桑原 政成

This study aimed to identify the clinical characteristics associated with spontaneous isolated dissection of superior mesenteric artery/celiac artery (SIDSMA/SIDCA). This observational study, conducted at Toranomon Hospital, Japan between 2009 and 2020, analyzed consecutive SIDSMA/SIDCA cases based on radiology data. The study compared clinical characteristics between symptomatic and asymptomatic patients with SIDSMA/SIDCA and investigated factors related to future vessel dilatation. Among 57 cases (44 SIDSMA, 17 SIDCA, and 4 both), the majority were male (87.7%), nearly half having hypertension (43.9%) and smokers (48.9%). Of those, 17 cases (29.8%) were symptomatic; abdominal pain (94.1%), back pain (23.5%), nausea (17.6%) and fever (5.9%). The symptomatic group was younger (52.6 ± 9.4 versus 67.2 ± 7.9 years, P < 0.001), had higher systolic and mean blood pressure (142.6 ± 20.0 versus 129.5 ± 16.5 mmHg, P = 0.017; 96.1 ± 14.6 versus 88.2 ± 17.7 mmHg, P = 0.038), a higher white blood cell count (9975 ± 5032 versus 6268 ± 1991 /µL, P = 0.012), and a higher LDL cholesterol level at diagnosis (129.7 ± 21.7 versus 87.2 ± 25.6 mg/dL, P = 0.002) than the asymptomatic group. The factors associated with future vessel dilatation included the presence of pseudo-lumen flow in the dissection vessel (73.9% versus 41.4%, p = 0.019) and a larger vessel diameter (13.5 ± 2.4 mm versus 11.5 ± 2.1 mm, p = 0.005) at diagnosis after multiple adjustments, pseudo-lumen flow was a predictor of future vessel dilatation (odds ratio, 4.80; 95% confidence interval, 1.11-20.75; p = 0.036). The study revealed that only 30% of SIDSMA/SIDCA cases were symptomatic. Symptomatic cases were generally younger and exhibited higher blood pressure and elevated white blood cell counts. These findings offer valuable insights for the acute diagnosis of SIDSMA/SIDCA.

Intravascular ultrasound (IVUS) has become a standard procedure for performing coronary intervention, but its impact on peripheral endovascular therapy (EVT) remains unclear. To assess the usefulness of IVUS during EVT, this study analyzed over 2000 consecutive patients from the TOkyo-taMA peripheral vascular intervention research COmraDE (TOMA-CODE) registry with peripheral arterial disease (PAD) in Japan. The primary outcome was chronic limb events (a composite of clinically driven target lesion revascularization (cTLR) and major amputation) during a two-year follow-up period. The secondary outcomes included the procedural success rate, in-hospital major adverse limb events (MALE), and major cardiac and cerebrovascular events (MACCE). Patients with and without IVUS were compared using propensity score matching. Among the 2227 eligible cases enrolled, with a median follow-up period of 10.4 months, there were no significant differences in limb events between IVUS (784 patients) and non-IVUS (1443 patients) groups during the follow-up period (15.4% vs. 14.4%, P = 0.53, unadjusted; 14.8% vs. 15.4%, P = 0.77, adjusted). In contrast, the IVUS group had higher procedural success rates (98.7% vs. 96.7%, P = 0.02) and lower in-hospital MALE (1.6% vs. 4.1%, P = 0.01), even after multiple adjustments. Additionally, there was no significant difference in the MACCE incidence (10.9% vs. 12.2%, P = 0.47) between the groups. This study demonstrated that IVUS usage did not reduce the occurrence of limb events among EVT patients in the chronic phase, but IVUS may improve in-hospital outcomes. Further research is necessary to verify these findings.

Uric acid, the final product of purine metabolism, plays a significant role in hypertension Research on uric acid has advanced significantly, particularly regarding its links to hypertension and cardiovascular disease (CVD). Our 2023 review covered the relationship between uric acid, hypertension; and CVD, however, numerous new studies have emerged since then. This paper provides an update, summarizing recent findings over the past two years on hyperuricemia and its association with hypertension, preeclampsia, arteriosclerosis, kidney disease, sleep-disordered breathing, CVD, and so on. Hyperuricemia, often driven by reduced uric acid excretion or increased production, is influenced by genetic factors and lifestyle habits, including high-purine foods, alcohol, and fructose intake. While hyperuricemia has been proposed to contribute to hypertension and CVD through mechanisms like inflammasome activation and oxidative stress, its causal role remains debated. Further clinical and basic science studies on hyperuricemia and purine metabolism are necessary to clarify its impact on CVD and guide therapeutic approaches.

OBJECTIVES: To identify clinical characteristics of patients with non-refractory Kawasaki disease (KD), which were defined as those who successfully responded to the standard initial intravenous immunoglobulin (IVIG) treatment (2 g/kg/day, single infusion) without any secondary or later additional specific treatments, and to investigate the factors associated with the development of coronary artery (CA) complications in patients with non-refractory KD. DESIGN: Retrospective cohort study. SETTING: Hospitals specialising in paediatrics and hospitals with ≥100 beds and a paediatric department throughout Japan. PATIENTS: A total of 122 489 patients who developed KD across Japan during 2011-2018. MAIN OUTCOME MEASURES: CA abnormalities identified after acute illness of KD (defined as CA sequelae). RESULTS: A total of 69 735 patients with non-refractory KD were identified, of which 672 (0.96%) experienced CA sequelae. Among patients with non-refractory KD, the presence of CA abnormalities identified at initial echocardiographic assessment was strongly associated with CA sequelae (adjusted OR (95% CI): 37.8 (31.9 to 44.7)). CA sequelae was also associated with male patients, infants (<12 months old), older patients (≥60 months old) and patients who received delayed initial IVIG treatment (>7 days from KD onset). Subgroup analyses demonstrated that delayed initial IVIG treatment was significantly associated with the development of CA sequelae in both patients with and without CA abnormalities identified at initial echocardiographic assessment. CONCLUSIONS: Approximately 1% of patients with non-refractory KD may develop CA sequelae. Our findings highlight the importance of initial echocardiographic assessment and early initiation of IVIG treatments for patients with KD.

Cancer and cardiovascular disease (CVD) are the leading causes of death in Japan, with an increasingly recognized interrelationship. Both diseases share numerous risk factors and pathophysiological mechanisms, suggesting a bidirectional influence on onset and progression. Recent studies reveal that cancer survivors face elevated CVD risks, particularly shortly after diagnosis, while CVD may predispose individuals to cancer. Cancer treatments, including chemotherapy, can lead to cardiotoxicity and increased CVD complications. A study by Suzuki et al. demonstrates that individuals with hypertension and a history of cancer, especially those treated with chemotherapy, have a higher risk of developing CVD events. Despite limitations in study design and data specificity, these findings highlight the importance of long-term cardiovascular monitoring in cancer survivors. As cardio-oncology evolves, developing evidence-based guidelines and fostering collaboration between oncologists and cardiologists is crucial for optimizing patient care and outcomes in both cancer and CVD management.

BACKGROUND: Extremely low uric acid (UA) levels or increased urinary UA (Uua) excretion might be risk factors for kidney disease in renal hypouricemia (RHU) patients, but their relationship with kidney dysfunction is unclear. This study investigated time-dependent changes in eGFR in RHU patients. METHODS: This multicenter retrospective study assessed UA metabolism and changes in eGFR (median 5.5 years) in 13 RHU patients. We then compared eGFR change in 7 of 13 RHU patients whose eGFR could be measured for 4 years with those in normouricemic group (n = 31). In addition, 7 RHU patients were divided into two groups based on URAT1 gene mutations: homozygote and compound heterozygote mutations (Homo/Com group, n = 3), and wild-type and heterogeneous mutations (WT/Hetero group, n = 4). RESULTS: In 13 RHU patients, the median and mean serum UA (SUA) were 0.8 (0.4-2.5) and 1.1 ± 0.7 mg/dL. The median and mean Uua were 44.3 (12.7-141.1) and 49.7 ± 36.2 mg/dL. The median and mean urinary urate clearance (Cua/Ccr) were 46.8 (11.3-73.6) and 43.3 ± 19.7%. Over 4 years, eGFR did not change in the RHU group but declined in the normouricemic group. Annual mean eGFR decline and change rate in the RHU group were the same as those in the normouricemic group (- 1.09 ± 1.11 vs. - 1.09 ± 1.92 mL/min/1.73 m2/year, p = 0.996) (- 1.74 ± 1.96 vs. - 1.36 ± 2.10%, p = 0.664). And no significant difference was found in eGFR decline or change rate between Homo/Com and WT/Hetero groups (- 0.33 ± 1.03 vs. - 1.67 ± 0.85 mL/min/1.73 m2/year, p = 0.116) (- 0.61 ± 1.62 vs. - 2.59 ± 1.91%, p = 0.210). CONCLUSION: RHU from URAT1 genetic mutation may not show eGFR decline over 4 consecutive years.

Background Hypouricemia, defined as a serum uric acid (SUA) level ≤2 mg/dL, could be a risk factor for death in hospitalized patients. However, how explanatory variables can explain hypouricemia as an objective variable in a logistic regression analysis remains unknown. Purpose To predict the risk factors for hypouricemia in hospitalized patients using a robust Bayesian logistic (RBL) model. Methods This study retrospectively enrolled patients who visited Yonago Medical Center between April 2020 and March 2021. The association between potential risk factors and hypouricemia was analyzed using the RBL model in Python-modulated PyMC3. The final model was selected based on the lowest Watanabe-Akaike information criterion (WAIC). Results Of the 618 patients, 64 (10.4%) had hypouricemia. Based on the model according to the lowest WAIC, independent risk factors for hypouricemia were febuxostat [odds ratio (OR) 5.46, 95% confidence interval (CI) 2.32-13.4], amino acids in parenteral nutrition (OR 5.19, 95% CI 1.62-15.1), TMP-SMX (OR 4.20, 95% CI 1.66-10.9), emaciation (OR 3.48, 95% CI 1.75-7.21), and serum sodium level (OR 0.90, 95% CI 0.84-0.96). Conclusion The RBL model predicted amino acids in parenteral nutrition, TMP-SMX, emaciation, and low serum sodium levels for hypouricemia, in addition to the authentic risk factor febuxostat.

OBJECTIVES: The prognosis of ventricular septal rupture (VSR) after acute myocardial infarction remains poor; hence, surgical repair is essential. However, the appropriate timing for surgical intervention remains unclear. We aimed to compare the prognosis between early (<96 hours) and delayed (≥96 hours) surgery for VSR. METHODS: This single-center, retrospective cohort study used data from 49 patients who underwent VSR repair after acute myocardial infarction (AMI) between 2007 and 2022 at our institution. In-hospital and one-, three-, and 10-year mortality and major adverse cardiac and cerebrovascular events were compared between the early (group A) and delayed (group B) surgery after AMI. RESULTS: No significant differences were found between the patients' backgrounds of the two groups. The in-hospital mortality rates were 37.5 and 16.0% for groups A and B, respectively (P = 0.114). The overall survival rates estimated using Kaplan-Meier analysis were 66.5 ± 6.9, 58.2 ± 7.5, and 28.8 ± 10.6% after one, three, and 10 years, respectively. The mortality rates in group B at three (hazard risk ratio: 2.691; 95% confidence interval: 1.02-7.097) and 10 (hazard risk ratio: 2.575; 95% confidence interval: 1.125-5.891) years were significantly better than those in group A. Major adverse cardiac and cerebrovascular events were significantly different between the two groups at all time points. CONCLUSIONS: These results showed that patients who underwent surgery for VSR 96 hours after AMI had better long-term survival than those who underwent surgery within 96 hours.

The prenatal diagnosis of fetal heart disease potentially influences parental decision-making regarding pregnancy termination. Existing literature indicates that the severity, whether in complexity or lethality, significantly influences parental decisions concerning abortion. However, questions remain as to how fetal heart disease severity impacts parental decisions, given recent advancements in postsurgical outcomes. Therefore, we investigated risk factors associated with parents' decision-making regarding abortion following a prenatal diagnosis of fetal heart disease. Our analysis included 73 (terminated: n = 37; continued: n = 36) pregnancies with a fetal heart disease diagnosed before 22 weeks of gestation. Increased gestational age at diagnosis reduced the likelihood of parents' decision on termination (Model 1: adjusted odds ratio, 0.94; 95% confidence interval 0.89-0.99; Model 2: 0.95 0.90-0.997). Critical disease (5.25; 1.09-25.19) and concurrent extracardiac or genetic abnormalities (Model 1: 4.19, 1.21-14.53; Model 2: 5.47, 1.50-19.96) increased the likelihood of choosing abortion. Notably, complex disease did not significantly influence parental decisions (0.56; 0.14-2.20). These results suggest that parental decision-making regarding abortion may be influenced by earlier gestational age at diagnosis, the lethality of heart disease, and extracardiac or genetic abnormalities, but not its complexity if prenatal diagnosis and parental counseling are provided at a cardiovascular-specialized facility.

BACKGROUND: The impact of a national initiative to provide cardiopulmonary resuscitation (CPR) education to the public on the rates of citizen-initiated CPR and survival following out-of-hospital cardiac arrest (OHCA) remains uncertain. METHODS: We examined 358,025 cases of citizen-witnessed OHCA with presumed cardiac origin, recorded in the Japanese nationwide registry from 2005 to 2020. We assessed the relationship between the number of individuals certified in CPR courses, citizen interventions, and neurologically favorable survival at one month. RESULTS: The cumulative number of certified citizens has linearly increased from 9,930,327 in 2005 to 34,938,322 in 2020 (incidence rate ratio for annual number = 1.03, p < 0.001), encompassing 32.3% of the Japanese population aged 15 and above. Similarly, the prevalence of citizen-initiated CPR has consistently increased from 40.6% in 2005 to 56.8% in 2020 (P for trend < 0.001). Greater citizen CPR engagement was significantly associated with better outcome in initial shockable rhythm patients [chest compression only: odds ratio (OR) 1.24; 95% confidence interval (CI) 1.02-1.51; P = 0.029; chest compression with rescue breathing: OR 1.33; 95% CI 1.08-1.62; P = 0.006; defibrillation with chest compression: OR 2.27; 95% CI 1.83-2.83; P < 0.001; defibrillation with chest compression and rescue breathing: OR 2.15; 95% CI 1.70-2.73; P < 0.001 vs. no citizen CPR]. CONCLUSIONS: The incidence of citizen-initiated CPR across Japan has consistently and proportionately increased with the rising number of individuals certified in CPR courses. Greater citizen CPR involvement has been linked to neurologically favorable survival, particularly in cases with an initial shockable rhythm.

BACKGROUND: Higher cholesterol absorption has been reported to be related to a higher incidence of cardiovascular events (CVEs). The KEEP (Kyushu Elderly Ezetimibe Phytosterol) study, a substudy of the EWTOPIA 75 (Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older) study, investigated the relationships of cholesterol absorption and synthesis markers with CVEs in older old individuals with hypercholesterolemia, particularly in relation to ezetimibe treatment. METHODS AND RESULTS: Eligible patients were those aged ≥75 years who had low-density lipoprotein cholesterol ≥140 mg/dL, no history of coronary artery disease, and no recent use of lipid-lowering drugs. Participants were randomly assigned into a diet-only or diet-plus-ezetimibe group. Baseline and 24-week follow-up blood samples were analyzed for cholesterol absorption (eg, campesterol) and synthesis markers (eg, lathosterol). Of 1287 patients, 1061 patients with baseline measurement were analyzed. Over a median follow-up of 4.0 years, 64 CVEs occurred. Higher campesterol levels at baseline were significantly associated with a lower risk of CVEs. After adjustment for sex, age, and treatment, the hazard ratios for the lowest to highest quartile categories of baseline campesterol were 1.00 (reference), 0.59 (95% CI, 0.30-1.17), 0.44 (95% CI, 0.21-0.94), and 0.44 (95% CI, 0.21-0.93), respectively (trend P=0.01). This association persisted after further adjustment for hypertension, diabetes, and other cardiovascular risk factors. Neither interactions with ezetimibe treatment nor mediating effects of the changes in cholesterol absorption markers were observed. CONCLUSIONS: The KEEP study indicated that higher campesterol levels without lipid-lowering drugs were associated with a lower incidence of CVEs in older old individuals with hypercholesterolemia who were subsequently treated with diet or ezetimibe. REGISTRATION: URL: https://www.umin.ac.jp; unique identifier: UMIN000017769.

Providing standardized, high-quality rehabilitation for critically ill patients is a crucial issue. In 2017, the Japanese Society of Intensive Care Medicine (JSICM) promulgated the "Evidence-Based Expert Consensus for Early Rehabilitation in the Intensive Care Unit" to advocate for the early initiation of rehabilitations in Japanese intensive care settings. Building upon this seminal work, JSICM has recently conducted a rigorous systematic review utilizing the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. This endeavor resulted in the formulation of Clinical Practice Guidelines (CPGs), designed to elucidate best practices in early ICU rehabilitation. The primary objective of this guideline is to augment clinical understanding and thereby facilitate evidence-based decision-making, ultimately contributing to the enhancement of patient outcomes in critical care settings. No previous CPGs in the world has focused specifically on rehabilitation of critically ill patients, using the GRADE approach. Multidisciplinary collaboration is extremely important in rehabilitation. Thus, the CPGs were developed by 73 members of a Guideline Development Group consisting of a working group, a systematic review group, and an academic guideline promotion group, with the Committee for the Clinical Practice Guidelines of Early Mobilization and Rehabilitation in Intensive Care of the JSICM at its core. Many members contributed to the development of the guideline, including physicians and healthcare professionals with multiple and diverse specialties, as well as a person who had been patients in ICU. Based on discussions among the group members, eight important clinical areas of focus for this CPG were identified. Fourteen important clinical questions (CQs) were then developed for each area. The public was invited to comment twice, and the answers to the CQs were presented in the form of 10 GRADE recommendations and commentary on the four background questions. In addition, information for each CQ has been created as a visual clinical flow to ensure that the positioning of each CQ can be easily understood. We hope that the CPGs will be a useful tool in the rehabilitation of critically ill patients for multiple professions.

The prevalence of patients with hyperuricemia or gout is increasing worldwide. Hyperuricemia and gout are primarily attributed to genetic factors, along with lifestyle factors like consuming a purine-rich diet, alcohol and/or fructose intake, and physical activity. While numerous studies have reported various comorbidities linked to hyperuricemia or gout, the range of these associations is extensive. This review article focuses on the relationship between uric acid and thirteen specific domains: transporters, genetic factors, diet, lifestyle, gout, diabetes mellitus, metabolic syndrome, atherosclerosis, hypertension, kidney diseases, cardiovascular diseases, neurological diseases, and malignancies. The present article provides a comprehensive review of recent developments in these areas, compiled by experts from the Young Committee of the Japanese Society of Gout and Uric and Nucleic Acids. The consolidated summary serves to enhance the global comprehension of uric acid-related matters.

Total 276 manuscripts were published in Hypertension Research in 2022. Here our editorial members picked up the excellent papers, summarized the current topics from the published papers and discussed future perspectives in the sixteen fields. We hope you enjoy our special feature, 2023 update and perspectives in Hypertension Research.

Serum uric acid (UA) level is associated with the high cumulative incidence or prevalence of coronary artery disease (CAD), and hyperuricemia is considered as an independent risk marker for CAD. Sleep-disordered breathing (SDB) is also associated with an increased risk of CAD. Several studies have shown that SDB is associated with hyperuricemia, but the mechanisms are unclear. We measured serum levels of UA and xanthine oxidoreductase (XOR) activity and urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), all of which were assessed at 6 p.m. and the following 6 a.m. in males with CAD. In addition, nocturnal pulse oximetry was performed for the night. Overall 32 eligible patients with CAD were enrolled. Serum UA levels significantly increased overnight. (5.32 ± 0.98 mg/dl to 5.46 ± 1.02 mg/dl, p < 0.001) Moreover, XOR activity and urinary 8-OHdG levels significantly increased from 6 p.m. to 6 a.m. Furthermore, 3% Oxygen desaturation index (ODI) was correlated with the overnight changes in XOR activity (r = 0.36, P = 0.047) and urinary 8-OHdG levels (r = 0.41, P = 0.02). In addition, 3%ODI was independently correlated with the changes in XOR activity (correlation coefficient, 0.36; P = 0.047) and 8-OHdG (partial correlation coefficient, 0.63; P = 0.004) in multivariable analyses. SDB severity was associated with the overnight changes in XOR activity and urinary 8-OHdG, suggesting that SDB may be associated with oxidative stress via UA production. This trial is registered at University Hospital Medical Information Network (UMIN), number: UMIN000021624.

Obesity is a heterogenous condition with multiple different phenotypes. Among these a particular subtype exists named as metabolically healthy obesity (MHO). MHO has multiple definitions and its prevalence varies according to study. The potential mechanisms underlying the pathophysiology of MHO include the different types of adipose tissue and their distribution, the role of hormones, inflammation, diet, the intestinal microbiota and genetic factors. In contrast to the negative metabolic profile associated with metabolically unhealthy obesity (MUO), MHO has relatively favorable metabolic characteristics. Nevertheless, MHO is still associated with many important chronic diseases including cardiovascular disease, hypertension, type 2 diabetes, chronic kidney disease as well as certain types of cancer and has the risk of progression into the unhealthy phenotype. Therefore, it should not be considered as a benign condition. The major therapeutic alternatives include dietary modifications, exercise, bariatric surgery and certain medications including glucagon-like peptide-1 (GLP-1) analogs, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and tirzepatide. In this review, we discuss the significance of MHO while comparing this phenotype with MUO.

The presence of obesity and metabolic syndrome is strongly linked with chronic kidney disease (CKD), but the mechanisms responsible for the association are poorly understood. Here, we tested the hypothesis that mice with obesity and metabolic syndrome might have increased susceptibility to CKD from liquid high fructose corn syrup (HFCS) by favoring the absorption and utilization of fructose. We evaluated the pound mouse model of metabolic syndrome to determine if it showed baseline differences in fructose transport and metabolism and whether it was more susceptible to chronic kidney disease when administered HFCS. Pound mice have increased expression of fructose transporter (Glut5) and fructokinase (the limiting enzyme driving fructose metabolism) associated with enhanced fructose absorption. Pound mice receiving HFCS rapidly develop CKD with increased mortality rates associated with intrarenal mitochondria loss and oxidative stress. In pound mice lacking fructokinase, the effect of HFCS to cause CKD and early mortality was aborted, associated with reductions in oxidative stress and fewer mitochondria loss. Obesity and metabolic syndrome show increased susceptibility to fructose-containing sugars and increased risk for CKD and mortality. Lowering added sugar intake may be beneficial in reducing the risk for CKD in subjects with metabolic syndrome.

Uric acid (UA) forms monosodium urate (MSU) crystals to exert proinflammatory actions, thus causing gout arthritis, urolithiasis, kidney disease, and cardiovascular disease. UA is also one of the most potent antioxidants that suppresses oxidative stress. Hyper andhypouricemia are caused by genetic mutations or polymorphism. Hyperuricemia increases urinary UA concentration and is frequently associated with urolithiasis, which is augmented by low urinary pH. Renal hypouricemia (RHU) is associated with renal stones by increased level of urinary UA, which correlates with the impaired tubular reabsorption of UA. Hyperuricemia causes gout nephropathy, characterized by renal interstitium and tubular damage because MSU precipitates in the tubules. RHU is also frequently associated with tubular damage with elevated urinary beta2-microglobulin due to increased urinary UA concentration, which is related to impaired tubular UA reabsorption through URAT1. Hyperuricemia could induce renal arteriopathy and reduce renal blood flow, while increasing urinary albumin excretion, which is correlated with plasma xanthine oxidoreductase (XOR) activity. RHU is associated with exercise-induced kidney injury, since low levels of SUA could induce the vasoconstriction of the kidney and the enhanced urinary UA excretion could form intratubular precipitation. A U-shaped association of SUA with organ damage is observed in patients with kidney diseases related to impaired endothelial function. Under hyperuricemia, intracellular UA, MSU crystals, and XOR could reduce NO and activate several proinflammatory signals, impairing endothelial functions. Under hypouricemia, the genetic and pharmacological depletion of UA could impair the NO-dependent and independent endothelial functions, suggesting that RHU and secondary hypouricemia might be a risk factor for the loss of kidney functions. In order to protect kidney functions in hyperuricemic patients, the use of urate lowering agents could be recommended to target SUA below 6 mg/dL. In order to protect the kidney functions in RHU patients, hydration and urinary alkalization may be recommended, and in some cases an XOR inhibitor might be recommended in order to reduce oxidative stress.

A direct relationship between serum uric acid levels and hypertension, cardiovascular, renal and metabolic diseases has been reported in many basic and epidemiological studies. Among these, high blood pression is one of the most common features associated with hyperuricemia. In this regard, several small-scale interventional studies have demonstrated a significant reduction in blood pressure in hypertensive or prehypertensive patients on uric acid-lowering drugs. These observation or intervention studies have led to affirm that there is a causal relationship between uric acid and hypertension. While the clinical association between uric acid and high blood pressure is notable, no clear conclusion has yet been reached as to whether lowering uric acid is beneficial to prevent cardiovascular and renal metabolic diseases. Recently, several prospective randomized controlled intervention trials using allopurinol and other uric acid-lowering drugs have been reported, and the results from these trials were almost negative, suggesting that the correlation between hyperuricemia and cardiovascular disease has no causality. However, it is important to note that in some of these recent studies there were high dropout rates and an important fraction of participants were not hyperuricemic. Therefore, we should carry caution in interpreting the results of these studies. This review article presents the results of recent clinical trials using uric acid-lowering drugs, focusing on hypertension and cardiovascular and renal metabolic diseases, and discusses the future of uric acid therapy.

OBJECTIVES: The aims of this study were to evaluate the association between hypouricemia and cardiometabolic diseases, such as hypertension, dyslipidemia, and reduced kidney function, and to explore the sex-specific optimal range for serum uric acid (sUA) associated with the lowest risk for these diseases. METHODS: In this cross-sectional study, we identified individuals with sUA data between April 2018 and March 2019 and recorded the frequency of cardiometabolic comorbidities according to sUA. Univariable and multivariable logistic regression analyses were performed for the overall population and after classifying by sex to assess the association between sUA and cardiometabolic comorbidities. RESULTS: Among 796,508 individuals, a J-shaped association was observed between the sUA level and cardiometabolic diseases in the overall population. The adjusted odds ratios (95% confidence interval) for hypertension, dyslipidemia, and reduced renal function in individuals with sUA ≤1.0 mg/dL compared with those with sUA ranging between 2.1 and 3.0 mg/dL were 1.38 (1.13-1.69), 1.52 (1.30-1.78), and 2.17 (1.47-3.20), respectively. A J-shaped association between sUA and hypertension was observed only in women. The optimal range of sUA associated with the lowest risk for hypertension was assumed to be <6 mg/dL in men and 1-4 mg/dL in women. A J-shaped association between the sUA and dyslipidemia and reduced renal function was observed in both men and women. The optimal range of sUA for dyslipidemia and reduced renal function was approximately 2-5 mg/dL in men and 1-4 mg/dL in women. CONCLUSIONS: Excess and extremely low uric acid levels may be related to an increased cardiometabolic risk.

Objectives: This study investigates the impact of xanthine oxidase inhibitors (XOI) on mortality in patients with cardiovascular diseases. XOI withdrawal has been reported to increased mortality risk due to rapid adenosine triphosphate (ATP) deficiency. This study aims to determine whether XOI treatment reduces mortality and whether XOI withdrawal increases mortality. Methods: This is a real-world database study using the Japanese Registry of All Cardiac and Vascular Diseases (J-ROAD). We analyzed 1,648,891 hospitalized patients aged 20-90 with acute coronary syndrome or heart failure. In the first study, mortality rates were compared between patients without urate-lowering agents (n = 1,292,486) and those with XOI agents (n = 315,388, excluding 41,017 on other urate-lowering agents). In the second study, mortality rates were compared between the XOI continuous medication group (n = 226,261) and the XOI withdrawal group (n = 89,127). Results: After multiple adjustments, XOI treatment group showed significantly lower mortality compared with that without any urate-lowering agent (odds ratio (OR), 0.576, 95% confidence interval (CI), 0.567-0.587, p < .001). In the sub-analysis, the group with allopurinol (OR, 0.578; 95% CI, 0.557-0.600), febuxostat (OR, 0.610; 95% CI, 0.599-0.622), and topiroxostat (HR, 0.545; 95% CI, 0.473-0.628) showed lower OR of mortality compared with that without any urate-lowering agent. XOI withdrawal group led to significantly higher death rates compared to XOI continuous group (19.8% vs. 0.03%; p < .001). Conclusion: XOI treatment for patients with cardiovascular diseases is associated with reduced mortality. Conversely, XOI withdrawal is linked to elevated mortality risk. This emphasizes the importance of both prescribing and discontinuing XOI carefully to optimize patient outcomes.

これまでに、尿酸と高血圧症との関係、尿酸と腎臓病との関係、尿酸と心血管疾患との関係、尿酸と心不全との関係について多くの研究がなされている。これらの疾患と尿酸との関係は明らかになっているが、尿酸降下薬の使用により予防できるかについては、高血圧症を除いては否定的である。しかし、高尿酸血症は痛風の原因となり、痛風発作が脳心血管イベントに影響することを考慮すると、高尿酸血症の治療を行うことは適切と考えられる。

IMPORTANCE: Global studies have reported that the incidence of Kawasaki disease (KD) declined during the COVID-19 pandemic. These studies suggest that the global pandemic and its accompanying mitigation measures may provide an important opportunity to explore the hypothesis of a KD pathogenesis. OBJECTIVE: To compare changes in KD incidence in Japan before and after the start of the COVID-19 pandemic. DESIGN, SETTING, AND PARTICIPANTS: This cohort study was conducted using the data set from Japan's 26th nationwide KD survey that obtained information on patients who were diagnosed with KD in Japan from January 1, 2019, through December 31, 2020. MAIN OUTCOMES AND MEASURES: Kawasaki disease incidence rates were calculated by referring to the national population data in the vital statistics data for Japan. RESULTS: A total of 28 520 patients were identified (16 236 male individuals [56.9%]; median [IQR] age, 26 [14-44] months). A total of 17 347 patients were diagnosed with KD in 2019 and 11 173 were diagnosed in 2020, representing a 35.6% reduction in the number of patients diagnosed in 2020 compared with the previous year. Patient distributions for days of illness at the first hospital visit were almost identical in 2019 and 2020, suggesting that the decrease in KD incidence likely was not associated with pandemic-related delays in seeking treatment. The proportion of patients diagnosed with KD who were younger than 12 months was significantly larger in 2020 than in 2019 (21.6% vs 19.4%; P < .001). Compared with KD incidence among younger patients, the incidence among those 24 months and older declined rapidly after initiation of COVID-19 special mitigation measures, with a greater percentage reduction (58.3% reduction in July), but rebounded faster after the end of the special mitigation period. By contrast, the incidence among patients younger than 12 months declined moderately after the initiation of the special mitigation period, with a lower percentage reduction (40.3% reduction in October), and rebounded at a later phase. CONCLUSIONS AND RELEVANCE: In this cohort study, the number of patients diagnosed with KD decreased by approximately one-third across Japan in 2020, with no indication that parents avoided a hospital visit. Differences in KD incidence reduction patterns before and after the initiation of COVID-19 pandemic mitigation measures were found in patients with KD aged younger than 12 months compared with those 24 months or older, suggesting a potential KD pathogenesis involving transmission among children.

Background Both renal hypouricemia (RHU) and gout are associated with renal dysfunction and urolithiasis. The difference in renal complications associated with RHU and gout, however, has not been studied. We characterized the urate metabolism and complications of patients with RHU and compared them with patients with gout. Methods Eighteen patients with RHU who had a serum uric acid (SUA) level <2 mg/dL (10 men and 8 women), 44 patients with gout (44 men) and 16 normouricemic patients (4 men and 12 women) were included. The blood and urinary biochemical data were evaluated. A genetic analysis of uric acid transporter 1 (URAT1) was also conducted in 15 cases with RHU. Results The SUA level of RHU was 0.9±0.5/mg/dl, and the Uur/Ucr and Cur/Ccr were 0.56%±0.14% and 45.7%±18.0%, respectively. A genetic analysis of URAT1 in 15 RHU patients showed that 13 harbored a URAT1 gene mutation, whereas 2 harbored the wild-type gene. The SUA level was significantly lower in RHU patients (n=11) than in either gout patients (n=44) or normouricemic patients (n=16). This reduction was accompanied by the elevation of Cua/Ccr. Urinary beta 2-microglobulin levels were higher in RHU patients than in gout or normouricemia patients. Cua/Ccr correlated with normalized urinary beta 2-microglobulin levels. The prevalence of urolithiasis was 18.2% in RHU cases and 6.8% in gout cases. A homozygous URAT1 mutation was associated with urolithiasis. Conclusion Besides urolithiasis, RHU can be associated with tubular dysfunction, such as elevated urinary beta 2-microglobulin levels.

Iatrogenic pseudoaneurysm is common vascular complications of angiographic procedures. Patients with uncomplicated pseudoaneurysms can be managed with ultrasound-guided techniques. However, for complicated pseudoaneurysms, surgical repair of the artery is mandatory. We report a case of successful repair of complicated pseudoaneurysm using an access-site closure device, Perclose ProGlide™ without a surgical approach.

No studies have assessed differences between the Japanese and Z score criteria in the echocardiographic detection sensitivity of coronary artery (CA) abnormalities using large-scale data containing samples from multiple facilities engaged in daily clinical practices of Kawasaki disease (KD). We analyzed data from the 25th Japanese nationwide KD survey, which identified 30,415 patients from 1357 hospitals throughout Japan during 2017-2018. Hospitals were classified according to their use of Z score criteria. We assessed differences in hospital and patient background factors and compared the prevalence of CA abnormalities among groups using the Z score criteria. Multivariable logistic regression analyses were performed to evaluate differences in the detection sensitivity for CA abnormalities. The Z score criteria were more likely to be utilized in larger hospitals with more pediatricians and cardiologists. Even after controlling for potential confounders, detection sensitivities by the Z score criteria were significantly higher than by the Japanese criteria in patients with CA dilatations (adjusted odds ratio (95% confidence interval) 1.77 (1.56-2.01)) and aneurysms (1.62 (1.17-2.24)). No significant difference was found in patients with giant CA aneurysms. Compared with the Japanese criteria, the Z score criteria were significantly more sensitive for detecting patients with CA dilatations regardless of age, and for those with CA aneurysms only in patients aged ≤ 1 year. Our results indicate that differences in the detection sensitivity for CA abnormalities between the Z score and the Japanese criteria were dependent on the CA size and patient age.

Steroid-sensitive nephrotic syndrome (SSNS) in childhood is usually due to minimal change disease (MCD). Unlike many glomerular conditions, SSNS/MCD is commonly precipitated by respiratory infections. Of interest, pulmonary inflammation releases surfactants in circulation which are soluble agonists of SIRPα, a podocyte receptor that regulates integrin signaling. Here, we characterized this pulmonary-renal connection in MCD and performed studies to determine its importance. Children with SSNS/MCD in relapse but not remission had elevated plasma surfactants and urinary SIRPα. Sera from relapsing subjects triggered podocyte SIRPα signaling via tyrosine phosphatase SHP-2 and nephrin dephosphorylation, a marker of podocyte activation. Further, addition of surfactants to MCD sera from patients in remission replicated these findings. Similarly, nasal instillation of toll-like receptor 3 and 4 agonists in mice resulted in elevated serum surfactants and their binding to glomeruli triggering proteinuria. Together, our data document a critical pulmonary-podocyte signaling pathway involving surfactants and SIRPα signaling in SSNS/MCD.

In 2021, 217 excellent manuscripts were published in Hypertension Research. Editorial teams greatly appreciate the authors' contribution to hypertension research progress. Here, our editorial members have summarized twelve topics from published work and discussed current topics in depth. We hope you enjoy our special feature, "Update on Hypertension Research in 2021".