N-terminal Pro-brain Natriuretic Peptide Levels Research Articles

Cardiological parameters predict mortality and cardiotoxicity in oncological patients.

Oncological patients suspected at risk for cardiotoxicity are recommended to undergo intensified cardiological surveillance. We investigated the value of cardiac biomarkers and patient-related risk factors [age, cardiovascular risk factors (CVRFs), and cardiac function] for the prediction of all-cause mortality (ACM) and the development of cardiotoxicity. Between January 2016 and December 2020, patients with oncological diseases admitted to the Cardio-Oncology Unit at the Heidelberg University Hospital were included. They were evaluated by medical history, physical examination, 12-lead electrocardiogram, 2D echocardiography, and cardiac biomarkers [high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP)]. The primary endpoint was defined as ACM and the secondary endpoint was defined as cardiotoxicity, as defined by the European Society of Cardiology. Of the 1971 patients enrolled, the primary endpoint was reached by 490 patients (25.7%) with a median of 363.5 [interquartile range (IQR) 121.8, 522.5] days after presentation. Hs-cTnT of ≥ 7ng/L [odds ratio (OR) 1.82, P<0.001] and NT-proBNP (OR 1.98, P<0.001) were independent predictors of ACM, while reduced left ventricular ejection fraction was not associated with increased ACM (P=0.85). The secondary endpoint was reached by 182 patients (9.2%) with a median of 793.5 [IQR 411.2, 1165.0] days. Patients with multiple CVRFs (defined as high risk, n=886) had an increased risk of cardiotoxicity (n=100/886, 11.3%; hazard ratio 1.57, P=0.004). They showed elevated baseline values of hs-cTnT (OR 1.60, P=0.006) and NT-proBNP (OR 4.00, P<0.001) and had an increased risk of ACM (OR 1.43, P=0.031). In cancer patients, CVRF accumulation predicts cardiotoxicity whereas elevated hs-cTnT or NT-proBNP levels are associated with ACM. Accordingly, less intensive surveillance protocols may be warranted in patients with low cardiac biomarker levels and absence of CVRFs.

Meta-Analysis Global Group in Chronic Heart Failure score for the prediction of mortality in valvular heart disease.

Valvular heart disease (VHD) is one of the leading causes of heart failure. Clinically significant VHD can induce different patterns of cardiac remodelling, and risk stratification is challenging in patients with various degrees of cardiac dysfunction. The study aimed to investigate the prognostic implications of Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score in patients with VHD. This study used data from the China Valvular Heart Disease (China-VHD) registry, which was a multicentre, prospective, observational cohort study for patients with significant (at least moderate) VHD. In total, 10446 patients with moderate or greater VHD from the China-VHD study were included in the present analysis. The primary outcome of interest was all-cause mortality within 2years. Among 10446 patients with VHD, the mean age was 61.98±13.47years, and 5819 (55.7%) were male. During 2years of follow-up, 895 (8.6%) patients died. The MAGGIC score was monotonically and independently associated with mortality in both total cohort [adjusted hazard ratio: 1.095, 95% confidence interval (CI): 1.084-1.107, P<0.001] and most types of VHD (aortic regurgitation, mitral stenosis, mitral regurgitation, tricuspid regurgitation, mixed aortic stenosis and aortic regurgitation, and multiple VHD). The score was also an independent prognostic factor in patients with or without symptoms or preserved left ventricular ejection fraction (LVEF) and exhibited both satisfactory discrimination and calibration properties in predicting mortality. The prognostic value of MAGGIC score was robust in most quartiles of N-terminal pro-brain natriuretic peptide level, with no significant interaction observed (Pinteraction =0.498). Compared with the EuroSCORE II, the MAGGIC score achieved significantly better predictive performance in overall population [C index: 0.769 vs. 0.727; net reclassification improvement index (95% CI): 0.354 (0.313-0.396), P<0.001; integrated discrimination improvement index (95% CI): 0.069 (0.052-0.085), P<0.001] and in subgroups of patients divided by therapeutic strategy, LVEF, symptomatic status, stage of VHD, and aetiology of VHD. The MAGGIC score is a reliable prognostic factor across the range of cardiac dysfunction in VHD and may assist in risk stratification and guide clinical decision-making.

Impact of Atrial Fibrillation on Heart Failure with Preserved Ejection Fraction: An Observational Cross-sectional Study from Western India

Background: Both atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) commonly coexist with overlapping symptoms, risk factors, and shared pathophysiology. Both conditions independently impact left atrial volume index (LAVI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, making it difficult to diagnose HFpEF in AF. Aim: The aim is to study the association of AF with NT-proBNP levels, LAVI, and left atrial (LA) size in HFpEF. Materials and Methods: An observational study of 40 patients was conducted at a Tertiary Care Center in Western India. Patients above 18 years of age with classical heart failure presentation were included and their clinical history and general and systemic examination were done along with NT-proBNP measurement and two-dimensional echocardiography for assessing heart structure and function. Results: Twenty-one patients had sinus rhythm; 19 had AF. AF patients had higher NT-proBNP levels (2599 pg/mL) compared to patients with sinus rhythm (785 pg/mL). AF patients had a greater degree of left ventricular (LV) dysfunction (higher LV end-diastolic dimensions, LV posterior wall thickness, LV mass index, LA diameter, LA volume and LAVI), more prevalence of pulmonary artery hypertension (n = 19 vs. n = 17), higher degrees of diastolic dysfunction (e.g. higher e’ septum, e’ lateral and E/e’), and higher right ventricle systolic pressure as compared to patients with sinus rhythm. Conclusions: The present study shows that AF occurs in around half of HFpEF patients, with a higher incidence in women and younger people. Patients with AF have higher rates of right heart failure, severe atrial and ventricular remodeling, and higher levels of NT-proBNP, which indicate an advanced form of the disease.

Hemorrhagic Fever with Renal Syndrome Patients Exhibit Increased Levels of Lipocalin-2, Endothelin-1 and NT-proBNP.

Hemorrhagic fever with renal syndrome (HFRS) is an acute zoonotic disease caused by viruses of the Orthohantavirus genus. This syndrome is characterized by renal and cardiopulmonary implications detectable with different biomarkers. Here, we explored the role of serum and urine levels of lipocalin-2, endothelin-1 and N-terminal pro-brain natriuretic peptide (NT-proBNP) in HFRS pathology. A total of twenty-eight patients hospitalized due to a Puumala orthohantavirus infection were included, with serum and urine samples collected on patient admission (acute phase) and discharge (convalescent phase). In comparison to healthy individuals, patients exhibited significantly higher acute-phase serum and urine levels of lipocalin-2, serum levels of endothelin-1 and serum and urine levels of NT-proBNP. Patients in the convalescent phase showed a significant decrease in urine lipocalin-2, serum endothelin-1 and serum and urine NT-proBNP levels. We recorded a strong correlation between serum levels of lipocalin-2 and endothelin-1 and urine levels of lipocalin-2 with several kidney injury markers, such as serum creatinine, urea, urine white blood cell count and proteinuria. We also demonstrated an independent correlation of serum and urine lipocalin-2 levels with acute kidney injury in HFRS. All in all, our results show an involvement of NT-proBNP, lipocalin-2 and endothelin-1 in the renal and cardiac pathology of HFRS.

Prognostic value of liver fibrotic markers in patients with heart failure

Abstract Background One of the major comorbidities in patients with heart failure (HF) is hepatic dysfunction, which may occur with prolonged hepatic hypoperfusion and congestion due to HF. Although several liver fibrotic markers are associated with prognosis in patients with HF, the optimal markers for outcome prediction remain unclear. Purpose The aim of this study was to simultaneously investigate the prognostic value of liver fibrotic markers and the associations between these markers and clinical parameters in HF patients without organic liver disease. Methods We prospectively examined 211 consecutive patients with chronic HF (116 male, mean age 66 ± 14 years, LVEF 48 ± 17%) between April 2018 and August 2021, excluding those with organic liver disease, using liver magnetic resonance imaging and ultrasound. We measured seven representative liver fibrotic markers, including hyaluronic acid, type III procollagen N-terminal peptide (P-III-P), type IV collagen 7s domain, mac-2 binding protein glycosylation isomer (M2BPGi), platelet ratio index (APRI), fibrosis 4 index (FIB-4), and FibroIndex. The primary outcome of interest was the composite of all-cause death and hospitalisation for HF. Results During a median follow-up period of 747 (interquartile range 465-1042) days, the primary outcome occurred in 45 patients (21%), including 15 (7%) all-cause deaths and 30 (14%) hospitalisations for HF. Patients with higher hyaluronic acid and P-III-P levels showed a significantly higher incidence of the primary outcome than those without (P &amp;lt;0.001 and P = 0.005, respectively). Multivariable Cox regression analysis showed that hyaluronic acid and P-III-P levels were independently associated with the risk of the primary outcome (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.18-2.87 and HR 2.89, 95% CI 1.32-6.34, respectively) even after adjustment for the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score, whereas other five liver fibrotic markers were not associated with the primary outcome. Discriminative value of the MAGGIC score for the primary outcome was significantly increased by adding hyaluronic acid and P-III-P levels (Harrel’s c-statistics; from 0.717 to 0.752 and 0.745, respectively) with significant net reclassification improvement (38% and 52%, respectively). Hyaluronic acid was predominantly correlated with age, haemoglobin, serum albumin, troponin T, N-terminal pro-brain natriuretic peptide (NT-proBNP), and pulmonary artery compliance (Figure). P-III-P levels were correlated with haemoglobin, estimated glomerular filtration rate, alkaline phosphatase, and NT-proBNP levels (Figure). Conclusion Among the representative liver fibrotic markers, hyaluronic acid and P-III-P might be optimal for outcome prediction in HF patients without organic liver disease. Hyaluronic acid and P-III-P levels were predominantly associated with several key prognostic indicators of HF simultaneously.

NTproBNP values for the diagnosis of congestive heart failure in dyspneic old patients regarding age

Abstract Background The diagnosis of heart failure (HF) in elderly patients is often difficult, due to overlap of typical signs and symptoms with those of comorbidities. Plasma N-Terminal Pro-Brain Natriuretic Peptide(NTproBNP) is known to increase with age and according to comorbidities. However, the diagnostic performance of this biomarker is unclear in those patients. Aims This study sought to define the diagnostic accuracy of plasma NTproBNP in patients over 75 yo in a large population referred for acute dyspnea in the Assistance Publique-Hôpitaux de Paris. Methods and Results In this retrospective, longitudinal multicenter cohort study, we collected data from 12,974 patients aged 75 years or older who were hospitalized for acute dyspnea with NTproBNP measurement in the 48 hours after admission between 2011 and 2021 in geriatrics, cardiology and pulmonology departments. The final diagnosis was classified with the International Classification of Diseases, 10th Revision (ICD 10) as either "AHF" or "other acute respiratory failure" (OARF), represented by pulmonary embolism, COPD and pneumonia. The Mean (SD) age of our population was 84.4 (6.1) years old, and 52.7% of patients were women. 8,385 (64.6%) patients had an AHF diagnosis at discharge. Regarding age of patients, NT-proBNP threshold values was higher in patients over 85 yo, 2530 ng/L, compared to that of patients &amp;lt; 85 yo, 1680 ng/L. The NTproBNP threshold for ‘ruling-out’ AHF had a 79% sensitivity in patient &amp;gt; 85 YO and 82% sensitivity in patient 75- 85 YO. In patients &amp;gt; 85 compared with patient 75-85 yo, predictive positive value was 85 and 86 %, specificity was 65% and 75% and AUC was 0.77 and 0.84. Finally, despite the consideration of other clinical and biological parameters, NTproBNP level remain more discriminating for the diagnosis of AHF in old patients with comorbidities. Conclusion In patients 75-85 and over 85 years of age referred for acute dyspnea with NTproBNP dosage at admission, a cutoff of 1680 and 2530 ng/L respectively allow for an accurate diagnosis of AHF.

Abstract 16838: Relation of Clinical Status in Heart Failure to Cardiac Lysophosphatidylethanolamine Accumulation in Hypertrophic Cardiomyopathy

Background: Patients with hypertrophic cardiomyopathy (HCM) represents diverse symptoms, morphology, and cardiovascular events. Although myocardium metabolism in patients with HCM has been studied, it is not well elucidated. In this study, we assessed the association between biomarkers, heart failure-related findings, genetic mutations, and myocardium lipid metabolism in HCM patients using imaging mass spectrometry. Method: We prospectively enrolled patients with HCM in Hamamatsu University hospital from July 2020 to October 2022. All patients underwent endomyocardial biopsy and genetic analysis. Obtained myocardial specimens were analyzed using a desorption electrospray ionization source attached to a mass spectrometer. Differences among groups were statistically evaluated with the Fisher’s exact test and Mann-Whitney U test. Correlations between the two values were analyzed using Spearman’s correlation coefficient values. Results: A total of 31 Japanese patients were enrolled in this study. These patients included 18 (58.0%) women, and the mean age was 67.6 ± 10.6 years. Genetic analysis revealed that six (19.4%) patients had pathogenic or likely pathogenic variant. (Frequency of causal genes was as follows: MYBPC3 2 [6.5%], TNNI3 2 [6.5%], MYH7 1 [3.2%], and MYOZ2 1 [3.2%].) We divided the patients into two groups according to their median intensity of candidate molecule to reveal between group differences. The group of high lysophosphatidylethanolamine (LPE) showed lower N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (330.0 [147.0-614.0] pg/mL vs. 933.0 [699.5-2576.5] pg/mL, P = 0.001). A correlation was observed between the intensity of LPE and the NT-proBNP levels (r = -0.455, P = 0.012). There was no association between the presence of genetic mutations and New York Heart Association class and LPE intensity. Conclusion: HCM patients with the high intensity of LPE in myocardial tissue had relatively low NT-proBNP levels.

Abstract 17187: The Relationship Between N-Terminal Pro-Brain Natriuretic Peptide Levels and Poor Outcomes in Covid-19 Patients

Introduction: N-terminal pro-brain natriuretic peptide (NT-proBNP) is a biomarker reflecting increased cardiac stress. It is a key variable in assessing patients with various pathologies. However, assessment of NT-proBNP as a variable in the prognostication of poor outcomes in COVID-19 patients is lacking. In addition, COVID-19 has brought its own variables and sequelae along with overlapping pathologies in a variety of systems. Hypothesis: With the systemic impact that COVID-19 can have, NT-proBNP represents a variable that will aid in identifying patients at higher risk of poor outcomes. We aim to assess the utility of NT-proBNP to help predict the incidence of major adverse cardiovascular events (MACE) and mortality in patients hospitalized with COVID-19. Methods: Using a multi-center observational database, we analyzed 1,692 hospitalized COVID-19 PCR-positive patients at Methodist Health System from March to July 2020. We examined NT-proBNP levels, in-hospital death or hospice referral rates, and incidence of MACE in the cohort. MACE was defined as congestive heart failure (CHF) exacerbation, pericardial effusion, cardiac tamponade, myocarditis, pericarditis, myocardial infarction (MI), stroke, pulmonary embolism/deep vein thrombosis, or shock. The incidence of mortality and MACE were compared between patients with and without elevated NT-proBNP levels. Elevated NT-proBNP levels were those &gt;900 pg/mL. A chi-square ( X 2 ) and odds ratio (OR) test were used to analyze observed variables. Results: Of the 1,692 hospitalized patients, 576 patients (34.0%) arrived with elevated NT-proBNP levels. Patients with elevated NT-proBNP had a higher incidence of mortality (OR=3.2559, 95% CI=2.522-5.203, p&lt;0.0001) and MACE (OR=6.564, 95% CI=5.255-8.199, p&lt;0.0001) compared to patients with NT-proBNP levels &lt;900 pg/mL. Additionally, the elevated NT-proBNP patients had a higher incidence of CHF exacerbation, MI, and shock compared to patients with NT-proBNP levels &lt;900 pg/mL. Conclusions: NT-proBNP levels can be a vital tool in recognizing COVID-19 patients who are at higher risk of poor outcomes. The use of NT-proBNP can further aid in prognostication in patients presenting to the hospital with COVID-19.

Changes of myocardial dysfunction and injury biomarkers over chemotherapy for multiple myeloma: difficulties in laboratory data interpretation

Aim. To study the changes of the levels of cardiac biomarkers (N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin I (hsTnI)) in patients with newly diagnosed multiple myeloma (MM) during programmatic treatment with bortezomib (VCd regimen).Material and methods. This prospective pilot study included patients with a newly diagnosed MM (n=30), who were scheduled for a cycle of chemotherapy including a proteasome inhibitor (bortezomib). All patients underwent standard laboratory (complete blood count, biochemical tests, serum protein electrophoresis), electrocardiography, echocardiography, as well as the level of specific laboratory markers of myocardial dysfunction (NT-proBNP) and injury (hsTnI) was determined immediately before treatment, after 3 and 6 cycles of chemotherapy.Results. The mean age was 63,8±10 years with a slight predominance of men (56,7%, n=17). The patients initially had an increased level of NT-proBNP (316 [75,9; 602,6] pg/mL) with its decrease to 144,0 [102,3; 294,0] pg/ml after 3 cycles and to 109,2 [59,9; 344,5] pg/ml after 6 cycles of chemotherapy. At the MM onset, the mean hsTnI values were 0,06 [0,03; 0,49] ng/mL, whereas after 3 and 6 chemotherapy cycles it accounted for 0,02 [0,01-0,68] and 0,65 [0,02; 1,51] ng/ml, respectively, with the normal range of less than 0,1 ng/ml. Despite this, no statistical significance has been obtained. There were no clinical and/or laboratory signs of heart failure, ischemia, or other non-cardiac causes of elevated NT-proBNP levels in this cohort. Multivariate regression analysis revealed the following significant factors influencing the initial hsTnI level: paraprotein, hemoglobin and erythrocyte sedimentation rate (ESR). The resulting regression model was characterized by a strong correlation (r=0,702, p&lt;0,001).Conclusion. MM and its pathogenetic features such as paraproteinemia may be challenging for NT-proBNP and hsTnI levels assessment in group of interest before treatment. An unreliable assessment of these markers before chemotherapy may lead to incorrect baseline cardiovascular risk stratification and make it difficult for a cardiologist/cardio-oncologist to choose proper management strategy.

Abstract 14347: Albuminuria, N-Terminal Pro-Brain Natriuretic Peptide and Incident Congestive Heart Failure in High-Risk Adults With Hypertension: A Post Hoc Analysis of the Systolic Blood Pressure Intervention Trial

Introduction: Abnormal levels of urinary albumin concentration (UAC) and N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) have each been independently associated with an increased risk of congestive heart failure (CHF). It remains unknown whether the concomitant presence of abnormal UAC and NT-proBNP increases an individual’s risk for future CHF beyond that contributed by each biomarker. Objective: To examine the joint association between abnormal UAC and NT-ProBNP with incident CHF in participants from the SPRINT (Systolic Blood Pressure Intervention Trial) study. Methods: This analysis included 8,176 participants from SPRINT with available data on baseline UAC and NT-proBNP. UAC was measured by urine albumin-creatinine ratio (UACR). Albuminuria was defined as UACR ≥30 mg/g. Abnormal NT-proBNP was defined as levels ≥125 pg/ml. Cox proportional hazard models were used to examine the association of UAC and NT-proBNP, as well as albuminuria and abnormal NT-proBNP, with incident CHF. Results: Over a median follow-up of 3.2 years, 179 incident cases of CHF were observed. In adjusted models, the risk of incident CHF (HR 95% CI) associated with each 1 (one) unit standard deviation increase in the levels of UAC and NT-proBNP was 1.10 (1.04-1.16; p &lt;0.001) and 1.13 (1.10-1.16; p &lt;0.0001), respectively. A statistically significant multiplicative interaction between UAC*NT-proBNP was observed in the fully adjusted model (p &lt;0.0001). The risk associated with the presence of abnormal UAC +/- abnormal NT-proBNP in the SPRINT cohort is depicted in the figure. Conclusions: Among SPRINT participants, we found a significant multiplicative interaction between UAC and NT-proBNP as predictors of incident CHF. Also, the risk of future CHF was over six times higher in individuals with abnormal UAC and NT-proBNP, compared with those with normal levels of both biomarkers. More studies are needed to further explore this interaction and the implications on CHF prevention.

The Interplay between Adipose Tissue Properties and Levels of NT-proBNP in People with HIV.

We aimed to assess the association between low N-terminal pro-brain natriuretic peptide (NT-proBNP) and body mass index (BMI), adipose tissue distribution, adiponectin, and HIV-specific risk factors among people with HIV (PWH). We included 811 PWH with measurement of height, weight and waist circumference, blood samples analyzed for NT-proBNP, and visceral-(VAT) and subcutaneous (SAT) adipose tissue areas measured from CT-scans. Low concentrations of NT-proBNP were defined as concentrations below the limit of quantification (5.9 pmol/L). Associations were explored with multivariable logistic regression analyses adjusted for relevant confounders. We identified 471 (58%) individuals with low concentrations of NT-proBNP. Increasing BMI was associated with higher odds of low NT-proBNP (adjusted OR (aOR) 1.06 (95% CI: 1.01-1.11) per 1 kg/m2). Central obesity and large areas of VAT were associated with higher odds of low NT-proBNP (aOR 1.66 (1.16-2.36) and aOR 1.69 (1.09-2.62), respectively). Higher adiponectin was associated with lower odds of low NT-proBNP (aOR 0.86 (0.79-0.95) per 10% increase). No associations were found between low NT-proBNP and HIV-specific risk factors. In PWH, low NT-proBNP is associated with an adverse adipose tissue profile with high BMI, central obesity, accumulation of VAT, and low adiponectin.

Variations in NT-proBNP Levels in Pregnant Patients with and without SARS-CoV-2 Infection: Consequences for the Newborns.

NT-proBNP (N-terminal pro-brain natriuretic peptide) has a high negative predictive value for ruling out heart failure, a disorder linked with volume overload of the ventricles, and is used for diagnosis, prognosis, and risk stratification. Pregnancy causes in healthy women changes in physical and hemodynamic parameters and appears to be a risk factor for severe COVID-19 illness. The purpose of this study is to highlight the significance of monitoring NT-proBNP levels during pregnancy, particularly in patients who were infected with COVID-19 during pregnancy or were infected with the virus while giving birth. The findings of this comparative research indicate the importance of NT-proBNP in terms of foetal prognosis and birthweight. We collected blood samples to measure NT-proBNP concentrations from a cohort of 186 pregnant patients divided into two groups based on the presence of SARS-CoV-2 viral infection. Elevated NT-proBNP had an unfavourable implication on the newborn birth weight and Apgar score and expressed its influence on lower values. We consider that NT-proBNP testing in pregnant patients, especially those with COVID-19 infection, can be relevant and be used as a predictive marker to be taken into consideration when it comes to management, outcome, and treatment regarding pregnant patients and their newborns.

Luspatercept Modulates Inflammation in the Bone Marrow, Restores Effective Erythropoiesis/Hematopoiesis, and Provides Sustained Clinical Benefit Versus Epoetin Alfa (EA): Biomarker Analysis from the Phase 3 COMMANDS Study

Introduction :Anemia is common in patients (pts) with myelodysplastic syndromes (MDS) due to ineffective erythropoiesis, characterized by increased dysplastic erythroid precursors (EPs) and abortive differentiation in the bone marrow (BM). Insufficient red blood cells (RBCs) lead to chronic anemia and heart failure due to oxygen deprivation. Luspatercept is approved to treat anemia after erythropoiesis-stimulating agent (ESA) failure in pts with transfusion-dependent, lower-risk MDS (LR-MDS). In the phase 3 COMMANDS trial (NCT03682536), 58.5% of ESA-naive luspatercept treated pts with LR-MDS experienced RBC transfusion independence for ≥ 12 wk with concurrent mean hemoglobin (Hb) increase ≥ 1.5 g/dL during wk 1-24, vs 31.2% of EA-treated pts. Aims :To differentiate the mechanism of action of luspatercept from EA and determine its correlation with clinical benefit in the COMMANDS study. Methods :Cytomorphology assessments were performed on BM aspirates at baseline, wk 24 and 48. Complete blood count, Hb, and reticulocytes (retics) were measured in peripheral blood. BM mononuclear cells (BMMC) were subjected to bulk RNA-seq. Serum cytokine analysis was performed at screening and wk 24 using Rules-Based Medicine's Human Inflammation MAP ® v.1.1 and a custom Human MAP ELISA panel. Results :In ITT population, EPs, retics, and Hb were increased vs baseline in the luspatercept arm at wk 24 ( P &amp;lt; 0.001) and wk 48 ( P &amp;lt; 0.005). EPs, retics, and Hb were increased in the EA arm at wk 24 ( P &amp;lt; 0.01), but this was not sustained to wk 48. Subgroup analysis showed similar trends for ring sideroblast (RS)+ pts in both arms. While RS− pts in the EA arm showed similar trends to the ITT population, luspatercept RS− pts showed trends of EP expansion post-wk 24 only. Retics increased significantly in RS− luspatercept pts at wk 24 ( P &amp;lt; 0.005). Hb increased more significantly at wk 24 with EA ( P &amp;lt; 0.003) but at wk 48 with luspatercept ( P &amp;lt; 0.005).Gene set enrichment analysis of BMMC revealed enrichment of early, mid, and late EP genes at baseline favored response to luspatercept, but enrichment of mid and late EP genes was unfavorable for EA (Figure A). Significant downregulation of REACTOME IL-1 signaling (normalized enrichment score [NES] = −2.27; adjusted [Adj] P &amp;lt; 0.0001 [vs EA = not significant (ns)]), BIOCARTA IL-6 pathway (NES = −1.99; Adj P = 0.0025 [vs EA = ns]) and IFNα response (NES: −2.26; Adj P &amp;lt; 0.0001 [vs EA = ns]) was observed with luspatercept. BIOCARTA IL-1R pathway was more significantly reduced with luspatercept (NES = −1.78; Adj P = 0.0073) compared with EA (NES = −1.79; Adj P = 0.0172), as was IL-10 signaling (luspatercept NES = −2.39; Adj P &amp;lt; 0.001 vs EA NES = −1.82; Adj P = 0.0125). TGF-β, apoptosis, and spliceosome pathways down regulation was also observed with luspatercept. At wk 24, luspatercept responders had a median 640 pg/mL decrease ( P = 0.0035) of N-terminal pro-brain natriuretic peptide (NT-proBNP), produced by the heart, compared with a median 360 pg/mL decrease in EA arm responders ( P = 0.37). At wk 24, non-responders had a median increase of 775 pg/mL ( P = 0.0032) in the EA arm and 31.5 pg/mL ( P = 0.95) in the luspatercept arm. Conclusions : Multiplatform analysis of primary BM samples from a phase 3 trial of luspatercept revealed novel response-associated biomarkers. Compared with EA, luspatercept led to sustained increase of EPs and retics over 48 wk with a concomitant Hb increase. RS− pts showed Hb accumulation peaked at wk 24 in the EA arm. Conversely, luspatercept in RS− pts significantly increased retics at wk 24 and EPs past wk 24 with concomitant peaking of Hb at wk 48, suggesting gradual and sustained clinical benefit. Unlike EA, which plays a role in early differentiation of hematopoietic stem cells (HSCs), luspatercept acts on different erythroid stages, leading to EP expansion and maturation. Furthermore, downregulation of IL-1, IL-1R, IFNα, IL-6 pro-inflammatory (Figure B), and IL-10 anti-inflammatory signaling with luspatercept suggests modulation of the BM inflammatory environment in MDS to restore HSC function for normal hematopoiesis (Wang J, et al. Front Immunol 2022;13:951937). Additionally, decreased or static levels of NT-proBNP with luspatercept suggest a positive effect in mitigating cardiac damage. These novel insights obtained from analysis of a large controlled clinical trial mechanistically differentiate the superior clinical benefit of luspatercept from EA in treating anemia due to MDS.

Clonal Hematopoiesis-Related Mutations Are Associated with Favorable Clinical Benefit Following Luspatercept Treatment in Patients with Lower-Risk Myelodysplastic Syndromes: A Subgroup Analysis from the Phase 3 COMMANDS Trial

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related condition arising from somatic mutations in hematopoietic stem cells that leads to mutant cell clonal progeny in the blood (variant allele frequency [VAF] &amp;gt; 2%) and is found in 10%-30% of people &amp;gt; 70 years of age. CHIP-related mutations (eg, DNA methyltransferase 3 alpha [ DNMT3A], tet methylcytosine dioxygenase 2 [ TET2], ASXL transcriptional regulator 1 [ ASXL1], splicing factor 3b subunit 1 [ SF3B1]) are associated with increased inflammation and elevated risk of developing hematologic malignancies, including myelodysplastic syndromes (MDS)/acute myeloid leukemia, and are an independent risk factor for cardiovascular complications. Recently, patients with MDS were reported to have high rates of cardiovascular co-morbidities including elevated levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of cardiovascular and all-cause mortality. Currently, no treatments targeting CHIP mutations or associated complications are available. Luspatercept is currently approved for anemia in adult patients with lower-risk MDS (LR-MDS) with ring sideroblasts who require red blood cell (RBC) transfusions (≥ 2 RBC units/8 weeks) after erythropoiesis-stimulating agent (ESA) treatment failure. Recently, the phase 3 COMMANDS trial (NCT03682536) reported superiority of luspatercept over ESAs in reducing transfusion burden in ESA-naive patients with LR-MDS. Aims: We investigated the association between the most frequent CHIP-related mutations ( DNMT3A, TET2, ASXL1, SF3B1) and clinical outcomes in patients treated with luspatercept from the COMMANDS trial. Methods: Genomic DNA was isolated from bone marrow (BM) mononuclear cells, and 36 myeloid-specific somatic gene mutations were identified by targeted next-generation sequencing (400X; sensitivity 3%; Munich Leukemia Laboratory information system) at baseline. Hematologic parameters (eg, hemoglobin [Hb], complete blood counts), transcriptome data (bulk BM RNA sequencing [RNA-Seq] data) and cytokines/chemokines (peripheral blood) were assessed at baseline and week 24. Results: Overall, 145 patients in the luspatercept arm of the COMMANDS trial were included in the current analyses, of whom 85% (123/145) (Figure 1A) had the most frequent CHIP-related mutations (eg, DNMT3A, TET2, ASXL1, and SF3B1) with a VAF of 3%-50%. Modest positive correlations were observed between DNMT3A, TET2 and SF3B1 baseline VAF and monocyte percentage ( P = 0.024, P = 0.015, and P = 0.005, respectively). Baseline Hb levels were lower in patients with frequent CHIP-related mutations than in those with less frequent/other somatic mutations. Luspatercept treatment significantly reduced anemia from baseline in patients with CHIP-related mutations (primary endpoint response 62%; n/N = 76/123). Concomitant with the Hb increase (∆ = +1.0 mg/dL; P &amp;lt; 0.001), we observed improvements in other cell counts, including white blood cell counts (∆ = +0.7 × 10 9 cells/L; P = 0.01). In addition, luspatercept treatment in patients with CHIP-related mutations was associated with downregulation of inflammatory gene signatures (Figure 1B) and proinflammatory cytokines/chemokines, including hepcidin (∆ = −43.9 ng/mL; P &amp;lt; 0.001). Furthermore, we observed upregulation of an anti-inflammatory regulator (growth/differentiation factor 15) following treatment. Most importantly, significant downregulation of NT-proBNP levels (∆ = −330 pg/mL; P &amp;lt; 0.05) was observed in patients with LR-MDS who received luspatercept. Conclusions: This retrospective subgroup analysis of patients in the COMMANDS trial with the most frequent CHIP-related mutations ( DNMT3A, TET2, ASXL1 and SF3B1) demonstrated novel effects of luspatercept in clonal hematopoiesis-related consequences including improvements in anemia, cytopenias, and reduced inflammation. Most importantly, NT-proBNP and elevated hepcidin levels were significantly downregulated in responders following luspatercept treatment. These results warrant evaluation of luspatercept in patients with high-risk CHIP mutations including clonal cytopenia of undetermined significance and patients with anemia of inflammation.

Early Initiation of Dapagliflozin during Hospitalization for Acute Heart Failure Is Associated with a Shorter Hospital Stay.

Objective Sodium-glucose co-transporter-2 inhibitors (SGLT2is), such as dapagliflozin, have a diuretic effect, and their early initiation to treat acute heart failure (AHF) may improve outcomes; however, the significance of the timing of starting dapagliflozin after hospital admission remains unclear. Methods We performed a post hoc analysis of a prospective, observational registry. Participants were divided into the early (E) group and late (L) group using the median time to the initiation of dapagliflozin (6 days) as the cut-off. We evaluated the relationship between the time to the initiation of dapagliflozin after hospital admission and patient characteristics and the length of the hospital stay. Patients Study subjects were 118 patients with AHF admitted between January 2021 and April 2022 who were started on dapagliflozin treatment (10 mg/day). Results Patients were divided into the E group (n=63) and L group (n=55). The HF severity as evaluated by the New York Heart Association class and the N-terminal pro-brain natriuretic peptide level was not significantly different between the groups. The time to the initiation of dapagliflozin and length of hospital stay showed a significant positive correlation (p<0.001, r=0.46). The hospital stay was significantly shorter in group E [median, 16.5 days; interquartile range (IQR): 13-22 days] than in group L (median, 22 days; IQR: 17-27 days; p=0.002). A multivariate logistic regression analysis showed that the early initiation of dapagliflozin was independently associated with a shorter hospital stay, even after multiple adjustments. Conclusion Early initiation of dapagliflozin after hospital admission is associated with a shorter hospital stay, suggesting it is a key factor for shortening hospital stays.

A Network Meta-analysis of the Efficacy and Safety of Targeted Drug Combinations in the Treatment of Pulmonary Arterial Hypertension

Objective: This network meta-analysis aims to compare the efficacy and safety of different targeted drug combination treatment for pulmonary arterial hypertension (PAH). Methods: Searches were conducted in Cochrane, PubMed, EMBASE, China National Knowledge Infrastructure, China Biomedical Literature Database, Wanfang Database, and VIP Chinese Science and Technology Journal Data to identify both published and unpublished randomized controlled trials from inception until January 1, 2022. The risk of bias in the included studies was assessed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. A network meta-analysis was performed using Stata 16.0 software. The efficacy and safety of different targeted drugs combined treatment for PAH were evaluated based on forest plot, funnel plot, and surface under the cumulative ranking. Results: A total of 29 randomized controlled trails with 4,448 patients treated with 10 different types of targeted drug combinations were included in this study. The results of the surface under the cumulative ranking showed that the combination regimen was the best clinical option to improve symptoms and delay progression in patients with pulmonary artery hypertension compared with monotherapy. Sildenafil in combination with ambrisentan significantly improved the 6-minute walk distance and reduced N-terminal pro-brain natriuretic peptide levels. Bosentan in combination with sildenafil significantly reduced mean pulmonary artery pressure, whereas bosentan in combination with epoprostenol was more effective than other combinations in reducing pulmonary vascular resistance. Bosentan in combination with tadalafil significantly improved the Borg dyspnea score, and bosentan in combination with iloprost was the best combination for improving World Health Organization functional class/New York Heart Association functional class. In terms of safety, there was no significant reduction in the incidence of adverse events, hospitalizations, or all-cause mortality for combination therapy compared with monotherapy. Bosentan combined with sildenafil significantly reduced the risk of serious adverse events, but the risk of discontinuation due to an adverse event was higher than monotherapy. Sildenafil combined with epoprostenol reduced the risk of clinical worsening in patients with PAH. Conclusion: Compared with monotherapy, targeted drug combinations for PAH significantly improves exercise tolerance, pulmonary hemodynamic parameters, and reduces the risk of serious adverse events and clinical worsening in patients. Bosentan in combination with sildenafil and bosentan in combination with iloprost are combinations of targeted agents with significant efficacy and better safety profile than monotherapy for the treatment of PAH. Sildenafil in combination with epoprostenol has a low risk of clinical worsening in PAH.

Long-term effects of angiotensin receptor neprilysin inhibitor therapy in heart failure patients with reduced ejection fraction: A retrospective cohort study.

Heart failure is an increasing public health issue with substantial morbidity and mortality rates. This study aimed to evaluate the efficacy, safety, and long-term outcomes of angiotensin receptor neprilysin inhibitor (ARNi) in the treatment of heart failure with reduced ejection fraction (HFrEF) 5 years after treatment initiation. This retrospective study analyzed a cohort of 75 patients diagnosed with HFrEF over a period of 5 years after the initiation of ARNi therapy. The initial clinical condition, laboratory and echocardiographic measurements including left ventricular ejection fraction (LVEF), New York Heart Association functional classes (NYHA-FC) and the prognostic nutritional index were compared to the corresponding values obtained after a 5-year period of ARNi therapy. In addition, the number of annual hospitalizations, mortality rates and any history of adverse effects during the follow-up period were recorded. The N-terminal pro-brain natriuretic peptide (NT-proBNP) level, LVEF, and NYHA-FC values demonstrated significant improvement at the end of the 5-year follow-up period (all parameters, P < .001). Although the observed increase in the prognostic nutritional index was not statistically significant (P = .077), it is worth noting. A significant reduction in daily diuretic doses and hospitalizations due to heart failure was observed following the use of ARNi (all comparisons, P < .001). The prevalence of hypotension was around 16% (being symptomatic in 4%), making it the most frequently observed adverse event. The 5-year cardiovascular mortality rate was 17.3%. The use of ARNi in HFrEF patients was associated with a notable improvement in NYHA-FC, LVEF, and NT-proBNP levels in the long-term, while also leading to a better nutritional status and reduced need for diuretics and annual hospitalization. Additionally, ARNi usage has been associated with improved nutritional status, decreased reliance on diuretics, and reduced frequency of annual hospitalizations. These effects were associated with a lack of significant increase in adverse effects. These results may contribute to a better understanding of ARNi's long-term effects on patient outcomes.

Assessment of N-terminal pro-brain natriuretic peptide in patients with arrhythmia due to undifferentiated connective tissue disease

Aim. To study the relationship between the level of N-terminal pro-brain natriuretic peptide (NT-proBNP) and myocardial abnormalities in patients with cardiac arrhythmias due to undifferentiated connective tissue disease (UCTD).Material and methods. This cross-sectional comparative study included young and middle-aged patients with arrhythmias due to UCTD: group 1 (18-44 years old, n=127), group 3 (45-59 years old, n=10). The control groups (n=30, group 2; n=8, group 4) included volunteers with single phenotypic signs of UCTD, comparable in age and sex. A standard clinical examination, 72-hour electrocardiographic monitoring, Speckletracking echocardiography, and NT-proBNP level assessment were performed.Results. In patients of groups 1 and 3, a significant increase in the concentration of NT-proBNP was noted compared to the control groups. At the same time, the average NT-proBNP level in the study groups did not exceed the reference values. Significant correlations were revealed between NT-proBNP and heart rate (r1=0,462, p=0,010; r3=0,397, p=0,034), UCTD diagnostic cut-off level (r1=0,496, p=0,001; r3=0,401, p=0,043), the presence of mitral valve prolapse (r1=0,469, p=0,002) and mitral regurgitation (r1=0,53, p=0,008), premature ventricular contractions (PVCs) of class III (r1=0,582, p=0,045), IVa (r1= 0,39, p=0,042) and V (r1=0,397, p=0,037); cardiac index (r1=-0,329, p=0,037) and ejection fraction (r1=-0,407, p=0,044). However, no significant correlation was found between the left ventricular global longitudinal strain and NT-proBNP level.Conclusion. The study demonstrated the association of NT-proBNP level with UCTD diagnostic cut-off level, mitral valve prolapse, mitral regurgitation, and PVCs, which makes possible the use of this biomarker as an additional diagnostic criterion for myocardial changes in against the background of UCTD.

Correlation of n-terminal pro-brain-type natriuretic peptide levels with the severity of single mitral regurgitation or accompanied by mild aorta valve dysfunction in patients with rheumatic heart disease in Sanglah general hospital.

The most frequent abnormality of the valves involved in rheumatic heart disease is mitral regurgitation. A promising supportive diagnostic tool for rheumatic heart disease is the N-terminal pro-brain natriuretic peptide, which can identify mitral valve damage. To prove a positive correlation between N-terminal pro-brain natriuretic peptide levels and the severity of mitral regurgitation or accompanied by mild aortic valve dysfunction in children with rheumatic heart disease. Children aged 1-18 years who had been identified as having rheumatic heart disease with a single mitral regurgitation or accompanied by mild aortic issues at Sanglah General Hospital, Denpasar, met the inclusion criteria for this cross-sectional study. Mitral regurgitation severity was determined using the parameters of vena contracta width, effective regurgitation orifice area, regurgitant jet area, and regurgitation volume. Bivariate analysis using the Spearman correlation test. From 36 research subjects, the mean age was 11.32 years. In this study, there was a moderate positive correlation between the levels of N-terminal pro-brain natriuretic peptide and the regurgitation jet area. N-terminal pro-brain natriuretic peptide levels also had a moderately positive correlation with the vena contracta width and a weakly positive correlation with the regurgitation volume. Effective regurgitation orifice area and N-terminal pro-brain natriuretic peptide levels did not significantly correlate. There was a moderately positive correlation between N-terminal pro-brain natriuretic peptide levels and the severity of mitral regurgitation on regurgitation jet area, a moderately positive correlation with the vena contracta width, and a weakly positive correlation with regurgitation volume in rheumatic heart disease patients.

Adjuvant treatment with shenfu injection improve quality of life in chronic heart failure patients: A meta-analysis of randomized controlled trials

ObjectiveShenfu Injection (SFI) derived from Shenfu decoction, has been widely used for treating heart failure in China. This meta-analysis aimed to assess the effect of SFI as an adjuvant therapy on quality of life in patients with chronic heart failure (CHF). MethodsA systematic literature search was conducted in CKNI, VIP, Wanfang, Sinomed, Cochrane Library, PubMed, and Embase database until March 16, 2023. Randomized controlled trials (RCTs) evaluating the effect of SFI plus conventional therapy versus conventional therapy alone for treating CHF were included. Outcome measures were quality of life defineded by the Minnesota Living with Heart Failure questionnaire (MLHFQ), left ventricular ejection fraction (LVEF), 6-min walking distance, and blood brain natriuretic peptide (BNP)/N-terminal pro-brain natriuretic peptide (NT-proBNP) level. ResultsThirteen RCTs enrolling 1042 CHF patients were included. SFI plus conventional therapy significantly reduced the total MLHFQ score (mean difference [MD] −8.69 points; 95% confidence intervals [CI] −13.46 to −3.91) compared with the conventional therapy alone. Moreover, adjuvant treatment with SFI significantly improved the 6-min walking distance (MD 65.42 m; 95% CI 44.23 to 86.62), LVEF (MD 3.89; 95% CI 1.03 to 6.75), and blood level of BNP/NT-proBNP (SMD -1.73; 95% CI -2.43 to −1.03). ConclusionsAdjuvant treatment with SFI can achieve additional benefits in improving quality of life and exercise tolerance in patients with CHF. These beneficial effects of SFI may correlate with its improving cardiac function. However, our findings should be interpreted with presence of significant heterogeneity and suboptimal quality of the analyzed trials.