bluuebunny/crossref_metadata_2025_split huggingface dataset:
P2254Impaired autophagic off-rate causes cardiac aging in progeria mouse model
Authors: Kamihara T , Kureishi Bando Y , Nishimura K , Yasheng R , Ozaki R , Murohara T 
Published: October 2019

Abstract

Background/Introduction
Aging is known to be one of the primary causes of heart failure. Werner syndrome is one of the aging disorder that caused by dysfunction of DNA helicase-regulatory protein (WRN). However, there is little information whether WRN may cause any specific myocardial remodeling and vulnability for heart failure. More interestingly, ample evidences demonstrated DNA damage occurred in progeria causes autophagic disorder, contributing to aging phenotype, in short, autophagy may be a guardian of the genome. Although autophagic disorder has been implicated to cause cardiac remodeling in heart failure; however, it remains uncertain whether autophagic disorder may link to the mechanism of aging-induced cardiac remodeling.

Purpose
To elucidate whether autophagic disorder may be mechanistically responsible for cardiac aging we hypothesized whether aging-related DNA injury may affect autophagy that may lead to myocardial remodeling.

Methods
We employed progeria mouse model harboring amino acid (AA) substitution of WRN at position 577 (WRN-K577M), which were evaluated in terms of cardiac function and remodeling at the phase of adult (18 week-old).

Results
WRN-K577M exhibited diffuse left-ventricular (LV) hypertrophy, enhanced fibrosis, and diastolic LV dysfunction with preserved systolic ejection fraction. DNA microarray analysis of WRN-K577M heart revealed that the 253 genes were upregulated compared to age- and gender-matched wild-type counterpart. Sixteen genes were increased >4 fold higher than wild-type as follows: hypertrophy (Myh7, Klkb11), fibrosis (Fgf21, CTGF), inflammatory molecules (Ap1s3, Pla2g2e, Has1, MMP9), and oxidative stress (catalase). Cardiac aging markers (PARP-1, p53 and γH2AX) increased in heart of WRN-K577M with concomitant increase in oxidative stress (DHE staining) and apoptosis (TUNEL). Notably, autophagic turnover markers (i.e., increased on-rate of autophagy; p62 and LC3-II/I) were increased in myocardium of WRN-K577M, which was refractory to fasting-induced autophagic activation, indicating the on-rate step of autophagy is pathologically augmented under cardiac aging observed in WRN-K577M. In contrast, one of the key regulators of autophagy is the target of rapamycin, TOR kinase, which is the major inhibitory signal that shuts off autophagy with concomitant activation of Akt signaling. In contrast, blockade of the lysosomal fusion into autophagosome by systemic treatment with chloroquine (50 microg/g body weight) reduced LC3-II/I ratio, indicating the retarded off-rate of autophagy mediated by impaired lysosome fusion is presumably responsible for cardiac aging.

Conclusion(s)
DNA damage impairs autophagy in heart, leading to myocardial oxidative stress. In WRN-mutant progeria model, off-rate disorder of cardiac autophagy is, at least in part, the cause of increase in oxidative stress and inflammation in heart leading to HFpEF.
P2255Senescence associated secretory phenotype exacerbates overload pressure-cardiac hypertrophy
Authors: Nugroho D B , Ikeda K , Haryono A , Rinastiti P , Barinda A J , Emoto N 
Published: October 2019

Abstract

Background
Advanced age is a significant risk factor for cardiovascular diseases such as hypertension and cardiac hypertrophy. The vascular system forms an essential component of cardiac tissue, to provide routes for circulation and transportation of nutrients and oxygen throughout the cardiac muscle. In addition to its function in vascular biology such as vasodilation and neovessel formation, endothelial cell (EC) also provides many secreted angiocrine factors that are crucially involved in maintaining tissue homeostasis. Ageing induces cellular senescence in various cells including EC. Senescent cells produce senescence-messaging secretomes that have deleterious effects on the tissue microenvironment, referred to as the senescence-associated secretory phenotype (SASP). Because of the crucial roles of EC in tissue homeostasis, EC senescence is presumed to play significant roles in age-related cardiac dysfunction, however, whether and the mechanism by which EC senescence affects age-related cardiac dysfunction remains to be elucidated.

Purpose
We aimed to investigate the role of senescent ECs in cardiac hypertrophy and heart function.

Methods
To investigate a contribution of senescent EC in age-related cardiac tissue dysfunction in vivo, we generated EC-specific progeroid mice that overexpress the dominant negative form of telomeric repeat-binding factor 2 (TRF2), which play a central role in the protection of chromosome ends, under the control of the vascular endothelial cadherin promoter (VEcad-TRF2DN-Tg). To induce pathological cardiac remodeling, Transverse Aortic Constriction (TAC) was performed in mice at the age of 10–12 weeks old. Cardiac function was assessed using fractional shortening percentage and ejection fraction measured with echocardiography every week until sacrifice day. Mice were sacrificed 4 weeks after TAC, heart tissue was collected for histological analysis, cardiac morphometry analysis, gene expression and protein expression analysis. In vitro, H9C2 rat cardiomyoblast cells were incubated with conditioned medium derived from control or senescent EC in the presence or absence of angiotensin II to induce cardiac hypertrophy.

Results
The serial echocardiographic analysis after TAC revealed the exacerbated LV dysfunction in VEcad-TRF2DN-Tg compared to that in wild-type mice. Morphometric and histological analysis 4 weeks after TAC showed increased heart weight and aggravated cardiac fibrosis in VEcad-TRF2DN-Tg mice. In vitro studies demonstrated that conditioned medium derived from senescent ECs enhanced cardiomyocyte hypertrophy in H9C2 cells. Of note, we found that treatment with Y2762, a Rho Kinase inhibitor, canceled the exacerbated cardiac hypertrophy caused by endothelial SASP.

Conclusion
These findings demonstrate for the first time that senescent ECs play causative roles in age-related cardiac disorders through the SASP, potentially by activating Rho-ROCK pathway in cardiomyocytes.
P2273Predictors of short- and mid-term outcomes after TAVR in low-flow, low-gradient aortic stenosis
Authors: Emer Egypto Rosa V , Echeverri D , Sztejfman M , Jaikel L A G , Dager A , Abud M , Charry P , Chauvet A A , Tarasoutchi F , Cura F , Ribeiro H B 
Published: October 2019

Abstract

Background
There is a lack of data on outcomes in classical (C-LFLG) and paradoxical low-flow, low-gradient aortic stenosis (P-LFLG) patients undergoing TAVR.

Purpose
We aim to compare baseline characteristic and procedural outcomes between C-LFLG, P-LFLG and high-gradient aortic stenosis (HG-AS) patients undergoing TAVR.

Methods
Patients included in the Transcatheter RegistrY of aorTic valve biOprosthesis in Latin-AMerica (TRYTOM Registry) were divided in 3 groups: 1) HG-AS: mean transaortic gradient (MG) ≥40 mmHg; 2) P-LFLG: MG <40 mmHg and left ventricular ejection fraction (LVEF) ≥50%; 3) C-LFLG: MG <40 mmHg and LVEF <50%. The outcomes were evaluated at 30-days and 1-year and were classified according to definitions of the VARC-2.

Results
1040 patients were included, 677 (65%) classified as HG-AS, 223 (21%) as P-LFLG and 140 (14%) as C-LFLG. Median follow-up was 16 months (range 0–109). There were baseline differences between HG-AS, P-LFLG and C-LFLG regarding age (80±7 vs 80±5 vs 78±8 years, respectively; p=0.017), NYHA FC III and IV (61.0 vs 72.6 vs 83.6%, respectively; p<0.001), coronary artery disease (44.1 vs 47.1 vs 57.9%, respectively; p=0.012), EuroSCORE II (7.2±6.3 vs 7.5±5.0 vs 12.9±10.4%, respectively; p<0.001), LVEF (56±11 vs 61±7 vs 32±9%, respectively; p<0.001), MG (53±13 vs 30±6 vs 27±7 mmHg, respectively; p<0.001), aortic valve area (0.65±0.16 vs 0.74±0.15 vs 0.70±0.16 cm2, respectively; p<0.001) and creatinine (1.2±0.7 vs 1.1±0.5 vs 1.5±1.3 mg/dl, respectively; p<0.001). Despite these significant baseline differences, we found similar outcomes after TAVR between HG-AS, P-LFLG and C-LFLG regarding device success (89.8 vs 95.1 vs 90.7%, respectively; p=0.057), in-hospital mortality (6.1 vs 5.9 vs 11.8%, respectively; p=0.144) and all other VARC-2 major outcomes, including major bleeding, major vascular complication and disabling stroke. In addition, female sex (OR 2.13, 95% CI 1.16–3.92, p=0.014), LVEF (OR 1.02, 95% CI 1.00–1.04, p=0.039) and MG (OR 0.97, 95% CI 0.95–0.99, p=0.004) were the only predictor of device success by multivariate analysis. Furthermore, 1-year mortality was similar among the groups (9.5 vs 8.3 vs 14.3%, respectively; p=0.358; Figure 1), and by multivariate analysis, diabetes (HR 2.44, 95% CI 1.10–5.41, p=0.028), creatinine (HR 1.65, 95% CI 1.17–2.33, p=0.004), conversion to general anesthesia (HR 7.93, 95% CI 2.08–30.20, p=0.002) and post-procedure disabling stroke (HR 12.84, 95% CI 3.09–53.40, p<0.001) predicted increased 1-year mortality, irrespective on the LVEF and MG.

Conclusions
Apart from baseline differences, TAVR in P-LFLG and C-LFLG was feasible and with similar clinical outcomes when compared to HG-AS. Mid-term mortality rates was associated with diabetes, creatinine and procedure complications.
P2274Single-center experience with different regimes of antiplatelet therapy and oral anticoagulation in transcatheter aortic valve replacement
Authors: Veulemans V , Hellhammer K , Afzal S , Maier O , Westenfeld R , Jung C , Kelm M , Zeus T , Polzin A 
Published: October 2019

Abstract

Background
Antithrombotic therapy in transcatheter aortic valve replacement (TAVR) is highly controversial. Dual antiplatelet therapy (DAPT) for 3–6 months with aspirin and clopidogrel is the current recommendation. Whereas in patients with indication for OAC several regimes were described, ranging from OAC monotherapy to dual and even triple therapy. Besides vitamin K antagonists (VKA), non-Vitamin K oral anticoagulants (NOAC) are frequently used in TAVR patients with indication for permanent OAC.

Purpose
We therefore aimed to evaluated different antithrombotic regimes and their impact on outcome.

Methods
We performed a single center retrospective analysis in 1160 patients treated by transfemoral approach (TF TAVR). Primary endpoints were 30-day mortality, stroke and bleeding according to VARC-2 criteria. Secondary endpoint was all-cause mortality at 1 year.

Results
In 1160 patients with TF TAVR, a broad range of regimes occurred in clinical practice. The majority of patients were on DAPT (637 patients, 55.0%), followed by VKA + clopidogrel (186 patients, 16%). Other patients received OAC mono (98 patients; 9%), triple therapy (93 patients; 8%), NOAC mono (31 patients; 3%), single antiplatelet therapy (SAPT, 40 patients; 4%) or NOAC + clopidogrel (31 patients, 3%).
All-cause mortality 30 days after TF TAVR differed between the regimens. (SAPT/OAC+SAPT/N-OAC+DAPT 0.0% vs DAPT 3.6% vs OAC 10.2% vs. NOAC 1.3% vs NOAC+SAPT 0.3%; pANOVA<0.0001). Severe bleeding events were comparable (SAPT 5.0% vs DAPT 2.4% vs OAC 7.1% vs NOAC 1.3% vs OAC+SAPT 3.2% vs NOAC+SAPT 0.0% vs. N-OAC+SDPT 4.3%; pANOVA=0.15). Stroke rates were comparable in all subcohorts as well (SAPT 5.0% vs DAPT 3.0% vs OAC 7.1% vs NOAC 2.7% vs OAC+SAPT 1.6% vs NOAC+SAPT 0.0% vs. N-OAC+DAPT 1.1%; pANOVA=0.13). Only 2 hemorrhagic strokes (5.6%) appeared under DAPT and OAC mono respectively, whereas all others were of thromboembolic origin (94.4%). Surprisingly, all-cause mortality at one-year after TF TAVR was higher in OAC patients compared to all other used regimes (logrankoverallp=0.0012).

Conclusion
Data from our retrospective analysis indicate that a variety of different antithrombotic regimes occur even in a single centre analysis. All-cause mortality was enhanced in patients with oral anticoagulation. Therefore, clinical trials need to investigate if this is only explained by additional atrial fibrillation.
P2446Defining values of volumes and longitudinal strain for the different types of left ventricular remodeling patterns in subjects with normal ejection fraction - a single center study
Authors: Jadav R , Nhola L , Thaden J , Pellikka P , Pislaru P , Villarraga H 
Published: October 2019

Abstract

Background
The left ventricle (LV) undergoes different types of remodeling to normalize its wall stress. There has been an increase in the trend in research regarding the process of remodeling but little is known about how LV volumes and global longitudinal strain (GLS) may vary depending upon the type of remodeling.

Purpose
To define the values of LV volumes and GLS in patients with different types of LV remodeling with normal ejection fraction (EF).

Methods
Single center retrospective study conducted from 2008 to 2018. We selected 10,356 subjects >18 years (5808 females, 4548 males) with normal EF and who underwent 2D echocardiography (2DE) at Mayo clinic, Rochester. They were categorized into 4 groups (Figure) i.e., group 1 = normal geometry, group 2 = concentric remodeling, group 3 = concentric hypertrophy, group 4 = eccentric hypertrophy based on their LV mass index (102 g/m2 in males, 88 g/m2 in females) and relative wall thickness (0.42) values measured by 2DE (figure). The patterns of LV GLS, end diastolic and end systolic volumes (EDV, ESV) indexed to body surface area were analyzed in these four groups by gender and body mass index (BMI). Mean±SD, One-way Anova, two sample t-test and Tukey- Kramer HSD were applied.

Results
The mean age of the selected population is 57.9 years ±14.9 (females=57.7±14.7, males=58.2±15.1) and the body surface area of 1.9 m2±0.2 (females=1.8±2 and males=2.1±0.2). The LV GLS values (Figure) of groups 1, 2, 3 and 4 were −20.7, −18.9, −17.5 and −19.9 and their EDV cc/m2 values were 63.6, 58.5, 61.2 and 68.2 respectively. LV GLS and Biplane EF values were higher in females while Biplane EDV and ESV were higher in males. When each gender is sub-divided based on their BMI (<25 and ≥25), the LV GLS, EDV and ESV values were higher in all groups with BMI<25 except in males with concentric remodeling and females with concentric hypertrophy where they were low.
Remodeling distribution

Conclusion
To our knowledge, this is the biggest single center study to evaluate LV GLS and volumes based on type of remodeling by gender and BMI. When compared with normal geometry, LV volumes and GLS values were statistically different among each type of remodeling as well as for gender and BMI. These results can be used as reference values in patient population studies where remodeling is being analyzed in subjects with normal LV EF.

Acknowledgement/Funding
None
P2459Do left atrial strain measurements provide information independent from left ventricular function parameters?
Authors: Malaescu G G , Petrescu A , Duchenne J , Capota R , Voigt J U 
Published: October 2019

Abstract

Introduction
LA strain has been proposed to be a reliable and independent prognostic marker, as well as a useful surrogate of LA function.

Purpose
To assess if LA deformation measurements add independent information to standard echocardiographic measurements.

Methods
We included 66 normals and patients with a wide range of pathology and diastolic dysfunction grade from the echo data base of our hospital if image quality was sufficient for both LA and LV strain analysis. Patients with a mobile interatrial septum, arrhythmias and more than mild valvular regurgitation were not considered. Standard echocardiographic measurements including LA and LV volumes were performed according to current guidelines. LA and LV longitudinal strains were assessed by 2D speckle tracking in the same cardiac cycle in apical 4 and 2 chambers views using peak R as time reference. Peak LA and LV strain as well as LA and LV strain at onset of LA contraction were measured to calculate the strain components of all three phases of the cardiac cycle (systolic, early diastolic and late diastolic).

Results
In our cohort, the ratio of LA and LV systolic strain was directly and strongly related to the volume ratio of the two chambers (R2=0,894, slope=-1.001, p<0.0001, see Figure 1). This was confirmed by a multivariate regression analysis, where systolic LA strain proved to be strongly dependent on systolic LV strain, LA volume and LV volume (R2=0.872, p<0.0001 for the final model).
For early diastolic strain, confounders were LV early diastolic strain, LA volume, LV volume and lateral wall E' tissue velocity (R2=0.784, p<0.0001); while LA late diastolic strain was dependent on LV late diastolic strain, LA volume, LV volume and lateral wall A' tissue velocity (R2=0.823, p<0.0001).
Strain ratio vs volume ratio

Conclusions
Our data suggest that systolic LA strain (reservoir strain) is strictly dependent on systolic LV strain and the volume ratio of both chambers and, therefore, its measurement cannot provide additional information beyond classical measurements. Diastolic LA strain components show a less strict dependence on LV function and may therefore provide additional information.
P2482Sex-based differences in cardioprotective role of SGLT-2 inhibitors in patients with type 2 diabetes mellitus
Authors: Madan N , Sohal S , Parapid B , Sperling L , Januzzi J L , Lalic K , Lundberg G , Butler J , Kosiborod M , Santos Volgman A 
Published: October 2019

Abstract

Background
Randomized studies have shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce major cardiovascular events in patients with type 2 diabetes mellitus. However, it is not known whether there are significant sex-based differences in the cardioprotective role of SGLT-2 inhibitors.

Purpose
To investigate whether sex differences exist in reduction of major cardiovascular events (MACE)in patients with type 2 diabetes mellitus when treated with SGLT2i.

Methods
A comprehensive PubMed search was conducted using keywords, (“Diabetes” AND (“Dapagliflozin” OR “Empagliflozin” OR “Canagliflozin” OR “Ertugliflozin”) AND “Outcomes”) that resulted in a total of 221 studies. Studies were included in our meta-analysis if they were randomized controlled trials, placebo-controlled, reported MACE as the primary outcome and reported sex-based subgroup analyses of these outcomes. Only 2 RCTs (EMPA-REG and DECLARE-TIMI 58) met our inclusion criteria.The sex-based event data for both trials was pooled to calculate risk ratios (RR) with 95% confidence intervals (CI). Analyses was performed using Comprehensive Meta-analysis (CMA) software. Fixed effect models, random effect models and mixed effect models were used.

Results
Pooled datafrom the 2 RCTs (EMPA-REG and DECLARE-TIMI 58) resulted in a total of 24,180 patients who were included in our primary analysis. Of these, 2331 patients were reported to have MACE. In our pooled data, SGLT2i reduced MACE in patients with diabetes with an overall risk ratio of 0.92 (0.85–0.99), p=0.03 (I2=0, p=0.31)using fixed effect model (Table 1). We also performed subgroup analysis of the pooled data categorizing by sex and using mixed effect model. Our subgroup analysis by sex showed a Q statistic of 1.88 with p-value of 0.17 suggesting that there is no significant difference in MACE reduction between men and women with diabetes when treated with SGLT2i. However, on further analyzing the sex differences in the individual trials, we found that women may have greater reduction in MACE compared with their male counterparts (RR in females: 0.66 (0.42–1.04); RR in males: 0.92 (0.84–1.00)), however this finding did not meet statistical significance (Table 2).

Conclusion
Our meta-analysis included the pooled data from 2 major RCTs (EMPA-REG and DECLARE-TIMI 58) assessing the cardioprotective role of SGLT2i in diabetic patients and shows that SGLT2i significantly reduce the risk of major adverse CV events in patients with type 2 diabetes mellitus. However, we did not find any significant sex-based differences in reduction of MACE between men and women with diabetes when treated with SGLT2i.
P2497Exercise training could reduce inflammatory activity of visceral adipose tissue in overweight women
Authors: Pahk K , Kwon H W , Eo J S , Seo H S , Kim W , Kim S 
Published: October 2019

Abstract

Objectives
Visceral adipose tissue (VAT) plays pivotal roles for an increased risk of cardiometabolic disease through triggering inflammatory process. This prospective study aimed to evaluate whether the exercise training could reduce inflammatory activity of VAT assessed by 18F-fluorodeoxyglucoase (FDG) positron emission tomography-computerized tomography (PET/CT).

Methods
Twenty-three overweight women who participated in exercise training program were included. Exercise training program was composed of aerobic exercise (45 min/session, 300 Kcal/day) and muscle strength training (20 min/session, 100 Kcal/day) 5 times per week for 3 months. They underwent F-18 FDG PET/CT before starting exercise program (baseline) and after completion of 3 months exercise program. Anthropometric data, clinical laboratory data, VAT area, and maximum standardized uptake value (SUVmax) of VAT were compared between baseline and after completion of the total exercise program.

Results
Baseline VAT SUVmax showed significant correlation with body weight, body mass index (BMI), waist circumference, and hip circumference. VAT SUVmax was significantly reduced by exercise training program. Exercise training program also reduced body weight, BMI, waist circumference, hip circumference, VAT area, subcutaneous adipose tissue area and blood pressure. The change of VAT SUVmax was significantly higher than the change of VAT area.

Conclusions
Exercise training could reduce the inflammatory activity of VAT assessed by F-18 FDG PET/CT. Thus, exercise would be a promising non-pharmacological strategy to reduce inflammatory activity of VAT. Furthermore, F-18 FDG PET/CT could be useful to evaluate the effect of therapeutic intervention targeted to inflammatory VAT activity.