Coronary artery calcium score and pre-test probabilities as gatekeepers to predict and rule out perfusion defects in positron emission tomography.

BACKGROUND: Little is known about the gatekeeper performance of coronary artery calcium score (CACS) before myocardial perfusion positron emission tomography (PET), compared with updated pre-test probabilities from American and European guidelines (pre-test-AHA/ACC, pre-test-ESC). METHODS: We enrolled participants without known coronary artery disease undergoing CACS and Rubidium-82 PET. Abnormal perfusion was defined as summed stress score ≥ 4. Using Bayes' formula, pre-test probabilities and CACS were combined into post-test probabilities. RESULTS: We included 2050 participants (54% male, mean age 64.6 years) with median CACS 62 (IQR 0-380), pre-test-ESC 17% (11-26), pre-test-AHA/ACC 27% (16-44), and abnormal perfusion in 437 participants (21%). To predict abnormal perfusion, area under the curve of CACS was 0.81, pre-test-AHA/ACC 0.68, pre-test-ESC 0.69, post-test-AHA/ACC 0.80, and post-test-ESC 0.81 (P < 0.001 for CACS vs. each pre-test, and each post-test vs. pre-test). CACS = 0 had 97% negative predictive value (NPV), pre-test-AHA/ACC ≤ 5% 100%, pre-test-ESC ≤ 5% 98%, post-test-AHA/ACC ≤ 5% 98%, and post-test-ESC ≤ 5% 96%. Among participants, 26% had CACS = 0, 2% pre-test-AHA/ACC ≤ 5%, 7% pre-test-ESC ≤ 5%, 23% post-test-AHA/ACC ≤ 5%, and 33% post-test-ESC ≤ 5% (all P < 0.001). CONCLUSIONS: CACS and post-test probabilities are excellent predictors of abnormal perfusion and can rule it out with very high NPV in a substantial proportion of participants. CACS and post-test probabilities may be used as gatekeepers before advanced imaging. Coronary artery calcium score (CACS) predicted abnormal perfusion (SSS ≥ 4) in myocardial positron emission tomography (PET) better than pre-test probabilities of coronary artery disease (CAD), while pre-test-AHA/ACC and pre-test-ESC performed similarly (left). Using Bayes' formula, pre-test-AHA/ACC or pre-test-ESC were combined with CACS into post-test probabilities (middle). This calculation reclassified a substantial proportion of participants to low probability of CAD (0-5%), not needing further imaging, as shown for AHA/ACC probabilities (2% with pre-test-AHA/ACC to 23% with post-test-AHA/ACC, P < 0.001, right). Very few participants with abnormal perfusion were classified under pre-test or post-test probabilities 0-5%, or under CACS 0. AUC: area under the curve. Pre-test-AHA/ACC: Pre-test probability of the American Heart Association/American College of Cardiology. Post-test-AHA/ACC: Post-test probability combining pre-test-AHA/ACC and CACS. Pre-test-ESC: Pre-test probability of the European Society of Cardiology. SSS: Summed stress score.

The power of zero calcium in 82-Rubidium PET irrespective of sex and age.

BACKGROUND: Despite clinical suspicion, many non-invasive tests for coronary artery disease (CAD) are normal. Coronary artery calcification score (CACS) is a well-validated method to detect and risk stratify CAD. Patients with zero calcium score (ZCS) rarely have abnormal tests. Therefore, aims were to evaluate CACS as a gatekeeper to further functional downstream testing for CAD and estimate potential radiation and cost savings. METHODS: Consecutive patients with suspected CAD referred for PET were included (n = 2640). Prevalence and test characteristics of ZCS were calculated in different groups. Summed stress score ≥ 4 was considered abnormal and summed difference score ≥ 7 equivalent to ≥ 10% ischemia. To estimate potential radiation/cost reduction, PET scans were hypothetically omitted in ZCS patients. RESULTS: Mean age was 65 ± 11 years, 46% were female. 21% scans were abnormal and 26% of patients had ZCS. CACS was higher in abnormal PET (median 561 vs 27, P < 0.001). Abnormal PET was significantly less frequent in ZCS patients (2.6% vs 27.6%, P < 0.001). Sensitivity/negative predictive value (NPV) of ZCS to detect/exclude abnormal PET and ≥ 10% ischemia were 96.8% (95%-CI 95.0%-97.9%)/97.4% (95.9%-98.3%) and 98.9% (96.7%-99.6%)/99.6% (98.7%-99.9%), respectively. Radiation and cost reduction were estimated to be 23% and 22%, respectively. CONCLUSIONS: ZCS is frequent, and most often consistent with normal PET scans. ZCS offers an excellent NPV to exclude an abnormal PET and ≥ 10% ischemia across different gender and age groups. CACS is a suitable gatekeeper before advanced cardiac imaging, and potential radiation/cost savings are substantial. However, further studies including safety endpoints are needed.

Soluble urokinase plasminogen activator receptor and functionally relevant coronary artery disease: a prospective cohort study.

BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR) is an emerging biomarker associated with anatomical CAD burden and cardiovascular outcomes including myocardial infarction (MI) and death. We aimed to validate previous findings of the prognostic value of suPAR and to evaluate its diagnostic potential for functional relevant CAD (fCAD). METHODS: Consecutive patients with suspected fCAD were enrolled. Adjudication of fCAD was performed blinded to suPAR concentrations by myocardial perfusion single-photon emission tomography (MPI-SPECT) and coronary angiography. Prognostic outcome measures included all-cause death, cardiovascular death, and incident MI during 2-year follow-up. RESULTS: Among consecutive 968 patients, suPAR concentrations were higher in patients with fCAD compared to those without (3.45 vs. 3.20 ng/mL, p = 0.007), but did not provide acceptable diagnostic accuracy (area under the curve [AUC]: 0.56, 95%CI 0.52-0.60). SuPAR correlated with high-sensitivity cardiac-troponin T (Spearman's rho (ρ) 0.393, p < 0.001), NT-proBNP (ρ = 0.327, p < 0.001), age (ρ = 0.364, p < 0.001) and very weakly with coronary atherosclerosis (ρ = 0.123, p < 0.001). Prognostic discrimination of suPAR was moderate for cardiovascular death (AUC = 0.72, 95%CI 0.62-0.81) and all-cause death (AUC = 0.72, 95%CI 0.65-0.79) at 2-years. SuPAR remained a significant predictor for all-cause death in multivariable Cox regression (HR = 1.96, p = 0.001). CONCLUSIONS: SuPAR was an independent predictor of all-cause death, without diagnostic utility for fCAD. CLINICAL TRIAL REGISTRATION: NCT01838148.

Gut microbiota-dependent metabolite trimethylamine N-oxide (TMAO) and cardiovascular risk in patients with suspected functionally relevant coronary artery disease (fCAD).

BACKGROUND: Trimethylamine N-oxide (TMAO) has been associated with cardiovascular outcomes. However, the diagnostic value of TMAO and its precursors have not been assessed for functionally relevant coronary artery disease (fCAD) and its prognostic potential in this setting needs to be evaluated. METHODS: Among 1726 patients with suspected fCAD serum TMAO, and its precursors betaine, choline and carnitine, were quantified using liquid chromatography tandem mass spectrometry. Diagnosis of fCAD was performed by myocardial perfusion single photon emission tomography (MPI-SPECT) and coronary angiography blinded to marker concentrations. Incident all-cause death, cardiovascular death (CVD) and myocardial infarction (MI) were assessed during 5-years follow-up. RESULTS: Concentrations of TMAO, betaine, choline and carnitine were significantly higher in patients with fCAD versus those without (TMAO 5.33 µM vs 4.66 µM, p < 0.001); however, diagnostic accuracy was low (TMAO area under the receiver operating curve [AUC]: 0.56, 95% CI [0.53-0.59], p < 0.001). In prognostic analyses, TMAO, choline and carnitine above the median were associated with significantly (p < 0.001 for all) higher cumulative events for death and CVD during 5-years follow-up. TMAO remained a significant predictor for death and CVD even in full models adjusted for renal function (HR = 1.58 (1.16, 2.14), p = 0.003; HR = 1.66 [1.07, 2.59], p = 0.025). Prognostic discriminative accuracy for TMAO was good and robust for death and CVD (2-years AUC for CVD 0.73, 95% CI [0.65-0.80]). CONCLUSION: TMAO and its precursors, betaine, choline and carnitine were significantly associated with fCAD, but with limited diagnostic value. TMAO was a strong predictor for incident death and CVD in patients with suspected fCAD. CLINICAL TRIAL REGISTRATION: NCT01838148.

Left ventricular ejection fraction, myocardial blood flow and hemodynamic variables in adenosine and regadenoson vasodilator 82-Rubidium PET.

AIMS: In most Rubidium-(Rb)-positron emission tomography (PET) studies, dipyridamole was used as vasodilator. The aim was to evaluate vasodilator PET left ventricular ejection fraction (LVEF), myocardial blood flow (MBF), hemodynamics, and the influence of adenosine and regadenoson on these variables. METHODS AND RESULTS: Consecutive patients (N = 2299) with prior coronary artery disease (CAD) or no prior CAD undergoing adenosine/regadenoson 82Rb-PET were studied and compared according to CAD status and normal/abnormal PET (summed stress score 0-3 vs. ≥4). Rest and stress LVEF differed significantly depending on CAD status and scan results. In patients with no prior CAD, rest/stress LVEF were 68% and 72%, in patients with prior CAD 60% and 63%. LVEF during stress increased 5 ± 6% in normal compared to 1 ± 8% in abnormal PET (P<0.001). Global rest myocardial blood flow(rMBF), stress MBF(sMBF) and myocardial flow reserve (sMBF/rMBF) were significantly higher in no prior CAD patients compared to prior CAD patients(1.3 ± 0.5, 3.3 ± 0.9, 2.6 ± 0.8 and 1.2 ± 0.4, 2.6 ± 0.8, 2.4 ± 0.8 ml/g/min, respectively, P<0.001) and in normal versus abnormal scans, irrespective of CAD status(no prior CAD: 1.4 ± 0.5, 3.5 ± 0.8, 2.8 ± 0.8 and 1.2 ± 0.8, 2.5 ± 0.8, 2.2 ± 0.7; prior CAD: 1.3 ± 0.4, 3.1 ± 0.8, 2.7 ± 0.8 and 1.1 ± 0.4, 2.3 ± 0.7, 2.2 ± 0.7 ml/g/min, respectively, P<0.001). LVEF and hemodynamic values were similar for adenosine and regadenoson stress. Stress LVEF ≥70% excluded relevant ischemia (≥10%) with a negative predictive value (NPV) of 94% (CI 92-95%). CONCLUSIONS: Rest/stress LVEF, LVEF reserve and MBF values are lower in abnormal compared to normal scans. Adenosine and regadenoson seem to have similar effect on stress LVEF, MBF and hemodynamics. A stress LVEF ≥70% has a high NPV to exclude relevant ischemia.

Influence of renin-angiotensin-aldosterone system inhibitors on plasma levels of angiotensin-converting enzyme 2.

AIMS: Concern has been raised that treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the expression of angiotensin-converting enzyme 2 (ACE2), which acts as the entry receptor for SARS-CoV-2, and lead to an increased risk of death from SARS-CoV-2. We aimed to address this concern by evaluating the in vivo relationship of treatment with ACE inhibitors and angiotensin receptor blockers (ARB) with circulating plasma concentrations of ACE2 in a large cohort of patients with established cardiovascular disease (n = 1864) or cardiovascular risk factors (n = 2144) but without a history of heart failure. METHODS AND RESULTS: Angiotensin-converting enzyme 2 was measured in 4008 patients (median age 68, 33% women, 31% on ACE-inhibitors, 31% on ARB) using the SOMAscan proteomic platform (SomaLogic Inc, Colorado, USA). Plasma concentration of ACE2 was comparable in 1250 patients on ACE inhibitors (mean 5.99) versus patients without ACE inhibitors (mean 5.98, P = 0.54). Similarly, plasma concentration of ACE2 was comparable in 1260 patients on ARB (mean 5.99) versus patients without ARB (mean 5.98, P = 0.50). Plasma concentration of ACE2 was comparable in 2474 patients on either ACE inhibitors or ARB (mean 5.99) versus patients without ACE inhibitors or ARB (mean 5.98, P = 0.31). Multivariable quantile regression model analysis confirmed the lack of association between treatment with ACE inhibitors or ARB and ACE2 concentrations. Body mass index showed the only positive association with ACE2 plasma concentration (effect 0.015, 95% confidence interval 0.002 to 0.028, P = 0.024). CONCLUSIONS: In a large cohort of patients with established cardiovascular disease or cardiovascular risk factors but without heart failure, ACE inhibitors and ARB were not associated with higher plasma concentrations of ACE2.

Using High-Sensitivity Cardiac Troponin for the Exclusion of Inducible Myocardial Ischemia in Symptomatic Patients: A Cohort Study.

Background: The optimal noninvasive method for surveillance in symptomatic patients with stable coronary artery disease (CAD) is unknown. Objective: To apply a novel approach using very low concentrations of high-sensitivity cardiac troponin I (hs-cTnI) for exclusion of inducible myocardial ischemia in symptomatic patients with CAD. Design: Prospective diagnostic cohort study. (ClinicalTrials.gov: NCT01838148). Setting: University hospital. Patients: 1896 consecutive patients with CAD referred with symptoms possibly related to inducible myocardial ischemia. Measurements: Presence of inducible myocardial ischemia was adjudicated using myocardial perfusion imaging with single-photon emission computed tomography, as well as coronary angiography and fractional flow reserve measurements where available. Staff blinded to adjudication measured circulating hs-cTn concentrations. An hs-cTnI cutoff of 2.5 ng/L, derived previously in mostly asymptomatic patients with CAD, was assessed. Predefined target performance criteria were at least 90% negative predictive value (NPV) and at least 90% sensitivity for exclusion of inducible myocardial ischemia. Sensitivity analyses were based on measurements with an hs-cTnT assay and an alternative hs-cTnI assay with even higher analytic sensitivity (limit of detection, 0.1 ng/L). Results: Overall, 865 patients (46%) had inducible myocardial ischemia. The hs-cTnI cutoff of 2.5 ng/L provided an NPV of 70% (95% CI, 64% to 75%) and a sensitivity of 90% (CI, 88% to 92%) for exclusion of inducible myocardial ischemia. No hs-cTnI cutoff reached both performance characteristics predefined as targets. Similarly, using the alternative assays for hs-cTnI or hs-cTnT, no cutoff achieved the target performance: hs-cTnT concentrations less than 5 ng/L yielded an NPV of 66% (CI, 59% to 72%), and hs-cTnI concentrations less than 2 ng/L yielded an NPV of 68% (CI, 62% to 74%). Limitation: Data were generated in a large single-center diagnostic study using central adjudication. Conclusion: In symptomatic patients with CAD, very low hs-cTn concentrations, including hs-cTnI concentrations less than 2.5 ng/L, do not generally allow users to safely exclude inducible myocardial ischemia. Primary Funding Source: European Union, Swiss National Science Foundation, Kommission für Technologie und Innovation (Innosuisse), Swiss Heart Foundation, Cardiovascular Research Foundation Basel, University of Basel, University Hospital Basel, Roche, Abbott, and Singulex.

Incremental value of high-frequency QRS analysis for diagnosis and prognosis in suspected exercise-induced myocardial ischaemia.

AIM: Exercise stress testing is used to detect myocardial ischaemia, but is limited by low sensitivity and specificity. The authors investigated the value of the analysis of high-frequency QRS components as a marker of abnormal depolarization in addition to standard ST-deviations as a marker of abnormal repolarization to improve the diagnostic accuracy. METHODS AND RESULTS: Consecutive patients undergoing bicycle exercise stress nuclear myocardial perfusion imaging were prospectively enrolled. Presence of myocardial ischaemia, the primary diagnostic endpoint, was adjudicated using MPI and coronary angiography. Automated high-frequency QRS analysis was performed in a blinded fashion. The prognostic endpoint was major adverse cardiac events (MACEs) during two years of follow-up. Exercise-induced ischaemia was detected in 147/662 patients (22%). The sensitivity of high-frequency QRS was similar to ST-deviations (46% vs. 43%, p=0.59), while the specificity was lower (75% vs. 87%, p<0.001). The combined use of high-frequency QRS and ST-deviations classified 59% of patients as 'rule-out' (both negative), 9% as 'rule-in' (both positive) and 32% in an intermediate zone (one test positive). The sensitivity for 'rule-out' and the specificity for 'rule-in' improved to 63% and 97% compared with ST-deviation analysis alone (both p<0.001). MACE-free survival was 90%, 80% and 42% in patients in the 'rule-out', intermediate and 'rule-in' groups (p<0.001). After adjustment for age, gender, ST-deviations and clinical post-test probability of ischaemia, high-frequency QRS remained an independent predictor for the occurrence of MACEs. CONCLUSION: The use of high-frequency QRS analysis in addition to ST-deviation analysis improves the diagnostic accuracy during exercise stress testing and adds independent prognostic information.

Prevalence and determinants of exercise-induced left ventricular dysfunction in patients with coronary artery disease.

BACKGROUND: The phenomenon of exercise-induced left ventricular dysfunction (LVD) is incompletely understood. Better understanding of its prevalence and determinants might help to address the current potential oversimplification of the relation between physical activity and cardiac health in patients with coronary artery disease (CAD). METHODS: We prospectively assessed the prevalence and determinants of exercise-induced LVD in patients with stable CAD and normal LV function at rest undergoing bicycle rest/stress myocardial perfusion imaging single-photon emission computed tomography (MPI-SPECT). Exercise-induced LVD was defined as a relevant (5% or more) drop in left ventricular ejection fraction after maximal exercise. High-sensitivity cardiac troponin I/T (Hs-cTnI/T) and N-terminal probrain natriuretic peptide (NT-proBNP) concentrations were measured before exercise to quantify cardiomyocyte injury and hemodynamic cardiac stress, respectively. RESULTS: Among 317 patients, exercise-induced LVD was present in 83 (26%) patients. Exercise-induced LVD was associated with the extent of exercise-inducible myocardial ischaemia as well as transient ischaemic dilatation. Still, 43% of patients developing exercise-induced LVD did not have functionally relevant CAD. Neither baseline characteristics, nor the quantification of the extent of cardiomyocyte injury and hemodynamic cardiac stress using hs-cTnI/T and NT-proBNP concentrations, respectively, allowed predicting exercise-induced LVD. CONCLUSION: One out of four patients with stable CAD develops exercise-induced LVD after bicycle exercise test. While the extent of exercise-inducible myocardial ischaemia is a predictor, other still unrecognized mechanisms also seem to play a major role, as nearly half of all patients with exercise-induced LVD do not have functionally relevant CAD.

Direct Comparison of Cardiac Troponin T and I Using a Uniform and a Sex-Specific Approach in the Detection of Functionally Relevant Coronary Artery Disease.

BACKGROUND: We aimed to directly compare high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT) in the detection of functionally relevant coronary artery disease (fCAD). METHODS: Consecutive patients referred with clinical suspicion of fCAD and no structural heart disease other than coronary artery disease were included. The presence of fCAD was based on rest/stress myocardial perfusion single-photon emission computed tomography/computed tomography and coronary angiography. hs-cTnI and hs-cTnT concentrations were measured in a blinded fashion. Diagnostic accuracy was quantified using the area under the ROC curve (AUC) and evaluated both for uniform use in all patients and for sex-specific use in women and men separately. The prognostic end point was major adverse cardiac events (MACEs; cardiovascular death or myocardial infarction) within 2 years. For the prognostic performance, we used a multivariable model comparison with the Akaike information criterion (AIC). RESULTS: fCAD was detected in 613 of 2062 patients (29.7%) overall, 112 of 664 of women (16.9%), and 501 of 1398 of men (35.8%). hs-cTnI and hs-cTnT had comparable diagnostic accuracy when assessed for uniform use in all patients (AUC, 0.68 vs 0.66; P = 0.107) and separately in women (AUC, 0.68 vs 0.63; P = 0.068) and men (AUC, 0.65 vs 0.64; P = 0.475). However, women required lower rule-out cutoffs to achieve high sensitivity, and men needed higher rule-in cutoffs to achieve high specificity. hs-cTnI and hs-cTnT were strongly and independently associated with MACE within 2 years (P < 0.001), with comparable prognostic accuracies by the AIC. CONCLUSIONS: hs-cTnI and hs-cTnT provide moderate and comparable diagnostic accuracy. Sex-specific cutoffs may be preferred. The prognostic utility of both troponins is comparable.

Automatically computed ECG algorithm for the quantification of myocardial scar and the prediction of mortality.

BACKGROUND: Myocardial scar is associated with adverse cardiac outcomes. The Selvester QRS-score was developed to estimate myocardial scar from the 12-lead ECG, but its manual calculation is difficult. An automatically computed QRS-score would allow identification of patients with myocardial scar and an increased risk of mortality. OBJECTIVES: To assess the diagnostic and prognostic value of the automatically computed QRS-score. METHODS: The diagnostic value of the QRS-score computed automatically from a standard digital 12-lead was prospectively assessed in 2742 patients with suspected myocardial ischemia referred for myocardial perfusion imaging (MPI). The prognostic value of the QRS-score was then prospectively tested in 1151 consecutive patients presenting to the emergency department (ED) with suspected acute heart failure (AHF). RESULTS: Overall, the QRS-score was significantly higher in patients with more extensive myocardial scar: the median QRS-score was 3 (IQR 2-5), 4 (IQR 2-6), and 7 (IQR 4-10) for patients with 0, 5-20 and > 20% myocardial scar as quantified by MPI (p < 0.001 for all pairwise comparisons). A QRS-score ≥ 9 (n = 284, 10%) predicted a large scar defined as > 20% of the LV with a specificity of 91% (95% CI 90-92%). Regarding clinical outcomes in patients presenting to the ED with symptoms suggestive of AHF, mortality after 1 year was 28% in patients with a QRS-score ≥ 3 as opposed to 20% in patients with a QRS-score < 3 (p = 0.001). CONCLUSIONS: The QRS-score can be computed automatically from the 12-lead ECG for simple, non-invasive and inexpensive detection and quantification of myocardial scar and for the prediction of mortality. TRIAL-REGISTRATION: http://www.clinicaltrials.gov . Identifier, NCT01838148 and NCT01831115.

Combining high-sensitivity cardiac troponin and B-type natriuretic peptide in the detection of inducible myocardial ischemia.

BACKGROUND: Single biomarker approaches provide only moderate accuracy in the non-invasive detection of exercise-induced myocardial ischemia. We therefore assessed the combination of the two most promising single biomarkers: high-sensitivity cardiac troponin I (hs-cTnI) and B-type natriuretic peptide (BNP). METHODS: Consecutive patients with suspected myocardial ischemia referred to stress myocardial perfusion single-photon emission tomography imaging (MPI) were enrolled. Clinical judgment (CJ) of the treating cardiologist regarding myocardial ischemia, quantified using a visual analogue scale, and blood concentrations of hs-cTnI and BNP were determined before and after stress. The presence of myocardial ischemia was adjudicated by independent cardiologists using MPI, blinded to biomarker measurements. Death and acute myocardial infarction (AMI) during follow-up were the prognostic endpoints. RESULTS: Among 1142 consecutive patients inducible myocardial ischemia was found in 456 (40%) of all patients. For the detection of inducible myocardial ischemia, CJ before exercise stress testing (CJb) showed an area under the receiver-operating-characteristics curve (AUC) of 0.66 (95%CI 0.63-0.69), hs-cTnI 0.70 (95%CI 0.67-0.73, p=0.07 vs CJb), and BNP 0.66 (95%CI 0.62-0.69, p=0.98). The use of a dual-biomarker strategy combining hs-cTnI and BNP with CJb did not provide a significant advantage over the combination of hs-cTnI alone and CJb (AUC 0.74, 95%CI 0.72-0.77 vs AUC 0.74, 95%CI 0.71-0.77, p=0.16). Hs-cTnI showed good prognostic value for AMI (HR 1.6, 95%CI 1.3-1.9), and BNP for death (HR 1.6, 95%CI 1.3-2.1). CONCLUSION: A dual-biomarker strategy combing BNP and hs-cTnI does not further increase diagnostic accuracy on top of clinical judgment and hs-cTnI alone. SUMMARY AND HIGHLIGHTS: We included 1142 consecutive patients with suspected inducible ischemia, and evaluated the added value of the biomarkers high-sensitivity cardiac troponin (hs-cTn) and B-type natriuretic peptide (BNP), alone and in combination, on top of clinical judgment. CLINICAL TRIAL REGISTRATION: Biochemical and Electrocardiographic Signatures in the Detection of Exercise-induced Myocardial Ischemia (BASEL VIII), NCT01838148, https://clinicaltrials.gov/ct2/show/NCT01838148.

Prospective Validation of a Biomarker-Based Rule Out Strategy for Functionally Relevant Coronary Artery Disease.

BACKGROUND: This study aimed to prospectively advance a rule-out strategy for functionally significant coronary artery disease (CAD) by use of high-sensitivity cardiac troponin I (hs-cTnI) from bench to bedside, by application of a 3-step approach: validation in serum, correlation in plasma, and application on a clinical platform. METHODS: Patients without known CAD referred for rest/stress myocardial perfusion single-photon emission tomography/computer tomography (MPI-SPECT/CT) were assigned to 3 consecutive cohorts: validation, correlation, and application. Functionally relevant CAD was adjudicated with the use of expert interpretation of MPI-SPECT/CT and, if available, coronary angiography. In the validation cohort resting hs-cTnI was measured in serum before stress testing with the research Erenna system, in serum and plasma in the correlation cohort with the research Erenna system, and in plasma in the application cohort with the clinical Clarity system. RESULTS: Overall, functionally relevant CAD was adjudicated in 21% (304/1478) of patients. In the validation cohort (n = 613), hs-cTnI concentrations were significantly higher in patients with functionally relevant CAD (median 2.8 ng/L vs 1.9 ng/L, P < 0.001) as compared to patients without functionally relevant CAD and allowed a rule out with 95% sensitivity in 14% of patients. In the correlation cohort (n = 606), hs-cTnI concentrations in serum and plasma strongly correlated (Spearman r = 0.921) and had similar diagnostic accuracy as quantified by the area under the receiver operating characteristic curve (0.686 vs 0.678, P = 0.425). In the application cohort (n = 555), very low hs-cTnI plasma concentrations (< 0.5 ng/L) ruled out functionally relevant CAD with 95% sensitivity in 10% of patients. CONCLUSIONS: A single resting plasma hs-cTnI measurement can safely rule out functionally relevant CAD in around 10% of patients without known CAD.

Direct Comparison of 4 Very Early Rule-Out Strategies for Acute Myocardial Infarction Using High-Sensitivity Cardiac Troponin I.

BACKGROUND: Four strategies for very early rule-out of acute myocardial infarction using high-sensitivity cardiac troponin I (hs-cTnI) have been identified. It remains unclear which strategy is most attractive for clinical application. METHODS: We prospectively enrolled unselected patients presenting to the emergency department with symptoms suggestive of acute myocardial infarction. The final diagnosis was adjudicated by 2 independent cardiologists. Hs-cTnI levels were measured at presentation and after 1 hour in a blinded fashion. We directly compared all 4 hs-cTnI-based rule-out strategies: limit of detection (LOD, hs-cTnI<2 ng/L), single cutoff (hs-cTnI<5 ng/L), 1-hour algorithm (hs-cTnI<5 ng/L and 1-hour change<2 ng/L), and the 0/1-hour algorithm recommended in the European Society of Cardiology guideline combining LOD and 1-hour algorithm. RESULTS: Among 2828 enrolled patients, acute myocardial infarction was the final diagnosis in 451 (16%) patients. The LOD approach ruled out 453 patients (16%) with a sensitivity of 100% (95% confidence interval [CI], 99.2%-100%), the single cutoff 1516 patients (54%) with a sensitivity of 97.1% (95% CI, 95.1%-98.3%), the 1-hour algorithm 1459 patients (52%) with a sensitivity of 98.4% (95% CI, 96.8%-99.2%), and the 0/1-hour algorithm 1463 patients (52%) with a sensitivity of 98.4% (95% CI, 96.8%-99.2%). Predefined subgroup analysis in early presenters (≤2 hours) revealed significantly lower sensitivity (94.2%, interaction P=0.03) of the single cutoff, but not the other strategies. Two-year survival was 100% with LOD and 98.1% with the other strategies (P<0.01 for LOD versus each of the other strategies). CONCLUSIONS: All 4 rule-out strategies balance effectiveness and safety equally well. The single cutoff should not be applied in early presenters, whereas the 3 other strategies seem to perform well in this challenging subgroup. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Diagnostic value of ST-segment deviations during cardiac exercise stress testing: Systematic comparison of different ECG leads and time-points.

BACKGROUND: Exercise ECG stress testing is the most widely available method for evaluation of patients with suspected myocardial ischemia. Its major limitation is the relatively poor accuracy of ST-segment changes regarding ischemia detection. Little is known about the optimal method to assess ST-deviations. METHODS: A total of 1558 consecutive patients undergoing bicycle exercise stress myocardial perfusion imaging (MPI) were enrolled. Presence of inducible myocardial ischemia was adjudicated using MPI results. The diagnostic value of ST-deviations for detection of exercise-induced myocardial ischemia was systematically analyzed 1) for each individual lead, 2) at three different intervals after the J-point (J+40ms, J+60ms, J+80ms), and 3) at different time points during the test (baseline, maximal workload, 2min into recovery). RESULTS: Exercise-induced ischemia was detected in 481 (31%) patients. The diagnostic accuracy of ST-deviations was highest at +80ms after the J-point, and at 2min into recovery. At this point, ST-amplitude showed an AUC of 0.63 (95% CI 0.59-0.66) for the best-performing lead I. The combination of ST-amplitude and ST-slope in lead I did not increase the AUC. Lead I reached a sensitivity of 37% and a specificity of 83%, with similar sensitivity to manual ECG analysis (34%, p=0.31) but lower specificity (90%, p<0.001). CONCLUSION: When using ECG stress testing for evaluation of patients with suspected myocardial ischemia, the diagnostic accuracy of ST-deviations is highest when evaluated at +80ms after the J-point, and at 2min into recovery.

Diagnostic and Prognostic Value of Lead aVR During Exercise Testing in Patients Suspected of Having Myocardial Ischemia.

We aimed to assess the diagnostic and prognostic value of ST-segment deviation in aVR, a lead often ignored in clinical practice, during exercise testing and to compare it to the most widely used criterion of ST-segment depression in V5. We enrolled 1,596 patients with suspected myocardial ischemia referred for nuclear perfusion imaging undergoing bicycle stress testing. ST-segment amplitudes in leads aVR and V5 were automatically measured. The presence of inducible myocardial ischemia was the diagnostic end point and adjudicated based on nuclear perfusion imaging and coronary angiography. Major adverse cardiac events (MACE) during 2 years of follow-up including death, acute myocardial infarction, and coronary revascularization were the prognostic end point. Exercise-induced myocardial ischemia was detected in 470 patients (29%). Median ST amplitudes for leads aVR and V5 differed significantly among patients with and without ischemia (p <0.01). The diagnostic accuracy of ST changes for myocardial ischemia as quantified by the area under the receiver operating characteristic curve was highest 2 minutes into recovery and similar in aVR and V5 (0.62, 95% confidence interval CI 0.60 to 0.65 vs 0.60, 95% confidence interval 0.58 to 0.63, p = 0.08 for comparison). In multivariate analysis, ST changes in lead aVR, but not lead V5, contributed independent diagnostic information on top of clinical parameters and manual electrocardiographic interpretation. Within 2 years of follow-up, MACE occurred in 33% of patients with ST elevations in aVR and in 16% without (p <0.001). In conclusion, ST elevation in lead aVR during exercise testing indicates inducible myocardial ischemia independently of ST depressions in lead V5 and clinical factors and also predicts MACE during follow-up.

Gender-specific uncertainties in the diagnosis of acute coronary syndrome.

BACKGROUND: It is unknown whether higher rates of delayed diagnosis and misdiagnosis of acute coronary syndrome (ACS) in women might have contributed to the poorer outcome of women. METHODS: In a prospective diagnostic multicenter study, we recruited patients presenting to the emergency department (ED) with any kind of chest discomfort/chest pain with onset or peak within the last 12 h. We quantified early diagnostic uncertainty for the presence of ACS among treating physicians at the ED after 90 min, possibly responsible for delayed diagnosis, using a visual analogue scale. Late diagnostic uncertainty, possibly responsible for misdiagnosis, was defined as disagreement among two independent cardiologists' adjudication of the final diagnosis after complete work-up. RESULTS: Among 2795 patients (897 women and 1898 men), ACS was the adjudicated final diagnosis in 24 % of women and 35 % of men. Early diagnostic accuracy of clinical judgment of the ED physician for ACS as quantified by the area under the receiver-operating characteristics curve was 0.89 (95 % CI 0.87-0.92) in women and 0.86 (95 % CI 0.85-0.88) in men (p = 0.046). Late diagnostic uncertainty regarding the diagnosis of ACS was 5 % in women and 7 % in men (p = 0.069). CONCLUSION: Diagnostic uncertainty for the presence of ACS in women is not more common as compared to men and does, therefore, not explain the poorer outcome observed in women with ACS. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00470587.

Impact of haemoconcentration during acute heart failure therapy on mortality and its relationship with worsening renal function.

AIMS: Treatment goals in acute heart failure (AHF) are poorly defined. We aimed to characterize further the impact of in-hospital haemoconcentration and worsening renal function (WRF) on short- and long-term mortality. METHODS AND RESULTS: Haematocrit, haemoglobin, total protein, serum creatinine, and albumin levels were measured serially in 1019 prospectively enrolled AHF patients. Haemoconcentration was defined as an increase in at least three of four of the haemoconcentration-defining parameters above admission values at any time during the hospitalization. Patients were divided into early (Day 1-4) and late haemoconcentration (>Day 4). Ninety-day mortality was the primary endpoint. Haemoconcentration occurred in 392 (38.5%) patients, with a similar incidence of the early (44.6%) and late (55.4%) phenotype. Signs of decongestion (reduction in BNP blood concentrations, P = 0.003; weight loss, P = 0.002) were significantly more pronounced in haemoconcentration patients. WRF was more common in haemoconcentration patients (P = 0.04). After adjustment for established risk factors for AHF mortality, including WRF and HF therapy at discharge, haemoconcentration was significantly associated with a reduction in 90-day mortality [hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.37-0.95, P = 0.01]. The beneficial effect of haemoconcentration seemed to be exclusive for late haemoconcentration (late vs. early: adjusted HR 0.41, 95% CI 0.19-0.90, P = 0.03) and persisted in patients with or without WRF. CONCLUSIONS: Haemoconcentration represents an inexpensive and easily assessable pathophysiological signal of adequate decongestion in AHF and is associated with lower mortality. WRF in the setting of haemoconcentration does not appear to offset the benefits of haemoconcentration.

Clinical Effect of Sex-Specific Cutoff Values of High-Sensitivity Cardiac Troponin T in Suspected Myocardial Infarction.

Importance: It is currently unknown whether the uniform (universal clinical practice for more than 2 decades) or 2 sex-specific cutoff levels are preferable when using high-sensitivity cardiac troponin T (hs-cTnT) levels in the diagnosis of acute myocardial infarction (AMI). Objective: To improve the management of suspected AMI in women by exploring sex-specific vs uniform cutoff levels for hs-cTnT. Design, Setting, and Participants: In an ongoing prospective, diagnostic, multicenter study conducted at 9 emergency departments, the present study evaluated patients enrolled from April 21, 2006, through June 5, 2013. The participants included 2734 adults presenting with suspected AMI. Duration of follow-up was 2 years, and data analysis occurred from June 5 to December 21, 2015. Interventions: The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including measurements of serial hs-cTnT blood concentrations twice: once using the uniform 99th percentile cutoff value level of 14 ng/L and once using sex-specific 99th percentile levels of hs-cTnT (women, 9 ng/L; men, 15.5 ng/L). Main Outcomes and Measures: Diagnostic reclassification in women and men using sex-specific vs the uniform cutoff level in the diagnosis of AMI. Results: Of the 2734 participants, 876 women (32%) and 1858 men (68%) were included. Median (interquartile range) age was 68 (55-77) and 59 (48-71) years, respectively. With the use of the uniform cutoff value, 127 women (14.5%) and 345 men (18.6%) received a final diagnosis of AMI. Among these, at emergency department presentation, levels of hs-cTnT were already above the uniform cutoff value in 427 patients (sensitivity, 91.3% [95% CI, 85%-95.6%] in women vs 90.7% [95% CI, 87.1%-93.5% in men]; specificity, 79.2% [95% CI, 76.1%-82.1%] in women vs 78.5% [95% CI, 76.4%-80.6%] in men). After readjudication using sex-specific 99th percentile levels, diagnostic reclassification regarding AMI occurred in only 3 patients: 0.11% (95% CI, 0.02-0.32) of all patients and 0.6% (95% CI, 0.13-1.85) of patients with AMI. The diagnosis in 2 women was upgraded from unstable angina to AMI, and the diagnosis in 1 man was downgraded from AMI to unstable angina. These diagnostic results were confirmed when using 2 alternative pairs of uniform and sex-specific cutoff values. Conclusions and Relevance: The uniform 99th percentile should remain the standard of care when using hs-cTnT levels for the diagnosis of AMI.

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.