Omega-3 fatty acid supplements and risk of atrial fibrillation and 'micro-atrial fibrillation': A secondary analysis from the OMEMI trial.

BACKGROUND & AIMS: Recent randomized clinical trials have raised concerns regarding potential off target adverse effects from supplementation of n-3 polyunsaturated fatty acids (PUFA) on atrial fibrillation (AF) risk. We aimed to assess risk and potential mediators of AF and 'micro-AF' from n-3 PUFA in post-myocardial infarction (MI) patients. METHODS: In the OMEMI trial, 70-82 y. o. patients with a recent MI were randomized to 1.8 g/day of eicosapentaenoic-/docosahexaenoic acid (EPA/DHA) or placebo (corn oil) for two years. New-onset AF and 'micro-AF' was recorded by clinical detection and by screening with Zenicor thumb-ECG (adjudicated by blinded investigators). Serum EPA and DHA were measured at baseline and study end. RESULTS: At baseline, 759 of 1014 (75%) patients had no AF history. These patients were aged 75 ± 4 years and 71% were male. During follow-up, 43 patients developed new-onset AF (39 clinically-detected and 4 by thumb-ECG screening). In addition, 27 patients had episodes of micro-AF, yielding a total of 70 patients with new-onset AF or 'micro-AF'. In the n-3 PUFA group 46 (11.9%) had AF/'micro-AF' (28 AF, 18 'micro-AF') and in the placebo group 24 (6.5%) had AF/micro-AF (15 AF, 9 micro-AF); HR 1.90 (95%CI 1.16-3.11), P = 0.011. Changes in serum EPA (but not DHA) mediated the effect from n-3 PUFA on AF risk, explaining 65% of the association. CONCLUSION: Supplementation of n-3 PUFA post MI increases the risk of 'micro-AF' and AF, and increases in EPA seems to be an important mediator of the treatment effect from n-3 PUFA on the risk of AF. STUDY REGISTRATION: OMEMI Study; ClinicalTrails.gov identifier: NCT0184194.

Total Bilirubin Yields Prognostic Information Following a Myocardial Infarction in the Elderly.

Total bilirubin consists of an unconjugated form, solubilized by its binding to albumin, and a conjugated form representing a minor part of the circulating bilirubin. As total bilirubin in physiological concentrations is a powerful antioxidant, its concentration gradient may reflect the health status of an individual, and serve as a prognostic indicator of outcome in primary and secondary cardiovascular disease prevention. The aim of this study was to assess the association between total bilirubin and incident cardiovascular events following a myocardial infarction. Total bilirubin in serum was measured at baseline 2-8 weeks after hospitalization for an MI in 881 patients, aged 70 to 82 years, included in the OMEMI (Omega-3 Fatty acids in Elderly with Myocardial Infarction) study, where patients were followed-up for up to 2 years. The first major adverse clinical event (MACE) was the primary endpoint and consisted of nonfatal MI, unscheduled coronary revascularization, stroke, hospitalization for heart failure or all-cause death. As total bilirubin was non-normally distributed, log-transformed values and quartiles of bilirubin were analyzed using Cox regression models. The median (Q1, and Q3) baseline concentration of bilirubin was 11 (9, and 14) µmol/L, and higher log-transformed concentrations were associated with male sex, lower New York Heart Association (NYHA) class and non-smoking. MACE occurred in 177 (20.1%) patients during the follow-up. Higher concentrations of bilirubin were associated with a lower risk of MACE: HR 0.67 (95%CI 0.47-0.97) per log-unit increase, p = 0.032. Patients in the lowest quartile of bilirubin (<9 µmol/L) had the highest risk with HR 1.61 (95%CI 1.19-2.18), p = 0.002, compared to quartiles 2-4. This association remained significant even after adjusting for age, sex, body mass index (BMI), smoking status, NYHA class and treatment allocation: HR 1.52 (1.21-2.09), p = 0.009. Low concentrations of bilirubin (<9 µmol/L) are associated with increased nonfatal cardiovascular events or death in elderly patients with a recent myocardial infarction.

The clinical importance of high-sensitivity cardiac troponin measurements for risk prediction in non-cardiac surgery.

INTRODUCTION: The global healthcare burden associated with surgery is substantial, with many patients experiencing perioperative complications. Cardiac troponin I and T measured with high-sensitivity assays are cardiac specific biomarkers that associate closely with adverse outcomes in most patient populations. Perioperative physiological stress can induce troponin release from cardiomyocytes, a condition known as perioperative myocardial injury (PMI). PMI is associated with increased risk of poor short- and long-term outcomes, and current European guidelines recommend screening for PMI in at-risk individuals undergoing non-cardiac surgery. AREAS COVERED: In this review we summarize current knowledge of the prognostic attributes of cardiac troponins, as well as the challenges associated with their application as biomarkers in the perioperative phase. EXPERT OPINION: Measurement of circulating levels of cardiac troponins identify individuals at increased risk of poor postoperative outcomes. Systematic screening of at-risk individuals undergoing non-cardiac surgery will result in a large proportion of patients in need of further diagnostic workup to establish the exact nature of their PMI. The lack of concrete evidence of clinical benefit and the increased cost associated with such a strategy is concerning and underscore the need for further research.

Screen-detected atrial fibrillation and 'micro-atrial fibrillation' and risk of cardiovascular events after myocardial infarction in elderly patients.

BACKGROUND: Incident atrial fibrillation (AF) occurs in 5-10% of patients after acute myocardial infarction (AMI) and is associated with adverse outcomes. Guidelines now recommend screening for AF in all elderly patients. However, the relevance of screen-detected AF and short episodes of irregular supraventricular ectopic beats ('micro-AF') after AMI is unknown. OBJECTIVES: To investigate the value of two-week intermittent ECG screening to detect incident AF and 'micro-AF' in elderly patients 12 months after an AMI, and its association with risk of cardiovascular events. METHODS: This was an investigator-initiated, multicenter substudy of the OMega-3 fatty acids in Elderly patients with Myocardial Infarction (OMEMI) trial, in Norway. Women and men aged 70-82 years, with a recent AMI, were recruited during 2012-2018. All participants had a 12-lead ECG performed at 3, 12 and 24 months. Patients without AF one year after the index AMI underwent 2 weeks of intermittent 30-second 'thumb ECG' screening. Incident AF and 'micro-AF' (episodes of ≥3 consecutive irregular supraventricular ectopic beats) were registered, and the association with risk of major cardiovascular events (MACE; non-fatal AMI, stroke, coronary revascularization, hospitalization for heart failure, or all-cause death) was analyzed with logistic regression. RESULTS: Among 1014 patients (198 (28.7%) women), 255 (25.1%) had known AF or AF identified at baseline. New-onset AF was detected clinically or at study visits in 39 (3.8%) patients. By screening participants without AF (n=567), unknown AF was identified in 4 (0.7%) and 'micro-AF' in 27 (4.8%) patients. Among 43 patients with incident AF, 21 (48.8%) experienced a MACE, which was significantly higher than those without AF (n=114, 15.9%; p<0.001), driven by a higher risk of AMI or revascularization. Nine (33.3%) patients with 'micro-AF' and 75 (13.9%) without 'micro-AF' experienced a MACE (p=0.002), explained mostly by a higher risk of heart failure hospitalization (p<0.001). Using patients without AF and 'micro-AF' as reference, 'micro-AF' was associated with an intermediate risk of MACE (OR 2.8; 95% CI 1.2-6.4) and new-onset AF with a high risk of MACE (OR 5.3; 95% CI 2.8-10.0). CONCLUSIONS: Two-week intermittent ECG screening identified few cases of new-onset AF, but a substantial number of patients with 'micro-AF'. 'Micro-AF' was associated with an increased risk of major cardiovascular events, albeit with an intermediate risk compared to those with new-onset AF.

Cardiac troponin I and T for ruling out coronary artery disease in suspected chronic coronary syndrome.

To compare the performance of high-sensitivity cardiac troponin I and T (hs-cTnI; hs-cTnT) in diagnosing obstructive coronary artery disease (CAD50) in patients with suspected chronic coronary syndrome (CCS). A total of 706 patients with suspected CCS, referred for Coronary Computed Tomography Angiography, were included. cTn concentrations were measured using the Singulex hs-cTnI (limit of detection [LoD] 0.08 ng/L) and Roche hs-cTnT (LoD 3 ng/L) assays. Obstructive coronary artery disease (CAD50) was defined as ≥ 50% coronary stenosis. Cardiovascular risk was determined by the NORRISK2-score. Median age of the patients was 65 (range 28-87) years, 35% were women. All patients had hs-cTnI concentrations above the LoD (median 1.9 [Q1-3 1.2-3.6] ng/L), 72% had hs-cTnT above the LoD (median 5 [Q1-3 2-11] ng/L). There was a graded relationship between hs-cTn concentrations and coronary artery calcium. Only hs-cTnI remained associated with CAD50 in adjusted analyses (OR 1.20 95% Confidence Interval [1.05-1.38]), p = 0.009). The C-statistics for hs-cTnI and hs-cTnT were 0.65 (95% CI [0.60-0.69]) and 0.60 (0.56-0.64). The highest specificity and negative predictive values for CAD50 were in the lowest NORRISK2-tertile. hs-cTn concentrations provide diagnostic information in patients with suspected CCS, with superior performance of hs-cTnI compared to hs-cTnT in regard to CAD50. The diagnostic performance appeared best in those with low cardiovascular risk.

Changes in eicosapentaenoic acid and docosahexaenoic acid and risk of cardiovascular events and atrial fibrillation: A secondary analysis of the OMEMI trial.

BACKGROUND: The cardiovascular benefit from n-3 polyunsaturated fatty acids (PUFAs) after acute myocardial infarction (AMI) is controversial, and the importance of serum eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) concentrations for clinical events is unclear. OBJECTIVES: To assess changes in EPA and DHA serum concentrations during n-3 PUFA supplementation and their association with incident cardiovascular events. METHODS: In the OMEMI trial, elderly patients with a recent AMI were randomized to 1.8 g/day of EPA/DHA or control (corn oil) for 2 years. The primary outcome was a composite of AMI, coronary revascularization, stroke, heart failure hospitalization, or all-cause death (major adverse cardiovascular event [MACE]) and the secondary outcome was new-onset atrial fibrillation (AF). RESULTS: EPA and DHA measurements were available in 881 (92% of survivors) participants at randomization and study completion. EPA and DHA increased in the active treatment arm (n = 438) by a median of 87% and 16%, respectively. Greater on-treatment increases in EPA and DHA were associated with decreasing triglycerides, increasing high-density lipoprotein cholesterol, and lower baseline EPA and DHA concentrations. Greater on-treatment increases in EPA were associated with lower risk of MACE (adjusted hazard ratio 0.86 [95% confidence interval, CI, 0.75-0.99], p = 0.034), and higher risk of AF (adjusted hazard ratio (HR) 1.36 [95% CI 1.07-1.72], p = 0.011). Although there were similar tendencies for DHA changes and outcomes, these associations were not statistically significant (HR 0.84 [0.66-1.06] for MACE and 1.39 [0.90-2.13] for AF). CONCLUSION: Greater on-treatment increases in EPA were associated with lower risk of MACE and higher risk of new-onset AF. These data suggest that the cardiovascular effects of increasing n-3 PUFA levels through supplements are complex, involving both potential benefits and harm.

Performance of a Novel Research-Use-Only Secretoneurin ELISA in Patients with Suspected Acute Coronary Syndrome: Comparison with an Established Secretoneurin Radioimmunoassay.

BACKGROUND: Circulating secretoneurin (SN) concentrations, as measured by established radioimmunoassay (RIA), risk stratify patients with cardiovascular disease. We now report data for a recently developed research-use-only SN enzyme-linked immunosorbent assay (ELISA) in patients with suspected acute coronary syndrome (ACS). METHODS: SN ELISA was developed according to industry standards and tested in 401 unselected chest pain patients. Blood samples were drawn <24 h from admission, and we adjudicated all hospitalizations as ACS or non-ACS. The mean follow-up was 6.2 years. RESULTS: SN ELISA with 2 monoclonal sheep anti-SN antibodies has a measuring range of 10-250 pmol/L and demonstrates excellent analytical precision and accuracy across the range of SN concentrations. SN measured by ELISA and RIA correlated in the chest pain patients: rho = 0.39, p < 0.001. SN concentrations were higher in ACS patients (n = 161 [40%]) than in non-ACS patients (n = 240) for both assays, with an area under the curve (AUC) of 0.66 (95% CI: 0.61-0.71) for ELISA and 0.59 (0.54-0.65) for RIA. SN concentrations were also higher in nonsurvivors (n = 65 [16%]) than survivors, with an AUC of 0.72 (0.65-0.79) for ELISA versus 0.64 (0.56-0.72) for RIA, p = 0.007, for difference between assays. Adjusting for age, sex, blood pressure, previous myocardial infarction, atrial fibrillation, and heart failure in multivariable analysis, SN concentrations as measured by ELISA, but not RIA, remained associated with mortality, with a hazard ratio of 1.71 (1.03-2.84), p = 0.038. CONCLUSIONS: The novel SN ELISA has excellent performance, higher AUC for diagnosis, and superior prognostic accuracy compared to the established RIA in chest pain patients.

Differential associations of cardiac troponin T and cardiac troponin I with coronary artery pathology and dynamics in response to short-duration exercise.

BACKGROUND: We aimed to assess the associations between cardiac troponin (cTn) T and I concentrations, physical exercise and the presence and severity of angiographic coronary artery disease (CAD) in patients evaluated for suspected chronic coronary syndrome (CCS). METHODS AND RESULTS: All patients performed an exercise stress test on a bicycle ergometer and underwent invasive coronary angiography with weighted anatomical evaluation using the Gensini score. Blood samples were collected before and after exercise and analysed with high-sensitivity (hs) cTnT and cTnI assays. Of 297 patients (median age 62 (Quartile [Q]1-3 56-69) years, 35% female), 46% were categorized as "severe CAD" (Gensini score ≥ 20). Resting hs-cTnT and hs-cTnI concentrations were detectable in 88% and 100% of patients, with medians of 6 (Q1-3 4-9) ng/L and 1.5 (0.9-2.4) ng/L, respectively. In adjusted normalized linear regression analyses, higher resting concentrations were associated with increasing Gensini score (hs-cTnT: B 0.19, 95% Confidence Interval [CI] [0.09-0.41], p < 0.001; hs-cTnI: B 0.18, [0.06-0.30], p = 0.002). The area under the receiver operating characteristics curve for predicting severe CAD was 0.72 (95% CI [0.66-0.78]) and 0.68 (0.62-0.74) for resting hs-cTnT and hs-cTnI, p = 0.11 for difference. The median (Q1-3) relative increase in hs-cTnT and hs-cTnI concentrations were 5 (0-12) % and 13 (3-27) %, respectively, with no significant associations with CAD severity. CONCLUSIONS: In patients with suspected CCS, higher hs-cTn concentrations at rest were associated with increasing angiographic severity of CAD, without any significant differences between the troponin isotypes. Post-exercise hs-cTn concentrations did not have discriminatory power for CAD.

Effects of n-3 Fatty Acid Supplements in Elderly Patients After Myocardial Infarction: A Randomized, Controlled Trial.

BACKGROUND: High intake of marine n-3 polyunsaturated fatty acids (PUFA) has been associated with reduced risk of cardiovascular events; however, this has not been confirmed in patients with a recent acute myocardial infarction (AMI). Elderly patients are at particularly increased cardiovascular risk after myocardial infarction, but few trials address this group specifically. Omega-3 fatty acids hold the potential to reduce cardiovascular events with limited adverse effects in this vulnerable group. The hypothesis was that daily addition of 1.8g n-3 PUFA to standard of care secondary prophylaxis in elderly patients who have survived an AMI would reduce the risk of subsequent cardiovascular events during 2 years follow-up. METHODS: The OMEMI trial (Omega-3 Fatty acids in Elderly with Myocardial Infarction) is an investigator-initiated, multicenter, randomized clinical trial adding 1.8 g n-3 PUFA (930 mg eicosapentaenoic acid and 660 mg docosohexaenoic acid) versus placebo (corn oil) daily to standard of care in patients aged 70 to 82 years with recent (2-8 weeks) AMI. The primary endpoint was a composite of nonfatal AMI, unscheduled revascularization, stroke, all-cause death, heart failure hospitalization after 2 years. The secondary outcome was new atrial fibrillation. The safety outcome was major bleeding. Serum fatty acids were measured as biomarkers of adherence. RESULTS: In total, 1027 patients were randomized. Follow-up data were available for 1014 patients who were included in the intention-to-treat analysis. Mean±SD age was 75±3.6 years, 294 (29%) were female, and mean triglycerides were 111.4±61.9 mg/dL. The primary endpoint occurred in 108 (21.4%) patients on n-3 PUFA versus 102 (20.0%) on placebo (hazard ratio, 1.08 [95% CI, 0.82-1.41]; P=0.60). The secondary endpoint occurred in 28 (7.2%) patients on n-3 PUFA versus 15 (4.0%) on placebo (1.84 [0.98-3.45]; P=0.06). Median changes in eicosapentaenoic acid and docosahexaenoic acid were +87% and +16% for n-3 PUFA versus -13% and -8% for placebo. Major bleeding occurred in 54 (10.7%) and 56 (11.0%) in the n-3 PUFA and placebo groups, respectively (P=0.87). Similar results were found in per-protocol analysis (n=893). CONCLUSIONS: We could not detect reduction in clinical events in our elderly patients with recent AMI who were treated with 1.8 g n-3 PUFAs daily for 2 years. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01841944.

Superiority of high sensitivity cardiac troponin T vs. I for long-term prognostic value in patients with chest pain; data from the Akershus cardiac Examination (ACE) 3 study.

BACKGROUND: Cardiac troponins (cTn) are essential in the diagnostic assessment of non-ST-segment-elevation acute coronary syndrome (NSTE-ACS). Elevated concentrations of cTnT and cTnI predict cardiovascular events in non-acute settings, but the individual troponin isotype association with long-term mortality in patients with suspected unstable angina pectoris (UAP) is less clear. METHODS: Patients hospitalized with chest pain between June 2009 and December 2010 were included in the Akershus Cardiac Examination 3 Study and followed for median 6.6 (IQR 6.2-7.1) years. The index diagnosis was adjudicated by an independent committee as NSTE-myocardial infarction (NSTEMI), UAP or non-ACS. Blood samples were collected within 24 h of admission and analyzed with high sensitivity assays for cTnT (hs-cTnT, Roche) and cTnI (hs-cTnI, Singulex). RESULTS: Of 402 patients included, 74 (18%) were classified as NSTEMI, 88 (22%) UAP and 240 (60%) non-ACS. hs-cTnI concentrations were detectable in all patients (median 3 [IQR 1-11] ng/L), while hs-cTnT concentrations were above the level of blank in 205 (51%) (median 3 [IQR 3-16] ng/L). In patients with UAP, both log2-transformed hs-cTnT and hs-cTnI were associated with all-cause mortality in analyses that adjusted for other risk factors: HR 2.40 [95% CI 1.75-3.30], p < 0.001 and HR 1.44 [1.14-1.81], p = 0.002. There were no significant sex-dependent differences in the association between hs-cTnT or hs-cTnI and outcome. Time dependent receiver-operating characteristics area under the curve was 0.85 (95% CI 0.79-0.92) for hs-cTnT and 0.74 (0.64-0.84) for hs-cTnI, p = 0.008 for difference between values. CONCLUSIONS: Higher concentrations of hs-cTnT and hs-cTnI were both associated with all-cause mortality in patients with UAP, but the association with outcome was stronger for hs-cTnT than for hs-cTnI.

Leukocyte telomere length and serum polyunsaturated fatty acids, dietary habits, cardiovascular risk factors and features of myocardial infarction in elderly patients.

BACKGROUND: Telomeres are non-coding sequences at the end of eukaryote chromosomes, which in complex with associated proteins serve to protect subtelomeric DNA. Telomeres shorten with each cell division, are regarded as a biomarker for aging and have also been suggested to play a role in atherosclerosis and cardiovascular disease (CVD). The aim of the present study was to explore the associations between leukocyte telomere length and serum polyunsaturated fatty acids, diet, cardiovascular risk factors and features of myocardial infarction (MI) in elderly patients. METHODS: The material is based upon the first 299 included patients in the OMEMI trial, where patients aged 70-82 years of age are randomized to receive omega-3 supplements or corn oil (placebo) after MI. Patients were included 2-8 weeks after the index MI. DNA was extracted from whole blood, and leukocyte telomere length (LTL) was analyzed by qPCR and reported as a number relative to a reference gene. Serum long chain polyunsaturated fatty acid (LCPUFA) content was analyzed by gas chromatography. Diet was evaluated with the validated SmartDiet food frequency questionnaire. Medical records, patient interviews and clinical examination provided previous medical history and anthropometric data. Non-parametric statistical tests were used. RESULTS: Median (25, 75 percentile) LTL was 0.55 (0.42, 0.72). Patients had a median age of 75 years, 70.2% were male and 45.2% used omega-3 supplements. There was a weak, but significant correlation between LTL and linoleic acid (r = 0.139, p = 0.017), but not with other LCPUFAs. There was a trend towards longer telomeres with a healthier diet, but this did not reach statistical significance (p = 0.073). No associations were found between LTL and CVD risk factors or features of MI. CONCLUSIONS: In our population of elderly with a recent myocardial infarction LTL was associated with linoleic acid concentrations, but not with other LCPUFAs. Patients with a healthy diet tended to have longer telomeres. The limited associations may be due to age and the narrow age-span in our population. Further studies, designed to detect longitudinal changes should be performed to explore the role of telomeres in cardiovascular aging. TRIAL REGISTRATION: Clinical trials no. NCT01841944, registration date April 29, 2013.