Irregular Beating Research Articles

Immune response caused by M1 macrophages elicits atrial fibrillation-like phenotypes in coculture model with isogenic hiPSC-derived cardiomyocytes

BackgroundAtrial fibrillation has an estimated prevalence of 1.5–2%, making it the most common cardiac arrhythmia. The processes that cause and sustain the disease are still not completely understood. An association between atrial fibrillation and systemic, as well as local, inflammatory processes has been reported. However, the exact mechanisms underlying this association have not been established. While it is understood that inflammatory macrophages can influence cardiac electrophysiology, a direct, causative relationship to atrial fibrillation has not been described. This study investigated the pro-arrhythmic effects of activated M1 macrophages on human induced pluripotent stem cell (hiPSC)-derived atrial cardiomyocytes, to propose a mechanistic link between inflammation and atrial fibrillation.MethodsTwo hiPSC lines from healthy individuals were differentiated to atrial cardiomyocytes and M1 macrophages and integrated in an isogenic, pacing-free, atrial fibrillation-like coculture model. Electrophysiology characteristics of cocultures were analysed for beat rate irregularity, electrogram amplitude and conduction velocity using multi electrode arrays. Cocultures were additionally treated using glucocorticoids to suppress M1 inflammation. Bulk RNA sequencing was performed on coculture-isolated atrial cardiomyocytes and compared to meta-analyses of atrial fibrillation patient transcriptomes.ResultsMulti electrode array recordings revealed M1 to cause irregular beating and reduced electrogram amplitude. Conduction analysis further showed significantly lowered conduction homogeneity in M1 cocultures. Transcriptome sequencing revealed reduced expression of key cardiac genes such as SCN5A, KCNA5, ATP1A1, and GJA5 in the atrial cardiomyocytes. Meta-analysis of atrial fibrillation patient transcriptomes showed high correlation to the in vitro model. Treatment of the coculture with glucocorticoids showed reversal of phenotypes, including reduced beat irregularity, improved conduction, and reversed RNA expression profiles.ConclusionsThis study establishes a causal relationship between M1 activation and the development of subsequent atrial arrhythmia, documented as irregularity in spontaneous electrical activation in atrial cardiomyocytes cocultured with activated macrophages. Further, beat rate irregularity could be alleviated using glucocorticoids. Overall, these results point at macrophage-mediated inflammation as a potential AF induction mechanism and offer new targets for therapeutic development. The findings strongly support the relevance of the proposed hiPSC-derived coculture model and present it as a first of its kind disease model.

Role of the vessel morphology on the lenticulostriate arteries hemodynamics during atrial fibrillation: A CFD-based multivariate regression analysis

Background and objectiveAtrial fibrillation (AF) is the most common cardiac arrhythmia, inducing accelerated and irregular beating. Beside well-known disabling symptoms - such as palpitations, reduced exercise tolerance, and chest discomfort - there is growing evidence that an alteration of deep cerebral hemodynamics due to AF increases the risk of vascular dementia and cognitive impairment, even in the absence of clinical strokes. The alteration of deep cerebral circulation in AF represents one of the least investigated among the possible mechanisms. Lenticulostriate arteries (LSAs) are small perforating arteries mainly departing from the middle cerebral artery (MCA) and susceptible to small vessel disease, which is one of the mechanisms of subcortical vascular dementia development. The purpose of this study is to investigate the impact of different LSAs morphologies on the cerebral hemodynamics during AF. MethodsBy combining a computational fluid dynamics (CFD) analysis of LSAs with 7T high-resolution magnetic resonance imaging (MRI), we performed different CFD-based multivariate regression analyses to detect which geometrical and morphological vessel features mostly affect AF hemodynamics in terms of wall shear stress. We exploited 17 cerebral 7T-MRI derived LSA vascular geometries extracted from 10 subjects and internal carotid artery data from validated 0D cardiovascular-cerebral modeling as inflow conditions. ResultsOur results revealed that few geometrical variables - namely the size of the MCA and the bifurcation angles between MCA and LSA - are able to satisfactorily predict the AF impact. In particular, the present study indicates that LSA morphologies exhibiting markedly obtuse LSA-MCA inlet angles and small MCA size downstream of the LSA-MCA bifurcation may be more prone to vascular damage induced by AF. ConclusionsThe present MRI-based computational study has been able for the first time to: (i) investigate the net impact of LSAs vascular morphologies on cerebral hemodynamics during AF events; (ii) detect which combination of morphological features worsens the hemodynamic response in the presence of AF. Awaiting necessary clinical confirmation, our analysis suggests that the local hemodynamics of LSAs is affected by their geometrical features and some LSA morphologies undergo greater hemodynamic alterations in the presence of AF.

Human in vitro disease modeling of ATTR cardiac amyloidosis

Abstract Background Amyloidosis is a systemic protein-folding disorder characterized by extracellular misfolded fibrillar protein aggregates that are insoluble and resistant to proteolysis, leading to progressive and vital organ damage [1]. Transthyretin amyloidosis (ATTR) is one of the primary amyloidosis types that affect the heart. Based on the TTR gene sequence, ATTR is further classified into wild-type ATTR (ATTRwt) and hereditary ATTR (ATTRv). Advanced stage TTR amyloid infiltration of the myocardium results in progressive thickening and stiffening of the ventricle wall, and symptoms of restrictive cardiomyopathy and congestive heart failure. Due to the lack of specificity of cardiac amyloidosis symptoms, misdiagnosis and delays in diagnosis are common, resulting in worsening symptoms, organ damage, and increased mortality [2]. Despite the development of several disease-modifying agents [3], current experimental cell and animal models do not adequately represent the human situation, thereby limiting disease understanding and therapeutic discovery. Purpose This project aims to develop an in vitro ATTR disease model, which is critical to define early disease stages and disease progression, map human disease-specific pathways, and screen for novel drugs or validating cutting-edge therapeutic strategies. Methods Recombinant WT-TTR and V122I mutated TTR (V122I) were prepared using E.coli protein production system. TTR purification and acid-mediated TTR-fibril were characterized by SDS-PAGE, Thioflavin T fluorescence measurement, and transmission electron microscope (EM). iPSC-derived cardiomyocytes (iPS-CMs) were differentiated using GiWi protocol as described [4,5]. iPS-CMs or HUVECs were seeded on TTR or TTR-fibril, and we measured beating rate, cell viability (AlamarBlue and LiveDead), and cell/fibril morphology using immunofluorescence. Results Purified recombinant WT and V122I TTR was successfully generated (Figure 1A). Fluorescence increase (Thioflavin T) and EM revealed the presence of TTR-fibril (Figure 1B). iPS-CMs seeded on TTR-fibril resulted in a dose- and time-dependent increase in cell death. Confocal microscopy revealed the attachment of TTR-fibril on iPS-CMs, leading to sarcomere disarray, loss of cell-to-cell coupling, resulting in irregular beating (Figure 2A). Additionally, we found drastically affected viability of HUVECs upon TTR-fibril exposure (Figure 2B). Conclusion Here, we demonstrate an established method to generate purified TTR and TTR-fibril. TTR-fibril attached to the surface of iPS-CMs decreased cell viability and functionality. Similar reduction in HUVEC viability were observed as well. These findings reflect the cytotoxicity of TTR-fibril in a human in vitro model.TTR and TTR-fibril characterizationCell viability up TTR-fibril exposure

Abstract P3148: Wnt/β-catenin Signaling Inhibits T-type Calcium Current And Causes Sinoatrial Node Dysfunction

Background: The T-type Ca 2+ channels (I Ca,T ) are expressed in the fetal and neonatal cardiomyocytes, but in the adult heart they are exclusively expressed in the cardiac conduction system, including the sinoatrial node (SAN). In contrast, the L-type Ca 2+ channels (I Ca,L ) are expressed ubiquitously in the adult heart and are important for cardiac contraction. The Wnt/β-catenin signaling (Wnt signaling) is activated in various heart disease and we and others have recently demonstrated that Wnt signaling inhibits cardiac Na + current. In the present study, we investigated if calcium channels are also regulated by Wnt signaling. Methods and Results: Because neonatal rat ventricular myocytes (NRVMs) express both I Ca,L and I Ca,T , we investigated the effect of Wnt signaling on NRVMs by treatment with either Wnt3a protein or CHIR-99021 (CHIR) (two different activators of the Wnt signaling). PCR array and RNA sequencing studies showed that Wnt signaling did not affect the mRNA of Cacna1c (encoding the α subunit of I Ca,L , Ca v 1.2), but the mRNA of Cacna1g (encoding the α subunit of I Ca,T , Ca v 3.1) was reduced in NRVMs (p<0.05, n=3) after treatment with either Wnt3a or CHIR. These observations were verified by qRT-PCR which showed dose-dependent reductions (p<0.05, n=4) in Cacna1g mRNA after CHIR treatment. Western blot and patch-clamp also demonstrated reductions (p<0.01, n=5) in channel protein and ionic current density of T-type, but not L-type, Ca 2+ channels after treatment with Wnt3a or CHIR. These observations suggest that Wnt signaling selectively inhibits T-type Ca 2+ channels in cardiomyocytes. Consistent with a critical role of T-type Ca 2+ channels in the pacemaker activity of SAN (the primary pacemaker of the heart), the spontaneous firing rates of isolated rat and mouse SAN tissues were reduced by ML-218 (an I Ca,T blocker) in a dose-dependent manner (p<0.01, n=5). In addition, activation of Wnt signaling in adult rat SAN tissues by CHIR led to slower and irregular beating, indicative of SAN dysfunction (p<0.01, n=5). Conclusions: These observations are consistent with the conclusions that Wnt/β-catenin signaling selectively inhibits T-type calcium current and may play a role in sinoatrial node dysfunction.

Metabolic Maturation Exaggerates Abnormal Calcium Handling in a Lamp2 Knockout Human Pluripotent Stem Cell-Derived Cardiomyocyte Model of Danon Disease.

Danon disease (DD) is caused by mutations of the gene encoding lysosomal-associated membrane protein type 2 (LAMP2), which lead to impaired autophagy, glycogen accumulation, and cardiac hypertrophy. However, it is not well understood why a large portion of DD patients develop arrhythmia and sudden cardiac death. In the current study, we generated LAMP2 knockout (KO) human iPSC-derived cardiomyocytes (CM), which mimic the LAMP2 dysfunction in DD heart. Morphologic analysis demonstrated the sarcomere disarrangement in LAMP2 KO CMs. In functional studies, LAMP2 KO CMs showed near-normal calcium handling at base level. However, treatment of pro-maturation medium (MM) exaggerated the disease phenotype in the KO cells as they exhibited impaired calcium recycling and increased irregular beating events, which recapitulates the pro-arrhythmia phenotypes of DD patients. Further mechanistic study confirmed that MM treatment significantly enhanced the autophagic stress in the LAMP2 KO CMs, which was accompanied by an increase of both cellular and mitochondrial reactive oxygen species (ROS) levels. Excess ROS accumulation in LAMP2 KO CMs resulted in the over-activation of calcium/calmodulin dependent protein kinase IIδ (CaMKIIδ) and arrhythmogenesis, which was partially rescued by the treatment of ROS scavenger. In summary, our study has revealed ROS induced CaMKIIδ overactivation as a key mechanism that promotes cardiac arrhythmia in DD patients.

Cerebral hemodynamics during atrial fibrillation: Computational fluid dynamics analysis of lenticulostriate arteries using 7 T high-resolution magnetic resonance imaging.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, inducing irregular and faster heart beating. Aside from disabling symptoms-such as palpitations, chest discomfort, and reduced exercise capacity-there is growing evidence that AF increases the risk of dementia and cognitive decline, even in the absence of clinical strokes. Among the possible mechanisms, the alteration of deep cerebral hemodynamics during AF is one of the most fascinating and least investigated hypotheses. Lenticulostriate arteries (LSAs)-small perforating arteries perpendicularly departing from the anterior and middle cerebral arteries and supplying blood flow to basal ganglia-are especially involved in silent strokes and cerebral small vessel diseases, which are considered among the main vascular drivers of dementia. We propose for the first time a computational fluid dynamics analysis to investigate the AF effects on the LSAs hemodynamics by using 7 T high-resolution magnetic resonance imaging (MRI). We explored different heart rates (HRs)-from 50 to 130 bpm-in sinus rhythm and AF, exploiting MRI data from a healthy young male and internal carotid artery data from validated 0D cardiovascular-cerebral modeling as inflow condition. Our results reveal that AF induces a marked reduction of wall shear stress and flow velocity fields. This study suggests that AF at higher HR leads to a more hazardous hemodynamic scenario by increasing the atheromatosis and thrombogenesis risks in the LSAs region.

Role of Scl39a13/ZIP13 in cardiovascular homeostasis.

Zinc plays a critical role in many physiological processes, and disruption of zinc homeostasis induces various disorders, such as growth retardation, osteopenia, immune deficiency, and inflammation. However, how the imbalance in zinc homeostasis leads to heart disease is not yet fully understood. Cardiovascular diseases are a major cause of death worldwide, and the development of novel therapeutic targets to treat it is urgently needed. We report that a zinc transporter, ZIP13, regulates cardiovascular homeostasis. We found that the expression level of Zip13 mRNA was diminished in both primary neonatal cardiomyocytes and mouse heart tissues treated with the cardiotoxic agent doxycycline. Primary neonatal cardiomyocytes from Zip13 gene-knockout (KO) mice exhibited abnormal irregular arrhythmic beating. RNA-seq analysis identified 606 differentially expressed genes in Zip13-KO mouse-derived primary neonatal cardiomyocytes and Gene ontology (GO) analysis revealed that both inflammation- and cell adhesion-related genes were significantly enriched. In addition, telemetry echocardiography analysis suggested that arrhythmias were likely to occur in Zip13-KO mice, in which elevated levels of the cardiac fibrosis marker Col1a1, vascular inflammation-related gene eNOS, and Golgi-related molecule GM130 were observed. These results indicate the physiological importance of ZIP13—it maintains cardiovascular homeostasis by resolving inflammation and stress response. Our findings suggest that optimizing ZIP13 expression and/or function may improve cardiovascular disease management.

Atrial fibrillation (AF) pilot screening programme in primary care in Ireland: an implementation study protocol

IntroductionAtrial fibrillation (AF) is a major risk factor for stroke. There is a fivefold increase in stroke risk in the presence of AF. The irregular beating of the heart enables...

Palpitations in the Cancer Patient.

Cancer and cardiovascular diseases (CVD) are among the leading causes of death worldwide. In response to the growing population of cancer patients and survivors with CVD, the sub-specialty of cardio-oncology has been developed to better optimise their care. Palpitations are one of the most common presenting complaints seen in the emergency room or by the primary care provider or cardiologist. Palpitations are defined as a rapid pulsation or abnormally rapid or irregular beating of the heart and present a complex diagnostic entity with no evidence-based guidelines currently available. Palpitations are a frequent occurrence in people with cancer, and investigations and treatment are comparable to that in the general population although there are some nuances. Cancer patients are at a higher risk of arrhythmogenic causes of palpitations and non-arrhythmogenic causes of palpitations. This review will appraise the literature with regards to the development and management of palpitations in the cancer patient.

QuinoMit Q10-Fluid attenuates hydrogen peroxide-induced irregular beating in mouse pluripotent stem cell-derived cardiomyocytes

BackgroundCoenzyme Q10 (CoQ10) is a crucial component of the mitochondrial structure which is involved in producing more than 90% of cellular ATP. This study aimed to investigate the protective effects and underlying mechanisms of QuinoMit Q10-Fluid against hydrogen peroxide (H2O2)-induced arrhythmias on cardiomyocytes (CMs). MethodsUndifferentiated stem cell-derived CMs were cultured in the presence of different concentrations of QuinoMit Q10-Fluid. To investigate if CoQ10 has anti-apoptotic activity, CMs were exposed to H2O2 for up to 100 h with or without CoQ10. The expression levels of cardiac reference genes were determined by RT-PCR. The structural and functional properties of CMs were examined by immunofluorescence and the xCELLigence system. Caspase 3/7 assay was also performed for cell apoptosis study. ResultsThe study showed that QuinoMit Q10-Fluid inhibits the proliferation of pluripotent stem cells at high concentrations and had less effect on cardiomyogenesis. However, the beating rate of clusters containing CMs generated under QuinoMit Q10-Fluid (1:100) was significantly increased. This increase was accompanied by the up-regulated expression level of some important cardiac markers during differentiation. Treatment of CMs with H2O2 notably induced irregular beating and decreased the amplitude of the beating signal of CMs, concomitantly with increased caspase-3/7 activity. However, CMs pretreated with QuinoMit exhibited a protective effect against H2O2-induced arrhythmia. ConclusionOur results reveal that QuinoMit Q10-Fluid attenuates H2O2-induced irregular beating in mouse pluripotent stem cell-derived CMs, at least partly by reducing the generation of ROS, suggesting a protective effect against CM dysfunctions.

Impairment of the ER/mitochondria compartment in human cardiomyocytes with PLN p.Arg14del mutation

The phospholamban (PLN) p.Arg14del mutation causes dilated cardiomyopathy, with the molecular disease mechanisms incompletely understood. Patient dermal fibroblasts were reprogrammed to hiPSC, isogenic controls were established by CRISPR/Cas9, and cardiomyocytes were differentiated. Mutant cardiomyocytes revealed significantly prolonged Ca2+ transient decay time, Ca2+‐load dependent irregular beating pattern, and lower force. Proteomic analysis revealed less endoplasmic reticulum (ER) and ribosomal and mitochondrial proteins. Electron microscopy showed dilation of the ER and large lipid droplets in close association with mitochondria. Follow‐up experiments confirmed impairment of the ER/mitochondria compartment. PLN p.Arg14del end‐stage heart failure samples revealed perinuclear aggregates positive for ER marker proteins and oxidative stress in comparison with ischemic heart failure and non‐failing donor heart samples. Transduction of PLN p.Arg14del EHTs with the Ca2+‐binding proteins GCaMP6f or parvalbumin improved the disease phenotype. This study identified impairment of the ER/mitochondria compartment without SR dysfunction as a novel disease mechanism underlying PLN p.Arg14del cardiomyopathy. The pathology was improved by Ca2+‐scavenging, suggesting impaired local Ca2+ cycling as an important disease culprit.

Нелинейное возбуждение гиперзвуковых колебаний в ферритовой пластине в условиях комбинированного воздействия на двух частотах. Часть 2. Вариация постоянного поля

Нелинейное возбуждение гиперзвуковых колебаний в ферритовой пластине в условиях комбинированного воздействия на двух частотах. Часть 2. Вариация постоянного поля

Deep-Learning-Based Registration of Diagnostic Angiogram and Live Fluoroscopy for Percutaneous Coronary Intervention

Percutaneous coronary intervention (PCI) is an effective treatment for increasing blood flow in narrowed coronary arteries by implanting stents. When inserting a guidewire during PCI, a cardiologist watches two X-ray videos, a cine loop of angiography and a real-time video of live fluoroscopy to navigate the guidewire to the target location while avoiding entering wrong branches of blood vessels. However, watching the two separate X-ray videos increases a cardiologist's mental efforts and intervention time. Moreover, more contrast agents may need to be injected to validate the correct insertion. To address this problem, dynamic coronary roadmapping (DCR) has been suggested because it provides registered images of two different X-ray images. In this study, we propose a novel patient-specific deep-learning-based approach for DCR that uses only two types of X-ray images without using an electrocardiogram (ECG). In the proposed approach, a trained deep generative model generates a registered image from the guidewire images in live fluoroscopy and angiographic sequence from diagnostic coronary angiography. Because the proposed approach can implicitly compensate for both cardiac and respiratory motions, it can be applied to arrhythmia patients with irregular ECG signals, unlike conventional image registration through ECG. Qualitative evaluation of 34 PCI cases, including three irregular heartbeat cases, showed low registration errors (26% lower than that of the latest work) and high image quality (more than 30 dB peak signal-to-noise ratio (PSNR)). All registration results were classified as “fit for use” (70.6% “Good” and 29.4% “Acceptable”) by three cardiologists. Furthermore, three irregular beating cases were classified as having “Good” registration quality.

Intermittent Optogenetic Tachypacing of Atrial Engineered Heart Tissue Induces Only Limited Electrical Remodelling.

Atrial tachypacing is an accepted model for atrial fibrillation (AF) in large animals and in cellular models. Human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CM) provide a novel human source to model cardiovascular diseases. Here, we investigated whether optogenetic tachypacing of atrial-like hiPSC-CMs grown into engineered heart tissue (aEHT) can induce AF-remodeling. After differentiation of atrial-like cardiomyocytes from hiPSCs using retinoic acid, aEHTs were generated from ∼1 million atrial-like hiPSC-CMs per aEHT. AEHTs were transduced with lentivirus expressing channelrhodopsin-2 to enable optogenetic stimulation by blue light pulses. AEHTs underwent optical tachypacing at 5 Hz for 15 seconds twice a minute over 3 weeks and compared with transduced spontaneously beating isogenic aEHTs (1.95 ± 0.07 Hz). Force and action potential duration did not differ between spontaneously beating and tachypaced aEHTs. Action potentials in tachypaced aEHTs showed higher upstroke velocity (138 ± 15 vs. 87 ± 11 V/s, n = 15-13/3; P = 0.018), possibly corresponding to a tendency for more negative diastolic potentials (73.0 ± 1.8 vs. 68.0 ± 1.9 mV; P = 0.07). Tachypaced aEHTs exhibited a more irregular spontaneous beating pattern (beat-to-beat scatter: 0.07 ± 0.01 vs. 0.03 ± 0.004 seconds, n = 15-13/3; P = 0.008). Targeted expression analysis showed higher RNA levels of KCNJ12 [Kir2.2, inward rectifier (IK1); 69 ± 7 vs. 44 ± 4, P = 0.014] and NPPB (NT-proBNP; 39,690 ± 4834 vs. 23,671 ± 3691; P = 0.024). Intermittent tachypacing in aEHTs induces some electrical alterations found in AF and induces an arrhythmic spontaneous beating pattern, but does not affect resting force. Further studies using longer, continuous, or more aggressive stimulation may clarify the contribution of different rate patterns on the changes in aEHT mimicking the remodeling process from paroxysmal to persistent atrial fibrillation.

Computational Diagnostic Techniques for Electrocardiogram Signal Analysis.

Cardiovascular diseases (CVDs), including asymptomatic myocardial ischemia, angina, myocardial infarction, and ischemic heart failure, are the leading cause of death globally. Early detection and treatment of CVDs significantly contribute to the prevention or delay of cardiovascular death. Electrocardiogram (ECG) records the electrical impulses generated by heart muscles, which reflect regular or irregular beating activity. Computer-aided techniques provide fast and accurate tools to identify CVDs using a patient’s ECG signal, which have achieved great success in recent years. Latest computational diagnostic techniques based on ECG signals for estimating CVDs conditions are summarized here. The procedure of ECG signals analysis is discussed in several subsections, including data preprocessing, feature engineering, classification, and application. In particular, the End-to-End models integrate feature extraction and classification into learning algorithms, which not only greatly simplifies the process of data analysis, but also shows excellent accuracy and robustness. Portable devices enable users to monitor their cardiovascular status at any time, bringing new scenarios as well as challenges to the application of ECG algorithms. Computational diagnostic techniques for ECG signal analysis show great potential for helping health care professionals, and their application in daily life benefits both patients and sub-healthy people.

Support Vector Method with Radial Basis Function and Multi-Segment of Electrocardiogram for Paroxysmal Atrial Fibrillation Recognition

Paroxysmal Atrial fibrillation (PAF) is a heart problem relating to irregular and rapid beating of the heart atria. It has risk of stroke and is independently associated with risk of mortality. Early information of PAF episode is important for a patient to have appropriate treatment to reduce atrial fibrillation complications. This article presents a new strategy to detect PAF with base of statistical electrocardiographic features and a support vector machine (SVM). R-peak series of electrocardiogram were segmented and were extracted to find the statistics of RR intervals. Different approaches in relation with the segmentation were investigated. Two-class SVM with radial basis function (RBF) and the statistics of RR intervals were examined for PAF detection. Using clinical data of patients with PAF, the proposed strategy showed excellent performance of 99.17% in terms of accuracy. The experimental result indicated that the appropriate statistics of RR intervals and SVM-RBF with its suitable parameters can perform well for PAF detection.

Appropriate use of echocardiography for palpitations in paediatric cardiology clinics.

Identify diagnostic yield and frequency of echocardiograms for palpitation-related indications at outpatient paediatric cardiology clinics in relation to the 2014 ACC/AAP/AHA/ASE/HRS/SCAI/SCCT/SCMR/SOPE appropriate use criteria for Initial Transthoracic Echocardiography in Outpatient Paediatric Cardiology. A single-centre, retrospective study of children presenting for evaluation of a chief complaint of palpitations to outpatient paediatric cardiology clinics from 2015 to 2017. Palpitations were defined as an unpleasant sensation of rapid, irregular, and/or forceful beating of the heart. Indications for echocardiogram in patients were retrospectively classified based on the appropriate use criteria as "appropriate," "may be appropriate," or "rarely appropriate." The incidence of abnormal and incidental echocardiographic findings for each category was determined. A total of 286 patients presented with palpitations, with 128 (52% female) meeting inclusion criteria. Exclusion criteria included patients with additional cardiac complaints, prior echocardiogram, or history of congenital heart disease. Echocardiograms were performed on 36 (28%) patients. The appropriate use criteria were retrospectively applied, and indications for their performance were classified as "appropriate" (n = 4), "may be appropriate" (n = 17), or "rarely appropriate" (n = 15). Minor echocardiographic abnormalities were present in 22% (n = 8) of echocardiograms obtained for all appropriate use criteria classifications. No moderate or severe echocardiographic abnormalities were found. Incidental findings were noted in eight echocardiograms. Echocardiography in the evaluation of "rarely appropriate" and "may be appropriate" palpitation-related indications is of low diagnostic yield.

Cardiovascular Effects of Polychlorinated Biphenyls and Their Major Metabolites.

Background:Xenobiotic metabolism is complex, and accounting for bioactivation and detoxification processes of chemicals remains among the most challenging aspects for decision making with in vitro new approach methods data.Objectives:Considering the physiological relevance of human organotypic culture models and their utility for high-throughput screening, we hypothesized that multidimensional chemical-biological profiling of chemicals and their major metabolites is a sensible alternative for the toxicological characterization of parent molecules vs. metabolites in vitro.Methods:In this study, we tested 25 polychlorinated biphenyls (PCBs) [PCB 3, 11, 52, 126, 136, and 153 and their relevant metabolites (hydroxylated, methoxylated, sulfated, and quinone)] in concentration–response () for effects in human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) and endothelial cells (ECs) (iPSC-derived and HUVECs). Functional phenotypic end points included effects on beating parameters and intracellular flux in CMs and inhibition of tubulogenesis in ECs. High-content imaging was used to evaluate cytotoxicity, mitochondrial integrity, and oxidative stress.Results:Data integration of a total of 19 physicochemical descriptors and 36 in vitro phenotypes revealed that chlorination status and metabolite class are strong predictors of the in vitro cardiovascular effects of PCBs. Oxidation of PCBs, especially to di-hydroxylated and quinone metabolites, was associated with the most pronounced effects, whereas sulfation and methoxylation of PCBs resulted in diminished bioactivity.Discussion:Risk characterization analysis showed that although in vitro derived effective concentrations exceeded the levels measured in the general population, risks cannot be ruled out due to the potential for population variability in susceptibility and the need to fill data gaps using read-across approaches. This study demonstrated a strategy for how in vitro data can be used to characterize human health risks from PCBs and their metabolites. https://doi.org/10.1289/EHP7030

Genome-wide profiling reveals atrial fibrillation-related circular RNAs in atrial appendages

Atrial fibrillation (AF) is an abnormal heart rhythm characterized by rapid and irregular beating of the atria. The non-coding RNAs (ncRNAs) have attracted much attention of AF researchers, as they play a critical role in the transcriptional and post-transcriptional regulation, which could greatly benefit the interpretation of the pathogenesis of AF. However, circRNAs, as a special member of the ncRNAs, and their role in the pathogenesis of AF is less understood. In the present study, we detected a total of 14,215 circRNAs in AF patients and healthy controls. Differential expression analysis of these circRNAs revealed 20 upregulated and 3 downregulated circRNAs, which were differentially expressed in both left and right atrial appendages. The association analysis of the AF-related circRNAs and their parental genes revealed that hsa_circ_0003965 had significantly negative correlation with its parental gene TMEM245 (PCC = −0.51), suggesting that the dysregulation of hsa_circ_0003965 was not regulated by the transcription of its parental gene, but could be associated with glucagon signaling pathway. The competing endogenous RNA (ceRNA) network analysis revealed two upregulated genes, IFNG and GDF7, and one downregulated gene, BMP7, all of which were involved in TGF-beta signaling pathway, which further suggested that these circRNAs, namely hsa_circ_0000075 and hsa_circ_0082096, participated in the AF pathogenesis via TGF-beta signaling pathway. Consistently, TGF-beta signaling pathway was a well-recognized player for its association with atrial fibrosis in AF. In summary, we aimed to discover and provide key circRNAs involved in AF for AF-related researchers, which had the potential to greatly improve our understanding of the underlying mechanism behind circRNAs and AF.

Comprehensive metabolomic and proteomic analyses reveal candidate biomarkers and related metabolic networks in atrial fibrillation

Atrial fibrillation (AF) is an abnormal heart rhythm characterized by an irregular beating of the atria and is associated with an increased risk of heart failure, dementia, and stroke. Currently, the perturbation of plasma content due to AF disease onset is not well known. To investigate dysregulated molecules in blood plasma of untreated AF patients, with the goal of identifying biomarkers for disease screening and pathological studies. LC-MS based untargeted metabolomics, lipidomics and proteomics analyses were performed to find candidate biomarkers. A targeted quantification assay and an ELISA were performed to validate the results of the omics analyses. We found that 24 metabolites, 16 lipids and 16 proteins were significantly dysregulated in AF patients. Pathway enrichment analysis showed that the purine metabolic pathway and fatty acid metabolism were perturbed by AF onset. FA 20:2 and FA 22:4 show great linear correlational relationship with the left atrial area and could be considered for AF disease stage monitoring or prognosis evaluation. we used a comprehensive multiple-omics strategy to systematically investigate the dysregulated molecules in the plasma of AF patients, thereby revealing potential biomarkers for diagnosis and providing information for pathological studies.