Further insights into the molecular complexity of the human sinus node - The role of 'novel' transcription factors and microRNAs.

RESEARCH PURPOSE: The sinus node (SN) is the heart's primary pacemaker. Key ion channels (mainly the funny channel, HCN4) and Ca2+-handling proteins in the SN are responsible for its function. Transcription factors (TFs) regulate gene expression through inhibition or activation and microRNAs (miRs) do this through inhibition. There is high expression of macrophages and mast cells within the SN connective tissue. 'Novel'/unexplored TFs and miRs in the regulation of ion channels and immune cells in the SN are not well understood. Using RNAseq and bioinformatics, the expression profile and predicted interaction of key TFs and cell markers with key miRs in the adult human SN vs. right atrial tissue (RA) were determined. PRINCIPAL RESULTS: 68 and 60 TFs significantly more or less expressed in the SN vs. RA respectively. Among those more expressed were ISL1 and TBX3 (involved in embryonic development of the SN) and 'novel' RUNX1-2, CEBPA, GLI1-2 and SOX2. These TFs were predicted to regulate HCN4 expression in the SN. Markers for different cells: fibroblasts (COL1A1), fat (FABP4), macrophages (CSF1R and CD209), natural killer (GZMA) and mast (TPSAB1) were significantly more expressed in the SN vs. RA. Interestingly, RUNX1-3, CEBPA and GLI1 also regulate expression of these cells. MiR-486-3p inhibits HCN4 and markers involved in immune response. MAJOR CONCLUSIONS: In conclusion, RUNX1-2, CSF1R, TPSAB1, COL1A1 and HCN4 are highly expressed in the SN but not miR-486-3p. Their complex interactions can be used to treat SN dysfunction such as bradycardia. Interestingly, another research group recently reported miR-486-3p is upregulated in blood samples from severe COVID-19 patients who suffer from bradycardia.

Post-Mortem Diagnosis and Autopsy Findings in SARS-CoV-2 Infection: Forensic Case Series.

Towards the end of 2019, a novel coronavirus was identified as the culprit for a cluster of pneumonia cases in Wuhan, China. Since then, it has rapidly spread worldwide, affecting more than 43 million people, and in March 2020, the World Health Organization (WHO) declared it a pandemic. The purpose of the study is to present the findings of 15 forensic autopsies performed in Romania, on SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) positive subjects, and to present the case of one SARS-CoV-2 infected patient who experienced a violent death, as established during their autopsy. A total of 11 male and 4 female patients were autopsied, and SARS-CoV-2 infection was diagnosed post-mortem in two cases. The most frequent symptoms before death were dry cough, dyspnoea, and fever. Hypertension, ischemic cardiac disease, and a history of stroke were the most frequent associated diseases. The mean duration from the symptoms' debut to a RT-PCR positive SARS-CoV-2 test was 3.7 days, while the mean survival time from the RT-PCR positive test was 4.2 days. A histological examination was performed in seven cases and revealed, in most of them, hyaline membranes, and mixed inflammatory cell infiltration of the interstitium, alveoli, and perivascular areas. In addition, all of the examined cases developed small vessel thrombosis. A case of violent death was also reported, regarding a 87-year-old male subject who suffered a femur fracture (domestic fall) and was diagnosed with SARS-CoV-2 infection the following day after surgery. After transfer to a COVID-19 (coronavirus disease-19) support hospital, during an episode of behavioral disorder, the patient jumped from the first floor window. Death occurred a few days later, and the cause was established as bronchopneumonia superimposed on SARS-CoV-2 infection. In conclusion, autopsies should be conducted while providing a safe environment for professionals to perform them, because they are crucial procedures that can help gain a better understanding of the role of SARS-CoV-2 infection in thanatogenesis.