Hemostatic balance between pro- and anticoagulant is maintained during glucocorticoid treatment.

BACKGROUND: Glucocorticoids are associated with an increased risk of venous thrombosis. Glucocorticoid treatment increases coagulation factor and anticoagulant levels; however, its effect on hemostatic function remains unclear. This study aimed to investigate the changes in comprehensive coagulation profiles after glucocorticoid treatment in noninflammatory diseases to elucidate the direct contribution of glucocorticoids to hemostatic function. PROCEDURE: Patients diagnosed with primary immune thrombocytopenia requiring glucocorticoid treatment were prospectively enrolled in this study. Changes in coagulation factors and anticoagulants during glucocorticoid treatment and changes in thrombin generation potential were determined in the absence and presence of soluble thrombomodulin (sTM). RESULTS: Seven treatment cases (four for steroid pulse therapy and three for oral glucocorticoid therapy) in six patients with immune thrombocytopenia were examined. After glucocorticoid treatment, activated partial thromboplastin time significantly shortened, and activities of factor VIII, IX, XI, and XII significantly increased, except for von Willebrand factor antigen. Moreover, antithrombin and protein C (PC) activities significantly increased after glucocorticoid treatment. Two major parameters of thrombin generation potential, endogenous thrombin potential (ETP) and peak thrombin (Peak), significantly increased in the absence of sTM after glucocorticoid treatment. However, no significant increases in either parameter were observed in the presence of sTM. ETP-TM and Peak-TM ratios, which represent resistance to the anticoagulant effect of the PC pathway, significantly decreased after glucocorticoid treatment, suggesting that anticoagulant function via the PC pathway is elevated after glucocorticoid treatment. CONCLUSIONS: As glucocorticoids increase intrinsic coagulation factor and anticoagulant levels, hemostatic balance between pro- and anticoagulant functions is maintained.

A case with familial hypercholesterolemia complicated with severe systemic atherosclerosis intensively treated for more than 30 years.

We present a case of a Japanese patient with familial hypercholesterolemia (FH) caused by a low-density lipoprotein (LDL) receptor gene mutation. A 47-year-old female was referred to our hospital due to her systemic xanthomatosis associated with elevated LDL-cholesterolemia (292 mg/dl). She was diagnosed with heterozygous FH, and started to be treated with simvastatin 10 mg. During her clinical course, she underwent percutaneous coronary intervention (PCI) (at 69 years), coronary artery bypass grafting (CABG) twice (at 62 years, and 75 years), femoral popliteal bypass surgery (at 67 years), together with intensification of lipid-lowering therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. She was admitted to our hospital due to dyspnea on effort, caused by severe aortic valve stenosis as well as sick sinus syndrome at the age of 78 years. transcatheter aortic valve implantation (TAVI) using balloon expandable valve was successfully performed after DDD pacemaker implantation. She was discharged from our hospital without any symptoms. During more than 30 years of treatment period in our institute, we have introduced the latest therapeutic strategies, and treated her intensively. We are proud that we can save life even in this severe case through multiple strategies developed over the decades; however, this case clearly suggests that lipid-lowering therapies should be started much earlier in patients with FH. .

Hokuriku-plus familial hypercholesterolaemia registry study: rationale and study design.

INTRODUCTION: Familial hypercholesterolaemia (FH) is an autosomal-dominant inherited genetic disease. It carries an extremely high cardiovascular risk associated with significantly elevated low-density lipoprotein (LDL) cholesterol. The diagnostic rate of this disease in some European nations is quite high, due to the presence of multiple prospective registries. On the other hand, few data-and in particular multicentre data-exist regarding this issue among Japanese subjects. Therefore, this study intends to assemble a multicentre registry that aims to comprehensively assess cardiovascular risk among Japanese FH patients while taking into account their genetic backgrounds. METHODS AND ANALYSIS: The Hokuriku-plus FH registry is a prospective, observational, multicentre cohort study, enrolling consecutive FH patients who fulfil the clinical criteria of FH in Japan from 37 participating hospitals mostly in Hokuriku region of Japan from April 2020 to March 2024. A total of 1000 patients will be enrolled into the study, and we plan to follow-up participants over 5 years. We will collect clinical parameters, including lipids, physical findings, genetic backgrounds and clinical events covering atherosclerotic and other important events, such as malignancies. The primary endpoint of this study is new atherosclerotic cardiovascular disease (ASCVD) events. The secondary endpoints are as follows: LDL cholesterol, secondary ASCVD events and the occurrence of other diseases including hypertension, diabetes and malignancies. ETHICS AND DISSEMINATION: This study is being conducted in compliance with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable laws and guidelines in Japan. This study protocol has been approved by the Institutional Review Board at Kanazawa University. We will disseminate the final results at international conferences and in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000038210.

Clinical Impact of Carotid Plaque Score rather than Carotid Intima-Media Thickness on Recurrence of Atherosclerotic Cardiovascular Disease Events.

AIM: Carotid plaque score (cPS) reflecting throughout the carotid artery plaque burden may be a better marker than carotid intima-media thickness (cIMT) is. We aimed to compare the prognostic utility of these measurements in patients with atherosclerotic cardiovascular disease (ASCVD). METHODS: We retrospectively examined 2,035 Japanese patients with ASCVD who underwent carotid ultrasonography between January 2008 and December 2015 at Kanazawa University Hospital. Median follow-up period was 4 years. We used Cox models that adjusted for established risk factors of ASCVD, including age, gender, hypertension, diabetes, smoking, and serum lipids to assess the association of cIMT as well as cPS with major adverse cardiac events (MACE). MACE was defined as all-cause mortality or rehospitalization for a cardiovascular-related illness. RESULTS: During follow-up, 243 participants experienced MACE. After adjustment for established risk factors, cPS was associated with MACE (hazard ratio [HR]=3.38 for top quintile vs. bottom quintile of cPS; 95% confidence interval [CI] 1.82-6.27; P trend ＜0.001), while cIMT was not (HR=0.88, P=0.57). Addition of the cPS to established risk factors significantly improved risk discrimination (C-index 0.726 vs. 0.746; P=0.017). CONCLUSION: These results suggest that cPS, rather than cIMT may be a better marker to identify increased risk for recurrence of MACE among patients with secondary prevention setting.

Huge right ventricular mass lesion associated with genital malignant tumor: a case report.

BACKGROUND: Primary heart tumors are rare, whereas metastatic heart tumors occur more frequently. CASE PRESENTATION: We report a case of a 75-year-old Japanese woman who had metastatic heart tumors of the right ventricle. Although she initially received antibiotic therapy following a diagnosis of pneumonia and pleuritis, her symptoms worsened, and she developed dyspnea and bilateral lower limb edema. Echocardiography showed a huge mass lesion occupying the entire right ventricle. Because the patient's tumor markers were elevated, we used computed tomography to search for the primary lesion, which was located in the vagina or the uterus. Histology demonstrated the presence of basaloid squamous cell carcinoma in the vaginal tissue. Chemotherapy with paclitaxel and carboplatin was initiated. CONCLUSIONS: These data suggest that the tumor in the right ventricle metastasized from the genital organs.

Regional colorectal cancer screening program using colonoscopy on an island: a prospective Nii-jima study.

Objective: Colorectal cancer screening program using fecal immunochemical test had been conducted on an isolated island named Nii-jima. However, the participation rate of the program had been approximately 12%, which was lower than average level of Japan. This study aimed to evaluate the participation rate, safety and efficacy of a colorectal cancer screening program using colonoscopy on the island. Methods: Educational campaigns were actively conducted every month using information bulletins and special propaganda pamphlets. The primary recommended modality was colonoscopy, followed by fecal immunochemical test. The participants of this program were 1671 individuals aged 40­79 years (men, 819; women, 852). Results: A total of 789 (47.2%) individuals provided consent for this screening program, and 89.2% (704/789) of participants chose colonoscopy as the primary screening procedure. The completion rate of total colonoscopy was 99.7%, and there was no complication during this program. Detection rates of invasive cancer, intramucosal cancer, advanced neoplasia and any adenoma were 0.9% (n = 6), 2.4% (n = 17), 11.8% (n = 83) and 50.0% (n = 352), respectively. The adenoma detection rate and incidence of advanced neoplasia were significantly higher in men than in women in all age groups. Conclusions: The colorectal cancer screening program using colonoscopy that was conducted on an island achieved considerably higher participation rate than the conventional screening program using fecal immunochemical test. Completion rate and safety of screening colonoscopy were excellent during this program.

[Functional Residual Capacity Measurement Based on Lung Structure Model Analysis Using the Helium Gas Dilution Technique].

In the helium gas dilution method, functional residual capacity (FRC) is calculated from a helium concentra- tion equilibrium curve. In this study, we analyzed the helium concentration equilibrium curves of healthy patients, clarified the determinants of the equilibrium concentration, and studied the effects of an uneven lung distribution. We collected data from 200 patients (92 males and 108 females) whose FRC values had been measured at our institution over the past 6 years. Their FRC values ranged from 80% to 120%, and theit other pulmo- nary function values were within the normal range. In the compartmental model analysis, we discovered that the helium concentration equilibrium curve was composed of one compartment, and that it did not have a polyphasic structure. Each 0.25-minute (15-second) segment of the helium concentration equilibrium curve obtained from the patients was evaluated using univariate and multivariate regression analyses. The helium concentration equilibrium curve decreased exponentially over the time course of the analysis, and the multiple correlation coefficient for the relationship between the 0.25-minute to 0.75-minute segments and the 1.00-minute to 1.50-minute segments in the final model was 0.949. Finally, we examined the influence of an uneven peripheral lung distribution. A model based on the con- centration change seen between the initial and middle periods during at rest ventilation indicated that the latter parameter was not affected by the ventilation volume of the peripheral lung. [Original].

Impact of real-time three-dimensional transesophageal echocardiography on procedural success for mitral valve repair.

BACKGROUND: For mitral valve repair, minimally invasive cardiac surgery as well as transcatheter valvular intervention have been developed. Under these conditions, three-dimensional transesophageal echocardiography (3D-TEE) plays a key role for planning the surgical treatment strategy. However, few data exist regarding the role of 3D-TEE in mitral valve repair. Therefore, we examined the impact of 3D-TEE on procedural success of mitral valve repair. METHODS AND RESULTS: We examined 86 consecutive patients who underwent mitral valve repair for degenerative mitral valve prolapse. Among them, 39 patients were examined by only two-dimensional transesophageal echocardiography (2D-TEE) and 47 patients underwent 3D-TEE in addition to 2D-TEE. The cardiac surgeons and physicians discussed the repair procedure preoperatively with the echocardiographic images. As a result, 18 patients of the 2D-TEE group and 37 patients of the 3D-TEE group underwent mitral valve repair by small thoracotomy including robotic approach. Simple repair was done in 21 with 2D-TEE and 21 with 3D-TEE and complex repair was done in 18 with 2D-TEE and 26 with 3D-TEE. Importantly, three patients with 2D-TEE before surgery had to undergo reoperation due to recurrent severe mitral regurgitation with dehiscence of the annuloplasty rings, although none with 3D-TEE did. CONCLUSIONS: These results demonstrate that 3D-TEE is helpful in assessing the morphology of mitral apparatus and complexity of mitral valve repair, particularly in minimally invasive cardiac surgery including robotic ones. We would suggest that sonographers, cardiologists, and cardiac surgeons should be familiar with 3D-TEE and work together throughout the perioperative period for better outcomes.

Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation.

BACKGROUNDS: Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by hypercholesterolemia, tendon xanthomas, and premature coronary heart disease. FH is caused by mutations of "FH genes," which include the LDL-receptor (LDLR), apolipoprotein B-100 (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9). We evaluated the usefulness of FH gene analysis for diagnosing homozygous FH (homo-FH), particularly in cases caused by gain-of-function (g-o-f) mutations in PCSK9 (PCSK9 E32K). OBJECTIVES: To evaluate the frequency of homo-FH caused by PCSK9 E32K compared with FH due to other genetic causes and to report the phenotypic features of homo-FH caused by PCSK9 E32K. METHODS: Genomic DNA was prepared from white blood cells, and LDLR and PCSK9 mutations were identified using the Invader assay method. RESULTS: Of the 1055 hetero-FH patients, 62 patients (5.9%) carried the PCSK9 E32K mutation, while in the 82 alleles of 41 homo-FH patients, 13 (15.9%) had double mutations of LDLR allele and PCSK9 E32K mutation. Mean plasma total cholesterol (TC) (9.93 ± 2.95 mmol/L, mean ± SD) in true homo-FH cases with PCSK9 E32K or double hetero-FH cases with PCSK9 E32K and LDLR mutations were significantly lower than those in true homo-FH (18.06 ± 4.96 mmol/L) and compound heterozygous cases with LDLR mutations (14.84 ± 1.62 mmol/L). Mean plasma TC concentrations in the 59 hetero-FH cases with PCSK9 E32K (7.21 ± 1.55 mmol/L) were significantly lower than those (8.94 ± 1.53 mmol/L) in the hetero-FH by LDLR mutations. CONCLUSIONS: FH caused by PCSK9 g-o-f mutations is relatively common in Japan and causes a mild type of homo- and hetero-FH compared with FH caused by LDLR mutations.

Efficacy and safety of coadministration of rosuvastatin, ezetimibe, and colestimide in heterozygous familial hypercholesterolemia.

Aggressive low-density lipoprotein (LDL) cholesterol-lowering therapy is important for high-risk patients. However, sparse data exist on the impact of combined aggressive LDL cholesterol-lowering therapy in familial hypercholesterolemia (FH), particularly on side effects to changes in plasma coenzyme Q10 and proprotein convertase subtilisin/kexin type 9 levels. We enrolled 17 Japanese patients with heterozygous FH (12 men, 63.9 ± 7.4 years old) with single LDL receptor gene mutations in a prospective open randomized study. Permitted maximum doses of rosuvastatin (20 mg/day), ezetimibe (10 mg/day), and granulated colestimide (3.62 g/day) were introduced sequentially. Serum levels of LDL cholesterol decreased significantly by -66.4% (p <0.001) and 44% of participants achieved LDL cholesterol levels <100 mg/dl. There were no serious side effects or abnormal laboratory data that would have required the protocol to have been terminated except for 1 patient with myalgia. Coadministration of ezetimibe and granulated colestimide further lowered serum LDL cholesterol more than rosuvastatin alone without changing plasma coenzyme Q10 and proprotein convertase subtilisin/kexin type 9 levels. In conclusion, adequate introduction of this aggressive cholesterol-lowering regimen can improve the lipid profile of FH.

Molecular genetic epidemiology of homozygous familial hypercholesterolemia in the Hokuriku district of Japan.

AIM: Familial hypercholesterolemia (FH) is caused by mutations of FH genes, i.e. LDL-receptor (LDLR), PCSK9 and apolipoprotein B (ApoB) gene. We evaluated the usefulness of DNA analysis for the diagnosis of homozygous FH (homo-FH), and studied the frequency of FH in the Hokuriku district of Japan. METHODS: Twenty-five homo-FH patients were recruited. LDLR mutations were identified using the Invader assay method. Mutations in PCSK9 were detected by PCR-SSCP followed by direct sequence analysis. RESULTS: We confirmed 15 true homozygotes and 10 compound heterozygotes for LDLR mutations. Three types of double heterozygotes for LDLR and PCSK9 were found. No FH patients due to ApoB mutations were found. The incidences of homo-FH and hetero-FH in the Hokuriku district were 1/171,167 and 1/208, respectively. CONCLUSIONS: Our observations underlined the value of FH gene analysis in diagnosing homo-FH and confirmed extraordinarily high frequency of FH in the Hokuriku district of Japan.

A novel method for determining functional LDL receptor activity in familial hypercholesterolemia: application of the CD3/CD28 assay in lymphocytes.

BACKGROUND: The objective of this study was to develop a new and simple method for measuring low-density lipoprotein receptor (LDLR) activity using peripheral lymphocytes enabling us to clinically diagnose familial hypercholesterolemia (FH) and ascertain the involved mutations (such as K790X mutation), that might not be clearly detected in the conventional method. METHODS: Our method comprised the following 2 features: first, we used anti-CD3/CD28 beads to stimulate T-lymphocytes to obtain a uniform fraction of lymphocytes and maximum up-regulation of LDLR. Second, we excluded the possibility of overestimation of lymphocyte signals bound only to its surface, by adding heparin to the cultured lymphocytes used for the LDLR assay. RESULTS: Based on the genetic mutation, the FH subjects were divided into 2 groups, K790X, (n=20) and P664L, (n=5), and their LDLR activities was measured by this method, which was found to be 55.3+/-8.9% and 63.9+/-13.8%, respectively, of that of the control group (n=15). In comparison, the LDLR activity was 86.1+/-11.6% (K790X) and 73.3+/-6.3% (P664L) of that of the control group when measured by the conventional method, indicating that impairment of LDLR function in FH K790X subjects was much more clearly differentiated with our method than with the conventional method (paired t-test, p<0.0001). The levels of LDLR expression also showed similar tendencies, that is, 89.4+/-13.2% (K790X) and 76.9+/-17.4% (P664L) of that of the control group when measured by the conventional method, and 78.1+/-9.7% (K790X) and 70.3+/-26.5% (P664L) when measured by our new method. In addition, we confirmed that there was little influence of statin treatment on LDLR activity among the study subjects when our method was used. CONCLUSION: These results demonstrate that our new method is applicable for measuring LDLR activity, even in subjects with an internally defective allele, and that T-lymphocytes of the FH K790X mutation possess characteristics of that allele.

Acid-suppression therapy offers varied laryngopharyngeal and esophageal symptom relief in laryngopharyngeal reflux patients.

It is widely accepted that laryngopharyngeal reflux requires more aggressive and prolonged therapy than gastro-esophageal reflux disease. Otolaryngologists often observe that laryngopharyngeal symptoms, such as throat clearing, hoarseness, cough, and globus pharyngeus, are slower to resolve than esophageal symptoms, such as heartburn and regurgitation. The aim of this was to provide empirical evidence to support this observation and to carry out a detailed investigation of the differences between these symptoms. Forty-five patients with laryngopharyngeal and esophageal symptoms received acid-suppression therapy that involved the continuous administration of a proton-pump inhibitor for up to 6 months. We investigated the differences in response to acid-suppression therapy between patients suffering from laryngopharyngeal and esophageal symptoms, respectively, who received upper gastrointestinal endoscopy and were assayed for serum Helicobacter pylori antibodies. The significance of the rate of symptom improvement was estimated by Kaplan-Meier analysis and the logrank test. Laryngopharyngeal symptoms improved significantly more slowly than esophageal symptoms following acid-suppression therapy (49.8 vs. 78.3%, 60 days after the start of acid suppression; P = 0.003). These differences were observed both in patients with erosive esophagitis (P = 0.008) and in H. pylori-seronegative patients (P = 0.001).

Helicobacter pylori seropositivity predicts outcomes of acid suppression therapy for laryngopharyngeal reflux symptoms.

OBJECTIVES: Although an inverse relationship has been reported between the rates of reflux esophagitis and Helicobacter pylori infection in Japan, infection rates among patients complaining of laryngopharyngeal reflux symptoms, such as abnormal laryngopharyngeal sensation, chronic coughing, and hoarseness, have not previously been investigated. The effects of H. pylori infection on outcomes of acid suppression therapy have not been studied. STUDY DESIGN: Retrospective cohort study. METHODS: We investigated the relationships between H. pylori antibody positivity, laryngopharyngeal reflux symptoms, objective laryngopharyngeal findings, and rate of response to acid-suppression therapy in 42 subjects who were diagnosed with gastroesophageal reflux disease, using upper gastrointestinal endoscopy, and were assayed for the serum H. pylori antibody. RESULTS: The incidence of H. pylori antibody positivity in the targeted patient group was 59.5%. Kaplan-Meier analysis showed that the laryngopharyngeal symptom-improvement rate, measured using the symptom score, was significantly lower for H. pylori antibody-negative cases than for H. pylori antibody-positive cases (30.0 vs. 84.6%; P = .002) 60 days after the start of acid-suppression therapy. No significant differences in the esophageal symptom-improvement rate were noted between the two groups (76.2 vs. 89.5%; P = .576) CONCLUSIONS: By focusing on the involvement of H. pylori infection in laryngopharyngeal reflux, we determined the relationships between H. pylori antibody positivity and response to acid-suppression therapy among patients. The laryngopharyngeal, not esophageal, symptom relief by acid-suppression therapy was significantly lower among H. pylori antibody-negative cases than among antibody-positive cases.

The prevalence of laryngeal pseudosulcus among Japanese patients with laryngopharyngeal reflux related symptoms.

Infraglottic edema extending from the anterior commissure to the posterior larynx, called the laryngeal pseudosulcus, may have some value in the diagnosing of laryngopharyngeal reflux (LPR). The purpose of this study is to evaluate the prevalence, sensitivity and specificity of this finding among Japanese patients with LPR-related symptoms. Forty-three patients diagnosed as LPR based on their symptoms and 42 control patients without LPR were enrolled. The presence of pseudosulcus was determined with transnasal fiberoptic laryngoscopy. Thirty-seven of the 43 patients with LPR and 13 of the 42 control patients had evidence of laryngeal pseudosulcus (p<0.001). The sensitivity and specificity of pseudosulcus in the symptom-based diagnosis of LPR are 86 and 69%, respectively. This study shows that laryngeal pseudosulcus is highly correlated with LPR-related symptoms. The presence of this finding is suggestive of LPR.