Putative Pathogenic Variants of ABCG5 and ABCG8 of Sitosterolemia in Patients With Hyper-Low-Density Lipoprotein Cholesterolemia.

Objective: Sitosterolemia is a rare autosomal recessive disease caused by the deleterious variants of adenosine 5'-triphosphate (ATP)-binding cassette sub-family G member 5 (ABCG5) or ATP-binding cassette sub-family G member 8 (ABCG8). There are only few data on the pathogenicity of ABCG5 and ABCG8. This study aimed to propose a scheme for determining variant pathogenicity and to catalog the putative pathogenic variants in sitosterolemia. Methods: This study enrolled 377 consecutive Japanese patients with hyper-low-density lipoprotein cholesterolemia (mean age: 46.5±19.8 years, with 192 men) who have targeted-sequenced data on ABCG5 or ABCG8 (among 21 Mendelian lipid genes for any dyslipidemias) and serum sitosterol levels at Kanazawa University Hospital from 2016 to 2021. Serum sitosterol levels were divided by 0.79 in patients treated with ezetimibe, accounting for the average reduction with this drug. ABCG5 or ABCG8 variants were defined as putative pathogenic if associated with serum sitosterol levels ≥5 µg/mL or homozygous if associated with serum sitosterol levels ≥10 µg/mL. Results: Twenty-three ABCG5 or ABCG8 variants (16 missense, 2 nonsense, 2 frameshift, 2 deletion, and 1 splice mutation) were identified. Based on our definition, 11 putative pathogenic variants (median sitosterol level: 10.1 [6.5-17.1] µg/mL) were found in 36 individuals and 12 benign variants (median sitosterol: 3.5 [2.5-4.1] µg/mL) in 14 individuals. Conclusion: The scheme proposed for assessing the pathogenicity of genetic variations (ABCG5 and ABCG8) is useful. Using this scheme, 11 putative pathogenic, and 12 benign variants in ABCG5 or ABCG were classified.

Healthy lifestyle, lipoprotein (a) levels and the risk of coronary artery disease.

BACKGROUND: Lipoprotein (a) [Lp(a)] is associated with coronary artery disease (CAD). However, the role of healthy lifestyle against the risk of CAD with consideration of high Lp(a) levels remains unclear. METHODS: This study examined 4512 participants who underwent serum Lp(a) level assessment at Kanazawa University Hospital from 2008 to March 2016. Their lifestyle habits were examined based on four questionnaires regarding dietary pattern, exercise habits, smoking status and body weight. Logistic regression analyses were performed to identify the association between healthy lifestyle and CAD independent of Lp(a) levels. RESULTS: The Lp(a) levels were significantly associated with CAD (odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.08-1.17, p = 1.3 × 10-7 per 10 mg/dL). Under these circumstances, the lifestyle risk score was also significantly associated with CAD (OR: 1.24, 95% CI: 1.12-1.36, p = 2.4 × 10-8 ). Compared with patients with a favourable lifestyle who have Lp(a) levels of <30 mg/dL, those with an intermediate or unfavourable lifestyle were at higher risk for CAD (OR: 1.11, 95% CI: 1.02-1.20, p = 0.003 and OR: 1.40, 95% CI: 1.16-1.54, p = 3.6 × 10-5 , respectively). Further, patients with a favourable, intermediate or unfavourable lifestyle who have Lp(a) levels of ≥30 mg/dL were at high risk for CAD (OR: 1.21, 95% CI: 1.08-1.34, p = 0.0014; OR: 1.31, 95% CI: 1.14-1.48, p = 1.2 × 10-4 ; and OR: 1.81, 95% CI: 1.44-2.18, p = 2.2 × 10-7 , respectively). CONCLUSIONS: Healthy lifestyle was associated with a lower risk of CAD regardless of Lp(a) levels.

Impact of the severe familial hypercholesterolemia status on atherosclerotic risks.

Risks of atherosclerotic events substantially vary even among patients with familial hypercholesterolemia (FH) with extremely high risk based on life-long exposure to high low-density lipoprotein cholesterol levels. This study aimed to examine the impact of the severe FH status defined by the International Atherosclerosis Society (IAS). Data of patients with FH (N = 1050, male = 490) who were admitted to Kanazawa University Hospital between 2000 and 2020 and who were followed up were retrospectively reviewed. The number of major adverse cardiac events (MACEs), including mortality associated with cardiovascular disease, acute coronary syndrome, and ischemic heart disease requiring coronary revascularization per 1000 person-years, was calculated. Hazard ratio was also calculated using Cox proportional model. Overall, 545 (51.9%) patients had severe FH. The median follow-up duration was 12.6 years. In total, 171 MACEs were recorded during the follow-up period. Severe FH was significantly associated with MACE (hazard ratio = 6.48, 95% confidence interval = 2.56-10.40, P = 1.2 × 10-5). The event rates per 1000 person-years in the primary prevention group of non-severe FH and severe FH, were 0.0 and 15.6, respectively. The event rates per 1000 person-years in the secondary prevention group of non-severe FH and severe FH, were 2.0 and 32.3, respectively. Patients with severe FH exhibited significantly higher risks in primary and secondary prevention settings. This simple criterion provides useful information for identifying patients with even higher risk who may need further management.

Mechanisms of fever-induced QT prolongation and torsades de pointes in patients with KCNH2 mutation.

AIMS: Patients with particular mutations of type-2 long QT syndrome (LQT2) are at an increased risk for malignant arrhythmia during fever. This study aimed to determine the mechanism by which KCNH2 mutations cause fever-induced QT prolongation and torsades de pointes (TdP). METHODS AND RESULTS: We evaluated three KCNH2 mutations, G584S, D609G, and T613M, in the Kv11.1 S5-pore region, identified in patients with marked QT prolongation and TdP during fever. We also evaluated KCNH2 M124T and R269W, which are not associated with fever-induced QT prolongation. We characterized the temperature-dependent changes in the electrophysiological properties of the mutant Kv11.1 channels by patch-clamp recording and computer simulation. The average tail current densities (TCDs) at 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller and less increased with rising temperature from 35°C to 40°C than those for WT, M124T, and R269W. The ratios of the TCDs at 40°C to 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller than for WT, M124T, and R269W. The voltage dependence of the steady-state inactivation curve for WT, M124T, and R269W showed a significant positive shift with increasing temperature; however, that for G584S, WT+D609G, and WT+T613M showed no significant change. Computer simulation demonstrated that G584S, WT+D609G, and WT+T613M caused prolonged action potential durations and early afterdepolarization formation at 40°C. CONCLUSION: These findings indicate that KCNH2 G584S, D609G, and T613M in the S5-pore region reduce the temperature-dependent increase in TCDs through an enhanced inactivation, resulting in QT prolongation and TdP at a febrile state in patients with LQT2.

Impact of Healthy Lifestyle in Patients With Familial Hypercholesterolemia.

Background: Pathogenic mutations are associated with poor outcomes in patients with familial hypercholesterolemia (FH). However, data on the effects of a healthy lifestyle on FH phenotypes are limited. Objectives: The authors investigated the interaction between a healthy lifestyle and FH mutation with prognosis in patients with FH. Methods: We investigated the associations of the interaction between genotypes and lifestyle, with the occurrence of major adverse cardiac events (MACE), such as cardiovascular-related mortality, myocardial infarction, unstable angina, and coronary artery revascularization, in patients with FH. We assessed their lifestyle based on 4 questionnaires (healthy dietary pattern, regular exercise, not smoking, and absence of obesity). The Cox proportional hazards model was used to assess the risk for MACE. Results: The median follow-up duration was 12.6 (IQR: 9.5-17.9) years. During the follow-up duration, 179 MACE were observed. Independent of classic risk factors, FH mutation and lifestyle score were significantly associated with MACE (HR: 2.73; 95% CI: 1.03-4.43; P = 0.02; and HR: 0.69, 95% CI: 0.40-0.98, P = 0.033, respectively). The estimated risk of coronary artery disease by 75 years of age varied according to lifestyle, ranging from 21.0% among noncarriers with a favorable lifestyle to 32.1% among noncarriers with an unfavorable lifestyle and ranging from 29.0% among carriers with a favorable lifestyle to 55.4% among carriers with an unfavorable lifestyle. Conclusions: A healthy lifestyle was associated with reduced risk for MACE among patients with FH with or without genetic diagnosis.

Attainment of the low-density lipoprotein cholesterol treatment target and prognosis of heterozygous familial hypercholesterolemia.

BACKGROUND AND AIMS: No previous study has investigated the association between attainment of low-density lipoprotein (LDL) cholesterol treatment target and better prognosis in patients with familial hypercholesterolemia (FH). The current research aimed to examine the association between attainment of LDL cholesterol treatment target and major adverse cardiac events (MACEs) in patients with FH to validate the current LDL cholesterol treatment targets in primary (<100 mg/dL) and secondary (<70 mg/dL) prevention settings. METHODS: The data of patients with FH who were admitted to Kanazawa University Hospital between 2000 and 2020 and who were followed-up were retrospectively reviewed. The number of MACEs, including mortality associated with cardiovascular disease, unstable angina, and myocardial infarction per 1000 person-years, was calculated for each stratum for the attainment of LDL cholesterol target. RESULTS: The median follow-up duration was 12.6 years. In total, 132 MACEs were recorded during the follow-up period. The numbers of patients who attained the LDL cholesterol target in the primary and secondary prevention groups were 228 (31.9%) and 40 (11.9%), respectively. The event rates per 1000 person-years for LDL cholesterol levels of <100 and ≥100 mg/dL in the primary prevention group were 2.6 and 4.4, respectively. The event rates per 1000 person-years for LDL cholesterol levels of <70 and ≥70 mg/dL in the secondary prevention group were 15.3 and 27.5, respectively. CONCLUSIONS: Attainment of the LDL cholesterol target is associated with better prognosis in patients with FH. However, the attainment rate is currently inadequate among Japanese.

Characterization of baseline clinical factors associated with incident worsening kidney function in patients with non-valvular atrial fibrillation: the Hokuriku-Plus AF Registry.

Evidence suggests that atrial fibrillation (AF) could increase the risk of worsening kidney function (WKF) which is linked to an increased risk of stroke, bleeding, and death in AF patients. However, limited data exist regarding the factors that could lead to WKF in these patients. Therefore, we sought to identify the potential factors associated with the development of WKF in patients with non-valvular AF (NVAF). We analyzed prospectively recruited 1122 NVAF patients [men 71.9%, median age 73.0 years (interquartile range: 66.0-79.0)] with a baseline estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m2 from the Hokuriku-Plus AF Registry. The primary outcome was incident WKF, defined as the %eGFR change from the baseline ≥ 30% during the follow-up period. We evaluated the association between baseline variables and incident WKF using univariate and multivariate Cox proportional hazard models. We also evaluated the non-linear association between the identified factors and incident WKF. During a median follow-up period of 3.0 years (interquartile range: 2.7-3.3), incident WKF was observed in 108 patients (32.6 per 1000 person-years). Compared to the patients without incident WKF, the patients with incident WKF were older and had a higher prevalence of heart failure (HF), diabetes mellitus (DM), and vascular disease at baseline. Those who experienced incident WKF also had higher diastolic blood pressure, lower hemoglobin, lower eGFR, higher B-type natriuretic peptide (BNP) and used warfarin more frequently. Upon multivariate analysis, age ≥ 75 years, HF, DM, and anemia were independently associated with incident WKF. Additionally, age and hemoglobin were linearly associated with the risk of incident WKF, whereas a J- or U-shaped association was observed for HbA1c and BNP. Age ≥ 75 years, HF, DM, and anemia were associated with the development of WKF in Japanese patients with NVAF. In patients with these risk factors, a careful monitoring of the kidney function and appropriate interventions may be important when possible.

The Assessment of Carotid Atherosclerotic Plaque among Young Patients with Familial Hypercholesterolemia.

Objective Few data exist regarding when atherosclerotic changes occur among patients with familial hypercholesterolemia (FH). Carotid ultrasonography is a non-invasive method of evaluating this issue. The present study (1) compared the clinical utilities of carotid intima-media thickness (cIMT) and carotid plaque score (cPS) and (2) estimated the onset and progression of carotid atherosclerosis among patients with heterozygous FH (HeFH). Methods We retrospectively analyzed 511 patients under 30 years old who underwent carotid ultrasonography at our hospital from 2006 to 2019. We classified them into the HeFH group (n=78, 21.4±5.9 years old) and non-FH group (n=433, 23.4±6.0 years old) based on the clinical diagnosis and compared their cIMT and cPS values. In addition, we estimated the onset and progression of carotid atherosclerosis among young HeFH patients. Results There was no significant difference in the cIMT between the HeFH and non-FH groups (0.44 mm vs. 0.42 mm, p=0.25). In contrast, the cPS was significantly higher in the HeFH group than in the non-FH group (1.11 vs. 0.26, p=0.002). The regression equation for cPS of HeFH group was Y=-2.05+0.15X (r=0.37, p<0.001). Conclusion An assessment based on the cPS rather than the cIMT appears to be better to capture the progress of carotid atherosclerosis among young HeFH patients. Carotid atherosclerosis may start to develop at 14 years old in patients with HeFH.

Impact of variants of uncertain significance of LDL receptor on phenotypes of familial hypercholesterolemia.

BACKGROUND: Data on the effect of variants of uncertain significance (VUS) of LDL receptor (LDLR) on familial hypercholesterolemia (FH) phenotype is limited. OBJECTIVE: To investigate the associations between genotypes and phenotypes, including low-density lipoprotein (LDL) cholesterol level and occurrence of major adverse cardiac events (MACEs), in FH patients (N = 1050, male/female = 490/560). METHODS: We retrospectively assessed the data of patients with FH admitted at Kanazawa University Hospital between 1990 and 2020. Based on genotype, the patients were divided into patients without variants, with VUS of LDLR, and with pathogenic variants. Cox proportional hazard model was used to identify the factors associated with MACEs. RESULTS: The median follow-up duration was 12.6 years (interquartile range: 9.5-17.9 years). Altogether, 777 patients had FH mutation and 273 had pathogenic mutation, with 92 having VUS. Over the follow-up duration, 175 MACEs were observed. LDL cholesterol level was found to be significantly higher in patients with pathogenic variants (251 mg/dL) than in patients with VUS (225 mg/dL) and without variants (203 mg/dL). Pathogenic variants and VUS are significantly associated with MACEs (hazard ratio [HR] = 1.52, 95% confidence interval [CI] = 1.02-2.02, P = 0.033 and HR = 3.18, 95% CI = 2.00-4.36, P = 1.9 × 10-5, relative to patients without any variants, respectively), independent of classical risk factors. CONCLUSION: VUS of LDLR was significantly associated with poor outcomes in FH patients. Genetic testing is useful for the diagnosis and risk stratification of FH patients.

A Case of Pulmonary Hypertension in a 67-Year-Old Woman with Thiamine Deficiency Following Partial Gastrectomy and Exacerbated by Diuretics.

BACKGROUND Thiamine deficiency often occurs in patients with alcohol abuse and unbalanced diets. However, gastric surgery and/or use of diuretics can also cause this situation. Importantly, thiamine deficiency can cause pulmonary hypertension, which is completely reversible. This report is of a case of a 67-year-old woman who presented with pulmonary hypertension and thiamine deficiency following partial gastrectomy and exacerbated by diuretics. CASE REPORT A 67-year-old woman with histories of partial gastrectomy because of non-Hodgkin lymphoma (at age 36 years) and sigmoid colectomy because of colon cancer (at age 58 years) presented with bilateral leg edema and dyspnea on exertion. Electrocardiography and right heart catheterization revealed pulmonary hypertension. Despite diuretic administration (initially indapamide, then changed to torsemide), the symptoms gradually worsened. Although she was neither an alcohol drinker nor a fussy eater, we found that her blood thiamine concentration was extremely low. We diagnosed her as having thiamine deficiency caused by gastrectomy and administered diuretics. After intravenous thiamine administration, her symptoms showed immediate improvement, associated with the normalization of the pulmonary hypertension. After detailed analysis of the cause of her pulmonary hypertension, including Swan-Ganz catheterization and echocardiography, we concluded that her pulmonary hypertension was caused by thiamine deficiency following partial gastrectomy and exacerbated by diuretics. CONCLUSIONS This case highlights the importance of recognizing that thiamine deficiency can be a cause of pulmonary hypertension, and that thiamine deficiency can be associated with gastrectomy and the use of diuretics.

Association between Cardiovascular Health and Incident Atrial Fibrillation in the General Japanese Population Aged ≥40 Years.

This study explores the association between lifestyle behavior and incident atrial fibrillation (AF) in the general Japanese population. Japanese residents aged ≥40 years undergoing a national health checkup in Kanazawa City were included. We hypothesized that better lifestyle behavior is associated with lower incidence of AF. Lifestyle behavior was evaluated by the total cardiovascular health (CVH) score (0 = poor to 14 = ideal), calculated as the sum of the individual scores on seven modifiable risk factors: smoking status, physical activity, obesity, patterns of eating schedule, blood pressure, total cholesterol, and blood glucose. The association between CVH and incident AF was assessed, adjusting for other factors. A total of 37,523 participants (mean age 72.3 ± 9.6 years, 36.8% men, and mean total CVH score 9 ± 1) were analyzed. During the median follow-up period of 5 years, 703 cases of incident AF were observed. Using a low CVH score as a reference, the upper group (ideal CVH group) had a significantly lower risk of incident AF (hazard ratio [HR] = 0.79, 95% confidence interval 0.65-0.96, p = 0.02), especially among those aged <75 years (HR = 0.68, 95% confidence interval 0.49-0.94, p = 0.02). Thus, ideal CVH is independently associated with a lower risk for incident AF, particularly in younger Japanese individuals (<75 years).

Myocyte-specific enhancer factor 2c triggers transdifferentiation of adipose tissue-derived stromal cells into spontaneously beating cardiomyocyte-like cells.

Cardiomyocyte regeneration is limited in adults. The adipose tissue-derived stromal vascular fraction (Ad-SVF) contains pluripotent stem cells that rarely transdifferentiate into spontaneously beating cardiomyocyte-like cells (beating CMs). However, the characteristics of beating CMs and the factors that regulate the differentiation of Ad-SVF toward the cardiac lineage are unknown. We developed a simple culture protocol under which the adult murine inguinal Ad-SVF reproducibly transdifferentiates into beating CMs without induction. The beating CMs showed the striated ventricular phenotype of cardiomyocytes and synchronised oscillation of the intracellular calcium concentration among cells on day 28 of Ad-SVF primary culture. We also identified beating CM-fated progenitors (CFPs) and performed single-cell transcriptome analysis of these CFPs. Among 491 transcription factors that were differentially expressed (≥ 1.75-fold) in CFPs and the beating CMs, myocyte-specific enhancer 2c (Mef2c) was key. Transduction of Ad-SVF cells with Mef2c using a lentiviral vector yielded CFPs and beating CMs with ~ tenfold higher cardiac troponin T expression, which was abolished by silencing of Mef2c. Thus, we identified the master gene required for transdifferentiation of Ad-SVF into beating CMs. These findings will facilitate the development of novel cardiac regeneration therapies based on gene-modified, cardiac lineage-directed Ad-SVF cells.

Treatment with a Direct Oral Anticoagulant for Nonbacterial Thrombotic Endocarditis.

We herein report a case of nonbacterial thrombotic endocarditis (NBTE) in a patient with previously undiagnosed lung cancer. A 62-year-old woman presented to our hospital with multiple cerebral infarctions. There was no evidence of valvular heart disease or vegetations. Whole-leg ultrasonography revealed deep vein thrombosis of the left peroneal vein. We administered direct oral anticoagulants (DOACs) for a presumed diagnosis of paradoxical embolisms caused by patent foramen ovale. Unfortunately, she experienced further embolization and died. At a postmortem examination, she was diagnosed with NBTE and metastatic adenocarcinoma of the lung. Our experience with this patient suggests that DOACs may be an insufficient treatment for NBTE.

Clinical Diagnostic Criteria of Familial Hypercholesterolemia　- A Comparison of the Japan Atherosclerosis Society and Dutch Lipid Clinic Network Criteria.

BACKGROUND: This study is aimed to compare the efficacy of the 2017 Japan Atherosclerosis Society (JAS) familial hypercholesterolemia (FH) criteria, which focuses on only 3 essential clinical manifestations, with that of Dutch Lipid Clinic Network (DLCN) FH criteria, which adopts a scoring system of multiple elements.Methods and Results:A total of 680 Japanese dyslipidemic participants (51% men) were enrolled between 2006 and 2018, all of whom had full evaluations of low-density lipoprotein (LDL) cholesterol, Achilles tendon X-rays, family history records, and genetic analysis of FH-associated genes (LDLR,APOB, andPCSK9). Predictive values for the existence of FH mutations by both clinical criteria were evaluated. Overall, 173 FH patients were clinically diagnosed by using the 2017 JAS criteria and 100, 57, 156, and 367 subjects were also diagnosed as having definite, probable, possible, and unlikely FH by the DLCN FH criteria, respectively. The positive and negative likelihood ratio predicting the presence of FH mutations by using the 2017 JAS FH criteria were 19.8 and 0.143, respectively; whereas, using the DLCN criteria of definite, probable, and possible FH, the ratios were 29.2 and 0.489, 9.70 and 0.332, and 3.43 and 0.040, respectively. CONCLUSIONS: Among Japanese patients, the JAS 2017 FH criteria is considered superior to diagnose FH mutation-positive patients and simultaneously rule out FH mutation-negative patients compared with the DLCN FH criteria.

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.

Regenerative Therapy for Liver Cirrhosis Based on Intrahepatic Arterial Infusion of Autologous Subcutaneous Adipose Tissue-Derived Regenerative (Stem) Cells: Protocol for a Confirmatory Multicenter Uncontrolled Clinical Trial.

BACKGROUND: Liver cirrhosis results from chronic hepatitis, and is characterized by advanced fibrosis due to long-term hepatic inflammation. Cirrhosis ultimately leads to manifestations of jaundice, ascites, and encephalopathy, and increases the risk of hepatocellular carcinoma. Once cirrhosis is established, resulting in hepatic failure, no effective treatment is available. Therefore, novel therapies to inhibit disease progression of cirrhosis are needed. OBJECTIVE: The objective of this investigator-initiated clinical trial is to assess the safety and efficacy of autologous adipose tissue-derived regenerative (stem) cell therapy delivered to the liver via the hepatic artery in patients with liver cirrhosis. METHODS: Through consultation with the Japan Pharmaceuticals and Medical Devices Agency, we designed a clinical trial to assess a therapy for liver cirrhosis based on autologous adipose tissue-derived regenerative (stem) cells, which are extracted using an adipose tissue dissociation device. The primary endpoints of the trial are the serum albumin concentration, prothrombin activity, harmful events, and device malfunction. RESULTS: Enrollment and registration were initiated in November 2017, and the follow-up period ended in November 2019. Data analysis and the clinical study report will be completed by the end of March 2020. CONCLUSIONS: Completion of this clinical trial, including data analysis, will provide data on the safety and efficacy of this novel liver repair therapy based on autologous adipose tissue-derived regenerative (stem) cells using an adipose tissue dissociation device. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000022601; https://tinyurl.com/w9uqw3q. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/17904.

Takotsubo cardiomyopathy complicated by cardiac tamponade due to non-hemorrhagic pericardial effusion: a case report.

BACKGROUND: Cardiac tamponade is a rare but serious complication of Takotsubo cardiomyopathy (TC). Two cases of cardiac tamponade subsequent to TC have been reported. The pericardial effusion in these cases was hemorrhagic and caused by ventricular rupture. Cardiac tamponade induced by an inflammatory effusion complicated with TC has not been reported. This is the first case report of TC, which developed cardiac tamponade during the recovery phase with a large volume non-hemorrhagic inflammatory effusion. CASE PRESENTATION: We describe a case of an 81-year-old woman admitted to our hospital because of severe chest pain. Her symptoms began soon after her son's hospitalization. We diagnosed her with TC based on results of an electrocardiogram, echocardiogram, and emergent coronary angiography. Her symptoms and left ventricular dysfunction improved gradually. She developed newly confirmed chest pain and dyspnea on day 9 after admission. A large pericardial effusion developed, resulting in cardiac tamponade. Her symptoms and hemodynamic status improved immediately after the pericardiocentesis. The effusion was non-hemorrhagic and exudative. No specific signs of infection, collagen disease, or malignant tumors were observed, except for TC. CONCLUSIONS: We experienced a case of circulatory collapse induced by TC-related inflammatory pericardial effusion at recovery phase. This case emphasizes the importance of careful follow-up even after improved left ventricular dysfunction in a patient with TC.

Adipose tissue-derived stem cells prevent fibrosis in murine steatohepatitis by suppressing IL-17-mediated inflammation.

BACKGROUND AND AIM: The pathological features of non-alcoholic steatohepatitis (NASH) have not been determined, so fundamental treatment has not been established. Adipose-tissue-derived stromal/stem cells (ADSCs) are beneficial for repair/regenerative therapy of impaired organs because of their immuno-modulatory capability. In this study, we assessed how liver damage progresses during the early development phase of the murine NASH model and investigated whether ADSCs are preventatively efficacious against the fibrosis progression of NASH. METHODS: C57BL/6J mice were fed with atherogenic high fat or high-fat diet 60 developing into NASH or simple steatosis. Their hepatic inflammatory cells (HICs) were analyzed by cDNA microarray. NASH mice were treated with ADSCs injected into spleen when hepatic inflammation was initially observed, and liver samples were analyzed. The effect of ADSCs on the mice hepatic stellate cell (HSC) line stimulated by recombinant IL-17 and HICs from NASH mice was analyzed. RESULTS: The gene expression features of HICs implicated as humoral cytokine mediators of lymphoid cells during NASH development, compared with a simple steatosis model. One of the featured cytokines was IL-17. The development of hepatic fibrosis was alleviated when NASH mice were treated with ADSCs as well as treated with anti-IL-17 antibody, and the frequency of IL-17-secreting HICs decreased. NASH-HICs enhanced proliferation of HSCs, in which proliferation was sensitive to IL-17 stimulation. The stimulatory effect of NASH-HICs on the activation of HSCs was attenuated by co-culture with ADSCs. CONCLUSION: ADSCs treatment prevented progression of NASH fibrosis by suppressing IL-17-mediated inflammation, which was associated with HSCs activation.

Occult constrictive pericardial disease emerging 40 years after chest radiation therapy: a case report.

BACKGROUND: The main etiology of constrictive pericarditis (CP) has changed from tuberculosis to therapeutic mediastinal radiation and cardiac surgery. Occult constrictive pericardial disease (OCPD) is a covert disease in which CP is manifested in a condition of volume overload. CASE PRESENTATION: A 60-year-old patient with a history of thoracic radiation therapy for non-Hodgkin's lymphoma (40 years earlier) was transferred to our hospital for treatment of repeated congestive heart failure. For a preoperative hemodynamic study, pre-hydration with intravenous normal saline (50 mL/hour) was used to manifest the pericardial disease and prevent contrast-induced nephropathy. The hemodynamic study showed a right ventricular dip-plateau pattern and discordance of right and left ventricular systolic pressures during inspiration, which was not seen in the volume-controlled state. These responses were concordant with OCPD. A pericardiectomy, aortic valve replacement, and mitral and tricuspid valve repair were performed. Postoperatively, the heart failure was controlled with standard medication. CONCLUSIONS: This case revealed a volume-induced change in hemodynamics in OCPD with severe combined valvular heart disease, which suggests the importance of considering OCPD in patients who had undergone radiation therapy 40 years before.

Impact of left atrial size on isolation area in the acute phase of pulmonary vein isolation using 28 mm cryoballoon.

BACKGROUND: The impact of left atrial (LA) size on isolation area (ISA) using a 28-mm second-generation cryoballoon (CB) in the acute phase after pulmonary vein isolation (PVI) and the differences of CB from contact force-guided radiofrequency (RF) ablation have not been fully investigated. METHODS: We examined 85 consecutive patients (CB group, 35; RF group, 50) with drug-refractory paroxysmal atrial fibrillation who underwent their first PVI procedure at two institutions. We evaluated ISA after PVI using 3D-Merge computed tomography images (GE Healthcare, Little Chalfont, UK) and high-resolution electroanatomical mapping. RESULTS: Total ISA was significantly smaller in the CB group (20.6 ± 6.0 cm2 ) than in the RF group (29.0 ± 7.1 cm2 ; P < 0.0001). In the CB group, ISA of the left pulmonary vein (LPV), right pulmonary vein (RPV), and total ISA were not correlated with the left atrial surface area (LASA). The ratios of ISA to LASA (%ISA) of LPV and total ISA negatively correlated with LASA in the CB group (LPV: r = -0.4001, P = 0.0173; total ISA: r = -0.4733, P = 0.0041). In contrast, in the RF group, ISA of LPV, RPV, and total ISA positively correlated with LASA; (LPV: r = 0.5155, P = 0.001; RPV: r = 0.6398, P < 0.0001; total ISA: r = 0.7299, P < 0.0001). CONCLUSION: ISA created using CB was significantly smaller than that using RF and did not change regardless of LASA increment. Differences in ISA between the two groups became more prominent in the large atrium.