bluuebunny/crossref_metadata_2025_split huggingface dataset:
5131Unmet need for secondary prevention in individuals from the general population with increased lipoprotein(a): a contemporary population-based study
Authors: Madsen C M , Kamstrup P R , Langsted A , Varbo A , Nordestgaard B G 
Published: October 2019

Abstract

Background
There is strong evidence linking high lipoprotein(a) (Lp(a)) to development of incident cardiovascular disease (CVD), but it is not clear whether Lp(a) is associated with risk of recurrent CVD events in individuals from the general population with preexisting CVD. This is of importance as the first drugs specifically aimed at lowering Lp(a) are currently in development, and these would likely be used primarily in individuals with established CVD for secondary prevention of recurrent CVD events.

Purpose
We tested the hypothesis that high concentrations of Lp(a) are associated with high risk of recurrent CVD in individuals from the general population with preexisting CVD.

Methods
From the Copenhagen General Population Study (CGPS) (2003–2015) of 58,527 individuals with measurements of Lp(a) at baseline, 2,527 aged 20–79 with a history of CVD were studied. The primary endpoint was major adverse cardiovascular event (MACE). We also studied 1,115 individuals with CVD at baseline from the Copenhagen City Heart Study (CCHS) (1991–1994) and the Copenhagen Ischemic Heart Disease Study (CIHDS) (1991–1993).

Results
During a median follow-up of 5 years (range: 0–13, 13,974 person-years), 493 individuals (20%) experienced a MACE in the CGPS. MACE incidence rates per 1,000 person-years were 29 (95% CI: 25–34) for individuals with Lp(a) <10mg/dL (<18nmol/L), 35 (30–41) for 10–49mg/dL (18–104nmol/L), 42 (34–51) for 50–99mg/dL (105–213nmol/L), and 54 (42–70) for ≥100mg/dL (≥214nmol/L) (see Figure). Compared to individuals with Lp(a) <10mg/dL (<18nmol/L), the MACE incidence rate ratios were 1.21 (0.98–1.50) for 10–49mg/dL (18–104nmol/L), 1.43 (1.12–1.82) for 50–99mg/dL (105–213nmol/L), and 1.85 (1.38–2.49) for ≥100mg/dL (≥214nmol/L). Independent confirmation was obtained in individuals from the CCHS and CIHDS with MACE incidence rates per 1,000 person-years of 94 (95 CI: 84–106) for individuals with Lp(a) <10mg/dL (<18nmol/L), 115 (103–129) for 10–49mg/dL (18–104nmol/L), 134 (115–156) for 50–99mg/dL (105–213nmol/L), and 140 (116–169) for ≥100mg/dL (≥214nmol/L).

Conclusion
High concentrations of Lp(a) are associated with high risk of recurrent CVD in individuals from the general population with preexisting CVD. This points to a possible unmet need for secondary prevention in individuals with increased Lp(a), and such individuals could be a target group for upcoming randomized cardiovascular outcome trials.

Acknowledgement/Funding
The Novo Nordisk Foundation, Herlev and Gentofte Hospital, Chief Physician Johan Boserup and Lise Boserup's Fund
5132Effect of PCSK9 inhibitors treatment on acute coronary syndrome and stroke incidence: a metanalysis of currently available clinical trials
Authors: Cordero A , Facila L , Rodriguez-Manero M , Gomez-Martinez M , Bertomeu-Gonzalez V , Martinez R , Seijas S , Valle A , Moreno-Arribas J , Agra-Bermejo R , Martin Toro M , Bertomeu Martinez V , Gonzalez Juanatey J R 
Published: October 2019

Abstract

Background
Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors have demonstrated to induce large reductions in low-density lipoprotein cholesterol (LDLc) and major cardiovascular events but none of the studies was statistically powered to demonstrate reductions in specific endpoints rather than a combined end-point of major cardiovascular events.

Methods
We performed an intention-to-treat meta-analysis in line with recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement using currently available studies involving PCSK9 inhibitors. The endpoint assessed were acute coronary syndrome (ACS) and stroke.

Results
We included 81,544 patients, 41,147 treated with a PSCK9 inhibitors: 17,179 with evolocumab; 13,718 with bococizumab and 10,250 with alirocumab (table 1). A total of 1,316 ACS were registered in the treatment group vs. 1,608 in controls, resulting in 18.0% reduction associated with PCSK9 treatment (figure 1). This result was reproduced exactly in the EBCT althougt a non-significant heterogeneity was detected (p=0.052). Metaregression analyses did not demonstrate the implication of the study (p=0.45), study drugs (p=0.26), age (p=0.89), hypertension (p=0.81) or diabetes (p=0.81) on such result.
Results on stroke incidence are presented in figure 2. PCSK9 inhibitors treatment resulted in a 24% reduction of stroke when all studies were analyzed together; heterogeneity was statistically significant (p=0.021) but it was not observed in the EBCT analysis where PCSK9 inhibitors were associated with 24% stroke incidence reduction.

Conclusions
The meta-analysis of currently available studies demonstrates that PCSK9 inhibitors treatment reduces the incidence of ACS by 18% and stroke by 24%.
5201Intra-cardiac thrombus in patients undergoing ventricular tachycardia ablation. a computed tomographic scan study
Authors: Sacher F , Roumegou P , Duchateau J , Derval N , Denis A , Pambrun T , Escande W , Takigawa M , Lam A , Andre C , Chauvel R , Hocini M , Haissaguerre M , Jais P , Cochet H 
Published: October 2019

Abstract

Background
Embolic event is one of the complications of VT ablation. This may be due to the presence of intra-cardiac thrombus before ablation. However, there is no clear consensus on how to rule out thrombus before the procedure.

Objective
We sought to examine the prevalence and risk factors of intra-cardiac thrombus with cardiac computed tomographic (CT) scan in patients undergoing scar-related VT ablation.

Methods
In absence of contra-indication, all patients undergoing scar-related VT ablation at our institution underwent contrast-enhanced cardiac CT within one week before ablation. 324 consecutive patients (292 male, 59±16 yo) have been included in this study. The etiology was ischemic cardiomyopathy (CMP) (n=191), arrhythmogenic right ventricular CMP (ARVC) (n=37), congenital CMP (n=11) or other CMP (n=85). LVEF was <40% in 154 patients (48%).

Results
Intra-cardiac thrombus was diagnosed in 29 (9%) patients: in the left atrium (n=8), in the right atrium (n=1), in the left ventricle (n=15), in the right ventricle (n=3), in right and left atrium (n=1), and in left atrium and right ventricle (n=1). Moreover in 2, a bilateral pulmonary embolism was identified. The population with thrombus was older (65±12 vs 58±16 years, p=0,005), with more permanent atrial fibrillation (AF) (28% vs 8%; p=0.005). Patients with left ventricular (LV) aneurysm were at higher risk of thrombus 50% vs 3% (p<0.001). The average CHADSVASC score was similar for both groups (2,5 vs 2,1; p=0.179). After matching for age and sex, only ischemic CMP and LV aneurysm were risk factors for thrombus. Because of arrhythmic storm, ablation was performed by epicardial approach only, in 5 patients with intra-ventricular thrombus and by retroaortic approach only, in 2 patients with LAA thrombus. No embolic event occurred during these procedures.

Conclusion
CT scans help eliminating intra-cardiac thrombus before VT ablation procedure. A high proportion of thrombus (9%) was identified. Whereas LV thrombus should systematically be ruled out before scar related VT ablation, in patients with AF, a LAA thrombus should also be eliminated as well as RV thrombus in patients with ARVC.

Acknowledgement/Funding
ANR-10-IAHU-04
5202Zero- or near-zero fluoroscopy radiofrequency catheter ablation for aortic sinus cusp idiopathic ventricular arrhythmias
Authors: Stec S , Styczkiewicz K , Sledz J , Chrabaszcz M , Ludwik B 
Published: October 2019

Abstract

Background
Complete elimination of fluoroscopy during radiofrequency catheter ablation (RFCA) of idiopathic ventricular arrhythmias (IVA) originating from aortic sinus cusp (ASC) may be challenging, requires confirmation of coronary arteries ostia and could be associated with potential risk of collateral damage and severe complications.

Purpose
To validate the implementation, feasibility, learning curve, safety and efficacy of zero-fluoroscopy (ZF) approach in centers using near-zero fluoroscopy (NOX) approach for RFCA of idiopathic premature ventricular complexes/ventricular tachycardias (PVCs/VTs) from ASC.

Methods
From 2012 to 2018, we prospectively enrolled 106 consecutive patients (age: 49±19, males: 58%, children: 7%, 108 PVC/VT focuses from ASC, PVCs/24h: 23808±22006) with ASC-IVA. Patients were unselected and referred for ZF or NOX approach using three dimensional electroanatomic system- 3D EAM without intracardiac or transesophageal echocardiography. The choice of ZF and NOX was based on the first operator experience and from 2014 three experienced operators and three fellows performed ZF as an intention-to-treat approach. The peri-procedural, short-term outcome as well as learning curve of ZF in ASC were evaluated with documentation of reasons for cross-over to NOX approach.

Results
Out of 108 focuses there were majority of left coronary cusps and left/right junctions sites of origin [other rare locations: right coronary cusp (n=7); non-coronary cusp, n=6)]. On intention-to-treat 61/76 (80%) cases were completed without fluoroscopy in ZF-approach. Additionally, 30/30 (100%) cases were completed with NOX. The main reasons for fluoroscopy use in ZF approach (conversion to NOX) were: the need for elective valsalvography plus coronary angiography (n=6), urgent coronary angiography due to validation of transient uncomplicated coronary spasms and ST elevation (n=2), catheter stability checking (n=2), femoral access site confirmation (n=1) and navigation problem (n=1). No significant differences were found in the acute and short-term success rates between ZF and NOX (90% vs 88%, P=NS) and no major complications occurred. The procedure time, fluoroscopy time and ablation time were 66.8±26.9; 3.6±7.2 and 7.3±5.5 min, respectively. The gathering experience of ZF approach, computer-assisted ECG analysis and 3D-EAM reconstruction of aortic root and coronary artery ostia resulted in significant reduction of NOX approach between early and late period [median (n=53): 2012–2016 vs 2017–2018, 40/53 (76%) vs 5/53 (8%), p<0.001].

Conclusion
ZF can be completed in majority of patients with ASC-IVA especially after appropriate training and operators' experience with NOX. ZF approach guided by 3D-EAM is feasible, safe, and effective for treatment of ASC-IVA with importance of training and preprocedural imaging for exclusion of coronary anomalies or validation of coronary arteries ostia by 3D-EAM.
5220Maternal high-fat diet exaggerates the development of diet-induced insulin resistance in adult offspring by enhancing pyroptosis through augmented gasdermin D-mediated pore formation
Authors: Wada N , Yamada H , Motoyama S , Saburi M , Sugimoto T , Miyawaki D , Kubota H , Wakana N , Matoba S 
Published: October 2019

Abstract

Background
Maternal high-fat diet (HFD) has been shown to promote the development of insulin resistance (IR) in adult offspring; however, the underlying mechanisms remain unclear.

Approach and results
Eight-week-old female wild-type mice (C57BL/6) were fed a HFD or normal diet (ND) one week prior to mating, and received during pregnancy and lactation. Eight-week-old male offspring of both groups were fed a HFD for 8 weeks. Offspring of HFD-fed dams (O-HFD) showed significantly enhanced IR compared with offspring of ND-fed dams (O-ND). There was no difference in body weight, epidydimal white adipose tissue (eWAT) weight, and cumulative caloric intake between the 2 groups. However, eWAT adipocyte size was significantly increased in O-HFD, accompanied by the abundant crown-like structures. Flow cytometric analysis revealed an increased percentage of M1, but not M2, macrophages. Serum and eWAT concentrations of IL-1β, but not TNF-α, were significantly higher in O-HFD than O-ND (3.7-fold and 2.0-fold, respectively, P<0.05). Treatment with NLRP3 inflammasome inhibitor MCC950 completely abrogated the enhanced IR in O-HFD to a similar extent of that in O-ND, although IR was modestly, but not significantly, ameliorated in O-ND even after MCC950 treatment. Consistent with in vivo findings, in vitro polarization of bone marrow-derived macrophages (BMDMs) did not show any difference in TNF-α mRNA expression after conventional stimulation. In contrast, palmitate acid (PA)-mediated metabolic activation of BMDMs following LPS priming showed a significantly higher concentration of IL-1β in culture supernatants from O-HFD (45%, P<0.05). However, protein expression levels of NLRP-3, ASC, and procaspase-1 after LPS priming were equivalent between the 2 groups. Consistently, intracellular flow cytometric analysis of caspase-1 activity after PA activation did not show any difference, which was compatible with the finding that ex vivo caspase-1 activity of eWAT assessed by fluorescent image of IVIS revealed no difference between the 2 groups. To further examine the mechanism of augmented IL-1β release in BMDM of O-HFD, we examined the cleavage of caspase substrate gasdermin D (GSDMD) and subsequent pore formation. Protein and gene expression levels of GSDM-D after LPS priming were significantly higher in O-HFD (50% and 381%, respectively, P<0.05). At 2 hrs after PA stimulation following LPS priming, cleaved GSDM-D was significantly increased in O-HFD (80%, P<0.01). Consistently, percentage of pore formation assessed by ethidium bromide staining was significantly higher in O-HFD (60%, P<0.05), while LDH release could not be observed.

Conclusions
Our findings demonstrate that maternal HFD exaggerates diet-induced insulin resistance in adult offspring by enhancing pyroptosis through augmented GSDM-D-mediated pore formation.
5221Knockout of purinergic receptor Y13 (P2Y13) results in an improved outcome in metabolic syndrome in mice
Authors: Merz J , Rofa K , Dimanski D , Ahmed I , Hoppe N , Bode C , Zirlik A , Stachon P 
Published: October 2019

Abstract

Background
Metabolic syndrome clusters the main risk factors for cardiovascular diseases and endocrine dysfunction. Novel studies show that the important underlying mechanism is a long term inflammation of adipose tissue with a gradual shift from the anti-inflammatory M2 towards the pro-inflammatory M1 macrophages (pathognomonic). Massive hypertrophy induces adipocyte death, which releases DAMPs like nucleotides recognized by purinergic receptors orchestrating ongoing inflammatory process. Interestingly, we found Gi coupled P2Y13R only expressed on M1 macrophages, not in M0 (unstimulated) and M2 macrophages.
Nevertheless, the role of P2Y13R in the immune system and especially macrophages is currently unknown. Given its pivotal role in central metabolic processes (P2Y13R has been described in insulin secretory signalling) together with its unique expression in its pathognomonic inflammatory macrophage subtype makes it an interesting candidate to investigate its role in metabolic syndrome.

Purpose
Due to the unique expression of P2Y13R on M1 macrophages we hypothesise an improved outcome in a high-fat diet induced metabolic syndrome by interfering with the P2Y13 signalling cascade.

Methods
BMDM differentiation to macrophages using M-CSF and subsequent stimulation with medium (M0), LPS and IFNγ (M1) or IL4 (M2); Expression of P2Rs quantified using Taqman qPCR.
Male C57Bl6/J wild-type (WT) and P2Y13-deficient (KO) mice were fed with a high-fat diet (HFD) for 20 weeks; On week 15 we performed the ITT, on week 16 the GTT. Metabolic performance was monitored by metabolic caging.

Results
We observed a unique expression of P2Y13R on M1 macrophages. Adult P2Y13-deficient mice showed a higher O2 consumption compared to adult C57Bl6/J wild-type mice (AUC of O2 consumption 2nd day= KO: 61620±2261mL/kg vs WT: 53830±916.1mL/kg, p=0.0331). Although both P2Y13−/− mice and WT littermates consumed comparable amount of food (daily food intake per mouse → KO: 3.97±0.25g vs WT: 3.76±0.18g), P2Y13 deficient animals showed significantly decelerated weight gain (e.g. on week 15 → KO: 142±2% (n=10) vs WT: 198±5% (n=10), p<0.0001). Obese P2Y13−/− animals outperformed obese WT littermates in a peritoneal glucose tolerance test (2h after glucose injection → KO: 272.9±21.0 mg/dL (n=10) vs WT: 532.6±21.2 (n=10) mg/dL, p<0.0001). There was no difference in the cell amount of stromal vascular fraction cells.

Conclusion
Global P2Y13 deficiency leads to an improved outcome in metabolic syndrome with an increased protection against developing an insulin resistance as shown through an improved glucose tolerance and basal glucose levels, a decelerated weight gain despite comparable food consumption and a better metabolic turnover. Observing these beneficial metabolic improvements, we hypothesise that antagonization of P2Y13R could be a promising therapeutic target in the field of metabolic syndrome.
5941Improvement of cardiac output after transcatheter repair of severe tricuspid regurgitation impacts all-cause mortality
Authors: Stocker T J , Orban M , Braun D , Hertell H , Englmaier A , Roesler D , Reithmayer T , Nabauer M , Massberg S , Hausleiter J 
Published: October 2019

Abstract

Background
Severe tricuspid regurgitation (TR) impairs right-ventricular forward stroke volume and left-ventricular preload leading to a reduction of cardiac output (CO). Transcatheter tricuspid valve repair (TTVR) is a novel experimental treatment strategy for TR and an alternative to surgery in fragile patients. The clinical impact of improved CO after TTVR on the prognosis of chronic heart failure patients is currently unknown.

Purpose
This study has been designed to analyze the impact of TTVR on CO and the association to post-interventional hospitalization for congestive heart failure (CHF) and all-cause mortality.

Methods
Between February 2017 and October 2018 we prospectively enrolled 70 patients suffering from chronic heart failure (median age 78 years; 54% female; 90% NYHA III or IV; median NT-pro-BNP of 3,540 ng/ml) due to severe TR (all ≥ grade 3 of 4). All patients underwent TTVR with isolated intervention to the tricuspid valve (n=41) or combined mitral and tricuspid intervention due to concomitant mitral regurgitation (n=29). Invasive CO was measured shortly before TTVR under general anesthesia using transpulmonary thermodilution. For a more physiologic assessment, non-invasive CO was measured using the inert gas rebreathing technique (Innocor, Innovision, Glamsbjerg, Denmark). Non-invasive CO was assessed 2 weeks prior TTVR (baseline), at the day of discharge from the hospital (post-procedural) and after a median of 193 days (interquartile range, IQR 53 to 360 days; follow-up).

Results
Invasive CO significantly correlated to non-invasive assessment of CO at baseline (Pearsons correlation coefficient r=0.36, p<0.01). Baseline median non-invasive CO (3.3 l/min, IQR 2.4 to 4.2 l/min) improved with TTVR in the post-procedural analysis (4.0 l/min, IQR 2.8 to 5.1 l/min, p<0.001). At follow-up, median non-invasive CO improved by 0.5 l/min (IQR 0.0 to 1.6 l/min). CO changed ≤0.5 l/min in 37 patients (low ΔCO) and >0.5 l/min in 33 patients (high ΔCO). Hospitalization for CHF was significantly lower with high ΔCO (18%), when compared to low ΔCO (54%; p<0.01). Furthermore, all-cause mortality was significantly reduced in the high ΔCO-group (3%), when compared to the low ΔCO-group (43%; p<0.001). Significant differences in mortality were also observed in the subgroup of patients with isolated tricuspid intervention (10% vs. 45%, p=0.016).

Conclusion
Successful TTVR with maintenance of improved CO impacts patient prognosis and is associated to a reduced rate of hospitalization and all-cause mortality.
5942Clinical outcomes and prognostic implications of effective regurgitant orifice area. Defining severe mitral regurgitation
Authors: Monteagudo Ruiz J M , Gonzalez Gomez A , Hinojar Baydes R , Casas Rojo E , Garcia Martin A , Moya Mur J L , Aquila I , Jimenez Nacher J J , Barrios V , Ruiz Leira S , Marco Del Castillo A , Pardo Sanz A , Zamorano Gomez J L , Fernandez Golfin C 
Published: October 2019

Abstract

Background
Previous studies showed that the effective regurgitant orifice area (EROA) is a strong predictor of clinical outcomes. However, there is controversy over the optimal threshold that identifies patients at high-risk, especially in secondary mitral regurgitation (MR).

Purpose
To determine the optimal EROA threshold that identifies a subgroup patients with an increased risk of cardiac death and hospitalization for heart failure (HF), in both, primary and secondary MR.

Methods
A total of 6022 consecutive transthoracic echocardiograpic studies were analysed. Patients with significant MR were prospectively included. The EROA was calculated by the PISA method. Each patient was followed up for three years. Cox regression was performed to study predictors of the combined end-point. ROC curve analysis was performed to determine the optimal cut-off values of EROA.

Results
Significant primary MR was found in 115 patients (62%), whereas significant secondary MR was described in 71 studies (38%). In primary MR, the optimal threshold of EROA for predicting the combined end-point was 45mm2 (Sn=85.7%; Sp=82.2%). After adjusting for NYHA class, ejection fraction and chronic kidney disease, an EROA ≥45mm2 was strongly associated with cardiac death and admissions due to HF (HR 15.65, 95% CI 4.34–56.47, p<0.001). Regarding secondary MR, the optimal cut-off value was 21mm2 (Sn=75.0%; Sp=61.8%) and the adjusted HR was 2.57 (95% CI 1.03–6.37, p=0.042).
Sensitivity and specificity curves

Conclusions
Our study demonstrates that an EROA of at least 45mm2 in primary MR or of at least 21mm2 in secondary MR is independently associated with a significantly increased risk of cardiac death and hospitalization for HF.