Increasing numbers of patients are presenting worldwide to emergency departments with suspected myocardial infarction. The use of point-of-care troponin assays might enable faster decision-making in ...this high-risk population and reduce the burden on emergency facilities. Here, we evaluate the diagnostic performance of a point-of-care high-sensitivity troponin I assay.
We conducted a prospective cohort study including patients presenting to the emergency department with suspected myocardial infarction from July 2013 to July 2016. A diagnostic algorithm for a high-sensitivity troponin I point-of-care assay was developed in a derivation data set with 669 patients and validated in an additional 610 patients.
The derived 0/1 h algorithm for the point-of-care assay consisted of an admission troponin I <4 ng/L and a δ from 0 h to 1 h <3 ng/L for rule out and an admission troponin I ≥90 ng/L or a δ from 0 h to 1 h ≥20 ng/L for rule in of non-ST-elevation myocardial infarction. Application to the validation cohort showed a negative predictive value of 99.7% (95% CI, 98.1%-100.0%) and 48.0% of patients ruled out, whereas 14.6% were ruled in with a positive predictive value of 86.5% (95% CI, 77.6%-92.8%). The diagnostic performance of the point-of-care high-sensitivity assay was highly comparable to guideline-recommended use of a laboratory-based high-sensitivity troponin assay.
The clinical application of a 0/1 h diagnostic algorithm based on a high-sensitivity troponin I point-of-care assay is safe, and diagnostic performance is comparable to a laboratory-based high-sensitivity troponin I assay.
Data regarding high-sensitivity troponin concentrations in patients presenting to the emergency department with symptoms suggestive of myocardial infarction may be useful in determining the ...probability of myocardial infarction and subsequent 30-day outcomes.
In 15 international cohorts of patients presenting to the emergency department with symptoms suggestive of myocardial infarction, we determined the concentrations of high-sensitivity troponin I or high-sensitivity troponin T at presentation and after early or late serial sampling. The diagnostic and prognostic performance of multiple high-sensitivity troponin cutoff combinations was assessed with the use of a derivation-validation design. A risk-assessment tool that was based on these data was developed to estimate the risk of index myocardial infarction and of subsequent myocardial infarction or death at 30 days.
Among 22,651 patients (9604 in the derivation data set and 13,047 in the validation data set), the prevalence of myocardial infarction was 15.3%. Lower high-sensitivity troponin concentrations at presentation and smaller absolute changes during serial sampling were associated with a lower likelihood of myocardial infarction and a lower short-term risk of cardiovascular events. For example, high-sensitivity troponin I concentrations of less than 6 ng per liter and an absolute change of less than 4 ng per liter after 45 to 120 minutes (early serial sampling) resulted in a negative predictive value of 99.5% for myocardial infarction, with an associated 30-day risk of subsequent myocardial infarction or death of 0.2%; a total of 56.5% of the patients would be classified as being at low risk. These findings were confirmed in an external validation data set.
A risk-assessment tool, which we developed to integrate the high-sensitivity troponin I or troponin T concentration at emergency department presentation, its dynamic change during serial sampling, and the time between the obtaining of samples, was used to estimate the probability of myocardial infarction on emergency department presentation and 30-day outcomes. (Funded by the German Center for Cardiovascular Research DZHK; ClinicalTrials.gov numbers, NCT00470587, NCT02355457, NCT01852123, NCT01994577, and NCT03227159; and Australian New Zealand Clinical Trials Registry numbers, ACTRN12611001069943, ACTRN12610000766011, ACTRN12613000745741, and ACTRN12611000206921.).
Heart failure following myocardial infarction (MI) remains one of the major causes of death worldwide, and its treatment is a crucial challenge of cardiovascular medicine. An attractive therapeutic ...strategy is to stimulate endogenous mechanisms of myocardial regeneration.
This study evaluates the potential therapeutic treatment with annexin A1 (AnxA1) to induce cardiac repair after MI.
AnxA1 knockout (AnxA1
) and wild-type mice underwent MI induced by ligation of the left anterior descending coronary artery. Cardiac functionality was assessed by longitudinal echocardiographic measurements. Histological, fluorescence-activated cell sorting, dot blot analysis, and in vitro/ex vivo studies were used to assess the myocardial neovascularization, macrophage content, and activity in response to AnxA1.
AnxA1
mice showed a reduced cardiac functionality and an expansion of proinflammatory macrophages in the ischemic area. Cardiac macrophages from AnxA1
mice exhibited a dramatically reduced ability to release the proangiogenic mediator vascular endothelial growth factor (VEGF)-A. However, AnxA1 treatment enhanced VEGF-A release from cardiac macrophages, and its delivery in vivo markedly improved cardiac performance. The positive effect of AnxA1 treatment on cardiac performance was abolished in wild-type mice transplanted with bone marrow derived from Cx
cr1cre
Vegf
or in mice depleted of macrophages. Similarly, cardioprotective effects of AnxA1 were obtained in pigs in which full-length AnxA1 was overexpressed by use of a cardiotropic adeno-associated virus.
AnxA1 has a direct action on cardiac macrophage polarization toward a pro-angiogenic, reparative phenotype. AnxA1 stimulated cardiac macrophages to release high amounts of VEGF-A, thus inducing neovascularization and cardiac repair.
Onset of cardiovascular complications as a consequence of atherosclerosis exhibits a circadian incidence with a peak in the morning hours. Although development of atherosclerosis extends for long ...periods of time through arterial leukocyte recruitment, we hypothesized that discrete diurnal invasion of the arterial wall could sustain atherogenic growth. Here, we show that myeloid cell recruitment to atherosclerotic lesions oscillates with a peak during the transition from the activity to the resting phase. This diurnal phenotype is regulated by rhythmic release of myeloid cell-derived CCL2, and blockade of its signaling abolished oscillatory leukocyte adhesion. In contrast, we show that myeloid cell adhesion to microvascular beds peaks during the early activity phase. Consequently, timed pharmacological CCR2 neutralization during the activity phase caused inhibition of atherosclerosis without disturbing microvascular recruitment. These findings demonstrate that chronic inflammation of large vessels feeds on rhythmic myeloid cell recruitment, and lay the foundation for chrono-pharmacology-based therapy.
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•Myeloid cells adhere to atherosclerotic lesions in a circadian fashion•Circulating myeloid cells deposit CCL2 rhythmically on the arterial endothelium•Myeloid cell adhesion patterns in macro- and microcirculation are 12 hr phase shifted•Chrono-pharmacological treatment strategy targets early atherosclerosis development
Winter et al. identify an oscillatory myeloid cell recruitment pattern to atherosclerotic lesions regulated, in part, by rhythmic deposition of CCL2 on arterial endothelium. These findings lay the foundation for a chrono-pharmacological treatment strategy targeting early lesion development without disturbing microvascular recruitment of myeloid cells.
Abstract
Aims
The recently released 4th version of the Universal Definition of Myocardial Infarction (UDMI) introduces an increased emphasis on the entities of acute and chronic myocardial injury. We ...applied the 4th UDMI retrospectively in patients presenting to the emergency department with symptoms potentially indicating myocardial infarction (MI) to investigate its effect on diagnosis and prognosis.
Methods and results
We included 2302 patients presenting to the emergency department with symptoms suggestive of MI. The final diagnosis was adjudicated sequentially according to the 3rd and 4th UDMI. Reclassification after readjudication was assessed. Established diagnostic algorithms for patients with suspected MI were applied to compare diagnostic accuracy. All patients were followed to assess mortality, recurrent MI, revascularization, and rehospitalization to investigate the effect of the 4th UDMI on prognosis. After readjudication, 697 patients were reclassified. Most of these patients were reclassified as having acute (n = 78) and chronic myocardial injury (n = 585). Four hundred and thirty-four (18.9%) patients were diagnosed with MI, compared with 501 (21.8%) MIs when adjudication was based on the 3rd UDMI. In the non-MI population, patients with myocardial injury (n = 663) were older, more often female and had worse renal function compared with patients without myocardial injury (n = 1205). Application of diagnostic algorithms for patients with suspected MI revealed a high accuracy after readjudication. Reclassified patients had a substantially higher rate of cardiovascular events compared with not-reclassified patients, particularly patients reclassified to the category of myocardial injury.
Conclusion
By accentuating the categories of acute and chronic myocardial injury the 4th UDMI succeeds to identify patients with higher risk for cardiovascular events and poorer outcome and thus seems to improve risk assessment in patients with suspected MI. Application of established diagnostic algorithms remains safe when using the 4th UDMI.
Genome-wide association studies (GWAS) for atrial fibrillation (AF) have uncovered numerous disease-associated variants. Their underlying molecular mechanisms, especially consequences for mRNA and ...protein expression remain largely elusive. Thus, refined multi-omics approaches are needed for deciphering the underlying molecular networks. Here, we integrate genomics, transcriptomics, and proteomics of human atrial tissue in a cross-sectional study to identify widespread effects of genetic variants on both transcript (cis-eQTL) and protein (cis-pQTL) abundance. We further establish a novel targeted trans-QTL approach based on polygenic risk scores to determine candidates for AF core genes. Using this approach, we identify two trans-eQTLs and five trans-pQTLs for AF GWAS hits, and elucidate the role of the transcription factor NKX2-5 as a link between the GWAS SNP rs9481842 and AF. Altogether, we present an integrative multi-omics method to uncover trans-acting networks in small datasets and provide a rich resource of atrial tissue-specific regulatory variants for transcript and protein levels for cardiovascular disease gene prioritization.
Circulating microRNAs (miRNAs) have been described as potential diagnostic biomarkers in cardiovascular disease and in particular, coronary artery disease (CAD). Few studies were undertaken to ...perform analyses with regard to risk stratification of future cardiovascular events. miR-126, miR-197 and miR-223 are involved in endovascular inflammation and platelet activation and have been described as biomarkers in the diagnosis of CAD. They were identified in a prospective study in relation to future myocardial infarction.
The aim of our study was to further evaluate the prognostic value of these miRNAs in a large prospective cohort of patients with documented CAD.
Levels of miR-126, miR-197 and miR-223 were evaluated in serum samples of 873 CAD patients with respect to the endpoint cardiovascular death. miRNA quantification was performed using real time polymerase chain reaction (RT-qPCR).
The median follow-up period was 4 years (IQR 2.78-5.04). The median age of all patients was 64 years (IQR 57-69) with 80.2% males. 38.9% of the patients presented with acute coronary syndrome (ACS), 61.1% were diagnosed with stable angina pectoris (SAP). Elevated levels of miRNA-197 and miRNA-223 reliably predicted future cardiovascular death in the overall group (miRNA-197: hazard ratio (HR) 1.77 per one standard deviation (SD) increase (95% confidence interval (CI) 1.20; 2.60), p = 0.004, C-index 0.78; miRNA-223: HR 2.23 per one SD increase (1.20; 4.14), p = 0.011, C-index 0.80). In ACS patients the prognostic power of both miRNAs was even higher (miRNA-197: HR 2.24 per one SD increase (1.25; 4.01), p = 0.006, C-index 0.89); miRA-223: HR 4.94 per one SD increase (1.42; 17.20), p = 0.012, C-index 0.89).
Serum-derived circulating miRNA-197 and miRNA-223 were identified as predictors for cardiovascular death in a large patient cohort with CAD. These results reinforce the assumption that circulating miRNAs are promising biomarkers with prognostic value with respect to future cardiovascular events.
Abstract
Aims
There is inconsistent evidence on the relation of alcohol intake with incident atrial fibrillation (AF), in particular at lower doses. We assessed the association between alcohol ...consumption, biomarkers, and incident AF across the spectrum of alcohol intake in European cohorts.
Methods and results
In a community-based pooled cohort, we followed 107 845 individuals for the association between alcohol consumption, including types of alcohol and drinking patterns, and incident AF. We collected information on classical cardiovascular risk factors and incident heart failure (HF) and measured the biomarkers N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I. The median age of individuals was 47.8 years, 48.3% were men. The median alcohol consumption was 3 g/day. N = 5854 individuals developed AF (median follow-up time: 13.9 years). In a sex- and cohort-stratified Cox regression analysis alcohol consumption was non-linearly and positively associated with incident AF. The hazard ratio for one drink (12 g) per day was 1.16, 95% CI 1.11–1.22, P < 0.001. Associations were similar across types of alcohol. In contrast, alcohol consumption at lower doses was associated with reduced risk of incident HF. The association between alcohol consumption and incident AF was neither fully explained by cardiac biomarker concentrations nor by the occurrence of HF.
Conclusions
In contrast to other cardiovascular diseases such as HF, even modest habitual alcohol intake of 1.2 drinks/day was associated with an increased risk of AF, which needs to be considered in AF prevention.
Graphical Abstract
Hazard ratio for incident atrial fibrillation for alcohol consumption in gram per day by non-linear Cox regression plotted on the log-scale (N = 92 452). The model uses age as time scale and is sex and cohort stratified. The reference value is 0 g/day.
The safety of the European Society of Cardiology (ESC) 0/1-h algorithm for rapid rule-out and rule-in of non–ST-segment elevation myocardial infarction (NSTEMI) using high-sensitivity cardiac ...troponin (hs-cTn) has been questioned.
This study aimed to validate the diagnostic performance of the 0/1-h algorithm in a large multicenter study.
The authors prospectively enrolled unselected patients in 6 countries presenting to the emergency department with symptoms suggestive of NSTEMI. Final diagnosis was centrally adjudicated by 2 independent cardiologists. Hs-cTnT and hs-cTnI blood concentrations were measured at presentation and after 1 h. Safety of rule-out was quantified by the negative predictive value (NPV) for NSTEMI, accuracy of rule-in by the positive predictive value (PPV), and overall efficacy by the proportion of patients triaged towards rule-out or rule-in within 1 h.
Prevalence of NSTEMI was 17%. Among 4,368 patients with serial hs-cTnT measurements available, safety of rule-out (NPV 99.8%, 2,488 of 2,493), accuracy of rule-in (PPV 74.5%, 572 of 768), and overall efficacy were high by assigning three-fourths of patients either to rule-out (57%, 2,493 to 4,368) or rule-in (18%, 768 to 4,368). Similarly, among 3,500 patients with serial hs-cTnI measurements, safety of rule-out (NPV 99.7%, 1,528 of 1,533), accuracy of rule-in (PPV 62.3%, 498 of 800), and overall efficacy were high by assigning more than two-thirds of patients either to rule-out (44%, 1,533 of 3,500) or rule-in (23%, 800 of 3,500). Excellent safety was confirmed in multiple subgroup analyses including patients presenting early (≤3 h) after chest pain onset.
The ESC 0/1-h algorithm using hs-cTnT and hs-cTnI is very safe and effective in triaging patients with suspected NSTEMI. (Advantageous Predictors of Acute Coronary Syndromes Evaluation APACE; NCT00470587; and Biomarkers in Acute Cardiac Care BACC; NCT02355457)
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