bluuebunny/crossref_metadata_2025_split huggingface dataset:
P731High-density lipoproteins rescue diabetes-impaired angiogenesis by restoring cellular metabolic reprogramming responses to hypoxia
Authors: Bursill C , Primer K R , Solly E , Psaltis P J , Tan J T M 
Published: October 2019

Abstract

Background
We have previously identified that high-density lipoproteins (HDL) rescue hypoxia-induced angiogenesis in diabetes, however the underlying mechanisms remain unknown. A central component of hypoxia-induced angiogenesis is the reprogramming of endothelial cell (EC) metabolism to improve tolerance of hypoxia at the site of injury/repair, including following myocardial infarction. Pyruvate dehydrogenase kinase 4 (PDK4) suppresses mitochondrial respiration in hypoxia to decrease oxygen consumption and preserve cell survival. Diabetes impairs this adaptation to hypoxia, causing cellular dysfunction and may underlie delayed angiogenic responses to ischaemia in hyperglycaemia.

Purpose
To determine the role of metabolic reprogramming in angiogenesis and diabetes and the effect of reconstituted HDL (rHDL).

Methods and results
Using an in vitro functional angiogenesis assay, siRNA-mediated knockdown of PDK4 impaired human coronary artery endothelial cell (HCAEC) tubulogenesis in hypoxia by 82% versus siScrambled controls (P<0.0001). HCAECs were treated with rHDL (20μM, apolipoproteinA-I + phosphatidylcholine) or PBS (vehicle) and exposed to glucose (5 or 25 mM, 72 h), then normoxia or hypoxia (1.2% O2, 6 h). PDK4 expression was increased by 65% in hypoxia versus the normoxia control (P<0.05). By contrast, in high glucose PDK4 expression failed to increase in response to hypoxia. Incubation with rHDL rescued this impairment and elevated PDK4 expression by 40% in hypoxia and in high glucose (P<0.01), versus the PBS control. In parallel, rHDL rescued high glucose-impaired tubulogenesis in hypoxia by 64% versus the PBS/normoxia control (P<0.001). We next used a murine model of diabetic wound healing that tracks angiogenesis in the wound bed. We found daily topical application of rHDL (50μg/wound/day) increased wound angiogenesis by 10% (as assessed by Laser Doppler perfusion imaging) and promoted CD31+ neovessel formation by 46% in diabetic wounds, supporting an increased rate of wound closure in diabetic animals of 30% (P<0.05). rHDL treated wounds from diabetic mice had a striking increase in PDK4 gene (180%) and protein expression (350%) in the early-mid stages (24 h and 3-day time points, P<0.05) post-wounding, when the angiogenic response to wound ischaemia is most important.

Conclusions
We have demonstrated that the key protein controlling the metabolic reprogramming response to hypoxia, PDK4, plays an important role in endothelial cell angiogenesis. We also show that the PDK4 and angiogenesis responses to hypoxia are impaired in high glucose and can be rescued by rHDL. In vivo we find that topical rHDL increases wound angiogenesis and PDK4 levels, explaining the enhanced rate of wound closure in diabetic mice and has implications for improving cardiovascular outcomes for diabetic patients following myocardial infarction.
P735Interleukin-33 induced eosinophilia restores perivascular adipose tissue function in obesity
Authors: Saxton S , Potter R J , Withers S B , Grencis R , Heagerty A M 
Published: October 2019

Abstract

Background/Purpose
Perivascular adipose tissue (PVAT) is essential in the modulation of vascular tone. Recently we have shown that resident eosinophils play a vital role in regulating PVAT function. In obesity, eosinophil numbers are reduced and PVAT anticontractile function is lost, resulting in increased vascular tone, which will contribute to development of hypertension and type-2 diabetes. Evidence suggests that eosinophilia resulting from parasitic infection may be useful in improving glucose tolerance; therefore, we investigated the effects of eosinophilia on PVAT function in health and obesity.

Methods
Control mice and a high fat fed mouse model of obesity were administered intraperitoneal injections of interleukin-33 (IL-33, 0.1μg) over a five day period. Blood pressure, blood glucose and plasma insulin were measured and compared with un-injected control and obese mice. Wire myography was used to assess the vascular contractility of mesenteric arteries (<250μm, +/− PVAT) from both injected and un-injected control and obese mice in response to noradrenaline. ELISAs and immunohistochemistry were used to examine eosinophil numbers.

Results
High fat feeding induced significant elevations in blood pressure, blood glucose and plasma insulin, which were reduced using IL-33 injections. Eosinophilia was confirmed in blood plasma using an eosinophil cationic protein ELISA. Using wire myography, mesenteric arteries from control mice PVAT exerted an anticontractile effect on the vessels, which was enhanced in control mice injected with IL-33. In obese mice, the PVAT anticontractile effect was lost, but was restored in IL-33 injected obese mice. Using immunohistochemistry, we confirm that eosinophils numbers in PVAT were reduced in obesity and increased in IL-33 treated PVAT.

Conclusions
IL-33 injections induced eosinophilia in both control and obese mice. IL-33 treatment restored PVAT function in obesity, and enhanced the anticontractile function of PVAT in healthy animals. In addition, only five consecutive injections of IL-33 reversed development of hypertension and type-2 diabetes in obese mice. These data suggest that IL-33 induced eosinophilia presents a novel approach to treatment of hypertension and type-2 diabetes in obesity.

Acknowledgement/Funding
British Heart Foundation
P741Next generation miRNA sequencing and changes in coagulation measured by thrombelastography (TEG) in patients with cardiovascular disease
Authors: Kreutz R , Ipe J , Kassab K , Kanuri S , Gao H , Liu Y , Skaar T 
Published: October 2019

Abstract

Background
Thrombelastography (TEG), an ex-vivo clotting assay can identify subjects at high risk of subsequent coronary thrombotic events. Synthesis of clotting factors is subject to post-translational regulation, which is modulated at least in part by miRNA.

Hypothesis
We hypothesized that miRNA sequencing may identify specific miRNA linked with measures of hypercoaguability by TEG.

Methods
Kaolin activated thrombelastography was performed in platelet poor citrate plasma from 61 subjects referred for cardiac catheterization. Time to clot formation (R), clot stabilization time (K), and maximal fibrin clot strength (MA) was measured. Next generation miRNA sequencing was done from RNA isolated from whole blood samples, which includes miRNA derived from leukocytes and platelets. Prediction of miRNA gene targets was performed with targetscan.

Results
Sequencing resulted in quantification of 371 distinct miRNA from whole blood samples. We found 13 miRNA correlating with alteration in TEG-R, 33 miRNA correlating with TEG-K, and 21 miRNA correlating with TEG-MA. Coagulation factors or genes associated with coagulation were found to be among predicted targets in 49 out of these 67 miRNA. Most common predicted targets included factors II, V, VII, X, XIII, fibrinogen, plasminogen-activator inhibitor, and tissue factor. Factor XIIIA1 was highly conserved gene target by miR-96-5p (one of only 3miRNA predicted for this gene). MiR-96-5p correlated with clot stabilization time (ρ=-0.26, p=0.047) which has been shown to be dependent on FXIIIa activity. MiR-22-3p was significantly correlated with TEG-K (ρ=0.28, p=0.034) and was only miRNA with highly conserved target site for prothrombin (Factor II).

Conclusions
In patients with cardiovascular disease miRNA sequencing combined with coagulation phenotype in silico analysis may identify novel links to coagulation that are associated with increased thrombotic risk.

Acknowledgement/Funding
Charles Fisch Cardiovascular Research Award endowed by S. Knoebel
P766The impact of a nurse-led heart failure service on complex device need
Authors: Graby J , Tibbs G , Giblett D , Dayer M , Gosling O 
Published: October 2019

Abstract

Introduction
The prevalence of left ventricular systolic dysfunction (LVSD) continues to rise. It is recognised that optimal medical therapy can improve ejection fraction (EF) in a proportion of patients. A nurse-led Heart Failure Service (HFS) was established in a district general hospital to deliver this, and previous analysis has demonstrated its efficacy in optimising HF drugs to recognised therapeutic doses.
Complex devices (Implantable Cardiac Defibrillators [ICDs] or Cardiac Re-synchronisation Therapy Devices [CRTs]) are established treatments for HF patients if on Optimal Medical Therapy (OMT). The European Society of Cardiology (ESC) and National Institute for Clinical Excellence (NICE) guidelines have expanded their role with a broad cohort of patients eligible for this therapy.

Aim
We sought to determine how many patients, who at baseline had an indication for device therapy, improved after OMT to an extent that they no longer had an indication for device therapy.

Methods
A retrospective analysis was undertaken of the HFS database over a 5 year period recording ECG for QRS duration & morphology, surveillance of EF, device outcome. Exclusion criteria: Baseline EF >35%; device in-situ or listed for prior to HFS referral; no identifiable baseline EF or ECG.

Results
502 patients were analysed and 264 patients met criteria for a new device or upgrade at baseline – 191 male (72%), 73 female (28%), median age 73 (IQR 64–80).
76/97 (78%) of potential CRT candidates (Pacing or Defibrillator component) were male. 16/97 (16%) improved to an EF >35% (median age 68 [IQR 64–72], 14 male [88%], 2 female [12%]). 4/16 (25%) of these patients underwent pharmacological or electrical cardioversion, which can contribute to EF improvement.
There were 167 potential ICD candidates (115 male [69%]). 53 /167 (32%) improved to an EF >35% (median age 68 [IQR 56–75], 33 male [61%]). 7/53 (13%) of these patients had other treatments that can also improve EF (cardioversion, 4; re-vascularisation, 2; valvuloplasty, 1).
69/264 (26.1%) patients did not require a device after optimal therapy had been delivered.

Conclusions
We have demonstrated that in a significant proportion of HFS patients, the delivery of high quality OMT translates into an improvement in EF.
Not all patients that strictly “meet guideline criteria” will be offered a device, nor will all patients take up offer of a device. However, this improvement in EF is likely to benefit the patient symptomatically and prognostically, and carry a significant cost saving to healthcare institutions. A cost analysis study will be undertaken to further assess this.
P870A genetic risk score is associated with increased coronary plaque burden but not specific plaque features: a coronary computed tomography study
Authors: Christiansen M K , Nissen L , Winther S , Frost L , Johansen J K , Jensen H K , Botker H E , Bottcher M , Nyegaard M 
Published: October 2019

Abstract

Background
Genetic risk scores (GRSs) based on risk variants identified from genome-wide association studies (GWASs) predict coronary artery disease (CAD) risk. However, it is unknown whether the GRS is associated with coronary plaque burden or specific high-risk plaque features responsible for the clinical disease onset.

Purpose
To investigate if a GRS is associated with coronary plaque burden and specific plaque characteristics, in patients with suspected stable CAD referred for coronary computed tomography angiography (CTA).

Methods
We consecutively included and genotyped 1645 patients undergoing coronary CTA. Using LDPred, a previously validated GRS was calculated as the weighted sum of the number of CAD risk variants identified from the CARDIoGRAMplusC4D GWAS meta-analysis. Plaques were evaluated using an 18-segment model and characterized by stenosis severity (0%, 1–49%, 50–69%, 70–100%) and composition (calcified (>80% calcified), mixed-calcified (50–80% calcified), mixed-soft (20–50% calcified), or soft (<20% calcified)). The segment stenosis score and the coronary artery calcium score (CACS) were used as measures of plaque burden. Multivariate regression models were used to assess the effect per standard deviation (SD) of the GRS with adjustment for age, sex, hypertension, hypercholesterolemia, BMI, chest pain symptoms, and active smoking.

Results
For each SD increase in the GRS, the segment stenosis score increased with 49% (p=8.6e-27) and CACS increased with 110% (p=2.3e-24). The GRS was associated with a higher risk of plaque stenosis >50% (OR: 1.74, p=3.2e-15), calcified (OR: 1.65, p=3.0e-16), mixed-calcified (OR: 1.64, p=1.5e-8), mixed-soft (OR: 1.44, p=1.6e-6), and soft plaques (OR: 1.40, p=3.0e-6), and all coronary vessels were more often affected with plaques (all p-values <1.0e-4).
When analyzing the plaque characteristics (3007 plaques in 849 patients), the GRS was associated with stenosis severity (OR per severity category: 1.15 (p=0.005), but not with extent of calcification, proximal location, or presence in any of the major coronary vessels (all p-values >0.05).
GRS and Plaque burden

Conclusion
The GRS was strongly associated with the extent and severity of CAD at coronary CTA, but not any specific plaque characteristics per se. The results may suggest that polygenic risk based on large CAD-GWAS increases CAD risk through increased coronary plaque burden rather than specific plaque features.
P878Prevalence and prognosis of patients with myocardial infarction with nonobstructive coronary arteries: a nationwide registry based study
Authors: Janosi A , Ferenci T , Andreka P 
Published: October 2019

Abstract

Background
There are conflicting data about the proportion and prognosis of patients (pts) with acute myocardial infarction (AMI) with nonobstructive coronary arteries (MINOCA).

Purpose
To define the incidence and prognosis of MINOCA pts in different types of AMI.

Methods
The Hungarian Myocardial Infarction Registry (HUMIR) is a nationwide, mandatory database in which the clinical and demographic informations of patients with AMI are recorded. Between January 1, 2014 and June 30, 2018, a total of 45,223 AMI (ST-elevation myocardial infarction (STEMI) n=22,469) pts were registered. After excluding pts with previous AMI, PCI, CABG, and congestive heart failure, 2003 MINOCA pts were found (MINOCA group), while 43,220 AMI pts had obstructive coronary artery disease (MI-CAD group).

Results
The proportion of pts with MINOCA disease was 4.4% among the total pts with AMI. The prevalence was higher in the non ST-elevation myocardial infarction (NSTEMI) group (n=1546, 6.8%) than in the STEMI (n=457, 2.0%) group. The pts with MINOCA disease were slightly younger compared to the pts with MI-CAD (mean age 64.0±14.4 vs. 65.5±12.2 years respectively). The proportion of women was higher in the MINOCA group than in the MI-CAD group (55.7% vs. 36.5%). At discharge, pts with MINOCA disease were less likely to be prescribed certain drugs compared to the pts with MI-CAD. These include aspirin (85.4% vs. 95.6%), RAAS blockers (83.8% vs. 90.4%), statins (86.2% vs. 94.7%), β-blockers (86.8% vs. 89.8%) for the MINOCA and MI-CAD groups respetively. At the 1-year follow-up, the incidence of new AMI events was 1.6% in the MINOCA group compared with 5.0% in the MI-CAD group (HR=2.79). All-cause mortality was higher among the pts with MI-CAD compared to the pts with MINOCA disease. In the MINOCA group, among the pts with NSTEMI, men and women had similar outcomes at 30 days, but men had somewhat higher mortality at one and two years. In contrast, in the STEMI group, women had higher mortality compared to men at all time points during the study (Table 1).
Mortality among MINOCA and MI-CAD pts Mortality MINOCA (n=2003) MI-CAD (n=43,220) MINOCA – STEMI MINOCA – NSTEMI Men (n=218) Women (n=239) Men (n=669) Womenr (n=877) 30-day 5.9% [4.9–7.0] 8.4% [8.1–8.7] 8.7% [4.9–12.4] 13.4% [9–17.6] 4.3% [2.8–5.9] 4.4% [3.1–5.8] 1-year 12.5% [11.0–14.0] 15.6% [15.3–16.0] 12.1% [7.6–16.4] 20.3% [15–25.2] 12.2% [9.6–14.7] 10.8% [8.7–12.8] 2-year 16.7% [14.9–18.5] 19.9% [19.5–20.3] 18.2% [12.4–23.6] 23.6% [17.8–29] 16.9% [13.8–20] 14.3% [11.7–16.7] 95% confidence interval in brackets.

Conclusion
The population-level incidence of MINOCA disease was 4.4% in AMI; the incidence was higher in the NSTEMI group compared to the STEMI group (6.8% vs. 2.0%). Despite the benign anatomy, the long-term prognosis is poor, especially in women after STEMI: 1 out of 4 pts died at the two-year follow up.

Acknowledgement/Funding
None
P931Direct left ventricular wire pacing during transcatheter aortic valve implantation
Authors: Stapor M , Trebacz J , Wiewiorka L , Ostrowska-Kaim E , Nawara-Skipirzepa J , Sobczynski R , Konstanty-Kalandyk J , Musial R , Trebacz O , Zmudka K , Kapelak B , Legutko J 
Published: October 2019

Abstract

Background
Rapid ventricular pacing is mandatory during balloon valvuloplasty or balloon-expandable transcatheter aortic valve implantation (TAVI). Traditionally right ventricular (RV) lead pacing was used. Direct left ventricular (LV) wire pacing is considered safe and effective in balloon-expandable TAVI (EASY-TAVI study).

Aim
The purpose of this study is to determine whether a direct LV wire pacing during TAVI reduces procedure duration and complications in population of unselected patients.

Methods
LV pacing was provided via commercially available pre-shaped guide wires. The cathode was connected to the tip of the wire and the anode to a needle inserted into subcutaneous tissue of the groin.

Results
143 patients underwent transfemoral TAVI. Self-expandable (79,7%), balloon-expandable (18,2%) and mechanically-expandable (2,1%) valves were implanted. LV pacing was dominant (57,3%) and its efficacy was 97,6%. Procedural duration was shorter in LV pacing group (83.7±20.3 vs. 88±33.5 min, p=0.0203). LV pacing required higher radiation dose (754.7±586.4 vs. 547.7±394 mGy, p=0.0168) and more contrast agent (157.8±56.8 vs. 134.8±61.8 ml, p=0.0072). There was no cardiac tamponde in LV pacing group in comparison with 2 in RV pacing group (3%, p=0.3438). In RV pacing group more patients required blood transfusion (21.5% vs. 7.3%, p=0.0075). Pacing method did not affect the outcome or length of hospitalization.
TAVI complications LV wire pacing RV lead pacing p Valve displacement 1 (1.2%) 1 (1.5%) 0.4998 Second valve (bail-out) 1 (1.4%) 3 (4.9%) 0.1021 Perivalvular regurgitation (more than mild) 6 (7.1%) 5 (7.8%) 0.4583 Cardiac tamponade 0 (0%) 2 (3%) 0.3438 Postprocedural permanent pacemaker 4 (5.1%) 10 (16.4%) 0.0025 Cerebrovascular accident 3 (3.8%) 1 (1.6%) 0.8506 VARC-2 bleeding 5 (5.9%) 5 (7.6%) 0.3923 Maximum creatinine level (umol/l) 114.6±45.8 116.9±92.8 0.5351 Lowest hemoglobin (g/dl) 11±7.3 10.1±1.6 0.6967 Blood transfusion 6 (7.3%) 14 (21.5%) 0.0075 Hospitalization (days) 7.1±7.2 8.2±10.6 0.3142 In-hospital mortality 1 (1.2%) 1 (1.6%) 0.8506

Conclusions
Direct LV wire pacing during TAVI is simple, reproducible and safe, provides stable stimulation with a low rate of complications and a potential reduction in procedural time.
P945Abnormalities in ankle-brachial indices are independently associated with new-onset atrial fibrillation
Authors: Tseng A , Girardo M , Atwal D , Firth C , Shipman J , Liedl D , Cooper L , Wennberg P , Shamoun F 
Published: October 2019

Abstract

Introduction
Lower extremity physiologic studies are an important non-invasive diagnostic tool in peripheral arterial disease (PAD). PAD and atrial fibrillation (AF) are associated with increased cardiovascular and all-cause mortality.

Purpose
To evaluate the association between PAD and new-onset AF and the risk of stroke.

Methods
We performed a study of all patients without AF undergoing ankle-brachial index (ABI) for any indication between January 1996 to June 2018. The ABI cut-off were as follows: abnormal ABI (0–0.99), normal ABI (1.00–1.39) and poor vessel compressibility (PC) (1.40+). Demographic, comorbidity, and outcome variables were extracted using the electronic medical record.

Results
Overall, 34,441 patients (mean age 66.8±14.3, 57.3% male, 88.2% white) were included in the study with a median follow-up of 7.2 years (interquartile range, 3.0–12.9 years). Multivariate Cox proportional hazard analysis showed increased risk of new-onset AF for male sex, older age, hypertension, coronary artery disease, cerebrovascular disease, chronic kidney disease stage III or greater, congestive heart failure, chronic obstructive pulmonary disease, and cancer (all p<0.0001). After adjustment, ABI results were significantly associated with new-onset AF, particularly poorly-compressible vessels (adjusted HR: 1.42 (1.30–1.55), p<0.0001) compared to abnormal ABI (adjusted HR: 1.12 (1.05–1.20), p=0.0012). Patients with atrial fibrillation were more likely to experience ischemic stroke (39.2% versus 16.1%, p<0.0001).

Conclusion
Abnormalities in ABI results, particularly poorly-compressible vessels, are independently associated with new-onset atrial fibrillation in a large ambulatory cohort. While the mechanism cannot be assessed, common inflammatory mechanisms and increased vascular stiffness may play an important role. Identification of AF in these at-risk patients may improve cardiovascular outcomes.
P961Investigator versus Core Lab evaluation of coronary blood flow in PCI of patients in cardiogenic shock: a substudy of the CULPRIT-SHOCK trial
Authors: Zeitouni M , Barthelemy O , Rouanet S , Guedeney P , Hauguel-Moreau M , Hage G , Overtchouk P , Brugier D , Vignolles N , Kerneis M , Silvain J , Collet J P , Vicaut E , Thiele H , Montalescot G 
Published: October 2019

Abstract

Background
Thrombolysis In Myocardial Infarction (TIMI) flow is a prognostic factor which assessment is complex in life-threatening situations. Because TIMI flow evaluation by site investigator (SI) is subject to bias, independent Core-Laboratory (CL) adjudication is the reference standard in clinical trials.

Purpose
To evaluate the concordance between CL and SI in the evaluation of the culprit artery TIMI flow, and the associated prognosis in the CULPRIT-SHOCK trial.

Methods
All patients of the CULPRIT-SHOCK trial with CL adjudications were included in this analysis. CL adjudicators were blinded to patient's characteristics and outcomes: pre and post-PCI TIMI flows were solely evaluated on the basis of coronary angiograms. SI determined the TIMI flow before and immediately after PCI of the culprit lesion. The concordance was determined by Cohen's κ coefficient. A multivariate analysis was used to evaluate 1) factors of discordance 2) the association between each method of evaluation and the mortality at 30 days and 1 year.

Results
Among CULPRIT-SHOCK patients, 663 patients were eligible for this analysis. Of the 214 patients adjudicated TIMI flow 3 by CL before PCI, SI over-estimated the obstruction to TIMI flow 0–1-2 in 121 (56.5%). Of the 139 patients scored TIMI flow 0–1-2 by CL after PCI, SI over-graded their results to TIMI flow 3 in 79 (56.8%). Overall, the K coefficient of agreement was 0.44, 95% CI [0.36; 0.51] before PCI and 0.44, 95% CI [0.35; 0.53] after PCI. Mechanical circulatory support and culprit left main were the main factors of discordance of TIMI flow after PCI. The association between TIMI flow 0–1-2 after PCI and 30-days mortality was significant, whether adjudicated by SI or CL (figure). Post-PCI TIMI-flow 0–1-2 was associated to 1-year mortality only when evaluated by SI (figure).
Association between TIMI and mortality

Conclusions
In comparison to the independant CL evaluation, SI overestimated the severity of coronary slow flow before PCI, and the success of PCI in improving coronary flow. The level of agreement between CL and SI was moderate. While both evaluations predicted 30-days mortality, only SI scoring was associated to 1-year mortality.

Acknowledgement/Funding
European Union Seventh Framework Program, the German Heart Research Foundation, German Cardiac Society.