ブルガダ症候群の心室細動リスクの層別化におけるタイムドメイン法を用いたT波交互現象の有用性

内容の要旨 , 審査の要旨広島大学(Hiroshima University)博士(医学)Doctor of Philosophy in Medical Sciencedoctora

The Frizzled 3 gene is associated with methamphetamine psychosis in the Japanese population

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

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

The Impact of Myocardial Bridging on the Coronary Functional Test in Patients with Ischaemia with Non-Obstructive Coronary Artery Disease

Background: The possibility of myocardial bridging (MB) causing chest pain has been widely reported; however, the effect of MB on coronary microvessels has not been thoroughly investigated. Therefore, this study evaluated the effects of MB on epicardial coronary artery and coronary microvascular function during coronary angiography (CAG) and coronary function test (CFT) in patients with ischaemia with non-obstructive coronary artery disease (INOCA). Methods: This study included 62 patients with INOCA who underwent CAG and CFT for the left anterior descending coronary artery (LAD) to evaluate chest pain. In the CFT, acetylcholine was first administered intracoronarily in a stepwise manner, followed by chest symptoms, electrocardiographic ST-T changes and CAG. Positive coronary spasm was defined as coronary vasoconstriction of >90% on CAG accompanied by chest symptoms or electrocardiographic ST-T changes. After nitroglycerin administration, CAG was performed to assess MB, which was defined as systolic narrowing of the coronary artery diameter by >20% compared with that in diastole. Coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) were subsequently obtained via transvenous adenosine triphosphate infusion using a pressure wire. Coronary microvascular vasodilatory dysfunction (CMD) was defined as a CFR of <2.0 or an IMR of ≥25 units. Results: Of the 62 patients, 15 (24%) had MB. The patients’ characteristics did not differ between the two groups. Regarding the CAG and CFT results, the presence of coronary spasm in the LAD was higher in the MB (+) group (87%) than in the MB (−) group (53%, p = 0.02), whereas the values of CFR (MB (+): 2.7 ± 1.4, MB (−): 2.8 ± 1.1) and IMR (MB (+): 26.9 ± 1.0, MB (−): 30.0 ± 17.3) and the presence of CMD (MB (+): 53%, MB (−): 60%) were similar in the two groups. Conclusions: The findings suggest that MB predisposes patients with INOCA to coronary spasms. Conversely, MBs may have a limited effect on microvessels, particularly in such patients

Clinical Characteristics and Prognosis of Patients with Vasospastic Angina Subjected to the Spasm Provocation Test and the Unavoidable Use of Nitroglycerin

Background: Multi-vessel spasm (MVS) has a prognostic impact in patients with vasospastic angina (VSA). Thus, the presence of coronary spasm in both the left coronary artery (LCA) and right coronary artery (RCA) should be assessed through the spasm provocation test (SPT). Nitroglycerin (NTG) is used to avoid SPT-related complications; however, this unavoidable use of NTG may decrease the detection of MVS. Therefore, we investigated the frequency of the unavoidable use of NTG during SPT and clarified the clinical characteristics in patients with VSA who underwent the unavoidable use of NTG during STP. Methods: A total of 141 patients with positive SPT were evaluated. A positive SPT was defined as > 90% constriction in epicardial coronary arteries in response to acetylcholine, accompanied by the usual chest symptoms and/or ischaemic ST-T changes on electrocardiography. When a coronary spasm occurred, we usually wait for the spontaneous relief of the coronary spasm. However, if a prolonged coronary spasm or unstable haemodynamics occurred, 0.3 mg NTG was administered intracoronarily to promptly relieve the coronary spasm and this was defined as the unavoidable use of NTG. Even when the unavoidable use of NTG was administered in one coronary artery, an additional SPT was performed on another coronary artery. If a coronary spasm occurred in another coronary artery, a positive SPT was diagnosed. In contrast, if a coronary spasm was not induced after the unavoidable use of NTG, the judgement was classified as undiagnosed. The patients were divided into two groups according to the unavoidable use of NTG: U-NTG (n = 42) and the final use of NTG: F-NTG (n = 99). The clinical characteristics and frequencies of MVS (≥2 major coronary arteries in which a coronary spasm was provoked) and complications (malignant arrhythmia and unstable haemodynamics requiring catecholamines) during the SPT were compared between the groups. Results: Except for smoking status, all other clinical characteristics did not differ significantly between the groups. More current smokers were observed in the U-NTG group (29%) than in the F-NTG group (12%, p = 0.02). The frequency of MVS did not vary significantly between the groups (p = 0.28), with 64% for U-NTG and 55% for F-NTG. No significant difference was found between the groups in the frequency of severe complications during SPT (p = 0.83), with 2% for U-NTG and 3% for F-NTG. In the U-NTG group, the positive induction rate of coronary spasm in another coronary artery was 40% (17/42). Conclusions: The unavoidable use of NTG occurred in ~30% of patients with VSA, most of whom were current smokers. It did not decrease the detection of MVS and potentially prevented severe complications during SPT. Therefore, the unavoidable use of NTG is acceptable during SPT. However, an additional test may need to be performed to assess the presence of MVS

Intracoronary Thrombogenicity in Patients with Vasospastic Angina: An Observation Using Coronary Angioscopy

Background: Despite significant interest in intracoronary thrombi in patients with vasospastic angina (VSA), the phenomenon remains unclarified. Therefore, we investigated a possible relationship using coronary angioscopy (CAS) in VSA patients. Methods: Sixty patients with VSA, for whom we could assess the spastic segment using CAS, were retrospectively studied. An intracoronary thrombus on CAS was a white thrombus and an erosion-like red thrombus. We verified the clinical characteristics and lesional characteristics as they determined the risk of intracoronary thrombus formation. Results: There were 18 (30%) patients with intracoronary thrombi. More of the patients with intracoronary thrombi were male, current smokers and had severe concomitant symptoms; however, no statistically significant difference was observed upon logistic regression analysis. There were 18 (26%) coronary arteries with intracoronary thrombi out of 70 coronary arteries recognised in the spastic segments. Furthermore, atherosclerotic changes and segmental spasms were significant factors responsible for such lesions. Conclusion: Intracoronary thrombi occurred in 30% of VSA patients and much attention should be paid to the intracoronary thrombogenicity of VSA patients

Factors Contributing to Coronary Microvascular Dysfunction in Patients with Angina and Non-Obstructive Coronary Artery Disease

Background: Coronary microvascular dysfunction (CMD), characterised by a reduced coronary flow reserve (CFR) or an increased index of microcirculatory resistance (IMR), has received considerable attention as a cause of chest pain in recent years. However, the risks and causes of CMD remain unclear; therefore, effective treatment strategies have not yet been established. Heart failure or coronary artery disease (CAD) is a risk factor for CMD, with a higher prevalence among women. However, the other contributing factors remain unclear. In this study, we assessed the risk in patients with angina and non-obstructive coronary artery disease (ANOCA), excluding those with heart failure or organic stenosis of the coronary arteries. Furthermore, we analysed whether the risk of CMD differed according to component factors and sex. Methods: This study included 84 patients with ANOCA (36 men and 48 women; mean age, 63 years) who underwent coronary angiography and functional testing (CFT). The CFT included a spasm provocation test (SPT), followed by a coronary microvascular function test (CMVF). In the SPT, patients were mainly provoked by acetylcholine (ACh), and coronary spasm was defined as >90% transient coronary artery constriction on coronary angiography, accompanied by chest pain or ischaemic changes on electrocardiography. In 15 patients (18%) with negative ACh provocation, ergonovine maleate (EM) was administered as an additional provocative drug. In the CMVF, a pressure wire was inserted into the left anterior descending coronary artery using intravenous adenosine triphosphate, and the CFR and IMR were measured using previously described methods. A CFR p p = 0.020) and the use of EM (p = 0.020). The factors that correlated with a CFR p = 0.013), which showed a weak but positive correlation with the CFR (r = 0.268, p = 0.013). Conversely, the factors correlated with an IMR ≥ 25 included RAS inhibitor usage (p = 0.018) and smoking (p = 0.042). Assessment of the risk of CMD according to sex revealed that smoking (p = 0.036) was the only factor associated with CMD in men, whereas the left ventricular mass index (p = 0.010) and low glycated haemoglobin levels (p = 0.012) were associated with CMD in women. Conclusions: Our results indicated that smoking status and EM use were associated with CMD. The risk of CMD differed between the two CMD components and sex. Although these factors should be considered when treating CMD, smoking cessation remains important. In addition, CMD assessment should be performed carefully when EM is used after ACh provocation. Further validation of our findings using prospective studies and large registries is warranted

Frequency and Clinical Impact of Family History of Coronary Artery Disease in Patients with Vasospastic Angina

Background: Family history (FH) of coronary artery disease (CAD) [FH-CAD] is a well-known risk factor for atherosclerotic CAD. However, FH-CAD frequency in patients with vasospastic angina (VSA) remains unknown, and the clinical characteristics and prognosis of VSA patients with FH-CAD are unclear. Therefore, this study compared FH-CAD frequency between patients with atherosclerotic CAD and those with VSA and examined the clinical characteristics and prognosis of VSA patients with FH-CAD. Methods: Coronary angiography and spasm provocation tests (SPT) were used to investigate chest pain of coronary artery origin in patients classified into atherosclerotic CAD (362 cases), VSA (221 cases; positive for SPT) and non-VSA (73 cases; negative for SPT) groups, with FH-CAD being defined. In the VSA group, flow-mediated vasodilation (FMD) and nitroglycerin-independent vasodilation (NID) via brachial artery echocardiography and clinical symptoms in the groups with and without FH-CAD were checked, with Kaplan–Meier curves revealing major adverse cardiovascular events (cardiac death and rehospitalisation for cardiovascular disease) between the two groups. Results: The atherosclerotic CAD group had a significantly lower FH-CAD frequency (12%, p = 0.029) than the VSA (19%) and non-VSA groups (19%). FH-CAD was more common in females in the VSA and non-VSA groups than in the atherosclerotic CAD group (p p = 0.017). In the VSA group, FH-CAD tended to be more common in females (p = 0.052). Although no differences in FMD of the brachial artery were observed between the groups, the FH-CAD (+) group had significantly higher NID than the FH-CAD (−) group (p = 0.023). Kaplan–Meier’s analysis revealed a similar prognosis between the two groups, and other clinical characteristics did not differ. Conclusion: Patients with VSA have a higher FH-CAD frequency than those with atherosclerotic CAD, especially in females. Although FH-CAD may affect vascular function in patients with VSA, its effect on the severity and prognosis of VSA appears to be minimal. FH-CAD and its confirmation may assist in CAD diagnosis, especially in female patients