High sensitivity troponin I as a biomarker for cardiac allograft vasculopathy: Evaluation of diagnostic potential and clinical utility.

INTRODUCTION: Cardiac allograft vasculopathy (CAV) limits long-term survival in heart transplant (HTx) recipients. The use of biomarkers in CAV surveillance has been studied, but none are used in clinical practice. The predictive value of high-sensitivity troponin I (hsTnI) has not been extensively investigated in HTx recipients. METHODS: HTx patients undergoing surveillance coronary angiograms and enrolled in the Emory Cardiovascular Biobank had plasma hsTnI measured. CAV grade was assessed using ISHLT nomenclature. Multivariable cumulative link mixed modeling was performed to determine association between hsTnI level and CAV grade. Patients were followed for adverse outcomes over a median 10-year period. Kaplan-Meier survival analysis and Cox proportional hazard modeling were performed. RESULTS: Three hundred and seventy-two angiograms were analyzed in 156 patients at a median 8.9 years after transplant. hsTnI levels were positively correlated with concurrent CAV grade after adjustment for age, age at transplant, sex, BMI, hypertension, diabetes, hyperlipidemia, estimated glomerular filtration rate, and history of acute cellular rejection (p = .016). In an adjusted Cox proportional hazard model, initial hsTnI level above the median (4.9 pg/mL) remained a predictor of re-transplantation or death (hazard ratio 1.82; 95% confidence interval 1.16-2.90; p = .01). CONCLUSION: An elevated hsTnI level reflects severity of CAV and is associated with poor long-term outcomes in patients with HTx.

Association Between High Sensitivity Troponin I and NTproBNP With Rejection and Graft Loss in Pediatric Heart Transplant Recipients.

BACKGROUND: Troponin I is a blood biomarker of cardiac injury and levels measured using a high-sensitivity assay after pediatric heart transplantation (HT) have not been described. We sought to assess the association between high-sensitivity troponin I (hsTnI) and N-terminal pro-B-type natriuretic peptide (NTproBNP) with treated acute rejection (AR) and graft loss in pediatric heart transplant (HT) recipients. METHODS: Serum was collected and banked from pediatric HT recipients prior to cardiac catheterization. Patients with samples drawn within 365 days post-HT were included and followed for up to 5 years. Generalized linear mixed-effect models examined the association between hsTnI and treated AR using a random intercept per patient. Cox proportional hazards models tested the association between maximal hsTnI and NT-proBNP and death/graft loss. RESULTS: HsTnI and NTproBNP values decline in the weeks following HT, after which these biomarkers stabilize. HsTnI was higher in AR versus no AR (6.2 vs. 3.5 ng/L, p < 0.001); doubling of hsTnI increased the odds of AR by 33% (p = 0.004). HsTnI showed moderate discrimination for AR with an AUC of 0.811 (95% CI 0.76, 0.87) and a NPV of 96.4% (95% CI 93.0, 98.1). Elevation in NT-proBNP was not associated with AR. In multivariable Cox modeling, a doubling of maximal NT-proBNP was associated with graft loss (HR 8.96, p = 0.014). CONCLUSIONS: In this pediatric HT cohort, HsTnI was moderately discriminative for AR and higher maximal NT-proBNP was associated with graft loss. HsTnI may add value in pediatric HT non-invasive AR surveillance, and elevated NTproBNP could suggest an increased risk of graft loss.

Circulating Biomarkers for Cardiotoxicity Risk Prediction.

OPINION STATEMENT: Improvements in cancer survival have led to the emergence of cardiovascular disease as an important determinant of adverse outcome in survivors. Cancer therapeutics-related cardiac dysfunction is the most well-known form of cardiotoxicity. However, newer cancer therapies bring a broader range of cardiotoxicities. The optimal method to identify patients at risk of these complications is unclear, but circulating biomarkers comprise one possible approach. Troponins and natriuretic peptides have garnered the broadest evidence base for cardiotoxicity risk prediction, but other markers are being investigated. In this review, we explore evidence for circulating biomarkers in cardiotoxicity prediction associated with cancer therapies.

Cardio-Oncology Training: A Proposal From the International Cardioncology Society and Canadian Cardiac Oncology Network for a New Multidisciplinary Specialty.

There is an increasing awareness and clinical interest in cardiac safety during cancer therapy as well as in optimally addressing cardiac issues in cancer survivors. Although there is an emerging expertise in this area, known as cardio-oncology, there is a lack of organization in the essential components of contemporary training. This proposal, an international consensus statement organized by the International Cardioncology Society and the Canadian Cardiac Oncology Network, attempts to marshal the important ongoing efforts for training the next generation of cardio-oncologists. The necessary elements are outlined, including the expectations for exposure necessary to develop adequate training. There should also be a commitment to local, regional, and international education and research in cardio-oncology as a requirement for advancement in the field.

Right Heart Involvement in Patients with Sarcoidosis.

The left ventricle (LV) is affected in 20-25% of patients with sarcoidosis and its involvement is associated with morbidity and mortality. However, effects of sarcoidosis on the right ventricle (RV) are not well documented. Our aims were to investigate the prevalence of RV dysfunction in patients with sarcoidosis and determine whether it is predominantly associated with direct cardiac involvement, severity of lung disease, or pulmonary hypertension (PH). We identified 50 patients with biopsy-proven extra-cardiac sarcoidosis and preserved LV function, who underwent echocardiography, pulmonary function (PF) testing, and cardiovascular magnetic resonance. RV function was quantified by free wall longitudinal strain. Tricuspid valve Doppler and estimated right atrial pressure were used to estimate systolic pulmonary artery pressure. Myocardial late gadolinium enhancement was considered diagnostic for cardiac sarcoidosis and assumed to involve both ventricles. Of the 50 patients, 28 (56%) had RV dysfunction, 4 with poorly defined PF status. Of the remaining 24 patients, 16 (67%) had lung disease, 8 (33%) had PH, and 10 (42%) had LV involvement. Ten patients had greater than one of these findings, and 4 had all 3. In contrast, in 4/24 patients (17%), RV dysfunction could not be explained by these mechanisms, despite severely reduced RV strain. In conclusion, RV dysfunction is common in patients with sarcoidosis and is usually associated with either direct LV involvement, lung disease, or PH, but may occur in the absence of these mechanisms, suggesting the possibility of isolated RV involvement and underscoring the need for imaging protocols that would include RV strain analysis.

Improved detection of myocardial damage in sarcoidosis using longitudinal strain in patients with preserved left ventricular ejection fraction.

BACKGROUND: Cardiac infiltration is an important cause of death in sarcoidosis. Transthoracic echocardiography (TTE) has limited sensitivity for the detection of cardiac sarcoidosis (CS). Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) is used to diagnose CS but has limitations of cost and availability. We sought to determine whether TTE-derived global longitudinal strain (GLS) may be used to identify individuals with CS, despite preserved left ventricular ejection fraction (LVEF), and whether abnormal GLS is associated with major cardiovascular events (MCE). METHODS: We studied 31 patients with biopsy-proven extra-cardiac sarcoidosis, LVEF>50% and LGE on CMR (CS+ group), and 31 patients without LGE (CS- group), matched by age, sex, and severity of lung disease. GLS was measured using vendor-independent speckle tracking software. Parameters of left and right ventricular systolic and diastolic function were also studied. Receiver-operating characteristic curves were used to identify GLS cutoff for CS detection, and Kaplan-Meier plots to determine the ability of GLS to predict MCE. RESULTS: LGE was associated with reduced GLS (-19.6±1.9% in CS- vs -14.7±2.4% in CS+, P<.01) and with reduced E/A ratio (1.1±0.3 vs 0.9±0.3, respectively, P =.01). No differences were noted in other TTE parameters. GLS magnitude inversely correlated with LGE burden (r=-.59). GLS cutoff of -17% showed sensitivity and specificity 94% for detecting CS. Patients who experienced MCE had worse GLS than those who did not (-13.4±0.9% vs -17.7±0.4%, P=.0003). CONCLUSIONS: CS is associated with significantly reduced GLS in the presence of preserved LVEF. GLS measurements may become part of the TTE study performed to screen for CS.

Strategies for early detection of cardiotoxicities from anticancer therapy in adults: evolving imaging techniques and emerging serum biomarkers.

Significant advances have been made in detecting cancer therapeutics-related cardiac dysfunction with serum biomarkers, cardiovascular MRI, echocardiography and multi-modality approaches. Serum biomarkers, notably cardiac troponins and natriuretic peptides, have been evaluated for their prognostic ability in predicting left ventricular dysfunction. Imaging modalities, such as cardiovascular MRI and echocardiography, have been used for cardiac surveillance of patients with cancer undergoing chemotherapy. Developments in imaging, specifically myocardial deformation imaging, also known as strain, have been shown to be sensitive tools in detecting early changes in cardiac function. This review aims to synthesize the evidence that supports emerging serum biomarkers and complementary imaging modalities that continue to enhance the detection of cancer therapeutics-related cardiac dysfunction.

Circulating biomarkers in the diagnosis and prognosis of immune checkpoint inhibitor-related myocarditis: time for a risk-based approach.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block immune checkpoints and therefore activate immune cells, allowing them to recognize and attack cancer cells. ICIs have revolutionized oncology practice, but their use has been complicated by immune-related adverse events (irAEs). Of cardiovascular (CV) irAEs, ICI-related myocarditis has received significant attention due to high mortality rates, ranging from 25% to 50%, despite its overall low incidence. Establishing the early diagnosis of ICI-myocarditis is important for early initiation of steroids and consideration of hospitalization in patients who are at risk for hemodynamic compromise and need high acuity care in a tertiary setting. In this review, we summarize the diagnostic and prognostic tools for ICI-myocarditis, including electrocardiography, echocardiography, cardiac magnetic resonance imaging, with emphasis on circulating biomarkers. Cardiac troponins (cTns) are an essential component of the diagnosis of ICI-myocarditis, and we provide a summary of the recent studies that utilized different assays (cTnI vs. cTnT) and outcomes (diagnosis vs. prognosis including major adverse cardiac outcomes). With the exponential increase in ICI use across different oncology indications, there is a major need to include biomarkers in risk stratification to guide diagnosis and treatment. Our review proposes a framework for future multisite registries, including cTn evaluation at baseline and at the time of irAE suspicion, with development of central biobanking to allow head-to-head evaluation and clinical validation of different biomarker assays in ICI-myocarditis. This approach, with the inclusion of CV biomarkers into clinical and pragmatic oncology trials, holds promise to improve the early recognition and management of ICI-myocarditis and CV irAEs, thus leading to better outcomes.

MicroRNAs are associated with cardiac biomarkers, cardiac structure and function and incident outcomes in heart failure.

AIMS: The association between microRNAs (miRNAs) and established cardiac biomarkers is largely unknown. We aimed to measure the association between plasma miRNAs and N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac troponin I, soluble urokinase-type plasminogen activator receptor (suPAR), and galectin-3 with cardiac structure and function and clinical outcomes. METHODS AND RESULTS: We quantified 32 plasma miRNAs using the FirePlex miRNA assay and measured biomarkers in 139 individuals with symptomatic heart failure (HF). We used principal component (PC) analysis and linear regression to evaluate the association between miRNAs and biomarkers with ventricular size and function by echocardiography and Cox modelling for the incidence of a first composite event of HF hospitalization, heart transplant, left ventricular assist device implant, or death. The mean (standard deviation) age at baseline was 64.3 (12.4) years, 33 (24%) were female, and 122 (88%) were White. A total of 45 events occurred over a median follow-up of 368 (interquartile range 234, 494) days. Baseline NT-proBNP (ß = -2.0; P = 0.001) and miRNA PC2 (ß = 2.6; P = 0.002) were associated with baseline left ventricular ejection fraction. NT-proBNP (ß = 20.6; P = 0.0004), suPAR (ß = -39.6; P = 0.005), and PC4 (ß = 21.1; P = 0.02) were associated with baseline left ventricular end-diastolic volumes. NT-proBNP [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.28-2.18, P = 0.0002], galectin-3 (HR 2.02, 95% CI 1.05-3.91, P = 0.036), PC3 (HR 1.75, 95% CI 1.23-2.49, P = 0.002), and PC4 (HR 1.67, 95% CI 1.1-2.52, P = 0.016) were independently associated with incident events. CONCLUSIONS: Biomarkers and miRNA PCs are associated with cardiac structure and function and incident cardiovascular outcomes. Combining information from miRNAs provides prognostic information beyond biomarkers in HF.

Reduced congestion and improved response to a fluid/sodium challenge in chronic heart failure patients after initiation of sacubitril/valsartan: The NATRIUM-HF study.

AIMS: The effects of initiating sacubitril/valsartan in patients with stable heart failure with reduced ejection fraction (HFrEF) on response to fluid and sodium expansion are unknown. METHODS AND RESULTS: We have explored changes in natriuresis, diuresis, and congestion in response to the administration of intravenous fluid/sodium load in patients with HFrEF before as compared to after the initiation of sacubitril/valsartan. At baseline (before sacubitril/valsartan initiation) and 2 and 3 months after the initiation, patients underwent an evaluation that consisted of three phases of 3 h: the rest phase (0-3 h), the load phase (3-6 h) in which 1 L of intravenous Ringer solution was administered, and the diuretic phase (6-9 h) at the beginning of which furosemide was administered. Overall, 216 patients completed the study. In comparison to baseline values, at 2 and 3 months after sacubitril/valsartan initiation, patients' diuresis and natriuresis in response to Ringer administration significantly increased (mean difference: 38.8 [17.38] ml, p = 0.0040, and 9.6 [2.02] mmol, p < 0.0001, respectively). Symptoms and signs of congestion after the fluid/sodium challenge were significantly decreased at months 2 and 3 compared to baseline. Compared to baseline, there was also an increment of natriuresis after furosemide administration on sacubitril/valsartan (9.8 [5.13] mmol, p = 0.0167). There was a significant decrease in body weight in subsequent visits when compared to baseline values (-0.50 [-12.7, 7.4] kg at 2 months, and -0.75 [-15.9, 7.5] kg at 3 months; both p < 0.0001). CONCLUSIONS: The initiation of sacubitril/valsartan in HFrEF patients was associated with improvements in natriuresis, diuresis, and weight loss and better clinical adaptation to potentially decongestive stressors.

N terminal pro-brain natriuretic peptide level and benefits of chronic total occlusion revascularization.

BACKGROUND: The management of revascularization of chronic total occlusions (CTOs) remains controversial. Whether specific patients gain survival benefit from CTO revascularization remains unknown. OBJECTIVES: We investigated whether (i) patients with CTO have higher N terminal pro-brain natriuretic peptide (NT pro-BNP) levels than patients without CTO, (ii) in patients with CTO, NT pro-BNP levels predict adverse events, and (iii) those with elevated levels benefit from revascularization. METHODS: In 392 patients with stable, significant coronary artery disease (CAD) and CTO undergoing coronary angiography, rates of all-cause mortality, cardiovascular death, and a composite (cardiovascular death, myocardial infarction and heart failure hospitalizations) were investigated. Unadjusted and adjusted Cox proportional and Fine and Gray sub-distribution hazard models were performed to determine the association between NT pro-BNP levels and incident event rates in patients with CTO. RESULTS: NT pro-BNP levels were higher in patients with, compared to those without CTO (median 230.0 vs. 177.7 pg/mL, p ≤0.001). Every doubling of NT pro-BNP level in patients with CTO was associated with a > 25% higher rate of adverse events. 111 (28.5%) patients underwent CTO revascularization. In patients with elevated NT pro-BNP levels (> 125 pg/mL), those who underwent CTO revascularization had substantially lower adverse event rates compared to patients without CTO revascularization (adjusted cardiovascular death hazard ratio 0.29, 95% confidence interval (0.09-0.88). However, in patients with low NT pro-BNP levels (≤ 125 pg/mL), event rates were similar in those with and without CTO revascularization. CONCLUSION: NT pro-BNP levels can help identify individuals who may benefit from CTO revascularization.

Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial.

IMPORTANCE: Prevention strategies for heart failure are needed. OBJECTIVE: To determine the efficacy of a screening program using brain-type natriuretic peptide (BNP) and collaborative care in an at-risk population in reducing newly diagnosed heart failure and prevalence of significant left ventricular (LV) systolic and/or diastolic dysfunction. DESIGN, SETTING, AND PARTICIPANTS: The St Vincent's Screening to Prevent Heart Failure Study, a parallel-group randomized trial involving 1374 participants with cardiovascular risk factors (mean age, 64.8 [SD, 10.2] years) recruited from 39 primary care practices in Ireland between January 2005 and December 2009 and followed up until December 2011 (mean follow-up, 4.2 [SD, 1.2] years). INTERVENTION: Patients were randomly assigned to receive usual primary care (control condition; n=677) or screening with BNP testing (n=697). Intervention-group participants with BNP levels of 50 pg/mL or higher underwent echocardiography and collaborative care between their primary care physician and specialist cardiovascular service. MAIN OUTCOMES AND MEASURES: The primary end point was prevalence of asymptomatic LV dysfunction with or without newly diagnosed heart failure. Secondary end points included emergency hospitalization for arrhythmia, transient ischemic attack, stroke, myocardial infarction, peripheral or pulmonary thrombosis/embolus, or heart failure. RESULTS: A total of 263 patients (41.6%) in the intervention group had at least 1 BNP reading of 50 pg/mL or higher. The intervention group underwent more cardiovascular investigations (control, 496 per 1000 patient-years vs intervention, 850 per 1000 patient-years; incidence rate ratio, 1.71; 95% CI, 1.61-1.83; P<.001) and received more renin-angiotensin-aldosterone system-based therapy at follow-up (control, 49.6%; intervention, 56.5%; P=.01). The primary end point of LV dysfunction with or without heart failure was met in 59 (8.7%) of 677 in the control group and 37 (5.3%) of 697 in the intervention group (odds ratio [OR], 0.55; 95% CI, 0.37-0.82; P = .003). Asymptomatic LV dysfunction was found in 45 (6.6%) of 677 control-group patients and 30 (4.3%) of 697 intervention-group patients (OR, 0.57; 95% CI, 0.37-0.88; P = .01). Heart failure occurred in 14 (2.1%) of 677 control-group patients and 7 (1.0%) of 697 intervention-group patients (OR, 0.48; 95% CI, 0.20-1.20; P = .12). The incidence rates of emergency hospitalization for major cardiovascular events were 40.4 per 1000 patient-years in the control group vs 22.3 per 1000 patient-years in the intervention group (incidence rate ratio, 0.60; 95% CI, 0.45-0.81; P = .002). CONCLUSION AND RELEVANCE: Among patients at risk of heart failure, BNP-based screening and collaborative care reduced the combined rates of LV systolic dysfunction, diastolic dysfunction, and heart failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00921960.

Circulating Cardiovascular Biomarkers in Cancer Therapeutics-Related Cardiotoxicity: Review of Critical Challenges, Solutions, and Future Directions.

Cardiotoxicity is a growing concern in the oncology population. Transthoracic echocardiography and multigated acquisition scans have been used for surveillance but are relatively insensitive and resource intensive. Innovative imaging techniques are constrained by cost and availability. More sensitive, cost-effective cardiotoxicity surveillance strategies are needed. Circulating cardiovascular biomarkers could provide a sensitive, low-cost solution. Biomarkers such as troponins, natriuretic peptides (NPs), novel upstream signals of oxidative stress, inflammation, and fibrosis as well as panomic technologies have shown substantial promise, and guidelines recommend baseline measurement of troponins and NPs in all patients receiving potential cardiotoxins. Nonetheless, supporting evidence has been hampered by several limitations. Previous reviews have provided valuable perspectives on biomarkers in cancer populations, but important analytic aspects remain to be examined in depth. This review provides comprehensive assessment of critical challenges and solutions in this field, with focus on analytical issues relating to biomarker measurement and interpretation. Examination of evidence pertaining to common and serious forms of cardiotoxicity reveals that improved study designs incorporating larger, more diverse populations, registry-based approaches, and refinement of current definitions are key. Further efforts to harmonize biomarker methodologies including centralized biobanking and analyses, novel decision limits, and head-to-head comparisons are needed. Multimarker algorithms incorporating machine learning may allow rapid, personalized risk assessment. These improvements will not only augment the predictive value of circulating biomarkers in cardiotoxicity but may elucidate both direct and indirect relationships between cardiovascular disease and cancer, allowing biomarkers a greater role in the development and success of novel anticancer therapies.

High Sensitivity Troponin Level and Benefits of Chronic Total Occlusion Revascularization.

Background The survival benefit of revascularization of chronic total occlusion (CTO) of the coronary arteries remains a subject of controversy. We measured high sensitivity troponin-I (hsTn-I) levels as an estimate of myocardial ischemia in patients with stable coronary artery disease, with the hypothesis that (1) patients with CTO have higher levels of hsTn-I than patients without CTO, (2) hsTn-I levels will predict adverse cardiovascular events in patients with CTO, and (3) patients with elevated hsTn-I levels will have a survival benefit from CTO revascularization. Methods and Results In 428 patients with stable coronary artery disease and CTO undergoing coronary angiography, adverse event rates were investigated. Cox proportional hazards models and Fine and Gray subdistribution hazard models were performed to determine the association between hsTn-I level and incident event rates in patients with CTO. HsTn-I levels were higher in patients with compared with those without CTO (median 6.7 versus 5.6 ng/L, P=0.002). An elevated hsTn-I level was associated with higher adverse event rates (adjusted all-cause mortality hazard ratio, 1.19 [95% CI, 1.08-1.32]; P=0.030) for every doubling of hsTn-I level. CTO revascularization was performed in 28.3% of patients. In patients with a high (>median) hsTn-I level, CTO revascularization was associated with substantially lower all-cause mortality (adjusted hazard ratio, 0.26 [95% CI, 0.08-0.88]; P=0.030) compared with those who did not undergo revascularization. In patients with a low (

Aggregate Clinical and Biomarker-Based Model Predicts Adverse Outcomes in Patients With Coronary Artery Disease.

Despite guideline-based therapy, patients with coronary artery disease (CAD) are at widely variable risk for cardiovascular events. This variability demands a more individualized risk assessment. Herein, we evaluate the prognostic value of 6 biomarkers: high-sensitivity C-reactive protein, heat shock protein-70, fibrin degradation products, soluble urokinase plasminogen activator receptor, high-sensitivity troponin I, and B-type natriuretic peptide. We then develop a multi-biomarker-based cardiovascular event prediction model for patients with stable CAD. In total, 3,115 subjects with stable CAD who underwent cardiac catheterization at Emory (mean age 62.8 years, 17% Black, 35% female, 57% obstructive CAD, 31% diabetes mellitus) were randomized into a training cohort to identify biomarker cutoff values and a validation cohort for prediction assessment. Main outcomes included (1) all-cause death and (2) a composite of cardiovascular death and nonfatal myocardial infarction (MI) within 5 years. Elevation of each biomarker level was associated with higher event rates in the training cohort. A biomarker risk score was created using optimal cutoffs, ranging from 0 to 6 for each biomarker exceeding its cutoff. In the validation cohort, each unit increase in the biomarker risk score was independently associated with all-cause death (hazard ratio 1.62, 95% confidence interval [CI] 1.45 to 1.80) and cardiovascular death/MI (hazard ratio 1.52, 95% CI 1.35 to 1.71). A biomarker risk prediction model for cardiovascular death/MI improved the c-statistic (∆ 6.4%, 95% CI 3.9 to 8.8) and net reclassification index by 31.1% (95% CI 24 to 37), compared with clinical risk factors alone. Integrating multiple biomarkers with clinical variables refines cardiovascular risk assessment in patients with CAD.

Machine Learning to Assess for Acute Myocardial Infarction Within 30 Minutes.

Variations in high-sensitivity cardiac troponin I by age and sex along with various sampling times can make the evaluation for acute myocardial infarction (AMI) challenging. Machine learning integrates these variables to allow a more accurate evaluation for possible AMI. The goal was to test the diagnostic and prognostic utility of a machine learning algorithm in the evaluation of possible AMI. We applied a machine learning algorithm (myocardial-ischemic-injury-index [MI3]) that incorporates age, sex, and high-sensitivity cardiac troponin I levels at time 0 and 30 minutes in 529 patients evaluated for possible AMI in a single urban emergency department. MI3 generates an index value from 0 to 100 reflecting the likelihood of AMI. Patients were followed at 30-45 days for major adverse cardiac events (MACEs). There were 42 (7.9%) patients that had an AMI. Patients were divided into 3 groups by the MI3 score: low-risk (≤ 3.13), intermediate-risk (> 3.13-51.0), and high-risk (> 51.0). The sensitivity for AMI was 100% with a MI3 value ≤ 3.13 and 353 (67%) ruled-out for AMI at 30 minutes. At 30-45 days, there were 2 (0.6%) MACEs (2 noncardiac deaths) in the low-risk group, in the intermediate-risk group 4 (3.0%) MACEs (3 AMIs, 1 cardiac death), and in the high-risk group 4 (9.1%) MACEs (4 AMIs, 2 cardiac deaths). The MI3 algorithm had 100% sensitivity for AMI at 30 minutes and identified a low-risk cohort who may be considered for early discharge.

Biomarker prognostication across Universal Definition of Heart Failure stages.

AIM: The Universal Definition of Heart Failure (UDHF) provides a framework for staging risk for HF events. It is not clear whether prognostic biomarkers have different meaning across UDHF stages. We sought to evaluate performance of biomarkers to predict HF events among high-risk patients undergoing coronary and/or peripheral angiography categorized into UDHF stages. METHODS: One thousand two hundred thirty-five individuals underwent coronary and/or peripheral angiography were enrolled. Study participants were categorized into UDHF Stage A (at risk), Stage B (pre-HF), and Stage C or D (HF, including end stage) and grouped into Stage A/B and C/D. Biomarkers and clinical variables were used to develop prognostic models. Other measures examined included total HF hospitalizations. RESULTS: Over a median of 3.67 years of follow-up, 155 cardiovascular (CV) deaths occurred, and 299 patients were hospitalized with acute HF. In patients with Stage A/B, galectin-3 (HR = 1.52, P = 0.03), endothelin-1 (HR = 2.16, P = 0.001), and N-terminal pro-B-type natriuretic peptide (NT-proBNP; HR = 1.43, P < 0.001) were associated with incident CV death/HF hospitalization. In Stage C/D, NT-proBNP (HR = 1.26, P = 0.006), soluble urokinase-type plasminogen activator receptor (suPAR; HR = 1.57, P = 0.007) and high-sensitivity C-reactive protein (hs-CRP; HR = 1.15, P = 0.01) were associated with these outcomes. Higher biomarker concentrations were associated with greater total burden of HF events in Stages A/B and C/D. CONCLUSIONS: Among higher risk individuals undergoing angiographic procedures, different biomarkers improve risk stratification in different UDHF stages of HF. More precise prognostication may offer a window of opportunity to initiate targeted preventive measures.

Serial cardiac biomarkers for risk stratification of patients with COVID-19.

OBJECTIVES: Several studies have demonstrated an association between elevated cardiac biomarkers and adverse outcomes in patients with COVID-19. However, the prognostic and predictive capability of a multimarker panel in a prospectively collected, diverse "all-comers" COVID-19 population has not been fully elucidated. DESIGN & METHODS: We prospectively assessed high sensitivity cardiac troponin I (hsTnI), NT-pro B-type Natriuretic Peptide (NT-proBNP), Galectin-3 (Gal-3), and procalcitonin (PCT) in 4,282 serial samples from 358 patients admitted with symptomatic, RT-PCR confirmed SARS-CoV-2 infection. Outcomes examined were 30-day in-hospital mortality and requirement for intubation within 10 days. RESULTS: Baseline hsTnI had the highest AUC for predicting 30-day mortality (0.81; 95% CI, 0.73-0.88), followed by NT-proBNP (0.80; 0.74-0.86), PCT (0.77; 0.70-0.84), and Gal-3 (0.68; 0.60-0.76). HsTnI < 3.5 ng/L at baseline identified patients at low risk for in-hospital mortality (NPV 95.9%, sensitivity 97.3%) and 10-day intubation (NPV 90.4%, sensitivity 88.5%). Continuous, log-2 increases in troponin concentration were associated with reduced survival (p < 0.001) on Kaplan-Meier curves and increased risk of 30-day mortality: HR 1.26 (1.16-1.37) in univariate and 1.19 (1.03-1.4) in multivariate models. Time-varying doubling of concentrations of hsTnI and Gal-3 were associated with increased risk of 30-day mortality (adjusted HR 1.21, 1.06-1.4, and 1.92, 1.40-2.6). CONCLUSION: HsTnI, NT-proBNP, Gal-3, and PCT are elevated at baseline in patients that have worse outcomes from COVID-19. HsTnI was the only independent predictor of 30-day mortality and intubation. Time-varying, doubling in hsTnI and Gal-3 further aided in prognostication of adverse outcomes. These results support the use of hsTnI for triaging patients with COVID-19.

Relation of High-Sensitivity Cardiac Troponin I and Obstructive Coronary Artery Disease in Patients Without Acute Myocardial Infarction.

The relation of high-sensitivity cardiac troponin I (hs-cTnI) concentration and presence of obstructive coronary artery disease (CAD) in patients without myocardial infarction (MI) is unclear. Study participants selected from patients free of MI who underwent coronary angiography with or without intervention were enrolled, and hs-cTnI measured. A gradient boosting model was implemented to build a model for detection of CAD. Cox proportional hazard regression was used to assess the association of hs-cTnI and adverse cardiovascular (CV) outcome. Among 978 study participants, 607 patients (62%) had CAD. Higher concentrations of hs-cTnI were associated with chronic kidney disease, heart failure, CAD, male gender, current tobacco use, anemia, age, and low-density lipoprotein cholesterol. History of CAD, male gender, type 2 diabetes mellitus, hs-cTnI, anemia, age, and high-density lipoprotein cholesterol were the most influential factors for detection of CAD. The gradient boosting model had an area under the curve of 0.82, accuracy of 75%, sensitivity of 88%, specificity of 52%, positive predictive value of 76%, and negative predictive value of 72% for detection of CAD. Increase in 1 log unit of hs-cTnI was significantly associated with increased risk of incident MI (hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.22 to 1.47, p <0.001), CV mortality (HR 1. 24, 95% CI 1.11 to 1.39, p <0.001), and composite of incident MI or CV mortality (HR 1.29, 95% CI 1.20 to 1.40, p <0.001). In conclusion, among patients without acute MI and CAD, higher concentrations of hs-cTnI were associated with the presence of CAD and linked to increased risk of future CV events. ClinicalTrials.gov Identifier: NCT00842868.

Performance of the Abbott Architect Immuno-Chemiluminometric NT-proBNP Assay.

Background: We evaluated the performance of the Abbott N-terminal pro-brain natriuretic peptide (NT-proBNP) assay against the Roche NT-proBNP immunoassay across two sites. Methods: Precision, linearity, and sensitivity studies were performed. A combined method of comparison and regression analysis was performed between the Roche and Abbott assays using samples from both sites (n = 494). To verify biotin interference, lyophilised biotin powder was reconstituted and spiked into serum samples at two medical decision levels (final concentration 500/4250 ng/mL) and compared to controls. NT-proBNP was also measured in anonymised leftover sera (n = 388) in a cardio-renal healthy population and stratified into three age bands­<50 (n = 145), 50−75 (n = 183) and >75 (n = 60). Results: Between-run precision (CV%) for NT-proBNP was 4.17/4.50 (139.5/142.0 pg/mL), 3.83/2.17 (521.6/506.3), and 4.60/2.51 (5053/4973), respectively. The assay was linear from 0.7−41,501 pg/mL. The limit of blank/quantitation was 1.2/7.9 pg/mL. The assay showed no interference from biotin up to 4250 ng/mL. Passing−Bablok regression analysis showed excellent agreement between the two assays (r = 0.999, 95% CI 0.999 to 0.999, p < 0.0001). The Roche assay had a slightly persistent, negative bias across different levels of NT-proBNP. ESC age cut-offs for diagnosing acute heart failure are applicable for the Abbott assay, with the median NT-proBNP of subjects < 50 years old at 43.0 pg/mL (range 4.9−456 pg/mL), 50−75 years old at 95.1 pg/mL (range 10.5−1079 pg/mL), and >75 years old at 173.1 pg/mL (range 23.2−1948 pg/mL). Conclusions: The Abbott Architect NT-proBNP assay has good performance that agrees with the manufacturer's specifications. ESC/AHA recommended NT-proBNP age groups for acute heart failure diagnosis are applicable to this assay.