bluuebunny/crossref_metadata_2025_split huggingface dataset:
P1530Vasorelaxation as a mechanism of procyanidin B2 cardioprotective effect
Authors: Marinko M , Jankovic G , Milojevic P , Stojanovic I , Nenezic D , Kanjuh V , Yang Q , He G W , Novakovic A 
Published: October 2019

Abstract

Introduction
Findings from epidemiological studies indicate that polyphenols, widespread in human diet and with numerous biological activities, act cardioprotectively. Procyanidins are subclass of polyphenols with high content in commonly consumed foods and beverages, such as grapes, tea, chocolate, nuts and apples. Cardioprotective abilities of procyanidins, might, at least in part, attribute to their vasodilator properties.

Purpose
Because the exact mechanisms by which procyanidin B2 causes vasorelaxation are unclear, we aimed to investigate relaxant effect of procyanidin B2 on the isolated human internal mammary artery (HIMA) and its underlying mechanisms.

Methods
The HIMA segments were collected from patients suffering from coronary artery disease who were undergoing coronary artery bypass surgery and studied in organ bath.

Results
Procyanidin B2 induced strong concentration-dependent relaxation of HIMA rings pre-contracted by phenylephrine. Pretreatment with L-NAME, a NO synthase inhibitor, hydroxocobalamin, a NO scavenger, and ODQ, an inhibitor of soluble guanylate cyclase, significantly inhibited procyanidin B2-induced relaxation of HIMA, while indomethacin, a cyclooxygenase inhibitor, considerably reduced effects of low concentrations. Among K+ channel blockers, iberiotoxin, a selective blocker of large conductance Ca2+-activated K+ channels (BKCa), abolished procyanidin B2-induced relaxation, glibenclamide, a selective ATP-sensitive K+ (KATP) channel blocker, induced partial inhibition, while 4-aminopyridine, a blocker of voltage-gated K+ (KV) channels, and TRAM-34, an inhibitor of intermediate-conductance Ca2+-activated K+ (IKCa) channels, slightly reduced maximal relaxation of HIMA.

Conclusion
Our results demonstrate that, in HIMA, procyanidin B2 produces strong endothelium-dependent vasorelaxant effect. It seems that this relaxation is primarily the result of an increased NO synthesis and secretion by endothelial cells and partially of prostacyclin, although it involves activation of BKCa and KATP, as well as KV and IKCa channels in high concentrations of procyanidin B2.

Acknowledgement/Funding
The study was supported by a Scientific Research Grant (P175088) from Ministry of Science and Technology Serbia.
P1537Cardiotoxicity induced by the combinatorial treatment based on the immune checkpoint inhibitor pembrolizumab associated to trastuzumab
Authors: Maurea N , Quagliariello V , Passariello M , Coppola C , Rea D , Barbieri A , Arra C , Scherillo M , Iaffaioli R V , Botti G , De Lorenzo C 
Published: October 2019

Abstract

Background
The immunotherapy has revolutionized the world of oncology in the last decades with considerable advantages in terms of overall survival in cancer patients. A combination therapy based on the co-administration of Pembrolizumab (an antibody against PD-1) and Trastuzumab (the humanized anti-Her2 mAb) was recently proposed in clinical trials for the treatment of Trastuzumab-resistant advanced HER2-positive breast cancer. Although immunotherapies are frequently associated with a wide spectrum of immune-related adverse events, the cardiac toxicity has not been properly studied.

Purpose
We studied, for the first time, the putative cardiotoxic effects of Pembrolizumab associated to Trastuzumab turning the light on the pro-inflammatory effects of this novel combined therapy

Methods
Cell viability, intracellular calcium quantification and pro-inflammatory assays (analyzing the production of Interleukin 1β, 6 and 8 as well as the expression of p65/NFkB and Leukotriene B4) were performed in human fetal cardiomyocytes in vitro. Preclinical studies were also performed in vivo on C57BL6 mice untreated (Sham) or treated with Pembrolizumab and Trastuzumab alone or in combination by analyzing (in cardiac tissue extracts) the same markers of inflammation used in cellular studies.

Results
Combination therapy leads to an increase of the intracellular calcium overload (more than 3 times compared to untreated cells) and to a reduction of the cardiomyocytes viability (of more than 65 and 20–25%, compared to untreated and Pembrolizumab or Trastuzumab treated cells, respectively) thus indicating cardiotoxic effects. Notably, combination therapy increases the inflammation of cardiomyocytes enhancing significantly the production of p65/NFkB and Interleukins. Moreover, in in vivo studies on mice, the association of Pembrolizumab and Trastuzumab shows pro-inflammatory effects in cardiac tissue by stimulating the Interleukin 1β, 8 and 6 expression of 40–50% more than the single treatments; the expression of p65/NFkB and Leukotriene B4 was also increased indicating pro-inflammatory effects.

Conclusion
Combination therapy based on Pembrolizumab associated to Trastuzumab leads to significant cardiac pro-inflammatory effects mediated by overexpression of NFkB/p65 and Leukotriene B4 related pathways
P1541The relation between right ventricular-pulmonary circulation coupling and aging in healthy population
Authors: Vriz O V , Ferrara F F , Galzerano D G , Adams M A , Shisamma E S , Naeije R N , Bossone E B 
Published: October 2019

Abstract

Purpose
The aim of the study was to evaluate the right ventricular (RV) structure and functional adaptation to age, in particular the RV pulmonary circulation (PC) coupling and physiologic correlates.

Methods
1177 healthy subjects aged 16–100 years were enrolled. They underwent general medical evaluation and a comprehensive TTE included RV systolic such as tricuspid annular plane systolic excursion (TAPSE), pulmonary artery systolic pressure (PASP) derived from the tricuspid regurgitation (TR), the derived RV-pulmonary circulation (PC) coupling or TAPSE/PASP, pulmonary vascular resistances (PVR) derived from TR/RV outflow tract velocity (RVOT VTI) and diastolic function parameters. The cohort was divided in 4 groups of age: group 1: 300 subjects from 18 to 35 years; group 2: 383 subjects from 36 to 50; group 3: 451 from 50 to 79 years and group 4: 43 subjects > than 80 years of age The oldest subjects were completely independent in daily living activities. The groups were compared by ANOVA and the difference was adjusted by gender, BMI and mean arterial pressure. For each group the difference between genders was tested by T-Test. Multivariate analysis was used to evaluate the relationship between RV function and structure indexes and covariates selected according to pathologic relevance.

Results
There was a progressive increase in blood pressure (BP) according to age. The RV longitudinal diameter, right E/A ratio, right ventricular outflow tract acceleration time and TAPSE/PASP decreased according to age increase (p<0.0001). The right atrial volume indexed by BSA, PASP, PVR increase with age (p<0.0001). Either TAPSE or Sm were unaffected by age. Women had constantly smaller RV longitudinal diameters, right atrium volume index, TAPSE and TAPSE/PASP (p<0.001). In the multiple regression analysis, though the proportion of variance of the dependent variables predicted by the independent ones was very small, age, BSA, gender, E/Em and the longitudinal diameter of the RV were independent predictors of TAPSE/PASP. Heart rate, left ventricular (LV) diastolic function, stroke volume (SV) and TR were independently related to Sm, while age, BSA, LV diastolic function and SV were independently related to TAPSE.

Conclusion
With ageing there is a progressive involvement not only of the LV in terms of adaptation to increase afterload related to arterial stiffness but also of the RV. With age PVR and PASP increase while RV contractility is still unchanged. While the RV adapts very well to volume overload, even the physiologic increase in PASP with age, causes a RV-PC coupling impairment.
P1555Agreement of coronary calcium scoring on chest CT and ECG triggered cardiac CT: a population-based study
Authors: Xia C , Alsurayhi A , Pelgrim G J , Rook M , Vonder M , Oudkerk M , Vliegenthart R 
Published: October 2019

Abstract

Background
Low-dose chest computed tomography (CT) is increasingly used in lung cancer screening. The heart is inherently visualized on chest CT. Coronary artery calcium (CAC) identified on chest scans has predictive value for risk of cardiovascular disease. There is discussion whether non-ECG-triggered chest CT is reliable for CAC scoring.

Purpose
To investigate the agreement between chest CT and ECG-triggered cardiac CT in CAC identification and risk classification.

Methods
We included 1000 ImaLife participants who underwent a cardiac scan immediately followed by a non-ECG triggered chest scan. Third-generation dual-source CT and dedicated software were used for scan acquisition and CAC measurement. Chest scans were analyzed after cardiac scans with an interval of at least a month and in a different order. To ensure a comparable prevalence of CAC with previous studies and adequate samples in CAC strata, after the inclusion of the 500th consecutive participants with zero CAC, only participants with >0 CAC based on dedicated cardiac CT were included. CAC scores were divided into four risk strata: 0, 1–99, 100–399, 400. Kappa was used to assess agreement in CAC identification (0 versus >0) and risk classification.

Results
The mean age was 54 years (range 45–77), 42.5% were women, average body mass index (BMI) was 26.1kg/m2. Compared with dedicated cardiac CT, non-ECG triggered chest CT had an accuracy of 0.97, sensitivity of 0.96 and specificity of 0.99 for identifying CAC, and agreement between scans was very high (kappa 0.95) for CAC presence. In terms of CAC risk strata, chest CT had a very high agreement with cardiac CT (kappa 0.95). Total misclassification rate of CAC strata was 6.5%, with most misclassified cases shifting one risk category downward (55/65, 85%). BMI of discordant pairs was significantly higher than concordant pairs, while no difference in heart rate was found.

Conclusion
Non-ECG triggered chest CT may be reliably used for CAC identification and risk classification since chest CT has very high agreement with dedicated cardiac CT results.
P1559Frailty is an independent predictor of one-year mortality in patients with ST-segment elevation myocardial infarction, regardless of age, clinical severity and left ventricular function
Authors: Arroyo Espliguero R , Silva-Obregon A , Viana-Llamas M C , Estrella-Alonso A , Saboya-Sanchez S , Uribe-Heredia G , Eguileor-Marin Z , Castillo-Sandoval A , Arriero-Fernandez N , Garcia-Magallon B , Toran-Martinez C , Marian-Crespo C 
Published: October 2019

Abstract

Background
Frailty is characterized by decline in physiologic reserve and function leading to increased vulnerability. Sarcopenia, one of its features, has been associated with cardiac dysfunction.

Purpose
Assess frailty-based mortality in ST-segment elevation myocardial infarction (STEMI) patients following primary angioplasty.

Methods
Retrospective cohort of 427 consecutive STEMI patients (64 years [55–75]; 78% men) admitted to a general ICU between November-2013 and February-2017. We assessed frailty with the Clinical Frailty Scale (CFS). We used Kaplan-Meier and Cox regression models for survival analysis, stratified by CFS score categories (Figure). For clinical relevance, patients were dichotomized in robust (CFS 1–3) and vulnerable (CFS ≥4).

Results
Vulnerable patients were older, had more comorbidities and a higher GRACE 2.0. They had lower CK and albumin levels and higher BNP levels, despite the lack of frailty-based differences in LVEF and MI size and location. One-year mortality rate was higher in vulnerable patients (Table). After Cox regression analysis, vulnerable patients (CFS ≥4) showed a 3.37-fold higher risk of one-year mortality than robust ones (95% CI, 1.59–7.15; P=0.002), independently of age, gender, GRACE 2.0 or LVEF.
Baseline characteristics Vulnerable (CFS ≥4) Robust (CFS 1–3) P value (n=60) (n=367) One-year mortality, n (%) 15 (25) 14 (4.1) <0.001 Age (years) 78 [67–85] 61 [54–72] <0.001 Gender (women), n (%) 28 (46.7) 65 (17.7) <0.001 Hypertension, n (%) 47 (78.3) 156 (42.5) <0.001 Diabetes mellitus, n (%) 31 (51.7) 79 (21.5) <0.001 GRACE 2.0 150 [129–170.8] 112 [93–136] <0.001 Left ventricular ejection fraction (%) 52 [40–60] 55 [45–60] 0.151 MI location (anterior), n (%) 26 (43.3) 168 (45.8) 0.781 Creatin-phosphokinase (UI/L) 921 [286.8–2072] 1496 [607–2786] 0.011 High-sensitivity troponin I (pg/mL) 3699.5 [38–47968.1] 8789.8 [65.8–61970] 0.537 B-natriuretic peptide (pg/mL) 267.9 [117.3–901.6] 104.3 [29.5–268.7] <0.001 Albumin (g/L) 34.9 [32.8–37.4] 38.4 [35.7–40.4] <0.001
Kaplan-Meier and Cox survival curves.

Conclusions
Frailty is an independent predictor of one-year mortality in STEMI patients, independently of age, clinical severity and ventricular function. Frailty assessment should be routinely included in the clinical examination and decision-making process of STEMI patients.
P1572Cardiovascular and inflammatory biomarkers in cancer patients and their impact on mortality
Authors: Lueck L C , Lena A , Hadzibegovic S , Weinlaender P , Letsch A , Karakas M , Landmesser U , Anker S D , Anker M S , Von Haehling S 
Published: October 2019

Abstract

Background
Cardiovascular (CV) blood biomarkers are considered prognostic markers of CV dysfunction during anti-cancer treatment. It is largely unknown, whether they are also prognostic markers for mortality.

Purpose
To investigate the prognostic impact of CV and inflammatory biomarker levels in cancer patients without significant CV disease at baseline on all-cause mortality.

Methods
We enrolled 138 unselected cancer patients without significant CV disease from November 2017 until December 2018 (age 63±14yrs, 45%male, body mass index (BMI) 25.5±7.7kg/m2) and 25 healthy controls (age 57±10yrs, 36% male, BMI 25.1±3.4kg/m2). The cancer group consisted of 85 lymphoma (62%), 25 breast cancer (18%), 10 colorectal cancer (7%), 11 non-small cell lung cancer (8%) and 7 other types of cancer (5%) patients. All cancer stages were represented (25% I/II, 76% III/IV). For biomarker analyses, blood samples were taken from an antecubital vein.

Results
N-terminal pro brain natriuretic peptide (NT-proBNP), high-sensitive Troponin T (hsTnT) and C-reactive protein (CRP) were significantly increased in cancer patients vs. healthy controls (90 ng/L [85–94] vs. 40 ng/L [35–45], p<0.0001; 89 ng/L [IQR 85–93] vs. 44 ng/L [39–48], p<0.0001; 84.3 mg/L [78.8–89.7] vs. 27.9 mg/L [22.5–33.4], p<0.0001). 29 cancer patients (21%) died during a mean follow-up time of 172 days (range 1–405) (6-month mortality 23% [95% CI 15–32]). In univariable Cox analyses all biomarkers predicted survival: NT-proBNP (per 100ng/L, HR 1.049 [1.013–1.085], p=0.0082), hsTnT (per 1ng/L, HR 1.017 [95% CI 1.006–1.029], p=0.0017) and CRP (per 1mg/L, HR 1.019 [1.009–1.030], p<0.0001). Including the two CV biomarkers and the inflammatory biomarker, cancer entity, cancer stage and other clinical variables in multivariable Cox analysis, all three biomarkers remained significant prognostic markers of mortality (NT-proBNP per 100ng/L, HR 1.044 [1.007–1.082], p=0.021; hsTnT per 1ng/L, HR 1.017 [1.005–1.030], p=0.0067; CRP per 1ng/L, HR 1.017 [1.005–1.029], p=0.0047). To predict survival, the best cut-offs for the highest product of specificity and sensitivity were 260ng/L for NT-proBNP, 12ng/L for hsTnT and 9mg/L for CRP.

Conclusion
In cancer patients without significant CV disease, plasma levels of the CV biomarkers NT-proBNP, hsTnT and the inflammatory biomarker CRP are elevated compared to healthy controls. All three blood biomarkers are independent prognostic markers of short-term mortality.
P1585Increased circulating galectin 1 level is associated with progression of kidney function decline in patients with suspected coronary artery disease, independent of diabetes
Authors: Kuo C S , Chou R H , Lu Y W , Lin S J , Huang P H 
Published: October 2019

Abstract

Background
Galectin-1 modulates acute and chronic inflammation, and is associated with glucose homeostasis and chronic renal disease. Whether serum Galectin-1 levels could predict the short-term and long-term renal outcomes after contrast exposure in patients with suspected coronary artery disease remains uncertain.

Purpose
This study aimed to evaluate the relationship between serum Galectin-1 levels and the incidence of contrast-induced nephropathy and to investigate the predictive role of circulating galectin-1 levels in renal function decline in patients undergoing coronary angiography.

Methods
In total, 798 patients who had received coronary angiography were enrolled. Serum galectin-1 levels were determined before administration of contrast media. Contrast-induced nephropathy was defined as a rise in serum creatinine of 0.5 mg/dL or a 25% increase from baseline within 48 h after the procedure. Progressive renal function decline was defined as >30% decrease in estimated glomerular filtration rate after discharge. All patients were followed up for at least one year or until the occurrence of death after coronary angiography.

Results
Overall, contrast-induced nephropathy occurred in 41 (5.1%) patients. During a median follow-up of 1.4±1.1 years, 80 (10.0%) cases had subsequent decline in renal function. After adjustment for demographic characteristics, kidney function, traditional risk factors, and medications, higher galectin-1 level was found to be independently associated with a higher risk for mortality and renal function decline (tertile 2, HR=3.12 95% CI,1.25–7.78; tertile 3, HR=3.25, 95% CI,1.42–7.41) but not for contrast-induced nephropathy, regardless of the presence of diabetes.

Conclusions
Higher baseline serum galectin-1 levels were associated with a higher risk of mortality and renal function decline in patients undergoing coronary angiography. Galectin-1 may play a pivotal role in progressive renal dysfunction, but further studies are needed to verify these results.

Acknowledgement/Funding
Ministry of Science and Technology of Taiwan (MOST 104-2314-B-075-047), Taipei Veterans General Hospital (V105C-0207, V106C-045, V108C-195)
P1597Two novel mutations in SCN5A gene cause enhanced inactivation and lead to Brugada syndrome
Authors: Zaytseva A , Karpushev A V , Karpushev A V , Fomicheva Y , Fomicheva Y , Vasichkina E S , Vasichkina E S , Michaylov E N , Michaylov E N , Kostareva A A , Kostareva A A , Zhorov B Z , Zhorov B Z 
Published: October 2019

Abstract

Background
Mutations in gene SCN5A, encoding cardiac potential-dependent sodium channel Nav1.5, are associated with various arrhythmogenic disorders among which the Brugada syndrome (BrS) and the Long QT syndrome (LQT) are the best characterized. BrS1 is associated with sodium channel dysfunction, which can be reflected by decreased current, impaired activation and enhanced inactivation. We found two novel mutations in our patients with BrS and explored their effect on fast and slow inactivation of cardiac sodium channel.

Purpose
The aim of this study was to investigate the effect of BrS (Y739D, L1582P) mutations on different inactivation processes in in vitro model.

Methods
Y739D and L1582P substitutions were introduced in SCN5A cDNA using site-directed mutagenesis. Sodium currents were recorded at room temperature in transfected HEK293-T cells using patch-clamp technique with holding potential −100 mV. In order to access the fast steady-state inactivation curve we used double-pulse protocol with 10 ms prepulses. To analyze voltage-dependence of slow inactivation we used two-pulse protocol with 10s prepulse, 20ms test pulse and 25ms interpulse at −100mV to allow recovery from fast inactivation. Electrophysiological measurements are presented as mean ±SEM.

Results
Y739D mutation affects highly conserved tyrosine 739 among voltage-gated sodium and calcium channels in the segment IIS2. Mutation L1582P located in the loop IVS4-S5, and leucine in this position is not conserved among voltage-gated channels superfamily. We have shown that Y739D leads to significant changes in both fast and slow inactivation, whereas L1582P enhanced slow inactivation only. Steady-state fast inactivation for Y739D was shifted on 8.9 mV towards more negative potentials compare with that for WT, while L1582P did not enhanced fast inactivation (V1/2 WT: −62.8±1.7 mV; Y739D: −71.7±2.3 mV; L1582P: −58.7±1.4 mV). Slow inactivation was increased for both substitutions (INa (+20mV)/INa (−100mV) WT: 0.45±0.03; Y739D: 0,34±0.09: L1582P: 0.38±0.04).
Steady-state fast inactivation

Conclusions
Both mutations, observed in patients with Brugada syndrome, influence on the slow inactivation process. Enhanced fast inactivation was shown only for Y739D mutant. The more dramatic alterations in sodium channel biophysical characteristics are likely linked with mutated residue conservativity.

Acknowledgement/Funding
RSF #17-15-01292
P1621m6A RNA-methylation in the progression of heart failure
Authors: Buchholz E , Berulava T , Ellerdashvilli V , Pena T , Lbik D , Mohamed B , Sloan K , Bohnsack M , Hasenfuss G , Fischer A , Toischer K 
Published: October 2019

Abstract

Introduction
N6-Methyladenosine (m6A) is the most abundant modification of RNA and was found to be a dynamic and reversible process. It is found in many classes of RNA, such as mRNA, noncodingRNA (ncRNA) and microRNA (miR). mRNA methylation can affect splicing, transport and storage or decay, ncRNA methylation might influence signal transduction directly as well as it might affect miR interference. Deregulation of such epigenetic processes and aberrant gene expressions are important mechanisms in heart failure. Here we studied the potential relevance of m6A RNA-methylation in cardiac hypertrophy and heart failure development.

Methods and results
m6A RNA-methylation was analysed via methylated RNA immunoprecipitation (meRIP) and subsequent next generation sequencing (NGS). Our data shows that approximately one quarter of the transcripts in the healthy mouse (24.09%) and human heart (14.6%) exhibit m6A RNA-methylation. A mild positive correlation of m6A RNA-methylation at the 5'UTR and coding region with transcript level was observed while m6A RNA-methylation at the 3'UTR showed a mild negative correlation.
We analysed heart failure in mice and humans and observed that changes in m6A RNA-methylation exceed changes in gene-expression (in human data 1219 differentially methylated and 198 diff. expressed, with 30 showing changes in both methylation and expression; in mouse data 1135 diff. methylated and 127 diff. expressed, with 47 showing changes in both methylation and expression). In mouse and human heart failure, transcripts with altered m6A RNA-methylation were mainly linked to metabolic and regulatory pathways while changes in transcript level mainly represented changes in structural plasticity. In the diseased state m6A RNA-methylation showed no correlation to transcript level. To gain further insight into m6A mediated effects on the translational level, polysome-sequencing was applied. These data provide evidence that in the diseased heart changes in m6A RNA-methylation affect RNA translation, represented by a positive correlation (r=0.37, p=2.2e-16) of log2fc changes in translation and m6A methylation.

Conclusions
Our study describes m6A RNA-methylation at the genome-wide level in the human heart. The mouse model provides evidence that changes in m6A RNA-methylation plays an important role in heart failure development by affecting regulatory pathways distinct from those genes with altered expression levels. Our data suggest that modulation of epitranscriptomic processes such as m6A-methylation might be an interesting target for therapeutic interventions.

Acknowledgement/Funding
CRC 1002