Clinical utility of circulating interleukin-6 concentrations in the detection of functionally relevant coronary artery disease.

BACKGROUND: Inflammation plays a major role in the pathogenesis of coronary artery disease (CAD). METHODS: We hypothesized, that quantifying inflammation by measuring circulating interleukin-6 concentrations help in the diagnosis and/or prediction of functionally relevant CAD. Among consecutive patients with symptoms suggestive of CAD, functionally relevant CAD was adjudicated in two domains: first, diagnosis according to myocardial perfusion single photon emission tomography (MPI-SPECT) and coronary angiography; second, cardiovascular death and all-cause death during 2-years follow-up. Adjudication was done blinded to the interleukin-6 concentrations. RESULTS: Among 1553 patients, symptoms were adjudicated to be causally related to CAD in 43% (665/1553). Interleukin-6 concentrations were higher in patients with functionally relevant CAD as compared to those without (1.56 pg/mL versus 1.30 pg/mL, p < 0.001), but overall had only low-to-modest diagnostic accuracy (area under the curve [AUC]: 0.57, 95%CI 0.55-0.61) and were no independent predictor of functionally relevant CAD after multivariable adjustment (p = 0.068). Interleukin-6 concentrations had moderate-to-high accuracy in the prediction of cardiovascular death (AUC 0.75, 95%CI 0.69-0.82) and all-cause death (AUC 0.72, 95%CI 0.66-0.78) at 2-years, and remained a significant predictor after multivariable adjustment (p < 0.001). Compared to patients with interleukin-6 concentrations below the median (1.41 pg/mL), patients with concentrations above the median had a significantly higher cumulative incidence of cardiovascular death (1% vs. 4%, log-rank p < 0.001) and all-cause death (2% vs. 8%, log-rank p < 0.001) at 2 years. CONCLUSION: Interleukin-6 concentrations are strong and independent predictors of cardiovascular death and all-cause death.

Clinical benefit of high-sensitivity cardiac troponin I in the detection of exercise-induced myocardial ischemia.

BACKGROUND: A pilot study using a novel high-sensitivity cardiac troponin I (hs-cTnI) assay suggested that cTnI might be released into blood during exercise-induced myocardial ischemia. We investigated the potential clinical value of this signal. METHODS: We included 819 patients with suspected exercise-induced myocardial ischemia referred for rest/bicycle myocardial perfusion single-photon emission computed tomography. The treating cardiologist used all available clinical information to quantify clinical judgment regarding the presence of myocardial ischemia using a visual analog scale twice: prior and after stress testing. High-sensitivity cTnI measurements were obtained before, immediately after peak stress, and 2 hours after stress testing in a blinded manner. Myocardial ischemia was adjudicated using perfusion single-photon emission computed tomography and coronary angiography findings. RESULTS: Exercise-induced myocardial ischemia was detected in 278 (34%) patients. High-sensitivity cTnI levels were significantly higher at all time points in patients with myocardial ischemia as compared with those without (P < .001 for all). Combining clinical judgment prior exercise testing with baseline hs-cTnI levels increased diagnostic accuracy as quantified by the area under the receiver operating characteristics curve (AUC) from 0.672 to 0.757 (P < .001). Combining clinical judgment after exercise testing (AUC 0.704) with baseline or poststress hs-cTnI levels also increased the diagnostic accuracy (AUC 0.761-0.771, P < .001 for all). In contrast, exercise-induced changes in hs-cTnI during exercise did not seem useful, as they were small and similar in patients with or without myocardial ischemia. CONCLUSIONS: High-sensitivity cTnI concentrations at rest and after exercise, but not its exercise-induced changes, provide substantial incremental value to clinical judgment including exercise electrocardiography regarding the presence of myocardial ischemia.

Delayed release of brain natriuretic peptide to identify myocardial ischaemia.

BACKGROUND: A recent pilot study suggested that exercise-induced myocardial ischaemia may lead to a delayed release of cardiac biomarkers, so that later sampling, for example, at 4 h after exercise could be used for diagnostic purpose. MATERIALS AND METHODS: In an observational study, we enrolled 129 consecutive patients referred for evaluation of a suspected coronary artery disease by rest/stress myocardial perfusion single-photon emission computed tomography. The treating cardiologist used all available clinical information to quantify clinical judgment regarding the presence of myocardial ischaemia using a visual analogue scale twice: prior and after stress testing. BNP levels were determined in a blinded fashion at rest, at peak stress and 4 h after peak stress. The presence of myocardial ischaemia was adjudicated based on perfusion single-photon emission computed tomography and coronary angiography findings by an independent cardiologist. RESULTS: Myocardial ischaemia was detected in 58 patients (45%). Patients with myocardial ischaemia had significantly higher BNP levels at all times, compared to patients without ischaemia: BNP rest (99 vs. 61 pg/mL P = 0·007), BNP stress (125 vs. 77 pg/mL P = 0·02) and BNP 4 h (114 vs. 71 pg/mL P = 0·018). Diagnostic accuracy as quantified by the area under the receiver operating characteristics curve (AUC) was moderate for all time points (AUC 0·64-0·66). The change in BNP between rest and 4 h did not provide added value, neither to the baseline BNP level nor to clinical judgment. CONCLUSION: In contrast to our hypothesis, myocardial ischaemia did not lead to a differential delayed release of BNP. Late sampling did not seem clinically useful.

Misdiagnosis of Myocardial Infarction Related to Limitations of the Current Regulatory Approach to Define Clinical Decision Values for Cardiac Troponin.

BACKGROUND: Misdiagnosis of acute myocardial infarction (AMI) may significantly harm patients and may result from inappropriate clinical decision values (CDVs) for cardiac troponin (cTn) owing to limitations in the current regulatory process. METHODS AND RESULTS: In an international, prospective, multicenter study, we quantified the incidence of inconsistencies in the diagnosis of AMI using fully characterized and clinically available high-sensitivity (hs) cTn assays (hs-cTnI, Abbott; hs-cTnT, Roche) among 2300 consecutive patients with suspected AMI. We hypothesized that the approved CDVs for the 2 assays are not biologically equivalent and might therefore contribute to inconsistencies in the diagnosis of AMI. Findings were validated by use of sex-specific CDVs and parallel measurements of other hs-cTnI assays. AMI was the adjudicated diagnosis in 473 patients (21%). Among these, 86 patients (18.2%) had inconsistent diagnoses when the approved uniform CDV was used. When sex-specific CDVs were used, 14.1% of female and 22.7% of male AMI patients had inconsistent diagnoses. Using biologically equivalent CDV reduced inconsistencies to 10% (P<0.001). These findings were confirmed with parallel measurements of other hs-cTn assays. The incidence of inconsistencies was only 7.0% for assays with CDVs that were nearly biologically equivalent. Patients with inconsistent AMI had long-term mortality comparable to that of patients with consistent diagnoses (P=NS) and a trend toward higher long-term mortality than patients diagnosed with unstable angina (P=0.05). CONCLUSIONS: Currently approved CDVs are not biologically equivalent and contribute to major inconsistencies in the diagnosis of AMI. One of 5 AMI patients will receive a diagnosis other than AMI if managed with the alternative hs-cTn assay. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Incremental value of a single high-sensitivity cardiac troponin I measurement to rule out myocardial ischemia.

BACKGROUND: The aim of this study was to investigate the value of a novel high-sensitivity cardiac troponin I measurement to rule out exercise-induced myocardial ischemia in patients without known coronary artery disease. METHODS: We included 714 patients without previously known coronary artery disease who were referred for rest/stress myocardial perfusion single photon emission tomography. All clinical information available to the treating cardiologist was used to quantify the clinical judgment regarding the presence of exercise-induced myocardial ischemia using a visual analogue scale twice: once before and once after bicycle exercise stress testing. High-sensitivity cardiac troponin I measurements were obtained before stress testing in a blinded manner. The presence of exercise-induced myocardial ischemia was adjudicated on the basis of myocardial perfusion single photon emission tomography combined with coronary angiography findings. RESULTS: Exercise-induced myocardial ischemia was detected in 167 participants (23.4%). High-sensitivity cardiac troponin I levels were significantly higher in patients with exercise-induced myocardial ischemia (4.0 ng/L [95% confidence interval, 2.8-8.6] vs 2.6 ng/L [95% confidence interval, 1.8-4.1], P < .001) and remained an independent predictor of ischemia in multivariable analysis (P < .001). Combining clinical judgment before exercise testing with high-sensitivity cardiac troponin I levels increased diagnostic accuracy as quantified by the area under the receiver operating curve from 0.64 to 0.73 (P < .001), which also tended to be superior to clinical judgment after exercise testing (0.69, P = .056). A single resting high-sensitivity cardiac troponin I measurement provided similar diagnostic accuracy as integrated clinical judgment after exercise testing including work load, as well as symptoms and electrocardiogram changes (0.70 vs 0.69, P = not significant). CONCLUSIONS: High-sensitivity cardiac troponin I measurements seem to complement noninvasive clinical assessment in patients with suspected coronary artery disease.

B-type natriuretic peptide and clinical judgment in the detection of exercise-induced myocardial ischemia.

BACKGROUND: Myocardial ischemia has been shown to be associated with increased levels of B-type natriuretic peptide (BNP). However, it remains unclear whether and how BNP levels could be used clinically in patients with suspected exercise-induced myocardial ischemia. METHODS: We enrolled 274 consecutive patients with suspected exercise-induced myocardial ischemia referred for evaluation by rest/bicycle myocardial perfusion single-photon emission computed tomography (SPECT). All clinical information available to the treating cardiologist was used to quantify the clinical judgment regarding the presence of myocardial ischemia using a visual analogue scale twice: once before and once after bicycle exercise stress testing. BNP measurements were obtained before, immediately after, and 2 hours after stress testing in a blinded manner. The presence of myocardial ischemia was adjudicated on the basis of perfusion SPECT combined with coronary angiography findings. RESULTS: Exercise-induced myocardial ischemia was adjudicated to be present in 103 patients (38%). BNP levels were significantly higher at all time points in patients with myocardial ischemia compared with those without (P < .01 for all). The accuracy of BNP levels as quantified by the area under the receiver operating characteristic curve (AUC) was similar among the time points evaluated (AUC, 0.677-0.697). Combining clinical judgment before exercise testing with BNP levels at rest increased diagnostic accuracy from AUC 0.708 to 0.754 (P = .018). When combining clinical judgment after exercise testing with BNP levels, AUC increased from 0.741 to 0.771 (P = .055). CONCLUSIONS: Combining clinical judgment with BNP levels increased the diagnostic accuracy regarding the presence of myocardial ischemia.

Direct comparison of three natriuretic peptides for prediction of short- and long-term mortality in patients with community-acquired pneumonia.

BACKGROUND: Early and accurate risk stratification for patients with community-acquired pneumonia (CAP) is an unmet clinical need. METHODS: We enrolled 341 unselected patients presenting to the ED with CAP in whom blinded measurements of N-terminal pro-B-type natriuretic peptide (NT-proBNP), midregional pro-atrial natriuretic peptide (MR-proANP), and B-type natriuretic peptide (BNP) were performed. The potential of these natriuretic peptides to predict short- (30-day) and long-term mortality was compared with the pneumonia severity index (PSI) and CURB-65 (confusion, urea plasma level, respiratory rate, BP, age over 65 years). The median follow-up was 942 days. RESULTS: NT-proBNP, MR-proANP, and BNP levels at presentation were higher in short-term (median 4,882 pg/mL vs 1,133 pg/mL; 426 pmol/L vs 178 pmol/L; 436 pg/mL vs 155 pg/mL, all P < .001) and long-term nonsurvivors (3,515 pg/mL vs 548 pg/mL; 283 pmol/L vs 136 pmol/L; 318 pg/mL vs 103 pg/mL, all P < .001) as compared with survivors. Receiver operating characteristics analysis to quantify the prognostic accuracy showed comparable areas under the curve for the three natriuretic peptides to PSI for short-term (PSI 0.76, 95% CI, 0.71-0.81; NT-proBNP 0.73, 95% CI, 0.67-0.77; MR-proANP 0.72, 95% CI, 0.67-0.77; BNP 0.68, 95% CI, 0.63-0.73) and long-term (PSI 0.72, 95% CI, 0.66-0.77; NT-proBNP 0.75, 95% CI, 0.70-0.80; MR-proANP 0.73, 95% CI, 0.67-0.77, BNP 0.70, 95% CI, 0.65-0.75) mortality. In multivariable Cox-regression analysis, NT-proBNP remained an independent mortality predictor (hazard ratio 1.004, 95% CI, 1.00-1.01, P = .02 for short-term; hazard ratio 1.004, 95% CI, 1.00-1.01, P = .001 for long-term, increase of 300 pg/mL). A categorical approach combining PSI point values and NT-pro-BNP levels adequately identified patients at low, medium, and high short- and long-term mortality risk. CONCLUSIONS: Natriuretic peptides are simple and powerful predictors of short- and long-term mortality for patients with CAP. Their prognostic accuracy is comparable to PSI.