced and cardiovascular survival optimized when LDL cholesterol is reduced to <70 mg/dl. Secondary prevention trials have shown a decrease in all-cause mortality in proportion to the magnitude of LDL cholesterol reduction. An original analysis of available data shows that the ability of a lipid-lowering therapy to reduce the C-reactive protein level is closely correlated with its efficacy in LDL cholesterol reduction. Randomized trial data have shown no relation between either percentage LDL cholesterol decrease or final LDL cholesterol level achieved and the risk for myopathy or hepatic transaminase elevations associated with statins. Therefore, intensive LDL cholesterol reduction to levels of 30 to 70 mg/dl should be pursued in subjects with or at high risk for coronary artery disease. [Copyright &y& Elsevier]

Objectives: We tested the hypothesis that one health status measure, the Kansas City Cardiomyopathy Questionnaire (KCCQ), provides prognostic information independent of other clinical data in outpatients with heart failure (HF). Background: Health status measures are used to describe a patient’s clinical condition and have been shown to predict mortality in some populations. Their prognostic value may be particularly useful among patients with HF for identifying candidates for disease management in whom increased care may reduce hospitalizations and prevent death. Methods: We evaluated 505 HF patients from 13 outpatient clinics who had an ejection fraction <40% using the KCCQ summary score. Proportional hazards regression was used to evaluate the association between the KCCQ summary score (range, 0 to 100; higher scores indicate better health status) and the primary outcome of death or HF admission, adjusting for baseline patient characteristics, 6-min walk distance, and B-type natriuretic peptide (BNP). Results: The mean age was 61 years, 76% of patients were male, 51% had an ischemic HF etiology, and 5% were New York Heart Association functional class IV. At 12 months, among the 9% of patients with a KCCQ score <25, 37% had been admitted for HF and 20% had died, compared with 7% (HF admissions) and 5% (death) of those with a KCCQ score ≥75 (33% of patients, p < 0.0001 for both comparisons). In sequential multivariable models adjusting for clinical variables, 6-min walk, and BNP levels, the KCCQ score remained significantly associated with survival free of HF hospitalization. Conclusions: A low KCCQ score is an independent predictor of poor prognosis in outpatients with HF. [Copyright &y& Elsevier]

Background: The RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial demonstrated that higher-risk patients with atrial fibrillation had lower rates of stroke or systemic embolism and a similar rate of major bleeding, on average, when treated with dabigatran 150mg compared to warfarin. Since population-level averages may not apply to individual patients, estimating the heterogeneity of treatment effect can improve application of RE-LY in clinical practice. Methods and results: For 18040 patients randomized in RE-LY, we used patient-level data to develop multivariable models to predict the risk for stroke or systemic embolism and for major bleeding including all three treatment groups (dabigatran 110mg, dabigatran 150mg, and warfarin) over a median follow up of 2.0 years. The mean predicted absolute risk reduction (ARR) for stroke/systemic embolism with dabigatran 150mg compared to warfarin was 1.32% (range 11.6% lower to 3.30% higher risk). The mean predicted ARR for bleeding was 0.41% (range 8.93% lower to 63.4% higher risk). Patients with increased stroke/systemic embolism risk included those with prior stroke/TIA (OR 2.01), diabetics on warfarin (OR 2.00), and older patients on dabigatran 150mg (OR 1.68 for every 10-year increase). Major bleeding risk was higher in patients on aspirin (OR 1.25), with a history of diabetes (OR 1.34) or prior stroke/TIA (OR 1.22), those with heart failure on dabigatran 110mg (OR 1.52), older patients on either dabigatran 110mg or 150mg (OR 1.57 and 1.93, respectively, for each 10-year increase), and heavier patients on dabigatran 110mg or 150mg; patients in a region outside the United States and Canada and with better renal function had lower bleeding risk. Conclusions: There is substantial heterogeneity in the benefits and risks of dabigatran relative to warfarin among patients with atrial fibrillation. Using individualized estimates may enable shared decision making and facilitate more appropriate use of dabigatran; as such, it should be prospectively tested. Clinical trial registration: www.clinicaltrials.gov number, NCT00262600. [ABSTRACT FROM AUTHOR]

• An obesity paradox was not seen in the ISCHEMIA-CKD cohort. • Obesity may increase death and myocardial infarction risk in advanced chronic kidney disease and chronic coronary disease. • Obesity is associated with greater dyspnea in advanced chronic kidney disease and chronic coronary disease. • There was no body mass index by treatment assignment interaction for the primary outcome in the ISCHEMIA-CKD trial. This study aimed to assess whether an obesity paradox (lower event rates with higher body mass index [BMI]) exists in participants with advanced chronic kidney disease (CKD) and chronic coronary disease in the International Study of Comparative Health Effectiveness of Medical and Invasive Approaches (ISCHEMIA)-CKD, and whether BMI modified the effect of initial treatment strategy. Baseline BMI was analyzed as both a continuous and categorical variable (< 25, ≥ 25 to < 30, ≥ 30 kg/m2). Associations between BMI and the primary outcome of all-cause death or myocardial infarction (D/MI), and all-cause death, cardiovascular death, and MI individually were estimated. Associations with health status were also evaluated using the Seattle Angina Questionnaire-7, the Rose Dyspnea Scale, and the EuroQol-5D Visual Analog Scale. Body mass index ≥ 30 kg/m2 vs < 25 kg/m2 demonstrated increased risk for MI (hazard ratio [HR] [95% confidence interval] = 1.81 [1.12-2.92]) and for D/MI (HR 1.45 [1.06-1.96]) with a HR for MI of 1.22 (1.05-1.40) per 5 kg/m2 increase in BMI in unadjusted analysis. In multivariate analyses, a BMI ≥ 30 kg/m2 was marginally associated with D/MI (HR 1.43 [1.00-2.04]) and greater dyspnea throughout follow-up (P <.05 at all time points). Heterogeneity of treatment effect between baseline BMI was not evident for any outcome. In the ISCHEMIA-CKD trial, an obesity paradox was not detected. Higher BMI was associated with worse dyspnea, and a trend toward increased D/MI and MI risk. Larger studies to validate these findings are warranted. [ABSTRACT FROM AUTHOR]

We used data from 1,344 patients enrolled in the Prospective Registry Evaluating Myocardial Infarction: Events and Recovery study to examine the adoption of drug-eluting stents (DESs) and the effect of the release of the Food and Drug Administration’s preliminary public health notification, which raised concerns about DES safety. Overall, there was a dramatic increase in the use of DESs over the study period, from 32% in April 2003 to 81% in March 2004. The notification issued on October 29, 2003 was associated with a 26% relative decrease in DES use. By January 2004, DES use had returned to the prenotification rate and continued to increase thereafter. In conclusion, the Food and Drug Administration’s notification had a modest but temporary effect on clinical practice. [Copyright &y& Elsevier]

The determinants of change in left ventricular (LV) ejection fraction (EF) over time in patients with impaired LV function at baseline have not been clearly established. Using a nuclear database to assess changes in LV function over time, we included patients with a baseline LVEF of 25% to 40% on a gated single-photon emission computed tomographic study at rest and only if second-gated photon emission computed tomography performed approximately 18 months after the initial study showed an improvement in LVEF at rest of ≥10 points or a decrease in LVEF at rest of ≥7 points. In all, 148 patients qualified for the EF increase group and 59 patients for the EF decrease group. LVEF on average increased from 33 ± 4% to 51 ± 8% in the EF increase group and decreased from 35 ± 4% to 25 ± 5% in the EF decrease group. The strongest multivariable predictor of improvement of LVEF was β-blocker therapy (odds ratio 3.9, p = 0.002). The strongest independent predictor of LVEF decrease was the presence of a permanent right ventricular apical pacemaker (odds ratio 6.6, p = 0.002). Thus, this study identified β-blocker therapy as the major independent predictor for improvement in LVEF of ≥10 points, whereas a permanent pacemaker (right ventricular apical pacing) was the strongest predictor of a LVEF decrease of ≥7 points. [Copyright &y& Elsevier]

An exercise ankle–brachial index (ABI) test can provide further insight into the functional significance of peripheral artery disease (PAD). The variability in its use, associated patient factors and its relation to patients' symptoms are unknown. From the international PORTRAIT registry, we identified 1131 patients with PAD. We fit a hierarchical logistic regression model, adjusting for patient factors, country and site, to examine predictors of and variation in ordering exercise ABI testing. We also examined the associations between test components and health status as quantified by the Peripheral Artery Questionnaire (PAQ) using semi-parametric regression methods. Testing was ordered in 22% in the United States versus 80% in the Netherlands and 90% in Australia. Testing was likely to be performed if the patient was male, younger, had typical symptoms and a higher resting ABI, with substantial variability across sites (median odds ratio=5.9, 95% CI: 3.2–19.5). Adjusting for country and site, the resting ABI and all exercise ABI metrics were associated with the PAQ Physical Limitation score. In addition, important components of the test, namely time to onset of claudication, pain-free walking distance (PFWD), and maximum walking distance (MWD), were also associated with PAQ Symptoms and Summary scores. More importantly, even after adjusting for resting ABI, a patient with a post-exercise ABI of 0.29 (25th percentile), compared to 0.61 (75th percentile), achieved 4.4 (95% CI: 0.4–8.4, p=0.031) points less on the PAQ Physical Limitation score. Exercise ABI test use is remarkably variable, and less used in the United States. Its data, specifically PFWD and MWD, might help in objectively assessing the impact of PAD on patients' functioning and quality of life. [ABSTRACT FROM AUTHOR]

Outpatient cardiac rehabilitation (OCR) reinforces patients' efforts to quit smoking, but the association between participation in OCR and long-term smoking status after acute myocardial infarction (AMI) is unknown. We studied hospitalized smokers with confirmed AMI from two multicenter prospective registries (PREMIER, from January 1, 2003, to June 28, 2004, and TRIUMPH, from April 11, 2005, to December 31, 2008) to describe the association of OCR participation with smoking cessation. Eligible patients smoked at least 1 cigarette per day on average in the 30 days prior to enrollment and completed 12-month follow-up (N = 1307). Structured interviews were completed on subjects at baseline and during follow-up. OCR participation and abstinence from smoking within the prior 30-days (30-day point prevalence abstinence, PPA) were self-reported. We constructed a propensity model of OCR participation based on 22 baseline sociodemographic and clinical characteristics, and constructed hierarchical modified Poisson regression models of 30-day PPA at 12 months after matching on the propensity for OCR participation (with clinical site treated as a random effect). Seventy-four percent of subjects were referred to OCR at hospital discharge, but only 36% participated during follow-up. At 12-month follow-up, 30-day PPA was 57% in OCR participants, compared to 41% in matched OCR non-participants. Participation in OCR was a significant predictor of 30-day PPA at 12 months (adjusted RR 1.38, 95% CI 1.20-1.57). In conclusion, smokers who participated in OCR were significantly more likely to abstain from smoking 12 months after AMI hospitalization. [ABSTRACT FROM AUTHOR]

In this paper, we study the identification of Bayesian regression models, when an ordinal covariate is subject to unidirectional misclassification. Xia and Gustafson [Bayesian regression models adjusting for unidirectional covariate misclassification. Can J Stat. 2016;44(2):198–218] obtained model identifiability for non-binary regression models, when there is a binary covariate subject to unidirectional misclassification. In the current paper, we establish the moment identifiability of regression models for misclassified ordinal covariates with more than two categories, based on forms of observable moments. Computational studies are conducted that confirm the theoretical results. We apply the method to two datasets, one from the Medical Expenditure Panel Survey (MEPS), and the other from Translational Research Investigating Underlying Disparities in Acute Myocardial infarction Patients Health Status (TRIUMPH). [ABSTRACT FROM PUBLISHER]

Background: Compared with men, women are at higher risk of rehospitalization in the first month after discharge for acute myocardial infarction (AMI). However, it is unknown whether this risk extends to the full year and varies by age. Explanatory factors potentially mediating the relationship between sex and rehospitalization remain unexplored and are needed to reduce readmissions. The aim of this study was to assess sex differences and factors associated with 1-year rehospitalization rates after AMI.Methods: We recruited 3536 patients (33% women) ≥18 years of age hospitalized with AMI from 24 US centers into the TRIUMPH study (Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status). Data were obtained by medical record abstraction and patient interviews, and a physician panel adjudicated hospitalizations within the first year after AMI. We compared sex differences in rehospitalization using a Cox proportional hazards model, following sequential adjustment for covariates and testing for an age-sex interaction.Results: One-year crude all-cause rehospitalization rates for women were significantly higher than men after AMI (hazard ratio, 1.29 for women; 95% confidence interval, 1.12-1.48). After adjustment for demographics and clinical factors, women had a persistent 26% higher risk of rehospitalization (hazard ratio, 1.26; 95% confidence interval, 1.08-1.47). However, after adjustment for health status and psychosocial factors (hazard ratio, 1.14; 95% confidence interval, 0.96-1.35), the association was attenuated. No significant age-sex interaction was found for 1-year rehospitalization, suggesting that the increased risk applied to both older and younger women.Conclusions: Regardless of age, women have a higher risk of rehospitalization compared with men over the first year after AMI. Although the increased risk persisted after adjustment for clinical factors, the poorer health and psychosocial state of women attenuated the difference. [ABSTRACT FROM AUTHOR]

Background: A series of models have been developed to identify patients at high risk for poor outcomes after transcatheter aortic valve replacement (TAVR) to help guide treatment choices, offer patients realistic expectations of long-term outcomes, and support decision making.Objectives: This study examined the performance of the previously developed TAVR Poor Outcome risk models in an external dataset and explored the incremental contribution of geriatric domains to model performance.Methods: Poor outcome after TAVR was defined as death, poor quality of life (QOL), or decline in QOL, as assessed using the Kansas City Cardiomyopathy Questionnaire. We tested 4 TAVR Poor Outcome risk models: 6-month and 1-year full and clinical (reduced) models. We examined each model's discrimination and calibration in the CoreValve trial dataset, and then tested the incremental contribution of frailty and disability markers to the model's discrimination using the incremental discrimination index.Results: Among 2,830 patients who underwent TAVR in the CoreValve US Pivotal Extreme and High Risk trials and associated continued access registries, 31.2% experienced a poor outcome at 6 months following TAVR (death, 17.6%; very poor QOL, 11.6%; QOL decline, 2.0%) and 50.8% experienced a poor outcome at 1 year (death, 30.2%; poor QOL, 19.6%; QOL, decline 1.0%). The models demonstrated similar discrimination as in the Placement of Aortic Transcatheter Valves Trial cohorts (c-indexes, 0.637 to 0.665) and excellent calibration. Adding frailty as a syndrome increased the c-indexes by 0.000 to 0.004 (incremental discrimination index, p < 0.01 for all except the 1-year clinical model), with the most important individual components being disability and unintentional weight loss.Conclusions: Although discrimination of the TAVR Poor Outcome risk models was generally moderate, calibration was excellent among patients with different risk profiles and treated with a different TAVR device. These findings demonstrated the value of these models for individualizing outcome predictions in high-risk patients undergoing TAVR. [ABSTRACT FROM AUTHOR]

Purpose: Interpreting the clinical significance of changes in patient-reported outcomes (PROs) is critically important. The most commonly used approach is to anchor mean changes on PRO scores against a global assessment of change. Whether the assessor of global change should be patients or their physicians is unknown. We compared patients' and physicians' assessments of change over time to examine which was more aligned with patients' changes in PRO measures.Methods: A total of 459 chronic heart failure patients aged >30 years were enrolled from 13 US centers. Data were obtained by medical record abstraction, physical assessments, and patient interviews at a baseline clinic visit and 6 weeks later. Health status was measured with the disease-specific Kansas City Cardiomyopathy Questionnaire (KCCQ), and both patients and physicians completed a validated 15-level global assessment of change, ranging from large deterioration to large improvement.Results: There was substantial variation between physicians/patients' global assessment of clinical change (weighted kappa = 0.36, 95 % CI 0.28, 0.43). Overall, physician assessments were more strongly correlated with change on the KCCQ summary score than were patients' assessments (physician R = 0.37, patient R = 0.29).Conclusion: There was substantial variation between patients' and physicians' global assessment of 6-week change in heart failure status. Physician assessments of the importance of clinical changes were more strongly associated with changes in all domains of patient-reported health status, as assessed by the KCCQ, and may provide a more consistent method for defining the clinical importance of changes in patients' health status. [ABSTRACT FROM AUTHOR]

The design and synthesis of highly potent, selective orally bioavailable inhibitors of PDE10A is reported. Starting with an active compound of modest potency from a small focused screen, we were able to evolve this series to a lead molecule with high potency and selectivity versus other PDEs using structure-based design. A systematic refinement of ADME properties during lead optimization led to a lead compound with good half-life that was brain penetrant. Compound 39 was highly potent versus PDE10A (IC 50 = 1.0 nM), demonstrated high selectivity (>1000-fold) against other PDEs and was efficacious when dosed orally in a rat model of psychosis, PCP-induced hyperlocomotion with an EC 50 of 1 mg/kg. [ABSTRACT FROM AUTHOR]