Jaffe, Allan S.

Abstract Background The prognostic implications of cardiac procedural myocardial injury and infarction (MI) in chronic coronary syndrome patients undergoing elective percutaneous coronary intervention (PCI) is still debated. Objective To determine the optimal cardiac troponin threshold for identifying prognostically important events. Methods Using a pooled dataset of nine registries and one randomized trial, we analysed individual data of 14,433 patients undergoing elective PCI with a normal or moderately elevated baseline pre-PCI cardiac troponin (cTn). A multivariate model was performed to evaluate the associations between post-PCI cTn elevation and 1-year mortality after PCI, including thresholds used by existing procedural myocardial injury definitions (Fourth Universal Definition of MI [UDMI] and Academic Research Consortium 2 [ARC-2] / Society for Cardiovascular Angiography and Interventions (SCAI)). The association between type 4a MI and 1-year mortality was also evaluated. Results Procedural myocardial injury defined by the Fourth UDMI occurred in 52.5% of patients and was not associated with 1-year mortality (adjOR 1.27, 95% CI [0.90–1.81] p=0.18). The association between post-PCI cTn elevation and 1-year mortality was significant above a 3-fold increase above the upper reference limit, and was optimal for a 5.2-fold increase which corresponded to an 18.3% rate of event, and an adjOR of 2.03 (95% CI [1.31–3.14], p=0.002) (figure). Procedural myocardial injury defined by the ARC-2/SCAI definition occurred in 1.3% of the patients, had a strong association with 1-year mortality (adjOR 4.15, 95% CI [1.62–10.64], p<0.01) but lacked sensitivity (5.2% sensitivity). Type 4a MI occurred in 12.7% of patients, was strongly associated with 1-year mortality (adjOR 3.18, 95% CI [1.47–6.90], p=0.002), but could only be evaluated in a subset of patients (n=3 084) with available data on new myocardial ischaemia post-PCI. Conclusions We have demonstrated that a post-PCI cTn elevation ≥5x the 99th percentile URL in CCS patients with normal baseline cTn, represents the optimal threshold for defining prognostically important or “Major” procedural myocardial injury in the absence of evidence for new myocardial ischaemia. Major procedure related myocardial injury and type 4a MI should be considered as a quality metric and endpoints in clinical trials. Adjusted OR of mortality at 1 year Funding Acknowledgement Type of funding source: None

Abstract Background and introduction Cardioversion is commonly used to terminate cardiac arrhythmias. Some previous reports have suggested that cardioversion results in myocardial injury as evidenced by increased levels of cardiac troponin. However, many of these studies were done years ago with less sensitive troponin assays and monophasic waveform defibrillators. Purpose To determine if external direct current (DC) cardioversion with biphasic rectilinear waveform shocks results in myocardial injury as assessed by high sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI). Methods Patients scheduled for elective DC cardioversion for atrial fibrillation or atrial flutter were recruited. Plasma samples for measurement of hs-cTnT and hs-cTnI were obtained pre-cardioversion and as late as feasible but at least 6 hours post-cardioversion [median of 9 (7–11) hours]. Results A total of 96 patients were recruited. One patient was excluded because the pre-cardioversion sample was hemolysed. Median (25th–75th interquartile range) cumulative energy delivered was 121.6J (62.4–277.4J) and median highest energy individual shock was 121.0J (62.1–146.2J). A total of 39 (41.1%) patients received more than 1 shock, 23 (24.2%) patients received a cumulative energy of 300J or higher and 5 (5.3%) patients received a cumulative energy of 1,000J or more. The median pre-cardioversion hs-cTnT value was 11.48 (7.19–18.38) ng/L and the median hs-cTnI value was 5.1 (2.0–9.4) ng/L. Median post-cardioversion hs-cTnT value were 12.46 (7.98–20.28) ng/L and hs-cTnI value were 6.3 (3.5–10.0) ng/L. Wilcoxon-Signed ranks test showed a statistically significant change between the pre-and-post cardioversion hs-cTnT values (Z=−4.237, p<0.001) and hs-cTnI values (Z=−4.822, p<0.001). In only 5 (hs-cTnT) and 4 patients (hs-cTnI) was there an increase of >5 ng/L. There were 5 cases where the post-cardioversion values of both hs-cTnT and hs-cTnI were above the 50% reference change value. There was no relation between the change in hs-cTn values and sex, number of shocks, total energy delivered (even in those who received more than 1,000J), highest energy per shock, total current delivered, highest current delivered per shock or transthoracic impedance. Conclusion(s) There is a statistically significant but very small change in median hs-cTnT and hs-cTnI values (1 ng/L and 1.2 ng/L respectively) after DC cardioversion. The results were similar even in patients where high energy shocks were delivered and did not vary based on the pre cardioversion baseline value. Patients who have marked troponin elevations after cardioversion should be assessed for other causes of myocardial injury. It should not be assumed that they have myocardial injury from the cardioversion alone. Figure 1 Funding Acknowledgement Type of funding source: Other. Main funding source(s): Dr. Allan Jaffe has substantial research funds from both grants and private industry. Funds were used to pay for blood sample collection and analysis of high sensitivity cardiac troponin T at Mayo Clinic. Abbott Laboratories donated reagents for the high sensitivity cardiac troponin I analysis.

Background: Myocardial injury results in release of cardiac troponin (cTn) into the bloodstream, readily detected by high-sensitivity cTn (hs-cTn) assays. A noninvasive, rapid, home-based test to exclude acute myocardial injury at the time of the test and for the next 7 hours would help manage patients with suspected myocardial infarction. Since myocyte injury is associated with ECG changes, we hypothesized an artificial intelligence ECG (AI-ECG) could identify absence of injury. Objective: To train and test an AI-ECG convolutional neural network (CNN) to identify patients using a single ECG who are suspected of myocardial infarction who are low risk, with hs-cTn levels below the 99 th percentile at test time and for the subsequent 7 hours. Methods: A CNN tuned to identify the absence of a hs-cTnT (5 th Gen cTnT Roche Diagnostics) >15ng/L for men and >10ng/L for women was developed. All ECGs were recorded within one hour of the hs-cTnT assay. We used 73,012 ECGs and hs-cTnT pairs from 47,542 unique patients to train the network, 9031 ECGs from 5,811 patients for internal validation to optimize hyperparameters, and 11,904 ECGs with 21,191 hs-cTnT measurements up to 7 hours after the ECG, from 11,904 different patients as a holdout test set. Results: The mean age was 63.9±17.5 years, and 30,348 of the 59,446 patients (51%) were male. 5,852 patients (49.1%) had no elevation of hs-cTnT and 6,052 (50.9%) had an hs-cTnT above the 99 th percentile at baseline or within 7 hours of the test. Of the 11,904 patients in the test set, using a sensitive threshold, the 12 lead AI ECG identified 1037 patients (8.7%) likely to have a low risk for subsequent hs-cTnT increases > 99 th % (AUC 0.86), and the single lead ECG identified 685 patients. Of the 1037 low risk pts, 59 had an hs-cTnT > 99 th percentile within 7 hours. The mean maximum hs-cTnT among the 59 low-risk patients was 53 ng/L ± 92 vs 184 ng/L ± 1474 in the others. None of these low risk patients died within 14 days of the test. Conclusion: Use of the AI ECG to identify patients without cardiac injury at the time of the test and for 7 subsequent hours is feasible. This may permit rapid, point of care, home-based, bloodless, painless testing to exclude cardiac injury, facilitating care and management of patients with suspected ischemia.

Background: High-sensitivity cardiac troponin (hs-cTn) assays quantify cTn in patients at very low concentrations. Myocyte injury due to ischemia or other pathologies cause blood levels to increase, which is prognostic. A noninvasive, rapid, broadly available, home-based test to detect hs-cTn increases would facilitate risk-stratification. Since myocyte injury is associated with ECG changes, we hypothesized an artificial intelligence ECG (AI-ECG) could non-invasively predict current or impending hs-cTnT elevations. Objective: To develop an AI-ECG convolutional neural network (CNN) to detect an abnormal hs-cTnT (5 th Gen cTnT, Roche Diagnostics) concentration using a 12-lead ECG, and a single lead ECG (lead I), which would enable smartphone, home-based detection. Methods: We developed single lead and 12-lead ECG CNNs to detect a) hs-cTnT concentrations that were at or above the 6ng/L limit that can be reported b) above the 99 th percentile upper limits of >15ng/L for men and >10ng/L for women. All ECGs were recorded within one hour of the hs-cTnT measurements. We used 73,012 ECG and hs-cTnT pairs from 47,542 unique patients to train the network, 9031 ECGs from 5,811 patients for internal validation to optimize hyperparameters, and 18,276 ECG and hs-cTnT pairs from 11,904 different patients as a holdout test set to determine the area under the receiver-operator curve (AUC). Results: The mean age was 63.9±17.5 years, and 30,348 of the 59,446 patients (51%) were male. Of the 91,288 hs-cTnT pairs 73,271 (80.2%) were above 6ng/L and 50,799 (55.6%) are above the 99 th percentile. In the test set, the AUC for the detection of a hs-cTnT level higher than 6ng/L was 0.88 using the 12 lead ECG and 0.834 with the single lead. For the detection of hs-cTnT level above of 99 th percentile, the 12 lead ECG AUC was 0.853 and the single lead was 0.806. Conclusion: The AI-ECG permits detection of levels of hs-cTnT consistent with myocardial injury. This may allow a home-based, non-invasive test that would be massively scalable and could further enhance rapid-risk stratification and patient triage with potentially significant cost reductions and enable novel triage strategies at sites without hs-cTn assays.

Abstract Plasma concentrations of low-density-lipoprotein cholesterol (LDL-C) are directly associated with risk for coronary artery disease (CAD). Multisociety guidelines define LDL-C>160mg/dL as a risk factor for CAD and LDL-C>190mg/dL as an indication for lipid lowering medication, regardless of other clinical factors. Subfractionation of LDL according to size (LDL-s) enables differentiation between two LDL phenotypes: large-buoyant LDL and small-dense LDL. The small-dense LDL phenotype reportedly conveys increased risk for CAD. Major societies do not recommend LDL subfractions be used for clinical decision making and most payers do not cover LDL subfraction testing. Despite these restrictions, LDL subfraction is routinely requested by clinicians. Nuclear magnetic resonance (NMR) spectroscopy measures LDL-C and LDL-s. Following inquiries regarding interpretation of conflicting LDL-C and LDL-s results, we investigated associations between LDL-C and LDL-s measured by NMR in order to determine how often they provide contradicting or additive information. Verification of NMR LDL-C accuracy was confirmed by ß-quantification in a subset of patient samples (n=250). The average bias was -4.5mg/dL and the correlation coefficient was 0.92. High-risk was defined as LDL-C>160mg/dL or LDL-s<20.5 nm (small-dense LDL); and low-risk was defined as LDL-C<70mg/dL or LDL-s>20.5nm (large-buoyant LDL). In 26,710 clinical NMR analyses, the median LDL-C was 94.0mg/dL (range:5-436mg/dL) with median LDL-s of 20.8 nm (range:19.4–23.0nm). LDL-s moderately correlated with LDL-C (Ï#129;=0.51;p<0.01). Small-dense-LDL was identified in only 18% (407/2,191) of patients with elevated LDL-C (>160mg/dL) and was more common (73.2% of 6,093) in patients with low LDL-C (<70mg/dL;p<0.001). Associations with CAD were investigated among patients without cholesterol-lowering medication treatment referred for angiography (n=356). CAD (defined as stenosis >50% in one or more coronary artery) was diagnosed in 14% (1/7) of subjects with low LDL-C (<70mg/dL) compared to 59% (47/80) of subjects with elevated LDL-C (p=0.01). When stratifying by LDL-s, CAD was diagnosed in 50% (57/115) of subjects with small-dense LDL compared to 43% (104/241) of subjects with large-buoyant LDL (p=0.2). Small-dense LDL was identified in only 33% (26/80) of cases with elevated LDL-C. Limiting to subjects with elevated LDL-C, CAD was diagnosed in 50% (13/26) of subjects with concordant (high-risk) small-dense LDL compared to 61% (33/54) of subjects with discordant (low-risk) large-buoyant LDL (LDL-s>20.5nm) (p=0.3). Our data confirm that LDL-s subfraction measured by NMR is reported discordantly in most cases when LDL-C is unequivocally high or low. Furthermore, CAD diagnosis was significantly associated with LDL-C, but not with LDL-s. Our data also show that in discrepant samples, elevated LDL-C correlates better with disease state compared to LDL-s. Therefore, LDL-s should not be used to justify treatment decisions in patients with elevated LDL-C. Laboratories should consider carefully whether or not to report LDL-s when it is known that misleading and discordant values will be reported in a majority of cases.

Background: There are limited data on how sex influences the outcomes of acute myocardial infarction-cardiogenic shock (AMI-CS) in young adults. Methods: A retrospective cohort of AMI-CS admissions aged 18 to 55 years, during 2000 to 2017, was identified using the National Inpatient Sample. Use of coronary angiography, percutaneous coronary intervention, mechanical circulatory support and noncardiac interventions was identified. Outcomes of interest included in-hospital mortality, use of cardiac interventions, hospitalization costs, and length of stay. Results: A total 90 648 AMI-CS admissions ≤55 years of age were included, of which 26% were women. Higher rates of CS were noted in men (2.2% in 2000 to 4.8% in 2017) compared with women (2.6% in 2000 to 4.0% in 2017; P <0.001). Compared with men, women with AMI-CS were more frequently of Black race, from a lower socioeconomic status, with higher comorbidity, and admitted to rural and small hospitals (all P <0.001). Women had lower rates of ST-segment elevation presentation (73.0% versus 78.7%), acute noncardiac organ failure, cardiac arrest (34.3% versus 35.7%), and received less-frequent coronary angiography (78.3% versus 81.4%), early coronary angiography (49.2% versus 54.1%), percutaneous coronary intervention (59.2% versus 64.0%), and mechanical circulatory support (50.3% versus 59.2%; all P <0.001). Female sex was an independent predictor of in-hospital mortality (23.0% versus 21.7%; adjusted odds ratio, 1.11 [95% CI, 1.07–1.16]; P <0.001). Women had lower hospitalization costs ($156 372±$198 452 versus $167 669±$208 577; P <0.001) but comparable lengths of stay compared with men. Conclusions: In young AMI-CS admissions, women are treated less aggressively and experience higher in-hospital mortality than men.

Objective: Vasopressin increases water permeability and activity of the epithelial sodium channel ENaC in the distal nephron of the kidney, favoring increased water and sodium retention. We hypothesized that genetically mediated differences in circulating vasopressin concentrations could contribute to features of hypertension that vary between non-Hispanic blacks and whites. To test this hypothesis we measured copeptin, a fragment of pre-pro arginine vasopressin with a prolonged half-life that is more easily quantified. Methods: The Genetic Epidemiology of Responses to Antihypertensives (GERA) I study was designed to identify predictors of response to diuretic therapy in non-Hispanic black and non-Hispanic white adults with essential hypertension. Blood samples were obtained after a 4 week washout of anti-hypertensive medication while on a sodium intake of 2 mmol/kg. Copeptin was measured from thawed EDTA plasma samples using the copeptin proAVP homogeneous automated immunofluorescent assay on the BRAHMS Kryptor Compact PLUS (Thermo Fisher). Results: Copeptin was significantly higher in blacks (median: 7.4 pmol/L, IQR: 4.4-10.2 pmol/L) than in whites (median: 5.4 pmol/L, IQR: 3.6-8.0 pmol/L) (p <0.001), while renin was lower (Table 1). Racial differences remained significant (p = 0.001) in multivariate models that included 24 hour urine sodium excretion and calculated plasma osmolality. Conclusions: Higher copeptin (vasopressin) concentrations in non-Hispanic blacks compared to whites may contribute to the distinct differences in the hypertensive phenotypes between these racial groups. The underlying mechanism(s) require further study.

Background: There is a paucity of contemporary data on the burden of intracranial hemorrhage (ICH) complicating acute myocardial infarction (AMI). This study sought to evaluate the temporal trends, predictors, and outcomes of ICH in AMI. Methods: The National Inpatient Sample (2000–2017) was used to identify adult (>18 years) AMI admissions with ICH. In-hospital mortality, hospitalization costs, length of stay, and measure of functional ability were the outcomes of interest. The discharge destination along with use of tracheostomy and percutaneous endoscopic gastrostomy were used to estimate functional burden. Results: Of a total 11,622,528 AMI admissions, 23,422 (0.2%) had concomitant ICH. Compared to those without, the ICH cohort was on average older, female, of non-White race, had greater comorbidities, and had higher rates of arrhythmias (all p < 0.001). Female sex, non-White race, ST-segment elevation AMI presentation, use of fibrinolytics, mechanical circulatory support, and invasive mechanical ventilation were identified as individual predictors of ICH. The AMI admissions with ICH received less frequent coronary angiography (46.9% vs. 63.8%), percutaneous coronary intervention (22.7% vs. 41.8%), and coronary artery bypass grafting (5.4% vs. 9.2%), as compared to those without (p < 0.001). ICH was associated with a significantly higher in-hospital mortality (41.4% vs. 6.1%; adjusted OR 5.65 (95% CI 5.47–5.84); p < 0.001), longer hospital length of stay, higher hospitalization costs, and greater use of percutaneous endoscopic gastrostomy (all p < 0.001). Among ICH survivors (N = 13, 689), 81.3% had a poor functional outcome at discharge. Conclusions: ICH causes a substantial burden in AMI due to associated higher in-hospital mortality and poor functional outcomes.

Background: The observed incidence of type 2 myocardial infarction (T2MI) is expected to increase with the implementation of increasingly sensitive cTn assays. However, it remains to be determined how to diagnose, risk-stratify, and treat patients with T2MI. We aimed to discriminate and risk-stratify T2MI using biomarkers. Methods: Patients presenting to the emergency department with chest pain, enrolled in the CHOPIN study (Copeptin Helps in the early detection Of Patients with acute myocardial INfarction), were retrospectively analyzed. Two cardiologists adjudicated type 1 MI (T1MI) and T2MI. The prognostic ability of several biomarkers alone or in combination to discriminate T2MI from T1MI was investigated using receiver operating characteristic curve analysis. The biomarkers analyzed were cTnI, copeptin, MR-proANP (midregional proatrial natriuretic peptide), CT-proET1 (C-terminal proendothelin-1), MR-proADM (midregional proadrenomedullin), and procalcitonin. The prognostic utility of these biomarkers for all-cause mortality and major adverse cardiovascular event (a composite of acute myocardial infarction, unstable angina pectoris, reinfarction, heart failure, and stroke) at 180-day follow-up was also investigated. Results: Among the 2071 patients, T1MI and T2MI were adjudicated in 94 and 176 patients, respectively. Patients with T1MI had higher levels of baseline cTnI, whereas those with T2MI had higher baseline levels of MR-proANP, CT-proET1, MR-proADM, and procalcitonin. The area under the receiver operating characteristic curve for the diagnosis of T2MI was higher for CT-proET1, MR-proADM, and MR-proANP (0.765, 0.750, and 0.733, respectively) than for cTnI (0.631). Combining all biomarkers resulted in a similar accuracy to a model using clinical variables and cTnI (0.854 versus 0.884, P =0.294). Addition of biomarkers to the clinical model yielded the highest area under the receiver operating characteristic curve (0.917). Other biomarkers, but not cTnI, were associated with mortality and major adverse cardiovascular event at 180 days among all patients, with no interaction between the diagnosis of T1MI or T2MI. Conclusions: Assessment of biomarkers reflecting pathophysiologic processes occurring with T2MI might help differentiate it from T1MI. All biomarkers measured, except cTnI, were significant predictors of prognosis, regardless of the type of myocardial infarction.