Propeptide Research Articles

The Implication of NT-proBNP in the Assessment of the Clinical Phenotype of Patients with Type 2 Diabetes Mellitus, Without Established Cardiovascular Disease

Background: Natriuretic peptide (NP) levels have been proposed for characterization and risk stratification of heart failure (HF) among patients with cardiovascular disease (CVD). However, their role in patients with diabetes mellitus type 2 (T2DM) has not been well studied and understood. The aim of this study was to assess phenotypical, functional characteristics and imaging parameters in relation to N-terminal pro b-type natriuretic peptide (NT-proBNP) values in T2DM patients without known CVD that may predispose to overt HF. Methods: This was a cross-sectional study of 100 consecutive T2DM patients (mean overall age of 67 ± 9 years, 40% women and 60% men) who were enrolled from the outpatient diabetic clinic. Patients underwent a cardiopulmonary exercise test (CPET), and echocardiographic and cardiac magnetic resonance imaging (CMR); serum NT-proBNP was also measured. Results: The mean (standard deviation) NT-proBNP was 149 (±186) pg/mL. Patients in the highest tertile of NT-proBNP values (>107 pg/mL) had lower values of predicted maximum oxygen consumption compared to the lowest quartile (<55 pg/mL) (84% vs. 92%, p = 0.018) in the CPET and higher ratio of early diastolic mitral inflow velocity to early diastolic mitral annulus velocity (E/e′) (9.0 vs. 7.2, p = 0.05) in echocardiography. Finally, there was a negative correlation between right ventricle end diastolic volume in CMR and predicted maximum oxygen consumption (b = −0.225 ± 0.11, p = 0.046). Conclusions: NT-proBNP levels seemed to be a useful marker in people with T2DM, as elevated levels reflected ongoing appearance of HF with preserved ejection fraction and were related to CPET and echocardiographic indices of impaired left ventricular diastolic and right ventricular systolic function.

Characterisation of patients who develop atrial fibrillation-induced cardiomyopathy

IntroductionAtrial fibrillation (AF)-induced cardiomyopathy (AIC) is retrospectively defined after normalisation of left ventricular ejection fraction (LVEF) in sinus rhythm. It is unclear why some patients develop AIC.HypothesisPatients with AIC have...

Parenteral prostacyclin utilization in patients with pulmonary arterial hypertension in the intermediate-risk strata: a retrospective chart review and cross-sectional survey

BackgroundCurrent clinical guidelines support use of parenteral prostacyclin therapy for patients with pulmonary arterial hypertension (PAH) at intermediate risk. The objective of this study was to assess parenteral prostacyclin therapy use among patients at intermediate risk according to the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) 2.0 four-strata risk assessment model.MethodsThis was a retrospective chart review and cross-sectional online survey of healthcare professionals (HCPs). Included patients were classified as intermediate-low or intermediate-high risk per COMPERA 2.0 between 2016 and 2020 (index visit), initiated on a parenteral prostacyclin any time following intermediate risk assessment, and had World Health Organization (WHO) Functional Class (FC), 6-minute walk distance (6MWD), and B-type natriuretic peptide/N-terminal pro B-type natriuretic peptide (BNP/NT-proBNP) assessments at index and first comprehensive follow-up visits (follow-up).ResultsA total of 139 HCPs (53% community-based, 47% Pulmonary Hypertension Care Center-based) participated in the survey and provided 350 patient records; among these, mean age (SD) was 54.1 (15.3) years and 52% were female. Median (IQR) time from parenteral prostacyclin initiation to follow-up was 3.0 months (2.0, 7.0). At parenteral prostacyclin initiation for the 280 patient records with available COMPERA 2.0 assessments, 62% of patients were intermediate-high risk, 33% were intermediate-low risk and 3% were low risk, improving to 38%, 53%, and 8%, respectively, at follow-up.ConclusionsImprovements were seen for the individual COMPERA 2.0 risk calculator parameters and for several other clinical parameters. Findings from this study substantiate recent guidelines suggesting earlier use of this treatment in intermediate-risk patients with PAH.Clinical trial numberNot applicable.

Machine learning-based prediction of elevated N terminal pro brain natriuretic peptide among US general population.

Natriuretic peptide-based pre-heart failure screening has been proposed in recent guidelines. However, an effective strategy to identify screening targets from the general population, more than half of which are at risk for heart failure or pre-heart failure, has not been well established. This study evaluated the performance of machine learning prediction models for predicting elevated N terminal pro brain natriuretic peptide (NT-proBNP) levels in the US general population. Individuals aged 20-79years without cardiovascular disease from the nationally representative National Health and Nutrition Examination Survey 1999-2004 were included. Six prediction models (two conventional regression models and four machine learning models) were trained with the 1999-2002 cohort to predict elevated NT-proBNP levels (>125pg/mL) using demographic, lifestyle, and commonly measured biochemical data. The model performance was tested using the 2003-2004 cohort. Of the 10237 individuals, 1510 (14.8%) had NT-proBNP levels >125pg/mL. The highest area under the receiver operating characteristic curve (AUC) was observed in SuperLearner (AUC [95% CI]=0.862 [0.847-0.878], P<0.001 compared with the logistic regression model). The logistic regression model with splines showed a comparable performance (AUC [95% CI]=0.857 [0.841-0.874], P=0.08). Age, albumin level, haemoglobin level, sex, estimated glomerular filtration rate, and systolic blood pressure were the most important predictors. We found a similar prediction performance even after excluding socio-economic information (marital status, family income, and education status) from the prediction models. When we used different thresholds for elevated NT-proBNP, the AUC (95% CI) in the SuperLearner models 0.846 (0.830-0.861) for NT-proBNP>100pg/mL and 0.866 (0.849-0.884) for NT-proBNP>150pg/mL. Using nationally representative data from the United States, both logistic regression and machine learning models well predicted elevated NT-proBNP. The predictive performance remained consistent even when the models incorporated only commonly available variables in daily clinical practice. Prediction models using regularly measured information would serve as a potentially useful tools for clinicians to effectively identify targets of natriuretic-peptide screening.

A Proteomics-Based Approach for Prediction of Different Cardiovascular Diseases and Dementia.

Many studies have explored whether individual plasma protein biomarkers improve cardiovascular disease risk prediction. We sought to investigate the use of a plasma proteomics-based approach in predicting different cardiovascular outcomes. Among 51 859 UK Biobank participants (mean age, 56.7 years; 45.5% male) without cardiovascular disease and with proteomics measurements, we examined the primary composite outcome of fatal and nonfatal coronary heart disease, stroke, or heart failure (major adverse cardiovascular events), as well as additional secondary cardiovascular outcomes. An exposome-wide association study was conducted using relative protein concentrations, adjusted for a range of classic, demographic, and lifestyle risk factors. A prediction model using only age, sex, and protein markers (protein model) was developed using a least absolute shrinkage and selection operator-regularized approach (derivation: 80% of cohort) and validated using split-sample testing (20% of cohort). Their performance was assessed by comparing calibration, net reclassification index, and c statistic with the PREVENT (Predicting Risk of CVD Events) risk score. Over a median 13.6 years of follow-up, 4857 participants experienced first major adverse cardiovascular events. After adjustment, the proteins most strongly associated with major adverse cardiovascular events included NT-proBNP (N-terminal pro B-type natriuretic peptide; hazard ratio [HR], 1.68 per SD increase), proADM (pro-adrenomedullin; HR, 1.60), GDF-15 (growth differentiation factor-15; HR, 1.47), WFDC2 (WAP four-disulfide core domain protein 2; HR, 1.46), and IGFBP4 (insulin-like growth factor-binding protein 4; HR, 1.41). In total, 222 separate proteins were predictors of all outcomes of interest in the protein model, and 86 were selected for the primary outcome specifically. In the validation cohort, compared with the PREVENT risk factor model, the protein model improved calibration, net reclassification (net reclassification index +0.09), and c statistic for major adverse cardiovascular events (+0.051). The protein model also improved the prediction of other outcomes, including ASCVD (c statistic +0.035), myocardial infarction (+0.023), stroke (+0.024), aortic stenosis (+0.015), heart failure (+0.060), abdominal aortic aneurysm (+0.024), and dementia (+0.068). Measurement of targeted protein biomarkers produced superior prediction of aggregated and disaggregated cardiovascular events. This study represents an important proof of concept for the application of targeted proteomics in predicting a range of cardiovascular outcomes.

Exercise limitations in amyloid cardiomyopathy assessed by cardiopulmonary exercise testing-A multicentre study.

Amyloid cardiomyopathy is caused by the deposition of light chain (AL) or transthyretin amyloid (ATTR) fibrils, that leads to a restrictive cardiomyopathy, often resulting in heart failure (HF) with preserved or reduced ejection fraction. This study aimed to determine whether cardiac output reduction or ventilation inefficiency plays a predominant role in limiting exercise in patients with amyloid cardiomyopathy. We conducted a multicentre prospective study in patients with AL or ATTR cardiomyopathy who underwent cardiopulmonary exercise testing across four centres. Patients were compared with a propensity-score matched HF cohort based on age, gender, left ventricular ejection fraction (LVEF), and peak oxygen consumption (VO2). Data from 267 amyloid patients aged 77 (72, 81) years, 86% male, with a median N-terminal pro B-type natriuretic peptide (NT-proBNP) of 2187 (1140, 4383) ng/L, exercise parameters of peak VO2 of 14.1 (11.6;16.9) mL/min/kg, a minute ventilation to carbon dioxide production (VE/VCO2) slope of 37.4 (32.5, 42.6) and a LVEF of 50% (44%, 59%) were analysed. We identified 251 amyloid cardiomyopathy-HF matches. Amyloid patients had a signifnicantly higher VE/VCO2 slope [37.4, inter quartile range (IQR): 32.7, 43.1 vs. 32.1, IQR: 28.7, 37.0, P<0.0001], NT-proBNP (2249, IQR: 1187, 4420 vs. 718, IQR: 405, 2161ng/L, P<0.001), peak heart rate (121±28 vs. 115±27 beats/min, P=0.007) and peak ventilation (51, IQR: 42, 62 vs. 43, IQR: 33, 53L/min, P<0.0001) with earlier anaerobic threshold (VO2 at AT: 8.9, IQR: 6.8, 10.8 vs. 10.8, IQR: 8.9, 12.7mL/min/kg, P<0.0001) compared with HF. Between amyloid patients, AL patients (n=27) were younger (63, IQR: 58, 70 vs. 78, IQR: 72, 81years, P<0.0001), had lower VE/VCO2 slope (35.0, IQR: 30.0, 38.7 vs. 38.0, IQR: 32.8, 43.1, P=0.019), higher end-tidal carbon dioxide partial pressure both at AT (35.1±4.8 vs. 31.4±4.7mmHg, P<0.001) and peak exercise (32, IQR: 28, 35 vs. 30, IQR: 26, 33mmHg, P=0.039) as compared with ATTR (n=233). A higher VE/VCO2 slope and an earlier AT, determining functional capacity impairment, was assessed in patients with amyloid cardiomyopathy compared with the matched HF cohort. Additionally, patients with ATTR might display more severe exercise limitations as compared with AL.

Abstract 4138269: The Association Between Automatically Assessed Broad P-wave and Cardiovascular Events in Patients with Cardiovascular Risks

Background: A broad P wave in electrocardiography reflects atrial remodeling and is associated with cardiovascular events. Although there are several reports on the association between a broad P wave and cardiovascular events, the association between automatically assessed P-wave duration and cardiovascular events in cardiovascular high-risk patients has not been clarified. Hypothesis: We hypothesized that a greater automatically assessed P-wave duration would be associated with cardiovascular events in patients with cardiovascular risk factors. Methods: We included 4,654 patients with access to automated electrocardiography (ECG) analysis of those in the Cardiovascular Prognostic Coupling Study in Japan (a registry of subjects with one or more cardiovascular risk factors, excluding patients with atrial fibrillation). Twelve-lead ECG was conducted, and the P-wave duration in each lead was analyzed automatically using the 12-lead ECG Analysis system (Fukuda Denshi, Tokyo). We selected the maximum P wave duration (Pmax) among the 12 leads. The primary endpoint was a composite endpoint (cardiovascular death, nonfatal myocardial infarction/stroke), and the secondary endpoint was heart failure hospitalization. We assessed two P-wave cut-offs (Pmax ≥ 140, 150 msec) in relation to cardiovascular events. Results: There were 218 patients with Pmax ≥140 ms and 123 patients with Pmax ≥150 ms. N-Terminal pro brain natriuretic peptide (NT-proBNP) was significantly higher in patients with Pmax ≥140 ms than in those with Pmax &lt;140 ms (median 134.0 vs. 65.7 pg/mL, p&lt;0.001). NT-ProBNP was also higher in patients with Pmax ≥150 ms than in those with Pmax &lt;150 ms (median 192.0 vs. 66.9 pg/mL, p&lt;0.001). The mean follow-up period was 53 ± 17 months. The primary endpoint occurred in 180 cases and the secondary endpoint in 73 cases. A broad P-wave defined as Pmax ≥140 ms was independently associated with the primary endpoint (hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.04–2.70, p=0.034) but not with the secondary endpoint (HR 1.96, 95% CI 0.99–3.90, p=0.055) after adjustment for covariates including NT-proBNP. A broad P-wave defined as Pmax ≥150 ms was independently associated with both the primary endpoint (HR 2.08, 95% CI 1.06–4.09, p=0.034) and the secondary endpoint (HR 3.22, 95% CI 1.38–7.52, p=0.007). Conclusions: Automatically assessed P-wave duration of Pmax ≥ 150 ms was a significant predictor of cardiovascular events and heart failure.

Abstract 4125729: Elevated Pre-Procedural Serum Natriuretic Peptide Levels Are Associated with All-Cause Mortality in Patients Undergoing Transcatheter Edge-to-Edge Mitral Valve Repair: A Systematic Review and Meta-Analysis

Background: Transcatheter edge-to-edge mitral valve repair (TEER) is an established procedure in patients with severe mitral regurgitation (MR) and elevated surgical risk on optimal medical therapy. However, there remains considerable mortality in this patient population. Some studies have shown that serum brain natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) predict all-cause mortality after TEER, whereas other studies have shown mortality to be independent of these markers. To address this gap in knowledge, we sought to examine the existing literature to determine whether there is an association between pre-procedural serum natriuretic peptides and mortality after TEER. Hypothesis: Among patients undergoing TEER, elevated pre-procedural BNP and NT-proBNP are associated with increased all-cause mortality. Methods: Databases including MEDLINE, Embase, and Cochrane Library were searched from inception through September 2023 for studies assessing pre-procedural serum natriuretic peptide levels and mortality among patients undergoing TEER. Pooled hazard ratios (HR) and standardized mean differences (SMD) were calculated using a random-effects model estimated by restricted maximum likelihood with the Hartung-Knapp modification. Results: A total of 30 studies comprising 10259 patients undergoing TEER met inclusion criteria. 25 studies measured NT-proBNP and 5 studies measured BNP. Elevated pre-procedural NT-proBNP (&gt;5000 or &gt;10000 pg/mL) was associated with increased all-cause mortality in both adjusted (HR = 2.94; 95% CI = 1.75 - 4.95; I2 = 46.8%) and unadjusted (HR = 5.16; 95% CI = 1.85 - 14.40; I2 = 0.0%) analyses (Figures 1 and 2). Pre-procedural BNP and NT-proBNP were also significantly lower among survivors at 12 months compared to non-survivors (SMD = 0.82; 95% CI = 0.37 - 1.27; I2 = 78.3%) (Figure 3). This association was demonstrated in patients with primary or secondary MR. Conclusions: Pre-procedural BNP and NT-proBNP levels are significant predictors of all-cause mortality in patients undergoing TEER for primary or secondary MR. This supports the inclusion of BNP or NT-proBNP in pre-procedural assessments to help inform patient discussions and guide post-procedural follow-up and monitoring.

CSIG-05. IS THERE ANY BRAIN TUMOR PREDISPOSITION IN RELATED PALLISTER-HALL SYNDROMES AT THE NEW GENOMICS ERA

Abstract Pallister-Hall Syndrome (PHS) and its related syndromes are a spectrum of congenital malformations. They are associated to GLI3 mutations and specific brain tumors. Considered as lethal, it is now well established that this disease may be miss-diagnosed with the report of adult cases. Here, we discuss the management of the genetic counselling and the risk of neurologic tumor predisposition in GLI3-related PHS. We comprehensively reviewed the scientific literature using various databases to explore the risk of neurologic tumors and evolving practice of neuro-cancer genetic counseling in GLI3-related PHS. The review of literature showed that GLI3 is involved in tissue development as well as in cancer. GLI3 was identified as either a pro or anti-cancerous protein. In fact, GLI3 is described as upregulated in multiple cancers and is found to positively regulate malignant behavior. In neuro-oncology GLI gene was first identified as a highly expressed gene in human glioma and then as having an anti-cancerous role in medulloblastoma where GLI3 seems act as a tumor suppressor. In mutational studies, GLI3-germinal mutations are characterized by a high recurrence of hypothalamic hamartoma in syndromic patients. GLI3-somatic alterations have been also demonstrated in cell samples of patients with non-syndromic hypothalamic hamartoma. In addition, while inactivation of GLI3 is suggested to be associated with medulloblastoma, mutations are not common in sporadic medulloblastoma. The association of germinal GLI3 variants in syndromic patients with medulloblastoma has been identified in only one patient harboring GLI3 H302X variant. Our review permitted us to conclude that germline GLI3 mutations may predispose to a specific non-severe form of delayed hypothalamic hamartoma, which can be revealed in pauci or asymptomatic and unrecognized mutated individuals. The likelihood of having a neuro-cancer predisposition in GLI3 mutated families seems to be insignificant.

Phase 3 Open-Label Study Evaluating the Efficacy and Safety of Mavacamten in Japanese Adults With Obstructive Hypertrophic Cardiomyopathy - The HORIZON-HCM Study.

Mavacamten, a cardiac myosin inhibitor, significantly improved symptoms and cardiac function vs. placebo in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) in EXPLORER-HCM. However, the efficacy and safety profiles of mavacamten in Japanese patients are unclear. HORIZON-HCM is a Phase 3 single-arm study in Japanese patients with symptomatic obstructive HCM. The mavacamten starting dose was 2.5 mg; individualized dose titration occurred in Weeks 6-20 based on Valsalva left ventricular outflow tract (LVOT) gradient and resting left ventricular ejection fraction (LVEF). Overall, 38 patients were treated; 36 completed the 30-week primary treatment analysis period. Clinically significant improvements in postexercise LVOT gradient were observed after 30 weeks of treatment (mean change from baseline -60.7 mmHg). Improvements in N-terminal pro B-type natriuretic peptide, New York Heart Association class, and Kansas City Cardiomyopathy Questionnaire-23 Clinical Summary Score were observed over 30 weeks, and mean LVEF was ≥74% at all visits. Treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 63.2% and 7.9% of patients, respectively; none resulted in treatment discontinuation. One patient experienced a transient asymptomatic reduction in LVEF to <50%. No deaths occurred during the study. In Japanese patients with obstructive HCM, mavacamten was associated with similar improvements in LVOT gradients, cardiac biomarkers, and symptoms to those observed in EXPLORER-HCM. Treatment was well tolerated with no new safety concerns.

NT-proBNP improves prediction of cardiorenal complications in type 2 diabetes: the Hong Kong Diabetes Biobank.

N-terminal pro B-type natriuretic peptide (NT-proBNP) is a natriuretic peptide that is strongly associated with congestive heart failure (CHF). The utility of NT-proBNP for prediction of cardiovascular events and renal endpoints, compared with clinical risk factors, has not been evaluated in detail. We hypothesise that NT-proBNP can improve risk stratification and prediction of cardiorenal events in type 2 diabetes, beyond that provided by clinical risk factors. NT-proBNP was measured in 1993 samples from the Hong Kong Diabetes Biobank, a multicentre prospective diabetes cohort and biobank. A cut-off of ≥125 pg/ml was used to define elevated NT-proBNP. Associations between elevated NT-proBNP and incident cardiovascular and renal endpoints were examined using Cox regression, adjusted for sex, age and duration of diabetes, as well as other covariates. Prognostic and incremental predictive values of NT-proBNP in diabetes cardiorenal complications, compared with those of the Joint Asia Diabetes Evaluation risk equations for CHD, CHF and kidney failure, were evaluated using the concordance index (C index), net reclassification improvement index, integrated discrimination improvement index and relative integrated discrimination improvement index. A total of 24.7% of participants had elevated NT-proBNP. Participants with elevated NT-proBNP at baseline had a more adverse cardiometabolic profile, with 2-4-fold higher frequency of complications at baseline. Adjusting for age at baseline, sex and duration of diabetes, elevated NT-proBNP was associated with incident atrial fibrillation (HR 4.64 [95% CI 2.44, 8.85]), CHD (HR 4.21 [2.46, 7.21]), CVD (HR 3.32 [2.20, 5.01]) and CHF (HR 4.18 [2.18, 8.03]; all p<0.001). All these associations remained significant after further adjustment for additional covariates. Elevated NT-proBNP had good discriminative ability for various cardiorenal endpoints, with C index of 0.83 (95% CI 0.76, 0.90) for CHD, 0.88 (0.81, 0.94) for atrial fibrillation, 0.89 (0.83, 0.95) for CHF, 0.81 (0.77, 0.84) for 40% drop in eGFR and 0.88 (0.84, 0.92) for kidney failure. Models incorporating NT-proBNP had improved prediction compared with established clinical risk models. Sensitivity analyses including alternative cut-off of NT-proBNP, as well as use of other risk engines of CHD, yielded similar results. NT-proBNP demonstrated a promising ability to serve as a prognostic marker for a variety of cardiorenal complications in type 2 diabetes. Considering NT-proBNP in clinical assessments could potentially help identify high-risk individuals who may benefit from more intensive therapies.

Preoperative D-dimer and outcomes in obstructive hypertrophic cardiomyopathy after myectomy

BackgroundThe prognostic significance of D-dimer in patients with hypertrophic cardiomyopathy undergoing septal myectomy has not been well established. MethodsWe retrospectively analyzed D-dimer levels in 728 patients who underwent septal myectomy at our hospital between 2009 and 2018. Baseline D-dimer levels were categorized into tertiles (<0.21, 0.21–0.3, ≥0.3 mg/L) The primary and secondary endpoints were all-cause mortality and cardiovascular mortality, respectively. Cox regression and competing risk models were used to evaluate risk factors for all-cause and cardiovascular mortality, respectively. ResultsHigher D-dimer levels were associated with older age, female sex, more severe mitral regurgitation, and elevated N-terminal pro B-type natriuretic peptide levels (P < 0.05). Over a median follow-up of 4.2 years, 31 (4.3 %) patients reached the primary endpoint; 23 deaths were attributed to cardiovascular causes. The optimal cutoff D-dimer level for predicting 5-year mortality was 0.29 mg/L. After adjusting for covariates, D-dimer levels of >0.29 mg/L were significantly associated with an increased risk of all-cause mortality (hazard ratio [HR], 3.12; 95 % confidence interval [CI], 1.42–6.86; p = 0.005) and cardiovascular mortality (HR, 3.29; 95 % CI, 1.12–9.62; p = 0.030). Body mass index and left atrial diameter were also independent predictors of both all-cause mortality (HR, 1.12; p = 0.026, and HR, 1.08; p = 0.006, respectively) and cardiovascular mortality (HR, 1.12; p = 0.043, and HR, 1.11; p = 0.004, respectively). The inclusion of D-dimer levels of >0.29 mg/L improved the net reclassification index for all-cause mortality (p = 0.016). ConclusionD-dimer is a robust predictor of mid-to-long-term all-cause and cardiovascular mortality in patients undergoing septal myectomy.

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

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

Implication of heart rhythm complexity in predicting long-term outcomes in pulmonary hypertension

Pulmonary hypertension (PH) is a serious disease, however simple tools to predict outcomes are lacking. In our previous investigation, we found that heart rate variability (HRV) and heart rhythm complexity (HRC) were associated with the detection and severity of PH, however their association with PH mortality remains unclear.The aim of this study was to investigate these metrics as a tool for determining long-term outcomes in PH patients. We enrolled 74 Asian PH patients with WHO PH group 1 or 4 at a single hospital in Taiwan between March 2012 and June 2018. After a median follow-up duration of 58 months (to January 2023), 22 patients had died. The patients who died had a significantly lower lean body mass index (BMI), impaired renal function, higher N-terminal pro B-type natriuretic peptide (NT-proBNP) level, lower very low-frequency (VLF), lower short-term detrended fluctuation analysis α1 (DFAα1), and lower multiscale entropy scale 5 value. In multivariable analysis, BMI, VLF and multiscale entropy scale 5 were significantly associated with survival. The best cut-off VLF and scale 5 values were 115.13 and 0.738, respectively. We then categorized the study population into three groups: both elevated VLF/scale 5 (group 1), either depressed VLF or depressed scale 5 (group 2), and both depressed VLF/scale 5 (group 3). The results showed that group 1 had the best outcomes, whereas group 3 had the worst survival (P < 0.001).Combining HRV and HRC metrics appears to be a good non-invasive tool to predict the long-term outcomes of patients with PH.

Prognostic utility and cutoff differences of NT-proBNP level across subgroups in heart failure with preserved ejection fraction: Insights from the PURSUIT-HFpEF Registry

ObjectivesN-terminal pro brain natriuretic peptide (NT-proBNP) is a biomarker for myocardial stress used in diagnosing and prognosticating heart failure (HF). However, its interpretation is complicated by clinical factors. This study aims to clarify the prognostic value of NT-proBNP in patients with heart failure with preserved ejection fraction (HFpEF), and risk-prediction cutoffs considering various clinical factors. MethodsThe study utilized data of prospective multicenter observational Asian HFpEF registry. Patients with acute decompensated HF and left ventricular ejection fraction ≥ 50% were included. NT-proBNP levels were measured at discharge. The primary endpoint was a composite of all-cause death and hospitalization for HF within 1 year after discharge. ResultsA total of 1,231 patients (83 [77, 87] years, 551 (45%) male) were enrolled, with 916 eligible patients analyzed. The median NT-proBNP level was 1,060 pg/m. In multivariable logistic regression model, NT-proBNP was significantly associated with the primary endpoint (adjusted OR for log-transformed NT-proBNP:2.71, 95%CI:1.78-4.18, p<0.001). Subgroup analysis revealed varying NT-proBNP distributions and differential safety cutoffs (329-929 pg/mL) at sensitivity of 0.8 based on factors like atrial fibrillation and chronic kidney disease, maintaining its discriminatory performance (Area under the curve: 0.587-0.734). ConclusionsNT-proBNP at discharge is a significant prognostic marker for HFpEF. Although NT-proBNP showed different distributions in various subgroups and cutoff values were distinctive for each, the prognostic utility was found to be equivalent in almost all subgroups with similar moderate discriminative performance. The study highlights the necessity of personalized NT-proBNP cutoffs for better management and prognostication of HFpEF.

The in-hospital administration of sacubitril/valsartan in acute myocardial infarction: A meta-analysis.

There is a need to address the evidence gap regarding the in-hospital administration of sacubitril/valsartan in acute myocardial infarction patients. After searching MEDLINE, Google Scholars and Scopus, a random-effects meta-analysis of randomized controlled trials comparing the in-hospital administration of the angiotensin receptor-neprilysin inhibitors (ARNis) versus the standard therapy in patients with reduced heart failure due to myocardial infarction was performed. The primary outcome was major adverse cardiovascular events. All-cause mortality, cardiac death, rehospitalization for heart failure, non-fatal myocardial infarction (MI), changes in left ventricular ejection fraction, left ventricular volumes, N terminal pro brain natriuretic peptide and adverse events were the secondary endpoints. Nine studies (eight randomized controlled trials and one echo-substudy) with a total 6597 individuals (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker: 3300 patients vs. ARNis: 3297 patients) were included for quantitative analysis. Median follow-up was 6months. Patients receiving an in-hospital coadministration of ARNi had a lower risk of major cardiovascular event [odds ratio (OR) 0.45, 95% confidence interval (CI) 0.32-0.63, P<0.0001] and lower rate of repeat rehospitalization for heart failure (OR 0.40, 95% CI 0.26-0.62, P<0.0001), compared with a standard regimen. Additionally, left ventricle volumes were significantly lower in the ARNi group [left ventricular end-diastolic volume, mean difference (MD) 11.48mL, 95% CI 6.10-16.85, P<0.0001; left ventricular end-systolic volume, MD 7.09mL, 95% CI 2.89-11.29, P=0.0009] with a significant change in left ventricular ejection fraction (MD 3.07, 95% CI 1.61-4.53, P<0.0001), compared with standard therapy. No significant differences were observed in terms of cardiac death, all cause of mortality, non-fatal myocardial infarction and N terminal pro brain natriuretic peptide. Higher rates of iatrogenic hypotensive events were observed in the ARNi group compared with the standard therapy (OR 1.42, 95% CI 1.26-1.60, P value<0.00001). In patients with acute myocardial infarction related heart failure, the in-hospital administration of ARNis was associated with a reduced risk of major cardiovascular events and re-hospitalization for heart failure, as well as cardiac remodelling, but higher rates of hypotensive events compared with standard therapy.

Integrated, person-centred care for patients with complex cardiovascular disease, diabetes mellitus and chronic kidney disease: a randomized trial.

Patients with cardiovascular disease (CVD), diabetes mellitus (DM) and chronic kidney disease (CKD) often experience fragmented care, which negatively impacts outcomes and health-related quality of life (HRQoL). This study assessed whether multidisciplinary, person-centred care at an integrated clinic improves clinical outcomes and HRQoL. This prospective, open, blinded-endpoint trial (CareHND; NCT03362983) included 131 patients with CVD, DM and CKD stages 3-4, most of whom were enrolled during or shortly after acute hospitalization. The intervention group received person-centred care from cardiologists, nephrologists, endocrinologists and specialist nurses at an integrated clinic; the control group received traditional care from separate specialists. Primary disease progression outcome was the composite of major adverse renal and cardiovascular events (MARCE) including death, heart failure (HF) readmission, myocardial infarction, percutaneous coronary intervention/coronary artery bypass graft, acute or end-stage kidney failure, or transient ischaemic attack/stroke at 2 years. Co-primary person-centred outcomes was self-reported HRQoL by RAND-36. In a pre-specified interim analysis, patients randomized to integrated care had lower estimated glomerular filtration rate and higher NT-proBNP (N-terminal pro brain natriuretic peptide) than traditional care. Follow-up ranged from 2.0 to 5.7 years. Kaplan-Meier analysis showed no difference in MARCE between groups. Cox-regression adjusting for baseline differences, indicated a trend towards reduced HF hospitalizations for integrated care (hazard ratio 0.53; confidence interval 0.28-1.01; P=.054). Integrated care improved role physical and social function scores, and self-rated health (P=.021, P=.019 and P=.011, respectively). Integrated care improved several dimensions of HRQoL but did not improve MARCE compared with traditional care in this small trial. We observed a trend towards reduced HF hospitalizations. Overall, integrated care presents a promising alternative.

Changes in N-terminal pro b-type natriuretic peptide according to SGLT2 inhibitor utilization patterns in patients hospitalized for decompensated heart failure: a prospective cohort study

Abstract Introduction Sodium-glucose cotransporter-2 (SGLT2) inhibitors have found success in treating patients with chronic heart failure (HF) across the entire spectrum of left ventricular ejection fraction (EF). Their benefits may also extend to patients with acute HF decompensation, as they may aid effective decongestion. Purpose This study aims to present the various patterns in changes of N-terminal pro b-type natriuretic peptide (NT-proBNP) according to SGLT2 inhibitor use in patients hospitalized for acute HF decompensation. Methods In this prospective cohort study, we enrolled consecutive patients hospitalized for HF decompensation during a 4-month period in a cardiology department. Prior medical history and cardiovascular risk factors were recorded. The patterns in SGLT2 inhibitor use were noted and patients were classified into three groups; Group 1 (No SGLT2 inhibitor use/Discontinuation), Group 2 (Prior SGLT2 inhibitor use and continuation), and Group 2 (SGLT2i-naïve and initiation). Categorization according to left ventricular (EF) to HF with reduced EF (HFrEF), HF with mildly reduced EF (HFmrEF), and HF with preserved EF (HFpEF) was also performed. Moreover, estimated glomerular filtration rate (eGFR) was used as an estimate of renal function. Results In this analysis, 159 patients were included (median age: 79 years old, male sex: 64.8%, median duration of hospitalization: 6 days). In this population, 67.9% of the patients were not receiving a SGLT2 inhibitor on admission. Concerning demographic and clinical variables (Figure 1), there were no major differences in age, sex distribution, history of diabetes mellitus, dyslipidemia, and atrial fibrillation, as well as in renal function. Group 2 patients had a lower prevalence of arterial hypertension compared to Group 3 (36.6% vs. 52.6%, p&amp;lt;0.05). Moving to the changes in NTproBNP (Figure 2), we observed that patients who did not use SGLT2 inhibitors and did not initiate them during hospitalization had negligible changes in NTproBNP, either as an absolute change (Group 1: 506 (8792) pg/ml vs. Group 2: -5610 (9461) pg/ml vs. Group 3: -3602 (4409) pg/ml, p=0.001) or as percentage change (Group 1: -2.1 (63.4) % vs. Group 2: -30.3 (39.0) % vs. Group 3: -38.3 (41.5) %, p=0.001), compared to the rest of the study population who were already taking SGLT2 inhibitors or initiated them during hospitalization. Conclusion In this study we found NTproBNP, a widely used biomarker of congestion and prognosis in HF, was significantly reduced in decompensated HF patients receiving SGLT2 inhibitors, with the greatest change being observed in those being treatment-naïve prior to admission. These findings further highlight the role of this drug class even in the acute phase of the disease.Figure 1Figure 2

Eicosanoids in coronary sinus negatively correlate with natriuretic peptides in heart failure with reduced ejection fraction: insights from Eicosanoids in Human Heart Failure Study

Abstract Background The diagnostic and therapeutic potential of eicosanoids, metabolites of arachidonic acid with positive cardio-renal activity in preclinical heart failure models, remains unclear in human chronic heart failure with reduced ejection fraction (HFrEF). Purpose The aim of this part of a traslational Eicosanoids in Human Heart Failure Study was to investigate levels of eicosanoids in different body compartments and their relation to natriuretic peptides. Methods Eleven consecutive patients with HFrEF indicated to cardiac resynchronisation therapy (CRT) were enrolled to measure plasmatic 14,15-epoxyeicosatrienoic acid (14,15-EET) and 14,15-dihydroxyicosatrienoic acid (14,15-DHET) levels from venous, arterial, and coronary sinus (CS) blood samples and correlate them with N-terminal pro B-type natriuretic peptide (NT-proBNP) from the same compartments. Results In CS, NT-proBNP levels negatively correlated with plasmatic 14,15-EET levels (r = -0.63, p = 0.03) and positively with the DHET/EET ratio (r = 0.73, p = 0.02). This correlation was not found in the other compartments. Plasmatic 14,15-EET nor 14,15-DHET levels in measured compartments did not differ statistically (p = 0.21, p = 0,64, respectively). In individual patients, the levels of both eicosanoids correlated across all compartments. Peripheral plasma 14,15-EET levels in controls were lower compared to HF patients. Conclusion Peripheral venous eicosanoid (14,15-EET, 14,15-DHET) levels correlate and do not differ from arterial and CS levels in patients with HFrEF indicated to CRT. In CS, NT-proBNP levels negatively correlated with plasmatic 14,15-EET levels and positively with the DHET/EET ratio, an indirect soluble epoxide hydrolase activity parameter.Graphical AbstractFigures

Development and validation of a predicting model for risk of rehospitalization within 30 days in heart failure patients with preserved ejection fraction

Abstract Objective This study aimed to develop and validate a predicting model for risk of rehospitalization within 30 days post discharge in patients diagnosed with Heart Failure with Preserved Ejection Fraction (HFpEF). Methods Clinical data of 9555 HFpEF patients registered in the heart failure registry from 2014 to 2022 at our hospital were analyzed. A total of 8160 patients (from 2014-2021) were designated as the training set, and 1395 patients (from 2022) as the validation set. A predictive model was established based on risk factors associated with 30-day rehospitalization due to heart failure identified by the Least Absolute Shrinkage and Selection Operator (LASSO) regression and logistic regression analysis. The model's stability was ensured through Bootstrap internal validation and Temporal validation external validation. Results LASSO and logistic regression analyses identified eight risk factors associated with increased risk of 30-day rehospitalization, including New York Heart Association (NYHA) classification, albumin, c-reactive protein, N-terminal pro b-type natriuretic peptide (NT-proBNP) divided by 100, anemia, pleural effusion, atrial fibrillation, and pulmonary hypertension. The established predictive model demonstrated good discriminative ability in the internal validation with an Area Under the Curve (AUC) value of 0.714, and a 95% confidence interval (CI) of 0.693-0.736 after 500 Bootstrap replicates. In the Temporal validation external validation, the model exhibited robust stability with an AUC value of 0.740 and a 95% CI of 0.693-0.781. When compared to analogous models from prior studies, present model showcased superior predictive accuracy in that both Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI) values were positive and within their respective 95% confidence intervals (P-values &amp;lt;0.05). Conclusion This study successfully developed and validated a predictive model for 30-day rehospitalization due to heart failure in patients diagnosed with HFpEF. This model might allow the timely identification of high-risk HFpEF patients for 30-day rehospitalization due to heart failure and optimizes the patient management accordingly.