Lower Aldosterone-Renin Ratio Is a Risk Factor for Death
Lower Aldosterone-Renin Ratio Is a Risk Factor for Death
The Takahata study is a population-based cross-sectional study of Japanese people over 40 years old, which was performed to identify possible risk factors for lifestyle-related diseases, such as diabetes and hypertension. Takahata is an agricultural and suburban area about 300 km north of Tokyo. In 2005, among the 26 026 people living in Takahata, 15 357 individuals were over 40. Between 2004 and 2006, 3520 residents were enrolled in the Takahata study. Of these, 1310 (mean age: 63·9 ± 9·8 years; men/women: 588/722) had complete clinical data including their plasma aldosterone concentration (PAC) (pg/ml) and plasma renin activity (PRA) (ng/ml/h) at baseline and participated in the study. The incidence of death was monitored annually until 10 January 2012. There were 64 deaths in this time. The cause of death was determined by reviewing death certificates through to the end of 2011. Causes of death in 2012 were unknown (n = 1). Death certificates of deceased participants were collected with permission from the Management and Coordination Agency of the Japanese Government once yearly. The death code (ICD-10), date and place of death were reviewed. Subjects who moved away during the follow-up period were identified by residence transfer documents (n = 14). The median and maximum durations of follow-up were 2691 and 2760 days, respectively. To further evaluate the association between ARR at baseline and mortality, subjects were stratified into tertiles of ARR (tertiles 1–3: ≤50·0 and ≥118·2, respectively) and into patients at risk (≤72) or not at risk (>72).
This study was approved by the Ethics Committee of the Yamagata University School of Medicine, and written informed consent was obtained from all participants. Blood samples were collected by phlebotomy, mostly between 7 am and 10 am, in a sitting position after at least 5 min rest. PAC and PRA was determined using radioimmunoassay (SPAC-S Aldosterone Kit; TFB Inc., Tokyo, Japan and Renin-RIA bead; Abbot, Tokyo, Japan, respectively). The following clinical characteristics were measured: height, body weight, body mass index, fasting plasma glucose, HbA1c, fasting serum insulin, insulin resistance indexes assessed by homoeostasis model assessment using fasting plasma glucose and insulin levels (HOMA-IR), systolic blood pressure, diastolic blood pressure, serum levels of angiotensin converting enzyme (ACE), total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, total protein, uric acid, urea nitrogen, creatinine, B-type natriuretic peptide (BNP) and adiponectin. HbA1c (%) was measured using the previous Japanese standard substance and measurement method (Japan Diabetes Society (JDS) value) and converted to the National Glycohemoglobin Standardization Program (NGSP) value using the formula: HbA1c (NGSP) = 1·02 × HbA1c (JDS) + 0·25. Diabetes was defined according to 1998 World Health Organization criteria (FPG levels ≥126 mg/dl). In subjects whose FPG levels were not measured, diabetes was defined as a postprandial glucose level ≥200 mg/dl. Subjects with an HbA1c level ≥6·5% were also defined as diabetic as were those on medication for diabetes. Subjects known to have type 1 diabetes were excluded from the study. There were 133 subjects with diabetes. Hypertension was defined as blood pressure ≥140/90 mmHg or being on treatment for hypertension (n = 738). Hyperlipidaemia was defined as total cholesterol ≥240 mg/dl, TG ≥150 mg/dl or being on treatment for hyperlipidaemia (n = 407). Alcohol intake (current or nondrinker) and smoking habits (never, past or current) were evaluated by questionnaire. PA was not defined, as no confirmatory testing for PA was possible as a nature of general health examination.
The clinical characteristics are given as mean ± SD. The statistical significance of differences in characteristic values between two groups (parametric) and a case–control association between groups stratified by ARR and the incidence of death (nonparametric) were assessed by Student's t-tests and χ tests, respectively. Mortality rates were compared among subjects stratified by ARR using the Kaplan–Meier method. Multivariate Cox proportional hazard regression models were used to calculate hazard ratios (HR) of ARR for mortality with adjustment for factors different between the ARR-at-risk and ARR-not-at-risk groups (e.g. age, sex, medication for hypertension). All analyses were conducted using StatView software version 5.0 (SAS Institute Inc., Cary, NC, USA). Receiver operating characteristic (ROC) curves were plotted to determine the ARR cut-off values to predict the ARR-at-risk group for total death. ROC curves were plotted using GraphPad Prism Version 4.00 for Macintosh (GraphPad Software, San Diego, CA, USA). A P-value <0·05 was considered statistically significant for all analyses.
Materials and Methods
Subjects
The Takahata study is a population-based cross-sectional study of Japanese people over 40 years old, which was performed to identify possible risk factors for lifestyle-related diseases, such as diabetes and hypertension. Takahata is an agricultural and suburban area about 300 km north of Tokyo. In 2005, among the 26 026 people living in Takahata, 15 357 individuals were over 40. Between 2004 and 2006, 3520 residents were enrolled in the Takahata study. Of these, 1310 (mean age: 63·9 ± 9·8 years; men/women: 588/722) had complete clinical data including their plasma aldosterone concentration (PAC) (pg/ml) and plasma renin activity (PRA) (ng/ml/h) at baseline and participated in the study. The incidence of death was monitored annually until 10 January 2012. There were 64 deaths in this time. The cause of death was determined by reviewing death certificates through to the end of 2011. Causes of death in 2012 were unknown (n = 1). Death certificates of deceased participants were collected with permission from the Management and Coordination Agency of the Japanese Government once yearly. The death code (ICD-10), date and place of death were reviewed. Subjects who moved away during the follow-up period were identified by residence transfer documents (n = 14). The median and maximum durations of follow-up were 2691 and 2760 days, respectively. To further evaluate the association between ARR at baseline and mortality, subjects were stratified into tertiles of ARR (tertiles 1–3: ≤50·0 and ≥118·2, respectively) and into patients at risk (≤72) or not at risk (>72).
This study was approved by the Ethics Committee of the Yamagata University School of Medicine, and written informed consent was obtained from all participants. Blood samples were collected by phlebotomy, mostly between 7 am and 10 am, in a sitting position after at least 5 min rest. PAC and PRA was determined using radioimmunoassay (SPAC-S Aldosterone Kit; TFB Inc., Tokyo, Japan and Renin-RIA bead; Abbot, Tokyo, Japan, respectively). The following clinical characteristics were measured: height, body weight, body mass index, fasting plasma glucose, HbA1c, fasting serum insulin, insulin resistance indexes assessed by homoeostasis model assessment using fasting plasma glucose and insulin levels (HOMA-IR), systolic blood pressure, diastolic blood pressure, serum levels of angiotensin converting enzyme (ACE), total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, total protein, uric acid, urea nitrogen, creatinine, B-type natriuretic peptide (BNP) and adiponectin. HbA1c (%) was measured using the previous Japanese standard substance and measurement method (Japan Diabetes Society (JDS) value) and converted to the National Glycohemoglobin Standardization Program (NGSP) value using the formula: HbA1c (NGSP) = 1·02 × HbA1c (JDS) + 0·25. Diabetes was defined according to 1998 World Health Organization criteria (FPG levels ≥126 mg/dl). In subjects whose FPG levels were not measured, diabetes was defined as a postprandial glucose level ≥200 mg/dl. Subjects with an HbA1c level ≥6·5% were also defined as diabetic as were those on medication for diabetes. Subjects known to have type 1 diabetes were excluded from the study. There were 133 subjects with diabetes. Hypertension was defined as blood pressure ≥140/90 mmHg or being on treatment for hypertension (n = 738). Hyperlipidaemia was defined as total cholesterol ≥240 mg/dl, TG ≥150 mg/dl or being on treatment for hyperlipidaemia (n = 407). Alcohol intake (current or nondrinker) and smoking habits (never, past or current) were evaluated by questionnaire. PA was not defined, as no confirmatory testing for PA was possible as a nature of general health examination.
Statistical Methods
The clinical characteristics are given as mean ± SD. The statistical significance of differences in characteristic values between two groups (parametric) and a case–control association between groups stratified by ARR and the incidence of death (nonparametric) were assessed by Student's t-tests and χ tests, respectively. Mortality rates were compared among subjects stratified by ARR using the Kaplan–Meier method. Multivariate Cox proportional hazard regression models were used to calculate hazard ratios (HR) of ARR for mortality with adjustment for factors different between the ARR-at-risk and ARR-not-at-risk groups (e.g. age, sex, medication for hypertension). All analyses were conducted using StatView software version 5.0 (SAS Institute Inc., Cary, NC, USA). Receiver operating characteristic (ROC) curves were plotted to determine the ARR cut-off values to predict the ARR-at-risk group for total death. ROC curves were plotted using GraphPad Prism Version 4.00 for Macintosh (GraphPad Software, San Diego, CA, USA). A P-value <0·05 was considered statistically significant for all analyses.
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