bluuebunny/crossref_metadata_2025 huggingface dataset:
P656Risk of major gastrointestinal bleed in relation to vascular disease risk in 0.5M UK Biobank participants
Authors: Hammami I , Mafham M , Armitage J , Parish S
Published: October 2019

Background

Low-dose aspirin is of established benefit for secondary prevention of cardiovascular events but in primary prevention the benefit is finely balanced with the hazard of major bleeds, and in particular gastrointestinal (GI) bleeds.

Purpose

To investigate non-vascular, non-genetic risk factors for major GI bleeds and derive a score for GI bleed risk which may help identify who will receive most net benefit from aspirin.

Methods

In the UK Biobank prospective study of 0.5M participants aged 40–69 at recruitment, prior history of cardiovascular disease, bleeds and other medical conditions was ascertained from self-reported diagnoses and electronic heath records (EHR) prior to recruitment. Major GI bleed during 6 years of follow-up was defined based on coded diagnoses and duration of hospital stay. Non-vascular risk factors for bleed were identified from amongst 100 baseline and prior disease factors using a stepwise regression with adjustment for established vascular risk factors, aspirin and warfarin use. 10-way cross-validation was used when making risk scores.

Results

Among the primary prevention population without prior intracranial bleed, serious extracranial bleed or gastrointestinal ulcer in the 6 months prior to recruitment, 1682 (0.06%/y) participants had a major GI bleed (1006 upper GI, 676 lower GI) with a mean stay in hospital of 3.2 days. Antiplatelet use (in 11%) and anticoagulant use (in 1%), were associated with 1.5 and 4 fold risks of GI bleed, respectively. Stepwise regression identified a non-vascular risk score for major bleed with a 4-fold risk ratio across fifths (Figure). But the score was also associated with a 2-fold risk ratio for major vascular events.

Conclusions

Major GI bleeds cause substantial morbidity. A 4-fold difference in bleed risk across quintiles was distinguishable by a score based largely on EHR prior disease information and frailty measures. This score is applicable in other contexts and will be applied in the ASCEND randomised trial of daily aspirin to provide randomized evidence of the net benefit of aspirin in different risk categories. However, vascular risk factors predicted risk of GI bleeds, and non-vascular risk factors for GI bleed predicted risk of major vascular events; so the net benefit from aspirin may vary only modestly across categories by vascular and bleed risks.
P665Incidence and predictors of intracerebral haemorrhage recurrence in patients with and without atrial fibrillation: a cohort study
Authors: Overvad T F , Andersen S D , Larsen T B , Lip G Y H , Soegaard M , Skjoeth F , Nielsen P B
Published: October 2019

Background

Intracerebral haemorrhage is a devastating vascular event. Clinical predictors of recurrence facilitating individualised post-bleeding patient management are sparsely described. Concomitant atrial fibrillation is common in patients with intracerebral haemorrhage due to widespread use of oral anticoagulation in this specific population.

Objective

We aimed to describe incidence of intracerebral haemorrhage recurrence and explore the prognostic value of 25 clinical predictors for recurrence in patients with and without atrial fibrillation, including various comorbidities, civil status, lifestyle, medication, and measures of bleeding severity reflected by the Scandinavian Stroke Scale score.

Methods

Cohort study of patients with incident intracerebral haemorrhage diagnosed from 2003–2016 identified using nationwide Danish administrative registries. Results reported as cumulative incidence of intracerebral recurrence accounting for competing risk of death. Univariate and multivariate predictors of recurrence were estimated using Cox regression analyses (hazard ratios [HRs], 95% confidence intervals [CI]).

Results

We identified 9,255 patients with incident intracerebral haemorrhage (median age 73 years, 46.6% females, 16% with atrial fibrillation). Five-year risks of intracerebral haemorrhage recurrence were approximately 10% in the study population, although slightly higher for patients without atrial fibrillation (Figure). Predictors of recurrence were broadly similar for patients with and without atrial fibrillation. Age in categories <60 years (reference), age 60–70 years (HR 1.30, 95% CI 1.03–1.65), age 70–80 years (HR 1.60, 95% CI 1.27–2.01), age >80 years (HR 1.20, 95% CI 0.91–1.57), nursing home residency (HR 1.48, 95% CI 1.03–2.15), and Scandinavian Stroke Scale score (“mild” versus “moderate” (HR 1.40, 95% CI 1.13–1.72) and “severe” (HR 1.94, 95% CI 1.59–2.37) were the strongest predictors of intracerebral haemorrhage recurrence.

Conclusions

Intracerebral haemorrhage recurrence risk after five years was approximately 10%. Robust clinical predictors of recurrence were few and broadly similar for patients with and without atrial fibrillation, with age and measures of bleeding severity being the most important.

Acknowledgement/Funding

The study was supported by “The BMS/Pfizer ERISTA Program 2016”. The sponsor had no role in the preparation of the manuscript
P669Frequency of venous thromboembolic risk evaluation and adequate in-hospital thromboprophylaxis administration
Authors: Galindo S , Juan Esteban Gomez Mesa J E G
Published: October 2019

Introduction

The most common in-hospital complication is venous thromboembolism (VTE). High risk patients have an incidence of VTE as higher as 18.3%. Padua and Caprini Scores allow to identify the thromboembolic risk for each type of patients. Thromboprophylaxis administration reduces VTE risk, but as low as 16–33% of medical patients and 25–44% of surgical patients receive this intervention during hospitalization.

Purpose

This study aims to identify basal adherence to evidence-based recommendations for thromboprophylaxis in hospitalized patients (annual evaluation) and its variation following monthly thromboprophylaxis risk evaluation.

Methods

A prospective, descriptive and observational study that included data from annual VTE risk evaluation (Padua/Caprini scores) and thromboprophylaxis administration (from 2015 to july 2018) followed by monthly risk assessments and thromboprophylaxis administration (August to November/2018) in 2.140 medical/surgical hospitalized patients.

Results

A total of 1290 patients (54,15%) had high risk for VTE: 787medical patients (Padua Score) and 503 surgical patients (Caprini score) and therefore they required thromboprophylaxis administration. In total population, adequate thromboprophylaxis administration inceased from 55% (annual evaluation) to 81,4% (monthly evaluation). In medical patients, adequate thromboprophylaxis increased from 59% (Annual evaluation) to 81,3% (monthly evaluation). In surgical patients, adequate thromboprophylaxis increased from 49% during annual evaluation to 81.5% during monthly evaluation (Figure 1).

Figure 1. Correct thromboprophylaxis (2018)

Conclusions

Annual thromboprophylaxis risk evaluation and thromboprophylaxis administration can be improved in medical patients when performed on a monthly basis. This difference does not apply to surgical patients, where monthly evaluations and interventions remains stable. Besides that, more aggressive risk evaluation should be implemented in order to reach thromboprophylaxis administration rates higher than 90%, and this can be done with weekly or daily measurement and intervention.

Acknowledgement/Funding

None
P672Ischemic and bleeding risk after an acute coronary syndrome in patients with prior history of cancer treated with dual antiplatelet therapy
Authors: Munoz Pousa I , Raposeiras Roubin S , Abu-Assi E , Manzano Fernandez S , D'Ascenzo F , Simao Henriques P J , Saucedo J , Ariza Sole A , Cambronero Sanchez F , Flores Blanco P J , Cespon Fernandez M , Caneiro Queija B , Cobas Paz R , Iniguez Romo A
Published: October 2019

Introduction

Very few patients with history of cancer are included in clinical trials. With this study from real-life patients, we try to analyze the ischemic and bleeding risk of patients with history of cancer who were treated with dual antiplatelet therapy (DAPT) after an acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI).

Methods

The data analyzed in this study were obtained from the fusion of 3 clinical registries of ACS patients: BleeMACS (2004–2013), CardioCHUVI/ARRITXACA (2010–2016) and RENAMI (2013–2016). All 3 registries include consecutive patients discharged after an ACS with DAPT and undergoing PCI. The merged data set contain 26,076 patients. A propensity-matched analysis was performed to match the baseline characteristics of patients with and without previous history of recent cancer. The impact of prior cancer in the ischemic and bleeding risk was assessed by a competitive risk analysis, using a Fine and Gray regression model, with death being the competitive event. For ischemic risk we have considered a new acute myocardial infarction (AMI), whereas for bleeding risk we have considered major bleeding (MB) defined as bleeding requiring hospital admission. All events occurred with DAPT, as follow-up time was censored by DAPT suspension/withdrawal.

Results

From the 26,076 ACS patients, 1,661 have prior history of cancer (6.4%). Patients with cancer were older, and with more cardiovascular risk factors. DAPT with prasugrel/ticagrelor was less frequently prescribed in patients with cancer in comparison with the rest of the population (14.5% vs 22.4%, p<0.001). During a mean follow-up of 12.2±4.8 months, 964 patients died (3.7%), and 640 AMI (2.5%) and 685 MB (2.6%) were reported. The unadjusted cumulative incidences of AMI and MB were higher in patients with prior cancer (5.1 and 5.2 per 100 patients/year, respectively) than in those with prior cancer (2.4 and 2.6 per 100 patients/year, respectively). After propensity-score matching, we obtained two matched groups of 1,656 patients. Patients with prior cancer showed a significant higher risk of AMI (sHR 1.44, 95% CI 1.01–2.04, p=0.044), but not higher risk of MB (sHR 1.21, 95% CI 0.88–1.68, p=0.248), in comparison with those without prior cancer.

Conclusions

In ACS patients discharged with DAPT after PCI, prior history of cancer is an independent factor of higher ischemic risk – in terms of AMI, but it is not an independent predictor of increased hemorrhagic risk.
P678Pericardiocentesis in thrombocytopenic cancer patients
Authors: Lee M , Gill C , Serauto Canache A , Donisan T , Balanescu D , Marah N , Stone D , Stone J , Boone D , Cervoni Curet F , Agha A , Iliescu C , Palaskas N
Published: October 2019

Background

Pericardial effusion is a known complication in cancer patients, resulting in chest pain, cardiac tamponade, and cardiogenic shock. Although technological advances allow for early detection, treatment options are limited for those also suffering from thrombocytopenia.

Purpose

Our study aims to evaluate survivorship of thrombocytopenic cancer patients who underwent pericardiocentesis.

Methods

From 2008 to 2019, we assessed overall mortality and follow-up post-pericardiocentesis in cancer patients with concurrent thrombocytopenia (<150,000 cells/microliter) at our cancer center. Thrombocytopenia grading was determined on the procedure day via serology platelet cell count with the following thresholds: Grade 1 (<50x103 cells/mL), Grade 2 (51–100x103 cells/mL), and Grade 3 (101–149x103 cells/mL).

Results

In 137 patients, we identified 65 (47%) patients with Grade 1, 30 (22%) with Grade 2, and 42 (31%) with Grade 3 thrombocytopenia. The calculated platelet count average was 66x103 cells/mL, median was 59x103 cells/mL, and range was 6 to 147x103 cells/mL. Of note, 7 (5%) patients had platelets <10x103 cells/mL. One patient developed a hematoma at the percutaneous site of pericardial drain, no other complications were noted. Kaplan Meier survival analysis by log-rank (mantel-cox) showed statistical significance (p=0.025). Comparatively, the cumulative survival of patients at 30 days was 63% in Grade 1, 67% in Grade 2, and 83% in Grade 3 patients. At one year, it was 26% in Grade 1, 37% in Grade 2, and 48% in Grade 3 patients.

Conclusion

Pericardiocentesis offers rapid symptomatic relief and can be life-saving in cardiac tamponade. In cancer patients, the development of pericardial effusions and thrombocytopenia increases due to the underlying malignancy and cancer therapeutics. Although thrombocytopenia is thought to increase peri-procedural risks, in this cohort there was only one minor complication and this occurred in Grade 2 thrombocytopenia. For thrombocytopenic cancer patients suffering from large pericardial effusions, high pre-operative risk scores often exclude them from receiving surgical pericardial windows. Although mortality was higher in severe thrombocytopenia, this is likely due to the competing risk of more severe cancer; there were no complications with Grade 1 thrombocytopenia. Especially noteworthy, no complications in those with platelets <10,000 cells/uL. Our study shows that in this population of patients, pericardiocentesis is a feasible intervention with low complication rate to help improve quality of life and potentially life-saving treatment.
P679Long-term cardiovascular outcomes after percutaneous coronary interventions in patients with acute coronary syndrome and cancer
Authors: Ma Y , Cheng Y J , Ohene B E , Yang L X , Zhou Y J
Published: October 2019

Background

Over time, the use of PCI increased and mortality decreased comparably in patients with ACS and cancers. Although the adverse cardiac effect of cancer has been widely reported, we know less on whether lung cancer confers worse clinical outcomes in patients with established ACS, particularly those undergoing PCI.

Methods

All cancer patients who were admitted in the hospital with ACS as initial diagnosis and underwent PCI from January 2006 to December 2016 were enrolled, and were divided into 2 groups according to their malignancy types: lung cancer and others. Population data was collected and clinical follow-up was performed by either telephone contact or office visit. Survival was graphically represented using Kaplan-Meier curves. Differences in survival rates were compared using the log-rank test. Analysis was performed with SPSS statistical software, version 22.0 for Windows. See Figure 1.

Results

16,062 patients suffered from various cancers and 55,401 patients underwent PCI. After cross referencing the two patient lists, 337 patients were enrolled who underwent cancer prior to ACS, and 15.1% (n=51) had a medical history of lung cancer. See Figure 2 and 3. Male gender was more prevalent in the lung cancer group than other cancers group (84.3% vs 60.5%, P=0.01). There was no significant difference between lung cancer and other cancers group in the presence of traditional cardiovascular risk factors, such as hypertension, hyperlipidemia, obesity, diabetes mellitus, history of smoking, history of drinking and the family history of coronary artery disease (P>0.05 for all). Among all coronary complex lesions, calcified lesions was more prevalent in lung cancer group (21.6% vs 11.5%, P=0.04), although there was no significant difference between two groups in left main lesions, bifurcation lesions and CTO lesions (P>0.05 for all). For anticancer therapy, patients with lung cancer received more radiotherapy (29.4% vs 13.6%, P=0.01) and chemotherapy (37.3% vs 25.5%, P=0.08). Follow-up was available for 289 of the 337 patients (85.8%). See table 1. The incidence of cardiovascular death (5.9% vs 1.0%, P=0.02) was higher in the lung cancer group. As shown the Kaplan-Meier curves in Figure 1, the survival rate free from all-cause death (log rank P=0.034, Figure 4A) and cardiovascular death (log rank P=0.013, Figure 4B) was significantly lower in lung cancer group than in other cancers group during the follow-up.

Figures and Table

Conclusions

Lung cancer has a non-negligible prevalence in patients with ACS undergoing PCI, with significantly worse long-term cardiovascular outcomes. The results of our study reinforce the importance of understanding to patients who need closer follow-up, careful evaluation, and intervention.
P684Long-term outcomes in patients with cancer undergoing percutaneous coronary intervention: analysis from a Japan multicenter registry
Authors: Endo A , Sawano M , Ikemura N , Takei M , Suzuki K , Hasegawa T , Takahashi T , Nakagawa S , Fukuda K , Kohsaka S
Published: October 2019

Background

Cancer and cardiovascular disease (CVD) is the most common cause of death in developed countries, and substantial overlap exist in their medical care. However, the detailed and updated information on outcome of cancer patients with cardiovascular disease (CVD), particularly in clinically significant coronary artery disease (CAD) remain unknown.

Purpose

We sought to describe the prevalence and long-term outcomes of cancer patients undergoing percutaneous coronary intervention (PCI), which has become a coronerstone in the management of CVD.

Methods

Patient data extracted from a regional prospectiveprocedure-based multicenter registry for PCI was analyzed. A total of 4,455 patients who underwent PCI at 15 hospitals within metropolitan Tokyo from September 2008 to 2012 were followed for 2 years. “Active” cancer patient was defined as having a history of cancer not cured or in remission. We analyzed in acute and stable presentation.The occurrence of clinical outcomes was assessed via Kaplan-Meier survival curve, and Cox-regression hazard model to adjust for known clinical predictors.

Results

Within the studied patients, 173 (3.9%) had a concomitant “active” cancer at the time of intervention. There was a significant difference between the patients with and without active cancer in each situation. In stable presentation, cancer group were older, lower BMI, frequently had silent ischemia, COPD and cerebrovascular/peripheral disease, and less often had dyslipidemia compared with non-cancer group. In acute presentation, cancer group were older, frequently had COPD, CKD, peripheral disease and history of HF compared with non-cancer group. The prescription rate of RAAS inhibitor was lower in the cancer group than in the non-cancer group in acute presentation. Notably, in both acute and stable presentation, these patients had significantly higher risk of all-cause mortality (HR 8.01: 95%, p<0.001 and HR5.53: 95%, p<0.001, respectively), and they were also at higher risk of major cardo- and cerebrovascular events (MACCE; HR2.38, p<0.001, HR2.33, p=0.001), when referenced to non-cancer patients after 2 year of follow-up.

Conclusion

Cancer patient was present in 3.9% of all PCI patients and was strongly associated with both non-cardiac and cardiac adverse events.
P688Cardiac dysfunction as a predictor of hepatic sinusoidal obstruction syndrome after hematopoietic cell transplantation
Authors: Park H , Kim M , Jeong H K , Kim H Y , Kim K H , Cho J Y , Yoon H J , Park J C
Published: October 2019

Background

Hepatic sinusoidal obstruction syndrome (HSOS) is a well-known fatal complication of hematopoietic cell transplantation (HCT), but the impact of cardiac abnormalities on the occurrence of HSOS has been poorly evaluated. Therefore, the authors investigated whether the structural changes or dysfunction of the heart before HCT is associated with the future occurrence of HSOS.

Methods

A total of 92 patients who underwent HCT were divided into 2 groups; HSOS group (n=11, 6 males, 53.8±15.9 years) vs no HSOS group (n=81, 51 males, 48.6±14.7 years). According to the modified Seattle criteria, HSOS was defined as otherwise unexplained occurrence of 2 or more of the following events within 20 days of HCT; serum total bilirubin >2 mg/dL, hepatomegaly or right upper quadrant pain, sudden weight gain due to fluid accumulation (>2% of baseline body weight). Echocardiography examinations were performed 1 month before HCT, and echocardiographic findings were compared between the groups.

Results

HSOS was developed in 11 patients (12.0%). HSOS group had significantly larger left ventricular end-diastolic volume index (LVEDVI) (65.2±4.9 vs 53.2±6.9 ml/m2, p<0.001) and relatively worse systolic function than no HSOS group (LV ejection fraction: 56.4±3.4 vs 65.1±5.9%, p<0.001, LV global longitudinal strain: −17.9±1.4 vs −20.1±2.0%, p=0.001). LV diastolic functional parameters were also significantly worse in HSOS group than in no HSOS group (E/E' ratio: 11.3±1.8 vs 9.1±2.0, p=0.002, left atrial global longitudinal strain: 27.7±3.3 vs 34.9±5.9%, p<0.001). However, left atrial volume index was not different between the groups (30.8±2.8 vs 29.0±3.3 ml/m2, p=0.078). By receiver operation characteristic curve analysis, among significantly different variables, LVEDVI was the most powerful predictor for HSOS, and the optimal cutoff value was 59.25 mL/m2. (81.8% sensitivity and 77.8% specificity, AUC 0.909).

Predictor of HSOS: ROC analysis

Conclusions

The present study demonstrated that structural changes or dysfunction of the heart are more prevalent in patients with HSOS after HCT and larger LVEDVI, among them, can be a useful predictor of upcoming HSOS. Routine echocardiographic study before HCT would be useful to identify high risk group for HSOS, and the development of HSOS should be carefully monitored in HCT patients with cardiac structural changes or dysfunction on echocardiography.
P709Improvement in endothelial function and arterial elastic properties facilitates response to cardiac resynchronization therapy
Authors: Karamichalakis N D , Ikonomidis I , Parissis J , Simitsis P , Xydonas S , Letsas K , Manolatos D , Efremidis M , Sideris A , Filippatos G
Published: October 2019

Background

Cardiac resynchronization therapy (CRT) is a well-established therapy in heart failure (HF) patients with prolonged QRS. In HF patients, reduced nitric oxide availability and increased oxidative stress promote endothelial dysfunction (ED) and arterial stiffness.

Purpose

To investigate the pathophysiologic changes in endothelium and arterial elastic properties in CRT patients and their correlation to therapy.

Methods

We studied 32 HF patients before and 3 months after CRT implantation. In each visit we performed a 12-lead ECG and assessed markers of endothelial function. Specifically, we examined flow-mediated dilatation of the brachial artery (FMD), carotid to femoral pulse wave velocity (cfPWV), as well as the layer of endothelial glycocalyx using the Perfused Boundary Region (PBR) of the sublingual microvessel range: 5–25 microns. We also evaluated left ventricle ejection fraction (LVEF), left ventricle (LV) global longitudinal strain (GLS) and arterial elastance (Ea) to ventricular elastance (Ees) ratio (Ea/Ees) by echocardiography.

Results

32 HF CRT patients, at age 65.5 (±10.9) years, with reduced LVEF (baseline LVEF: 27±7%, LVESV: 151±42 ml, GLS: 6.47±2.89%) were followed-up for a median of 115 days (IQR: 36). During follow up, all markers of ED demonstrated significant change: FMD was increased by 4.37±3.34% (p<0.001), cfPWV and PBR 5–25 were reduced by 1.10±1.56 (p=0.003) and 0.13±0.25 microns (p=0.028) respectively. LVEF was significantly increased (mean change: 7.50±4.77%) and LVESV was significantly reduced (mean change: −26.91±17.20 ml). 16 of 32 patients were responders (LVESV change ≥15% compared to baseline). Among the changes of the examined markers during follow-up, response to CRT correlated with the change of FMD (OR: 3.10, 95% CI: 1.47–15.51, p=0.039) and change of Ea/Ees (OR: 0.000, 95% CI: 0.000–0.061, p=0,0239).

Effect of change in measurements during follow-up on response to CRT Measurement OR (95% CI) Main effect p-value FMD change 3.100 (1.470–15.513) 0.0397 cfPWV change 0.669 (0.295–1.354) 0.0622 PBR 5–25 change 1.773 (0.008–455.458) 0.828 Ea/Ees change 0.000 (0.000–0.061) 0.0239

Conclusion

Improvement in endothelial function and arterial elastic properties evaluated by FMD and Ea/Ees respectively are related with effective CRT.
P723A novel CD147 inhibitor SP-8356 attenuates plaque progression and stabilizes vulnerable plaque in ApoE-deficient mice
Authors: Pahk K , Joung C , Song H Y , Kim S , Kim W
Published: October 2019

Aim

Plaque vulnerability is the crucial pathophysiological feature in atherosclerosis-related cardiovascular event such as myocardial infarction and stroke. CD147 has been suggested to play key roles in plaque vulnerability through interacting with cyclophilin A (CypA) and resultant activation of matrix metalloproteinase-9 (MMP-9). Here we report that the novel synthetic CD147 inhibitor SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one) inhibits CD147/MMP-9 pathways and reduces plaque progression and stabilizes plaque vulnerability.

Methods

Advanced atherosclerotic plaque was induced in apolipoprotein E-deficient (ApoE KO) mice by partial ligation of the right carotid artery coupled with an atherogenic diet. SP-8356 (50 mg/kg) was orally given daily for 3 weeks. Histomolecular analysis was carried out on harvested carotid arteries.

Results

Surface plasmon resonance assay showed the specific binding of SP-8356 with CD147. SP-8356 inhibited CypA-CD147 interaction and MMP-9 activation. In ApoE KO mice model, SP-8356 inhibited plaque formation, reduced the number of macrophages, increased the number of vascular smooth muscle cells, increased the fibrous cap thickness, and increased the collagen type I contents in fibrous cap. SP-8356 also reduced the apoptotic cells in the plaque lesion.

Conclusions

Owing to its improvement of plaque stability and inhibitory effect on plaque development, SP-8356 could be a potential therapeutic drug candidate for atherosclerosis and related clinical manifestations.
P733Cholesterol uptake triggers macrophage proliferation in the plaque
Authors: Hilgendorf I , Haerdtner C , Kornemann J , Krebs K , Dufner B , Hoppe N , Stachon P , Wolf D , Zirlik A , Princen H , Bode C
Published: October 2019

Background

Guidelines recommend cholesterol lowering for primary and secondary prevention of cardiovascular disease. While lipid lowering has been reported to induce plaque regression, the underlying mechanisms have remained speculative.

Purpose

We hypothesize that lipid uptake triggers local macrophage proliferation in the plaque, and conversely, statin treatment inhibits local macrophage proliferation leading to plaque regression.

Methods

Mixed bone marrow chimeras were generated in LDLR−/− mice reconstituted with wild type and scavenger receptor deficient or cholesterol exporter deficient bone marrow cells to study cell autonomous effects on macrophage proliferation. APOE*3-Leiden.huCETP mice with established atherosclerosis were randomized to three groups: Continued cholesterol diet, cholesterol diet supplemented with 0.01% atorvastatin, and cholesterol free diet for 4 weeks to study mechanisms of plaque regression.

Results

Proliferation of scavenger receptor A and CD36 deficient macrophages with impaired lipid uptake was reduced by 30–50% in the plaque, while ABCA1/ABCG1 exporter deficiency resulted in cholesterol overloading and apoptosis. Oral atorvastatin treatment decreased total plasma cholesterol levels by 50% to the same extend as cholesterol free diet feeding in APOE*3-Leiden.huCETP. Cholesterol lowering resulted in a 50% reduction in local macrophage proliferation and plaque regression with reduced macrophage and lipid contents and increased collagen. GFP bone marrow reconstitution of APOE*3-Leiden.huCETP mice in which the aortas were shielded from irradiation showed infiltrating monocytes to contribute only 11% to the plaque macrophage pool during plaque progression, thereby underscoring the relevance of targeting macrophage proliferation for plaque regression. Finally, rates of macrophage proliferation in human carotid artery plaques correlated with serum LDL-cholesterol levels, in line with our experimental studies.

Conclusion

Foam cell formation in atherosclerotic plaques triggers their proliferation. Targeting macrophage proliferation leads to plaque regression.
P734Research on the mechamism of renal sympathetic denervation in the treatment of insulin resistance
Authors: Xu M , Lu C
Published: October 2019

Background

Insulin resistance is the main pathogenesis of type 2 diabetes. In order to better control the blood glucose of diabetic patients, the key is to improve the insulin sensitivity. With the in-depth study on the mechanism of insulin resistance, sympathetic nerve is an important part of it, but the specific mechanism is not clear.

Objective

This experiment aims to observe the effects of RDN on insulin resistance and skeletal muscle mitochondrial function in spontaneous diabetes ZDF rats.

Methods

6 SPF healthy male ZDF (fa/+) rats were selected as control group, 12 healthy males ZDF (fa/fa) rats were randomly divided into sham group and RDN group. In the sham group and RDN group, the rats were treated with sham operation or bilateral renal sympathetic denervation respectively. Insulin sensitivity was tested in all rats with Hyperinsulinemic-euglycemic clamp test 2 weeks after RDN. The skeletal muscle ATPsyn, COXIV, UCP3 and SOD2 were tested by Western-blot method.

Results

The result showed that 2 weeks after RDN, the blood glucose level of the RDN group decreased significantly (P=0.000) when compared with the sham group. The glucose infusion rate (GIR) in sham and RDN group decreased significantly when compared with the control group (P=0.000). After RDN, the GIR in RDN group increased significantly. ATPsyn, COXIV which were the key enzyme of oxidative metabolism in skeletal muscle mitochondria decreased significantly in the sham and RDN group when compared with control group (P=0.001). However, parameters improved dramatically after RDN (P=0.001).

Table 1. Comparision of Baseline in each group 2 weeks after RDN Control (n=6) Sham (n=6) RDN (n=6) Pa Pb Pc Weight (g) 311.1±8.5 410.8±10.7 377.9±15.3 0.000 0.001 0.002 BBG (mmol/L) 5.97±0.16 21.42±1.45 7.91±0.54 0.000 0.001 0.000 BISN (ng/mL) 100.67±4.18 162.17±3.13 134.67±2.50 0.000 0.001 0.001 TG (mmol/L) 2.71±0.28 6.90±0.24 4.88±0.23 0.000 0.001 0.002 TC (mmol/L) 2.38±0.17 6.98±0.15 5.40±0.09 0.000 0.000 0.000 HDL-C (mmol/L) 7.92±0.44 2.95±0.22 5.35±0.19 0.000 0.000 0.000 LDL-C (mmol/L) 3.72±0.37 4.12±0.17 3.98±0.17 0.001 0.000 0.000 aCompared with Control Group and Sham Group. bCompared with RDN Group and Sham Group. cCompared with Sham Group and RDN Group.

Relative results

Conclusion

Our results showed that RDN improved the insulin sensitivity in diabetes rats. The mechanism may be related to the decrease of oxidative stress and function improvement in skeletal muscle mitochondrial by RDN.
P736Histone marks induced by the methyltransferase SETD7 modulate angiogenic response in diabetes
Authors: Mohammed S A , Costantino S , Akhmedov A , Ambrosini S , Karsay G , Brown P , Luscher T F , Paneni F
Published: October 2019

Introduction

Despite advances in revascularization strategies, type 2 diabetic (T2D) patients with peripheral artery disease (PAD) continue to have a high risk of limb amputation. Hence, strategies that promote vascularization can be considered as a novel therapeutic option in T2D patients with PAD. Epigenetic modifications of histones and DNA have emerged as key modulators of gene expression. Mono-methylation of histone 3 at lysine 4 (H3K4m1) – a specific epigenetic signature induced by the methyltransferase SETD7 – favours a chromatin conformation enabling the transcription of genes involved in inflammation and oxidative stress.

Purpose

To investigate whether SETD7 modulates angiogenesis in experimental diabetes.

Methods

Human aortic endothelial cells (HAECs) were cultured in growth factor-free medium and exposed either to normal glucose (NG, 5 mM) or high glucose (HG, 25 mM) for 48 hours. SETD7 protein and H3K4me1 levels were investigated by Western blot and chromatin immunoprecipitation (ChIP). Knockdown of SETD7 was achieved by small interfering RNA (siRNA). Pharmacological blockade of SETD7 was performed by using the highly selective inhibitor (R)-PFI-2, while its inactive enantiomer, (S)-PFI-2, was used as a control. Scratch and tube formation assays were performed to investigate the impact of SETD7 on angiogenic properties of HAECs. RNA sequencing (RNA-seq) and Ingenuity Pathway Analysis (IPA) were employed to unveil putative genes regulated by SETD7 in HG-treated HAECs. SETD7 expression was also investigated in muscular specimens isolated from type 2 diabetic (db/db) mice and non-diabetic mice undergoing hindlimb ischemia for 21 days.

Results

HG exposure in HAECs led to a time-dependent increase of both SETD7 gene and protein expression, as compared to NG. SETD7 upregulation in HG-treated HAECs was associated with an increase of H3K4me1 levels as well as with impaired endothelial cell migration and tube formation. Of interest, both gene silencing and pharmacological blockade of SETD7 rescued hyperglycemia-induced impairment of angiogenic properties in HAECs. RNA-seq in HG-treated HAECs with and without SETD7 depletion unveiled an array of differentially expressed genes, which were mainly involved in blood vessel growth and angiogenic response, as assessed by IPA analysis. Among dysregulated genes, ChIP assays showed that SETD7-dependent chromatin changes enabled the transcription of Semaphorin 3G (SEMA-3G), a negative regulator of endothelial cell migration. Indeed, gene silencing of SETD7 blunted SEMA-3G expression in HAECs exposed to HG. Consistent with our in vitro observations, SETD7 was upregulated in adductor muscle specimens from db/db mice undergoing hindlimb ischemia as compared to non-diabetic animals.

Conclusions

Pharmacological blockade of SETD7 by (R)-PFI-2 may represent a potential therapeutic approach to boost post-ischemic vascularization in T2D patients with PAD.
P742Effects of platelet microparticles on the formation and stability of atherosclerotic plaque in ApoE knockout mice
Authors: Wang Z , Pan L , Chen L , Hu H
Published: October 2019

Background

After activation by different factors, platelets can release a large number of platelet microparticles (PMPs), and continue to play a more durable and extensive role in promoting inflammation and thrombosis. Previous studies by our group have shown that PMPs can promote endothelial cell migration and lumen formation in vitro, and promote the release of inflammatory factors from monocytes. However, it is unclear whether PMPs can promote angiogenesis in the plaque and promote vascular wall inflammation and further lead to plaque instability.

Purpose

To investigate the effect of platelet microparticles (PMPs) from C57BL/6 mice on promoting atherosclerotic plaque formation and plaque stability in ApoE−/− mice.

Methods

Forty male apolipoprotein E knockout (ApoE−/−) mice, aged 8 weeks and fed for 4 weeks with high-fat diet, were randomly divided into four groups (n=10 in each group)according to the table of random digit. The mice were respectively injected with PBS (PBS group), PMPs-free supernatants (SUP group), low-dose PMPs (LDP group) and high-dose PMPs (HDP group) once a week through tail vein injection for 8 weeks. At the end of the experiment, the mice were euthanized and the blood samples were collected to detect blood routine, blood lipids, liver and kidney function and inflammatory factors including CRP, IL-1β, TNF-α; The aorta and brachiocephalic trunk were sampled to detect the atherosclerotic plaque formation. Oil Red O staining, H&E staining, Masson staining and immunohistochemistry (CD68, MMP-9, α-SMA) were used to examine the stability of the atherosclerotic plaque in each group.

Results

There were no significant differences in body weight, blood routine (WBC, RBC, PLT, HGB), blood lipids (TG, TCH, LDL, HDL), liver (ALT, AST)and kidney function (UN, Cr)in each group. The levels of serum CRP, IL-1β and TNF-α in LDP group and HDP group were significantly higher than those in PBS group and SUP group (P<0.05). The total area of aortic atherosclerotic plaques in LDP group and HDP group were significantly greater than those in PBS group and SUP group (P<0.05). Compared with the PBS group, the lipid cores of the plaques in the other three groups were significantly increased (P<0.05). The content of collagen and the amount of smooth muscle cells in the plaques were significantly lower in HDP group than in PBS group (P<0.05), while macrophages increased significantly in HDP group (P<0.05).

Conclusion

PMPs promote the formation of atherosclerotic plaques in high-fat-fed ApoE−/− mice, as well as macrophage infiltration and inflammation in the plaques, reduce the content of collagen and the amount of smooth muscle cells, thus decreasing the stability of plaques.
P743The efficacy and the safety of the action of the complex drug of fibrin-specific streptokinase in arterial thrombosis in vivo
Authors: Adzerikho I E , Lutsik I L , Vladimirskaya T E , Cherniavsky E A
Published: October 2019

Introduction

The use of streptokinase (SK) in the clinic is limited by the absence of fibrin-specificity, low degree of recovery of the vessel lumen and hemorrhagic manifestations. We have developed a system of local delivery of SK based on fibrin-specific liposomes, which is a complex drug of streptokinase (SKf), containing “free” SK and SK “associated” with liposomes conjugated with monoclonal antibodies FnI-3C (IgG2 class) to fibrin in a ratio of 40%/60% respectively.

The purpose of this study was to evaluate the efficacy and the safety of the action of the SKf in different methods of its administration in arterial thrombosis in vivo.

Methods

Experiments were performed with 60 outbred male dogs weighing 15–18 kg on a 2-hour model thrombus of the femoral arteries. Experimental group (n=30) received SKf, control group (n=30) - native SK. The drugs were administered intravenously (IV) and intraarterially (IA) in the dose of SK 75000 ME. The observation time was 180 minutes. The pharmacokinetic parameters of the SKf and native SK were studied. Ultrasound, morphological and morphometrical methods of the arteries investigations were used. P<0.05 was taken as statistically significant.

Results

The SKf had better pharmacokinetic parameters than native SK. The duration of the half-life of SKf was significantly longer than that of native SK 24,1 [21,76; 27,53] min vs. 1,83 [1,64; 1,93] min, (p<0.001). The elimination constant of SKf was lower than that of native SK 0,0291 [0,0175; 0,0407] 1/min vs. 0,3867 [0,1679; 0,5135] 1/min, (p<0.001). Differences between pharmacokinetic parameters of SKf and the native SK, and the presence of fibrin-specificity of SKf contributed to increase of its thrombolytic effect. According to the data of the morphological analysis, the lysis of the central part of the thrombus was noted during the action of native SK. At the same time, the release of SKf initially caused the lysis of the central part of the thrombus with the further dissolution of the thrombus at the periphery. The morphometric evaluation of the artery samples showed that SKf leads to a significant increase in the degree of free vascular lumen compared to the native SK in different methods of its administration: IV - 65,25 [62,67; 68,53]% vs. 52,82 [50,60; 55,71]% respectively, p<0.001; IA - (74,27 [70,39; 77,39]% vs. 68,56 [67,36; 70,87]% respectively, p<0.001. The hemorrhagic complications were not revealed for different methods of SKf administration during the observation period.

Conclusions

The use of SKf with different methods of administration leads to highly efficient and safe fibrinolyc action in arterial thrombosis in vivo.
P746Protective role of the longevity associated variant of BPIFB4 in chronic ischemia
Authors: Veneziano C , Cervellin C , Caragnano A , Bulfoni M , Villa F , Sponga S , Livi U , Finato N , Cesselli D , Madeddu P , Puca A A , Beltrami A P
Published: October 2019

Background

A rare Longevity Associated Variant (LAV) of the gene BPIFB4, whose protein product can be secreted, is recessively associated with extreme longevity, positively impacting the cardiovascular system and promoting therapeutic angiogenesis in an hindlimb ischemia model.

Aim

Aim of this work is to verify if LAV-BPIFB4 may temper the phenotype of chronic ischemia in humans, thus suggesting its therapeutic potential.

Methods and results

39 hearts explanted from patients affected by end-stage ischemic heart disease were studied. Of these, 7 were homozygous for BPIFB4-LAV. Homozygous and non-homozygous patients did not differ in sex, age and in the prevalence of comorbidities or risk factors. However, the time elapsed from myocardial infarction to transplantation was significantly longer for LAV homozygous with respect to LAV heterozygous patients (159±95 vs 58±27 months, p=0.045). Histologically, while BPIFB4 levels did not differ in accordance with the genotype, the fraction of Tunel+and 53BP1+apoptotic and senescent myocytes was significantly lower in homozygous patients (1.2±0.4% vs 23.8±21.7%, p=0.026 and 31.5±6.7% vs 44.4±6.1%, p=0.031, respectively). Significantly lower levels of lipoperoxides and higher levels of Parkin were observed in homozygous hearts too. Next, we directly tested the role of BPIFB4 on PDGFRb+ NG2+Tbx18+cardiac pericytes/mural cells (PM) cultured from normal atria (PMnorm, n=10) and from ischemic failing hearts (PMfail, n=7). BPIFB4 gene transcript was significantly more expressed in PMnorm than PMfail. Silencing BPIFB4 expression in PMnorm significantly increased the proportion of senescent gH2AX+Ki67-cells (3.6±2.9% vs 13.6±9.5%, p=0.049). Conversely, addition of recombinant LAV BPIFB4 protein to PMfail cultures significantly reduced the rate of senescent cells (21.1±9.4% vs 6.0±4.8%, p=0.03), an effect that was not observed with the administration of WT BPIFB4. PMfail cultures exposed to LAV BPIFB4 significantly reversed alterations observed with pathology, such as the accumulation of both lipofuscins and of very elongated and interconnected mitochondria in the cell cytoplasm, as well as elevated mitochondrial superoxide anion levels. Finally, a larger fraction of PMnorm cells showed, with respect to PMfail, the nuclear translocation of vitamin D receptor (74.6±6.1% vs 50.1±14.4, p=0.04), coupled with a significant upregulation of its, longevity associated, target gene Klotho. Importantly, LAV BPIFB4 significantly increased the fraction of PMfail with vitamin D receptor nuclear localization (55.8±17.6% vs 85.1±8.2%, p=0.005).

Conclusion

LAV BPIFB4 could attenuate the progression of ischemic heart disease to heart failure. Part of its protective effect may be due to its ability to reduce mitochondrial oxidative stress and to revert the senescent phenotype of cardiac derived cells.

Acknowledgement/Funding

CARIPLO foundation
P767Survey of palliative sedation at the end-of-life in terminally ill heart failure patients - a five year experience in national cardiovascular center
Authors: Nakai E , Hamatani Y , Miyata M , Nakamura E , Kawano Y , Takada Y , Anchi Y , Funabashi S , Hirayama A , Kuroda K , Amano M , Sugano Y , Anzai T , Izumi C
Published: October 2019

Background

Palliative sedation is a therapeutic option when symptom relief is difficult to achieve at the end-of-life. However, little is known regarding palliative sedation in terminally ill heart failure (HF) patients.

Purpose

To survey the practice of palliative sedation in terminally ill HF patients at a tertiary referral cardiovascular center, and to investigate the efficacy and safety of sedative agents in HF patients.

Methods

We retrospectively reviewed consecutive patients who were referred to palliative care team at our institution between September 2013 and August 2018. Patients who were hospitalized for HF and died during hospitalization despite optimal medical therapy were selected and defined as terminally ill HF. We investigated the practice of palliative sedation in terminally ill HF patients and analysed the vital signs and sedation scale before starting sedative agents and about 1 hour afterward.

Results

Among 95 terminally ill HF patients, 37 were prescribed palliative sedation at the end-of-life (Picture). Of 37 patients (mean age: 70 years, median B-type natriuretic peptide: 1018 pg/ml, median creatinine: 3.0 mg/dl, intravenous inotrope: 81%), 25 were prescribed dexmedetomidine, and 12 were prescribed midazolam as first agent for sedation. Patient's backgrounds were comparable between the two groups. Richmond Agitation-Sedation Scale was significantly reduced (P<0.01), whereas blood pressure and heart rate were not altered after treatments in both groups. In midazolam group, significant decreases were noted regarding respiratory rate (P=0.01) and oxygen saturation (P=0.02); however, these parameters were not changed in dexmedetomidine group (Table).

Table 1. Vital signs and sedation scale Dexmedetomidine group (n=25) Midazolam group (n=12) Baseline After P value Baseline After P value Richmond Agitation-Sedation Scale 1 (0, 1) −1 (−2, 0) <0.01 1 (0, 1) −2 (−3, −1) <0.01 Vital signs   Systolic blood pressure (mmHg) 90±15 89±16 0.51 89±21 84±23 0.33   Diastolic blood pressure (mmHg) 52±13 54±11 0.34 60±14 56±23 0.48   Heart rate (beats per minute) 95±20 91±22 0.17 90±21 90±19 0.70   Respiratory rate (breaths per minute) 22±5 20±5 0.24 21±5 17±2 0.01   Oxygen saturation (%) 97±3 96±6 0.59 96±5 94±5 0.02

Picture. Study flowchart

Conclusions

Dexmedetomidine and midazolam were commonly used in real-word practice for HF patients at the end-of-life. Although impact on respiratory system differed by treatments, both agents could be prescribed effectively and safely in terminally ill HF patients.