Positive Predictors for Response to Ambrisentan Combination Therapy in Pulmonary Arterial Hypertension.

The AMBITION study (NCT01178073) provided the first long-term clinical evidence for initial combination therapy with ambrisentan and tadalafil in patients with pulmonary arterial hypertension (PAH). Nevertheless, predictors of treatment response were not assessed.To identify predictors for response to initial combination therapy, we examined data from 302 patients with PAH (World Health Organization Functional Class II or III) who received initial combination therapy from the modified intention-to-treat population of the AMBITION study (n = 605). A responder was defined as not having undergone a clinical failure event. Univariate and multivariate analyses were performed. Multivariate logistic regression with interactive backward selection was used to assess the independent association of potential predictors with response.Treatment responders were younger, more often female, and less likely to have comorbidities or a requirement for oxygen therapy, compared with nonresponders. At multivariate analysis, female sex (odds ratio [OR] 2.67; 95% confidence interval [CI] 1.29, 5.52; P = 0.0081), longer 6-minute walk distance (OR 1.01; 95% CI 1.00, 1.01; P = 0.0039), lower baseline log N-terminal-prohormone of brain natriuretic peptide (OR 0.70; 95% CI 0.52, 0.94; P = 0.0190), and aldosterone antagonist use (OR 2.54; 95% CI 1.03, 6.26; P = 0.0436) independently predicted response to initial combination therapy.Besides demographic factors, the absence of comorbidities and less severe disease state, and the use of aldosterone antagonist therapy identified patients with PAH most likely to respond to initial combination therapy with ambrisentan and tadalafil. Further study to evaluate the role of aldosterone antagonist therapy in PAH is warranted.

Three percent weight reduction is the minimum requirement to improve health hazards in obese and overweight people in Japan.

OBJECTIVE: Adequate goal-setting is important in health counselling and treatment for obesity and overweight. We tried to determine the minimum weight reduction required for improvement of obesity-related risk factors and conditions in obese and overweight Japanese people, using a nationwide intervention programme database. METHODS: Japanese men and women (n=3480; mean age±standard deviation [SD], 48.3±5.9 years; mean body mass index±SD, 27.7±2.5kgm(-2)) with "Obesity Disease" or "Metabolic Syndrome" participated in a 6-month lifestyle modification programme (specific health guidance) and underwent follow-up for 6 months thereafter. The relationship between percent weight reduction and changes in 11 parameters of obesity-related diseases were examined. RESULTS: Significant weight reduction was observed 6 months after the beginning of the programme, and it was maintained for 1 year. Concomitant improvements in parameters for obesity-related diseases were also observed. One-third of the subjects reduced their body weight by ≥3%. In the group exhibiting 1% to <3% weight reduction, plasma triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), haemoglobin A1c (HbA1c), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and γ-glutamyl transpeptidase (γ-GTP) decreased significantly, and high-density lipoprotein cholesterol (HDL-C) increased significantly compared to the control group (±1% weight change group). In addition to the improvements of these 7 parameters (out of 11), significant reductions in systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting plasma glucose (FPG) and uric acid (UA) (total 11 of 11 parameters) were observed in the group with 3% to <5% weight reduction. In the group with ≥5% weight reduction, the same 11 parameters also improved as those in the group with 3% to <5% weight reduction. CONCLUSION: The 6-month lifestyle modification programme induced significant weight reduction and significant improvement of parameters of obesity-related diseases. All the measured obesity-related parameters were significantly improved in groups with 3% to <5% and ≥5% weight reduction. Based on these findings, the minimum weight reduction required for improvement of obesity-related risk factors or conditions is 3% in obese and overweight (by WHO classification) Japanese people.

[Evaluation of sub-maximal aerobic capacity level determined by double product break point (DPBP) among Japanese adults].

OBJECTIVES: The purpose of this study was to determine sub-maximal aerobic capacity levels evaluated by metabolic equivalents (unit is METs) at the double product break point (DPBP) and elucidate the safe and effective average exercise intensity among Japanese adults. A total of 438 subjects (123 males and 315 females) who participated in the exercise prescription course with measurement of the DPBP during a continuous incremental exercise test with a bicycle METHODS: ergometer were enrolled in this study. The DP (heart rate-systolic blood pressure product) featured rapid increase with increasing exercise load during the continuous incremental exercise test. RESULTS: The metabolic equivalents at the DPBP level for males and females were 5.3+/-0.9 METs and 4.9+/-0.7 METs, respectively. Interestingly, the metabolic equivalent at the DPBP level in 87.2% of the study subjects was less than 6 METs. CONCLUSIONS: This study indicated that some physical activities above moderate intensity, such as the stair climbing (8 METs), might be inappropriate as health promotion exercises. Thus, the upper limit of exercise intensity for health promotion was 6 METs, especially if the subject was at cardiovascular risk. In addition, it was found necessary to make synthetic judgments in consideration of heart rate and rating of perceived exertion (RPE) during exercise.

[Is whole body bone mineral density measured by the dual energy X-ray absorptiometry applied to evaluate risk of osteoporosis among Japanese adult females?].

To measure whole body fat accurately, the dual energy X-ray absorptiometry (DXA) is widely utilized. Simultaneously, bone mineral density (BMD) of the whole body can also be measured. BMD is one of important information to diagnose osteoporosis. However, it is not established to use whole body BMD for this diagnosis. It is recommended that lumbar and/or hip BMD should be used for diagnosing osteoporosis by the guideline for prevention and treatment of osteoporosis. Although it is possible to measure whole body BMD and lumbar and/or hip BMD separately at the same visit, it is inevitable to expose patients to more X-ray. Therefore, an aim of this study is to elucidate the relationship between whole body BMD and lumbar BMD to find the cut off point of whole body BMD for screening of osteoporosis. Two hundred and thirty six Japanese adult females were ascertained to this study. Whole body BMD and lumbar BMD of each subject were measured with the use of Delphi W (Hologic, USA). One hundred and sixty five subjects were judged as possible osteoporosis (less than 80% of young adult mean (YAM) of lumbar BMD and/or definite fracture of lumbar vertebras). The cut off point of whole body BMD for screening possible osteoporosis was estimated by receiver operated characteristic (ROS) analysis. The cut off point of whole body BMD was 84% of YAM, equivalent to 80% of YAM of lumbar BMD, with the following sensitivity and specificity (0.84 and 0.79, respectively), indicating that whole body BMD could be used for screening osteoporosis.

Relationship between obesity and physical fitness and periodontitis.

BACKGROUND: Obesity and exercise are important elements associated with lifestyle-related diseases, and studies suggested that these factors may also be related to periodontitis. This study investigates the relationship between obesity and physical fitness and periodontitis. METHODS: One thousand, one hundred and sixty Japanese subjects, aged 20 to 77 years, who participated in health examinations at Fukuoka Health Promotion Center were analyzed. Periodontal conditions were evaluated using the Community Periodontal Index (CPI), and subjects with > or =3 sextants of CPI code 3 or 4 were defined as having severe periodontitis. We used the body mass index (BMI) and percentage of body fat as indicators of obesity and estimated the maximal oxygen consumption (VO(2max)) during exercise as an indicator of physical fitness. We divided these variables into quintiles. We examined the single effect and interactions of the obesity index and VO(2max) on severe periodontitis. RESULTS: The lowest quintile in BMI and the highest quintile in VO(2max) were inversely associated with severe periodontitis, singly, in multivariate logistic regression analyses. Subjects with the combined lowest quintile in BMI and the highest quintile in VO(2max) had a significantly lower risk of severe periodontitis compared to subjects with other combined quintiles in BMI and in VO(2max) (odds ratio: 0.17; 95% confidence interval: 0.05 to 0.55). CONCLUSION: This study suggests that obesity and physical fitness may have some interactive effect on periodontal health status.

Waist circumference is the main determinant of elevated C-reactive protein in metabolic syndrome.

BACKGROUND: Metabolic syndrome (MetS) is known to increase the risk of cardiovascular disease. C-reactive protein (CRP) has been reported to be elevated in subjects with MetS. However, which component of MetS contributes mostly to the elevation has not been studied in detail. METHODS: We studied 628 apparently healthy Japanese subjects (men 262, women 366, age 19-85 years). Body mass index, waist circumference (WC), blood pressure, lipids, glucose, insulin and CRP were measured. MetS was defined according to the National Cholesterol Education Program's Adult Treatment Panel III report. RESULTS: In partial correlation analysis, WC showed the strongest correlation with CRP among the variables related to MetS. CRP increased as the number of MetS components increased. The mean CRP value adjusted for demographic variables was higher in subjects with MetS than those without MetS, and further adjustments with variables related to MetS revealed that the significant difference between the two groups disappeared only when further adjustment was made for WC. In multiple linear regression analysis, the independent variable that most strongly explained the CRP level was WC, which was followed by HDL-cholesterol. Finally, comparison of the CRP levels in groups stratified by abdominal obesity and the number of MetS components revealed that those with abdominal obesity tended to show higher CRP levels compared with those without abdominal obesity regardless of the number of MetS components other than WC. CONCLUSIONS: Subjects with MetS showed higher levels of CRP and the main determinant of the CRP elevation was WC.

Vasospastic angina and microvascular angina are differentially influenced by PON1 A632G polymorphism in the Japanese.

BACKGROUND: Ethnicity and smoking are well-known risk factors for the pathogenesis of coronary vasospasm. Oxidative stress induced by smoking plays a crucial role in coronary vasospasm, but is not enough to account for the pathogenesis of coronary vasospasm, indicating that genetic factors are strongly involved. METHODS AND RESULTS: The study group comprised 162 vasospastic angina patients (VSAs), 61 microvascular angina patients (MVAs) and 61 non-responders (NRs) diagnosed by acetylcholine provocation test. Four polymorphisms of the oxidative stress related genes, cytochrome b-245, alpha polypeptide gene (CYBA) C242T and A640G, paraoxonase 1 gene (PON1) A632G, phospholipase A2 group VII gene (PLA2G7) G994T were genotyped. Allele frequency of PON1 632-G was significantly higher in both the VSA with dominant fashion and the MVA with recessive fashion compared with NR. This association was strongly influenced by gender in the MVA only. There were no significant associations between the other polymorphisms and coronary vasospasm. In addition, the allele frequency of PON1 632-G in the Japanese was higher than in Caucasians. CONCLUSIONS: There was a significant association between PON1 A632G polymorphism and MVA as well as VSA, but the impact of this on VSA and MVA is different in the Japanese.

Disparity of MCP-1 mRNA and protein expressions between the carotid artery and the aorta in WHHL rabbits: one aspect involved in the regional difference in atherosclerosis.

OBJECTIVE: This study was designed to examine why in WHHL rabbits, muscular arteries, such as the carotid artery, are relatively resistant to atherosclerosis compared with the aorta, with a special reference to monocyte chemoattractant protein (MCP)-1. METHODS AND RESULTS: MCP-1 mRNA expression was quantitated by Northern blot analysis, and its protein expression was quantitated by immunostaining and ELISA at the age of 1, 3, 6, and 12 months (n=5 to 6 each). In the aorta, atherosclerotic lesions were progressively developed with aging, and MCP-1 was highly expressed in endothelial cells and infiltrating macrophages. By contrast, in the carotid artery, atherosclerotic lesions and MCP-1 immunoreactivity were not evident throughout the experimental period. Unexpectedly, however, the extent of MCP-1 mRNA expression was comparable between the aorta and the carotid artery throughout the experimental period. Endothelial cells in primary culture from the aorta and the carotid artery expressed the same extent of MCP-1 mRNA on stimulation by oxidized LDL. There was no abnormality in primary structure of MCP-1 cDNA in WHHL. CONCLUSIONS: These results suggest that in WHHL, the atherosclerosis process, including MCP-1 protein expression, may be reduced in the carotid artery (and possibly in other muscular arteries), accounting in part for the regional resistance to atherosclerosis.

Coronary revascularization in Japan. Part 3: percutaneous coronary intervention during 1997.

A survey by the Japanese Coronary Intervention Study (JCIS) group revealed that 109,788 percutaneous coronary intervention (PCI) procedures were performed at 1,023 laboratories during 1997. The present study aimed to describe the demographic and clinical characteristics, treatment strategies, in-hospital outcomes, and long-term outcomes of these patients. A total of 10,642 PCIs performed in 8,814 patients, which corresponded to approximately 10% of the overall PCIs, were selected at random. The mean patient age was 65 years, and 75% were males. The patients often had extensive coronary risk factors. The most prevalent clinical diagnosis was stable angina (36%), followed by myocardial infarction (MI) excluding acute myocardial infarction (AMI; 28%) and AMI (25%). Plain old balloon angioplasty was used as the sole procedure in 58% of lesions for which an attempt to heal was made, and coronary stent placement in 38%. Angiographic success was achieved in 92% of attempted lesions. Mortality, MI and emergency coronary artery bypass grafting (CABG) rates during the hospitalization were 2.6%, 2.0% and 0.7%, respectively. In-hospital mortality rate for AMI was 7.6%, whereas that for elective PCI in cases without AMI was 0.6%. The overall mortality for 1.8 years was 8%. Repeat PCI was performed for 35% and CABG for 6% during the follow-up period. In Japan, PCI was performed in patients with coronary artery disease and extensive risk factors, but a high rate of angiographic success was achieved. The rates of in-hospital mortality and emergency CABG were low in non-AMI patients, but the 1-year rate of repeat PCI was as high as 32%.

Coronary revascularization in Japan. Part 4: coronary artery bypass surgery during 1997.

The Japanese Coronary Intervention Study (JCIS) has revealed that 17,667 coronary artery bypass grafting (CABG) procedures were performed at 477 facilities during 1997, and this report describes the demographic and clinical characteristics, treatment strategies, and the in-hospital and the long-term outcomes in patients treated with CABG in Japan. A total of 1,862 CABG cases, which corresponded to approximately 10% of the overall CABGs, were selected at random. The mean age was 65 years, and 76% of cases were males. The most prevalent clinical diagnosis was stable angina (54%), followed by myocardial infarction (MI) excluding acute myocardial infarction (AMI) (48%), unstable angina (25%), and AMI (5%). A large proportion of cases had multivessel coronary artery disease: 3-vessel disease (56%) and left main trunk disease (29%). The CABG procedures were emergency in 16%, and 93% of anastomotic sites were patent. In-hospital mortality and MI occurred in 5.1% and 3.5% of cases, respectively. The in-hospital mortality rate for emergency CABG was 12.0%, whereas that for elective CABG was 3.8%. The overall mortality rate during the follow-up period of 2.3 years was 10%. During the follow-up period, MI and angina occurred in 2% and 8% of cases, respectively. Percutaneous coronary intervention (PCI) was performed for 8%, and repeat CABG for 0.8%. In Japan, CABG was performed in patients with multivessel coronary artery disease with extensive risk factors. Angiographically determined success was achieved in 93% and the need for subsequent revascularization was relatively low.

Severe pulmonary hypertension in a patient with systemic lupus erythematosus and minimal lupus activity.

Pulmonary hypertension (PH) sometimes occurs in patients with systemic lupus erythematosus (SLE). We report a case of 51-year-old-woman with PH associated with SLE. She had been diagnosed as SLE on the basis of pericardial effusion, hematological disorder, positive antinuclear antibody, and hypocomplementemia. Despite minimal lupus activity, she had marked elevation of pulmonary arterial pressure (101/53 mmHg) and decreased cardiac index (1.5 l/min/m2). Symptoms related to PH were progressive under treatment with oral corticosteroids, oxygen, calcium antagonists, and warfarin. After 17 months of epoprostenol treatment, she died of pulmonary infarction. SLE-associated PH is often severe and progressive even in association with minimal activity.