bluuebunny/crossref_metadata_2025_split huggingface dataset:
P1625A pivotal role for cytotoxic CD8+ T cells in development of cardiac fibrosis
Authors: Kyaw T , Kanellakis P , Toh B H , Bobik A 
Published: October 2019

Abstract

Background/Introduction
Pressure overload-induced cardiac fibrosis increases myocardial stiffness leading to reductions in cardiac performances and cardiac failure. CD8+ T cells have been shown to accumulate during development of fibrosis but their role has not been defined.

Purpose
We examined the role and significance of CD8+ T cells in development of cardiac fibrosis.

Methods
Trans-aortic constriction (TAC) or 2-kidney-1-clip (2K1C) procedures were used to generate pressure overload-induced cardiac fibrosis in mice. Rat anti-mouse CD8β (lyt-3) monoclonal antibody (clone YTS 156.7) was used to deplete CD8+ T cells. A mixed bone marrow chimera strategy was used to specifically delete innate receptor Natural Killer Group 2D (NKG2D) or cytotoxin perforin from CD8+ T cells.

Results
Depleting CD8+ T cells in mice subjected to TAC or 2K1C-renal hypertension attenuated left ventricular fibrosis by 93% and 84% without affecting blood pressure. In TAC mice this was associated with a 68% reduction in apoptotic cardiomyocytes, a 74% reduction in macrophage accumulation, a 65% reduction in TGF-beta positive cells and a 95% reduction in TGF-beta positive macrophages, whilst CD4+ T cells were unaffected. Cardiomyocytes in regions of developing cardiac fibrosis contained cytoplasmic DNA and expressed the NKG2D ligand, Rae-1, indicative of activation of a DNA damage response; CD8+ T cells expressed the NKG2D receptor. Deletion of the NKG2D receptor from CD8+ T cells attenuated cardiac fibrosis by 82%; deletion of cytotoxin perforin has similar effects.

Conclusion(s)
We conclude that CD8+ T cells contribute to development of cardiac fibrosis by targeting stressed/damaged cardiomyocytes via an NKG2D-Rae-1 cytotoxic mechanism inducing their apoptosis. Macrophages then accumulate in the heart in response to increased numbers of apoptotic cardiomyocytes, clearing the apoptotic cells through engulfment and increasing their expression of the pro-fibrotic factor TGF-beta1.

Acknowledgement/Funding
The National Health and Medical Research Council of Australia
P1627Increased pericardial fibrosis and cardiac dysfunction in smooth muscle cell-specific SOCS3 deficient mice
Authors: Yanai T , Yasukawa H , Mawatari K , Sasaki T , Takahashi J , Nohara S , Shimozono K , Shibata T , Okabe K , Yamamoto M , Fukumoto Y 
Published: October 2019

Abstract

Background
Suppressor of cytokine signaling-3 (SOCS3) is an intrinsic negative-feedback regulator of signal transducer and activator of transcription-3 (STAT3) signaling pathway. We have previously shown that myocardial SOCS3 plays an important role in cardiac hypertrophy and survival; however, the role of SOCS3 in smooth muscle cells in cardiovascular pathophysiology remains elusive. In this study, we determined whether STAT3 and SOCS3 in smooth muscle cells would play a role in cardiovascular pathophysiology.

Methods and results
To target inactivation of the SOCS3 gene to smooth muscle cells, SOCS3-flox mice were bred with transgenic mice expressing Cre recombinase under control of the mouse SM22-α promoter (sm-SOCS3-KO mice). Left ventricular weight to body weight ratio was significantly increased in sm-SOCS3-KO mice compared with wild-type mice at 52 weeks of age (p<0.05). Echocardiographic analyses of sm-SOCS3-KOmice showed significantly decreased cardiac function compared with wild-typefrom 52 weeks of age (p<0.05). Interestingly, Sirius-red staining revealed that thickness of pericardium in sm-SOCS3-KOmice was markedly greater compared with wild-typemice at 52 weeks of age (p<0.05). Cardiac interstitial fibrosis in sm-SOCS3-KOmice was also greater compared with wild-typemice (p<0.05). Western blot analyses showed that phosphorylated STAT3 was significantly increased in sm-SOCS3-KOhearts compared with wild-typemice at 52 weeks of age (p<0.05), whereas no significant differences were observed at 7 weeks of age. Immunostaining revealed that phosphorylated STAT3 positive cells were in thickened pericardial area in sm-SOCS3-KOhearts. Some infiltrated inflammatory cells were also found in thickened pericardial area in sm-SOCS3-KOmice hearts.

Conclusion
These results suggest that STAT3 and its negative-feedback regulator SOCS3 in smooth muscle cells play an important role in the pathogenesis of pericardial fibrosis and cardiac dysfunction.
P1632A possible independent contribution of liver stiffness to the development of heart failure in its early stage
Authors: Iwasaki Y , Tomiyama H , Shiina K , Matsumoto C , Kimura K , Fujii M , Takata Y , Yamashina A , Chikamori T 
Published: October 2019

Abstract

Background
Heart failure (HF) is a heterogeneous condition. The reduced liver blood flow and hepatic congestion associated with HF causes liver damages leading to liver sclerosis. Fibrosis 4 score (FIB-4 score), a marker of liver sclerosis, is easily calculated from age, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) level and blood platelet count (PLT). Liver stiffness is known to be associated with vascular damages, including arterial stiffness and central hemodynamics. These vascular damages also cause the new onset of HF. However, it remains to be clarified whether liver stiffness is a direct risk factor for HF or whether its association with HF is mediated by vascular damage. We conducted cross-sectional and prospective longitudinal studies to examine whether FIB-4 score is directly associated with the serum NT-pro-BNP levels or the association is mediated by arterial stiffness and/or abnormal central hemodynamics.

Methods and results
In 3,040 health Japanese subjects with serum NT-pro-BNP levels <125 pg/ml, the FIB-4 score was calculated, and the serum NT-pro-BNP levels, brachial-ankle pulse wave (baPWV) velocity, radial augmentation index (rAI), second peak of the radial pressure waveform (SBP2) and PP2 (SBP2 – diastolic blood pressure) were measured. These parameters were measured again after a 3-year interval in 2,135 subjects. Pearson's correlation analysis demonstrated that FIB-4 score was significantly correlated with baPWV, rAI, SBP2, PP2 and the log-transformed the serum NT-pro-BNP levels. Multivariate linear regression analysis demonstrated a significant cross-sectional association of the FIB-4 scores with the log-transformed the serum NT-pro-BNP levels (beta = 0.08, p<0.01), but not with the baPWV, rAI, SBP2 and PP2. The change of serum NT-pro BNP levels during the study period was significantly higher in subjects with increase of the FIB-4 score during the study period (8.2±22.5 pg/ml) than that in those with decrease/no change (5.4±22.3 pg/ml) (p<0.05). The change of FIB-4 score during the study period was significantly associated with the change of the serum NT-pro-BNP levels during the study period (beta = 0.09, p<0.01).

Conclusion
Liver stiffness may have a significant direct association with the development of HF from the early stage, without the mediation of arterial stiffness and/or abnormal central hemodynamics. Therefore, the FIB-4 score appears to serve as a direct risk factor for HF from the early stage, and its association with HF may not be mediated by vascular damages.
P1646Do Extracellular Vesicles repair chronic ischemic heart disease by replenishing the cardiomyocyte pool?
Authors: Lima Correa B , El Harane N , Perotto M , Tence N , Pidial L , Desgres M , Barron E , Bellamy V , Perier M C , Renault N K , Gnecchi M , Silvestre J S , Menasche P 
Published: October 2019

Abstract

Introduction
Extracellular Vesicles (EV) seem to mediate the benefits of cell therapy for ischemic heart failure. Although their mechanism of action remains poorly understood, one hypothesis is that they might trigger the generation of new cardiomyocytes.
The doubly transgenic fate-mapping MerCreMer/ZEG mice model was thus used to distinguish whether these putative new cardiomyocytes originated from the division of preexisting ones (GFP+, Troponin T [TnT+], EdU+) or differentiated from endogenous progenitors, in which case they would stain positive for TnT+/EdU+ but negative for GFP.

Methods
Myocardial infarction was induced in 35 MerCreMer/ZEG mice by permanent occlusion of the left anterior descending coronary artery. Three weeks later, the surviving mice (n=18) with a left ventricular ejection fraction (LVEF) ≤45% received transcutaneous echo-guided injections in the peri-infarct myocardium of either EV (from 1.4 million human iPS-derived cardiovascular progenitor cells; 10 billion particles, n=9) or PBS (n=9); osmotic pumps were implanted to deliver EdU for 7 days in order to track the proliferation of new and native cardiomyocytes. Four-6 weeks after treatment all mice were evaluated by echocardiography (n=9 per group) and MRI (7 in each group), and then sacrificed for histological assessment, blindly.

Results
Based on echocardiography (MRI data pending), EV improved LVEF by 16% relative to baseline while a decrease of 4% was observed in the PBS group (p=0.46).
The number of new cardiomyocytes (TnT+/EdU+/GFP+) did not significantly differ between the EV-treated hearts and the controls, and averaged 0.54% of the total heart cell content in infarct, peri-infarct and remote areas. However, EV treatment better preserved preexisting GFP+/WGA+/TnT+ cardiomyocytes in the peri-infarct area as their number was greater by 5.15% compared to PBS (32 sections analyzed for each mouse). Compared to the PBS control group, EV delivery was also associated with a 2.5% decrease in fibrosis, a reduction of infarct size by 14.9%, and an increase in angiogenesis in the peri-infarct area (with a between-group absolute difference of 71 capillaries, on the basis of isolectin staining).

Conclusions
EV secreted by iPS-derived cardiovascular progenitors improve the function of chronically infarcted hearts. Preservation of the existing cardiomyocyte pool and limitation of adverse remodeling and scarred tissue, likely favored by increased neoangiogenesis, are the main mechanisms mediated by the EV, while fate mapping allowed to exclude the generation of new cardiomyocytes.
P1652Limited correlation of calculated plasma volume status with invasive right heart pressures in patients with heart failure
Authors: Campbell R , Barton A , Docherty K F , Kristensen S L , Payne J , Dalzell J R , Gardner R S , McMurray J V , Petrie M C 
Published: October 2019

Abstract

Background
Estimated plasma volume (ePV) can be calculated from haematocrit and body weight, and has been shown to correlate with PV measured using 125Iodine labelled human serum albumin. Comparing a patient's ePV to ideal PV (iPV), an estimate of a patient's relative congestion, called PV status (PVS), is possible. Higher PVS is associated with increased mortality in patients with heart failure (HF), and has been proposed as a simple, cheap, and non-invasive way of assessing congestion.

Purpose
Whether PVS is associated with invasively measured markers of congestion is unknown. We calculated PVS in patients with HF who had right heart catheterisation (RHC), and assessed any correlation between PVS and invasive measures of congestion.

Methods
We calculated PVS in consecutive patients who had RHC performed as part of transplant assessment. iPV was calculated as: iPV = c × weight (kg) where c=39 in males and c=40 in females. ePV was calculated using subjects' haematocrit and weight as follows: ePV = (1 − haematocrit) × [a + (b × weight in kg)], where haematocrit is a fraction, a=1530 in males and a=864 in females, and b=41 in males and b=47.9 in females. PVS was calculated as: PVS = PVS = (ePV − iPV) /iPV × 100%. Correlation between PVS and invasive wedge pressure, mean right atrial (RA) pressure, and NTproBNP were made using Pearson correlation.

Results
PV indices and RHC data were available for 61 patients, 43 (71%) were male. Median age was 55 [IQR 48, 58] years. 20 (33%), 24 (39%), and 15 (25%) were NYHA association class II, III, and IV respectively. The median NTproBNP was 1390 [IQR 512, 3612] pg/ml and median ejection fraction was 29 [IQR 20, 35] %. The median PVS was −5.9% (IQR −12.5, −1.6]. Median wedge and mean-RA pressures were 14 [7, 21] and 4 [1, 8] mmHg, respectively. Correlation between mean RA pressure and PVS is shown in the figure. There was no correlation between PVS and mean RA pressure (r=0.12, p=0.34) or wedge pressure (r=0.01, p=0.92). There was a weak correlation between NTproBNP and PVS (r=0.31, p=0.01)
Correlation mean RA pressure and PVS

Conclusion
PVS did not correlate with the invasive measures of congestion, mean RA and wedge pressure, but was weakly correlated with NTproBNP. Although there were limited number of patients in this study, we question the conclusion that PVS is a marker of congestion, and whether it can be used clinically for this purpose.
P1667Comparison of post-implant anticoagulation agents in left ventricular assist devices
Authors: Bigeh A , Keuth J , Gerkin R , Gopalan R 
Published: October 2019

Abstract

Background
Left ventricular assist devices (LVADs) improve survival in patients with end-stage heart failure. Despite technological advancements, there is still a high risk of bleeding and thromboembolic events. To minimise device clotting, anticoagulation is usually started three days after implant. Unfractionated heparin (UFH) is the standard as a bridge to coumadin, however, current guidelines lack comparative evidence and do not delineate between anticoagulation agents (such as enoxaparin).

Purpose
To evaluate the safety of post-implant anticoagulation in LVAD patients using UFH and low molecular weight heparin enoxaparin (LMWH).

Methods
From October 2007 to October 2018, 83 patients underwent LVAD implantation (Heartmate II, III or HVAD) at Banner University Medical Center-Phoenix. Retrospective analysis was performed on 68 patients who received post-implant anticoagulation with a goal INR 1.8–2.5. Patients were bridged with either UFH (n=46) or LMWH (n=22).

Results
Demographics and patient characteristics were comparable between groups. We analysed adverse events, survival, and time to adverse events. The heparin group had a nonsignificant longer event-free period after implant compared with LMWH, median 9.4 and 1.8 months, respectively (p=0.428). The LMWH group had a significantly increased proportion of adverse events across all categories (p=0.021). Bleeding was the most common event for both groups, although substantially more for those receiving LMWH. Most notably 14 heparin patients (30.4%) had no adverse events compared to zero in the LMWH group.
Types of Adverse Events Post-Implant Bleeding Hemorrhagic Stroke Ischemic Stroke Pump Thrombus None Total Bridging Agent Heparin Count 18 3 8 3 14 46 % 39.1% 6.5% 17.4% 6.5% 30.4% 100% Enoxaparin Count 14 2 4 2 0 22 % 63.6% 9.1% 18.2% 9.1% 0% 100% Total Count 32 5 12 5 14 68 % 47.1% 7.4% 17.6% 7.4% 20.6% 100% p=0.021.
Post-Implant Event-Free Survival

Conclusions
Minimising bleeding and clotting are a persistent challenge in LVAD patients. Use of LMWH was associated with significantly more adverse events compared to UFH, with bleeding constituting the majority of events. Establishing institutional protocols and standards are necessary to improve patient outcomes; therefore, larger prospective studies are needed.
P1676De novo aortic insufficiency following long term LVAD support can be successfully treated with TAVI and a pre-stenting technique
Authors: Kofler M , Unbehaun A , Buz S , Klein C , Meyer A , Potapov E , Eggert-Doktor D , Falk V , Kempfert J 
Published: October 2019

Abstract

Background/Introduction
Long-term continuous flow left ventricular assist device (cf-LVAD) can result in the development of relevant aortic regurgitation (AR). Although its impact on survival is still controversial, it causes heart failure related symptoms. Current evidence for less invasive strategies to treat AR in cf-LVAD patients is limited.

Purpose
This study sought to investigate the value of transcatheter aortic valve implantation (TAVI) to treat severe de novo AR in patients on long-term cf-LVAD support. Methods
We performed a retrospective analysis of 13 patients with severe AR following cf-LVAD implantation treated with TAVI between 2010 and 2019. TAVI's were performed via transfemoral (n=11), transapical (n=1) and transaxillary (n=1) access route. CoreValve (n=2), LotusValve (n=1), SapienXT (n=1) and Sapien3 (n=9) were used as transcatheter heart valves. In 4 patients, a new off-label strategy using landing-zone pre-stenting with a Sinus-XL stent was used (Figure 1).

Results
The median time interval from LVAD-implantation to TAVI was 1.7 years [interquartile range (IQR): 1.0 - 3.1]. Median age was 62 years [IQR: 57 - 67]. No procedural mortality or stroke was observed. Overall, device success according to VARC-II criteria was low due to a high rate of second valve necessity (54%). In contrast to the standard implantation technique, device success was 100% when the newly developed pre-stenting technique was applied (Table 1). Aortic regurgitation at discharge was none/trace in all patients. Valve function remained stable in all patients during a median echocardiographic follow-up time of 105 days [IQR: 11 - 298].
Table 1 Overall Sinus-XL prestenting (n=4) NO prestenting (n=9) Device success 7 (54) 4 (100) 3 (33) Procedural mortality 0 (0) 0 (0) 0 (0) Correct positioning of a single valve 7 (54) 4 (100) 3 (33) Intended valve performance 13 (100) 4 (100) 9 (100) Moderate or severe aortic regurgitation 0 (0) 0 (0) 0 (0)
Figure 1

Conclusions
Transcatheter aortic valve implantation is an efficient tool to treat cf-LVAD induced severe AR. The challenging anatomy of the non-calcified device landing zone causes a relatively high rate of primary device failure, which could be overcome with a pre-stenting technique.

Acknowledgement/Funding
None
P1680High density lipoprotein cholesterol (HDL-C) levels and endothelial glycocalyx integrity in treated hypertensive patients
Authors: Triantafyllidi H , Benas D , Schoinas A , Vlachos S , Vlastos D , Pavlidis G , Voutsinos D , Ikonomidis I 
Published: October 2019

Abstract

Background
Endothelial dysfunction indicates target organ damage in hypertensive patients. The integrity of endothelial glycocalyx (EG) plays a vital role in vascular permeability, inflammation and elasticity and finally to cardiovascular disease. We aimed to investigate the role of increased HDL cholesterol levels (HDL-C), which usually are considered protective against cardiovascular disease, in EG integrity in older hypertensive patients.

Methods
We studied 120 treated hypertensive patients older than 50 years were divided regarding HDL-C tertiles in group HDLH, (HDL-C >71 mg/dl, upper HDL-C tertile) and group HDLL, (HDL-C <71 mg/dl, two lower HDL-C tertiles). Increased perfusion boundary region (PBR) of the sublingual arterial microvessels (ranged from 5–9 micrometers) using Sideview Darkfield imaging was measured as a non-invasive accurate index of reduced EG thickness.

Results
PBR 5–9 was significantly decreased in group HDLH (p=0.04). In the whole population, HDL-C was inversely but moderately related with PBR 5–9 (r=−0.22, p=0.01). In a multiple linear regression analysis model, using age, BMI, smoking habit, HDL-C, LDL-C and office SBP, as independent variables, we found that BMI (β=0.25, p=0.006) independently predicted PBR 5–9 in the whole population.
Differences in PBR5-9 between HDL groups

Conclusions
In older hypertensive patients, HDL-C ranged between 71–101 mg/dl might moderately protect EG and subsequently endothelial function. Future studies in several groups of low or high risk hypertensives are needed in order to evaluate the beneficial role of extremely elevated HDL-C regarding cardiovascular risk evaluation as well as endothelial glycocalyx as a novel index of target organ damage in essential hypertension.
P1681Clinical profile of patients initiating evolocumab in Spanish Cardiology Units: A RETrospective, Observational Study of Real-World Clinical Practice (RETOSS-Cardio)
Authors: Barrios V , Antorrena Miranda M I , Bonanad Lozano C , Cosin Sales J , Diaz De Castro O , Fernandez Del Olmo M R , Garcia Del Egido A , Garcia Fuertes D , Garcia Izquierdo E , Mera Romero M , Otero Chulian E , Rincon Diaz L M , Vazquez Garcia R , Roldan Suarez C , Arrarte Esteban V 
Published: October 2019

Abstract

Background/Introduction
Cardiovascular (CV) disease represents the leading cause of death and disability in developed countries with elevated LDL-C among the main risk factors for CV events.

Purpose
We conducted a study to describe the clinical profile of patients initiating evolocumab in real-world clinical practice, specifically hospital cardiology units in Spain.

Methods
Retrospective, observational, serial chart review of consecutive hyperlipidemic patients (≥18 years) who initiated evolocumab in 31 Spanish hospital cardiology units from February-2016 to May-2017. Relevant patients characteristics and clinical data were collected from medical records at 12 weeks pre- and 12±4 weeks post-evolocumab initiation. Baseline values correspond to data collected up to 12 weeks prior to initiation of evolocumab.

Results
186 patients were enrolled: 72.0% men, mean (SD) age 60.3 (9.8) years, mean (SD) body mass index 28.5 (4.3) kg/m2. CV history and CV risk factors at evolocumab initiation are summarised below (Figure). Half of all patients were statin intolerant and almost all (94.1%) were secondary prevention. At baseline, half (51.1%) of all patients were receiving ezetimibe and 44.1% were receiving high-intensity statins. At baseline, mean (SD) LDL-C was 144.0 (49.0) mg/dL; 38.7% of patients had LDL-C 100-<130 mg/dL, 28.0% had LDL-C 130-<160 mg/dl, 12.4% had LDL-C ≥160 mg/dL, 12.9% had LDL-C ≥190 mg/dL. Mean (SD) baseline HDL-C was 47.7 (13.0) mg/dL. After 12 weeks of evolocumab treatment, mean (SD) LDL-C was reduced by 57.6% (21.6) to 62.2% (44.1) mg/dL (p<0.0001; LDL-C reductions of 57.5% [23.2]/57.6% [21.6] in patients with/without FH and 46.0% [21.5]/58.5% [22.1] in primary/secondary prevention patients, respectively). At week 12, 64.9% patients reached LDL-C levels <70 mg/dL, and 49.1% <50 mg/dL, while statin use remained stable (data not shown). Only 3.2% (n=6) patients discontinued evolocumab (voluntary withdrawal, mostly).
Baseline CV history and CV risk factors

Conclusions
In Spanish Cardiology Units, evolocumab was typically prescribed in patients with FH and/or atherosclerotic cardiovascular disease, aligned with 2016 ESC/EAS guidelines recommendation on PCSK9i usage. Patients tended to have LDL-C levels above the recommended thresholds with LDL- levels markedly reduced after 12 (± 4) weeks of evolocumab treatment.

Acknowledgement/Funding
This work was supported by Amgen.