bluuebunny/crossref_metadata_2025_split huggingface dataset:
P653PCSK-9 inhibitors and acute coronary syndrome in hyperlipidemic patients: a systematic review and meta-analysis
Authors: Asbeutah A A , Asbeutah A M , Abu-Assi M A , Welty F K 
Published: October 2019

Abstract

Introduction
Hyperlipidemia has been associated with several adverse cardiac and cerebrovascular events. Treatment with statins has proven to reduce the risk of cardiovascular events, however not all patients could reach adequate low-density lipoprotein targets or tolerate statin therapy. This has led to a recent increase in the use of PCSK-9 inhibitors for management of uncontrolled hyperlipidemia.

Purpose
Effect of PCSK-9 inhibitors on the reduction of acute coronary events in patients with hyperlipidemia.

Methods
A systematic search of electronic databases for published phase 2 or 3 randomized controlled trials involving hyperlipidemic adults on PCSK-9 inhibitors was conducted. Trials involving evolocumab or alirocumab were included in the analysis. The end points of myocardial infarction and unstable angina were computed together as the composite outcome of acute coronary events. Meta-analysis using a random effects model, with dichotomous outcomes expressed as odds ratios (OR) with 95% confidence intervals (CI), was performed.

Results
Thirty randomized controlled trials comprising 62,961 patients were included in the meta-analysis, including the recently published ODYSSEY OUTCOMES trial with 18,942 patients. Analysis was stratified according to PCSK-9 inhibitor, either evolocumab or alirocumab. In the stratified analysis, evolocumab was associated with a significantly lower rate of acute coronary events with an OR: 0.79 (95% CI, 0.72–0.87; P<0.001). In contrast, alirocumab was not associated with a significantly lower rate of acute coronary events with an OR: 0.71 (95% CI, 0.47–1.10; P=0.12). For the combined group, compared with no PCSK-9 inhibitor therapy, PCSK9 inhibitor therapy was associated with a significantly lower rate of acute coronary events (4.3% versus 5.8%; OR: 0.81 (95% CI, 0.75–0.87; P<0.001). The modest reduction of risk of acute coronary events of 1.5% translates into a number needed to treat of 67. Neither publication bias, nor significant heterogeneity was observed in the analysis.
Acute coronary events

Conclusions
PCSK-9 inhibitor therapy significantly reduces the risk of acute coronary syndrome when compared to the usual standard of care in adults with uncontrolled hyperlipidemia.
P686Cancer is not associated with increased cardiac and bleeding events after 2nd- and 3rd-generation drug-eluting stents implantation
Authors: Muramatsu Y , Minami Y , Ishida K , Kato A , Katsura A , Sato T , Kakizaki R , Nemoto T , Hashimoto T , Fujiyoshi K , Meguro K , Shimohama T , Ako J 
Published: October 2019

Abstract

Background
Previous studies demonstrated the impact of concomitant cancer on the increased risk of adverse cardiac and bleeding events after percutaneous coronary intervention (PCI). However, the impact in this 2nd- and 3rd-generation drug-eluting stent (DES) era remains to be elucidated.

Purpose
To clarify the impact of cancer on clinical outcomes in patients after 2nd- or 3rd -generation DES implantation.

Methods
A total of 932 patients who underwent PCI with 2nd- or 3rd -generation DES were included. Patients who were diagnosed with cancer after PCI were excluded from the present cohort. The incidence of major adverse cardiac events (MACE) including cardiac death, myocardial infarction and target or non-target vessel revascularization, and bleeding events was compared between the patients with cancer or the history of treatment for cancer (cancer group, n=140) and the patients without cancer (no cancer group, n=792). Bleeding events were evaluated according to the Thrombolysis in Myocardial Infarction definition. Further comparisons were performed between the 2 groups (cancer group, n=126; no cancer group, n=252) after the adjustment of baseline clinical characteristics using 1:2 propensity score-matching analysis.

Results
The incidence of MACE at median 577 [340–1043] days after the PCI was comparable between the 2 groups in both unadjusted (15.0% vs. 15.0%, p=0.984) (Panel A) and adjusted cohorts (14.3 vs. 13.1%, p=0.796), although the incidence of all cause death in the cancer group was significantly greater than the no cancer group (15.1 vs. 9.5%, p=0.007, in the adjusted cohort). The increased risk of MACE was not observed in any types of cancer or treatment (Panel B). The incidence of bleeding events was also comparable between the 2 groups (4.0 vs. 2.0%, p=0.297, in the adjusted cohort).

Conclusion
The increased incidence of MACE and bleeding events in patients with cancer was not demonstrated after the 2nd- or 3rd-generation DES implantation. Further studies are required to clarify the safety and efficacy of PCI in patients with cancer.
P698The KCa2 channel inhibitor AP14145, but not dofetilide or ondansetron, provides functional atrial selectivity in guinea pig hearts
Authors: Bentzen B H , Kirchhoff J E , Skarsfeldt M A , Abildgaard L , Edvardsson N , Soerensen U S , Grunnet M , Diness J G 
Published: October 2019

Abstract

Background and purpose
Prolongation of cardiac action potentials is considered antiarrhythmic in the atria but can be proarrhytmic in ventricles if the current carried by Kv11.1-channels (IKr) is inhibited. The current mediated by KCa2-channels, IKCa, is considered a promising new target for treatment of atrial fibrillation.
Selective inhibitors of IKr— (dofetilide) and I-KCa (AP14145) were used to compare the effects on ventricular and atrial repolarisation. Ondansetron which has been reported to be a potent blocker of both IKr and IKCa was included to examine its potential atrial antiarrhythmic properties.

Methods
The expression of KCa2- and Kv11.1-channels in the guinea pig heart was investigated using qPCR. Whole-cell patch clamp technique was used to investigate the effects of dofetilide, AP14145, and ondansetron on IKCa and/or IKr. The effect of dofetilide, AP14145, and ondansetron on atrial and ventricular repolarisation was investigated in isolated hearts. A novel atrial paced in vivo guinea pig model was further validated using AP14145 and dofetilide.

Results
AP14145 increased AERP (29 ms ex vivo and 38 ms in vivo) without prolonging QTcB both ex vivo and in vivo. In contrast, dofetilide increased QTcB (41 ms) and, to a lesser extent, AERP (16 ms) in isolated hearts and prolonged QTcB (61ms) with no effects on AERP in the in vivo guinea pig model. Ondansetron did not inhibit IKCa, but did inhibit IKr in vitro. Ondansetron prolonged ventricular (25 ms), but not atrial repolarisation ex vivo.

Conclusion
IKCa inhibition by AP14145 selectively increased atrial repolarisation whereas IKr inhibition by dofetilide and ondansetron increases ventricular repolarisation to a larger extent than atrial repolarisation. Data support that IKCa inhibition may be of value in treating atrial fibrillation without causing adverse effects in the ventricles.

Acknowledgement/Funding
Innovation Fund Denmark and Wellcome Trust
P699Mechanisms of action of the small conductance Ca2+-activated K+-channel modulator AP30663, a novel compound being developed for treatment of atrial fibrillation in man
Authors: Bomholtz S H , Simo-Vicens R , Abildgaard L , Edvardsson N G , Soerensen U S , Grunnet M , Diness J G , Bentzen B H 
Published: October 2019

Abstract

Background
Small conductance Ca2+-activated K+-channels (SK-channels) are a promising new atrial selective target for treatment of atrial fibrillation (AF). AP30663 is a small molecule inhibitor of SK-channels that is effective in converting vernakalant-resistant AF in tachy-paced pigs. Detailed understanding of the molecular mechanism of AP30663 is important for the development of SK channel inhibition for use in man.

Purpose
To establish the electrophysiological profile, mechanism of action and efficacy in prolonging atrial refractoriness ex vivo of AP30663.

Methods
AP30663 potency and mechanism of action were established by whole cell and inside-out patch clamp recordings of expressed SK channels. The ion channel selectivity profile of AP30663 was investigated on heterologous expressed channels. Effects of AP30663 or vehicle (DMSO) on atrial refractoriness (AERP) and ventricular repolarization (QTcB) were investigated on isolated perfused guinea pig hearts.

Results
AP30663 was found to be a selective negative allosteric modulator of SK channels (IC50=0.77±x0.13 μM) with no or minor effects on a panel of other cardiac ion channels, including hERG/KV11.1, (IKr), KV7.1/KCNE1 (IKs), KV4.3/KChiP2 (Ito), Kir2.1 (IK1), Kir3.1/Kir3.4 (IKACh), KV1.5 (IKur), NaV1.5 (INa) and CaV1.2 (ICa). AP30663 inhibited the SK-channel by right-shifting the calcium activation curve of the SK-channel (the EC50 of Ca2+ increased from 0.43±0.02 μM (control, n=6) to 1.37±0.05 μM (in the presence of 7μM AP30663, n=6).
In isolated guinea pig hearts, administration of vehicle had no effect on AERP or QTcB. AP30663 significantly prolonged the AERP in 3 μM (to 131±6% of baseline) and 10 μM (to 165±3% of baseline) without any effects on the QTcB.

Conclusion
AP30663 is a selective negative allosteric modulator of SK channels, acting by means of shifting the calcium dependence of SK-channel activation. AP30663 prolonged atrial refractoriness without affecting the QT-interval in isolated perfused heart preparations. These properties support continued development of AP30663 for treatment of AF in man.

Acknowledgement/Funding
Innovation Fund Denmark, Wellcome Trust
P707Endothelial function and testosterone deficiency in men with type 2 diabetes mellitus
Authors: Khripun I , Vorobyev S , Khripun A , Kogan M , Belousov I 
Published: October 2019

Abstract

Background
To date, the currently available data aboutthe effect of testosterone (T) on the cardiovascular system of men are highly controversial. The particular interest is its effect on the endothelium in men with type 2 diabetes mellitus (T2DM) having a high risk of vascular complications.
The purpose of this work was to evaluate the effect of endogenous T on function of endothelium in men with T2DM.

Methods
The study included 204 men, aged 40–65 years, with T2DM. Patients underwent clinical examinations, analysis of carbohydrate metabolism, evaluation of biochemical parameters of endothelial function such as nitric oxide (NO), endothelial synthase type 3 (eNOS3), VCAM-1, ICAM-1, p- and e-selectins, endothelin. The ultrasound assessment of flow-mediated dilatation of the brachial artery (FMD-BA) and intima-media thickness (IMT) of brachial arteries were performed. Patients were divided into 2 groups: 1 – 93 men with late onset hypogonadism established according to EAU 2015 criteria and 2 – 111 men having normal level of endogenous T and absence of clinical symptoms of hypogonadism. Statistical analysis of the data was carried out using the Mann-Whitney U-test (STATISTICA 10 software package).

Results
The parameters of carbohydrate metabolism and the duration of T2DM were comparable in two groups. The concentrations of NO (85.0 [60.4; 210.4] vs 137.5 [87.8; 281.5] μmol/l, p=0.001) and eNOS3 (192.2 [109.6; 407.3] vs 293.3 [117.1; 686.2] pg/ml, p=0.03) were lower in the 1st group compared to the 2nd one. There was an increase in the levels of VCAM-1 by 32.6% and ICAM-1 by 43% (p<0.0001), p-selectin by 19.5% (p=0.003) in the 1st group compared to the 2nd group. The endothelium-dependent FMD-BA was less pronounced (9.4 [6.9; 13.0] vs 12.2 [10.0; 16.7] %, p=0.0007) and had a delay in time of dilation by 33.3% in patients with hypogonadism compared to eugonadal men. There was an increase in IMT (1.0 [0.9; 1.2] vs 0.9 [0.7; 1.1] mm, p=0.03) in the 1st group compared to the 2nd.

Conclusion
T deficiency in men with T2DM leads to endothelial dysfunction, decreasing secretory and vasomotor function of endothelium. This indicates the raise of cardiovascular risk and predicts progression of vascular complications in men with T2DM and late onset hypogonadism.

Acknowledgement/Funding
Supported by Russian Science Foundation, grant #14-25-00052.
P713Short term treatment of a low dose erythropoietin improves vascular function in a rat model of insulin resistance
Authors: Toba H , Yamaoka A , Sakurai S , Tanaka Y , Miyamoto A , Nessa N , Watanabe Y , Kobara M , Nakata T 
Published: October 2019

Abstract

Background/Introduction
Erythropoietin (EPO) exerts haematopoiesis-independent cardiovascular and renal protective effects by binding to EPO receptors expressed in hearts, arteries, and kidneys. We have reported that EPO inhibits vascular and renal injury in rat models of hypertension and type 1 diabetes. Recent studies report that EPO improves glucose tolerance in insulin resistant animals.

Purpose
This study investigated whether EPO would inhibit vascular and renal dysfunction in the setting of insulin resistance.

Methods
Rats were treated with sucrose (12% in drinking water) for 10 weeks to induce insulin resistance. EPO (3 times/week, s.c) was administered at the dose of 150U/kg for 10 weeks from the beginning (group A) or at the dose of 75U/kg for the last 4 weeks (group B) of sucrose treatment. Blood pressure was measured every second week by the tail-cuff method. HOMA-IR, haematocrit, and urinary protein excretion were measured. Using isolated aortas, acetylcholine-induced vasorelaxation under phenylephrine-induced pre-contraction was examined. Aortic sections were stained with haematoxylin-eosin.

Results
Both groups A and B showed higher haematocrit levels compared with the control and sucrose alone-treated groups. Sucrose treatment increased HOMA-IR (7.7±2.0 vs. 24±4.5, p<0.05), which was attenuated in groups A (3.6±0.9) and B (9.7±4.0). EPO treatment (150U/kg) had no effects on blood pressure for the first 4 weeks but caused time-dependent increases in blood pressure from the 6th week. Increased proteinuria and impaired aortic vasorelaxation in sucrose-treated rats were exacerbated by EPO (150U/kg) maybe because of hypertension (Control 122±2mmHg, Sucrose 125±2mmHg, group A 148±5mmHg), one of the major side effects of EPO. According to these results, we treated a half dose of EPO only for the last 4 weeks (group B). A lower dose of EPO treatment for a shorter period did not increase proteinuria (Control 15±2mg/day, Sucrose 25±3mg/day, group B 24±3mg/day) despite a mild increase in blood pressure (132±2mmHg). Impaired endothelium-dependent vasodilation and aortic thickening in the aorta of sucrose alone-treated rats were attenuated by lower and shorter EPO treatment (group B).

Conclusions
EPO inhibited insulin resistance and vascular injury in sucrose-induced insulin resistant rats. Further investigation into the mechanisms of tissue protective effects of EPO, especially focusing on the effects on insulin signalling in not only hepatic and muscle cell but also vascular and renal cells, will be needed.
P724Antibody treatment against pathological pancreatic islet amyloid polypeptide (IAPP) aggregates restores endothelial dysfunction in human-IAPP transgenic rats
Authors: Taheri A , Doytcheva P , Tarasco E , Gut W , Engeli M , Hugentobler L , Lutz T A , Osto E 
Published: October 2019

Abstract

Background
Islet amyloid polypeptide (IAPP; or amylin) is produced in pancreatic B-cells and co-secreted with insulin in response to nutrients. In insulin resistance and type 2 diabetes (T2D), higher secretion and impaired processing of IAPP results in its aggregation, contributing to amyloid-induced apoptosis of pancreatic B-cells. Insight into IAPP's role in diabetic endothelial dysfunction is scarce.

Purpose
Rats transgenic for human IAPP (hIAPP), which in contrast to rodent IAPP produces amyloid deposits and contributes to diabetes due to B-cell failure, were studied to understand the mechanisms of endothelial dysfunction in T2D and test the vasoprotective actions of an anti-hIAPP antibody.

Methods
Male hemizygous transgenic Sprague-Dawley rats with islet B-cell expression of hIAPP (TG) and wild-type (WT) controls were sacrificed at 2, 3, 6- and 9-months age to assess endothelial function. In a second experiment, TG rats received weekly injections of antibody against aggregated hIAPP (3 mg/kg; TG-Ab) from 3–12 months of age; TG and WT controls received PBS. Oral glucose tolerance was assessed before harvesting. At the respective time points (12 mts in exp. 2), thoracic aortic rings were isolated and subjected to ex vivo isometric tension recording. After contraction with norepinephrine (NE 1x10–7 mol/L), cumulative relaxation responses were performed to glucagon-like peptide-1 (GLP-1; 10–12 to 10–6 mol/L) and insulin (10–11 to 10–6 mol/L). Pancreas and aortic arch samples were used for immunostaining of hIAPP antibody engagement.

Results
GLP-1 and insulin-mediated vasodilation was impaired in 3 month-old TG rats compared to WT. Glucose intolerance appeared in TG rats at 6 months in comparison to WT (p<0.0001), indicating that endothelial dysfunction in TG rats precedes the onset of glucose intolerance. Anti-hIAPP antibody showed selectivity against aggregated IAPP in pancreatic islets, but there was no target engagement in the aortic arch, questioning a pathogenic role of IAPP deposition in the aortic wall. At 12 months, glucose control in TG-Ab rats was improved in comparison to TG control rats (p<0.013). Vasodilatation in TG-Ab rats was restored in response to GLP-1 (35.5% ± 4.6 vs. 16.0% ± 3.1 in TG controls), similar to that of WT rats (35.5% ± 6.5). Vasodilatation in response to insulin (48.9% ± 4.2) was improved in comparison to both TG (29.4% ± 3.0) and WT controls (32.5% ± 5.7) (p<0.0001; 2-way ANOVA, n=6–11 for all groups.

Conclusion
Early endothelial dysfunction develops in hIAPP rats compared to WT. Endothelial dysfunction is restored by the anti-hIAPP antibody treatment via improved oral glucose tolerance, but it remains unclear whether this effect is due to a local action in the aorta or a secondary effect, e.g. due to a reduction in pancreatic IAPP deposition.
P725Molecular genetics of familial hypercholesterolemia in Israel revisited
Authors: Durst R , Ken Ibe U K I , Shpitzen S S , Schurr D S , Futema M F , Whittall R W , Humphries S H , Leitersdorf E L 
Published: October 2019

Abstract

Objective
Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the genes for LDL receptor (LDLR), apolipoprotein B (APOB) and Proprotein convertase subtilisin/kexin type9 (PCSK9). The purpose of the current investigation was to define the current spectrum of mutations causing FH in Israel.

Methods
New families were collected through the MEDPED (Make Early Diagnosis Prevent Early Death) FH program. Molecular analysis of the LDLR, PCSK9 and APOB genes were done using High Resolution Melt and direct sequencing in 67 index cases. A 6-SNP LDL-C gene score calculation for polygenic hypercholesterolaemia was done using TaqMan genotyping.

Results
Mean serum cholesterol was 7.48±1.89mmol/L and the mean serum LDL-C was 5.99±1.89mmol/L. Mutations in the LDLR and APOB gene were found in 24 cases (35.8%), with 16 in LDLR, none in PCSK9 and one, p.(R3527Q) in the APOB gene, which is the first APOB mutation carrier identified in the Israeli population. Of the LDLR mutations, two were novel; p.(E140A) and a promoter variant, c.-191C>A. The c.2479G>A p.(V827I) in exon 17 of the LDLR gene was found in 8 patients (33.3% of the mutations) with modestly elevated LDL-C but also in a compound heterozygous patient with a clinical homozygous FH phenotype, consistent with this being a “mild” FH-causing variant. A significantly higher 6-SNP LDL-C score was found in mutation-negative cases compared with a normal Caucasian cohort (p=0.03), confirming that polygenic inheritance of common LDL-C raising SNPs can produce an FH phenocopy.

Conclusions
The results indicate a different spectrum of genetic causes of FH from that found previously, in concordance with the heterogeneous and changing origins of the Israeli population, and confirm that a polygenic cause is also contributing to the FH phenotype in Israel.
P728Subclinical atherosclerosis and its progression are modulated by perilipin-2 through a feed-forward loop between LXR and autophagy
Authors: Ehrenborg E , Saliba Gustafsson P , Pedrelli M , Gertow K , Pourteymour S , Baldassarre D , Tremoli E , De Faire U , Humphries S E , Goncalves I , Orho-Melander M , Boren J , Eriksson P , Magne J , Parini P 
Published: October 2019

Abstract

Background
Hyperlipidemia is a major risk factor for cardiovascular disease and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin-2 reduces plasma triglycerides and may therefore be beneficial for atherosclerosis development.

Purpose
We sought to delineate putative beneficial effects of the Pro251 variant of perlipin-2 on subclinical atherosclerosis and the mechanism by which it acts.

Methods
A pan-European cohort of high-risk individuals where carotid intima-media thickness has been assessed was adopted. Human primary monocyte-derived macrophages were prepared from whole blood from individuals recruited by perilipin-2 genotype, or from buffy coats from the our University hospital blood central.

Results
The Pro251 variant of perilipin-2 is associated with decreased intima-media thickness at baseline and 30 months follow-up. Using human primary monocyte-derived macrophages from carriers of the beneficial Pro251 variant we show that this variant increases autophagy activity, cholesterol efflux, and a controlled inflammatory response. Through extensive mechanistic studies we demonstrate that increase in autophagy activity is accompanied with an increase in LXR activity and that LXR and autophagy reciprocally activate each other in a feed-forward loop, regulated by CYP27A1 and 27OH-cholesterol.

Conclusions
For the first time, we show that perilipin-2 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin-2 modulates levels of the LXR ligand 27OH-cholesterol and initiates a feed-forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin-2 exerts its beneficial effects on subclinical atherosclerosis.

Acknowledgement/Funding
The Swedish Research Council, Swedish Heart-Lung Foundation, Marianne and Marcus Wallenberg's Foundation, Swedish Medical Society