bluuebunny/crossref_metadata_2025_split huggingface dataset:
172Coronary 18F-sodium fluoride uptake predicts progression of coronary arterial calcification
Authors: Doris M , Moss A J , Andrews J P M , Williams M , Van Beek E J R , Forsyth L , Dweck M R , Newby D E , Adamson P D 
Published: October 2019

Abstract

Background
Combined positron emission tomography and computed tomography (PET-CT) using 18F-sodium fluoride (18F-NaF) to detect microcalcification provides the opportunity to gain important insights into disease activity in coronary atherosclerosis. However, the relationship between 18F-NaF uptake and progression of coronary calcification has not been determined.

Purpose
To determine the relationship between 18F-NaF uptake and progression of coronary calcification in patients with clinically stable coronary artery disease (CAD).

Methods
Patients with established, multivessel CAD underwent 18F-NaF PET-CT and CT coronary calcium scoring at baseline, with repeat CT calcium scoring at one year. Coronary arterial PET uptake was analysed qualitatively and semi-quantitatively in diseased vessels by measuring maximum tissue-to-background ratio (TBRmax) – defined as the maximum standardised uptake value in a plaque divided by mean blood pool activity measured in the right atrium. Coronary calcification was quantified by measuring calcium mass, volume, average calcium density and total Agatston score (AU).

Results
In total, 185 patients underwent baseline and repeat imaging (median age 66 years, 80% men), and 118 (64%) had increased 18F-NaF uptake in at least one vessel. Median total calcium score, volume, mass and average density were higher in patients with compared to those without increased 18F-NaF uptake (Table 1). At one year, patients with evidence of increased 18F-NaF uptake demonstrated more rapid progression of coronary calcification (97 [39–166] AU) versus those without uptake (35 [7–93] AU; p<0.0001). Amongst 18F-NaF-positive patients, the calcium score increased only in coronary segments with 18F-NaF uptake (baseline 90.5 [27.5–202] AU versus one year 135.5 [59.3–281.8] AU; p<0.0001) and not in 18F-NaF-negative segments (baseline 44.5 [16–110.5] AU versus one year 46.5 [18.25–114] AU; p=0.446). There was a moderate correlation between TBRmax and change in total calcium score, volume and mass at 1 year (Spearman's Rho = 0.37, 0.38, 0.46 respectively; p<0.0001 for all).
Coronary calcification at baseline in PET-negative and PET-positive patients All patients (n=185) 18F-NaF Positive (n=118) 18F-NaF Negative (n=67) P value Agatston Score (AU) 381 [107–892] 541 [245–1130] 136 [55–361] p<0.0001 Calcium Volume (mm3) 358 [131–787] 506 [251–1014] 131 [64–343] p<0.0001 Calcium Mass (mg) 71 [23–155] 100 [48–222] 24 [11–69] p<0.0001 Average Density (mg/mm3) 0.19 [0.17–0.22] 0.20 [0.18–0.23] 0.18 [0.16–0.20] p<0.0001

Conclusions
Coronary 18F-NaF uptake identifies both patients and individual coronary segments with greater disease and more rapid progression of coronary calcification over one year.

Acknowledgement/Funding
AstraZeneca (unrestricted educational grant). British Heart Foundation (CH/09/002, RE/13/3/30183, FS/17/79/33226) Wellcome Trust (WT103782AIA).
209Glucose is associated with future atrial fibrillation and heart failure already at prediabetes levels, a 19 year follow up of 243,665 subjects
Authors: Lind V , Hammar N , Lundman P , Friberg L , Tallback M , Walldius G , Norhammar A 
Published: October 2019

Abstract

Background
Dysglycaemia is associated with cardiovascular disease even below the diagnostic diabetes threshold. Atrial fibrillation (AF) has been found to be associated with the metabolic syndrome and life-style changes after AF have been found to reduce recurrence of AF.

Purpose
We explored the association glucose and risk of first event of AF, HF and combined event.

Methods
Subject with fasting glucose in the AMORIS cohort, obtained 1985–1996 at routine occupational health check-ups or primary care in the Stockholm area were included. Subjects with prevalent AF, HF, ischemic heart disease, revascularization and cerebrovascular disease were excluded. Glucose levels were categorised as low (<3.9 mmol/L), normal (3.9–6.0mmol/L), impaired (IFG; 6.1–6.9 mmol/L) and diabetes (≥7.0 mmol/L or a diabetes diagnosis) according to WHO definition in 2006. First events of AF, HF or a combined event was identified until December 2011 by linkage to national registries. Information on co-morbidities was obtained from the National Patient Register. Hazard ratios (HR and 95% CI) by glucose group for AF and heart failure were calculated using Cox proportional hazards with attained age as timescale and adjusting for gender, total cholesterol and triglycerides. The change in AF risk by increasing glucose level was described by using splines (Figure).

Results
243 665 subjects with mean age 48.3 at index date, 54% male were included. During a mean follow-up time of 19.1 years and 4,7 million person years, 23 522 events of AF, 21 411 events of HF and 35 131 combined events occurred. The proportion with IFG and diabetes were 3.2% and 3.3% respectively. In the diabetes group about half were diagnosed prevalent cases (1.5%). Glucose was continuously associated with developement of AF (Table and Figure) and even more of HF (Table).
Events (n) and HR by glucose category Atrial fibrillation Heart failure Combined event Event HR [95% CI] Event HR [95% CI] Event HR [95% CI] Low 405 0.97 [0.88–1.08] 326 0.97 [0.87–1.08] 598 1.00 [0.92–1.09] Normal 20 663 1.00 17 811 1.00 30 159 1.00 IFG 1185 1.20 [1.13–1.28] 1319 1.43 [1.35–1.51] 1901 1.30 [1.24–1.36] Diabetes 1269 1.28 [1.20–1.35] 1955 2.19 [2.08–2.29] 2473 1.73 [1.66–1.81] Events (n) of AF, HF and combined and HR (95% CI) by fasting glucose category.
HR for AF by glucose level spline graph

Conclusion
Dysglycaemia, including glucose levels below the diabetes threshold, is continuously associated with future risk of both AF and HF. These data are important considering the large population with undetected dysglycaemia at risk for AF and HF where preventive measures including life-style changes could be of importance even before the onset of overt diabetes.

Acknowledgement/Funding
Swedish Heart and Lung foundation
217Metabolomic profile of patients with new onset heart failure; more microvascular dysfunction in patients with preserved ejection fraction compared to reduced ejection fraction - the PREFERS Study
Authors: Hage C , Lofgren L , Michopoulos F , Nilsson R , Davidsson P , Ekstrom M , Eriksson M J , Lynga P , Persson B , Wallen H , Gan L M , Persson H , Linde C 
Published: October 2019

Abstract

Background
Heart failure with preserved (HFpEF) and reduced (HFrEF) ejection fraction are both associated with metabolic derangements which may have different pathophysiological implications

Purpose
To identify metabolites and pathways differentially altered with the potential to differentiate HFpEF from HFrEF.

Methods
In the PREFERS Stockholm study (Preserved and Reduced Ejection Fraction Epidemiological Regional Study) 121 endogenous plasma metabolites were assessed by targeted mass spectrometry. Partial Least Squares Discriminant Analysis (PLS-DA) was used to identify metabolites differentially altered in new onset HF divided into HFpEF (EF ≥50%, n=46) versus HFrEF (ÈF<40%, n=75) patients. Multivariable logistic regression was used to assess independent associations between HF group and selected metabolites, including sex, age and eGFR as co-variates.

Results
Compared to HFrEF, HFpEF patients were older; 77 vs 65 years (p<0.001), more often female 54% vs 46% (p=0.004) with hypertension 60% vs 40% (p<0.001) and diabetes 63% vs 37% (p=0.007), and lower NT-proBNP 720 vs 1295 ng/L (p=0.014) and eGFR 63 vs 72 mL/min/1.73 m2 (p<0.001).
HFpEF patients had higher levels of hydroxyproline, cysteine, symmetric dimethyl arginine, alanine, kynurenine and acylcarinitines and lower levels of cAMP, lysoPC, L-carnitine, arginine, cGMP, serine and lactate (Figure). HFpEF was independently associated with reduced levels of cGMP (OR 0.98 [95% CI: 0.97–0.99; p=0.008]), serine (0.97 [0.95–1.00; 0.047]) and cAMP (0.97 [0.94–0.99; 0.009]).
Figure 1

Conclusions
In new onset HF patients, HFpEF was associated with decreased cGMP, cAMP and serine indicating increased oxidative stress, impaired innate immune function and myocardial hypertrophy. HFpEF patients displayed a distinct metabolic profile reflecting increased endothelial dysfunction, hypoxia, inflammation and myocardial fibrosis pointing towards more involvement of microvascular dysfunction compared to HFrEF.

Acknowledgement/Funding
Science for Life Laboratory–Astra Zeneca; Mölndal, Sweden collaborative grant No. 1377
251Revacept, an inhibitor of platelet adhesion in symptomatic carotid stenosis: Results from a phase II study
Authors: Groschel K , Richards T , Weimar C , Neugebauer R , Poli S , Weissenborn K , Imray C , Michalski D , Rashid H , Loftus I , Ritter M , Hauser T.-K , Muench G , Poppert H 
Published: October 2019

Abstract

Revacept is a novel lesion-specific inhibitor for platelet adhesion and thrombus formation. The biological drug is based on the platelet GPVI receptor and prevents collagen-mediated platelet activation from the atherosclerotic plaque. The unique characteristic of Revacept is the specific inhibition of plaque-mediated thrombus formation without alteration of hemostasis.
To test this concept in patients with plaque-mediated thrombosis we investigated patients with symptomatic carotid artery stenosis (at least 50% cf. ECST) with a recent ischemic cerebral stroke or transient ischemic attack (TIA). 150 patients were evenly randomized in blinded fashion to receive placebo, 40mg or 120 mg Revacept by IV infusion. To investigate anti-thrombotic efficacy, we assessed microemboli in the middle cerebral artery by transcranial Doppler (MES) and micro-infarctions in the brain by diffusion-weighted nuclear magnetic resonance (DWI-NMR) imaging. Ischemic complications such as myocardial infarctions and ischemic stroke were clinically followed up to 3 and 12 months. Bleeding complications were thoroughly monitored according to the RE-LY study group criteria. All patients were on standard anti-platelet therapy and underwent guideline conform treatment with carotid endarterectomy (CEA),carotid artery stent implantation or intensified conservative treatment.
The study was conducted in 16 centers in Germany and the UK from May 2013 to September 2018. Due to lost to follow-up investigations the planned patient numbers were slightly exceeded to 158 patients, who were finally included in the study according to intention to treat. Currently data clearance and detailed analysis of unblinded data is going on. 7.6% of patients underwent carotid artery stenting, 11.4% were under intensified conservative treatment and 81.0% were surgically treated with CEA. The safety data of the overall 158 patients which was closely monitored by an independent data safety board are available. In the overall study population (before unblinding for treatment) ischemic strokes and myocardial infarctions were numerically lower compared to previous studies with symptomatic carotid stenosis patients undergoing CEA or stenting (meta analysis from the EVA-3S, SPACE and ICSS study). Despite comparable basal anti-thrombotic therapy addition of Revacept did not increase bleeding complications in the overall study population.
The Revacept CS02 study has successfully achieved the aimed patient recruitment. Safety analysis shows a favorable profile. Bleeding complications in these high-risk patients with recent ischemic stroke were not increased compared to historic data from similar control patients. There is a trend for increased anti-thrombotic and anti-ischemic potency with regard to clinical events. Final data will be presented at the congress.

Acknowledgement/Funding
None
256Heart transplant recipients with cardiac allograft vasculopathy have increased platelet aggregation before and after low-dose aspirin therapy
Authors: Bjerre K P , Clemmensen T S , Berg K , Poulsen S H , Dalby S , Hvas A M , Grove E L , Eiskjaer H 
Published: October 2019

Abstract

Background
Following heart transplantation (HTx), long-term survival is reduced mainly due to development of a specific form of coronary artery disease, coronary allograft vasculopathy (CAV). Using optical coherence tomography to visualize the coronary artery wall, we have recently shown that layered fibrotic plaques resembling organized clots are the dominant plaque component in CAV. Thus, thrombosis is suggested as a possible mechanism contributing to development and progression of CAV. Aspirin is widely used after HTx despite limited evidence and lack of specific guidelines. The antiplatelet effect of aspirin has not been thoroughly examined in HTx-patients.

Purpose
To investigate baseline platelet aggregation and the antiplatelet effect of aspirin in HTx-patients with and without CAV.

Methods
We included 68 HTx-patients (median 8.6 years from HTx). In 66 patients taking 75 mg aspirin for a minimum of 7 days, platelet aggregation was measured in whole blood using impedance aggregometry with the following agonists: Adenosine diphosphate (ADP) stimulating ADP-receptors and arachidonic acid (AA) for monitoring of aspirin treatment. Aspirin compliance was confirmed by measuring serum-thromboxane B2. Platelet aggregation prior to aspirin therapy was measured in 59 patients as it was not considered clinically safe to interrupt ongoing aspirin treatment for one week prior to blood sampling in 9 patients mainly due to previous coronary stenting. CAV burden was determined by coronary angiography and echocardiography based on international classification. Patients were divided into two groups; no CAV (n=37) and CAV (n=29).

Results
In HTx-patients not treated with aspirin, we found significantly increased ADP-induced platelet aggregation in patients with CAV vs. patients without CAV (904 (95% CI 813–995) vs. 786 (95% CI 728–843) AU*min, P=0.02). Baseline AA-induced aggregation was also higher in patients with CAV vs. patients without CAV, though non-significant (994 (95% CI 907–1081) vs. 905 (95% CI 839–972) AU*min, P=0.10). Even though aspirin reduced AA-induced platelet aggregation in both groups, patients with CAV had significantly increased AA-induced platelet aggregation compared with patients without CAV on aspirin treatment (380 (95% CI 295–465) vs. 286 (95% CI 239–334) AU*min, P=0.04) (Fig. 1).

Conclusions
HTx-patients with CAV have increased platelet aggregation before and after aspirin treatment compared with HTx-patients without CAV. Aspirin monotherapy may not provide sufficient platelet inhibition in HTx-patients with CAV.

Acknowledgement/Funding
Aarhus University (PhD-salary)
259Higher risk of myocardial infarction in the first year following 5-fluorouracil treatment
Authors: Shanmuganathan J W D , Kragholm K H K , Tayal B T , Poulsen L P , El-Galaly T C E G , Fosbol E L F , Gislason G G , Kober L K , Sogaard P S , Torp-Pedersen C T T P , Freeman P F 
Published: October 2019

Abstract

Abstract

Background
5-fluorouracil (5-FU) is the third most commonly used chemotherapeutic agent in the treatment of solid malignancies across the world. The most common manifestation of cardiotoxicity associated with 5-FU is chest pain, presenting as atypical chest pain, angina on exertion or rest and acute coronary syndromes including myocardial infarction and in worse case even death.
Nevertheless, a widespread appreciation of 5-FU related cardiotoxicity including myocardial infarction is poorly understood.

Purpose
This study aims to examine risk of myocardial infarction in patients treated with 5-FU compared to age- and sex-matched population controls.

Methods and results
Methods: Individuals treated with 5-FU between 2004 and 2014 in the Danish National Patient Register were identified and risk set matching was used to find background population controls matched on age and sex in a 1:5 ratio. Furthermore, two years follow-up time were added with total 13 years. Neither
5-FU patients nor controls had prior ischemic disease. Aalen-Johansen and Kaplan-Meier estimates were used to report the cumulative incidence of myocardial infarction and all-cause mortality, respectively.
A multivariable Shared Frailty Cox regression analysis (adjusted for patient age, sex, hypertension, hypercholesterolemia, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, heart failure and atrial fibrillation as well as selected anti-anginal medications including nitrates, beta- and calcium-blockers) was used to determine the association between 5-FU treatment and the one-year risk of myocardial infarction.

Results
A total of 9,012 5-FU patients and 45,060 controls formed the study population. Differences in comorbid conditions (diabetes, chronic obstructive pulmonary disease, chronic kidney disease, heart failure and atrial fibrillation) and selected anti-anginal medications (nitrates, beta- and calcium-blockers) were non-significant (all P>0.05). The one-year cumulative incidence of myocardial infarction is significantly higher for 5-FU patients at 0.8% versus 0.6% among population controls (Figure 1A), with a competing risk of death of 25.1% versus 1.2%. The risk diminishes beyond one year and becomes lower for 5-FU patients with time (Figure 1A), along with an increasing all-cause mortality (Figure 1B). The unadjusted and adjusted hazard ratio for the one-year risk of myocardial infarction were 1.38 [95% CI 1.07–1.78] and 1.54 [95% CI 1.19–1.99].

Conclusions
Although the one-year risk of myocardial infarction is higher among 5-FU patients compared with population controls, the absolute risk is small and becomes insignificant beyond one year of follow-up.
264The long noncoding RNA H19 modulates cardiac remodeling after infarction
Authors: Choong O K , Chen C Y , Lin J H , Lin P J , Zhang J H , Kamp T J , Hsieh P C H 
Published: October 2019

Abstract
Noncoding RNAs account for 80% of human transcripts, but functional studies on noncoding RNAs are relatively few and limited. Long noncoding RNAs (lncRNAs) are known to have an important role in cardiac development, and lately, high-throughput RNA sequencing has been extensively utilized to profile and explore the transcriptome landscape of lncRNAs in failing hearts. These studies have revealed that lncRNAs are mostly dysregulated in failing hearts and their expression signature can discriminate failing hearts of different etiologies.
H19 is abundantly expressed in failing human hearts and its polymorphism was shown to possess a significant correlation with the risk of coronary artery diseases. In our study using murine hearts, we discovered that H19 was significantly up regulated in the heart after ischemic injury, with predominant expression in cardiac fibroblasts. This finding piqued our interest to further investigate the function of H19 in the heart.
We demonstrated that ectopic overexpression of H19 using the AAV approach led to severe cardiac fibrosis in mouse hearts following myocardial infarction. In light of this finding, we generated H19 knockout mice to further investigate the functionality of H19 and we found that cardiac fibrosis was attenuated in these mice. Altogether, these findings suggested that H19 is a fibrosis regulator during cardiac remodeling process after infarction. Due to the multiple regulatory roles of lncRNAs, we then took advantage of chromatin isolation by RNA purification (ChIRP) to identify the H19-interacting protein, YB-1. Surprisingly, mice with YB-1 knockdown displayed severe cardiac fibrosis even without injury. Furthermore, we demonstrated that YB-1 is a transcriptional suppressor of collagen 1A1. Knockout of H19 in YB-1 knockdown partially suppressed Col1a1 expression, which suggests a negative regulatory role of H19 on YB-1 towards the expression of Col1a1.
Taking into account all of these findings, we concluded that H19 mediates collagen expression in fibroblasts through the inhibition of YB-1 activity during cardiac remodeling.
266Loss of pumilio 1 phosphorylation turns off the regulation of miRNA-221 on gene p27kip1 in the heart
Authors: Zhou Y Z , Richards A M R , Wang P P W 
Published: October 2019

Abstract

Background
MicroRNAs regulate gene expression post-transcriptionally via complementary sequence pairing of mRNA 3'UTR and miRNA seed region. MiR-221 downregulates p27kip1 Cyclin-dependent kinase inhibitor 1B (p27), a cell cycle inhibitor, through direct targeting. The down-regulation of p27 caused by miR-221 upregulation induces cancer cell proliferation and has been reported to be closely associated with human cancer metastasis. This regulation is dependent on the existence of pumilio 1 (PUM1). Meanwhile miR-221 mimics protect cardiac myocytes against ischemic injury. It is a potential therapeutic target for cardioprotection. We investigated whether miR-221 targeted p27 in the heart.

Purpose
To test the hypothesis that the regulation of miR-221 on p27 is abolished in the heart due to lack of RNA binding protein (RBP) PMU1 phosphorylation but not due to p27 3'UTR shortening.

Methods
Primary cardiac fibroblasts (cFB) were isolated and cultured under normoxia and hypoxia. After transfections of miR-221 mimics and mimic control (MC), cell proliferation was assessed by cell number, CCk-8 and Ki67 staining. In vivo rats undergoing left coronary artery ligation (MI) and Sham were treated with intravenous miR-221 mimics. Cells or cardiac tissue were collected to measure p27 and PUM1 by RT-qPCR and Western blot (WB). Full length p27 (coding plus 3'UTR sequence) and 3'UTR p27 sequence were quantified using specific primers. The ratio of 3'UTR/Full length was compared to indicate changes between groups. The ratios of 3'UTR/Full length were compared to indicate changes between groups.

Results
MiR-221 mimics significantly downregulated the expression of p27 mRNA and protein in cFB in both normoxia and hypoxia. P27 downregulation led to cFB proliferation, which could be abrogated by p27 overexpression. miR-221 mimic treatment increased cardiac miR-221 by ∼2–5 fold in Sham and ∼15 fold in MI. Whilst p27 expression was not affected in either Sham or MI hearts. Simultaneously α-SMA+ cells, an indication of cFB number and activation, were reduced by miR-221 mimic in Sham and MI heart. The ratios of p27 3'UTR/full length did not vary significantly between cultured cFB and heart (Sham and MI), indicating the 3'UTR length did not vary between cFB and the whole heart. PUM1 mRNA expression was stable in cFB and the heart. However, phosphorylated PUM1 was highly expressed in cFB but completely diminished in Sham and MI hearts.

Conclusion
MiR-221 downregulated p27 in primary cFB and induced cell proliferation in vitro. miR-221 could not regulate cardiac p27 expression nor increase cFB proliferation in vivo. MiR-221 induced p27 regulation was correlated with the presence or absence of phosphorylated PUM1. For the first time, we demonstrated that loss of phosphorylated PUM1 turns off the regulation of miRNA-221 on gene p27 in the heart. The mechanism of PUM1 phosphorylation warrant future investigation.