bluuebunny/crossref_metadata_2025_split huggingface dataset:
P5437The BNP reporter mouse by knock-in technology is useful for the analysis of mechanism in reactivation of BNP in adult heart
Authors: Okamoto R , Hashizume R , Ito R , Suzuki N , Kiyonari H , Ito M 
Published: October 2019

Abstract

Background
It has been thought BNP is induced by undetermined stretch-activated receptors, however, which receptor is associated remains unknown. The stretch-activated receptors include mechanically gated channels, which can be activated by a mechanical stimulus alone, and mechanically modulated channels, which require nonmechanical stimuli such as agonists. It has been recently shown that 1.1kb segment of mouse NPPB promoter dose not reproduce the pattern of reactivation of BNP in adult heart, although it could monitor the expression of BNP in neonatal cardiomyocytes.

Purpose
Our aim is to develop a true BNP reporter mouse and examine whether this mouse is useful or not for the investigation of BNP reactivation mechanism in adult heart and for the measurement of serum-induced BNP expression in patients with heart failure.

Methods
We generated the BNP reporter mice by knocking luciferase cDNA in the initiation site of NPPB. In vivo imaging of luciferase was performed in the BNP reporter mice after the intraperitoneal injection of luciferin. The luciferase activity was examined in neonatal cardiomyocyte, isolated adult cardiomyocytes, adult cardiac dissected tissue with or without 120–150% stretch or angiotensin II stimulation. Left anterior descending (LAD) coronary artery was ligated to study myocardial infarction. Cardiac dissected tissue segments from the BNP reporter mouse were incubated for 8 hours with 20% serum from patients with or without heart failure and the luciferase activity was measured after homogenization.

Results
The in vivo imaging system showed the activity of BNP was high in 1 day-old neonates and the reactivation of BNP in the adult heart after LAD ligation could be monitored by the luciferase activity (figure). The treatment of Ang II could increase the activity of pBNP more than ten folds in heart tissue from adult mice. On the other hand, the 120–150% stretch did not show any effect on the activity of pBNP in this system. We could not observe any activation of pBNP in cultured neonatal or adult cardiomyocytes demonstrated by immunostain with antibodies against luciferase after 120–150% stretch. Interestingly, the luciferase activity was extensively higher in cultured heart tissue segments from the BNP reporter mice after the treatment of serum from patients with heart failure than without heart failure.
In vivo imaging of BNP reporter mice

Conclusion
These results indicate the BNP reporter mouse by knock-in technology is useful for the analysis of mechanism in reactivation of BNP in adult heart and the elevation of BNP in patients of heart failure partly due to the serum-derived induction of BNP from heart.
P5443NOD2 knock down worsens diastolic dysfunction in murine angiotensin II-induced heart failure
Authors: Mueller I , Lin J , Pappritz K , Tschoepe C , Van Linthout S 
Published: October 2019

Abstract

Background
Heart failure with preserved ejection fraction (HFpEF) is associated with cardiac inflammatory responses, indicating a potential role of the immune system in the pathology of diastolic dysfunction. The cytoplasmatic pattern recognition receptor, nucleotide binding oligomerization domain 2 (NOD2) belongs to the innate immune system and induces among others the NLRP3 inflammasome, known to be involved in myocarditis and coronary heart disease.

Purpose
The aim of this study was to explore the role of NOD2 in Angiotensin II (AngII)-induced diastolic heart failure.

Methods
In NOD2−/− knock down and C57Bl6/j-wild type (WT) mice, diastolic dysfunction was induced by subcutaneous administration of 1.4mg/kg*day–1 AngII. Twenty-one days after first AngII administration, left ventricular (LV) function was evaluated by pressure tip catheter. Cardiac fibrosis, inflammation, and the expression of NOD2 and the NLRP3 component Apoptosis-associated speck like protein containing a caspase recruitment domain (ASC) were determined via immunohistochemistry, real-time PCR or Western Blot.

Results
LV NOD2 mRNA expression was 2.3-fold (p<0.0005) and 1.9-fold (p<0.0005) lower in NOD2−/− control and NOD2−/− AngII mice compared to their respective WT littermates. In parallel, LV protein expression of the downstream NLRP3 component Apoptosis-associated speck like protein containing a caspase recruitment domain (ASC) was 1.5-fold (p<0.05) lower in NOD2−/− AngII mice versus WT AngII mice, whereas LV protein IL-1β levels were unchanged. LV diastolic dysfunction was more pronounced in NOD2−/− AngII mice versus WT AngII mice, as displayed by a 19% (p<0.05) increased LV relaxation time and 24% (p<0.057) impaired dP/dtmin, with no changes in the ejection fraction (EF: NOD2−/− AngII 72.5%±5.4 versus WT AngII 65.6±3.5). In parallel, LV presence of CD68-positive cells was 1.8-fold (p<0.05) higher in NOD2−/− AngII compared to WT AngII mice. Concomitantly, NOD2−/− AngII mice displayed 1.3-fold (p<0.05) and 1.7-fold (p<0.05) higher LV mRNA expression of the chemokine macrophage inflammatory protein (MIP)-2 and monocyte chemotactant protein (MCP)-1 compared to WT AngII mice, respectively. Furthermore, cardiac interstitial fibrosis in NOD2−/− mice with AngII-induced diastolic dysperformance was more pronounced versus the WT AngII group, as indicated by a 2.0-fold (p<0.0005), 2.0-fold, and 1.6-fold (p<0.05) higher LV ColI/ColIII ratio, and TGF-β and TIMP-1 mRNA expression, respectively.

Conclusion
NOD2−/− deteriorates LV diastolic dysfunction and worsens pathophysiological key mechanisms in mice with AngII-induced diastolic heart failure.
P5456The role of ST2 as an early marker of endothelial dysfunction in hypertensive patients
Authors: Farcas A D , Stoia M A , Mocan M , Chiorescu R M , Mocan-Hognogi D L , Goidescu C M , Anton F P 
Published: October 2019

Abstract

Background
The association between endotelial dysfunction and progression of diastolic dysfunction suggests that endotelial and myocardial impairment might have similar pathogenic pathways. Moreover, in hypertensive diabetics the endotelial function is worse in those with impaired diastolic performance compared to normal diastolic performance. ST2 provides additional data to echocardiography in early detection of diastolic performance alteration in hypertension (HT) and is a prominent predictive marker of worse clinical outcome in hypertensive patients. There is scarce data on ST2 role in detection of early vascular involvement in hypertensive patients.

Purpose
The aim of the study is to evaluate whether ST2 levels correlate with impaired endotelial function in hypertensive patients.

Methods
Our prospective study included 84 hypertensive patients (mean age 52.9±14.4 yrs, 54.3% males and 45.7% females), after they signed an informed consent. All patients underwent clinical and laboratory (including ST2) evaluation. To investigate endothelial function, we performed ultrasound measurement of the brachial artery diameter both at rest and during reactive hyperemia in the muscle distal to the brachial artery (BA) which causes endothelium-dependent vasodilatation. The study methodology was approved by the Ethical Committee and statistical data processing was performed with SPSS.

Results
Patients were assigned to group A – those without left ventricular hypertrophy (LVH) and group B – those with LVH. There were no significant differences regarding gender, age and HT stage between groups A and B. Patients in group A had lower ST2 levels [18.83 (13.98 - 42.05) vs 55.63 (48.6 - 100.21) vs, p<0.001] and fewer risk factors (1.4 vs 2.6, p<0.01) compared to group B. We found significant differences regarding diastolic performance parameters between the groups. The relative increase in diameter (% FMD; DD = D 100) was significantly higher in group A than group B (6.67±0.43% vs 3.10±0.33%, p<0.01). ST2 levels were greater in group B and correlated with the degree of endotelial dysfunction evaluated by flow-mediated dilatation (FMD) (r=0.411, p<0.01). Multiple regression analysis showed that ST2 had a significant negative correlation with the relative increase in arterial diameter while multivariate Cox regression analysis showed ST2 was an independent predictor of endothelial dysfunction severity in hypertensive patients (hazard ratio: 4.012, 95% confidence interval: 1.207–31.24, P=0.031).

Conclusions
ST2 levels correlate with cardiovascular risk and are a significant predictive marker of endothelial dysfunction in hypertensive patients regardless of diastolic dysfunction.
P5475Essential thrombocytosis is associated with worse hospital outcomes in patients presented with acute myocardial infarction: a propensity score analysis of the National Inpatient Sample
Authors: Wu L , Liu B , Zheng Y 
Published: October 2019

Abstract

Background/Introduction
Essential thrombocytosis (ET) is a rare disease characterized by vasomotor symptom, thrombotic event, and hemorrhage. Due to its rare occurrence, limited data are available to examine the impact of ET on acute myocardial infarction (AMI).

Purpose
To evaluate the impact of ET on hospital outcomes of AMI.

Methods
We use the 2016 National Inpatient sample database to identify all the admissions with a principal diagnosis of AMI with or without ET. A matched control group was then generated using propensity score from age, sex, race, location, insurance, income, hospital type, hospital location, Charlsoncat Comorbidity Score. Prevalence, baseline characteristic of AMI patient with or without ET was described and compared. Univariable logistic regression was used to measure mortality and the rate of catheterization.

Results
ET was found in 0.28% (1,814) in total AMI admissions (641,854). Age (69.52 vs 69.70), female percentage (48.04% vs 48.03%) and baseline comorbidities including STEMI (27.49% vs 25.08%), diabetes (33.03% vs 30.51%), heart failure (40.18 vs 45.89%) and chronic kidney disease (22.05% vs 26.28%) was found to be comparable between two groups (p>0.05, table 1). Compared to non ET group, ET is associated with significantly higher hospital mortality (5.74% vs 2.43%, OR 2.44 [1.09–5.48], p=0.03), prolonged length of stay (7.61 vs 4.30 days, p<0.01). Interestingly, ET is also associated with lower utilization of cardiac catheterization (37.46% vs 46.52%, p=0.01).
Essential Thrombocytosis and AMI Parameter AMI with ET Matched control: AMI without ET Odds ratio (95% CI) P value (n=1,814) (n=1,814) Age, years 69.52±0.72 69.70±0.70 p>0.05 Female, % 48.04 48.03 p>0.05 STEMI, % 27.49 25.08 p>0.05 Hypertension, % 81.57 83.08 p>0.05 Diabetes, % 33.03 30.51 p>0.05 Heart failure, % 40.18 45.89 p>0.05 Chronic kidney disease, % 22.05 26.28 p>0.05 Mortality, % 5.74 2.43 2.44 (1.09–5.48) p=0.03 Catheterization, % 37.46 46.52 0.68 (0.51–0.91) P=0.01 Length of stay, days 7.61±0.48 4.30±0.21 P<0.01 Values are reported as mean ± S.E. Categorical variables are represented as frequency.

Conclusion
ET is infrequently observed in patients with AMI. Having ET is associated with higher hospital mortality, longer hospital stay and lower utilization of cardiac catheterization.

Acknowledgement/Funding
None
P5479Educational attainment is an independent predictor of adverse outcomes in patients with coronary artery disease
Authors: Ghazzal B Z , Kelli H M , Mehta A , Tahhan A S , Kim J H , Dong T A , Dhindsa D S , Sandesara P B , Hayek S S , Alkhoder A A , Liu C , Ko Y , Vaccarino V , Sperling L S , Quyyumi A A 
Published: October 2019

Abstract

Background
Educational attainment is an indicator of socioeconomic status and is inversely associated with cardiovascular risk factors and risk for incident coronary artery disease (CAD). Whether the level of educational attainment (EL) in patients with CAD influences outcomes remains understudied.

Purpose
To ascertain the relationship between EL and adverse outcomes in patients with CAD. We hypothesize that EL will be inversely associated with adverse outcomes in this high-risk patient population.

Methods
Subjects undergoing cardiac catheterization for known or suspected CAD were recruited in a cardiovascular biobank and had their highest level of educational attainment assessed using predefined options of elementary/middle school, high school, college, or graduate education. The primary outcome of interest was all-cause mortality and secondary outcomes included a composite of cardiovascular deaths and nonfatal myocardial infarction (MI) events, and nonfatal MI events during follow-up. Cox proportional hazards regression models were used to analyze the association between EL and adverse outcomes after adjustment for demographic characteristics, cardiovascular risk factors, cardiovascular medication use, and estimated zip code-based annual family income.

Results
Among the 6,318 subjects (mean age 64 years, 63% male, 23% black) enrolled, 998 (16%) had received graduate or a higher qualification, 2,689 (43%) had received a college education, 2,403 (38%) had received a high school education, and 228 (3%) had received elementary/middle school education. During a median follow-up of 3 years,there were 1,110 deaths from all causes, 851 cardiovascular deaths/nonfatal MI, and 286 nonfatal MI events. After adjusting for covariates and compared to patients with graduate education or higher, those with lower EL (elementary/middle school, high school, or college education) had a higher risk of all-cause mortality [hazard ratio 1.66, (95% CI 1.08, 2.54), 1.58 (95% CI 1.22, 2.04), and 1.45 (95% CI 1.13, 1.57), respectively]. Similar findings were observed for secondary outcomes. EL dichotomized at graduate education was associated with all-cause mortality (hazard ratio 1.48, 95% CI 1.16, 1.88), but this relationship was significantly modified by sex (p-interaction 0.023) and the association was attenuated among male patients (hazard ratio 1.23, 95% CI 0.94, 1.61) but not female patients (hazard ratio 2.70, 95% CI 1.53, 4.77).

Conclusions
Lower educational attainment is an independent predictor of adverse outcomes in patients with CAD. The causal link between low education level and increased CV risk needs further investigation.

Acknowledgement/Funding
Dr. Quyyumi is supported by NIH grants 5P01HL101398-02, 1P20HL113451-01, 1R56HL126558-01, 1RF1AG051633-01, R01 NS064162-01, R01 HL89650-01, HL095479-0
P5509Apabetalone (RVX-208) inhibits key drivers of vascular inflammation, calcification, and plaque vulnerability through a BET-dependent epigenetic mechanism
Authors: Kulikowski E , Tsujikawa L M , Gilham D , Rakai B , Halliday C , Stotz S C , Sarsons C , Fu L , Daze E , Wasiak S , Studer D , Rinker K D , Sweeney M , Johansson J O , Wong N C W 
Published: October 2019

Abstract
Apabetalone (RVX-208) is an orally available small molecule bromodomain & extraterminal (BET) protein inhibitor that targets the second bromodomain (BD2) of BET proteins. Apabetalone returns dysregulated BET-dependent transcription toward normal physiological levels. In phase 2 trials, apabetalone treatment reduced the incidence of major adverse cardiac events by 44% in CVD patients and by 57% in diabetic CVD patients. Previous studies have highlighted apabetalone's positive impact on vascular calcification (VC) and inflammation (VI) marker expression in vitro, as well as its ability to lower serum alkaline phosphatase (ALP) levels, and improve atherosclerotic plaque stability parameters in treated patients. In CVD, elevated inflammatory mediators and cell surface adhesion molecules drive VI, resulting in leukocyte adhesion, infiltration, uptake of oxLDL, and ultimately plaque formation. Here we show in vitro that THP-1 monocyte adhesion to human aortic endothelial cells (HAECs) increases with TNFα stimulation and is attenuated by apabetalone treatment, with fewer monocytes attaching to HAECs under flow conditions. This functional outcome is attributed to apabetalone's reduction of key endothelial adhesion genes, VCAM-1 (50%, p=0.0001) and SELE (37%, p=9x10–5). Apabetalone also prevents TNFα induction of endothelial recruitment genes (MCP-1; 75%, p=0.0002) and genes involved in plaque rupture (IL8; 24%, p=2x10–5). Basal HAEC ALP expression, a potential contributor to endothelial dysfunction and VC, also decreases with apabetalone treatment (70%, p=0.005). Induction of VI genes by TNFα is BET-dependent as degradation of BET proteins by MZ-1 prevents an increase in transcripts in response to TNFα treatment. Ingenuity® Pathway Analysis (IPA®), GSEA, and GO analysis of HAEC gene expression data predicts apabetalone inhibition of pro-atherogenic pathways, gene sets, and upstream regulators induced by TNFα. These include cytokine and chemokine, Toll-Like Receptor (TLR), NFkβ, Interferon and TNFα signaling. In addition, IPA® disease and biological function analysis predicts inhibition of immune cell activation and recruitment by apabetalone. Plasma proteomics (SOMAscan®) and IPA® analysis from apabetalone-treated CVD patients in ASSERT and ASSURE phase 2 trials indicate that apabetalone inhibits pro-atherogenic upstream regulators (IL-6 and IFNy), canonical pathways, and diseases and functions. Serum ALP also decreases dose dependently with apabetalone treatment (ASSERT). Epigenetic inhibition of VI and VC driven atherogenesis likely contributes to the reduction in MACE observed in phase 2 apabetalone treated patients. The ongoing phase 3 post-acute coronary syndrome (ACS) clinical trial in T2DM patients, BETonMACE, is currently testing this hypothesis.
P5526Vascular endothelial growth factor-D and mortality in suspected or known coronary heart disease patients with chronic kidney disease: a subanalysis of the ANOX study
Authors: Wada H , Suzuki M , Matsuda M , Ajiro Y , Shinozaki T , Sakagami S , Yonezawa K , Shimizu M , Funada J , Takenaka T , Morita Y , Wada M , Abe M , Akao M , Hasegawa K 
Published: October 2019

Abstract

Background
Chronic kidney disease (CKD) is an independent risk factor for the development and progression of coronary heart disease (CHD). Vascular endothelial growth factor-D (VEGF-D) is a secreted glycoprotein that can act as lymphangiogenic and angiogenic growth factors through binding to its specific receptors, VEGFR-3 (Flt-4) and VEGFR-2 (KDR/Flk-1). VEGF-D signaling via VEGFR-3 plays an important role in lipoprotein metabolisms which may contribute to CHD. VEGF-D signaling has been used as a therapeutic target of human diseases such as lymphangioleiomyomatosis and refractory angina. Furthermore, in clinical settings, the VEGF-D level is already established as a diagnostic biomarker for lymphangioleiomyomatosis. However, the prognostic value of VEGF-D in suspected or known CHD patients with CKD is unknown.

Methods
Serum VEGF-D levels were measured in 999 suspected or known CHD patients with CKD undergoing elective coronary angiography, enrolled in the development of novel biomarkers related to angiogenesis or oxidative stress to predict cardiovascular events (ANOX) study, and followed up for 3 years. The primary outcome was all-cause death. The secondary outcomes were cardiovascular death, and major adverse cardiovascular events (MACE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.

Results
During the follow-up, 154 patients died from any cause, 61 died from cardiovascular disease, and 96 developed MACE. After adjustment for established risk factors, VEGF-D levels were significantly associated with all-cause death (hazard ratio [HR] for 1-SD increase, 1.41; 95% confidence interval [CI], 1.27–1.56), cardiovascular death (HR, 1.48; 95% CI, 1.28–1.71), and MACE (HR, 1.34; 95% CI, 1.18–1.53). Even after incorporation of N-terminal pro-brain natriuretic peptide, contemporary sensitive cardiac troponin-I, and high-sensitivity C-reactive protein into a model with established risk factors, the addition of VEGF-D levels further improved the prediction of all-cause death (continuous net reclassification improvement [NRI], 0.272; 95% CI, 0.100–0.445; P=0.002; integrated discrimination improvement [IDI], 0.015; 95% CI, 0.003–0.027; P=0.013), but not that of cardiovascular death (NRI, 0.230; 95% CI, −0.029 to 0.488; P=0.082; IDI, 0.012; 95% CI, −0.007 to 0.031; P=0.207) or MACE (NRI, 0.102; 95% CI, −0.106 to 0.310; P=0.337; IDI, 0.005; 95% CI, −0.005 to 0.015; P=0.337).

Conclusions
In suspected or known CHD patients with CKD undergoing elective coronary angiography, elevated VEGF-D levels may predict all-cause mortality independent of established risk factors and cardiovascular biomarkers.

Acknowledgement/Funding
The ANOX study is supported by a Grant-in-Aid for Clinical Research from the National Hospital Organization
P5559Biopsy-proven myocarditis: clinical and diagnostic correlates of late gadolinium enhancement
Authors: Baritussio A , Cheng C , Gianstefani S , Seguso M , Gallo N , Leoni L , Perazzolo Marra M , Tarantini G , Marcolongo R , Plebani M , Rizzo S , Basso C , Iliceto S , Caforio A 
Published: October 2019

Abstract

Background
Cardiovascular magnetic resonance (CMR) is an accurate diagnostic tool providing detailed myocardial tissue characterization. Correlates of late gadolinium enhancement (LGE) with clinical and diagnostic features are poorly defined in endomyocardial biopsy (EMB)-proven myocarditis.

Purpose
We sought to identify clinical, laboratory and imaging correlates of LGE in patients with EMB-proven myocarditis.

Methods
We analyzed our prospective cohort of patients with EMB-proven myocarditis (n=366) to identify patients who underwent CMR (n=154, aged 39±13, 108 males). Presence of LGE was qualitatively assessed. CMR and EMB were performed in all cases at the time of hospitalization. Clinical, laboratory, and imaging features at diagnosis were analyzed to identify correlates of LGE presence.

Results
Demographic characteristics (age, gender), cardiovascular risk factors (hypertension, diabetes) and cardiovascular therapy did not differ between patients with and without LGE. Patients with history of myocarditis tended to have a higher prevalence of LGE (25 vs 4 patients, p=0.07). There was a trend towards a higher prevalence of LGE in patients presenting with heart failure or acute coronary syndrome (p=0.07) as opposed to those presenting with arrhythmias. Patients with LGE were more symptomatic in the 6 months preceding diagnosis (palpitations, p=0.03, chest pain p=0.02). Clinical left and right ventricular systolic dysfunction at presentation were more common in patients with LGE (p=0.02, p=0.02 respectively). LGE presence failed to distinguish patients according to EMB findings (active vs. borderline myocarditis) (p=0.66) or to the histological type of myocarditis. Troponin I levels were higher in patients with LGE (p=0.03). There was no difference in bi-ventricular volumes and function, as assessed both by echocardiography and heart catheterization. There was no correlation between anti-heart antibodies and LGE presence, nor were patients with LGE more likely to receive immunosuppressive therapy; however, response to immunosuppression tended to be more common in patients without LGE (13/13 vs 29/38 patients, p=0.09). The rate of heart transplant, death and myocarditis relapse did not differ between patients with and without LGE.

Conclusions
Presence of LGE on CMR was associated with longer symptom duration before diagnosis, presentation with heart failure and higher troponin release, but failed to correlate with specific EMB features or myocarditis aetiopathogenetic markers.

Acknowledgement/Funding
None