bluuebunny/crossref_metadata_2025_split huggingface dataset:
P5374Genetic deletion of IL-22 increased cardiac rupture after myocardial infarction in mice
Authors: Yamamoto M , Yasukawa H , Takahashi J , Nohara S , Sasak T , Shimozono K , Shibata T , Yanai T , Okabe K , Mawatari K , Fukumoto Y 
Published: October 2019

Abstract

Background
Interleukin-22 (IL-22) is a member of the IL-10 cytokine family, which mainly targets epithelial cells and does not target immune cells. Recently, it has been reported that IL-22 play roles in tissue repair in the skin and the liver; however, role of IL-22 in the process of tissue repair after myocardial infarction (MI) is unknown. Here, we investigated the role of IL-22 in tissue repair process after MI.

Methods and results
First, we examined the expression of IL-22 and its receptor IL-22RA1 in the wild type (WT) mice by real-time PCR. The expression of IL-22 and IL-22RA1 in the hearts were significantly increased 3 days after MI (p<0.05). To clarify the role of IL-22 in the heart after MI, we produced MI model in the WT mice and IL-22 knockout (KO) mice. We found that the IL-22 KO mice had significantly higher mortality than the WT mice after MI (p<0.05). Approximately 80% of the IL-22 KO mice died with cardiac rupture after MI. The infarct size which was estimated by evans blue dye and triphenyltetrazolium chloride staining at 3 days after MI was comparable between the IL-22 KO mice and the WT mice. Next, we performed real time PCR and PCR array analysis for tissue fibrosis and repair genes. We found that alpha-smooth muscle actin (aSMA), NF-kB, TNF-a and MMP13 (also known as collagenase-3) were significantly increased in the infarct area of IL-22 KO mice compared to WT mice. Immunostaining showed that the myofibroblast marker aSMA positive cells in the border area after MI were markedly higher in the IL-22 KO mice compared with the WT mice (p<0.05). Approximately 70% of cardiac rupture after MI in the IL-22 KO mice were occurred in the infarct area adjacent to the border area. Furthermore, we found aSMA positive cells and MMP13 positive cells around the ruptured site of the heart.

Conclusion
Thus, IL-22 KO mice exhibit high mortality and increased cardiac rupture after MI. And expression of aSMA and MMP13 were highly expressed in the ruptured site after MI in the IL-22 KO mice. These results suggest that IL-22 may play an important role in the tissue repair process after MI.
P5388N-cadherin promotes cardiac regeneration by stabilizing beta-catenin
Authors: Tseng Y S , You M Y , Hsu Y C , Yang K C 
Published: October 2019

Abstract

Background
Although the adult mammalian heart fails to regenerate after injury, it is known that newborn mice within a week have full cardiac regenerative capacity. The molecular determinants underlying the disparate regenerative capacity between neonatal and adult mice, however, remain incompletely understood. Exploiting RNA sequencing in isolated cardiomyocytes from neonatal and adult mouse heart, we identified Cdh2, which encodes the adherence junction protein N-cadherin, as a potential novel mediator of cardiac regeneration. Cdh2 expression levels were much higher in neonatal, compared with adult, cardiomyocytes and showed a strong positive correlation with that of multiple cell cycle genes. N-cadherin has been reported to be essential for embryonic cardiac development; its role in cardiac regeneration, however, remains unknown.

Purpose
To determine the role of Cdh2 (N-cadherin) in cardiac regeneration and to investigate the underlying molecular mechanisms.

Methods
Apical resection in postnatal day 1 mice was used as a cardiac regenerative model. The in vitro gain/loss-of function studies of Cdh2/N-cadherin was performed in postnatal day 1 neonatal mouse cardiomyocytes (P1CM) and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM). N-cadherin inhibitor exherin was used to study the effects of N-cadherin in vivo.

Results
Comparing to sham-operated control, Cdh2 was significantly upregulated in mouse cardiac apex and border zone following apical resection, which was accompanied with increased cardiomyocyte proliferation activity. In vitro, knocking down Cdh2 or inhibition of N-cadherin activity with exherin in P1CM significantly reduced the proliferative activity of cardiomyocytes, whereas overexpression of Cdh2 markedly increased the proliferation of P1CM. In addition, forced expression of Cdh2 resulted in significant upregulation of multiple cell cycle genes, including Ccnd1 (Cyclin D1) and Pcna (proliferating cell nuclear antigen), in P1CM. In vivo inhibition of N-cadherin in P1 neonatal mice with exherin following apical resection impaired cardiac regeneration and increased scar formation (Figure). Knocking down CDH2 in human iPSC-CMs significantly reduced the proliferative activity and the expression levels of cell cycle gene CCND1 in iPSC-CMs. Mechanistically, we demonstrated that the pro-mitotic effects of N-cadherin in cardiomyocytes were mediated, at least partially, by stabilizing β-catenin, a pro-mitotic transcription factor, through direct interaction with its cytoplasmic domain and/or inactivation of GSK3β, a critical component of β-catenin destruction complex.
N-Cad blocker impairs heart regeneration

Conclusion
Our study uncovered a previously unrecognized role of Cdh2 (N-cadherin) in cardiomyocyte proliferation and cardiac regeneration. Enhancing cardiac expression or activity of N-cadherin, therefore, could be a potential novel therapeutic approach to promote cardiac regeneration and restore cardiac function in adult heart following injury.
P5410Combination assessment of renal and hepatic dysfunction improves the predictability of prognosis in patients with acute decompensated heart failure
Authors: Shibata N , Sumi T , Umemoto N , Kajiura H , Inoue S , Iio Y , Sugiura T , Taniguchi T , Asai T , Yamada M , Shimizu K , Murohara T 
Published: October 2019

Abstract

Background
Renal dysfunction is associated with poor mortality in patients with heart failure (HF). Hepatic dysfunction, assessed by Fibrosis-4 (FIB4) index, has also prediction ability in acute decompensated HF (ADHF) patients. We investigated whether the assessment of the combination of FIB4 index and renal dysfunction improves predictability in patients with ADHF.

Methods
We retrospectively enrolled consecutive 758 patients who admitted due to ADHF from January 2011 to February 2018 and followed up for one year. FIB4 index on admission was calculated by the formula: age (yrs) × AST[U/L] / (platelets [103/μL] × (ALT[U/L])1/2). Study subjects were divided into high FIB4 index (>3.25) and low FIB4 index (≤3.25), furthermore each group were classified by the presence/absence of CKD (estimated glomerular filtration rate <60 ml/min/1.73m). We have generated four groups; low FIB4/without CKD (n=154), low FIB4/with CKD (n=294), high FIB4/without CKD (n=56), and high FIB4/with CKD (n=254). The primary outcome was defined as all-cause mortality in one year. We performed Kaplan-Meyer analysis and multivariable Cox regression models. Furthermore, we evaluated the incremental value with C-index, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) when FIB4 index and renal dysfunction added to a baseline model.

Results
In total, 106 patients died in one year. High FIB4 index and CKD showed significantly higher 1-year mortality (high FIB4 index: 19.7% vs 10.3%, p<0.001, CKD: 17.0% vs 6.7%, p<0.001, respectively). Kaplan-Meyer analysis shows that high FIB4 index with CKD showed statistically higher mortality than the others (vs low FIB4/without CKD, p<0.001, vs high FIB4/without CKD, p=0.031, vs low FIB4/with CKD, p<0.001, respectively).
Multivariate Cox regression model revealed that both high FIB4 index and CKD were an independent risk predictor of 1-year mortality (FIB4 index: p<0.001, HR 1.06, 95% CI 1.035–1.087, CKD: p=0.004, HR 1.834, 95% CI 1.213–2.773, respectively) in patients with ADHF.
A baseline model for prediction of 1-year mortality was determined by multivariable logistic regression including age, body mass index, systolic blood pressure, and serum albumin (C-index: 0.688). Adding high FIB4 index and CKD to the baseline model, all of C-index (0.738, p=0.04), NRI (0.122, p=0.067), and IDI (0.024, p=0.004) were improved.
Receiver operating characteristic curves

Conclusions
Combination assessment of renal and hepatic dysfunction could improve the predictability of prognosis in patients with ADHF.

Acknowledgement/Funding
None
P5411Prognostic communication with hospitalized heart failure patients; the patients' perspective
Authors: Kitakata H , Kohno T , Kohsaka S , Fujisawa D , Nakano N , Shiraishi Y , Katsumata Y , Yuasa S , Fukuda K 
Published: October 2019

Abstract

Background
Informing heart failure (HF) patients about their prognosis is an important part of clinical management, particularly at the time of hospitalization. Current European Society of Cardiology guidelines recommend communicating this information to HF patients at the time of hospitalization and with any change in clinical status. However, little is known about actual patient preferences, understanding, and attitudes towards prognostic communication with their treating physicians.

Methods
We surveyed 113 consecutive hospitalized HF patients in a single university hospital. We assessed patient understanding of prognosis (likelihood of survival beyond 2 years), and compared patient expectations to model predictions. Model-predicted 2-year survival rate was calculated by the Seattle Heart Failure Model (SHFM). We also assessed patient preferences for information disclosure using the Prognosis and Treatment Perception Questionnaire (PTPQ). The PTPQ assesses patient beliefs regarding 1) the importance of knowing about prognosis, 2) the importance of knowing about treatment option, and 3) frequency of having a conversation about prognosis during the hospital stay.

Results
Enrolled patients were predominantly male (65.5%), with a mean age of 73.6±9.6 years and mean left ventricular ejection fraction was 46.2±15.4%. Median SHFM-estimated 2-year survival rate was 89.2% (interquartile range: 83.8–92.9%). Overall, patient understanding about prognosis was suboptimal. Among patients with a guarded 2-year survival (SHFM <90%: N=60), 44% reported that their likelihood of 2-year survival was >90% (Figure; red box). However, among patients with favorable 2-year survival (>90%: N=53), 38% reported a likelihood of <90% (Figure; blue box). Regarding treatment options, most patients (98%) desired to learn as many details as possible. Responses varied with regard to information on individual prognosis; whereas 51% wanted to know more about prognosis than their present status alone, a significant number (28%) of subjects answered “never” or “less often” to a query on the frequency of discussion about prognosis. Patient preference for more information about prognosis was associated with female sex (odds ratio [OR]: 2.52; 95% confidence interval [CI]: 1.12–5.69), fewer symptoms of depression (1-point increase on Patient Health Questionnaire-2, OR: 0.66; 95% CI: 0.49–0.87), and previous stroke (OR: 2.92; 95% CI: 1.04–8.19), but not other social/demographic or clinical factors (e.g., age, education, caregiver support, HF phenotype and severity, and other comorbid conditions).
Figure 1

Conclusions
There were substantial discrepancies in patient understanding of prognosis and in desire for more information from physicians. Interventions to improve prognostic understanding are warranted for HF patients, and hospitalization for HF could represent an opportunity for optimization.
P5429Mechanical dyssynchrony has a higher predictive value for CRT response than different ECG-based definitions of LBBB
Authors: Beela A , Duchenne J , Voigt J U 
Published: October 2019

Abstract

Background/Aim
To investigate the value of baseline assessment of mechanical dyssynchrony (Dyss) in predicting response to cardiac resynchronization therapy (CRT) in comparison to the classic ECG definition of left bundle branch block (LBBB) (Classic-def) as well as the recently proposed Sex- based definition (Sex-def.).

Methods
The baseline ECGs of 194 patients (31% females, 39% with ischemic cardiomyopathy, mean QRS width 159±25 ms and mean LVEF 29±8%) were investigated for identifying the criteria of LBBB before CRT implantation. Classic-def., defined as notched or slurred QRS complex in at least two of the leads I, aVL, V1, V2, V5 and V6 with a total width of at least 120 ms in addition to the absence of Q wave in lead I, V5 and V6 was identified in 74% of the study population. Sex-def. was identified in 69%, which is a QRS duration of at least 140 and 130 ms for men and women respectively with otherwise the same criteria of the Classic definition. Dyss was defined as the presence of either apical rocking and/or septal flash in 2D echocardiography prior to implantation. Volumetric response to CRT was defined as a reduction of at least 15% of the LV-end systolic volume (ESV) at follow up echocardiography (12±6 months after device implantation).

Results
Patient with baseline Dyss showed the highest response rates (76%) with a sensitivity of 88%, a specificity of 63% and an area under the curve (AUC) of 0.76 (P<0.001) compared to 70% (sensitivity 82%, specificity 47%, AUC 0.65, P<0.01) in patients with Sex-def. and 65% (sensitivity 84%, specificity 40%, AUC 0.62, P=0.01) in patients with Classic-def. (Figure A).
Pairwise comparisons showed that the accuracy of the Sex-def. did not differ significantly from the Classic-def. in response prediction (AUC=0.65 vs. 0.62 for Sex-def. vs. Classic-def. respectively, P=0.27). Alternatively, Dyss showed a significantly higher accuracy in predicting response to therapy (AUC=0.76) as compared to Sex-def. and Classic-def. (P=0.02 and <0.01 respectively, Figure B).
Mech. dyssynchrony vs. ECG-based LBBB

Conclusion
The presence of Apical rocking and/or septal flash before CRT is associated with better response to CRT as compared to various ECG definitions of LBBB. Although a Sex-based definition of LBBB showed a trend of better response to CRT as compared to the Classic definition, it was not statistically significant.
P5436Angiotensin receptor-neprilysin inhibitor preserved cardiac function via improving angiogenetic ability in mice model of atherosclerosis
Authors: Suematsu Y S , Ideishi A I , Tashiro K T , Kuwano T K , Miura S M 
Published: October 2019

Abstract

Introduction
Angiotensin receptor-neprilysin inhibitor (ARNI) increases natriuretic peptide and improves heart failure. We previously reported that ARNI has the effects of suppression of myocardial hypertrophy and fibrosis in addition to reduction of afterload by natriuretic effect. We investigated the effects of ARNI against mice model of atherosclerosis and heart failure.

Method and results
Apolipoprotein E knockout mice fed high cholesterol diet for 4 weeks were divided into four groups: no treatment (CTL), valsartan 30 mg/kg (VAL), sacubitril (neprilysin inhibitor) 30 mg/kg (SAC), and ARNI 60mg/kg for additional 13 weeks. Body weight and systolic blood pressure in the VAL, SAC and ARNI groups did not show significant differences compared to those in the CTL group. Serum brain natriuretic peptide (BNP) in ARNI group (605±221 pg/ml) was significantly increased than that in VAL (391±57 pg/ml) and SAC (357±91 pg/ml) groups, but not CTL group (393±192 pg/ml). Although the rate of atherosclerotic area in aorta was 16.3±5.8% after treatment, there were no significant differences between the groups. In the CTL group, left ventricular ejection fraction (LVEF, 81.6±4.8%) and fractional shortening (FS, 44.8±5.8%) at baseline were significantly reduced after treatment (67.8±8.2% and 33.3±6.1%). Interestingly, LVEF (76.6±6.7%) and FS (40.1±6.1%) after treatment in the ARNI group were significantly preserved compared to those in the CTL group. In real time polymerase chain reaction analysis of LV after treatment, relative mRNA expression of BNP and angiogenetic factors including ATPase sarcoplasmic/endoplasmic reticulum Ca transporting 2, vascular endothelial growth factor A, cluster of differentiation 34 in ARNI group were significantly increased than those in the CTL group. Transforming growth factor-β in ARNI group was significantly reduced than that in the CTL group.

Conclusion
Although ARNI did not suppress atherosclerosis in mice, it preserved LVEF via improving angiogenetic ability.
P5445PCSK9 and 6-month Left Ventricular Ejection Fraction after ST-segment Elevation Myocardial Infarction. A Pilot Study
Authors: Nunez Villota J , Minana G , Bayes-Genis A , Nunez E , Revuelta-Lopez E , Sanchis J , Rios-Navarro C , Lopez-Lereu M , Monmeneu J V , Chorro F J , Lupon J , Bodi V 
Published: October 2019

Abstract

Background
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a therapeutic target for reducing plasma LDL. Beyond lipid control, recent findings suggest a deleterious effect of this protein in the pathogenesis of post-myocardial infarction left ventricle remodeling and heart failure-related complications. The aim of this work was to assess the relationship between circulating PCSK9 and 6-month cardiac magnetic resonance (CMR) imaging-derived left ventricle ejection fraction (LVEF) after a first ST-segment elevation myocardial infarction (STEMI).

Methods
We prospectively evaluated 40 patients with a first STEMI treated with primary percutaneous coronary intervention (PPCI) and LVEF<50% in which PCSK9 was measured 24h post-reperfusion. All patients underwent CMR imaging 1 week and 6 months after STEMI. The association between serum PCSK9 and 6-month LVEF was evaluated by ANCOVA. The following covariates were included in the final model; 1-week CMR-derived LVEF, age, gender, 1-week CMR-infarct size, plasma suppression of tumorigenicity-2 (ST2), low density lipoprotein-cholesterol, ante treatment with statins.

Results
The mean age of the sample was 60±12 years and 33 patients (82.5%) were male. Mean 1-week and 6-month LVEF were 41±7% and 48±10%, respectively. The mean±SD of PCSK9 was 1.93±0.38 U/mL. PCSK9 values were inversely related with 6-month LVEF (r=−0.35, p=0.028). The mean values of PCSK9 were significantly higher in patients with LVEF<50% at 6 months (2.06±0.29 vs. 1.80±0.41 U/mL, p=0.028). After a multivariate adjustment, circulating PCSK9 remained significant and inversely associated with 6-month LVEF (p=0.001).
Figure 1

Conclusions
In patients with a first STEMI treated with PCCI and reduced ejection fraction, circulating PCSK9 was associated with lower LVEF at 6 months.
P5459Comparison of the predictive role of changes in left ventricular mass and arterial stiffness for coronary artery disease in essential hypertension: Data from a 8-year-follow-up study
Authors: Leontsinis I , Tsioufis C , Dimitriadis K , Kasiakogias A , Liatakis I , Koutra E , Kouremeti M , Iliakis P , Vogiatzakis N , Karaminas N , Asimaki E , Tousoulis D 
Published: October 2019

Abstract

Background/Introduction
Although arterial stiffening is related to atherosclerosis progression, its prognostic role in hypertension is not fully elucidated, while augmented left ventricular mass index (LVMI) is linked to adverse outcome.

Purpose
The aim of the present study was to compare the predictive role of changes in arterial stiffness and LVMI for the incidence of coronary artery disease (CAD) in a cohort of essential hypertensive patients.

Methods
We followed up 1082 essential hypertensives (mean age 55.9 years, 562 males, office blood pressure (BP)=145/91 mmHg) free of cardiovascular disease for a mean period of 8 years. All subjects had at least one annual visit and at baseline and last visit underwent complete echocardiographic study for estimation of LVMI and measurements of arterial stiffness on the basis of carotid to femoral pulse wave velocity (PWV), by means of a computerized method. The distribution of PWV was split by the median (8.2 m/sec) and accordingly subjects were classified into those with high (n=546) and low values (n=536). Moreover, LV hypertrophy (LVH) was defined as LVMI ≥125 g/m2 in males and LVMI ≥110 g/m2 in females, while CAD was defined as the history of myocardial infarction or significant coronary artery stenosis revealed by angiography or coronary revascularization procedure.

Results
The incidence of CAD over the follow-up period was 3.5%. Hypertensives who developed CAD (n=38) compared to those without CAD at follow-up (n=1044) had at baseline higher waist circumference (101.7±10.1 vs 96.2±11.6 cm, p=0.004), LVMI (123.9±22.1 vs 105.8±21.3 g/m2, p=0.026), prevalence of LVH (46% vs 25%, p=0.018) and prevalence of high PWV levels (67% vs 40%, p=0.021). No difference was observed between hypertensives with CAD and those without CAD with respect to baseline office BP, serum creatinine and lipid levels (p=NS for all). By univariate Cox regression analysis, it was revealed that changes in PWV levels between baseline and last visit predicted CAD (hazard ratio=1.243, p=0.014). However, in multivariate Cox regression model baseline glomerular filtration rate (hazard ratio=1.029, p=0.015) and changes in LVMI (hazard ratio=1.036, p<0.0001) but not alterations of PWV turned out to be independent predictors of CAD.

Conclusions
In essential hypertensive patients changes in LVMI predict future development of CAD, whereas PWV alterations exhibit no independent prognostic value. These findings support that LVMI constitutes a superior prognosticator of events than PWV and its estimation is essential in order to improve overall risk stratification in hypertension.