Optimal graft diameter and location reduce postoperative complications after total arch replacement with long elephant trunk for arch aneurysm

ObjectiveTotal arch replacement with an elephant trunk is a standard treatment for arch aneurysm, but serious complications, such as paraplegia and peripheral embolization caused by flapping of the elephant trunk, remain. Moreover, dilation of the descending aorta and retrograde flow into the peri-graft space at the distal elephant trunk are frequent problems. We hypothesized that optimal graft diameter and location would reduce complications after total arch replacement with a long elephant trunk by achieving complete thrombosis and minimal dilation of the descending aorta around the elephant trunk.MethodsWe treated 65 patients with arch aneurysm by total arch replacement with a long elephant trunk anastomosed at the base of the innominate artery. The graft diameter was undersized (10%–20% of the distal aorta’s diameter). Elephant trunk length was determined by preoperative computed tomography to locate the distal end at Th6 to Th8. Thrombosis around the elephant trunk, diameter of the descending aorta, and distance between the descending aorta and the graft near the distal end of the elephant trunk were evaluated using computed tomography.ResultsThe distal end of the elephant trunk was located at Th 8 ± 1. There were no operative deaths, 3 patients (5%) died in the hospital, and 3 patients (5%) experienced spinal cord injury, including 1 in whom permanent paraplegia developed. Computed tomography revealed complete thrombosis around the elephant trunk in 58 patients (89%). The descending aorta did not dilate further, and distance between the descending aorta and the graft progressively decreased.ConclusionsOptimal graft diameter and location minimized postoperative complications, with complete thrombosis and no dilation of the descending aorta around the long elephant trunk in most patients

Improved long-term performance of pulsatile extracorporeal left ventricular assist device

SummaryBackground and purposeThe majority of heart transplant (HTx) candidates require left ventricular assist device (LVAD) support for more than 2 years before transplantation in Japan. However, the only currently available device is the extracorporeal pulsatile LVAD. The long-term management of extracorporeal LVAD support has improved remarkably over the years. To determine which post-operative management factors are related to the long-term survival of patients on such LVAD, we retrospectively compared the incidence of complications and their management strategies between the initial and recent eras of LVAD use, classified by the year of LVAD surgery.MethodsSixty-nine consecutive patients supported by extracorporeal pulsatile LVAD as a bridge to HTx between 1994 and 2007 were reviewed retrospectively. The patients were assigned according to the time of LVAD surgery to either group A (n=30; between 1994 and 2000) or group B (n=39; between 2001 and 2007).ResultsPatients in group B survived significantly longer on LVAD support than those in group A (674.6 vs. 369.3 days; p<0.001). The 1- and 2-year survival rates were significantly higher in group B than that in group A (82% vs. 48%, p<0.0001; 68% vs. 23%, p<0.0001, respectively). The proportion of deaths due to cerebrovascular accidents was lower (17% vs. 50%, p<0.001) in group B compared with group A. The incidences of systemic infection were similar in both groups, but the proportions of patients alive and achieving transplant surgery after systemic infection were higher in group B than those in group A (55% vs. 14%, p<0.01; 14% vs. 36%, p<0.05, respectively).ConclusionsThe long-term survival of patients even on “first-generation” extracorporeal LVAD has improved significantly in the recent era. Careful management of cerebrovascular accidents and systemic infection will play important roles in the long-term LVAD management

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

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

Non-Gaussian athermal fluctuations in active gels

Dynamic networks designed to model the cell cytoskeleton can be reconstituted from filamentous actin, the motor protein myosin and a permanent cross-linker. They are driven out of equilibrium when the molecular motors are active. This gives rise to athermal fluctuations that can be recorded by tracking probe particles that are dispersed in the network. We have here probed athermal fluctuations in such “active gels” using video microrheology. We have measured the full distribution of probe displacements, also known as the van Hove correlation function. The dominant influence of thermal or athermal fluctuations can be detected by varying the lag time over which the displacements are measured. We argue that the exponential tails of the distribution derive from single motors close to the probes, and we extract an estimate of the velocity of motor heads along the actin filaments. The distribution exhibits a central Gaussian region which we assume derives from the action of many independent motor proteins far from the probe particles when athermal fluctuations dominate. Recording the whole distribution rather than just the typically measured second moment of probe fluctuations (mean-squared displacement) thus allowed us to differentiate between the effect of individual motors and the collective action of many motors

Pulmonary hypertension predicts adverse cardiac events after restrictive mitral annuloplasty for severe functional mitral regurgitation

ObjectivesPulmonary hypertension (PH) is an indicator of a poor prognosis in patients with dilated cardiomyopathy. Few studies have investigated the prognostic role of PH in patients undergoing restrictive mitral annuloplasty (RMA) for severe functional mitral regurgitation secondary to advanced cardiomyopathy.MethodsA total of 46 patients undergoing RMA were classified into 3 groups on the basis of the Doppler-derived systolic pulmonary artery pressure (PAP) at baseline. Of the 46 patients, 19 had a systolic PAP less than 40 mm Hg (mild PH group), 17 had a systolic PAP of 40 to 60 mm Hg (moderate PH group), and 10 had a systolic PAP greater than 60 mm Hg (severe PH group).ResultsPostoperative cardiac catheterization showed that the RMA procedure resulted in a significant reduction of the left ventricular (LV) preload and improvements in LV systolic function in all 3 groups, along with the relief of symptoms. During the follow-up period (mean, 36 ± 19 months), cardiac death occurred in 6 patients, readmission because of heart failure in 3, and fatal arrhythmia in 1. The rate of freedom from these cardiac events at 3 years was 93% ± 7%, 88% ± 8%, and 56% ± 17% in the mild, moderate, and severe PH groups (P < .001). Serial echocardiography showed that significant LV reverse remodeling occurred in 89%, 71%, and 25% of the mild, moderate, and severe PH groups, respectively. Multivariate Cox regression analysis identified severe PH (systolic PAP > 60 mm Hg) as a significant predictor of adverse cardiac events, as well as LV remodeling after RMA.ConclusionsNoninvasive assessment of preoperative PH has a prognostic value in patients undergoing RMA for severe functional mitral regurgitation secondary to advanced cardiomyopathy