Propeptide Research Articles

Renal venous Doppler ultrasound – a new parameter for predicting outcomes in patients with decompensated heart failure

Aim. To assess the frequency, dynamics, and prognostic value of renal venous congestion using Doppler ultrasound in patients with decompensated heart failure (DHF).Materials and methods. A prospective, single-center study included 124 patients with DHF (mean age 70 ± 12 years, 51.6% were males), left ventricular ejection fraction (LVEF) 44 [34; 55] %, N-terminal pro B-type natriuretic peptide (NT-proBNP) 1,609 [591; 2,700] pg / ml. All patients underwent a standard physical examination and laboratory and instrumental tests, including the assessment of the NT-proBNP level. Renal venous blood flow was assessed using pulsed-wave Doppler ultrasound. The presence of continuous renal blood flow was considered as the absence of venous congestion, while intermittent blood flow (two-phase and single-phase flow) indicated venous congestion. Rehospitalization for DHF and reaching a composite endpoint (rehospitalization for DHF and cardiovascular mortality) within 12 months after discharge were selected as endpoints.Results. At admission, continuous renal venous blood flow was observed in 34 (27.4%) patients, intermittent renal venous blood flow was found in 90 (72.6%) patients: two-phase flow in 62 (50%) and single-phase flow in 28 (22.6%) patients with DHF. At discharge, 66 (53.2%) patients had intermittent renal venous blood flow: two-phase flow in 50 (40.3%) and single-phase flow in 16 (12.9%) patients. Correlations of renal venous congestion with the levels of NT-proBNP, serum iron, uric acid, creatinine, LVEF, systolic pressure in the pulmonary artery (SPPA), and the development of acute kidney injury (AKI) were revealed. Persistent renal venous congestion at discharge was significantly associated with a higher probability of rehospitalization for DHF (hazard ratio (HR) 1.93 95% confidence interval (CI) (1.017–3.67); p = 0.044) and a composite endpoint (HR 2.66, 95% CI (1.43–4.96); p = 0.002).Conclusion. In patients with DHF, it is necessary to evaluate renal venous blood flow using pulsed-wave Doppler ultrasound to stratify patients with development of cardiovascular complications within 12 months.

Heart failure risk scores in advanced heart failure patients: insights from the LEVO-D registry.

The prevalence of advanced heart failure (HF) is increasing due to the growing number of patients with HF and their better treatment and survival. There is a scarcity of data on the accuracy of HF web-based risk scores in this selected population. This study aimed to assess mortality prediction performance of the Meta-Analysis Global Group in Chronic HF (MAGGIC-HF) risk score and the model of the Barcelona Bio-HF Risk Calculator (BCN-Bio-HF) containing N terminal pro brain natriuretic peptide in HF patients receiving intermittent inotropic support with levosimendan as destination therapy. Four hundred and three advanced HF patients from 23 tertiary hospitals in Spain receiving intermittent inotropic support with levosimendan as destination therapy were included. Discrimination for all-cause mortality was compared by area under the curve (AUC) and Harrell's C-statistic at 1year. Calibration was assessed by calibration plots comparing observed versus expected events based on estimated risk by each calculator. The included patients were predominantly men, aged 71.5 [interquartile range 64-78] years, with reduced left ventricular ejection fraction (27.5±9.4%); ischaemic heart disease was the most prevalent aetiology (52.5%). Death rate at 1year was 26.8%, while the predicted 1-year mortality by BCN-Bio-HF and MAGGIC-HF was 17.0% and 22.1%, respectively. BCN-Bio-HF AUC was 0.66 (Harrell's C-statistic 0.64), and MAGGIC-HF AUC was 0.62 (Harrell's C-statistic 0.61). The two evaluated risk scores showed suboptimal discrimination and calibration with an underestimation of risk in advanced HF patients receiving levosimendan as destination therapy. There is a need for specific scores for advanced HF.

HYDROCATALYTIC PROCESSING OF FUEL OILS WITH THE USE OF NANOCATALYSTS BASED ON NICKEL AND ZINC

The article presents the results of a study of hydrocatalytic processing of two fuel oils in the presence of nanocatalytic systems in the form of oil-soluble precursors based on nickel and zinc. The process was carried out on a pilot plant for hydroprocessing with a flow reactor at a temperature of 440 ℃, a hydrogen pressure of 6 MPa, a feed space velocity of 1.0 s-1, and a hydrogen circulation ratio of 1000 nl/l. The catalyst efficiency was evaluated by changes in the material balance, in hydrogenate desulfurization degree, in 450+ °C fraction conversion degree, and by changes in density and hydrogenate refractive index. An analysis of material balances showed that the addition of nanocatalyst precursors increases the 180–350 °C fraction yield, reduces the coke yield on the fixed layer, which is a layer of ceramic balls, and reduces the 450+ °C residual fraction yield. The gas and gasoline fraction yield is slightly reduced. The analysis of hydrogenates showed a decrease in sulfur content, a decrease in density and refractive index in hydrogenates obtained during the hydroprocessing of raw materials with the addition of nanocatalyst precursors. The optimal concentrations of catalysts were experimentally determined; for nickel, the concentration is 0.1 wt %, and for zinc is 0.15 wt %. A comparison of two methods for the synthesis of nanoscale catalytic systems in raw materials was made: directly in the reaction zone in situ and outside the reaction zone ex situ. The method for synthesizing nanoscale catalytic systems outside the reaction zone makes it possible to further increase the feedstock conversion, the hydrogenate desulfurization degree, and the hydrogenate quality.

Causal associations between cardiorespiratory fitness and type 2 diabetes

Higher cardiorespiratory fitness is associated with lower risk of type 2 diabetes. However, the causality of this relationship and the biological mechanisms that underlie it are unclear. Here, we examine genetic determinants of cardiorespiratory fitness in 450k European-ancestry individuals in UK Biobank, by leveraging the genetic overlap between fitness measured by an exercise test and resting heart rate. We identified 160 fitness-associated loci which we validated in an independent cohort, the Fenland study. Gene-based analyses prioritised candidate genes, such as CACNA1C, SCN10A, MYH11 and MYH6, that are enriched in biological processes related to cardiac muscle development and muscle contractility. In a Mendelian Randomisation framework, we demonstrate that higher genetically predicted fitness is causally associated with lower risk of type 2 diabetes independent of adiposity. Integration with proteomic data identified N-terminal pro B-type natriuretic peptide, hepatocyte growth factor-like protein and sex hormone-binding globulin as potential mediators of this relationship. Collectively, our findings provide insights into the biological mechanisms underpinning cardiorespiratory fitness and highlight the importance of improving fitness for diabetes prevention.

Prognostic Value of Cardiac and Noncardiac Biomarkers in Infective Endocarditis: A Prospective Cross-sectional Study

Background and Aims: Infective endocarditis (IE) is associated with several morbidities and high rate of mortality. Predicting these morbidities can be helpful in managing patients and can prevent possible complications, result from IE. In this study, we aimed to evaluate the association between C-reactive protein (CRP), N-terminal pro brain natriuretic peptide (BNP), monocyte to high density lipoprotein (HDL) ratio Charlson comorbidity index, and European System for Cardiac Operative Risk Evaluation (Euro SCORE) in complicated cases of IE. Materials and Methods: This prospective study was conducted on a referral center from January 2017 to December 2020. Patients with definite or possible diagnosis of IE based on the modified Duke criteria were included in this study. Demographic information and serum levels of N-terminal pro BNP, D-Dimer, CRP were evaluated in patients. In addition, we used Charlson comorbidity index and The Euro SCORE for subjective assessment. Results: One hundred and four patients (64 males, median age: 58) included in the final analysis. Intracardiac involvement, central nervous system (CNS) complications and systemic complications were observed in nine patients (9.7%), 16 patients (15.4%), and eight patients (7.7%) respectively. The mortality rate was 14.4%. D-dimer (P = 0.008), pro-BNP (P = 0.008), and Charlson criteria (P = 0.012) were higher in patients with systematic complications. In addition, NT pro-BNP was significantly associated with CNS complications (P = 0.04) and D-Dimer level was significantly associated with in-hospital mortality (P = 0.008). Conclusion: Serum biomarkers such as pro-BNP and D-dimer, and comorbidity indices can be used for risk stratification of patients with IE. The level of pro-BNP is significantly associated with CNS complications and the level of D-dimer is significantly with mortality in patients with IE.

Prognostic utility of N-terminal pro B-type natriuretic peptide ratio in mixed aortic valve disease

ObjectiveWe aimed to assess the incremental prognostic value of N-terminal-pro-B-type natriuretic peptide (Nt-proBNP) for risk stratification in mixed aortic valve disease (MAVD) patients.MethodsWe included 556 (73±12 years, 37% women) consecutive...

Growth differentiation factor 15 predicts cardiovascular events in stable coronary artery disease.

Growth differentiation factor 15 (GDF-15) has been explored as a potential biomarker for various inflammatory diseases and cardiovascular events. This study aimed to assess the predictive role of GDF-15 levels in cardiovascular events and all-cause mortality, considering traditional risk factors and other biomarkers. A prospective study was conducted and 3699 patients with stable coronary artery disease (CAD) were enrolled into the research. Baseline GDF-15 levels were measured. Median follow-up was 3.1 years during the study. We analyzed clinical variables and several biomarkers. Multivariable Cox regression analysis was performed to evaluate prognostic performance of GDF-15 levels in predicting myocardial infarction (MI), heart failure, stroke, cardiovascular death, and non-cardiovascular death. Baseline GDF-15 levels for 3699 patients were grouped by quartile (≤ 1153, 1153-1888, 1888-3043, > 3043 ng/L). Higher GDF-15 levels were associated with older age, male gender, history of hypertension, and elevated levels of N-terminal pro B-type natriuretic peptide (NT-pro BNP), soluble suppression of tumorigenesis-2 (sST2), and creatine (each with P < 0.001). Adjusting for established risk factors and biomarkers in Cox proportional hazards models, a 1 standard deviation (SD) increase in GDF-15 was associated with elevated risk of clinical events [hazard ratio (HR) = 2.18, 95% confidence interval (CI): (1.52-3.11)], including: MI [HR = 2.83 95% CI: (1.03-7.74)], heart failure [HR = 2.71 95% CI: (1.18-6.23)], cardiovascular and non-cardiovascular death [HR = 2.48, 95% CI (1.49-4.11)] during the median follow up of 3.1 years. Higher levels of GDF-15 consistently provides prognostic information for cardiovascular events and all cause death, independent of clinical risk factors and other biomarkers. GDF-15 could be considered as a valuable addition to future risk prediction model in secondary prevention for predicting clinical events in patient with stable CAD.

Overview of Long-Term Outcome in Adults with Systemic Right Ventricle and Transposition of the Great Arteries: A Review.

The population of patients with a systemic right ventricle (sRV) in biventricular circulation includes those who have undergone an atrial switch operation for destro-transposition of the great arteries (d-TGA) and those with congenitally corrected transposition of the great arteries (ccTGA). Despite the life expectancy of these patients is significantly increased, the long-term prognosis remains suboptimal due to late complications such as heart failure, arrhythmias, and premature death. These patients, therefore, need a close follow-up to early identify predictive factors of adverse outcomes and to implement all preventive therapeutic strategies. This review analyzes the late complications of adult patients with an sRV and TGA and clarifies which are risk factors for adverse prognosis and which are the therapeutic strategies that improve the long-term outcomes. For prognostic purposes, it is necessary to monitor sRV size and function, the tricuspid valve regurgitation, the functional class, the occurrence of syncope, the QRS duration, N-terminal pro B-type natriuretic peptide levels, and the development of arrhythmias. Furthermore, pregnancy should be discouraged in women with risk factors. Tricuspid valve replacement/repair, biventricular pacing, and implantable cardioverter defibrillator are the most important therapeutic strategies that have been shown, when used correctly, to improve long-term outcomes.

The Effect of Elective Ligation of the Arteriovenous Fistula on Cardiac and Renal Functions in Kidney Transplant Recipients.

Kidney transplantation (KTx) is considered as the best kidney replacement therapy and arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis. The systematic ligation of a functioning AVF in stable kidney transplant recipients remains debatable. In this prospective study, we investigated the hemodynamic impact of the surgical closure of AVF in KTRs. Forty-three KTRs underwent an ambulatory blood pressure monitoring (24h-ABPM) before surgical closure of AVF (T0) and 12 months later (M12), as well as measurement of serum cardiac biomarkers (i.e., soluble suppression of tumorigenicity 2 (ST2), N-terminal pro b-type natriuretic peptide (NT-proBNP) and Galectin-3). Serum tests were also performed 6 months after AVF closure (M6). An echocardiographic exam was done at each time-point. All serum creatinine values were collected to compare the individual eGFR slopes before versus after AVF closure. The latest measure of the AVF flow (QAVF) prior to KTx was recorded. Diastolic blood pressure (DBP) significantly raised from T0 to M12: + 4.4±7.3 mmHg (p=0.0003) for 24h, + 3.8±7.4 mmHg (p=0.0018) during the day, and + 6.3±9.9 mmHg (p=0.0002) during the night, leading to an increased proportion of KTRs with ESH-defined arterial hypertension after AVF ligation. No change was observed for systolic BP. NT-proBNP significantly dropped between T0 and M6 (345 [190; 553] to 230 [118; 458] pg/mL, p=0.0001) and then remained stable from M6 to M12, while ST2 and Galectin-3 levels did not change from T0 to M12. We observed a significant decrease of left ventricular (LV) end-diastolic volume, LV end-systolic volume, LV mass, interventricular septum diameter, left atrial (LA) volume, and tricuspid annular plane systolic excursion from T0 to M6, and then a stability from M6 to M12. LV ejection fraction and eGFR slope remained stable during the whole study. These observations remained unchanged after adjustment for QAVF. The closure of a patent AVF in KTRs is associated with elevation of DBP, drop of serum NT-proBNP levels, reduction of LV/LA dimensions, and stable eGFR slope.

Cardiac troponin T, NT-proBNP and GDF-15 associate with future focal myocardial scar types, but not diffuse fibrosis assessed by cardiac magnetic resonance

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Akershus University Hospital Trust, Vestre Viken Hospital Trust, South-Eastern Norway Regional Health Authority, Roche Diagnostics provided reagents for hs-cTnT analyses Background In cardiovascular risk prediction, there is growing evidence that imaging and circulating cardiac biomarkers provide incremental prognostic value compared to single biomarkers or traditional risk factors. In patients with suspected or established cardiovascular disease (CVD), cardiac troponin T (cTnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP) associate with focal and diffuse fibrosis assessed by cardiac magnetic resonance (CMR) imaging. There is limited data on the associations between established and emerging circulating cardiac biomarkers with subsequent myocardial fibrosis in subjects without CVD recruited from the general population. Purpose Assess the associations between biomarkers of cardiac injury (cTnT), stress (NT-proBNP) and fibrosis and inflammation (growth differentiation factor-15, GDF-15), and subsequent focal and diffuse myocardial fibrosis assessed by CMR imaging. Methods We recruited 200 study participants born in 1950 from the general population. All participants were without known coronary artery disease or renal dysfunction. cTnT, NT-proBNP, and GDF-15 were measured in samples collected at baseline in 2012–2015, and CMR was performed 4–7 years later. Presence and type (ischemic/non-ischemic) of focal myocardial fibrosis were assessed by late gadolinium enhancement (LGE) imaging. Diffuse fibrosis was assessed by the extracellular volume (ECV) in the midventricular septum. Logistic regression analysis was used to examine relationships between log transformed concentrations of cardiac biomarkers and CMR parameters. Results The median age was 63.9 (63.4–64.5) and 52% were male (Table 1). cTnT was associated with presence of any LGE scar adjusted for common cardiovascular risk factors (OR 1.85, 95% CI 1.25–2.72), but this association was attenuated when left ventricular mass was added to the model (Table 2). NT-proBNP (OR 1.66, 95% CI 1.10–2.72) and GDF-15 (OR 4.45, 95% CI 1.29–15.27) were associated with presence of any LGE scar in the fully adjusted models (Table 2). cTnT (OR 1.90, 95% CI 1.06–3.39) and NT-proBNP (OR 2.72, 95% CI 1.29–5.76) were associated with ischemic scars. Only GDF-15 (OR 4.52, 95% CI 1.09–18.72) associated with non-ischemic scars in adjusted models. None of the biomarkers were significantly associated with ECV. Conclusion(s) In a general population cohort, biomarkers of myocardial injury and stress associate with ischemic type scars, but not diffuse fibrosis. GDF-15, an emerging circulating biomarker of fibrosis and inflammation, associates with non-ischemic type scars.

Cardiac imaging and biomarkers for assessing myocardial fibrosis in children with hypertrophic cardiomyopathy

Myocardial fibrosis, as diagnosed on cardiac magnetic resonance imaging (cMRI) by late gadolinium enhancement (LGE), is associated with adverse outcomes in adults with hypertrophic cardiomyopathy (HCM), but its prevalence and magnitude in children with HCM have not been established. We investigated: (1) the prevalence and extent of myocardial fibrosis as detected by LGE cMRI; (2) the agreement between echocardiographic and cMRI measurements of cardiac structure; and (3) whether serum concentrations of N-terminal pro hormone B-type natriuretic peptide (NT-proBNP) and cardiac troponin-T are associated with cMRI measurements. A cross-section of children with HCM from 9 tertiary-care pediatric heart centers in the U.S. and Canada were enrolled in this prospective NHLBI study of cardiac biomarkers in pediatric cardiomyopathy (ClinicalTrials.gov Identifier: NCT01873976). The median age of the 67 participants was 13.8 years (range 1-18 years). Core laboratories analyzed echocardiographic and cMRI measurements, and serum biomarker concentrations. In 52 children with non-obstructive HCM undergoing cMRI, overall low levels of myocardial fibrosis with LGE >2% of left ventricular (LV) mass were detected in 37 (71%) (median %LGE, 9.0%; IQR: 6.0%, 13.0%; range, 0% to 57%). Echocardiographic and cMRI measurements of LV dimensions, LV mass, and interventricular septal thickness showed good agreement using the Bland-Altman method. NT-proBNP concentrations were strongly and positively associated with LV mass and interventricular septal thickness (P < .001), but not LGE. Low levels of myocardial fibrosis are common in pediatric patients with HCM seen at referral centers. Longitudinal studies of myocardial fibrosis and serum biomarkers are warranted to determine their predictive value for adverse outcomes in pediatric patients with HCM.

The Prognostic Value of Cardiac Troponin in a Contemporary Cohort of Patients With First-Time Myocardial Infarction

The prognostic value of cardiac troponin following myocardial infarction (MI) is well documented; however, the benefit in a predominantly revascularised cohort is less certain. This study reported the prognostic role of peak cardiac troponin in the Multi-Ethnic New Zealand Study of Acute Coronary Syndromes (MENZACS). Due to varying troponin assays across hospitals, peak troponin data from the index admission were standardised as the peak troponin divided by the upper limit of normal (ULN) for each troponin assay (“peak troponin ratio”). Troponin ratio was categorically investigated (≤1, >1–10, >10–100, >100 over ULN) and as a continuous variable. The relationship between troponin and all-cause death or cardiovascular readmission was investigated using Cox regression including restricted cubic splines. Models were adjusted for the MENZACS clinical summary score (comprising 20 clinical factors including age and sex), ethnicity, and log2 N-terminal pro B-type natriuretic peptide (NT-proBNP). A total of 1,876 patients admitted with first-time MI from 2015 to 2019 were included (mean age 61 years, 21% women, 43% ST-elevation MI, 57% non-ST elevation MI); 99% received coronary angiography and 88% were revascularised during the index admission. Peak troponin ratio was 1% ≤1, 19% >1–10, 36% >10–100,and 44% >100. The NT-proBNP increased with increasing troponin category. Overall, 20% patients died or were readmitted over a median of 3.5 years. After multivariable adjustment, peak troponin ratio was not associated with death or readmission (Figure 1). Peak troponin was not an independent predictor of death or cardiovascular readmission in a highly revascularised cohort of patients in New Zealand surviving admission for a first-time MI.

Assessing the Accuracy of Algorithms That Predict Ejection Fraction for Research in a Cohort of Patients With Heart Failure

Left ventricular ejection fraction (EF) is required to differentiate heart failure (HF) phenotypes but is not collected in national datasets in Aotearoa/New Zealand. This study assessed the accuracy of models derived from the SWEDE-HF registry for predicting HF phenotypes in patients with HF. Six SWEDE-HF models were applied to the PEOPLE study: three predicted EF <50% vs ≥50% and three predicted <40% vs ≥40%. For each EF threshold, Model A used all predictors (age, sex, ischaemic heart disease, anaemia, atrial fibrillation, chronic obstructive pulmonary disease, diabetes, hypertension, valve disease, cancer, device therapy, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta blockers, mineralocorticoid receptor antagonists, digoxin, diuretics, New York Heart Association, mean arterial pressure, heart rate, body mass index, estimated glomerular filtration rate, and N-terminal pro B-type natriuretic peptide [NT-proBNP]); Model B excluded NT-proBNP; Model C excluded clinical measurements (last six in list). Agreement between actual and predicted EF categories was assessed using Cohen’s kappa, which assesses the degree of agreement beyond that expected by chance. Of 941 people with HF (mean age 69 years, 30% women), 610 (65%) had EF <50% and 476 (51%) had EF <40%. Model A predicting EF <40%/≥40% resulted in the greatest agreement between predicted and actual EF category beyond chance (kappa 22.9%). Removing NT-proBNP (Model B) or clinical predictors (Model C) reduced kappa to 17.2% and 19.7%, respectively. For models predicting EF <50%/≥50%, kappa for each model was 9.3%, 4.9%, and 12.5%, respectively. Models that predict EF <40% classify NZ patients into the correct EF group up to 23% better than chance. This is unlikely to be an acceptable degree of accuracy for determining EF phenotype when assessing administrative datasets involving patients with HF in NZ.

The Novel Biomarker Growth Differentiation Factor-15 in Patients with Chronic Heart Failure at a Heart Failure Clinic in the Asia-Pacific Region: A Prospective Observational Study

Background: Growth differentiation factor-15 (GDF-15) is an emerging prognostic biomarker in heart failure (HF). However, there are limited data on its role in HF patients in southeast Asia. This prospective observational study investigated the association between GDF-15 and various clinical parameters, and its role in predicting all-cause mortality. Methods: 160 patients with chronic HF and reduced left ventricular ejection fraction (LVEF) enrolled between October 2020 and April 2021. At study entry, baseline GDF-15 and N-terminal pro B-type natriuretic peptide (NT-proBNP) were evaluated. Patients were followed up per clinical routine. Results: The median GDF-15 was 1,715 ng/l. Patients were divided into two groups: GDF-15 &lt;2,000 or ≥2,000 ng/l. This cut-off has been shown to represent prognostic threshold in previous studies. The GDF-15 ≥2,000 group was older, had more severe HF and higher comorbidity burden, and lower use of renin–angiotensin–aldosterone system inhibitors (RAASi). GDF-15 was positively correlated with a history of MI, diabetes, chronic kidney disease and use of loop diuretics, but negatively correlated with RAAsi use. GDF-15 ≥2,000 was not associated with all-cause mortality at 60 weeks. The pooled stratum of GDF-15 ≥2,000/NT-proBNP ≥1,000 pg/ml had significantly higher mortality than GDF-15 &lt;2,000/NT-proBNP &lt;1,000 pg/ml. NT-proBNP and the Meta-Analysis Global Group In Chronic risk score but not GDF-15, were independently predictive of all-cause mortality. Conclusion: In our cohort of chronic HF patients with reduced LVEF who were relatively younger than the cohorts studied in previous GDF-15 in HF trials, well-managed and largely asymptomatic, GDF-15 did not independently predict all-cause mortality. The prognostic cut-off of GDF-15 ≥2,000 ng/l was not significantly associated with higher all-cause mortality at 60 weeks.

Prognostic Factors for Cardiotoxicity among Children with Cancer: Definition, Causes, and Diagnosis with Omics Technologies.

Improvements in the treatment of childhood cancer have considerably enhanced survival rates over the last decades to over 80% as of today. However, this great achievement has been accompanied by the occurrence of several early and long-term treatment-related complications major of which is cardiotoxicity. This article reviews the contemporary definition of cardiotoxicity, older and newer chemotherapeutic agents that are mainly involved in cardiotoxicity, routine process diagnoses, and methods using omics technology for early and preventive diagnosis. Chemotherapeutic agents and radiation therapies have been implicated as a cause of cardiotoxicity. In response, the area of cardio-oncology has developed into a crucial element of oncologic patient care, committed to the early diagnosis and treatment of adverse cardiac events. However, routine diagnosis and the monitoring of cardiotoxicity rely on electrocardiography and echocardiography. For the early detection of cardiotoxicity, in recent years, major studies have been conducted using biomarkers such as troponin, N-terminal pro b-natriuretic peptide, etc. Despite the refinements in diagnostics, severe limitations still exist due to the increase in the above-mentioned biomarkers only after significant cardiac damage has occurred. Lately, the research has expanded by introducing new technologies and finding new markers using the omics approach. These new markers could be used not only for early detection but also for the early prevention of cardiotoxicity. Omics science, which includes genomics, transcriptomics, proteomics, and metabolomics, offers new opportunities for biomarker discovery in cardiotoxicity and may provide an understanding of the mechanisms of cardiotoxicity beyond traditional technologies.

A Step Forward toward Selective Activation/Inhibition of Bak, a Pro-Apoptotic Member of the Bcl-2 Protein Family: Discovery of New Prospective Allosteric Sites Using Molecular Dynamics.

Bak is a pro-apoptotic protein and a member of the Bcl-2 family that plays a key role in apoptosis, a programmed cell death mechanism of multicellular organisms. Its activation under death stimuli triggers the permeabilization of the mitochondrial outer membrane that represents a point of no return in the apoptotic pathway. This process is deregulated in many tumors where Bak is inactivated, whereas in other cases like in neurodegeneration, it exhibits an excessive response leading to disorders such as the Alzheimer disease. Members of the Bcl-2 family share a common 3D structure, exhibiting an extremely similar orthosteric binding site, a place where both pro and antiapoptotic proteins bind. This similarity raises a selectivity issue that hampers the identification of new drugs, capable of altering Bak activation in a selective manner. An alternative activation site triggered by antibodies has been recently identified, opening the opportunity to undertake new drug discovery studies. Despite this recent identification, an exhaustive study to identify cryptic pockets as prospective allosteric sites has not been yet performed. Thus, the present study aims to characterize novel hotspots in the Bak structure. For this purpose, we have carried out extensive molecular dynamics simulations using three different Bak systems including Bak in its apo form, Bak in complex with its endogen activator Bim and an intermediate form, set up by removing Bim from the previous complex. The results reported in the present work shed some light on future docking studies on Bak through the identification of new prospective allosteric sites, not previously described in this protein.

Association of clinical characteristics and biomarkers with recurrent atrial fibrillation after hybrid ablation

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Atrial fibrillation ablation research at our institution was supported by an unrestricted grant from AtriCure. Background Hybrid ablation is an alternative treatment for both persisting and therapy-resistant, symptomatic atrial fibrillation (AF), combining the strengths of endocardial catheter and epicardial surgical ablation. Although results exhibit lower rates of recurrence and higher reduction of AF burden, there is a considerable risk of procedure-related complications. Therefore, the identification of patient groups who benefit most of this procedure can help in pre-procedural selection and tailoring of optimal therapy post-ablation. Purpose This study aimed to identify clinical factors and blood biomarkers associated with recurrence of AF within 1 year post-ablation. Methods A total of 96 consecutive patients undergoing hybrid ablation between January 2015 and December 2018 in a tertiary care center were enrolled. Blood samples were collected pre-ablation. Seven biomarkers [Bone Morphogenetic Protein 10 (BMP10), angiopoietin-2 (ANG2), Dickkopf WNT Signaling Pathway Inhibitor 3 (DKK3), Endothelial Cell Specific Molecule 1 (ESM1), Fibroblast Growth Factor 23 (FGF23), Insulin Like Growth Factor Binding Protein 7 (IGFBP7) and total N-terminal pro b-type natriuretic peptide (NT-proBNP)] were assayed at Roche Diagnostics based on their possible association with recurrence of AF. Clinical follow-up visits combined with 12-lead ECG and 24-hour Holter monitoring were scheduled at 3, 6 and 12 months post-procedure. Cox proportional hazards regression models were used to study the association with recurrence of AF. Results Out of the 96 patients (mean age 58±8 years; 18% women), 17 (17.7%) developed recurrence of AF within 1 year post-ablation. Median time to diagnosis was 191 days (range: 92-344). Comparisons between patients with and without recurrence of AF are depicted in Table 1. Multivariable Cox proportional hazard regression, adjusted for sex, showed that older age (HR 1.104, 95% CI 1.003-1.215, p=0.043), type of AF (HR 0.322, 95% CI 0.117-0.886, p=0.028), a history of peripheral vascular disease (HR 13.84, 95% CI 3.13-61.14, p&amp;lt;0.001) and recurrence in the blanking period (HR 14.25, 95% CI 3.99-50.85, p&amp;lt;0.001) were associated with recurrence of AF within 1 year post-ablation, but no blood biomarkers (Figure 1). Conclusion In AF patients undergoing extensive ablation, older age, type of AF, a history of peripheral vascular disease and recurrence in the blanking period were determinants of AF recurrence within 1 year post-ablation.

Decline of physical performance in patients with transthyretin amyloid cardiomyopathy assessed by cardiopulmonary exercise testing

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by the Medical Scientific Fund of the Mayor of the City of Vienna. Introduction The Transthyretin Amyloid Cardiomyopathy [ATTR-CM] is a progressive disease. Tafamidis is the only approved treatment for ATTR-CM. Nevertheless, extensional evidence above short follow up periods for improvement in physical performance [PP] still lacks. Purpose The purpose of this prospective analysis was to assess the PP in patients with ATTR-CM at baseline compared to follow-up visits over a long-term follow-up period. Methods Patients underwent Cardiopulmonary exercise testing [CPET] and blood testing at baseline, first follow-up [1st FUP] (9 ± 3 months after initiating Tafamidis therapy) and second FUP [2nd FUP] (19 ± 12 months after initiating Tafamidis therapy). We analysed CPET parameters during rest, exercise and recovery and laboratory values prior to CPET. The baseline data was compared with data from 1st FUP and 2nd FUP. Concerning cohorts, patients at baseline were Tafamidis naïve, while patients at 1st FUP and 2nd FUP received Tafamidis 61mg once daily during entire study duration of 26 (± 11) months. An improvement in VO2 at maximum level of exercise [VO2 max] was defined as an increase in ∆max VO2 ≥ 1 mL/kg/min, compared to baseline. A decline was defined as a negative ∆max VO2 mL/kg/min compared to baseline. Results We analysed 11 male patients, with a median age at study entry of 75 (± 9) years and a median Body Mass Index of 26 kg/m2 (± 6 kg/m2). Use of Betablockers was higher at 2nd FUP compared to baseline (54.5% vs 27.3%). Further, Diuretics and/or mineralocorticoid antagonist use was higher at 2nd FUP compared to baseline (63.6% vs. 54.5%). We analysed 33 CPET measurements, evenly divided into baseline, 1st FUP and 2nd FUP. Maximal physical performance was increased at 1st FUP compared to baseline (104.27 Watt vs. 91.45 Watt), but reduced at 2nd FUP compared to 1st FUP (99.36 Watt vs. 104.27 Watt) as illustrated in Figure 1. An increase in VO2 max was evaluated in the 1st FUP compared to baseline (18.75 mL/kg/min vs. 17.70 mL/kg/min). Further, we observed a reduction of VO2 max at 2nd FUP compared to the baseline values (15.80 mL/kg/min vs. 17.10 mL/kg/min). Minute ventilation and exhaled CO2 [VE/VCO2] slope was higher in 1st FUP compared to baseline (35.96 vs. 35.38) and higher compared to 1st FUP (30.31 vs. 35.96). Long term assessment of laboratory values, such as high sensitivity Troponin-T showed an increase at 2nd FUP compared to baseline by 19.30% (51.00 ng/L vs. 42.75 ng/L), further assessment showed a worsening in N-terminal pro brain natriuretic peptide value by 12.14% by comparing 2nd FUP versus baseline (2194.56 ng/L vs. 1956.93 ng/L) as illustrated in Figure 2. Conclusion ATTR-CM is a progressive disease, a decline of physical performance under Tafamidis and optimal background therapy is common in ATTR-CM patients. Future studies are needed to evaluate the benefit of specific interventions such as rehabilitation to maintain and improve physical performance in ATTR-CM patients.

Carcinoid Heart Disease Management: A Multi-Disciplinary Collaboration.

Carcinoid heart disease (CaHD) is an important complication among patients with metastatic neuroendocrine tumors and carcinoid syndrome (CS). CS patients (25%-65%) eventually develop CaHD; these patients face a significantly increased risk of morbidity and mortality. Guidance papers (eg, clinical practice guidelines, consensus guidelines, and expert statements) have been established by major organizations across the disciplines of cardiology and oncology; however, these recommendations are not routinely implemented. The aim of this article is to encourage the integration of current recommendations from national societies into clinical practice. Early screening upon recognition of CS and prior to the development of CaHD symptoms is paramount, as no existing therapies are approved to reverse the fibrotic damage to the heart once it occurs. Valvular replacement is the only definitive treatment for CaHD once it has developed. When patients are noted to have urinary 5-hydroxyindoleacetic acid (5-HIAA) levels ≥300 µmol/24 h and/or serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels >260 pg/mL, echocardiography is recommended. Systemic approaches to control tumor growth and hormonal secretion include somatostatin analogs (SSAs), followed by options including peptide receptor radiotherapy (PRRT), everolimus and liver embolization. Telotristat is the primary choice for control of diarrhea refractory to SSA. Diuretics are the mainstay of heart failure symptom management for patients who develop CaHD. Considerations for future research are discussed, including the ongoing TELEHEART (TELotristat Ethyl in a HEART biomarker study) trial involving telotristat and not yet activated CHARRT (Carcinoid Heart disease And peptide Receptor Radiotargetted Therapy) study involving PRRT with lutetium 177 (177Lu) dotatate.

Elongated Styloid Process Can be Made Responsible for Recurrent Embolic Stroke Only if Eagle Syndrome is Present

With interest we read the article by Xu et al. on a 59 year-old male with recurrent episode of left hemispheric, embolic stroke [1]. Elongated styloid process (ESP) and carotid web pocket were identified as causes of recurrent stroke [1]. After resection of the ESP and resection of the carotid web, the patient became asymptomatic during a 6 months follow-up [1]. The study is excellent but has limitations that are cause of concerns and should be discussed. The main limitation of the study is that alternative causes of embolic stroke were not entirely ruled out. We should know whether there were any indications for alternative causes of embolic stroke, such as heart failure, atrial fibrillation, Takotsubo syndrome. noncompaction, endocarditis, valve abnormalities, or myocarditis. Missing in this respect are echocardiography and ultrasound of vertebral arteries. As long as all these alternative sources of embolism were not adequately ruled out, ESP and carotid web pocket cannot be made responsible for recurrent stroke with certainty. There is also no mention of inflammatory parameters, blood coagulation parameters, platelet counts, troponin values, and pro brain-natriuretic peptide (proBNP). A strong argument against the ESP as the cause of recurrent stroke is that ESP presumably existed already for a long time. No explanation is provided why it became symptomatic just at age 58 years. Where there ever any sudden neurological deficits recognised during previous years (&gt;1.5 years before)? Another argument against ESP as the cause of recurrent stroke is that the index patient did not present with typical Eagle syndrome also referred as stylohyoid syndrome, styloid syndrome, or styloid–carotid artery syndrome [2]. Eagle syndrome is clinically characterised by orofacial and cervical pain often triggered by neck movements, by dysphagia, facial palsy, slurred speech, and vertigo [2]. Eagle syndrome can be associated with ankyloting spondylitis [3], which should have been ruled out in the index patient. The diffusion weighted imaging (DWI) lesions shown in figure 1 panel A do not explain right-sided weakness of the upper limb and amaurosis. The precentral lesions are too small and not directly in the area of the cortical upper limb representation to explain limb weakness. Regarding unilateral amaurosis, we should know whether ophthalmologists ever documented occlusion of the central retinal artery. Amaurosis triggered by head flexion suggests that each time the head is flexed embolization into the left central retinal artery occurs, which is rather unlikely. Clamping of the carotid artery by head flexion is unlikely since no cerebral symptoms with head flexion were reported [1]. Another argument against amaurosis as a manifestation of ESP is that no such cases have been previously reported. Overall, the interesting study has limitations that call the results and their interpretation into question. Addressing these issues would strengthen the conclusions and could improve the status of the study. Before attributing recurrent embolic stroke to ESP and carotid web, it is crucial to adequately rule out all alternative causes of embolic stroke. Recurrent unilateral amaurosis triggered by head flexion cannot be easily explained by ESP.