Visualization of Minute Mechanical-Excitation/Relaxation Wave-front Propagation in Myocardial Tissue

Unlike the case of skeletal muscle, the direction of myocardial contraction does not coincide with the direction of work necessary to eject the intraventricular blood, contributing to great complexity of the wall deformation sequence of cardiac contraction. The advent of advanced techniques (CT^1^, MRI^2,3^, SPECT^4^, echocardiology^5-9^, electrocardiography^10^, and magnetocardiography^11,12^) has enabled to the evaluation of cardiac function and disorders by the measurement of blood flow, pressure, electrical reaction process, and other factors. However, complexity of the contraction sequence is still not fully understood because the dynamic mechanical excitation process, which directly correlates with contraction, cannot be accurately measured based on these electro-magnetic phenomena. Here, developing and using a noninvasive novel imaging modality with high temporal and spatial resolutions^13-17^, we show that the propagation of the mechanical wave-front occurs at the beginning of each cardiac contraction and relaxation sequence for the first time. The former occurs about 60 ms prior to the ordinarily accepted onset time of the contraction (R-wave of the electrocardiogram). From the apical side of the interventricular septum, close to the terminal of the Purkinje fibers (specialized to carry contraction impulses), a minute velocity component with an amplitude of several tenth micrometers is generated and propagates sequentially to the entire left ventricle, that is, it propagates from the apex to the base of the posterior wall, and then from the base to the apex of the septum, with a propagation speed of 3-9 m/s. The latter occurs at the end of the first heart sound at the apical side and propagates to the base side with a speed of 0.6 m/s. These physiological findings, unlike the widely accepted myocardial excitation process, have potential for accurate assessment of myocardial tissue damage in coronary disease and cardiomyopathy. This dynamic measurement modality is also applicable to various tissues in biology

Noninvasive evaluation of local myocardial thickening and its color-coded imaging

科研費報告書収録論文(課題番号:08555096・基盤研究(B)(2)・H8～H9/研究代表者:金井, 浩/心筋の早期診断を可能とする心臓壁微小振動の超音波計測及び解析装置の開発

Blood flow structure and dynamics, and ejection mechanism in the left ventricle: Analysis using echo-dynamography

SummaryUsing our “echo-dynamography”, blood flow structure and flow dynamics during ventricular systole were investigated in 10 normal volunteers. The velocity vector distribution demonstrated blood flow during ejection was laminar along the ventricular septum. The characteristic flow structure was observed in each cardiac phases, early, mid- and late systole and was generated depending on the wall dynamic events such as peristaltic squeezing, hinge-like movement of the mitral ring plane, bellows action of the ventricle and dimensional changes in the funnel shape of the basal part of the ventricle, which were disclosed macroscopically by using the new technology of high speed scanning echo-tomography and microscopically by the strain rate distribution measured by phase tracking method.The pump function was reflected on the changes in the flow structure represented by the flow axis line distribution and the acceleration along the flow axis line. The acceleration of the ejection had three modes, “A”, “B” and “C”, and generated by the wall dynamic events. “A” appeared from the apical to the outflow area along the main flow axis line, “B” along the anterior mitral leaflet and the branched flow axis line, and “C” generated by the high speed vortex behind the mitral valve. The magnitude of the acceleration was estimated quantitatively from the velocity gradient along the flow axis line. Macroscopic and microscopic asynchrony in the myocardial contraction and extension appeared systematically in the local part of the ventricular wall, which was helpful for making the flow structure and for performing the smooth pump function

Non-uniform distribution of the contraction/extension (C–E) in the left ventricular myocardium related to the myocardial function

AbstractObjectiveWe attempted to disclose the microscopic characteristics of the non-uniform distribution of the contraction and extension (C–E) of the left ventricular (LV) myocardium using a new methodology (echo-dynamography).MethodsThe distributions of the “axial strain rate” (aSR) and the intra-mural velocity in the local areas of the free wall including the posterior wall (PW) and interventricular septum (IVS) were microscopically obtained using echo-dynamography with a high accuracy of 821μm in the spatial resolution. The results were shown by the color M-mode echocardiogram or curvilinear graph. Subjects were 10 presumably normal volunteers.Results(1)Both the C–E in the pulsating LV wall showed non-uniformity spatially and time-sequentially.(2)The C–E property was better evaluated by the aSR distribution method rather than the intra-mural velocity distribution method.(3)Two types of non-uniformity of the aSR distribution were observed: i.e. (i) the difference of its (+)SR (contraction: C) or (−)SR (extension: E) was solely the “magnitude”; (ii) the coexistence of both the (+) SR and (−)SR at the same time.(4)The aSR distribution during systole was either “spotted,” or “multi-layered,” or “toned” distribution, whereas “stratified,” “toned,” or “alternating” distributions were observed during diastole.(5)The aSR distribution in the longitudinal section plane was varied in the individual areas of the wall even during the same timing.(6)To the mechanical function of the LV, there was a different behavior between the IVS and PW.ConclusionsThe aSR and its distribution were the major determinants of the C–E property of the LV myocardium. Spatial as well as time-sequential uniformity of either contraction or extension did not exist. The myocardial function changed depending on the assemblage of the aSR distribution, and by the synergistic effect of (+)SR and (−)SR, the non-uniformity itself potentially served to hold the smooth LV mechanical function

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

A less invasive Emax estimation method for weaning from cardiac assistance

科研費報告書収録論文(課題番号:07557309・基盤研究(A)(1)・H7～H9/研究代表者:仁田, 新一/高周波振動流を用いた生体臓器血流制御法の薬物輸送システムへの応用に関する研究