bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of environmental pollution and climate changes on the incidence of ST-elevation myocardial infarction
Authors: Biondi-Zoccai G , Frati G , Gaspardone A , Mariano E , Di Giosa A , Bolignano A , Dei Giudici A , Calcagno S , Scappaticci M , Sciarretta S , Valenti V , Peruzzi M , Federici M , Romeo F , Versaci F
Published: November 2020

Background/Introduction

Several reports have highlighted the detrimental impact of environmental pollution and climate changes on cardiovascular disease. However, detailed analyses aiming at disentangling the differential impact of pollution versus climate are lacking. Most importantly, limited research has focused on ST-elevation myocardial infarction (STEMI), the most severe yet distinctive form of acute coronary syndrome.

Purpose/Methods

We aimed at appraising the impact of environmental pollution and climate changes on the incidence of STEMI, analyzing the bivariate and multivariate association between several environmental and atmospheric parameters and the daily incidence of STEMI in two large Italian urban areas. Specifically, we appraised: carbon monoxide (CO), nitrogen dioxide (NO2), nitric oxide (NOX), ozone, particulate matter smaller than 10 μm (PM10) and than 2.5 μm (PM2.5), temperature, atmospheric pressure, humidity, and rainfall. On top of same day association, we appraised STEMI risk 1, 2, and 3 days later. Computations were performed using a multilevel mixed-effects generalized linear model with Poisson likelihood and log link, yielding incidence ratios (95% confidence intervals) and corresponding p values.

Results

A total of 4458 days at risk were appraised, 3473 cases of STEMI. Specifically, no STEMI occurred in 1920 (44.8%) days, whereas one or more occurred in the remaining 2365 (55.2%) days. Multilevel modeling identified several pollution and climate predictors of STEMI, either occurring on the same day, or on the following ones. In particular, concentrations of CO (p=0.024), NOX (p=0.039), O3 (p=0.003), PM10 (p=0.033), and PM2.5 (p=0.042) predicted STEMI as early as three day before the event, as well subsequently, and NO predicted STEMI one day before (p=0.010), as well as on the same day. A similar predictive role was evident for temperature and atmospheric pressure (all p<0.05). Notably, strong correlations were evident between same-day temperature, pollutants and climate.

Conclusions

The risk of STEMI in the current primary percuntaneous coronary intervention area is strongly associated with pollution and climate features. Most notably, environmental and climate changes can be exploited to predict STEMI risk in the following days.

Funding Acknowledgement

Type of funding source: None
Maximum artificial intelligence and complete reconstruct of population-based AMI care
Authors: Mehta S , Gibson M , Niklitschek S , Fernandez F , Villagran C , Escobar E , Vera F , Frauenfelder A , Vieira D , Vijayan Y , Quintero S , Vallenilla I , Pinto G , Cardenas J , Merchant S
Published: November 2020

Background

After creating a behemoth hub and spoke AMI network that encompasses more than 100 million patients in 5 countries, we have begun to incorporate Artificial Intelligence (AI) algorithms into our telemedicine strategy with the goal of creating comprehensive, very early AMI diagnosis and physician-free triage. In doing so, we have replaced door-to-balloon times (d2b) with symptom-to-balloon times (s2b) as an immutable objective.

Purpose

To incorporate AI attributes for very early AMI detection, triage, and management.

Methods

We expanded our effective telemedicine strategy (100 million population; 877,178 telemedicine encounters; 55% overall mortality reduction; $291 million cost savings) with a logistic reset to impact s2b. To do this, we incorporated our Single Lead 1.0 (lead I) and Single Lead 2.0 (lead V2) technology for self-administered AMI detection with our physician-free STEMI diagnosis and triage AI algorithms. Single Lead algorithms and physician-free protocols were generated by utilizing Machine Learning from our mammoth annotated EKG repository.

Results

In addition to three logistic markers of efficiency Time-to-Telemedicine Diagnosis (TTD), Door-In-Door-Out (DIDO) and Transfer Times (TT); we are monitoring s2b. A gradual release of the algorithms and single lead is occurring at the telemedicine spokes. Detailed results will be available at the time of presentation.

Conclusions

Impacting s2b, the Achilles Heel of Primary PCI, may be achieved with the use of patient-administered AMI detection tools. Incorporation of these technologies into AI algorithms will add to telemedicine efficiencies for population-based AMI care.

Funding Acknowledgement

Type of funding source: None
The first disease centred network in Spain: a bottom-up cardiovascular hospital and primary care network focused on reducing variability, improving population health and efficiency
Authors: Bengoa Terrero C , Bas Villalobos M , Macaya Miguel C , Maroto Castellanos L.C , Fernandez Rozas I , Garcia Lledo A , Perez Villacastin J
Published: November 2020

Introduction

In an autonomous region in Spain, the heads of cardiovascular disease from four hospitals, forty-three primary care centres and the ambulance provider, have come together to collectively reduce variability, improve outcomes and patient experience, increase efficiency and focus on population health through prevention. As a result, a cardiovascular network was founded to address the needs of the population through eight projects, each with a group of professionals dedicated to its completion. This region has Beveridge-type universal healthcare and the clinical network must operate under a choice model in which patients can choose where they wish to be treated. This approach has never been carried forward in Spain previously nor, as far as we are aware, in Europe from the bottom-up with clinical leaders achieving buy-in from the political level.

Purpose

With the well-known demographic challenge putting the system under strain, our hypothesis is that this innovative collaborative approach where by hospitals pool resources and implement collective improvements from the bottom-up will results in better health for its population of over one million people.

Methods

The Institute for Healthcare Improvement's Assessment Scale for Collaboratives is used to track project progress through the valuation of project leads assigned to each project and the senior project manager. This scale divides progress from: forming team, activity but no changes, modest improvement, significant improvement, and outstanding sustainable results; some are further subdivided as shown in the image. Projects each have their set of indicators to ensure project objectives are achieved.

Results

The network has 8 working projects which include different specialists, professional groups and organizations including primary care and the main ambulance provider. The four hospitals have pulled together their resources to recruit two project managers. Progress measured with the Assessment Scale for Collaboratives indicates that projects have moved forward 18% in a three month period, reaching an average progress of 35%.

Conclusion

The closer collaboration across four hospital sites has put this network at the forefront of Spanish health policy by focusing work on diseases rather than by geographical areas. This allows clinical leaders to decide and focus on objectives that most suit the needs of its population whilst building a culture of continuous improvement across multiple care sites and professional groups.

Funding Acknowledgement

Type of funding source: Foundation. Main funding source(s): Fundaciόn Interhospitalaria para la Investigaciόn Cardiovascular - Fundaciόn FIC
A cost effectiveness study into the detection of functionally significant coronary artery disease in patients with chronic coronary syndrome: a decision-analytic modelling approach
Authors: Nazir M.S , Rodriguez-Guadarrama Y , Rua T , Chiribiri A , Pennington M , Plein S
Published: November 2020

Background

ESC guidelines recommend functional or anatomical imaging for stable coronary artery disease (CAD) diagnosis. We investigated cost-effective diagnostic strategies for CAD detection with invasive coronary angiography (ICA) and fractional flow reserve (FFR) as reference standard [1,2], using NHS reference costs.

Methods

Deterministic and probabilistic decision-analytic models for diagnostic strategies in low (25%), intermediate (50%) and high (75%) risk CAD were devised. Strategies: standalone or combined testing with computed tomographic coronary angiography (CTCA), stress echocardiography (SE), CT-FFR, single-photon emission computed tomography (SPECT), cardiac magnetic resonance (CMR), positron emission tomography (PET), ICA, and ICA-FFR. Proportion of correct diagnosis served as measure of clinical effectiveness. Incremental cost-effectiveness ratios were calculated for dominant strategies. Cost-effectiveness acceptability curves (CEAC) tested variation of cost-effectiveness threshold (CET).

Results

Base case (Table 1) consistent with probabilistic analysis (Figure 1 left). CEACs (Figure 1 right).

Conclusions

Direct ICA is not cost-effective. Functional testing has significant role in low/intermediate risk. CMR is cost-effective in all risk and most likely cost-effective in CETs <£10,000. ICA-FFR yields highest correct diagnoses in all at highest cost. Future long-term follow-up studies with quality of life measures are needed.

References

1. Knuuti et al EHJ. 2018; 39(35):3322–30

2. Danad et al. EHJ. 2016; 38(13):991–8.

Figure 1. A: low, B: intermediate, C: high.

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): The authors acknowledge financial support from the Department of Health through the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust and by the NIHR MedTech Co-operative for Cardiovascular Disease at Guy's and St Thomas' NHS Foundation Trust. This abstract presents independent research funded by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfPB) Programme (Grant Reference Number PB-PG-0416-20008). This work was supported by the Wellcome/EPSRC Centre for Medical Engineering [WT 203148/Z/16/Z]. MSN was funded by the UK Medical Research Council under grant number MR/P01979X/1. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care, EPSRC, MRC or the Wellcome Trust.
Left ventricular hypertrophy detection system based on electrocardiogram signal
Authors: Liu C.W , Pan R.H , Hu Y.L
Published: November 2020

Background

Left ventricular hypertrophy (LVH) is associated with increased risks of cardiovascular diseases. Electrocardiography (ECG) is generally used to screen LVH in general population and electrocardiographic LVH is further confirmed by transthoracic echocardiography (Echo).

Purpose

We aimed to establish an ECG LVH detection system that was validated by echo LVH.

Methods

We collected the data of ECGs and Echo from the previous database. The voltage of R- and S-amplitude in each ECG lead were measured twice by a study assistance blinded to the study design, (artificially measured). Another knowledge engineer analyzed row signals of ECG (the algorithm). We firstly check the correlation of R- and S-amplitude between the artificially measured and the algorythm. ECG LVH is defined by the voltage criteria and Echo LVH is defined by LV mass index >115 g/m2 in men and >95 g/m2 in women. Then we use decision tree, k-means, and back propagation neural network (BPNN) with or without heart beat segmentation to establish a rapid and accurate LVH detection system. The ratio of training set to test set was 7:3.

Results

The study consisted of a sample size of 953 individuals (90% male) with 173 Echo LVH. The R- and S-amplitude were highly correlated between artificially measured and the algorithm R- and S-amplitude regarding that the Pearson correlation coefficient were >0.9 in each lead (the highest r of 0.997 in RV5 and the lowest r of 0.904 in aVR). Without heart beat segmentation, the accuracy of decision tree, k-means, and BPNN to predict echo LVH were 0.74, 0.73 and 0.51, respectively. With heart beat segmentation, the signal of Echo LVH expanded to 1466, and the accuracy to predict ECG LVH were obviously improved (0.92 for decision tree, 0.96 for k-means, and 0.59 for BPNN).

Conclusions

Our study showed that machine-learning model by BPNN had the highest accuracy than decision trees and k-means based on ECG R- and S-amplitude signal analyses.

Figure 1. Three layers of the decision tree

Funding Acknowledgement

Type of funding source: None
Patient consent in emergency cardiovascular medicine: lessons from the ARREST trial in out-of-hospital cardiac arrest
Authors: Perkins A , Patterson T , Evans R , Clayton T , Fothergill R , Redwood S
Published: November 2020

Introduction

Randomised trials in emergency cardiovascular medicine are challenging but vital for improving patient care. Obtaining informed consent in such an environment is a particular issue and can be controversial. The ARREST trial is assessing whether out-of-hospital cardiac arrest patients without an obvious cause should be taken to a specialist heart centre or the closest emergency department in London, UK. This patient group presents specific difficulties: patients lack capacity to consent, presentation is unpredictable, care must not be delayed, and mortality rates can be >50%.

Purpose

Within existing consent and methodological frameworks we aimed to design a randomised clinical trial to pragmatically, safely and ethically recruit cardiac arrest patients pre-hospital.

Methods

During the set-up of ARREST we accessed the following sources of information: 1) ARREST research team; 2) cardiovascular patient groups; 3) researchers running similar trials; 4) regulatory bodies; and, 5) published literature on research in emergency contexts. The information that we collected guided the design of the trial with a focus on patient consent, documentation and follow-up.

Results

The ARREST trial uses deferred consent with remote online randomisation to enrol patients without delaying care. To minimise the risk of bias, baseline and primary endpoint data are collected on patients who die or are discharged prior to consent. Remote follow-up using electronic health records reduces the burden on the patients and researchers. Full ethical approval was received in January 2018 and the first patient was enrolled in February 2018. ARREST is recruiting to target and is on track to finish within the projected timelines.

Conclusions

Deferred consent has been key to the success of ARREST and patients have been receptive. However, further research into the experience of patients in emergency cardiovascular medicine trials using deferred consent is needed to better understand when it is an appropriate model. More broadly, there is a shortfall in high quality research in challenging environments such as emergency cardiovascular care. Innovation in consent methods and proportional research governance would facilitate higher quality research and benefit patient care.

Funding Acknowledgement

Type of funding source: Foundation. Main funding source(s): British Heart Foundation
Simultaneous endo-epicardial mapping of the human sinus node in patients undergoing cardiac surgery
Authors: Kharbanda R , Wesselius F.J , Taverne Y.J.H.J , Kik C , Van Schaagen F.R.N , Roos-Serote M.C , Bogers A.J.J.C , De Groot N.M.S
Published: November 2020

Introduction

Conduction disorders in the right atrium (RA) are predominantly observed in the superior part. Presence of the sinoatrial node (SAN) in this region could be contributing to increased heterogeneity in activation patterns. However, mapping studies focusing on SAN activation are scarce.

Purpose

The aim of the present study was to analyze activation patterns of the human SAN during sinus rhythm.

Methods

A dataset containing simultaneous endo-epicardial mapping data (256 electrodes, inter-electrode spacing: 2mm) of RA was screened for focal activation patterns (FAPs) potentially arising from SAN activation (SN-FAP). Conduction time, endo-epicardial delay and electrogram morphology (R/S-ratio) were described in the surrounding 1cm of SN-FAPs. Areas of conduction block (CB) were defined as conduction delays of ≥12ms and endo-epicardial asynchrony (EEA) as activation time differences of exact opposite electrodes of ≥15ms.

Results

In 20 patients (75% male, 66±7 years) a total of 28 SN-FAPs with unique activation patterns were observed only in superior RA (n=22) and mid RA (n=6). Conduction velocity of SN-FAPs was 1.3m/s [0.8–2.5] and percentage of EEA was 5% [2–18]. Conduction velocity was lower when lines of CB were present within 6mm of the SN-FAPs (p=0.040). Significantly larger R-peaks were observed in mid RA compared to superior RA. (mid R/S-ratio:0.15 [0.067–0.34] vs. superior R/S-ratio:0.045 [0.026–0.062], p=0.004).

Conclusions

Conduction velocities around the SAN area are comparable to the remainder of the atria. SN-FAPs occurred in both superior and mid RA, suggesting presence of multiple exit sites of the SAN. Furthermore, inter-individual differences in rS-morphology indicate that SAN activation may originate from multiple layers within the atrial wall.

Funding Acknowledgement

Type of funding source: None
Membrin/GOSR2 is a novel NaV1.5-interacting protein modulating cardiac conduction
Authors: Offerhaus J , Podliesna S , Verkerk A.O , Marchal G , Lodder L.E , Boukens B.J.B , Remme C.A , Bezzina C.R
Published: November 2020

Background

Genome-wide association studies have associated a locus spanning GOSR2 with QRS- and QT-interval. GOSR2 encodes Membrin, a protein located at the cis-Golgi, which plays a role in protein trafficking. Altered trafficking of the cardiac sodium channel (NaV1.5), encoded by SCN5A, has been shown to reduce cardiac conduction.

Purpose

To explore the modulatory role of Membrin on cardiac conduction and sodium channel availability.

Methods and results

Tandem Affinity Purification in H10 cells (derived from neonatal rat cardiomyocytes) overexpressing the NaV1.5 C-terminus identified Membrin as a putative interactor of NaV1.5. We subsequently confirmed the interaction between NaV1.5 and Membrin by means of a co-immunoprecipitation assay in HEK293A cells that overexpress NaV1.5 and Membrin.

To investigate whether Membrin affects cardiac conduction we recorded optical action potentials from the left ventricle (LV) of Langendorff-perfused hearts from Gosr2+/− mice and wild type (WT) littermate controls. Conduction velocity was measured at steady state pacing (cycle length 120ms) and at the minimal possible cycle length (S2min), during S1S2 pacing. Longitudinal conduction velocity was increased in Gosr2+/− mice compared to WT at steady state- (76.44 vs. 67.00 cm/s) as well as at S2min (62.00 vs. 51.86 cm/s, p=0.039, n=10 and 9, resp.). Single cell patch-clamp studies revealed a shortened action potential duration at 90% repolarization at all pacing frequencies (390 vs 342 V/s at 2Hz, p=0.036) in isolated mid-LV cardiomyocytes of Gosr2+/− mice compared to WT. In addition, the maximal upstroke velocity was increased in Gosr2+/− mid-LV cardiomyocytes at frequencies of 6Hz and higher (390 vs 342 V/s at 6Hz, p=0.044).

Conclusion

Our findings identify Membrin as a novel interacting protein of NaV1.5 and a modulator of cardiac conduction. We propose that Membrin acts through ion channel trafficking or by modulating the posttranslational maturation of ion channels.

Funding Acknowledgement

Type of funding source: Foundation. Main funding source(s): Leducq foundation
Ataxia-telangiectasia mutated protein protects cardiac cells from stress by rewiring glucose metabolism
Authors: Paolillo R
Published: November 2020

Introduction

Pressure overload-induced cardiac hypertrophy is associated with increased reactive oxygen species (ROS), inducing DNA damage and activating the protein kinase Ataxia-Telangiectasia Mutated (ATM). Recently, ATM has been also involved in the regulation of several metabolic processes, but whether and how it affects cardiac metabolism is still poorly understood.

Purpose

We hypothesized that ATM might play crucial roles in the maintenance of cardiomyocyte metabolic homeostasis and in the development of cardiac dysfunction in response to pressure overload.

Methods

Atm+/+ and Atm homozygous mutated mice (Atm−/−) underwent transverse aortic constriction (TAC) or sham operation (sham). After one week (1w), sham and TAC mice were anesthetized, cardiac function and morphometry were analyzed, and gene expression reprogramming, cardiac histology, mitochondrial morphology were performed. Metabolic profiling was carried out through untargeted metabolomics (LC-MS/MS and GC/MS), mRNA and/or protein levels analysis to investigate glycolyis, pyruvate oxidation, Krebs cycle, aminoacid synthesis, gluconeogenesis and lipid oxidation.

Results

Atm genetic inactivation induced cardiomyocytes hypertrophy and fetal gene reprogramming in sham mice, with normal cardiac function and in the absence of fibrosis or mitochondrial dysfunction (Figure 1A). After TAC 1w, cardiac function was significantly decreased in Atm−/− mice, compared to Atm+/+ (Figure 1B). In both sham and TAC 1w Atm−/− mice, significant metabolic abnormalities were identified, including switching of glycolysis, reduction of pyruvate oxidation (Figure 1B), activation of aminoacid synthesis and accumulation of long and short-chain fatty acid conjugated with carnitine. Pyruvate accumulation was associated to a significant reduction of pyruvate carrier (MPC1-MPC2) and pyruvate dehydrogenase (PDH) levels in sham and TAC 1w Atm−/− mice.

Conclusions

ATM regulates gene expression, cardiomyocyte hypertrophy and cardiac responses to pressure overload, modulating cardiac metabolism and the profile of intracellular substrate utilization in the heart. Thus, ATM might represent a novel important player in the development of cardiac dysfunction and a novel therapeutic target.

Figure 1

Funding Acknowledgement

Type of funding source: Other. Main funding source(s): CP was supported by Ministero dell'Istruzione, Università e Ricerca Scientifica grant (2015583WMX) and Programma STAR grant by Federico II University and Compagnia di San Paolo. RP was supported by a research grant provided by the Cardiopath PhD program.
Mimetic nanoparticles regulate the inflammation of ischemic myocardium
Authors: Chen J , Huang Z.Y , Ge J.B
Published: November 2020

Background

Most drug delivery systems are lack of accurate targets, so the poor efficiency significantly limited the therapeutic effects. Neutrophil plays an important role in the acute phase of myocardial infarction. There are multiple chemokine receptors on the surface of cell membrane proteins, which participate in inflammatory chemotaxis and immune regulation.

Purpose

Through syntheses and target delivery of biomimetic neutrophil liposomes (Neu-Lipos), it is possible to increase the delivery efficiency, reduce inflammation of ischemic region and promote the progression of myocardium repair.

Methods and results

Biomimetic nanoparticles (Neu-Lipos) were synthesized using membrane proteins purified from activated neutrophils. Neu-Lipos were characterized using dynamic light scattering and were found to have a diameter of 163.5±3.6 nm, a surface charge of −28.7±1.6 mV. For in vivo studies, C57 mice were constructed of ischemia-reperfusion model. Mice were injected with either PBS, Lipos (5 mg/kg), or Neu-Lipos (5 mg/kg) one day after reperfusion. The targeting ability of Neu-Lipos to injured myocardium was significantly higher than Lipos. In mice treated with Neu-Lipo, the result of immunofluorescence revealed fewer M1 and more M2 infiltrating in border region compared with untreated mice and Lipo treated mice. Furthermore, macrophage polarization correlated with downward trends Inflammatory chemokines. Neu-Lipos–treated mice also displayed significantly decreased IL-1α, IL-1β and IL-6 in the injured myocardium. Histological analysis showed no significant toxicological alterations displayed in lung, spleen, kidney, or liver in Neu-Lipos treated group.

Conclusions

We showed that our Neu-Lipos showed a decrease in proliferating macrophage population that was accompanied by the reduction of key proinflammatory cytokines and changes in myocardial repair. This proof of concept showed that our platform was capable of altering macrophage polariton within the injured tissue after treated and with a favorable toxicity profile. This treatment could be a promising intervention for the acute ischemia of myocardium.

Funding Acknowledgement

Type of funding source: Foundation. Main funding source(s): The National Natural Science Foundation of China
DNMT3A clonal hematopoiesis-driver mutations are associated with profound changes in monocyte and T cell signatures in humans with heart failure
Authors: Abplanalp W , Cremer C , Cremer S , John D , John D , Hoffmann J , Hoffmann J , Rieger M.A , Rieger M.A , Vasa-Nicotera M , Vasa-Nicotera M , Zeiher A.M , Zeiher A.M , Dimmeler S , Dimmeler S
Published: November 2020

Background

Clonal hematopoiesis (CH) driven by mutations of DNA methyltransferase 3a (DNMT3A) is associated with increased incidence of cardiovascular disease and poor prognosis of patients with chronic heart failure (HF) and aortic stenosis. Although experimental studies suggest that DNMT3A CH-driver mutations may enhance inflammation, specific signatures of inflammatory cells in humans are missing. Single-cell RNA-sequencing provides a novel opportunity to define subsets of immune cells mediating inflammation in humans.

Methods

Transcriptomic profiles of peripheral blood mononuclear cells were analysed in N=6 HF patients harboring DNMT3A CH-drived mutations and with HF and N=5 patients with HF and DNMT3A mutations by single-cell RNA-sequencing.

Results

Monocytes of HF patients carrying DNMT3A mutations demonstrated a significantly increased expression of inflammatory genes compared to monocytes derived from patients with HF without DNMT3A mutations. Among the specific up-regulated genes were the prototypic inflammatory interleukins (IL) IL1B, IL6, and IL8, the macrophage inflammatory proteins CCL3 and CCL4 as well as restin, which augments monocyte-endothelial adhesion. The classical monocyte subset of DNMT3A mutation carriers showed increased expression of immunoglobulin superfamily members CD80, CD300LB, and SIGLEC12, as well as the cell adhesion molecule CD58, all of which may be involved in monocyte-T cell interactions. DNMT3A mutation carriers were further characterized by increased expression of T cell receptor chains and Th1, Th17, CD8+ and Treg specific signatures.

Conclusions

This study demonstrates that circulating monocytes and T cells of HF patients harboring CHIP-driver mutations in DNMT3A exhibit a highly inflamed transcriptome, which may contribute to the aggravation of chronic heart failure.

Funding Acknowledgement

Type of funding source: Public Institution(s). Main funding source(s): The German Research Foundation (SFB834, Project B1), and the German Center for Cardiovascular Research (DZHK).
Genome-wide association study based on cardiac magnetic resonance imaging in 23,634 individuals identifies five new loci associated with left atrial enlargement
Authors: Ahlberg G , Andreasen L , Ghouse J , Haunsoe S , Svendsen J.H , Olesen M.S
Published: November 2020

Left atrial enlargement is associated with mortality due to cardiovascular disease and all-cause mortality. The pathology behind and the association with cardiovascular outcomes are, however, poorly characterised. Compromised atrial function seems to predispose for stroke.

We obtained data from the UK Biobank cardiovascular magnetic resonance (CMR) protocol containing CMR scans from ∼31,000 individuals at the time of study (Fig. 1a). Genome-wide association studies were carried out on state-of-the-art imaging variables exposed to machine learning algorithms to investigate the genetic basis of left atrial volume and function. Deep learning algorithms segmented the atria in the CMR scans (Fig. 1b). Left atrial (LA) volume curves could then be extracted and analysed (Fig. 1c).

We tested 10.6 million variants for association with LA minimum/maximum volumes and LA emptying fraction (LAEF) in 23,624 European individuals without prevalent myocardial infarction or heart failure. We identified five genetic loci located in close proximity to the genes EIF2D, C9orf3, ANKRD1, FGFR2, and MYO18B. We observed a notable genetic correlation between both maximum and minimum LA volumes and stroke and cardioembolic stroke (Fig. 1d).

Conclusions

We report on five genetic loci and suggest several plausible candidate genes important for atrial structural pathology. Genetic correlation analyses indicate that the genetic determinants of LA volumes could be markers of stroke risk. These findings enhance our understanding of the importance of the LA and are potential novel therapeutic targets for cardiovascular disease, including stroke.

Figure 1. LA imaging GWAS

Funding Acknowledgement

Type of funding source: Foundation. Main funding source(s): Novo Nordisk, Halles Moeller
Diagnostic findings in relatives to victims of sudden unexplained death or non-autopsied possible sudden cardiac death
Authors: Dalgaard C.V , Hansen B.L , Jacobsen E.M , Kjerrumgaard A , Tfelt-Hansen J , Weeke P.E , Winkel B.G , Christensen A.H , Bundgaard H
Published: November 2020

Introduction

Sudden cardiac death (SCD) may be caused by several inherited cardiac diseases and screening and treatment of relatives may be lifesaving. Sudden unexplained death (SUD) victims have been autopsied, whereas non-autopsied possible SCD (pSCD) victims are only filtered on manner of death and medical records. Screening of relatives may identify an inherited cardiac disease.

Purpose

To assess the diagnostic yield at initial evaluation and during follow-up of relatives to SUD and pSCD victims. Furthermore, to evaluate the outcome in the relatives.

Methods

We retrospectively included first-degree relatives to SUD and pSCD victims referred to our tertiary center from 2005 to 2018. Probands with known antemortem inherited cardiac disease were excluded. Data from systematic screening and routine follow-up of the relatives were registered.

Results

We included 371 first-degree relatives from 187 families: 276 SUD relatives (age at initial evaluation 35±17 years, 54% men;) and 95 pSCD relatives (age at initial evaluation 40±15 years, 51% men). The diagnostic yield among SUD families was 18%, among pSCD families 13% (p>0.05 between groups). The diagnoses in SUD families were mainly channelopathies (68%), whereas the pSCD families were diagnosed with cardiomyopathies, channelopathies, and premature ischemic heart disease (Figure 1). The vast majority of diagnosed families (93%) were diagnosed at the initial evaluation and only two families were diagnosed during the mean follow-up of 5.4 years. During follow-up, 57 (15%) relatives had a cardiac-related hospitalization, 12 (3%) relatives had a cardiac device implanted, three (1%) relatives died of non-cardiac causes, and one (0.5%) relative had a myocardial infarction. There was no significant difference in cardiac event rates between the SUD and pSCD groups (all p>0.05).

Conclusion

One in 6–7 families with SUD or pSCD victims obtained a diagnosis based on screening of relatives; we mainly diagnosed channelopathies in SUD families and a broader spectrum of inherited cardiac disease in the pSCD families. The majority of affected relatives was diagnosed at the initial evaluation and clinical follow-up may not be warranted in all relatives with normal findings at initial screening.

Figure 1. Family diagnoses in categories, n (%)

Funding Acknowledgement

Type of funding source: Foundation. Main funding source(s): The Capital Regions Research Foundation and The A.P. Moeller Foundation.
ZEB2 regulates a transcriptional network of calcium-handling genes in the injured heart
Authors: Gladka M , De Leeuw A , Kohela A , Molenaar B , Versteeg D , Kooijman L , Van Geldorp M , Van Rooij E
Published: November 2020

Intracellular calcium (Ca2+) overload is known to play a critical role in the development of cardiac dysfunction. Despite the remarkable progress in managing the progression of the disease, the development of effective therapies for heart failure (HF) remains challenging. Therefore, it is of great importance to understand the molecular mechanisms that maintain calcium level and contractility in homeostatic conditions. Here we identified a transcription factor ZEB2 that regulates the expression of numerous contractile and calcium-related genes.

Zinc finger E-box-binding homeobox2 (ZEB2) is a transcription factor that plays a role during early fetal development and epithelial-to-mesenchymal transition (EMT); however, its function in the heart remains to be determined. Recently, we found that ZEB2 is upregulated in murine cardiomyocytes shortly after an ischemic event, but returns to baseline levels as the disease progresses. Gain- and loss-of-function genetic mouse models revealed the necessity and sufficiency of ZEB2 to maintain proper cardiac function after ischemic injury. We show that cardiomyocyte-specific ZEB2 overexpression (Zeb2 cTG) protected from ischemia-induced diastolic dysfunction and attenuated the structural remodeling of the heart. Moreover, RNA-sequencing of Zeb2 cTG hearts post-injury implicated ZEB2 in the regulation of numerous calcium-handling and contractile-related genes when compared to wildtype mice. Mechanistically, ZEB2 overexpression increased the phosphorylation of phospholamban (PLN) at both serine-16 and threonine-17, implying enhanced activity of the sarcoplasmic reticulum Ca2+-ATPase (SERCA2A), thereby augmenting contractility. Improved cardiac function in ZEB2-overexpressing hearts correlated with higher expression of several sarcomeric proteins like myosin-binding protein C3 (MYBPC3), desmin (DES) and myosin regulatory light chain 2 (MYL2) further contributing to the observed protective phenotype. Furthermore, we observed a decrease in the activity of Ca2+-depended calcineurin/NFAT signaling, which is the main driver of pathological cardiac remodeling. Conversely to Zeb2 cTg mice, loss of ZEB2 from cardiomyocytes perturbed the expression of calcium- and contractile-related proteins and increased the activity of calcineurin/NFAT pathway, exacerbating cardiac dysfunction. Together, we show that ZEB2 is a central regulator of contractile and calcium-handling components, consequently mediating contractility in the mammalian heart. Further mechanistic understanding of the role of ZEB2 in the regulation of calcium homeostasis in cardiomyocytes is a critical step towards the development of improved therapies for various forms of heart failure.

Funding Acknowledgement

Type of funding source: Foundation. Main funding source(s): DR. E. Dekker from Dutch Heart Foundation
Inhibition of the activin receptor improves cardiac remodelling in the ercc1 mouse model of accelerated ageing
Authors: Clavere N , Patel K , Kevei E , Boateng S.Y
Published: November 2020

Introduction

In the heart, ageing is associated with pathological remodelling due to an increase of DNA damage, oxidative stress and fibrosis that impairs function, often leading to heart failure. Ageing is also associated with activation of the activin signalling pathway which contributes to cardiac dysfunction. Previous studies have shown that inhibition of the activin signalling pathway preserves cardiac function during aging. However, the beneficial effects of this inhibition in cardiac disorders such as accelerated ageing remain unknown.

Purpose

We hypothesized that inhibition of the activin receptor would be beneficial for the pathological cardiac phenotype of the Ercc1Δ/− mouse model of accelerated ageing.

We aimed to determine the cardiac phenotype of the Ercc1 mouse, and how inhibition of activin signalling affects cardiac remodelling using immunological and biochemical analysis.

Methods

Using immunohistochemical staining, we investigated the cardiac phenotype in 16 week old Ercc1Δ/− progeric and Ercc1+/+ wildtype mice (n=4–6) with or without soluble activin receptor injections from the week 7 (sActRIIB, 10mg/kg). The Ercc1Δ/− mouse displays a deficiency in DNA repair, leading to an accelerated ageing phenotype. Experimentally, injections of the myostatin /activin antagonist called the soluble ActRIIB receptor trap (sActRIIB) can be used to pharmacologically target the activin signalling pathway.

Results

In Ercc1Δ/− mice at 16 weeks there was a 50% decrease in the heart weight in comparison to Ercc1+/+ wildtype mice (175±13 vs 85±4), (p<0.001). Activin inhibition did not have any effect on the heart weight. To determine the extent of DNA damage, cardiac tissue was stained for γH2Ax. γH2Ax accumulates at double stranded DNA breaks where histone 2A becomes phosphorylated. Ercc1Δ/− mice displayed a 20% increase in double stranded DNA breaks in comparison to the Ercc1+/+ wildtype (0.6±0.5 vs 22.5±2.5 vs 15.8±0.7), (p<0.01). Activin inhibition led to a significant 5% decrease (p<0.05). Oxidative stress was determined by dihydroethidium staining. Ercc1Δ/− mice showed a 30% increase in oxidative stress (33.33±3 vs 49.98±3 vs 36.19±3), (p<0.05). Activin inhibition reversed this increase of oxidative stress in Ercc1Δ/− mice (p<0.05). Finally, cardiac fibrosis was assessed using picrosirius red staining. No differences were observed between the Ercc1Δ/− progerics and Ercc1+/+ wildtype mice, while activin inhibition led to a 50% decrease (4.9±0.3 vs 7.7±1.3 vs 2.9±0.1), (p<0.01). Interestingly, Ercc1Δ/− mice display thicker cardiac interstitial collagen I (1.3±0.01 vs 1.4±0.05 vs 1.3±0.01), (p<0.05). Activin inhibition also reversed this increased interstitial collagen (p<0.05).

Conclusion

Inhibition of activin receptor signalling brings beneficial effects to the Ercc1Δ/− cardiac phenotype by attenuating oxidative stress, DNA damage and fibrosis.

Funding Acknowledgement

Type of funding source: None
PKG oxidation at Cys42 amplifies mTORC1 activation to worsen hypertrophic heart disease
Authors: Oeing C.U , Dunkerly-Eyring B , Pieske B , Kass D , Ranek M
Published: November 2020

Rationale

Protein kinase G-1a (PKG1a) phosphorylation of tuberous sclerosis complex 2 (TSC2, or tuberin) at serine 1365 (S1365) potently suppresses mTORC1 activation. This results in greater autophagy and limits pathological hypertrophy myocytes and the heart. Cardiac stress also induce oxidation of PKG1a between cysteine 42 residues in homo-monomers, which reduces cardioprotection.

Objective

We tested the hypothesis that pathological mTORC1 activation is potently amplified by concomitant PKG1a C42-oxidation, and that this is countered by stimulating soluble guanylyl cyclase-1 (GC-1).

Methods and results

In mice expressing only C42-redox inhibited PKG1a (PKG1aCS), pressure-overload (PO) induces markedly less mTORC1 activation, increasing autophagic flux and reducing protein aggregation, hypertrophy, and dysfunction compared to PO in PKG1aWT mice. Similar results were obtained in cardiomyocytes exposed to endothelin-1. Protection against PO in PKG1aCS mice was similar to PKG1aWT co-treated with the mTORC1-inhibitor everolimus. TSC2 S1365 phosphorylation increased more in PKG1aCS than PKG1aWT myocardium after PO. Knock-in mice with TSC2 S1365A and PKG1aCS mutations, to prevent TSC2 phosphorylation by PKG1a displayed amplified mTORC1, cardiodepression, and mortality after PO as compared to PKG1aCS. Lastly, the marked disparity between PKG1aWT and PKG1aCS PO phenotype for TSC2 S1365 phosphorylation, mTORC1 activation, and cardiac dysfunction is overcome by BAY-602770, a direct stimulator of GC-1.

Conclusion

Oxidant-induced PKG1a C42 dimerization blunts its attenuation of mTORC1 activity by reducing TSC2 S1365 phosphorylation, thereby contributing to inadequate autophagy and worsened hypertrophic dysfunction. This is ameliorated by direct GC-1 stimulation.

Funding Acknowledgement

Type of funding source: Public Institution(s). Main funding source(s): DFG
Basic mechanism of atrial and ventricular arrhythmia suppression by heavy ion irradiation in hypercholesterolemic elderly rabbits
Authors: Amino M , Kabuki S , Kunieda E , Sakai T , Sakama S , Ayabe K , Yagishita A , Shimokawa T , Yamazaki M , Ikari Y , Kodama I , Yoshioka K
Published: November 2020

Background

Recent development of electrophysiology-guided noninvasive cardiac radioablation therapy for ventricular tachycardia attracts a great deal of attention as a novel antiarrhythmic strategy (Robinson CG, Circulation 2019). As to underlying mechanisms, however, much remains to be clarified. We reported before that a single targeted heavy ion irradiation (THIR 15Gy) to rabbit hearts increased connexin43 (Cx43) expression, and a reduction of vulnerability to ventricular arrhythmias after myocardial infarction.

Purpose

We investigated the effects of THIR on in-vivo cardiac electrophysiology and vulnerability to atrial and ventricular tachyarrhythmias in aged rabbits with hypercholesterolemia.

Methods

Sixteen three-year old rabbits were fed with high fat/cholesterol chow (0.5% cholesterol and 10% coconut oil) for 14 weeks. A single THIR 15Gy was applied to 8 rabbits (HC+THIR) with a heavy ion medical accelerator. Eight rabbits without THIR were used as control (HC).

Results

Serum cholesterol levels in the HC and HC+THIR were 1545+386 and 1569+328 mg/dl (n=8, NS). Atrial (P-wave) late potential in signal-averaged ECG in HC+THIR showed a significantly larger root mean square voltage (RMS) than those in HC (12+0.5 vs. 2+0.5μV, n=4, p<0.01). Ventricular late potentials in HC+THIR showed significantly less fQRS-D than HC (81+5 vs. 89+7 ms); less LAS40 (21+7 vs. 30+4 ms), and larger RMS (99+27 vs. 44+13μV) (n=4, p<0.04). Atrial tachycardia or fibrillation (AT/AF) was induced spontaneously or by programmed/burst pacing of the left atria (LA) in 4 out of 4 HC, whereas in only 1 out of 4 HC+THIR. Ventricular tachycardia or fibrillation (VT/VF) was induced spontaneously or by programmed pacing or left stellate stimulation in 4 out of 4 HC rabbits, whereas in only 1 out of 4 HC+THIR. Immunolabeled Cx40 densities in LA and RA tissue from HC+THIR rabbits were significantly higher than those from HC rabbits by 44% and 60%, respectively (n=4, p<0.01). Comparable upregulation of immunoreactive Cx43 was observed in LV and RV tissue from HC+THIR rabbits. Sympathetic nerve densities in LA, RA, LV and RV tissues, which was labeled with anti-neuronal growth-associated protein 43 (GAP43) antibody and tyrosine hydroxylase (TH) antibody were both significantly less in HC+THIR than those in HC.

Conclusion

These results suggest that THIR may improve cardiac conductivity of HC rabbits in favor of reduction of vulnerability to atrial and ventricular tachycardia/fibrillation, and that this antiarrhythmic effect is attributed to upregulation of gap junction protein (Cx40 and Cx43) and in part to prevention of sympathetic nerve sprouting.

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): KAKENHI KIBAN (C) 53020
Bioenergetic and metabolic impairments in Duchenne Muscular Dystrophy (DMD) patients' iPSC-derived cardiomyocytes
Authors: Willi L , Agranovich B , Abramovich I , Freimark D , Arad M , Gottlieb E , Binah O
Published: November 2020

Introduction

DMD, an X-linked muscle degenerative fatal disease, is caused by mutations in the dystrophin gene. Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality in DMD patients. Treatments for DCM in DMD are limited to steroids and standard heart failure medications such as β-blockers and ACE-inhibitors, and therefore novel therapeutic modalities are urgently needed.

Purpose

We hypothesized that dystrophin mutations in DMD lead to cardiomyopathy-causing bioenergetic/metabolic impairments, which can be therapeutically targeted for improving cardiac function.

Methods

Induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) were generated from healthy volunteer and 3 DMD patients: young male (YM), adult male (AM) and adult female (AF). We investigated the bioenergetics, electrophysiology, mitochondrial and metabolic features of healthy and DMD iPSC-CMs using the Seahorse Flux analyzer, patch clamp, confocal fluorescence microscopy and Liquid chromatography mass spectrometry (LC-MS) technologies, respectively.

Results

To test the hypothesis, we measured respiration and glycolytic rates of healthy and DMD iPSC-CMs. Compared to healthy iPSC-CMs, in both AM and AF DMD, but not in YM DMD cardiomyocytes, there was a 75% decrease in ATP production, and 80% and 45% decrease in basal respiration, respectively. In agreement with the healthy-like bioenergetic status of YM, the iPSC-CMs showed no arrhythmias, in contrast to the prominent arrhythmias in AM and AF cardiomyocytes. To determine whether the impairment in the phosphorylation pathway (OXPHOS) affects glycolysis, we measured the cardiomyocytes' response to glycolytic stress test. These experiments showed that the glycolytic rates were similar in healthy and DMD iPSC-CMs. In agreement with impaired OXPHOS, mitochondrial activity measured by 3D life confocal microscopy was attenuated in the DMD male by 35%, compared to healthy cardiomyocytes. Furthermore, the metabolomic LC-MS analyses demonstrated significant differences in metabolite levels in YM, AM and AF DMD iPSC-CMs relative to healthy iPSC-CMs. For example, compared to healthy iPSC-CMs, there was a dramatic fall to undetected levels in phosphocreatine in both AM and AF, but not in YM DMD, indicating a dysfunctional phosphocreatine energy system.

Conclusions

DMD iPSC-CMs exhibit bioenergetic/metabolic impairments, which constitute novel targets for alleviating the cardiomyopathy in DMD patients.

Funding Acknowledgement

Type of funding source: Public grant(s) – National budget only. Main funding source(s): ISF - Israel Science Foundation