Trajectories of P2Y12 inhibitor adherence in patients with acute coronary syndromes.

PURPOSE: P2Y12 inhibitors (P2Y12i) reduce cardiac events after acute coronary syndromes (ACS). However, suboptimal P2Y12i adherence persists. We aimed to examine P2Y12i non-adherence using group-based trajectory methods and to identify adherence predictors. METHODS: We conducted a population-based, retrospective cohort study using administrative data in Ontario, Canada of patients ≥65 years admitted for ACS between April 2014 and March 2018 with a P2Y12i dispensed within 7 days of discharge. We used group-based trajectory models to characterize longitudinal 1-year adherence patterns. Predictors associated with each adherence trajectory were identified by multinomial logistic regression. RESULTS: We included 11 917 patients using clopidogrel and 9763 using ticagrelor, aged [mean ± SD]: 77.33 ± 8.31/73.59 ± 6.79 years; men: 56.2%/65.4%, respectively. We identified 3 longitudinal adherence trajectories, that differed by agent: 75% of clopidogrel and 68% of ticagrelor patients showed a consistently adherent trajectory, while 13%/17% were gradually, and 12%/15% were rapidly non-adherent, respectively (p < 0.001). Differing baseline characteristics in each cohort were associated with observed adherence trajectories. Concomitant atrial fibrillation and prior bleeding history were associated with non-adherence among clopidogrel users. Among ticagrelor users, women and older persons were more likely to be rapidly non-adherent, adherence declining steeply starting 1 month post-ACS. CONCLUSIONS: We identified distinct adherence trajectories for clopidogrel and ticagrelor post-ACS, with 3 out of 4 clopidogrel patients but only 2 out of 3 ticagrelor patients in the consistently adherent trajectory. Intensive interventions targeted to the period of steep adherence decline post-ACS, particularly for women and older persons initiating ticagrelor, and patients with atrial fibrillation on clopidogrel should be considered and investigated further.

Development and Validation of the CANHEART Population-Based Laboratory Prediction Models for Atherosclerotic Cardiovascular Disease.

BACKGROUND: Prediction of atherosclerotic cardiovascular disease (ASCVD) in primary prevention assessments exclusively with laboratory results may facilitate automated risk reporting and improve uptake of preventive therapies. OBJECTIVE: To develop and validate sex-specific prediction models for ASCVD using age and routine laboratory tests and compare their performance with that of the pooled cohort equations (PCEs). DESIGN: Derivation and validation of the CANHEART (Cardiovascular Health in Ambulatory Care Research Team) Lab Models. SETTING: Population-based cohort study in Ontario, Canada. PARTICIPANTS: A derivation and internal validation cohort of adults aged 40 to 75 years without cardiovascular disease from April 2009 to December 2015; an external validation cohort of primary care patients from January 2010 to December 2014. MEASUREMENTS: Age and laboratory predictors measured in the outpatient setting included serum total cholesterol, high-density lipoprotein cholesterol, triglycerides, hemoglobin, mean corpuscular volume, platelets, leukocytes, estimated glomerular filtration rate, and glucose. The ASCVD outcomes were defined as myocardial infarction, stroke, and death from ischemic heart or cerebrovascular disease within 5 years. RESULTS: Sex-specific models were developed and internally validated in 2 160 497 women and 1 833 147 men. They were well calibrated, with relative differences less than 1% between mean predicted and observed risk for both sexes. The c-statistic was 0.77 in women and 0.71 in men. External validation in 31 697 primary care patients showed a relative difference less than 14% and an absolute difference less than 0.3 percentage points in mean predicted and observed risks for both sexes. The c-statistics for the laboratory models were 0.72 for both sexes and were not statistically significantly different from those for the PCEs in women (change in c-statistic, -0.01 [95% CI, -0.03 to 0.01]) or men (change in c-statistic, -0.01 [CI, -0.04 to 0.02]). LIMITATION: Medication use was not available at the population level. CONCLUSION: The CANHEART Lab Models predict ASCVD with similar accuracy to more complex models, such as the PCEs. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

Predicting left main stenosis in stable ischemic heart disease using logistic regression and boosted trees.

BACKGROUND: The ISCHEMIA trial showed similar cardiovascular outcomes of an initial conservative strategy as compared with invasive management in patients with stable ischemic heart disease without left main stenosis. We aim to assess the feasibility of predicting significant left main stenosis using extensive clinical, laboratory and non-invasive tests data. METHODS: All adult patients who had stress testing prior to undergoing an elective coronary angiography for stable ischemic heart disease in Ontario, Canada, between April 2010 and March 2019, were included. Candidate predictors included comprehensive demographics, comorbidities, laboratory tests, and cardiac stress test data. The outcome was stenosis of 50% or greater in the left main coronary artery. A traditional model (logistic regression) and a machine learning algorithm (boosted trees) were used to build prediction models. RESULTS: Among 150,423 patients included (mean age: 64.2 ± 10.6 years; 64.1% males), there were 9,225 (6.1%) with left main stenosis. The final logistic regression model included 24 predictors and 3 interactions, had an optimism-adjusted c-statistic of 0.72 and adequate calibration (optimism-adjusted Integrated Calibration Index 0.0044). These results were consistent in subgroups of males and females, diabetes and non-diabetes, and extent of ischemia. The boosted tree algorithm had similar accuracy, also resulting in a c-statistic of 0.72 and adequate calibration (Integrated Calibration Index 0.0054). CONCLUSIONS: In this large population-based study of patients with stable ischemic heart disease using extensive clinical data, only modest prediction of left main coronary artery disease was possible with traditional and machine learning modelling techniques.

Variation and clinical consequences of wait-times for atrial fibrillation ablation: population level study in Ontario, Canada.

AIMS: Atrial fibrillation (AF) is the most common cardiac rhythm disorder. Emerging evidence supporting the efficacy of catheter ablation in managing AF has led to increased demand for this therapy, potentially outpacing the capacity to perform this procedure. Mismatch between demand and capacity for AF ablation results in wait-times which have not been comprehensively evaluated at a population level. Additionally, the consequences of such delays in AF ablation, namely the risk of hospitalization or adverse events, have not been studied. METHODS AND RESULTS: This observational cohort study included adults referred for catheter ablation to treat AF in Ontario, Canada, between 1 April 2016 and 31 March 2020. Wait-time was defined from referral to the earliest of ablation, death, off-list, or the study endpoint of 31 March 2022. The outcomes of interest included a composite of death, hospitalization for AF/heart failure, and emergency department visit for AF/heart failure. Our study cohort included 6253 patients referred for de novo AF ablation. The median wait-time for patients who received and who did not receive ablation was 218 days (IQR: 112-363) and 520 days (IQR: 270-763), respectively. Wait-time increased consistently for patients referred between October 2017 and March 2020. Mortality was rare, but significant morbidity was observed, affecting 19.2% of patients on the waitlist for AF ablation. Paroxysmal AF was associated with a statistically significant greater risk for adverse outcomes on the waitlist (HR 1.51, 95% CI 1.18-1.93). CONCLUSION: Wait-times for AF ablation are increasing and are associated with significant morbidity.

The Importance of Race and Ethnicity Data in Cardiovascular Health Research.

The COVID-19 pandemic has underscored the importance of addressing race and ethnic disparities in healthcare worldwide. In Canada, however, the lack of consistent capture of race and ethnicity data has hindered a comprehensive understanding of these potential disparities. This article explores the importance of and current progress in collecting race and ethnic data in Canada and provides examples of its importance in cardiovascular health outcomes. We believe that a successful implementation of standardized data collection tools on race and ethnicity data will shape evidence-based policies to minimize health disparities in Canada in the future.

Calibration and discrimination of the Framingham Risk Score and the Pooled Cohort Equations.

BACKGROUND: Although accurate risk prediction is essential in guiding treatment decisions in primary prevention of atherosclerotic cardiovascular disease, the accuracy of the Framingham Risk Score (recommended by a Canadian guideline) and the Pooled Cohort Equations (recommended by US guidelines) has not been assessed in a large contemporary Canadian population. Our primary objective was to assess the calibration and discrimination of the Framingham Risk Score and Pooled Cohort Equations in Ontario, Canada. METHODS: We conducted an observational study involving Ontario residents aged 40 to 79 years, without a history of atherosclerotic cardiovascular disease, who underwent cholesterol testing and blood pressure measurement from Jan. 1, 2010, to Dec. 31, 2014. We compared predicted event rates generated by the Framingham Risk Score and the Pooled Cohort Equations with observed event rates at 5 years using linkages from validated administrative databases. RESULTS: Our study cohort included 84 617 individuals (mean age 56.3 yr, 56.9% female). Over a maximum follow-up period of 5 years, we observed 2162 (2.6%) events according to the outcome definition of the Framingham Risk Score, and 1224 (1.4%) events according to the outcome definition of the Pooled Cohort Equations. The predicted event rate of 5.78% by the Framingham Risk Score and 3.51% by the Pooled Cohort Equations at 5 years overestimated observed event rates by 101% and 115%, respectively. The degree of overestimation differed by age and ethnicity. The C statistics for the Framingham Risk Score (0.74) and Pooled Cohort Equations (0.73) were similar. INTERPRETATION: The Framingham Risk Score and Pooled Cohort Equations significantly overpredicted the actual risks of atherosclerotic cardiovascular disease events in a large population from Ontario. Our finding suggests the need for further refinement of cardiovascular disease risk prediction scores to suit the characteristics of a multiethnic Canadian population.

Association Between Adherence to Fractional Flow Reserve Treatment Thresholds and Major Adverse Cardiac Events in Patients With Coronary Artery Disease.

Importance: Fractional flow reserve (FFR) is an invasive measurement used to assess the potential of a coronary stenosis to induce myocardial ischemia and guide decisions for percutaneous coronary intervention (PCI). It is not known whether established FFR thresholds for PCI are adhered to in routine interventional practice and whether adherence to these thresholds is associated with better clinical outcomes. Objective: To assess the adherence to evidence-based FFR thresholds for PCI and its association with clinical outcomes. Design, Setting, and Participants: A retrospective, multicenter, population-based cohort study of adults with coronary artery disease undergoing single-vessel FFR assessment (excluding ST-segment elevation myocardial infarction) from April 1, 2013, to March 31, 2018, in Ontario, Canada, and followed up until March 31, 2019, was conducted. Two separate cohorts were created based on FFR thresholds (≤0.80 as ischemic and >0.80 as nonischemic). Inverse probability of treatment weighting was used to account for treatment selection bias. Exposures: PCI vs no PCI. Main Outcomes and Measures: The primary outcome was major adverse cardiac events (MACE) defined by death, myocardial infarction, unstable angina, or urgent coronary revascularization. Results: There were 9106 patients (mean [SD] age, 65 [10.6] years; 35.3% female) who underwent single-vessel FFR measurement. Among 2693 patients with an ischemic FFR, 75.3% received PCI and 24.7% were treated only with medical therapy. In the ischemic FFR cohort, PCI was associated with a significantly lower rate and hazard of MACE at 5 years compared with no PCI (31.5% vs 39.1%; hazard ratio, 0.77 [95% CI, 0.63-0.94]). Among 6413 patients with a nonischemic FFR, 12.6% received PCI and 87.4% were treated with medical therapy only. PCI was associated with a significantly higher rate and hazard of MACE at 5 years compared with no PCI (33.3% vs 24.4%; HR, 1.37 [95% CI, 1.14-1.65]) in this cohort. Conclusions and Relevance: Among patients with coronary artery disease who underwent single-vessel FFR measurement in routine clinical practice, performing PCI, compared with not performing PCI, was significantly associated with a lower rate of MACE for ischemic lesions and a higher rate of MACE for nonischemic lesions. These findings support the performance of PCI procedures according to evidence-based FFR thresholds.

Adjunctive laser-stimulated stem-cells therapy to primary reperfusion in acute myocardial infarction in humans: Safety and feasibility study.

BACKGROUND: Low-level laser therapy (LLLT) has photobiostimulatory effects on stem cells and may offer cardioprotection. This cell-based therapy may compliment primary percutaneous coronary intervention (PPCI) in patients with ST-segment elevation myocardial infarction (STEMI). OBJECTIVE: In this randomized control trial, our primary objective was to determine the safety and feasibility of LLLT application to the bone marrow in patients with STEMI undergoing PPCI. METHODS: We randomly assigned patients undergoing PPCI to LLLT or non-laser therapy (NLT). In the LLLT group, 100 s of laser therapy was applied to the tibia bone prior to PPCI, as well as 24 and 72 h post-PPCI. In the control group, the power source was turned off. The primary outcome was the difference in door-to-balloon (D2B) time, and additional outcomes included differences in circulating cell counts, cardiac enzymes, and left-ventricular ejection fraction (LVEF) at pre-specified intervals post-PPCI. RESULTS: Twenty-four patients were randomized to LLLT (N = 12) or NLT (N = 12). No adverse effects of the treatment were detected. The D2B time was not significantly different between the groups (41 ± 8 vs 48 ± 1 min; P = 0.73). Creatinine Phosphokinase area under the curve, was lower after LLLT (22 ± 10) compared to NLT (49 ± 12), but this was not statistically significant (P = 0.08). Troponin-T was significantly lower after LLLT (2.7 ± 1.4 ng/mL) in comparison to NLT (5.2 ± 1.8 ng/mL. P < 0.05). At 9 months, LVEF improved in both groups without a significant difference between LLLT (55 ± 9%) and NLT (52 ± 9%; P = 0.90). CONCLUSION: LLLT is a safe and feasible adjunctive cell-based therapy to PPCI that may benefit ischemic myocardium.

More than meets the eye: False code STEMI.

In patients with suspected ST elevation myocardial infarction, it is of paramount importance to identify artifacts on the resting electrocardiogram that may be erroneously interpreted as ST segment deviations in order to prevent administration of potentially harmful pharmacotherapy and invasive coronary angiography. In this case report, we describe a pervasive square wave artifact, not previously reported, that was misdiagnosed as ST segment elevation by computer software and initial physician interpretation.

Cardiovascular disease in chronic kidney disease in 2015.

PURPOSE OF REVIEW: Chronic kidney disease (CKD) is strongly linked to premature cardiovascular disease, which is the leading cause of death before end-stage renal disease in these patients. Herein, we review recent literature from 2014 to 2015 that has advanced our understanding of cardiovascular outcomes in patients with advanced and/or progressive CKD. RECENT FINDINGS: We focus on new data describing the mechanisms of cardiac death in patients with CKD as well as the novel associations between cardiac events and the competing risks of end-stage renal disease and pre-end-stage renal disease death. We review new controversies in multivessel revascularization of complex coronary artery disease in CKD and, finally, the treatment of systolic heart failure in advanced CKD, including the use of implantable defibrillator therapy. SUMMARY: Marked advances in the understanding of cardiovascular disease in CKD have occurred in the past year, namely from retrospective and registry data. Although exciting, these recent studies highlight the urgent need for randomized control trials to guide therapeutic decisions.

Progression to Stage 4 chronic kidney disease and death, acute kidney injury and hospitalization risk: a retrospective cohort study.

BACKGROUND: Chronic kidney disease (CKD) Stage 4 is on the path to kidney failure, but there is little information on the risks associated with progression to Stage 4 per se. The objective of this study is to determine how progression from Stage 3 to Stage 4 CKD alters morbidity and mortality in a referred cohort of patients. METHODS: We conducted a retrospective cohort study consisting of 1607 patients with estimated glomerular filtration rate (eGFR) of 30-59 mL/min/1.73 m(2) referred to a nephrologist at a tertiary care center in Ontario, Canada, between January 2001 and December 2008. Interim progression from Stage 3 to Stage 4 chronic kidney disease was defined by two independent outpatient eGFR values <30 mL/min/1.73 m(2). Death, acute kidney injury (AKI) and all-cause hospitalizations subsequent to Stage 4 progression, but prior to the development of end-stage renal disease (ESRD), ascertained from administrative databases. RESULTS: The mean (standard deviation) baseline eGFR was 43 (8) mL/min/1.73 m(2). Over 2.66 years (interquartile range: 1.42-4.45), 344 (21%) patients progressed to Stage 4, 47 (3%) developed ESRD, 188 (12%) patients died, 143 (9%) were hospitalized with AKI and 688 (43%) were hospitalized for any reason. Compared with patients who did not progress to Stage 4, those who did progress had significantly higher adjusted risks of death [hazard ratio (HR) = 2.56, 95% confidence interval (95% CI): 1.75-3.75], AKI (HR = 2.32, 95% CI: 1.44-3.74) and all-cause hospitalization (HR = 1.87, 95% CI: 1.45-2.42). CONCLUSIONS: Progression from Stage 3 to Stage 4 CKD is associated with increased risks of death, AKI and hospitalization prior to ESRD.

High-frequency oscillatory ventilation versus conventional ventilation for acute respiratory distress syndrome.

BACKGROUND: High-frequency oscillation (HFO) is an alternative to conventional mechanical ventilation that is sometimes used to treat people with acute respiratory distress syndrome, but effects on oxygenation, mortality and adverse clinical outcomes are uncertain. This review was originally published in 2004 and was updated in 2013 and again in 2015. OBJECTIVES: To determine the effects of HFO compared to conventional mechanical ventilation on physiological outcomes, clinical outcomes, and mortality when used for the treatment of acute respiratory distress syndrome (ARDS). SEARCH METHODS: We electronically searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Ovid), MEDLINE (Ovid), EMBASE (Ovid), and ISI, from inception to December 2015. We conducted the original search in 2002. We manually searched reference lists from included studies and review articles; searched conference proceedings of the American Thoracic Society (1994 to 2015), Society of Critical Care Medicine (1994 to 2015), European Society of Intensive Care Medicine (1994 to 2015), and American College of Chest Physicians (1994 to 2015); contacted clinical experts in the field; and searched for unpublished and ongoing trials in clinicaltrials.gov and controlled-trials.com. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing treatment using HFO with conventional mechanical ventilation for children and adults diagnosed with ARDS. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data on clinical, physiological, and safety outcomes according to a predefined protocol. We contacted investigators of all included studies to clarify methods and obtain additional data. We used random-effects models in the analyses. MAIN RESULTS: We include 10 RCTs (n = 1850); almost all participants had moderate or severe ARDS. For the primary analysis, the risk of bias was low in three studies and unclear in five studies; the overall quality of evidence was very low due to imprecision, inconsistency, indirectness and methodologic limitations. In participants randomized to HFO, there was no significant difference in hospital or 30-day mortality (risk ratio (RR) 0.92, 95% confidence interval (CI) 0.72 to 1.16; P = 0.46, I² = 66%; 8 trials, 1779 participants, 807 deaths) compared with conventional ventilation. One large multicentre RCT was terminated early because of increased mortality in participants randomized to HFO compared to mechanical ventilation with low tidal volume and high positive end expiratory pressure, with HFO reserved only as a rescue therapy. We found substantial between-trial statistical heterogeneity (I² = 0% to 66%) for clinical outcomes, including mortality.  AUTHORS' CONCLUSIONS: The findings of this systematic review suggest that HFO does not reduce hospital and 30-day mortality due to ARDS; the quality of evidence was very low. Our findings do not support the use of HFO as a first-line strategy in people undergoing mechanical ventilation for ARDS.

ESRD and death after heart failure in CKD.

CKD is a risk factor for heart failure, but there is no data on the risk of ESRD and death after recurrent hospitalizations for heart failure. We sought to determine how interim heart failure hospitalizations modify the subsequent risk of ESRD or death before ESRD in patients with CKD. We retrospectively identified 2887 patients with a GFR between 15 and 60 ml/min per 1.73 m2 referred between January of 2001 and December of 2008 to a nephrology clinic in Toronto, Canada. We ascertained interim first, second, and third heart failure hospitalizations as well as ESRD and death before ESRD outcomes from administrative data. Over a median follow-up time of 3.01 (interquartile range=1.56-4.99) years, interim heart failure hospitalizations occurred in 359 (12%) patients, whereas 234 (8%) patients developed ESRD, and 499 (17%) patients died before ESRD. Compared with no heart failure hospitalizations, one, two, or three or more heart failure hospitalizations increased the adjusted hazard ratio of ESRD from 4.89 (95% confidence interval [95% CI], 3.21 to 7.44) to 10.27 (95% CI, 5.54 to 19.04) to 14.16 (95% CI, 8.07 to 24.83), respectively, and the adjusted hazard ratio death before ESRD from 3.30 (95% CI, 2.55 to 4.27) to 4.20 (95% CI, 2.82 to 6.25) to 6.87 (95% CI, 4.96 to 9.51), respectively. We conclude that recurrent interim heart failure is associated with a stepwise increase in the risk of ESRD and death before ESRD in patients with CKD.

Presentation blood glucose and death, hospitalization, and future diabetes risk in patients with acute heart failure syndromes.

PURPOSE: The prognostic implications of blood glucose on a wide range of outcomes including early mortality, hospitalizations, and incident diabetes diagnoses have not been fully elucidated in acute heart failure syndromes (AHFS). METHODS: In a population-based cohort of 16 524 AHFS patients presenting to the emergency department (ED) in Ontario, Canada between 2004 and 2007, we performed a competing risk analysis for 30-day mortality, new diabetes diagnoses, and hospitalization outcomes. Presentation blood glucose concentrations were categorized as follows: 3.9-6.1 [referent], >6.1-7.8, >7.8-9.4, >9.4-11.1, and >11.1 mmol/L. RESULTS: Among AHFS patients without diabetes presenting to the ED (n = 9275), blood glucose >6.1 mmol/L (n = 5252, 56.6%) was associated with increased risks of all-cause death [hazard ratio (HR) range: 1.26 (95% CI 1.05-1.50) to 1.50 (95% CI 1.11-2.02)], and cardiovascular death [HR range: 1.28 (95% CI 1.03-1.59) to 1.64 (95% CI 1.16-2.33)]. Among AHFS patients with diabetes (n = 7249), presenting blood glucose >11.1 mmol/L (n = 2286, 31.5%) was associated with increased risks of all-cause death (HR 1.48, 95% CI 1.10-2.00) and diabetes-related hospitalizations (HR 1.39, 95% CI; 1.20-1.61). Presentation blood glucose >9.4 mmol/L was associated with increased risks of hospitalization for HF or cardiovascular causes [HR range: 1.09 (95% CI 1.02-1.17) to 1.15 (95% CI 1.07-1.24)] in all patients. With higher presentation blood glucose, the risk of incident diabetes diagnosis increased, with adjusted HRs of 1.61 (>6.1-7.8 mmol/L) to 3.61 (>11.1 mmol/L) among those without the condition at baseline (all P < 0.001). CONCLUSIONS: Mildly elevated presentation blood glucose was associated with early death, future diabetes, and hospitalizations for diabetes, HF, and cardiovascular causes among patients with AHFS.

Risk of end-stage renal disease and death after cardiovascular events in chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease stages 3 to 5 (glomerular filtration rate <60 mL/min/1.73m(2)) are at increased risk of cardiovascular (CV) disease when compared with patients with less severe chronic kidney disease. How CV events modify the subsequent risk of progression to end-stage-renal disease (ESRD) or all-cause mortality (ACM) before ESRD is not well known. METHODS AND RESULTS: This retrospective cohort study involved 2964 chronic kidney disease subjects referred between January 2001 and December 2008 to the nephrology clinic at Sunnybrook Health Sciences Center, Toronto, Ontario. Interim CV events (heart failure, myocardial infarction, and stroke), ESRD, and ACM were ascertained from administrative data. Over a median follow-up time of 2.76 years (interquartile range, 1.45-4.62), 447 (15%) subjects had a CV event. In the same time period, 318 (11%) developed ESRD, and 446 (15%) experienced ACM before ESRD (156 [5%] from a CV and 290 [10%] from a non-CV-related cause). When analyzed as a time-dependent variable, an interim CV event was associated with a higher risk of subsequent ESRD (hazard ratio, 5.33; 95% confidence interval, 3.74-7.58) and ACM before ESRD (hazard ratio, 4.15, hazard ratio, 3.30-5.23). The hazard ratio for CV-related death versus non-CV-related death before ESRD was 12.38 (95% confidence interval, 8.30-18.45) versus 2.13 (95% confidence interval, 1.57-2.87). CONCLUSIONS: CV events are common in patients with chronic kidney disease stages 3 to 5 and are associated with a substantial increase in the risk of ESRD and ACM before ESRD. Intensive primary and secondary prevention strategies may help attenuate this risk.

A mechanistic role for DNA methylation in endothelial cell (EC)-enriched gene expression: relationship with DNA replication timing.

Proximal promoter DNA methylation has been shown to be important for regulating gene expression. However, its relative contribution to the cell-specific expression of endothelial cell (EC)-enriched genes has not been defined. We used methyl-DNA immunoprecipitation and bisulfite conversion to analyze the DNA methylation profile of EC-enriched genes in ECs vs nonexpressing cell types, both in vitro and in vivo. We show that prototypic EC-enriched genes exhibit functional differential patterns of DNA methylation in proximal promoter regions of most (eg, CD31, von Willebrand factor [vWF], VE-cadherin, and intercellular adhesion molecule-2), but not all (eg, VEGFR-1 and VEGFR-2), EC-enriched genes. Comparable findings were evident in cultured ECs, human blood origin ECs, and murine aortic ECs. Promoter-reporter episomal transfection assays for endothelial nitric oxide synthase, VE-cadherin, and vWF indicated functional promoter activity in cell types where the native gene was not active. Inhibition of DNA methyltransferase activity indicated important functional relevance. Importantly, profiling DNA replication timing patterns indicated that EC-enriched gene promoters with differentially methylated regions replicate early in S-phase in both expressing and nonexpressing cell types. Collectively, these studies highlight the functional importance of promoter DNA methylation in controlling vascular EC gene expression.

CKD stage at nephrology referral and factors influencing the risks of ESRD and death.

BACKGROUND: Patients with chronic kidney disease (CKD) stages 3-5 are at increased risk of progressing to end-stage renal disease (ESRD) or dying prior to the development of ESRD compared with patients with less severe CKD. The magnitude of these risks may vary by stage, which has important implications for therapy. Our objective was to apply a competing risk analysis in order to estimate these risks in a referred cohort of patients with CKD by stage at referral and identify risk factors associated with each outcome. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 3,273 patients with CKD stages 3-5 who were referred to the nephrology clinic at Sunnybrook Health Sciences Centre, Toronto, prior to December 31, 2008, with follow-up data available prior to December 31,2008. PREDICTORS: CKD stage at time of referral; demographic, laboratory, and clinical characteristics. OUTCOMES: ESRD, defined as the initiation of dialysis therapy or pre-emptive kidney transplantation, and death from any cause prior to ESRD. MEASUREMENTS: Baseline laboratory data. RESULTS: Over a median follow-up of 2.98 years, 459 patients (14%) developed ESRD and 540 (16%) died. Rates per 100 patient-years of ESRD versus death prior to ESRD for CKD stage 3A were 0.6 (95% CI, 0.1-1.0) versus 2.2 (95% CI, 1.2-3.1; P<0.001); for CKD stage 3B, 1.4 (95% CI, 0.8-2.1) versus 4.4 (95% CI, 3.3-5.6; P<0.001); for CKD stage 4, 7.7 (95% CI, 5.9-9.4) versus 8.0 (95% CI, 6.2-9.8; P=0.6); and for CKD stage 5, 41.4 (95% CI, 34.4-48.4) versus 9.4 (95% CI, 5.2-13.4; P<0.001). For those with CKD stage 4, we identified 12 variables associated with higher risk of ESRD and 7 variables associated with higher risk of death prior to ESRD. LIMITATIONS: A cohort analyzed retrospectively. CONCLUSIONS: ESRD and death prior to ESRD incidence was most similar in CKD stage 4. We identified variables easily assessed at the time of referral that could discriminate between these risks.

Effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome: a systematic review and meta-analysis.

BACKGROUND: Mechanical ventilation in the prone position is used to improve oxygenation and to mitigate the harmful effects of mechanical ventilation in patients with acute respiratory distress syndrome (ARDS). We sought to determine the effect of prone positioning on mortality among patients with ARDS receiving protective lung ventilation. METHODS: We searched electronic databases and conference proceedings to identify relevant randomized controlled trials (RCTs) published through August 2013. We included RCTs that compared prone and supine positioning during mechanical ventilation in patients with ARDS. We assessed risk of bias and obtained data on all-cause mortality (determined at hospital discharge or, if unavailable, after longest follow-up period). We used random-effects models for the pooled analyses. RESULTS: We identified 11 RCTs (n=2341) that met our inclusion criteria. In the 6 trials (n=1016) that used a protective ventilation strategy with reduced tidal volumes, prone positioning significantly reduced mortality (risk ratio 0.74, 95% confidence interval 0.59-0.95; I2=29%) compared with supine positioning. The mortality benefit remained in several sensitivity analyses. The overall quality of evidence was high. The risk of bias was low in all of the trials except one, which was small. Statistical heterogeneity was low (I2<50%) for most of the clinical and physiologic outcomes. INTERPRETATION: Our analysis of high-quality evidence showed that use of the prone position during mechanical ventilation improved survival among patients with ARDS who received protective lung ventilation.

Impact of Neighborhood Social Deprivation on Delays to Access for Transcatheter Aortic Valve Replacement: Wait-Times and Clinical Consequences.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has become the standard of care for severe aortic stenosis treatment. Exponential growth in demand has led to prolonged wait times and adverse patient outcomes. Social marginalization may contribute to adverse outcomes. Our objective was to examine the association between different measures of neighborhood-level marginalization and patient outcomes while on the TAVR waiting list. A secondary objective was to understand if sex modifies this relationship. METHODS AND RESULTS: We conducted a population-based retrospective cohort study of 11 077 patients in Ontario, Canada, referred to TAVR from April 1, 2018, to March 31, 2022. Primary outcomes were death or hospitalization while on the TAVR wait-list. Using cause-specific Cox proportional hazards models, we evaluated the relationship between neighborhood-level measures of dependency, residential instability, material deprivation, and ethnic and racial concentration with primary outcomes as well as the interaction with sex. After multivariable adjustment, we found a significant relationship between individuals living in the most ethnically and racially concentrated areas (quintile 4 and 5) and mortality (hazard ratio [HR], 0.64 [95% CI, 0.47-0.88] and HR, 0.73 [95% CI, 0.53-1.00], respectively). There was no significant association between material deprivation, dependency, or residential instability with mortality. Women in the highest ethnic or racial concentration quintiles (4 and 5) had significantly lower risks for mortality (HR values of 0.52 and 0.56, respectively) compared with quintile 1. CONCLUSIONS: Higher neighborhood ethnic or racial concentration was associated with decreased risk for mortality, particular for women on the TAVR waiting list. Further research is needed to understand the drivers of this relationship.