Michieli, Laura De

BACKGROUND: Thresholds to define prognosis with hs-cTnI (high-sensitivity cardiac troponin I) have not been systematically addressed in wild-type transthyretin amyloid cardiomyopathy, in part because of the multiplicity of hs-cTnI assays. The aims of this study were: first, to assess the prognostic performance of hs-cTnI measured with different assays in patients with wild-type transthyretin amyloid cardiomyopathy and, second, to identify assay-specific hs-cTnI thresholds for prognosis that could be integrated into staging systems for risk stratification. METHODS: Observational multicenter study of stable wild-type transthyretin amyloid cardiomyopathy patients from different cohorts using the Abbott Architect Stat hs-cTnI assay and the Beckman Coulter Access hs-cTnI assay (testing cohorts) and the Siemens Centaur XPT hs-cTnI assay (validation cohort). Outcome was all-cause mortality. RESULTS: In the Abbott cohort (n=136; median follow-up 22 [13–41] months; 31 [23%] deaths) and Beckman cohort (n=98; median follow-up 19 [12–28] months; 16 [16%] deaths), natural log-transformed hs-cTnI was an independent predictor of mortality (age- and sex-adjusted hazard ratio, 1.62 [95% CI, 1.11–2.35]; P =0.012 and 2.47 [95% CI, 1.48–4.14]; P <0.001, respectively). The best hs-cTnI threshold for 18-month mortality of the combined Abbott/Beckman cohorts (n=234) was 81 ng/L, rounded to 80 ng/L for simplicity of clinical use. A 2-variable staging system (based on the Mayo Clinic system) using hs-cTnI (>80 ng/L) and NPs (natriuretic peptides; NT-proBNP [N-terminal pro-B-type natriuretic peptide] >3000 ng/L or BNP [B-type natriuretic peptide] >250 ng/L) identified 3 groups with progressively worse prognosis. The staging system (using hs-cTnI >80 ng/L and NT-proBNP>3000 ng/L) was then applied to an independent cohort evaluated with the hs-cTnI Siemens assay (n=345, median follow-up 32 [24-42] months, 119 [34%] deaths). The significant differences between the groups were maintained. CONCLUSIONS: In patients with wild-type transthyretin amyloid cardiomyopathy, hs-cTnI is a strong and independent predictor of mortality. A threshold of hs-cTnI of 80 ng/L for these 3 assays provides effective risk stratification alone and in a staging system with NP.

Abstract Background Diagnosing myocardial infarction (MI) in patients with chronic kidney disease (CKD) is difficult as these patients often have elevated baseline high-sensitivity cardiac troponin T (hs-cTnT) concentrations. Methods Observational U.S. cohort study of emergency department (ED) patients undergoing hs-cTnT measurement. Cases with &gt;1 hs-cTnT increase &gt;99th percentile were adjudicated following the Fourth Universal Definition of MI. Diagnostic performance of baseline and serial 2- and 6-hour hs-cTnT thresholds for ruling-in acute MI was compared between those without and with CKD (eGFR &lt;60 ml/min/1.73m2). Results The study cohort included 1992 patients, amongst whom 501 (25%) had CKD. There were 701 (82%) patients with myocardial injury, 64 (7.5%) with type 1, and 91 (11%) with type 2 MI. In CKD patients with baseline hs-cTnT thresholds of &gt;52, &gt;100, &gt;200 or &gt;300 ng/L, PPVs for acute MI were 37% [95% CI 28-46], 53% (95% CI 39-67), 73% (95% CI 50-89) and 80% (95% CI 44-98), and in those without CKD, 64% (95% CI 50-77), 69% (95% CI 49-85), 59% (95% CI 33-82) and 54% (95% CI 25-81). In CKD patients with a 2-hour hs-cTnT delta of &gt;10, &gt;20 or &gt;30 ng/L, the corresponding PPVs were 65% (95% CI 50-78), 86% (95% CI 68-96) and 88% (95% CI 68-97), and in those without CKD, 65% (95% CI 51-78), 73% (95% CI 57-86) and 75% (95% CI 58-88) (Figure). Conclusion Diagnostic performance of standard baseline and serial 2-hour hs-cTnT thresholds to rule-in MI is suboptimal in patients with CKD. It significantly improves when using higher baseline thresholds and delta values.

Abstract Aims Diagnosing myocardial infarction (MI) in patients with chronic kidney disease (CKD) is difficult as they often have increased high-sensitivity cardiac troponin T (hs-cTnT) concentrations. Methods and results Observational US cohort study of emergency department patients undergoing hs-cTnT measurement. Cases with ≥1 hs-cTnT increase &gt; 99th percentile were adjudicated following the Fourth Universal Definition of MI. Diagnostic performance of baseline and serial 2 h hs-cTnT thresholds for ruling-in acute MI was compared between those without and with CKD (estimated glomerular filtration rate &lt; 60 mL/min/1.73 m2). The study cohort included 1992 patients, amongst whom 501 (25%) had CKD. There were 75 (15%) and 350 (70%) patients with CKD and 80 (5%) and 351 (24%) without CKD who had acute MI and myocardial injury. In CKD patients with baseline hs-cTnT thresholds of ≥52, &gt;100, &gt;200, or &gt;300 ng/L, positive predictive values (PPVs) for MI were 36% (95% CI 28–45), 53% (95% CI 39–67), 73% (95% CI 50–89), and 80% (95% CI 44–98), and in those without CKD, 61% (95% CI 47–73), 69% (95% CI 49–85), 59% (95% CI 33–82), and 54% (95% CI 25–81). In CKD patients with a 2 h hs-cTnT delta of ≥10, &gt;20, or &gt;30 ng/L, PPVs were 66% (95% CI 51–79), 86% (95% CI 68–96), and 88% (95% CI 68–97), and in those without CKD, 64% (95% CI 50–76), 73% (95% CI 57–86), and 75% (95% CI 58–88). Conclusion Diagnostic performance of standard baseline and serial 2 h hs-cTnT thresholds to rule-in MI is suboptimal in CKD patients. It significantly improves when using higher baseline thresholds and delta values.

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure (1,2). 99mTc- pyrophosphate cardiac scintigraphy (PYP) enables accurate, noninvasive diagnosis of ATTR-CM when coupled with appropriate clinical and laboratory evaluations to rule out light chain amyloidosis (3,4). High sensitivity cardiac troponin T (hs-cTnT) is routinely assessed for diagnostic purposes when ATTR-CM is suspected in clinical practice. Purpose To investigate the diagnostic performance of hs-cTnT in patients undergoing PYP for suspected ATTR-CM. Methods Observational study of patients undergoing PYP at a United States (US) cardiac amyloidosis referral center from 2013 to September 2022 and with at least one hs-cTnT value available within 1 year. 3-hour planar imaging followed by single photon-emission computed tomography with computed tomography was performed. Final diagnoses of ATTR-CM were validated using all clinical information. The lowest reportable clinical value for hs-cTnT in the US is &lt;6 ng/L (limit of quantitation). Results A total of 1572 patients underwent PYP and had a hs-cTnT value available within the study period. Of these, ATTR-CM was diagnosed in 475 patients (30%). Median (IQR) hs-cTnT was 48 (31-67) ng/L in patients with ATTR-CM and 26 (13-48) ng/L in those without. The area under the curve of hs-cTnT for the diagnosis of ATTR-CM was 0.69 (0.67-0.72). Among patients with a very low hs-cTnT value, i.e. &lt;6 ng/L (n=100, 6.4% of the overall cohort), 7 (7%) patients had a final ATTR-CM diagnosis while 93 (93%) did not. Therefore, a threshold of &lt;6 ng/L demonstrated a negative predictive value (NPV) of 93% (IQR 88, 98) and a sensitivity of 99% (97, 100) for ruling out ATTR-CM. The highest NPV was achieved with a threshold of 12 ng/L; 269 (17%) patients had hs-cTnT below this value and, of those, only 16 (6%) had a final diagnosis of ATTR-CM. This resulted in a NPV of 94% (91, 97) and a sensitivity of 97% (95, 98) for ruling out ATTR-CM. When considering progressively increasing hs-cTnT values as potential thresholds to aid in the prediction of ATTR-CM (Figure), we observed a progressive increase in specificity (above 90% for hs-cTnT values &gt; 95 ng/L), but the positive predictive value (PPV) remained low (below 50%). Conclusions Among patients undergoing PYP for suspected ATTR-CM at a US referral center, a very low hs-cTnT value was present in a minority of patients but demonstrated good performance in ruling out ATTR-CM. The highest NPV (94%) was achieved with a threshold of &lt; 12 ng/L. Higher hs-cTnT values showed a good specificity, but PPV remained low. Therefore, while a very low hs-cTnT might be of help in identifying those at low risk of ATTR-CM, the ubiquitous presence of increased hs-cTnT in many of these patients suggests the need for a multiparametric diagnostic approach to make the diagnosis.hs-cTnT in patients undergoing PYP scan

Abstract Background There are no robust data addressing the United States (US) experience with the 0/2 hours (h) European Society of Cardiology (ESC) algorithm using high-sensitivity cardiac troponin T (hs-cTnT). Purpose To evaluate the diagnostic performance of the 0/2h ESC-recommended absolute deltas in a US population. Methods Observational US cohort study of ED patients undergoing 0 and 2 h hs-cTnT measurements. The 99th percentiles upper reference limits (URL) used were 10 ng/L for women and 15 ng/L for men. Diagnostic outcomes were the adjudicated diagnoses of acute myocardial infarction (MI, type 1 or 2). Results A total of 1084 patients met inclusion criteria, amongst which 49% were women. Chest discomfort was reported in 521 (48%) patients. Among patients with a baseline hs-cTnT≤99th URL (n=434), 4 MIs occurred. To rule-out MI, an absolute 0-2h delta change &lt;4 ng/L resulted in a sensitivity of 100% (95% CI: 39.8, 100) and a negative predictive value (NPV) of 100% (95% CI: 99.1, 100). To rule-in MI, an absolute 0-2h delta ≥10 ng/L had a specificity of 99.8 % (95% CI: 98.7, 99.9) and positive predictive value (PPV) of 75% (95% CI: 19.4, 99.4). Among patients with a baseline hs-cTnT &gt;99th URL (n=650), 110 MIs occurred. In these patients, both rule-out (sensitivity 65%, NPV 91%) and rule-in (specificity 7.2%, PPV 11%) were poor using the ESC-recommended absolute deltas. Among patients with modest hs-cTnT increases (99th URL to 100 ng/L) neither the ESC-recommended absolute nor the Fourth Universal Definition of MI (UDMI)-recommended relative deltas provided acceptable performance. Among patients with marked hs-cTnT increases at presentation (&gt;100 ng/L), a relative delta change &gt;20% as recommended by the UDMI resulted in a superior rule-in performance, with a specificity of 92.0% (95% CI 74.0, 99.0) and PPV of 84.6% (57.4, 95.7). Conclusions In our unselected US-cohort of patients undergoing hs-cTnT, the 0/2h ESC algorithm had a good diagnostic performance in patients without myocardial injury at presentation. Conversely, in patients with myocardial injury at baseline, the ESC-recommended absolute deltas performed poorly to determine who had MI. In patients with marked hs-cTnT increases &gt;100 ng/L at presentation, the UDMI recommended 20% relative change showed good rule-in performance.

Abstract Background Guidelines suggest that the diagnosis of acute myocardial infarction (MI) is likely when high concentrations of high-sensitivity cardiac troponin (hs-cTn) are present in the initial sample. These concentration thresholds are much higher than the 99th percentile and are said to provide a high positive predictive value (PPV) for acute MI1. Purpose Evaluate the PPV of recommended baseline hs-cTnT thresholds (&gt;52 and &gt;100 ng/L) for the diagnosis of acute MI from our multi-center United States (US) experience. Methods Retrospective, multicenter (n=22), observational biomarker study involving consecutive, adult patients presenting to the emergency department (ED) in whom at least 1 hs-cTnT measurement was obtained within 12 hours of presentation (CV DataMart Biomarker cohort). The primary endpoint was also evaluated in an adjudicated cohort of consecutive patients presenting to the ED with at least 1 hs-cTnT &gt;99th percentile (ACTION cohort). These cases were adjudicated based on the Fourth Universal Definition of MI by trained physicians. The primary efficacy endpoint was the PPV of acute MI (type 1 or 2), type 1 MI and type 2 MI during index hospitalization using baseline hs-cTnT thresholds of &gt;52 ng/L and &gt;100 ng/L. Results The CV DataMart Biomarker cohort consisted of 143,709 patients, amongst whom 3,003 (2.1%) were diagnosed with acute MI using ICD codes. In the CV DataMart Biomarker cohort, baseline hs-cTnT concentrations of &gt;52 ng/L and &gt;100 ng/L resulted in PPVs of 12% (95% CI: 11, 12) and 17% (95% CI: 17, 19) for acute MI, respectively. In patients with chest pain and baseline hs-cTnT concentrations &gt;52 ng/L, PPV for acute MI was 17% (95% CI: 15, 18), and in those with hs-cTnT concentrations &gt;100 ng/L, PPV was 22% (95% CI: 19, 25). The adjudicated ACTION cohort consisted of 2,107 patients, amongst whom 155 (7.4%) were diagnosed with acute MI including 64 (41%) with type 1 MI and 91 (59%) with type 2 MI. In the ACTION cohort, baseline hs-cTnT concentrations of &gt;52 ng/L and &gt;100 ng/L resulted in PPVs of 46% (95% CI: 40, 53) and 62% (95% CI: 53, 70) for acute MI, respectively. In patients with chest pain and baseline hs-cTnT concentrations &gt;52 ng/L, PPV was 67% (95% CI: 57, 76) for acute MI, 52% (95% CI: 41, 62) for type 1 MI and 15% (95% CI: 8.4, 24) for type 2 MI. In those with chest pain and baseline hs-cTnT concentrations &gt;100 ng/L, PPV was 77% (95% CI: 65, 87) for acute MI, 64% (95% CI: 51, 75) for type 1 MI and 14% (95% CI 6.4, 24) for type 2 MI (Figure). Conclusion Using previously recommended high-risk hs-cTnT thresholds of 52 and 100 ng/L in US patients provides reasonable performance to rule-in acute MI when used in patients with chest pain. When used more broadly across all-comers, the diagnostic performance is poor.

Background: The 2021 ACC/AHA chest pain guidelines recommend risk scores such as HEAR (History, Electrocardiogram, Age, Risk Factors) for short term risk-stratification yet limited data exists integrating them with high-sensitivity cardiac troponin T (hs-cTnT). Methods: Retrospective, multicenter (n=2), observational, U.S. cohort study of consecutive ED patients without ST-elevation myocardial infarction (MI) who had at least one hs-cTnT (limit of quantitation, LoQ, <6 ng/L, and sex-specific 99 th percentiles of 10 ng/L for women and 15 ng/L for men) measurement on clinical indication in whom HEAR scores (0-8) were calculated. The composite major adverse cardiovascular (MACE) outcome was 30-day MI and death. Results: Among 1,979 ED patients undergoing hs-cTnT measurement, 1045 (53%) were classified as low-risk (0-3), 914 (46%) as intermediate-risk (4-6), and 20 (1%) as high-risk (7-8) based on HEAR scores. HEAR scores were not associated with an increased risk of 30-day MACE after adjusted analyses. Outcomes according to risk-strata based on HEAR scores and baseline hs-cTnT are shown in Table 1. Patients with quantifiable hs-cTnT (LoQ-99 th ) had an increased risk for 30-day MACE (3.4%) despite being estimated to be low-risk (0-3) per HEAR scores. Conversely, those with serial hs-cTnT<99 th percentile remained at low-risk (range 0% to 1.2%) for 30-day MACE across HEAR score strata. Conclusions: HEAR scores are of limited value in those with baseline hs-cTnT<LoQ or hs-cTnT>99 th percentile where hs-cTnT identifies very low and high-risk patients irrespective of HEAR scores. In those with baseline quantifiable hs-cTnT within the reference range (<99 th percentile), a higher risk (>1%) for 30-day MACE exists even in those with low HEAR scores. With serial hs-cTnT measurements, HEAR scores overestimate risk when hs-cTnT remains <99 th percentile.

Introduction: Differentiating type 2 myocardial infarction (T2MI) from myocardial injury can be difficult. The presence of objective evidence of acute myocardial ischemia may facilitate the identification of high-risk T2MI patients. Methods: Retrospective, observational cohort post-hoc analysis of adult emergency department patients undergoing hs-cTnT measurement. Patients with ≥1 hs-cTnT>99th percentile were adjudicated following the Fourth Universal Definition of MI. Patients were categorized as “subjective T2MI” when ischemic symptoms were the lone criteria supporting T2MI, or “objective T2MI” when there was ≥1 objective clinical feature (electrocardiography, imaging, angiography) of acute myocardial ischemia. The primary outcome was mortality. Results: A total of 857 patients were included, amongst which 55 (6.4%) were classified as subjective T2MI, 36 (4.2%) as objective T2MI, and 702 (82%) as myocardial injury. Among objective T2MIs, the most common criteria were ischemic electrocardiographic changes (n=29). Median (IQR) maximum hs-cTnT were 24 (18, 43) ng/L in myocardial injury, 34 (19, 80) in subjective T2MI, and 74 (35, 237) in objective T2MI. Those with objective T2MI had a higher risk of mortality during the index presentation (17% vs. 1.7%, p<0.0001; HR 11.1 95% CI 3.7-33.4) and at 2-year follow-up (47% vs. 31%, p=0.04; HR 1.92, 95% CI 1.17-3.14) than those with myocardial injury (Figure). Objective T2MI had a higher mortality than subjective T2MI at index presentation (17% vs. 2.0%, p=0.01) and at 1- (25% vs. 9.1%, p=0.04) and 3-months (31% vs. 13%, p=0.04) follow-up. There were no mortality differences between subjective T2MI and myocardial injury. Conclusions: In patients diagnosed with T2MI, those with objective evidence of myocardial ischemia have significantly worse outcomes compared to those with myocardial injury and subjective T2MI. A more rigorous definition of T2MI might be a more effective way to define this important entity.

Abstract Aims Our goal was to evaluate a previously validated artificial intelligence–augmented electrocardiography (AI-ECG) screening tool for left ventricular systolic dysfunction (LVSD) in patients undergoing high-sensitivity-cardiac troponin T (hs-cTnT). Methods and results Retrospective application of AI-ECG for LVSD in emergency department (ED) patients undergoing hs-cTnT. AI-ECG scores (0–1) for probability of LVSD (left ventricular ejection fraction ≤ 35%) were obtained. An AI-ECG score ≥0.256 indicates a positive screen. The primary endpoint was a composite of post-discharge major adverse cardiovascular events (MACEs) at two years follow-up. Among 1977 patients, 248 (13%) had a positive AI-ECG. When compared with patients with a negative AI-ECG, those with a positive AI-ECG had a higher risk for MACE [48 vs. 21%, P &lt; 0.0001, adjusted hazard ratio (HR) 1.39, 95% confidence interval (CI) 1.11–1.75]. This was largely because of a higher rate of deaths (32 vs. 14%, P &lt; 0.0001; adjusted HR 1.26, 95% 0.95–1.66) and heart failure hospitalizations (26 vs. 6.1%, P &lt; 0.001; adjusted HR 1.75, 95% CI 1.25–2.45). Together, hs-cTnT and AI-ECG resulted in the following MACE rates and adjusted HRs: hs-cTnT &lt; 99th percentile and negative AI-ECG: 116/1176 (11%; reference), hs-cTnT &lt; 99th percentile and positive AI-ECG: 28/107 (26%; adjusted HR 1.54, 95% CI 1.01–2.36), hs-cTnT &gt; 99th percentile and negative AI-ECG: 233/553 (42%; adjusted HR 2.12, 95% CI 1.66, 2.70), and hs-cTnT &gt; 99th percentile and positive AI-ECG: 91/141 (65%; adjusted HR 2.83, 95% CI 2.06, 3.87). Conclusion Among ED patients evaluated with hs-cTnT, a positive AI-ECG for LVSD identifies patients at high risk for MACE. The conjoint use of hs-cTnT and AI-ECG facilitates risk stratification.

Abstract Background Artificial intelligence-augmented electrocardiogram (AI-ECG) algorithms have been developed from the standard 12-lead ECG and validated for the recognition of left ventricular systolic dysfunction (LVSD), defined as LV ejection fraction (LVEF)≤35%. Whether AI-ECG facilitates identification of LVSD and is associated with adverse outcomes in emergency department (ED) patients undergoing high-sensitivity cardiac troponin (hs-cTnT) testing is uncertain. Purpose To investigate the diagnostic and prognostic performance of AI-ECG in ED patients undergoing hs-cTnT measurement. Methods Observational US cohort study of ED patients undergoing hs-cTnT measurement. Cases with hs-cTnT increases &gt;sex-specific 99th percentiles were adjudicated following the Fourth Universal Definition of Myocardial Infarction (MI). Post-discharge major adverse cardiac events (MACE) included death, MI, heart failure (HF) hospitalization, stroke or transient ischemic attack, and new onset atrial fibrillation/flutter during 2-years follow-up. The AI-ECG network output, which is a continuous number between 0–1, that provides a probability of LVSD, was obtained for each patient from the first ECG during the index presentation. An AI-ECG threshold of ≥0.256 indicates a positive screen that correlates with a high probability of LVSD. Results Among 1977 patients, 1729 (87%) had a negative AI-ECG screen, while 248 (13%) had a positive AI-ECG screen. Patients with a positive AI-ECG screen were older and had more comorbidities. As compared to patients with hs-cTnT≤99th percentile in whom AI-ECG was positive in 5.8%, those with hs-cTnT&gt;99th percentile had a positive AI-ECG in 22% of cases (p&lt;0.0001). Based on adjudicated diagnoses, the frequency of a positive AI-ECG was 20% in myocardial injury, 38% in type 1 MI, and 20% in type 2 MI. At 2-years follow-up, as compared to patients with a negative AI-ECG, those with a positive AI-ECG had a higher risk for MACE (48% vs. 21%, p&lt;0.0001, adjusted HR 1.39, 95% CI 1.11–1.75) (Figure 1), mainly because of more deaths (43% vs. 30%, p=0.004) and HF hospitalizations (36% vs. 13%, p&lt;0.0001). A positive AI-ECG was associated with a higher risk for MACE (60% vs. 41%, p&lt;0.0001, adjusted HR 1.30, 95% CI 1.02–1.64) in those with hs-cTnT increases &gt;99th percentile, but not in those without hs-cTnT increases. Among patients with an echocardiogram during index presentation or within 30-days (n=452), the diagnostic accuracy of AI-ECG for LVEF ≤35% was 81.4% (95% CI 77.5, 84.9) with a negative predictive value of 96.5% (95% CI 94.0, 98.2). A normal LVEF (&gt;50%) was observed in 87% of those with a negative AI ECG, whereas in those with a positive AI-ECG LVEF was reduced (&lt;50%) in 60%. Conclusions Among ED patients evaluated with hs-cTnT, a positive AI-ECG screen for LVSD identifies patients at high risk of MACE. These findings are largely because of more deaths and HF hospitalizations in those with hs-cTnT increases &gt;sex-specific 99th percentiles. Funding Acknowledgement Type of funding sources: None.