Antimicrobial Prophylaxis With Ampicillin-sulbactam Compared With Cefazolin for Esophagectomy: Nationwide Inpatient Database Study in Japan.

OBJECTIVE: To assess the effect of antimicrobial prophylaxis with ampicillin-sulbactam (ABPC/SBT) compared with cefazolin (CEZ) on the short-term outcomes after esophagectomy. BACKGROUND: CEZ is widely used for antimicrobial prophylaxis in esophagectomy without procedure-specific evidence, whereas ABPC/SBT is preferred in some hospitals to target both aerobic and anaerobic oral bacteria. METHODS: Data of patients who underwent esophagectomy for cancer between July 2010 and March 2019 were extracted from a nationwide Japanese inpatient database. Overlap propensity score weighting was conducted to compare the short-term outcomes [including surgical site infection (SSI), anastomotic leakage, and respiratory failure] between antimicrobial prophylaxis with CEZ and ABPC/SBT after adjusting for potential confounders. Sensitivity analyses were also performed using propensity score matching and instrumental variable analyses. RESULTS: Among 17,772 eligible patients, 16,077 (90.5%) and 1695 (9.5%) patients were administered CEZ and ABPC/SBT, respectively. SSI, anastomotic leakage, and respiratory failure occurred in 2971 (16.7%), 2604 (14.7%), and 2754 patients (15.5%), respectively. After overlap weighting, ABPC/SBT was significantly associated with a reduction in SSI [odds ratio 0.51 (95% CI: 0.43-0.60)], anastomotic leakage [0.51 (0.43-0.61)], and respiratory failure [0.66 (0.57-0.77)]. ABPC/SBT was also associated with reduced respiratory complications, postoperative length of stay, and total hospitalization costs. The proportion of Clostridioides difficile colitis and noninfectious complications did not differ between the groups. Propensity score matching and instrumental variable analyses demonstrated equivalent results. CONCLUSIONS: The administration of ABPC/SBT as antimicrobial prophylaxis for esophagectomy was associated with better short-term postoperative outcomes compared with CEZ.

Impact of Body Mass Index on Major Complications, Multiple Complications, In-hospital Mortality, and Failure to Rescue After Esophagectomy for Esophageal Cancer: A Nationwide Inpatient Database Study in Japan.

OBJECTIVE: To examine the association of BMI with mortality and related outcomes after oncologic esophagectomy. SUMMARY BACKGROUND DATA: Previous studies showed that high BMI was a risk factor for anastomotic leakage and low BMI was a risk factor for respiratory complications after esophagectomy. However, the association between BMI and in-hospital mortality after oncologic esophagectomy remains unclear. METHODS: Data for patients who underwent esophagectomy for esophageal cancer between July 2010 and March 2019 were extracted from a Japanese nationwide inpatient database. Multivariate regression analyses and restricted cubic spline analyses were used to investigate the associations between BMI and short-term outcomes, adjusting for potential confounders. RESULTS: Among 39,406 eligible patients, in-hospital mortality, major complications, and multiple complications (≥2 major complications) occurred in 1069 (2.7%), 14,824 (37.6%), and 3621 (9.2%), respectively. Compared with normal weight (18.5-22.9 kg/m 2 ), severe underweight (<16.0 kg/m 2 ), mild/moderate underweight (16.0-18.4 kg/m 2 ), and obese (≥27.5 kg/m 2 )were significantly associated with higher in-hospital mortality [odds ratio 2.20 (95% confidence interval 1.65-2.94), 1.25 (1.01-1.49), and 1.48 (1.05-2.09), respectively]. BMI showed U-shaped dose-response associations with mortality, major complications, and multiple complications. BMI also showed a reverse J-shaped association with failure to rescue (death after major complications). CONCLUSIONS: Both high BMI and low BMI were associated with mortality, major complications and multiple complications after esophagectomy for esophageal cancer. Patients with low BMI were more likely to die once a major complication occurred. The present results can assist with risk stratification in patients undergoing oncologic esophagectomy.

Impact of Prophylactic Corticosteroid Use on In-hospital Mortality and Respiratory Failure After Esophagectomy for Esophageal Cancer: Nationwide Inpatient Data Study in Japan.

OBJECTIVE: To assess the effect of preoperative prophylactic corticosteroid use on short-term outcomes after oncologic esophagectomy. BACKGROUND: Previous studies have shown that prophylactic corticosteroid use may decrease the risk of respiratory failure following esophagectomy by attenuating the perioperative systemic inflammation response. However, its effectiveness has been controversial, and its impact on mortality remains unknown. METHODS: Data of patients who underwent oncologic esophagectomy between July 2010 and March 2019 were extracted from a Japanese nationwide inpatient database. Stabilized inverse probability of treatment weighting, propensity score matching, and instrumental variable analyses were performed to investigate the associations between prophylactic corticosteroid use and short-term outcomes, such as in-hospital mortality and respiratory failure, adjusting for potential confounders. RESULTS: Among 35,501 eligible patients, prophylactic corticosteroids were used in 22,620 (63.7%) patients. In-hospital mortality, respiratory failure, and severe respiratory failure occurred in 924 (2.6%), 5440 (15.3%), and 2861 (8.1%) patients, respectively. In stabilized inverse probability of treatment weighting analyses, corticosteroids were significantly associated with decreased in-hospital mortality [odds ratio (OR)=0.80; 95% confidence interval (CI): 0.69-0.93], respiratory failure (OR=0.84; 95% CI: 0.79-0.90), and severe respiratory failure (OR=0.87; 95% CI: 0.80-0.95). Corticosteroids were also associated with decreased postoperative length of stay and total hospitalization costs. The proportion of anastomotic leakage did not differ with the use of Propensity score matching and instrumental variable analysis demonstrated similar results. CONCLUSIONS: Prophylactic corticosteroid use in oncologic esophagectomy was associated with lower in-hospital mortality as well as decreased respiratory failure and severe respiratory failure, suggesting a potential benefit for preoperative corticosteroid use in esophagectomy.

Early postoperative non-steroidal anti-inflammatory drugs and anastomotic leakage after oesophagectomy.

BACKGROUND: Previous studies have suggested that postoperative non-steroidal anti-inflammatory drug (NSAID) use may increase the risk of anastomotic leakage after colorectal surgery. However, the association between NSAIDs and anastomotic leakage after oesophagectomy is unclear. The aim of this retrospective study was to assess the effect of early postoperative NSAID use on anastomotic leakage after oesophagectomy. METHODS: The Data of patients who underwent oesophagectomy for cancer between July 2010 and March 2019 were extracted from a Japanese nationwide inpatient database. Stabilized inverse probability of treatment weighting (IPTW), propensity score matching, and instrumental variable analyses were performed to investigate the association between NSAID use in the early postoperative period (defined as the day of and the day after surgery) and short-term outcomes, adjusting for potential confounders. The primary outcome was anastomotic leakage. The secondary outcomes were acute kidney injury, gastrointestinal bleeding, and mortality. RESULTS: Among 39 418 eligible patients, early postoperative NSAIDs were used by 16 211 individuals (41 per cent). Anastomotic leakage occurred in 5729 patients (15 per cent). In stabilized IPTW analyses, NSAIDs were not associated with anastomotic leakage (odds ratio 1.04, 95 per cent c.i. 0.97 to 1.10). The proportions of acute kidney injury and gastrointestinal bleeding, as well as 30-day mortality and in-hospital mortality, did not differ according to NSAID use. Propensity score matching and instrumental variable analyses demonstrated similar results. CONCLUSION: Early postoperative NSAID use was not associated with anastomotic leakage or other complications in patients who underwent oesophagectomy.

Usefulness of the predicted percentage ventilatory efficiency for carbon dioxide output during exercise in patients with chronic heart failure.

The ventilatory efficiency for carbon dioxide output ([Formula: see text]CO2) during exercise, as measured by the minute ventilation vs. [Formula: see text]CO2 slope ([Formula: see text]E vs. [Formula: see text]CO2 slope), is a powerful prognostic index in patients with chronic heart failure (CHF). This measurement is higher in women than in men, and it increases with age. This study aimed to investigate the usefulness of the predicted value of the percentage [Formula: see text]E vs. [Formula: see text]CO2 slope (%[Formula: see text]E vs. [Formula: see text]CO2 slope) as a prognostic index in patients with CHF. A total of 320 patients with CHF and a left ventricular ejection fraction (LVEF) < 45% (male, 85.6%; mean age, 64.6 years) who underwent symptom-limited cardiopulmonary exercise tests using a cycle ergometer were included in the study. The %[Formula: see text]E vs. [Formula: see text]CO2 was calculated using predictive formulae based on age and sex. Cardiovascular-related death was defined as the primary endpoint. The mean follow-up duration was 7.5 ± 3.3 years. Of 101 patients who died during the study period, 75 experienced cardiovascular-related deaths. The average [Formula: see text]E vs. [Formula: see text]CO2 slope was 32.8 ± 8.0, and the average %[Formula: see text]E vs. [Formula: see text]CO2 slope was 119.6 ± 28.2%. The cumulative incidence of cardiovascular-related death after 10 years of follow-up were 44.7% (95% CI 34.4-54.6%) in patients with %[Formula: see text]E vs. [Formula: see text]CO2 slope > 120 and 15.0% (95% CI 9.4-21.8%) in patients with %[Formula: see text]E vs. [Formula: see text]CO2 slope ≤ 120. The multivariate Cox regression analysis indicated that a %[Formula: see text]E vs. [Formula: see text]CO2 slope > 120 was an independent predictor of cardiovascular-related death (adjusted hazard ratio, 3.24; 95% confidence interval 1.65-6.67; p < 0.01). The %[Formula: see text]E vs. [Formula: see text]CO2 slope can be used for risk stratification in patients with CHF and an LVEF < 45%.

Association of Blood Pressure Classification Using the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline With Risk of Heart Failure and Atrial Fibrillation.

BACKGROUND: Heart failure (HF) and atrial fibrillation (AF) are growing in prevalence worldwide. Few studies have assessed to what extent stage 1 hypertension in the 2017 American College of Cardiology/American Heart Association blood pressure (BP) guidelines is associated with incident HF and AF. METHODS: Analyses were conducted with a nationwide health claims database collected in the JMDC Claims Database between 2005 and 2018 (n=2 196 437; mean age, 44.0±10.9 years; 58.4% men). No participants were taking antihypertensive medication or had a known history of cardiovascular disease. Each participant was categorized as having normal BP (systolic BP <120 mm Hg and diastolic BP <80 mm Hg; n=1 155 885), elevated BP (systolic BP 120-129 mm Hg and diastolic BP <80 mm Hg; n=337 390), stage 1 hypertension (systolic BP 130-139 mm Hg or diastolic BP 80-89 mm Hg; n=459 820), or stage 2 hypertension (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg; n=243 342). Using Cox proportional hazards models, we identified associations between BP groups and HF/AF events. We also calculated the population attributable fractions to estimate the proportion of HF and AF events that would be preventable if participants with stage 1 and stage 2 hypertension were to have normal BP. RESULTS: Over a mean follow-up of 1112±854 days, 28 056 incident HF and 7774 incident AF events occurred. After multivariable adjustment, hazard ratios for HF and AF events were 1.10 (95% CI, 1.05-1.15) and 1.07 (95% CI, 0.99-1.17), respectively, for elevated BP; 1.30 (95% CI, 1.26-1.35) and 1.21 (95% CI, 1.13-1.29), respectively, for stage 1 hypertension; and 2.05 (95% CI, 1.97-2.13) and 1.52 (95% CI, 1.41-1.64), respectively, for stage 2 hypertension versus normal BP. Population attributable fractions for HF associated with stage 1 and stage 2 hypertension were 23.2% (95% CI, 20.3%-26.0%) and 51.2% (95% CI, 49.2%-53.1%), respectively. The population attributable fractions for AF associated with stage 1 and stage 2 hypertension were 17.4% (95% CI, 11.5%-22.9%) and 34.3% (95% CI, 29.1%-39.2%), respectively. CONCLUSIONS: Both stage 1 hypertension and stage 2 hypertension were associated with a greater incidence of HF and AF in the general population. The American College of Cardiology/American Heart Association BP classification system may help identify adults at higher risk for HF and AF events.

Glycemic status and the association of change in blood pressure with incident cardiovascular disease.

BACKGROUND: The clinical benefit of blood pressure (BP) reduction in individuals with diabetes has not been fully elucidated. We sought to identify the clinical impact of BP reduction on incident cardiovascular disease in people having diabetes and hypertension. METHODS: We conducted a retrospective cohort study including 754,677 individuals (median age 47 years, 75.8 % men) with stage 1/stage 2 hypertension. Participants were categorized using fasting plasma glucose (FPG) at baseline as normal FPG (FPG < 100 mg/dL) (n = 517,372), prediabetes (FPG:100-125 mg/dL) (n = 197,836), or diabetes mellitus (FPG ≥126 mg/dL) (n = 39,469). The primary outcome was heart failure (HF), and the secondary outcomes included ischemic heart disease (IHD) including myocardial infarction and angina pectoris, and stroke. RESULTS: Over a mean follow-up of 1111 ± 909 days, 18,429 HFs, 17,058 IHDs, and 8,795 strokes were recorded. Reduction in BP of< 120/80 mmHg at 1year was associated with a lower risk of developing HF (HR:0.77, 95% CI:0.72-0.82), IHD (HR:0.84, 95% CI:0.79-0.89), and stroke (HR:0.75, 95% CI:0.69-0.82) in individuals with normal FPG, whereas it was not associated with a risk of developing HF (HR:0.98, 95% CI:0.81-1.17) and stroke (HR:0.82, 95% CI:0.62-1.09) in those with DM. Interaction analyses showed that the influence of BP reduction on incident HF was attenuated with people with prediabetes or DM. A multitude of sensitivity analyses confirmed our results. CONCLUSIONS: The association of BP reduction with the risk of developing HF was attenuated with deteriorating glucose tolerance. The optimal management strategy for hypertensive people with prediabetes or DM for the prevention of developing cardiovascular disease (particularly HF) is needed to be established.

Short-Term Outcomes of Epidural Analgesia in Minimally Invasive Esophagectomy for Esophageal Cancer: Nationwide Inpatient Data Study in Japan.

BACKGROUND: Studies have shown that epidural analgesia (EDA) is associated with a decreased risk of pneumonia and anastomotic leakage after esophagectomy, and several guidelines strongly recommend EDA use after esophagectomy. However, the benefit of EDA use in minimally invasive esophagectomy (MIE) remains unclear. OBJECTIVE: The aim of this retrospective study was to compare the short-term outcomes between patients with and without EDA undergoing MIE for esophageal cancer. METHODS: Data of patients who underwent oncologic MIE (April 2014-March 2019) were extracted from a Japanese nationwide inpatient database. Stabilized inverse probability of treatment weighting (IPTW), propensity score matching, and instrumental variable analyses were performed to investigate the associations between EDA use and short-term outcomes, adjusting for potential confounders. RESULTS: Among 12,688 eligible patients, EDA was used in 9954 (78.5%) patients. In-hospital mortality, respiratory complications, and anastomotic leakage occurred in 230 (1.8%), 2139 (16.9%), and 1557 (12.3%) patients, respectively. In stabilized IPTW, EDA use was significantly associated with decreased in-hospital mortality (odds ratio [OR] 0.46 [95% confidence interval 0.34-0.61]), respiratory complications (OR 0.74 [0.66-0.84]), and anastomotic leakage (OR 0.77 [0.67-0.88]). EDA use was also associated with decreased prolonged mechanical ventilation, unplanned intubation, nonsteroidal anti-inflammatory drug use, acetaminophen use, postoperative length of stay, and total hospitalization costs and increased vasopressor use. One-to-three propensity score matching and instrumental variable analyses demonstrated equivalent results. CONCLUSIONS: EDA use in oncologic MIE was associated with low in-hospital mortality as well as decreased respiratory complications, and anastomotic leakage, suggesting the potential advantage of EDA use in MIE.

Comparison of cardiovascular outcomes between SGLT2 inhibitors in diabetes mellitus.

BACKGROUND: There have been scarce data comparing cardiovascular outcomes between individual sodium-glucose cotransporter-2 (SGLT2) inhibitors. We aimed to compare the subsequent cardiovascular risk between individual SGLT2 inhibitors. METHODS: We analyzed 25,315 patients with diabetes mellitus (DM) newly taking SGLT2 inhibitors (empagliflozin: 5302, dapagliflozin: 4681, canagliflozin: 4411, other SGLT2 inhibitors: 10,921). We compared the risks of developing heart failure (HF), myocardial infarction (MI), angina pectoris (AP), stroke, and atrial fibrillation (AF) between individual SGLT2 inhibitors. RESULTS: Median age was 52 years, and 82.5% were men. The median fasting plasma glucose and HbA1c levels were 149 (Q1-Q3:127-182) mg/dL and 7.5 (Q1-Q3:6.9-8.6) %. During a mean follow-up of 814 ± 591 days, 855 HF, 143 MI, 815 AP, 340 stroke, and 139 AF events were recorded. Compared with empagliflozin, the risk of developing HF, MI, AP, stroke, and AF was not significantly different in dapagliflozin, canagliflozin, and other SGLT inhibitors. For developing HF, compared with empagliflozin, hazard ratios of dapagliflozin, canagliflozin, and other SGLT2 inhibitors were 1.02 (95% confidence interval [CI] 0.81-1.27), 1.08 (95% CI 0.87-1.35), and 0.88 (95% CI 0.73-1.07), respectively. Wald tests showed that there was no significant difference in the risk of developing HF, MI, AP, stroke, and AF among individual SGLT2 inhibitors. We confirmed the robustness of these results through a multitude of sensitivity analyses. CONCLUSION: The risks for subsequent development of HF, MI, AP, stroke, and AF were comparable between individual SGLT2 inhibitors. This is the first study comparing the wide-range cardiovascular outcomes of patients with DM treated with individual SGLT2 inhibitors using large-scale real-world data.

Threshold of BMI for the Development of Hypertension among Japanese Adults.

BACKGROUND: The optimal value of BMI for the development of hypertension and the influence of BMI on the development of stage 1 or stage 2 hypertension remain unclear. OBJECTIVES: We sought to identify the BMI threshold for the prevention of hypertension and how changes in BMI would influence the risk of developing hypertension. METHODS: We analyzed 1,262,356 participants (median age: 43 y; 50.9% men) with normal blood pressure [BP; systolic BP (SBP) <120 mmHg and diastolic BP (DBP) <80 mmHg] or elevated BP (SBP: 120-129 mmHg and DBP <80 mmHg). The primary outcome was stage 1 (SBP 130-139 mmHg or DBP 80-89 mmHg) or stage 2 hypertension (SBP ≥140 mmHg or DBP ≥90 mmHg). We analyzed the relation between baseline BMI, change in BMI, and the risk of developing hypertension using generalized additive models with a smoothing spline. RESULTS: During the median follow-up of 851 d, 341,212 cases of stage 1 hypertension and 70,968 cases of stage 2 hypertension were detected. The risk of developing stage 1 or stage 2 hypertension increased steeply after BMI (kg/m2) exceeded 20. The annual change in BMI was positively correlated with the risk of developing stage 1 or 2 hypertension. Contour mapping using generalized additive models demonstrated an additive increase in the risk of developing hypertension with higher baseline BMI and increases in BMI over 1 y. Body-weight gain increases the risk of developing hypertension even in underweight or normal-weight individuals based on the WHO classification. CONCLUSIONS: In Japanese adults with normal or elevated BP, the risk of developing hypertension increased with BMI when baseline BMI was >20. Body-weight gain additively interacted with baseline BMI during hypertension development. Our results underscore the importance of maintaining body weight in preventing the development of hypertension.

Impact of Glucose Tolerance and Its Change on Incident Proteinuria: Analysis of a Nationwide Population-Based Dataset.

INTRODUCTION: Although diabetes mellitus (DM) increases the risk of proteinuria, the relationship between prediabetes and proteinuria remains not fully understood. Further, whether the change in glucose is associated with the risk for proteinuria is unknown. METHODS: This was a retrospective cohort study that included 1,849,074 participants (median age, 45 years; 59.3% men). No participants were taking glucose-lowering medications, and none had positive proteinuria at the initial health check-up. Each participant was categorized into three groups: normal (hemoglobin A1c [HbA1c] of <5.7%, n = 1,563,121), prediabetes (HbA1c of 5.7-6.4%, n = 253,490), and DM (HbA1c of ≥6.5%, n = 32,463) groups. We investigated the association between each HbA1c category and incident proteinuria using Cox proportional hazards models. We analyzed the association between the annual change in HbA1c and the risk for proteinuria. RESULTS: A total of 65,954 participants developed proteinuria during the observation period. Not only DM (hazard ratio [HR]: 2.15, 95% confidence interval [CI]: 2.07-2.24) but also prediabetes (HR: 1.14, 95% CI: 1.12-1.17) was associated with a greater risk for proteinuria. The relative risk reduction for proteinuria that was associated with prediabetes and DM was 12.3% and 53.5%, respectively. An annual increase in HbA1c was associated with a greater risk for proteinuria. This association was more pronounced in participants having prediabetes. CONCLUSION: Not only DM but also prediabetes increased the risk for proteinuria. The influence of change in HbA1c on incident proteinuria was pronounced in people with prediabetes. Optimizing glucose would provide more benefit to individuals having prediabetes for proteinuria prevention.

Change in Cardiovascular Health Metrics and Risk for Proteinuria Development: Analysis of a Nationwide Population-Based Database.

INTRODUCTION: Evidence is lacking regarding the association between cardiovascular health (CVH) metrics and the risk for proteinuria. METHODS: We performed this observational cohort study including 865,087 participants (median age, 46 years, 60.7% men) with negative proteinuria at the initial health check-up, who underwent repeated health check-ups within 4 years. Ideal CVH metrics included nonsmoking, body mass index <25 kg/m2, physical activity at goal, eating breakfast, blood pressure <120/80 mm Hg, fasting plasma glucose <100 mg/dL, and total cholesterol <200 mg/dL. The primary outcome was incident proteinuria, defined as ≥1 + on the urine dipstick test. RESULTS: Participants were categorized as having low CVH metrics defined as having 0-2 ideal CVH metrics (n = 84,439), middle CVH metrics defined as having 3-4 ideal CVH metrics (n = 335,773), and high CVH metrics defined as having 5-7 ideal CVH metrics (n = 444,875). Compared with low CVH metrics, middle CVH metrics (odds ratio (OR): 0.61, 95% CI: 0.59-0.63) and high CVH metrics (OR: 0.45, 95% CI: 0.43-0.46) were associated with a lower risk of proteinuria. The OR of a one-point increase in the ideal number of CVH metrics was 0.83 (95% CI: 0.82-0.83). All CVH metrics components except for ideal total cholesterol were associated with a decreased risk of proteinuria. A one-point improvement in the number of ideal CVH metrics at 1 year after the initial health check-up was associated with a decreased incidence of proteinuria (OR: 0.90, 95% CI: 0.89-0.92). CONCLUSION: Not only maintaining better CVH metrics but also improving CVH metrics would prevent developing proteinuria in a general population.

Semiquantitative assessed proteinuria and risk of heart failure: analysis of a nationwide epidemiological database.

BACKGROUND: Heart failure (HF) is increasing in prevalence worldwide. We explored whether adults with trace and positive proteinuria were at a high risk for incident HF compared with those with negative proteinuria using a nationwide epidemiological database. METHODS: This is an observational cohort study using the JMDC Claims Database collected between 2005 and 2020. This is a population-based sample [n = 1 021 943; median age 44 years (interquartile range 37-52); 54.8% men]. No participants had a known history of cardiovascular disease (CVD). Each participant was categorized into three groups according to the urine dipstick test results: negative proteinuria (n = 902 273), trace proteinuria (n = 89 599) and positive proteinuria (≥1+; n = 30 071). The primary outcome was HF. The secondary outcomes were myocardial infarction (MI), stroke and atrial fibrillation (AF). We performed multivariable Cox regression analyses to identify the association between the proteinuria category and incident HF and other CVD events. RESULTS: Over a mean follow-up of 1150 ± 920 days, 17 182 incident HF events occurred. After multivariable adjustment, hazard ratios for HF events were 1.09 [95% confidence interval (CI) 1.03-1.15] and 1.59 (95% CI 1.49-1.70) for trace proteinuria and positive proteinuria versus negative proteinuria, respectively. This association was present irrespective of clinical characteristics. A stepwise increase in the risk of MI, stroke and AF with proteinuria category was also observed. Our primary results were confirmed in participants after multiple imputations for missing values and in those having no medications for hypertension, diabetes mellitus and dyslipidemia. The discriminative predictive value for HF events improved by adding the results of urine dipstick tests to traditional risk factors [net reclassification improvement 0.0497 (95% CI 0.0346-0.0648); P < 0.001]. CONCLUSIONS: Not only positive proteinuria, but also trace proteinuria was associated with a greater incidence of HF in the general population. Semiquantitative assessment of proteinuria would be informative for the risk stratification of HF.

Metabolically Healthy Obesity and the Risk of Cardiovascular Disease in the General Population　- Analysis of a Nationwide Epidemiological Database.

BACKGROUND: Obesity and metabolic disorders frequently coexist, and both are established risk factors for cardiovascular disease (CVD). Although the phenotype of obesity without metabolic disorders, referred to as metabolically healthy obesity (MHO), is attracting clinical interest, the pathophysiological impact of MHO remains unclear.Methods and Results:Using the Japan Medical Data Center database, we studied 802,288 subjects aged ≥20 years without any metabolic disorders or a prior history of CVD. MHO, defined as obesity (body mass index ≥25 kg/m2) with no metabolic disorders, was observed in 9.8% of the study population. The subjects' mean (±SD) age was 42.8±9.4 years and 44.7% were men. The mean follow-up period was 1,126±849 days. Multivariable Cox regression analysis showed that MHO alone did not significantly increase the risk of any CVD. However, abdominal obesity alone increased the risk of heart failure and atrial fibrillation. Moreover, the coexistence of MHO and abdominal obesity increased the risk of myocardial infarction, angina pectoris, heart failure, and atrial fibrillation. The incidence of stroke was not associated with the presence of MHO and abdominal obesity. CONCLUSIONS: Among individuals with no metabolic disorders, MHO alone did not significantly increase the subsequent CVD risk. However, individuals with comorbid MHO and abdominal obesity had a higher risk of myocardial infarction, angina pectoris, heart failure, and atrial fibrillation, suggesting the prognostic importance of abdominal obesity in subjects with MHO.

Impact of hospital volume on clinical outcomes of hospitalized heart failure patients: analysis of a nationwide database including 447,818 patients with heart failure.

BACKGROUND: Hospital volume is known to be associated with outcomes of patients requiring complicated medical care. However, the relationship between hospital volume and prognosis of hospitalized patients with heart failure (HF) remains not fully understood. We aimed to clarify the impact of hospital volume on clinical outcomes of hospitalized HF patients using a nationwide inpatient database. METHODS AND RESULTS: We studied 447,818 hospitalized HF patients who were admitted from January 2010 and discharged until March 2018 included in the Japanese Diagnosis Procedure Combination database. According to the number of patients, patients were categorized into three groups; those treated in low-, medium-, and high-volume centers. The median age was 81 years and 238,192 patients (53%) were men. Patients who had New York Heart Association class IV symptom and requiring inotropic agent within two days were more common in high volume centers than in low volume centers. Respiratory support, hemodialysis, and intra-aortic balloon pumping were more frequently performed in high volume centers. As a result, length of hospital stay was shorter, and in-hospital mortality was lower in high volume centers. Lower in-hospital mortality was associated with higher hospital volume. Multivariable logistic regression analysis fitted with generalized estimating equation indicated that medium-volume group (Odds ratio 0.91, p = 0.035) and high-volume group (Odds ratio 0.86, p = 0.004) had lower in-hospital mortality compared to the low-volume group. Subgroup analysis showed that this association between hospital volume and in-hospital mortality among overall population was seen in all subgroups according to age, presence of chronic renal failure, and New York Heart Association class. CONCLUSION: Hospital volume was independently associated with ameliorated clinical outcomes of hospitalized patients with HF.

Reverse J-shaped relationship between body mass index and in-hospital mortality of patients hospitalized for heart failure in Japan.

Several lines of evidence demonstrated body mass index (BMI) to be inversely associated with outcomes of patients with HF, so-called obesity paradox. However, the relationship between BMI and outcomes of patients with HF in Japan has been poorly understood. This study sought to explore the relationship between BMI and in-hospital mortality of patients hospitalized for heart failure (HF) in Japan and whether BMI at hospital admission could be used for the risk stratification of hospitalized HF patients. We studied 407,722 patients hospitalized for HF between January 2010 and March 2018, using the Diagnosis Procedure Combination database, a national inpatient database in Japan. Patients were categorized into four groups: underweight (BMI < 18.5 kg/m2), 66,342 patients (16.3%); normal (18.5-24.9 kg/m2), 240,801 patients (59.1%); pre-obesity (25.0-29.9 kg/m2), 76,954 patients (18.9%); and obesity (≥ 30.0 kg/m2), 23,625 patients (5.8%). Pre-obese and obese patients were younger and more likely to be male. Advanced HF symptoms were more common among underweight patients. Multivariable logistic regression analysis fitted with generalized estimating equation showed that, compared with normal weight patients underweight patients had higher in-hospital mortality (odds ratio 1.50, 95% confidence interval 1.45-1.55), whereas pre-obese patients (odds ratio 0.80, 95% confidence interval 0.77-0.83) and obese patients (odds ratio 0.90, 95% confidence interval 0.84-0.97) had lower in-hospital mortality. Restricted cubic spline showed a reverse J-shaped relationship between BMI and in-hospital mortality with the bottoms of splines around BMI 26 kg/m2. In conclusion, underweight patients had higher, and pre-obese and obese patients had lower in-hospital mortality compared to patients with normal weight patients. Furthermore, restricted cubic spline indicated a reverse J-shaped relationship between BMI and in-hospital mortality. Our findings are informative for the risk stratification of patients hospitalized for HF according to BMI.

Possible Gender Difference in the Association Between Abdominal Obesity, Chronic Inflammation, and Preclinical Atherosclerosis in the General Population.

Chronic inflammation due to abdominal obesity plays a major role in the development of cardiovascular disease (CVD). Gender differences are well characterized in the development of CVD; however, in the association among abdominal obesity, chronic inflammation, and preclinical atherosclerosis, gender differences in the general population remain to be clarified. We retrospectively analyzed 1,163 subjects who underwent voluntary health checkups at our institute. We defined carotid artery plaque formation as carotid intima-media thickness ≥ 1.1 mm. Multiple regression analysis showed that waist circumference was a major independent predictor of increase in serum C-reactive protein (CRP) level in both men and women. Serum CRP level was significantly increased in men with carotid artery plaque formation, but not in women. Multivariable logistic regression analysis demonstrated that serum CRP level, as well as age and hypertension, was independently associated with carotid artery plaque formation only in men. This result may suggest a potential of gender-specific difference in the association between serum CRP level and the prevalence of carotid artery plaque formation. Further investigations are required to confirm our results and to clarify the underlying mechanism.

Percutaneous Mitral Valve Intervention Using MitraClip for Functional Mitral Regurgitation and Heart Failure.

Functional mitral regurgitation (FMR) frequently coexists with left ventricular systolic dysfunction and advanced heart failure, and typically has poor clinical outcomes. Although various therapeutic options including cardiac resynchronization therapy and surgical mitral intervention, have been proposed, an optimal treatment strategy for functional mitral regurgitation has not yet been established. Over the last decade, transcatheter mitral valve repair using MitraClip has emerged as a novel alternative therapeutic option for functional mitral regurgitation. In 2018, the COAPT trial demonstrated that MitraClip treatment reduced rehospitalization due to heart failure and all-cause death in patients with functional mitral regurgitation and heart failure. As a consequence, the MitraClip has become a very promising potential treatment for functional mitral regurgitation. In this review, we discuss and summarize the current status and future perspectives of the treatment for functional mitral regurgitation and heart failure.

Association of Cancer With Outcomes in Patients Hospitalized for Heart Failure.

BACKGROUND: The complex clinical status of heart failure (HF) patients with concomitant cancer is gaining clinical interest. This study sought to explore the prevalence of cancer in patients with HF and its effect on outcomes using a nationwide inpatient database.Methods and Results:In total, 447,818 HF patients who were admitted and discharged between January 2010 and March 2018 were studied and included in the Diagnosis Procedure Combination (DPC) database. The median age was 81 years; 238,192 patients (53.2%) were men and 25,951 (5.8%) had concomitant cancer. The prevalence of cancer peaked in patients aged in their 70 s and 80 s and increased with time. Patients with cancer were older and more likely to be male. Cigarette smoking was more common in patients with cancer. Patients with cancer more frequently had infectious complications during hospitalization. Advanced medical procedures were less frequently performed for patients with cancer. In-hospital mortality was higher in patients with cancer than those without (10.0% vs. 6.7%, P<0.001). Among patients with cancer, in-hospital mortality was higher in patients with metastasis than those without (18.9% vs. 9.4%, P<0.001). Multivariable logistic regression analysis, fitted with a generalized estimating equation, indicated cancer is associated with higher in-hospital mortality (odds ratio 1.51, 95% confidential interval 1.43-1.59, P<0.001). CONCLUSIONS: Cancer was frequently observed in patients hospitalized for worsened HF, and its prevalence increased with time. The presence of cancer increased the risk of in-hospital death. Further studies are warranted to establish the optimal management strategy for HF patients with cancer in the field of cardio-oncology.

Effect of cigarette smoking on carotid artery atherosclerosis: a community-based cohort study.

Cigarette smoking is closely associated with the development of cardiovascular diseases. However, the relationship between cigarette smoking and subclinical atherosclerosis has not been fully studied. We sought to clarify the association between cigarette smoking and carotid intima-media thickness (cIMT) in a general Japanese population. Among 1,209 participants who received a medical check-up with cardiovascular examination at our institution, 450 participants (37.2%) were smokers (including both past and current smokers). We evaluated cIMT as a marker of subclinical atherosclerosis. The value of cIMT and rate of carotid plaque defined as IMT ≥ 1.1 mm did not differ between smokers and never smokers. However, the rate of carotid high-risk atheroma, defined as carotid artery atheroma including hypoechoic dominant and ulceration, was significantly higher among smokers than never smokers (30.4%, vs 23.6%, p = 0.009). Even after adjustment for covariates, cigarette smoking was independently associated with high-risk atheroma formation (odds ratio 1.384, 95% CI 1.019-1.880; p = 0.038). The value of cIMT and the rate of high-risk atheroma were significantly higher in smokers than never smokers in the subgroup of participants aged ≥ 60 years, whereas the rate of high-risk atheroma only was higher in smokers than never smokers in the subgroup of participants aged < 60 years. In conclusion, the development of high-risk carotid artery atheroma may precede the thickening of cIMT in cigarette smokers, which suggests the novel insight for the pathological mechanism underlying cardiovascular events and cigarette smoking.