Genetic factors associated with elevation of uric acid after treatment with thiazide-like diuretic in patients with essential hypertension.

We investigated changes in blood pressure (BP) and metabolic adverse effects, especially elevation of uric acid (UA), after treatment with a thiazide-like diuretic (TD) in patients with essential hypertension. Furthermore, the role of genetic factors in the elevation of UA by TD was assessed by a 500 K SNP DNA microarray. The subjects included 126 hypertensive patients (57 women and 69 men, mean age 59 ± 12 years) who registered for the GEANE (Gene Evaluation for ANtihypertensive Effects) study. After one month of the nontreatment period, TD, indapamide, angiotensin II receptor antagonist valsartan, and Ca channel blocker amlodipine were administered to all patients for 3 months each in a randomized crossover manner. BP, renal function, serum UA level, and electrolytes were measured at baseline and at the end of each treatment period. Single nucleotide polymorphisms (SNPs) associated with UA elevation after treatment with indapamide were investigated by a genome-wide association study (GWAS). Indapamide significantly decreased both office and home BP levels. Treatment with indapamide also significantly reduced the estimated glomerular filtration rate and serum potassium and increased serum UA. Patients whose UA level increased more than 1 mg/dl showed significantly higher baseline office SBP and plasma glucose and showed greater decline in renal function compared with those who showed less UA increase (<1 mg/dl). Some SNPs strongly associated with an increase in UA after treatment with indapamide were identified. This study is the first report on SNPs associated with UA elevation after TD treatment. This information may be useful for the prevention of adverse effects after treatment with TD.

Association between subjective well-being and presence of primary care dentists in community-dwelling elderly people: A cross-sectional study.

OBJECTIVE: The aim was to investigate the relationships between subjective well-being and the existence of primary care dentists in community-dwelling elderly people. BACKGROUND: Some studies have reported subjective well-being focusing on oral health, but no studies have examined the relationship between subjective well-being and primary care dentists. METHODS: This cross-sectional study used data from community-dwelling elderly people aged ≥70 years (n = 624). The Philadelphia Geriatric Center Morale Scale (PGCMS; range = 0 [low morale]-17) was used to assess subjective well-being. Additional information regarding age group, sex, medical consulting situation (ambulatory care/home care), primary care dentists, family structure, economic status, health status was collected via questionnaire. RESULTS: The average PGCMS score in ambulatory care patients (ACP) group who have primary care dentists was highest among community-dwelling elderly people. In a logistic regression model, a low PGCMS score (0-11) was independently correlated to 80-89 age group (OR = 1.70; 95% CI, 1.13-2.54; P = 0.008), ≥90 age group (OR = 3.86; 95% CI, 1.83-8.18; P < 0.001), unsatisfied for economic status (OR = 2.68; 95% CI, 1.59-4.53; P < 0.001), unsatisfied for health status (OR = 3.94; 95% CI, 2.60-5.98; P < 0.001) and having no primary care dentists (OR = 1.81; 95% CI, 1.09-3.01; P = 0.021) in ACP group. CONCLUSIONS: The subjective well-being of ACP who have primary care dentists was higher than in other people. Primary dentists contributed to the subjective well-being of elderly people.

Genome-wide response to antihypertensive medication using home blood pressure measurements: a pilot study nested within the HOMED-BP study.

BACKGROUND: Patients with mild-to-moderate essential hypertension in the HOMED-BP trial were randomly allocated to first-line treatment with a calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB). METHODS: We recruited 265 (93 for CCB, 71 for ACEI and 101 for ARB) patients who completed the genomic study. Home blood pressure was measured for 5 days off-treatment before randomization and for 5 days after 2-4 weeks of randomized drug treatment. Genotyping was performed by 500K DNA microarray chips. The blood pressure responses to the three drugs were analyzed separately as a quantitative trait. For replication of SNPs with p < 10(-4), we used the multicenter GEANE study, in which patients were randomized to valsartan or amlodipine. RESULTS: SNPs in PICALM, TANC2, NUMA1 and APCDD1 were found to be associated with CCB responses and those in ABCC9 and YIPF1 were found to be associated with ARB response with replication. CONCLUSION: Our approach, the first based on high-fidelity phenotyping by home blood pressure measurement, might be a step in moving towards the personalized treatment of hypertension.

Antiproteinuric effect of cilnidipine in hypertensive Japanese treated with renin-angiotensin-system inhibitors - a multicenter, open, randomized trial using 24-hour urine collection.

Sustained proteinuria is an important risk factor for not only renal but also cardiovascular morbidity and mortality. Although inhibitors of the renin-angiotensin system (RAS) have been shown to reduce proteinuria. Monotherapy with those drugs is often insufficient for optimal blood pressure (BP)-lowering and therefore, combined therapy is needed. Recent reports suggested that cilnidipine, a dual L-/N-type calcium channel blocker, has renoprotective effect by dilating both efferent and afferent arterioles. In this study, a multicenter, open, randomized trial was designed to compare the antiproteinuric effect between cilnidipine and amlodipine when coupled with RAS inhibitors in hypertensive patients with significant proteinuria. Proteinuria was evaluated by 24-h home urine collection for all patients. A total of 35 proteinuric (>0.1 g/day) patients with uncontrolled BP (>135/85 mmHg) were randomized to receive either cilnidipine (n = 18) or amlodipine (n = 17) after a 6-month treatment with RAS inhibitors and were followed for 48 weeks. At baseline, the cilnidipine group was older and had lower body mass index (BMI) compared to the amlodipine group. After 32 weeks of treatment, diastolic blood pressure (DBP) was slightly, but significantly reduced, in the cilnidipine group, although systolic blood pressure (SBP) and mean BP did not differ. The urinary protein did not differ at baseline (cilnidipine group 0.48 g/day, amlodipine group 0.52 g/day); however, it significantly decreased in the cilnidipine group (0.22 g/day) compared to the amlodipine group (0.50 g/day) after 48 weeks of treatment. Our findings suggest that cilnidipine is superior to amlodipine in preventing the progression of proteinuria in hypertensive patients even undergoing treatment with RAS inhibitors.

[A DRG/PPS simulation in the medical care of tuberculosis].

PURPOSE: To study the expected usefulness of the introduction of the DRG-PPS (Diagnosis-Related Group/Prospective Payment System, in which an insurer pays a fixed medical fee per hospitalization) into the current medical care of tuberculosis (TB) in Japan. METHOD: The medical fees were reviewed for all TB inpatients at 19 hospitals under the National Hospital Organization who were discharged in either June 2007 or February 2008. The sum of the fixed fee by the DRG was assumed based on the bivariate regression analysis of each patient's hospital days and his or her total actual fees during the hospital stay under the current (fee for care) system, since it was difficult to directly calculate the daily fees for every patient that would be the basis of DRG-PPS. RESULTS: Linear regression analysis estimated that the medical fees (including fees for the medical examinations and the treatments) for a hospital stay of 60 days, which is the standard for TB treatment, was 1,192,470 yen (19,870 yen per person per day) in June 2007, and 1,167,600 yen (19,460 yen per person per day) in February 2008. DISCUSSION: If we assume an average medical fee of about Y1.1-1.2 million yen for the standard hospital care of TB, the economic balance of the hospitals is negative, with a deficit of 0.6-0.7 million yen, given the estimated expenses of 1.8 million yen (i.e., 30,000 yen per person per day x 60 days). CONCLUSION: If the DRG-PPS is to be implemented based on the current medical fee rating system, the hospital administrators could not accept its introduction to the TB medical care service as it is, because it may undermine the economic management of hospitals.

Blood pressure and lipid control status in Japanese hypertensive patients.

Strict blood pressure (BP) as well as lipid control is important to prevent cardiovascular events. The purpose of this study was to evaluate BP and lipid control status in hypertensive patients. Subjects were a total of 717 hypertensive patients who had been followed at National Kyushu Medical Center in FuKuoka, Japan. Goal BP was defined as < 130/85 mmHg (< 65 years) or < 140/90 mmHg (> or = 65 years). According to the Japanese guidelines, goal LDL cholesterol (LDL-C) levels were defined based on the patient category. Average BP level and the number of anti-hypertensive drugs were 133 + or - 12/74 + or - 9 mmHg and 2.1 + or - 1.1, respectively, and the LDL-C level was 119 + or - 27 mg/dl. Goal BP was achieved in 40% of the patients of < 65 years and 67% of the elderly patients. Goal LDL-C was achieved in 65% of the patients. Even in the patients taking lipid-lowering agents (n = 178), 30% failed to achieve goal LDL-C levels. In the patients who achieved BP < 130/85 mmHg, 67% also achieved goal LDL-C, whereas 61% of the patients whose BP > or = 140/90 mmHg achieved goal LDL-C. Both goal BP and LDL-C were achieved in 39% of the male and 36% of the female patients. In contrast, neither goal BP nor goal LDL-C was achieved in 16% of the male and 17% of the female patients. Results suggest that intensive intervention should be required to achieve satisfactory BP and lipid control in hypertensive patients.

Home blood pressure measurement may lead to less strict control of office blood pressure.

Home blood pressure (HBP) measurement is useful for detecting morning hypertension, white coat as well as masked hypertension. However, target BP levels based on HBP remain unknown. The purpose of the present study was to evaluate the relationship between HBP measurement and office BP control status in hypertensive patients. Subjects were a total of 720 hypertensive outpatients (mean age: 64 +/- 11 years; females: 57%). Two-time averaged office BP in 2005 were categorized as excellent (<130/85 mmHg), good (> or =130/85 and <140/90 mmHg), or poor (>140/90 mmHg) control. In all patients, 37% were classified as excellent, 37% as good, and 26% as poor control. A total of 393 (55%) patients regularly measured HBP (HBP group). More women belonged to the HBP group (62 vs. 52%, p < 0.05). The HBP group also showed lower body mass index (23.8 +/- 3.3 vs. 24.7 +/- 3.4 kg/m(2), p < 0.01), lower triglyceride (136 +/- 78 vs. 158 +/- 89 mg/dl, p < 0.01), and lower blood glucose (104 +/- 20 vs. 118 +/- 42 mg/dl, p < 0.01). HBP group showed a significantly higher prevalence of poor BP control (33 vs. 23%, p <0.01) and higher office SBP (134.5 +/- 14.5 vs. 131.3 +/- 11.7 mmHg, p < 0.01) than those who did not measure HBP (non-HBP). In a multivariate analysis for office SBP, age (partial r = 0.21, p < 0.05) and HBP measurement (partial r = 0.12, p < 0.05) were detected as significant independent variables. These results suggest that HBP measurement may lead to less strict office BP control unless the target HBP levels are clearly indicated. Until the recommendations or target HBP levels are available, we should make an effort to obtain goal office BP.

Usefulness of the alpha1-blocker doxazosin as a third-line antihypertensive drug.

It has been reported that a substantial majority of hypertensives receive insufficient blood pressure (BP) control. As combination therapy for the treatment of hypertension, Ca channel blockers (CCBs), angiotensin II (AII) receptor blockers (ARBs), and/or AII-converting enzyme (ACE) inhibitors are mainly prescribed, while the efficacy of alpha(1)-blockers in such combination therapy remains unknown. The aim of this study was to investigate the efficacy of a low dose of an alpha(1)-blocker added to combination therapy with CCBs and either ARBs or ACE inhibitors for the treatment of hypertension. Subjects were 41 hypertensive patients (23 women and 18 men, mean age 66+/-12 years) who had been followed at the National Kyushu Medical Center. All patients showed poor BP control despite haven taken a combination of CCBs and ARBs or ACE inhibitors for more than 3 months. Doxazosin at a dose of 1 to 2 mg was added to each treatment regimen. The changes in various clinical parameters, including BP and blood chemistry, following the addition of doxazosin were then evaluated. The mean follow-up period was 170 days. BP decreased from 152+/-14/81+/-12 mmHg to 135+/-14/70+/-11 mmHg after the addition of doxazosin at a mean dose of 1.5 mg/day (p<0.001). When good systolic blood pressure (SBP) control was defined as <140 mmHg, the prevalence of patients with good SBP control increased from 24% to 61% (p<0.01). Similarly, the prevalence of patients with good diastolic blood pressure (DBP) control (<90 mmHg) increased from 78% to 98% (p<0.01). Patients whose SBP decreased more than 10 mmHg (n=25) showed significantly higher baseline SBP, serum total cholesterol and low-density lipoprotein (LDL) cholesterol levels compared to those who showed less SBP reduction (<10 mmHg) (n=16, p<0.01). Comparable BP reductions were obtained between obese (body mass index [BMI] > or =25, DeltaBP at 3 months: -15+/-15/-12+/-9 mmHg, n=18) and non-obese (BMI<25, DeltaBP: -14+/-19/-7+/-8 mmHg, n=23) patients. The results suggest that addition of a low dose of the alpha(1)-blocker doxazosin effectively reduces BP in patients taking CCBs and ARBs or ACE inhibitors. Thus, doxazosin seems to be useful as a third-line antihypertensive drug.

Prevalence and lifestyle characteristics of hypertensive patients with metabolic syndrome followed at an outpatient clinic in fukuoka, Japan.

A new guideline on metabolic syndrome (MS) in Japanese was introduced in 2005. The purpose of this study was to evaluate the prevalence and lifestyle characteristics of Japanese hypertensive patients with MS. Subjects were 290 patients (mean age: 64+/-11 years) who had been followed at our hospital. The waist circumference (WC) and body mass index (BMI) were assessed. Subjects who had BMI >or=25 kg/m(2) were defined as having BMI obesity, while abdominal obesity was defined as a WC >or=85 cm in men and >or=90 cm in women, respectively. Since all patients had hypertension, the definition of MS was made when the patient had abdominal obesity plus either dyslipidemia or glucose intolerance, or both. Among the subjects, 230 patients underwent 24-h home urine collection to measure urinary salt and potassium excretions. Dietary habits were also assessed by use of a questionnaire. Mean values of BMI and WC were 24.2+/-3.4 kg/m(2) and 87.1+/-9.6 cm, respectively. Among the total subject group, 39% patients were classified as having BMI obesity, 49% as having abdominal obesity, and 27% as having MS. BMI was significantly correlated with WC both in men (r=0.86; p<0.01) and in women (r=0.79; p<0.01). More men than women belonged to the BMI obesity (46% vs. 33%, p<0.05), abdominal obesity (63% vs. 39%, p<0.01) and MS (39% vs. 18%, p<0.01) groups. There were no significant differences in blood pressure between patients with and without MS, while patients with MS needed a greater number of antihypertensive drugs than those without MS. Mean urinary salt and potassium excretions were 8.9+/-3.8 g/day and 1.9+/-0.7 g/day, respectively. Urinary salt excretion of <6 g (100 mmol of sodium)/day was achieved in 20% of the subjects. Urinary salt excretion in the patients with MS was significantly higher than that in the patients without (10.1+/-4.2 vs. 8.5+/-3.6 g/day; p<0.01). Only 16% of the patients with MS achieved salt restriction (<6 g/day). The patients with MS had a significantly greater the chance to eat out than the patients without MS. They were also less aware of the need to increase their vegetable consumption. The results suggested that MS is prevalent in Japanese hypertensive patients. Patients with MS showed higher urinary salt excretion and needed more antihypertensive drugs to manage their blood pressure. Dietary counseling focusing not only on sodium restriction but also on the need to increase fruit and vegetable consumption seems to be important.

Anti-proteinuric effect of an N-type calcium channel blocker, cilnidipine.

The objective of the present study was to determine anti-proteinuric effect of an N-type calcium channel blocker-cilnidipine. Subjects were 43 essential or renal hypertensive subjects who had been taking calcium channel blockers other than cilnidipine for at least 6 months. All patients had proteinuria greater than 0.2 g/day in spite of fair blood pressure control (<150/90 mmHg). Calcium channel blockers in 25 patients (62+/-3 years) were switched to cilnidipine (cilnidipine group), whereas other 18 patients (58+/-3 years) continued to take originally prescribed calcium channel blockers (control group). The 24-hr urine collections were done at baseline and after 6 months of the follow-up period. Baseline characteristics including age, blood pressure levels, body mass index and creatinine clearance were similar between cilnidipine and control groups. Urinary protein excretion also was comparable between cilnidipine (0.61+/-0.10 g/day) and control (0.86+/-0.17 g/day) groups. Urinary protein significantly decreased after 6 months in cilnidipine group (- 0.21+/- 0.11 g/day, - 36%, p< 0.01), whereas it did not change in control group (+ 0.01+/- 0.15 g/day, 0.4%, ns). There were no significant changes in blood pressure, serum creatinine, creatinine clearance, estimated protein intake, and urinary salt excretion during the follow-up period in either group. The reduction of urinary protein by cilnidipine was evident in essential hypertensives (- 54+/-9%, n=18, p<0.01) but not in renal hypertensives (+10+/-35%, n=7, ns). Results suggest that cilnidipine has an anti-proteinuric effect especially in patients with essential hypertension.

Long-term compliance with salt restriction in Japanese hypertensive patients.

The purpose of the present study was to investigate the long-term compliance with salt restriction in Japanese hypertensive patients. Subjects included 389 patients, 230 women and 159 men, mean age 58+/-11 years, who underwent successful 24-h home urine collection more than three times over an interval of a year. Urinary salt, potassium, and creatinine were measured. Additionally, family history, habitual alcohol intake, smoking habit, physical activities, and job status were assessed by use of a questionnaire. During the follow-up period (average 3.5 years), participants underwent urine collection 4.6 times in average. Urinary salt excretion at the last visit was significantly lower than that at the first visit (8.7+/-3.4 vs. 9.6+/-4.1 g/day; p<0.01). Urinary potassium excretion also decreased significantly during this period (from 2.0+/-0.7 to 1.9+/-0.7 g/day; p<0.05). Among the mean 4.6 urine collections, 45.2% (men 34.6%, women 52.6%) of the patients successfully achieved <6 g (100 mmol of sodium)/day of salt excretion on at least one occasion. The rate of achievement of averaged urinary salt excretion <6 g/day dropped to 10.3% (men 4.4%, women 14.3%). Only 2.3% (men 0.6%, women 3.5%) of the patients achieved <6 g/day on all occasions. There were no significant differences in age, habitual alcohol intake, smoking habit, physical activities, or job status between patients who complied with the salt-restricted diet and those who did not. Results suggest that long-term compliance with salt restriction is poor in Japanese hypertensive patients. Since no specifically defining characteristics were found in the compliant patients, repeated measurements of urinary salt excretion seem to be important to encourage salt restriction.

Relationship between the awareness of salt restriction and the actual salt intake in hypertensive patients.

A 24-h home urine collection was conducted to estimate accurate salt intake in hypertensive outpatients. Using 24-h urinary creatinine excretion as a criterion for success, urine samples were obtained from 534 hypertensive patients. The urinary salt excretion of hypertensive outpatients ranged widely from 1.5 to 23.4 g/day (mean value 9.7 +/- 3.9 g/day). Urinary salt excretion was higher in males than in females (10.6 +/- 4.0 vs. 9.2 +/- 3.7 g/day, p<0.01). Based on the questionnaires, the patients were divided into salt-conscious patients, or those who were careful to reduce their daily salt intake, and non-salt-conscious patients. It was found that urinary salt excretion was lower in the salt-conscious group than in the non-salt-conscious group (9.4 +/- 3.8 vs. 10.6 +/- 4.0 g/day, p<0.01), but that urinary salt excretion adjusted for body weight was not significantly different between the two groups (0.16 +/- 0.06 vs. 0.17 +/- 0.07 g/kg/day). Our results suggest that there was no obvious reduction in the actual salt intake in salt-conscious patients, suggesting the importance of monitoring salt intake by 24-h home urine collection and informing patients of their actual salt intake as a means of encouraging the achievement of salt restriction.

[Renoprotective effect of angiotensin II receptor blocker--does blood pressure play a pivotal role?].

Several recent randomized trials and clinical studies demonstrated that as well as angiotensin converting enzyme inhibitors angiotensin II receptor blockers(ARB) exerted renoprotective effect on diabetic and non-diabetic nephropathy. This renoprotective effect appears to be independent of the reduction of blood pressure, and be derived mainly from the suppression of renal renin-angiotensin system. Several mechanisms have been proposed regarding this renoprotective effect of ARB; e.g. hemodynamic effect in the intraglomerular pressure, reduction of proteinuria, decrease of collagen formation. Further investigation is required to clarify the precise mechanism.

[A unique case of recurrent malignant hypertension after removal of an adrenal tumor for primary aldosteronism].

We report here a unique case of recurrent malignant hypertension after the removal of an adrenal tumor for primary aldosteronism. The patient had a history of hypertension for 15 years. In 1995, he developed drug-resistant hypertension with hyperreninemia, hyperaldosteronemia and hypokalemia. He was diagnosed as having primary aldosteronism with a right adrenal tumor. His blood pressure did not normalize and renal dysfunction continued after the adrenalectomy. Although antihypertensive treatment was continued for residual hypertension, he soon refused medication. In 1997, he developed recurrent malignant hypertension. It was considered that the different underlying mechanisms might be attributable to the two episodes of malignant hypertension in this patient.