bluuebunny/crossref_metadata_2025 huggingface dataset:
Using the Age and Metallicity of 8 Star Clusters to confirm the Chemical Enrichment History of the LMC
Authors: Balaha Farah , Alhosani Maryam , Asa’d Randa , Chillingarian Igor V.
Published: October 2019

In this paper, we find the ages and metallicities of 8 Large Magellanic Cloud (LMC) star clusters obtained from integrated light spectra and use them to obtain the Chemical Enrichment History of the host galaxy. Our results are in good agreement with those obtained from resolved studies. This confirms that this method can be used for far away galaxies for which their star clusters are not resolved.
RETRACTED: The Nucleosynthesis and Reaction Rates of Fluorine 19 (19F) in the Sun
Authors: Mardini Mohammad K. , Ershiadat Nidal , Al-Wardat Mashhoor A. , Taani Ali A. , Özdemir Sergen , Al-Naimiy Hamid , Khasawneh Awni
Published: October 2019

We investigate the abundance of 19
F in the Sun through the nucleosynthesis scenario. In addition, we calculate the rate equations and reaction rates of the nucleosynthesis of 19
F at different temperature scale. Other important functions of this nucleosynthesis (nuclear partition function and statistical equilibrium conditions) are also obtained. The resulting stability of 19
F occurs at nucleus with A = 19 and Mass Excess = -1.4874 MeV. As a result, this will tend to a series of neutron captures and beta-decay until 19
F is produced. The reaction rate of 15
N (α, γ) 19
F was dominated by the contribution of three low-energy resonances, which enhanced the final 19
F abundance in the envelope.
Theoretical electronic structure with rovibrational and dipole moment calculation of SiN Molecule
Authors: El-Kork Nayla , Mahmoud Salman , Bechelany Mikhael , Miele Philippe , Korek Mahmoud
Published: October 2019

Atomic and molecular data are at the origin of the atmospheres of planetary and stellar objects discoveries. Based on the laboratory astrophysics and the computational molecular spectroscopy, the interpretation of this data can give the chemical compositions and temperatures of these astrophysical systems. The detection and the identification of the SiN radical in the interstellar medium has drawn the attention to the gas phase chemistry and the evidence of a link between the interstellar chemistry of silicon and that of nitrogen. The quantum chemistry methods used to predict the spectroscopic properties of the SiN molecule can be calibrated with some available experimental results. In order to obtain reliable theoretical data that may help in the interpretation of interstellar or laboratory spectra concerning the SiN molecule, we performed theoretical calculation of 31 low-lying electronic state, below 66000 cm−1, of the molecule SiN by using the Complete Active Space Self Consistent Field (CASSCF) method followed by the Multi Reference Configuration Interaction with Davidson correction MRCI+Q. The potential energy along with the dipole moment curves of these states have been calculated along with the spectroscopic constants Re, ωe, Be, and Te. The Rotation-vibration lines for the considered electronic states of SiN molecule were obtained by direct solution of the nuclear motion Schrödinger equation using the canonical approach with program Rovib-1. By comparing our investigated values of the calculated vibrational energy Ev, the rotational constant Bv and the turning points Rmin and Rmax. with those available in literature shows a very good agreement. To the best of our knowledge nine new electronic states have been studied here for the first time that have not been observed yet.
A hybrid model approach for estimating health burden from NO2 in megacities in China: a case study in Guangzhou
Authors: He Baihuiqian , Heal Mathew R , Humstad Kamilla H , Yan Liu , Zhang Qiang , Reis Stefan
Published: October 2019

Background: Nitrogen dioxide (NO2) poses substantial public health risks in large cities globally. Concentrations of NO2 shows high spatial variation, yet intra-urban measurements of NO2 in Chinese cities are sparse. The size of Chinese cities and shortage of some datasets is challenging for high spatial resolution modelling. The aim here was to combine advantages of dispersion and land-use regression (LUR) modelling to simulate population exposure to NO2 at high spatial resolution for health burden calculations, in the example megacity of Guangzhou. Methods: Ambient concentrations of NO2 simulated by the ADMS-Urban dispersion model at 83 ‘virtual’ monitoring sites, selected to span both the range of NO2 concentration and weighting by population density, were used to develop a LUR model of 2017 annual-mean NO2 across Guangzhou at 25 m × 25 m spatial resolution. Results: The LUR model was validated against both the 83 virtual sites (adj R
2: 0.96, RMSE: 5.48 μg m−3; LOOCV R
2: 0.96, RMSE: 5.64 μg m−3) and, independently, against available observations (n = 11, R
2:: 0.63, RMSE: 18.0 μg m−3). The modelled population-weighted long-term average concentration of NO2 across Guangzhou was 52.5 μg m−3, which contributes an estimated 7270 (6960−7620) attributable deaths. Reducing concentrations in exceedance of the China air quality standard/WHO air quality guideline of 40 μg m−3 would reduce NO2-attributable deaths by 1900 (1820–1980). Conclusions: We demonstrate a general hybrid modelling method that can be employed in other cities in China to model ambient NO2 concentration at high spatial resolution for health burden estimation and epidemiological study. By running the dispersion model with alternative mitigation policies, new LUR models can be constructed to quantify policy effectiveness on NO2 population health burden.
LRRK2 and GBA Variants Exert Distinct Influences on Parkinson’s Disease-Specific Metabolic Networks
Authors: Schindlbeck Katharina A , Vo An , Nguyen Nha , Tang Chris C , Niethammer Martin , Dhawan Vijay , Brandt Vicky , Saunders-Pullman Rachel , Bressman Susan B , Eidelberg David
Published: October 2019

The natural history of idiopathic Parkinson’s disease (PD) varies considerably across patients. While PD is generally sporadic, there are known genetic influences: the two most common, mutations in the LRRK2 or GBA1 gene, are associated with slower and more aggressive progression, respectively. Here, we applied graph theory to metabolic brain imaging to understand the effects of genotype on the organization of previously established PD-specific networks. We found that closely matched PD patient groups with the LRRK2-G2019S mutation (PD-LRRK2) or GBA1 variants (PD-GBA) expressed the same disease networks as sporadic disease (sPD), but PD-LRRK2 and PD-GBA patients exhibited abnormal increases in network connectivity that were not present in sPD. Using a community detection strategy, we found that the location and modular distribution of these connections differed strikingly across genotypes. In PD-LRRK2, connections were gained within the network core, with the formation of distinct functional pathways linking the cerebellum and putamen. In PD-GBA, by contrast, the majority of functional connections were formed outside the core, involving corticocortical pathways at the network periphery. Strategically localized connections within the core in PD-LRRK2 may maintain PD network activity at lower levels than in PD-GBA, resulting in a less aggressive clinical course.
Efficacy and Safety of a Single Dose of Ivermectin, Diethylcarbamazine, and Albendazole for Treatment of Lymphatic Filariasis in Côte d’Ivoire: An Open-label Randomized Controlled Trial
Authors: Bjerum Catherine M , Ouattara Allassane F , Aboulaye Méité , Kouadio Olivier , Marius Vanga K , Andersen Britt J , Weil Gary J , Koudou Benjamin G , King Christopher L
Published: October 2019

Background

Improved drug regimens are needed to accelerate elimination of lymphatic filariasis in Africa. This study determined whether a single co-administered dose of ivermectin plus diethylcarbamazine plus albendazole [IDA] is noninferior to standard 3 annual doses of ivermectin plus albendazole (IA) used in many LF-endemic areas of Africa.

Methods

Treatment-naive adults with Wuchereria bancrofti microfilaremia in Côte d’Ivoire were randomized to receive a single dose of IDA (n = 43) or 3 annual doses of IA (n = 52) in an open-label, single-blinded trial. The primary endpoint was the proportion of participants who were microfilaria (Mf) negative at 36 months. Secondary endpoints were Mf clearance at 6, 12, and 24 months; inactivation of adult worm nests; and safety.

Results

At 36 months posttreatment with IDA, 18/33 (55%; 95% CI, 38–72%) cleared Mf versus 33/42 (79%; 67–91%) with IA (P = .045). At 6 and 12 months IDA was superior to IA in clearing Mf (89% [77–99%] and 71% [56–85%]), respectively, versus 34% (20–48%) and 26% (14–42%) (P < .001). IDA was equivalent to IA at 24 months (61% [45–77%] vs 54% [38–72%]; P = .53). IDA was superior to IA for inactivating adult worms at all time points. Both treatments were well tolerated, and there were no serious adverse events.

Conclusions

A single dose of IDA was superior to 2 doses of IA in reducing the overall Mf burden by 24 months. Reinfection may have contributed to the lack of sustained clearance of Mf with IDA.

Clinical Trials Registration

NCT02974049.
Diabetes mellitus: a single cardiorenal syndrome umbrella
Authors: Rodríguez Eva , Arias-Cabrales Carlos , Pascual Julio
Published: October 2019

Diabetes and chronic kidney disease are among the fastest-growing causes of death worldwide. An optimized conceptual framework on the pathogenesis of diabetic kidney disease and its interplay with cardiovascular disease will facilitate the development of monitoring and therapeutic strategies to decrease the risk for severe clinical events and early mortality. In this issue of ckj, Pinier et al. provide data supporting the existence in diabetic patients of a single cardiorenal syndrome umbrella, rather than separate cardiorenal or renocardiac entities (e.g. acute cardiorenal syndrome or chronic renocardiac syndromes).
‘For Time is / nothing if not amenable’ — exemplarity, time, reception
Authors: Güthenke Constanze
Published: October 2019

This article revisits exemplarity as a strategy of approaching, reading, and using the past. By going beyond treating it mostly as a historical phenomenon, in terms of its use as a purely pre-modern rhetorical trope connected to historical and ethical writings in the Greek and Roman world, I suggest that exemplarity has critical potential to make us reconsider its ability to break through temporalities in a calculated and sceptical way. As such, it offers a provocation to Reception Studies to engage with exemplarity both in and as a more deliberate and strategic manner.
3040Plaque burden, but not the severity of carotid stenosis, predicts adverse cardiovascular events in patients at high and very high cardiovascular risk
Authors: Genkel V , Salashenko A , Shaposhnik I
Published: October 2019

Introduction

According to the current guidelines the visualization of atherosclerotic plaques in the carotid arteries is the only option that carotid ultrasound provides for the assessment of cardiovascular risk (CVR). The direction devoted to the development and implementation of markers based on the quantification of atheroma, is promising.

Purpose

The aim of the study was to evaluate the prognostic value of various markers of carotid atherosclerosis (plaque, carotid total plaque area (cTPA) and carotid stenosis) in patients at high and very high CVR.

Methods

The study included patients aged 40–75 years at high and very high CVR. All patients underwent carotid duplex ultrasound. The presence of carotid plaque was assessed according to Mannheim consensus. The percentage of stenosis was measured planimetrically in the B-mode by the diameter in the cross section of the vessel.

cTPA was estimated in the longitudinal position, which allows to achieve the best visualization of plaque, the area of plaque was measured in the manual trace mode. These measurements were performed for each rendered plaque, followed by the calculation of the total value.

The combined endpoint was cardiovascular death, non-fatal myocardial infarction or unstable angina (which required hospitalization), non-fatal stroke, and coronary revascularization.

Results

The study included 100 patients at high and very high risk. The duration of the follow-up period was 24.4 (14.1–34.3) months. The events constituting the combined endpoint occurred in 34 (34%) patients: cardiovascular death was recorded in 7 (7%) patients; non-fatal myocardial infarction or stroke in 3 (3%) patients; unstable angina, which required hospitalization in 24 (24%) patients, while emergency coronary angiography was performed in 8 (8%) patients, coronary artery stenting was performed in 3 (3%) cases.

The presence of carotid plaque in accordance with Cox regression after adjusting for factors such as sex, age, smoking, hypertension, BMI, eGFR, LDL-c and HbA1c, RR of adverse cardiovascular events was 10.5 (95% CI 1.27–86.5; p=0.008; see Figure 1).

The optimal cut-off values of cTPA and carotid stenosis were determined by ROC-analysis.

An increase in cTPA ≥69 mm2 corrected for sex, age, smoking, hypertension, BMI, eGFR, LDL-c, HbA1c, and the presence of carotid plaque was associated with an increase in the RR of adverse cardiovascular events by 5.86 times (95% CI 2.09–16.4; p=0.001; see Figure 1).

Also, there were no statistically significant associations between carotid arteries stenosis and adverse cardiovascular events (RR 1.29; 95% CI 0.61–2.76; p=0.504).

Kaplan–Meier curves for cTPA, stenosis

Conclusion

In patients at high and very high cardiovascular risk among carotid ultrasound parameters the presence of carotid plaque and cTPA, but not the degree of stenosis, had an independent predictive value regarding the development of adverse cardiovascular events.
3043Endotrophin, a fragment of collagen type VI, is correlated to IMT and associated with cardiovascular events in patients with atherosclerosis and diabetes: the IMI-SUMMIT cohort
Authors: Holm Nielsen S , Goncalves I , Shore A , Natali A , Khan F , Genovese F , Karsdal M , Nilsson J
Published: October 2019

Background/Introduction

Patients with micro- and macrovascular diseases, including atherosclerosis, have increased risk of cardiovascular events and early mortality. The atherosclerotic disease is characterised by accumulation of lipids, cells and proteins in the arterial wall, which includes remodelling of the extracellular matrix (ECM). Collagen type VI (COL6) is known to be over-expressed in patients with atherosclerosis. The biomarker PRO-C6, known as endotrophin, is a COL6 fragment that reflects formation of collagen type VI, and possess pro-inflammatory and pro-fibrotic activities.

Purpose

We explored whether increased endotrophin levels, measured by PRO-C6, were associated with intima-media thickness (IMT) and mortality in the IMI-SUMMIT cohort.

Methods

Circulating protein levels of PRO-C6 were measured in EDTA plasma from 1500 patients enrolled at four European University Hospitals, using an enzyme-linked immunosorbent assay. Follow-up data were available up to three years after sample collection. Associations between PRO-C6 and incidence of cardiovascular (CV) events and all-cause mortality were assessed by Kaplan-Meier curves and Cox proportional hazard regression analyses. Pearson correlation was performed to explore the association of PRO-C6, IMT and clinical variables. Known confounders defined by the Framingham Heart study (age, gender and diabetes) were included in the Cox proportional hazard regression analysis.

Results

Plasma PRO-C6 was significantly correlated with IMT in both the common carotid artery and the carotid bulb (r=0.09, p=0.002 and r=0.11, p=0.0003, respectively), HbA1c (r=0.11, p<0.0001) and C-reactive protein (r=0.14, p<0.0001). A total of 145 patients suffered from fatal or non-fatal cardiovascular events during the three-year follow-up period. Patients in the highest PRO-C6 tertile had a two-fold increased risk of experiencing a CV event during follow-up (p=0.002), independently of age, presence of CVD at baseline, type 2 diabetes, smoking and statin treatment in a regression model.

Conclusion

The present findings demonstrate that circulating levels of PRO-C6 are associated with atherosclerosis severity and increased incidence of cardiovascular events. Since PRO-C6 detects the signaling molecule endotrophin, the results may indicate that endotrophin is not only a biomarker of atherosclerotic disease, but may have a role in promoting disease progression.

Acknowledgement/Funding

This work was supported by the Danish Research Foundation, The Danish innovation foundation and the IMI-SUMMIT participants
3053High mortality in atrial fibrillation patients suffering ischemic stroke, intracranial hemorrhage or a gastrointestinal bleed and associations with the preceding antithrombotic treatment
Authors: Komen J J , Forslund T , Mantel - Teeuwisse A K , Klungel O H , Wettermark B , Von Euler M , Braunschweig F , Wallen H , Hjemdahl P
Published: October 2019

Background

Anticoagulation treatment reduces the risk of stroke but increases the risk of bleeding in atrial fibrillation (AF) patients. There is little data on survival after a stroke or a severe bleed.

Objective

To analyze 90-day mortality in AF patients after an ischemic stroke, an intracranial hemorrhage (ICH) or a gastrointestinal bleed (GIB) and assess associations with the type of antithrombotic treatment preceding the event.

Methods

From the Stockholm Healthcare database (n=2.3 million inhabitants) we selected all AF patients suffering from an ischemic stroke, an intracranial bleed, or a severe GIB requiring acute hospital care between July 2011 and August 2018 and assessed 90-day mortality rates. We assessed current use of warfarin, non-vitamin K oral anticoagulants (NOAC), or antiplatelet agents at the time of the event. We used a Cox regression to calculate adjusted hazard ratios (aHRs), adjusting for components of the Charlson Comorbidity Index, the CHADsVASc score, the HAS-BLED score, comedication, and year of inclusion, for the association between treatment preceding the event and mortality. In addition, we performed log-rank tests in propensity score matched cohorts.

Results

Of 105 313 patients with AF, 6 017 were included after an ischemic stroke, 3 006 after an ICH, and 4 291 after a GIB. 90-day mortality rates were 25.1%, 31.6% and 16.2%, respectively. Patients suffering from an ischemic stroke were the oldest at 81.6±9.8 (S.D:) years of age followed by patients suffering from an ICH (80.2±9.8 years) or a GIB (78.7±10.5 years). A large proportion of patients suffering ischemic stroke (72%) had no anticoagulant treatment preceding the event. After ICH, there was a significantly increased risk of mortality in warfarin compared to NOAC treated patients after adjusting for confounders (aHR: 1.36 CI: 1.04–1.78). Patients receiving antiplatelets or no treatment had significantly higher mortality rates than patients on NOAC treatment, both after an ischemic stroke and a GIB, but there was no significant difference between warfarin and NOACs (aHR 0.84 CI: 0.63–1.12 after ischemic stroke, aHR 0.91 CI: 0.66–1.25 after GIB). Propensity score matched analyses yielded similar results.

Survival curves after event

Conclusion

Mortality rates are high in AF patients suffering from an ischemic stroke, an ICH, or a GIB. NOAC treatment was associated with a lower 90-day mortality after ICH than warfarin, but no such difference was found after ischemic stroke or GIB. After ischemic stroke and GIB, mortality rates were higher in antiplatelet treated and untreated patients compared to NOAC treated patients.

Acknowledgement/Funding

Swedish Heart Lung Foundation
3069Epigenetic changes in heart failure cohorts: novel insights into methylation changes of protein and RNA coding genes in human cardiac tissue
Authors: Glezeva N , Moran B , Collier P , Moravec C , Phelan D , Donnellan E , Russell-Hallinan A , O'connor D , Gallagher W , Gallagher J , McDonald K , Ledwidge M , Baugh J , Das S , Watson C
Published: October 2019

Background

Limited knowledge exists of the extent of epigenetic alterations, such as DNA methylation, in Heart Failure (HF). We conducted targeted DNA methylation sequencing to identify DNA methylation alterations in coding and non-coding RNA across different etiological sub-types of HF.

Methods and results

A targeted bisulfite sequence capture sequencing platform was applied to DNA extracted from cardiac interventricular septal tissue of 30 male HF patients encompassing etiologies including Hypertrophic Obstructive Cardiomyopathy (HOCM, n=12), Ischemic Cardiomyopathy (ISCM, n=9), Dilated Cardiomyopathy (DCM, n=9), and 9 control patients with non-failing hearts (NF). We detected 62,678 differentially methylated regions (DMR) in the studied HF cohort. By comparing each HF sub-group to the NF control group we identified 195 unique DMRs: 5 in HOCM, 151 in DCM, and 55 in ISCM. These translated to 4 genes/1 non-coding RNA (ncRNA) in HOCM, 131 genes/17 ncRNA in DCM, and 51 genes/5 ncRNA in ISCM. Subsequent gene/ncRNA expression analysis was assessed using qRT-PCR and revealed 6 genes: 4 hypermethylated (HEY2, MSR1, MYOM3, COX17), 2 hypomethylated (CTGF, MMP2); and 2 microRNA: 1 hypermethylated (miR-24–1), 1 hypomethylated (miR-155) with significantly up- or down-regulated expression levels consistent with the direction of methylation in the particular HF sub-group.

Conclusions

For the first time DNA methylation alterations and associated gene expression changes were identified in etiologically-variant pathological heart failure tissue. The methylation-sensitive and disease-associated genes/non-coding RNA identified from this study represent a unique cohort of loci that demonstrate a plausible potential as a novel diagnostic and/or therapeutic target in HF and warrant further investigation.

Acknowledgement/Funding

Enterprise Ireland; European Regional Development Fund under Ireland's European Structural and Investment Funds Programmes 2014-2020
3072Myocardial delivery of therapeutic miR-133 via inhalable nanoparticles prevents the pathologic development in a model of ventricular pressure overload
Authors: Barandalla Sobrados M , Carullo P , Salvarani N , Condorelli G , Miragoli M , Catalucci D
Published: October 2019

Background

MicroRNAs (miRs) are regulators involved in several biological processes and have been recognized as potential novel therapeutic targets for the treatment and prevention of CDs. We previously demonstrated that the cardiac-enriched miR-133, which is inversely related to failing heart conditions, is involved in several aspects of pathological cardiac remodeling via mitigation of cardiac hypertrophy and fibrosis, fine-tuning of the β1-adrenergic receptor signaling, and protection against oxidative stress-mediated apoptosis. However, effective and clinically oriented interventions aiming to delivery exogenous miR-133 for preventing the stress-induced downregulation of miR-133 levels are still missing.

Here, we applied an unconventional and effective nanotechnology-based inhalation approach enabling the delivery to diseased heart of exogenous miR-133 loaded into biocompatible and biodegradable calcium phosphate-based nanoparticles (CaPs).

Methods

Male C57Bl/6J mice (8 weeks) were subjected to a trans-aortic constriction (TAC), to induce a ventricular pressure overload. 4 experimental groups of TAC animals were randomly assigned to different intratracheal administrations of: 1. Saline (TAC Control); 2. CaP-miR133 (TAC CaP-miR133); 3. Pristine miR-133 (TAC miR133); 4. Unloaded CaPs (TAC CaP). Not TAC operated mice served as SHAM group. Intratracheal nebulizations were performed immediately after TAC surgery once-a-day in alternative days for 4 consecutive weeks. Echocardiography (ECO) were conducted before TAC, at 2 and 4 weeks after surgery. ECO as well as molecular and histological analyses were performed at sacrifices.

Results

ECO analyses showed an effective CaP-miR133-associated reversal of the failure progression, preserving left ventricular internal diameter (LVID) during cardiac cycle, ejection fraction (EF) and fraction shortening (FS), both at 2 and 4 weeks after TAC. This improvement was associated with the restoration of physiological levels of miR-133 in TAC-stressed isolated cardiomyocytes as well as its contractile activity. TAC mice receiving CaP-mir133 showed reduced indexes of fibrosis. In contrast, no beneficial effects were observed when unloaded CaPs or pristine miR-133 were administered. No major alterations of the immunological status of mice were observed after CaP-miR133 administration.

Conclusions

Intratracheal nebulization of miR-133-loaded nanoparticles is an effective approach for the beneficial restoration of cardiac performance, cell contractility and remodeling in a mouse model of left ventricular pressure overload. Providing the evidence for a potential innovative application of the emerging nanotechnologies, our approach might represent an important step forward for the treatment of cardiovascular diseases.

Acknowledgement/Funding

Fondazione Umberto Veronesi and CUPIDO project (EU's Horizon 2020, Grant Agreement 720834)
3152Right ventricular function and long-term outcomes in cardiac resynchronization therapy patients enrolled in MADIT-CRT
Authors: Nagy V K , Merkely B , Geller L , Kosztin A , Solomon S , McNitt S , Goldenberg I , Kutyifa V
Published: October 2019

Background

Long-term predictive value of baseline right ventricular (RV) function and CRT-induced changes of RV function for the clinical outcomes, mortality or heart failure are not well understood, especially in mild HF patients implanted with CRT-D.

Methods

MADIT-CRT enrolled 1,820 patients at 110 centers worldwide, with either ischemic cardiomyopathy (New York Heart Association [NYHA] functional class I or II), or non-ischemic cardiomyopathy (NYHA functional class II only), sinus rhythm, ejection fraction of 30% or less, and a QRS duration of 130 ms or more. We assessed right ventricular function (RVF) as RV fractional area change by echocardiography at baseline and after 1 year of therapy in patients with LBBB assigned to CRT arm (n=633). Kaplan-Meier survival analyses and multivariate Cox models were utilized to identify RV parameters predicting long-term outcomes of HF or death events.

Results

During the median follow up of 5.6 years 192 (30.3%) patients had heart failure or death. CRT-D LBBB patients with below or above median RV end-systolic area (RVS) had lower cumulative probabilities of HF/death (p=0.02). Lower, than the median value of both RVS and RVF were associated with higher risk of HF events alone (p=0.004; p=0.01 respectively). In multivariate analysis, after adjustment of relevant clinical covariates more RV reverse remodeling in the terms of RV end-diastolic area (RVD) decrease proved to be an independent predictor for 5-year all-cause mortality (HR: 0.4; p=0.03).

Kaplan-Meier analysis of baseline RVF

Conclusions

Based on our results RV geometry and function before CRT implant and also significant RV reverse remodeling at 12 months follow up are significant predictors of long-term outcomes.
3260Prognostic value of cardiac power reserve in patients with normal left ventricular ejection fraction undergoing exercise stress echocardiography
Authors: Anand V , Kane G , Pislaru S , Adigun R , McCully R , Pellikka P , Pislaru C
Published: October 2019

Background

Cardiac power output-to-mass (CPOM) ratio is a measure of myocardial performance that incorporates both pressure and flow output, normalized to left ventricular (LV) mass generating that cardiac work. Prior small studies have shown that CPOM predicts outcomes in patients with ischemic cardiomyopathy and reduced LV ejection fraction (EF). We sought to evaluate the prognostic significance of peak exercise CPOM and power reserve (increase from rest to peak exercise) in patients with normal EF.

Methods and results

Retrospective study in 24,783 patients (age 59±13 years, 45% females) with EF≥50% and no significant valve disease or right ventricular (RV) dysfunction, undergoing exercise stress echocardiography between 2004–2018. CPOM was calculated as previously described (0.222 x cardiac output x mean blood pressure / LV mass) and expressed in Watts/100g myocardium. Power reserve was calculated as difference in CPOM between peak stress and rest. All-cause mortality was the primary endpoint. Patients were divided into quartiles of power reserve. Patients with higher power reserve were younger, had higher blood pressure and heart rate, lower LV mass, and lower prevalence of prior myocardial infarction. (Table). During follow-up (median (IQR) 3.9 (0.6–8.3) years), 931 (3.8%) patients died. Progressively lower power reserve was associated with increasing mortality (Figure A). Compared to patients with abnormal stress test, patients with the lowest power reserve but otherwise normal stress test had the same survival as those with infarction/cardiomyopathy or ischemia on stress test (Figure B). Resting CPOM had lower predictive value. After adjusting for age, sex, METs achieved, ischemia/infarction on stress test results, and diastolic function grade, both peak exercise CPOM and power reserve were independent predictors of mortality (p<0.0001), incremental to conventional measures.

Conclusion

Cardiac power output and reserve measured during exercise stress echo provides independent prognostic information in patients with normal resting EF and no significant valve disease or RV dysfunction. The survival of patients with low power reserve but normal stress test was similar to patients with prior infarction/ cardiomyopathy or ischemia on stress test.
3307Impaired reverse transendothelial migration capacity governs the enhanced abluminal accumulation of diabetic CD14+ monocytes
Authors: Semo D , Sidibe A , Shanmuganathan S K , Mueller N , Mueller U A , Boehmer F D , Imhof B , Godfrey R , Waltenberger J
Published: October 2019

Background

Chronic inflammation drives atherosclerosis. Monocyte recruitment and accumulation in the tissues contributes to chronic inflammation and is an important aspect of the pathobiology of atherosclerosis. Diabetes mellitus (DM) is a leading cardiovascular predisposing to the development of atherosclerosis. Monocytes represent the largest cell-population in the atherosclerotic plaque. However, the mechanisms that drive the accumulation of monocytes in the plaques are not clearly understood.

Purpose

The aim of this study is to understand the hyperglycemia/diabetes-induced changes in the transendothelial and reverse transendothelial migration processes of monocytes under physiological flow conditions and to characterize the underlying mechanisms.

Methods

Monocytes isolated from healthy donors by negative selection were conditioned in hyperglycemic or normoglycemic conditions for 48 hours. These monocytes or monocytes from type 2 diabetes mellitus (T2-DM) patients or from non-diabetic controls were allowed to interact with TNFα -activated HUVEC-monolayer. Experiments were performed under flow conditions found in post-capillary venules. Analysis of migration was performed using Fiji J software. Expression of molecules involved in transmigration and reverse migration was measured using FACS.

Results

Monocytes from T2-DM patients and hyperglycemia-conditioned cells revealed a significantly reduced transendothelial migration capacity. Even though these monocytes adhered to the HUVEC monolayer, only few of them transmigrated. Moreover, the transmigrated cells from diabetic patients and hyperglycemia-conditioned cells accumulated in the ablumen after transendothelial migration. Time in the ablumen was prolonged and there was a significant reduction in the reverse transendothelial migration. Expression levels of chemokine receptors, which had been shown to be essential for transendothelial migration process, were reduced in diabetic monocytes.

Conclusion

Our results revealed for the first time that the enhanced diabetic monocyte accumulation in the albumen is not secondary to the elevated transmigration through the endothelium. Instead, the accumulation of monocytes in the vessel wall is due to the direct consequence of dysfunctional reverse transendothelial migration. These novel findings could explain the underlying reasons leading to the elevated inflammatory monocyte accumulation, chronic inflammation and subsequent atherosclerosis development in T2-DM patients. Our results highlight the importance of restoring the reverse transendothelial migration capacity of monocytes to reduce monocyte accumulation and atherogenesis in the diabetic environment.
4087Functional assessment of the myocardium in non-ischaemic cardiomyopathy using manganese-enhanced T1 mapping
Authors: Spath N , Dweck M R , Baker A H , Newby D E , Semple S I
Published: October 2019

Background

Delayed-enhancement magnetic resonance imaging (DEMRI) with gadolinium detects macroscopic myocardial fibrosis, but does not directly assess myocardial function. Manganese, a paramagnetic calcium-analogue, enables direct dynamic assessment myocyte calcium handling and is a potential early marker of myocardial dysfunction. We have previously demonstrated manganese-enhanced MRI (MEMRI) can detect altered calcium-handling in remote remodelling myocardium in a rodent infarct model.

Purpose

To evaluate MEMRI as a marker of altered myocardial calcium handling in patients with non-ischaemic cardiomyopathy (NCT03607669).

Methods

Healthy volunteers (HV, n=20, 13 male, 42±11 years) and patients with hypertrophic (HCM, n=11, 5 male, 57±15 years) or dilated (DCM, n=5, 3 male, 56±14 years) cardiomyopathies underwent both DEMRI and MEMRI. Myocardial T1 was measured for 40 min after intravenous manganese dipyridoxyl diphosphate (Mn-DPDP, 5 μmol/kg) administration. Images were acquired at 3T with T1 imaging performed using Shortened Modified Look-Locker Inversion recovery [Figure A] (WIP #1048 Siemens Healthcare Ltd).

Results

No adverse effects were observed. In HV, the myocardialT1 profile following Mn-DPDP administration demonstrated a rapid initial descent (perfusion phase) followed by a slower, more gradual decrease which continued throughout the 40 min imaging period (mean reduction 25.2%, 283±9ms).

In patients with HCM, T1 values followed a different pattern following Mn-DPDP administration. In areas of focal myocardial fibrosis (defined by DEMRI) there was again a sharp initial shortening of T1 but this was followed by a steady increase towards baseline, which eventually recovered to >40% of its initial value at 40 minutes. In areas of diffuse myocardial fibrosis, the initial shortening in the perfusion phase was followed by a more gradual recovery which then plateaued, remaining stable at 21% of native T1 by 40 min [Figure B]. Hypertrophied non-fibrosed myocardium had higher native T1 than HV (1178±45 vs 1133±36 ms P=0.005) and the rate of T1 reduction following the perfusion phase was slower (P=0.0005), leading to less overall T1 shortening at 40 min (880±40 vs 841±28 ms, P=0.004, [Figure C]).

No patient with DCM had fibrosis by DEMRI. Native T1 was higher than HV (1234±26 vs 1133±36 ms, P<0.0001) and the rate of T1 reduction following the perfusion phase was lower in DCM myocardium (P<0.0001) resulting in less overall T1 shortening at 40 min (914±60 vs 841±28 ms, P=0.0006, [Figure D]).

MEMRI in non-ischaemic cardiomyopathy

Conclusion

MEMRI identifies altered calcium-handling in pathological myocardium of non-ischaemic cardiomyopathy, irrespective of fibrosis by DEMRI. This feasible, safe and novel method of functional myocardial tissue characterisation has exciting potential for future diagnostic, functional and clinical applications.

Acknowledgement/Funding

British Heart Foundation
4091Mechanical dispersion by speckle tracking echocardiography in fabry disease
Authors: Cianciulli T F , Saccheri M C , Risolo A M , Lax J A , Mendez R J , Morita L A , Beck M A , Balletti L R , Puente L J , Prieto O , Ferreiro D E , Fernandez S P , Fernandez C F , Rozenfeld P A , Gagliardi J A
Published: October 2019

Background

Fabry disease is a rare X-linked storage disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A and generally causes multi-organ dysfunction. Heart disease is the main cause of death, due to severe left ventricular (LV) systolic dysfunction and sudden death. In several heart diseases, the LV systolic dysfunction and ventricular arrhythmias are associated with mechanical dispersion (MD). The presence of MD in patients with FD has not been studied yet. In this cross-sectional study, we investigated the prevalence of MD in patients with FD.

Methods

Complete echocardiographic and speckle tracking echocardiographic (STE) data were collected. MD is an index of inter-segmental discoordination of contraction which has been used to quantify LV dyssynchrony and was defined as the standard deviation (SD) of time to peak negative strain in 17 left ventricular segments. Patients were divided into two groups according to whether or not they had left ventricular hypertrophy (LVH). MD was defined as an SD >49 msec.

Results

We studied 108 patients with FD, 24 patients (22%) were excluded due to inadequate imaging quality or presence of comorbidities, so the final study population consisted of 84 patients (mean age 33.3±14.6 years, 60.7% women). LVH in FD appears at older ages than in patients without LVH (48±12.5 y/o vs 27.8±11.1 y/o, p<0.0001). Patients with FD without LVH (Group I) showed normal global longitudinal peak strain (GLPS) (21.2±2.5%) and no MD (32.7±8.8 msec). In Group II (n=23) patients with FD with LVH, 17 (73.9%) had MD >49 msec prolonged mechanical dispersion (73.3±20.7 msec) and reduced GLPS (13.6±4.0%). MD was more pronounced in Fabry patients with LVH than in patients without LVH (63.4±24.7 msec vs. 32.7±8.8 msec, p<0.0001). GLPS was lower in Fabry patients with LVH than in patients without LVH (15.3±4.7% vs 21.2±2.5%, p<0.0001).

Figure 1

Conclusions

To our knowledge, this is the first study to demonstrate the prevalence of mechanical dispersion in patients with FD. Mechanical dispersion was seen in 73.9% of patients with FD with LVH. This dyssynchrony should be taken into account in patients who develop heart failure or life-threatening ventricular tachyarrhythmias.
4111Association of DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors with cardiovascular events stratified by renal function: a network meta-analysis
Authors: Roddick A , Zheng S L
Published: October 2019

Background

Chronic kidney disease is a frequent co-morbidity in patients with diabetes and is associated with poor outcomes and elevated cardiovascular risk. Several novel oral antidiabetic therapies have been shown to be efficacious in reducing cardiovascular events. However, the impact of baseline renal function on cardiovascular efficacy is not well-established.

Purpose

To assess the cardiovascular efficacy of Dipeptidyl Peptidase-4 inhibitors (DPP-4i), Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RA) and Sodium-Glucose Cotransporter-2 inhibitors (SGLT-2i) stratified by renal function.

Methods

Cardiovascular outcome trials enrolling at least 1000 patients with type 2 diabetes for >12 months' duration were included if they reported on a composite outcome of cardiovascular mortality, nonfatal myocardial infarction and nonfatal stroke and stratified outcome data by estimated glomerular filtration rate (eGFR) of >60 mL/min/1.73m2 or <60 mL/min/1.73m2. Studies enrolling patients with recent acute coronary events were excluded. Treatment and interaction effect estimates were aggregated by random-effects Bayesian network meta-analysis.

Results

9 studies were included (2 DPP-4i; 4 GLP-1RA; 3 SGLT-2i), enrolling 92,626 patients accounting for 315,167 patient-years of follow-up. The eGFR was <60 mL/min/1.73m2 in 21,302 patients (23.0%) and >60 mL/min/1.73m2 in 71,324 patients (77.0%). The mean eGFR was 64.8 mL/min/1.73m2 in DPP-4i trials, 78.6 mL/min/1.73m2 in GLP-1RA trials and 78.6 mL/min/1.73m2 in SGLT-2i trials.

Compared to placebo, DPP4i were not associated with reductions in the primary outcome (HR 1.00, 95% credible interval [CrI] 0.89–1.13). No reductions in the primary outcome were present for either strata of renal function (eGFR >60: HR 1.00, 95% CrI 0.77–1.29; and eGFR <60: HR 0.99, 95% CrI 0.81–1.20), with no significant interaction between renal function subgroups (interaction coefficient 1.00, 95% CrI 0.72–1.41).

GLP-1RA were associated with reductions in the primary outcome overall (HR 0.85, 95% CrI 0.77–0.93). There was no significant interaction between renal function subgroups (eGFR <60: HR 0.87, 95% CrI 0.70–1.06; and eGFR >60: HR 0.83, 95% CrI 0.71–0.94; interaction coefficient 1.05, 95% CrI 0.83–1.35). Similarly, SGLT-2i were associated with reductions in the primary cardiovascular composite outcome (HR 0.88, 95% CrI 0.79–0.97), with no significant interaction between renal function subgroups (eGFR <60: HR 0.82, 95% CrI 0.65–1.05; and eGFR >60: HR 0.91, 95% CrI 0.78–1.06; interaction coefficient 0.92, 95% CrI 0.69–1.21).

Conclusions

Both SGLT-2i and GLP-RA are associated with reductions in a composite cardiovascular outcome with no evidence of interaction by renal function, while DPP-4i were not associated with reductions in events, with no evidence of interaction by renal function. These data suggest that cardiovascular efficacy of these medications is not affected by baseline renal status.
4113Glucose lowering drugs or strategies, major adverse cardiovascular events and heart failure outcomes, and association with weight loss - meta-analysis of large cardiovascular outcome trials
Authors: Ghosh-Swaby O R , Goodman S G , Leiter L A , Cheng A , Connelly K , Fitchett D , Juni P , Farkouh M E , Udell J A
Published: October 2019

Background

Glucose lowering drugs or strategies (GLDS) have varied effects on major adverse cardiovascular events (MACE) and heart failure (HF) in cardiovascular outcomes trials. Mechanisms driving cardiovascular risk reduction remain elusive.

Methods

We searched MEDLINE, PubMed, and meeting abstracts up to 11/21/2018 for large GLDS cardiovascular outcome trials (CVOTs) in patients with or at risk for type 2 diabetes. Primary endpoints of MACE and HF were evaluated with random effects risk ratios (RR) and explored by baseline CVD subgroups and meta-regression by weight change across treatment arms.

Results

In 27 GLDS CVOTs, a total 207,820 patients, median age 63 years, 64% male, 64% CVD and 11% with prior HF were studied over a mean 3.8 years with 20,118 (10%) patients having MACE and 7,212 (4%) a HF event. Compared with standard care, GLDS overall lowered MACE (RR 0.92, P<0.ehz745.01171) but not HF (RR 1.01, P=0.91). Across GLDS, the magnitude and directionality varied modestly for MACE RR (P-int=0.07) but markedly for HF (P-int<0.ehz745.01171). Meta-regression showed a change in HF RR by 6% (95% CI 3%-9%) per 1 kg weight gain/loss between treatment arms (P=0.0006; Figure). In 9 trials of GLDS that achieved marked weight loss (lifestyle, GLP1 agonists, SGLT2 inhibitors), MACE benefit was confined to patients with baseline CVD (RR 0.89 [0.84–0.95] versus without (RR 1.02 [0.91–1.15]; P-int=0.01) with consistent HF effect (RR 0.80 [0.72–0.88] vs RR 0.76 [0.56–1.03]; P-int=0.74).

Heart Failure Risk and Changes in Weight

Conclusion

HF outcomes were improved with GLDS that lower weight. Among diabetes GLDS that lower weight, there was a robust risk reduction in atherothrombotic and heart failure events, with the MACE benefit confined to patients with established CVD.

Acknowledgement/Funding

Heart and Stroke Foundation
4114Efficacy of alirocumab treatment after acute coronary syndrome according to new ACC/AHA guidelines for lipid-lowering therapy
Authors: Roe M T , Szarek M , Li Q H , Bhatt D L , Bittner V , Goodman S G , Harrington R A , Lopez-Jaramillo P , Lopes R D , Louie M J , Moriarty P M , Vogel R A , Baccara-Dinet M T , Steg P G , Schwartz G G
Published: October 2019

Background

The 2018 ACC/AHA cholesterol management guidelines recommend additional lipid-lowering therapies for secondary prevention in patients with LDL-C ≥1.8 mmol/L despite maximally tolerated statin therapy who are considered “very high-risk” on the basis of history of multiple ischaemic events or an ischaemic event and multiple high-risk conditions.

Purpose

We examined the frequency of major adverse cardiovascular events (MACE) and efficacy of PCSK9 inhibition with alirocumab to reduce MACE in patients with recent acute coronary syndrome (ACS) categorized as very high-risk or not very high-risk by guideline criteria.

Methods

Patients in ODYSSEY OUTCOMES (n=18,924) with recent ACS and residual dyslipidaemia despite optimal statin therapy were randomized to alirocumab or placebo and followed for median 2.8 years. The primary MACE outcome was a composite of coronary heart disease death, non-fatal myocardial infarction (MI), ischaemic stroke, or hospitalization for unstable angina.

Results

Of 18,924 randomized patients, 11,935 (63.1%) were categorized as very high-risk and 6989 (36.9%) as not very high risk (per ACC/AHA guidelines criteria). In the very high-risk category, 4450 (37.3%) had a prior ischaemic event plus the trial-qualifying index ACS (MI, 3633; stroke, 524; peripheral artery disease, 759); 7485 (62.7%) had no ischaemic event before the index ACS but had ≥2 high-risk conditions (diabetes, 3319; age ≥65 years, 3087; current smoking, 2371; chronic kidney disease, 1583). In the placebo group, the incidence of MACE was higher among those in the very high-risk category (14.4%) vs those not at very high-risk (5.6%). Overall, alirocumab reduced the risk of MACE vs placebo (9.5% vs 11.1%, hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.78–0.93; P=0.003), with consistent relative reductions in both risk categories (very high risk HR 0.84, 95% CI 0.76–0.92; not very high risk HR 0.86, 95% CI 0.70–1.06). However, the absolute reduction in MACE with alirocumab was greater among patients classified as very high-risk (2.1%) vs not very high risk (0.8%), and greater in particular among those classified as very high risk based on multiple ischaemic events (2.4%, Figure).

Conclusions

Application of 2018 ACC/AHA cholesterol guidelines criteria accurately identifies patients with ACS and dyslipidaemia who are at very high risk for recurrent MACE, and who derive a large absolute benefit from alirocumab treatment. Patients categorized as very high-risk based upon multiple ischaemic events derive a particularly large absolute benefit from treatment with alirocumab.

Acknowledgement/Funding

Supported by Sanofi and Regeneron Pharmaceuticals