Enhancing the diagnosis of functionally relevant coronary artery disease with machine learning.

Functionally relevant coronary artery disease (fCAD) can result in premature death or nonfatal acute myocardial infarction. Its early detection is a fundamentally important task in medicine. Classical detection approaches suffer from limited diagnostic accuracy or expose patients to possibly harmful radiation. Here we show how machine learning (ML) can outperform cardiologists in predicting the presence of stress-induced fCAD in terms of area under the receiver operating characteristic (AUROC: 0.71 vs. 0.64, p = 4.0E-13). We present two ML approaches, the first using eight static clinical variables, whereas the second leverages electrocardiogram signals from exercise stress testing. At a target post-test probability for fCAD of <15%, ML facilitates a potential reduction of imaging procedures by 15-17% compared to the cardiologist's judgement. Predictive performance is validated on an internal temporal data split as well as externally. We also show that combining clinical judgement with conventional ML and deep learning using logistic regression results in a mean AUROC of 0.74.

Combining anatomical and biochemical markers in the detection and risk stratification of coronary artery disease.

AIMS: We aimed to test the hypothesis if combining coronary artery calcium score (Ca-score) as a quantitative anatomical marker of coronary atherosclerosis with high-sensitivity cardiac troponin as a quantitative biochemical marker of myocardial injury provided incremental value in the detection of functionally relevant coronary artery disease (fCAD) and risk stratification. METHODS AND RESULTS: Consecutive patients undergoing myocardial perfusion single-photon emission computed tomography (MPS) without prior CAD were enrolled. The diagnosis of fCAD was based on the presence of ischaemia on MPS and coronary angiography; fCAD was centrally adjudicated in the diagnostic and prognostic domain. Diagnostic accuracy was evaluated using the area under the receiver-operating characteristic curve (AUC). The composite of cardiovascular death and non-fatal acute myocardial infarction (AMI) within 730 days was the primary prognostic endpoint. Among 1715 patients eligible for the diagnostic analysis, 399 patients had fCAD. The combination of Ca-score and high-sensitivity cardiac troponin T (hs-cTnT) had good diagnostic accuracy for the diagnosis of fCAD (AUC 0.79, 95% confidence interval (CI) 0.77-0.81), but no incremental value compared with the Ca-score alone (AUC 0.79, 95% CI 0.77-0.81, P = 0.965). Similar results were observed using high-sensitivity cardiac troponin I (AUC 0.80, 95% CI 0.77-0.82) instead of hs-cTnT. Among 1709 patients (99.7%) with available follow-up, 59 patients (3.5%) suffered the composite primary prognostic endpoint (non-fatal AMI, n = 34; CV death, n = 28). Both Ca-score and hs-cTnT had independent prognostic value. Increased risk was restricted to patients with elevation in both markers. CONCLUSION: The combination of the Ca-score with hs-cTnT increases the prognostic accuracy for future events but does not provide incremental value vs. the Ca-score alone for the diagnosis of fCAD. STUDY REGISTRATION: Clinical trial registration: NCT00470587.

Comprehensive vasodilatation in women with acute heart failure: Novel insights from the GALACTIC randomized controlled trial.

AIMS: Sex-specific differences in acute heart failure (AHF) are both relevant and underappreciated. Therefore, it is crucial to evaluate the risk/benefit ratio and the implementation of novel AHF therapies in women and men separately. METHODS AND RESULTS: We performed a pre-defined sex-specific analysis in AHF patients randomized to a strategy of early intensive and sustained vasodilatation versus usual care in an international, multicentre, open-label, blinded endpoint trial. Inclusion criteria were AHF with increased plasma concentrations of natriuretic peptides, systolic blood pressure ≥100 mmHg, and plan for treatment in a general ward. Among 781 eligible patients, 288 (37%) were women. Women were older (median 83 vs. 76 years), had a lower body weight (median 64.5 vs. 77.6 kg) and lower estimated glomerular filtration rate (median 48 vs. 54 ml/min/1.73 m2 ). The primary endpoint, a composite of all-cause mortality or rehospitalization for AHF at 180 days, showed a significant interaction of treatment strategy and sex (p for interaction = 0.03; hazard ratio adjusted for female sex 1.62, 95% confidence interval 1.05-2.50; p = 0.03). The combined endpoint occurred in 53 women (38%) in the intervention group and in 35 (24%) in the usual care group. The implementation of rapid up-titration of renin-angiotensin-aldosterone system (RAAS) inhibitors was less successful in women versus men in the overall cohort and in patients with heart failure with reduced ejection fraction (median discharge % target dose in patients randomized to intervention: 50% in women vs. 75% in men). CONCLUSION: Rapid up-titration of RAAS inhibitors was less successfully implemented in women possibly explaining their higher rate of all-cause mortality and rehospitalization for AHF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, unique identifier NCT00512759.

Comparing the utility of clinical risk scores and integrated clinical judgement in patients with suspected acute coronary syndrome.

AIMS: The utility of clinical risk scores regarding the prediction of major adverse cardiac events (MACE) is uncertain. We aimed to directly compare the prognostic performance of five established clinical risk scores as well as an unstructured integrated clinical judgement (ICJ) of the treating emergency department (ED) physician. METHODS AND RESULTS: Thirty-day MACE including all-cause death, life-threatening arrhythmia, cardiogenic shock, acute myocardial infarction (including the index event), and unstable angina requiring urgent coronary revascularization were centrally adjudicated by two independent cardiologists in patients presenting to the ED with acute chest discomfort in an international multicentre study. We compared the prognostic performance of the HEART score, GRACE score, T-MACS, TIMI score, and EDACS, as well as the unstructured ICJ of the treating ED physician (visual analogue scale to estimate the probability of acute coronary syndrome, ranging from 0 to 100). Among 4551 eligible patients, 1110/4551 patients (24.4%) had at least one MACE within 30 days. Prognostic accuracy was high and comparable for the HEART score, GRACE score, T-MACS, and ICJ [area under the receiver operating characteristic curve (AUC) 0.85-0.87] but significantly lower and only moderate for the TIMI score (AUC 0.79, P < 0.001) and EDACS (AUC 0.74, P < 0.001), resulting in sensitivities for the rule-out of 30-day MACE of 93-96, 87 (P < 0.001), and 72% (P < 0.001), respectively. CONCLUSION: The HEART score, GRACE score, T-MACS, and unstructured ICJ of the treating physician, not the TIMI score or EDACS, performed well for the prediction of 30-day MACE and may be considered for routine clinical use. TRIAL REGISTRATION: ClinicalTrials.gov number NCT00470587.

Automated F18-FDG PET/CT image quality assessment using deep neural networks on a latest 6-ring digital detector system.

To evaluate whether a machine learning classifier can evaluate image quality of maximum intensity projection (MIP) images from F18-FDG-PET scans. A total of 400 MIP images from F18-FDG-PET with simulated decreasing acquisition time (120 s, 90 s, 60 s, 30 s and 15 s per bed-position) using block sequential regularized expectation maximization (BSREM) with a beta-value of 450 and 600 were created. A machine learning classifier was fed with 283 images rated "sufficient image quality" and 117 images rated "insufficient image quality". The classification performance of the machine learning classifier was assessed by calculating sensitivity, specificity, and area under the receiver operating characteristics curve (AUC) using reader-based classification as the target. Classification performance of the machine learning classifier was AUC 0.978 for BSREM beta 450 and 0.967 for BSREM beta 600. The algorithm showed a sensitivity of 89% and 94% and a specificity of 94% and 94% for the reconstruction BSREM 450 and 600, respectively. Automated assessment of image quality from F18-FDG-PET images using a machine learning classifier provides equivalent performance to manual assessment by experienced radiologists.

Hyperacute T Wave in the Early Diagnosis of Acute Myocardial Infarction.

STUDY OBJECTIVE: The diagnostic performance of T-wave amplitudes for the detection of myocardial infarction is largely unknown. We aimed to address this knowledge gap. METHODS: T-wave amplitudes were automatically measured in 12-lead ECGs of patients presenting with acute chest discomfort to the emergency department within a prospective diagnostic multicenter study. The final diagnosis was centrally adjudicated by 2 independent cardiologists. Patients with left ventricular hypertrophy, complete left bundle branch block, or paced ventricular depolarization were excluded. The performance for lead-specific 95th-percentile thresholds were reported as likelihood ratios (lr), specificity, and sensitivity. RESULTS: Myocardial infarction was the final diagnosis in 445 (18%) of 2457 patients. In most leads, T-wave amplitudes tended to be greater in patients without myocardial infarction than those with myocardial infarction, and T-wave amplitude exceeding the 95th percentile had positive and negative lr close to 1 or with confidence intervals (CIs) crossing 1. The exceptions were leads III, aVR, and V1, which had positive lrs of 3.8 (95% CI, 2.7 to 5.3), 4.3 (95% CI, 3.1 to 6.0) and 2.0 (95% CI, 1.4 to 2.9), respectively. These leads normally have inverted T waves, so T-wave amplitude exceeding the 95th percentile reflects upright rather than increased-amplitude hyperacute T waves. CONCLUSION: Hyperacute T waves, when defined as increased T-wave amplitude exceeding the 95th percentile, did not provide useful information in diagnosing myocardial infarction in this sample.

Serum neurofilament light chain in functionally relevant coronary artery disease and adverse cardiovascular outcomes.

Background: Functionally relevant coronary artery disease (fCAD), causing symptoms of myocardial ischemia, can currently only be reliably detected with advanced cardiac imaging. Serum neurofilament light chain (sNfL) is a biomarker for neuro-axonal injury known to be elevated by cardiovascular (CV) risk factors and cerebrovascular small-vessel diseases. Due to their pathophysiological similarities with fCAD and the link to CV risk factors, we hypothesised that sNfL may have diagnostic and prognostic value for fCAD and adverse cardiovascular outcomes.Methods: Of the large prospective Basel VIII study (NCT01838148), 4'016 consecutive patients undergoing cardiac work-up for suspected fCAD were included (median age 68 years, 32.5% women, 46.9% with history of CAD). The presence of fCAD was adjudicated using myocardial perfusion imaging single-photon emission tomography (MPI-SPECT) and coronary angiography. sNfL was measured using a high-sensitive single-molecule array assay. All-cause and cardiovascular death, myocardial infarction (MI), and stroke/transient ischaemic attack (TIA) during 5-year follow-up were the prognostic endpoints.Results: The diagnostic accuracy of sNfL for fCAD as quantified by the area under the curve (AUC) was low (0.58, 95%CI 0.56-0.60). sNfL was strongly associated with age, renal dysfunction, and body mass index and was a strong and independent predictor of all-cause death, cardiovascular death, and stroke/TIA but not MI. Time-dependent AUC for cardiovascular-death at 1-year was 0.85, 95%CI 0.80-0.89, and 0.81, 95%CI 0.77-0.86 at 2-years.Conclusion: While sNfL concentrations did not show a diagnostic role for fCAD, in contrast, sNfL was a strong and independent predictor of cardiovascular outcomes, including all-cause death, cardiovascular death and stroke/TIA.

Semi-automated volumetry of pulmonary nodules: Intra-individual comparison of standard dose and chest X-ray equivalent ultralow dose chest CT scans.

PURPOSE: To assess the performance of semi-automated volumetry of solid pulmonary nodules on single-energy tin-filtered ultralow dose (ULD) chest CT scans at a radiation dose equivalent to chest X-ray relative to standard dose (SD) chest CT scans and assess the impact of kernel and iterative reconstruction selection. METHODS: Ninety-four consecutive patients from a prospective single-center study were included and underwent clinically indicated SD chest CT (1.9 ± 0.8 mSv) and additional ULD chest CT (0.13 ± 0.01 mSv) in the same session. All scans were reconstructed with a soft tissue (Br40) and lung (Bl64) kernel as well as with Filtered Back Projection (FBP) and Iterative Reconstruction (ADMIRE-3 and ADMIRE-5). One hundred and forty-eight solid pulmonary nodules were identified and analysed by semi-automated volumetry on all reconstructions. Nodule volumes were compared amongst all reconstructions thereby focusing on the agreement between SD and ULD scans. RESULTS: Nodule volumes ranged from 58.5 (28.8-126) mm3 for ADMIRE-5 Br40 ULD reconstructions to 72.5 (39-134) mm3 for FBP Bl64 SD reconstructions with significant differences between reconstructions (p < 0.001). Interscan agreement of volumes between two given reconstructions ranged from ICC = 0.605 to ICC = 0.999. Between SD and ULD scans, agreement of nodule volumes was highest for FBP Br40 (ICC = 0.995), FBP Bl64 (ICC = 0.939) and ADMIRE-5 Bl64 (ICC = 0.994) reconstructions. ADMIRE-3 reconstructions exhibited reduced interscan agreement of nodule volumes (ICCs from 0.788 - 0.882). CONCLUSIONS: The interscan agreement of node volumes between SD and ULD is high depending on the choice of kernel and reconstruction algorithm. However, caution should be exercised when comparing two image series that were not identically reconstructed.

A proteomic surrogate for cardiovascular outcomes that is sensitive to multiple mechanisms of change in risk.

A reliable, individualized, and dynamic surrogate of cardiovascular risk, synoptic for key biologic mechanisms, could shorten the path for drug development, enhance drug cost-effectiveness and improve patient outcomes. We used highly multiplexed proteomics to address these objectives, measuring about 5000 proteins in each of 32,130 archived plasma samples from 22,849 participants in nine clinical studies. We used machine learning to derive a 27-protein model predicting 4-year likelihood of myocardial infarction, stroke, heart failure, or death. The 27 proteins encompassed 10 biologic systems, and 12 were associated with relevant causal genetic traits. We independently validated results in 11,609 participants. Compared to a clinical model, the ratio of observed events in quintile 5 to quintile 1 was 6.7 for proteins versus 2.9 for the clinical model, AUCs (95% CI) were 0.73 (0.72 to 0.74) versus 0.64 (0.62 to 0.65), c-statistics were 0.71 (0.69 to 0.72) versus 0.62 (0.60 to 0.63), and the net reclassification index was +0.43. Adding the clinical model to the proteins only improved discrimination metrics by 0.01 to 0.02. Event rates in four predefined protein risk categories were 5.6, 11.2, 20.0, and 43.4% within 4 years; median time to event was 1.71 years. Protein predictions were directionally concordant with changed outcomes. Adverse risks were predicted for aging, approaching an event, anthracycline chemotherapy, diabetes, smoking, rheumatoid arthritis, cancer history, cardiovascular disease, high systolic blood pressure, and lipids. Reduced risks were predicted for weight loss and exenatide. The 27-protein model has potential as a "universal" surrogate end point for cardiovascular risk.

International Validation of the Canadian Syncope Risk Score : A Cohort Study.

BACKGROUND: The Canadian Syncope Risk Score (CSRS) was developed to predict 30-day serious outcomes not evident during emergency department (ED) evaluation. OBJECTIVE: To externally validate the CSRS and compare it with another validated score, the Osservatorio Epidemiologico della Sincope nel Lazio (OESIL) score. DESIGN: Prospective cohort study. SETTING: Large, international, multicenter study recruiting patients in EDs in 8 countries on 3 continents. PARTICIPANTS: Patients with syncope aged 40 years or older presenting to the ED within 12 hours of syncope. MEASUREMENTS: Composite outcome of serious clinical plus procedural events (primary outcome) and the primary composite outcome excluding procedural interventions (secondary outcome). RESULTS: Among 2283 patients with a mean age of 68 years, the primary composite outcome occurred in 7.2%, and the composite outcome excluding procedural interventions occurred in 3.1% at 30 days. Prognostic performance of the CSRS was good for both 30-day composite outcomes and better compared with the OESIL score (area under the receiver-operating characteristic curve [AUC], 0.85 [95% CI, 0.83 to 0.88] vs. 0.74 [CI, 0.71 to 0.78] and 0.80 [CI, 0.75 to 0.84] vs. 0.69 [CI, 0.64 to 0.75], respectively). Safety of triage, as measured by the frequency of the primary composite outcome in the low-risk group, was higher using the CSRS (19 of 1388 [0.6%]) versus the OESIL score (17 of 1104 [1.5%]). A simplified model including only the clinician classification of syncope (cardiac syncope, vasovagal syncope, or other) variable at ED discharge-a component of the CSRS-achieved similar discrimination as the CSRS (AUC, 0.83 [CI, 0.80 to 0.87] for the primary composite outcome). LIMITATION: Unable to disentangle the influence of other CSRS components on clinician classification of syncope at ED discharge. CONCLUSION: This international external validation of the CSRS showed good performance in identifying patients at low risk for serious outcomes outside of Canada and superior performance compared with the OESIL score. However, clinician classification of syncope at ED discharge seems to explain much of the performance of the CSRS in this study. The clinical utility of the CSRS remains uncertain. PRIMARY FUNDING SOURCE: Swiss National Science Foundation & Swiss Heart Foundation.

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.

Lower diagnostic accuracy of hs-cTnI in patients with prior coronary artery bypass grafting.

BACKGROUND: High-sensitivity cardiac troponin T (hs-cTnT) and the ESC 0/1h-hs-cTnT-algorithm have worse performance in the early diagnosis of myocardial infarction (MI) in patients with prior coronary artery bypass grafting (CABG). It is unknown, whether this concern applies also to hs-cTnI, the most widely used analyte worldwide. METHODS: In an international multicenter diagnostic study, two cardiologists centrally adjudicated the final diagnosis in patients presenting to the emergency department with symptoms suggestive of MI according to the Third Universal Definition of MI. The objective was to compare the diagnostic accuracy of hs-cTnI assays and their performance within the ESC hs-cTnI 0/1h-algorithms in patients with versus without prior CABG. Findings were externally validated in an U.S. multicenter diagnostic study. RESULTS: A total of 392/5'200 patients (8%) had prior coronary artery bypass grafting (CABG). Diagnostic accuracy of hs-cTnI as quantified by the area under the receiver-operating characteristics-curve (AUC) in these patients was high, but lower versus patients without prior CABG (e.g. hs-cTnI-Architect 0.91 versus 0.95; p = 0.016). Sensitivity/specificity of rule-out/in by the European Society of Cardiology (ESC) 0/1h-hs-cTnI-algorithms remained very high [e.g. hs-cTnI-Architect 100% and 93.5%], but efficacy was lower (52% versus 74%, p < 0.01). External validation (n = 2113) confirmed these findings in 192 patients with prior CABG using hs-cTnI-Atellica, with 52% versus 36% (p < 0.001) remaining in the observe zone. CONCLUSIONS: Diagnostic accuracy of hs-cTnI and efficacy of the ESC 0/1h-hs-cTnI-algorithms are lower in patients with prior CABG, but sensitivity/specificity remain very high. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00470587, number NCT00470587.

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.

Health-Related Quality of Life Among United States Service Members with Low Back Pain Receiving Usual Care Plus Chiropractic Care vs Usual Care Alone: Secondary Outcomes of a Pragmatic Clinical Trial.

OBJECTIVE: This study examines Patient-Reported Outcome Measurement Information System (PROMIS®)-29 v1.0 outcomes of chiropractic care in a multi-site, pragmatic clinical trial and compares the PROMIS measures to: 1) worst pain intensity from a numerical pain rating 0-10 scale, 2) 24-item Roland-Morris Disability Questionnaire (RMDQ); and 3) global improvement (modified visual analog scale). DESIGN: A pragmatic, prospective, multisite, parallel-group comparative effectiveness clinical trial comparing usual medical care (UMC) with UMC plus chiropractic care (UMC+CC). SETTING: Three military treatment facilities. SUBJECTS: 750 active-duty military personnel with low back pain. METHODS: Linear mixed effects regression models estimated the treatment group differences. Coefficient of repeatability to estimate significant individual change. RESULTS: We found statistically significant mean group differences favoring UMC+CC for all PROMIS®-29 scales and the RMDQ score. Area under the curve estimates for global improvement for the PROMIS®-29 scales and the RMDQ, ranged from 0.79 to 0.83. CONCLUSIONS: Findings from this pre-planned secondary analysis demonstrate that chiropractic care impacts health-related quality of life beyond pain and pain-related disability. Further, comparable findings were found between the 24-item RMDQ and the PROMIS®-29 v1.0 briefer scales.

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.

Novel Criteria for the Observe-Zone of the ESC 0/1h-hs-cTnT Algorithm.

BACKGROUND: The non-ST-segment-elevation myocardial infarction (NSTEMI) guidelines of the European Society of Cardiology (ESC) recommend a 3h cardiac troponin determination in patients triaged to the observe-zone of the ESC 0/1h-algorithm; however, no specific cutoff for further triage is endorsed. Recently, a specific cutoff for 0/3h high-sensitivity cardiac troponin T (hs-cTnT) change (7 ng/L) was proposed, warranting external validation. METHODS: Patients presenting with acute chest discomfort to the emergency department were prospectively enrolled into an international multicenter diagnostic study. Final diagnoses were centrally adjudicated by 2 independent cardiologists applying the fourth universal definition of myocardial infarction, on the basis of complete cardiac workup, cardiac imaging, and serial hs-cTnT. Hs-cTnT concentrations were measured at presentation, after 1 hour, and after 3 hours. The objective was to externally validate the proposed cutoff, and if necessary, derive and internally as well as externally validate novel 0/3h-criteria for the observe-zone of the ESC 0/1h-hs-cTnT-algorithm in an independent multicenter cohort. RESULTS: Among 2076 eligible patients, application of the ESC 0/1h-hs-cTnT-algorithm triaged 1512 patients (72.8%) to either rule out or rule in NSTEMI, leaving 564 patients (27.2%) in the observe-zone (adjudicated NSTEMI prevalence, 120/564 patients, 21.3%). The suggested 0/3h-hs-cTnT-change of <7 ng/L triaged 517 patients (91.7%) toward rule-out, resulting in a sensitivity of 33.3% (95% CI, 25.5-42.2), missing 80 patients with NSTEMI, and ≥7 ng/L triaged 47 patients toward rule-in (8.3%), resulting in a specificity of 98.4% (95% CI, 96.8-99.2). Novel derived 0/3h-criteria for the observe-zone patients ruled out NSTEMI with a 3h hs-cTnT concentration <15 ng/L and a 0/3h-hs-cTnT absolute change <4 ng/L, triaging 138 patients (25%) toward rule-out, resulting in a sensitivity of 99.2% (95% CI, 96.0-99.9), missing 1 patient with NSTEMI. A 0/3h-hs-cTnT absolute change ≥6 ng/L triaged 63 patients (11.2%) toward rule-in, resulting in a specificity of 98% (95% CI, 96.2-98.9) Thereby, the novel 0/3h-criteria reduced the number of patients in the observe zone by 36%s and the number of type 1 myocardial infarction by 50%. Findings were confirmed in both internal and external validation. CONCLUSIONS: A combination of a 3h-hs-cTnT concentration (<15 ng/L) and a 0/3h absolute change (<4 ng/L) is necessary to safely rule out NSTEMI in patients remaining in the observe-zone of the ESC 0/1h-hs-cTnT-algorithm. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT00470587.

Effect of a strategy of comprehensive vasodilation versus usual care on health-related quality of life among patients with acute heart failure.

AIMS: We aimed to assess the long-term effect of a strategy of comprehensive vasodilation versus usual care on health-related quality of life (HRQL) among patients with acute heart failure (AHF). METHODS AND RESULTS: Health-related quality of life was prospectively assessed by the generic 3-levelled EQ-5D and the disease-specific Kansas City Cardiomyopathy Questionnaire (KCCQ) among adult AHF patients enrolled in an international, multicentre, randomised, open-label blinded-end-point trial of a strategy that emphasized early intensive and sustained vasodilation using maximally tolerated doses of established oral and transdermal vasodilators according to systolic blood pressure. Changes in EQ-5D and KCCQ from admission to 180 day follow-up were individually compared between the intensive vasodilatation and the usual care group. Among 666 patients eligible for 180 day follow-up, 284 (43%, median age 79 years, 35% women) and 198 (30%, median age 77 years, 35% women) had completed the EQ-5D and KCCQ at baseline and follow-up, respectively. There was a significant improvement in HRQL as quantified by both, EQ-5D and KCCQ, from hospitalization to 180 day follow-up, with no significant differences in the change of HRQL between both treatment strategies. For instance, 39 (26%) versus 33 (25%) patients had an improvement by at least one level in at least two categories in the EQ-5D. Median increase in KCCQ overall summary score (KCCQ-OSS) was 17.6 (IQR 2.0-42.6) in the intervention group versus 18.5 (IQR 3.9-39.3) in the usual care group (P < 0.001 vs. baseline, P = 0.945 between groups). CONCLUSIONS: Among patients with AHF, long-term HRQL quantified by EQ-5D and KCCQ improved substantially, with overall no significant differences between a strategy of comprehensive vasodilation versus usual care.

Human Nasal and Lung Tissues Infected Ex Vivo with SARS-CoV-2 Provide Insights into Differential Tissue-Specific and Virus-Specific Innate Immune Responses in the Upper and Lower Respiratory Tract.

The nasal mucosa constitutes the primary entry site for respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the imbalanced innate immune response of end-stage coronavirus disease 2019 (COVID-19) has been extensively studied, the earliest stages of SARS-CoV-2 infection at the mucosal entry site have remained unexplored. Here, we employed SARS-CoV-2 and influenza virus infection in native multi-cell-type human nasal turbinate and lung tissues ex vivo, coupled with genome-wide transcriptional analysis, to investigate viral susceptibility and early patterns of local mucosal innate immune response in the authentic milieu of the human respiratory tract. SARS-CoV-2 productively infected the nasal turbinate tissues, predominantly targeting respiratory epithelial cells, with a rapid increase in tissue-associated viral subgenomic mRNA and secretion of infectious viral progeny. Importantly, SARS-CoV-2 infection triggered robust antiviral and inflammatory innate immune responses in the nasal mucosa. The upregulation of interferon-stimulated genes, cytokines, and chemokines, related to interferon signaling and immune-cell activation pathways, was broader than that triggered by influenza virus infection. Conversely, lung tissues exhibited a restricted innate immune response to SARS-CoV-2, with a conspicuous lack of type I and III interferon upregulation, contrasting with their vigorous innate immune response to influenza virus. Our findings reveal differential tissue-specific innate immune responses in the upper and lower respiratory tracts that are specific to SARS-CoV-2. The studies shed light on the role of the nasal mucosa in active viral transmission and immune defense, implying a window of opportunity for early interventions, whereas the restricted innate immune response in early-SARS-CoV-2-infected lung tissues could underlie the unique uncontrolled late-phase lung damage of advanced COVID-19. IMPORTANCE In order to reduce the late-phase morbidity and mortality of COVID-19, there is a need to better understand and target the earliest stages of SARS-CoV-2 infection in the human respiratory tract. Here, we have studied the initial steps of SARS-CoV-2 infection and the consequent innate immune responses within the natural multicellular complexity of human nasal mucosal and lung tissues. Comparing the global innate response patterns of nasal and lung tissues infected in parallel with SARS-CoV-2 and influenza virus, we found distinct virus-host interactions in the upper and lower respiratory tract, which could determine the outcome and unique pathogenesis of SARS-CoV-2 infection. Studies in the nasal mucosal infection model can be employed to assess the impact of viral evolutionary changes and evaluate new therapeutic and preventive measures against SARS-CoV-2 and other human respiratory pathogens.

Cardiovascular Biomarkers in the Early Discrimination of Type 2 Myocardial Infarction.

Importance: Rapid and accurate noninvasive discrimination of type 2 myocardial infarction (T2MI), which is because of a supply-demand mismatch, from type 1 myocardial infarction (T1MI), which arises via plaque rupture, is essential, because treatment differs substantially. Unfortunately, this is a major unmet clinical need, because even high-sensitivity cardiac troponin (hs-cTn) measurement provides only modest accuracy. Objective: To test the hypothesis that novel cardiovascular biomarkers quantifying different pathophysiological pathways involved in T2MI and/or T1MI may aid physicians in the rapid discrimination of T2MI vs T1MI. Design, Setting, and Participants: This international, multicenter prospective diagnostic study was conducted in 12 emergency departments in 5 countries (Switzerland, Spain, Italy, Poland, and the Czech Republic) with patients presenting with acute chest discomfort to the emergency departments. The study quantified the discrimination of hs-cTn T, hs-cTn I, and 17 novel cardiovascular biomarkers measured in subsets of consecutively enrolled patients against a reference standard (final diagnosis), centrally adjudicated by 2 independent cardiologists according to the fourth universal definition of MI, using all information, including cardiac imaging and serial measurements of hs-cTnT or hs-cTnI. Results: Among 5887 patients, 1106 (18.8%) had an adjudicated final diagnosis of MI; of these, 860 patients (77.8%) had T1MI, and 246 patients (22.2%) had T2MI. Patients with T2MI vs those with T1MI had lower concentrations of biomarkers quantifying cardiomyocyte injury hs-cTnT (median [interquartile range (IQR)], 30 (17-55) ng/L vs 58 (28-150) ng/L), hs-cTnI (median [IQR], 23 [10-83] ng/L vs 115 [28-576] ng/L; P < .001), and cardiac myosin-binding protein C (at presentation: median [IQR], 76 [38-189] ng/L vs 257 [75-876] ng/L; P < .001) but higher concentrations of biomarkers quantifying endothelial dysfunction, microvascular dysfunction, and/or hemodynamic stress (median [IQR] values: C-terminal proendothelin 1, 97 [75-134] pmol/L vs 68 [55-91] pmol/L; midregional proadrenomedullin, 0.97 [0.67-1.51] pmol/L vs 0.72 [0.53-0.99] pmol/L; midregional pro-A-type natriuretic peptide, 378 [207-491] pmol/L vs 152 [90-247] pmol/L; and growth differentiation factor 15, 2.26 [1.44-4.35] vs 1.56 [1.02-2.19] ng/L; all P < .001). Discrimination for these biomarkers, as quantified by the area under the receiver operating characteristics curve, was modest (hs-cTnT, 0.67 [95% CI, 0.64-0.71]; hs-cTn I, 0.71 [95% CI, 0.67-0.74]; cardiac myosin-binding protein C, 0.67 [95% CI, 0.61-0.73]; C-terminal proendothelin 1, 0.73 [95% CI, 0.63-0.83]; midregional proadrenomedullin, 0.66 [95% CI, 0.60-0.73]; midregional pro-A-type natriuretic peptide, 0.77 [95% CI, 0.68-0.87]; and growth differentiation factor 15, 0.68 [95% CI, 0.58-0.79]). Conclusions and Relevance: In this study, biomarkers quantifying myocardial injury, endothelial dysfunction, microvascular dysfunction, and/or hemodynamic stress provided modest discrimination in early, noninvasive diagnosis of T2MI.

External validation of the clinical chemistry score.

BACKGROUND: Combining high-sensitivity cardiac troponin (hs-cTn) with estimated glomerular filtration rate and glucose within the Clinical Chemistry Score (CCS) could help in the assessment of patients with suspected acute myocardial infarction (AMI). METHODS: In patients presenting with suspected AMI to the emergency department, we aimed to externally validate the performance of the CCS in a prospective international multicenter study and to directly compare the diagnostic and prognostic performance of the CCS with hs-cTnT and hs-cTnI baseline levels alone using a single cut-off approach. The diagnostic endpoint was diagnostic accuracy for AMI as centrally adjudicated by two independent cardiologists including cardiac imaging and serial hs-cTnT/I measurements. The prognostic endpoint was 30-day AMI or death. RESULTS: AMI was the final diagnosis in 620/3827 patients (16.2%) adjudicated with hs-cTnT and 599 patients (15.7%) adjudicated with hs-cTnI. The CCS resulted in high diagnostic accuracy for AMI and prognostic accuracy for 30-days AMI/death as quantified by the area under the receiver-operating characteristic curve (AUC), using hs-cTnT 0.90 (95%CI 0.89-0.91) and 0.89 (95%CI 0.88-0.90), using hs-cTnI 0.91 (95%Cl 0.90-0.92) and 0.90 (95%CI 0.89-0.91) respectively. E.g. a CCS of 0 points resulted in a sensitivity of 99.8% (95%CI 99.1-100%) for rule-out of index AMI and 99.5% (95%CI 98.5-100%) for AMI/death at 30 days for hs-cTnT and 99.8% (95%CI 98.9-100%) and 99.6% (95%CI 98.6-100%) using hs-cTnI. Overall, the single hs-cTnT/I measurement approach provided comparable diagnostic (sensitivity 99.5-99.7%) and prognostic (sensitivity 98.9-99.5%) performance versus the CCS. INTERPRETATION: The CCS provided high diagnostic and prognostic performance also in this independent large validation cohort. A single hs-cTnT/I measurement approach for rule-out MI yielded similar estimates.