NT-pro B-type Natriuretic Peptide Research Articles

Interactions of circulating, digoxin-like, steroids with rate control therapy for atrial fibrillation in the RATE-AF randomised clinical trial

Abstract Background Numerous endogenous cardiotonic steroids (CTS) similar to digoxin are thought to exist in humans, but this remains unproven and their clinical impact is unknown. Purpose To identify and quantify CTS in patients with atrial fibrillation (AF) and heart failure (HF), and assess their interaction with the clinical efficacy of digoxin treatment within a randomised controlled trial. Methods Patients with permanent AF and symptoms of HF were randomised to low-dose digoxin or beta-blockers for rate control (Rate control Therapy Evaluation in permanent Atrial Fibrillation trial, RATE-AF). EDTA plasma was collected at baseline and 6 months, with a range of CTS measured using a novel ultra-high-performance liquid chromatography tandem-mass spectrometry assay. Outcomes at 6-months were the mEHRA class score, New York Heart Association (NYHA) class, NT-pro B-type natriuretic peptide (BNP), and a composite of all adverse events. Multiple regression models were used to assess treatment efficacy (intention-to-treat analysis) adjusted for age, sex and ejection fraction, with interaction terms for baseline CTS. Results 160 patients were randomised and contributed to this study. Mean age was 76 years (SD 8), 46% women and median NT-proBNP 1057 pg/mL (interquartile range [IQR] 778), with demographics comparable between group. 80 patients were randomised to digoxin and 80 patients were randomised to beta-blockers, principally bisoprolol. Patients randomised to digoxin had significantly better functional outcomes compared to beta-blockers, with two-class improvement in mEHRA score odds ratio 5.95 (95% CI 2.78 to 24.06; p<0.001) and mean adjusted difference in NYHA class -0.60 (95% CI -0.86 to -0.34; p<0.001). There were fewer patients with adverse events in those allocated to digoxin (13/76; 17.1%) versus beta-blockers (44/74; 59.5%), with odds ratio 0.29 (95% CI 0.12 to 0.52; p<0.001). The CTS bufalin, cinobufagin, cinobufotalin, digoxigenin, digitoxigenin, dihydroouabain, marinobufagenin, ouabain, ouabagenin and telinobufagenin were all identified in patient samples, but most were at low concentrations or below the lower quantification limits; Figure 1. Digoxigenin and digitoxigenin were the most abundant CTS, with median quantifications of 0.079 nM (IQR 0.152) and 0.024 nM (IQR 0.051). Baseline CTS concentrations did not interact with digoxin treatment efficacy for any outcome; Figure 2. No significant change was seen in CTS concentrations from baseline to 6-months in those treated with digoxin. Digoxin quantification using mass spectrometry was strongly correlated with the clinical immunoassay at 6-months (r=0.88; p<0.001). Conclusions Low-dose digoxin improves symptoms and functional class compared to beta-blockers in patients with permanent AF and HF, independently from a range of CTS with similar chemical structure. The role of CTS in humans remains uncertain, however they do not appear to interact with the therapeutic effect of digoxin.Figure 1

Diagnostic Test for Estimation of Plasma Volume on Assessment of Congestive Status in Acute Heart Failure Patients at Saiful Anwar General Hospital

Background: Heart failure is a health issue with high mortality and morbidity rates globally, including in Indonesia. Congestion is the main symptom of acute heart failure. B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-pro BNP) are well-known markers to confirm the condition. Plasma volume estimation (ePVS) is one of the procedures currently being developed to assess a patient's congestive status at a lower cost. Objective: This study aims to evaluate the sensitivity and specificity value of ePVS to assess the congestive status in acute heart failure patients Methods: This is a descriptive observational research with a cross-sectional study method that included all patients with dyspneu that come to emergency room between May 2018-February 2023. Baseline characteristics, medication history, and echocardiography were also included in the statistical analysis. We used univariate and bivariate analysis to assess the effect of each variable on the patient's congestive condition. A diagnostic test of plasma volume estimation was carried out using Receiver Operating Characteristics (ROC) Analysis compared to NT pro-BNP as a diagnostic tool of congestive in acute heart failure based on guideline. Plasma volume estimation calculated using Strauss-Duarte formula. Result: A total of 506 subjects with dyspnea at ER Dr. Saiful Anwar Malang Hospital, who met the inclusion and exclusion criteria. The mean age was older in congestive patients with 51.3% being male. Patients with congestive conditions have a lower ejection fraction with a higher estimated right atrial pressure from echocardiography. The estimation plasma volume status was also higher in congestive conditions (4.90 vs 3.5). The ePVS from ROC analysis has a good diagnostic value at the reduced and mildly reduced EF. Conclusion: The estimation of plasma volume status has a good sensitivity and specificity value to assess congestive status in patients with acute heart failure who are fluid-overloaded. Keyword: Acute Heart Failure, Congestive, Plasma Volume Status.

Mavacamten for Obstructive Hypertrophic Cardiomyopathy With or Without Hypertension: Post-Hoc Analysis of the EXPLORER-HCM Trial

BackgroundHypertension (HTN) is common in patients with hypertrophic cardiomyopathy (HCM), but its effect on the treatment of left ventricular outflow tract (LVOT) obstruction is undefined. Although elevated systolic blood pressure (SBP) may impact dynamic LVOT gradients, its response to cardiac myosin inhibition is unknown. ObjectivesIn a post hoc exploratory analysis of the EXPLORER-HCM trial (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy), the authors examined the characteristics of patients with obstructive HCM and HTN and the associations between HTN, SBP, and the response to mavacamten treatment of LVOT obstruction. MethodsPatients were stratified by baseline history of HTN and mean SBP during 30-week treatment with mavacamten or placebo. The study estimated treatment differences and evaluated HTN and SBP groups by treatment interaction. Analysis of covariance was used to model changes in continuous endpoints, and a generalized linear model was used for binary endpoints. ResultsHTN was present in 119 of 251 patients (47.4%), including 60 receiving mavacamten and 59 receiving placebo. Patients with HTN vs no HTN were older (63.4 vs 54.0 years; P < 0.001), had higher SBP (134 ± 15.1 mm Hg vs 123 ± 13.8 mm Hg; P < 0.001), more comorbidities, and lower peak oxygen consumption (19 ± 3 vs 20 ± 4 mL/kg/min; P = 0.021). Patients with HTN had similar NYHA functional class (NYHA functional class II, 72% vs 73%), Valsalva LVOT gradients (72 ± 34 mm Hg vs 74 ± 30 mm Hg), Kansas City Cardiomyopathy Questionnaire–Clinical Summary Scores (70.6 ± 18.8 vs 68.9 ± 23.1), and NT pro–B-type natriuretic peptide levels (geometric mean 632 ± 129 pg/mL vs 745 ± 130 pg/mL). Mavacamten-treated patients had improvement in all primary, secondary, and exploratory endpoints regardless of HTN status or mean SBP. ConclusionsThe clinical benefits of mavacamten in symptomatic, obstructive HCM were similar in patients with and without HTN, despite differences in baseline characteristics. (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy [EXPLORER-HCM]; NCT03470545)

Predictors and prognostic implications of hospital-acquired pneumonia in patients admitted for acute heart failure.

Data on predictors and prognosis of hospital acquired pneumonia (HAP) in patients admitted for acute heart failure (AHF) to intensive care units (ICU) are scarce. Better knowledge of these factors may inform management strategies. This study aimed to assess the incidence and predictors of HAP and its impact on management and outcomes in patients hospitalised for AHF in the ICU. this was a retrospective single-centre observational study. Patient-level and outcome data were collected from an anonymized registry-based dataset. Primary outcome was in-hospital all-cause mortality and secondary outcomes included length of stay (LOS), requirement for inotropic/ventilatory support, and prescription patterns of heart failure (HF) drug classes at discharge. Of 638 patients with AHF (mean age, 71.6 ± 12.7 years, 61.9% male), HAP occurred in 137 (21.5%). In multivariable analysis, HAP was predicted by de novo AHF, higher NT proB-type natriuretic peptide levels, pleural effusion on chest x-ray, mitral regurgitation, and a history of stroke, diabetes, and chronic kidney disease. Patients with HAP had a longer LOS, and a greater likelihood of requiring inotropes (adjusted odds ratio, OR, 2.31, 95% confidence interval, CI, 2.16-2.81; p < 0.001) or ventilatory support (adjusted OR 2.11, 95%CI, 1.76-2.79, p < 0.001). After adjusting for age, sex and clinical covariates, all-cause in-hospital mortality was significantly higher in patients with HAP (hazard ratio, 2.10; 95%CI, 1.71-2.84; p < 0.001). Patients recovering from HAP were less likely to receive HF medications at discharge. HAP is frequent in AHF patients in the ICU setting and more prevalent in individuals with de novo AHF, mitral regurgitation, higher burden of comorbidities, and more severe congestion. HAP confers a greater risk of complications and in-hospital mortality, and a lower likelihood of receiving evidence-based HF medications at discharge.

B-type natriuretic peptide and N-terminal Pro-B-type natriuretic peptide in severe aortic stenosis: a comprehensive literature review.

B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro BNP) are cardiac biomarkers that are released in response to increased ventricular and atrial wall stress. Aortic stenosis (AS) leads to hemodynamic changes and left ventricular hypertrophy and may be associated with natriuretic peptide levels. Several studies have shown that increased natriuretic peptide levels are correlated with AS severity and can predict the need for intervention. It can be useful in risk stratification, monitoring follow-up, and predicting cardiovascular outcomes of patients with severe AS. This paper aims to summarize the evidence of the role of BNP and NT-pro BNP in AS, before and after intervention.

The role of IL-6, IL-10, TNF-α and PD-1 expression on CD4 T cells in atrial fibrillation

BackgroundsWhile not completely understood, the electrical, structural, and communication pathways that play a role in the onset and progression of atrial fibrillation (AF) seem to be connected to the intricate interplay between neurohormones and cellular mediators. Our study's objective was to examine how the expression profiles of the inflammatory cytokines interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor (TNF), and programmed death 1 (PD-1) changed in Cluster of Differentiation 4 (CD4) T cells depending on whether atrial fibrillation was paroxysmal or permanent. This analysis would provide new diagnostic markers for the detection and management of atrial fibrillation. MethodsIn a cross-sectional study, 60 healthy controls, 49 patients with persistent atrial fibrillation, and 50 patients with paroxysmal atrial fibrillation were compared. Serum biomarker levels are found using the ELISA method, which uses enzyme-linked immunosorbent assay. Echocardiography was used to assess heart function. ResultsPatients with atrial fibrillation had serum concentrations of IL-6, TNF-a, and IL-10 that were considerably higher than but PD-1 was lower those in the non-AF control group and those in patients with persistent atrial fibrillation. According to the diameter of LA and the serum level of NT-proB-type natriuretic peptide (NT-proBNP) is greater than that of patients with paroxysmal atrial fibrillation than control group. Patients with persistent atrial fibrillation had increased serum levels of low-density lipoprotein cholesterol (LDL-C) compared with those without atrial fibrillation. While PD-1 in patients with paroxysmal atrial fibrillation is closely related to C-reactive protein (CRP), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and very low density lipoprotein cholesterol. In addition, PD-1 in patients with persistent atrial fibrillation is closely related to IL-6, TNF-a, and IL-10. ConclusionHigher blood concentrations of NT-proBNP, IL-6, IL-10, TNF-, and LDL-C but low level of PD-1 are associated with progression from paroxysmal or chronic AF.

Diagnosing sepsis in the ICU: Comparison of a gene expression signature to pre-existing biomarkers

PurposeWe aimed to identify a gene signature that discriminates between sepsis and aseptic inflammation in patients administered antibiotics in the intensive care unit and compare it to commonly utilised sepsis biomarkers. Methods91 patients commenced on antibiotics were retrospectively diagnosed as having: (i) blood culture positive sepsis; (ii) blood culture negative sepsis; or (iii) aseptic inflammation. Bloods were collected after <24 h of antibiotic commencement for both gene expression sequencing analysis and measurement of previously identified biomarkers. Results53 differentially expressed genes were identified that accurately discriminated between blood culture positive sepsis and aseptic inflammation in a cohort of patients given antibiotics [aROC 0.97 (95% CI, 0.95–0.99)]. This gene signature was validated in a publicly available database. The gene signature outperformed previously identified sepsis biomarkers including C-reactive protein [aROC 0.72 (95% CI, 0.57–0.87)], NT-Pro B-type Natriuretic Peptide [aROC 0.84 (95% CI, 0.73–0.96)], and Septicyte™ LAB [aROC 0.8 (95% CI, 0.68–0.93)], but was comparable to Procalcitonin [aROC 0.96 (95% CI, 0.9–1)]. ConclusionsA gene expression signature was identified that accurately discriminates between sepsis and aseptic inflammation in patients given antibiotics in the intensive care unit.

Dietary counselling to reduce moderate sodium intake: effects on cardiovascular and renal biomarkers: primary findings of the COSIP and STICK phase II feasibility randomised controlled trials.

While low sodium intake (<2.3g/day) is recommended, there is uncertainty about long-term feasibility and effects on cardiorenal biomarkers in populations with moderate intake. In two phase IIb, feasibility, randomised, parallel, open-label, controlled, single-centre trials, individuals aged >40 years with stable blood pressure (BP), without heart failure or postural hypotension were randomised to intensive dietary counselling (target sodium intake <2.3g/day) or usual care between March 2016 and July 2018. One trial included participants with chronic kidney disease (CKD); the other excluded those with CKD or cardiovascular disease. All participants received healthy eating advice. Primary outcomes were NT-pro B-type natriuretic peptide (NT-proBNP), high sensitivity troponin T (hsTnT), C-reactive protein (CRP), renin, aldosterone and, creatinine clearance (CrCl) at 2-years. These trials are registered with ClinicalTrials.gov, STICK trial (NCT02458248) and COSIP trial (NCT02738736). 373 participants, with mean 24-h urine sodium 3.16±1.47g/day, were randomised to intervention (n=187) or usual care (n=186). At 3-months, the intervention reduced 24-h urine sodium (intervention-0.11g/day, usual care+0.28g/day, p=0.003), BP (systolic-2.52mmHg, p=0.05; diastolic-1.92, p=0.02) and increased renin (+33.35 mIU/L [95%CI 3.78-62.91]). At 2-years, the intervention significantly reduced self-reported salt use (p<0.001), but not 24-h urine sodium (intervention-0.23g/day, usual care+0.05g/day, p=0.47). At 2-years, there were no significant between-group differences in BP (systolic p=0.66; diastolic p=0.09), NT-proBNP (p=0.68), hsTnT (p=0.20), CRP (p=0.56), renin (p=0.52), aldosterone (p=0.61), or CrCl (p=0.68). Among individuals with moderate sodium intake, intensive dietary counselling resulted in small short-term reductions in sodium intake and BP, but no significant effect on sodium intake, BP, or cardiorenal biomarkers at two years. Our trial suggests that it may not feasible to reduce sodium sustainably in those with a sodium intake around 3.0g/day, through an intensive dietary counselling intervention. The STICK trial was funded by the Health Research Board of Ireland and the COSIP trial was funded by the European Research Council.

Role of NT-pro B-type Natriuretic Peptide in Anemic Patients Presenting with High-output Cardiac Failure

ABSTRACT Background: Anemia commonly contributes to cardiovascular alterations, including heart failure (HF). High-output cardiac failure is a less common form of HF, characterized by heart’s inability to provide sufficient blood for the body’s demand. However, anemia sometimes remains undetected because the superficial cardiac function does not precisely reflect the adverse impact of anemia. Plasma B-type natriuretic peptide (BNP) is comes into role in these cases. Material and Method: This cross sectional study was conducted between August 2020 to September 2022 on 40 severe anaemic cases with Hb &lt; 8g/dl according to WHO classification irrespective of etiology with clinical signs of heart failure, age group- above 14 years. Results: Out of total 40 patients, 24 were male and 16 were female. In our study, among the anemic females, 9 (56%) belonged to the age group of &lt;30 years of age. In our study, out of 40 patients, 14 patients presented with high BNP and 26 patients presented with BNP within normal limits. The mean BNP range in patients with high BNP level was 290.6. Conclusion: Understanding the mechanisms of association between anemia and NT-proBNP may improve our understanding of cardiac pathophysiology and help target potential therapies to prevent the development and progression of HF.

6 EVALUATION OF ECHOCARDIOGRAPHIC PARAMETERS IN PATIENTS WITH MICROVASCULAR DYSFUNCTION: A PROSPECTIVE STUDY.

Abstract Background The prevalence of microvascular angina is underestimated in the general population because it is often difficult to detect. Microvascular dysfunction is defined by parameters of reduced coronary flow reserve (CFR &amp;lt;2) without epicardial stenosis and/or increased index of microvascular resistance (IMR&amp;gt; 25). Purpose The aim of this study was to evaluate the echocardiographic parameters in patients with symptoms of myocardial ischemia without evident coronary epicardial obstruction. Primary endpoint was to analyze the global longitudinal strain of the left ventricle and the left atria strain in patients with microvascular angina. Secondary endpoint was to analyze echocardiographic parameters to evaluate the diastolic function of the left ventricle, the prevalence of cardiovascular risk factors and the blood tests values. Methods Between 1st February 2019 and 1st May 2022, subjects with angina and not functionally significant epicardial stenosis (Resting Full-cycle Ratio &amp;gt; 0.91, Fractional flow reserve &amp;gt;0.80), underwent assessment of microvascular function and were divided into 2 cohorts. All patients had sinus rhythm, preserved left ventricular ejection fraction (LVEF&amp;gt; 55%), no severe left ventricular hypertrophy (interventricular septum &amp;lt;13 mm) or structural heart disease. For each patient we analyzed the left ventricular global longitudinal strain in the three apical views (4 chamber, 2 chamber and 3 chamber) and the left atria strain, PALS (peak atrial longitudinal strain) and PACS (peak atrial contraction strain), in two apical views (4 chamber and 2 chamber). We also measured the diastolic function indices (E/e’, isovolumic relaxation time, deceleration time), the left atrial area and pulmonary artery systolic pressure (PASP) evaluated on echocardiography. Results A total of 132 patients were enrolled. Of those, 47 had evidence of microvascular dysfunction and 85 had normal CFR/IMR. Primary Endpoint: patients with microvascular dysfunction had reduced values of left ventricular global longitudinal strain and reduced values of left atrial strain compared to controls (p&amp;lt;0,001). Secondary Endpoint: a higher prevalence of diabetic and obese women was associated with microvascular dysfunction. However, there were no significant differences in age, prevalence of hypertension, dyslipidemia, smoking and dysthyroidism. Numerically higher values of NTproB-type Natriuretic Peptide (NTproBNP) and C-reactive protein were seen in patients with microvascular dysfunction, while there were no significant differences in hemoglobin, white bold cells, platelets, cholesterol, creatinine and troponin values. Left ventricular isovolumic relaxation time, left atrium area, and pulmonary artery systolic pressure as well as E/e' values were significantly increased in patients with microvascular dysfunction. Furthermore, there was a significant reduction in deceleration time values. Conclusion Patient with microvascular dysfunction are frequently diabetic and obese women. Echocardiographic parameters show left ventricular diastolic dysfunction and possibly subsequent left atrial remodeling. Furthermore, the analysis of the global longitudinal strain of the left ventricle could reveal alterations in cardiac contractile mechanics that are difficult to identify with conventional echocardiography. NTproBNP values were not significantly higher, demonstrating that patients with microvascular dysfunction have an early diastolic dysfunction that is not clinically evident.

143 ASSOCIATIONS BETWEEN NTPROBNP AND COGNITION IN THE IRISH LONGITUDINAL STUDY ON AGEING (TILDA)

Abstract Background Cardiovascular insults increase the risk for future neurological diseases in late life. NT-proB-type Natriuretic Peptide (NTproBNP) is a hormone released in response to pressure changes inside the heart, often related to heart failure and other cardiac problems. We investigated whether levels of this biomarker are related to cognition in older adults from the Irish Longitudinal Study on Ageing (TILDA), a nationally representative cohort of adults aged 50 years and older living in Ireland. Methods NTproBNP levels were measured in 4,963 participants, mean age 62.6 years and 53.4% women, from blood drawn during wave 1 of the study (2009-2011). Cognitive outcomes collected at wave 1 included: memory function (the sum of scores of immediate word recall, delayed recall and prospective memory), a measure of global cognitive function (the Montreal Cognitive Assessment - MoCA), and a measure of semantic fluency (the Animal Naming task). Both NTproBNP and the MoCA scores were log-transformed to correct for skewedness. Results Cross-sectional analyses using multivariable linear regression found that NTproBNP was significantly and negatively associated with memory (std coeff. –0.049, std error 0.057, p=.001) and the MoCA (std coeff –0.034, std error .002, p=0.027) after adjusting for age, gender, education, and depressive symptoms. After further adjustment for cardiovascular risk factors (hypertension, high cholesterol, current smoking and problem drinking) and prevalent cardiovascular diseases (heart failure, myocardial infarction, angina pectoris, stroke, and transient ischemic attack), the associations remained for both cognitive measures (memory: std coeff –0.047, std error 0.061, p=.003; MoCA: std coeff. –0.036, std error .002, p=.029). No significant associations were found for the Animal Naming task (full model std coeff. –0.016, std error 0.087, p=0.37). Conclusion These results suggest that NTproBNP may be a useful early indicator for declines in some domains of cognitive function in older adults, with and without current cardiovascular diseases. Additional research is needed to evaluate the predictive value of this biomarker.

Prognostic value and clinical utility of NT-proBNP in acute emergency medical admissions.

NT-proB-type natriuretic peptide (NT-proBNP) is a frequently utilized test in congestive cardiac failure. There is little data on its utility in unselected emergency medical admissions. This study aims to investigate the clinical utility and prognostic value of NT-proBNP in emergency medical admissions and to determine whether such testing influenced downstream investigations and length of stay (LOS). We report on NT-proBNP tests performed in emergency medical admissions in a 2005/2006 and subsequent 7-year (2014-2020) retrospective cohort. We assessed 30-day in-hospital mortality with a multivariable logistic regression model. The utilization of procedures/services was related to LOS with zero-truncated Poisson regression. There were 64,212 admissions in 36,252 patients. Patients with a NT-proBNP test were significantly older at 75.3years vs. 63.0years and had longer LOS -9.4days vs. 4.9days. They had higher acute illness severity and comorbidity scores. Thirty-day in-hospital mortality was higher in those with a NT-proBNP test (8.8%) vs. no request (3.2%). NT-proBNP test level was prognostic in univariate - OR 2.87 (2.61, 3.15), and multivariate analyses - OR 1.40 (1.26, 1.56). Higher NT-proBNP levels predicted higher 30-day in-hospital mortality. Multivariable thirty-day in-hospital mortality was 3.8% (3.6%, 3.9%) for those without a test, increasing to 4.9% (4.7%, 5.2%) for ≥ 250ng/L and 5.8% (5.8%, 6.3%) for ≥ 3000ng/L. LOS was linearly related to the total number of procedures/services performed. NT-proBNP is prognostic in emergency medical admissions. Downstream resource utilization differed following an NT-proBNP test; this may reflect different case complexity or the 'uncertainty' surrounding such admissions.

Incremental utility of circulating biomarkers for cardiovascular risk prediction beyond the updated SCORE2 model

Abstract Background Accurate risk prediction for future cardiovascular disease (CVD) is crucial for timely initiation of preventive measures in high-risk individuals. Most risk scores, such as the recently updated SCORE2 risk-prediction model supported by the European Society of Cardiology, consider only traditional cardiovascular risk factors. Whether the addition of circulating biomarkers to the existing SCORE2 model may improve risk prediction is unclear. Purpose We aimed to evaluate the incremental utility of four widely available circulating biomarkers to improve the prediction of 10-year CVD-risk beyond SCORE2. Methods Data from ten prospective population-based cohorts from seven countries across Europe were collected if information on SCORE2-variables and at least one of the following four investigational biomarkers was available: high-sensitivity cardiac troponin I (hs-cTnI), NT-pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP) and creatinine-based estimated glomerular filtration rate (eGFR). Primary outcome was incidence of CVD at 10 years, defined as the composite of cardiovascular mortality, non-fatal myocardial infarction and non-fatal stroke. We used Fine and Gray models adjusted for competing-risk and SCORE2-variables as well as penalized cubic splines to assess and visualize the association of individual biomarkers with incident CVD. In a multimarker approach, we performed backward selection to identify biomarkers providing independent predictive value beyond SCORE2-components. C-indices and category-free net reclassification index (cfNRI) were used to compare the performance of the original SCORE2 model to the biomarker-extended model. Results In 78'507 individuals, median age was 50 years and 50.3% were females. NT-proBNP, hs-CRP and hs-cTnI but not eGFR showed strong associations with 10-year CVD-risk when adjusted for SCORE2 and provided incremental predictive value when individually added to SCORE2 (Figure 1). In a multimarker approach, all three biomarkers remained independently associated with CVD beyond SCORE2 with strongest association of NT-proBNP, followed by hs-CRP and hs-cTnI (Table 1). The simultaneous addition of these three biomarkers to the SCORE2 model significantly increased discrimination (C-index; 0.782 [95% CI, 0.757, 0.806] versus 0.793 [95% CI, 0.768, 0.817], Delta 0.011 [95% CI, 0.005, 0.016]) and risk reclassification, driven by an improvement in non-events (cfNRIoverall 0.17 [95% CI, 0.12, 0.22], cfNRIevents 0.06 [95% CI, 0.02, 0.11], cfNRInon-events 0.11 [95% CI, 0.10, 0.11]). Conclusion NT-proBNP, hs-CRP and hs-cTnI but not eGFR provide incremental predictive value when added to the SCORE2 risk-prediction model and may help to further improve personalized CVD-risk prediction. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Community's Seventh Framework Programme (FP7/2007-2013)

Sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction: A meta-analysis of randomized controlled trials.

BackgroundNearly half of patients with heart failure (HF) have preserved ejection fraction (EF) and the mortality and morbidity of patients with HF with preserved EF (HFpEF) are high. Patients with HFpEF are often elderly and their primary chronic symptom is severe exercise intolerance that results in a reduced quality of life. Thus, improvement of exercise capacity and quality of life presents another important clinical outcome in HFpEF patients. Recent randomized controlled trials (RCTs) and meta-analyses of RCTs reported that sodium–glucose cotransporter 2 (SGLT-2) inhibitors improved cardiovascular (CV) outcomes in patients with HF with reduced EF. Although the effects of SGLT-2 inhibitors in HFpEF patients have been examined in multiple RCTs, results are inconsistent due partly to limited power. We aimed to conduct a meta-analysis of RCTs on the effects of SGLT-2 inhibitors in HFpEF patients.Methods and ResultsThe search of electronic databases identified 11 RCTs including 10,845 patients. In pooled analyses, SGLT-2 inhibitors reduced the risk of a composite of hospitalization for HF and CV death (hazard ratio [95 % CI] = 0.78 [0.70, 0.87], Pfix < 0.001). SGLT-2 inhibitors significantly increased 6-minute walk distance (weighted mean difference [95 % CI] = 18.0 [6.8, 29.3] m; Pfix = 0.002) and the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (weighted mean difference [95 % CI] = 2.57 [0.19, 4.96] points; Prandom = 0.035) and reduced plasma NT-pro B-type natriuretic peptide levels (weighted mean difference [95 % CI] = −60.16 [−82.99, −37.33] pg/ml; Pfix < 0.001) compared with control.ConclusionThe present meta-analysis suggests that SGLT-2 inhibitors may be beneficial for HFpEF patients, especially in diabetic patients.

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

ObjectivesSeveral 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 & methodsWe 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. ResultsBaseline 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). ConclusionHsTnI, 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.

Incidence, Predictors, and Reversibility of Left Ventricular Dysfunction After Brain Death: The Donor Heart Study

<h3>Purpose</h3> Left ventricular (LV) dysfunction after brain death often prompts non-use of potential donor hearts for transplant, but little is known regarding its incidence, reversibility, and impact on outcomes. Shedding light on these unknowns was a primary aim of the Donor Heart Study -a first-of-its-kind, multisite, prospective study of potential heart donors. <h3>Methods</h3> We enrolled potential donors (n = 4333) at 8 organ procurement organizations across the United States from February 2015-May 2020. Data were collected on donor management, serial labs, and diagnostic tests. These included a transthoracic echocardiogram (TTE) performed within 48 hours after brain death and, if LV dysfunction was present, a repeat TTE 24 ± 6 hours later. LV dysfunction was defined as an ejection fraction (LVEF)<50%, as ascertained by a single expert reviewer, and was considered reversible if LVEF was >50% on the second TTE. LASSO models identified predictors of initial LV dysfunction and its reversibility. A conditional inference ("decision") tree was fit to identify threshold values that predict reversibility. <h3>Results</h3> An initial TTE was performed and interpretable for 3794 donors, and 493 (13%) had LV dysfunction. Significant predictors of LV dysfunction included: higher levels of troponin, nt-pro B-type natriuretic peptide (nt-proBNP), and lactate; higher mean arterial pressure, body temperature, use of vasopressors, and thyroid hormone; younger age; low body mass index (BMI≤ 20 kg/m2); and elevated blood urea nitrogen:creatinine ratio. A second TTE was performed for 224 donors with LV dysfunction and 130 (58%) of these demonstrated reversibility. Donors with baseline nt-proBNP levels >11,137 pg/ml were less likely to have LVEF improvement (30% vs 62%, p=0.008). Low BMI and reductions in serial nt-proBNP and lactate levels were the strongest predictors of reversibility. 59% of donor hearts with normal LV function were accepted for transplant, compared to 47% with reversible dysfunction and 29% with persistently low LVEF. <h3>Conclusion</h3> LV dysfunction after brain death is common among potential heart donors, but is reversible in the majority of cases. Commonly measured clinical variables are predictive of LV dysfunction and its subsequent improvement. Our results can better inform decisions made during donor management and evaluation, and can help guide donor heart acceptance.

Different Renal Function Patterns in Patients With Acute Heart Failure: Relationship With Outcome and Congestion.

BackgroundThe role of worsening renal function during acute heart failure (AHF) hospitalization is still debated. Very few studies have extensively evaluated the renal function (RF) trend during hospitalization by repetitive measurements.ObjectivesTo investigate the prognostic relevance of different RF trajectories together with the congestion status in hospitalized patients.MethodsThis is a post hoc analysis of a multi-center study including 467 patients admitted with AHF who were screened for the Diur-AHF Trial. We recognized five main RF trajectories based on serum creatinine and estimated glomerular filtration rate (eGFR) behavior. According to the RF trajectories our sample was divided into 1-stable (S), 2-transient improvement (TI), 3-permanent improvement (PI), 4-transient worsening (TW), and 5-persistent worsening (PW). The primary outcome was the combined endpoint of 180 days including all causes of mortality and re-hospitalization.ResultsWe recruited 467 subjects with a mean congestion score of 3.5±1.08 and a median creatinine value of 1.28 (1.00–1.70) mg/dl, eGFR 50 (37–65) ml/min/m2 and NTpro B-type natriuretic peptide (BNP) 7,000 (4,200–11,700) pg/ml. A univariate analysis of the RF pattern demonstrated that TI and PW patterns were significantly related to poor prognosis [HR: 2.71 (1.81–4.05); p < 0.001; HR: 1.68 (1.15–2.45); p = 0.007, respectively]. Conversely, the TW pattern showed a significantly protective effect on outcome [HR:0.34 (0.19–0.60); p < 0.001]. Persistence of congestion and BNP reduction ≥ 30% were significantly related to clinical outcome at univariate analysis [HR: 2.41 (1.81–3.21); p < 0.001 and HR:0.47 (0.35–0.67); p < 0.001]. A multivariable analysis confirmed the independently prognostic role of TI, PW patterns, persistence of congestion, and reduced BNP decrease at discharge.ConclusionsVarious RF patterns during AHF hospitalization are associated with different risk(s). PW and TI appear to be the two trajectories related to worse outcome. Current findings confirm the importance of RF evaluation during and after hospitalization.

NT-pro B-type natriuretic peptide, early menopause, and incident heart failure in postmenopausal women of the ARIC study.

N-Terminal pro B-type Natriuretic Peptide (NT-proBNP), a biomarker of heart failure (HF) has been associated with early menopause. We evaluated the modifying role of early menopause on the association of NT-proBNP with incident HF, and separately for HF subtypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). We included 4,352 postmenopausal women including 1,174 with early menopause, ages 63.5 ± 5.5 years, without prevalent HF at the Atherosclerosis Risk in Communities study Visit 4. Binary log-transformation was performed for NT-proBNP. Cox proportional hazards models were used to examine the association of NT-proBNP with incident HF, and separately for incident HFpEF and incident HFrEF, testing for effect modification by early menopause and adjusting for HF risk factors. We observed 881 HF events over a mean follow-up of 16.5 years. The interaction terms of NT-proBNP and early menopause were not significant for incident HF (Pinteraction 0.95) and incident HFpEF (Pinteraction 0.17) but were significant for incident HFrEF (Pinteraction 0.03). The adjusted hazard ratios resulting from each doubling of NT-proBNP levels amongst women with and without early menopause were 1.33 (1.20-1.47) and 1.34 (1.24-1.44), respectively, for incident HF; 1.57 (1.34-1.86) and 1.38 (1.24-1.54), respectively, for incident HFpEF; and 1.68 (1.42-1.99) and 1.36 (1.22-1.52), respectively, for incident HFrEF. The association of NT-proBNP with incident HFpEF is similar irrespective of early menopause status. However, the association of NT-proBNP with incident HFrEF is greater among women with early menopause when compared to those without early menopause.

Role of Clinical Characteristics and Biomarkers at Admission to Predict One-Year Mortality in Elderly Patients with Pneumonia.

Background: A hospitalization for community-acquired pneumonia results in a decrease in long-term survival in elderly patients. We assessed biomarkers at admission to predict one-year mortality in a cohort of elderly patients with pneumonia. Methods: A prospective observational study included patients >65 years hospitalized with pneumonia. Assessment of PSI, CURB-65, and biomarkers (C-reactive protein (CRP), procalcitonin (PCT), NT-pro-B-type natriuretic peptide (NT-proBNP), interleukin (IL)-6 and -8, tumor necrosis factor alpha (TNF-α), serum amyloid A (SAA), neopterin (NP), myeloperoxidase (MPO), anti-apolipoprotein A-1 IgG (anti-apoA-1), and anti-phosphorylcholine IgM (anti-PC IgM)) was used to calculate prognostic values for one-year mortality using ROC curve analyses. Post hoc optimal cutoffs with corresponding sensitivity (SE) and specificity (SP) were determined using the Youden index. Results: A total of 133 patients were included (median age 83 years [IQR: 78–89]). Age, dementia, BMI, NT-proBNP (AUROC 0.65 (95% CI: 0.55–0.77)), and IL-8 (AUROC 0.66 (95% CI: 0.56–0.75)) were significantly associated with mortality, with NT-proBNP (HR 1.01 (95% CI 1.00–1.02) and BMI (HR 0.92 (95% CI 0.85–1.000) being independent of age, gender, comorbidities, and PSI with Cox regression. At the cutoff value of 2200 ng/L, NT-proBNP had 67% sensitivity and 70% specificity. PSI and CURB-65 were not associated with mortality. Conclusions: NT-proBNP levels upon admission and BMI displayed the highest prognostic accuracy for one-year mortality and may help clinicians to identify patients with poor long-term prognosis.

711 A rare case of takotsubo syndrome induced by pacemaker implantation

Abstract Aims Takotsubo syndrome (TTS) is an acute cardiac condition characterized by a temporary wall motion abnormality of the left ventricle that mimics an acute coronary syndrome (ACS). TTS usually occurs following emotionally or physically triggering event. We report a rare case of Takotsubo syndrome following a pacemaker implantation. Methods and results A 77-year-old woman was admitted to our hospital with a third-degree atrioventricular block. She was asymptomatic with a history of hypertension, diabetes, hyperlipidaemia and extrapyramidal syndrome. Laboratory tests reported High-Sensitive cardiac Troponin T (HS-cTnT) 32.9 ng/L (ULN &amp;lt;14), creatine kinase muscle and brain (CK-MB) 4.1 ng/mL (ULN &amp;lt; 4.94) and NT-proB-type Natriuretic Peptide (NT-proBNP) 1465 pg/ml (ULN &amp;lt; 125). Echocardiography showed a normal left ventricular ejection fraction (EF = 58%) (Figure 2A). The patient underwent dual chamber pacemaker implantation without immediate complications. Three days later, a routine ECG showed new T wave inversions (Figure 1), in absence of symptoms. Echocardiography revealed apical akinesia, with ‘apical ballooning’ (EF 30%) (Figure 2B). Serum cardiac markers were increased (CK-MB 8.2 ng/ml, HS-cTnT 189.7 pg/ml, NT-proBNP 15 005 pg/ml. A coronary angiography excluded obstructive coronary artery disease (Figure 3). Given the impossibility of carrying out a cardiac RMI for the recent pacemaker implantation and after exclusion of other diagnoses, pacemaker implantation induced Takotsubo syndrome was suspected. Conclusions The trigger of this case of TTS was the pacemaker implantation, a relatively brief and painless procedure that, in her case could have constitute a considerable emotional and physical stress. To the best of our knowledge 13 cases of TTS after pacemaker implantation have been described to date. Of those cases, four had an asymptomatic course. Therefore, the real incidence of TTS following pacemaker implantation may be underestimated and ECG and echocardiography should always be performed after pacemaker implantation.