Johannes Tobias Neumann

Diagnosis of Myocardial Infarction Using a High-Sensitivity Troponin I 1-Hour Algorithm.

IMPORTANCE Rapid and accurate diagnosis of acute myocardial infarction (AMI) currently constitutes an unmet need. OBJECTIVE To test a 1-hour diagnostic algorithm to diagnose AMI using a high-sensitivity troponin I assay with a new cutoff level of 6 ng/L. DESIGN, SETTING, AND PARTICIPANTS The Biomarkers in Acute Cardiac Care study is a prospective study that investigated the application of the troponin I assay for the diagnosis of AMI in 1040 patients presenting to the emergency department with acute chest pain from July 19, 2013, to December 31, 2014. Results were validated in 2 independent cohorts of 4009 patients. Final follow-up was completed on July 1, 2015, and data were assessed from July 2 to December 15, 2015. EXPOSURE Acute chest pain suggestive of AMI. MAIN OUTCOMES AND MEASURES Accurate diagnosis or exclusion of AMI and 12-month mortality in patients with acute chest pain. RESULTS Of the 1040 patients included from the study cohort, 673 (64.7%) were male and had a median age of 65 (interquartile range, 52-75) years. With application of a low troponin I cutoff value of 6 ng/L, the rule-out algorithm showed a high negative predictive value of 99.8% (95% CI, 98.6%-100.0%) after 1 hour for non-ST-segment elevation MI type 1. The 1-hour approach was comparable to a 3-hour approach. Similarly, a rule-in algorithm based on troponin I levels provided a high positive predictive value with 82.8% (95% CI, 73.2%-90.0%). Moreover, application of the cutoff of 6 ng/L resulted in lower follow-up mortality (1.0%) compared with the routinely used 99th percentile (3.7%) for this assay. Two independent cohorts further validated the performance of this algorithm with high negative and positive predictive values. CONCLUSIONS AND RELEVANCE Patients with possible AMI can be triaged within 1 hour after admission with no loss of safety compared with a 3-hour approach, when a low and sensitive cutoff is applied. This concept enables safe discharge or rapid treatment initiation after 1 hour.

Comparison of Three Troponins as Predictors of Future Cardiovascular Events – Prospective Results from the FINRISK and BiomaCaRE Studies

Importance and Objective Besides their role in diagnosis of acute myocardial infarction (MI), troponins may be powerful biomarkers for risk stratification in the general population. The objective of our study was to compare the performance of three troponin assays in cardiovascular disease (CVD) risk prediction in a population-based cohort without a history of CVD events. Design, Setting and Participants Troponin I concentrations were measured using a contemporary-sensitivity, high-sensitivity, and super-sensitivity assay in 7,899 participants of the general-population based FINRISK 1997 cohort. We used Cox proportional hazards regression to determine relative risks, followed by measures of discrimination and reclassification using 10-fold cross-validation to control for over-optimism. Main Outcome As outcome measures we used CVD, MI, ischemic stroke, heart failure (HF), and major adverse cardiac events (MACE). During the follow-up of 14 years 1,074 incident MACE were observed. Results Values above the lower limit of detection were observed in 26.4%, 81.5% and 93.9% for the contemporary-sensitivity, high-sensitivity and super-sensitivity assay, respectively. We observed significant associations of troponin concentrations with the risk of future CVD events and the results tended to become stronger with increasing assay sensitivity. For the super-sensitivity assay the multivariate adjusted hazard ratios (per one standard deviation increase) for different outcomes were: MI 1.24 [95% CI 1.11–1.39], stroke 1.14 [1.01–1.28], CVD 1.15 [1.07–1.24], HF 1.28 [1.18–1.39], and MACE 1.18 [1.11–1.25]. In subjects with intermediate risk, we found an improvement of net reclassification for HF (10.2%, p<0.001), and MACE (5.1%, p<0.001). Conclusion Using a super-sensitivity assay, cardiac troponin was detectable in almost all healthy individuals. Its concentration improved risk prediction and reclassification for cardiovascular endpoints.

High-sensitivity assays for troponin in patients with cardiac disease

Troponin is a widely used biomarker in patients with cardiac disease. The use of troponin is well established in patients with suspected acute myocardial infarction (AMI), but troponin measurement is also used in other acute and nonacute settings. In patients with suspected AMI, early decision-making is crucial to allow rapid treatment and further diagnostic evaluation. Current guidelines recommend serial measurements of troponin with a cut-off concentration at the 99th percentile to triage patients in the emergency department. Newer, high-sensitivity assays for troponin enable the detection of distinctly lower concentrations. Using these assays and very low cut-off concentrations, several rapid diagnostic strategies have been reported to improve diagnosis in acute cardiac care. Furthermore, noncoronary and nonacute applications of troponin assays — for example as a biomarker in patients with heart failure, pulmonary embolism, or stable coronary artery disease — are on the horizon and might improve individual risk stratification. In this Review, we provide an overview on the development of high-sensitivity assays for troponin, and their application in patients with cardiac disease.

Immediate Rule-Out of Acute Myocardial Infarction Using Electrocardiogram and Baseline High-Sensitivity Troponin I

AIMS Serial measurements of high-sensitivity troponin are used to rule out acute myocardial infarction (AMI) with an assay specific cutoff at the 99th percentile. Here, we evaluated the performance of a single admission troponin with a lower cutoff combined with a low risk electrocardiogram (ECG) to rule out AMI. METHODS Troponin I measured with a high-sensitivity assay (hs-TnI) was determined at admission in 1040 patients presenting with suspected AMI (BACC study). To rule out AMI we calculated the negative predictive value (NPV) utilizing the optimal hs-TnI cutoff combined with a low risk ECG. The results were validated in 3566 patients with suspected AMI [2-h Accelerated Diagnostic Protocol to Assess Patients With Chest Pain Symptoms Using Contemporary Troponins as the Only Biomarker (ADAPT) studies]. Patients were followed for 6 or 12 months. RESULTS 184 of all patients were diagnosed with AMI. An hs-TnI cutoff of 3 ng/L resulted in a NPV of 99.3% (CI 97.3-100.0), ruling out 35% of all non-AMI patients. Adding the information of a low risk ECG resulted in a 100% (CI 97.5-100.0) NPV (28% ruled out). The 2 validation cohorts replicated the high NPV of this approach. The follow-up mortality in the ruled out population was low (0 deaths in BACC and Stenocardia, 1 death in ADAPT). CONCLUSIONS A single hs-TnI measurement on admission combined with a low risk ECG appears to rule out AMI safely without need for serial troponin testing. TRIAL REGISTRATION www.clinicaltrials.gov (NCT02355457).

Association of high-sensitivity cardiac troponin I concentration with cardiac outcomes in patients with suspected acute coronary syndrome

Importance High-sensitivity cardiac troponin I testing is widely used to evaluate patients with suspected acute coronary syndrome. A cardiac troponin concentration of less than 5 ng/L identifies patients at presentation as low risk, but the optimal threshold is uncertain. Objective To evaluate the performance of a cardiac troponin I threshold of 5 ng/L at presentation as a risk stratification tool in patients with suspected acute coronary syndrome. Data Sources Systematic search of MEDLINE, EMBASE, Cochrane, and Web of Science databases from January 1, 2006, to March 18, 2017. Study Selection Prospective studies measuring high-sensitivity cardiac troponin I concentrations in patients with suspected acute coronary syndrome in which the diagnosis was adjudicated according to the universal definition of myocardial infarction. Data Extraction and Synthesis The systematic review identified 19 cohorts. Individual patient-level data were obtained from the corresponding authors of 17 cohorts, with aggregate data from 2 cohorts. Meta-estimates for primary and secondary outcomes were derived using a binomial-normal random-effects model. Main Outcomes and Measures The primary outcome was myocardial infarction or cardiac death at 30 days. Performance was evaluated in subgroups and across a range of troponin concentrations (2-16 ng/L) using individual patient data. Results Of 11 845 articles identified, 104 underwent full-text review, and 19 cohorts from 9 countries were included. Among 22 457 patients included in the meta-analysis (mean age, 62 [SD, 15.5] years; n = 9329 women [41.5%]), the primary outcome occurred in 2786 (12.4%). Cardiac troponin I concentrations were less than 5 ng/L at presentation in 11 012 patients (49%), in whom there were 60 missed index or 30-day events (59 index myocardial infarctions, 1 myocardial infarction at 30 days, and no cardiac deaths at 30 days). This resulted in a negative predictive value of 99.5% (95% CI, 99.3%-99.6%) for the primary outcome. There were no cardiac deaths at 30 days and 7 (0.1%) at 1 year, with a negative predictive value of 99.9% (95% CI, 99.7%-99.9%) for cardiac death. Conclusions and Relevance Among patients with suspected acute coronary syndrome, a high-sensitivity cardiac troponin I concentration of less than 5 ng/L identified those at low risk of myocardial infarction or cardiac death within 30 days. Further research is needed to understand the clinical utility and cost-effectiveness of this approach to risk stratification.

Discrimination of patients with type 2 myocardial infarction

Aims The differentiation of type 1 and type 2 myocardial infarction (T1MI, T2MI) is important, but challenging in the emergency department. We aimed to investigate the clinical characteristics and cardiovascular outcome of T2MI patients and to develop a clinical decision tool to differentiate T1MI and T2MI patients. Methods and results We prospectively enrolled 1548 patients with suspected MI. All patients were followed for up to 2 years to assess mortality. We used logistic regression with backward step-down selection to determine the most important predictors of T2MI. Based on these regression coefficients, we developed a diagnostic prediction model (score) to diagnose T2MI. T2MI was the final diagnosis of 99 patients. Patients with T2MI showed a high 1-year mortality rate (13.8%), which equals that of T1MI patients (9.4%). Female sex (Beta 1.27 [95% confidence interval; CI 0.67-1.90]), not having radiating chest pain (Beta 1.62 [CI 0.96-2.34]) and a baseline high-sensitivity troponin I concentration ≤ 40.8 ng/L (Beta 1.30 [CI 0.74-1.89]) were the strongest predictors for T2MI. Their combination resulted in an area under the curve of 0.71 to discriminate T1MI and T2MI. The binary score based on this model assigns one point to each of the predictors. Patients with the highest score value of 3 had a 72% probability of T2MI. Conclusion T2MI patients are a heterogeneous population with high-cardiovascular risk. A score based on laboratory and clinical parameters might help to differentiate T1MI and T2MI patients. The additional use of this score in clinical routine needs to be investigated prospectively. Trial registration www.clinicaltrials.gov (NCT02355457).

Transcriptome-Wide Analysis Identifies Novel Associations With Blood Pressure

Hypertension represents a major cardiovascular risk factor. The pathophysiology of increased blood pressure (BP) is not yet completely understood. Transcriptome profiling offers possibilities to uncover genetics effects on BP. Based on 2 populations including 2549 individuals, a meta-analyses of monocytic transcriptome-wide profiles were performed to identify transcripts associated with BP. Replication was performed in 2 independent studies of whole-blood transcriptome data including 1990 individuals. For identified candidate genes, a direct link between long-term changes in BP and gene expression over time and by treatment with BP-lowering therapy was assessed. The predictive value of protein levels encoded by candidate genes for subsequent cardiovascular disease was investigated. Eight transcripts (CRIP1, MYADM, TIPARP, TSC22D3, CEBPA, F12, LMNA, and TPPP3) were identified jointly accounting for up to 13% (95% confidence interval, 8.7–16.2) of BP variability. Changes in CRIP1, MYADM, TIPARP, LMNA, TSC22D3, CEBPA, and TPPP3 expression associated with BP changes—among these, CRIP1 gene expression was additionally correlated to measures of cardiac hypertrophy. Assessment of circulating CRIP1 (cystein-rich protein 1) levels as biomarkers showed a strong association with increased risk for incident stroke (hazard ratio, 1.06; 95% confidence interval, 1.03–1.09; P=5.0×10–5). Our comprehensive analysis of global gene expression highlights 8 novel transcripts significantly associated with BP, providing a link between gene expression and BP. Translational approaches further established evidence for the potential use of CRIP1 as emerging disease-related biomarker.

Early diagnosis of acute myocardial infarction using high-sensitivity troponin I

Objective There is a clinical need for early and accurate diagnosis of acute myocardial infarction (AMI). Current European Society of Cardiology (ESC) guidelines recommend diagnosis of non-ST-elevation AMI based on serial troponin measurements. We aimed to challenge the ESC guidelines using 1) a high-sensitivity troponin I (hs-TnI) baseline cutoff, 2) an absolute hs-TnI change after 1 hour and 3) additional application of an ischemic ECG. Methods 1,516 patients with suspected AMI presenting to the emergency department were included. Hs-TnI was measured directly at admission, after 1 and 3 hours. We investigated baseline concentrations, absolute changes of hs-TnI and additional application of an ischemic ECG to diagnose AMI. A positive predictive value (PPV) of more than 85% was targeted. Results The median age of the study population was 65 years; 291 patients were diagnosed with AMI. The PPV of the 3-hours ESC algorithm was 85.5% (CI 79.7, 90.1) and 65.8% (CI 60.5,70.8) for the 1-hour algorithm. Using a high baseline hs-TnI concentration of 150 ng/L resulted in a PPV of 87.8% (CI 80.9,92.9). Alternatively, a hs-TnI change of 20 ng/L after 1 hour, resulted in a PPV of 86.5% (80.9,91.0), respectively for the diagnosis of AMI. Additional use of an ischemic ECG increased the PPV to 90.5% (CI 83.2,95.3), while reducing the efficacy. Conclusion The diagnosis of AMI based on hs-TnI is challenging. The application of absolute hs-TnI changes after 1 hour may facilitate rapid rule-in of patients. Trial registration www.clinicaltrials.gov (NCT02355457).

Challenging the 99th percentile: A lower troponin cutoff leads to low mortality of chest pain patients

BACKGROUND Rule-out of non-ST-elevation myocardial infarction is based on consecutive measurements of cardiac troponins using the 99th percentile of the respective assay as cutoff. The new ESC guidelines alternatively offer rapid 1h algorithms with lower cutoffs than the 99th percentile for rule-out of non-ST-elevation myocardial infarction. We aimed to compare a recently introduced 1h algorithm based on a high-sensitivity cardiac troponin I (hs-TnI) cutoff of 6ng/L at 0h and 1h to the current standard of care using the 99th percentile (27ng/L) as cutoff with reference to follow-up events in a large chest pain cohort. METHODS Hs-TnI was measured at three time points (0h, 1h and 3h) in 1625 patients presenting with suspected myocardial infarction to the emergency department of the University-Medical Center Hamburg-Eppendorf. Seventy-five patients with ST-elevation myocardial infarction were excluded from the analysis. All-cause mortality, cardiac death, acute myocardial infarction, revascularization and cardiac rehospitalization after 12months were assessed. RESULTS Patients ruled out by the 1h algorithm showed significantly less cardiac rehospitalizations (12.84% vs. 17.66%; p<0.001), and overall mortality (1.30% vs 3.46%, p<0.001) compared to using the 99th percentile as cutoff. The majority of deaths were caused by non-cardiac reasons. Cardiac deaths were rare using the 1h algorithm (0.21%). CONCLUSION The commonly used 99th percentile as cutoff neglects patients with a high risk in the setting of acute chest pain. TRIAL REGISTRATION www.clinicaltrials.gov (NCT02355457).

Cardiovascular Biomarkers in Hypertensive Patients with Medical Treatment—Results from the Randomized TEAMSTA Protect I Trial

BACKGROUND High blood pressure (BP) is associated with an increased rate of cardiovascular events and mortality. Cardiovascular biomarkers are able to predict long-term risk in the general population, particularly in diseased cohorts. We undertook an investigation of the effect of 2 different antihypertensive treatments on cardiovascular biomarkers in a randomized trial. METHODS The TEAMSTA study included 481 hypertensive patients. They were randomized to either 80-mg telmisartan + 5-mg amlodipine (TA) or 40-mg olmesartan + 12.5-mg hydrochlorothiazide (OH). The trial was performed as a prospective, randomized, double-blinded, controlled, single-center study. We measured BP, high-sensitivity cardiac troponin I (hs-cTnI), high-sensitivity cardiac troponin T (hs-cTnT), B-type natriuretic peptide (BNP), and N-terminal-pro-BNP (NT-proBNP) before randomization and after 6 months. RESULTS Individuals were randomized into 2 groups: 230 individuals to the OH-group and 251 to the TA-group. After 6 months of treatment, a reduction in BP (systolic/diastolic) was seen, from 135.2/85.2 mmHg to 122.5/75.7 mmHg with similar effects in both groups. hs-cTnT concentrations were measureable in 26.2% of the study population, while hs-cTnI was detected in 98.3%. hs-cTnI concentrations were significantly reduced from 4.6 to 4.2 ng/L in the overall population, from 4.7 to 4.4 ng/L in the OH-group, and from 4.6 to 4.0 ng/L in the TA-group (all P < 0.001). No significant changes of hs-cTnT were observed. BNP and NT-proBNP concentrations decreased from 15.0 to 12.4 ng/L (P < 0.001) and from 64.8 to 53.3 ng/L (P < 0.001), respectively, after 6 months. CONCLUSIONS The reduction in BP was associated with a decrease of high-sensitivity troponin I, BNP, and NT-proBNP concentrations, which might represent a cardiovascular risk reduction. CLINICAL TRIAL REGISTRATION EudraCT 2009-017010-68.