Quantitative Structure Use Relationships: Highlights from a technical summit meeting.

The Quantitative Structure Use Relationship (QSUR) Summit, held on November 2-4, 2022, focused on advancing the development, refinement, and use of QSURs to support chemical substance prioritization and risk assessment and mitigation. QSURs utilize chemical structures to predict the function of a chemical within a formulated product or an industrial process. This presumed function can then be used to develop chemical use categories or other information necessary to refine exposure assessments. The invited expert meeting was attended by 38 scientists from Canada, Finland, France, the UK, and the USA, representing government, business, and academia, with expertise in exposure science, chemical engineering, risk assessment, formulation chemistry, and machine learning. Workshop discussions emphasized the importance of collection and sharing of data and quantification of relative chemical quantities to progress QSUR development. Participants proposed collaborative approaches to address key challenges, including mechanisms for aggregating information while still protecting proprietary product composition and other confidential business information. Discussions also led to proposals for applications beyond exposure and risk modeling, including sustainable formulation discovery. In addition, discussions continue to construct, conduct, and circulate case studies tied to various specific problem formulations in which QSURs supply or derive information on chemical functions, concentrations, and exposures.

Using membrane-water partition coefficients in a critical membrane burden approach to aid the identification of neutral and ionizable chemicals that induce acute toxicity below narcosis levels.

The risk assessment of thousands of chemicals used in our society benefits from adequate grouping of chemicals based on the mode and mechanism of toxic action (MoA). We measure the phospholipid membrane-water distribution ratio (DMLW) using a chromatographic assay (IAM-HPLC) for 121 neutral and ionized organic chemicals and screen other methods to derive DMLW. We use IAM-HPLC based DMLW as a chemical property to distinguish between baseline narcosis and specific MoA, for reported acute toxicity endpoints on two separate sets of chemicals. The first set comprised 94 chemicals of US EPA's acute fish toxicity database: 47 categorized as narcosis MoA, 27 with specific MoA, and 20 predominantly ionic chemicals with mostly unknown MoA. The narcosis MoA chemicals clustered around the median narcosis critical membrane burden (CMBnarc) of 140 mmol kg-1 lipid, with a lower limit of 14 mmol kg-1 lipid, including all chemicals labelled Narcosis_I and Narcosis_II. This maximum 'toxic ratio' (TR) between CMBnarc and the lower limit narcosis endpoint is thus 10. For 23/28 specific MoA chemicals a TR >10 was derived, indicative of a specific adverse effect pathway related to acute toxicity. For 10/12 cations categorized as "unsure amines", the TR <10 suggests that these affect fish via narcosis MoA. The second set comprised 29 herbicides, including 17 dissociated acids, and evaluated the TR for acute toxic effect concentrations to likely sensitive aquatic plant species (green algae and macrophytes Lemna and Myriophyllum), and non-target animal species (invertebrates and fish). For 21/29 herbicides, a TR >10 indicated a specific toxic mode of action other than narcosis for at least one of these aquatic primary producers. Fish and invertebrate TRs were mostly <10, particularly for neutral herbicides, but for acidic herbicides a TR >10 indicated specific adverse effects in non-target animals. The established critical membrane approach to derive the TR provides for useful contribution to the weight of evidence to bin a chemical as having a narcosis MoA or less likely to have acute toxicity caused by a more specific adverse effect pathway. After proper calibration, the chromatographic assay provides consistent and efficient experimental input for both neutral and ionizable chemicals to this approach.

New Approach Methodologies for the Endocrine Activity Toolbox: Environmental Assessment for Fish and Amphibians.

Multiple in vivo test guidelines focusing on the estrogen, androgen, thyroid, and steroidogenesis pathways have been developed and validated for mammals, amphibians, or fish. However, these tests are resource-intensive and often use a large number of laboratory animals. Developing alternatives for in vivo tests is consistent with the replacement, reduction, and refinement principles for animal welfare considerations, which are supported by increasing mandates to move toward an "animal-free" testing paradigm worldwide. New approach methodologies (NAMs) hold great promise to identify molecular, cellular, and tissue changes that can be used to predict effects reliably and more efficiently at the individual level (and potentially on populations) while reducing the number of animals used in (eco)toxicological testing for endocrine disruption. In a collaborative effort, experts from government, academia, and industry met in 2020 to discuss the current challenges of testing for endocrine activity assessment for fish and amphibians. Continuing this cross-sector initiative, our review focuses on the current state of the science regarding the use of NAMs to identify chemical-induced endocrine effects. The present study highlights the challenges of using NAMs for safety assessment and what work is needed to reduce their uncertainties and increase their acceptance in regulatory processes. We have reviewed the current NAMs available for endocrine activity assessment including in silico, in vitro, and eleutheroembryo models. New approach methodologies can be integrated as part of a weight-of-evidence approach for hazard or risk assessment using the adverse outcome pathway framework. The development and utilization of NAMs not only allows for replacement, reduction, and refinement of animal testing but can also provide robust and fit-for-purpose methods to identify chemicals acting via endocrine mechanisms. Environ Toxicol Chem 2023;42:757-777. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Construction of an In Silico Structural Profiling Tool Facilitating Mechanistically Grounded Classification of Aquatic Toxicants.

The performance of chemical safety assessment within the domain of environmental toxicology is often impeded by a shortfall of appropriate experimental data describing potential hazards across the many compounds in regular industrial use. In silico schemes for assigning aquatic-relevant modes or mechanisms of toxic action to substances, based solely on consideration of chemical structure, have seen widespread employment─including those of Verhaar, Russom, and later Bauer (MechoA). Recently, development of a further system was reported by Sapounidou, which, in common with MechoA, seeks to ground its classifications in understanding and appreciation of molecular initiating events. Until now, this Sapounidou scheme has not seen implementation as a tool for practical screening use. Accordingly, the primary purpose of this study was to create such a resource─in the form of a computational workflow. This exercise was facilitated through the formulation of 183 structural alerts/rules describing molecular features associated with narcosis, chemical reactivity, and specific mechanisms of action. Output was subsequently compared relative to that of the three aforementioned alternative systems to identify strengths and shortcomings as regards coverage of chemical space.

A scheme to evaluate structural alerts to predict toxicity - Assessing confidence by characterising uncertainties.

Structure-activity relationships (SARs) in toxicology have enabled the formation of structural rules which, when coded as structural alerts, are essential tools in in silico toxicology. Whilst other in silico methods have approaches for their evaluation, there is no formal process to assess the confidence that may be associated with a structural alert. This investigation proposes twelve criteria to assess the uncertainty associated with structural alerts, allowing for an assessment of confidence. The criteria are based around the stated purpose, description of the chemistry, toxicology and mechanism, performance and coverage, as well as corroborating and supporting evidence of the alert. Alerts can be given a confidence assessment and score, enabling the identification of areas where more information may be beneficial. The scheme to evaluate structural alerts was placed in the context of various use cases for industrial and regulatory applications. The analysis of alerts, and consideration of the evaluation scheme, identifies the different characteristics an alert may have, such as being highly specific or generic. These characteristics may determine when an alert can be used for specific uses such as identification of analogues for read-across or hazard identification.

Right Ventricular Dysfunction and Short-Term Outcomes Following Left-Sided Valvular Surgery: An Echocardiographic Study.

Background The prognostic value of echocardiographic evaluation of right ventricular (RV) function in patients undergoing left-sided valvular surgery has not been well described. The objective of this study is to determine the role of broad echocardiographic assessment of RV function in predicting short-term outcomes after valvular surgery. Methods and Results Preoperative echocardiographic data, perioperative adverse outcomes, and 30-day mortality were analyzed in patients who underwent left-sided valvular surgery from 2006 to 2014. Echocardiographic parameters used to evaluate RV function include RV fractional area change, tricuspid annular plane systolic excursion, systolic movement of the RV lateral wall using tissue Doppler imaging (S'), RV myocardial performance index, and RV dP/dt. Subjects with at least 3 abnormal parameters out of the 5 aforementioned indices were defined as having significant RV dysfunction. The study included 269 patients with valvular surgery (average age: 67±15, 60.6% male, 148 aortic, and 121 mitral). RV dysfunction was found in 53 (19.7%) patients; 30-day mortality occurred in 20 patients (7.5%). Compared with normal RV function, patients with RV dysfunction had higher 30-day mortality (22.6% versus 3.8%; P=0.01) and were at risk for developing multisystem failure/shock (13.2% versus 3.2%; P=0.01). Multivariate analyses showed that preexisting RV dysfunction was the strongest predictor of increased 30-day mortality (odds ratio: 3.5; 95% CI, 1.1-11.1; P<0.05). Conclusions Preoperative RV dysfunction identified by comprehensive echocardiographic assessment is a strong predictor of adverse outcomes following left-sided valvular surgery.

Development of an Enhanced Mechanistically Driven Mode of Action Classification Scheme for Adverse Effects on Environmental Species.

This study developed a novel classification scheme to assign chemicals to a verifiable mechanism of (eco-)toxicological action to allow for grouping, read-across, and in silico model generation. The new classification scheme unifies and extends existing schemes and has, at its heart, direct reference to molecular initiating events (MIEs) promoting adverse outcomes. The scheme is based on three broad domains of toxic action representing nonspecific toxicity (e.g., narcosis), reactive mechanisms (e.g., electrophilicity and free radical action), and specific mechanisms (e.g., associated with enzyme inhibition). The scheme is organized at three further levels of detail beyond broad domains to separate out the mechanistic group, specific mechanism, and the MIEs responsible. The novelty of this approach comes from the reference to taxonomic diversity within the classification, transparency, quality of supporting evidence relating to MIEs, and that it can be updated readily.

Orthopedic Principles to Facilitate Enhanced Recovery After Cardiac Surgery.

Enhanced recovery after surgery (ERAS) protocols recognize early postoperative mobilization as a driver of faster postoperative recovery, return to normal activities, and improved long-term patient outcomes. For patients undergoing open cardiac surgery, an opportunity for facilitating earlier mobilization and a return to normal activity lies in the use of improved techniques to stabilize the sternal osteotomy. By following the key orthopedic principles of approximation, compression, and rigid fixation, a more nuanced approach to sternal precaution protocols is possible, which may enable earlier patient mobilization, physical rehabilitation, and recovery.

An Emergency Medicine-focused Summary of the HFSA/SAEM/ISHLT Clinical Consensus Document on the Emergency Management of Patients With Ventricular Assist Devices.

Mechanical circulatory support is increasingly used as a long-term treatment option for patients with end-stage heart failure. Patients with implanted ventricular assist devices are at high risk for a range of diverse medical urgencies and emergencies. Given the increasing prevalence of mechanical circulatory support devices, this expert clinical consensus document seeks to help inform emergency medicine and prehospital providers regarding the approach to acute medical and surgical conditions encountered in these complex patients.

Mode of Action Classifications in the EnviroTox Database: Development and Implementation of a Consensus MOA Classification.

Multiple mode of action (MOA) frameworks have been developed in aquatic ecotoxicology, mainly based on fish toxicity. These frameworks provide information on a key determinant of chemical toxicity, but the MOA categories and level of specificity remain unique to each of the classification schemes. The present study aimed to develop a consensus MOA assignment within EnviroTox, a curated in vivo aquatic toxicity database, based on the following MOA classification schemes: Verhaar (modified) framework, Assessment Tool for Evaluating Risk, Toxicity Estimation Software Tool, and OASIS. The MOA classifications from each scheme were first collapsed into one of 3 categories: non-specifically acting (i.e., narcosis), specifically acting, or nonclassifiable. Consensus rules were developed based on the degree of concordance among the 4 individual MOA classifications to attribute a consensus MOA to each chemical. A confidence rank was also assigned to the consensus MOA classification based on the degree of consensus. Overall, 40% of the chemicals were classified as narcotics, 17% as specifically acting, and 43% as unclassified. Sixty percent of chemicals had a medium to high consensus MOA assignment. When compared to empirical acute toxicity data, the general trend of specifically acting chemicals being more toxic is clearly observed for both fish and invertebrates but not for algae. EnviroTox is the first approach to establishing a high-level consensus across 4 computationally and structurally distinct MOA classification schemes. This consensus MOA classification provides both a transparent understanding of the variation between MOA classification schemes and an added certainty of the MOA assignment. In terms of regulatory relevance, a reliable understanding of MOA can provide information that can be useful for the prioritization (ranking) and risk assessment of chemicals. Environ Toxicol Chem 2019;38:2294-2304. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

HFSA/SAEM/ISHLT clinical expert consensus document on the emergency management of patients with ventricular assist devices.

Mechanical circulatory support is now widely accepted as a viable long-term treatment option for patients with end-stage heart failure (HF). As the range of indications for the implantation of ventricular assist devices grows, so does the number of patients living in the community with durable support. Because of their underlying disease and comorbidities, in addition to the presence of mechanical support, these patients are at a high risk for medical urgencies and emergencies (Table 1). Thus, it is the responsibility of clinicians to understand the basics of their emergency care. This consensus document represents a collaborative effort by the Heart Failure Society of America, the Society for Academic Emergency Medicine, and the International Society for Heart and Lung Transplantation (ISHLT) to educate practicing clinicians about the emergency management of patients with ventricular assist devices. The target audience includes HF specialists and emergency medicine physicians, as well as general cardiologists and community-based providers.

HFSA/SAEM/ISHLT Clinical Expert Consensus Document on the Emergency Management of Patients with Ventricular Assist Devices.

Mechanical circulatory support is now widely accepted as a viable long-term treatment option for patients with end-stage heart failure (HF). As the range of indications for the implantation of ventricular assist devices grows, so does the number of patients living in the community with durable support. Because of their underlying disease and comorbidities, in addition to the presence of mechanical support, these patients are at a high risk for medical urgencies and emergencies (Table 1). Thus, it is the responsibility of clinicians to understand the basics of their emergency care. This consensus document represents a collaborative effort by the Heart Failure Society of America, the Society for Academic Emergency Medicine, and the International Society for Heart and Lung Transplantation (ISHLT) to educate practicing clinicians about the emergency management of patients with ventricular assist devices. The target audience includes HF specialists and emergency medicine physicians, as well as general cardiologists and community-based providers.

Creation of a Curated Aquatic Toxicology Database: EnviroTox.

Flexible, rapid, and predictive approaches that do not require the use of large numbers of vertebrate test animals are needed because the chemical universe remains largely untested for potential hazards. Development of robust new approach methodologies and nontesting approaches requires the use of existing information via curated, integrated data sets. The ecological threshold of toxicological concern (ecoTTC) represents one such new approach methodology that can predict a conservative de minimis toxicity value for chemicals with little or no information available. For the creation of an ecoTTC tool, a large, diverse environmental data set was developed from multiple sources, with harmonization, characterization, and information quality assessment steps to ensure that the information could be effectively organized and mined. The resulting EnviroTox database contains 91 217 aquatic toxicity records representing 1563 species and 4016 unique Chemical Abstracts Service numbers and is a robust, curated database containing high-quality aquatic toxicity studies that are traceable to the original information source. Chemical-specific information is also linked to each record and includes physico-chemical information, chemical descriptors, and mode of action classifications. Toxicity data are associated with the physico-chemical data, mode of action classifications, and curated taxonomic information for the organisms tested. The EnviroTox platform also includes 3 analysis tools: a predicted-no-effect concentration calculator, an ecoTTC distribution tool, and a chemical toxicity distribution tool. Although the EnviroTox database and tools were originally developed to support ecoTTC analysis and development, they have broader applicability to the field of ecological risk assessment. Environ Toxicol Chem 2019;9999:1-12. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

Sternotomy closure using rigid plate fixation: a paradigm shift from wire cerclage.

BACKGROUND: Rigid plate fixation (RPF) is the cornerstone in managing fractures and osteotomies except for sternotomy, where most cardiac surgeons continue to use wire cerclage (WC). Results of a multicenter randomized trial evaluating sternal healing, sternal complications, patient reported outcome measures (PROMs), and costs after sternotomy closure with RPF or WC are summarized here. METHODS: Twelve US centers randomized 236 patients to either RPF (n=116) or WC (n=120). The primary endpoint, sternal healing at 6 months, was evaluated by a core laboratory using computed tomography and a validated 6-point scale (greater scores represent greater healing). Secondary endpoints assessed through 6 months included sternal complications and PROMs. Costs from the time of sternal closure through 90 days and 6 months were analyzed by a health economic core laboratory. RESULTS: RPF compared to WC resulted in better sternal healing scores at 3 (2.6±1.1 vs. 1.8±1.0; P<0.0001) and 6 months (3.8±1.0 vs. 3.3±1.1; P=0.0007) and higher sternal union rates at 3 [41% (42/103) vs. 16% (16/102); P<0.0001] and 6 months [80% (81/101) vs. 67% (67/100); P=0.03]. There were fewer sternal complications with RPF through 6 months [0% (0/116) vs. 5% (6/120); P=0.03] and a trend towards fewer sternal wound infections [0% (0/116) vs. 4.2% (5/120); P=0.06]. All PROMs including sternal pain, upper extremity function (UEF), and quality-of-life scores were numerically better in RPF patients compared to WC patients at all follow-up time points. Although RPF was associated with a trend toward higher index hospitalization costs, a trend towards lower follow-up costs resulted in total costs that were $1,888 less at 90 days in RPF patients compared to WC patients (95% CI: -$8,889 to $4,273; P=0.52) and $1,646 less at 6 months (95% CI: -$9,127 to $4,706; P=0.61). CONCLUSIONS: Sternotomy closure with RPF resulted in significantly better sternal healing, fewer sternal complications, improved PROMs and was cost neutral through 90 days and 6 months compared to WC.

Pre-operative right ventricular echocardiographic parameters associated with short-term outcomes and long-term mortality after CABG.

Background This analysis aims to assess the prognostic value of pre-operative right ventricular echocardiographic parameters in predicting short-term adverse outcomes and long-term mortality after coronary artery bypass graft (CABG). Methods Study design: Observational retrospective cohort. Pre-operative echocardiographic data, perioperative adverse outcomes (POAO) and long-term mortality were retrospectively analyzed in 491 patients who underwent isolated CABG at a single academic center between 2006 and 2014. Results Average age of enrolled subjects was 66 ± 11.5 years with majority being male (69%). 227/491 patients had 30 days POAO (46%); most common being post-operative atrial fibrillation (27.3%) followed by prolonged ventilation duration (12.7%). On multivariate analysis, left atrial volume index ≥42 mL/m2 (LAVI) (OR (95% CI): 1.98 (1.03-3.82), P = 0.04), mitral E/A >2 (1.97 (1.02-3.78), P = 0.04), right atrial size >18 cm2 (1.86 (1.14-3.05), P = 0.01), tricuspid annular plane systolic excursion (TAPSE) <16 mm (1.8 (1.03-3.17), P = 0.04), right ventricular systolic pressure (RVSP) ≥36 mmHg (pulmonary hypertension) (1.6 (1.03-2.38), P = 0.04) and right ventricle myocardial performance index (RVMPI) >0.55 (1.58 (1.01-2.46), P = 0.04) were found to be associated with increased 30-day POAO. On 3.5-year follow-up, cumulative survival was decreased in patients with myocardial performance index (MPI) ≥0.55 (log rank: 4.5, P = 0.034) and in patients with mitral valve E/e' ≥14 (log rank: 4.9, P = 0.026). Conclusion Pre-operative right ventricle dysfunction (RVD) is associated with increased perioperative complications. Furthermore, pre-operative RVD and increased left atrial pressures are associated with long-term mortality post CABG.

The Incremental Value of Three or More Arterial Grafts in CABG: The Effect of Native Vessel Disease.

BACKGROUND: We investigated whether extended arterial grafting with three or more arterial grafts in patients with a left internal thoracic artery to left anterior descending artery graft improves survival in coronary artery bypass graft surgery patients and whether its effects will depend on the extent of coronary artery disease; specifically three-vessel disease (3VD) versus two-vessel disease (2VD). METHODS: Fifteen-year mortality was analyzed in 11,931 patients with multivessel disease and primary isolated left internal thoracic artery to left anterior descending artery coronary artery bypass graft surgery with 2 or more grafts. Patients were aged 64.3 ± 10.5 years; 3,484 (29.2%) were women; 2,532 (21.2%) had 2VD and 9,399 (78.8%) had 3VD. Patients were grouped into one single-artery group (n = 6,782, 56.9%; reference group), and two multiple artery groups: two arteries (n = 3,678, 30.8%) and three arteries (n = 1,471, 12.3%). Long-term survival was compared by Kaplan-Meier estimates. Risk-adjusted mortality hazard ratio (HR) with 95% confidence interval (CI) were derived by covariate adjusted Cox regression to quantify multiple artery effects versus one artery in the overall cohort and separately among patients with 2VD and 3VD. RESULTS: Radial artery (94%) and right internal thoracic artery (6%) conduits were used for additional arterial grafts. For the entire multivessel cohort, increasing number of arterial grafts was associated with incrementally improved 15-year survival (two arteries HR 0.85, 95% CI: 0.78 to 0.92; three arteries HR 0.75, 95% CI: 0.65 to 0.85). The three arteries versus two arteries comparison was consistent, even if not significant (HR 0.89, 95% CI: 0.77 to 1.03). The benefits derived from additional arterial grafts were more pronounced in case of 3VD (two arteries HR 0.84 95% CI: 0.76 to 0.92; three arteries HR 0.73, 95% CI: 0.63 to 0.84), without survival benefit with 2VD. CONCLUSIONS: Our results support the use of extended arterial grafting to maximize long-term coronary artery bypass graft surgery patient survival, especially for 3VD patients.

The effect of completeness of revascularization during CABG with single versus multiple arterial grafts.

INTRODUCTION: Incomplete coronary revascularization is associated with suboptimal outcomes. We investigated the long-term effects of Incomplete, Complete, and Supra-complete revascularization and whether these effects differed in the setting of single-arterial and multi-arterial coronary artery bypass graft (CABG). METHODS: We analyzed 15-year mortality in 7157 CABG patients (64.1 ± 10.5 years; 30% women). All patients received a left internal thoracic artery to left anterior descending coronary artery graft with additional venous grafts only (single-arterial) or with at least one additional arterial graft (multi-arterial) and were grouped based on a completeness of revascularization index (CRI = number of grafts minus the number of diseased principal coronary arteries): Incomplete (CRI ≤ -1 [N = 320;4.5%]); Complete (CRI = 0 [N = 2882;40.3%]; reference group); and two Supra-complete categories (CRI = +1[N = 3050; 42.6%]; CRI ≥ + 2 [N = 905; 12.6%]). Risk-adjusted mortality hazard ratios (AHR) were calculated using comprehensive propensity score adjustment by Cox regression. RESULTS: Incomplete revascularization was rare (4.5%) but associated with increased mortality in all patients (AHR [95% confidence interval] = 1.53 [1.29-1.80]), those undergoing single-arterial CABG (AHR = 1.27 [1.04-1.54]) and multi-arterial CABG (AHR = 2.18 [1.60-2.99]), as well as in patients with 3-Vessel (AHR = 1.37 [1.16-1.62]) and, to a lesser degree, with 2-Vessel (AHR = 1.67 [0.53-5.23]) coronary disease. Supra-complete revascularization was generally associated with incrementally decreased mortality in all patients (AHR [CRI = +1] = 0.94 [0.87-1.03]); AHR [CRI ≥ +2] = 0.74 [0.64-0.85]), and was driven by a significantly decreased mortality risk in single-arterial CABG (AHR [CRI = +1] = 0.90 [0.81-0.99]; AHR [CRI ≥ +2] = 0.64 [0.53-0.78]); and 3-Vessel disease patients (AHR [CRI = +1] = 0.94 [0.86-1.04]; and AHR [CRI ≥ +2] = 0.75 [0.63-0.88]) with no impact in multi-arterial CABG (AHR [CRI = +1] = 1.07 [0.91-1.26]; AHR [CRI ≥ +2] = 0.93 [0.73-1.17]). CONCLUSIONS: Incomplete revascularization is associated with decreased late survival, irrespective of grafting strategy. Alternatively, supra-complete revascularization is associated with improved survival in patients with 3-Vessel CAD, and in single-arterial but not multi-arterial CABG.

Evidence and temporality of the obesity paradox in coronary bypass surgery: an analysis of cause-specific mortality.

OBJECTIVES: We evaluated the presence of an 'obesity paradox' in coronary artery bypass grafting (CABG) patients, determined its time course and ascertained whether it is associated with improved cardiovascular (CV) survival versus non-CV survival. METHODS: A retrospective analysis of 3 prospectively collected databases was conducted. A fifteen-year Kaplan-Meier analysis in 7091 CABG patients was performed and repeated in 5 body mass index [BMI (kg/m2)] cohorts [Normal (18.5-24.99 kg/m2), Overweight (25-29.99 kg/m2), Obese I (30-34.99 kg/m2), Obese II (35-39.99 kg/m2) and Obese III (≥40 kg/m2)]. Mortality hazard ratios {HR [95% confidence interval (CI)]} were derived using comprehensive multivariable competing risk Cox regression, accounting for BMI categories for overall (0-15), Early (0-1), Intermediate (1-8) and Late (8-15) postoperative years, to relax the proportional hazards assumption. The regression was repeated using BMI as a continuous variable. Mortality was classified into any, CV and non-CV. RESULTS: Obese patients were younger with more comorbidities. Fifteen-year survival was improved in the Overweight and Obese I groups (P < 0.001). Adjusted 15-year mortality was reduced in the Overweight [HR (95% CI) = 0.88 (0.79-0.98)] and Obese I [HR = 0.88 (0.78-0.99)] groups driven by improved CV and non-CV survival. This trend was noted in the early (Overweight) and intermediate postoperative periods (Overweight and Obese I) with no significance in the late period. Higher mortality in the Obese III [HR = 1.28 (1.06-1.55)] group was driven by a decreased CV survival. Using BMI as a continuous variable, a BMI of 29 kg/m2 was associated with optimal survival. CONCLUSIONS: We identified a protective partial obesity paradox in the early and intermediate postoperative periods among Overweight and mildly obese (Obese I) patients with improved CV and non-CV survival. The morbidly obese (the Obese III group) had higher early and late CV mortality.

Effectiveness of radial artery-based multiarterial coronary artery bypass grafting: Role of body habitus.

BACKGROUND: The multiarterial grafting survival advantage noted in the overall population undergoing coronary artery bypass grafting is not well defined in the obese. We investigated the early to late survival effects of the radial artery in left internal thoracic artery-based multiarterial bypass grafting (radial artery-multiarterial bypass grafting) versus single arterial bypass grafting (left internal thoracic artery-single arterial bypass grafting) in obese patients. METHODS: We analyzed 15-year Kaplan-Meier survival in 6102 patients receiving primary, left internal thoracic artery-based coronary artery bypass grafting with 2 or more grafts divided into body mass index groups: nonobese (<30 kg/m2) and all-obese, comprised of mildly obese (30-35 kg/m2) and morbidly obese (>35 kg/m2). Risk-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of radial artery-multiarterial bypass grafting versus left internal thoracic artery-single arterial bypass grafting were derived via Cox regression and applied separately for early (<0.5 years), intermediate (0.5-5 years), and late (5-15 years) follow-up in each body mass index cohort. Propensity score matching between radial artery-multiarterial bypass grafting and left internal thoracic artery-single arterial bypass grafting cohorts within the body mass index groups was performed as a corroborating analysis. RESULTS: Radial artery-multiarterial bypass grafting was more frequently used in obese patients who were younger (62 ± 10 years; mild/morbid: 45.4%/54.4% radial artery-multiarterial bypass grafting) compared with nonobese patients (66 ± 10 years; 37.4% radial artery-multiarterial bypass grafting). Unadjusted 15-year survival was significantly better for radial artery-multiarterial bypass grafting in all body mass index groups. Multivariate analysis showed a survival benefit of radial artery-multiarterial bypass grafting over the entire 0- to 15-year study period in the all-obese cohort (HR, 0.85; 95% CI, 0.74-0.98) and was more pronounced in the mildly obese (HR, 0.79; 95% CI, 0.66-0.96) versus morbidly obese (HR, 0.88; 95% CI, 0.69-1.13). The radial artery-multiarterial bypass grafting survival benefit was realized between 0.5 and 5 years postoperatively and was comparable for all-obese (HR, 0.69; 95% CI, 0.51-0.94) and nonobese (HR, 0.68; 95% CI, 0.52-0.88) groups. Propensity score matching was confirmatory. CONCLUSIONS: Radial artery-multiarterial bypass grafting confers a long-term survival advantage in both obese and nonobese patients.

Effect of new-onset atrial fibrillation on cause-specific late mortality after coronary artery bypass grafting surgery.

OBJECTIVES: Postoperative atrial fibrillation (POAF) is a common complication after coronary artery bypass grafting. Although transient, POAF is linked to increased late mortality. We hypothesized that POAF increases late cerebrovascular (CeV) and composite cerebrovascular/cardiovascular/vascular (CV* = CeV + CV + Other-V) but not non-cardiovascular (Non-CV) mortality. METHODS: We analysed 8807 non-salvage coronary artery bypass grafting patients (1994-2011). Fifteen-year and time-segmented (early, 0-1 year; intermediate, 1-6 years and late, 6-15 years) all-cause and cause-specific mortality were compared for POAF versus No-POAF patients. Corresponding POAF versus No-POAF adjusted hazard ratios [AHRs (95% confidence interval, CI)] were derived using the competing risk Cox regression. RESULTS: POAF occurred in 1992 (23%) patients. Complications other than POAF occurred in 1875 (21%) patients but were more frequent among POAF patients (31% vs 18%; P < 0.001). Overall mean follow-up was 9 ± 4 years. POAF patients had a higher 15-year unadjusted mortality (53% vs 39%; P < 0.001) and were consequently associated with higher adjusted all-cause [AHR (95% CI) = 1.23 (1.14-1.33)] and composite cardiovascular [CV*: AHR (95% CI) = 1.15 (1.02-1.30)] mortality. The trends towards a higher 15-year CeV [AHR (95% CI) = 1.34 (0.94-1.91)] and Non-CV [AHR (95% CI) = 1.12 (0.99-1.26)] mortality were not significant. Time-segmented analyses showed that (i) POAF increased all-cause mortality early, and this persisted in the intermediate and late periods and (ii) CeV [AHR (95% CI) = 2.14 (1.14-4.04)] and CV* [AHR (95% CI) = 1.31 (1.06-1.62)] mortality rates were increased in the intermediate but not in the early or late periods. Non-CV mortality was similar in POAF and No-POAF for all time intervals. These findings were corroborated in propensity-matched sub-cohorts and in sensitivity analyses in patients free of any other complication. CONCLUSIONS: POAF is associated with worse long-term survival principally driven by increased intermediate-term cerebrovascular and cardiovascular mortality, while Non-CV mortality was similar.