NT-proBNP Concentrations Research Articles

Age- and sex-specific upper reference limits for cardiac biomarkers in Chinese children and adolescents: a prospective study.

Cardiac biomarkers are being increasingly applied in pediatric populations, including those with cardiogenic and non-cardiogenic myocardial injury disease. The upper reference limits of biomarkers are an important reference for disease diagnosis and health evaluation. However, the upper reference limits of pediatric cardiac biomarkers remains unknown. A total of 1,797 serum samples were collected prospectively from healthy respondents aged 0 to 18 years old. These samples were analyzed using Roche cobas e411 to determine the concentrations of hs-cTnT, CK-MB mass, and NT-proBNP. The upper reference limits and 90% confidence interval were calculated according to Clinical and Laboratory Standards Institute C28- A3 guidelines. The study successfully established the upper reference limits for hs-cTnT, CK-MB mass, and NT-proBNP in healthy children and adolescents aged 0 to 18. The hs-cTnT, CK-MB mass, and NT-proBNP levels were visibly higher in neonatal serum. With the increase in age, hs-cTnT, CK-MB mass, and NT-proBNP decline gradually. They decrease quickly in the first year after birth and decrease slowly after 1 year old. Gender differences were observed in the concentrations of hs-cTnT and CK-MB mass among healthy children and teenagers aged 10 to 18 and 13 to 18. Specifically, boys had relatively higher concentrations of hs-cTnT and CK-MB mass. However, no gender difference was found in NT-proBNP concentration. The concentrations of hs-cTnT, CK-MB mass, and NT-proBNP were simultaneously tested in healthy Chinese children for the first time. The specific upper reference limits of age and gender in pediatrics were established. The results provide comprehensive references for medical institutions specializing in children's healthcare, which are conducive to preliminary screening, diagnosis, and treatment of pediatric cardiovascular diseases.

Abstract 4114417: Polygenic Risk in Heart Failure – Evaluating the Ability of a Polygenic Risk Score to Identify Risk of Future Heart Failure Events in 60,000 Patients from 6 TIMI Randomized Trials

Background: The ability of polygenic risk scores (PRS) to predict heart failure (HF) beyond classic risk factors is unclear. Aims: To evaluate the risk of a HF PRS with incident hospitalization for HF (HHF) in patients with established cardiovascular disease. Methods: We analyzed a 59 SNP HF PRS (HERMES collaboration, Henry et al) in genotyped patients from six multinational TIMI randomized controlled trials (DECLARE, ENGAGE AF, FOURIER, PEGASUS, SAVOR, SOLID). Patients were stratified to low (quintile, Q1), intermediate (Q2-Q4), or high (Q5) genetic risk. We investigated the association of the HF PRS with incident HHF (median of 2.5 years) i) stratified by prior HF, and ii) across NTproBNP concentrations at baseline, using Cox-proportional hazard models. Results are reported as HR [95% CI], per 1-SD or with Q1 as a reference, and adjusted for ancestry (principal components 1-5), age, sex, trial, BMI, smoking, systolic BP, prior CAD, DM, AF, and eGFR. Results: In 59,906 pts (median age 66 years; 71% male; 26% prior HF), the HF PRS was associated with incident HHF (HR adj per 1-SD 1.08 [1.03, 1.13], p<0.001). Compared to low genetic risk pts, the HR adj for HHF was 1.12 [1.00, 1.26] in intermediate and 1.17 [1.02, 1.35] in high-risk pts. There were significant interactions between the HF PRS and prior HF (P int 0.001), and NTproBNP (P int 0.038), respectively. In pts without prior HF (Fig A), compared to low-risk pts, the risk was increased in high- (HR adj 1.56 [1.25, 1.94], p<0.001) and intermediate-risk pts (HR adj 1.27 [1.05, 1.54], p=0.013). In contrast, there was no significant association in pts with known HF at baseline ( Fig B ). Similarly, the HF PRS was significantly associated with HHF in pts with low but not elevated NTproBNP at baseline ( Fig C ). Conclusion: Our study confirms the role of polygenic risk for HF and demonstrates that a 59 SNP PRS can identify pts at increased risk of future HF events beyond traditional clinical factors, specifically in patients without established HF or elevated NTproBNP. These findings suggest a potential application of a HF PRS for screening and early identification of pts at increased risk for HF.

Changes in heart rate variability and subclinical heart failure with preserved left ventricular ejection fraction in workers of the main professions at the coal industry

Introduction. The high prevalence of diseases of the circulatory system necessitates their detection and prevention at an early stage, especially in regions with high industrial potential. The occurrence of subclinical heart failure depends on a cascade of processes that are already occurring in the body and may eventually manifest themselves in clinically pronounced diseases. One of the possible mechanisms of its development is a violation of the balance of the autonomic nervous system with a violation of adaptive capabilities to the labour process, characterized by severe physical overloads among miners. The study aims to evaluate changes in heart rate variability in workers of the main professions at the coal industry with signs of heart failure with a preserved left ventricular ejection fraction. Materials and methods. The study included 78 employees of the main professions at the coal industry. Specialists performed ultrasound examination of the heart according to generally accepted methods with the study of longitudinal deformation of the myocardium. The concentration of NT-proBNP in the blood serum was determined by solid-phase enzyme immunoassay. The authors also conducted an analysis of heart rate variability, determined temporal, spectral and linear parameters. Results. Specialists revealed a decrease in longitudinal myocardial deformation in 38.5% of the examined patients, signs of diastolic dysfunction in 41%; in these groups, a tendency to increase the concentration of NT-proBNP was revealed. In the examined miners with heart failure with preserved ejection fraction, they revealed a significant decrease in the SDNN index and an increase in IC values. The increase in DFA and LF/HF indicators reflects a vegetative imbalance towards sympathetic activation observed in all surveyed miners. Limitations. This study is limited to a sample of employees of the main professions of the coal industry undergoing periodic medical examination at the Research Institute of Complex Problems of Hygiene and Occupational Diseases. Conclusion. The revealed relationship between indicators of heart failure and heart rate variability (SDNN, LF/HF, DFA and IC) in miners allows us to identify a group of people at greatest risk of adverse outcomes. Ethics. The study was conducted in compliance with the standards of the Bioethical Committee of the Research Institute of Complex Problems of Hygiene and Occupational Diseases, established in accordance with the Helsinki Declaration of the World Medical Association "Ethical Principles of Conducting medical Research with human participation as a subject" as amended in 2013 and the "Rules of Good Clinical Practice" approved by Order No. 200n of the Ministry of Health of the Russian Federation dated 04/01/2016. The subjects signed an informed consent to participate in the study.

Clinical Performance of an N-Terminal Pro-B-Type Natriuretic Peptide Assay in Acute Heart Failure Diagnosis.

We evaluated the Vitros® Immunodiagnostic Products N-terminal pro B-type natriuretic peptide (NT-proBNP) II assay for aiding in diagnosis of heart failure (HF) in patients with acute dyspnea. Serum concentrations of NT-proBNP were measured in patient samples from 20 emergency departments across the United States. Study endpoints included sensitivity, specificity, likelihood ratios, and predictive values for diagnosis of acute HF according to age-stratified cutoffs (450, 900, and 1800 pg/mL), and a rule-out age-independent cutoff (300 pg/mL). Additional measures were area under the curve (AUC) for receiver operating characteristic (ROC) curves. Results were also interpreted in patient subgroups with relevant comorbidities, and gray zone/intermediate assay values. Of 2200 patients, 1095 (49.8%) were diagnosed with HF by clinical adjudication. Sensitivity and specificity for Vitros NT-proBNP II ranged from 84.0% to 92.1%, and 81.4% to 86.5%, respectively, within and across age groups, and positive predictive values were 80.4% to 85.7%. Using the rule-out cutoff, the negative predictive value was 97.9%, with a negative likelihood ratio of 0.02. In subgroups with comorbidities potentially affecting NT-proBNP concentrations, sensitivities ranged from 82.6% to 89.5%, and AUCs for ROC curves were 0.899 to 0.915. The Vitros NT-proBNP II assay demonstrated excellent clinical performance using age-stratified cutoffs along with other clinical information for supporting diagnosis of HF, and can rule out HF with a high negative predictive value using the age-independent cutoff. The assay retained utility in patient subgroups with conditions that influence NT-proBNP concentration, and for those with gray zone results. NCT03548909.

Usefulness of preoperative NT-proBNP for prediction of acute heart failure, perioperative myocardial infarction/injury and mortality after non-cardiac surgery

Abstract Background Predicting cardiac complications after non-cardiac surgery is challenging. Purpose to determine the predictive accuracy of N-Terminal Pro–B-Type Natriuretic Peptide (NT-proBNP) and, to assess the utility of existing NT-proBNP cutoffs of the 2021 ESC Guidelines for the diagnosis of acute and chronic heart failure for prediction of postoperative acute heart failure (pAHF), perioperative myocardial infarction/injury (PMI) and mortality following non-cardiac surgery. Methods we prospectively determined preoperative NT-proBNP concentrations in consecutive patients at high cardiac risk undergoing inpatient non-cardiac surgery. Uni- and multivariable regression models were constructed to test the association between NT-proBNP concentrations and the outcomes (pAHF, PMI, 30-day and one-year mortality), using NT-proBNP as a continuous variable. We further stratified NT-proBNP into 5 categories according to guidelines (<125 pg/ml, 125 to 299pg/ml, 300 to 900 pg/ml, 901 to 1800pg/ml and >1800 pg/ml). Receiver operating characteristic curves were constructed to determine the predictive value of NT-proBNP. Results Among the 2,334 cases included, pAHF occurred in 83 (3.6%), PMI in 381 (17%), 45 (2.5%) patients died within 30 days and 179 (10%) within one year. After adjusting for confounders, NT-proBNP concentrations were independent predictors of pAHF (adjusted hazard ratio [aHR] 1.8 [95%CI, 1.5-2.1], p<0.001), PMI (aHR 1.3 [95%CI, 1.2-1.4],p<0.001) and 30 day/one year mortality (aHR 1.6[95%CI, 1.3-2.0], p<0.001)/aHR 1.5 [95%CI 1.4-1.7], p<0.001). By quintiles, higher the NT-proBNP levels were strongly associated with adverse outcome (Figure). Accuracy of preoperative NT-proBNP for prediction of pAHF was excellent (area under the curve [AUC] 0.825) and better than accuracy of the Revised Cardiac Risk Index score (AUC 0.692, p<0.001), whereas accuracy of NT-proBNP for prediction of PMI (AUC 0.654) and mortality (AUC 0.787) was only moderate. Conclusion NT-proBNP concentrations are independent predictors of pAHF, PMI and short and long-term mortality following non-cardiac surgery. Stratifying NT-proBNP concentrations using current recommended cut-offs could help to further determine the magnitude of the risk, mainly of pAHF.

Myocardial injury and heart failure biomarkers in acute intermittent porphyria

Abstract Background Acute intermittent porphyria (AIP) is a rare metabolic disorder caused by the defect in the hydroxymethylbilane synthase gene, encoding the third enzyme in heme biosynthesis pathway. The main symptoms include abdominal pain, vomiting, paralysis, confusion. Exacerbation of AIP may manifest with elevation of blood pressure and tachycardia due to hyperactivity of sympathetic nervous system. Data regarding cardiac function in AIP are scarce. Purpose The aim of this study was to assess the myocardial injury and heart failure biomarkers during AIP exacerbations and remission. Methods This cohort prospective study encompassed patients at the age 18-65 years who had at least one exacerbation of AIP in their lifetime. Patients examined during the AIP exacerbations were reassessed in the remission phase. The concentrations of sodium, troponin T, CK-MB mass, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and metoxycatecholamines in blood were assessed. Blood pressure was measured with 24-hour ABPM. Echocardiography was performed according to the current recommendations. Results The total number of 70 patients with AIP were enrolled to the study (April 2019 - March 2023). We assessed 36 patients in both phases of disease, mean age 37 years (21-63), 75% females. The median of prior AIP exacerbations was 8. During the exacerbations a significant increase in the concentrations of NT-proBNP (250 [97 ; 501] vs. 89 [48 ; 140] pg/mL, p<0.001), metanephrine (49.0 [37.8 ; 61.2] vs. 41.4 [36.8 ; 53.3] pg/mL, p=0.009) and normetanephrine (169.8 [118.2 ; 327.2] vs. 93.2 [78.1 ; 120.9] pg/mL, p<0.001) was observed. Conversely, sodium concentrations decreased (136 [133 ; 140] vs. 140 [139 ; 142] mmol/L, p<0.001). There were no significant differences in the values of troponin (5.4 [4.0 ; 11.3] vs. 5.6 [3.7 ; 9.5] ng/L, p=0.445), CK-MB mass (1.88 [0.84 ; 2.64] vs. 1.21 [0.83 ; 2.80] ng/mL, p=0.80). In the acute phases of AIP the levels of NT-proBNP were correlated negatively with the values of sodium concentrations (r=-0.36, p=0.032) and positively with average systolic blood pressure (r=0.32, p=0.06). Echocardiography showed an increase in left ventricular (LV) mass indices in some patients hospitalized due to AIP symptoms. Sodium concentrations correlated negatively with these changes (r=-0.36, p=0.032). LV ejection fraction was slightly higher during AIP exacerbations. There were no significant differences in other parameters of LV systolic and diastolic function. Conclusions During acute intermittent porphyria (AIP) exacerbations there is an increase in the concentrations of NT-proBNP and catecholamines in blood. In most patients the levels of markers of myocardial injury, such as troponin and CK-MB mass, do not differ significantly between phases of disease. During AIP exacerbations some patients experience an increase in LV mass which may be associated with hyponatremia. In most cases cardiac function do not change significantly.Frequency of abnormal laboratory resultsResults of echocardiography

Relationship between NT-proBNP, echocardiographic abnormalities and functional status in patients with subclinical diabetic cardiomyopathy

Abstract Background Persons with diabetes are at risk for developing a cardiomyopathy through several pathophysiological mechanisms independent of traditional risk factors for heart failure. Among those with so-called diabetic cardiomyopathy (DbCM), the relationship between natriuretic peptides, cardiac structural abnormalities and functional capacity is largely unknown. Purpose This study aimed to evaluate associations between NT-proBNP concentrations, clinical characteristics, echocardiographic findings, health status and activity, and outcomes from cardiopulmonary exercise testing Methods The Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure Trial (ARISE-HF) trial is evaluating the effects of AT-001, a novel aldose-reductase inhibitor in participants with DbCM without a prior history of heart failure (1). Participants were included if they had a known diagnosis of type 2 diabetes and age ≥60 (or ≥45 with a duration of diabetes of ≥10 years or estimated glomerular filtration rate ≤60 mL/min/1.73m2). Participants were required to have evidence of one of: structural cardiac abnormality, elevated cardiac biomarkers, or impaired exercise tolerance, defined as a peak oxygen uptake (VO2) ≤75% of predicted. In this prespecified subgroup analysis of the ARISE-HF trial, 685 participants with baseline echocardiography data, laboratory investigations, and functional assessment were included. Participants were stratified by N-terminal pro-B type natriuretic peptide (NT-proBNP) quartiles, and correlation with echocardiographic and functional parameters were assessed using Spearman correlation test. Results The mean age of participants was 67.4 years and 50% were female. The mean duration of type 2 diabetes was 14.5 years with a mean hemoglobin A1c of 6.98. The median NT-proBNP was 71 (Q1, Q3: 33, 135) ng/L. No association was observed between NT-proBNP concentrations and echocardiographic parameters of either diastolic or systolic dysfunction including global longitudinal strain, left ventricular ejection fraction, left ventricular mass index, left atrial volume index, E/e’, or right ventricular systolic pressure (Figure 1). In contrast, NT-proBNP was significantly correlated with components of the Kansas City Cardiomyopathy Questionnaire (P<0.001), the Physical Activity Scale in the Elderly (P=0.004), duration of cardiopulmonary exercise testing (P<0.001), peak VO 2 (P<0.001), and ratio of minute ventilation/carbon dioxide production (P=0.002; Figure 2). Conclusion Among highly selected patients with subclinical DbCM, elevated NT-proBNP concentrations are associated with worse health status, lower activity levels, and reduced functional capacity, but not with cardiac structural abnormalities. These findings suggest that regardless of cardiac structural abnormalities, biomarker concentrations reflect important deterioration in functional capacity in affected individuals.

Clinical application of biomarkers in obstructive hypertrophic cardiomyopathy: insights from SEQUOIA-HCM

Abstract Background Multiple studies show that circulating cardiac biomarkers, N-terminal pro-B type natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin I (hs-cTnI) are associated with key pathophysiological processes and clinical outcomes in obstructive hypertrophic cardiomyopathy (oHCM). Herein we describe the impact of aficamten on cardiac biomarkers in SEQUOIA-HCM (NCT05186818). Purpose In this pre-specified analysis, we describe associations between baseline NT-proBNP and hs-cTnI concentrations and assess the relationship between changes after treatment with aficamten and trial endpoints. Methods Patients with oHCM in NYHA Class II-III, were randomized 1:1 to 24 weeks of daily aficamten (5–20 mg, n=142) or placebo (n=140). Aficamten dose was adjusted to achieve Valsalva left ventricular outflow tract gradient (LVOT-G) <30 mmHg while maintaining left ventricular ejection fraction (LVEF) ≥50%. Peak oxygen consumption (pVO2) was measured by cardiopulmonary exercise testing at baseline and week 24. Cardiac biomarkers were measured at baseline, each dose titration (weeks 2, 4, and 6), every 4 weeks during treatment and after 4 weeks drug washout. Multivariable regression analysis was used to identify significant predictors of baseline biomarker values. Joint modeling and mediation analysis was used to determine how much of the treatment effect was indirectly mediated by NT-proBNP and hs-cTnI. Results In 282 symptomatic oHCM patients (mean age 59 years, 41% female), the median (IQR) NT-proBNP was 788 ng/L (346, 1699) and hs-cTnI was 12 ng/L (9, 27). At baseline, LVOT-G modestly correlated with NT-proBNP, rho = 0.26 (p<0.001) but not hs-cTnI, rho = 0.06 (p=0.36). Predictors of baseline biomarker values are summarized in Table 1. Compared to placebo, aficamten treatment was associated with an early relative reduction from baseline at week 8 in NT-proBNP (-79% (95% CI -83%, -76%, p<0.001) and in hs-cTnI -41% (-49%, -32%), p<0.001. This magnitude of change persisted to week 24 with biomarker return to baseline after aficamten washout (Figure 1). The mediation analysis suggested that NT-proBNP reduction over the 24-week treatment period reflected 101% (41%, 195%) of aficamten’s effect on pVO2. In contrast hs-cTnI reduction reflected 3% (-18%, 30%) of aficamten’s effect on pVO2. Conclusions Concentrations of NT-proBNP and hs-cTnI are associated with clinically relevant echocardiographic variables in oHCM. Compared with placebo, aficamten treatment markedly reduced plasma NT-proBNP and hs-cTnI concentrations, evident from week 2 and persisting until the end of treatment. NT-proBNP reduction may link LVOT-G with reduced exercise capacity in oHCM. These data support the use of biomarkers as a tool for managing patients with oHCM in order to monitor response to aficamten therapy.Effect of aficamten on biomarkersPredictors of baseline biomarkers

Incidence of acute cardiovascular hospitalizations and association with hemodynamic biomarkers in cancer patients treated with Immune Checkpoint Inhibitor therapy

Abstract Background/Introduction Immune checkpoint inhibitors (ICI) have significantly improved outcomes for several malignancies. Despite these benefits, patients with cancer face an increased risk for the development of cardiovascular disease due to mutual risk factors, similar biological mechanisms, as well as cardiotoxic side effects of therapy. Therefore, there is a pressing need for effective risk stratification strategies. Purpose This study aimed to explore the association between NT-proBNP levels and the risk of acute cardiovascular hospitalizations and death in patients who receive ICI. Methods We used electronic health records of patients treated with ICI who had available baseline NT-proBNP levels at our hospital, a tertiary academic center, between January 2017 and July 2022. The primary outcome of interest was the composite of acute cardiovascular hospitalization or death. The associations between NT-proBNP and outcomes were analyzed using cox regression models adjusted for age, sex, serum creatinine, diabetes, HF, CAD, hypertension, AF, LDL-C, and CRP. Results In total, 550 patients (35% female, median age 65 yrs) were included in the study. The median NT-proBNP levels were 272 pg/mL (IQR 102-742 pg/mL) and 388 (71%) patients had NT-proBNP levels ≥125 pg/mL. During a median FU of 67 weeks, 190 patients (35%) died, and 103 CV hospitalizations occurred in 76 patients (14%). Compared with patients with NT-proBNP concentrations <125, those with NT-proBNP concentrations ≥125 pg/ml had significantly higher event rates of the combined endpoint (12-Month KM event rates: 38% vs 21%, P<0.001). After multivariable adjustment, NT-proBNP remained independently associated with an increased risk of cardiovascular hospitalization and death (Adjusted HR for 1-SD increase in log-transformed biomarker 1.64, 95% CI 1.24 to 2.14; Figure). Conclusion These data highlight NT-proBNP levels as a valuable marker for identifying patients at increased risk of cardiovascular complications during ICI therapy.

Natriuretic peptides, kidney function and clinical outcomes in heart failure with mildly reduced or preserved ejection fraction: pooled data from the I-PRESERVE, TOPCAT, PARAGON and DELIVER trials

Abstract Background The prognostic utility of N-terminal pro-B-type (NT-proBNP) in patients with heart failure and chronic kidney disease (CKD) is incompletely understood since elevations in NT-proBNP could be related either to decreased clearance by the kidney or to increased severity of structural heart disease. Purpose We sought to assess the association of NT-proBNP with cardiovascular and mortality outcomes in patients with heart failure and mildly reduced or preserved ejection fraction, stratified by baseline kidney function. Methods We conducted a pooled analysis of individual participants with NT-proBNP and estimated glomerular filtration rate (eGFR) measured at baseline in the I-PRESERVE, TOPCAT (Americas region), PARAGON and DELIVER trials. We evaluated the relationship between NT-proBNP and kidney function using piecewise linear regression. Using multivariable Cox and Poisson regression models, we assessed the association of NT-proBNP with clinical outcomes across different levels of eGFR (≥60, 45-<60 and <45 mL/min/1.73m2). The primary outcome was hospitalisation for heart failure or cardiovascular death. Results Among 14,831 participants (mean age 72.1 years, 50.3% female, mean eGFR 63.3 mL/min/1.73m2 and median NT-proBNP 840 pg/mL) followed for a median 33.5 months, there were 3,092 primary outcomes, 2,184 heart failure hospitalisations, 1,465 cardiovascular and 1,049 non-cardiovascular deaths. Participants in lower eGFR categories were more likely to be older, female, and have atrial fibrillation and diabetes (all p<0.001). NT-proBNP levels increased by 9%, 8%, and 23% per 10 mL/min/1.73m2 lower eGFR in patients with baseline eGFR ≥60, 45-60, and <45 mL/min/1.73m2, respectively (P for non-linearity <0.001). For any given NT-proBNP concentration, participants with eGFR <45 mL/min/1.73m2 were at highest risk (Figure 1). Each doubling in NT-proBNP was associated with a 37% relative increase in the primary outcome (HR 1.37, 95% CI 1.34-1.41), consistent across different eGFR categories (P-interaction=0.42). Association between NT-proBNP and other clinical outcomes were also consistent across different levels of kidney function (all P-interaction>0.3; Figure 1). Equivalent risk for the primary outcome was apparent at NT-proBNP levels approximately 2.5- to 3.5-fold lower in patients eGFR <45 mL/min/1.73m2, compared to those with eGFR ≥60 mL/min/1.73m2. (Figure 2). Conclusion NTproBNP is a potent predictor of risk in patients with heart failure with mildly reduced or preserved ejection fraction across the spectrum of kidney function. However, in patients with reduced kidney function, lower NT-proBNP levels confer absolute risk of cardiovascular outcomes similar to substantially higher NT-proBNP levels in patients with normal kidney function. Accordingly, interpretation of NTproBNP levels should vary according to kidney function, particularly in those with eGFR <45 mL/min/1.73m2.

Machine learning to improve the performance of natriuretic peptides across age groups for the diagnosis of acute heart failure

Abstract Background Guidelines recommend N-terminal pro-B-type natriuretic peptide (NT-proBNP) thresholds for the diagnosis of acute heart failure but performance of these thresholds in different age groups is uncertain and could be improved using machine learning methods that incorporate age as a continuous measure. Purpose To evaluate the diagnostic performance of guideline-recommended NT-proBNP thresholds for different age groups and a validated decision-support tool using machine learning for the diagnosis of acute heart failure. Methods NT-proBNP concentrations and the output from the CoDE-HF decision-support tool that uses machine learning to combine NT-proBNP and age as continuous variables with other patient variables were determined in 10,369 patients (median age 73 [interquartile range 59-82]) with suspected acute heart failure pooled from fourteen studies. The diagnostic performance of guideline-recommended NT-proBNP uniform rule-out thresholds (300 pg/mL), and age-stratified rule-in thresholds (450 pg/mL, 900 pg/mL and 1,800 pg/mL for <50, 50-75 and ≥75 years, respectively) and CoDE-HF were evaluated using random effects meta-analysis across patient age groups. Results Overall, 43.9% (4549/10 369) of patients had an adjudicated diagnosis of acute heart failure. The negative predictive value (NPV) of the rule-out threshold of 300 pg/mL was lower in patients with increasing age (NPV 88.2% [confidence interval (CI) 83.5-91.8%] ≥75 years versus 98.9% [97.6-99.5%] <50 years) (Figure 1). Conversely, the positive predictive value (PPV) of age stratified rule-in thresholds was lower in younger patients (PPV 61.8% [55.9-67.4%] <50 years versus 80.5 % [71.1-87.4%] ≥75 years) (Figure 2). CoDE-HF had improved diagnostic performance compared to NT-ProBNP thresholds for all age groups, with the lowest NPV and PPV being 96.4% (93.8-97.9%) and 78.6% (59.8-90.0%), respectively. Conclusion The diagnostic performance of guideline recommended thresholds of NT-proBNP to rule-in and rule-out acute heart failure varies significantly with age. A decision-support tool that incorporates NT-proBNP with age as continuous variables provides a more consistent and accurate approach.Figure 1.Negative predictive valueFigure 2.Positive predictive value

Prognostic importance of persistent elevations in high-sensitivity troponin T in the early convalescent phase (two weeks) following high-risk myocardial infarction: insights from the PARADISE-MI trial

Abstract Introduction Myocardial infarction (MI) is defined by a rise and fall in cardiac troponin (cTn) with clinical evidence of acute myocardial ischemia. How often cTn remains elevated in high-risk patients stabilized following MI and the relation between convalescent cTn levels and subsequent clinical outcomes in these patients is unknown. Aims To evaluate the prognostic importance of high-sensitivity cTn T (hs-cTnT) in the early convalescent phase of a MI for a range of cardiovascular (CV) outcomes in patients enrolled in the Prospective ARNI vs ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI). Methods Patients ≥18 years without prior heart failure (HF) (n=5661) were randomized to sacubitril/valsartan or ramipril within 0.5 to 7 days of MI complicated by transient pulmonary congestion, LVEF ≤40%, or both. Hs-cTnT was measured using the Roche Elecsys Troponin T-high-sensitive assay in 1093 patients two weeks after randomization (median 2.6 weeks after the index MI). Associations between log (2)-transformed hs-cTnT and clinical outcomes were investigated in landmark analyses using Cox regression models adjusted for clinical covariates of known prognostic importance and NT-proBNP (Figure). Results Median week 2 hs-cTnT concentration was 34 ng/L [IQR 17-94 ng/L] and exceeded the 99th percentile upper reference limit in 69% of patients. Patients with persistently elevated hs-cTnT concentrations (n=753) were older, more likely men, more commonly had atrial fibrillation and lower estimated glomerular filtration rate and less likely had a prior MI. They more commonly had presented with ST-segment elevation MI and pulmonary congestion and had higher concentrations of NT-proBNP. Rates of primary reperfusion were similar. Log(2)-transformed hs-cTnT was only weakly correlated with LVEF (rho = -0.15, p<0.001), irrespective of the type of MI. hs-cTnT was independently and linearly associated with the primary composite outcome of CV death or incident HF (adj HR 1.17 per doubling; 95% CI, 1.03 – 1.34), all-cause death (adj HR 1.20; 95% CI, 1.01 – 1.44) and CV death (adj HR 1.25; 95% CI, 1.02 – 1.52) but not with non-CV death (adj HR 1.04; 95% CI, 0.70-1.54). hs-cTnT was not significantly associated with recurrent fatal or non-fatal MI (adj HR 1.00; 95% CI, 0.85-1.18) (Figure). Concentrations of week 2 hs-cTnT were not altered by sacubitril/valsartan relative to ramipril (+4%; 95% CI, -8% to 18%). Conclusions Persistent elevations in hs-cTnT during the early convalescent phase following high-risk MI are common and are associated with heightened risk of all-cause death, CV death and incident HF but not of recurrent MI or non-CV death. hs-cTnT measured ~2.5 weeks after high-risk MI provides incremental prognostic information beyond traditional risk factors and NT-proBNP.

Neurodegeneration is highly associated with comorbidity burden in HFrEF patients

Abstract Background Heart failure (HF) is associated with cognitive decline and risk for dementia. Blood levels of amyloid beta 40 and 42 (Aβ40, Aβ42), tau protein (tau), and neurofilament light chain (NfL) have been found to be altered in neurodegenerative disease. Previous research has established a clear association between these neuromarkers and the risk of developing cognitive dysfunction and mortality in the general population. Objective The aim of this study was to investigate the association between the respective neuromarkers and comorbidity burden, as well as to explore whether comorbidity burden impacts the relationship between neuromarkers and outcome in HF patients. Methods Plasma levels of Aβ40, Aβ42, tau, and NfL were quantified using a single-molecule array assay. The primary outcome parameter was all-cause mortality. Results A total of 470 HFrEF patients were enrolled in the study, with a median age of 62 years (IQR: 52–72); 77% were male. Median NT-proBNP concentration was 1812 pg/ml (IQR: 718–3881). Elevated levels of all biomarkers were closely associated with comorbidity burden (Figure 1). All neuromarkers showed increased levels in individuals with chronic kidney disease (CKD) and known carotid artery stenosis (CAS), except for Aβ40, which did not show significant elevation in CAS (NfL: p<0.001 for both; t-tau: p<0.001 and p=0.041; Aβ40: p<0.001 and p=0.050; Aβ42: p<0.001 and p=0.033, respectively). In patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD), only NfL levels were significantly elevated (p<0.001 for both), whereas atrial fibrillation (AF) was associated with higher levels of NfL and t-tau (p<0.001 for both). In individuals with iron deficiency, only Aβ42 levels were significantly higher (p=0.025). All biomarkers showed significant associations with all-cause mortality [crude HR for an increase in 1-log unit (95%CI): NfL 4.44 (3.02-6.53), t-tau 5.04 (2.97-8.58), Aβ40 3.90 (2.27-6.72), Aβ42 5.14 (2.84-9.32); p<0.001 for all] (Figure 2). These associations remained statistically significant after adjusting for comorbidity burden including AF, T2DM, CAD, CKD, CAS and ID [adjusted HR for an increase in 1-log unit (95%CI): NfL 3.28 (1.93-5.57), t-tau 3.96 (2.07-7.57), Aβ40 2.42 (1.34-4.38), Aβ42 3.05 (1.56-5.97); p<0.01 for all]. Conclusion The findings suggest a close connection between elevated levels of markers of neurodegeneration and increased comorbidity burden in HFrEF patients. While this association may indicate the cumulative risk leading to neuronal injury and HFrEF progression, a causal relationship cannot be excluded. The observed accelerated neurodegeneration in HFrEF underscores the need for further investigation into this complex interplay.Figure 1Figure 2

Relationship between six-minute walk distance and cardiopulmonary exercise testing in non-obstructive hypertrophic cardiomyopathy

Abstract Background Recent studies have shown the promise of new approaches to the management of hypertrophic cardiomyopathy (HCM) symptoms. However, as HCM is a chronic disorder that evolves slowly over decades with low annual event rates, therapeutic trials in the disease rely on surrogate measures of disease severity and progression rather than hard endpoints such as mortality. Exercise capacity is one potential surrogate endpoint. Purpose To examine the relationship between peak oxygen uptake (VO2) and six-minute walk test distance (6MWD) in patients with non-obstructive hypertrophic cardiomyopathy (nHCM) and describe the association with clinical parameters and quality of life. Methods We examined baseline data from patients with nHCM enrolled in a randomised placebo-controlled trial of trimetazidine therapy. The study was conducted in a single European centre. Cardiopulmonary exercise testing (CPET) was performed to assess peak oxygen consumption (pVO2), ventilatory anaerobic threshold (VAT) and ventilatory equivalent for carbon dioxide (minute ventilation to carbon dioxide production (VEVCO2). Health related quality of life was assessed with the Minnesota Living with Heart Failure Questionnaire (MLHFQ). ECG and echocardiography were performed on the same day and biomarkers (NT-proBNP and cardiac Troponin T, cTnT) were measured prior to exercise testing. Results In 51 patients (age 50 ± 13 years; 71% male) with nHCM, pVO2 ranged from 10 to 24.3 ml/kg/min and 6MWD from 188 to 650 metres. 6MWD correlated with peak VO2 (Pearson r=0.41, 95% CI 0.15 to 0.67, p=0.003) and anaerobic threshold (r=0.32, 95%CI 0.04 to 0.55, p=0.024). After adjusting for age and sex, NT-proBNP concentration correlated with peak VO2 (radi=-0.35, 95% CI -0.69 to -0.01, p=0.042) but not 6MWD (radj=-0.05, 95% CI -0.42 to 0.32, p=0.779). Health related quality of life assessed by the Minnesota Living with Heart Failure Questionnaire (MLHFQ) correlated moderately with 6MWD (radi=-0.54, 95% CI -0.79 to -0.29, p<0.001) but weakly with peak VO2 (radi 0.28, 95% CI -0.55 to -0.01, p=0.042). I Conclusions There is a modest correlation between peak VO2 and 6MWD in nHCM. The pVO2 correlates more strongly with NT-proBNP whereas 6MWD better reflects quality of life. These data suggest pVO2 and 6MWD provide complementary information about health status in nHCM.Relationship between 6MWD and CPETCharacteristics of study cohort

Continuous monitoring of heart failure biomarker using a sensitive graphene-based electrical sensor

Abstract Heart Failure (HF) is a complex condition that imposes significant burdens on both patients and healthcare systems. The economic impact of HF therapy and management is substantial, underscoring the urgency for proactive measures to mitigate its development. Regular assessments play a pivotal role in identifying individuals at risk and initiating timely interventions to prevent or delay HF progression [1, 2]. NT-proBNP, an amine-terminated form of brain natriuretic peptide, emerges as a promising biomarker in the realm of chronic HF diagnosis, prognosis, and risk assessment [3]. Its utility lies in providing valuable insights into disease progression and prognosis. In recent years, biosensors based on Field Effect Transistors with Graphene (Gr) gate (GFET) have garnered attention for their rapid response, sensitivity, and on-chip integration [4]. Here, we present a sensitive miniaturized GFET sensor for continuous NT-proBNP measurement. The sensor is an array of GFET devices with sensing gates of a monolayer Gr decorated with aptamers as catch probes. Averaging over similar devices in an array approach ensures measurement consistency throughout the experiment. Moreover, the significant challenge posed by the Debye length in FET biosensors is effectively addressed through the functionalization with short folding aptamers [4]. The sensor is built based on a chip comprising an array of 28 individual micro GFETs (Fig. 1a). For the functionalization of Gr gates, we utilized 1-pyrene butyric acid N-hydroxysuccinimide ester as a linker between the aptamer probes and the Gr surface. Subsequently, the Gr surface was incubated with an amine-terminated aptamer solution (Fig. 1c). A schematic diagram of the sensory chip having a droplet of the sample is shown in Fig. 1b. To quantify NT-proBNP levels an 8µL droplet of the buffer solution containing a specific NT-proBNP concentration was deposited onto the sensor. The drain current (IDS) served as the sensor signal for each target concentration (Figs. 2a and 2b). The sensor signal decreased with increasing target concentration, while negligible response was observed when injecting blank buffers. This phenomenon can be attributed to the folding of aptamers upon binding to their target. Also, continuous measurement was conducted at a fixed gate voltage of 0.9V, recording the drain current while the target concentration gradually increased in the sample droplet. This process revealed a decrease in sensor current as we expected (Fig. 2c). The sensor exhibits remarkably low detection limits of 50 pg/mL and a linear range from 100 pg/mL to 10 ng/mL, which are highly conducive for early HF diagnosis and aligning well with reported NT-proBNP levels in patient biofluid [5]. The proposed sensor holds promise as a wearable device for continuous monitoring of high-risk patients. Additionally, this technology shows potential as a detection tool for acute heart failure in hospitalized patients.Sensor viewSensor responses

Sex differences related changes in cardiac structure and function after ST-segment elevation myocardial infarction

Abstract Background Sex disparities in presentation, treatment, and outcomes after ST-segment Elevation Myocardial Infarction (STEMI) are well recognized. However, little is known about sex related changes in cardiac structure and function following a STEMI in this contemporary era of early PCI. Purpose To compare sex differences in change of echocardiographic parameters of structure and function following a first-time STEMI. Methods This echocardiographic study involved 380 non-diabetic first-time STEMI patients. Structural and functional parameters were evaluated during initial hospitalization (median 1 day after presentation) and at 4-months. Adverse remodelling was defined as a 20% increase in left ventricular end-diastolic volume (LVEDV) at 4 months compared to the hospitalisation echo. Functional parameters included left ventricular ejection fraction (LVEF) and wall motion score index (WMSI). According to current guidelines, eccentric hypertrophy was defined as left ventricular mass index (LVMI) >95 g/m2 for women and >115 g/m2 for men with a relative wall thickness (RWT) ≤0.42; concentric hypertrophy was defined as LVMI >95 g/m2 for women and >115 g/m2 for men with RWT >0.42. The different patterns in geometry were assessed at 4-months. Results Among 380 patients, comprising 285 males and 95 females, females had a higher prevalence of hypertension (42% vs. 25.6%, p=0.004), lower hemoglobin levels (8.40 mmol/l vs. 9.10, p<0.001), and higher plasma NT-proBNP concentrations upon admission (132 ng/L vs 67, p<0.001) and after 24 hours (1322 ng/l vs 784, p<0.001). During the initial echocardiogram conducted upon hospitalization, as well as during the echocardiogram at 4 months, women had significantly lower LV diameters, LV volumes, LV mass, LAVI and wall thickness compared to man. However, during both evaluations women showed higher E/e’ ratio’s and LVEF. The change in echocardiographic variables between both timepoints did not differ significantly between sexes. Furthermore, no significant difference in LV geometry patterns (eccentric or concentric) were observed between sexes and adverse LV remodelling was similar between both groups at approximately 22-23% (p=0.991). Conclusions Although differences exist between sexes in patient characteristics and individual echocardiographic parameters, no disparity is observed in geometry patterns, adverse LV remodelling, or the change in echocardiographic parameters after STEMI.

Utility of urinary NT-proBNP in congenital diaphragmatic hernia: a prospective pilot study.

Echocardiography is the reference standard for diagnosing pulmonary hypertension (PH) and cardiac dysfunction (CD) in congenital diaphragmatic hernia (CDH). The use of an adjunct non-invasive biomarker would be invaluable. Plasma N-terminal brain Natriuretic Peptide (NT-proBNP) has been evaluated as a biomarker in CDH. Our objective was to investigate the utility of urinary NT-proBNP as an adjunct biomarker in CDH. Prospective observational study of neonates with CDH. Urinary NT-proBNP and its ratio to urinary creatinine (UNBCR) were analyzed at 24 h of life (HOL). Spearman's correlation was used to quantify the association between the urinary NT-proBNP with corresponding plasma concentrations. Logistic regression and receiver operating characteristic (ROC) curve analyses were used to examine urinary NT-proBNP and UNBCR's association with need for ECMO. The Kruskal-Wallis test was used to compare urinary NT-proBNP concentrations with echocardiography parameters of PH and CD. Urinary NT-proBNP and UNBCR positively correlated with plasma concentrations. Patients with high right ventricular (RV) pressures had higher urinary NT-proBNP concentrations. Both urinary NT-proBNP and UNBCR concentrations increased with worsening left and right ventricular dysfunction on first postnatal echocardiogram. We report the feasibility of urinary NT-proBNP as a non-invasive biomarker to assess PH and CD in CDH. Non-invasive biomarkers are an important area of research in neonates as they have the potential to decrease the need for blood sampling, which may cause pain, stress, and induce iatrogenic anemia. Use of non-invasive biomarkers could be especially useful in congenital diaphragmatic hernia (CDH) who may need Extra-Corporeal Life Support (ECLS) for their management. We evaluated the potential utility of the urinary NT-proBNP in CDH. Plasma NT-proBNP has been studied in neonates with CDH; however, urinary NT-proBNP has not been explored, making this the first study to examine its potential as a biomarker.

Assessment of the Level of NT-proBNP in Patients with Arterial Hypertension Aged 80 Years and Older, Depending on the Presence of Heart Failure and Senile Asthenia Syndrome

Objectives. To evaluate the informativeness of the N-terminal brain-promoting natriuretic peptide (NT-proBNP) for the diagnosis of chronic heart failure (CHF), depending on the presence of senile asthenia syndrome (SSA) in patients with arterial hypertension (AH) 80 years and older.Materials and Methods. 320 patients with hypertension, depending on the presence of CHF and SSA, were divided into groups: group 1A — patients with hypertension, SSA and CHF (n=84), group 1B — patients with hypertension, SSA without CHF (n=77), group 2A — patients with hypertension, CHF without SSA (n=84), group 2B — patients with hypertension without CHF and without SSA (n=75). The CSA was identified by the questionnaire “Age is not a hindrance”. The level of NT-proBNP was determined in blood serum by enzyme immunoassay. ROC analysis was used to determine the threshold value of markers.Results. In patients with hypertension and SSA without CHF, the concentration of NT-proBNP in the blood is 2.3 times higher (p=0.003) compared with patients with hypertension without SSA and without CHF, which indicates the effect of SSA on the level of NT-proBNP. In patients with hypertension and CHF without SSA, the level of NT-proBNP is 4.3 times higher compared with patients with hypertension without SSA and without CHF (p<0.001), in whom the concentration of NT-proBNP was noted below the threshold level (106.2 pg/ml). In patients with hypertension and SSA and CHF, the highest concentrations of NT-proBNP were recorded, which are 2.9 times (p<0.001) higher than in “fragile” patients with hypertension without CHF and 1.5 times higher than in “strong” patients with hypertension and CHF (p<0.001). A new threshold level of NT-proBNP has been calculated for the diagnosis of CHF in patients with hypertension and SSA aged 80 years and older — 365.9 pg/ml.Conclusion. For the diagnosis of CHF in patients with hypertension 80 years and older without CSA, the NT-proBNP marker is informative, since, according to the data obtained, its level did not depend on the age of the patients. When using NT-proBNP to detect CHF in patients with hypertension and SSA 80 years and older, the calculated threshold marker level (365.9 pg/ml) should be used, since in these patients the concentration of NT-proBNP is increased, regardless of the presence of CHF.

The role of markers of endothelial dysfunction in the pathogenesis of coronary microvascular dysfunction in patients with non-obstructive coronary artery disease

Aim. To study the potential of non-invasive biomarkers in the diagnosis of coronary microvascular dysfunction (CMD) and prediction of the course of heart failure with preserved ejection fraction (HFpEF) in non-obstructive coronary artery disease.Materials and methods. The 12-month observational study included 118 consecutive patients (6 patients dropped out of the study due to contact loss) with non-obstructive coronary artery disease (CAD) and HFpEF (62 [59; 64]%). At the beginning of the study, serum levels of several biomarkers were assessed using the enzyme immunoassay: N-terminal pro-B-type natriuretic peptide (NT-proBNP), vascular endothelial growth factor (VEGF), and endothelin-1. Coronary flow reserve (CFR) was examined using dynamic single photon emission computed tomography. In the absence of obstructive CAD, CMD was defined as a global decrease in CFR ≤ 2. Echocardiography was used to determine parameters of hemodynamics, LV diastolic dysfunction, and myocardial stress. LV global longitudinal strain (GLS) was assessed using 2D speckle tracking.Results. The patients were divided into groups depending on the presence of CMD: group 1 included patients with CMD (n = 43), group 2 included those without it (n = 75). In patients in group 1, serum levels of endothelin-1 were 1.9 times higher (p = 0.012), levels of VEGF were 2.16 times higher (p = 0.008), and the concentration of NT-proBNP was 2.6 times higher (p = 0.004) than in patients in group 2. According to the ROC analysis, the concentrations of endothelin-1 ≥ 6.9 pg / ml (AUC = 0.711; p = 0.040) and VEGF ≥ 346.7 pg / ml (AUC = 0.756; p = 0.002) were considered as markers associated with the presence of CMD in patients with non-obstructive CAD. The multivariate regression analysis showed that only the presence of CMD (odds ratio (OR) 2.42; 95% confidence interval (95% CI) 1.26–5.85; p < 0.001) and an increase in NT-proBNP ≥ 760.5 pg / ml (OR 1.33; 95% CI 1.08–3.19; p = 0.023) were factors associated with adverse events, and their combination increased the risk of HFpEF progression by more than 3 times (OR 3.18; 95% CI 2.76–7.98; p < 0.001), whereas markers of endothelial dysfunction were not independent predictors. Conclusion. Endothelin-1 ≥ 6.9 pg / ml and VEGF ≥ 346.7 pg / ml can be used as non-invasive markers for the diagnosis of CMD. However, markers of endothelial dysfunction were not independent predictors of HFpEF progression in patients with non-obstructive CAD during 12-month follow-up.

Clinical features and in-hospital mortality predictors of concurrent cardio-cerebral infarction: insights from a dual-center retrospective study.

This study aimed to enhance the understanding of cardio-cerebral infarction (CCI) clinical features and identify key prognostic factors, thereby providing an empirical foundation for advancing prevention and treatment strategies and ultimately improving clinical outcomes for CCI patients. We retrospectively analyzed 17,645 AIS and 7,584 AMI patients admitted to two hospitals from 2014 to 2023. Univariate analysis, Spearman correlation, and multivariate logistic regression were performed to identify independent risk factors. Receiver operating characteristic (ROC) curves were used to determine optimal cutoff values. This study enrolled 85 patients with CCI, representing an overall CCI incidence of approximately 0.34%. Males comprised 64.71% of the cohort. ST-segment elevation myocardial infarction and cardiogenic cerebral infarction were the most predominant subtypes. The in-hospital mortality rate was 30.59%, with 65.38% of deaths attributed to cardiac causes. Multivariate logistic regression analysis identified three independent risk factors for in-hospital mortality: elevated neutrophil-to-lymphocyte ratio (NLR), decreased serum albumin, and increased peak N-terminal pro-B-type natriuretic peptide levels (NT-proBNP). ROC curve analysis demonstrated that the area under the curve (AUC) for the NLR, albumin concentration and peak NT-proBNP concentration were 0.863, 0.723, and 0.824, respectively. The optimal cutoff values were 6.914 for NLR, 33.80 g/L for albumin, and 9474.50 pg/mL for peak NT-proBNP. The AUC of the combined diagnostic model reached 0.959, significantly outperforming the individual indicators. Elevated NLR, decreased serum albumin, and increased peak NT-proBNP levels independently predict in-hospital mortality in CCI patients. Combining these biomarkers enhances predictive capability for adverse outcomes.