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Hiroki Teragawa, Yuko Uchimura, Chikage Oshita, Yu Hashimoto, Shuichi Nomura Department of Cardiovascular Medicine, JR Hiroshima Hospital, Hiroshima, JapanCorrespondence: Hiroki Teragawa, Department of Cardiovascular Medicine, JR Hiroshima Hospital, 3-1-36 Futabanosato, Higashi-ku, Hiroshima, 732-0057, Japan, Tel +81 82 262 1171, Fax +81 82 262 1499, Email hiroteraga71@gmail.comPurpose: The clinical background and prognostic impact of diabetes mellitus (DM) on vasospastic angina (VSA) are unclear; thus, in this retrospective study, we investigated whether they differ based on the presence or absence of DM in patients with VSA.Patients and Methods: We included 272 Japanese patients with VSA diagnosed by coronary angiography (CAG) and the spasm provocation test (SPT). The diagnosis of DM was determined by measuring fasting blood glucose and hemoglobin A1C and by the patient’s current oral medications. On CAG, the presence of atherosclerotic lesions (20%– 50%) was checked. On SPT, the coronary spasm was defined as transient coronary vasoconstriction > 90% on CAG, accompanied by chest symptoms and/or ST-T changes. Focal spasm was defined as coronary spasm occurring within one segment of the American Heart Association classification on CAG. Blood and urine tests and vascular endothelial function were also evaluated when possible. A major adverse cardiovascular event (MACE), which is defined as cardiac mortality and rehospitalization due to cardiovascular illness, was the basis for determining the prognosis.Results: There were 49 patients (18%) in the DM group and 223 (82%) in the non-DM group. No significant differences in urinary albumin levels and peripheral vascular function were between groups. On CAG, atherosclerotic lesions were observed significantly more frequently in the DM group (63% vs 46%; P = 0.028). Results of SPT showed a trend toward fewer focal spasms in the DM group (24% vs 39%; P = 0.072). No significant differences in MACE were noted between groups in the primary analysis of DM, whereas sub-analyses of focal spasms showed lower MACE-free survival in the DM group (P = 0.042).Conclusion: The study results support the hypothesis that DM associated with VSA should be treated appropriately, especially in cases of focal spasm, which may require more attention in treatment.Keywords: atherosclerotic change, coronary spasm, coronary spastic angina, diabetes mellitus, focal spasm

Abstract Background High-grade gliomas including glioblastoma multiforme (GBM) are among the most malignant and aggressive of tumors, and have a very poor prognosis despite a temozolomide-based intensive treatment. Therefore, a novel therapeutic approach to controlling recurrence is needed. In the present study, we investigated the effect of activated dendritic cell (DC) (α-type-1 polarized DC)-based immunotherapy on high-grade glioma patients with the HLA-A2 or A24 genotype. Methods Nine patients with recurrent high-grade gliomas including 7 with GBMs who fulfilled eligibility criteria were enrolled into a phase I study of monocyte-derived DC-based immunotherapy. HLA-genotyping revealed 1 case of HLA-A*0201 and 8 cases of A*2402. Enriched monocytes obtained using OptiPrepTM from leukapheresis products on day1, were incubated with GM-CSF and IL-4 in a closed serum-free system, and activated on day6 with TNF-α, IL-1β, IFN-α, IFN-γ, and poly I/C. After pulsing with a cocktail of 5 synthetic peptides (WT-1, HER2, MAGE-A3, and MAGE-A1 or gp100) restricted to HLA-A2 or A24 and KLH, cells were cryopreserved until used. Thawed DCs were injected intradermally in the posterior neck at a dose per cohort of 1.0, 2.0 and 5.0× 107/body. Results The frequency of CD14+ monocytes increased to 44.6% from 11.9% after gradient centrifugation. After a 7-day-incubation with cytokines, the mean percentage of DCs rated as lin-HLA-DR+ in patients was 56.2 ± 19.1%. Most DCs expressed high levels of maturation markers, co-stimulatory molecules and type-1 phenotype (CD11c+HLA-DR+) with a DC1/2 ratio of 35.6. The amount of IL-12 produced from activated DCs was 1025 ± 443 pg/ml per 105 cells. All 76 DC injections were well tolerated except for transient liver dysfunction with grade II. Six patients showed positive immunological responses to peptides in an ELISPOT assay, and positive skin tests to peptide-pulsed DC and KLH were recognized in 4 cases. The clinical response to DC injections was as follows :1 SD and 8 PD. Interestingly, the SD patient, given 24 DC injections, showed a long-term recurrence-free and immunological positive response period. Conclusions These results indicate peptide cocktail-treated activated α-type-1 DC-based immunotherapy to be a potential therapeutic tool against recurrent high-grade glioma with mainly HLA-A*2402. Trial registration Current non-randomized investigational trial UMIN-CTR UMIN ID: 000000914.

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 < 2.0 or IMR ≥ 25 was indicative of CMD. The correlations between various laboratory indices and CMD and its components were investigated, and logistic regression analysis was performed, focusing on factors where p < 0.05., Results: Of the 84 patients, a CFR < 2.0 was found in 22 (26%) and an IMR ≥ 25 in 40 (48%) patients, with CMD identified in 46 (55%) patients. CMD was correlated with smoking ( p = 0.020) and the use of EM ( p = 0.020). The factors that correlated with a CFR < 2.0 included the echocardiograph index E/e' ( 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.

Background: Although the spasm provocation test (SPT) can diagnose coronary spasms, it would be helpful if it could also predict their occurrence., Aim: To investigate whether coronary spasms can be predicted using changes in intracoronary artery pressure measured using a pressure wire during the SPT., Methods: Seventy patients underwent SPTs with pressure-wire measurement of intracoronary artery pressure. During each SPT, the pressure wire was advanced into the distal portion of the right coronary artery (RCA) and left anterior descending coronary artery, and the ratio of intracoronary pressure to aortic pressure (Pd/Pa) was monitored. Coronary spasm was defined as an arterial narrowing of > 90% in response to the administration of acetylcholine (ACh), with chest symptoms and/or ischemic electrocardiographic changes. ACh was administered to the RCA at low, moderate, or high doses of 20, 50, or 80 µg, respectively, and to the left coronary artery (LCA) at low, moderate, or high doses of 50, 100, or 200 µg, respectively. Coronary arteries with coronary spasms at low doses of ACh were defined as group L, and those with coronary spasms at moderate or high doses were defined as group MH. Those who did not occur coronary spasms at any ACh dose were designated as group N., Results: Among the 132 coronary arteries assessed using a pressure wire, there were 49 in group N, 25 in group L, and 58 in group MH. Baseline Pd/Pa was the lowest in group L ( P = 0.001). The decrease in the Pd/Pa between baseline to low doses of ACh was lower in group MH than in group N ( P < 0.001). A receiver-operating characteristics analysis showed that the cutoff baseline Pd/Pa value for predicting group L was 0.95, with a sensitivity of 0.600 (15/25) and a specificity of 0.713 (76/107) and that the cutoff value of Pd/Pa from baseline to low doses of ACh for predicting group MH was -0.04, with a sensitivity of 0.741 (43/58) and a specificity of 0.694 (34/49)., Conclusion: These findings suggest that indices of intracoronary pressure during SPT may be useful means for predicting the occurrence of coronary spasms., Competing Interests: Conflict-of-interest statement: Hiroki Teragawa, Yuko Uchimura and Chikage Oshita have no Conflict-of-interest statement regarding the present manuscript., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

A 46-year-old man presented to our hospital with chest pain followed by coughing and dyspnea. His myocardial enzyme levels were almost normal, and electrocardiography and echocardiography showed no obvious abnormalities. Chest radiography revealed congestion. He was diagnosed with heart failure with a preserved ejection fraction (HFpEF). Although subjective symptoms improved with intravenous diuretics, the patient was admitted to the hospital for a close examination. Coronary angiography showed no obvious stenosis, and a subsequent spasm provocation test demonstrated the presence of multi-vessel and diffuse spasms. Coronary spasm should be considered as a differential cause of heart failure, even in patients with HFpEF.

Background: The spasm provocation test (SPT) is a critical test for diagnosing vasospastic angina (VSA). However, the choice of vessel to be preferred for initiating the SPT-the right coronary artery (RCA) or the left coronary artery (LCA)-is unclear. This study aimed to assess SPT results including SPT-related complications while initiating the SPT in the RCA and LCA., Methods: We enrolled 225 patients who underwent coronary angiography and SPTs. The SPT was first performed in the RCA in 133 patients (RCA group) and the LCA in 92 patients (LCA group). We defined VSA as >90% narrowing of the coronary artery during the SPT, accompanied by chest pain and/or ST-T changes on the electrocardiogram. When coronary spasm occurs in two or more major coronary arteries, it is referred to as a multivessel spasm (MVS). SPT-related complications comprised atrial fibrillation, ventricular fibrillation, and unstable hemodynamics following catecholamine use. Analyses using propensity score matching (PSM) were performed in 120 patients., Results: No significant differences in the frequencies of VSA and complications were observed between the two groups (RCA: 79% and 19%, respectively; LCA: 85% and 22%, respectively). In both groups, spasms were most frequently provoked in the left anterior descending coronary artery (both p < 0.001) whereas spasms in the left circumflex coronary artery (LCX) were higher in the LCA group than in the RCA group ( p = 0.015). Furthermore, no significant difference in the frequency of MVS was observed between both groups (RCA: 50%, LCA: 62%; p = 0.122). After PSM, no significant difference in the frequencies of VSA and complications were observed between the two groups (RCA: 82% and 15%, respectively; LCA: 88% and 18%, respectively). The frequencies of LCX spasms (RCA: 8%, LCA: 23%; p = 0.022) and MVS (RCA: 40%, LCA: 62%; p = 0.020) were higher in the LCA group than in the RCA group., Conclusions: Although the diagnostic rate of VSA and frequency of SPT-related complications were similar in the two groups, the frequency of MVS was higher in the LCA group than in the RCA group because of the increase in the number of LCX spasms. A routine SPT may be started from the LCA.

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 < 0.001). Nonpharmacological treatment for CAD in FH-CAD was more common in the atherosclerotic CAD group ( 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.

Patients presenting with the syndrome of symptoms and signs suggesting ischemic heart disease but found to have no obstructed coronary arteries (INOCA) are increasingly recognized. Although there are non-invasive tests for the diagnosis of INOCA, such as transthoracic Doppler echocardiography, positron emission tomography, and cardiac magnetic resonance imaging to evaluate increased blood flow with adenosine and other agents, the diagnosis of INOCA by coronary angiography with the coronary spasm provocation test and coronary microvascular function evaluation using pressure wires has become the gold standard, but it is not well established in the treatment of INOCA. Despite the lack of objection to lifestyle modification and the use of coronary dilators, mainly calcium-channel blockers, for conditions involving epicardial coronary artery spasm, there is no entirely effective long-term treatment for microvascular spasm or coronary microvascular dysfunction. Although some combinations of drugs have been empirically administered in certain cases, it is difficult to conclude that they are sufficiently effective. Recently, it has been reported that some Japanese herbal medicines (Kampo) have been effective in the treatment of INOCA. In order to increase the knowledge on the treatment of INOCA, this review focuses on the effects of Japanese herbal medicine on INOCA and its presumed mechanisms and problems., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Teragawa et al.)

Background: We frequently encounter cases of women with vasospastic angina (VSA). Additionally, some women with VSA are younger than 60 years old. However, it is unknown whether the characteristics of VSA in women aged < 60 years are different from those in women aged ≥ 60 years., Aim: To investigate and compare the clinical characteristics and prognosis of VSA in women aged < 60 years from those in women aged ≥ 60 years., Methods: We enrolled 94 women with VSA who were diagnosed using the spasm provocation test. According to the age at diagnosis, the patients were divided into two groups: Group Y (age < 60 years, n = 17) and Group O (age ≥ 60 years, n = 77). Flow-mediated dilation (FMD) and nitroglycerin (NTG)-induced dilation (NID) of the brachial artery were performed and assessed using brachial ultrasonography. Moreover, conventional coronary risk factors, such as atherosclerotic lesions (stenosis > 20%) detected using coronary angiography and focal spasms (coronary spasm within one segment of one coronary artery), and major cardiovascular adverse events (MACE) were assessed in both groups., Results: Smoking was more prevalent in Group Y than in Group O ( P = 0.04). FMD was similar in both groups (Group O: 4.3% ± 3.2%, Group Y: 4.5% ± 3.3%; P = 0.75), whereas NID was higher in Group Y (20.5% ± 8.6%) than in Group O (13.6% ± 5.3%, P < 0.01). Atherosclerosis was not detected in Group Y but was detected in Group O (61%, P < 0.01). Focal spasms were less frequent in Group Y (12%) than in Group O (38%, P = 0.04). The incidence of major adverse cardiac events did not differ between the two groups (P = 0.40)., Conclusion: Women aged < 60 years with VSA have less atherosclerotic lesions and focal spasms. These characteristics may be affected by smoking habits and vascular smooth muscle dysfunction., Competing Interests: Conflict-of-interest statement: All the authors declare that they have no conflict of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Several reports show that two types of coronary vasospasm (diffuse and focal spasm) are associated with the severity or prognosis of coronary spasm in patients with vasospastic angina (VSA). It is unclear whether intracoronary pressure differs between the two spasm types., Aim: To investigate such relationships using a pressure wire during the spasm provocation test (SPT) in patients with VSA., Methods: Eighty-seven patients with VSA (average age: 67 years; 50 men, 37 women) underwent SPT. During the SPT, a pressure wire was advanced into the distal portion of the right coronary artery and left anterior descending coronary artery, and the ratio of the intracoronary pressure to the aortic pressure (Pd/Pa) was continuously monitored. An SPT was performed using acetylcholine (ACh), and the presence of coronary spasm was defined as the presence of > 90% arterial narrowing in response to an ACh infusion, with the usual chest symptoms and/or ischemic ECG changes. Focal spasm was defined as total or subtotal spasm within one segment of the AHA classification, while diffuse spasm was defined as > 90% spasm with two or more segments., Results: Among 87 patients, the frequencies of metabolic syndrome and having coronary atherosclerosis were higher in the focal group ( n = 33) than in the diffuse spasm group ( n = 54, P < 0.05). In the vessel analyses, in these 134 spastic segments, diffuse and focal spasms were detected in 100 and 34 vessels, respectively. The Pd/Pa at baseline was similar in both groups (diffuse: 0.96 ± 0.05, focal: 0.95 ± 0.05, P = 0.35); however, the Pd/Pa during coronary spasm was lower in focal spastic vessels (0.66 ± 0.20) than in diffuse spastic vessels (0.76 ± 0.11, P < 0.01), and the reduction in Pd/Pa during an SPT was also lower in focal spastic vessels (-0.29 ± 0.20) than in diffuse spastic vessels (-0.18 ± 0.11, P < 0.01). The presence of focal spasm was a significant factor responsible for reduction in Pd/Pa during SPT., Conclusion: These findings suggest that focal spasm may be more severe than diffuse spasm, judging from the intracoronary pressure during coronary spasm., Competing Interests: Conflict-of-interest statement: None of the authors have any conflict of interest to declare., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

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.

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.

(1) Background: We have sometimes experienced patients with vasospastic angina (VSA) who presented multi-vessel spasm (MVS) on coronary angiography and spasm provocation test (SPT). However, the clinical characteristics of VSA patients with MVS and the prognosis of such patients in the clinical setting have not been clarified. Therefore, we compared the clinical characteristics and prognosis in VSA patients with MVS with those in VSA patients with single-vessel spasm (SVS). (2) Methods: A total of 152 patients (mean age, 67 years, 74 men and 78 women) with VSA, in which the presence of coronary spasm was assessed in both left coronary artery (LCA) and right coronary artery (RCA) on SPT, were enrolled. We defined VSA as the presence of >90% narrowing of the epicardial coronary artery on angiograms, accompanied by usual chest symptoms and/or ischaemic ST-T changes on the electrocardiogram. On SPT, MVS was defined as the presence of spasms on ≥2 major coronary arteries. Based on the presence of MVS, patients were divided into the MVS group and the SVS group. The frequencies of conventional coronary risk factors, blood chemical parameters, average times of anginal attack, SPT findings such as spasm provocation induced by a low dose of acetylcholine (L-ACh) and total occlusion due to coronary spasm (TOC), number of coronary vasodilators at discharge and major cardiovascular events (MACE, including cardiac death and readmission due to any cause of cardiovascular diseases) were compared between the two groups. (3) Results: The MVS and SVS groups were comprised of 98 (64%) and 54 (36%) patients, respectively. The level of fasting blood glucose (FBS) was lower (p < 0.01), and the level of cystatin-C (n = 89) tended to be higher (p = 0.07) in the MVS group than in the SVS group. The frequencies of L-ACh-induced coronary spasm (33% in MVS and 17% in SVS, p = 0.04) and TOC (12% in MVS, 0% in SVS, p < 0.01) were higher in the MVS group than in the SVS group. The average number of coronary vasodilators at discharge was higher in the MVS group (1.2 ± 0.4) than in the SVS group (0.9 ± 0.5, p < 0.01). The frequency of MACE was not different between the two groups. (4) Conclusions: Patients with MVS may have higher VSA activity on SPT and have more aggressive medications, leading to a comparable prognosis in VSA patients with SVS. MVS is an important indicator of at least VSA activity, and cardiologists should confirm this in SPT whenever possible. Further studies should confirm whether lower FBS levels and higher cystatin-C levels are any markers of MVS.

Background: In the clinical setting; the microvascular vasodilatory function test (MVFT) with a pressure wire has been used in ischaemia patients with non-obstructive coronary arteries (INOCA), including vasospastic angina (VSA) and microvascular angina (MVA). The exact factors that affect the microvascular vasodilatory function (MVF) in such patients are still unknown. We aimed to identify the factors, including clinical parameters and lesion characteristics, affecting the MVF in such patients., Methods: A total of 53 patients who underwent coronary angiography, spasm provocation tests (SPTs) and MVFTs were enrolled. In the MVFT, the coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) were measured. Of the 53 patients, MVFT data in the left anterior descending coronary artery (LAD) were obtained from 49 patients, and the clinical parameters were checked in all of them. Based on the results of the SPT, coronary spasms were divided into focal spasm, diffuse spasm, and microvascular spasm (MVS). To assess the lesion characteristics influencing MVF, MVFT data were compared according to the types of coronary spasm and coronary vessels in 73 vessels of the 53 patients., Results: In 49 patients who underwent the MVFT in the LAD, the IMR was higher in active smokers ( n = 7) than in former smokers ( n = 15) and never smokers ( n = 27, p < 0.01). In the 73 coronary arteries in this study, the type of coronary spasm did not correlate with the CFR or IMR, whereas a higher IMR were more frequently observed in cases of focal spasm than in cases of diffuse spasm ( p = 0.03). In addition, the IMR was higher in the right coronary artery (RCA) than in the LAD ( p = 0.02)., Conclusion: These results indicate that the smoking status affected the MVF in patients with INOCA, suggesting the possibility of improvement in the MVF by smoking cessation in such patients. In addition, in the assessment of MVF, it may be important to take into account which coronary artery or types of coronary spasm are being evaluated.

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.

Background: Patients with vasospastic angina (VSA) sometimes experience prolonged chest symptoms. The clinical characteristics of these patients have not been clarified., Aim: To investigate the clinical characteristics of prolonged VSA patients., Methods: This study included 167 patients with VSA diagnosed by spasm provocation tests (SPTs) using acetylcholine, which recorded the frequencies of positive reactions to a low dose of acetylcholine (L-ACh), total occlusion due to spasm (TOC), focal spasm, and the unavoidable use of nitroglycerin (unavoidable-NTG) during SPTs. The patients underwent a medical interview that investigated the maximum duration and frequency of chest symptoms as well as the frequencies of variant angina and other serious symptoms. The patients were divided into two groups based on the maximal duration: The short-duration group (< 15 min; n = 114) and the long-duration group (≥ 15 min; n = 53). They were also divided into two groups based on the frequency of chest symptoms: The low-frequency group (< 4/mo; n = 88) and the high-frequency group (≥ 4/mo; n = 79)., Results: The long-duration group showed higher frequencies of other serious symptoms ( P < 0.001) and variant angina ( P < 0.05) as well as higher frequencies of spasm induction by L-ACh ( P < 0.05), TOC ( P < 0.05), focal spasm ( P < 0.01), and unavoidable-NTG ( P < 0.01) than the short-duration group. These parameters did not differ significantly between the low-frequency and high-frequency groups., Conclusion: These findings suggest that patients with VSA who experience prolonged chest symptoms may have more severe characteristics of VSA., Competing Interests: Conflict-of-interest statement: The authors declare no potential financial interests., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Many causes of noncardiac chest pain (NCCP) have been studied and gastroesophageal reflux disease is considered to be the major cause. However, studies have reported that treatment with a proton pump inhibitor does not effectively provide relief for NCCP-related symptoms, and these symptoms frequently recur. These findings suggest that patients with cardiac disease may be excluded completely from the NCCP group. Several examinations can be conducted to verify the presence of cardiac disease. Such examinations include the assessment of biochemical markers, rest and exercise electrocardiogram, echocardiography, cardiac computed tomography, stress myocardial perfusion imaging, cardiac magnetic resonance imaging, and coronary angiography (CAG). However, the presence of functional coronary artery diseases (CADs), such as vasospastic angina and/or microvascular angina, cannot be detected using these modalities. These functional CADs can be diagnosed by CAG with spasm-provocation testing and/or physiological coronary measurement. Thus, when a patient who is suspected of having NCCP takes a proton pump inhibitor and does not respond well, further examination-including assessment for possible functional CADs-may be needed., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

A 61-year-old man experienced chest oppression for 1 hour. He was positive for troponin T and underwent emergent coronary angiography (CAG), which did not reveal significant coronary stenosis. He was diagnosed with myocardial infarction with nonobstructive coronary arteries (MINOCA). We performed a spasm-provocation test, which revealed a focal spasm at the segment of the myocardial bridge. After receiving a calcium-channel blocker, he exhibited a good clinical course. Coronary spasm is considered an underlying cause of MINOCA; therefore, the presence of a myocardial bridge may help with the diagnosis.

It is well known that patients with gastroesophageal reflux disease (GERD) experience GERD-related chest pain, but little is known about the relationship between GERD and coronary artery disease (CAD). We evaluated medical history of GERD in patients with suspected CAD and its association with types of CAD. We enrolled 236 patients who underwent coronary angiography (CAG). We assessed past medical history of each patient, making note of esophageal or stomach diseases such as GERD including reflux esophagitis and non-erosive reflux disease. The patients were divided into the following three subgroups based on the CAG results. Group I, patients with o-CAD (> 50% stenosis with ischemic findings, n = 141); Group II, patients with vasospastic angina (VSA, with positive spasm provocation test without organic coronary stenosis, n = 52); and Group III, patients without organic coronary stenosis or VSA (n = 43). Group I included more men than women (p < 0.001) and the frequencies of smoking, lipid disorders, and diabetes mellitus in this group were higher than those in the other groups (p < 0.01). The frequency of medical history of GERD was significantly higher in Group II (21%) than in Group I (3%) or Group III (7%, p < 0.0001). Logistic regression analysis showed that a medical history of GERD (OR 7.8; p < 0.01) was one of the factors associated with the presence of VSA. Our findings showed that a medical history of GERD was frequently observed in approximately one-fifth of patients with VSA, indicating that VSA may be present in patients with chest pain and a medical history of GERD.

The spasm provocation test (SPT) is important for diagnosing vasospastic angina (VSA), and acetylcholine (ACh) is usually used for this test in Japan. However, some patients with VSA have negative SPT results with the use of the standard ACh regimen alone. We herein report two cases in which VSA was diagnosed by the SPT with the combined use of ACh and ergonovine (EM). VSA could not be diagnosed in either case by the SPT using ACh infusions alone. For patients with negative SPT results, cardiologists should consider performing the SPT using a combination of ACh and EM.

A myocardial bridge (MB) is an anatomical abnormality of the coronary artery and is characterized by the systolic narrowing of the epicardial coronary artery caused by myocardial compression during systole. An MB is frequently observed on cardiac computed tomography or coronary angiography and generally appears to be harmless in the majority of patients. However, the presence of MB is reportedly associated with abnormalities of the cardiovascular system, including coronary artery diseases, arrhythmia, certain types of cardiomyopathy, and cardiac death, indicating that MB serves a pivotal role in the occurrence and/or development of such cardiovascular events. Recently, there has been an increasing interest in the coexistence of MB and coronary spasm in research due to opposing aspects regarding their treatments. For example, monotherapy using β-blockers, which are effective in patients with MB, may worsen symptoms in patients with coronary spasm. By contrast, nitroglycerin, which is an effective treatment option for coronary spasm, may worsen symptoms in patients with MB. This review focuses on the pathophysiology and diagnosis of MB and MB-related cardiovascular diseases, including coronary spasm, and on the treatment strategies for MB., Competing Interests: Declaration of Conflicting Interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The frequent recurrence of glioblastoma multiforme (GBM) after standard treatment with temozolomide (TMZ) is a crucial issue to be solved in the clinical field. O6‑methylguanine‑DNA methyltransferase (MGMT) is considered one of the major mechanisms involved in TMZ resistance. However, some important mechanisms for TMZ resistance other than MGMT have recently been identified. In the present study, we established a TMZ-resistant (TMZ-R) U87 glioblastoma cell line in vitro and in vivo and investigated novel targeting molecules other than MGMT in those cells. The TMZ-R U87 glioblastoma cell line was established in vitro and in vivo. TMZ-R U87 cells showed a more invasive activity and a shorter survival time in vivo. Gene expression analysis using DNA microarray and quantitative PCR (qPCR) demonstrated that YKL‑40, MAGEC1 and MGMT mRNA expression was upregulated 100-, 83- and 6-fold, respectively in the TMZ-R U87 cell line. Western blot analysis and qPCR demonstrated that STAT3 phosphorylation, STAT3 target genes and stem cell and mesenchymal marker genes were upregulated to a greater extent in the TMZ‑resistant cell line. Notably, short hairpin (sh)RNA‑based inhibition against the YKL‑40 gene resulted in moderate growth inhibition in the resistant cells in vitro and in vivo. Additionally, YKL‑40 gene inhibition exhibited significant suppression of the invasive activity and particularly partially restored the sensitivity to TMZ. Therefore, YKL‑40 may be a novel key molecule in addition to MGMT, that is responsible for TMZ resistance in glioblastoma cell lines and could be a new target to overcome TMZ resistance in recurrent glioblastomas in the future.

Antibody direct cloning from single B cells is simple and efficient and has been successful in antibody identification of infectious diseases. However, although a recent whole-exome sequencing revealed abundant heterogeneic mutation accumulation in cancers, identification and synthesis of autoantibodies against specific cancer-associated antigens is still difficult in cancer patients owing to the very small number of B cells producing autoantibodies. In the present study, to identify autoantibodies targeting tumor antigens, we measured the titer of autoantibodies in high-grade glioma patients' plasma and identified two patients with elevated autoantibodies to a few transmembrane proteins. Specific B cells producing autoantibody against vascular endothelial growth factor receptor (VEGFR) 2 were immunostained with labeled protein and anti-human IgG antibody, and then collected by a single cell sorter. Finally, 22 antibody genes were successfully identified using direct IgG cloning from single B cell mRNA, and two antibody clones were found to have significant VEGFR2-specific binding affinity. The current direct human IgG gene cloning technique for identifying human antibodies derived from IgG-memory B cells avoids time-consuming procedures such as phage display-based antibody-library screening, and therefore may be applicable to identifying human autoantibodies in a variety of disorders including cancers even when antibody elevation is not detected because of a very small number of memory B cells., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Glioblastoma multiforme (GBM) is one of the most malignant and aggressive tumors, and has a very poor prognosis with a mean survival time of <2 years, despite intensive treatment using chemo-radiation. Therefore, novel therapeutic approaches including immunotherapy have been developed against GBM. For the purpose of identifying novel target antigens contributing to GBM treatment, we developed 17 primary glioma cell lines derived from high-grade glioma patients, and analyzed the expression of various tumor antigens and glioma-associated markers using a quantitative PCR and immunohistochemistry (IHC). A quantitative PCR using 54 cancer-testis (CT) antigen-specific primers showed that 36 CT antigens were positive in at least 1 of 17 serum-derived cell lines, and 17 antigens were positive in >50% cell lines. Impressively, 6 genes (BAGE, MAGE-A12, CASC5, CTAGE1, DDX43 and IL-13RA2) were detected in all cell lines. The expression of other 13 glioma-associated antigens than CT genes were also investigated, and 10 genes were detected in >70% cell lines. The expression of CT antigen and glioma-associated antigen genes with a high frequency were also verified in IHC analysis. Moreover, a relationship of antigen gene expressions with a high frequency to overall survival was investigated using the Repository of Molecular Brain Neoplasia Data (REMBRANDT) database of the National Cancer Institute, and expression of 6 genes including IL-13RA2 was inversely correlated to overall survival time. Furthermore, 4 genes including DDX43, TDRD1, HER2 and gp100 were identified as MGMT-relevant factors. In the present study, several CT antigen including novel genes were detected in high-grade glioma primary cell lines, which might contribute to developing novel immunotherapy and glioma-specific biomarkers in future.

Background: Real-time three-dimensional transthoracic echocardiography (3DTTE) has been developed and provides detailed 3D information, noninvasively. However, the accuracy and usefulness of 3DTTE in the evaluation of aortic root geometry are still not clear., Methods: 2DTTE and 3DTTE were performed in 161 patients with various cardiac diseases. Multidetector computed tomography (MDCT) was performed in 35 of the 161 patients. The diameters and areas of the aortic annulus were evaluated by these three methods and compared. To evaluate the shape of the aortic annuli, eccentricity index (EI) (1 - minimum diameter/long-axis diameter) were calculated., Results: Maximum dimensions of the aortic annulus measured by MDCT were significantly larger than those by 3DTTE and 2DTTE. The aortic annular areas measured by MDCT and 3DTTE were significantly larger than areas by 2DTTE. A good correlation (r = 0.85) was observed between the areas obtained by 3DTTE and MDCT; however, the correlation between the values by 2DTTE and MDCT was rough (r = 0.44). EI values in 46 % of the patients were greater than 0.1, i.e., the aortic annulus was elliptical., Conclusion: The images obtained by 3DTTE provided accurate values of the aortic annular area, which were equal to the values measured by MDCT. 3DTTE is a useful method to evaluate the aortic annular geometry.

Of all potential biological therapeutics, monoclonal antibody (mAb)-based therapies are becoming the dominant focus of clinical research. In particular, smaller recombinant antibody fragments such as single-chain variable fragments (scFv) have become the subject of intense focus. However, an efficient affinity ligand for antibody fragment purification has not been developed. In the present study, we designed a consensus sequence for the human antibody heavy or light chain-variable regions (Fv) based on the antibody sequences available in the ImMunoGeneTics information system (IMGT), and synthesized these consensus sequences as template Fv antibodies. We then screened peptide ligands that specifically bind to the repertoire-derived human Fv consensus antibody using a 12-mer-peptide library expressed-phage display method. Subsequently, 1 peptide for the VH template and 8 peptides for the VK template were selected as the candidate ligands after 4 rounds of panning the phage display. Using peptide-bead-based immunoprecipitation, the code-4 and code-13 peptides showed recovery rates of the VH and VK templates that were 20-30% and 40-50%, respectively. Both peptides exhibited better recovery rates for trastuzumab scFv (approximately 40%). If it were possible to identify the best combination of VH and VK-binding peptides among the ligand peptides suitable for the human mAb Fv sequence, the result could be a promising purification tool that might greatly improve the cost efficiencies of the purification process.

Signal transducer and activator of transcription (STAT) 3, a member of a family of DNA-binding molecules, is a potential target in the treatment of cancer. The highly phosphorylated STAT3 in cancer cells contributes to numerous physiological and oncogenic signaling pathways. Furthermore, a significant association between STAT3 signaling and glioblastoma multiforme stem-like cell (GBM-SC) development and maintenance has been demonstrated in recent studies. Previously, we reported a novel small molecule inhibitor of STAT3 dimerization, STX-0119, as a cancer therapeutic. In the present study, we focused on cancer stem-like cells derived from recurrent GBM patients and investigated the efficacy of STX-0119. Three GBM stem cell lines showed many stem cell markers such as CD133, EGFR, Nanog, Olig2, nestin and Yamanaka factors (c-myc, KLF4, Oct3/4 and SOX2) compared with parental cell lines. These cell lines also formed tumors in vivo and had similar histological to surgically resected tumors. STAT3 phosphorylation was activated more in the GBM-SC lines than serum-derived GB cell lines. The growth inhibitory effect of STX-0119 on GBM-SCs was moderate (IC50 15-44 µM) and stronger compared to that of WP1066 in two cell lines. On the other hand, the effect of temozolomide was weak in all the cell lines (IC50 53-226 µM). Notably, STX-0119 demonstrated strong inhibition of the expression of STAT3 target genes (c-myc, survivin, cyclin D1, HIF-1α and VEGF) and stem cell-associated genes (CD44, Nanog, nestin and CD133) as well as the induction of apoptosis in one stem-like cell line. Interestingly, VEGFR2 mRNA was also remarkably inhibited by STX-0119. In a model using transplantable stem-like cell lines in vivo GB-SCC010 and 026, STX-0119 inhibited the growth of GBM-SCs at 80 mg/kg. STX-0119, an inhibitor of STAT3, may serve as a novel therapeutic compound against GBM-SCs even in temozolomide-resistant GBM patients and has the potential for GBM-SC-specific therapeutics in combination with temozolomide plus radiation therapy.

Many cancer-testis antigen genes have been identified; however, few human leukocyte antigen (HLA)-A24-restricted cytotoxic T cell (CTL) epitope peptides are available for clinical immunotherapy. To solve this problem, novel tools increasing the efficacy and accuracy of CTL epitope detection are needed. In the present study, we utilized a highly active dendritic cell (DC)-culture method and an in silico HLA-A24 peptide-docking simulation assay to identify novel CTL epitopes from MAGE-A6 and MAGE-A12 antigens. The highly active DCs, called α-type-1 DCs, were prepared using a combination of maturation reagents to produce a large amount of interleukin-12. Meanwhile, our HLA-A24 peptide-docking simulation assay was previously demonstrated to have an obvious advantage of accuracy over the conventional prediction tool, bioinformatics and molecular analysis section. For CTL induction assays, peripheral blood mononuclear cells derived from six cases of HLA-A24(+) melanoma were used. Through CTL induction against melanoma cell lines and peptide-docking simulation assays, two peptides (IFGDPKKLL from MAGE-A6 and IFSKASEYL from MAGE-A12) were identified as novel CTL epitope candidates. Finally, we verified that the combination of the highly active DC-culture method and HLA-A24 peptide-docking simulation assay might be tools for predicting CTL epitopes against cancer antigens.

Metastatic and chemoresistant melanoma can be a good target of immunotherapy because it is an intractable cancer with a very poor prognosis. Previously, we tested a dendritic cell (DC)-based phase I vaccine, and confirmed that it was safe. In the present study, we performed a phase II trial of a DC vaccine for metastatic melanoma patients with mainly the HLA-A24 genotype, and investigated the efficacy of the vaccine. Twenty-four patients with metastatic melanoma were enrolled into a phase II study of DC-based immunotherapy. The group included 19 HLA-A24-positive (A*2402) patients and 3 HLA-A2-positive (A*0201) patients. The protocol for DC production was similar to that in the phase I trial. Briefly, a cocktail of 5 melanoma-associated synthetic peptides (gp100, tyrosinase, MAGE-A2, MAGE-A3 and MART-1 or MAGE‑A1) restricted to HLA-A2 or A24 and KLH were used for DC pulsing. Finally, DCs were injected subcutaneously (s.c.) into the inguinal region in the dose range of 1-5x107 per shot. The DC ratio (lin-HLA-DR+) of the vaccine was 38.1±13.3% and the frequency of CD83+ DCs was 25.7±20.8%. Other parameters regarding DC processing were not different from phase I. Immune response-related parameters including the ELISPOT assay, DTH reaction to peptide or KLH, DC injection numbers were shown to be related to a good prognosis. The ELISPOT reaction was positive in 75% of the patients vaccinated. The increase of anti-melanoma antigen antibody titer before vaccination was also shown to be a prognosis factor, but that post-vaccination was not. Based on immunohistochemical analysis, CD8 and IL-17 were not involved in the prognosis. Adverse effects of more than grade III were not seen. Overall survival analysis revealed a significant survival prolongation effect in DC-given melanoma patients. These results suggest that peptide cocktail-treated DC vaccines may be a safe and effective therapy against metastatic melanoma in terms of prolongation of overall survival time.

A 35-year-old woman was admitted for progressive dyspnea with lower limb edema. Transthoracic echocardiography showed severe left ventricular hypertrophy (LVH) and heart failure with preserved ejection fraction (HFPEF). Electron microscopy of an endomyocardial biopsy sample revealed a high density of mitochondria of abnormal size and shape. We report a case of mitochondrial disease with severe LVH and HFPEF.