NT-proBNP Research Articles

The Level of Markers Stimulating Growth Factor 2 (ST2), N-Terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP), and D-Dimer in Healthy Volunteer Testers in 21-Day Head-Down -6° Tilt Bed Rest as a Model of Hypodynamia.

The paper presents an analysis of the proteomic composition in relation to both the risk of thrombosis and changes in the state of cardiomyocytes associated with the risk of cardiac fibrosis and heart failure. We examined 12 practically healthy male volunteers exposed to head-down -6° tilt bed rest (HDBR) for 21 days. The revealed decrease in the level of stimulating growth factor 2 (ST2) on days 10 and 21 relative to the initial values (background; 5 days before HDBR) indicated a decrease in the myocardial load and cardiomyocyte extensibility. The level of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) increased on day 2, decreased on days 10 and 21 of HDBR relative to the background levels, and returned to baseline values after the recovery period (5 days after HDBR). The revealed changes in the level of NT-proBNP reflected the increase in circulating blood volume corresponding to HDBR duration and the role of the gravity component in increasing the functional load on the myocardium. Unchanged blood level of D-dimer at all points of the study indicates that there is no risk of thrombosis under the conditions of this study.

Serum concentrations of chromogranin A, serotonin and natriuretic peptide are decreased in patients with neuroendocrine tumors with overweight and obesity compared to healthy donors

Background: Neuroendocrine tumors (NETs) are a group of neoplasms, in which circulating biomarkers chromogranin A (CgA), serotonin, and N-terminal brain natriuretic pro-peptide (NT-proBNP), used as a marker of carcinoid heart disease, are especially important in the diagnosis and monitoring. A number of pre-analytical factors, including patients' body mass index (BMI), have an impact on NETs biomarker concentrations. Aim: To perform a comparative analysis of serum concentrations of CgA, serotonin and NT-proBNP in patients with NETs of various locations with normal body weight and with overweight or obesity. Methods: This cross-sectional study included 94 patients with NETs of various locations and 78 provisionally healthy individuals without cancer and cardiovascular disorders, matched by gender and age to the patients. Serum biochemical markers were measured before a course of chemotherapy/biotherapy or surgery with the use of standardized enzyme-linked immunosorbent assays Chromogranin A NEOELISA (Eurodiagnostica), Serotonin ELISA (IBL), and the electrochemiluminescent assay (Cobas e601 analyzer, Roche). All NETs patients were divided into 2 subgroups: 46 patients with normal bodyweight (BMI 18 to 24.9) and 48 patients with overweight/obesity (BMI ≥ 25). Results: The median BMI in the NET patients did not vary depending on their tumor extension, functional activity and malignancy grade. The median concentrations of CgA (150 ng/ml), serotonin (188 ng/ml) and NT-proBNP (117 pg/ml) in the NET patients with obesity and overweight were significantly lower (p = 0.008, p = 0.005 and p = 0.012, respectively) than in the NET patients with normal body weight (769 ng/ml, 704 ng/ml and 197 pg/ml, respectively). In the control group, significantly (p = 0.0001) lower levels in the subgroup with BMI ≥ 25 were obtained only for serotonin. The ROC analysis showed a decrease of the diagnostic efficiency of NET biomarkers in obesity: in the normal BMI group AUC (CgA) was 0.87 and AUC (serotonin) 0.78, whereas in those with BMI ≥ 25, the AUC (CgA) and AUC (serotonin) were 0.81 and 0.62, respectively. Conclusion: Obesity may make it difficult to identify biochemical markers of NETs – CgA, serotonin and NT-proBNP.

DNAm scores for serum GDF15 and NT-proBNP levels associate with a range of traits affecting the body and brain

BackgroundPlasma growth differentiation factor 15 (GDF15) and N‐terminal proB‐type natriuretic peptide (NT‐proBNP) are cardiovascular biomarkers that associate with a range of diseases. Epigenetic scores (EpiScores) for GDF15 and NT-proBNP may provide new routes for risk stratification.ResultsIn the Generation Scotland cohort (N ≥ 16,963), GDF15 levels were associated with incident dementia, ischaemic stroke and type 2 diabetes, whereas NT-proBNP levels were associated with incident ischaemic heart disease, ischaemic stroke and type 2 diabetes (all PFDR < 0.05). Bayesian epigenome-wide association studies (EWAS) identified 12 and 4 DNA methylation (DNAm) CpG sites associated (Posterior Inclusion Probability [PIP] > 95%) with levels of GDF15 and NT-proBNP, respectively. EpiScores for GDF15 and NT-proBNP were trained in a subset of the population. The GDF15 EpiScore replicated protein associations with incident dementia, type 2 diabetes and ischaemic stroke in the Generation Scotland test set (hazard ratios (HR) range 1.36–1.41, PFDR < 0.05). The EpiScore for NT-proBNP replicated the protein association with type 2 diabetes, but failed to replicate an association with ischaemic stroke. EpiScores explained comparable variance in protein levels across both the Generation Scotland test set and the external LBC1936 test cohort (R2 range of 5.7–12.2%). In LBC1936, both EpiScores were associated with indicators of poorer brain health. Neither EpiScore was associated with incident dementia in the LBC1936 population.ConclusionsEpiScores for serum levels of GDF15 and Nt-proBNP associate with body and brain health traits. These EpiScores are provided as potential tools for disease risk stratification.

Shikonin mitigates cyclophosphamide-induced cardiotoxicity in mice: the role of sirtuin-1, NLRP3 inflammasome, autophagy, and apoptosis.

The aim of this study was to elucidate the protective potential of shikonin (SHK) on cyclophosphamide (CP)-induced cardiotoxicity in Swiss albino mice. Mice received SHK in three different doses by oral gavage daily for 14 days and CP at 100mg/kg, intraperitoneally once on the seventh day. On the 15th day, mice were euthanized, blood collected, and hearts were removed to estimate various biochemical and histopathological parameters. CP significantly increased serum lactate dehydrogenase, creatine kinase-MB, troponin I and NT pro-BNP, and cardiac malondialdehyde and decreased cardiac total antioxidant capacity and Nrf2, whereas increased inflammatory markers in the cardiac tissues. CP also caused hypertrophy and fibrosis in the cardiac tissues via activation of IL6/JAK2/STAT3 while depressed SIRT1 and PI3K/p-Akt pathway with consequent increased apoptosis and dysregulation of autophagy. SHK treatment reversed these changes in a dose-dependent manner and showed a significant protective effect against CP-induced cardiotoxicity via suppressing oxidative stress, inflammation, and apoptosis with modulation of autophagy via induction of SIRT1/PI3K/p-Akt signaling. Shikonin may be used as an adjuvant to cyclophosphamide in cancer treatment, but further research is needed to investigate its effects on cardiotoxicity in distinct animal cancer models.

International prevalence of transthyretin amyloid cardiomyopathy in high-risk patients with heart failure and preserved or mildly reduced ejection fraction

Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed cause of heart failure (HF). Methods This epidemiology study assessed the international prevalence of ATTR-CM among patients aged ≥60 years with a history of HF, left ventricular ejection fraction (LVEF) >40%, an end-diastolic interventricular septum thickness (IVST) ≥12 mm, but without diagnosed amyloidosis, history of LVEF ≤40%, cardiomyopathy of known cause, severe valvular, or coronary heart disease. ATTR-CM was determined using cardiac scintigraphy alongside exclusionary testing for light chain amyloidosis. The study was terminated early due to slow recruitment, without safety concerns. Results Overall, 56/315 (18%; 95% CI: 13.7–22.5) patients with evaluable scintigraphy had ATTR-CM, with a numerically higher prevalence in: Europe (24%) vs. other regions (9% Asia; 5% North America); at specialist vs non-specialist centres (26% vs. 11%); in males vs. females (24% vs. 10%); and in older vs. younger patients (e.g. >40% among those ≥85 years). Other risk markers (p<.05) included a history of carpal tunnel syndrome, higher N-terminal pro B-type natriuretic peptide concentration, and higher end-diastolic IVST. Conclusions ATTR-CM was diagnosed in 18% (95% CI: 13.7–22.5) of evaluable patients with HF, LVEF >40%, and risk markers for ATTR-CM, but no previous diagnosis of amyloidosis. Recruitment bias may have contributed to regional variability. NCT04424914

Metabolomic profiling identifies novel metabolites associated with cardiac dysfunction

Metabolic comorbidities, such as obesity and diabetes, are associated with subclinical alterations in both cardiac structure/function and natriuretic peptides prior to the onset of heart failure (HF). Despite this, the exact metabolic pathways of cardiac dysfunction which precede HF are not well-defined. Among older individuals without HF in the Multi-Ethnic Study of Atherosclerosis (MESA), we evaluated the associations of 47 circulating metabolites measured by 1H-NMR with echocardiographic measures of cardiac structure and function. We then evaluated associations of significant metabolites with circulating N-terminal pro-B-type natriuretic peptide (NT-proBNP). In a separate cohort, we evaluated differences between top metabolites in patients with HF with preserved ejection fraction (HFpEF) and comorbidity-matched controls. Genetic variants associated with top metabolites (mQTLs) were then related to echocardiographic measures and NT-proBNP. Among 3440 individuals with metabolic and echocardiographic data in MESA (62 ± 10 years, 52% female, 38% White), 10 metabolites broadly reflective of glucose and amino acid metabolism were associated with at least 1 measure of cardiac structure or function. Of these 10 metabolites, 4 (myo-inositol, glucose, dimethylsulfone, carnitine) were associated with higher NT-proBNP and 2 (d-mannose, acetone) were associated with lower NT-proBNP. In a separate cohort, patients with HFpEF had higher circulating myo-inositol levels compared with comorbidity-matched controls. Genetic analyses revealed that 1 of 6 known myo-inositol mQTLs conferred risk of higher NT-proBNP. In conclusion, metabolomic profiling identifies several novel metabolites associated with cardiac dysfunction in a cohort at high risk for HF, revealing pathways potentially relevant to future HF risk.

Evaluation of some nonroutine cardiac biomarkers among adults and children with beta-thalassemia major.

Cardiac injury caused by iron overload is the leading cause of mortality and morbidity in patients with beta-thalassemia, owing to frequent blood transfusion, increased iron overload, and blood hemolysis. This research aimed to assess several novel cardiac biomarkers in the blood samples of children and adult patients with beta-thalassemia major (βTM), along with their respective control groups. These biomarkers included endothelin 1 (ET-1), N-terminal pro-brain natriuretic peptide (NT-proBNP), atrial natriuretic peptide (ANP), growth differentiation factor-15 (GDF-15), and renalase (RNLS). This case-control study was done on 46 patients with βTM (23 children <18 years, and 23 adults ≥18 years) from the Genetic Hematology Center in Thi-Qar province, Iraq, and 42 comparable controls in 2 groups (21 for each group) in the period from February to April 2023. Levels of ET-1, NT-proBNP, ANP, GDF-15, RNLS, and ferritin were higher in the children and adults with βTM than in the control subjects. Elevations of the novel cardiac biomarkers ET-1, NT-proBNP, ANP, GDF-15, and RNLS in the sera of children and adult patients with βTM when compared with comparable control subjects confirm that the majority of patients with βTM are at risk of cardiac and cardiovascular complications even when there are no obvious symptoms, especially in children, which gives suitable predictive biomarkers.

Hypothesis paper: GDF15 demonstrated promising potential in Cancer diagnosis and correlated with cardiac biomarkers

BackgroundCardiovascular toxicity represents a significant adverse consequence of cancer therapies, yet there remains a paucity of effective biomarkers for its timely monitoring and diagnosis. To give a first evidence able to elucidate the role of Growth Differentiation Factor 15 (GDF15) in the context of cancer diagnosis and its specific association with cardiac indicators in cancer patients, thereby testing its potential in predicting the risk of CTRCD (cancer therapy related cardiac dysfunction).MethodsAnalysis of differentially expressed genes (DEGs), including GDF15, was performed by utilizing data from the public repositories of the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Cardiomyopathy is the most common heart disease and its main clinical manifestations, such as heart failure and arrhythmia, are similar to those of CTRCD. Examination of GDF15 expression was conducted in various normal and cancerous tissues or sera, using available database and serum samples. The study further explored the correlation between GDF15 expression and the combined detection of cardiac troponin-T (c-TnT) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), assessing the combined diagnostic utility of these markers in predicting risk of CTRCD through longitudinal electrocardiograms (ECG).ResultsGDF15 emerged as a significant DEG in both cancer and cardiomyopathy disease models, demonstrating good diagnostic efficacy across multiple cancer types compared to healthy controls. GDF15 levels in cancer patients correlated with the established cardiac biomarkers c-TnT and NT-proBNP. Moreover, higher GDF15 levels correlated with an increased risk of ECG changes in the cancer cohort.ConclusionGDF15 demonstrated promising diagnostic potential in cancer identification; higher GDF15, combined with elevated cardiac markers, may play a role in the monitoring and prediction of CTRCD risk.

Correlates of sleep-disordered breathing and Cheyne-Stokes respiration in patients with atrial fibrillation who have undergone pulmonary vein isolation.

Sleep disordered breathing (SDB) is a common comorbidity in patients with atrial fibrillation (AF). Patients undergoing pulmonary vein isolation (PVI) for AF have a high prevalence of SDB. In previous studies, some patients with AF had Cheyne-Stokes respiration (CSR). The aim of the present study was to assess the prevalence of SDB and the correlates of SDB severity and CSR in AF patients who have undergone PVI. The study was conducted using a single-center observational design. All participants underwent a home sleep apnea test (ApneaLink Air, ResMed, Australia), which could determine the severity of SDB as assessed by the apnea-hypopnea index (AHI) and the percentage of CSR (%CSR) pattern. 139 AF patients who underwent PVI were included in the study. Overall, 38 (27.3%) patients had no SDB (AHI < 5), 53 (38.1%) had mild SDB (5 ≤ AHI < 15), 33 (23.7%) had moderate SDB (15 ≤ AHI < 30), and 15 (10.8%) had severe SDB (AHI ≥ 30). Correlates of the increased AHI included male sex (β = 0.23, p = 0.004), age (β = 0.19, p = 0.020), high body mass index (β = 0.31, p < 0.001), and β blockers usage (β = 0.18, p = 0.024). Conversely, correlates with the %CSR rate included male sex (β = 0.18, p = 0.020), age (β = 0.19, p = 0.015), non-paroxysmal AF (β = 0.22, p = 0.008), and high glycohemoglobin A1c (β = 0.36, p < 0.001) and N-terminal pro-brain natriuretic peptide (β = 0.24, p = 0.005) levels. SDB is prevalent in patients with AF who have undergone PVI; predisposing factors for SDB include male sex, older age, and obesity. CSR occurs in patients with AF who have undergone PVI; predisposing factors for CSR include male sex, older age, high left ventricular filling pressure, and abnormal blood glucose level.

Plasma N-terminal pro-brain natriuretic peptide concentrations may help to identify patients with very low-risk acute pulmonary embolism: A preliminary study.

Patients with an acute pulmonary embolism (APE) are a heterogeneous group, and some of them may benefit from early discharge and an ambulatory care referral. We aimed to evaluate the use of N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma level assessment in patients with low-risk APE based on clinical findings (0 points on the simplified Pulmonary Embolism Severity Index (sPESI)). Preliminary analysis of an ongoing prospective study including 1,151 normotensive patients with at least a segmental APE. In the final analysis, 348 patients with a 0-point sPESI were included. Blood samples were collected within the first 24 h of admission. The clinical endpoint (CE) included APE-related mortality and/or rescue thrombolysis in patients with clinical deterioration. Clinical endpoints occurred in 3 patients who had higher plasma NT-proBNP levels than study participants with a favorable clinical course (164 [64-650] pg/mL compared to 2,930 [2,285.5-13,965] pg/mL; p = 0.01). Receiver operating characteristic (ROC) analysis showed that the area under the curve (AUC) for NT-proBNP for the prediction of the CEs was 0.918 (95% confidence interval [95% CI]: 0.831-1.00; p = 0.013). We defined the cutoff value of NT-proBNP at ≥1,641 pg/mL. Among subjects with 0 points on the sPESI, those with concentrations of NT-proBNP exceeding 1,641 pg/mL might require closer attention; remaining patients could be considered candidates for outpatient treatment. However, these findings warrant further investigation in a large, prospective group of patients.

Prognostic Significance and Biologic Associations of Senescence-Associated Secretory Phenotype Biomarkers in Heart Failure.

The role of cellular senescence in human heart failure (HF) remains unclear. The senescence-associated secretory phenotype (SASP) is composed of proteins released by senescent cells. We assessed the prognostic significance and biologic pathways associated with the SASP in human HF using a plasma proteomics approach. We measured 25 known SASP proteins among 2248 PHFS (Penn HF Study) participants using the SOMAScan V4 assay. We extracted the common variance in these proteins to generate SASP factor scores and assessed the relationship between these SASP factor scores and (1) all-cause death and (2) the composite of death or HF hospital admission. We also assessed the relationship of each SASP factor to 4746 other proteins, correcting for multiple comparisons, followed by pathway analyses. Two SASP factors were identified. Both factors were associated with older age, lower estimated glomerular filtration rate, and more advanced New York Heart Association class, among other clinical variables. Both SASP factors exhibited a significant positive association with the risk of death independent of the Meta-Analysis of Global-Group in Chronic HF score and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. The 2 identified SASP factors were associated with 1201 and 1554 proteins, respectively, belonging to various pathways including the coagulation system, complement system, acute phase response signaling, and retinoid X receptor-related pathways that regulate cell metabolism. Increased SASP components are independently associated with adverse outcomes in HF. Biologic pathways associated with SASP are predominantly related to coagulation, inflammation, and cell metabolism.

Clinical characteristics and prognostic impact of atrial fibrillation among older patients with heart failure with preserved ejection fraction hospitalized for acute heart failure.

Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) are often coexisting conditions, but their interrelationship has not yet been clarified. This study investigated the clinical characteristics and prognostic impact of AF among older patients with HFpEF hospitalized for acute HF (AHF). The study included patients 65years of age and older who were admitted to the Emergency Department due to AHF from 1 January 2016 to 31 December 2019. Patients were divided into two groups according to the presence of AF. The primary endpoint was all-cause, in-hospital mortality. Overall, 770 patients with HFpEF were included, mean age 82years, 53% were females. Nearly, a third (30%) of these patients had a concomitant AF and they were significantly older and had higher N-Terminal pro-B-type natriuretic peptide (NT-proBNP) values. Overall, the in-hospital mortality rate was much higher among HFpEF patients with AF compared to those without AF (11.4% vs 6.9%, respectively; p = 0.037). At multivariate analysis, AF emerged as an independent risk factor for death (OR 1.73 [1.03-2.92]; p = 0.038). Among older patients with HFpEF admitted for AHF, the coexistence of AF was associated with a nearly twofold increased risk of all-cause in-hospital mortality. Patients with HFpEF and AF describe a phenotype of older and more symptomatic patients, with higher NT-proBNP, left atrial enlargement, right ventricular dysfunction, and higher CV mortality.

A Study of Tpeak-Tend/QT Interval Ratio in Predicting Heart Failure in ST-Elevation Myocardial Infarction and Its Correlation With N-terminal Pro B-type Natriuretic Peptide (NT-proBNP).

Background Acute ST-elevation myocardial infarction (STEMI) is the most common cause of mortality across the world. The electrocardiogram (ECG) Tpeak-Tend/QT interval appears to be a measure of the left ventricle's transmural dispersion of repolarization (TDR). Prolongation of this time could indicate adverse cardiac events like heart failure, arrhythmias, etc. Heart failure is a clinical syndrome that includes signs and symptoms such as peripheral edema and high jugular vein pressure. N-terminal pro B-type natriuretic peptide (NT-proBNP) is an effective predictor of left ventricular function and also helps in predicting the disease prognosis. Elevated levels of NT-proBNP are seen in many cases of left ventricular dysfunction. This study aims to evaluate the predictive utility of the Tpeak-Tend/QT interval ratio in predicting major adverse cardiac events (MACEs), such as heart failure, by examining the Tend/QT interval ratio values with NT-proBNP in STEMI. Methodology This cross-sectional study was conducted at a tertiary hospital between April 2024 and June 2024. It included STEMI patients, excluding those with non-STEMI (NSTEMI), valvular heart diseases, bundle branch block, or pacemakers. The patients with a Tpeak-Tend/QT ratio < 0.3 were included in group A, and the Tpeak-Tend/QT ratio > 0.3 in group B. They were monitored for MACE-like heart failure during hospitalization and were compared with a study of the Tpeak-Tend/QT interval ratio in predicting heart failure in STEMI and its correlation with NT-proBNP levels. Results In this study, out of 45 patients, male predominance was observed, with 35 (78%) being men and 10 (22%) being women. In group A, the most common age group was 60-70 years, with 16 (51%) patients; in Group B, it was 50-60 years, with six (42.8%) patients. Out of 31 patients in group A, 25 were male, and six were female. In group B, out of 14 patients, 10 were male, and four were female. In this study, out of the 45 patients included, 12 (85%) among 14 patients who had MACEs like heart failure had a Tpeak-Tend/QT interval ratio of more than 0.3, and their measured NT-proBNP levels were also more than 900 pg/mL, thus showing a statistically significant association between Tpeak-Tend/QT interval ratio and NT-proBNP. Conclusion The present study showed an increased Tpeak-Tend/QT interval ratio and NT-proBNP in patients who developed heart failure in STEMI. As ECG is a readily available and affordable tool, the Tpeak-Tend/QT interval ratio can be used along with conventional markers like NT-proBNP to predict MACE in patients with STEMI.

Heart Failure Risk Assessment Using Biomarkers in Patients With Atrial Fibrillation: Analysis From COMBINE-AF

BackgroundHeart failure (HF) is common among patients with atrial fibrillation (AF), and accurate risk assessment is clinically important. ObjectivesThe goal of this study was to investigate the incremental prognostic performance of N-terminal pro–B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and growth differentiation factor (GDF)-15 for HF risk stratification in patients with AF. MethodsIndividual patient data from 3 large randomized trials comparing direct oral anticoagulants (DOACs) with warfarin (ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction 48], and RE-LY [Randomized Evaluation of Long-Term Anticoagulation Therapy]) from the COMBINE-AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) cohort were pooled; all patients with available biomarkers at baseline were included. The composite endpoint was hospitalization for HF (HHF) or cardiovascular death (CVD), and secondary endpoints were HHF and HF-related death. Cox regression was used, adjusting for clinical factors, and interbiomarker correlation was addressed using weighted quantile sum regression analysis. ResultsIn 32,041 patients, higher biomarker values were associated with a graded increase in absolute risk for CVD/HHF, HHF, and HF-related death. Adjusting for clinical variables and all biomarkers, NT-proBNP (HR per 1 SD: 1.68; 95% CI: 1.59-1.77), hs-cTnT (HR: 1.39; 95% CI: 1.33-1.44), and GDF-15 (HR: 1.20; 95% CI: 1.15-1.25) were significantly associated with CVD/HHF. The discrimination of the clinical model improved significantly upon addition of the biomarkers (c-index: 0.70 [95% CI: 0.69-0.71] to 0.77 [95% CI: 0.76-0.78]; likelihood ratio test, P < 0.001). Using weighted quantile sum regression analysis, the contribution to risk assessment was similar for NT-proBNP and hs-cTnT for CVD/HHF (38% and 41%, respectively); GDF-15 provided a statistically significant but lesser contribution to risk assessment. Results were similar for HHF and HF-related death, individually, and across key subgroups of patients based on a history of HF, AF pattern, and reduced or preserved left ventricular ejection fraction. ConclusionsNT-proBNP, hs-cTnT, and GDF-15 contributed significantly and independently to the risk stratification for HF endpoints in patients with AF, with hs-cTnT being as important as NT-proBNP for HF risk stratification. Our findings support a possible future use of these biomarkers to distinguish patients with AF at low or high risk for HF.

Improved Risk Prediction Using a Refined European Guidelines Instrument in Pulmonary Arterial Hypertension Related to Congenital Heart Disease

European guidelines advocate a goal-oriented treatment approach in pulmonary arterial hypertension (PAH), based on a comprehensive risk assessment instrument, which has been validated in several PAH subgroups. We investigated its discriminatory ability, and explored tricuspid annular plane systolic excursion (TAPSE) and revised thresholds to improve its predictability within the adult congenital heart disease (CHD) population.In total, 223 adults (42±16 years, 66% female, 68% Eisenmenger) were enrolled from five European PAH-CHD expert centers. Patients were classified as ‘Low’, ‘Intermediate’, or ‘High’ risk at baseline visit and at follow-up within 4-18 months. By the general PAH guidelines instrument, survival did not differ between the risk groups (P=n.s.), mostly due to skewed group distribution. Reclassifying patients using revised thresholds for N-terminal pro-brain natriuretic peptide (NT-proBNP) and 6-minute walk distance (6MWD) (i.e., ‘Low’, ‘Intermediate’, ‘High’ as <500, 500-1400, >1400 ng/l and >400, 165-400 and <165 m, respectively) and use of TAPSE (‘Low’, ‘Intermediate’, ‘High’ as >20, 16-20 and <16mm) significantly improved discrimination between the risk groups both at baseline and follow-up (P=0.001, ROC increase from 0.648 to 0.701), reclassifying 64 (29%) patients. Irrespective of follow-up risk group, survival was better for patients with higher proportions of low-risk variables. Improvement to a ‘Low-risk’ profile at a median of 9 months follow-up provided improved survival comparable to survival of patients who remained in the ‘Low risk’ group.In conclusion, the external validity of general risk instrument for PAH appeared to be of limited discriminatory value in PAH-CHD patients. We propose a refined risk instrument with improved discrimination for PAH-CHD.

Cardiac biomarkers and effects of aficamten in obstructive hypertrophic cardiomyopathy: the SEQUOIA-HCM trial.

The role of biomarker testing in the management of obstructive hypertrophic cardiomyopathy (oHCM) is not well defined. This pre-specified analysis of SEQUOIA-HCM (NCT05186818) sought to define the associations between clinical characteristics and baseline concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI), and to evaluate effect of treatment with aficamten on biomarker concentrations. Cardiac biomarkers were measured at baseline and serially throughout the study. Regression analyses determined predictors of baseline NT-proBNP and hs-cTnI concentrations, and to evaluate whether early changes in these biomarkers relate to later changes in left ventricular outflow tract gradient (LVOT-G), other echocardiographic measures, health status, and functional capacity. Baseline concentration of NT-proBNP was associated with LVOT-G and measures of diastolic function, while hs-cTnI was associated with left ventricular thickness. Within 8 weeks of treatment with aficamten, NT-proBNP was reduced by 79% (95% CI 83%-76%, P < .001) and hs-cTnI by 41% (95% CI 49%-32%, P < .001); both biomarkers reverted to baseline after washout. Reductions in NT-proBNP and hs-cTnI by 24 weeks were strongly associated with a lowering of LVOT-G, improvement in health status, and increased peak oxygen uptake. NT-proBNP reduction strongly correlated with the majority of improvements in exercise capacity. Furthermore, the change in NT-proBNP by Week 2 was associated with the 24-week change in key endpoints. NT-proBNP and hs-cTnI concentrations are associated with key variables in oHCM. Serial measurement of NT-proBNP and hs-cTnI appears to reflect clinical response to aficamten therapy.

Diabetes mellitus in stable chronic heart failure and the combination with humoral activation, their association, and prediction of 2-year adverse outcomes. Data from the FAR NHL registry.

The study aims to describe the role of diabetes in patients with heart failure. In all, 1052 chronic heart failure patients were included in the FARmacology and NeuroHumoral Activation (FAR NHL) multicenter prospective registry. They had ejection fraction below 50% and were on stable medication for at least 1 month. More than one-third (38.9%) of the patients had diabetes mellitus (DM). Diabetic patients (N = 409) were older (median 67 vs. 64, p < 0.001), had higher body mass index (BMI) (30 vs. 28 kg/m2, p < 0.001), much more frequently had ischemic heart disease (71 vs. 47%, p < 0.001), hypertension (80 vs. 67%, p < 0.001), dyslipidemia (89 vs. 69%, p < 0.001), worse renal function (estimated glomerular filtration rate [eGFR] median 63 vs. 73 mL/min/1.73 m2, p < 0.001), and higher N-terminal pro-brain natriuretic peptide (NT-proBNP) (median 681 vs. 463 pg/mL, p = 0.003). All-cause death, left ventricle assist device implantation, and orthotopic heart transplantation were set as the combined primary end point, which was present in 15.5% (163 patients) within the 2-year follow-up. In the 2-year follow-up, 81.0% of patients with diabetes survived without a primary end point, while 85.4% of the patients without diabetes survived, the difference being on the verge of statistical significance (p = 0.089). DM is a statistically significant predictor of NT-proBNP value in univariate analysis, but it is not an independent predictor in a multivariate analysis. When the NT-proBNP level was high, the presence of DM did not influence the prognosis. The combination of diabetes and NT-proBNP levels may better stratify the prognosis of patients with chronic heart failure.

Impact of Aficamten on Echocardiographic Cardiac Structure and Function in Symptomatic Obstructive Hypertrophic Cardiomyopathy

BackgroundAficamten, a next-in-class cardiac myosin inhibitor, improved peak oxygen uptake (pVO2) and lowered resting and Valsalva left ventricular outflow (LVOT) gradients in adults with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM), a phase 3, multicenter, randomized, double-blinded, placebo-controlled study. ObjectivesThe authors sought to evaluate the effect of aficamten on echocardiographic measures of cardiac structure and function in SEQUOIA-HCM. MethodsSerial echocardiograms were performed over 28 weeks in patients randomized to receive placebo or aficamten in up to 4 individually titrated escalating doses (5-20 mg daily) over 24 weeks based on Valsalva LVOT gradients and left ventricular ejection fraction (LVEF). ResultsAmong 282 patients (mean age 59 ± 13 years; 41% female, 79% White, 19% Asian), mean LVEF was 75% ± 6% with resting and Valsalva LVOT gradients of 55 ± 30 mm Hg and 83 ± 32 mm Hg, respectively. Over 24 weeks, aficamten significantly lowered resting and Valsalva LVOT gradients, and improved left atrial volume index, lateral and septal eʹ velocities, and lateral and septal E/eʹ (all P ≤ 0.001). LV end-systolic volume increased and wall thickness decreased (all P ≤ 0.003). Aficamten resulted in a mild reversible decrease in LVEF (−4.8% [95% CI: −6.4% to −3.3%]; P < 0.001) and absolute LV global circumferential strain (−3.7% [95% CI: 1.8%-5.6%]; P < 0.0010), whereas LV global longitudinal strain was unchanged. Several measures, including LVEF, LVOT gradients, and E/eʹ returned to baseline following washout. Among those treated with aficamten, improved pVO2 and reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP) were associated with improvement in lateral eʹ velocity and septal and lateral E/eʹ (all P < 0.03), whereas improvement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (KCCQ-CSS) was associated with a decrease in both LVOT gradients (all P < 0.001). ConclusionsCompared with placebo, patients receiving aficamten demonstrated significant improvement in LVOT gradients and measures of LV diastolic function, and several of these measures were associated with improvements in pVO2, KCCQ-CSS, and NT-proBNP. A modest decrease in LVEF occurred yet remained within normal range. These findings suggest aficamten improved multiple structural and physiological parameters in oHCM without significant adverse changes in LV systolic function. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818)

Monitoring of myocardial injury by serial measurements of QRS area and T area: The MaastrICCht cohort.

Manually derived electrocardiographic (ECG) parameters were not associated with mortality in mechanically ventilated COVID-19 patients in earlier studies, while increased high-sensitivity cardiac troponin-T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were. To provide evidence for vectorcardiography (VCG) measures as potential cardiac monitoring tool, we investigated VCG trajectories during critical illness. All mechanically ventilated COVID-19 patients were included in the Maastricht Intensive Care Covid Cohort between March 2020 and October 2021. Serum hs-cTnT and NT-proBNP concentrations were measured daily. Conversion of daily 12-lead ECGs to VCGs by a MATLAB-based script provided QRS area, T area, maximal QRS amplitude, and QRS duration. Linear mixed-effect models investigated trajectories in serum and VCG markers over time between non-survivors and survivors, adjusted for confounders. In 322 patients, 5461 hs-cTnT, 5435 NT-proBNP concentrations and 3280 ECGs and VCGs were analyzed. Non-survivors had higher hs-cTnT concentrations at intubation and both hs-cTnT and NT-proBNP significantly increased compared with survivors. In non-survivors, the following VCG parameters decreased more when compared to survivors: QRS area (-0.27 (95% CI) (-0.37 to -0.16, p < .01) μVs per day), T area (-0.39 (-0.62 to -0.16, p < .01) μVs per day), and maximal QRS amplitude (-0.01 (-0.01 to -0.01, p < .01) mV per day). QRS duration did not differ. VCG-derived QRS area and T area decreased in non-survivors compared with survivors, suggesting that an increase in myocardial damage and tissue loss play a role in the course of critical illness and may drive mortality. These VCG markers may be used to monitor critically ill patients.

Avoiding Treatment in Hospital With Subcutaneous Furosemide for Worsening Heart Failure: A Pilot Study (AT HOME-HF)

BackgroundTherapies are needed to address worsening congestion, without hospitalization, in patients with chronic heart failure (HF). ObjectivesThis pilot study assessed outcomes of a novel subcutaneous (SC) furosemide formulation compared to usual care in outpatients with worsening congestion. MethodsParticipants with chronic HF and worsening congestion were randomized open-label 2:1 to SC furosemide compared to usual care (UC). Decongestion was estimated by tracking body weight. The primary endpoint was a win ratio of a 30-day hierarchical composite of cardiovascular death, HF events, and change in N-terminal pro–B-type natriuretic peptide. Secondary endpoints included dyspnea severity, functional capacity, and quality of life. ResultsThirty-four participants were randomized to SC furosemide and 17 to UC. SC furosemide caused greater reduction in body weight: between-group difference in least square mean change was −2.02 kg at day 3 (95% CI: −3.9 to −0.14; P = 0.035). SC furosemide-to-UC win ratio was 1.11 (95% CI: 0.48-2.50; P = 0.806). Significant between-group least square mean differences favoring SC furosemide occurred in 7-point dyspnea score (P = 0.017) and 6-minute walk test (P = 0.032), with trend in Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 Overall Summary Score of 9.15 (95% CI: 1.95-20.3; P = 0.106). The most common related adverse event with SC furosemide was mild infusion site pain (11.8%). ConclusionsSC furosemide augmented weight loss in patients with HF and worsening congestion. The composite primary endpoint was not statistically significant in this pilot investigation. However, findings of improved dyspnea scores and functional capacity, with favorable trend in KCCQ-12 score, warrant additional investigation to further document the clinical value of SC furosemide as an alternative to hospitalization (AT HOME-HF [Avoiding Treatment in the Hospital With Furoscix for the Management of Congestion in Heart Failure—A Pilot Study]; NCT04593823)