Background The role of children in household transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains uncertain. Here, we describe the epidemiological and clinical characteristics of children with COVID-19 in Catalonia (Spain) and investigate the dynamics of household transmission. Methods Prospective, observational, multicenter study performed during summer and school periods (1 July-31 October, 2020), in which epidemiological and clinical features, and viral transmission dynamics were analyzed in COVID-19 patients <16 years. A pediatric index case was established when a child was the first individual infected within a household. Secondary cases were defined when another household member tested positive for SARS-CoV-2 before the child. The secondary attack rate (SAR) was calculated, and logistic regression was used to assess associations between transmission risk factors and SARS-CoV-2 infections. Results The study included 1040 COVID-19 patients <16 years. Almost half (47.2%) were asymptomatic, 10.8% had comorbidities, and 2.6% required hospitalization. No deaths were reported. Viral transmission was common among household members (62.3%). More than 70% (756/1040) of pediatric cases were secondary to an adult, whereas 7.7% (80/1040) were index cases. The SAR was significantly lower in households with COVID-19 pediatric index cases during the school period relative to summer (p=0.02), and when compared to adults (p=0.006). No individual or environmental risk factors associated with the SAR were identified. Conclusions Children are unlikely to cause household COVID-19 clusters or be major drivers of the pandemic even if attending school. Interventions aimed at children are expected to have a small impact on reducing SARS-CoV-2 transmission.

Background Left Ventricular (LV) stiffening contributes to Heart Failure with preserved Ejection Fraction (HFpEF), a syndrome with no effective treatment options. Increasing titin’s compliance in the heart has become possible recently through inhibition of the splicing factor RBM20. Here we investigated the effects of increasing titin’s compliance in mice with diastolic dysfunction. Methods Mice in which the RNA recognition motif (RRM) of one of the RBM20 alleles was floxed and which expressed the MerCreMer transgene under control of the αMHC promoter (referred to as cRbm20ΔRRM mice) were used. Mice underwent transverse aortic constriction (TAC) surgery and deoxycorticosterone acetate (DOCA) pellet implantation (TAC/DOCA). RRM deletion in adult mice was triggered by injecting raloxifene (cRbm20ΔRRM-raloxifene) with DMSO injected mice (cRbm20ΔRRM-DMSO) as the control. Diastolic function was investigated using echocardiography and pressure volume analysis; passive stiffness was studied in LV muscle strips and isolated cardiac myocytes before and after elimination of titin-based stiffness. Treadmill exercise performance was also studied. Titin isoform expression was evaluated with Agarose gels. Results cRbm20ΔRRM-raloxifene mice expressed large titins in the hearts, named super compliant titin (N2BAsc), which, within 3 weeks after raloxifene injection, made up ~45% of total titin. TAC/DOCA cRbm20ΔRRM-DMSO mice developed LV hypertrophy and a marked increase in LV chamber stiffness as shown by both pressure-volume analysis and echocardiography. LV chamber stiffness was normalized in TAC/DOCA cRbm20ΔRRM-raloxifene mice that expressed N2BAsc. Passive stiffness measurements on muscle strips isolated from the LV free wall revealed that extracellular matrix (ECM) stiffness was equally increased in both groups of TAC/DOCA mice (cRbm20ΔRRM-DMSO and cRbm20ΔRRM-raloxifene). However, titin-based muscle stiffness was reduced in the mice that expressed N2BAsc (TAC/DOCA cRbm20ΔRRM-raloxifene). Exercise testing demonstrated significant improvement in exercise tolerance in TAC/DOCA mice that expressed N2BAsc. Conclusions Inhibition of the RBM20-based titin splicing system upregulates compliant titins, which improves diastolic function and exercise tolerance in the TAC/DOCA model. Titin holds promise as a therapeutic target for HFpEF.

Funding Acknowledgements Type of funding sources: None. Background. Myocardial work (MW) is a new imaging technique to assess left ventricular (LV) systolic function. It incorporates both deformation parameters (global longitudinal strain -GLS-) and loading conditions and gives information on global constructive work (GCW), global wasted work (GWW), global LV myocardial work index (GWI) and global LV myocardial work efficiency (GWE). Purpose. The aim of this study was to describe the prognostic role of MW in predicting major adverse cardiovascular events (MACE) in patients with reduced LV ejection fraction (LVEF), and to compare it with GLS and LVEF. Methods. We retrospectively included consecutive patients from 2012 to 2019 with dilated LV and LVEF < 50% of any aetiology.  Clinical variables were collected and LVEF, GLS and MW were evaluated from baseline echocardiogram. MACE was defined as heart failure (HF) and/or ventricular arrhythmia (VA) and/or cardiac arrest and/or all cause death.  Results. 99 patients were included, 26 were women (26.3%), mean age at diagnosis was 57 years (SD 23). Mean LVEF was 32.5% (SD 10.3). Baseline patients characteristics are described in Table 1. During a median follow-up of 25 months (IQR 12), 24 MACE were recorded (24.4%). Patients with MACE had worse MW parameters: significantly lower MWI (805 ± 360 % vs 638 ± 277 %, p = 0.04) and lower GCW (1116 ± 535 mmHg vs 874 ± 458 mmHg, p = 0.05), and a tendency to lower GWE (83 ± 11 % vs 77 ± 16 %, p = 0.084).  Of note, both LVEF (33 ± 10% vs 29 ± 9%, p = 0.123) and GLS (-9.99 ± 3.7% vs -8.8 ± 3.0, p = 0.170) showed a trend but were not significantly associated with outcomes. This might suggest that MW variables are stronger prognostic predictors than traditional imaging parameters. Conclusions. In patients with reduced LVEF, MW parameters including global  MWI and GCW were associated with major adverse cardiovascular events. Of note, both EF and GLS seem to have less prognostic implications in this cohort when compared with MW. Our results are preliminary and larger studies are needed in order to fully understand the clinical utility of MW beyond traditional parameters. Baseline patient characteristics GLOBAL EVENTS NO EVENTS p Hypertension, % 41 67 29 0.014 Ischaemic etiology, % 14 20 12 0.448 Creatinine, mean (SD) - mg/dL 0.96 (0.04) 1.11 (0.09) 0.90 (0.04) 0.021 Bblockers, % 98 100 97 0.514 Nitrates, % 4 13 0 0.025 Diuretics, % 65 93 53 0.006 SD standard deviation Abstract Figure. Results

Background Myocardial work (MW) is a new imaging technique to assess left ventricular (LV) systolic function. It incorporates both deformation parameters (global longitudinal strain -GLS-) and loading conditions and gives information on global constructive work (GCW), global wasted work (GWW), global LV myocardial work index (GWI) and global LV myocardial work efficiency (GWE). Purpose The aim of this study was to describe the prognostic role of MW in predicting major adverse cardiovascular events (MACE) in patients with reduced LV ejection fraction (LVEF), and to compare it with GLS and LVEF. Methods We retrospectively included consecutive patients from 2012 to 2019 with dilated LV and LVEF <50% of any aetiology. Clinical variables were collected and LVEF, GLS and MW were evaluated from baseline echocardiogram. MACE was defined as heart failure (HF) and/or ventricular arrhythmia (VA) and/or cardiac arrest and/or all cause death. Results 99 patients were included, 26 were women (26.3%), mean age at diagnosis was 57 years (SD 23). Mean LVEF was 32.5% (SD 10.3). Baseline patients characteristics are described in Table 1. During a median follow-up of 25 months (IQR 12), 24 MACE were recorded (24.4%). Patients with MACE had worse MW parameters: significantly lower MWI (805±360% vs 638±277%, p=0.04) and lower GCW (1116±535 mmHg vs 874±458 mmHg, p=0.05), and a tendency to lower GWE (83±11% vs 77±16%, p=0.084). Of note, both LVEF (33±10% vs 29±9%, p=0.123) and GLS (−9.99±3.7% vs −8.8±3.0, p=0.170) showed a trend but were not significantly associated with outcomes. This might suggest that MW variables are stronger prognostic predictors than traditional imaging parameters. Conclusions In patients with reduced LVEF, MW parameters including global MWI and GCW were associated with major adverse cardiovascular events. Of note, both EF and GLS seem to have less prognostic implications in this cohort when compared with MW. Our results are preliminary and larger studies are needed in order to fully understand the clinical utility of MW beyond traditional parameters. Results Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Universitary Hospital Vall d'Hebron

Increasing titin length in the heart through functional deletion of the RNA recognition motif (RRM) of RBM20 protein leads to a reduction of left ventricular (LV) chamber stiffness in sedentary mice. We tested the therapeutic effect of upregulating compliant titins by creating diastolic dysfunction in a mouse model with inducible RBM20 inhibition (MerCreMer;cRbm20ΔRRM). Under transcriptional control of an MHC6 promoter, RBM20 function of MerCreMer;cRbm20ΔRRM mice was inhibited in time- and cardiac-specific manners. Adult male MerCreMer;cRbm20ΔRRM mice had undergone transaortic constriction (TAC) surgery with Deoxycorticosterone acetate (DOCA) pellet implantation. Two weeks after TAC+DOCA surgery, mice developed LV hypertrophy and diastolic dysfunction as demonstrated by echocardiography. Four weeks after surgery, pressure volume analysis revealed that LV chamber stiffness was markedly increased in TAC+DOCA mice (140% increased versus sham). However, the TAC+DOCA mice with RBM20 inhibition developed less severe LV chamber stiffness (29% increased versus sham). Passive stiffness measurements showed a reduction of cardiomyocyte stiffness in TAC+DOCA mice with RBM20 inhibition. Inhibition of the RBM20-based splicing system results in expression of compliant mutant N2BA titin which consequently lead to reduction of cardiomyocyte stiffness and LV chamber stiffness in a mouse model with diastolic dysfunction.

INTRODUCTION Patients with D- transposition of the great arteries (TGA) treated with Senning or Mustard surgeries have several atrial scars that predispose them to develop atrial tachycardias (AT). Identification of scar zones and possible arrhythmic isthmus in voltage mapping will help to guide the ablation. AIM To describe the feasibility of using a specific mapping catheter to identify possible arrhythmic isthmus in this set of patients. METHODS Prospective observational study in patients with history of SVT and atrial switch surgery, that underwent electrophysiologic study (EP) and electroanatomic (EA) mapping with a new 8Fr deflectable, multipoint wavefront-activation-orientation independent Grid catheter, in a third level hospital since April 2018 until May 2019, with medium-term follow-up. RESULTS A total of 8 EPs were performed in 7 patients (3 (57%) Female, median age 35 ± 6,3 y.o.). Figure 1A shows the localization and percentage of scar identified in both atria. A total of 6 AT were induced. In this, an arrhythmogenic isthmus was identified and, in all patients, at least one non-arrhytmogenic isthmus was documented. Figure 1B shows anatomical and electrophysiological characteristics of the isthmus. Arrhythmogenic isthmus had slower conduction velocity than non-arrhytmogenic ( mean 0,44m/s (IQI 0,17-0,62)  vs  1,05 m/s (IQI 0,86-1,39) p = 0.008) and fractionated potentials were detected more frequently (100% vs 50% p = 0.089) CONCLUSION EA mapping with a new a multipoint, high-definition, Grid Cather is feasible and allows the identification and electrophysiological characterization of arrhythmogenic and non-arrhytmogenic isthmus in patients with TGA treated with atrial switch surgery. Abstract Figure 1

indicating a slower myosin cross-bridge turnover rate of the mutant. Likewise, stopped flow kinetics of the ATP induced dissociation of the acto-myosin complex showed a significantly reduced slope of the kobs-[MgATP] relationship for IVS6-1 reconstituted myosin (4.350.02Â105 M-1 s-1, n=5), depicting slower second-order MgATP binding rates compared with WT (5.350.02Â105 M-1 s-1, n=5). Steady-state fluorescence binding experiments of mutant vs. WT reconstituted myosin to pyrene labeled F-actin under rigor conditions demonstrated significantly reduced binding affinity of IVS6-1 (Kd=16.752.8 nM, n=3) compared with WT (Kd=4.651.3 nM, n=3). In skinned porcine cardiac muscles, a significant decrease in maximal force was observed for IVS6-1 reconstituted fibers compared with WT (27.151.0 kN/m2 vs. 34.952.4 kN/m2, n=6). The Ca 2þ sensitivity and cooperativity were significantly different in IVS6-1 (pCa50=5.6650.01, nH=2.950.15) vs. WT (pCa50=5.4850.01, nH=2.250.14). In conclusion, we demonstrate that IVS6-1 may lead to cardiac dysfunction by disrupting the acto-myosin interaction (steady-state and kinetics) and compromising the ability of the mutant myosin to develop contractile force.

Introduction: Obstructive sleep apnea (OSA) is associated with cardiac dysfunction in children without congenital heart disease (CHD). Children with CHD are at increased risk for OSA and may be susceptible to further cardiovascular consequences due to OSA but the extent and nature of such cardiovascular effects of OSA are unknown. Methods: Children (6-17 years old) with corrected CHD without current cyanosis or Down syndrome were recruited from pediatric cardiology clinic. Home sleep tests were done to determine the presence and severity of OSA. OSA was defined as an obstructive apnea hypopnea index (oAHI) ≥1. Mild OSA was defined as an oAHI of ≥1 to <5 and moderate OSA was defined as an oAHI of ≥5 to <10. Standard clinically indicated echocardiograms were performed in clinic. Echocardiographic findings were compared between children with CHD with and without comorbid OSA using t-tests, Wilcoxon-sign rank tests as well as linear or logistic regression as appropriate. Results: Thirty-two children had sleep study and echocardiographic data available. OSA was present in 18 children (56%). OSA was mild in 89% and moderate in 11% of cases. There were no significant differences in age, body mass index, CHD severity, gender or ethnicity between children with and without OSA. Children with OSA had larger height-indexed right ventricular end-diastolic diameter (RVDi) compared to those without OSA (median 1.35, 95% CI 1.09, 1.56 vs. 1.21, 95% CI 1.01, 1.57; p=0.04). Children with moderate OSA had a reduced left ventricular shortening fraction compared to both those with mild OSA and no OSA (30.0 ± 6.1% vs. 38.7 ± 4.4%; p=0.009 and 39.2 ± 3.6%; p=0.007, respectively). Children with moderate OSA had increased left ventricular end-systolic diameter compared to those with mild OSA and no OSA (3.4 ± 0.4 cm vs. 2.5 ± 0.4; p=0.007 and 2.4 ± 0.5; p=0.001, respectively). Children with an RVDi above the median were seven times more likely to have OSA than those with an RVDi below the median (odds ratio 6.9.; 95% CI 1.3, 35; p=0.02). Conclusions: OSA is associated with changes in cardiac morphology and reduced contractility in children with CHD. Additionally, the presence of right ventricular dilation may suggest the need for OSA evaluation in children with CHD.