To Örebro University

BACKGROUND: Around 5-10% of all myocardial infarction patients have non-obstructive coronary arteries. Studies investigating the importance of follow-up and achievement of conventional secondary prevention targets in these patients are lacking.

METHODS: In this analysis from the SWEDEHEART registry, we investigated 5830 myocardial infarction patients with non-obstructive coronary arteries (group 1) and 54,637 myocardial infarction patients with significant coronary artery disease (≥50% stenosis; group 2). Multivariable- and propensity score-adjusted statistics were used to assess the reduction in the one-year risk of major adverse events associated with prespecified secondary preventive measures: participation in follow-up at 6-10 weeks after the hospitalization; achievement of secondary prevention targets (blood pressure and low-density lipoprotein cholesterol levels in the target ranges, non-smoking, participation in exercise training).

RESULTS: Patients in group 1 were less often followed up compared to patients in group 2 and less often achieved any of the secondary prevention targets. Participation in the 6-10 week follow-up was associated with a 3-20% risk reduction in group 1, similar as for group 2 according to interaction analysis. The improvement in outcome in group 1 was mainly mediated by achieving target range low-density lipoprotein cholesterol levels (24-32% risk reduction) and, to a smaller extent, by participation in exercise training (10-23% risk reduction).

CONCLUSIONS: Selected secondary preventive measures are associated with prognostic benefit in myocardial infarction patients with non-obstructive coronary arteries, in particular achieving target range low-density lipoprotein cholesterol levels. Our results indicate that these patients should receive similar follow-up as myocardial infarction patients with significant coronary stenoses.

BACKGROUND: Myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) is receiving increasing interest as a prognostically adverse entity distinct from myocardial infarction with significant coronary artery disease (MI-CAD). However, data are still limited regarding long-term cardiovascular morbidity and cause-specific mortality in MINOCA.

METHODS: This is a registry-based cohort study using data from patients admitted to Swedish coronary care units. We investigated various nonfatal outcomes (recurrent MI, hospitalization for heart failure or stroke) and fatal outcomes (cardiovascular, respiratory or cancer-related mortality) in 4069 patients without apparent acute cardiovascular disease, used as non-MI controls, 7266 patients with first-time MINOCA and 69 267 patients with first-time MI-CAD.

RESULTS: Almost all event rates (median follow-up 3.8 years) increased in a stepwise fashion across the three cohorts [rates of major adverse events (MAE; composite of all-cause mortality, recurrent MI, hospitalization for heart failure or stroke): n = 268 (6.6%), n = 1563 (21.5%), n = 17 777 (25.7%), respectively]. Compared to non-MI controls, MINOCA patients had an adjusted hazard ratio (HR) of 2.12 (95% confidence interval 1.84-2.43) regarding MAE. MINOCA patients had a substantial risk of cardiovascular mortality and the highest numerical risks of respiratory and cancer-related mortality. Male sex, previous heart failure and chronic obstructive pulmonary disease had a stronger prognostic impact in MINOCA than in MI-CAD. Female MINOCA patients with atrial fibrillation were at particular risk.

CONCLUSIONS: Patients with first-time MINOCA have a considerable risk of adverse events. This stresses the need for a comprehensive search of the cause of MINOCA, thorough treatment of underlying disease triggers and close follow-up.

BACKGROUND: Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a heterogeneous condition. Recent studies suggest that MINOCA patients may have a proinflammatory disposition. The role of inflammation in MINOCA may thus be distinct to myocardial infarction with significant coronary artery disease (MI-CAD).

HYPOTHESIS: We hypothesized that inflammation reflected by C-reactive protein (CRP) levels might carry unique clinical information in MINOCA.

METHODS: This retrospective registry-based cohort study (SWEDEHEART) included 9916 patients with MINOCA and 97 970 MI-CAD patients, used for comparisons. Multivariable-adjusted regressions were applied to investigate the associations of CRP levels with clinical variables, all-cause mortality and major cardiovascular events (MACE) during a median follow-up of up to 5.3 years.

RESULTS: Median admission CRP levels in patients with MINOCA and MI-CAD were 5.0 (interquartile range 2.0-9.0) mg/dl and 5.0 (interquartile range 2.1-10.0 mg/dl), respectively. CRP levels in MINOCA exhibited independent associations with various cardiovascular risk factors, comorbidities and estimates of myocardial damage. The association of CRP with peripheral artery disease tended to be stronger compared to MI-CAD. The associations with female sex, renal dysfunction and myocardial damage were stronger in MI-CAD. CRP independently predicted all-cause mortality in MINOCA (hazard ratio 1.22 [95% confidence interval 1.17-1.26]), similar to MI-CAD (p interaction = 0.904). CRP also predicted MACE (hazard ratio 1.08 [95% confidence interval 1.04-1.12]) but this association was weaker compared to MI-CAD (p interaction<.001).

CONCLUSIONS: We found no evidence indicating the presence of a specific inflammatory pattern in acute MINOCA compared to MI-CAD. However, CRP levels were independently, albeit moderately associated with adverse outcome.

OBJECTIVE: Early evaluation of patients with chest pain is important not only for the detection of acute myocardial infarction (AMI) but also for identification of patients at high risk for future cardiac events. A multimarker strategy applying results of early measurements of different biochemical markers of cardiac necrosis in combination may improve risk prediction in chest pain patients.

METHODS: Rapid measurements of troponin I (TnI), creatine kinase MB and myoglobin were performed in 191 consecutive patients with chest pain and a non-diagnostic electrocardiogram for AMI. The prognostic value of these markers and different multimarker strategies was evaluated and compared.

RESULTS: Ten (5.2%) patients died during follow-up, which for eight (4.2%) patients was due to cardiac causes. Myocardial reinfarctions occurred in 17 (6.8%) patients. TnI was most predictive for cardiac mortality (TnI>or=0.1 microg/l, 10.7% event rate compared with TnI<0.1 microg/l, 0%, P<0.001) and myocardial reinfarction (14.9% compared with 1.7%, P<0.001). The other markers and multimarker strategies had a lower capacity for predicting adverse events apart from myoglobin and the combination of TnI or myoglobin regarding the endpoint of total mortality.

CONCLUSION: The combinations of different markers were prognostically non-superior compared to TnI, which thus, should be preferred as a biochemical marker for risk stratification in patients with chest pain.

OBJECTIVE: To evaluate the prognostic value of point of care troponin I (TnI) results in combination with findings from the admission electrocardiogram (ECG) in patients with chest pain.

METHODS: Rapid measurements of TnI were performed in 191 consecutive patients with chest pain and a non-diagnostic ECG for myocardial infarction.

RESULTS: Within 6 h from admission, maximum TnI elevations of > or = 0.07 microg/l and > or = 0.1 microg/l were noted in 59 and 39% of all patients, respectively. TnI elevations in the range of 0.07-0.09 microg/l were found in many patients with diagnoses other than acute coronary syndrome. By 6-month follow-up, cardiac death had occurred in 7.1 and 11% of patients with maximum TnI > or = 0.07 microg/l and > or = 0.1 microg/l, respectively and myocardial reinfarction was documented in 12 and 15%, respectively. ST-segment depression on the admission ECG was present in 16% of all patients and was the electrocardiographic abnormality with the highest risk (cardiac death 7.7%, myocardial reinfarction 15%). The combination of TnI > or = 0.1 microg/l and ST-segment depression or an abnormal admission ECG in general allowed the identification of patients at low, intermediate and high cardiac risk, 3 h after admission.

CONCLUSION: A threshold of TnI > or = 0.1 microg/l corresponding to the 10% coefficient of variation is prognostically most suitable for prediction of cardiac events in patients with chest pain. The combination of TnI results and findings from the admission ECG improves prognostic assessment and allows early and reliable risk stratification in this patient population.

BACKGROUND: Despite improved laboratory assays for cardiac markers and a revised standard for definition of myocardial infarction (AMI), early detection of coronary ischemia in unselected patients with chest pain remains a difficult challenge.

METHODS: Rapid measurements of troponin I (TnI), creatine kinase MB (CK-MB), and myoglobin were performed in 197 consecutive patients with chest pain and a nondiagnostic electrocardiogram for AMI. The early diagnostic performances of these markers and different multimarker strategies were evaluated and compared. Diagnosis of AMI was based on European Society of Cardiology/American College of Cardiology criteria.

RESULTS: At a given specificity of 95%, TnI yielded the highest sensitivity of all markers at all time points. A TnI cutoff corresponding to the 10% coefficient of variation (0.1 microg/L) demonstrated a cumulative sensitivity of 93% with a corresponding specificity of 81% at 2 hours. The sensitivity was considerably higher compared to CK-MB and myoglobin, even considering patients with a short delay until admission. Using the 99th percentile of TnI results as a cutoff (0.07 microg/L) produced a cumulative sensitivity of 98% at 2 hours, but its usefulness was limited due to low specificities. Multimarker strategies including TnI and/or myoglobin did not provide a superior overall diagnostic performance compared to TnI using the 0.1 microg/L cutoff.

CONCLUSION: A TnI cutoff corresponding to the 10% coefficient of variation was most appropriate for early diagnosis of AMI. A lower TnI cutoff may be useful for very early exclusion of AMI. CK-MB and in particular myoglobin did not offer additional diagnostic value.

Background/Objectives: Familial hypercholesterolemia (FH) is a common genetic disorder which is primarily caused by pathogenic variants in the LDLR, APOB, and PCSK9 genes. Approximately 10% of pathogenic variants in LDLR may be CNVs. Here, we combine NGS, MLPA, and Optical Genome Mapping (OGM) to investigate CNVs in LDLR.

Methods: A NGS panel was designed for whole gene sequencing (8 genes) of 100 FH patients using Twist technology and Illumina platform. CNVs were detected using CNVexpo, and an in-house pipeline for base-resolved normalized coverage. Identified CNVs were validated using MLPA and OGM. Bionano Services Lab performed the OGM procedure. Purified gDNA was labeled using Direct Label and Stain DNA Labeling Kit. Saphyr chip was run aiming for 100X coverage. De novo assembly and Variant Annotation pipelines were executed on Bionano Solve v3.7. Bionano Access v1.7 was used for CNV reporting and visualization.

Results: In five out of 100 samples NGS and MLPA data showed heterozygous deletions in LDLR. Three deletions, affecting different exons, was analyzed and confirmed using OGM. In two samples, OGM better defined the breakpoints as well as the size of the event, which expanded far beyond the gene of interest. In one sample, an additional CNV of SLCO1B1, a pharmaco-gene, important for transport of statins used for FH treatment was identified.

Conclusion: CNVs in FH genes in FH patients could be detected using targeted NGS, which was further confirmed by MLPA and characterized using OGM.

BACKGROUND AND AIMS: The familial risk among patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) is unknown. Previous studies of family history in myocardial infarction (MI), have not made a distinction between MINOCA and MI due to coronary artery disease (MI-CAD), based on angiographic findings. We therefore sought to investigate familial risk of MI without and with obstructive coronary arteries.

METHODS: Register-based cohort study with a total of 15,462 MINOCA cases, 204,424 MI-CAD cases, 38,220 control subjects without MI and with non-obstructive coronary arteries. First-degree relatives were identified 1995-2020. Cox proportional hazard regression models were used to compare familial risk in MINOCA and MI-CAD with control subjects.

RESULTS: During a mean follow-up of 8.1 ± 4.2 years, MINOCA occurred in 1.0% of first-degree relatives with MINOCA whereas MI-CAD occurred in 9.7% of first-degree relatives of MINOCA. The age- and sex-adjusted hazard ratio (HR) for a MINOCA-relative experiencing MINOCA and MI-CAD, compared to control subjects, was 0.99 (95% confidence interval [CI] 0.80-1.23) and 1.10 (95% CI 1.03-1.18), respectively. During a mean follow-up of 8.5 ±4.8 years, MI-CAD occurred in 12.2% of first- degree relatives with MI-CAD with age- and sex-adjusted HR 1.43 (95% CI 1.37-1.49).

CONCLUSIONS: No increased familial risk of MINOCA was observed for MINOCA-patients whereas there was an increased familial risk for MI-CAD when compared to control subjects. These results may indicate that genetic factors and shared environmental factors within a family leading to CAD are important also for MINOCA, thus MI-CAD and MINOCA could share underlying mechanisms.

Background: A previous study has shown an increased prevalence of late gadolinium enhancement cardiovascular magnetic resonance (LGE CMR) detected unrecognized myocardial infarction (UMI) with increasing extent and severity of coronary artery disease. However, the coronary artery disease was evaluated on a patient level assuming normal coronary anatomy. Therefore, the aims of the present study were to investigate the prevalence of UMI identified by LGE CMR imaging in patients with stable angina pectoris and no known previous myocardial infarction; and to investigate whether presence of UMI is associated with stenotic lesions in the coronary artery supplying the segment of the myocardium in which the UMI is located, using coronary angiography to determine the individual coronary anatomy in each patient.

Methods: In this prospective multicenter study, we included patients with stable angina pectoris and without prior myocardial infarction, scheduled for coronary angiography. A LGE CMR examination was performed prior to the coronary angiography. The study cohort consisted of 235 patients (80 women, 155 men) with a mean age of 64.8 years.

Results: UMIs were found in 25 % of patients. There was a strong association between stenotic lesions (>= 70 % stenosis) in a coronary artery and the presence of an UMI in the myocardial segments supplied by the stenotic artery; it was significantly more likely to have an UMI downstream a stenosis >= 70 % as compared to <70 % (OR 5.1, CI 3.1-8.3, p < 0.0001). 56 % of the UMIs were located in the inferior and infero-lateral myocardial segments, despite predominance for stenotic lesions in the left anterior descending artery.

Conclusion: UMI is common in patients with stable angina and the results indicate that the majority of the UMIs are of ischemic origin due to severe coronary atherosclerosis. In contrast to what is seen in recognized myocardial infarctions, UMIs are predominately located in the inferior and infero-lateral myocardial segments.

Rapid antigen tests may enhance the diagnostic yield of respiratory syncytial virus (RSV) infections, but studies have shown low sensitivity in adults. We evaluated the novel ImmuView RSV test in adult patients with influenza-like symptoms who were prospectively enrolled at three emergency departments in two Swedish hospitals during two influenza seasons, 2017 to 2018 and 2018 to 2019. The ImmuView RSV test was performed on nasopharyngeal swabs and results were compared to those of the BinaxNOW RSV test. In the first season, tests were performed on frozen samples, while unfrozen samples were used in the second season. For comparison, tests were also performed on selected samples from children. Of 333 included adult patients, the sensitivity of ImmuView and BinaxNOW was 27% for both tests and specificities were 98% and 100%, respectively. The interassay agreement was good (κ = 0.61). There was no significant difference in test performance between frozen and unfrozen samples. In samples from children, the sensitivities of ImmuView and BinaxNOW were 67% and 70%, respectively. In conclusion, the ImmuView RSV test showed low sensitivity and high specificity for identifying RSV in adult patients with influenza-like symptoms, comparable with the BinaxNOW RSV test. Rapid RSV testing is of limited value for diagnosing RSV infection in adults.

IMPORTANCE: By timely RSV diagnosis among patients with influenza-like symptoms, especially when influenza diagnostics turn negative, it is possible to prevent unnecessary antibiotic usage as well as reduce diagnostic testing, nosocomial transmission, and hospital stay. Previous rapid RSV tests have demonstrated poor sensitivity in adults, and we could demonstrate that the novel ImmuView RSV test similarly showed limited value for diagnosing RSV infection in adult patients. However, in contrast to many other studies, we investigated patient characteristics in cases with false-positive tests and we compared the performance between unfrozen and frozen samples. Thus, our results are important, as they generate new knowledge about rapid antigen tests.

BACKGROUND: Myocardial infarction with nonobstructive coronary arteries (MINOCA) occurs in 5% to 10% of all patients with myocardial infarction. Clinical trials of secondary prevention treatment in MINOCA patients are lacking. Therefore, the aim of this study was to examine the associations between treatment with statins, renin-angiotensin system blockers, β-blockers, dual antiplatelet therapy, and long-term cardiovascular events.

METHODS: This is an observational study of MINOCA patients recorded in the SWEDEHEART registry (the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapy) between July 2003 and June 2013 and followed until December 2013 for outcome events in the Swedish Cause of Death Register and National Patient Register. Of 199 162 myocardial infarction admissions, 9466 consecutive unique patients with MINOCA were identified. Among those, the 9136 patients surviving the first 30 days after discharge constituted the study population. Mean age was 65.3 years, and 61% were women. No patient was lost to follow-up. A stratified propensity score analysis was performed to match treated and untreated groups. The association between treatment and outcome was estimated by comparing between treated and untreated groups by using Cox proportional hazards models. The exposures were treatment at discharge with statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, and dual antiplatelet therapy. The primary end point was major adverse cardiac events defined as all-cause mortality, hospitalization for myocardial infarction, ischemic stroke, and heart failure.

RESULTS: At discharge, 84.5%, 64.1%, 83.4%, and 66.4% of the patients were on statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, and dual antiplatelet therapy, respectively. During the follow-up of a mean of 4.1 years, 2183 (23.9%) patients experienced a major adverse cardiac event. The hazard ratios (95% confidence intervals) for major adverse cardiac events were 0.77 (0.68-0.87), 0.82 (0.73-0.93), and 0.86 (0.74-1.01) in patients on statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and β-blockers, respectively. For patients on dual antiplatelet therapy followed for 1 year, the hazard ratio was 0.90 (0.74-1.08).

CONCLUSIONS: The results indicate long-term beneficial effects of treatment with statins and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on outcome in patients with MINOCA, a trend toward a positive effect of β-blocker treatment, and a neutral effect of dual antiplatelet therapy. Properly powered randomized clinical trials to confirm these results are warranted.

BACKGROUND: Electroconvulsive therapy (ECT) is used to treat severe psychiatric disorders and is associated with reduced risk of suicide and all-cause mortality in patients with severe depression. We investigated the causes of death occurring shortly after ECT and identified potential risk factors for medical causes of death.

METHODS: Patients treated with ECT between 2012 and 2018 were included in this Swedish register-based study. Multivariate binary logistic regression was used to calculate odds ratios for covariates to determine potential predictors of 30-day mortality.

RESULTS: Of the 20,225 included patients, 93 (0.46 %) died of suicide and 123 (0.61 %) died of medical causes after ECT. Cardiovascular disease was the most common medical cause of death (n = 49, 40 %). An older age, a Charlson Comorbidity Index of 1 or more, atrial fibrillation, kidney disease, reflux disease, dementia, and cancer were associated with increased risk of death by medical causes.

LIMITATIONS: Real-life observational studies based on registry data may demonstrate associations, but cannot determine causality. If medical records had been available, we would be better able to determine if deaths were due to the ECT, anesthesia, pre-existing medical conditions, or the mental disorder.

CONCLUSIONS: ECT appears to be a low-risk medical procedure. Older individuals with severe somatic diseases have the highest risk of death and extra measures should be considered to optimize their medical health during the pre-ECT workup, and during and after ECT.

Aim: The overarching aim of the thesis was to explore the occurrence and clinical importance of two manifestations of myocardial injury; unrecognized myocardial injury (UMI) and altered levels of cardiac biochemical markers in patients with stable coronary artery disease (CAD).

Methods: A prospective multicenter cohort study investigated the prevalence, localization, size, and prognostic implication of UMI in 235 patients with stable CAD. Late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) imaging and coronary angiography were used. The relationship between UMI and severe CAD and cardiac biochemical markers was explored. In a substudy the short- and longterm individual variation in cardiac troponins I and T (cTnI, cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were investigated.

Results: The prevalence of UMI was 25%. Subjects with severe CAD were significantly more likely to exhibit UMI than subjects without CAD. There was a strong association between stenosis ≥70% and presence of UMI in the myocardial segments downstream. The presence of UMI was associated with a significant threefold risk of adverse events during follow up. After adjustments UMI was associated with a nonsignificant numerically doubled risk. The levels of cTnI, NT-proBNP, and Galacin-3 were associated with the presence of UMI in univariate analyses. The association between levels of cTnI and presence of UMI remained significant after adjustment. The individual variation in cTnI, cTnT, and NT-proBNP in subjects with stable CAD appeared similar to the biological variation in healthy individuals.

Conclusions: UMI is common and is associated with significant CAD, levels of biochemical markers, and an increased risk for adverse events. A change of >50% is required for a reliable short-term change in cardiac troponins, and a rise of >76% or a fall of >43% is required to detect a long-term reliable change in NT-proBNP.

Myocardial infarction with non-obstructive coronary arteries (MINOCA) is common and occurs in 6-8% of all patients fulfilling the diagnostic criteria for acute myocardial infarction (AMI). This paper describes the rationale behind the trial 'Randomized Evaluation of Beta Blocker and ACE-Inhibitor/Angiotensin Receptor Blocker Treatment (ACEI/ARB) of MINOCA patients' (MINOCA-BAT) and the need to improve the secondary preventive treatment of MINOCA patients. METHODS: MINOCA-BAT is a registry-based, randomized, parallel, open-label, multicenter trial with 2:2 factorial design. The primary aim is to determine whether oral beta blockade compared with no oral beta blockade, and ACEI/ARB compared with no ACEI/ARB, reduce the composite endpoint of death of any cause, readmission because of AMI, ischemic stroke or heart failure in patients discharged after MINOCA without clinical signs of heart failure and with left ventricular ejection fraction ≥40%. A total of 3500 patients will be randomized into four groups; e.g. ACEI/ARB and beta blocker, beta blocker only, ACEI/ARB only and neither ACEI/ARB nor beta blocker, and followed for a mean of 4 years. SUMMARY: While patients with MINOCA have an increased risk of serious cardiovascular events and death, whether conventional secondary preventive therapies are beneficial has not been assessed in randomized trials. There is a limited basis for guideline recommendations in MINOCA. Furthermore, studies of routine clinical practice suggest that use of secondary prevention therapies in MINOCA varies considerably. Thus results from this trial may influence future treatment strategies and guidelines specific to MINOCA patients.

BACKGROUND: A rise or fall of cardiac troponin is a prerequisite for the diagnosis of acute myocardial infarction. Defining significant changes requires knowledge of both biological and analytical variation. The short-term biological variation of cardiac troponin in healthy individuals is 3%-48%. However, healthy individuals may not be representative for patients in whom cardiac troponin measurement is often of clinical importance. Therefore, we studied the individual variation of cardiac troponin in patients with symptoms of stable coronary artery disease.

METHODS: Twenty-four patients scheduled for elective coronary angiography were included. Blood samples were drawn once at enrollment and serially at six 4-h intervals on the day before coronary angiography. Cardiac troponin was measured with hs-cTn assays from Abbott Laboratories (premarket cTnI assay) and Roche Diagnostics (Elecsys® cTnT assay with two different lots).

RESULTS: The short-term individual variation in cardiac troponin I (cTnI) was 14%, the reference change value (RCV) 49%, and RCV-log-normal (rise/fall) 54%/-35%. The corresponding values for cTnT were 7%, 23%, and 26%/-21%. The long-term variation for cTnI was 24%, RCV 69%, and RCV-log-normal (rise/fall) 97%/-49%. The corresponding values for cTnT were 11%, 32%, and 37%/-27%.

CONCLUSIONS: The short-term individual variation of cardiac troponin in patients with symptoms of stable coronary artery disease is similar to the biological variation previously demonstrated in healthy individuals. Our results suggest that a change in cardiac troponin concentrations of >50% can be used in attempting to diagnose acute myocardial injury. To detect significant long-term changes in cardiac troponin concentrations, larger changes will be required.

Background: In addition to diagnosis of heart failure (HF) natriuretic peptides (BNP and NT-proBNP) may be used for risk prediction in stable and acute coronary artery disease. The aim of the study was to evaluate the short- and long-term individual variation of NT-proBNP in patients with stable coronary artery disease.

Methods: Twenty-four patients with suspected stable coronary artery disease and scheduled for elective coronary angiography were included. Blood samples were drawn at enrolment and, on average 3 weeks later, serially the day prior to coronary angiography. NT-proBNP was determined using Elecsys proBNP sandwich immunoassay (Roche Diagnostics).

Results: The individual variation in NT-proBNP over 4 h was 11.8%, over 20 h 12.4% and over 3 weeks 20.4%. The corresponding positive and negative lognormal reference change values (RCV) were +41/-29%, +42/-30% and + 76/-43%, respectively. No significant circadian variation was found.

Conclusions: Our results suggest that an increase in NT-proBNP levels of >42% or a decrease of >30% is needed to indicate a reliable short-term change; and for a long-term change an increase of >76% or a decrease of >43% is required. This should be considered when interpreting changes in NT-proBNP levels.

Background: Myocardial infarction (MI) with non-obstructive coronary arteries (MINOCAs) is an increasingly recognized entity. No previous study has evaluated predictors for new major adverse cardiacvascular events (MACEs) and death in patients with MINOCA.

Methods: We conducted an observational study of MINOCA patients recorded between July 2003 and June 2013 and followed until December 2013 for outcome events. Out of 199,163 MI admissions, 9092 consecutive unique patients with MINOCA were identified. The mean age was 65.5 years and 62% were women. MACE was defined as all-cause mortality, rehospitalization for acute MI, ischemic stroke and heart failure. Hazard ratio and 95% confidence interval (HR; 95% CI) was calculated using Cox-regression.

Results: A total of 2147 patients (24%) experienced a new MACE and 1254 patients (14%) died during the mean follow-up of 4.5 years. Independent predictors for MACE after adjustment, were older age (1.05; 1.04-1.06), diabetes (1.44; 1.21-1.70), hypertension (1.25; 1.09-1.43), current smoking (1.38; 1.15-1.66), previous myocardial infarction (1.38; 1.04-2.82), previous stroke (1.69; 1.35-2.11), peripheral vascular disease (1.55; 1.97-2.23), chronic obstructive pulmonary disease (1.63; 1.32-2.00), reduced left ventricular ejection fraction (2.00; 1.54-2.60), lower level of total cholesterol (0.88; 0.83-0.94) and higher level of creatinine (1.01; 1.00-1.03). Independent predictors for all cause death were age, current smoking, diabetes, cancer, chronic obstructive pulmonary disease, previous stroke, reduced left ventricular fraction, lower level of total cholesterol and higher levels of creatinine and CRP.

Conclusions: The clinical factors predicting new MACE and death of MINOCA patients seem to be strikingly similar to factors previously shown to predict new cardiovascular events in patients with MI and obstructive coronary artery disease.

BACKGROUND: Many acute cardiovascular events such as myocardial infarction (MI) follow circadian rhythms. Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a newly noticed entity with limited data on onset pattern and its impact on prognosis.

MATERIAL AND METHODS: In this observational study of Swedish MINOCA patients registered in the SWEDEHEART registry between 2003-2013 and followed until December 2013 we identified 9,092 unique patients with MINOCA out of 199,163 MI admissions in total. Incidence rate ratios (IRR) were calculated for whole hours, parts of the day, weekdays, months, seasons and major holidays.

RESULTS: The mean age was 65.5 years, 62.0% were women and 16.6% presented with STEMI. The risk for MINOCA proved to be most common in the morning (IRR = 1.70, 95% CI [1.63-1.84]) with a peak at 08.00 AM (IRR = 2.25, 95% CI [1.96-2.59]) and on Mondays (IRR = 1.28, 95% CI [1.18-1.38]). No altered risk was detected during the different seasons, the Christmas and New Year holidays or the Swedish Midsummer festivities. There was no association between time of onset of MINOCA and short- or long-term prognosis.

CONCLUSION: The onset of MINOCA shows a circadian and circaseptan variation with increased risk at early mornings and Mondays, similar to previous studies on all MI, suggesting stress related triggering. However, during holidays were traditional MI increase, we did not see any increase for MINOCA. No association was detected between time of onset and prognosis, indicating that the underlying pathological mechanisms of MINOCA and the quality of care are similar at different times of onset but triggering mechanism may be more active early mornings and Mondays.

Background: Clinically unrecognized myocardial infarctions (UMI) are not uncommon and may be associated with adverse outcome. The aims of this study were to determine the prognostic implication of UMI in patients with stable suspected coronary artery disease (CAD) and to investigate the associations of UMI with the presence of CAD.

Methods and Findings: In total 235 patients late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) imaging and coronary angiography were performed. For each patient with UMI, the stenosis grade of the coronary branch supplying the infarcted area was determined. UMIs were present in 25% of the patients and 67% of the UMIs were located in an area supplied by a coronary artery with a stenosis grade >= 70%. In an age-and gender-adjusted model, UMI independently predicted the primary endpoint (composite of death, myocardial infarction, resuscitated cardiac arrest, hospitalization for unstable angina pectoris or heart failure within 2 years of follow-up) with an odds ratio of 2.9; 95% confidence interval 1.1-7.9. However, this association was abrogated after adjustment for age and presence of significant coronary disease. There was no difference in the primary endpoint rates between UMI patients with or without a significant stenosis in the corresponding coronary artery.

Conclusions: The presence of UMI was associated with a threefold increased risk of adverse events during follow up. However, the difference was no longer statistically significant after adjustments for age and severity of CAD. Thus, the results do not support that patients with suspicion of CAD should be routinely investigated by LGE-CMR for UMI. However, coronary angiography should be considered in patients with UMI detected by LGE-CMR.

Background: Both unrecognized myocardial infarction (UMI) and elevated levels of biomarkers are common in patients with stable coronary artery disease (CAD). The objective of this study was to determine the association between levels of cardiac biomarkers, UMI and extent of CAD in patients with stable CAD.

Methods: A total of 235 patients (median age: 65years; 34% women) with stable CAD without previously known myocardial infarction were examined with late gadolinium enhancement cardiovascular magnetic resonance imaging and coronary angiography. Blood samples were drawn at enrolment and high sensitivity cardiac troponin I (cTnI), NT-proBNP and Galectin-3 were analyzed.

Results: UMI was detected in 58 patients (25%). The median levels of cTnI, NT-proBNP and Galectin-3 were significantly higher in patients with UMI compared to those without, (p<0.001, p=0.006 and p=0.033, respectively). After adjustment for cardiovascular risk factors, left ventricular ejection fraction and renal function, cTnI remained independently associated with the presence of UMI (p=0.031) and the extent of CAD (p=0.047). Neither NT-proBNP, nor Galectin-3, was independently associated with UMI or extent of CAD.

Conclusions: The independent association between levels of cTnI and UMI indicates a common pathophysiological pathway for the cTnI elevation and development of UMI.

Clinical trial registration: ClinicalTrials.gov (NCT01257282).

Background: Unrecognized myocardial infarctions (UMIs) are common. The study is an extension of a previous study, aiming to investigate the long-term (>5 year) prognostic implication of late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) detected UMI in patients with suspected stable coronary artery disease (CAD) without previously diagnosed myocardial infarction (MI).

Methods: In 235 patients with suspected stable CAD without previous MI, LGE-CMR imaging and coronary angiography were performed. LGE with a subendocardial component detectable in more than one imaging plane was required to indicate UMI. The stenosis grade of the coronary arteries was determined, including in the artery supplying an infarcted area. Stenosis >= 70% stenosis was considered significant. Patients were followed for 5.4 years in mean regarding a composite endpoint of cardiovascular death, MI, hospitalization due to heart failure, stable or unstable angina.

Results: UMI were present in 58 of 235 patients (25%). Thirty-nine of the UMIs were located downstream of a significant coronary stenosis. During the follow-up 40 patients (17.0%) reached the composite endpoint. Of patients with UMI, 34.5% (20/58) reached the primary endpoint compared to 11.3% (20/177) of patients with no UMI (HR 3.7, 95% CI 2.0 +/- 6.9, p<0.001). The association between UMI and outcome remained (HR 2.3, 95% CI 1.2 +/- 4.4, p = 0.012) after adjustments for age, gender, extent of CAD and all other variables univariate associated with outcome. Sixteen (41%) of the patients with an UMI downstream of a significant stenosis reached the endpoint compared to four (21%) patients with UMI and no relation to a significant stenosis (HR 2.4, 95% CI 0.8 +/- 7.2, p = 0.12).

Conclusion: The presence of UMI was independently associated with an increased risk of cardiovascular events during long-term follow up.

Aims: Influenza may cause myocardial injury and trigger acute cardiovascular events. The aim of this study was to investigate the prevalence and prognostic implications of elevated high-sensitivity cardiac troponin I (hs-cTnI) in patients with influenza.

Methods and results: In this prospective cohort study, we consecutively enrolled patients with influenza-like illness from two emergency departments in Sweden during three seasons of influenza, 2017-20. Ongoing Influenza infection was diagnosed by polymerase chain reaction and blood samples were collected for later analysis of hs-cTnI. All patients were followed-up for a composite endpoint of major adverse cardiovascular events (MACE) including death, myocardial infarction, unstable angina, heart failure, atrial fibrillation, and stroke within 1 year. Of the 466 patients with influenza-like symptoms, 181 (39%) were positive for influenza. Fifty (28%) patients were hospitalized. High-sensitivity cTnI was elevated in 11 (6%) patients and 8 (4%) experienced MACE. In univariate analyses, MACE was associated with age [hazard ratio (HR): 1.14, 95% confidence interval (CI): 1.05-1.23], hypertension (HR 5.56, 95%CI: 1.12-27.53), estimated glomerular filtration rate (HR: 0.94, 95%CI: 0.91-0.97), and elevated hs-cTnI (HR: 18.29, 95%CI: 4.57-73.24), N-terminal prohormone of brain natriuretic peptide (HR: 14.21, 95%CI: 1.75-115.5), hs-CRP (HR: 1.01, 95%CI: 1.00-1.02), and white blood cell count (HR: 1.12, 95%CI: 1.01-1.25). In multivariate analysis, elevated hs-cTnI was independently associated with MACE (HR: 4.96, 95%CI: 1.10-22.41).

Conclusion: The prevalence of elevated hs-cTnI is low in unselected patients with influenza. Elevated hs-cTnI was associated with poor prognosis. A limitation is that the estimated associations are uncertain due to few events.

BACKGROUND: Myocardial infarction (MI) with non-obstructive coronary arteries (MINOCA) is common. There are limited data on the mechanisms and prognosis for reinfarction in MINOCA patients.

METHODS: In this observational study of MINOCA patients hospitalized in Sweden and registered in the SWEDEHEART registry between July 2003 and June 2013 and followed until December 2013 we identified 9,092 unique patients with MINOCA out of 199,163 MI admissions in total. The 570 (6.3%) MINOCA patients who were hospitalized due to a recurrent MI constituted the study group.

RESULTS: The mean age was 69.1 years and 59.1% were women. The median time to readmission was 17 months. A total of 340 patients underwent a new coronary angiography and 180 (53%) had no obstructive coronary artery disease (CAD) and 160 (47%) had obstructive CAD; 123 had one-vessel, 26 had two-vessel, 9 had three-vessel disease and two had left main together with one-vessel disease. Male gender, diabetes, peripheral vascular disease, higher levels of creatinine and ST-elevation at presentation were more common in patients with MI with obstructive CAD than in patients with a recurrent MINOCA. Mortality during a median follow-up of 38 months was similar whether the reinfarction event was MINOCA or MI with obstructive CAD 13.9% vs. 11.9% (p=0.54).

CONCLUSIONS: About half of patients with reinfarction after MINOCA who underwent coronary angiography had progression of coronary stenosis. Angiography should be strongly considered in patients with MI after MINOCA. Mortality associated with recurrent events was substantial, though there was no difference in mortality between those with or without significant CAD.

BACKGROUND: The cardiovascular response during electroconvulsive therapy (ECT) could induce major adverse cardiovascular events (MACE) in the short-term, while reduced depression could decrease the risk of MACE in the long-term. The balance between these potential effects has not been thoroughly investigated.

METHODS: This nationwide, registry-based cohort study included all patients admitted to Swedish hospitals due to moderate or severe unipolar depression between 2011 and 2018. Patients were divided into an ECT group and a non-ECT group, and followed for 1 year. Patients were matched by risk factors for cardiovascular disease by propensity score matching. Cox regression was used to examine the association between ECT and MACE.

RESULTS: Out of a total of 28 584 inpatients, 5476 patients who had received ECT were matched to 5476 non-ECT patients. ECT was associated with reduced risk of MACE within 90 days and 1 year. Within 1 year after admission, a total of 127 patients (2.3%) in the non-ECT group and 82 patients (1.4%) in the ECT group had at least one MACE (hazard ratio [HR], 0.65; 95% confidence interval, 0.49-0.85).

LIMITATIONS: Real-life observational studies carry risk for residual confounding.

CONCLUSIONS: ECT in patients hospitalized for depression was not associated with any significant short-term risks of cardiovascular events. Instead, ECT was associated with a reduced risk of MACE within 1 year after admission compared with patients not treated with ECT. This association may be explained by reduced depressive symptoms after ECT, improved risk factor management in the ECT-group or by residual confounding by indication.

BACKGROUND: Suspected myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) occurs in ≈5% to 10% of patients with MI referred for coronary angiography. The prognosis of these patients may differ to those with MI and obstructive coronary artery disease (MI-CAD) and those without a MI (patients without known history of MI [No-MI]). The primary objective of this study is to evaluate the 12-month all-cause mortality of patients with MINOCA.

METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the terms "MI," "nonobstructive," "angiography," and "prognosis" were searched in PubMed and Embase databases from inception to December 2018, including original, English language MINOCA studies with >100 consecutive patients. Publications with a heterogeneous cohort, unreported coronary stenosis, or exclusively focusing on MINOCA-mimicking conditions, were excluded. Unpublished data were obtained from the MINOCA Global Collaboration. Data were pooled and analyzed using Paule-Mandel, Hartung, Knapp, Sidik & Jonkman, or restricted maximum-likelihood random-effects meta-analysis methodology. Heterogeneity was assessed using Cochran's Q and I² statistics. The primary outcome was 12-month all-cause mortality in patients with MINOCA, with secondary comparisons to MI-CAD and No-MI.

RESULTS: The 23 eligible studies yielded 55 369 suspected MINOCA, 485 382 MI-CAD, and 33 074 No-MI. Pooled meta-analysis of 14 MINOCA studies accounting for 30 733 patients revealed an unadjusted 12-month all-cause mortality rate of 3.4% (95% CI, 2.6%-4.2%) and reinfarction (n=27 605; 10 studies) in 2.6% (95% CI, 1.7%-3.5%). MINOCA had a lower 12-month all-cause mortality than those with MI-CAD (3.3% [95% CI, 2.5%-4.1%] versus 5.6% [95% CI, 4.1%-7.0%]; odds ratio, 0.60 [95% CI, 0.52-0.70], P<0.001). In contrast, there was a statistically nonsignificant trend towards increased 12-month all-cause mortality in patients with MINOCA (2.6% [95% CI, 0%-5.9%]) compared with No-MI (0.7% [95% CI, 0.1%-1.3%]; odds ratio, 3.71 [95% CI, 0.58-23.61], P=0.09).

CONCLUSIONS: In the largest contemporary MINOCA meta-analysis to date, patients with suspected MINOCA had a favorable prognosis compared with MI-CAD, but statistically nonsignificant trend toward worse outcomes compared to those with No-MI. Registration: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42020145356.

Introduction: Myocardial infarction with non-obstructive coronary arteries (MINOCA) occurs in ~10% of all patients with acute myocardial infarction (AMI), with an over-representation amongst women. Remarkably, it is estimated that as many as 1 in 4 patients with MINOCA experience ongoing angina at 12 months despite having no flow-restricting stenoses in their epicardial arteries. This manuscript presents the rationale behind Randomized Evaluation of Beta Blocker and Angiotensin-converting enzyme inhibitors/Angiotensin Receptor Blocker Treatment (ACEI/ARB) for Post Infarct Angina in MINOCA patients-The MINOCA BAT post infarct angina sub study.

Methods: This trial is a registry-based, randomized, parallel, open-label, multicenter trial with 2 × 2 factorial design. The primary aim is to determine whether oral beta blockade compared with no oral beta blockade, and ACEI/ARB compared with no ACEI/ARB, reduce post infarct angina in patients discharged after MINOCA without clinical signs of heart failure and with left ventricular ejection fraction ≥40%. A total of 664 patients will be randomized into four groups; (i) ACEI/ARB with beta blocker, (ii) beta blocker only, (iii) ACEI/ARB only, or (iv) neither ACEI/ARB nor beta blocker and followed for 12 months.

Results: The trial is currently recruiting in Australia and Sweden. Fifty six patients have been recruited thus far. Both sexes were equally distributed (52% women and 48% men) and the mean age was 56.3 ± 9.9 years.

Conclusions: It remains unclear whether conventional secondary preventive therapies are beneficial to MINOCA patients in regard to post infarct angina. Existing registry-based literature suggest cardioprotective agents are less likely to be used in MINOCA patients. Thus, results from this trial will provide insights for future treatment strategies and guidelines specific to MINOCA patients.

BACKGROUND: Cardiovascular events are the leading cause of death in end stage renal disease (ESRD), but traditional markers of dyslipidemia are not clearly associated with cardiovascular risk in this population. Proprotein Convertase Subtilsin/Kexin type 9 (PCSK-9) could be of interest as a novel cardiovascular risk marker in ESRD due to the emergence of lipid lowering therapy based on PCSK-9 inhibition. The aim of the present study was to investigate if the convertase PCSK-9 is a potential risk marker for mortality among patients starting hemodialysis treatment.

MATERIALS AND METHODS: This is a cohort study of 265 patients starting hemodialysis between 1991-2009, with three years follow-up. The association between baseline PCSK-9 levels and mortality was assessed using Cox proportional hazards- and quantile regression models, with adjustment for potential confounders.

RESULTS: PCSK-9 levels at initiation of hemodialysis were associated to mortality in multivariable adjusted analysis. PCSK-9 levels exhibited an U-shaped association to mortality. Inclusion of the quadratic term of PCSK-9 in regression modeling optimized model performance. At baseline, PCSK-9 levels had positive correlations to Davies comorbidity score, hemoglobin and C-reactive protein while negative correlations were found for high-density lipoprotein and total cholesterol. PCSK-9 levels were higher in statin users and patients with a history of cardiovascular disease.

CONCLUSIONS: This study shows, for the first time, that the level of PCSK-9 is associated with all-cause mortality in hemodialysis patients, independently of a number of potential confounders.