Effects of routine early treatment with PCSK9 inhibitors in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: a randomised, double-blind, sham-controlled trial.

BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI), early initiation of high-intensity statin therapy, regardless of low-density lipoprotein (LDL) cholesterol levels, is the standard of practice worldwide.  Aims: We sought to determine the effect of a similar early initiation strategy, using a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor added to the high-intensity statin, on LDL cholesterol in acute STEMI. METHODS: In a randomised, double-blind trial we assigned 68 patients with STEMI undergoing primary percutaneous coronary intervention (PCI) to early treatment with alirocumab 150 mg subcutaneously or to a matching sham control. The first injection was given before primary PCI regardless of the baseline LDL level, then at 2 and 4 weeks. The primary outcome was the percent reduction in direct LDL cholesterol up to 6 weeks, analysed using a linear mixed model.   Results: High-intensity statin use was 97% and 100% in the alirocumab and sham-control groups, respectively. At a median of 45 days, the primary outcome of LDL cholesterol decreased by 72.9% with alirocumab (2.97 mmol/L to 0.75 mmol/L) versus 48.1% with the sham control (2.87 mmol/L to 1.30 mmol/L), for a mean between-group difference of -22.3% (p<0.001). More patients achieved the European Society of Cardiology/European Atherosclerosis Society dyslipidaemia guideline target of LDL ≤1.4 mmol/L in the alirocumab group (92.1% vs 56.7%; p<0.001). Within the first 24 hours, LDL declined slightly more rapidly in the alirocumab group than in the sham-control group (-0.01 mmol/L/hour; p=0.03) with similar between-group mean values.  Conclusions: In this randomised trial of routine early initiation of PCSK9 inhibitors in patients undergoing primary PCI for STEMI, alirocumab reduced LDL cholesterol by 22% compared with sham control on a background of high-intensity statin therapy. A large trial is needed to determine if this simplified approach followed by long-term therapy improves cardiovascular outcomes in patients with acute STEMI. (ClinicalTrials.gov: NCT03718286).

High-Sensitivity Troponin I after Cardiac Surgery and 30-Day Mortality.

BACKGROUND: Consensus recommendations regarding the threshold levels of cardiac troponin elevations for the definition of perioperative myocardial infarction and clinically important periprocedural myocardial injury in patients undergoing cardiac surgery range widely (from >10 times to ≥70 times the upper reference limit for the assay). Limited evidence is available to support these recommendations. METHODS: We undertook an international prospective cohort study involving patients 18 years of age or older who underwent cardiac surgery. High-sensitivity cardiac troponin I measurements (upper reference limit, 26 ng per liter) were obtained 3 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We performed Cox analyses using a regression spline that explored the relationship between peak troponin measurements and 30-day mortality, adjusting for scores on the European System for Cardiac Operative Risk Evaluation II (which estimates the risk of death after cardiac surgery on the basis of 18 variables, including age and sex). RESULTS: Of 13,862 patients included in the study, 296 (2.1%) died within 30 days after surgery. Among patients who underwent isolated coronary-artery bypass grafting or aortic-valve replacement or repair, the threshold troponin level, measured within 1 day after surgery, that was associated with an adjusted hazard ratio of more than 1.00 for death within 30 days was 5670 ng per liter (95% confidence interval [CI], 1045 to 8260), a level 218 times the upper reference limit. Among patients who underwent other cardiac surgery, the corresponding threshold troponin level was 12,981 ng per liter (95% CI, 2673 to 16,591), a level 499 times the upper reference limit. CONCLUSIONS: The levels of high-sensitivity troponin I after cardiac surgery that were associated with an increased risk of death within 30 days were substantially higher than levels currently recommended to define clinically important periprocedural myocardial injury. (Funded by the Canadian Institutes of Health Research and others; VISION Cardiac Surgery ClinicalTrials.gov number, NCT01842568.).

Novel Biomarkers for Change in Renal Function in People With Dysglycemia.

OBJECTIVE: Diabetes is a major risk factor for renal function decline and failure. The availability of multiplex panels of biochemical markers provides the opportunity to identify novel biomarkers that can better predict changes in renal function than routinely available clinical markers. RESEARCH DESIGN AND METHODS: The concentration of 239 biochemical markers was measured in stored serum from participants in the biomarker substudy of Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial. Repeated-measures mixed-effects models were used to compute the annual change in eGFR (measured as mL/min/1.73 m2/year) for the 7,482 participants with a recorded baseline and follow-up eGFR. Linear regression models using forward selection were used to identify the independent biomarker determinants of the annual change in eGFR after accounting for baseline HbA1c, baseline eGFR, and routinely measured clinical risk factors. The incidence of the composite renal outcome (i.e., renal replacement therapy, renal death, renal failure, albuminuria progression, doubling of serum creatinine) and death within each fourth of change in eGFR predicted from these models was also estimated. RESULTS: During 6.2 years of median follow-up, the median annual change in eGFR was -0.18 mL/min/1.73 m2/year. Fifteen biomarkers independently predicted eGFR decline after accounting for cardiovascular risk factors, as did 12 of these plus 1 additional biomarker after accounting for renal risk factors. Every 0.1 mL/min/1.73 m2 predicted annual fall in eGFR predicted a 13% (95% CI 12, 14%) higher mortality. CONCLUSIONS: Adding up to 16 biomarkers to routinely measured clinical risk factors improves the prediction of annual change in eGFR in people with dysglycemia.

Joint association of urinary sodium and potassium excretion with cardiovascular events and mortality: prospective cohort study.

OBJECTIVE: To evaluate the joint association of sodium and potassium urinary excretion (as surrogate measures of intake) with cardiovascular events and mortality, in the context of current World Health Organization recommendations for daily intake (<2.0 g sodium, >3.5 g potassium) in adults. DESIGN: International prospective cohort study. SETTING: 18 high, middle, and low income countries, sampled from urban and rural communities. PARTICIPANTS: 103 570 people who provided morning fasting urine samples. MAIN OUTCOME MEASURES: Association of estimated 24 hour urinary sodium and potassium excretion (surrogates for intake) with all cause mortality and major cardiovascular events, using multivariable Cox regression. A six category variable for joint sodium and potassium was generated: sodium excretion (low (<3 g/day), moderate (3-5 g/day), and high (>5 g/day) sodium intakes) by potassium excretion (greater/equal or less than median 2.1 g/day). RESULTS: Mean estimated sodium and potassium urinary excretion were 4.93 g/day and 2.12 g/day, respectively. After a median follow-up of 8.2 years, 7884 (6.1%) participants had died or experienced a major cardiovascular event. Increasing urinary sodium excretion was positively associated with increasing potassium excretion (unadjusted r=0.34), and only 0.002% had a concomitant urinary excretion of <2.0 g/day of sodium and >3.5 g/day of potassium. A J-shaped association was observed of sodium excretion and inverse association of potassium excretion with death and cardiovascular events. For joint sodium and potassium excretion categories, the lowest risk of death and cardiovascular events occurred in the group with moderate sodium excretion (3-5 g/day) and higher potassium excretion (21.9% of cohort). Compared with this reference group, the combinations of low potassium with low sodium excretion (hazard ratio 1.23, 1.11 to 1.37; 7.4% of cohort) and low potassium with high sodium excretion (1.21, 1.11 to 1.32; 13.8% of cohort) were associated with the highest risk, followed by low sodium excretion (1.19, 1.02 to 1.38; 3.3% of cohort) and high sodium excretion (1.10, 1.02 to 1.18; 29.6% of cohort) among those with potassium excretion greater than the median. Higher potassium excretion attenuated the increased cardiovascular risk associated with high sodium excretion (P for interaction=0.007). CONCLUSIONS: These findings suggest that the simultaneous target of low sodium intake (<2 g/day) with high potassium intake (>3.5 g/day) is extremely uncommon. Combined moderate sodium intake (3-5 g/day) with high potassium intake is associated with the lowest risk of mortality and cardiovascular events.

Joint association of urinary sodium and potassium excretion with cardiovascular events and mortality: prospective cohort study

PARTICIPANTS: 103 570 people who provided morning fasting urine samples. MAIN OUTCOME MEASURES: Association of estimated 24 hour urinary sodium and potassium excretion (surrogates for intake) with all cause mortality and major cardiovascular events, using multivariable Cox regression. A six category variable for joint sodium and potassium was generated: sodium excretion (low (<3 g/day), moderate (3-5 g/day), and high (>5 g/day) sodium intakes) by potassium excretion (greater/equal or less than median 2.1 g/day). RESULTS: OBJECTIVE: To evaluate the joint association of sodium and potassium urinary excretion (as surrogate measures of intake) with cardiovascular events and mortality, in the context of current World Health Organization recommendations for daily intake (<2.0 g sodium, >3.5 g potassium) in adults. DESIGN: International prospective cohort study. SETTING: 18 high, middle, and low income countries, sampled from urban and rural communities. ARTICIPANTS: 103 570 people who provided morning fasting urine samples. MAIN OUTCOME MEASURES: Association of estimated 24 hour urinary sodium and potassium excretion (surrogates for intake) with all cause mortality and major cardiovascular events, using multivariable Cox regression. A six category variable for joint sodium and potassium was generated: sodium excretion (low (<3 g/day), moderate (3-5 g/day), and high (>5 g/day) sodium intakes) by potassium excretion (greater/equal or less than median 2.1 g/day). RESULTS: Mean estimated sodium and potassium urinary excretion were 4.93 g/day and 2.12 g/day, respectively. After a median follow-up of 8.2 years, 7884 (6.1%) participants had died or experienced a major cardiovascular event. Increasing urinary sodium excretion was positively associated with increasing potassium excretion (unadjusted r=0.34), and only 0.002% had a concomitant urinary excretion of <2.0 g/day of sodium and >3.5 g/day of potassium. A J-shaped association was observed of sodium excretion and inverse association of potassium excretion with death and cardiovascular events. For joint sodium and potassium excretion categories, the lowest risk of death and cardiovascular events occurred in the group with moderate sodium excretion (3-5 g/day) and higher potassium excretion (21.9% of cohort). Compared with this reference group, the combinations of low potassium with low sodium excretion (hazard ratio 1.23, 1.11 to 1.37; 7.4% of cohort) and low potassium with high sodium excretion (1.21, 1.11 to 1.32; 13.8% of cohort) were associated with the highest risk, followed by low sodium excretion (1.19, 1.02 to 1.38; 3.3% of cohort) and high sodium excretion (1.10, 1.02 to 1.18; 29.6% of cohort) among those with potassium excretion greater than the median. Higher potassium excretion attenuated the increased cardiovascular risk associated with high sodium excretion (P for interaction=0.007). CONCLUSIONS: These findings suggest that the simultaneous target of low sodium intake (<2 g/day) with high potassium intake (>3.5 g/day) is extremely uncommon. Combined moderate sodium intake (3-5 g/day) with high potassium intake is associated with the lowest risk of mortality and cardiovascular events. (AU)

A Mendelian Randomization-Based Approach to Identify Early and Sensitive Diagnostic Biomarkers of Disease.

BACKGROUND: Identifying markers of chronic kidney disease (CKD) that occur early in the disease process and are specific to loss of kidney function rather than other underlying causes of disease may allow earlier, more accurate identification of patients who will develop CKD. We therefore sought to identify diagnostic blood markers of early CKD that are caused by loss of kidney function by using an innovative "reverse Mendelian randomization" (MR) approach. METHODS: We applied this technique to genetic and biomarker data from 4147 participants in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, all with known type 2 diabetes, impaired fasting glucose, or impaired glucose tolerance. Two-sample MR was conducted using variants associated with creatinine-based eGFR (eGFRcrea) from the CKDGen Consortium (n = 133814) to estimate the effect of genetically decreased eGFRcrea on 238 serum biomarkers. RESULTS: With reverse MR, trefoil factor 3 (TFF3) was identified as a protein that is increased owing to decreased eGFRcrea (ß = 1.86 SD per SD decrease eGFRcrea; 95% CI, 0.95-2.76; P = 8.0 × 10-5). Reverse MR findings were consistent with epidemiological associations for incident CKD in ORIGIN (OR = 1.28 per SD increase in TFF3; 95% CI, 1.18-1.38; P = 4.58 × 10-10). Addition of TFF3 significantly improved discrimination for incident CKD relative to eGFRcrea alone (net reclassification improvement = 0.211; P = 9.56 × 10-12) and in models including additional risk factors. CONCLUSIONS: Our results suggest TFF3 is a valuable diagnostic marker for early CKD in dysglycemic populations and acts as a proof of concept for the application of this novel MR technique to identify diagnostic biomarkers for other chronic diseases. CLINICALTRIALSGOV IDENTIFIER: NCT00069784.

The association of basal insulin treatment versus standard care with outcomes in anti-GAD positive and negative subjects: A post-hoc analysis of the ORIGIN trial.

We compared cardiovascular and other outcomes in patients with dysglycaemia with or without anti-glutamic acid dehydrogenase (GAD) antibodies participating in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial. Of the 12 537 participants, 8162 had anti-GAD measured at baseline and 267 were anti-GAD positive. The effects of insulin glargine versus standard care and of n-3 fatty acids supplements versus placebo were compared by testing the interaction of the treatment effects and anti-GAD status. The effect of glargine on development of new diabetes was assessed in participants without previous diabetes at baseline. The overall incidence of outcomes did not differ between anti-GAD positive and anti-GAD negative subjects. The incidence of the composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke did not differ between anti-GAD positive participants randomized to insulin glargine or to standard care, with a hazard ratio (HR) (95% confidence interval [CI]) of 0.80 (0.44-1.44) or in anti-GAD negative participants with a HR of 1.07 (0.96-1.20) (P for interaction = 0.20).

Association of Apolipoproteins B and A-1 With Markers of Vascular Health or Cardiovascular Events.

BACKGROUND: Apolipoprotein B (apoB) and apolipoprotein A-1 (apoA-1) are markers of lipoprotein metabolism. Although their relationship to cardiovascular disease has been well documented, little is known regarding their correlation to measures of vascular structure and function. This study was conducted to investigate the relationship between apoA-1, apoB, and measures of vascular function, as well their relationship to adverse cardiovascular events. Moreover, we evaluated whether apoB or the apoB/apoA-1 ratio was more closely related to vascular markers than was low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C). METHODS: One thousand five hundred twenty-two healthy middle-aged men of the Firefighters and Their Endothelium (FATE) cohort were assessed for risk factors and flow-mediated dilatation (FMD), hyperemic velocity (VTI), and carotid intima-media thickness (CIMT). Participants were then followed for 7.2 ± 1.7 years. ApoA-1 and apoB levels were measured at baseline. RESULTS: ApoA-1 was not correlated with VTI, FMD, or CIMT, whereas apoB was significantly related to VTI and CIMT. Multiple regression analyses confirmed apoB as being related to both VTI (ß = -0.083; P = 0.001) and CIMT (ß = 0.055; P = 0.022) in models adjusted for age; blood pressure; high-density lipoprotein C (HDL-C), triglyceride and insulin levels; waist circumference; and C-reactive protein levels. In substituted models, LDL-C (ß = -0.092; P < 0.001) and non-HDL-C (ß = -0.089; P = 0.001) levels appeared to have the same degree of association as apoB for VTI but were not associated with CIMT. ApoB was found to be associated with cardiovascular events (hazard ratio, 1.349; 95% confidence interval, 1.073-1.695; P = 0.010). CONCLUSIONS: ApoB had an independent but weak relationship with indices of microvascular health. Nevertheless, it was associated with occurrence rates of adverse cardiovascular events.

Association of Postoperative High-Sensitivity Troponin Levels With Myocardial Injury and 30-Day Mortality Among Patients Undergoing Noncardiac Surgery.

IMPORTANCE: Little is known about the relationship between perioperative high-sensitivity troponin T (hsTnT) measurements and 30-day mortality and myocardial injury after noncardiac surgery (MINS). OBJECTIVE: To determine the association between perioperative hsTnT measurements and 30-day mortality and potential diagnostic criteria for MINS (ie, myocardial injury due to ischemia associated with 30-day mortality). DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of patients aged 45 years or older who underwent inpatient noncardiac surgery and had a postoperative hsTnT measurement. Starting in October 2008, participants were recruited at 23 centers in 13 countries; follow-up finished in December 2013. EXPOSURES: Patients had hsTnT measurements 6 to 12 hours after surgery and daily for 3 days; 40.4% had a preoperative hsTnT measurement. MAIN OUTCOMES AND MEASURES: A modified Mazumdar approach (an iterative process) was used to determine if there were hsTnT thresholds associated with risk of death and had an adjusted hazard ratio (HR) of 3.0 or higher and a risk of 30-day mortality of 3% or higher. To determine potential diagnostic criteria for MINS, regression analyses ascertained if postoperative hsTnT elevations required an ischemic feature (eg, ischemic symptom or electrocardiography finding) to be associated with 30-day mortality. RESULTS: Among 21 842 participants, the mean age was 63.1 (SD, 10.7) years and 49.1% were female. Death within 30 days after surgery occurred in 266 patients (1.2%; 95% CI, 1.1%-1.4%). Multivariable analysis demonstrated that compared with the reference group (peak hsTnT <5 ng/L), peak postoperative hsTnT levels of 20 to less than 65 ng/L, 65 to less than 1000 ng/L, and 1000 ng/L or higher had 30-day mortality rates of 3.0% (123/4049; 95% CI, 2.6%-3.6%), 9.1% (102/1118; 95% CI, 7.6%-11.0%), and 29.6% (16/54; 95% CI, 19.1%-42.8%), with corresponding adjusted HRs of 23.63 (95% CI, 10.32-54.09), 70.34 (95% CI, 30.60-161.71), and 227.01 (95% CI, 87.35-589.92), respectively. An absolute hsTnT change of 5 ng/L or higher was associated with an increased risk of 30-day mortality (adjusted HR, 4.69; 95% CI, 3.52-6.25). An elevated postoperative hsTnT (ie, 20 to <65 ng/L with an absolute change ≥5 ng/L or hsTnT ≥65 ng/L) without an ischemic feature was associated with 30-day mortality (adjusted HR, 3.20; 95% CI, 2.37-4.32). Among the 3904 patients (17.9%; 95% CI, 17.4%-18.4%) with MINS, 3633 (93.1%; 95% CI, 92.2%-93.8%) did not experience an ischemic symptom. CONCLUSIONS AND RELEVANCE: Among patients undergoing noncardiac surgery, peak postoperative hsTnT during the first 3 days after surgery was significantly associated with 30-day mortality. Elevated postoperative hsTnT without an ischemic feature was also associated with 30-day mortality.

Validation of the ORIGIN Cardiovascular Biomarker Panel and the Value of Adding Troponin I in Dysglycemic People.

Background: Analyses of stored blood from the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) trial identified biomarkers that supplemented clinical risk factors for cardiovascular (CV) events or death. Their performance in participants with diabetes in the Heart Outcomes Prevention Evaluation (HOPE) study and the incremental value of adding high-sensitivity assays of serum troponin I (hsTnI) in the ORIGIN study were assessed. Methods: Levels of the 10 ORIGIN biomarkers for the composite CV outcome of myocardial infarction, stroke, or CV death were measured in 350 HOPE study participants with diabetes and stored serum that included all 77 who experienced this outcome. The effect of adding hsTnI levels to this panel, and the previously identified ORIGIN biomarkers for this composite outcome, this outcome, or revascularization or heart failure, and for mortality was also analyzed. Results: Within the HOPE cohort, the ORIGIN biomarker panel increased the C statistic from 0.63 for clinical risk factors alone to 0.67 with the addition of the 10 biomarkers, and the net reclassification improvement was 0.14 (95% confidence interval, 0.01, 0.28). Within the ORIGIN cohort, hsTnI levels predicted all three outcomes during follow-up both alone, and independently of the other biomarkers, which all remained independent predictors of outcomes after inclusion of the hsTnI levels. The hsTnI level interacted with follow-up time such that it was a stronger predictor of earlier vs later events. Conclusion: The ORIGIN biomarkers predicted CV outcomes in the independent HOPE cohort. Adding hsTnI levels to the previously identified models in ORIGIN modestly improved their performance.

Validation of a Capillary Electrophoresis Assay for Monitoring Iodine Nutrition in Populations for Prevention of Iodine Deficiency: An Interlaboratory Method Comparison.

BACKGROUND: A capillary electrophoresis (CE) assay was recently introduced as a new method for monitoring iodine nutrition in large-scale epidemiological studies. However, further tests revealed unanticipated matrix-dependent interferences when analyzing submicromolar levels of iodide in human urine as the predominate ionic form of dietary iodine. Herein, we describe a rigorous validation study that was used to identify sources of bias and establish modifications to the original CE method to improve method accuracy. METHODS: An interlaboratory method comparison using CE with UV detection and inductively coupled plasma-mass spectrometry (ICP-MS) was performed to quantify urinary iodide concentrations (n = 71) independently at McMaster University and Hamilton General Hospital, as well as the CDC as part of their quality assurance program. A positive bias in the original CE method was indicated, and buffer conditions were subsequently optimized to overcome matrix interferences for reliable iodine status determination. RESULTS: Positive bias in CE was attributed to variable concentrations of sulfate, a major urinary anion interference with similar mobility to iodide under the conditions originally reported. By increasing the concentration of α-cyclodextrin in the background electrolyte, the CE method was able to tolerate urinary sulfate over its normal physiological range without loss in signal response for iodide. The optimized CE assay generated results that were consistent with ICP-MS using 2 different internal standards (187Re and 130Te) with a median bias under 10%. CONCLUSIONS: CE offers a simple, selective, and cost-effective separation platform for surveillance of the iodine status of a population requiring only small volumes (<10 µL) of biobanked urine specimens, which is comparable to previously validated screening methods currently used in global health initiatives for prevention of iodine deficiency disorders.

Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study.

BACKGROUND: Stroke is a leading cause of death and disability, especially in low-income and middle-income countries. We sought to quantify the importance of potentially modifiable risk factors for stroke in different regions of the world, and in key populations and primary pathological subtypes of stroke. METHODS: We completed a standardised international case-control study in 32 countries in Asia, America, Europe, Australia, the Middle East, and Africa. Cases were patients with acute first stroke (within 5 days of symptom onset and 72 h of hospital admission). Controls were hospital-based or community-based individuals with no history of stroke, and were matched with cases, recruited in a 1:1 ratio, for age and sex. All participants completed a clinical assessment and were requested to provide blood and urine samples. Odds ratios (OR) and their population attributable risks (PARs) were calculated, with 99% confidence intervals. FINDINGS: Between Jan 11, 2007, and Aug 8, 2015, 26 919 participants were recruited from 32 countries (13 447 cases [10 388 with ischaemic stroke and 3059 intracerebral haemorrhage] and 13 472 controls). Previous history of hypertension or blood pressure of 140/90 mm Hg or higher (OR 2·98, 99% CI 2·72-3·28; PAR 47·9%, 99% CI 45·1-50·6), regular physical activity (0·60, 0·52-0·70; 35·8%, 27·7-44·7), apolipoprotein (Apo)B/ApoA1 ratio (1·84, 1·65-2·06 for highest vs lowest tertile; 26·8%, 22·2-31·9 for top two tertiles vs lowest tertile), diet (0·60, 0·53-0·67 for highest vs lowest tertile of modified Alternative Healthy Eating Index [mAHEI]; 23·2%, 18·2-28·9 for lowest two tertiles vs highest tertile of mAHEI), waist-to-hip ratio (1·44, 1·27-1·64 for highest vs lowest tertile; 18·6%, 13·3-25·3 for top two tertiles vs lowest), psychosocial factors (2·20, 1·78-2·72; 17·4%, 13·1-22·6), current smoking (1·67, 1·49-1·87; 12·4%, 10·2-14·9), cardiac causes (3·17, 2·68-3·75; 9·1%, 8·0-10·2), alcohol consumption (2·09, 1·64-2·67 for high or heavy episodic intake vs never or former drinker; 5·8%, 3·4-9·7 for current alcohol drinker vs never or former drinker), and diabetes mellitus (1·16, 1·05-1·30; 3·9%, 1·9-7·6) were associated with all stroke. Collectively, these risk factors accounted for 90·7% of the PAR for all stroke worldwide (91·5% for ischaemic stroke, 87·1% for intracerebral haemorrhage), and were consistent across regions (ranging from 82·7% in Africa to 97·4% in southeast Asia), sex (90·6% in men and in women), and age groups (92·2% in patients aged ≤55 years, 90·0% in patients aged >55 years). We observed regional variations in the importance of individual risk factors, which were related to variations in the magnitude of ORs (rather than direction, which we observed for diet) and differences in prevalence of risk factors among regions. Hypertension was more associated with intracerebral haemorrhage than with ischaemic stroke, whereas current smoking, diabetes, apolipoproteins, and cardiac causes were more associated with ischaemic stroke (p<0·0001). INTERPRETATION: Ten potentially modifiable risk factors are collectively associated with about 90% of the PAR of stroke in each major region of the world, among ethnic groups, in men and women, and in all ages. However, we found important regional variations in the relative importance of most individual risk factors for stroke, which could contribute to worldwide variations in frequency and case-mix of stroke. Our findings support developing both global and region-specific programmes to prevent stroke. FUNDING: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Health Research Board Ireland, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland (Sweden), AstraZeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MSD, Chest, Heart and Stroke Scotland, and The Stroke Association, with support from The UK Stroke Research Network.

Assessment of Dietary Sodium and Potassium in Canadians Using 24-Hour Urinary Collection.

BACKGROUND: Although salt intake derived from data on urinary sodium excretion in free-living populations has been used in public policy, a population study on urinary sodium excretion has not been done in Canada. We assessed dietary sodium and potassium intake using a 24-hour urine collection in a large survey of urban and rural communities from 4 Canadian cities and determined the association of these electrolytes with blood pressure (BP). METHODS: One thousand seven hundred consecutive individuals, aged 37-72 years, attending their annual follow-up visits of the ongoing Prospective and Urban Rural Epidemiology (PURE) study in Vancouver, Hamilton, Ottawa, and Quebec City, Canada, collected a 24-hour urine sample using standardized procedures. RESULTS: Mean sodium excretion was 3325 mg/d and mean potassium excretion was 2935 mg/d. Sodium excretion ranged from 3093 mg/d in Vancouver to 3642 mg/d in Quebec City, after adjusting for covariates. Potassium excretion ranged from 2844 mg/d in Ottawa to 3082 mg/d in Quebec City. Both electrolytes were higher in men than in women and in rural populations than in urban settings (P < 0.001 for all). Sodium excretion was between 3000 and 6000 mg/d in 48.3% of the participants, < 3000 mg/d in 46.7%, and > 6000 mg/d in only 5%. No significant association between sodium or potassium excretion and BP was found. CONCLUSIONS: Sodium consumption in these Canadians is within a range comparable to other Western countries, and intake in most individuals is < 6000 mg/d, with only 5% at higher levels. Within this range, sodium or potassium levels were not associated with BP.

Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study

Stroke is a leading cause of death and disability, especially in low-income and middle-income countries. We sought to quantify the importance of potentially modifi able risk factors for stroke in diff erent regions of the world,and in key populations and primary pathological subtypes of stroke. Methods We completed a standardised international case-control study in 32 countries in Asia, America, Europe, Australia, the Middle East, and Africa. Cases were patients with acute fi rst stroke (within 5 days of symptom onset and72 h of hospital admission). Controls were hospital-based or community-based individuals with no history of stroke,and were matched with cases, recruited in a 1:1 ratio, for age and sex. All participants completed a clinical assessment and were requested to provide blood and urine samples. Odds ratios (OR) and their population attributable risks(PARs) were calculated, with 99% confi dence intervals...

Identifying Novel Biomarkers for Cardiovascular Events or Death in People With Dysglycemia.

BACKGROUND: Serum biomarkers may identify people at risk for cardiovascular (CV) outcomes. Biobanked serum samples from 8494 participants with dysglycemia in the completed Outcome Reduction With Initial Glargine Intervention trial were assayed for 284 biomarkers to identify those that could identify people at risk for a CV outcome or death when added to clinical measurements. METHODS AND RESULTS: A multiplex analysis measured a panel of cardiometabolic biomarkers in 1 mL of stored frozen serum from every participant who provided biobanked blood. After eliminating undetectable or unanalyzable biomarkers, 8401 participants who each had a set of 237 biomarkers were analyzed. Forward-selection Cox regression models were used to identify biomarkers that were each independent determinants of 3 different incident outcomes: (1) the composite of myocardial infarction, stroke, or CV death; (2) these plus heart failure hospitalization or revascularization; and (3) all-cause death. When added to clinical variables, 10 biomarkers were independent determinants of the 1405 CV composite outcomes observed during follow-up; 9 biomarkers (including 8 of these 10) were independent determinants of the 2435 expanded composite outcomes; and 15 (including the 10 CV composite biomarkers) were independent determinants of the 1340 deaths. Adjusted C statistics increased from 0.64 for the clinical variables to 0.71 and 0.68 for the 2 CV composite outcomes, respectively, with the greatest increase to 0.75 for death (P<0.001 for the change). CONCLUSIONS: A systematic hypothesis-free approach identified combinations of up to 15 cardiometabolic biomarkers as independent determinants of CV outcomes or death in people with dysglycemia. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00069784.

The Relationship Between Trimethylamine-N-Oxide and Prevalent Cardiovascular Disease in a Multiethnic Population Living in Canada.

BACKGROUND: Microflora-dependent trimethylamine-N-oxide (TMAO) formation, which results from intake of choline and L-carnitine-rich food, shows promise as a predictor of cardiovascular disease (CVD) risk, but these associations have not been examined in ethnically diverse populations. In a multiethnic population-based study of adults in Canada, we assessed the stability of TMAO and L-carnitine in stored serum samples and their association with intimal medial thickness, prevalent risk factors, and clinical events. METHODS: In a randomly sampled cross-sectional study of 1286 Canadians, fasting serum samples were collected and stored. In 292 consecutive individuals (99 CVD cases and 193 unmatched control subjects), L-carnitine and TMAO concentrations were assessed using validated analytical approaches. RESULTS: The mean (± SD) TMAO level was 1.998 ± 3.13 µM and L-carnitine was 42.29 ± 11.35 µM. The relative levels of the samples did not appreciably change after 3 freeze-thaw cycles (coefficient of variation, 5.6% and 4.7%, respectively). No significant association between L-carnitine levels and prevalent CVD was found, with adjustment for covariates (odds ratio, 1.57; 95% confidence interval, 0.58-4.26; P trend = 0.65), for highest vs lowest quintile group. TMAO levels showed a significant, graded association with prevalent CVD (odds ratio, 3.17; 95% confidence interval, 1.05-9.51; P trend = 0.02). After further adjustment for diabetes status, meat, fish, and cholesterol intake, the association remained significant. No significant association between carotid intimal medial thickness and L-carnitine (P = 0.64) or TMAO (P = 0.18) was found. CONCLUSIONS: Serum TMAO and L-carnitine analysis on stored samples is reliable. Our findings support an association between TMAO with prevalent CVD in a multiethnic population. This finding requires replication in larger studies in which dietary intake and stored serum samples exist.

Association of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) With Cardiovascular Risk in Primary Prevention.

OBJECTIVE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the modulation of low-density lipoprotein metabolism. This study was conducted to evaluate the relationship between serum PCSK9 concentrations and measures of vascular health, subclinical atherosclerosis, and adverse cardiovascular events. The relationship between traditional risk factors and PCSK9 concentrations was also examined. APPROACH AND RESULTS: The cohort consisted of 1527 middle-aged men enrolled in the Firefighters and Their Endothelium (FATE) study, who were free of vascular disease and followed up over a mean period of 7.2±1.7 years. Baseline evaluation included assessment of traditional cardiovascular risk factors and measurements of flow-mediated dilation, reactive hyperemic velocity time integral, and carotid intima-media thickness. Biochemical parameters, including serum PCSK9 concentrations, were analyzed to determine predictors of vascular measures and to evaluate the role of PCSK9 in the occurrence of adverse cardiovascular events. Multivariate linear regression analyses indicated that body mass index, insulin, low-density lipoprotein-cholesterol, and triglycerides were independent predictors of PCSK9. Further modeling revealed no correlation between PCSK9 concentration and carotid intima media thickness, flow-mediated dilation, or reactive hyperemic velocity time integral. Analyses indicated no significant association between PCSK9 concentrations and cardiovascular event occurrences. CONCLUSIONS: Although correlated with low-density lipoprotein-cholesterol, insulin, and triglycerides, PCSK9 was not associated with measures of vascular function or structure. There was also no significant relationship between PCSK9 concentrations and cardiovascular events. Thus, although PCSK9 is an important therapeutic target to reduce circulating low-density lipoprotein-cholesterol concentrations, it is unlikely to be a biomarker of atherosclerotic risk or vascular health.

Genome-wide studies to identify risk factors for kidney disease with a focus on patients with diabetes.

Chronic kidney disease (CKD) affects 10-13% of the general population and diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). In addition to known demographic, biochemical and lifestyle risk factors, genetics is also contributing to CKD risk. In recent years, genome-wide association studies (GWAS) have provided a hypothesis-free approach to identify common genetic variants that could account for the genetic risk component of common diseases such as CKD. The identification of these variants might reveal the biological processes underlying renal impairment and could aid in improving risk estimates for CKD. This review aims to describe the methods as well as strengths and limitations of GWAS in CKD and to summarize the findings of recent GWAS in DN. Several loci and SNPs have been found to be associated with distinct CKD traits such as eGFR and albuminuria. For diabetic kidney disease, several loci were identified in different populations. Subsequent functional studies provided insights into the mechanism of action of some of these variants, such as UMOD or CERS2. However, overall, the results were ambiguous, and a few of the variants were not consistently replicated. In addition, the slow progression from albuminuria to ESRD could limit the power of longitudinal studies. The typically small effect size associated with genetic variants as well as the small portion of the variability of the phenotype explained by these variants limits the utility of genetic variants in improving risk prediction. Nevertheless, identifying these variants could give a deeper understanding of the molecular pathways underlying CKD, which in turn, could potentially lead to the development of new diagnostic and therapeutic tools.

Variability of ethics education in laboratory medicine training programs: results of an international survey.

BACKGROUND: Ethical considerations are increasingly important in medicine. We aimed to determine the mode and extent of teaching of ethics in training programs in clinical chemistry and laboratory medicine. METHODS: We developed an on-line survey of teaching in areas of ethics relevant to laboratory medicine. Reponses were invited from directors of training programs who were recruited via email to leaders of national organizations. RESULTS: The survey was completed by 80 directors from 24 countries who directed 113 programs. The largest numbers of respondents directed postdoctoral training of scientists (42%) or physicians (33%), post-masters degree programs (33%), and PhD programs (29%). Most programs (82%) were 2years or longer in duration. Formal training was offered in research ethics by 39%, medical ethics by 31%, professional ethics by 24% and business ethics by 9%. The number of reported hours of formal training varied widely, e.g., from 0 to >15h/year for research ethics and from 0 to >15h for medical ethics. Ethics training was required and/or tested in 75% of programs that offered training. A majority (54%) of respondents reported plans to add or enhance training in ethics; many indicated a desire for online resources related to ethics, especially resources with self-assessment tools. CONCLUSION: Formal teaching of ethics is absent from many training programs in clinical chemistry and laboratory medicine, with heterogeneity in the extent and methods of ethics training among the programs that provide the training. A perceived need exists for online training tools, especially tools with self-assessment components.