Derivation and validation of predictive indices for 30-day mortality after coronary and valvular surgery in Ontario, Canada.

BACKGROUND: Coronary artery bypass grafting (CABG) and surgical aortic valve replacement (AVR) are the 2 most common cardiac surgery procedures in North America. We derived and externally validated clinical models to estimate the likelihood of death within 30 days of CABG, AVR or combined CABG + AVR. METHODS: We obtained data from the CorHealth Ontario Cardiac Registry and several linked population health administrative databases from Ontario, Canada. We derived multiple logistic regression models from all adult patients who underwent CABG, AVR or combined CABG + AVR from April 2017 to March 2019, and validated them in 2 temporally distinct cohorts (April 2015 to March 2017 and April 2019 to March 2020). RESULTS: The derivation cohorts included 13 435 patients who underwent CABG (30-d mortality 1.73%), 1970 patients who underwent AVR (30-d mortality 1.68%) and 1510 patients who underwent combined CABG + AVR (30-d mortality 3.05%). The final models for predicting 30-day mortality included 15 variables for patients undergoing CABG, 5 variables for patients undergoing AVR and 5 variables for patients undergoing combined CABG + AVR. Model discrimination was excellent for the CABG (c-statistic 0.888, optimism-corrected 0.866) AVR (c-statistic 0.850, optimism-corrected 0.762) and CABG + AVR (c-statistic 0.844, optimism-corrected 0.776) models, with similar results in the validation cohorts. INTERPRETATION: Our models, leveraging readily available, multidimensional data sources, computed accurate risk-adjusted 30-day mortality rates for CABG, AVR and combined CABG + AVR, with discrimination comparable to more complex American and European models. The ability to accurately predict perioperative mortality rates for these procedures will be valuable for quality improvement initiatives across institutions.

Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway.

Elevated concentrations of unconjugated bilirubin (UCB) are responsible for neonatal jaundice and can eventually lead to kernicterus or death. The molecular mechanism of UCB toxicity is incompletely elucidated. The purpose of this study was to analyze changes in gene regulation mediated by UCB to determine novel pathways that contribute to UCB-mediated toxicity. We employed microarray analysis to determine changes in gene regulation mediated by UCB at both pro- (50 microM) and antioxidant (70 nM) concentrations in Hepa 1c1c7 cells at 1 and 6 h. The changes observed in select genes were validated with qPCR. Using immunoblot analysis, we validated these changes at the protein level for select genes and documented the activation of two proteins involved in the endoplasmic reticulum (ER) stress pathway, eIF2 alpha and PERK. Following treatment with 50 microM UCB, microarray analysis revealed the upregulation of many genes involved in ER stress (ATF3, BiP, CHOP, Dnajb1, and Herp). We demonstrate that upregulation of the proapoptotic transcription factor CHOP results in increased intracellular protein content. It was determined that activation of proteins involved in ER stress was an early event in UCB toxicity as eIF2 alpha and PERK were both phosphorylated and activated by 1 h posttreatment. We also demonstrate that procaspase-12 content, a proposed initiator caspase in ER stress-mediated apoptosis, is decreased by 4 h posttreatment. In conclusion, this study demonstrates that elevated concentrations of UCB (50 microM) are able to activate select components of the ER stress pathway in Hepa 1c1c7 cells, which may contribute to UCB-mediated apoptosis.

The Transcatheter Aortic Valve Implantation (TAVI) Quality Report: A Call to Arms for Improving Quality in Canada.

Transcatheter aortic valve implantation (TAVI) is a disruptive technology that has dramatically changed the way clinicians care for patients with aortic stenosis. In 15 short years, this technology has progressed from first-in-human to the standard of care for high-risk and inoperable patients with aortic stenosis. In 2016 the Canadian Cardiovascular Society published the first ever report of quality of care for TAVI in Canada. This report provided multiple insights into evaluating such care delivered to Canadians and the challenges that lie ahead. In this article, we summarize these challenges and encourage cardiologists to join the call to arms for improving quality of TAVI care in Canada.

The Development and Feasibility Assessment of Canadian Quality Indicators for Atrial Fibrillation.

In 2010, the Canadian Cardiovascular Society embarked on an initiative to develop pan-Canadian quality indicators (QIs) and standardized data definitions with the ultimate goal of monitoring, comparing, and contrasting national cardiovascular care and its outcomes. One of the first working groups to be established was tasked with identifying and then defining a set of QIs for atrial fibrillation/flutter (AF/AFL). The Canadian Cardiovascular Society "Best Practices for Developing Cardiovascular Quality Indicators" methodology was used to develop an initial catalogue of 25 QIs intended to measure critical issues around access, process, and outcomes relating to AF/AFL management. This list was subsequently pared down to 5 QIs felt to have the greatest relative importance for quality assurance and measurability so as to facilitate early adoption. Three of these QIs were finally selected to assess the feasibility of their measurement using existing administrative datasets. These were the number of patients with a diagnosis of nonvalvular AF/AFL at high risk of stroke (75 years or older, or CHADS2 ≥ 2) receiving an oral anticoagulant, and the rates of stroke and major haemorrhage in patients with nonvalvular AF/AFL according to CHA2DS2-VASc score and anticoagulant use. Despite their clear importance in assessing AF/AFL care, none of these 3 QIs were found to be readily measurable across Canada using existing national datasets. Investment in new medical data infrastructure is required to facilitate regular monitoring of QIs to improve cardiovascular care.

Quality of Care for Transcatheter Aortic Valve Implantation: Development of Canadian Cardiovascular Society Quality Indicators.

Transcatheter aortic valve implantation (TAVI) is a relatively new procedure to treat aortic stenosis in patients at high surgical risk, and it is becoming increasingly available in Canada. Variation exists in the clinical care, program coordination, evaluation, and funding across provinces and centres. As a part of the Canadian Cardiovascular Society (CCS) quality initiative, the TAVI Quality Indicator (QI) Working Group was established in 2014 to develop a set of indicators to measure quality of care for Canadians undergoing TAVI for aortic stenosis. The TAVI QI Working Group is composed of expert clinical and government agency representatives. The group developed consensus agreements for the selection of the first iteration of measurable structure, process, and outcome indicators reflective of the quality of care for patients undergoing TAVI. The objectives of the project are to develop quality indicators with the eventual goal of standardizing TAVI quality reports across Canada and to support local and national quality assurance, as well as engage multiple stakeholders to build a national strategy for the evaluation of quality of care.

Quality of Care for Percutaneous Coronary Intervention: Development of Canadian Cardiovascular Society Quality Indicators.

Currently there are more than 40 centres in Canada that perform more than 65,000 percutaneous coronary interventions (PCIs) in a year. Considering the high volume of procedures and number of operators, the potential for variation in processes of care is high, and might lead to variation in the quality of care. As part of its quality initiative, the Canadian Cardiovascular Society convened a working group to develop a set of PCI Quality Indicators (QIs) that would be relevant, scientifically acceptable, and feasible to measure and report. The working group was comprised of clinical experts from across Canada and members of provincial and federal organizations involved in promoting the quality of health care. Using the Canadian Cardiovascular Society "Best Practices for Developing Cardiovascular Quality Indicators" methodology, a total of 23 QIs were proposed. Subsequent ranking and discussion led to the selection of 8 QIs. The selection and ranking of QIs were on the basis of clinical importance and relevance, scientific acceptability, and feasibility of their operationalization at a national level. The data definitions and technical notes of the QIs were refined after feasibility testing and Web consultation. Feasibility testing indicated that standardization and enhancements of knowledge infrastructure are essential to provide the comprehensive patient data necessary to evaluate the quality of PCI across Canada.

Pan-Canadian development of cardiac rehabilitation and secondary prevention quality indicators.

The Canadian Cardiovascular Society (CCS) is implementing the Canadian Heart Health Strategy and Action Plan recommendation to build knowledge infrastructure, through its Data Definitions and Quality Indicator (QI) project. The CCS selected cardiac rehabilitation (CR) and secondary prevention as a content area for QI development. In accordance with the CCS QI Best Practice Methodology, rapid reviews of the literature were conducted. A long list of 37 QIs, in the areas of structure, process, and outcome were developed. Through an online survey, 26 (42%) of all contacted external experts rated each QI on importance, scientific acceptability, and feasibility, using a 7-point scale. The overall mean rating was 5.4 ± 1.4. Through a consensus process, the working group excluded 8 QIs based on this feedback, and several others were revised. A 30-day Web consultation was then undertaken, to solicit input from the broader CCS and CR community. A "top 5" list of QIs was requested by the CCS, which were: (1) inpatients referred to CR; (2) wait times from referral to CR enrollment; (3) patient self-management education; (4) increase in exercise capacity; and (5) emergency response strategy. Knowledge translation activities are now under way to promote utilization of the QIs and ultimately improve CR care.

Early steps in bilirubin-mediated apoptosis in murine hepatoma (Hepa 1c1c7) cells are characterized by aryl hydrocarbon receptor-independent oxidative stress and activation of the mitochondrial pathway.

Unconjugated bilirubin (UCB), the end product of heme catabolism, causes apoptosis in cells of the central nervous system, endothelial cells, and hepatotoma cells. However, the molecular mechanisms that contribute to UCB cytotoxicity remain unclear. The purpose of this study was to characterize the sequence of early events leading to UCB-mediated cytotoxicity in murine hepatoma Hepa 1c1c7 cells. In the present study, UCB (5-50 microM) was found to markedly increase the intracellular generation of reactive oxygen species (ROS) in a concentration-dependent manner, which is significantly elevated by 30 min post-treatment. This generation of ROS by UCB is not dependent on aryl hydrocarbon receptor (Ahr) signaling, as cells deficient in the Ahr (C12 cells) or the Ahr nuclear translocator protein (Arnt; C4 cells) were as efficient at generating ROS as wild type (WT) Hepa 1c1c7 cells. Mitochondrial membrane depolarization, evaluated with the lipophilic cationic dye, JC-1, occurred at least by 2 h after treatment with 50 muM UCB. Analysis of the caspase cascade demonstrated that activation of caspase-9 preceded activation of caspase-3. No conversion of procaspase-2 to active caspase-2 was detected in this study. These results demonstrate that UCB-mediated apoptosis in Hepa 1c1c7 cells is associated with increased oxidative stress and that caspase-9, and definitely not caspase-2, is the initiator caspase for apoptosis in UCB-treated Hepa 1c1c7 cells.