Dipeptidyl peptidase-4 inhibitors reduce the incidence of first cardiovascular events in Japanese diabetic patients.

BACKGROUND: Dipeptidyl Peptidase-4 (DPP-4) inhibitors do not suppress cardiovascular events in diabetic patients with a history of cardiovascular disease. However, the effect of DPP-4 inhibitors on cardiovascular events in Japanese diabetic patients is unclear. Therefore, we investigated whether DPP-4 inhibitors alter the incidence of cardiovascular events in Japanese diabetic patients without a history of cardiovascular events. METHODS: The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial was a multicenter, prospective, randomized, open label, blinded, end-point study conducted from 2002 to 2008. After completion of the JPAD trial, we followed up the patients until 2019. Patients who had had a cardiovascular event by the 2013 follow-up were excluded from the study. JPAD patients were divided into a DPP-4 group and a non-DPP-4 group based on whether they were taking DPP-4 inhibitors at the 2013 follow-up because few patients took DPP-4 inhibitors before 2013. We investigated the incidence of cardiovascular events consisting of coronary events, cerebrovascular events, heart failure requiring hospitalization, and aortic and peripheral vascular disease in 1099 JPAD patients until 2019. RESULTS: During the observation period from 2013 to 2019, 37 (7%) first cardiovascular events occurred in the DPP-4 group (n = 518) and 66 (11%) in the non-DPP-4 group (n = 581). The incidence of cardiovascular events was significantly lower in the DPP-4 group than in the non-DPP-4 group (Log-Rank P = 0.0065). Cox proportional hazards model analysis revealed that the use of DPP-4 inhibitors (hazard ratio 0.65; 95% confidence interval 0.43-0.98; P = 0.038) was an independent factor after adjustment for age ≥ 65 years, hypertension, statin usage, and insulin usage. CONCLUSIONS: Our findings have demonstrated that the use of DPP-4 inhibitors may be associated with a reduced incidence of first cardiovascular events in Japanese diabetic patients. The results require confirmation in randomized controlled trials.

Centrilobular Emphysema Is Associated with Pectoralis Muscle Reduction in Current Smokers without Airflow Limitation.

BACKGROUND: Physiological and prognostic associations of centrilobular emphysema (CLE) and paraseptal emphysema (PSE) in smokers with and without chronic obstructive pulmonary disease (COPD) have been increasingly recognized, but the associations with extrapulmonary abnormalities, such as muscle wasting, osteoporosis, and cardiovascular diseases, remain unestablished. OBJECTIVES: The aim of the study was to investigate whether CLE was associated with extrapulmonary abnormalities independent of concomitant PSE in smokers without airflow limitation. METHODS: This retrospective study consecutively enrolled current smokers without airflow limitation who underwent lung cancer screening with computed tomography and spirometry. CLE and PSE were visually identified based on the Fleischner Society classification system. Cross-sectional areas of pectoralis muscles (PM) and adjacent subcutaneous adipose tissue (SAT), bone mineral density (BMD), and coronary artery calcification (CAC) were evaluated. RESULTS: Of 310 current smokers without airflow limitation, 83 (26.8%) had CLE. The PSE prevalence was higher (67.5% vs. 23.3%), and PM area, SAT area, and BMD were lower in smokers with CLE than in those without (PM area (mean), 34.5 versus 38.6 cm2; SAT area (mean), 29.3 versus 36.8 cm2; BMD (mean), 158.3 versus 178.4 Hounsfield unit), while CAC presence did not differ. In multivariable models, CLE was associated with lower PM area but not with SAT area or BMD, after adjusting for PSE presence, demographics, and forced expiratory volume in 1 s. CONCLUSIONS: The observed association between CLE and lower PM area suggests that susceptibility to skeletal muscle loss could be high in smokers with CLE even without COPD.

Kidney function deterioration is dependent on blood pressure levels: 11.2 year follow-up in diabetic patients.

There is little evidence of how blood pressure level over 10 years affects the decline of estimated glomerular filtration rate (eGFR) in diabetic patients. The Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial was a multicenter, randomized, clinical trial done from 2002 to 2008. After completion of the JPAD trial, we followed up the patients until 2019 as a cohort study. We defined late-stage kidney disease (LSKD) as eGFR < 30 ml/min/1.73 m2 or hemodialysis. Based on the mean value of systolic blood pressure (SBP) obtained average 7 times during the follow-up, we divided the patients into three groups: a high SBP group (n = 607, SBP ≥ 140 mm Hg); a moderate SBP group (n = 989, 140 > SBP ≥ 130 mm Hg); or a low SBP group (n = 913, SBP < 130 mm Hg). There was no significant deference in the mean eGFR among the high SBP, moderate SBP and low SBP groups on registration. The incidence rate of LSKD was significantly higher in the high SBP (HR 2.02, 95% CI 1.36-3.01) and moderate SBP (HR 1.54, 95% CI 1.07-2.20) groups than in the low SBP group (Log-Rank P = 0.0018). Cox proportional hazards model analysis revealed that the high SBP (HR, 1.57, P = 0.049) and moderate SBP (HR, 1.52, P = 0.037) were independent factors after adjustment for proteinuria ≥ ± , age ≥ 65 years, men, body mass index ≥ 24 kg/m2, duration of diabetes ≥ 7.0 years, statin usage, eGFR ≥ 60 ml/min/1.73 m2, hemoglobin A1c ≥ 7.2%, and smoking status. Our 11.2 year follow-up study demonstrated that mean SBP was independently associated with the progression to LSKD in diabetic patients. These findings may become new evidence that SBP less than 130 mm Hg is recommended for diabetic patients to prevent progression to LSKD.

Association Between Statins and Cancer Incidence in Diabetes: a Cohort Study of Japanese Patients with Type 2 Diabetes.

BACKGROUND: The antitumor effect of statins has been highlighted, but clinical study results remain inconclusive. While patients with diabetes are at high risk of cancer, it is uncertain whether statins are effective for cancer chemoprevention in this population. OBJECTIVE: This study evaluated the association between statins and cancer incidence/mortality in patients with type 2 diabetes. DESIGN: This study was a follow-up observational study of the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, which was a randomized controlled trial of low-dose aspirin in Japanese patients with type 2 diabetes. PARTICIPANTS: This study enrolled 2536 patients with type 2 diabetes, age 30-85 years, and no history of atherosclerotic cardiovascular disease, from December 2002 until May 2005. All participants recruited in the JPAD trial were followed until the day of any fatal event or July 2015. We defined participants taking any statin at enrollment as the statin group (n = 650) and the remainder as the no-statin group (n = 1886). MAIN MEASURES: The primary end point was the first occurrence of any cancer (cancer incidence). The secondary end point was death from any cancer (cancer mortality). KEY RESULTS: During follow-up (median, 10.7 years), 318 participants developed a new cancer and 123 died as a result. Cancer incidence and mortality were 10.5 and 3.7 per 1000 person-years in the statin group, and 16.8 and 6.3 per 1000 person-years in the no-statin group, respectively. Statin use was associated with significantly reduced cancer incidence and mortality after adjustment for confounding factors (cancer incidence: adjusted hazard ratio [HR], 0.67; 95% CI, 0.49-0.90, P = 0.007; cancer mortality: adjusted HR, 0.60; 95% CI, 0.36-0.98, P = 0.04). CONCLUSIONS: Statin use was associated with a reduced incidence and mortality of cancer in Japanese patients with type 2 diabetes.

Associations between visceral obesity and renal impairment in health checkup participants: a retrospective cohort study.

BACKGROUND: Obesity is a risk factor for chronic kidney disease. Although body mass index (BMI) or waist circumference is indicators of obesity, actual measurements of visceral fat area (VFA) more accurately reflect the amount of visceral fat. We aimed to determine the most sensitive obesity indicator for predicting renal impairment among VFA, BMI, waist circumference, waist-to-height ratio, and visceral-to-subcutaneous fat ratio (VSR). METHODS: Subjects who underwent VFA measurements during health checkups in 2012 were included. Obesity was defined using a separate baseline value for each indicator [VFA (100 cm2), BMI (25 kg/m2), waist circumference (85 cm for men and 90 cm for women), waist-to-height ratio (0.5), VSR (0.4)]. Changes in estimated glomerular filtration rate (eGFRcr) and time to new-onset proteinuria were measured. The relationships between obesity indicators and eGFRcr were evaluated using a linear mixed-effects model. The relationships between obesity indicators and new-onset proteinuria were evaluated using Poisson regression analysis. RESULTS: Analysis was performed on 2753 subjects (mean age 50.3 years). The VFA ≥ 100 cm2 group exhibited a larger annual difference in eGFRcr compared to the < 100 cm2 group (- 0.24 mL/min/1.73 m2, P = 0.03). There was a statistically significant difference in the proteinuria incidence rate ratio, which was 1.54 times (95% confidence interval 1.01-2.35) in the VFA ≥ 100 cm2 group. Statistically significant correlations were not observed with any of the other obesity indicators. CONCLUSION: VFA is suggested to be the most sensitive obesity indicator for decline in kidney function and new-onset proteinuria.

Low-Dose Aspirin for Primary Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: 10-Year Follow-Up of a Randomized Controlled Trial.

BACKGROUND: The long-term efficacy and safety of low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes mellitus are still inconclusive. METHODS: The JPAD trial (Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes) was a randomized, open-label, standard care-controlled trial examining whether low-dose aspirin affected cardiovascular events in 2539 Japanese patients with type 2 diabetes mellitus and without preexisting cardiovascular disease. Patients were randomly allocated to receive aspirin (81 or 100 mg daily; aspirin group) or no aspirin (no-aspirin group) in the JPAD trial. After that trial ended in 2008, we followed up with the patients until 2015, with no attempt to change the previously assigned therapy. Primary end points were cardiovascular events, including sudden death, fatal or nonfatal coronary artery disease, fatal or nonfatal stroke, and peripheral vascular disease. For the safety analysis, hemorrhagic events, consisting of gastrointestinal bleeding, hemorrhagic stroke, and bleeding from any other sites, were also analyzed. The primary analysis was conducted for cardiovascular events among patients who retained their original allocation (a per-protocol cohort). Analyses on an intention-to-treat cohort were conducted for hemorrhagic events and statistical sensitivity. RESULTS: The median follow-up period was 10.3 years; 1621 patients (64%) were followed up throughout the study; and 2160 patients (85%) retained their original allocation. Low-dose aspirin did not reduce cardiovascular events in the per-protocol cohort (hazard ratio, 1.14; 95% confidence interval, 0.91-1.42). Multivariable Cox proportional hazard model adjusted for age, sex, glycemic control, kidney function, smoking status, hypertension, and dyslipidemia showed similar results (hazard ratio, 1.04; 95% confidence interval, 0.83-1.30), with no heterogeneity of efficacy in subgroup analyses stratified by each of these factors (all interaction P>0.05). Sensitivity analyses on the intention-to-treat cohort yielded consistent results (hazard ratio, 1.01; 95% confidence interval, 0.82-1.25). Gastrointestinal bleeding occurred in 25 patients (2%) in the aspirin group and 12 (0.9%) in the no-aspirin group (P=0.03), and the incidence of hemorrhagic stroke was not different between groups. CONCLUSIONS: Low-dose aspirin did not affect the risk for cardiovascular events but increased risk for gastrointestinal bleeding in patients with type 2 diabetes mellitus in a primary prevention setting. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00110448.

Non-obese visceral adiposity is associated with the risk of atherosclerosis in Japanese patients with rheumatoid arthritis: a cross-sectional study.

Rheumatoid arthritis (RA) patients often have altered body composition including reduced muscle mass and increased fat mass. Some RA patients are likely to increase visceral fat without obesity [Body Mass Index (BMI) ≥ 25]. The objective of the study was to determine the association between obesity and/or visceral adiposity and the risk for atherosclerosis in Japanese RA patients. Obesity was evaluated using the BMI, with visceral adiposity evaluated using the visceral fat area (VFA) and the visceral/subcutaneous fat ratio (V/S ratio), quantified using the dual bioelectrical impedance method. Atherosclerosis was evaluated based on the intima-media thickness (IMT) and Plaque score (PS) of the carotid artery, measured using ultrasonography. Multivariate analysis was performed to determine the factors associated with IMT and PS. IMT and PS were compared among groups of patients sub-classified according to BMI and VFA levels. The V/S ratio was higher in RA patients than healthy controls, after adjustment for age, BMI, and waist circumference. On multivariate analysis, the V/S ratio, but not the BMI, was independently associated with the IMT and PS. Among the sub-classifications for BMI and VFA, non-obese patients with a high visceral adiposity (18.5 ≤ BMI < 25 kg/m2 and VFA ≥ 100 cm2) had the highest IMT (mean IMT, 0.93 ± 0.29 mm; maximum IMT, 1.44 ± 0.71 mm) and PS (1.43 ± 0.61), compared to all other BMI and VFA subgroups. RA patients have increased visceral adiposity, which is associated with a high prevalence of atherosclerotic of plaques. Non-obese RA patients who have visceral adiposity have a specifically higher risk for atherosclerosis.

Effect of exercise-based cardiac rehabilitation on non-culprit mild coronary plaques in the culprit coronary artery of patients with acute coronary syndrome.

Approximately, 70 % of acute myocardial infarctions are known to develop from mild atherosclerotic lesions. Therefore, it is important to evaluate mild coronary plaques to prevent acute coronary syndrome (ACS). The aim of the present study was to investigate the effects of exercise-based cardiac rehabilitation (CR) on mild coronary atherosclerosis in non-culprit lesions in patients with ACS. Forty-one men with ACS who underwent emergency percutaneous coronary interventions and completed a 6-month follow-up were divided into CR and non-CR groups. Quantitative coronary angiography (QCA) was performed using the automatic edge detection program. The target lesion was a mild stenotic segment (10-50 % stenosis) at the distal site of the culprit lesion, and the segment to be analyzed was determined at a segment length ranging from 10 to 15 mm. The plaque area was significantly decreased in the CR group after 6 months, but was significantly increased in the non-CR group (P < 0.05). The low-density lipoprotein (LDL) cholesterol, LDL/high-density lipoprotein (HDL) ratio and high-sensitivity C-reactive protein (Hs-CRP) levels were significantly reduced in both groups (P < 0.01). Peak VO2 in the CR group was significantly increased (P < 0.01). Changes in the plaque area correlated with those in Hs-CRP in both groups, while that association with those in HDL-C was observed in only CR group. Stepwise regression analysis revealed the decrease in Hs-CRP as an independent predictor of plaque area regression in the CR group. CR prevented the progression of mild coronary atherosclerosis in patients with ACS.

Differences between rosuvastatin and atorvastatin in lipid-lowering action and effect on glucose metabolism in Japanese hypercholesterolemic patients with concurrent diabetes. Lipid-lowering with highly potent statins in hyperlipidemia with type 2 diabetes patients (LISTEN) study ­.

BACKGROUND: Little is known about the differences between standard-dose statins effects on glucose level and lipids in Japanese patients with diabetes mellitus (DM). METHODS AND RESULTS: The 1,049 patients were randomly assigned to either the rosuvastatin group or atorvastatin group. There were no significant differences between the 2 groups in the effect on non-high-density lipoprotein cholesterol (non-HDL-C) and HbA1c at 12 months. However, physicians tended to switch to more intensive therapy for DM in the atorvastatin group. CONCLUSIONS: Rosuvastatin 5 mg and atorvastatin 10 mg have a similar lowering effect on non-HDL-C, but might be different in terms of adverse effect on glucose levels.

Preoperative chronic kidney disease as a strong predictor of postoperative infection and mortality after coronary artery bypass grafting.

BACKGROUND: The aim of this study was to determine the influence of preoperative kidney dysfunction (ie, chronic kidney disease (CKD)) on postoperative cardiovascular events, infection, acute kidney injury and hospital mortality in patients undergoing coronary artery bypass grafting (CABG). METHODS AND RESULTS: A multi-institutional retrospective study was performed at 14 hospitals of adult patients undergoing isolated CABG from 2007 to 2008 (n=1,522). We classified CKD level according to preoperative estimated glomerular filtration rate (eGFR): normal, eGFR >90 ml·min(-1)·1.73 m(-2); mild, eGFR 60-90 ml·min(-1)·1.73 m(-2); moderate, eGFR 30-59 ml·min(-1)·1.73 m(-2); and severe, eGFR <30 ml·min(-1)·1.73 m(-2), and assessed postoperative outcome. Preoperative CKD distribution was as follows: normal, n=121 (8%); mild, n=713 (47%); moderate, n=515 (34%); and severe, n=169 (11%). Risk of infection was strongly correlated with CKD level (normal, 3.3%; mild, 7.0%; moderate, 8.3%; severe, 17.0%; P<0.01). The risk of in-hospital death was also strongly correlated with CKD level (normal, 1.7%; mild, 1.0%; moderate, 1.6%; severe, 5.9%; P<0.01). On multivariate logistic regression analysis, CKD level was identified as a significant risk factor for postoperative infection, acute kidney injury, and in-hospital death. CONCLUSIONS: Advanced preoperative CKD is a strong predictor of postoperative infection, acute kidney injury and in-hospital death after CABG.

Change in carotid intima-media thickness in a high-risk group of patients by intensive lipid-lowering therapy with rosuvastatin: subanalysis of the JART study.

Carotid intima-media thickness (IMT), a measure of atherosclerosis, is modulated by multiple risk factors. Accordingly, comprehensive control of risk factors is indispensable for management of atherosclerosis. In this study, as a posthoc analysis of the JART Study we planned two analyses. In the main analysis, we evaluated the effect of intensive lipid-lowering therapy with rosuvastatin on carotid IMT in high-risk patients. We also evaluated efficacy in the presence or absence of each risk factor using the full analysis population in the JART Study. Patients with low-density lipoprotein cholesterol (LDL-C) ≥ 140 mg/dL and max-IMT ≥ 1.1 mm were randomized to rosuvastatin or pravastatin therapy for 12 months. Dosages were allowed to increase to 10 mg/day and 20 mg/day to achieve LDL-goals (aggressive goals for rosuvastatin group and guideline goals for pravastatin group). For the main analysis, we assessed 200 high-risk patients (105 in the rosuvastatin group), as category III or secondary prevention according to the Japan Atherosclerosis Society guideline 2007, whereas we assessed 289 patients in the other analysis. Rosuvastatin significantly slowed the percentage change in mean-IMT at 12 months compared with pravastatin (1.40 ± 10.03% versus 6.43 ± 13.77%, P = 0.005). LDL-C was reduced by 48.1% in the rosuvastatin group and 27.9% in the pravastatin group. The rate of achieving the LDL-C goal was significantly greater in the rosuvastatin group compared with the pravastatin group (P < 0.001). Rosuvastatin slowed the change in mean-IMT in the presence of every risk factor. Thus, intensive lipid-lowering therapy reduced progression of carotid IMT in high-risk patients.

Age-wise examination of the association of obesity based on body mass index and waist circumference with metabolic diseases in comprehensive health checkup participants.

Aim: Body mass index and waist circumference are used for obesity diagnosis and screening of visceral fat; however, their evidence in older adults is insufficient. This study investigated the age-specific association of body mass index and waist circumference with metabolic diseases, assessing their applicability as diagnostic criteria for individuals aged ≥65 years. Methods: Analysis included 46,324 individuals aged ≥18 years, categorized into five age groups: 18-44, 45-54, 55-64, 65-74, and ≥75 years. Logistic regression analyses identified associations between obesity and metabolic diseases, stratified by age and sex. Results: Men with obesity based on body mass index had a significantly high risk of hypertension, diabetes mellitus, and dyslipidemia across all age groups (all, p < 0.05). Obesity based on waist circumference was significantly positively associated with all metabolic diseases (all, p < 0.05). Women with obesity based on body mass index and waist circumference had a significantly high risk of all metabolic diseases across all age groups (all, p < 0.05), except for diabetes mellitus in individuals aged ≥75 years. Conclusions: Participants with obesity based on body mass index and waist circumference exhibited a high risk of hypertension, diabetes mellitus, and dyslipidemia among those aged 18-74 years and men aged ≥75 years. This study contributes to the early prevention and control of metabolic diseases.

Five percent weight loss is a significant 1-year predictor and an optimal 5-year cut-off for reducing the number of obesity-related cardiovascular disease risk components: the Japan Obesity and Metabolic Syndrome Study.

Objective: This study aimed to identify the amount of weight loss needed in patients with obesity to improve metabolic syndrome (MetS), a risk factor for cardiovascular disease (CVD), over a long period of time. Methods: A total of 576 patients with obesity were enrolled in this study. Effects of continuous physician-supervised weight loss on the cumulative MetS components excluding abdominal circumference (defined as obesity-related CVD risk score) were investigated during a 5-year follow-up period. The extent of weight loss required to reduce the obesity-related CVD risk components was assessed using receiver operating characteristic (ROC) curve analyses. Results: Of the 576 participants, 266 completed 5-year follow-up, with 39.1% and 24.1% of them achieving ≥5.0% and ≥7.5% weight loss at the 5-year follow-up, respectively. The area under the ROC curve for reducing the obesity-related CVD risk components was 0.719 [0.662-0.777] at 1 year and 0.694 [0.613-0.775] at 5 years. The optimal cut-off value for weight loss was 5.0% (0.66 sensitivity and 0.69 specificity) and the value with 0.80 specificity was 7.5% (0.45 sensitivity) at 5 years. Greater reductions in weight were associated with greater improvements in the obesity-related CVD risk score at all follow-up periods (P-trend <0.001). Obesity-related CVD risk score was significantly improved by 5.0-7.5% and ≥7.5% weight loss at 1 year (P = 0.029 and P < 0.001, respectively) and ≥7.5% weight loss at 5 years (P = 0.034). Conclusions: A weight loss of ≥5.0% at 1 year and ≥7.5% at 5 years could reduce the number of obesity-related CVD risk components in patients with obesity.

Centrilobular emphysema and airway dysanapsis: factors associated with low respiratory function in younger smokers.

Background: Low respiratory function in young adulthood is one of the important factors in the trajectory leading to the future development of COPD, but its morphological characteristics are not well characterised. Methods: We retrospectively enrolled 172 subjects aged 40-49 years with ≥10 pack-years smoking history who underwent lung cancer screening by computed tomography (CT) and spirometry at two Japanese hospitals. Emphysema was visually assessed according to the Fleischner Society guidelines and classified into two types: centrilobular emphysema (CLE) and paraseptal emphysema (PSE). Airway dysanapsis was assessed with the airway/lung ratio (ALR), which was calculated by the geometric mean of the lumen diameters of the 14 branching segments divided by the cube root of total lung volume on a CT scan. Results: Among the subjects, CLE and PSE were observed in 20.9% and 30.8%, respectively. The mean ALR was 0.04 and did not differ between those with and without each type of emphysema. Multivariable regression analysis models adjusted for age, sex, body mass index and smoking status indicated that CLE and a low ALR were independently associated with lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (estimate -1.64 (95% CI -2.68- -0.60) and 6.73 (95% CI 4.24-9.24), respectively) and FEV1 % pred (estimate -2.81 (95% CI -5.10- -0.52) and 10.9 (95% CI 5.36-16.4), respectively). Conclusions: CLE and airway dysanapsis on CT were independently associated with low respiratory function in younger smokers.

A reference equation for lung volume on computed tomography in Japanese middle-aged and elderly adults.

BACKGROUND: Effective use of lung volume data measured on computed tomography (CT) requires reference values for specific populations. This study examined whether an equation previously generated for multiple ethnic groups in the United States, including Asians predominantly composed of Chinese people, in the Multi-Ethnic Study of Atherosclerosis (MESA) could be used for Japanese people and, if necessary, to optimize this equation. Moreover, the equation was used to characterize patients with chronic obstructive pulmonary disease (COPD) and lung hyperexpansion. METHODS: This study included a lung cancer screening CT cohort of asymptomatic never smokers aged ≥40 years from two institutions (n = 364 and 419) to validate and optimize the MESA equation and a COPD cohort (n = 199) to test its applicability. RESULTS: In all asymptomatic never smokers, the variance explained by the predicted values (R2) based on the original MESA equation was 0.60. The original equation was optimized to minimize the root mean squared error (RMSE) by adjusting the scaling factor but not the age, sex, height, or body mass index terms of the equation. The RMSE changed from 714 ml in the original equation to 637 ml in the optimized equation. In the COPD cohort, lung hyperexpansion, defined based on the 95th percentile of the ratio of measured lung volume to predicted lung volume in never smokers (122 %), was observed in 60 (30 %) patients and was associated with centrilobular emphysema and air trapping on inspiratory/expiratory CT. CONCLUSIONS: The MESA equation was optimized for Japanese middle-aged and elderly adults.

Effect of long-term intensive lipid-lowering therapy with rosuvastatin on progression of carotid intima-media thickness--Justification for Atherosclerosis Regression Treatment (JART) extension study.

BACKGROUND: Recently, it was reported from the Justification for Atherosclerosis Regression Treatment (JART) Study that intensive therapy with rosuvastatin significantly slowed progression of carotid intima-media thickness (IMT) compared with conventional therapy with pravastatin at 12 months. To assess the long-term efficacy of intensive therapy, the present extension study was conducted. METHODS AND RESULTS: Subjects in the intensive therapy group of the JART Study were asked to participate in the extension study and to continue rosuvastatin treatment. A total of 113 subjects were enrolled into the extension study and were included in the analysis. At 24 months, the mean daily dose of rosuvastatin (±SD) was 7.9±2.9 mg. Mean change in mean IMT was -0.005 mm (range, -0.024 to 0.015 mm) at 24 months (P=0.633, compared with baseline). Rosuvastatin lowered low-density lipoprotein cholesterol (mean±SD) by 46.4±13.8% and elevated high-density lipoprotein cholesterol (mean±SD) by 8.9±24.0% at 24 months compared with baseline. Gray scale median was measured in 25 subjects. It increased by 16.93±33.12 (mean±SD) % at 12 months and by 22.50±52.83% at 24 months from baseline (P=0.017, P=0.044, respectively). CONCLUSIONS: Two-year treatment with rosuvastatin inhibited progression of carotid IMT. Rosuvastatin also improved the plaque composition, and this qualitative change occurred relatively early after starting therapy.

Intensive lipid-lowering therapy for slowing progression as well as inducing regression of atherosclerosis in Japanese patients: subanalysis of the JART study.

This paper describes a subanalysis of the JART Study comparing rosuvastatin and pravastatin treatment. A total of 314 subjects were analyzed in this subanalysis, 282 of whom were eligible for evaluation of the relationship between LDL-C and carotid mean-IMT change. In the subanalysis, we evaluated the extent to which intensive lipid-lowering therapy slowed the mean-IMT progression by a correlation analysis between LDL-C and mean-IMT change after 12 months of statin treatment. Nearly half were male (49.4%) and elderly (49.7%). The majority (84.4%) were treated for primary prevention. Patients with hypertension and diabetes mellitus accounted for 65.3% and 44.0%, respectively. At the 12-month measurement point, mean-IMT change was correlated with LDL-C (R = 0.187; P = 0.0016), LDL-C/ HDL-C ratio (R = 0.152; P = 0.0105), and non-HDL-C (R = 0.132; P = 0.0259). Mean-IMT after 12 months was divided into 4 subgroups by LDL-C at 12 months; < 80, ≥ 80 to < 100, ≥ 100 to < 120, and ≥ 120 mg/dL. A trend analysis using the Jonckheere-Terpstra test showed statistical signifi cance (P = 0.0002). Even for prevention in Japanese patients who have lower risk of atherosclerotic disease than Western patients, lowering the LDL-C level to below the therapeutic target prevented mean-IMT progression after 12 months more strongly. These findings suggest that more intensive control of LDL-C to levels lower than those in current JAS guidelines should be required to achieve slowing of progression as well as induction of regression of atherosclerosis.

Physiological impacts of computed tomography airway dysanapsis, fractal dimension, and branch count in asymptomatic never smokers.

Dysanapsis, a mismatch between airway tree caliber and lung size, contributes to a large variation in lung function on spirometry in healthy subjects. However, it remains unclear whether other morphological features of the airway tree could be associated with the variation in lung function independent of dysanapsis. This study used lung cancer screening chest computed tomography (CT) and spirometry data from asymptomatic never smokers. Dysanapsis and the complexity of airway tree geometry were quantified on CT by measuring airway to lung ratio (ALR) and airway fractal dimension (AFD). Moreover, total airway count (TAC), ratio of airway luminal surface area to volume (SA/V), longitudinal tapering and irregularity of the radius of the internal lumen from the central to peripheral airways (Tapering index and Irregularity index) were quantified. In 431 asymptomatic never smokers without a history of lung diseases, lower ALR was associated with lower forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FEV1/FVC). The associations of ALR with AFD and TAC (r = 0.41 and 0.13) were weaker than the association between TAC and AFD (r = 0.64). In multivariable models adjusted for age, sex, height, and mean lung density, lower AFD and TAC were associated with lower FEV1 and FEV1/FVC independent of ALR, whereas SA/V and Tapering index were not. These results suggest that the smaller airway tree relative to a given lung size and the lower complexity of airway tree shape, including lower branch count, are independently associated with lower lung function in healthy subjects.NEW & NOTEWORTHY This study showed that fractal dimension and total airway count of the airway tree on computed tomography are associated with lung function on spirometry independent of a smaller airway for a given lung size (dysanapsis) in asymptomatic never smokers without a history of lung diseases. In addition to dysanapsis, the morphometric complexity of the airway tree and the airway branch count may cause a substantial variation of lung function in these subjects.

Association of age with computed tomography airway tree morphology in male and female never smokers without lung disease history.

BACKGROUND: Sex and aging may affect the airway tree structure in patients with airway diseases and even healthy subjects. Using chest computed tomography (CT), this study sought to determine whether age is associated with airway morphological features differently in healthy males and females. METHODS: This retrospective cross-sectional study consecutively incorporated lung cancer screening CT data of asymptomatic never smokers (n = 431) without lung disease history. Luminal areas were measured at the trachea, main bronchi, bronchus intermedius, segmental and subsegmental bronchus, and the ratio of their geometric mean to total lung volume (airway-to-lung size ratio, ALR) was determined. Airway fractal dimension (AFD) and total airway count (TAC) were calculated for the segmented airway tree resolved on CT. RESULTS: The lumen areas of the trachea, main bronchi, segmental and subsegmental airways, AFD and TAC visible on CT were smaller in females (n = 220) than in males (n = 211) after adjusting for age, height, and body mass index, while ALR or count of the 1st to 5th generation airways did not differ. Furthermore, in males but not in females, older age was associated with larger lumen sizes of the main bronchi, segmental and subsegmental airways, and ALR. In contrast, neither male nor female had any associations between age and AFD or TAC on CT. CONCLUSION: Older age was associated with larger lumen size of the relatively central airways and ALR exclusively in males. Aging may have a more profound effect on airway lumen tree caliber in males than in females.

Derivation and validation of a clinical predictive model of NT-proBNP ≥125 pg/mL to detect pre-heart failure.

BACKGROUND: Several guidelines recommend the measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) to diagnose heart failure (HF); however, no screening criteria for measuring NT-proBNP in asymptomatic patients exist. We develop/validate a clinical prediction model for elevated NT-proBNP to support clinical outpatient decision-making. METHODS: In this multicenter cohort study, we used a derivation cohort (24 facilities) from 2017 to 2021 and a validation cohort at one facility from 2020 to 2021. Patients were aged ≥65 years with at least one risk factor of HF. The primary endpoint was NT-proBNP ≥125 pg/mL. The final model was selected using backward stepwise logistic regression analysis. Diagnostic performance was evaluated for sensitivity and specificity, the area under the curve (AUC), and calibration. In total, 1645 patients (derivation cohort, n = 837; validation cohort, n = 808) were included, of whom 378 (23.0 %) had NT-proBNP ≥125 pg/mL. Body mass index, age, systolic blood pressure, estimated glomerular filtration rate, cardiothoracic ratio, and heart disease were used as predictors and aggregated into a BASE-CH score of 0-11 points. RESULTS: Internal validation resulted in an AUC of 0.74 and an external validation AUC of 0.70. CONCLUSIONS: Based on available clinical and laboratory variables, we developed and validated a new risk score to predict NT-proBNP ≥125 pg/mL in patients at risk for HF or with pre-HF.