bluuebunny/crossref_metadata_2025_split huggingface dataset:
Air pollution and out-of-hospital cardiac arrest risk
Authors: Moderato L , Lazzeroni D , Biagi A , Spezzano T , Matrone B , Piepoli M.F , Binno S , Villani G.Q , Aschieri D 
Published: November 2020

Abstract

Introduction
Out-of-hospital cardiac arrest (OHCA) is a leading cause of death worldwide; it accounts for up to 50% of all cardiovascular deaths.It is well established that ambient air pollution triggers fatal and non-fatal cardiovascular events. However, the impact of air pollution on OHCA is still controversial. The objective of this study was to investigate the impact of short-term exposure to outdoor air pollutants on the incidence of OHCA in the urban area of Piacenza, Italy, one of the most polluted area in Europe.

Methods
From 01/01/2010 to 31/12/2017 day-by-day PM10 and PM2.5 levels, as well as climatic data, were extracted from Environmental Protection Agency (ARPA) local monitoring stations. OHCA were extracted from the prospective registry of Community-based automated external defibrillator Cardiac arrest “Progetto Vita”. OHCA data were included: audio recordings, event information and ECG tracings. Logistic regression analysis was used to estimate the association between the risk of OHC, expressed as odds ratios (OR), associated with the PM10 and PM2.5 levels.

Results
Mean PM10 levels were 33±29 μg/m3 and the safety threshold (50 μg/m3) recommended by both WHO and Italian legislation has been exceeded for 535 days (17.5%). Mean PM 5 levels were 33±29 μg/m3. During the follow-up period, 880 OHCA were recorded on 750 days; the remaining 2174 days without OHCA were used as control days. Mean age of OHCA patients was 76±15 years; male gender was prevalent (55% male vs 45% female; &lt;0.001). Concentration of PM10 and PM 2.5 were significantly higher on days with the occurrence of OHCA (PM10 levels: 37.7±22 μg/m3 vs 32.7±19 μg/m3; p&lt;0.001; PM 2.5 levels: 26±16 vs 22±15 p&lt;0.001). Risk of OHCA was significantly increased with the progressive increase of PM10 (OR: 1.009, 95% CI 1.004–1.015; p&lt;0.001) and PM2.5 levels (OR 1.012, 95% CI 1.007–1.017; p&lt;0.001). Interestingly, the above mentioned results remain independent even when correct for external temperature or season (PM 2.5 levels: p=0.01 – PM 10 levels: p=0.002), Moreover, dividing PM10 values in quintiles, a 1.9 fold higher risk of cardiac arrest has been showed in the highest quintile (Highest quintile cut-off: &lt;48μg/m3)

Conclusions
In large cohort of patients from a high pollution area, both PM10 and PM2.5 levels are associated with the risk of Out-of-hospital cardiac arrest.
PM10 and PM2.5 levels and risk of OHCA

Funding Acknowledgement
Type of funding source: None
LVAD as destination therapy in Belgium: unmet needs and political bias
Authors: Timmermans P 
Published: November 2020

Abstract

Objective
To determine the impact, unmet needs and the role of left ventricular assist device (LVAD) treatment as destination therapy (DT) of heart failure (HF) in Belgium. At the moment, LVAD is only approved as “bridge to transplant” since health economical analysis calculated an unacceptable high price per QALY (84.00€).

Design
Retrospective epidemiological study on HF.

Setting and parameters
Parameters in advanced HF for Belgium, the UK (both non-DT adopters), Germany and the Netherlands (DT policies) are compared. Heart transplant (HTx) rates were consulted from (inter)national transplant organisations; implantation rates were requested from the 2 manufacturers.To quantify the impact of HF in Belgium, indirect measures on hospital admission were obtained by using the International Codes of Disease. Equity between HF and oncology was assessed by analysing approval of novel treatments. Timeframe is from 2009 till 2018.

Results
The last 10 years, mean HTx rates per million inhabitants are 6.8 in Belgium, 3.8 in Germany, 2.4 in the Netherlands and 2.5 in the UK. Transplant waiting lists are progressively exceeding the number of transplants – except in Germany. Combination of HTx and LVAD use show distinct patterns in advanced HF, with a 3-fold difference between the highest user (15,1: Germany in 2017) compared to the lowest user (4,9: UK in 2016). The need for advanced HF therapies is calculated at 14.9 per million. 8 additional LVAD implants were required in Belgium in 2018 to reach this goal.
ICDcodings in Belgium show an upwards trend, indicating that the burden of HF is increasing in Belgium. Cardiovascular diseases are still the most important cause of death in Belgium according to the latest OECD report. From 2009 till 2016, 100 new cancer drugs were approved by the EMA. Only 18 of them showed a significant survival benefit as compared to standard treatment. From them, only 1 (trastuzumab) was evaluated in a health economical assessment for the Belgian health care system.

Conclusions
There is a growing discrepancy between supply and demand in advanced HF in Belgium. The additional number of LVADs and associated impact on total healthcare expenditure is calculated to be low due to a successful HTx program. LVAD as DT should therefore be considered to cover the needs for the Belgian population.
The Netherlands and the UK are adopting “opt out” default organ donation legislations in 2020, and this could decrease the demand-supply mismatch in advanced HF.
The lack of robust epidemiological data in HF could be the cause of political bias towards oncology as compared to cardiology. The ESC should therefore strive to improve registration of LVAD use to better monitor changing health care needs, promote epidemiological research and facilitate interaction with policy makers.
Figure 1

Funding Acknowledgement
Type of funding source: None
Cost Needed to Treat (CNT) and Number Needed to Treat (NNT) analysis of drugs for treatment of heart failure in India
Authors: Mullavelil K , George V , Thannikkal A , Aravindakshan R , John D , Koshy C , Venugopal K 
Published: November 2020

Abstract

Background
Only little attention has been paid to treatment strategies of chronic disease conditions that require long term treatment and repeated hospitalizations

Purpose
Our aim was to review cost-effectiveness of guideline directed medical therapy of heart failure in India and identify drugs that can be made available free of cost or at subsidized rates to the patient population.

Methods
Data extracted from ten landmark trials in heart failure was used to compute Number Needed to Treat (NNT) and Cost Needed to Treat (CNT) of drugs used in heart failure, to prevent cardiovascular mortality and heart failure re-hospitalization using HDS Plotter- Incremental Cost Effectiveness Calculator. Since various brands (i.e. trade names) with wide cost range are available in Indian market, the average retail price in Indian Rupees for year 2019 was considered and converted to US dollars and used for the analysis.NNT and CNT of each drug was computed and the cost-effectiveness was analyzed. WHO recommendation of three times per capita GDP was used as the cost effectiveness threshold.

Results
Medications that were labeled as class I for the treatment of heart failure, were included in our analysis. Ivabradine, Valsartan and Angiotensin Receptor Neprilysin inhibitor (ARNi) did not meet the cost effectiveness criteria for preventing cardio-vascular mortality. For prevention of heart failure re-hospitalization, all drugs except ARNi, met the cost effectiveness threshold.

Conclusion
Any future research would need to consider compliance factor along with Willingness to Pay (WTP) to understand the real acceptance of these drugs on the ground in India.
Log prices (in US$) of various HF drugs

Funding Acknowledgement
Type of funding source: None
Trends in ischaemic heart disease and cerebrovascular disease mortality in Europe: an observational study from 1990–2017
Authors: Hammond-Haley M , Hartley A , Essa M , Delago A , Marshall D.C , Salciccioli J.D , Shalhoub J.D 
Published: November 2020

Abstract

Background
Cardiovascular disease remains the leading cause of death worldwide. Previously, we identified a growing disparity between Western and Eastern European countries for mortality from ischaemic heart disease (IHD) and cerebrovascular disease (CVD).

Purpose
To describe current trends in mortality from IHD and CVD.

Methods
IHD and CVD age-standardized death rates (ASDR) for European countries between 1990–2017 were extracted from the World Health Organization mortality database using the International Classification of Diseases 9th and 10th Edition codes. Jointpoint regression analysis was used to describe trends over this period.

Results
Between 1990–2017, IHD mortality declined in all included countries except Croatia (+3% in males and +23% in females). Largest mortality improvements were generally seen in Western European countries, including the Netherlands, UK and Sweden, which saw greater than 65% improvements for both sexes. Estonia was a notable exception, which, after the Netherlands, demonstrated the second highest improvement in mortality (−69% in males, −74% in females). Hungary and Greece saw the smallest improvements in IHD mortality (approximately −12% to −27%). Results of jointpoint regression analysis for selected European countries are shown in Figure 1. In 2017 Lithuania had the highest mortality rate in both males and females (279.4/100,000 and 261.3/100,000, respectively) whilst the Netherlands had the lowest mortality in males and females (32.6/100,00 and 15.3/100,000, respectively). This represents an approximately 8.5-fold difference in IHD mortality in males and a 10.5-fold difference in females between these two countries. CVD mortality declined in all included countries between 1990–2017. Estonia saw the greatest improvements in both males and females (−80.8% and −84.9%, respectively), followed by Austria, Portugal and the Czech Republic (over 70% reductions in both sexes). Bulgaria, Romania and Lithuania saw the smallest reductions (approximately −17% to −33%). In 2017, Bulgaria had the highest CVD mortality rate in both males and females (149.9/100,000 and 113.1/100,000, respectively), whilst the lowest mortality rate was observed in Austria (21.8/100,000 and 19.5/100,000 for males and females, respectively). This represents an approximately 7-fold difference in CVD mortality in males and a 6-fold difference in females between these two countries.

Conclusions
IHD and CVD mortality rates continue to decrease for men and women across Europe. While certain Eastern European countries have demonstrated considerable mortality improvements over this observation period, in general the disparity between Eastern and Western Europe persists, with further work required to understand and address these inequalities.
Squares: male. Circles: female

Funding Acknowledgement
Type of funding source: None
Waddling beyond door to balloon times and impinging true ischemic times with artificial intelligence-guided single lead EKG for STEMI detection
Authors: Mehta S , Niklitschek S , Fernandez F , Villagran C , Vera F , Frauenfelder A , Vieira D , Ceschim M , Quintero S , Pinto G , Vallenilla I , Perez Del Nogal G , Cardenas J , Prieto L , Luna M 
Published: November 2020

Abstract

Background
The present process of STEMI detection is cumbersome as it utilizes outdated equipment and requires a trained technician and an expert cardiologist. We have developed a patient-administered, Artificial Intelligence (AI) guided, Single Lead EKG for early STEMI detection.

Purpose
To answer the question “Is early STEMI detection possible with a Single Lead EKG?”

Methods
We experimented with an AI-guided algorithm for a single-lead EKG for STEMI detection with the following step-wise developments: 1) An AI algorithm that predictably interprets STEMI using a 12-lead EKG; 2) An AI algorithm for STEMI detection using a single-lead EKG; 3) A methodology for identifying the best single lead to detect STEMI; 4) Advanced AI algorithms for STEMI localization with a single-lead EKG. The AI methodology was as follows: Sample: The mammoth Latin American Telemedicine Infarct Network telemedicine database that provides an umbrella of AMI management to 100 million patients in Brazil, Colombia, Mexico, Chile, and Argentina was queried for cardiologist annotated EKG. A total of 8,511 EKG and 90,592 classified heartbeats were selected for the experiments. Preprocessing: segmentation of each ECG into individual heartbeats. Training & Testing: 90% and 10%, respectively, of the total dataset. Classification: 1-D Convolutional Neural Network; classes were construed for each heartbeat. Performance indicators were calculated per lead.

Results
The algorithm was able to provide an accuracy of 91.9%. Lead V2 yielded the best results among individual leads for STEMI detection.

Conclusions
Early experiments provide a framework for augmenting STEMI detection with the use of AI-guided, single lead techniques. Such approaches seem rational as we target the reduction of true STEMI ischemic times.

Funding Acknowledgement
Type of funding source: None
Identification and functional characterization of circular RNAs in pericytes
Authors: Glaser S , Heumueller A.W , Klangwart M , Wiederer A , John D , Zeiher A.M , Zehendner C.M , Dimmeler S 
Published: November 2020

Abstract

Background
Circular RNAs (circRNAs) are generated by back-splicing. They are known to be robustly expressed in a variety of mammalian cell types and organism and have been reported to influence cell biology by acting e.g. as microRNA sponges or regulating host gene expression. Recently, our group reported functionally relevant circRNA expression in endothelial cells. Despite their important role in the cardiovascular system, the expression and function of circRNAs in pericytes is not well studied. Pericytes are perivascular mural cells, important for vessel maturation and endothelial barrier function. Their recruitment towards endothelial cells is mainly meditated by platelet-derived growth factor (PDGF) signaling. However, a more precise understanding of the regulation of pericyte differentiation and survival is necessary.

Objective
Here, we analyse circRNA expression in pericytes and demonstrate biological relevance of the hypoxia regulated circular RNA PLOD2 (cPLOD2).

Methods and results
Using RNA Sequencing in ribosomal depleted RNA we characterized the expression of circRNAs in human pericytes under normoxic and hypoxic (1% O2, 48h) conditions. We identified several circular RNAs being regulated upon hypoxia. The identified circular RNAs demonstrated resistance towards RNase-R digestion and lacking of poly-adenylation. Some of them were found to be localized and in the cytosol, whereas others also occur in the nucleus of the cells. Especially cPLOD2 raised our attention since it is significantly upregulated and robustly expressed upon hypoxia. Silencing cPLOD2 by siRNA resulted in significant de-differentiation of pericytes that went along with a loss of cell viability. Mechanistically, transcription factor screening assays revealed that silencing of cPLOD2 enhances the activity of the transcription factors ELK1/SRF, which have been documented to result in de-differentiation of smooth muscle cells.

Conclusion
Here we characterize the expression pattern of circRNAs in human primary pericytes. Among others, cPLOD2 significantly regulates pericyte function. Our results indicate hypoxia as a major regulator of circRNA expression in pericytes and show that circRNAs are capable of regulating pericyte function by modulating activity of transcription factors.

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): Deutsche Forschungsgesellschaft (DFG) - SFB834; Deutsche Gesellschaft für Herz-Kreislaufforschung (DZHK)
Phosphorylation of mitophagic receptor protein Bcl2-like protein 13 plays an important role in maintaining cardiac function under pressure overload
Authors: Murakawa T , Otsu K 
Published: November 2020

Abstract

The most prominent role for mitochondria is to supply the cell with metabolic energy in the form of ATP generated by oxidative phosphorylation. Therefore, the quality control of mitochondria is essential for the maintenance of normal cellular functions. Accumulation of damaged mitochondria is characteristic of various diseases including heart failure. Damaged mitochondria are removed by a mitochondria-specific autophagy, called mitophagy.
Recently, we identified Bcl2-like protein 13 (Bcl2-L-13) as a mammalian functional homolog of Atg32, which is an essential mitophagy receptor in yeast. Bcl2-L-13, localized in outer mitochondrial membrane, induces mitochondrial fragmentation and mitophagy in HEK293 cells. Bcl2-L-13 induces mitophagy through the binding with microtubule-associated protein 1A/1B-light chain 3 (LC3).
We attempted to elucidate the activation mechanism of Bcl2-L-13-mediated mitophagy. Ser272 is close to the LC3 interacting motif in Bcl2-L-13. Overexpression of Bcl2-L-13 induced its Ser/Thr phosphorylation in HEK293 cells. The phosphorylation level of Bcl2-L-13 S272A was significantly attenuated compared with wild-type Bcl2-L-13, suggesting Ser272 is one of the phosphorylation sites. GST-pull down assay revealed that Bcl2-L-13 S272A showed less ability for binding with LC3, while immunocytochemical analysis using anti-ATP synthase and anti-LC3B antibodies showed that the mutant induced less mitophagic activity.
Next, we generated sheep polyclonal antibody for the detection of Bcl2-L-13 phosphorylated at Ser272. The antibody recognized wild-type Bcl2-L-13 but not Bcl2-L-13 S272A mutant. The phosphorylation level of Bcl2-L-13 at Ser272 was upregulated in wild-type hearts 4 weeks after transverse aortic constriction (TAC). In order to examine the in vivo role of the phosphorylation, we generated Bcl2-L-13 S272A mutant knock-in mice. The mice showed no abnormal cardiac phenotypes at baseline. However, the knock-in mice showed significantly larger left ventricular end-diastolic and end-systolic dimensions and lower fractional shortening than wild-type mice 4 weeks after TAC.
Taken together, the phosphorylation of Ser272 in Bcl2-L-13 regulates its mitophagic activity and plays an important role in maintaining cardiac function under pressure overload.

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): British Heart Foundation
Curcumin-loaded extracellular vesicles endowed with heart targeting properties facilitate treatment of myocardial infarction
Authors: Kang J.Y , Kim H.E , Mun D.S , Yun N.R , Joung B.Y 
Published: November 2020

Abstract

Background
Myocardial infarction (MI) is a public health problem and a leading cause of death worldwide. Due to insufficient current treatments, it is essential to develop effective alternatives for MI treatment. Curcumin is known to exhibit a variety of protective effects on the cardiovascular system such as MI, hypertension, and diabetic cardiomyopathy. However, due to its low solubility/stability and quick systemic elimination, curcumin has limited bioavailability. Extracellular vesicles (EVs) have lately emerged as a promising drug delivery vehicles by overcoming drug delivery hurdles. However, strategies are needed for delivery of EVs into the heart avoiding accumulation of other organs.

Purpose
The aim of this study is to investigate whether curcumin-loaded EVs functionalized with cardiac targeting peptide (CTP) may function as efficient heart-targeted delivery vehicles of curcumin, and further identify the molecular mechanisms underlying curcumin-mediated therapeutic effects in the MI.

Methods
EVs functionalized to express CTP (CTP-EVs) were isolated from culture medium of HEK293 cells transfected with mCherry-CD81–10 plasmid and CTP-LAMP2 plasmid by differential centrifugation, and then loaded with curcumin by coincubation, named CTP-EVs-Cur. The effect of CTP-EVs-Cur were evaluated H9C2 cardiomyocytes and mouse MI model. For the in vivo experiments, CTP-EVs-Cur (approximately 8–10 × 109 particles) were administered by intravenous injection into the tail vein and mice were subjected to the left anterior descending (LAD) artery ligation with a 6–0 silk suture.

Results
CTP-EVs were safely and successfully delivered curcumin to H9C2 cardiomyocytes and mouse hearts (4-fold; P&lt;0.05), and CTP-EVs-Cur have a protective effect against MI in vitro and in vivo models. After validating potential utility of CTP-EVs-Cur in MI treatment, we investigated the mechanism of curcumin-mediated recovery effects after MI. In H2O2 treated-cardiomyocytes, curcumin significantly reduced apoptosis by regulating the PTEN/AKT pathway following upregulation of miR-144-3p expression. Furthermore, mice injected with CTP-EVs-Cur reduced infarct size and apoptosis with the regulation of miR-144-3p/PTEN/Akt pathway.

Conclusion
These findings suggest highly stable/effective ability of CTP-EVs for heart-targeted delivery and the novel mechanism of curcumin-mediated cardioprotective effects after MI, therefore, CTP-EVs-Cur are potentially powerful therapeutic strategy for MI treatment.

Funding Acknowledgement
Type of funding source: None
Small extracellular vesicles from epicardial fat of patients with atrial fibrillation induce inflammation, fibrosis and re-entrant arrhythmias
Authors: Shaihov-Teper O , Ram E , Brzezinski R , Volvovitch D , Zuroff E , Amunts S , Schary Y , Naftali-Shani N , Ballan N , Gepstein L , Sternik L , Raanani E , Leor J 
Published: November 2020

Abstract

Background and aim
Epicardial fat (eFat) has been linked to atrial remodeling and fibrillation (AF). Small extracellular vesicles (sEVs) are heterogeneous membrane vesicles released by all cell types. They can both protect and damage tissues by the delivery of multiple different messengers. Surprisingly, the role of sEVs in the pathogenesis of AF has not been studied. Thus, we aimed to determine whether sEVs derived from eFat play a role in the pathogenesis of AF.

Methods and results
We collected eFat specimens from patients with and without chronic or paroxysmal AF undergoing open-heart surgery. Isolated eFat specimens were cut into small pieces and incubated as organ cultures. We isolated sEVs from the medium of the explant by differential ultra-centrifugation, high-density gradient or size exclusion chromatography (SEC), and characterized vesicle size distribution, morphology, specific markers, histology and molecular cargo. Immunostaining for macrophage accumulation, fibrosis and apoptosis confirmed the pro-inflammatory and pro-fibrotic properties of eFat sEVs from patients with AF (Fig. 1). eFat sEVs labeled with PKH26 were massively up taken by endothelial cells (Fig. 2). Real-time PCR showed an increased level of oxidative stress genes in endothelial cells. eFat sEVs from patients with AF caused more fibrosis after injection into rat hearts than those without AF. (Fig. 3). Finally, while eFat sEVs from patients with and without AF induced shorter action potential duration, only eFat sEVs from patients with AF induced sustained re-entry (rotor) in human induced pluripotent stem cell (iPS)-derived cardiomyocytes (Fig. 4)

Conclusion
We show, for the first time, that sEVs from eFat of patients with AF demonstrate unique pro-inflammatory, pro-fibrotic and pro-arrhythmic properties. Our findings suggest that eFat sEVs can induce cellular, molecular and electrophysiological remodeling that can subsequently lead to the development of AF.

Funding Acknowledgement
Type of funding source: None