Predicted benefit of an implantable cardioverter-defibrillator: the MADIT-ICD benefit score.

AIMS: The benefit of prophylactic implantable cardioverter-defibrillator (ICD) is not uniform due to differences in the risk of life-threatening ventricular tachycardia (VT)/ventricular fibrillation (VF) and non-arrhythmic mortality. We aimed to develop an ICD benefit prediction score that integrates the competing risks. METHODS AND RESULTS: The study population comprised all 4531 patients enrolled in the MADIT trials. Best-subsets Fine and Gray regression analysis was used to develop prognostic models for VT (≥200 b.p.m.)/VF vs. non-arrhythmic mortality (defined as death without prior sustained VT/VF). Eight predictors of VT/VF (male, age < 75 years, prior non-sustained VT, heart rate > 75 b.p.m., systolic blood pressure < 140 mmHg, ejection fraction ≤ 25%, myocardial infarction, and atrialarrhythmia) and 7 predictors of non-arrhythmic mortality (age ≥ 75 years, diabetes mellitus, body mass index < 23 kg/m2, ejection fraction ≤ 25%, New York Heart Association ≥II, ICD vs. cardiac resynchronization therapy with defibrillator, and atrial arrhythmia) were identified. The two scores were combined to create three MADIT-ICD benefit groups. In the highest benefit group, the 3-year predicted risk of VT/VF was three-fold higher than the risk of non-arrhythmic mortality (20% vs. 7%, P < 0.001). In the intermediate benefit group, the difference in the corresponding predicted risks was attenuated (15% vs. 9%, P < 0.01). In the lowest benefit group, the 3-year predicted risk of VT/VF was similar to the risk of non-arrhythmic mortality (11% vs. 12%, P = 0.41). A personalized ICD benefit score was developed based on the distribution of the two competing risks scores in the study population (https://is.gd/madit). Internal and external validation confirmed model stability. CONCLUSIONS: We propose the novel MADIT-ICD benefit score that predicts the likelihood of prophylactic ICD benefit through personalized assessment of the risk of VT/VF weighed against the risk of non-arrhythmic mortality.

Multicenter Automatic Defibrillator Implantation Trial-Subcutaneous Implantable Cardioverter Defibrillator (MADIT S-ICD): Design and clinical protocol.

Patients with diabetes mellitus, prior myocardial infarction, older age, and a relatively preserved left ventricular ejection fraction remain at risk for sudden cardiac death that is potentially amenable by the subcutaneous implantable cardioverter defibrillator with a good risk-benefit profile. The launched MADIT S-ICD study is designed to test the hypothesis that post-myocardial infarction diabetes patients with relatively preserved ejection fraction of 36%-50% will have a survival benefit from a subcutaneous implantable cardioverter defibrillator.

Magnitude, decadal changes, and impact of regional background ozone transported into the greater Houston, Texas, area.

Two independent analyses of the daily maximum 8 h average ozone concentrations measured during the high ozone season (May through October) at Continuous Ambient Monitoring Stations are used to quantify the regional background ozone transported into the Houston-Galveston-Brazoria (HGB) area. The dependence on wind direction is examined, and long-term trends are determined using measurements made between 1998 and 2012. Both analyses show that the regional background ozone has declined during periods of continental outflow: i.e., the conditions associated with most high ozone episodes in HGB. The changes in regional background ozone found for northeasterly and southeasterly flow are -0.50 ± 0.54 and -0.79 ± 0.65 (95% confidence limit) ppbv yr(-1), respectively, which correspond to decreases of ∼7-11 ppbv between 1998 and 2012. This finding is consistent with the summertime downward trend of -0.45 ppbv yr(-1) (range of sites: -0.87 to +0.07 ppbv yr(-1)) for ozone in the eastern U.S. between 1990 and 2010 reported by Cooper et al. and shows that changing background concentrations are at least partially responsible for the decreased surface ozone in the HGB area over the past decade. Baseline ozone concentrations in air flowing into Texas from the Gulf of Mexico have not changed significantly over this period.

Understanding ozone episodes during the TRACER-AQ campaign in Houston, Texas: The role of transport and ozone production sensitivity to precursors.

This study investigated transport pathways and photochemical formation responsible for ozone exceedances during the September 2021 deployment of the Tracking Aerosol Convection Interactions ExpeRiment/Air Quality (TRACER-AQ) campaign in Houston, Texas. We focused on two ozone episodes, September 6th-September 11th ("Episode 1") and September 23rd-September 26th ("Episode 2"), when the maximum daily eight-hour average (MDA8) ozone at surface monitors exceeded 70 ppbv. Long-range transport patterns of air masses during these episodes were from the central/northern US. High-resolution (4 km resolution) trajectory analysis with FLEXible PARTicle (FLEXPART) dispersion model revealed local recirculation of air masses and the accumulation of pollutants across Houston contribute to the ozone exceedances. Comprehensive Air Quality Model with extensions (CAMx) driven by 1.33-km resolution meteorology from the Weather Research and Forecast (WRF) tool simulated elevated ozone production rates during ozone episodes across the Houston metropolitan area, with ozone production hotspots mostly over Houston city and industrial districts of the Houston Ship Channel (HSC). The regional increase in ozone production rates was due to the transport of VOC-rich air masses (via northerly flows) that brought ozone precursors to the region, which ultimately caused a transition in the ozone formation tendency from generally VOC-limited to NOx-limited conditions. However, the city of Houston and the HSC remained in a VOC-limited regime because of local NOx emissions that, to some extent, preponderated the impact of transported VOCs. While approximately 37 % of the elevated ozone production was attributed to local photochemistry, the remaining ∼63 % increase in ozone production was due to the transported ozone to the region during episodes, bringing ozone to the Houston region and contributing to ozone exceedances. The outcomes of this study illustrated the synergy between transport and ozone production, both long-range and local scale, which resulted in ozone exceedances in Houston.

Long-term trend in surface ozone in Houston-Galveston-Brazoria: Sectoral contributions based on changes in volatile organic compounds.

This study investigated the long-term variations in ambient levels of surface ozone, volatile organic compounds (VOCs), and nitrogen oxides (NOx) within the Houston-Galveston-Brazoria (HGB) region. Analysis of ozone levels revealed an overall reduction in the maximum daily 8-h average ozone (MDA8 O3) from 2000 to 2019 (April-October) with an average rate of âˆ¼ -0.48 ppb/yr across HGB. With a few exceptions, the MDA8 O3 reduction rates were more pronounced for the monitoring sites closer to the Houston Ship Channel (HSC). Meanwhile, ambient levels of NOx and most VOC species (across the three representative sites as Houston Bayland Park, Haden Road, and Lynchburg Ferry) decreased significantly within the same investigation period, reflecting the impact of emission reductions. The positive matrix factorization (PMF) model applied to the mentioned sites identified regional background ozone, petrochemical emissions, engine combustion, natural gas/fuel evaporation, and solvent/painting/rubber industries as the major sources of MDA8 O3. The regional background ozone was the predominant source, accounting for 59-70% of MDA8 O3 across the three sites. Regarding the local anthropogenic emissions, natural gas/fuel evaporation was the largest contributor (19.5 ± 6.1%) to MDA8 O3 at Houston Bayland Park, whereas petrochemical facilities (10.9 ± 4.9%) and solvent/painting/rubber industries (18.1 ± 9.5%) were the largest factor at Haden Road and Lynchburg Ferry, respectively. Notable reductions were found in the contributions of petrochemical emissions, engine combustion, and natural gas/fuel evaporation to MDA8 O3 within 2000-2019, but an increasing trend was revealed in the role of solvent/painting/rubber industries on MDA8 O3 most probably due to the enhanced demand for their products. Results of this study corroborated the success of emission control policies in limiting ozone precursors and provided useful details for prioritizing emission reduction policies to further reduce ozone pollution in the HGB.

Natural killer cells promote tissue injury and systemic inflammatory responses during fatal Ehrlichia-induced toxic shock-like syndrome.

Human monocytotropic ehrlichiosis is caused by Ehrlichia chaffeensis, a Gram-negative bacterium lacking lipopolysaccharide. We have shown that fatal murine ehrlichiosis is associated with CD8(+)T cell-mediated tissue damage, tumor necrosis factor-alpha, and interleukin (IL)-10 overproduction, and CD4(+)Th1 hyporesponsiveness. In this study, we examined the relative contributions of natural killer (NK) and NKT cells in Ehrlichia-induced toxic shock. Lethal ehrlichial infection in wild-type mice induced a decline in NKT cell numbers, and late expansion and migration of activated NK cells to the liver, a main infection site that coincided with development of hepatic injury. The spatial and temporal changes in NK and NKT cells in lethally infected mice correlated with higher NK cell cytotoxic activity, higher expression of cytotoxic molecules such as granzyme B, higher production of interferon-gamma and tumor necrosis factor-alpha, increased hepatic infiltration with CD8alphaCD11c(+) dendritic cells and CD8(+)T cells, decreased splenic CD4(+)T cells, increased serum concentrations of IL-12p40, IL-18, RANTES, and monocyte chemotactic protein-1, and elevated production of IL-18 by liver mononuclear cells compared with nonlethally infected mice. Depletion of NK cells prevented development of severe liver injury, decreased serum levels of interferon-gamma, tumor necrosis factor-alpha, and IL-10, and enhanced bacterial elimination. These data indicate that NK cells promote immunopathology and defective anti-ehrlichial immunity, possibly via decreasing the protective immune response mediated by interferon-gamma producing CD4(+)Th1 and NKT cells.

Survival After Implantable Cardioverter-Defibrillator Shocks.

BACKGROUND: There are conflicting data on the impact of implantable cardioverter-defibrillator (ICD) shocks on subsequent mortality. OBJECTIVES: The aim of this study was to determine whether the arrhythmic substrate leading to ICD therapy or the therapy itself increases mortality. METHODS: The study cohort included 5,516 ICD recipients who were enrolled in 5 landmark ICD trials (MADIT-II, MADIT-RISK, MADIT-CRT, MADIT-RIT, RAID). The authors evaluated the association of device therapy with subsequent mortality in 4 separate time-dependent models: model I, type of ICD therapy; model II, type of arrhythmia for which ICD therapy was delivered; model III, combined assessment of all arrhythmia and therapy types during follow-up; and model IV, incremental risk associated with repeated ICD shocks. RESULTS: When analyzed by the type of ICD therapy (model I), a first appropriate ICD shock was associated with increased risk of subsequent mortality with or without concomitant occurrence of inappropriate shock during follow-up (hazard ratio [HR]: 2.78 and 2.31; p < 0.001 and p = 0.12), whereas inappropriate shock alone was not associated with mortality risk (HR: 1.23; p = 0.42). Similarly, ICD therapy for ventricular tachycardia (VT) ≥200 beats/min or ventricular fibrillation (VF) (model II) was associated with increased risk of death with or without concomitant therapy for VT <200 beats/min (HRs: 2.25 and 2.62; both p < 0.001), whereas appropriate therapy for VT <200 beats/min or inappropriate therapy (regardless of etiology) did not reach statistical significance (all p > 0.10). Combined assessment of all therapy and arrhythmia types during follow-up (model III) showed that appropriate ICD shocks for VF, shocks for fast VT (≥200 beats/min) without prior antitachycardia pacing (ATP), as well as shocks for fast VT delivered after failed ATP, were associated with the highest risk of subsequent death (HR: all >2.8; p < 0.001). Finally, 2 or more ICD appropriate shocks were not associated with incremental risk to the first appropriate ICD shock (model IV). CONCLUSION: The combined data from 5 landmark ICD trials suggest that the underlying arrhythmic substrate rather than the ICD therapy is the more important determinant of mortality in ICD recipients.

Sports and arrhythmias: a report of the International Workshop Venice Arrhythmias 2009.

This article is a report of an international symposium, endorsed by the Section on Sports Cardiology of the European Association for Cardiovascular Prevention and Rehabilitation, the Italian Society of Sports Cardiology, and the Italian Federation of Sports Medicine, which was held within the 11th International Workshop on Cardiac Arrhythmias (Venice Arrhythmias 2009, Venice, Italy, October 2009). The following main topics were discussed during the symposium: the role of novel diagnostic examinations to assess the risk of sudden death in athletes, controversies on arrhythmic risk evaluation in athletes, controversies on the relationship between sports and arrhythmias, and controversies on antiarrhythmic treatment in athletes.

Beta-adrenergic antagonists in hypertension: a review of the evidence.

OBJECTIVE: To evaluate the effects of beta-adrenergic antagonist therapy on cardiovascular and cerebrovascular outcomes in the treatment of hypertension. DATA SOURCES: Literature searches were conducted using MEDLINE (1966-August 2009), International Pharmaceutical Abstracts (1970-August 2009), and Cochrane Database of Systematic Reviews (until third quarter 2009) to locate clinical trials and meta-analyses comparing beta-blocker therapy with placebo or other antihypertensive agents in patients with hypertension. Bibliographies from relevant research and review articles were reviewed for additional references. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were reviewed. Articles describing original research with cardiovascular or cerebrovascular outcomes and/or death as either primary or secondary endpoints were included. Articles describing the use of beta-blocker therapy for conditions other than hypertension were not included. DATA SYNTHESIS: Five placebo-controlled studies and 10 active-controlled studies were reviewed. In addition, 11 meta-analyses were evaluated. Placebo-controlled trials of beta-blockers in hypertension provide evidence of reduced risk for stroke, cardiovascular events, and heart failure. Only 2 studies comparing beta-blockers with other antihypertensives found significant benefit with beta-blockers. However, the majority of meta-analyses comparing beta-blockers with other antihypertensive agents show increased risk for stroke with beta-blockers, and some data suggest increased risk for cardiovascular events and all-cause mortality. The majority of data results from studies of atenolol, and many studies employed combination antihypertensive therapies, which often included thiazide diuretics. CONCLUSIONS: Overall, data supporting beta-blockers as preferred therapy in hypertension are inadequate. Although most negative cardiovascular and cerebrovascular outcomes of beta-blockers were associated with atenolol therapy, data supporting other beta-blockers in hypertension are lacking.

Application of geostatistical approaches to predict the spatio-temporal distribution of summer ozone in Houston, Texas.

Mitigation of adverse effects of air pollution requires understanding underlying exposures, such as ambient ozone concentrations. Geostatistical approaches were employed to analyze temporal trends and estimate spatial patterns of summertime ozone concentrations for Houston, Texas, based on hourly ozone observations obtained from the Texas Commission on Environmental Quality. We systematically assess the accuracy of several spatial interpolation methods, comparing inverse distance weighting, simple kriging, ordinary kriging, and universal kriging methods utilizing the hourly ozone observations and meteorological measurements from monitoring sites. Model uncertainty was assessed by leave-one-out cross-validation. Kriging methods performed better, showing greater consistency in the generated surfaces, fewer interpolation errors, and lower biases. Universal kriging did not significantly improve the interpolation results compared to ordinary kriging, and thus ordinary kriging was determined to be the optimal method, striking a balance between accuracy and simplicity. The resulting spatial patterns indicate that the more industrialized areas east and northeast of Houston exhibit the highest summertime ozone concentrations. Estimated daily maximum 8 h ozone concentration fields generated will be used to inform research on population health risks from exposure to surface ozone in Houston.

Role of magnetic resonance imaging in arrhythmogenic right ventricular dysplasia: insights from the North American arrhythmogenic right ventricular dysplasia (ARVD/C) study.

BACKGROUND: Prior reports describing magnetic resonance (MR) imaging abnormalities in arrhythmogenic right ventricular dysplasia (ARVD/C) were limited by nonuniform inclusion criteria. The aim of our study was to define the prevalence, sensitivity, and specificity of quantitative MR imaging findings in the probands of multidisciplinary study of right ventricular dysplasia. METHODS: Individuals with ventricular arrhythmias of left bundle-branch block morphology meeting the Task Force criteria for ARVD/C underwent MR imaging. The MR images were compared with 10 patients with idiopathic ventricular tachycardia (VT) and 25 controls. Of the 42 study probands, 40 met the Task Force criteria exclusive of MR imaging findings. All MR images were interpreted in a blinded fashion. RESULTS: Right ventricle fat infiltration was reported in 24 (60%) probands and none of the patients with idiopathic VT or controls. Six patients (15%) had fat infiltration of the left ventricle. Right ventricle regional dysfunction was observed in 32 probands (80%) and none of the patients with idiopathic VT or controls. Qualitative RV function was abnormal in 26 probands (60%); however, quantitative RV ejection fraction was abnormal in 85% (24/28) of the probands. An RV ejection fraction <50% had a sensitivity of 73% and a specificity of 95% in diagnosis of ARVD/C. CONCLUSIONS: Fat infiltration is seldom the only MR imaging abnormality and is less sensitive for ARVD/C diagnosis compared with RV regional dysfunction. Qualitative estimates of RV function may underestimate the prevalence of RV dysfunction in ARVD/C. Quantitative evaluation of RV by MR imaging may have a high sensitivity and specificity for ARVD/C diagnosis.

Live, Attenuated Venezuelan Equine Encephalitis Virus Vaccine (TC83) Causes Persistent Brain Infection in Mice with Non-functional αß T-Cells.

Intranasal infection with vaccine strain of Venezuelan equine encephalitis virus (TC83) caused persistent viral infection in the brains of mice without functional αß T-cells (αß-TCR -/-). Remarkably, viral kinetics, host response gene transcripts and symptomatic disease are similar between αß-TCR -/- and wild-type C57BL/6 (WT) mice during acute phase of infection [0-13 days post-infection (dpi)]. While WT mice clear infectious virus in the brain by 13 dpi, αß-TCR -/- maintain infectious virus in the brain to 92 dpi. Persistent brain infection in αß-TCR -/- correlated with inflammatory infiltrates and elevated cytokine protein levels in the brain at later time points. Persistent brain infection of αß-TCR -/- mice provides a novel model to study prolonged alphaviral infection as well as the effects and biomarkers of long-term viral inflammation in the brain.

Formaldehyde column density measurements as a suitable pathway to estimate near-surface ozone tendencies from space.

In support of future satellite missions that aim to address the current shortcomings in measuring air quality from space, NASA's Deriving Information on Surface Conditions from Column and Vertically Resolved Observations Relevant to Air Quality (DISCOVER-AQ) field campaign was designed to enable exploration of relationships between column measurements of trace species relevant to air quality at high spatial and temporal resolution. In the DISCOVER-AQ data set, a modest correlation (r 2 = 0.45) between ozone (O3) and formaldehyde (CH2O) column densities was observed. Further analysis revealed regional variability in the O3-CH2O relationship, with Maryland having a strong relationship when data were viewed temporally and Houston having a strong relationship when data were viewed spatially. These differences in regional behavior are attributed to differences in volatile organic compound (VOC) emissions. In Maryland, biogenic VOCs were responsible for ~28% of CH2O formation within the boundary layer column, causing CH2O to, in general, increase monotonically throughout the day. In Houston, persistent anthropogenic emissions dominated the local hydrocarbon environment, and no discernable diurnal trend in CH2O was observed. Box model simulations suggested that ambient CH2O mixing ratios have a weak diurnal trend (±20% throughout the day) due to photochemical effects, and that larger diurnal trends are associated with changes in hydrocarbon precursors. Finally, mathematical relationships were developed from first principles and were able to replicate the different behaviors seen in Maryland and Houston. While studies would be necessary to validate these results and determine the regional applicability of the O3-CH2O relationship, the results presented here provide compelling insight into the ability of future satellite missions to aid in monitoring near-surface air quality.

Device trials in heart failure: a focused summary.

Despite considerable progress in heart failure management with pharmacologic agents, measures to bring about significant improvements in morbidity and mortality are still needed. Cardiac resynchronization therapy (CRT) is a means to enhance myocardial function by stimulating the failing left ventricle at or near the time of right ventricular activation to synchronize ventricular depolarization. Current data from randomized, controlled trials suggest that CRT benefits patients with moderate to severe heart failure and have shown that this therapy significantly reduces mortality and hospital admissions in this group. In addition to CRT, implantable cardioverter-defibrillators have been evaluated in heart failure patients with significantly reduced left ventricular function and have been shown to reduce mortality from sudden cardiac death. This article summarizes recent device trials and discusses how best to apply their results to clinical practice.

Cardiac resynchronization therapy reduces left atrial volume and the risk of atrial tachyarrhythmias in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy).

OBJECTIVES: We hypothesized that reductions in left atrial volume (LAV) with a cardiac resynchronization therapy-defibrillator (CRT-D) would translate into a subsequent reduction in the risk of atrial tachyarrhythmias (AT). BACKGROUND: There is limited information regarding the effect of CRT-D on the risk of AT. METHODS: Percent reduction in LAV at 1 year following CRT-D implantation (pre-specified as low [lowest quartile: <20% reduction in LAV] and high [≥20% reduction in LAV] response to CRT-D) were related to the risk of subsequent AT (comprising atrial fibrillation, atrial flutter, atrial tachycardia, and supraventricular tachyarrhythmias) among patients enrolled in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy). RESULTS: The cumulative probability of AT 2.5 years after assessment of echocardiographic response was lowest among high LAV responders to CRT-D (3%) and significantly higher among both low LAV responders to CRT-D (9%) and implantable cardioverter-defibrillator-only patients (7%; p = 0.03 for the difference among the 3 groups). Consistently, multivariate analysis showed that high LAV responders to CRT-D experienced a significant 53% (p = 0.01) reduction in the risk of subsequent AT as compared with implantable cardioverter-defibrillator-only patients, whereas low LAV responders did not derive a significant risk reduction with CRT-D therapy (hazard ratio [HR]: 1.05 [95% confidence interval (CI): 0.54 to 2.00]; p = 0.89). Patients who developed in-trial AT experienced significant increases in the risk for both the combined endpoint of heart failure or death (HR: 2.28 [95% CI: 1.45 to 3.59]; p < 0.001) and the separate occurrence of all-cause mortality (HR: 1.89 [95% CI: 1.08 to 3.62]; p = 0.01). CONCLUSIONS: In the MADIT-CRT study, favorable reverse remodeling of the left atrium with CRT-D therapy was associated with a significant reduction in risk of subsequent AT. (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271).

Estimation of biogenic emissions with satellite-derived land use and land cover data for air quality modeling of Houston-Galveston ozone nonattainment area.

The Houston-Galveston Area (HGA) is one of the most severe ozone non-attainment regions in the US. To study the effectiveness of controlling anthropogenic emissions to mitigate regional ozone nonattainment problems, it is necessary to utilize adequate datasets describing the environmental conditions that influence the photochemical reactivity of the ambient atmosphere. Compared to the anthropogenic emissions from point and mobile sources, there are large uncertainties in the locations and amounts of biogenic emissions. For regional air quality modeling applications, biogenic emissions are not directly measured but are usually estimated with meteorological data such as photo-synthetically active solar radiation, surface temperature, land type, and vegetation database. In this paper, we characterize these meteorological input parameters and two different land use land cover datasets available for HGA: the conventional biogenic vegetation/land use data and satellite-derived high-resolution land cover data. We describe the procedures used for the estimation of biogenic emissions with the satellite derived land cover data and leaf mass density information. Air quality model simulations were performed using both the original and the new biogenic emissions estimates. The results showed that there were considerable uncertainties in biogenic emissions inputs. Subsequently, ozone predictions were affected up to 10 ppb, but the magnitudes and locations of peak ozone varied each day depending on the upwind or downwind positions of the biogenic emission sources relative to the anthropogenic NOx and VOC sources. Although the assessment had limitations such as heterogeneity in the spatial resolutions, the study highlighted the significance of biogenic emissions uncertainty on air quality predictions. However, the study did not allow extrapolation of the directional changes in air quality corresponding to the changes in LULC because the two datasets were based on vastly different LULC category definitions and uncertainties in the vegetation distributions.