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Objectives: Biomarker concentrations and their changes during acute coronary syndrome (ACS) provide clinically useful information on pathophysiological processes, e.g. myocardial necrosis, hemodynamic stress and inflammation. However, current evidence on temporal biomarker patterns early during ACS is limited, and studies investigating multiple biomarkers are lacking. Methods: We measured concentrations of high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI), NT-terminal pro-B-type natriuretic peptide, C-reactive protein, and growth-differentiation factor-15 (GDF-15) in plasma samples obtained at randomization in ACS patients from the PLATelet inhibition and patient Outcomes (PLATO) trial. Linear regressions with interaction analyses were used to investigate the associations of biomarker concentrations with the time from symptom onset and to model temporal biomarker concentration patterns. Results: The study population consisted of 16,944 patients (median age 62 years; 71.3 % males) with 6,853 (40.3 %) having ST-elevation myocardial infarction (STEMI) and 10,141 (59.7 %) having non-ST-elevation ACS (NSTE-ACS). Concentrations of all biomarkers were associated with time from symptom onset (pinteraction<0.001), apart for GDF-15 (pinteraction=0.092). Concentration increases were more pronounced in STEMI compared to NSTE-ACS. Temporal biomarker patterns for hs-cTnT and hs-cTnI were different depending on sex whereas biomarker patterns for the other biomarkers were similar in cohorts defined by age and sex. Conclusions: Temporal concentration patterns differ for various biomarkers early during ACS, reflecting the variability in the activation and duration of different pathophysiological processes, and the amount of injured myocardium. Our data emphasize that the time elapsed from symptom onset should be considered for the interpretation of biomarker results in ACS.

Background: The pathobiology of myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) is often uncertain. Investigating biomarker concentrations and their changes may offer novel pathophysiological insights. Methods and Results: In this post hoc study of the PLATO (Platelet Inhibition and Patient Outcomes) trial, concentrations of hs‐cTnT (high‐sensitivity cardiac troponin T), NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), hs‐CRP (high‐sensitivity C‐reactive protein), and GDF‐15 (growth differentiation factor 15) were measured in patients with MINOCA at baseline (n=554) and at 1‐month follow‐up (n=107). For comparisons, biomarkers were also measured in patients with MI with obstructive (stenosis ≥50%) coronary artery disease (baseline: n=11 106; follow‐up: n=2755]). Adjusted linear regression models were used to compare concentrations and their short‐ and long‐term changes. The adjusted geometric mean ratios (GMRs) in patients with MINOCA (median age, 61 years; 50.4% women) indicated lower hs‐cTnT (GMR, 0.77 [95% CI, 0.68–0.88]) but higher hs‐CRP (GMR, 1.21 [95% CI, 1.08–1.37]) and GDF‐15 concentrations (GMR, 1.06 [95% CI, 1.02–1.11]) at baseline compared with patients with MI with obstructive coronary artery disease, whereas NT‐proBNP concentrations were similar. Temporal decreases in hs‐cTnT, NT‐proBNP, and hs‐CRP concentrations until 1‐month follow‐up were more pronounced in patients with MINOCA. At follow‐up, patients with MINOCA had lower concentrations of hs‐cTnT (GMR, 0.71 [95% CI, 0.60–0.84]), NT‐proBNP (GMR, 0.45 [95% CI, 0.36–0.56]), and hs‐CRP (GMR, 0.68 [95% CI, 0.53–0.86]). One‐month GDF‐15 concentrations were similar between both groups with MI. Conclusions: Biomarker concentrations suggest greater initial inflammatory activity, similar degree of myocardial dysfunction, and less pronounced myocardial injury during the acute phase of MINOCA compared with MI with obstructive coronary artery disease but also faster myocardial r, Title in dissertation list of papers: Biomarker concentrations and their temporal changes in myocardial infarction patients with non-obstructive compared to obstructive coronary arteries: results from the PLATelet inhibition and patient Outcomes (PLATO) trial

Despite poor prognosis, patients with type 2 myocardial infarction (MI) tend to be underdiagnosed and undertreated compared to those with type 1 MI. Whether this discrepancy has improved over time is uncertain. We conducted a registry-based cohort study investigating type 2 MI patients managed at Swedish coronary care units (n = 14,833) during 2010–2022. Multivariable-adjusted changes (first three vs last three calendar years of the observation period) were assessed regarding diagnostic examinations (echocardiography, coronary assessment), provision of cardioprotective medications (betablockers, renin–angiotensin–aldosterone-system inhibitors, statins) and 1-year all-cause mortality. Compared to type 1 MI patients (n = 184,329), those with type 2 MI less often had diagnostic examinations and cardioprotective medications. Increases in the use of echocardiography (OR 1.08 [95% confidence interval 1.06–1.09]) and coronary assessment (OR 1.06 [95% confidence interval 1.04–1.08]) were smaller compared to type 1 MI (pinteraction < 0.001). The provision of medications did not increase in type 2 MI. All-cause mortality rate in type 2 MI was 25.4% without temporal change (OR 1.03 [95% confidence interval 0.98–1.07]). Taken together, the provision of medications and all-cause mortality did ot improve in type 2 MI despite modest increases in diagnostic procedures. This emphasizes the need of defining optimal care pathways in these patients.

Background: Coronavirus disease 2019 (COVID-19) mRNA vaccines are associated with an increased risk of myocarditis using hospital discharge diagnoses as an outcome. The validity of these register-based diagnoses is uncertain. Methods: Patient records for subjects < 40 years of age and a diagnosis of myocarditis in the Swedish National Patient Register were manually reviewed. Brighton Collaboration diagnosis criteria for myocarditis were applied based on patient history, clinical examination, laboratory data, electrocardiograms, echocardiography, magnetic resonance imaging and myocardial biopsy. Poisson regression was used to estimate incidence rate ratios, comparing the register-based outcome variable to validated outcomes. Interrater reliability was assessed by a blinded re-evaluation. Results: Overall, 95.6% (327/342) of cases registered as myocarditis were confirmed (definite, probable or possible myocarditis according to Brighton Collaboration diagnosis criteria, positive predictive value 0.96 [95% CI 0.93–0.98]). Of the 4.4% (15/342) cases reclassified as no myocarditis or as insufficient information, two cases had been exposed to the COVID-19 vaccine no more than 28 days before the myocarditis diagnosis, two cases were exposed >28 days before admission and 11 cases were unexposed to the vaccine. The reclassification had only minor impact on incidence rate ratios for myocarditis following COVID-19 vaccination. In total, 51 cases were sampled for a blinded re-evaluation. Of the 30 randomly sampled cases initially classified as either definite or probably myocarditis, none were re-classified after re-evaluation. Of the in all 15 cases initially classified as no myocarditis or insufficient information, 7 were after re-evaluation re-classified as probable or possible myocarditis. This re-classification was mostly due to substantial variability in electrocardiogram interpretation. Conclusion: This validation of register-based diagnoses of myocarditis by manual

Objectives Measurement of high-sensitivity (hs) cardiac troponin (cTn) T and I is widely studied for cardiac assessment of stable populations. Recent data suggest clinical and prognostic discrepancies between both hs-cTn. We aimed at reviewing published studies with respect to underlying causes and clinical implications. Content We summarized current evidence on release and clearance mechanisms of cTnT and I, and on preanalytical and assay-related issues potentially portending to differences in measured concentrations. We also performed a systematic review of outcome studies comparing both hs-cTn in the general population, patients with congestive heart failure, stable coronary artery disease and atrial fibrillation. Summary and outlook For the interpretation of concentrations of hs-cTnT, stronger association with renal dysfunction compared to hs-cTnI should be considered. Hs-cTnT also appears to be a stronger indicator of general cardiovascular morbidity and all-cause mortality. Hs-cTnI concentrations tend to be more sensitive to coronary artery disease and ischemic outcomes. These findings apparently reflect variations in the mechanisms of cardiac affections resulting in cTn release. Whether these differences are of clinically relevance remains to be elucidated. However, having the option of choosing between either hs-cTn might represent an option for framing individualized cardiac assessment in the future.

Aims To define plasma concentrations, determinants, and optimal prognostic cut-offs of soluble suppression of tumorigenesis-2 (sST2), high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in women and men with chronic heart failure (HF). Methods and results Individual data of patients from the Biomarkers In Heart Failure Outpatient Study (BIOS) Consortium with sST2, hs-cTnT, and NT-proBNP measured were analysed. The primary endpoint was a composite of 1 year cardiovascular death and HF hospitalization. The secondary endpoints were 5 year cardiovascular and all-cause death. The cohort included 4540 patients (age 67 +/- 12 years, left ventricular ejection fraction 33 +/- 13%, 1111 women, 25%). Women showed lower sST2 (24 vs. 27 ng/mL, P < 0.001) and hs-cTnT level (15 vs. 20 ng/L, P < 0.001), and similar concentrations of NT-proBNP (1540 vs. 1505 ng/L, P = 0.408). Although the three biomarkers were confirmed as independent predictors of outcome in both sexes, the optimal prognostic cut-off was lower in women for sST2 (28 vs. 31 ng/mL) and hs-cTnT (22 vs. 25 ng/L), while NT-proBNP cut-off was higher in women (2339 ng/L vs. 2145 ng/L). The use of sex-specific cut-offs improved risk prediction compared with the use of previously standardized prognostic cut-offs and allowed to reclassify the risk of many patients, to a greater extent in women than men, and for hs-cTnT than sST2 or NT-proBNP. Specifically, up to 18% men and up to 57% women were reclassified, by using the sex-specific cut-off of hs-cTnT for the endpoint of 5 year cardiovascular death. Conclusions In patients with chronic HF, concentrations of sST2 and hs-cTnT, but not of NT-proBNP, are lower in women. Lower sST2 and hs-cTnT and higher NT-proBNP cut-offs for risk stratification could be used in women.

Background: While the clinical importance of cardiac troponin is well-known in type 1 myocardial infarction (MI), evidence on this topic in type 2 MI is limited. We assessed the clinical and prognostic implications of high sensitivity cardiac troponin (hs-cTnT) concentrations in a large sample of patients with type 2 MI. Methods: Retrospective registry-based cohort study (SWEDEHEART) including 4607 patients with type 2 MI and 43,405 patients with type 1 MI, used for comparisons. Patients with ST-elevation MI were excluded. Multivariable-adjusted regressions were applied to investigate the associations of hs-cTnT concentrations (highest measured value during each hospitalization) with clinical variables and prognosis during a median follow-up of up to 1.9 years. Results: Hs-cTnT concentrations (median 264 [25th, 75th percentiles 112-654] ng/L) were significantly associated with various cardiovascular risk factors and comorbidities in type 2 non-ST elevation MI (NSTEMI) but only weakly with the underlying triggering condition. Most of these findings including the magnitude of hs-cTn release were similar to type 1 NSTEMI. Hs-cTnT (ln) independently predicted all-cause mortality (hazard ratio 1.13 [95% confidence interval 1.09-1.17]) and major adverse events (hazard ratio 1.13 [95% confidence interval 1.10-1.17]) in type 2 NSTEMI, similar as for type 1 NSTEMI according to interaction analysis. The associations of hs-cTnT (ln) with poor prognosis tended to be stronger in type 2 NSTEMI patients without known cardiovascular disease. Conclusions: Hs-cTnT concentrations independently predict adverse outcome in type 2 NSTEMI. The similarities to type 1 NSTEMI however, are striking and emphasize the difficulty to distinguish both MI types.

Background: Echocardiographic measures are known predictors of cardiovascular disease (CVD) in the general population. This study compared the predictive value of such measures to that of circulating cardiac biomarkers for a composite cardiovascular disease outcome in an aging population. Methods: In this prospective population-based cohort study, echocardiography was performed at baseline together with assessments of traditional CVD risk factors and circulating cardiac biomarkers, NT-proBNP and troponin I, in 1016 individuals all aged 70 years. Assessments were repeated at ages 75 and 80. A composite CVD outcome (myocardial infarction, heart failure or ischemic stroke) was charted over 15 years. All echocardiography variables, except for the E/A ratio, were analyzed on a continuous scale. Results: Over 10 years, left atrial (LA) diameter, left ventricular mass index (LVMI) and high E/A ratio (>1.5) increased, while left ventricular ejection fraction (LVEF) remained unchanged. Using Cox proportional hazard analyses with time-updated variables for echocardiographic measures and traditional risk factors, an enlarged LA diameter and a low LVEF were independently related to incident CVD in 222 participants. The addition of LA diameter and LVEF to traditional risk factors increased the C-statistic by 1.5% (p = 0.008). However, the addition of troponin I and NT-proBNP to traditional risk factors increased the C-statistic by 3.0% (p<0.001). Conclusion: An enlarged LA diameter and a low LVEF improved the prediction of incident CVD compared to traditional risk factors. However, given that troponin I and NT-proBNP improved prediction to a similar extent, the use of simple blood tests to improve clinical cardiovascular disease risk prediction is only further supported by this study.

Background Elevations of high-sensitivity cardiac troponin (hs-cTn) concentrations not related to type 1 myocardial infarction are common in chest pain patients presenting to emergency departments. The discrimination of these patients from those with type 1 myocardial infarction (MI) is challenging and resource-consuming. We aimed to investigate whether the hs-cTn I/T ratio might provide diagnostic and prognostic increment in this context. Methods We calculated the hs-cTn I/T ratio in 888 chest pain patients having hs-cTnI (Abbott Laboratories) or hs-cTnT (Roche Diagnostics) concentrations above the respective 99(th) percentile at 2 hours from presentation. All patients were followed for one year regarding mortality. Results The median hs-cTn I/T ratio was 3.45 (25(th), 75(th) percentiles 1.80-6.59) in type 1 MI patients (n = 408 (sic) 46.0%]), 1.18 (0.81-1.90) in type 2 MI patients (n = 56 (sic) 6.3%]) and 0.67 (0.39-1.12) in patients without MI. The hs-cTn I/T ratio provided good discrimination of type 1 MI from no type 1 MI (area under the receiver-operator characteristic curve 0.89 (sic) 95% confidence interval 0.86-0.91]), of type 1 MI from type 2 MI (area under the curve 0.81 (sic) 95% confidence interval 0.74-0.87]), and was associated with type 1 MI in adjusted analyses. The hs-cTn I/T ratio provided no consistent prognostic value. Conclusions The hs-cTn I/T ratio appears to be useful for early diagnosis of type 1 MI and its discrimination from type 2 MI in chest pain patients presenting with elevated hs-cTn. Differences in hs-cTn I/T ratio values may reflect variations in hs-cTn release mechanisms in response to different types of myocardial injury.

Background: Current guidelines stress the importance of early invasive assessment of patients with non -ST-elevation acute coronary syndrome (NSTE-ACS), in particular those at high risk. However, supporting scientific evidence is limited. Aims: We aimed to investigate the prognostic impact of the timing of coronary angiography in a large cohort of NSTE-ACS patients. Methods: We performed a retrospective analysis including 34,666 NSTE-ACS patients registered from 2013 to 2018 in the SWEDEHEART registry. The prognostic implications of the timing of coronary angi-ography on a continuous scale and within <24 vs 24-72 hours were assessed using Cox regression analyses. Results: The median time interval from admission to invasive assessment was 32.8 (25th, 75th percentiles 20.4-63.8) hours. There was no apparent time window within 96 hours from admission that provided prog-nostic benefit. Coronary angiography within 24-72 hours (vs <24 hours) was not associated with worse out-come overall (all-cause mortality: hazard ratio 1.01, 95% confidence interval [CI] 0.92-1.11; major adverse events: hazard ratio 1.04, 95% CI: 0.98-1.12). Interaction analyses indicated a greater relative benefit of coronary angiography <24 hours in some lower-risk groups (women, non-diabetics, patients with minor tro-ponin elevation) but neutral effects in higher-risk groups (defined by age or the GRACE 2.0 score). Conclusions: These Swedish data do not provide support for an early invasive strategy in NSTE-ACS, especially in high-risk patients. Our results suggest that the timing of invasive assessment should rather be based on individualised decisions integrating symptoms and risk panorama than on strictly defined time intervals.