Associations of potential ADRD plasma biomarkers in cognitively normal volunteers.

INTRODUCTION: This study examined the relationships between 13 novel blood-plasma biomarkers and dementia-related demographic and health factors in a cohort of 237 cognitively normal research volunteers whose average age was ≈82 years and who were 63% female. METHODS: We regressed each biomarker on selected covariates to explore the associations between the biomarkers and selected factors to assess whether they may contribute to biomarker values. Post hoc sensitivity analyses were done with updated data and consistent variable sets for robustness and batch effects. RESULTS: Biomarker concentrations were largely not associated with demographics or health conditions, but some expected associations (e.g., apolipoprotein E [APOE] status with amyloid beta [Aß]42/Aß40) were observed. Post hoc results remained similar to those of the main analysis. DISCUSSION: The absence of strong associations between the biomarkers with age, gender, or medical conditions suggests that changes in these biomarkers, when observed, may be attributable to neuropathological changes. HIGHLIGHTS: Among N = 237 cognitively normal adults, we studied candidate Alzheimer's disease and related dementia (ADRD) plasma biomarkers. Biomarkers were largely not associated with demographic or health factors. Apolipoprotein E (APOE) status was associated with amyloid beta (Aß)42/Aß40 ratio. These results support hypotheses that plasma biomarkers are informative for ADRD.

A Comparison of Methods for Predicting Future Cognitive Status: Mixture Modeling, Latent Class Analysis, and Competitors.

PURPOSE: The present work compares various methods for using baseline cognitive performance data to predict eventual cognitive status of longitudinal study participants at the University of Kentucky's Alzheimer's Disease Center. METHODS: Cox proportional hazards models examined time to cognitive transition as predicted by risk strata derived from normal mixture modeling, latent class analysis, and a 1-SD thresholding approach. An additional comparator involved prediction directly from a numeric value for baseline cognitive performance. RESULTS: A normal mixture model suggested 3 risk strata based on Consortium to Establish a Registry for Alzheimer's Disease (CERAD) T scores: high, intermediate, and low risk. Cox modeling of time to cognitive decline based on posterior probabilities for risk stratum membership yielded an estimated hazard ratio of 4.00 with 95% confidence interval 1.53-10.44 in comparing high risk membership to low risk; for intermediate risk membership versus low risk, the modeling yielded hazard ratio=2.29 and 95% confidence interval=0.98-5.33. Latent class analysis produced 3 groups, which did not have a clear ordering in terms of risk; however, one group exhibited appreciably greater hazard of cognitive decline. All methods for generating predictors of cognitive transition yielded statistically significant likelihood ratio statistics but modest concordance statistics. CONCLUSION: Posterior probabilities from mixture modeling allow for risk stratification that is data-driven and, in the case of CERAD T scores, modestly predictive of later cognitive decline. Incorporating other covariates may enhance predictions.

Left ventricular assist device-related infections: does the time of onset matter?

A frequent complication of left ventricular assist devices (LVAD) is the LVAD-associated infections (LVADIs). Contamination may occur during initial surgery/admission or at a later time. We studied the clinical manifestations and outcomes of LVADIs depending on the time of the onset. Patients implanted with LVADs at our institution between August 2009 and December 2014 were included. Patients were stratified into 2 groups based on whether the infection occurred early (< 180 days) or late (≥ 180 days) after LVAD implantation. Out of 37 overall LVADI episodes, 16 (43%) and 21 (57%) occurred early or late after device implantation, respectively. Median time to first LVADI was 88 ± 35 vs. 456 ± 187 days between groups. While superficial driveline-related infection was the most common LVADI type for both groups (56 vs. 71%, p = 0.489), driveline drainage was more prevalent in the late group (24 vs. 69%; p = 0.009). Early LVADIs involved more gram-positive flora, mostly Staphylococcus aureus (69 vs. 33%, p = 0.049), whereas late LVADIs involved more gram-negative pathogens, mostly Pseudomonas aueroginosa (25 vs. 57%; p = 0.045). High rates of treatment failure were consistent between groups (88 vs. 71%, p = 0.384). Compared with superficial LVADI, deeper infections were associated with an increase in mortality (13 vs 46%, p = 0.046). We concluded that early onset with likely in-hospital contamination involved more gram-positive flora, whereas late infection involved more gram-negative flora. Regardless of timing, success of antibacterial treatment was dismal, and infection depth correlated with poorer outcomes.

Using a respiratory navigator significantly reduces variability when quantifying left ventricular torsion with cardiovascular magnetic resonance.

BACKGROUND: Left ventricular (LV) torsion is an important indicator of cardiac function that is limited by high inter-test variability (50% of the mean value). We hypothesized that this high inter-test variability is partly due to inconsistent breath-hold positions during serial image acquisitions, which could be significantly improved by using a respiratory navigator for cardiovascular magnetic resonance (CMR) based quantification of LV torsion. METHODS: We assessed respiratory-related variability in measured LV torsion with two distinct experimental protocols. First, 17 volunteers were recruited for CMR with cine displacement encoding with stimulated echoes (DENSE) in which a respiratory navigator was used to measure and then enforce variability in end-expiratory position between all LV basal and apical acquisitions. From these data, we quantified the inter-test variability of torsion in the absence and presence of enforced end-expiratory position variability, which established an upper bound for the expected torsion variability. For the second experiment (in 20 new, healthy volunteers), 10 pairs of cine DENSE basal and apical images were each acquired from consecutive breath-holds and consecutive navigator-gated scans (with a single acceptance position). Inter-test variability of torsion was compared between the breath-hold and navigator-gated scans to quantify the variability due to natural breath-hold variation. To demonstrate the importance of these variability reductions, we quantified the reduction in sample size required to detect a clinically meaningful change in LV torsion with the use of a respiratory navigator. RESULTS: The mean torsion was 3.4 ± 0.2°/cm. From the first experiment, enforced variability in end-expiratory position translated to considerable variability in measured torsion (0.56 ± 0.34°/cm), whereas inter-test variability with consistent end-expiratory position was 57% lower (0.24 ± 0.16°/cm, p < 0.001). From the second experiment, natural respiratory variability from consecutive breath-holds translated to a variability in torsion of 0.24 ± 0.10°/cm, which was significantly higher than the variability from navigator-gated scans (0.18 ± 0.06°/cm, p = 0.02). By using a respiratory navigator with DENSE, theoretical sample sizes were reduced from 66 to 16 and 26 to 15 as calculated from the two experiments. CONCLUSIONS: A substantial portion (22-57%) of the inter-test variability of LV torsion can be reduced by using a respiratory navigator to ensure a consistent breath-hold position between image acquisitions.

Association between left ventricular mechanics and diffuse myocardial fibrosis in patients with repaired Tetralogy of Fallot: a cross-sectional study.

BACKGROUND: Patients with repaired tetralogy of Fallot (TOF) have progressive, adverse biventricular remodeling, leading to abnormal contractile mechanics. Defining the mechanisms underlying this dysfunction, such as diffuse myocardial fibrosis, may provide insights into poor long-term outcomes. We hypothesized that left ventricular (LV) diffuse fibrosis is related to impaired LV mechanics. METHODS: Patients with TOF were evaluated with cardiac magnetic resonance in which modified Look-Locker (MOLLI) T1-mapping and spiral cine Displacement encoding (DENSE) sequences were acquired at three LV short-axis positions. Linear mixed modeling was used to define the association between regional LV mechanics from DENSE based on regional T1-derived diffuse fibrosis measures, such as extracellular volume fraction (ECV). RESULTS: Forty patients (26 ± 11 years) were included. LV ECV was generally within normal range (0.24 ± 0.05). For LV mechanics, peak circumferential strains (-15 ± 3%) and dyssynchrony indices (16 ± 8 ms) were moderately impaired, while peak radial strains (29 ± 8%) were generally normal. After adjusting for patient age, sex, and regional LV differences, ECV was associated with log-adjusted LV dyssynchrony index (ß = 0.67) and peak LV radial strain (ß = -0.36), but not LV circumferential strain. Moreover, post-contrast T1 was associated with log-adjusted LV diastolic circumferential strain rate (ß = 0.37). CONCLUSIONS: We observed several moderate associations between measures of fibrosis and impaired mechanics, particularly the LV dyssynchrony index and peak radial strain. Diffuse fibrosis may therefore be a causal factor in some ventricular dysfunction in TOF.

Atrioventricular dyssynchrony from empiric device settings is common in cardiac resynchronization therapy and adversely impacts left ventricular morphology and function.

BACKGROUND: Echocardiographic atrioventricular (AV) optimization after cardiac resynchronization therapy (CRT) is uncommon due to time constraints and the use of vendor-specific device algorithms. It remains unclear whether optimization of mitral inflow velocities can still be useful. We aimed to investigate post implantation left ventricular (LV) inflow patterns to determine the incidence of AV dyssynchrony from empirically set devices. METHODS: This was a retrospective study of patients undergoing CRT using empiric device settings. Forty-eight patients with clinical, echocardiographic, and pacemaker follow-up were grouped by their post implantation LV filling pattern. Baseline characteristics and echocardiographic measurements were compared with post implantation findings at median 6.3 months (interquartile range [IQR], 3.9-17.0). RESULTS: Twenty-four patients demonstrated AV dyssynchrony (Group 1) after CRT, and 24 patients did not (Group 2). Group 1 patients had less LV reverse remodeling compared to Group 2 patients (ΔLV end-diastolic volume: -3.6 mL vs -49.5 mL, P<.05; ΔLV end-systolic volume: -16.9 mL vs -53.5 mL, P<.05) and did not experience significant improvements in LV outflow tract velocity time integral, stroke volume, or LV ejection fraction. There were no differences in new-onset atrial fibrillation, heart failure readmissions, or mortality between groups. CONCLUSION: Our study suggests that up to 50% of patients with empiric device settings have AV dyssynchrony at 6 months despite atrioventricular delay optimization (AVO) algorithms. As AV dyssynchrony is common and has proven to be modifiable, a strategic approach to Doppler echocardiography-guided AVO after CRT is warranted, particularly in nonresponders where the LV filling pattern is fused or truncated.

Outpatient versus observation/inpatient parotidectomy: patient factors and perioperative complications.

The objective of this manuscript is to review a single institution's experience with superficial or total parotidectomy in outpatient and observation/inpatient groups. All patients who underwent superficial or total parotidectomy between 2009 and 2015 were identified. Patients were excluded if they had undergone concurrent surgery such as neck dissection, had prior radiation treatment or surgery at the operative site. Main outcomes were perioperative complications in both groups. 215 consecutive patients were included in the study, 116 (54%) patients in the inpatient group and 99 (46%) in the outpatient group. Aside from a higher observed rate of cardiac disease in the outpatient group (24.2 vs. 11.2%, p = 0.014) and larger mean body mass index (BMI) in the inpatient group (32.448 vs. 30.034, p = 0.017), there were no significant differences for age, sex or smoking status. Average operative time differed between groups with 2 h 42 min for inpatients and 2 h 18 min for outpatients (p < 0.001). There were 26 complications in the inpatient group (22.4%, including two hematomas) and 8 in the outpatient group (8.1%). The rate of seroma/sialocele formation was significantly higher in the inpatient group at 15.5% (n = 18) compared with the outpatient group at 3% (n = 3, p = 0.001). Our study shows that parotidectomy, superficial or total, was performed safely as an outpatient procedure without significant increase in complications when compared to patients observed for at least one night after surgery.

Impact of individual acute phase serum amyloid A isoforms on HDL metabolism in mice.

The acute phase (AP) reactant serum amyloid A (SAA), an HDL apolipoprotein, exhibits pro-inflammatory activities, but its physiological function(s) are poorly understood. Functional differences between SAA1.1 and SAA2.1, the two major SAA isoforms, are unclear. Mice deficient in either isoform were used to investigate plasma isoform effects on HDL structure, composition, and apolipoprotein catabolism. Lack of either isoform did not affect the size of HDL, normally enlarged in the AP, and did not significantly change HDL composition. Plasma clearance rates of HDL apolipoproteins were determined using native HDL particles. The fractional clearance rates (FCRs) of apoA-I, apoA-II, and SAA were distinct, indicating that HDL is not cleared as intact particles. The FCRs of SAA1.1 and SAA2.1 in AP mice were similar, suggesting that the selective deposition of SAA1.1 in amyloid plaques is not associated with a difference in the rates of plasma clearance of the isoforms. Although the clearance rate of SAA was reduced in the absence of the HDL receptor, scavenger receptor class B type I (SR-BI), it remained significantly faster compared with that of apoA-I and apoA-II, indicating a relatively minor role of SR-BI in SAA's rapid clearance. These studies enhance our understanding of SAA metabolism and SAA's effects on AP-HDL composition and catabolism.

Effect of peripheral circadian dysfunction on metabolic disease in response to a diabetogenic diet.

BMAL1 is a core component of the transcription/translation machinery that regulates central and peripheral circadian rhythms that coordinate behavior and metabolism, respectively. Our objective was to determine the impact of BMAL1 in adipose alone or in combination with liver on metabolic phenotypes. Control, adipose-Bmal1 knockout (ABKO), and liver- and adipose-Bmal1 knockout (LABKO) female mice were placed in TSE System metabolic chambers for metabolic phenotyping. A second cohort of male mice was fed a control or diabetogenic diet, and body weight and composition, glucose tolerance, insulin sensitivity, and serum and hepatic lipids were measured. Both female ABKO and LABKO mice exhibited increased food consumption compared with control mice. ABKO mice also exhibited increased overall activity predominantly during the light phase compared with both control and LABKO mice and were protected from increased weight gain. When the male cohort was challenged with a diabetogenic diet, LABKO mice had increased body weight due to increased fat mass compared with control and ABKO mice. However, these mice did not present further impairments in glycemic control, adipose inflammation, or liver injury. LABKO mice had increased hepatic cholesterol and elevated expression of cholesterol synthesis and uptake genes. Our data indicate that deletion of this allele in adipose or in combination with liver alters feeding behavior and locomotor activity. However, obesity is exacerbated only with the combination of liver and adipose deletion.

Deficiency of Endogenous Acute-Phase Serum Amyloid A Protects apoE-/- Mice From Angiotensin II-Induced Abdominal Aortic Aneurysm Formation.

OBJECTIVE: Rupture of abdominal aortic aneurysm (AAA), a major cause of death in the aged population, is characterized by vascular inflammation and matrix degradation. Serum amyloid A (SAA), an acute-phase reactant linked to inflammation and matrix metalloproteinase induction, correlates with aortic dimensions before aneurysm formation in humans. We investigated whether SAA deficiency in mice affects AAA formation during angiotensin II (Ang II) infusion. APPROACH AND RESULTS: Plasma SAA increased ≈60-fold in apoE(-/-) mice 24 hours after intraperitoneal Ang II injection (100 µg/kg; n=4) and ≈15-fold after chronic 28-day Ang II infusion (1000 ng/kg per minute; n=9). AAA incidence and severity after 28-day Ang II infusion was significantly reduced in apoE(-/-) mice lacking both acute-phase SAA isoforms (SAAKO; n=20) compared with apoE(-/-) mice (SAAWT; n=20) as assessed by in vivo ultrasound and ex vivo morphometric analyses, despite a significant increase in systolic blood pressure in SAAKO mice compared with SAAWT mice after Ang II infusion. Atherosclerotic lesion area of the aortic arch was similar in SAAKO and SAAWT mice after 28-day Ang II infusion. Immunostaining detected SAA in AAA tissues of Ang II-infused SAAWT mice that colocalized with macrophages, elastin breaks, and enhanced matrix metalloproteinase activity. Matrix metalloproteinase-2 activity was significantly lower in aortas of SAAKO mice compared with SAAWT mice after 10-day Ang II infusion. CONCLUSIONS: Lack of endogenous acute-phase SAA protects against experimental AAA through a mechanism that may involve reduced matrix metalloproteinase-2 activity.

Left and right ventricular dyssynchrony and strains from cardiovascular magnetic resonance feature tracking do not predict deterioration of ventricular function in patients with repaired tetralogy of Fallot.

BACKGROUND: Patients with repaired tetralogy of Fallot (rTOF) suffer from progressive ventricular dysfunction decades after their surgical repair. We hypothesized that measures of ventricular strain and dyssynchrony would predict deterioration of ventricular function in patients with rTOF. METHODS: A database search identified all patients at a single institution with rTOF who underwent cardiovascular magnetic resonance (CMR) at least twice, >6 months apart, without intervening surgical or catheter procedures. Seven primary predictors were derived from the first CMR using a custom feature tracking algorithm: left (LV), right (RV) and inter-ventricular dyssynchrony, LV and RV peak global circumferential strains, and LV and RV peak global longitudinal strains. Three outcomes were defined, whose changes were assessed over time: RV end-diastolic volume, and RV and LV ejection fraction. Multivariate linear mixed models were fit to investigate relationships of outcomes to predictors and ten potential baseline confounders. RESULTS: One hundred fifty-three patients with rTOF (23 ± 14 years, 50 % male) were included. The mean follow-up duration between the first and last CMR was 2.9 ± 1.3 years. After adjustment for confounders, none of the 7 primary predictors were significantly associated with change over time in the 3 outcome variables. Only 1-17 % of the variability in the change over time in the outcome variables was explained by the baseline predictors and potential confounders. CONCLUSIONS: In patients with repaired tetralogy of Fallot, ventricular dyssynchrony and global strain derived from cine CMR were not significantly related to changes in ventricular size and function over time. The ability to predict deterioration in ventricular function in patients with rTOF using current methods is limited.

Thromboinflammatory response and predictors of outcomes in patients undergoing transcatheter aortic valve replacement.

Transcatheter aortic valve replacement (TAVR) has been increasingly used to treat patients with symptomatic aortic stenosis. Despite improvements in valve deployment, patients that have undergone TAVR are at high risk for major adverse events following the procedure. Blood cell numbers, platelet function, and biomarkers of systemic inflammation were analyzed in 58 patients undergoing TAVR with the Edward's SAPIEN valve. Following valve deployment, platelet count and agonist-induced platelet activity declined and plasma markers of systemic inflammation (interleukin-6 and S100A8/A9) increased. Baseline platelet activity prior to TAVR correlated with perioperative changes plasma interleukin-6 levels. Moreover, perioperative changes in plasma inflammatory markers predicted the decline in platelet count in the days following the TAVR procedure. Additionally, a significant effect of gender on platelet count following TAVR and was observed. Finally, post-procedural mortality was associated with sustained thrombocytopenia after TAVR. Our findings suggest that TAVR elicits a thromboinflammatory state that may contribute to post-procedural thrombocytopenia. Importantly, our results add to the growing body of literature that suggests the thromboinflammatory changes that occur early after TAVR may predict long-term outcomes.

Incidence, nature, and temporal trends of adverse events associated with noncardiac procedures among veterans with drug-eluting coronary artery stents.

BACKGROUND: The incidence of adverse events with noncardiac procedures (NCP) after the use of drug eluting stents (DES) is not well studied. We sought to determine the incidence and temporal trends of adverse events in patients undergoing NCP after coronary DES. METHODS: We performed a retrospective review of patients receiving DES during percutaneous coronary intervention (PCI) in the Lexington VAMC between January 1, 2004 and December 31, 2010 to determine the circumstances and the results of their NCP. RESULTS: We identified 1,092 patients who underwent at least one PCI with DES who were followed for at least 3 years. Of those, 452 patients (41%) had a NCP at a median of 534 days after PCI with 1,081 procedures (894 low-, 160 Intermediate-, and 27 high-risk) performed. Clinically relevant NCP-related complications were defined as significant bleeding or stent thrombosis and occurred in 13 individuals (nine perioperative bleeding and four probable/possible stent thrombosis including two mortalities). Five adverse events occurred within the first year at a rate of 0.014 event/patient-year. During the remainder of follow-up (up to 9 years), eight events were documented at a rate of 0.0004 event/patient-years. During the first year of follow-up, there was no significant increase in risk of recurrent myocardial infarction (MI) or target vessel revascularization (TVR) in patients undergoing NCP but higher risk of all-cause mortality in those who did not undergo NCP. However, in patients who underwent NCP, there was a statistically significant increase in myocardial infarction (MI), target vessel revascularization (TVR), and rehospitalization for cardiac reasons compared with those without NCP during long term follow-up (median of 5.6 years). CONCLUSION: NCP after DES requiring management of DAT are relatively common among veterans following PCI using DES. The risk of bleeding and stent thrombosis is concentrated in the first year but remains very low.

Gadolinium free cardiovascular magnetic resonance with 2-point Cine balanced steady state free precession.

BACKGROUND: Cardiovascular magnetic resonance (CMR) of ventricular structure and function is widely performed using cine balanced steady state free precession (bSSFP) MRI. The bSSFP signal of myocardium is weighted by magnetization transfer (MT) and T1/T2-relaxation times. In edematous and fibrotic tissues, increased T2 and reduced MT lead to increased signal intensity on images acquired with high excitation flip angles. We hypothesized that acquisition of two differentially MT-weighted bSSFP images (termed 2-point bSSFP) can identify tissue that would enhance with gadolinium similar to standard of care late gadolinium enhancement (LGE). METHODS: Cine bSSFP images (flip angles of 5° and 45°) and native-T1 and T2 maps were acquired in one mid-ventricular slice in 47 patients referred for CMR and 10 healthy controls. Afterwards, LGE images and post-contrast T1 maps were acquired and gadolinium partition coefficient (GPC) was calculated. Maps of ΔS/So were calculated as (S45-S5)/S5*100 (%), where Sflip_angle is the voxel signal intensity. RESULTS: Twenty three patients demonstrated areas of myocardial hyper-enhancement with LGE. In enhanced regions, ΔS/So, native-T1, T2, and GPC were heightened (p < 0.05 vs. non-enhanced tissues). ΔS/So, native-T1, and T2 all demonstrated association with GPC, however the association was strongest for ΔS/So. Bland-Altman analysis revealed a slight bias towards larger volume of enhancement with ΔS/So compared to LGE, and similar transmurality. Subjective analysis with 2-blinded expert readers revealed agreement between ΔS/So and LGE of 73.4 %, with false positive detection of 16.7 % and false negative detection of 15.2 %. CONCLUSIONS: Gadolinium free 2-point bSSFP identified tissue that enhances at LGE with strong association to GPC. Our results suggest that with further development, MT-weighted CMR could be used similar to LGE for diagnostic imaging.

Left ventricular mechanical dysfunction in diet-induced obese mice is exacerbated during inotropic stress: a cine DENSE cardiovascular magnetic resonance study.

BACKGROUND: Obesity is a risk factor for cardiovascular disease. There is evidence of impaired left ventricular (LV) function associated with obesity, which may relate to cardiovascular mortality, but some studies have reported no dysfunction. Ventricular function data are generally acquired under resting conditions, which could mask subtle differences and potentially contribute to these contradictory findings. Furthermore, abnormal ventricular mechanics (strains, strain rates, and torsion) may manifest prior to global changes in cardiac function (i.e., ejection fraction) and may therefore represent more sensitive markers of cardiovascular disease. This study evaluated LV mechanics under both resting and stress conditions with the hypothesis that the LV mechanical dysfunction associated with obesity is exacerbated with stress and manifested at earlier stages of disease compared to baseline. METHODS: C57BL/6J mice were randomized to a high-fat or control diet (60 %, 10 % kcal from fat, respectively) for varying time intervals (n = 7 - 10 subjects per group per time point, 100 total; 4 - 55 weeks on diet). LV mechanics were quantified under baseline (resting) and/or stress conditions (40 µg/kg/min continuous infusion of dobutamine) using cine displacement encoding with stimulated echoes (DENSE) with 7.4 ms temporal resolution on a 7 T Bruker ClinScan. Peak strain, systolic strain rates, and torsion were quantified. A linear mixed model was used with Benjamini-Hochberg adjustments for multiple comparisons. RESULTS: Reductions in LV peak longitudinal strain at baseline were first observed in the obese group after 42 weeks, with no differences in systolic strain rates or torsion. Conversely, reductions in longitudinal strain and circumferential and radial strain rates were seen under inotropic stress conditions after only 22 weeks on diet. Furthermore, stress cardiovascular magnetic resonance (CMR) evaluation revealed supranormal values of LV radial strain and torsion in the obese group early on diet, followed by later deficits. CONCLUSIONS: Differences in left ventricular mechanics in obese mice are exacerbated under stress conditions. Stress CMR demonstrated a broader array of mechanical dysfunction and revealed these differences at earlier time points. Thus, it may be important to evaluate cardiac function in the setting of obesity under stress conditions to fully elucidate the presence of ventricular dysfunction.

The effect of rosuvastatin on thromboinflammation in the setting of acute coronary syndrome.

In patients with acute coronary syndromes (ACS), early therapy with high-dose statins may reduce short-term adverse clinical outcomes. The mechanisms responsible are not known but could involve anti-inflammatory or anti-thrombotic effects. Compelling evidence from experimental models and clinical studies suggests that the interplay between inflammatory and thrombotic systems, typified by platelet-monocyte and platelet-neutrophil interactions, might be a key regulator of ischemic vascular events. The study sought to determine if early, high-dose administration of the HMG-CoA reductase inhibitor rosuvastatin in the setting of ACS exerts beneficial vascular effects by reducing, and inhibiting biomarkers of thromboinflammation, such as platelet-monocyte and platelet-neutrophil interactions, and biomarkers of myocardial necrosis. A total of 54 patients presenting with ACS within 8 h of symptom onset were randomized to rosuvastatin 40 mg or placebo. Rosuvastatin significantly reduced interactions between platelets and circulating neutrophils (P = 0.015) and monocytes (P = 0.009) within 24 h. No significant effects were observed on platelet aggregation or plasma levels of PF4, sP-selectin, or sCD40L, whereas significant reductions of RANTES occurred over time in both treatment groups. Plasma levels of myeloperoxidase (MPO) declined more rapidly with rosuvastatin therapy than placebo. In a subset of patients with normal cardiac necrosis biomarkers at randomization, rosuvastatin therapy was associated with less myocardial damage as measured by troponin-I or CK-MB. Early administration of high-dose statin therapy in patients with ACS appears to improve biomarkers of inflammation within 8 h, which may translate into fewer ischemic events.

Enhancing condom use among Black male youths: a randomized controlled trial.

OBJECTIVES: We tested the efficacy of a brief intervention to promote correct and consistent use of condoms among Black male youths attending sexually transmitted infection (STI) clinics in 3 southern US cities. METHODS: In 2010 to 2012, we screened (n = 1102) and enrolled (n = 702) youths aged 15 to 23 years who identified as Black and reported recent (past 2 months) sexual activity and randomized them to a private, brief, interactive intervention (n = 349) or an attention-equivalent control condition (n = 353). Assessments occurred at baseline and 2 and 6 months after the intervention. RESULTS: At 6 months, with adjustment for age and pretest nonequivalence of the outcome variable, an estimated odds ratio (EOR) of 1.63 (95% confidence interval [CI] = 1.07, 2.49; P = .02) indicated efficacy for correct condom use. An adjusted generalized estimating equations model with both 2- and 6-month condom use variables produced an EOR of 1.49 (95% CI = 1.06, 2.08; P = .02). We did not observe significant effects on chlamydia and gonorrhea incidence. CONCLUSIONS: This brief intervention, delivered as part of STI clinical care, could help alleviate the disproportionate STI-HIV burden among young Black men.

QRS duration predicts death and hospitalization among patients with atrial fibrillation irrespective of heart failure: evidence from the AFFIRM study.

AIMS: The association of QRS duration (QRSd) with morbidity and mortality is understudied in patients with atrial fibrillation (AF). We sought to assess any association of prolonged QRS with increased risk of death or hospitalization among patients with AF. METHODS AND RESULTS: QRS duration was retrieved from the baseline electrocardiograms of patients enroled in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study and divided into three categories: <90, 90-119, ≥120 ms. Cox models were applied relating the hazards of mortality and hospitalizations to QRSd. Among 3804 patients with AF, 593 died and 2305 were hospitalized. Compared with those with QRS < 90 ms, patients with QRS ≥ 120 ms, had an increased mortality [hazard ratio (HR) 1.61, 95% confidence interval (CI): 1.29-2.03, P < 0.001] and hospitalizations (HR 1.14, 95% CI: 1.07-1.34, P = 0.043) over an average follow-up of 3.5 years. Importantly, for patients with QRS 90-119 ms, mortality and hospitalization were also increased (HR 1.31, P = 0.005 and 1.11, P = 0.026, respectively). In subgroup analysis based on heart failure (HF) status (previously documented or ejection fraction <40%), mortality was increased for QRS ≥ 120 ms patients with (HR 1.87, P < 0.001) and without HF (HR 1.63, P = 0.02). In the QRS 90-119 ms group, mortality was increased (HR 1.38, P = 0.03) for those with HF, but not significantly among those without HF (HR 1.23, P = 0.14). CONCLUSION: Among patients with AF, QRSd ≥ 120 ms was associated with a substantially increased risk for mortality (all-cause, cardiovascular, and arrhythmic) and hospitalization. Interestingly, an increased mortality was also observed among those with QRS 90-119 ms and concomitant HF.

Increased mortality among patients taking digoxin--analysis from the AFFIRM study.

AIMS: Digoxin is frequently used for rate control of atrial fibrillation (AF). It has, however, been associated with increased mortality. It remains unclear whether digoxin itself is responsible for the increased mortality (toxic drug effect) or whether it is prescribed to sicker patients with inherently higher mortality due to comorbidities. The goal of our study was to determine the relationship between digoxin and mortality in patients with AF. METHODS AND RESULTS: The association between digoxin and mortality was assessed in patients enrolled in the AF Follow-Up Investigation of Rhythm Management (AFFIRM) trial using multivariate Cox proportional hazards models. Analyses were conducted in all patients and in subsets according to the presence or absence of heart failure (HF), as defined by a history of HF and/or an ejection fraction <40%. Digoxin was associated with an increase in all-cause mortality [estimated hazard ratio (EHR) 1.41, 95% confidence interval (CI) 1.19-1.67, P < 0.001], cardiovascular mortality (EHR 1.35, 95% CI 1.06-1.71, P = 0.016), and arrhythmic mortality (EHR 1.61, 95% CI 1.12-2.30, P = 0.009). The all-cause mortality was increased with digoxin in patients without or with HF (EHR 1.37, 95% CI 1.05-1.79, P = 0.019 and EHR 1.41, 95% CI 1.09-1.84, P = 0.010, respectively). There was no significant digoxin-gender interaction for all-cause (P = 0.70) or cardiovascular (P = 0.95) mortality. CONCLUSION: Digoxin was associated with a significant increase in all-cause mortality in patients with AF after correcting for clinical characteristics and comorbidities, regardless of gender or of the presence or absence of HF. These findings call into question the widespread use of digoxin in patients with AF.