Effects of a high-fat diet on the electrical properties of porcine atria

AbstractBackgroundBecause obesity is an important risk factor for atrial fibrillation (AF), we conducted an animal study to examine the effect of a high-fat diet (HFD) on atrial properties and AF inducibility.MethodsTen 8-week-old pigs (weight, 18–23kg) were divided into two groups. For 18 weeks, five pigs were fed a HFD (HFD group) and five were fed a normal diet (control group). Maps of atrial activation and voltages during sinus rhythm were created for all pigs using the EnSite NavX system. Effective refractory period (ERP) and AF inducibility were also determined. When AF was induced, complex fractionated atrial electrogram (CFAE) mapping was performed. At 18 weeks, hearts were removed for comparing the results of histological analysis between the two groups. Body weight, lipid levels, hemodynamics, cardiac structures, and electrophysiological properties were also compared.ResultsTotal cholesterol levels were significantly higher (347 [191–434] vs. 81 [67–88]mg/dL, P=0.0088), and left atrium pressure was higher (34.5 [25.6–39.5] vs. 24.5 [21.3–27.8]mmHg, P=0.0833) in the HFD group than in the control group, although body weight only increased marginally (89 [78–101] vs. 70 [66–91]kg, P=0.3472). ERPs of the pulmonary vein (PV) were shorter (P<0.05) and AF lasted longer in the HFD group than in the control group (80 [45–1350] vs. 22 [3–30]s, P=0.0212). Neither CFAE site distribution nor histopathological characteristics differed between the two groups.ConclusionsThe shorter ERPs for the PV observed in response to the HFD increased vulnerability to AF, and these electrophysiological characteristics may underlie obesity-related AF

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Wavefront direction and cycle length affect left atrial electrogram amplitude

Background: The relationship between atrial electrogram (EGM) characteristics in atrial fibrillation (AF) and those in sinus rhythm (SR) are generally unknown. The activation rate and direction may affect EGM characteristics. We examined characteristics of left atrial (LA) EGMs obtained during pacing from different sites. Methods: The study included 10 patients undergoing pulmonary vein isolation for AF. Atrial EGMs were recorded from a 64-pole basket catheter placed in the LA, and bipolar EGM amplitudes from the distal electrode pair (1–2) and proximal electrode pair (6–7) from 8 splines were averaged. The high right atrium (HRA), proximal coronary sinus (CSp), and distal coronary sinus (CSd) were paced at 600 ms and 300 ms. Results: When the LA voltage at SR was ≥1.5 mV, bipolar voltages of the HRA were greater than those of the CSp, which were greater than those of the CSd, regardless of the pacing cycle length. The shorter pacing cycle length resulted in a reduction of the LA EGM voltage at sites of SR voltage ≥1.5 mV, but no significant difference was seen at sites where the SR EGM amplitude was between >0.5 and <1.5 mV. No significant differences were seen in intra-basket conduction times between pacing cycle lengths of 600 ms and 300 ms at any pacing site. Conclusion: The rate and direction-dependent reduction of the amplitude of atrial EGMs may explain, in part, the voltage discordance during SR and AF