bluuebunny/crossref_metadata_2025 huggingface dataset:
P5509Apabetalone (RVX-208) inhibits key drivers of vascular inflammation, calcification, and plaque vulnerability through a BET-dependent epigenetic mechanism
Authors: Kulikowski E , Tsujikawa L M , Gilham D , Rakai B , Halliday C , Stotz S C , Sarsons C , Fu L , Daze E , Wasiak S , Studer D , Rinker K D , Sweeney M , Johansson J O , Wong N C W
Published: October 2019

Apabetalone (RVX-208) is an orally available small molecule bromodomain & extraterminal (BET) protein inhibitor that targets the second bromodomain (BD2) of BET proteins. Apabetalone returns dysregulated BET-dependent transcription toward normal physiological levels. In phase 2 trials, apabetalone treatment reduced the incidence of major adverse cardiac events by 44% in CVD patients and by 57% in diabetic CVD patients. Previous studies have highlighted apabetalone's positive impact on vascular calcification (VC) and inflammation (VI) marker expression in vitro, as well as its ability to lower serum alkaline phosphatase (ALP) levels, and improve atherosclerotic plaque stability parameters in treated patients. In CVD, elevated inflammatory mediators and cell surface adhesion molecules drive VI, resulting in leukocyte adhesion, infiltration, uptake of oxLDL, and ultimately plaque formation. Here we show in vitro that THP-1 monocyte adhesion to human aortic endothelial cells (HAECs) increases with TNFα stimulation and is attenuated by apabetalone treatment, with fewer monocytes attaching to HAECs under flow conditions. This functional outcome is attributed to apabetalone's reduction of key endothelial adhesion genes, VCAM-1 (50%, p=0.0001) and SELE (37%, p=9x10–5). Apabetalone also prevents TNFα induction of endothelial recruitment genes (MCP-1; 75%, p=0.0002) and genes involved in plaque rupture (IL8; 24%, p=2x10–5). Basal HAEC ALP expression, a potential contributor to endothelial dysfunction and VC, also decreases with apabetalone treatment (70%, p=0.005). Induction of VI genes by TNFα is BET-dependent as degradation of BET proteins by MZ-1 prevents an increase in transcripts in response to TNFα treatment. Ingenuity® Pathway Analysis (IPA®), GSEA, and GO analysis of HAEC gene expression data predicts apabetalone inhibition of pro-atherogenic pathways, gene sets, and upstream regulators induced by TNFα. These include cytokine and chemokine, Toll-Like Receptor (TLR), NFkβ, Interferon and TNFα signaling. In addition, IPA® disease and biological function analysis predicts inhibition of immune cell activation and recruitment by apabetalone. Plasma proteomics (SOMAscan®) and IPA® analysis from apabetalone-treated CVD patients in ASSERT and ASSURE phase 2 trials indicate that apabetalone inhibits pro-atherogenic upstream regulators (IL-6 and IFNy), canonical pathways, and diseases and functions. Serum ALP also decreases dose dependently with apabetalone treatment (ASSERT). Epigenetic inhibition of VI and VC driven atherogenesis likely contributes to the reduction in MACE observed in phase 2 apabetalone treated patients. The ongoing phase 3 post-acute coronary syndrome (ACS) clinical trial in T2DM patients, BETonMACE, is currently testing this hypothesis.
P5526Vascular endothelial growth factor-D and mortality in suspected or known coronary heart disease patients with chronic kidney disease: a subanalysis of the ANOX study
Authors: Wada H , Suzuki M , Matsuda M , Ajiro Y , Shinozaki T , Sakagami S , Yonezawa K , Shimizu M , Funada J , Takenaka T , Morita Y , Wada M , Abe M , Akao M , Hasegawa K
Published: October 2019

Background

Chronic kidney disease (CKD) is an independent risk factor for the development and progression of coronary heart disease (CHD). Vascular endothelial growth factor-D (VEGF-D) is a secreted glycoprotein that can act as lymphangiogenic and angiogenic growth factors through binding to its specific receptors, VEGFR-3 (Flt-4) and VEGFR-2 (KDR/Flk-1). VEGF-D signaling via VEGFR-3 plays an important role in lipoprotein metabolisms which may contribute to CHD. VEGF-D signaling has been used as a therapeutic target of human diseases such as lymphangioleiomyomatosis and refractory angina. Furthermore, in clinical settings, the VEGF-D level is already established as a diagnostic biomarker for lymphangioleiomyomatosis. However, the prognostic value of VEGF-D in suspected or known CHD patients with CKD is unknown.

Methods

Serum VEGF-D levels were measured in 999 suspected or known CHD patients with CKD undergoing elective coronary angiography, enrolled in the development of novel biomarkers related to angiogenesis or oxidative stress to predict cardiovascular events (ANOX) study, and followed up for 3 years. The primary outcome was all-cause death. The secondary outcomes were cardiovascular death, and major adverse cardiovascular events (MACE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.

Results

During the follow-up, 154 patients died from any cause, 61 died from cardiovascular disease, and 96 developed MACE. After adjustment for established risk factors, VEGF-D levels were significantly associated with all-cause death (hazard ratio [HR] for 1-SD increase, 1.41; 95% confidence interval [CI], 1.27–1.56), cardiovascular death (HR, 1.48; 95% CI, 1.28–1.71), and MACE (HR, 1.34; 95% CI, 1.18–1.53). Even after incorporation of N-terminal pro-brain natriuretic peptide, contemporary sensitive cardiac troponin-I, and high-sensitivity C-reactive protein into a model with established risk factors, the addition of VEGF-D levels further improved the prediction of all-cause death (continuous net reclassification improvement [NRI], 0.272; 95% CI, 0.100–0.445; P=0.002; integrated discrimination improvement [IDI], 0.015; 95% CI, 0.003–0.027; P=0.013), but not that of cardiovascular death (NRI, 0.230; 95% CI, −0.029 to 0.488; P=0.082; IDI, 0.012; 95% CI, −0.007 to 0.031; P=0.207) or MACE (NRI, 0.102; 95% CI, −0.106 to 0.310; P=0.337; IDI, 0.005; 95% CI, −0.005 to 0.015; P=0.337).

Conclusions

In suspected or known CHD patients with CKD undergoing elective coronary angiography, elevated VEGF-D levels may predict all-cause mortality independent of established risk factors and cardiovascular biomarkers.

Acknowledgement/Funding

The ANOX study is supported by a Grant-in-Aid for Clinical Research from the National Hospital Organization
P5559Biopsy-proven myocarditis: clinical and diagnostic correlates of late gadolinium enhancement
Authors: Baritussio A , Cheng C , Gianstefani S , Seguso M , Gallo N , Leoni L , Perazzolo Marra M , Tarantini G , Marcolongo R , Plebani M , Rizzo S , Basso C , Iliceto S , Caforio A
Published: October 2019

Background

Cardiovascular magnetic resonance (CMR) is an accurate diagnostic tool providing detailed myocardial tissue characterization. Correlates of late gadolinium enhancement (LGE) with clinical and diagnostic features are poorly defined in endomyocardial biopsy (EMB)-proven myocarditis.

Purpose

We sought to identify clinical, laboratory and imaging correlates of LGE in patients with EMB-proven myocarditis.

Methods

We analyzed our prospective cohort of patients with EMB-proven myocarditis (n=366) to identify patients who underwent CMR (n=154, aged 39±13, 108 males). Presence of LGE was qualitatively assessed. CMR and EMB were performed in all cases at the time of hospitalization. Clinical, laboratory, and imaging features at diagnosis were analyzed to identify correlates of LGE presence.

Results

Demographic characteristics (age, gender), cardiovascular risk factors (hypertension, diabetes) and cardiovascular therapy did not differ between patients with and without LGE. Patients with history of myocarditis tended to have a higher prevalence of LGE (25 vs 4 patients, p=0.07). There was a trend towards a higher prevalence of LGE in patients presenting with heart failure or acute coronary syndrome (p=0.07) as opposed to those presenting with arrhythmias. Patients with LGE were more symptomatic in the 6 months preceding diagnosis (palpitations, p=0.03, chest pain p=0.02). Clinical left and right ventricular systolic dysfunction at presentation were more common in patients with LGE (p=0.02, p=0.02 respectively). LGE presence failed to distinguish patients according to EMB findings (active vs. borderline myocarditis) (p=0.66) or to the histological type of myocarditis. Troponin I levels were higher in patients with LGE (p=0.03). There was no difference in bi-ventricular volumes and function, as assessed both by echocardiography and heart catheterization. There was no correlation between anti-heart antibodies and LGE presence, nor were patients with LGE more likely to receive immunosuppressive therapy; however, response to immunosuppression tended to be more common in patients without LGE (13/13 vs 29/38 patients, p=0.09). The rate of heart transplant, death and myocarditis relapse did not differ between patients with and without LGE.

Conclusions

Presence of LGE on CMR was associated with longer symptom duration before diagnosis, presentation with heart failure and higher troponin release, but failed to correlate with specific EMB features or myocarditis aetiopathogenetic markers.

Acknowledgement/Funding

None
P5568Disease stages of structural and functional cardiac changes associate with outcomes in patients with mitral regurgitation receiving mitral valve intervention
Authors: Niikura H , Sorajja P , Goessl M , Bae R , Garcia S , Sun B , Askew J , Harris K , Fukui M , Stanberry L , Cavalcante J L
Published: October 2019

Background/Introduction

Severe mitral regurgitation (MR) produces volume overload resulting in progressive cardiac dysfunction that can extend beyond the left-sided chambers. It is unknown whether a specific MR staging system, that would quantify the extent of structural and functional cardiac changes, would be associated with outcomes in severe MR patients receiving mitral valve (MV) intervention.

Purpose

To examine the clinical utility of a novel MR staging system, based on the extent of cardiac damage, for prediction of clinical outcomes for patients with severe MR who underwent surgical or transcatheter therapy.

Methods

Patients were categorized into five stages using pre-procedural echocardiography; Stage 0: no other cardiac damage detected; Stage 1: Left atrium (LA) abnormality, as defined by the presence of atrial fibrillation or LA chamber enlargement; Stage 2: LV dysfunction, as defined by LV ejection fraction <60%; Stage 3: Pulmonary artery vasculature or tricuspid valve abnormality, as defined by the presence of systolic pulmonary arterial pressure ≥60 mmHg) or ≥grade 2 tricuspid regurgitation; and Stage 4: Right ventricular (RV) disease as defined by the presence of >mild RV dysfunction. The primary outcomes were all-cause mortality, and the combined endpoint of death or heart failure rehospitalization at one-year follow-up.

Results

A total of 696 patients with MR (age 70±14 years; 60% men) who underwent MV surgery (69%) or transcatheter MV repair with MitraClip device (31%) were examined. Prevalences of stage 0, 1, 2, 3, and 4 were 6.6%, 34.6%, 20.0%, 26.6%, and 12.2%, respectively. The median follow-up time was 15 months (IQR, 6.4, 24.4 months). At one-year, there was graded increase in all-cause death and in the combined endpoint of death or heart failure rehospitalization with each MR stage (Figure). In multivariate models, these associations remained independently associated with both one-year endpoints for patients receiving either surgical or transcatheter interventions.

Figure 1

Conclusion

This novel MR staging system is practical and may improve clinical risk stratification of patients with severe MR being considered for MV interventions.
P5576Outcomes and clinical impact of mitral regurgitation in patients with aortic stenosis undergoing with transcatheter aortic valve replacement
Authors: Munoz-Garcia E , Munoz-Garcia M , Munoz Garcia A J , Dominguez-Franco A J , Carrasco-Chinchilla F , Alonso-Briales J H , Hernandez-Garcia J M , Gomez-Doblas J J , Jimenez-Navarro M F
Published: October 2019

Background

Many patients undergoing Trancatheter aortic valve replacement (TAVR) for aortic stenosis also have significant mitral regurgitation (MR). We sought to understand the association of concomitant MR with TAVR clinical outcomes, as well changes in MR after TAVR.

Methods

Patients who underwent TAVR at our center, between April 2008 to December 2017, were studied, with longer-term clinical outcomes.

Results

Of 667patients, 92 (13.8%) had moderate MR, and 47 (2.1%) had severe MR. At 3.2±2.2 years, mortality was 39.4%, 46.1%, 39.1%, 57.6% and 50% and heart failure (HF) rehospitalization was 7%, 7.9%, 17.6%, 21.9% and 46.2% (p<0.001) in the no, mild, moderate, moderate-severe and severe MR patients, respectively. After procedure, 64 patients (9.9%) had moderate MR and 24 patients (3.7%) had severe MR. At follow-up, the mortality was 35.9%, 46.5%, 48.4%, 52.9% and 85.7%, p<0.001 and HF rehospitalization 9.1%, 5.5%, 23.4%, 35.3% and 40% in the no, mild, moderate, moderate-severe and severe MR patients, respectively. MR improved early after TAVI grade in 88 patients (13.2%). Baseline MR is not associated with mortality (HR= 0.883 [95 CI 0.708–1.102], p=0.114), but MR post-TAVR was associated with increase risk of mortality (HR= 1.539 [95 CI 1.187–1.996], p=0.001. In 7 patients with persistent MR received percutaneous mitral repair with MitraClip®.

Conclusions

In our series, Moderate or severe MR after TAVR is associated with increased mortality or HF rehospitalization, this increased risk may be attributable to the minority of patients whose MR does not improve and could benefit from percutaneous mitral procedures (Mitraclip®).
P5587Elevated D-dimer level after 1 month anticoagulant therapy as a predictor for adverse outcomes in patients with venous thromboembolism: 10-year follow-up results
Authors: Vorobyeva N M , Dobrovolsky A B , Panchenko E P , Titaeva E V , Karabasheva M B , Yarovoy S Y , Danilov N M , Kirienko A I
Published: October 2019

Background

Our previous study showed that elevated D-dimer (D-D) level after 1 month of the anticoagulant therapy was an independent predictor of deep vein thrombosis (DVT) recurrences and combined endpoint (DVT recurrence and/or death from any causes) during 18 months. Prognostic value of elevated D-D level after 1 month of the anticoagulant therapy for the long-term venous thromboembolism (VTE) outcomes is unknown.

Purpose

To estimate the elevated D-D level influence after 1 month of the anticoagulant therapy on the 10-year prognosis in VTE pts.

Methods

One hundred and twelve pts (77 men) aged 18–76 (mean 54±14) years with DVT and/or pulmonary embolism were included in the study. Pts received unfractionated or low molecular weight heparin for at least 5 days followed by the long-term warfarin therapy (target international normalized ratio 2,0–3,0). D-D level was measured after 1 month from the start of the anticoagulant therapy by a quantitative assay with an estimated cut-off level of 0,5 ug/ml. The follow-up period was 10 years. Endpoints were VTE recurrence and combined endpoint (VTE recurrence and/or death from any causes).

Results

In all pts, median of follow-up was 2,77 years (min 2 weeks, max 11,61 years, IQR 1,44 to 10,31 years). Seventy seven (69%) pts had ended the 10-year follow-up period completely or achieved the endpoint. In these pts, median of follow-up was 9,23 years (IQR 1,70 to 10,53 years). Thirty-five cases were censored. During 10 years, the VTE recurrences rate was 27,7%, 14 pts died, the combined endpoint rate was 36,6%. Kaplan-Meier analysis showed that pts with elevated D-D level after 1 month of the anticoagulant therapy had higher 10-year cumulative risk for adverse outcomes (chi-square=6,0, p=0,014 for VTE recurrence; chi-square=13,7, p<0,001 for combined endpoint). Cox regression confirmed that elevated D-D level after 1 month of the anticoagulant therapy was associated with a 2,5-fold increase in the 10-year VTE recurrences risk (HR 2,52; 95% CI 1,18–5,42; p=0,018) and a 3,2-fold increase in the 10-year combined endpoint risk (HR 3,21; 95% CI 1,68–6,15; p<0,001) compared pts with normal D-D level after 1 month of the anticoagulant therapy.

Conclusions

During 10 years, the VTE recurrences rate was 27,7%, combined endpoint rate (VTE recurrence and/or death from any causes) was 36,6%. Elevated (>0,5 ug/ml) D-D level after 1 month of the anticoagulant therapy had a prognostic value and was associated with the 2,5-fold increase in the 10-year VTE recurrences risk and the 3,2-fold increase in the 10-year adverse outcomes risk.
P5602Comparison of innominate vs axillary artery cannulation for cerebral protection on neurocognitive outcomes in aortic surgery: a pre-specified analysis of the ACE CardioLink-3 randomised trial
Authors: Garg V , Verma S , Peterson M D , Chu M W A , Quan A , Zuo F , Teoh H , Mazer C D , Smith E E
Published: October 2019

Background

Success after aortic surgery depends on avoidance of neurocognitive dysfunction, thus novel adjuncts to proximal aortic surgery must be evaluated for efficacy of cerebral protection during circulatory arrest. We report the primary neurocognitive results from the ACE CardioLink-3 randomised controlled trial comparing innominate to axillary artery cannulation for cerebral protection (NCT02554032).

Methods

The primary safety endpoint was the proportion of patients with new radiologically severe ischaemic cerebral lesions found on post-operative versus pre-operative diffusion weighted magnetic resonance imaging (DW-MRI). Neurocognitive outcomes were assessed using the Mini-Mental State Exam (MMSE), and the Montreal Cognitive Assessment (MoCA). Continuous and binary outcomes were analysed using ANCOVA (controlling for baseline score) and chi-square/Fisher's exact tests.

Results

Of the 111 patients randomised, 102 patients were included in the primary safety per-protocol analysis. The primary safety outcome (significant new ischaemic lesions on DW-MRI) occurred in 34% in the innominate group and 38.8% in the axillary group (OR 0.81; 0.41 to 1.60; P=0.0009 for non-inferiority). Rates of post-operative stroke/transient ischaemic attack, seizure, delirium, and encephalopathy were similar between groups. The rate of patients with a post-operative MoCA score less than 26 was 44.9% and 39.1% in the innominate and axillary groups respectively (P=0.807). A post-operative MMSE score of less than 24 was observed in 2% vs. 6.5% of the patients in the innominate and axillary groups respectively (P=0.866). A >1-point decrease in the MoCA score from pre-operatively to post-operatively was seen in 32.7% and 34.8% in the innominate and axillary groups respectively (P=0.962). A >1-point decrease in the MMSE score from pre-to post-operative was observed in 20.4% in the innominate artery group compared with 30.4% in the axillary group (P=0.346).

Conclusion

Post-operative neurocognitive dysfunction and DW-MRI incidence of severe ischaemic lesions did not differ in patients randomised to innominate artery cannulation vs, conventional axillary artery cannulation, though the burden of new severe ischaemic lesions is high in both groups.
P5604Combining aortic size with measures of aortic stiffness and pulsatile hemodynamics enhances prediction of future thoracic aortic aneurysm expansion
Authors: Zhu T , Boodhwani M , Beauchesne L , Chan K , Dennie C , Wells G , Coutinho T
Published: October 2019

Introduction

Thoracic aortic aneurysm (TAA) is a clinically silent disease which can lead to significant morbidity when complicated by an acute aortic syndrome. Although TAA size is the only variable used in decision-making, it is an imperfect predictor of risk. Conversely, hemodynamic measures that reflect the aorta's function, such as aortic stiffness and pulsatile hemodynamics, may provide additional insights into risk of TAA expansion.

Purpose

We hypothesized that combining aortic size with measures of arterial function (stiffness and pulsatile hemodynamics) would improve prediction of TAA expansion, as compared to aortic size alone.

Methods

105 unoperated participants with TAA were recruited between 2014 and 2017 and followed prospectively for ≥1 yr. TAA size was measured at enrolment and at the latest imaging study according to published consensus; TAA expansion was calculated as mm/year. Arterial function was non-invasively assessed at baseline with validated methods that integrate arterial tonometry with echocardiography. Multivariable linear regression assessed independent associations of baseline TAA size and each arterial function measure, initially separately and then in combination (by multiplying them when direction of association was the same, and dividing them when direction of association was opposite), with future TAA expansion. Standardized beta coefficients were calculated to allow direct comparisons. Models were adjusted for age, sex, body size, aneurysm location and etiology, type of imaging modality, follow-up time, mean arterial pressure, and history of hypertension, diabetes and smoking.

Results

Seventy-seven percent of participants were men, and the ratio of degenerative to heritable TAAs was 62/43. Mean ± SD age, baseline TAA size, and follow-up time were 62.8±11.3yrs, 46.3±3.9cm, and 2.2±0.7 years, respectively. Results of the multivariable linear regression models are summarized in the Table. While baseline TAA size and each arterial function measure were independently associated with TAA expansion, some of the arterial function measures were superior in predicting TAA growth (Table, left). In addition, combining aortic size and function further improved the prediction of TAA growth beyond each variable alone (Table, right).

Conclusion(s)

Combining aortic size with arterial function improved prediction of TAA expansion over any individual variable alone, independently of confounders. Assessing arterial function may confer a clinical advantage, when compared to current practice, in determining TAA disease activity and estimating one's TAA-related risk.

Acknowledgement/Funding

Canadian Institute of Health Research, Canadian Vascular Network, and Heart and Stroke Foundation of Canada
P5624Late acquired tissue protrusion after drug-eluting stent implantation: a serial follow-up of 1-month optical coherence tomography imaging
Authors: Otagaki M , Fujii K F , Matsumura K M , Noda T N , Shibutani H S , Park H P , Yamamoto Y Y , Shiojima I S
Published: October 2019

Background

Tissue protrusion (TP) between the stent struts after stent implantation has been implicated as a potential factor in the subsequent development of stent thrombosis. However, the incidence, natural history, and predictive factor of TP after stent implantation remains unclear.

Purpose

To elucidate the fate of TP, we undertook the study assessing TP using short term serial optical coherence tomography (OCT), immediately after deployment of stents and at 1-month follow-up.

Methods

This was a prospective, single-center study evaluating vascular healing responses with OCT both immediately after and at 1-month after biodegradable-polymer sirolimus-eluting stent (SES) implantation. A total of 18 stable angina patients having OCT-guided PCI with SESs underwent assessment of TP with OCT pre-procedure, post-procedure, and at 1-month follow-up. TP was defined as a tissue prolapse for more than 200 μm between stent struts that directly correlates with the underlying plaque, without abrupt transition and different optical properties. TP was classified into the following 3 groups on the basis of serial assessment: (1) healed, TP present after the procedure but covered by tissue with smooth surface at 1-month follow-up; (2) persistent, TP present both after the procedure and 1-month follow-up; and (3) late-acquired, TP not present at baseline but present at 1-month follow-up.

Results

Immediately after the procedure, 29 TPs in 13 patients (72%) were identified. Of those, 16 (55%) were healed and 13 (45%) were persistent at 1-month follow-up. Although the size of TP on post-procedural OCT was similar, neointimal area in lesions with healed TP was significantly larger than in lesions with persistent TP due to neointimal proliferation at 1-month follow-up. A synchronous comparison between the post-procedural OCT and the follow-up OCT image showed that 5 TPs were observed only at 1-month follow-up (late-acquired). In lesions with late-acquired TP, calcified nodule or thin-cap fibroatheroma was identified as an underlying plaque morphology on pre-procedural OCT. A representative example is presented in Figure.

Incidence of TP and representative case

Conclusion

Short term serial OCT analysis found that TP can occur not only immediately after SES implantation, but also 1 month after SES implantation. This new concept may provide a new insight into the mechanism of in-stent restenosis and stent thrombosis development after stent implantation.

Acknowledgement/Funding

None
P5660Clinical impact of polycythemia on cardiovascular outcome from the general population: a nationwide cohort study
Authors: Kim I.-S , Lee B K , Yang P S , Yu H T , Kim T H , Uhm J S , Pak H N , Lee M H , Kim J Y , Joung B
Published: October 2019

Background

Although adverse effect of anemia had been reported, effect of polycythemia on cardiovascular outcome from the general population had not been revealed yet.

Methods

We included 451,107 subjects who received national health examinations from the Korean National Health Insurance Service-based National Sample Cohort from 2009–2013. Medical records were screened from January 2002 to investigate the subjects' disease-free baseline period. They were followed until December 2013. We divided male and female subjects into four categories each based on hemoglobin level (normal, moderate to severe and mild anemia, polycythemia) to assess each outcome.

Results

During 1,735,964 person·years, 12,107 major adverse cardiovascular and cerebrovascular events (MACCE), 862 incident acute myocardial infarction (MI), 5,850 incident ischemic stroke, and 2,430 incident atrial fibrillation (AF) were observed. Compared to normal hemoglobin range group, polycythemia group showed higher MACCE (HR=1.23 [1.12–1.35] in male, HR=1.79 [1.20–2.67] in female, each p<0.001), incident MI (HR=1.37 [1.05–1.79] in male, HR=3.46 [1.06–14.00] in female, each p<0.001), incident ischemic stroke (HR=1.27 [1.10–1.46] in male, HR=1.72 [1.02–2.91] in female, each p<0.001), and incident AF (HR=1.46 [1.21–1.74] in male, HR=2.13 [1.03–4.77] in female, each p<0.001). Each outcome was linearly increased with the increase of hemoglobin among subjects with polycythemia (p<0.001), and with the decrease of hemoglobin among subjects with anemia (each p<0.001, U-shaped relationship). These relationship was more profound in obese female younger than 60-year-old.

Conclusion

Not only anemia but also polycythemia were significantly associated with higher rate of MACCE including death, incident MI, ischemic stroke, and AF among the general population.
P5663Impact of proteinuria on cardiovascular outcomes in Japanese diabetic patients with atrial fibrillation: the Fushimi AF Registry
Authors: Ikeda S , Iguchi M , Ogawa H , Ishigami K , Aono Y , Doi K , An Y , Ishii M , Masunaga N , Esato M , Wada H , Hasegawa K , Abe M , Akao M
Published: October 2019

Background

Previous studies have suggested that proteinuria is independently associated with clinical outcomes in diabetic patients, irrespective of the presence of renal dysfunction. However, data regarding the impact of proteinuria on clinical outcomes in diabetic patients with atrial fibrillation (AF) are limited.

Methods

The Fushimi AF Registry is a community-based prospective survey of AF patients in our city in Japan. Follow-up data were available in 4,454 patients, and 634 diabetic patients with available data of proteinuria and estimated glomerular filtration rate (eGFR) were examined. We compared the clinical background and outcomes between patients with proteinuria (n=251) and those without (n=383). Then, we divided the patients into 4 subgroups according to the presence of proteinuria and renal dysfunction, and compared the clinical outcomes between groups; group 1 (without proteinuria, eGFR ≥60 ml/min/1.73 m2; n=203), group 2 (with proteinuria, eGFR ≥60; n=96), group 3 (without proteinuria, eGFR <60; n=180), group 4 (with proteinuria, eGFR <60; n=155).

Results

Age was comparable between patients with or without proteinuria. Patients with proteinuria had higher prevalences of previous heart failure (HF), stroke/systemic embolism, hypertension and renal dysfunction. The prevalences of previous myocardial infarction, and major bleeding were similar between two groups. During the median follow-up of 1,505 days, the incidence rates of HF hospitalization (4.1/100 person-years vs. 2.5/100 person-years; p<0.01) and cardiovascular death (1.8/100 person-years vs. 0.4/100 person-years; p<0.01) were higher in patients with proteinuria. When we divided patients into 4 subgroups, the incidences of HF hospitalization (group 1: 1.8/100 person-years vs. group 2: 3.4/100 person-years vs. group 3: 3.8/100 person-years vs. group 4: 4.9/100 person-years; p<0.01) and cardiovascular death (group 1: 0.3/100 person-years vs. group 2: 1.8/100 person-years vs. group 3: 0.5/100 person-years vs. group 4: 2.2/100 person-years; p<0.01) tended to be higher in not only group 3 and group 4 but also group 2 than group 1 (Figure). Multivariate Cox proportional hazards regression analysis including female gender, age (≥75 years), hypertension, pre-existing HF, renal dysfunction (eGFR <60),low left ventricular ejection fraction (<40%) and proteinuria revealed that proteinuria was an independent determinant of both of HF hospitalization (adjusted hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 1.05–2.34) and cardiovascular death (HR: 3.76, 95% CI: 1.59–8.88).

Figure 1

Conclusion

In Japanese diabetic patients with AF, proteinuria was associated with higher incidences of HF hospitalization and cardiovascular death, irrespective of the presence of renal dysfunction.
P5665The independent effect of insulin resistance on incidence of atrial fibrillation in non-diabetics
Authors: Park J K , Park J H , Lee Y G , Shin J H , Lim Y H , Heo R , Shin J
Published: October 2019

Purpose

Patients with diabetes mellitus have an elevated risk of atrial fibrillation (AF). However, whether insulin resistance may elevate risk of AF incidence in non-diabetic is inconsistent. The aim of our study was to verify the association between insulin resistance and incidence of AF in non-diabetics.

Methods

We evaluated population-based cohorts embedded in the Korean Genome Epidemiology Study. Insulin resistance was expressed as Homeostasis Model Assessment for Insulin resistance (HOMA-IR). Baseline data including HOMA-IR and electrocardiography (ECG) were obtained at 2001. Subsequent biennial ECG was performed for identification of AF until 2016.

Results

Among the 8220 participants (46.8% male; median age 49 years), 25 participants had AF (0.3%) at baseline and 101 participants developed AF (1.2%) during follow up of 12 years. In multivariate Cox regression analysis, high HOMA-IR (≥1.4) was significantly associated with incident AF compared with low HOMA-IR (<1.40) (adjusted hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.3–3.0). In subgroup analysis, these association was consistent regardless of obesity (BMI<25; adjust HR 1.8, 95% CI 1.1–3.0, BMI≥25; adjust HR 2.3, 95% CI 1.3–4.0)

Subgroup analysis

Conclusion

Based on prospective cohort study, insulin resistance (HOMA-IR) was associated with AF independently of obesity in non-diabetics.
P5673Combination of high-sensitivity cardiac troponin and B-Type natriuretic peptide (BNP) for diagnosis and risk-stratification of syncope
Authors: Zimmermann T , Du Fay De Lavallaz J , Badertscher P , Puelacher C , Nestelberger T , Boeddinghaus J , Walter J E , Wussler D , Twerenbold R , Kuehne M , Reichlin T , Mueller C
Published: October 2019

Background

While high-sensitivity cardiac troponin (hs-cTn) and B-Type natriuretic peptide (BNP) have been assessed separately for the diagnosis and risk-stratification of patients with syncope, their combined accuracy is unknown.

Methods

We assessed the diagnostic and prognostic accuracy of the combination of hs-cTnI and BNP in a prospective international multicenter study enrolling patients 40 years and older presenting with syncope to the emergency department (ED). Hs-cTnI (Architect) and BNP (Architect) concentrations were measured in a blinded fashion. Cardiac syncope, as adjudicated by two independent physicians using all available clinical information including one year follow-up, was the diagnostic endpoint. MACE were defined as death, resuscitation, life-threatening arrhythmia, implantation of a pacemaker or implantable cardioverter defibrillator (ICD), acute myocardial infarction, pulmonary embolism, stroke/transient ischemic attack (TIA), intracranial bleeding or valvular intervention. Patients were classified in three risk groups (low (<10%), medium (10–30%), high (>30%)) for cardiac syncope based on hs-cTnI and BNP levels.

Results

Among 1533 patients, cardiac syncope was the adjudicated final diagnosis in 233 (15.2%). Hs-cTnI and BNP concentrations both remained independent predictors of cardiac syncope in multivariable models. The diagnostic accuracy of the combination hs-cTnI/BNP for cardiac syncope was good with an area under the curve (AUC) of 0.81 (95%-CI 0.78–0.84) and significantly better than each biomarker separately or a set of clinical variables (each p<0.001). The classification of patients in three risk groups, depending on the probability for cardiac syncope based on their hs-cTnI and BNP values, translated well in predictions for MACE (AUC 0.79, 95%-CI 0.77–0.82) and death (AUC 0.78, 95%-CI 0.74–0.82) at 2 years follow-up. Based on these results, we designed a visual tool allowing convenient patient-specific diagnostic and prognostic risk evaluation based solely on hs-cTnI and BNP concentrations (Figure).

Risk stratification based on hs-cTnI/BNP

Conclusion

The combination hs-cTnI/BNP may have clinical utility in patients presenting to the ED with syncope as it allows good diagnostic as well as prognostic discrimination.

Acknowledgement/Funding

Swiss National Science Foundation, Swiss Heart Foundation, Cardiovascular Research Foundation Basel, University Basel
P5688Is renal dysfunction associated with the outcome of CRT patients?
Authors: Bertaglia E , Reggiani A , Palmisano P , D'Onofrio A , De Simone A , Caico S , Pecora D , Arena G , Ricciardi G , Marini M , Rapacciuolo A , Parisi Q , Maglia G , Malacrida M , Stabile G
Published: October 2019

Background

The benefit of cardiac resynchronization therapy (CRT) in patients (pts) with chronic kidney disease (CKD) remains controversial despite frequent use. Pts with impaired renal function have systematically been excluded from randomized clinical trials and therefore specific recommendations for the use of CRT in these pts are still lacking.

Purpose

Study objectives were to assess long-term outcomes and clinical/echocardiographic response in a large population of patients with moderate-to-severe impaired renal function implanted with a CRT device in accordance with the current standard of care.

Methods

We prospectively analyzed clinical, instrumental data and survival of pts with CKD who received a CRT device in the CRT-MORE registry from 2011 to 2014. Adverse events for the analysis of clinical outcome comprised death from any cause and nonfatal HF events requiring hospitalization after CRT implantation. LV reverse remodeling and Clinical Response (CR) were also evaluated at 12-month follow-up. Patients were stratified according to current definition of CKD stage: low-moderate CKD with a GFR = 45–59 mL/min (stage 3A); moderate CKD with a GFR = 30–44 mL/min (stage 3B) and severe CKD with a GFR = 15–29 mL/min (stage 4).

Results

Of the 922 consecutive patients enrolled in the registry, 416 (45%) pts had a moderate-to-severe impaired renal function (43% Stage 3A, 43% Stage 3B and 14% Stage 4). The mean follow-up was 935±506 days. By the end of the study, 85 pts had died and 47 pts had been hospitalized for HF. The combined end-point of death or HF hospitalization was reached by 121 (29%) pts. After 12 months the absolute LVEF improvement was greater than 10% in 37% of pts and 58% of pts displayed a positive clinical response. The percentage of pts who died was higher in the group of pts with severe CKD (32.8% vs 18.4%; p=0.012, compared to the group of pts with moderate CKD). On the contrary the percentage of pts who had at least one HF hospitalization was lower in the group with more severe CKD (2% vs 13%; p=0.011). According to CKD stage both LV remodeling (LVEF improvement ranging from 43.7% - 3A - to 30.8% - 4) and CR (positive response ranging from 63.9% - 3A - to 50% - 4) were higher in low-moderate stage and decreased with CKD severity. At multivariate Cox regression analysis adjusted for baseline confounders, CKD class at implantation [HR=1.5; 95% CI: 1.06–2.14; p=0.0219], chronic obstructive pulmonary disease [HR=1.89; 1.18–3.01; p=0.0077], persistent/permanent AF [HR=1.86; 1.15–3.01; p=0.0115] and male gender [HR=1.92; 1.07–3.46; p=0.0301] remained associated with death.

Conclusions

Among CKD patients in the CRT-MORE registry, severity of renal dysfunction at the time of CRT implantation was associated with worse prognosis, lower clinical response and LV reverse remodeling.

Acknowledgement/Funding

None
P5700Comparison of efficacy and safety of ventricular lesions formation by unipolar and bipolar radiofrequency ablation on an animal model
Authors: Soucek F , Caluori C , Lehar F , Jez J , Pesl M , Wolf J , Wojtaszczyk A , Belaskova S , Starek Z
Published: October 2019

Aims

Despite all this technical progress, VT recurrence after unipolar ablation remains relatively high (12–47%). Bipolar ablation has been proposed as an appealing solution, which may overcome boundaries associated with unipolar ablation settings. Therefore, we have proposed an animal study to compare bipolar (BPA) vs sequential unipolar ablation (UPA) using a contact-force sensing technology on both catheters.

Methods

20 large white female pigs (6 months-old, 60–70kg) underwent multiple RF ablations (30W, 60s, 30ml/min irrigation) on ventricular myocardium, from epicardial and endocardial sides. After the procedure, the animal underwent euthanasia, cardioplegia and organ excision. The hearts were fixed and underwent high-resolution cardiac MRI. Each lesion was characterized primarily in terms of volume, depth, width and transmurality.

Results

We evaluated 35 lesions across the intraventricular septum. No difference in volume, linear dimensions and impedance drop was observed in this area, between the two ablation settings. However, for the generation of unipolar lesions, twice the ablation time was needed. Transmurality of the lesions shows a trend in favor of BPA. We then analyzed 73 lesions from the endocardial side and 34 from the epicardial one of the ventricular free walls. Lesion transmurality was found remarkably improved in BPA (p=0.030, OR 23.73 [4.71,11.96]). Ventricular BPA lesions were significantly deeper on the epicardial side (p<0.0001)

Conclusion

BPA is more likely to create transmural lesions in the ventricle, when compared to UPA. Half the time is needed for the creation of comparably deep and large lesions. BPA is specifically more effective in creating epicardial lesions.
P5715Trends in indications and outcome in thrombolytic therapy: a retrospective single center study
Authors: Engelen M M , Vanassche T , Vandenbriele C , Sinnaeve P , Fourneau I , Maleux G , Lemmens R , Van Der Linden L , Verhamme P
Published: October 2019

Background

Thrombolytic therapy is used as a lifesaving treatment for a broad range of acute thrombotic events. The role of thrombolysis for its various indications has rapidly evolved.

Purpose

To provide a contemporary overview of current indications and outcome of thrombolytic therapy in clinical practice.

Methods

This retrospective single-center study analyzed indications, complications and short-term mortality of systemic thrombolytic therapy between 2010 and 2016 in a university hospital, totaling 763 cases. Major bleedings were defined using criteria published by the International Society on Thrombosis and Haemostasis (ISTH).

Results

Thrombolytic drugs were mostly used for ischemic strokes (66.6%) and peripheral arterial disease (16.9%). Acute coronary syndrome only represented a minority of cases (in this PCI-center). Overall seven- and thirty-day-mortality were 7.3% and 12.0%, respectively. Major bleeding occurred in 8.3% of patients and was fatal in 0.9% of all patients. Both major bleeding and mortality differed by the indication for thrombolysis. Thrombolytic therapy for pulmonary embolism and peripheral arterial disease were associated with the highest rates of major bleeding, 28.6% and 23.3% respectively. Short-term mortality was highest in patients receiving thrombolysis for pulmonary embolism. Predictors for major bleeding included use of antiplatelet and anticoagulation drugs prior to thrombolysis. Major bleedings, age and concomitant anticoagulation were associated with lower survival rates.

Indications in absolute numbers – 2010 – – 2011 – – 2012 – – 2013 – – 2014 – – 2015 – – 2016 – Ischemic Stroke 56 63 66 57 96 88 82 Peripheral Arterial Disease 21 23 21 28 14 16 6 Pulmonary Embolism 4 9 10 10 5 8 8 Deep Vein Thrombosis 2 1 2 0 2 3 3 Acute Coronary Syndrome 0 1 0 1 0 0 0 Mechanical Heart Valve Thrombosis 1 3 3 1 2 7 1 Other 5 8 3 10 2 5 6 TOTAL 89 108 105 107 121 127 106

Mortality and major bleeding in %

Conclusion

The use of thrombolytic therapy has evolved, with stroke now being the most frequent indication. Mortality and bleeding rates are significant and vary considerably per indication. Major bleedings, age and maintenance anticoagulant therapy were risk factors associated with lower survival rates, but the underlying disease and patient population seem to play a major role in survival as well.
P5716Cardioprotective anti inflammatory effects of empaglifozin in doxorubicin induced cardiotoxicity: the role of leukotriene B4 and interleukin 1
Authors: Maurea N , Quagliariello V , Coppola C , Rea D , Barbieri A , Arra C , Botti G
Published: October 2019

Background

Empagliflozin (EMPA), a selective inhibitor of the sodium glucose co-transporter 2 (SGLT2), reduces the risk of hospitalization for heart failure or cardiovascular death in type 2 diabetic patients.

Purpose

We studied the putative cardioprotective and anti-inflammatory effects of EMPA in Doxorubicin (DOXO)-Induced cardiotoxicity.

Methods

For this purpose, we tested the effects of EMPA (at 100 or 500 nM) alone or in combination with DOXO (20 μM) in HL-1 adult cardiomyocytes evaluating: mitochondrial viability, lipid peroxidation (quantifying cellular Malondialdehyde [MDA] and 4-hydroxynonenal [4-HNA]), Leukotriene-B4 expression, p65-NF-κB activation and Interleukin 1β, 8 and 6 secretion. Preclinical studies were also performed in C57BL6 mice, dividing them in 4 groups (n=6): Sham (untreated mice), EMPA (mice treated with EMPA at 10 mg/kg/day, administrated orally for 7 days); DOXO (mice treated with DOXO at 2.25 mg/kg/day, intraperitoneally administered for 7 days); EMPA-DOXO (pre-treatment with EMPA for 3 days and 7 days of co-administration EMPA and DOXO). As predictor of cardiotoxicity, the Global Longitudinal Strain (GLS) was measured using 2D speckle tracking echocardiography. Cardiac lysates were processed for analysis of pro-inflammatory interleukins.

Results

We demonstrated that EMPA, co-incubated with DOXO, increases cardiomyocyte viability of 33,6 and 82% at 100 and 500 nM, respectively (compared to only DOXO treated cells). EMPA inhibits the lipid peroxidation by decreasing MDA and 4-HNA production of around 23,6 and 28,7%, at 100 nM and of 47,8 and 52,1% at 500 nM, respectively, compared to untreated cells (p<0,01 for all). Moreover, EMPA has anti-inflammatory activity reducing the Leukotriene B4 and p65-NFkb expression of 37,4% and 31% at 100 nM and of 58,4 and 64,3% at 500 nM, respectively (all compared to only DOXO treated cells). EMPA also decreased the expression of Interleukin 1β (of 28,5 and 68,8%), Interleukin-8 (of 21,2 and 57,3%) and Interleukin-6 (of 28,1 and 49,8%) at 100 and 500 nM, respectively, compared to only DOXO exposed cells (p<0,05 for all). In our in vivo studies, after 7 days with DOXO, the GLS decreased. Interestingly, in mice treated with EMPA/DOXO, we observed that EMPA prevents the GLS's reduction: GLS was −19.24±1.5 (p<0,01) vs DOXO alone, indicating cardioprotective effects. In DOXO-EMPA groups the cardiac IL-1β, IL-6 and IL-8 were reduced of 48, 54,4 and 58%, compared to only DOXO group (p<0,001 for all).

Conclusion

EMPA has strong anti-inflammatory and cardioprotective effects in DOXO-Induced cardiotoxicity and these effects are mainly mediated by a reduction of the lipid peroxidation, Leukotriene-B4 and NF-κB activation bringing to a strong inhibition of the Interleukin 1β, 8 and 6 production.
P5734The outcome of intra-aortic balloon pumping support for acute myocardial infarction with extracorporeal membrane oxygenation therapy
Authors: Kida H , Hikoso S , Nakatani D , Suna S , Dohi T , Mizuno H , Okada K , Kitamura T , Kojima T , Oeun B , Sunaga A , Sakata Y
Published: October 2019

Background

It has been reported that intra-aortic balloon pumping (IABP) support for acute myocardial infarction (AMI) with cardiogenic shock did not reduce short and long-term mortality. However, the significance of IABP support for AMI patients with extracorporeal membrane oxygenation (ECMO) therapy remains unclear. The aim of this study was to investigate the effect of IABP support for the short and long-term outcome in AMI patients who received ECMO.

Methods

Using the database of the Osaka Acute Coronary Insufficiency Study (OACIS), 12,093 consecutive AMI patients were enrolled in this analysis. Among these, we analyzed 520 patients with ECMO. We classified the patients into two groups, patients who received IABP support [IABP group (n=460)] and patients who did not [no IABP group (n=60)]. Primary outcome was all-cause death.

Results

Study patients had following baseline clinical characteristics, age: 66.8±12.0 year old, male: 78.3%, diabetes mellitus: 41.0%, Killip class≥II: 66.2%, multi-vessel disease: 72.3%, peak creatine phosphokinase >3000IU/L: 68.1%. During a mean follow-up period of 349±625 days, Kaplan-Meier analysis revealed that the all-cause death was significantly lower in IABP group than no IABP group for 30-day (45.5% vs 72.7%, log-rank p<0.001) and long-term (66.2% vs 78.4%, Log rank p=0.005) follow-up period. Cox multivariate analysis revealed that IABP support was significantly associated with a reduced risk of mortality (Hazard ratio 0.445, 95% confidence interval 0.289 to 0.687, p<0.001).

Conclusions

IABP support for AMI patients with ECMO was significantly associated with reduced risks of the short and long-term mortality, suggesting that IABP support might contribute to improvement of the survival in AMI patients with ECMO.