bluuebunny/crossref_metadata_2025 huggingface dataset:
P661Nocturnal hypoxemic burden in ambulatory patients with atrial fibrillation: a disease-orientated assessment of sleep-disordered breathing severity
Authors: Linz D , Nalliah C , Baumert M , Kadhim K , Middeldorp M , Elliott A , Lau D , McEvoy D , Kalman J , Sanders P
Published: October 2019

Background

Studies investigating the relationship between sleep-disordered breathing (SDB) and atrial fibrillation (AF) have largely assessed SDB-severity by the apnea–hypopnea index (AHI). However, the AHI does not incorporate nocturnal hypoxemic burden, which may increase the risk of non-paroxysmal AF (nPAF) as the clinical manifestation of more progressed AF substrates. This investigation sought to systematically characterize and compare the composition of AHI and hypoxemic burden with the aim to defining a disease-orientated metric for SDB-severity best associated with prevalent nPAF.

Methods

Polysomnography including overnight oximetry data were obtained in 435 consecutive ambulatory AF patients to determine the composition of AHI (apneas vs. hypopneas), the number of acute episodic desaturations per hour (oxygen desaturation index, ODI) and the composition of total time spent below 90% oxygen saturation (T90Total) attributed to acute desaturations (T90Desaturation). Logistic regression analysis was used to characterize the association with prevalent nPAF.

Results

One hundred sixty-nine AF patients (38%) had nPAF and one third (n=149, 34%) had moderate-to-severe SDB (AHI>15). 82% of the median total AHI (9.4 [3.6–20.1]) could be attributed to hypopneas. Only 29% of events were associated with episodic desaturations, which contributed to 96% (T90Desaturation) of the variation in T90Total. The high variability in durations and nadirs of distinct desaturation events can expose patients to long T90Total, even if the AHI is low. Not AHI, but T90Total and ODI were associated with nPAF independent of gender and age. However, diabetes, hypertension and body mass index contributed more significantly to the overall risk of nPAF.

Conclusions

In AF patients, hypopneas constitute a majority of respiratory events during sleep. Patients with low AHI can still be exposed to high nocturnal hypoxemic burden, which is mainly a cumulative consequence of episodic desaturations. T90Total and ODI, but not AHI, were associated with nPAF independent of gender and age, but concomitant modifiable risk factors made a more significant contribution to the overall risk of nPAF versus PAF.
P662Association of baseline disability and major adverse outcomes in patients with atrial fibrillation: an analysis from the SPORTIF trials
Authors: Proietti M , Lip G Y H
Published: October 2019

Introduction

The modified Rankin Scale (mRS) is usually used to evaluate the degree of disability in patients who have suffered a stroke. Some data suggest that pre-stroke mRS may be associated with clinical outcomes. No data exist about atrial fibrillation (AF) patients.

Purpose

To evaluate if baseline level of disability, evaluated as mRS, is associated with major adverse outcomes in patients with AF

Methods

Data from the SPORTIF III and V trials were used to evaluate study aims. mRS was categorized as follows: i) mRS 0 = No Disability; ii) mRS 1 = Operational Limitation; iii) mRS ≥2 = Disability. Stroke/systemic embolism (SE), death and composite of stroke/SE/acute myocardial infarction (AMI)/death were considered as major adverse outcomes.

Results

Among 7329 patients enrolled in SPORTIF trials, 7325 (99.9%) had data about baseline mRS, with 5587 (76.3%) with mRS 0, 1156 (15.8%) with mRS 1 and 582 (7.9%) with mRS ≥2. Mean (SD) and median [IQR] CHA2DS2-VASc was progressively higher across the three mRS categories (both p<0.001). An adjusted linear regression analysis confirmed that mRS was associated with an increasing CHA2DS2-VASc (unstandardized B: 0.354, 95% confidence interval [CI]: 0.317–0.390, p<0.001]. After a mean (SD) 1.55 (0.40) years of follow-up 184 (2.5%) stroke/SE, 392 (5.4%) death and 597 (8.2%) composite events were recorded. Log-rank test showed that cumulative risk of stroke/SE (p=0.005), death (p<0.001) and composite outcome (p<0.001) was progressively higher across the mRS categories [Figure]. Cox adjusted regression analysis found no independent association between mRS categories and stroke/SE occurrence, but baseline disability (mRS ≥2) was independently associated with death (hazard ratio [HR]: 2.17, 95% CI: 1.65–2.86 compared with no disability). Both operational limitation (mRS 1) and disability (mRS ≥2) were associated with the composite outcome (HR: 1.28, 95% CI: 1.04–1.59 and HR: 1.91, 95% CI: 1.51–2.42, respectively) compared to no disability.

Kaplan-Meier curves

Conclusions

In a large cohort of AF patients derived from a randomized controlled trial, baseline disability was associated with an increased risk of death and composite outcome of stroke/SEAMI/death.

Acknowledgement/Funding

None
P663Identifying patients at risk for atrial fibrillation in the community: a systematic review and meta-analysis of prediction models
Authors: Himmelreich J C L , Veelers L , Lucassen W A M , Van Weert H C P M , Harskamp R E
Published: October 2019

Background

Atrial fibrillation (AF) presents a considerable burden on our health care systems. Early detection of AF may prevent AF-associated complications, such as stroke and heart failure. Given our aging populations, the number of new AF cases is expected to double over the next decades. As such, there is renewed interest to screen for AF in the community. To optimise screening efforts, risk prediction models may help us identify at-risk patients.

Purpose

To identify and evaluate the performance of prediction models for AF that may be applicable for screening in community settings.

Methods

We searched PubMed, Embase, and CINAHL databases for studies that derived and/or validated AF risk models from population-based cohorts. Three investigators independently assessed risk of bias (CHARMS checklist), and performed data extraction and evidence synthesis. The primary expression of associations in meta-analysis was the C-statistic for discrimination between AF and non-AF cases during follow-up, using a random effects model. We calculated 95% prediction intervals (PI) due to high heterogeneity (I2 >30%) in all analyses.

Results

We identified 23 studies that presented data on 8 risk models derived from 18 cohorts with a total of 1,4 million participants from across the globe. Average age in these cohorts ranged from 43–76 years and follow-up ranged from 3 to 20 years. Two of the 8 risk models had a sufficient number of validation studies to be included in the meta-analysis. The CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology) score had a summary C-statistic of 0.72 (95%-PI: 0.67–0.77; n=7 cohorts, n=53.040 patients). The FHS (Framingham Heart Study) score for AF had a summary C-statistic of 0.71 (95%-PI: 0.59–0.83; n=4 cohorts, n=19.300 patients). Both models include age, height and weight, blood pressure, prevalent heart failure, and antihypertensive medication use as variables. CHARGE-AF additionally includes race, current smoking, and history of diabetes and myocardial infarction. FHS additionally includes sex, PR interval, and significant murmur.

Conclusions

Currently two risk scores, CHARGE-AF and FHS, have been rigorously tested for predicting atrial fibrillation in general populations. The CHARGE-AF score may present the more promising, user-friendly score for future community screening efforts, as it solely relies on readily available clinical parameters.

Acknowledgement/Funding

This work was supported by the Netherlands Organisation for Health Research and Development (ZonMw) [80-83910-98-13046]
P668Aspirin for primary prevention of cardiovascular disease
Authors: Gelbenegger G , Postula M , Pecen L , Halvorsen S , Lesiak M , Schoergenhofer C , Jilma B , Hengstenberg C , Siller-Matula J M
Published: October 2019

Background

Platelet inhibition by aspirin reduces ischemic events but increases the risk of bleeding events. Yet, the role of aspirin in primary prevention of cardiovascular disease remains unclear.

Purpose

To produce a clinically relevant benefit-risk assessment of aspirin for primary prevention of cardiovascular disease.

Methods

We performed a meta-analysis of aspirin effects in primary prevention of cardiovascular disease comprising 13 randomized-controlled trials in 164.225 patients comparing aspirin versus placebo/control during a mean follow-up period of 6.4 years. Using a random effect model, relative risks and 95% confidence intervals were calculated for each outcome.

Results

Aspirin reduced the relative risk of ischemic stroke by 10% (RR: 0.90; 95% CI: 0.82–0.99), myocardial infarction by 14% (RR: 0.86; 95% CI: 0.77–0.95) and the major adverse cardiovascular events by 9% (RR: 0.91; 95% CI: 0.86–0.95) but was associated with a 46% relative risk increase of major bleeding events (RR: 1.46; 95% CI: 1.30–1.64). Aspirin did not reduce the risk of cardiovascular mortality (RR: 0.99; 95% CI: 0.90–1.08), all-cause mortality (RR: 0.98; 95% CI: 0.93–1.02) or cancer (RR 1.05; 95% CI, 0.87–1.26). Aspirin use did not translate into a net clinical benefit adjusted for event-associated mortality risk (mean 0.034%; 95% CI: −0.18 to 0.25%).

Forest plot of major outcomes.

Conclusions

Aspirin use in primary prevention is associated with a reduced risk of stroke and myocardial infarction, but at a cost of an increased risk of major bleeding.

Acknowledgement/Funding

None
P675Current status of anticoagulation in patients with breast cancer and atrial fibrillation
Authors: Pardo Sanz A , Rincon L M , Guedes Ramallo P , Belarte L , De Lara G , Tamayo A , Cruz A , Contreras H , Martinez A , Huertas S , Portero J J , Monteagudo J M , Marco A , Del Prado S , Zamorano J L
Published: October 2019

Aims

Balance between embolic and bleeding risk is challenging in patients with cancer. There is a lack of specific recommendations for the use of antithrombotic therapy in oncologic patients with atrial fibrillation (AF). We compared the embolic and bleeding risk, the preventive management and the incidence of events between patients with and without cancer. We further evaluated the effectiveness and safety of direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) within patients with cancer.

Methods

The AMBER-AF registry is an observational multicentre study that analysed patients with non-valvular AF treated in Oncology and Cardiology Departments in Spain. 1237 female patients with AF were enrolled: 637 with breast cancer and 599 without cancer. Mean follow-up was 3.1 years.

Results

Both groups were similar in age, CHA2DS2-VASc and HASB-LED scores. Lack of guidelines recommended therapies was more frequent among patients with cancer. Compared with patients without cancer, adjusted rates of stroke (hazard ratio [95% confidence interval]) in cancer patients were higher (1.56 [1.04–2.35]), whereas bleeding rates remained similar (1.25 [0.95–1.64]). Within the group of patients with cancer, the use of DOACs vs VKAs did not entail differences in the adjusted rates of stroke (0.91 [0.42–1.99]) or severe bleedings (1.53 [0.93–2.53]).

Follow-up events

Conclusions

Antithrombotic management of AF frequently differs in patients with breast cancer. While breast cancer is associated with a higher risk of incident stroke, bleeding events remained similar. Patients with cancer treated with DOACs experienced similar rates of stroke and bleeding as those with VKAs.
P682Radiotherapy-induced malfunction in cancer patients with cardiac implantable electronic devices
Authors: Imberti J F , Placentino F , Malavasi V L , Demarco G , Lohr F , Boriani G
Published: October 2019

Background

The number of patients with cardiac implantable electronic devices (CIED) requiring a radiation therapy (RT) for cancer treatment is increasing over time. Nevertheless, the rate and predictors of CIED malfunctions are still controversial.

Purpose

The aim of our study is to estimate the prevalence and possible predictors of RT-related CIED malfunctions and to describe malfunction characteristics.

Methods

We retrospectively reviewed medical records of all pacemaker (PM)/implantable cardioverter defibrillator (ICD) patients who underwent RT at our centre between January 2004 and July 2018. We included data from the CIED interrogation performed before the RT course to the first interrogation after the end of the RT course. As a safety measure, during RT a magnet was applied to every ICD and, in all PM-dependent patients, the device was temporarily reprogrammed in V00. Device relocation from the RT field was performed in 2/150 (1.3%) RT courses.

Results

One hundred twenty-seven patients were included, who underwent 150 separate RT courses. Eighty one percent of patients had a PM, while 19% had an ICD. Of note 17.4% of patients were PM-dependent. Neutron producing RT was used in 37/139 (26.6%) patients, whereas marginal neutron producing and non-neutron producing RT was used in 9/139 (6.4%) and 93/139 (67%) patients respectively. The cumulative dose (Dmax) delivered to the CIED exceeded 5Gy only in 2/132 (1.5%) cases. Three device-related malfunctions were found (2%). None of them were life-threatening or lead to a clinical event. All dysfunctions were resolved by reprogramming the device and did not require CIED substitution or leads extraction. Details of dysfunctions included: 1) a partial reset of an ICD, leading to self-reprogramming in safety mode, 2) full reset of a PM, which required the re-initialisation of the device and 3) programming change of the magnetic PM frequency to 30bpm (instead of 90 bpm). In all cases the Dmax delivered to the CIED was <1Gy. A neutron producing RT was used in the first two cases, whereas a non-neutron producing RT was used in the last case.

Conclusions

In accordance with the current literature, our results show that RT in patients with CIED is substantially safe. Malfunctions are uncommon and do not result in clinical events, but can develop even if the Dmax delivered to the CIED is <1 Gy. Device interrogation on a regular basis is advisable to promptly recognise CIED malfunctions.
P6893D echocardiography, arterial stiffness, and biomarkers for detection and prediction of late cardiotoxicity in non-Hodgkin lymphoma
Authors: Mihalcea D , Memis H , Balinisteanu A , Vladareanu A M , Vinereanu D
Published: October 2019

CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) in non-Hodgkin lymphoma (NHL) is limited by risk of cardiotoxicity. Aim. To define new parameters to detect late cardiotoxicity.

Methods

64 patients (27 men, 59±11 years) with NHL, scheduled for CHOP, with LVEF>50%, were assessed at baseline, after chemotherapy ended and 1 year later, by 3D echo for LVEF and deformation (longitudinal, radial, circumferential, area strain: LS, RS, CS, AS), by echo-tracking for pulse wave velocity (PWV) and wave intensity (WI), and by troponin I and NTproBNP. Cardiotoxicity was defined as LVEF decrease<50%, with >10% from baseline.

Results

10 patients (group I) developed late cardiotoxicity, while 54 patients did not (group II). There was a reduction of LS, CS, AS, and increase of PWV and WI, with greater changes in group I (table). LVEF decrease correlated with LS, CS, AS, PWV, WI, troponin changes (r=0.57, r=0.37, r=0.41, r=−0.53, r=−0.43, r=−0.34 p<0.05). LS reduction after chemotherapy ended was the best independent predictor for LVEF decrease 1 year after therapy completion (R2=0.42 p=0.001). Decrease of LS >22% at the end of treatment predicted late cardiotoxicity with 85% sensitivity and 74% specificity.

Late cardiovascular toxicity parametrs CHOP Group I Group II LS (-%) Baseline 22±2 21±2 Final 14±2† 18±2† After 1 year 11±1† 16±2† CS (-%) Baseline 21±2 21±2 Final 16±2† 19±2† After 1 year 13±2† 15±1† AS (%) Baseline 39±3 40±2 Final 33±2† 37±2† After 1 year 28±2† 35±1 PWV (m/s) Baseline 3.4±1.2 3.3±0.7 Final 6.9±1.5† 4.3±1.4† After 1 year 8.9±2.1† 5.5±1.3† WI (m/s) Baseline 4.2±0.8 4.4±0.6 Final 7.7±1.4† 5.1±0.8† After 1 year 9.4±0.9† 6.1±0.9† Abbreviations in text. †p<0.001.

Conclusion

Assessment of 3D myocardial deformation is able to detect late cardiovascular toxicity, and to predict further LVEF decline in NHL patients.

Acknowledgement/Funding

Grant PCCDI 83/2018 (BIOVEA)
P690Incidence of events between vitamin K antagonists and direct oral anticoagulants in patients with cancer
Authors: Pardo Sanz A , Rincon L M , De Lara G , Tamayo A , Belarte L C , Cruz A , Contreras H , Guedes P , Huertas S , Portero J , Martinez A , Alddin-Rajjoub E , Marco A , Monteagudo J M , Zamorano J L
Published: October 2019

Background

Balance between embolic and bleeding risk is challenging in patients with cancer. There is a lack of specific recommendations for the use of antithrombotic therapy in oncologic patients with atrial fibrillation (AF).

We aimed to evaluate the effectiveness and safety of direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) within patients with breast cancer. We also compared the embolic and bleeding risk, the preventive management and the incidence of events between patients with and without cancer.

Methods

It is an ambispective observational multicentric study that analysed patients with non-valvular AF treated in Oncology and Cardiology Departments in Spain in the period 2011–2018. A total of 1237 female patients with AF were enrolled: 637 with breast cancer and 599 without cancer. The incidence of thromboembolic and major bleeding events according to the antithrombotic strategy with VKAs or DOACs was evaluated in the cohort of 637 patients with cancer. Analysis were conducted using SPSS software V.22.0 and R V.3.5.1, with a two-tailed significance value of 0.05.

Results

Mean follow-up was 3.1 years. Both groups were similar in age, CHA2DS2-VASc and HASB-LED scores. There was no evidence that the incidence of ischemic stroke/systemic embolism differed between patients with cancer treated with AVK and DOAC after CHA2DS2-VASc adjustment: HR 0.91 (95% CI, 0.42–1.99). In addition, no significant differences in the incidence of major bleeding events were found between DOACs and VKA after adjustment for HAS-BLED score: HR 1.53 (95% CI, 0.93–2.53) (Figure 3). Gastrointestinal bleeding was the main source of haemorrhages in both groups (45% of bleedings among patients treated with DOACs and, 37% in VKAs group). Metastatic disease or active chemotherapy were studied as potential covariates but none of them posed any relevant change in the result.

Kaplan-Meier analysis

Conclusions

Cancer patients treated with DOACs did not differ versus those treated with VKAs with regards to stroke or systemic embolism in a model adjusted for CHA2DS2-VASc. Neither significant differences were found for bleeding events in a model adjusted for baseline HASBLED.
P691Left ventricular systolic function in long term survivors of allogeneic hematopoietic stem cell transplantation
Authors: Massey R , Diep P P , Ruud E , Aakhus S , Beitnes J O
Published: October 2019

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is increasingly utilized in young patients. Allo-HSCT usually requires myeloablative therapy that is potentially cardiotoxic. In addition, allo-HSCT survivors have a high prevalence of cardiovascular risk factors.

Purpose

We aim to describe left ventricular systolic function in long term survivors after allo-HSCT.

Methods

This study included 104 patients, aged (mean±SD) 18±10 years at allo-HSCT, and follow-up time was 17±6 years. 74% were sufferers of malignant disease. Pre-transplantation therapies consisted of anthracyclines (AnT) in 44% and mediastinal radiotherapy in 2%. Conditioning regimes consisted of cyclophosphamide with bulsulfsan in 77%. 22% received anti-lymphocyte globulin and 6% received total body irradiation. Left ventricular (LV) function was evaluated by 2D and 3D echocardiography. Healthy controls matched for age, sex and BMI were used in group comparisons. Group comparisons were performed by t-tests and chi-square. A linear regression was used to identify contributing factors to reduced systolic LV function in allo-HSCT survivors.

Results

Most parameters of LV systolic function including 2D and 3D LV ejection fraction (LVEF), global longitudinal strain (GLS), mitral annulus excursion (MAPSE) and s' were all significantly impaired after allo-HSCT as compared to the control group. Significant (p<0.05) contributors to LVEF in the multivariate regression analysis were age, AnT dosage, graft versus host disease (GVHD, occurring in 67%) and hypertension (HT, occurring in 31%).

Allo-HSCT Control p value n 104 55 – Gender (female) 56 (54) 29 (53) 0.89 Age (yr) 35±12 36±11 0.44 BMI (kg/m2) 25±5 24±3 0.57 Fractional Shortening (%) 31±6 32±4 0.26 2D LVEF (%) 55±6 59±3 <0.005 3D LVEF (%) 54±5 58±3 <0.005 MAPSE (mm) 13±2 15±2 <0.005 Mean s' (mm) 81±17 89±17 <0.005 2D GLS (%) −17±2 −20±2 <0.005 Values: mean ± SD or n (%), t-test or chi-square.

Conclusion

LV systolic function is reduced in long term survivors of allo-HSCT. Pre-transplantation AnT, HT and GVHD are significantly associated with increased risk of cardiotoxicity.

Acknowledgement/Funding

Norwegian Cancer Foundation and Norwegian ExtraFoundation for Health and Rehabilitation
P695Impact of atrial fibrillation on 10y all-cause mortality in curatively treated breast cancer patients
Authors: Jacobs J , L'hoyes W , Beckx M , Weltens C , Janssens S , Van Aelst L
Published: October 2019

Background

Contemporary treatment options for breast cancer have significantly improved survival during the last two decades. To estimate cancer survival, current practice typically relies on cancer size and the presence of metastases, whereas cardiovascular comorbidities such as atrial arrhythmias are typically not taken into account.

Aim

To evaluate the incidence of atrial fibrillation and flutter among curatively treated breast cancer patients and assess its impact on survival in an all-comer population at a tertiary care centre.

Methods

In a large, single centre, retrospective study we enrolled all patients with a diagnosis of breast cancer in 2007 and 2008 who received radiation therapy as part of their curative treatment regimen. We performed Kaplan-Meier and Cox survival analyses to calculate mortality risk over 10-year follow up.

Results

We included 1338 patients, 1326 (99.1%) of whom were women. Mean age (± standard deviation) at diagnosis was 57.6±13.4 years and the distribution of left sided breast cancer versus right sided or bilateral breast cancer was 655 (49.0%) patients versus 645 (48.2%) and 38 (2.9%) patients, respectively. A total of 805 (60.1%) patients had at least one ECG recorded during the 10 year follow up. In this subgroup, atrial fibrillation or flutter was present in 70 (8.7%); 23 patients had pre-existing atrial fibrillation or flutter (32.9%), 26 patients had had radiation therapy for left sided breast cancer (37.1%) versus 21 patients for right sided breast cancer (30%; p=0.375 for left versus right sided radiation therapy). Of the total cohort, 327 (24.4%) patients died during 10 year follow-up. In the subgroup with at least a single ECG recording, mortality equaled 44.3% (31/70) in patients with one or more documented episodes of atrial fibrillation or flutter during follow-up, compared to 21.9% (161/735) in patients who remained in sinus rhythm (p<0.0001). In patients with pre-existing atrial fibrillation or flutter, mortality equaled 47.8% (11/23) versus 42.6% (20/47) in patients with atrial fibrillation or flutter manifesting after treatment initiation (p=0.683).

Survival Atrial Fibrillation/Flutter

Conclusion

Atrial fibrillation and flutter are common in patients with curative breast cancer treatment and have a significant impact on overall survival. Our study highlights the impact of cardiac comorbidities on overall survival following cancer treatment and emphasizes the importance of a dedicated cardiac follow-up in cancer survivors.
P710S100A4, a key player in plaque stabilization?
Authors: Sakic A , Ambartsumian N , Klingelhofer J , Kwak B R , Grigorian M , Bochaton-Piallat M.-L
Published: October 2019

During atherosclerosis, intimal smooth muscle cells (SMCs) acquire a synthetic phenotype. We previously isolated spindle-shaped (S) and rhomboid (R) SMCs from porcine coronary artery. R-SMCs display the features of synthetic/dedifferentiated SMCs. S100A4 was identified as being a marker of R-SMCs in vitro and of intimal SMCs, in pig and man.

S-SMCs were treated with multimeric recombinant S100A4, which resulted in partial transition from S- to R-phenotype and NFκB activation. Remarkably, treatment of S-SMCs with multimeric S100A4 and platelet-derived growth factor-BB (PDGF-BB) together induced a complete SMC transition toward a R-phenotype associated with NFκB activation compared with multimeric S100A4 or PDGF-BB alone, likely through toll-like receptor-4 (TLR-4). RNA sequencing showed strong upregulation of pro-inflammatory genes such as granulocyte-macrophage colony stimulating factor (GM-CSF) and matrix-matalloproteinase-3 (MMP-3, Figure A) when cells were treated with multimeric S100A4 and PDGF-BB together compared with multimeric S100A4 or PDGF-BB alone.

In vivo, ApoE−/− mice were fed with high-cholesterol diet for 9 weeks. The 3 last weeks they were injected intraperitoneally with neutralizing monoclonal S100A4 antibody (clone 6B12, n=11) or with control IgG1 (n=12). Neutralization of extracellular S100A4 induced: decreased area of atherosclerotic lesions (Figure B), decreased necrotic core and cholesterol cleft, decreased number of CD68 positive cells and increased number of α-smooth muscle actin (Figure C) and smooth muscle myosin heavy chains-positive cells when compared to control groups.

S100A4 and SMCs

Our results indicate that extracellular S100A4 could be a new target to influence the evolution of atherosclerotic plaque, leading to plaque stabilization.

Acknowledgement/Funding

Swiss National Science Foundation grant #310030_166357/1
P711Histamine promotes atherosclerotic plaque instability via STAT6-dependent macrophage pyroptosis
Authors: Xu L , Yang X , Ding S , Qian J , Ge J
Published: October 2019

Background

Atherosclerotic plaque formation and rupture is the primary cause for cardiovascular diseases. It's known that cell death and inflammation are crucial processes leading to atherosclerosis, which involves an important role of histamine. The aim of the present study is to determine the function of signal transducer and activator of transcription 6 (STAT6) in histamine-induced macrophage pyroptosis and plaque instability.

Methods

We constructed APOE/STAT6 double knock out (DKO) mice via hybridization of ApoE−/− and STAT6−/− mice. 20 ApoE−/− mice (control) and 20 DKO mice were challenged with high-fat diet for 12 weeks while 10 in each group were intraperitoneally infused with histamine (400ug/kg) every other day. The extent and instability of atherosclerotic plaque were determined by oil-red staining, HE staining, immunofluorescence staining and electron microscopy. Changes in subsets of immune cells were evaluated by flow cytometry. Plasma cytokines were assessed by ELISA. Microarray analysis was applied to detect gene expressions while Western blot and real-time PCR was used to assess gene expression levels.

Results

Morphology studies revealed that histamine could promote plaque formation and vulnerability in ApoE−/− mice, whereas this effect was inhibited in DKO mice. FACS data showed that histamine injection could increase CD11b+Ly6Chigh M1 macrophages differentiation and pyroptosis and facilitate foam cells formation in ApoE−/− mice, which was also inhibited in DKO mice. Microarray analysis and in vitro studies exhibited that histamine could induce the up-regulation of pyrotosis-related proteins such as NLRP3, caspase-1 and MMPs via a STAT6-dependent pathway to promote macrophage pyroptosis and foam cell formation.

Conclusions

We have characterized a novel role for histamine in modulating atherosclerotic lesion development and progression. Moreover, our work have figured out the detailed mechanisms by which histamine modulates the pyroptosis of macrophages and the progress of unstable atherosclerotic plaques. We envision that this study may provide several potential therapeutic targets benefit for atherosclerosis treatment.
P718Genome-wide copy number profiling of atherosclerotic plaques
Authors: Sleptcov A , Nazarenko M S , Kazantsev A N , Burkov N N , Skryabin N A , Krakhmal N V , Tashireva L A , Denisov E V , Lebedev I N , Barbarash O L , Puzyrev V P
Published: October 2019

Background

Atherosclerotic plaque formation results from complex cellular interactions in the intima of arteries, which take place between resident cells of the vessel wall (smooth muscle cells (SMC) and endothelial cells) and cells of the immune system (macrophages (MF)). Less well known is the genomic alterations in cells involving in the atherosclerotic process as can be important in plaque progression and instability.

Aim

The main purpose of the study is to assess the spectrum of structural genomic alterations in the tissue of atherosclerotic artery wall and to evaluate of difference between structural variants (SV) in SMC and MF.

Materials and methods

Samples of atherosclerotic plaques of the internal carotid artery (ICA) was collected from patients during endarterectomy (n=100) and the atherosclerotic coronary arteries (ACA) was obtained by coronary artery bypass surgery (n=10, group: bpACA) and by autopsy (n=8, apACA). Specimens were stored in liquid nitrogen. White blood cells (WBC) derived from the same patients. Control group was the health persons with same age (WBC, n=100). The genomic imbalances in bpACA were assessed by array comparative genomic hybridization (array-CGH, CGH Microarray 2x400K). Identified SVs was verified by droplet-digital PCR using TaqMan-assays (reference assay is RNAse P) in bpACA and ICA groups.SMC and MF were immunostained (Anti-Human CD68 Antibody and Alpha-SMA Antibody) and collected by laser capture microdissection of fresh frozen apACA samples (30–40 cells of each per sample). Collected cells were lysed and DNA amplified by whole genome amplification technique along with WBC of the same person, then analyzed by array-CGH.

Results

We found 90 SV in atherosclerotic coronary arteries, 13% of them were no mentioned before in Database of Genomic Variants. We selected interested SVs that contains only one gene (ACACB, ABCC9, ERLIN1, SFMBT1, PRKRA, and SIRPB1). The loss in the 3p21.1 region (SFMBT1) was in 11.48% patients and 8.5% in control group. Among patients who had diabetes mellitus (DM2) had more frequently loss of SFMBT1 (16%) than patients without DM2 (8%). The frequency of gain 2q31.2 (PRKRA) was 6% in patients whereas in control group we identified it in only one person. The frequency of loss 20p13 (SIRPB1) was approx. 67% in both groups. Several aneuploidies were found in MF (9 trisomies and 3 monosomies) and SMCs (1 trisomy and 8 monosomies). In two patients, SMCs had a normal karyotype. The ratio of duplications and deletions in MF and SMCs was 1:0.8 and 1:7, respectively. In MF of 6 patients identified same duplication in chromosome region 9q34.13-q34.2, (arr[hg19] 9q34.13(9:134337452-135931774)x3) about 2Mb in size.

Conclusion

Our study indicates that genomic alterations are diverse in their structure and are widely represented in cells involved in the atherosclerotic process.
P720Atheroprotective effects of 17beta-estradiol are mediated by PPARgamma in human coronary artery smooth muscle cells
Authors: Jehle J , Tiyerili V , Adler S , Groll K , Nickenig G , Becher U M
Published: October 2019

Background

17β-estradiol (E2) mediates vasculoprotection in various preclinical and clinical models of atherosclerosis and neointimal hyperplasia. However, the molecular mechanisms underlying these effects are still not fully elucidated. Previous studies have demonstrated the essential role of the peroxisome-proliferator-activated-receptor-γ (PPARγ) in mediating vasculoprotective effects of E2 in vivo. The aim of the current study was to investigate whether PPARγ is implicated in mediating vasculoprotective mechanisms of E2 in human coronary artery smooth muscle cells (HCASMC).

Methods

Primary HCASMC were purchased and stimulated with E2 [10 nM], the selective estrogen receptor α (ERα) agonist propylpyrazole triol (PPT) [50 nM] and the selective ERα antagonist methyl-piperidino-pyrazole (MPP) [1 μM], respectively. Changes in PPARγ mRNA and protein expression upon stimulation of ERα were assessed by qPCR and Western blot analyses. Nuclear PPARγ protein expression and DNA binding affinity was assessed after the isolation of the nuclear protein fraction. Hereafter, HCASMC were incubated with E2, PPARγ-antagonist GW9662 [1 μM – 30 μM], or both. HCASMC proliferation was assessed by nuclear BrdU staining and reactive oxygen species (ROS) formation was assessed by L-012- and DCF-DA assays.

Results

E2 significantly increased PPARγ expression in HCASMC (1.95±0.41 –fold; n=5; p=0.0335). This effect was mimicked by ERα agonist PPT (1.63±0.27 –fold; n=7; p=0.0489) and was abrogated by co-incubation with ERα antagonist MPP (1.17±0.18 –fold; n=3; pvs. control >0.05). Nuclear PPARγ expression was enhanced by E2 (1.53±0.16 –fold; n=4; pvs. control = 0.0074; Fig. 2A) whereas PPARγ's DNA binding activity to PPRE remained unchanged upon stimulation with E2 (0.94±0.11 –fold; n=4; pvs. control >0.05). Pharmacological inhibition of PI3K/Akt by LY294002 abrogated E2-induced expression of PPARγ (0.24±0.09 –fold; n=3; pvs. E2 = 0.0017), arguing for a PI3K/Akt-dependent activation by E2. The role of PPARγ in mediating vasculoprotective effects of E2 was assessed in functional assays using PPARγ-antagonist GW9662. E2 diminished HCASMC proliferation which was restored by GW9662. While E2 only slightly decreased ROS production by HCASMC, GW9662 significantly increased ROS levels (1,036±169 RLU x s–1 x cell–1 versus 561±99 RLU x s–1 x cell–1; n=5–6; p=0.0287).

Conclusion

In summary, the present study identifies PPARγ as a downstream mediator of E2-related atheroprotective effects in HCASMC. 17β-estradiol regulates vascular PPARγ-expression in HCASMC via the ERα receptor and the PI3K/Akt pathway. PPARγ agonism might be a promising therapeutic strategy to prevent cardiovascular events in postmenopausal women with depleted E2 plasma levels.

Acknowledgement/Funding

This work was supported by the Bonfor program of the University of Bonn [grant number O-109.0057 to JJ].
P721Shear stress induced unfolding of von willebrand factor may be involved in the premature development of myocardial infarction
Authors: Melnikov I , Avtaeva Y , Kozlov S , Nozadze D , Gabbasov Z
Published: October 2019

Background

Normally, von Willebrand factor (vWF) becomes highly reactive with platelets upon unfolding into a fibrillar conformation at critical shear rate (more than 5000 s–1), that may occur in stenotic arteries. At shear rates below critical value (1200–1300 s–1), which occur in intact coronary arteries, normally there is no conformational rearrangement of vWF. Pathologic unfolding of vWF at shear rates below critical value may increase a risk of the development of coronary thrombosis. There is little information on the role of shear stress induced conformational rearrangement of vWF in the development of myocardial infarction in young individuals.

Purpose

To investigate vWF-dependent platelet adhesion of patients with premature myocardial infarction at shear rates below critical value (1200–1300 s–1).

Methods

Using a microfluidic system, we measured platelet adhesion to a fibrinogen-coated optical surface at shear rates of 1200–1300 s–1 during 10 minutes. We assessed platelet-rich plasma of 8 male persons 40–52 years old, who had previous myocardial infarction at the age of 34–39. The control group comprised 6 healthy male volunteers 30–55 years old. We compared the intensity of scattered laser light measured in volts (V) at 10th minute. To study vWF-dependent platelet adhesion, we blocked GPIb receptor with monoclonal antibody to inhibit platelet interaction with vWF. To compare the intensity of vWF-dependent platelet adhesion with normally occurring adhesion to fibrinogen, we blocked GPIIb/IIIa receptor with monoclonal antibody.

Results

The inhibition of GPIb vWF-receptor decreased platelet adhesion to fibrinogen surface at shear rates of 1200–1300 s–1 by 17.8±4.7% in healthy volunteers and by 92±2.8% in persons with premature myocardial infarction (p<0.05). Inhibition of GPIIb/IIIa receptor decreased platelet adhesion by 91.5±3.8% in healthy volunteers and by 97.3±3.2% in persons with premature myocardial infarction.

Conclusion

Pathologic unfolding of vWF at shear rates below critical value may be involved in the development of premature myocardial infarction.

Acknowledgement/Funding

This work was supported by the grant of the Russian Science Foundation (project #16-15-10098)
P722Glycemic control with canagliflozin, a SGLT-2 inhibitor, attenuates atherosclerosis and endothelial dysfunction in diabetic apolipoprotein e-deficient mice
Authors: Rahadian A , Fukuda D , Salim H , Yagi S , Kusunose K , Yamada H , Soeki T , Sata M
Published: October 2019

Background

Canagliflozin is a SGLT-2 inhibitor, a novel type of drug for type 2 diabetes mellitus treatment. Recent studies have shown that SGLT-2 inhibitors reduce cardiovascular events, although the mechanism is still unknown.

Purpose

The aim of our study was to examine the effect of canagliflozin on vascular endothelial cell.

Method

Eight-week-old apolipoprotein E-deficient (ApoE−/−) mice were treated with streptozotocin (STZ, 75 mg/kg/day) in three consecutive days by intraperitoneal injection to induce diabetes. Diabetic ApoE−/− mice were treated with canagliflozin (30 mg/kg/day) by gavage for 12 weeks or 8 weeks to examine its effect on atherosclerosis or endothelial function, respectively.

Results

Canagliflozin significantly decreased blood glucose level (P<0.001), triglyceride level (P<0.05), and total cholesterol level (P<0.05). Sudan IV staining on the aortic arch showed that canagliflozin decreased atherosclerotic lesion progression (P<0.05). Histological analyses using atherosclerotic lesions in the aortic root showed that canagliflozin reduced lipid disposition (P<0.01), macrophage accumulation (P<0.001, and expression of adhesion molecules such as ICAM-1, and VCAM-1 (P<0.01, and P<0.05 respectively). Canagliflozin also attenuated the development of endothelial dysfunction as determined by acetylcholine-dependent vasodilation (P<0.05), and reduced the expression of inflammatory molecules, such as ICAM-1 and VCAM-1 (P<0.01), also MCP-1, F4/80, IL6, and iNOS (P<0.05) in the aorta. Canagliflozin reduced oxidative stress as determined by the reduction of the expression of NOX2, NOX4, p22phox, p47phox in the aorta and by the urinary excretion of 8-OHdG. In in vitro experiment using human umbilical vein endothelial cells (HUVEC), methylglyoxal (MGO), a precursor of advanced glycation end products, significantly increased the expression of inflammatory molecules such as ICAM-1, MCP-1, and p22phox in (P<0.05, respectively). MGO also decreased the phosphorylation of eNOSser1177 and Akt, and increased phosphorylation of P38 MAPK in HUVEC.

Conclusion

Glucose lowering effect by canagliflozin attenuates the development of endothelial dysfunction and atherogenesis in diabetic ApoE−/− mice. Anti-inflammatory effect due to the reduction of glucose toxicity on endothelial cells might be one of the mechanisms.
P759Electrocardiographic predictors of adverse in-hospital outcomes in the Takotsubo syndrome
Authors: Jha S
Published: October 2019

Background

The takotsubo syndrome is a life-threatening acute cardiac condition. However, little is known about risk factors associated with worse outcomes in TS, and no high-risk electrocardiographic criteria have been defined for patients with TS. We sought to identify high-risk admission ECG findings among patients with TS.

Methods

Using the Swedish Angiography and Angioplasty Registry (SCAAR) we identified all cases of TS who were treated at our university hospital between 2008 and 2017. We reviewed all cases and included patients who met the revised Gothenburg diagnostic criteria. We conducted an in-depth review of all presenting electrocardiograms, using a pre-defined case report form (CRF), including the following variables: heart rate; rhythm; PR-interval; QRS axis; QTc-interval; T-wave inversion.; presence of Q-wave; T-wave axis; and the magnitude of ST-segment deviation in each individual lead. The primary endpoint was the occurrence of in-hospital major adverse cardiac event (MACE), defined as the composite of death, ventricular tachycardia or fibrillation (VT/VF), atrioventricular block ≥2 or asystole >10 seconds.

Results

We identified 161 patients with TS, of whom 151 (93.8%) were women. The mean age was 69±13 years. MACE occurred in 19 patients (11.8%), and VT/VF occurred in 14 patients (8.7%). No clinical variables were significantly different between patients with and without MACE. Patients with MACE were less likely than those without MACE to have sinus rhythm (79.0% versus 95.8%, p=0.02) or T-wave inversion (15.8% versus 52.8%, p=0.02). T-wave inversion was less common among patients with than without VT/VF (14.3% versus 51.7%, p=0.01). After adjustment for age and sex T-wave inversion was independently associated with lower risk of MACE (Odds ratio 0.13, 95% confidence interval 0.04 to 0.48, p>0.001).

Conclusions

T-wave inversion is common in TS and is associated with lower risk of adverse events, driven by a lower risk of VT/VF.
P763Home Monitoring is associated with fewer gastrointestinal bleeding events following ventricular assist device implantation
Authors: Gkouziouta A , Aravanis N , Zarkalis D , Bonios M , Fragkoulis S , Adamopoulos S , Kogerakis N
Published: October 2019

Introduction

Patients (pts) treated with a continuous flow left ventricular assist device (LVAD) are at increased risk for both bleeding and thromboembolic events. Maintenance of oral anticoagulation (AC) in the therapeutic range is difficult to achieve.

Hypothesis

Increased frequency of international normalized ratio (INR) home monitoring (HM) decreases the incidence of gastrointestinal bleeding and thromboembolic events (stroke, pump thrombosis) compared to standard of care (SOC).

Methods

We analyzed the efficacy of outpatient AC monitoring in consecutive pts who underwent VAD implantation at our institution between 2008–2018. Time in therapeutic range (TTR) was defined as percent of time with INR 2.5–2.8. HM pts had biweekly INR measurements using the Coagucheck XS ROCHE, while SOC pts had INR measured every 1–3 weeks. Gastrointestinal bleeding (GIB) and thromboembolic events were assessed by retrospective blinded chart review. Logistic regression was used to model the impact of TTR on the risk of GIB and THROMB.

Results

There were 85 pts: 44 in HM and 40 in SC arm with similar characteristics. SOC patients were more likely to have ischemic cardiomyopathy (63% vs 30%, p=0.006) and an LVAD (60% vs 25%, p=0.002). The use of HM was associated with a 19.7% reduction in the risk of GIB (8.8% vs 28.5%, p=0.043) and a trend towards lower risk of THROMB (6.8% vs 14.9%, p=0.19). HM pts had significantly longer TTR (52±20% vs 39±22%, p=0.007). Each percentage increase in TTR was associated with a 5.2% decrease in the risk of GIB [Odds Ratio (OR) 0.95, 95% Confidence Interval (CI) 0.91–0.99, p=0.009] even after adjustment for aspirin use and monitoring duration (OR 0.95, 95% CI 0.91–0.99, p=0.020). There was a similar decrease in the risk of overall bleeding (OR 0.94, 95% CI 0.90–0.98, p=0.008).

Conclusions

Increased frequency of home INR monitoring achieved a higher TTR and was associated with a 20% reduction in risk of gastrointestinal bleeding.
P764A quality improvement program for heart failure involving structured patient data, diagnosis and organization of care - results from the 4D heart failure project
Authors: Matan D , Lofstrom U , Cabrera-Corovic C , Eriksson B L , Ekstrom M , Hage C , Ljunggren G , Lynga P , Persson B , Eriksson M J , Wallen H , Janerot Sjoberg B , Malmqvist K , Linde C , Persson H
Published: October 2019

Background

Heart failure (HF) management is suboptimal in Sweden despite available evidence-based treatments.

Purpose

We hypothesized that a comprehensive organizational improvement programme could improve HF management, treatment and outcome.

Methods

Between 2012 and 2017 a HF improvement programme (the 4D Heart Failure project) was conducted in an urban region in Sweden (>2.2 million inhabitants). The steering committee led working groups 2012–17 including all health care providers with 250 primary care centers to build a standardized care process. HF outpatient care was centralized at five hospital-based HF clinics and included multidisciplinary health care teams.

The outcomes were: 1) prescription withdrawals of HF medication (RAS-inhibitors and beta-blockers, MRA) per year, expressed as percentage (%), 2) one-year all-cause mortality or heart failure readmission by multivariable Cox regression, 3) total number of admitted HF patients, subdivided by new-onset and previously known HF, per million inhabitants and year.

Results

Between 2012 and 2017, yearly visits to the five HF clinics increased 3.5 times from 3200 to 11700, to a total of 47400 visits or 15800 patients (average 3 visits/patient). Prescription withdrawals of MRAs for readmitted HF patients increased from 37% to 60%, of beta-blockers and RAS-inhibitors from 80 to 90%. Similar increases were noted for all admitted patients. One-year mortality or HF readmission was 48% (n=17124/35880) over the period and decreased significantly (adjusted HR 0.98 per year, 95% CI 0.97–0.99, p<0.001). Number of admitted HF patients, new-onset or readmitted HF patients decreased by 16%, 13% and 20%, respectively (p<0.0001, Figure).

Numbers of admitted patients 2012-2017

Conclusion

A comprehensive standardized care HF management programme in an urban region substantially increased access to multidisciplinary hospital-based HF clinics, and increased use of evidence-based medications. HF admissions and readmissions were reduced, as was the risk of one-year mortality or HF rehospitalization.

Acknowledgement/Funding

County of Stockholm and the Karolinska Institute