Genome Editing and Inherited Cardiac Arrhythmias.

Inherited arrhythmic disorders are a group of heterogeneous diseases predisposing to life-threatening arrhythmias and sudden cardiac death. Their diagnosis is not always simple due to incomplete penetrance and genetic heterogeneity. Furthermore, the available treatments are usually invasive and merely preventive. Genome editing and especially CRISPR/Cas9 technologies have the potential to correct the genetic arrhythmogenic substrate, thereby offering a cure for these fatal diseases. To date, genome editing has allowed reproducing cardiac arrhythmias in vitro, providing a robust platform for variant pathogenicity, mechanistic, and drug-testing studies. However, in vivo approaches still need profound research regarding safety, specificity, and efficiency of the methods.S

Titin Missense Variants as a Cause of Familial Dilated Cardiomyopathy.

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Early preventive treatment with Enalapril improves cardiac function and delays mortality in mice with arrhythmogenic right ventricular cardiomyopathy type 5.

Background: Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5) is an inherited cardiac disease with complete penetrance and an aggressive clinical course caused by mutations in TMEM43 (transmembrane protein 43). There is no cure for ARVC5 and palliative treatment is started once the phenotype is present. A transgenic mouse model of ARVC5 expressing human TMEM43-S358L (TMEM43mut) recapitulates the human disease, enabling the exploration of preventive treatments. The aim of this study is to determine whether preventive treatment with heart failure drugs (β-blockers, ACE [angiotensin-converting enzyme] inhibitors, mineralocorticoid-receptor antagonists) improves the disease course of ARVC5 in TMEM43mut mice. Methods: TMEM43mut male/female mice were treated with metoprolol (β-blockers), enalapril (ACE inhibitor), spironolactone (mineralocorticoid-receptor antagonist), ACE inhibitor + mineralocorticoid-receptor antagonist, ACE inhibitor + mineralocorticoid-receptor antagonist + β-blockers or left untreated. Drugs were initiated at 3 weeks of age, before ARVC5 phenotype, and serial ECG and echocardiograms were performed. Results: TMEM43mut mice treated with enalapril showed a significantly increased median survival compared with untreated mice (26 versus 21 weeks; P=0.003). Enalapril-treated mice also exhibited increased left ventricular ejection fraction at 4 months compared with controls (37.0% versus 24.9%; P=0.004), shorter QRS duration and reduced left ventricle fibrosis. Combined regimens including enalapril also showed positive effects. Metoprolol decreased QRS voltage prematurely and resulted in a nonsignificant decrease in left ventricular ejection fraction compared with untreated TMEM43mut mice. Conclusions: Preventive enalapril-based regimens reduced fibrosis, improved ECG, echocardiographic parameters and survival of ARVC5 mice. Early metoprolol did not show positive effects and caused premature ECG abnormalities. Our findings pave the way to consider prophylactic enalapril in asymptomatic ARVC5 genetic carriers.pre-print326 K

Titin Missense Variants as a Cause of Familial Dilated Cardiomyopathy.

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Impacto de la pandemia de COVID-19 en la lactancia y cuidados al nacimiento: Importancia de recuperar las buenas prácticas

The SARS-CoV-2 pandemic has had a major impact on birth care and lactation. The lack of knowledge regarding the transmission mechanisms and the potential risks for the mother and the newborn, even when the vertical transmission of the virus has not been demonstrated, has led to the abandonment of practices such as skin-to-skin and the early initiation of breastfeeding (BF), which offer great benefits for maternal and child health. Taking into account the available scientific evidence and the protective effect of BF, the World Health Organization (WHO), and other organisms recommend, in cases of suspected or confirmed SARS-CoV-2 infection of the mother, maintaining mother-child contact and BF, adopting preventive measure procedures to minimize the risk of contagion. These measures include hand hygiene, before and after contact with the newborn and the use of a mask. If a temporary separation of mother and child is required, it is recommended to feed the newborn with expressed breast milk. The presence of IgA antibodies against SARSCoV- 2 has been confirmed in the milk of infected women, so BF could reduce the clinical impact of the disease in the infant, if it becomes infected.La pandemia por el SARS-CoV-2 ha tenido un gran impacto en la atención al nacimiento y la lactancia. El desconocimiento de los mecanismos de contagio y los riesgos potenciales para la madre y el recién nacido (RN), aun cuando no se ha demostrado la transmisión vertical del virus, ha propiciado el abandono de prácticas como el piel con piel y el inicio precoz de la lactancia materna (LM), que ofrecen grandes beneficios para la salud materno-infantil. Teniendo en cuenta la evidencia científica disponible y el efecto protector de la LM, la Organización Mundial de la Salud (OMS) y otros organismos recomiendan mantener el contacto madre-hijo y la LM en casos de sospecha o infección confirmada por SARS-CoV-2 en la madre, adoptando procedimientos preventivos para minimizar el riesgo de contagio, como la higiene de las manos, antes y después del contacto con el RN, así como el uso de mascarilla. Si se precisa una separación temporal de la madre y el niño, se recomienda alimentar al RN con leche materna extraída. Se ha confirmado la presencia de anticuerpos IgA frente al SARS-CoV-2 en leche de mujeres infectadas, por lo que la LM podría disminuir el impacto clínico de la enfermedad en el lactante, si llega a contagiarse

Biallelic Loss of Function Variants in Myocardial Zonula Adherens Protein Gene (MYZAP) Cause a Severe Recessive Form of Dilated Cardiomyopathy.

This study has been funded by grants from the Spanish Society of Cardiology (basic research grant 2021) to Dr Ochoa, Spanish Ministry of Science PLEC2022-009235 MCIN/AEI/10.13039/501100011033 co-funded by the European Union NextGenerationEU/PRTR to Drs Lara-Pezzi, Gómez-Gaviro, and Garcia-Pavia, and PID2021-124629OB-I00 and TED2021-129774B-C22 to Dr Lara-Pezzi, and from Instituto de Salud Carlos III (ISCIII) DTS22/00030 co-funded by the European Union to Dr Gómez-Gaviro. Drs Lara-Pezzi, Ware, and Garcia-Pavia are funded by the Pathfinder Cardiogenomics Programme of the European Innovation Council of the European Union (DCM-NEXT project; project 101115416). The CNIC is supported by the ISCIII, the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/ AEI/10.13039/501100011033). Drs Ware, McGurk, and Barton have been funded by the Medical Research Council (United Kingdom), Sir Jules Thorn Charitable Trust (21JTA), Wellcome Trust (107469/Z/15/Z), British Heart Foundation (RE/18/4/34215, FS/IPBSRF/22/27059), and the National Institute for Health and Care Research (NIHR) Imperial College Biomedical Research Centre. Part of this research was made possible through access to the data and findings generated by the 100 000 Genomes Project. The 100 000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100 000 Genomes Project is funded by the NIHR and National Heart Service (NHS) England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100 000 Genomes Project uses data provided by patients and collected by the NHS as part of their care and support. The UK Biobank recruited 500 000 participants aged 40 to 69 years across the UK between 2006 and 2010 (National Research Ethics Service, 11/NW/0382; 10.1371/journal. pmed.1001779). This study was conducted under terms of access approval number 47602. Written informed consent was provided.S

Association of the presence of a COVID-19 infection at the time of birth and the rates of exclusive breastfeeding upon discharge in BFHI hospitals: a multicenter, prospective cohort study

Abstract Background Very few studies have assessed the association between COVID-19 infection and the rates of exclusive breastfeeding (EBF) upon discharge following the first waves of the pandemic and after initiation of vaccination. The primary objective of this study is to compare the rates of EBF since birth upon discharge in mothers diagnosed with COVID-19 infection at the time of the delivery versus a group of non-infected mothers in maternity hospitals with Baby Friendly Hospital Initiative (BFHI) accreditation. The secondary objectives include determining the rates of any breastfeeding at three and six months of life in both groups, as well as determining the possible factors associated with EBF rates observed upon discharge. Methods An observational, Spanish multi-center hospital, prospective cohort study conducted from 1 to 2021 to 31 March 2022 and with follow-up during the first six months of life. Follow-up was performed via telephone contact with calls performed at three and six months. A multivariate logistic regression analysis model was used to identify the factors related to a lower probability of EBF upon discharge. Results 308 mother-infant pairs participated in the study, 111 in the cohort of women with COVID infection and 197 in the comparison group. EBF upon discharge was 62.7% in the COVID group vs. 81.2% in the comparison group (p = 0.002); at three months; 52.4% vs. 57.0% (p = 0.33) were performing EBF, with the rates of EBF at six months being 43.0% vs. 39.3% (p = 0.45), respectively. Exposure to COVID-19 at delivery (AOR 5.28; 95% CI 2.01, 13.86), not practicing BF previously (AOR 36.3; 95% CI 7.02, 187.74), birth via Cesarean section (AOR 5.06; 95% CI 1.62, 15.79) and low birth weight of the newborn (AOR 1.01; 95% CI 1.01, 1.01) were associated with a greater risk of not performing EBF upon discharge. Conclusions Mothers with a mild or asymptomatic COVID-19 infection at the time of the delivery were less likely to have exclusively breastfed during their hospital stay than other mothers in these BFHI-accredited hospitals. However, there were no differences in breastfeeding rates between the groups at three and six months postpartum