NT-proBNP Research Articles

A clinical challenge of cardiomyopathies: Beyond the heart

Introduction: The relation between the cancer and the heart is diverse. It can be affected all parts of the heart directly or indirectly caused by the systemic manifestation of the cancer or by cancer therapy. Paraneoplastic dermatomyositis and tumor lysis syndrome (TLS) are two examples of systemic manifestations of cancer. Being systemic, the cardiovascular system can be affected. Heart failure and arrhythmias are the main cardiac manifestations. Case Report: A 68-year-old man with a recent diagnosis of diffuse large B-cell lymphoma waiting to begin chemotherapy, and paraneoplastic dermatomyositis, presented at the emergency department (ED) with palpitations and dyspnea with a week of evolution. At the physical examination, he presented with pulmonary edema and the novo rapid atrial fibrillation. Also, an Nt-pro BNP of 8957 pg/mL, and echocardiography with severe dilated left ventricle, with a severe reduced ejection fraction. Already in the ward, the patient developed a spontaneous TLS. The etiological interpretation was that paraneoplastic dermatomyositis and TLS were the triggers of atrial fibrillation (AF). Then, the combination of them was responsible for development of the dilated cardiomyopathy (tachymyocardiopathy). The chemotherapy regimen was changed to R-CEOP (Rituximab, cyclophosphamide, etoposide, vincristine sulfate, and prednisone). Conclusion: This clinical case perfectly shows how the world of cardiomyopathies can be challenging and hard to understand all the complexity of the patients.

Diagnosis and management of a more advanced stage of preclinical myxomatous mitral valve disease in dogs without echocardiography.

Myxomatous mitral valve disease (MMVD) is the most common cardiac disease in dogs. Appropriate diagnosis and staging can be performed by means of an echocardiographic examination. Early disease stages might be accompanied by valvular insufficiency and, in more advanced phases, by cardiac dilatation. A correct diagnosis of this preclinical phase and identification of cardiac enlargement should be carried out in order to advise appropriate medical treatment. When echocardiography is not available or declined by the dog's owners, alternative methods to identify the disease and predict clinically relevant cardiomegaly, can be performed. Among these, cardiac auscultation and assessment of heart murmur intensity, cardiac dimensions obtained by thoracic radiography, by means of vertebral heart size, and cardiac biomarkers, in particular N-terminal pro-B-type natriuretic peptide (NT-proBNP), can be carried out as single tests or in combination, in order to identify dogs with increased risk of congestive heart failure, and needing an early treatment with pimobendan. In particular, a heart murmur intensity ≥3/6 (moderate or louder), a vertebral heart size ≥11,5 units obtained from a latero-lateral thoracic radiographic view, and plasma concentrations of N-terminal pro-B-type natriuretic peptide value > 1100 pmol/l, are findings that might suggest presence of clinically relevant cardiomegaly with a good specificity. A practical algorithm to guide clinicians in managing dogs with suspicion of valvular disease has been created, starting from clinical examination, and using the aforementioned additional tests in order to advise the appropriate controls and therapy.

Mitral valve transcatheter edge-to-edge repair in the elderly-A safe and effective therapy.

Prevalence of mitral regurgitation (MR) and comorbidity burden rise with age. Mitral valve transcatheter edge-to-edge repair (M-TEER) is increasingly performed in elderly patients, but only limited data are available for this specific subgroup. In this study, outcomes of octogenarians and nonagenarians undergoing M-TEER were analysed using a large real-world dataset. This retrospective study included consecutive patients undergoing M-TEER at the Ulm University Heart Center between January 2010 and December 2021. The cohort was divided into an elderly group and a younger group based on the cohorts' median age. Group differences regarding 1 and 3year mortality and heart failure hospitalization rates were assessed using Kaplan-Meier survival analysis and Cox proportional hazard models. A total of 1118 patients [median age 79 (inter-quartile range 74-83) years; 42% female] were included and divided into 513 elderly (≥80years) and 605 younger (<80years) patients. Primary MR was more frequent in the elderly group (56% vs. 27%, P<0.001). Pre-procedural and post-procedural MR grades were comparable between groups (pre-procedural MR grade 4: 69% in the elderly group vs. 71% in the younger group, P=0.67; post-procedural MR grade 1: 60% in the elderly group vs. 58% in the younger group, P=0.77) as well as in-hospital mortality rates (0.2% vs. 0.3%, P=0.66). Three-year heart failure hospitalization rates did not differ significantly between both groups (30.7% in the older age cohort vs. 36.0% in the younger cohort, P=0.191). While 1year all-cause mortality rates were comparable (18% vs. 16.4%, P=0.577), 3year all-cause mortality was significantly higher in the elderly [43.1% vs. 33.0%; hazard ratio (HR) 1.29 (95% confidence interval 1.02-1.65), P=0.035]. Pre-procedural N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥3402pg/mL [HR 2.29 (95% CI 1.34-3.90), P=0.002], pre-interventional MR grade [HR 1.79 (95% CI 1.01-3.17), P=0.045] and European System for Cardiac Operative Risk Evaluation (EuroSCORE) II [HR 1.06 (95% CI 1.03-1.08), P<0.001] were identified as independent predictors of 3year mortality in the elderly. M-TEER displays a safe and effective treatment option for elderly patients with symptomatic MR, offering symptom relief and comparable 1year outcomes to younger patients. Elderly patients with elevated EuroSCORE II and advanced heart failure might benefit from additional care to further reduce 3year mortality.

The effect of trimetazidine on cardiac haemodynamics and mitochondrial function in wild-type transthyretin amyloidosis.

Wild-type transthyretin cardiac amyloidosis (ATTRwt) is a cardiomyopathy causing myocardial hypoperfusion and impaired cardiac mitochondrial function. Trimetazidine is an antianginal agent used in patients with stable angina pectoris, which improves cardiac contractility and mitochondrial function. The aim of the study was to investigate the effect of trimetazidine on invasive haemodynamics and cardiac mitochondrial function in ATTRwt. In a randomized, double-blind, placebo-controlled, crossover trial, 22 patients with ATTRwt received 4weeks of trimetazidine and placebo in randomized order. After each treatment period followed examinations with endomyocardial biopsies taken for high-resolution respirometry and right heart catheterization at rest and during a cardiopulmonary exercise test. The primary endpoint was mean pulmonary artery wedge pressure (mPAWP) during peak exercise. The secondary endpoint was cardiac mitochondrial oxidative phosphorylation capacity. Exploratory endpoints were echocardiographic parameters, cardiac biomarker levels and quality of life. Trimetazidine did not significantly reduce mPAWP during peak exercise (31±12 vs. 31±13mmHg, P=0.61) or improve the cardiac mitochondrial oxidative phosphorylation capacity (73.4±7.7 vs. 75.3±7.7pmol O2/(mg*s), P=0.81) compared with placebo, nor did treatment with trimetazidine improve ejection fraction (P=0.93), global longitudinal strain (P=0.23), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (P=0.92) or the patients' quality of life (P=0.98). In ATTRwt, treatment with trimetazidine did not improve mPAWP or cardiac mitochondrial oxidative phosphorylation capacity compared with placebo.

Effect of optimisation to contemporary HFrEF medical therapy with sacubitril/valsartan (Entresto) and dapaglifloziN on left Ventricular reverse remodelling as demonstrated by cardiac magnetic resonance (CMR) Imaging: the ENVI study

IntroductionHeart failure with reduced ejection fraction (HFrEF) guidelines recommend ‘four pillars’ of medical therapy and device therapy if left ventricular ejection fraction (LVEF) remains ≤35% after 3 months optimum medical...

Real-life experience with disease-modifying drugs in hereditary transthyretin amyloid polyneuropathy: A clinical and electrophysiological appraisal.

New treatments have dramatically improved the prognosis for Hereditary Transthyretin Amyloid Polyneuropathy (ATTRv-PN). However, there is a lack of routine follow-up studies outside of therapeutic trials. Our aim was to report the long-term clinical and electrophysiological evolution of a cohort of ATTRv-PN patients and to determine which biomarkers are most sensitive to change. We retrospectively collected neuropathy impairment scale (NIS), polyneuropathy disability scale (PND), overall neuropathy limitation scale (ONLS), rash built overall disability scale (RODS), electrodiagnostic data, motor unit number index (MUNIX), troponin and N-terminal pro-brain natriuretic peptide levels. Electrophysiological worsening was defined as a 20% decrease in previous values. Thirty-five patients, with a median age of 58 (interquartile ranges 42-71) years, were followed for a median of 36 (24-48) months. All patients received a transthyretin stabiliser, gene silencer or liver transplant. Overall assessment of the cohort showed clinical, biological and electrophysiological stability. However, on an individual basis, NIS worsened in 45% of patients (14/31), ONLS in 46% (13/28), PND in 28% (9/32) and RODS in 39% (11/28) at the last follow-up. Motor amplitude sum score decreased in 33% (11/33), amplitude recorded on tibialis anterior muscle in 44% (12/27), sensory amplitude sum score in 39% (11/28) and MUNIX sum score in 27% (7/26). Overall effectiveness of ATTRv-PN treatments in routine care is good. However, individual assessments show up to 40% deterioration over time. Electrophysiological measures are valuable monitoring tools but are not more sensitive to change than clinical scores. Results must be confirmed in larger cohorts.

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 (&gt;107 pg/mL) had lower values of predicted maximum oxygen consumption compared to the lowest quartile (&lt;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...

Analysis of the clinical characteristics of patients with Kawasaki disease complicated with cholestasis

BackgroundTo explore the clinical characteristics, related factors, and prognosis of Kawasaki disease (KD) combined with acute febrile cholestasis and improve the understanding of the liver complications of KD to avoid misdiagnosis and missed diagnosis.MethodsWe retrospectively analyzed the demographic, clinical, and laboratory data of 1803 patients with KD between January 2019 and July 2023 in our hospital. Based on the presence of cholestasis, patients were divided into the cholestatic and control groups. Logistic regression analysis was performed for the statistically significant indicators between the two groups to examine the risk factors for KD with coronary artery abnormalities (CAA) and intravenous immunoglobulin (IVIG) unresponsiveness. Additionally, patients with KD and cholestasis were compared with patients with acute febrile cholestasis due to other causes during the same period.ResultsCompared to the control group (n = 1720), patients in the cholestatic group (n = 83) were older, had higher levels of white blood cell count (WBC), C-reactive protein (CRP), D-dimer, N-terminal pro-brain natriuretic peptide (NT-proBNP), a shorter fever duration, and high incidences of IVIG unresponsiveness and CAA. KD was the leading cause of acute febrile cholestasis in children (72.6%). In the multivariate logistic regression analysis, younger age, cholestasis, hypoalbuminemia, and a high NT-proBNP level were risk factors for IVIG unresponsiveness, whereas male sex, longer fever duration before treatment, and high alanine aminotransferase (ALT), and CRP levels were risk factors for CAA.ConclusionKD with cholestasis was associated with a higher risk of IVIG unresponsiveness and coronary artery abnormalities. KD was the leading cause of acute febrile cholestasis in children. Attention to the possibility of KD is warranted in children with acute febrile cholestatic jaundice, especially if associated with elevated WBC, CRP, and D-dimer levels, or hypoalbuminemia.

Multimodal Data-Driven Prognostic Model for Predicting Long-Term Prognosis in Patients With Ischemic Cardiomyopathy and Heart Failure With Preserved Ejection Fraction After Coronary Artery Bypass Grafting: A Multicenter Cohort Study.

Limited data from the literature are available to assess the efficacy of coronary artery bypass grafting in patients with ischemic cardiomyopathy and heart failure with preserved ejection fraction. Therefore, our objective was to use machine learning techniques integrating clinical features, biomarker data, and echocardiography data to enhance comprehension and risk stratification in patients diagnosed with ischemic cardiomyopathy and heart failure with preserved ejection fraction who have undergone coronary artery bypass grafting surgery. For this study, 294 patients with ischemic cardiomyopathy and heart failure with preserved ejection fraction who underwent coronary artery bypass grafting surgery were assigned to the development cohort (n=176) and the independent validation cohort (n=118). A total of 52 clinical variables were extracted for each patient. The principal clinical end point was the incidence of major adverse cardiovascular events, encompassing cardiac mortality, acute myocardial infarction, acute heart failure, and graft failure. From least absolute shrinkage and selection operator regression, 4 predictors were selected for the final prediction nomogram: diabetes, hypertension, the systemic immune-inflammation index, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). The prediction nomogram achieved satisfactory prediction performance in both the development cohort (C index, 0.768 [95% CI, 0.701-0.835]) and independent validation cohort (C index, 0.633 [95% CI, 0.521-0.745]). Adequate calibration was noted for the likelihood of major adverse cardiovascular events in both the development and independent validation cohorts. Decision curve analysis confirmed the clinical usefulness of the established prediction nomogram. A clinically feasible prognostic model, based on preoperative multimodal data, was developed for risk stratification of patients with ischemic heart and heart failure with preserved ejection fraction who receive coronary artery bypass grafting surgery. https://www.chictr.org.cn; Unique identifier: ChiCTR2300074439.

Laboratory and instrumental parameters associated with the risk of death in the long-term follow-up period in patients after myocardial infarction

BACKGROUND: In patients who successfully survived the 1st year after myocardial infarction, the risk of death remains elevated. AIM: To determine laboratory and instrumental parameters of myocardial remodeling associated with a lethal outcome in the long-term follow-up period in patients 1 year after myocardial infarction. MATERIAL AND METHODS: The study included 184 patients 12 months after myocardial infarction: the first group — living patients at the 5-year follow-up point (n=160), the second group — deceased patients at the 5-year follow-up point (n=24). A comparative analysis of inflammation and myocardial dysfunction biomarkers, as well as echocardiographic parameters reflecting the types of left ventricular remodeling, linear dimensions of the cavities and wall thickness of the heart, chamber volumes, and ventricular systolic function was retrospectively performed. After assessing the distribution of quantitative data, the Student's t-test or Mann–Whitney U-test and the χ2 criterion for categorical data were used. The model was built on the basis of logistic regression. The ROC curve, the Hosmer–Lemeshow test, and the bootstrap method were used to assess the model itself and its reliability. RESULTS: Patients in the second group were older (p=0.007), and more often had myocardial infarction with ST-segment elevation during hospitalization (p 0.001). Twelve months after myocardial infarction, a multidirectional pattern of changes in the level of N-terminal brain natriuretic propeptide was revealed: a decrease was registered in the first group, while an increase was registered in the second group. In the dynamics of the second group, the index of end-diastolic volume (p=0.014) and the size of left ventricular asynergy were higher (p=0.043), and the ejection fraction was lower (p=0.015) than in the first group. The model for predicting 4-year mortality in patients who survived myocardial infarction during the 1st year included such parameters as the index of the left ventricular end-diastolic volume, the content of the N-terminal fragment of the natriuretic peptide and the presence of concentric hypertrophy of the left ventricle. CONCLUSION: In patients who survived 1 year after myocardial infarction, the long-term risk of death is associated with a set of parameters reflecting left ventricular remodeling and the development of heart failure.

Correlation of the FIB-4 Liver Biomarker Score with the Severity of Heart Failure

Background and Objectives: Heart failure is associated with high morbidity and mortality and linked with several pre-existing health conditions and risk factors. Early detection and prompt management in heart failure improves patient outcomes. Liver involvement is associated with heart failure disease progression, and hence liver biomarkers and liver fibrosis may have a prognostic impact. Several blood test based markers and scoring systems estimate liver fibrosis and hence can be useful prognostic tools. Materials and Methods: We retrospectively analyzed a series of 303 patients with decompensated heart failure in a city in western Romania over a period of 6 months. Several biochemical parameters were measured, the FIB-4 score was estimated and echocardiography was performed. Results for targeted variables are presented using descriptive statistics. Patients were analyzed based on their LVEF categories. Statistical analysis was based on ANOVA one-way tests for continuous variables and Chi-square tests for categorical variables. Pairwise comparisons were performed based on Bonferroni adjusted significance tests. The correlations between FIB-4 score, LVEF and NT-pro BNP in patients with and without diabetes and hypertension were explored using Spearman’s correlation coefficient. Result: Age, gender, NYHA class, death, history of (h/o) type 2 diabetes mellitus (T2DM), h/o coronary artery disease (CAD), h/o arrhythmias, sodium, potassium, creatinine, eGFR, uric acid, NT-pro BNP, left atrial volume, LDL, HDL, and TG were analyzed by LVEF categories using ANOVA one-way tests, Chi-square tests, and Bonferroni correction comparisons. We found a strong statistically significant correlation between each of NT-pro BNP, left atrial volume, LDL, and HDL with the LVEF categories. Discussion: Early detection of cardiac dysfunction leads to better management in patients with cardiovascular risk factors including diabetes and hypertension. High LDL and low HDL levels contribute to a reduction in left ventricular (LV) function. Available literature suggests the FIB-4 score as superior to other non-invasive markers of fibrosis. It utilizes the patient’s age, platelet count, AST, and ALT, which can be available retrospectively, making it an easy and inexpensive tool. FIB-4 score has a few limitations. Conclusions: Our study has shown a statistically significant positive correlation between severity categories of LVEF and FIB-4 score for heart failure patients with and without diabetes, and for heart failure patients with or without hypertension. We propose the implementation of FIB-4 score as a prognostic tool for heart failure.

Prevalence of Transthyretin Amyloid Cardiomyopathy Among Acute Heart Failure Patients with Hypertrophy Across the Left Ventricular Ejection Fraction Spectrum

Background/Objectives: Transthyretin amyloid (ATTR) cardiomyopathy mimics left ventricular hypertrophy (LVH) and has been identified as a specific cause of heart failure (HF). The aim of this study was to assess the prevalence of ATTR among patients presenting to the Emergency Department (ED) with acute HF (AHF) and LVH and explore their clinical characteristics and outcomes. Methods: Of 127 AHF patients with LVH, 95 completed the diagnostic protocol, which included monoclonal paraprotein testing and technetium-99 m pyrophosphate scintigraphy. Patients were followed for 6 months, and adverse events, including mortality and HF-related hospitalizations, were recorded. Results: ATTR was diagnosed in 8.4% of patients. The mean left ventricular ejection fraction (EF) was 46 ± 7% in ATTR subjects, with 25% classified as HF with reduced EF, 37.5% HF with mildly reduced EF, and 37.5% HF with preserved EF. N-terminal pro b-type natriuretic peptide (NT-proBNP) and high sensitivity troponin T (hs-TnT) were higher in ATTR compared to the non-ATTR group [NT-proBNP: 5863 (6519–12382) pg/mL versus 3586 (1393.5–6322) pg/mL, p = 0.007; hs-TnT: 35.9 (47.9–83.8) pg/mL versus 30.0 (19.4–49.5) pg/mL, p = 0.0006]. During follow-up, twenty-three patients from the cohort died: six in the ATTR and seventeen in the non-ATTR group. The estimated survival rate was significantly lower in ATTR versus non-ATTR patients (log-rank p &lt; 0.0001). Conclusions: In this cohort of AHF patients with LVH presenting to the ED, ATTR cardiomyopathy was detected in 8.4%. Using routinely used cardiac biomarkers and basic echocardiography allows for the raising of suspicion of the disease from the ED setting, potentially facilitating earlier diagnosis in this population.

SGLT2 Inhibitors in Patients with Heart Failure: A Model-Based Meta-Analysis.

This study aimed to quantify the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a therapeutic approach for heart failure. A systematic literature review was conducted to collect pharmacokinetics (PK) and pharmacodynamics (PD) data on empagliflozin, dapagliflozin, and canagliflozin. Population pharmacokinetic models were developed separately for each drug, along with PK/PD turnover models for SGLT2 inhibitors, to describe the time course of NT-proBNP and simulate its changes over 52 weeks. A total of 42 publications were included in this study. The results showed that baseline NT-proBNP levels, estimated glomerular filtration rate levels, and body weight significantly influenced the therapeutic effects of SGLT2 inhibitors. Among the studied drugs, canagliflozin demonstrated a greater reduction in NT-proBNP at comparable baseline levels. Baseline NT-proBNP concentration, renal function, and body weight were covariates affecting the efficacy of SGLT2 inhibitors in reducing NT-proBNP. Canagliflozin showed the most favorable treatment outcomes at similar baseline levels. This model-based meta-analysis approach may support further drug development for SGLT2 inhibitors.

Effect of voxelotor on cerebral perfusion and cerebral oxygen metabolism and cardiac stress in adult patients with sickle cell disease.

Sickle cell disease (SCD) is complicated by silent cerebral infarcts (SCIs), for which anemia is an important risk factor. Despite normal oxygen delivery (OD), cerebral vascular reserve (CVR), and cerebral metabolic rate of oxygen (CMRO2) are diminished in SCD, possibly causing the formation of SCIs. Voxelotor inhibits polymerization by increasing the hemoglobin oxygen binding, ameliorating hemolytic anemia. Furthermore, anemia is related to cardiac complications. Our aims were to assess the effect of voxelotor on markers of cerebral perfusion, cerebral oxygen metabolism, and markers of cardiac stress in SCD patients. Cerebral hemodynamics and oxygen metabolism were measured with MRI before and after 3 months of voxelotor treatment (1500 mg/day) in 18 adults with SCD (HbSS/HbSβ0-thalassemia). Hemoglobin levels significantly increased (p = .001) and markers of hemolysis decreased (p < .05). OD increased from 6.5 (IQR, 6.0-7.1) mL O2/100 g/min to 8.1 (IQR, 7.2-8.7) mL O2/100 g/min (p = .001). CBF and CVR did not change. CMRO2 decreased from 2.0 (IQR, 1.9-2.1) mL O2/100 g/min to 1.9 (IQR, 1.6-2.1) mL O2/100 g/min (p = .03). N-terminal pro-B type natriuretic peptide (NT-proBNP) levels decreased (p = .048) and maximum tricuspid regurgitation flow velocity (TRVmax) normalized in all but one patient with increased TRVmax. Voxelotor treatment in patients with severe SCD did not decrease CBF despite increased Hb levels. Cerebral oxygen metabolism slightly decreased, despite raised OD, most likely due to drug-induced increase in oxygen binding. Nonetheless, voxelotor improved clinically validated markers of cardiac stress.

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.

Advanced Parameters of Myocardial Strain and Cardiac Biomarkers Indicate Subclinical Systolic Myocardial Dysfunction in Patients with Systemic Lupus Erythematous.

Background: Systemic lupus erythematosus (SLE) is characterized by inflammation and cardiovascular complications. Our study aimed to investigate subclinical and early indicators of systolic myocardial dysfunction in SLE patients using advanced echocardiographic methods and biomarkers. Methods: In this cross-sectional study, we enrolled 102 SLE patients without known cardiac impairment and 51 healthy controls. Demographics, disease characteristics, laboratory results, disease activity (SLEDAI), and organ damage (SDI) indices were recorded. Left ventricular global longitudinal strain (GLS) and myocardial work indices were assessed by utilizing speckle tracking echocardiography. In addition, high-sensitivity C-reactive protein (hsCRP), high-sensitivity troponin (hsTn), and N-terminal-pro B-type natriuretic peptide (NT-proBNP) levels were measured in blood samples. Results: In comparison with controls, SLE patients had significantly higher GLS (-19.94 ± 2.71% vs. -21.15 ± 1.55%, p < 0.001) and global wasted work (GWW) (94 ± 71 mmHg% vs. 71 ± 49 mmHg%, p = 0.025). Notably, NT-proBNP and hsTn were threefold and twofold higher in the SLE group compared with the control group, respectively (p < 0.001). Within the SLE cohort, in patients with at least moderate disease activity (SLEDAI ≥ 4), both biomarkers were significantly more elevated than those with low disease activity (SLEDAI < 4). Notably, hsTn levels remained within the normal range. Conclusions: Advanced echocardiographic parameters combined with specific biomarkers have a promising role in detecting systolic dysfunction in SLE patients, potentially enabling timely interventions to mitigate cardiovascular risk.

Long-Term Efficacy and Safety of Acoramidis in ATTR-CM: Initial Report From the Open-Label Extension of the ATTRibute-CM Trial

Background: In the phase 3 randomized controlled study, ATTRibute-CM, acoramidis, a transthyretin (TTR) stabilizer, demonstrated significant efficacy on the primary endpoint. Participants with transthyretin amyloid cardiomyopathy (ATTR-CM) who completed ATTRibute-CM were invited to enroll in an open-label extension study (OLE). We report efficacy and safety data of acoramidis in participants who completed ATTRibute-CM and enrolled in the ongoing OLE. Methods: Participants who previously received acoramidis through Month 30 (M30) in ATTRibute-CM continued to receive it (continuous acoramidis), and those who received placebo through M30 were switched to acoramidis (placebo to acoramidis). Participants who received concomitant tafamidis in ATTRibute-CM were required to discontinue it to be eligible to enroll in the OLE. Clinical efficacy outcomes analyzed through Month 42 (M42) included time to event for all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH), ACM alone, first CVH alone, ACM or recurrent CVH, change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP), 6-minute walk distance (6MWD), serum TTR, and the Kansas City Cardiomyopathy Questionnaire Overall Summary score (KCCQ-OS). Safety outcomes were analyzed through M42. Results: Overall, 438 of 632 participants in ATTRibute-CM completed treatment and 389 enrolled in the ongoing OLE (263 continuous acoramidis, 126 placebo to acoramidis). The hazard ratio (HR) (95% CI) for ACM or first CVH was 0.57 (0.46, 0.72) at M42 based on a stratified Cox proportional hazards model ( P -value &lt; 0.0001) favoring continuous acoramidis. Similar analyses were performed on ACM alone and first CVH alone, with HRs (95% CI) of 0.64 (0.47, 0.88) and 0.53 (0.41, 0.69), respectively, at M42. Treatment effects for NT-proBNP and 6MWD also favored continuous acoramidis. Upon initiation of open-label acoramidis in the placebo-to-acoramidis arm there was a prompt increase in serum TTR. Quality of life assessed by KCCQ-OS was well preserved in continuous acoramidis participants compared with the placebo to acoramidis participants. No new clinically important safety issues were identified in this long-term evaluation. Conclusions: Early initiation and continuous use of acoramidis in the ATTRibute-CM study through M42 of the ongoing OLE study was associated with sustained clinical benefits in a contemporary ATTR-CM cohort, with no clinically important safety issues newly identified.

CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy.

Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, often fatal disease. Nexiguran ziclumeran (nex-z) is an investigational therapy based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) targeting the gene encoding transthyretin (TTR). In this phase 1, open-label trial, we administered a single intravenous infusion of nex-z to patients with ATTR-CM. Primary objectives included assessment of the effect of nex-z on safety and pharmacodynamics, including the serum TTR level. Secondary end points included changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, high-sensitivity cardiac troponin T levels, the 6-minute walk distance, and the New York Heart Association (NYHA) class. A total of 36 patients received nex-z and completed at least 12 months of follow-up. Of these patients, 50% were in NYHA class III and 31% had variant ATTR-CM. The mean percent change from baseline in the serum TTR level was -89% (95% confidence interval [CI], -92 to -87) at 28 days and -90% (95% CI, -93 to -87) at 12 months. Adverse events were reported in 34 patients. Five had transient infusion-related reactions, and two had transient liver-enzyme elevations that were assessed as treatment-related. Serious adverse events, most of which were consistent with ATTR-CM, were reported in 14 patients. The geometric mean factor change from baseline to month 12 was 1.02 (95% CI, 0.88 to 1.17) in the NT-proBNP level and 0.95 (95% CI, 0.89 to 1.01) in the high-sensitivity cardiac troponin T level. The median change from baseline to month 12 in the 6-minute walk distance was 5 m (interquartile range, -33 to 49). A total of 92% of the patients had either improvement or no change in their NYHA class. In this phase 1 study involving patients with ATTR-CM, treatment with a single dose of nex-z was associated with transient infusion-related reactions and consistent, rapid, and durable reductions in serum TTR levels. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.).

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.