Causal relationship between the AHSG gene and BMD through fetuin-A and BMI: multiple mediation analysis.

UNLABELLED: Using mediation analysis, a causal relationship between the AHSG gene and bone mineral density (BMD) through fetuin-A and body mass index (BMI) mediators was suggested. INTRODUCTION: Fetuin-A, a multifunctional protein of hepatic origin, is associated with bone mineral density. It is unclear if this association is causal. This study aimed at clarification of this issue. METHODS: A cross-sectional study was conducted among 1,741 healthy workers from the Electricity Generating Authority of Thailand (EGAT) cohort. The alpha-2-Heremans-Schmid glycoprotein (AHSG) rs2248690 gene was genotyped. Three mediation models were constructed using seemingly unrelated regression analysis. First, the ln[fetuin-A] group was regressed on the AHSG gene. Second, the BMI group was regressed on the AHSG gene and the ln[fetuin-A] group. Finally, the BMD model was constructed by fitting BMD on two mediators (ln[fetuin-A] and BMI) and the independent AHSG variable. All three analyses were adjusted for confounders. RESULTS: The prevalence of the minor T allele for the AHSG locus was 15.2%. The AHSG locus was highly related to serum fetuin-A levels (P < 0.001). Multiple mediation analyses showed that AHSG was significantly associated with BMD through the ln[fetuin-A] and BMI pathway, with beta coefficients of 0.0060 (95% CI 0.0038, 0.0083) and 0.0030 (95% CI 0.0020, 0.0045) at the total hip and lumbar spine, respectively. About 27.3 and 26.0% of total genetic effects on hip and spine BMD, respectively, were explained by the mediation effects of fetuin-A and BMI. CONCLUSIONS: Our study suggested evidence of a causal relationship between the AHSG gene and BMD through fetuin-A and BMI mediators.

Clinical pharmacology of cyclooxygenase inhibition and pharmacodynamic interaction with aspirin by floctafenine in Thai healthy subjects.

Floctafenine, a hydroxyquinoline derivative with analgesic properties, is widely used in Thailand and many other countries. The objectives of this study were to evaluate in Thai healthy volunteers: i) the inhibition of whole blood cyclooxygenase(COX)-2 and COX-1 activity by floctafenine and its metabolite floctafenic acid in vitro and ex vivo after dosing with floctafenine; ii) the possible interference of floctafenine administration with aspirin antiplatelet effects. We performed an open-label, cross-over, 3-period study, on 11 healthy Thai volunteers, who received consecutively floctafenine(200mg/TID), low-dose aspirin(81mg/daily) or their combination for 4 days, separated by washout periods. Floctafenine and floctafenic acid resulted potent inhibitors of COX-1 and COX-2 in vitro (floctafenic acid was more potent than floctafenine) showing a slight preference for COX-1. After dosing with floctafenine alone, whole blood COX-1 and COX-2 activities were inhibited ex vivo in a time-dependent fashion which paralleled floctafenic acid plasma concentrations. Aspirin alone inhibited profoundly and persistently platelet COX-1 activity and AA-induced platelet aggregation throughout 24-h dosing interval which was affected by the co-administration of floctafenine. At 24 h after dosing with aspirin and floctafenine, the inhibition of platelet thromboxane(TX)B2 generation and aggregation were significantly(P less than 0.05) lower than that caused by aspirin alone. Therapeutic dosing with floctafenine profoundly inhibited prostanoid biosynthesis through the rapid conversion to floctafenic acid. Floctafenine interfered with the antiplatelet effect of aspirin. Our results suggest that floctafenine should be avoided in patients with cardiovascular disease under treatment with low-dose aspirin.

Hypertension is statistically associated with higher body mass index but not with vitamin D level in a Thai population.

Vitamin D deficiency has been linked to hypertension. Although vitamin D deficiency is common in tropical regions, no data on its association with hypertension were available. We randomly selected 137 cases and controls whose plasma in 1985 was available for the assessment of vitamin D status and calculated the odds ratio of having hypertension in 1997. In all, 36% of the participants were vitamin D deficient. The odds ratio of having hypertension was marginally significant for vitamin D deficiency (0.59, P=0.05) and statistically significant for body mass index (BMI)-defined overweight (1.8, P=0.02). The inverse relationship between vitamin D deficiency and hypertension became statistically significant after further adjustment for BMI, high-density lipoprotein cholesterol and triglyceride (0.55, P=0.03). Stepwise regression identified BMI-defined overweight and vitamin D deficiency as the variables of significance in relation to hypertension. Our data suggest that vitamin D deficiency, although not a rarity in Thailand, was not associated with an increased risk of developing hypertension in Thai people.

The metabolic syndrome and chronic kidney disease in a Southeast Asian cohort.

US adults with metabolic syndrome, as defined by National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria, have been shown to be at increased risk of chronic kidney disease (CKD), but there is limited information in other populations. The relationship between metabolic syndrome and CKD (defined as estimated glomerular filtration rate <60 ml/min/1.73 m(2)) was examined in a Southeast Asian cohort. This relationship was examined when the subjects (n=3195) were initially recruited in a cross-sectional analysis. The risks of developing new CKD associated with metabolic syndrome were also examined prospectively in a subgroup (n=2067) without CKD at entry after 12 years follow-up. Metabolic syndrome was defined according to both NCEP ATP III and the new International Diabetes Federation (IDF) criteria. The prevalence of CKD was 1.6%, and the incidence of new CKD was 6.3%. Metabolic syndrome by NCEP ATP III definition was associated with the increased risk of CKD at baseline (adjusted odds ratio (OR) 2.48 and 95% confidence interval 1.33-4.62), and of developing new CKD at follow-up (adjusted OR 1.62 and 95% confidence interval 1.00-2.61). There was a significant graded relationship between the number of metabolic syndrome components present and risk of CKD. By contrast, metabolic syndrome by IDF definition was not associated with increased risk of CKD. These results suggest the relationship between CKD and metabolic syndrome in a Southeast Asian population is highly dependent on the criteria used to define metabolic syndrome.

Cardiovascular risk prediction tools for populations in Asia.

BACKGROUND: Cardiovascular risk equations are traditionally derived from the Framingham Study. The accuracy of this approach in Asian populations, where resources for risk factor measurement may be limited, is unclear. OBJECTIVE: To compare "low-information" equations (derived using only age, systolic blood pressure, total cholesterol and smoking status) derived from the Framingham Study with those derived from the Asian cohorts, on the accuracy of cardiovascular risk prediction. DESIGN: Separate equations to predict the 8-year risk of a cardiovascular event were derived from Asian and Framingham cohorts. The performance of these equations, and a subsequently "recalibrated" Framingham equation, were evaluated among participants from independent Chinese cohorts. SETTING: Six cohort studies from Japan, Korea and Singapore (Asian cohorts); six cohort studies from China; the Framingham Study from the US. PARTICIPANTS: 172,077 participants from the Asian cohorts; 25,682 participants from Chinese cohorts and 6053 participants from the Framingham Study. MAIN RESULTS: In the Chinese cohorts, 542 cardiovascular events occurred during 8 years of follow-up. Both the Asian cohorts and the Framingham equations discriminated cardiovascular risk well in the Chinese cohorts; the area under the receiver-operator characteristic curve was at least 0.75 for men and women. However, the Framingham risk equation systematically overestimated risk in the Chinese cohorts by an average of 276% among men and 102% among women. The corresponding average overestimation using the Asian cohorts equation was 11% and 10%, respectively. Recalibrating the Framingham risk equation using cardiovascular disease incidence from the non-Chinese Asian cohorts led to an overestimation of risk by an average of 4% in women and underestimation of risk by an average of 2% in men. INTERPRETATION: A low-information Framingham cardiovascular risk prediction tool, which, when recalibrated with contemporary data, is likely to estimate future cardiovascular risk with similar accuracy in Asian populations as tools developed from data on local cohorts.

Prevalence of the G1691A mutation in the factor V gene (factor V Leiden) and the G20210A prothrombin gene mutation in the Thai population.

We investigated the prevalence of a genetic variation in the factor V gene (G1691A Leiden mutation) and the prothrombin gene (G20210A) using polymerase chain reaction techniques in samples from 500 normal Thai population and among 50 unselected Thai patients with an objectively confirmed history of deep venous thrombosis. The prevalence of factor V Leiden and the prothrombin G20210A gene mutation in a group of 500 healthy controls was 0.2% in both groups (allele frequency of 0.1%). Of the 50 adult patients studied, none was a carrier of factor V Leiden or the prothrombin G20210A gene mutation. Our findings confirm that the prevalence of factor V Leiden and prothrombin G20210A gene mutation is lower among Asians than Caucasians and that the distribution of factor V Leiden is similar to that of the prothrombin G20210A variant. The low prevalence of these two mutations can, at least in part, account for the lower frequency of deep venous thrombosis reported in the Thai population. Screening for factor V Leiden and prothrombin gene mutation is of limited benefit and may not be cost-effective in Thai patients with the first episode of deep venous thrombosis.

Utilization of electron beam CT scan in diagnosis of pulmonary embolism.

Pulmonary embolism is a difficult entity to diagnose clinically and pulmonary angiogram has been the gold standard for the diagnosis. Our objective was to evaluate the usefulness of electron beam (Ultrafast) CT scan in aiding the diagnosis of such an entity, thus avoiding an invasive procedure. Between April 1995 and March 1996 we prospectively studied 20 patients with clinical suspicion of pulmonary embolism by conventional perfusion scan of the lung, by invasive pulmonary angiography and by contrast enhanced electron beam CT scan. Simple statistic correlation between the 3 methods was obtained in regard to sensitivity and specificity utilizing the pulmonary angiogram as the gold standard. The sensitivity and specificity of contrast enhanced electron beam CT scanning was 95 per cent and 100 per cent respectively. The correlation of positive and negative result of all three imaging modalities was 60 per cent. Contrast enhanced electron beam (Ultrafast) CT scan is a good alternative diagnostic modality for pulmonary embolism.

Reduced in-hospital mortality from acute myocardial infarction with general adoption of thrombolytic treatment in the North West Thames health region 1979-1991.

OBJECTIVE: To determine the impact of studies of thrombolytic treatment in acute myocardial infarction on inhospital mortality. DESIGN: Retrospective study. SETTING: All 21 major hospitals in the North West Thames health region. PATIENTS: 63,903 patients with acute myocardial infarction. STUDY PERIOD: 1979-1991. MAIN OUTCOME MEASURES: in-hospital mortality. RESULTS: Overall mortality decreased by 5.2% from 25.4% to 20.2% (P < 0.0001) (95% confidence interval (CI) 3.4 to 6.6). Male mortality decreased by 6.5% from 22.3% to 15.8% (P < 0.0001) (95% CI 4.8 to 8.4); female mortality decreased by 4.3% from 32.6% to 28.3% (P < 0.01) (95% CI 1.3 to 7.4). Reductions in mortality occurred in all age and sex groups but were greater in younger patients. Logistic regression analysis of death rates showed that the odds ratio of death in 1991 compared with that in 1979 was 0.75 (95% CI 0.69 to 0.82). After allowing for the effects of age and sex, this odds ratio became 0.54 (95% CI 0.49 to 0.59), as more elderly patients were treated in 1991. Purchase of streptokinase increased 31-fold from 116 doses in 1983 to 3554 doses in 1991. There was a pronounced negative association between annual purchases of streptokinase and mortality (Kendall's rank correlation = -0.86, P = 0.003). Changes in clinical practice resulted in the saving of the lives of an estimated 600 patients with acute myocardial infarction in 1991. This extrapolates to an annual saving of 10,500 lives in the United Kingdom. CONCLUSIONS: In the past few years thrombolytic treatment has been widely adopted for the management of acute myocardial infarction. This has been paralleled by a substantial reduction in in-hospital mortality.

Improvement of inhaler efficacy by home-made spacer.

The delivery of aerosol from a metered dose inhaler (MDI) was reported to be more efficient with a spacer. Hence, a home-made spacer modified from a 950 ml low cost plastic bottle, was compared with a MDI and with a 750 ml imported spacer (Nebuhaler). On three consecutive days, at the same time of day, 20 adult patients with chronic asthma inhaled two puffs of terbutaline sulphate (0.5 mg), delivered from MDI alone, MDI with a 750 ml Nebuhlaer and MDI with a home-made spacer. The following measurements were made: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and pulse rate. These measurements were carried out immediately before and at 5, 20, 60 min after inhalation of terbutaline. FEV1 was significantly increased (P < 0.05) at 5, 20 and 60 min after administration of terbutaline with MDI via either spacers than with MDI alone but no significant difference was observed between Nebuhaler and the home-made spacer. FVC and pulse rate showed no significant change with each method of administration. In conclusion, terbutaline delivered by MDI and home-made spacer was more effective in bronchodilatation than by MDI alone and was just as effective as MDI and Nebuhaler. The home-made spacer therefore offers a simple, inexpensive and more effective method for delivering aerosol drug.

Aspirin, but not heparin, suppresses the transient increase in thromboxane biosynthesis associated with cardiac catheterization or coronary angioplasty.

OBJECTIVES: We sought to study the dose dependence of in vivo suppression by aspirin of enhanced thromboxane biosynthesis in the setting of coronary angioplasty and to evaluate the effects of heparin and aspirin during cardiac catheterization. BACKGROUND: Percutaneous transluminal coronary angioplasty induces a controlled injury of the intima of the diseased arterial segment, with rapid deposition of platelets at the site of dilation. Thus, it provides a clinical model of intracoronary platelet activation. METHODS: The urinary excretion of a major enzymatic metabolite of thromboxane A2, 11-dehydro-thromboxane B2, was measured in 57 patients with stable coronary artery disease undergoing cardiac catheterization (n = 28) or elective single-vessel percutaneous transluminal coronary angioplasty (n = 29). Three consecutive urine collections were obtained from all patients before during and after either procedure. Patients undergoing catheterization were treated with the following regimens: a) no aspirin for > or = 10 days and no heparin (n = 12); b) no aspirin for > or = 10 days but heparin, 10,000 IU, at the time of catheterization (n = 5); c) aspirin, 300 mg/day, for at least 5 days (n = 11). Patients undergoing coronary angioplasty were randomly assigned to short-term treatment with aspirin given as a) 75 mg/day for > or = 5 days before angioplasty (n = 11); b) 300 mg/day for > or = 3 days before angioplasty (n = 9); or c) 300 mg/day for > or = 3 days before angioplasty followed by 1,000 mg during angioplasty (n = 9). RESULTS: In patients undergoing catheterization, urinary 11-dehydro-thromboxane B2 excretion (pg/mg creatinine) increased from 563 +/- 481 (mean +/- SD) to 1,684 +/- 1,332 in the absence and from 620 +/- 191 to 1,588 +/- 597 in the presence of heparin. No increase was observed in the group receiving aspirin (from 240 +/- 141 to 215 +/- 115). In patients undergoing coronary angioplasty treated with aspirin, 75 mg/day, urinary 11-dehydro-thromboxane B2 averaged 180 +/- 112, 223 +/- 178 and 294 +/- 260, respectively, before, during and after the procedure. At 300 mg/day, the corresponding values were 185 +/- 48, 217 +/- 70 and 197 +/- 93. In patients also receiving aspirin, 1,000 mg, during angioplasty, 11-dehydro-thromboxane B2 averaged 151 +/- 66, 138 +/- 43 and 133 +/- 77, respectively. CONCLUSIONS: Enhanced thromboxane biosynthesis associated with cardiac catheterization or coronary angioplasty can be largely suppressed by low dose aspirin. This finding is consistent with the view that this alteration reflects platelet activation.

Inappropriate constriction of small coronary vessels as a possible cause of a positive exercise test early after successful coronary angioplasty.

BACKGROUND: The mechanism responsible for exercise-induced myocardial ischemia early after successful coronary angioplasty (PTCA) is poorly understood. METHODS AND RESULTS: Twelve patients who underwent one-vessel PTCA were studied. Exercise testing was performed before and on day 7 after PTCA, which was repeated after 10 mg sublingual isosorbide dinitrate if the test was positive. Quantitative coronary arteriography was also performed on day 8 after PTCA in the basal state, after intracoronary infusion of 0.9% saline, 1, 5, 10, and 20 micrograms ergonovine, and after 300 micrograms nitroglycerin. All patients had a positive exercise test before PTCA but on day 7, six patients had a positive exercise test (group 1) and six patients (group 2) had a negative exercise test. In group 1, all positive exercise tests on day 7 became negative when repeated after isosorbide dinitrate. Intracoronary ergonovine was associated with a dose-dependent constriction of the PTCA segment, a segment distal to it, and a control segment, with no significant difference in the magnitude of the response between the two groups; maximum constriction for group 1 was 19 +/- 3%, 23 +/- 2%, and 16 +/- 3% (p less than 0.001 versus basal), and in group 2 was 20 +/- 4%, 18 +/- 4%, and 9 +/- 2% (p less than 0.01 versus basal). No angina, ischemic ST segment changes, occlusive, or subocclusive spasm occurred in any patient of either group. CONCLUSIONS: We could find no evidence that exercise-induced myocardial ischemia early after PTCA is related to the presence of fixed angiographic restenosis or to dynamic constriction of any epicardial coronary segment. Therefore, inappropriate small coronary vessel constriction responsive to nitrates should be considered as a possible alternative explanation.

Abnormal vasomotor changes early after coronary angioplasty. A quantitative arteriographic study of their time course.

BACKGROUND: To study the impact of percutaneous transluminal coronary angioplasty (PTCA) on coronary vasomotion, we prospectively analyzed spontaneous changes in coronary diameter and the response to the cold pressor test and intracoronary nitroglycerin in 11 patients subjected to successful single-vessel PTCA. METHODS AND RESULTS: All antianginal medications were stopped 48 hours before each study. The minimum diameter of the PTCA segment and the diameter of a distal segment in the angioplastied vessel and of a segment in a control vessel not manipulated by the balloon catheter or guide wire were measured by computerized edge detection immediately before PTCA and 5 minutes after, 4 hours after, and 8 days after PTCA. At 4 hours, PTCA and distal segments were constricted by 38 +/- 9% and 16 +/- 5%, respectively, compared with the values at 5 minutes (p less than 0.01). Before angioplasty, the cold pressor test caused vasoconstriction of PTCA and distal segments by 23 +/- 6% (p less than 0.0001) and 15 +/- 4% (p less than 0.008), respectively, but no constrictor response was elicited at 5 minutes or 4 hours after angioplasty. Eight days after PTCA, the basal coronary diameters were similar to those observed 5 minutes after PTCA and the response to the cold pressor test was similar to that observed before PTCA. All segments dilated significantly with nitroglycerin at all times, and no vasoconstriction changes were found in the control segments. CONCLUSIONS: Four hours after PTCA, transient spontaneous vasoconstriction of the PTCA and distal segments occurs, which is so intense that the cold pressor test does not cause any further constriction. These abnormalities resolve within 8 days of PTCA.