bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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
4118Cisplatin therapy as a risk factor for incident atrial fibrillation
Authors: Chalazan B , Samra H , Patel K , Ash D , Mehta A , Konda S , McCauley M , Dawood D 
Published: October 2019

Abstract

Background
Although aging is a major contributor to the rising epidemic of atrial fibrillation (AF), increased numbers of cancer survivors who suffer from chemotherapy and radiotherapy mediated cardiovascular disease also appear to be especially vulnerable to developing the arrhythmia. Currently, little is known about the long-term risk of AF in patients treated with these two treatment modalities for cancer.

Purpose
To define the incidence and prevalence of AF in a thoracic tumour cohort following radiotherapy and chemotherapy.

Methods
We conducted a retrospective study from the electronic health records (EHR) of patients who had a primary tumour of the breast and lung. Patients with AF, radiotherapy or chemotherapy prior to cancer diagnosis were excluded. All patients were followed for incident AF until last censoring or death using a validated AF algorithm (positive predictive value 96%). Radiation oncology treatment reports were reviewed and chemotherapy data was extracted from the EHR and manually reviewed for 43 chemotherapeutic agents.

Results
In the tumour registry, 17,402 patients were identified by histological and pathological reports. We examined 3,336 patients with a thoracic tumour diagnosis (breast and lung) with a mean age of 62.7±12.5 (SD) years. The AF incident rate for breast and lung cancer was 1.2 and 13.5 cases per every 100 persons with a cumulative rate of 2.49 and 0.67 respectively. We observed an overall AF prevalence of 3.4% and 7.4% in the breast and lung cohorts respectively. The average follow-up duration was 4.69 years (0.0–17.8 years) in breast cancer and 1.36 years (0.0–13.9 years) in lung cancer patients. A Cox regression model revealed no association between radiotherapy and AF in either cancer type (breast: P=0.18 and lung: P=0.16). However, patients who received cisplatin had 4-fold increased risk of developing AF after covariate adjustment (HR = 4.22, 95% CI: 0.10–17.85, P=0.05).

Conclusions
We show for the first time in a large thoracic tumour registry and using the EHR that patients treated with cisplatin were more likely to develop AF. Additional studies are needed to validate our findings and to further investigate the underlying mechanisms of these cardiotoxic effects.

Acknowledgement/Funding
This work was supported in part by grants from the AHA 17MCPRP33420153 (Brandon Chalazan) and NIH/NHLBI R01 HL092217 and HL138737 (Dawood Darbar).
4180Expression profile of microRNAs in cardiac tissue from pediatric patients with heart failure (HF) supported by Ventricular Assist Device and their involvement in pathophysiological mechanisms of HF
Authors: Ragusa R , Di Molfetta A , Rizzo M , Mercatanti A , Amodeo A , Trivella M G , Pitto L , Caselli C 
Published: October 2019

Abstract

Background
Ventricular Assist Device (VAD) has been increasingly used as bridge to transplantation for the treatment both of adult and pediatric patients with end-stage Heart Failure (HF). Several studies reported that VAD support could affect cardiac molecular mechanisms, including miRNA expression, in HF adult patients. However, little is known about the miRNA profile in pediatric HF patients supported by VAD.

Purpose
Aim of this study was to evaluate the effects of VAD support on expression profile of miRNAs in cardiac tissue from pediatric patients with HF, and to enrich the analysis by an in silico exploration of their potential functions and pathways.

Methods
Cardiac biopsies from HF children collected at the time of VAD implant [8 HF children; 57±33 (mean±SD) months; 2 males; 14.2±13.5 weight; 29±8 LVEF%] and at the time of heart transplantation after 155±33 days of VAD support [5 children; 90±46 months; 4 males; 30±15.8 weight; 38±3.9 LVEF%] were used for profiling miRNA expression by Next Generation Sequencing (NGS). Bioinformatic analyses were performed to identify the differentially expressed miRNAs in cardiac tissues after VAD support, to elucidate their potential functions (Gene Ontology), and to predict their target genes (miRWalk database).

Results
We identified two upregulated miRNAs (miR-29b-1-5p, miR-338-3p) and four downregulated miRNAs (miR-199a-5p, miR-199b-5p, miR-19a-3p, miR-1246) after VAD support. Gene enrichment analysis identified heart development/function, apoptosis and metabolism as main process modulated by the selected miRNAs (Fig A). Moreover, twenty genes were selected as putative miRNA targets involved in the pathophysiology of HF (Fig B).

Conclusion
In summary, the results of the present study suggest that modification of six miRNAs in cardiac tissue from HF children after VAD support may be involved in the regulation of several pathophysiological mechanisms underlying HF, thus providing novel perspectives for future researches.