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It has been reported that cardiovascular events often occur on Monday morning, especially in the young working population. Because hypertension is a major cardiovascular risk, we examined whether blood pressure was elevated on Monday, especially in the morning during work. However, there were no weekly rhythms in blood pressure itself. Instead, we found significant interactions between the double product (systolic blood pressure × heart rate) and weekly (high on Monday) and circadian (high in the morning) rhythms. Further studies are required to determine whether Monday morning preference in cardiovascular events is caused by increased double product.

Background Dyslipidemia is a risk factor for the progression of chronic kidney disease (CKD). While conventional lipid lowering therapy provides a benefit to CKD management, the effect of statins on eGFR remains unclear. Methods A prospective, multi-center, open-labeled, randomized trial. Total of 349 CKD patients with hyperlipidemia were randomized into 2 groups, and followed for 2 years. Group A included patients who were treated with atorvastatin. Group C were treated with conventional lipid lowering drugs other than statin. Primary endpoint was changes in eGFR. Secondary endpoints included changes in urinary albumin excretion, serum LDL-C, serum triglyceride, cardio-vascular events and all-cause mortality. Results As the primary endpoint, eGFR decreased by 2.3 ml/min/1.73 m2 in Group A and by 2.6 ml/min/1.73 m2 in Group C, indicating that there was no difference in change of eGFR between the two groups. As secondary endpoints, atorvastatin succeeded to reduce serum LDL-C level significantly and rapidly, but conventional therapy did not. In fact, mean LDL-C level did not reach the target level of 100 mg/dl in Group C. Serum triglyceride was lowered only by atorvastatin, but not conventional drugs. The number of cardiovascular events and all-cause mortality did not differ between in two groups. Conclusion The ASUCA (Assessment of Clinical Usefulness in CKD Patients with Atorvastatin) trial demonstrated that atorvastatin failed to exhibit reno-protections compared to conventional therapy in Japanese patients with dyslipidemia and CKD. It would be due in part to the ability of atorvastatin to more potently reduce serum LDL and triglycerides compared to conventional therapy.

Primarily the sodium-glucose cotransporter 2 (SGLT2) inhibitors suppress the cotransport of glucose and sodium from the tubular lumen of proximal tubules to the blood and enhance the glucose excretion into urine. Therefore, glucose and caloric balances become negative, making the blood glucose level as well as insulin secretion both reduced. On the other hand, the proximal tubular fluid, constituting with low chloride concentration because of SGLT2 inhibition, is transferred to the loop of Henle. On the low chloride conditions, the reabsorption mechanisms in the loop of Henle do not work, as if loop diuretics are given. Finally, blood pressure is also lowered secondarily due to the loop diuretic action by SGLT2 inhibitions. Thus, the metabolic and hemodynamic combined systems synergistically interact further to suppress the risks leading to atherosclerosis and organs damage. Precise mechanisms for SGLT2 inhibitors to work in various aspects especially in preventing organ damage and cardiovascular events must be clarified further.

We tested the hypothesis that uric acid levels predict new-onset hypertension in the Japanese general population. Normotensive individuals who visited our hospital for a yearly health checkup (n=8157, men=61.0% and age=50.7±12.2 years) were enrolled in the present study. After baseline evaluation, participants were followed up for a median of 48.3 months (range 4.9-101.0 months), with the endpoint being the development of hypertension, defined as systolic blood pressure (BP)or = 140 mm Hg, diastolic BPor = 90 mm Hg or the use of antihypertensive medication. The impact of uric acid and other cardiovascular risk factors at baseline on future BP and development of hypertension was assessed. During follow-up, 19.0% of women (n=605) and 29.5% of men (n=1469) participants developed hypertension. Incident hypertension was increased across the quartiles for baseline uric acid levels (P0.0001), and multivariate Cox proportional hazards analysis revealed a significant and independent association between the uric acid level and the onset of hypertension in both men and women participants (P0.05). Furthermore, uric acid was independently and positively correlated with future BP (P0.05). Thus, uric acid is an independent predictor of new-onset hypertension in both women and men.

Introduction: We have reported that the circadian rhythm of urinary potassium excretion (U K V) is determined by the rhythm of urinary sodium excretion (U Na V) in patients with chronic kidney disease (CKD). We also reported that treatment with an angiotensin receptor blocker (ARB) increased the U Na V during the daytime, and restored the non-dipper blood pressure (BP) rhythm into a dipper pattern. However, the circadian rhythm of U K V during ARB treatment has not been reported. Materials and methods: Circadian rhythms of U Na V and U K V were examined in 44 patients with CKD undergoing treatment with ARB. Results: Whole-day U Na V was not altered by ARB whereas whole-day U K V decreased. Even during the ARB treatment, the significant relationship persisted between the night/day ratios of U Na V and U K V ( r =0.56, p

A man in his late seventies was suffering from right-sided pleural effusion and worsening leg edema. He was diagnosed with a rare case of secondary protein-losing enteropathy caused by constrictive pericarditis (CP) using technetium 99m-labeled human serum albumin abdominal scintigraphy and comprehensive Doppler echocardiography. We herein report the importance of evaluating a low cardiac output in addition to established Doppler echocardiographic findings for making a diagnosis of CP coexistent with protein-losing enteropathy.

OBJECTIVES: Microalbuminuria is closely associated with an increased risk of renal and cardiovascular adverse outcomes. The present study tested the hypothesis that titration of telmisartan reduces urinary excretion of albumin more than does addition of amlodipine in patients treated with a standard dose of telmisartan combined with a low-dose diuretic for the same degree of blood pressure (BP) reduction. METHODS: Hypertensive patients with type 2 diabetes mellitus and microalbuminuria under treatment with a combination of a standard dose of telmisartan (40 mg/day) and trichlormethiazide (1 mg/day) were randomly assigned to receive either an increased dose of telmisartan (80 mg/day) combined with trichlormethiazide [increased dose angiotensin receptor blocker (ARB) group, n = 20] or a combination consisting of telmisartan (40 mg/day), trichlormethiazide, and amlodipine (5 mg/day) (triple combination group, n = 20) for 6 months. The primary endpoint was a reduction in urinary albumin levels. RESULTS: Although BP was reduced to a similar extent by the two regimens, patients receiving the increased dose ARB showed a higher reduction in urinary albumin (-37.4 ± 16.9%) than those on the triple combination regimen (-8.9 ± 23.7%; P < 0.0001). The reduction in urinary albumin was correlated with the drop in BP in the latter group, but not in the increased dose ARB group. CONCLUSION: Uptitration of telmisartan more effectively reduces urinary albumin than addition of amlodipine in hypertensive patients with diabetes treated with a combination of telmisartan and diuretic for the same degree of BP reduction.

Primarily, the sodium-glucose cotransporter 2 (SGLT2) inhibitors suppress the cotransport of glucose and sodium from the tubular lumen of the proximal tubules to the blood, and excrete glucose into the urine. Therefore, glucose and caloric balances become negative, reducing both the blood glucose level and insulin secretion. On the other hand, the proximal tubular fluid, constituted with low chloride concentration because of SGLT2 inhibition, is transferred to the loop of Henle. Under low chloride conditions, the reabsorption mechanisms in the loop of Henle do not work, similar to when loop diuretics are given. Subanalysis data on heart failure (HF) from the EMPA-REG OUTCOME trials are discussed, assuming that SGLT2 inhibitors are loop diuretics. Renin-angiotensin system inhibitors and β-blockers contribute to prognostic improvements of HF, independent of SGLT2 inhibitors, and therefore, both regimens are essential for the treatment of HF. On the other hand, the prognostic improvements by SGLT2 inhibitors are not significant under treatment including conventional diuretics such as loop diuretics and aldosterone antagonists, suggesting that the prognostic improvement in HF by SGLT2 inhibitors is mostly through their diuretic action. (Circ J 2016; 80: 2277-2281).

Eur J Clin Invest 2012; 42 (12): 1287–1294 Abstract Background Although visceral obesity, a key abnormality in the metabolic syndrome, is an important risk for cardiovascular diseases, reduction in visceral fat is hard to achieve despite intensive efforts directed at lifestyle modification. The present study was designed to investigate whether ezetimibe, an inhibitor of intestinal cholesterol absorption through its binding to Niemann-Pick C1-like 1, reduces visceral fat in patients with metabolic syndrome. Materials and Methods Seventy-eight outpatients (63·7 ± 10·4 years old) with metabolic syndrome were enroled and randomly assigned to receive either ezetimibe (10 mg/day) or nothing for 6 months. Changes in visceral fat were assessed by computed tomography. Results Treatment with ezetimibe significantly improved lipid profiles. Visceral fat was decreased 7·2%, from 161·3 ± 58·6 cm2 to 148·4 ± 52·7 cm2 (P

Since dyslipidemia has been shown to be an independent risk factor for the progression of chronic kidney disease (CKD), low-density lipoprotein cholesterol (LDL-C)-lowering therapy can be potentially associated with inhibition of CKD progression. The ASsessment of clinical Usefulness in CKD patients with Atorvastatin (ASUCA) trial was designed to determine whether atorvastatin has protective effects on renal function in patients with dyslipidemia and CKD.We decided to carry out a prospective multi-center, open-labeled, randomized trial to compare the reno-protective effects between diet therapy alone and atorvastatin plus diet therapy in patients with dyslipidemia (LDL-C ≥ 140 mg/dL if not treated or LDL-C ≥ 100 mg/dL if treated with lipid-lowering drugs in subjects taking dyslipidemia-treating agents other than statins) and CKD [estimated glomerular filtration rate (eGFR)60 mL/min/1.73 m(2)]. The primary endpoint is the change in eGFR (mL/min/1.73 m(2)) as calculated by the modified MDRD equation for Japanese after 2 years of treatment.Enrollment began in April 2009 and was completed in March 2011. A total of 334 patients (213 male and 121 female) were randomly assigned to either diet therapy alone or atorvastatin plus diet therapy and included in an intent-to-treat population. In the atorvastatin and control groups, the mean ages were 63.2 and 63.1 years, mean eGFRs were 55.9 and 54.0 mL/min/1.73 m(2), and median urinary albumin/creatinine ratios were 24.9 and 29.1 mg/g, respectively.This study distinguishes itself from similar studies by increasing statistical accuracy derived from its significantly larger sample size and longitudinal magnitude. The results of this study will help to determine whether atorvastatin has reno-protective effects in patients with dyslipidemia and CKD.

High salt-sensitivity and nondipper blood pressure (BP) rhythm are highly associated with each other, because both are caused by impaired renal sodium excretion capability. We proposed that nocturnal hypertension and resultant pressure natriuresis could compensate for daytime sodium retention. If so, high BP may continue until sodium is sufficiently excreted at night. In fact, it takes longer for the night-time BP to fall in patients with more severe renal dysfunction. The time appears to be an essential component of the nondipper BP rhythm and, therefore, we defined the duration as the dipping time. Also, renal function was the sole determinant of a nocturnal BP dip other than age, sex, or BMI. Furthermore, we reported that diuretic therapy or dietary salt restriction, which can prevent sodium retention, restored the circadian BP rhythm into a dipper pattern. Large-scale studies are needed to explore whether these interventions can decrease the risks.

Central blood pressure is more closely associated with cardiovascular events and target organ damage than peripheral blood pressure measured over the brachium using a conventional method. This study was designed to investigate the distribution of central systolic blood pressure values estimated by Omron HEM-9000AI in the Japanese general population. A cross-sectional study were performed in 10,756 subjects without overt cardiovascular disease (male=6574; mean age 55.3±12.5 years, range 20-91 years). Of these, 7348 subjects received no antihypertensive, antidiabetic or lipid-lowering drug treatment, and were used for the present analysis. Estimated central systolic blood pressure was higher than brachial systolic blood pressure and was significantly correlated with age and brachial blood pressure. The central systolic blood pressure values obtained from subjects without cardiovascular risk factors other than hypertension were 125.8±37.2 (mean±2 s.d., n=3760) mm Hg. The values obtained from subjects with no cardiovascular risk factors were 112.6±19.2 (n=1975) mm Hg for optimal and 129.2±14.9 mm Hg for normal brachial blood pressure categories (n=697). This study is the first to show the distribution of central systolic blood pressure values estimated using the Omron HEM-9000AI, marking an important step toward implementing the clinical use of central blood pressure in the diagnosis and management of hypertension.

After myocardial infarction (MI), left ventricular (LV) remodelling is observed in noninfarcted LV myocardium. LV remodelling is closely associated with systolic heart failure. Since myocardial dysfunction is related to the downregulation of cardiac postsynaptic beta-adrenergic receptors (β-AR), we hypothesized that a reduction in β-AR density may be manifested in the remote noninfarcted region and such reduction may be related to myocardial systolic dysfunction. Accordingly, we assessed β-AR density with a focus on the remote noninfarcted region. Cardiac PET was performed in 15 patients with a prior MI and 10 age-matched healthy controls using 11C-CGP 12177, a radioligand for β-receptors. The maximum number of available specific 11C-CGP 12177 binding sites per gram of tissue was calculated in regions of interest using an established graphical method. LV regional systolic function was assessed based on peak systolic myocardial strain on the LV wall in the longitudinal direction using two-dimensional ultrasound speckle tracking imaging. LV volumes and LV ejection fraction (EF) were also measured. The LV end-diastolic volume index was significantly larger in patients than in controls (67.8 ± 16.9 vs. 49.1 ± 12.3 ml/m2, p

BACKGROUND Diagnosis of left ventricular (LV) diastolic dysfunction by blood testing is expedient in the clinical setting. METHODS AND RESULTS In 98 patients with LV ejection fraction ≥50% who underwent cardiac catheterization for evaluation of coronary artery disease, LV pressure (LVP) was measured using a catheter-tipped micromanometer. A time constant, τ, of LV relaxation was computed from LVP decay; the inertia force (IF) of late systolic aortic flow, a surrogate index of LV elastic recoil, was also computed from the LVP-dP/dt relation (phase loop). Patients were classified into 2 groups: those with impaired LV relaxation (τ ≥48 ms) and those with preserved LV relaxation (τ

Recently, we found that an angiotensin II receptor blocker (ARB) restored the circadian rhythm of the blood pressure (BP) from a nondipper to a dipper pattern, similar to that achieved with sodium intake restriction and diuretics (Fukuda M, Yamanaka T, Mizuno M, Motokawa M, Shirasawa Y, Miyagi S, Nishio T, Yoshida A, Kimura G. J Hypertens 26: 583–588, 2008). ARB enhanced natriuresis during the day, while BP was markedly lower during the night, resulting in the dipper pattern. In the present study, we examined whether the suppression of tubular sodium reabsorption, similar to the action of diuretics, was the mechanism by which ARB normalized the circadian BP rhythm. BP and glomerulotubular balance were compared in 41 patients with chronic kidney disease before and during ARB treatment with olmesartan once a day in the morning for 8 wk. ARB increased natriuresis (sodium excretion rate; UNaV) during the day (4.5 ± 2.2 to 5.5 ± 2.1 mmol/h, P = 0.002), while it had no effect during the night (4.3 ± 2.0 to 3.8 ± 1.6 mmol/h, P = 0.1). The night/day ratios of both BP and UNaV were decreased. The decrease in the night/day ratio of BP correlated with the increase in the daytime UNaV ( r = 0.42, P = 0.006). Throughout the whole day, the glomerular filtration rate ( P = 0.0006) and tubular sodium reabsorption ( P = 0.0005) were both reduced significantly by ARB, although UNaV remained constant (107 ± 45 vs. 118 ± 36 mmol/day, P = 0.07). These findings indicate that the suppression of tubular sodium reabsorption, showing a resemblance to the action of diuretics, is the primary mechanism by which ARB can shift the circadian BP rhythm into a dipper pattern.

We reported a remarkable regional difference within Japan in the incidence of end-stage renal disease. Regional differences were also well-known for salt intake, blood pressure (BP), and mortality from stroke, which remains one of the leading causes of death. Noting these regional differences, we examined mutual relationships among salt intake, BP, and stroke mortality in 12 regions of Japan. Data of salt intake, BP, and stroke mortality in 12 regions were collected from National Nutrition Survey (NNS-J), reanalysis of NNS-J, and Vital Statistics of National Population Dynamic Survey (Ministry of Health, Labor and Welfare), respectively. Significant regional differences were found in salt intake (P < .0001), mean arterial BP (P = .0001), and stroke mortality (P < .0001). Although annual changes in these parameters were also significant, their regional differences persisted. Salt intake had positive relationships with both mean arterial BP (r = 0.26, P = .0009) and stroke mortality (r = 0.26, P < .0001) across 12 regions, whereas mean arterial BP was not correlated with stroke mortality. Multiple regression analysis further identified salt intake as an independent factor to increase stroke mortality, but mean arterial BP was not a determinant. Compared with the four regions with lowest salt intake, odds ratios of stroke mortality adjusted by mean arterial BP were 1.04 (95% CI, 1.03-1.06) for the intermediate four regions and 1.25 (95% CI, 1.23-1.27) for the four regions with highest salt intake. These findings suggest that salt intake may have an adverse effect on stroke mortality independently of BP.

Although obesity has been reported to be associated with decreased plasma B-type natriuretic peptide (BNP) levels, it is unknown whether the reduced BNP levels in obesity results from decreased left ventricular (LV) hemodynamic load.We examined the relationships between body mass index (BMI), plasma BNP levels, and LV systolic and diastolic function (ejection fraction [EF] and end-diastolic pressure [EDP]) in 271 consecutive patients undergoing cardiac catheterization for coronary artery disease. When patients were grouped by tertile of BMI, with increasing tertiles of BMI, there was a progressive increase in EDP (lower, middle, and upper tertiles of BMI, 13.5 ± 5.8, 14.9 ± 5.3, and 16.3 ± 5.4 mmHg, respectively; p for trend0.01) and a progressive decrease in log BNP levels (lower, middle, and upper tertiles of BMI, 3.52 ± 1.29, 2.96 ± 1.08, and 2.87 ± 1.21 ln[pg/ml], respectively, p for trend0.001). There was no clear difference in EF across BMI tertiles (p for trend0.1). Plasma BNP levels correlated positively with EDP (r = 0.38, p0.001). In multivariate linear regression including EDP and known correlates of plasma BNP levels, BMI correlated negatively with BNP levels (standardized β = -0.31, p0.001).We found that increased BMI was associated with LV diastolic abnormalities without change in systolic function and that patients with increased BMI had reduced plasma BNP levels despite having elevated EDP. These results suggest that the reduced BNP levels in obesity are not explained by altered LV hemodynamics.

We previously showed that there are marked geographic differences in the incidence of end-stage renal disease (ESRD) within Japan. In addition, the use of renin–angiotensin system inhibitors was found to be inversely correlated with the increasing ESRD rate. It was recently demonstrated that the incidence of ESRD due to diabetic nephropathy is declining in both Europe and USA. Therefore, we investigated the increasing ESRD rate and its geographic difference in Japan. Each year, the Japanese Society for Dialysis Therapy reports the numbers of patients initiating maintenance dialysis therapy in each prefecture of Japan. We used old (1984–1991) and recent (2001–2008) data to compare the increasing ESRD rate, which was estimated from the slope of the regression line of the annual incidence corrected for population, between the two periods in 11 regions of Japan. Increasing ESRD rate almost halved, from 11.1 ± 5.6 to 5.4 ± 0.7/million per year from the old to the recent period. Deceleration of the increasing ESRD rate from the old to the recent period was correlated with the incidence in the old period across 11 regions (r = 0.81, p < 0.003); i.e., the deceleration was greater in the regions where ESRD incidence had been higher. Whereas the increasing ESRD rate was significantly different among regions in the old period, this was not the case in the recent period, resulting in uniformity throughout Japan. The increasing ESRD rate is slowing in Japan, and its geographic differences, previously observed, have disappeared.

BACKGROUND The present study was designed to test the hypothesis that brachial-ankle pulse wave velocity (baPWV) predicts longitudinal increases in blood pressure (BP) and new onset of hypertension in individuals with normal BP. METHODS baPWV was measured using a semiautomated device in 2,496 participants (27-84 years) without hypertension who visited our hospital for a yearly health check-up. They were followed up for 4 years with the endpoint being development of hypertension. RESULTS During the follow-up period (median, 733 days; actual follow-up, 5,215 person-years), hypertension developed in 698 participants (133.8/1,000 person-years). Kaplan-Meier analysis revealed that risk for hypertension was increased across the tertiles of baseline baPWV. The hazard ratio (first tertile as reference) was 2.02 (95% confidence interval (CI) 1.55-2.64) and 3.49 (95% CI 2.66-4.57) in the second and third tertiles, respectively, after adjustment for possible risk factors. Multivariate Cox proportional hazard regression analysis adjusted for known risk factors, where baPWV was used as a continuous variable, also indicated that the baseline value of baPWV independently predicted new onset of hypertension (P < 0.001). Furthermore, baseline baPWV was significantly associated with a longitudinal increase in BP after adjustment for known risk factors in multiple regression analysis (P < 0.001). CONCLUSION This study provides the first evidence that baPWV is an independent predictor of longitudinal increases in BP as well as of new onset of hypertension.

Evaluation of: Hayashi K, Saruta T, Goto Y, Ishii M; JATOS Study Group: Impact of renal function on cardiovascular events in elderly hypertensive patients treated with efonidipine. Hypertens. Res. 33(11), 1211–1220 (2010). Antihypertensive therapy with efonidipine-based regimens increased estimated glomerular filtration rate (eGFR) throughout the trial period in elderly patients with hypertension in both strict- and mild-treatment groups. The incidence of cardiovascular events was higher in patients with proteinuria than in those without proteinuria at baseline, while disappearance of proteinuria during antihypertensive therapy was closely associated with a reduced incidence of cardiovascular events. Furthermore, cardiovascular event rate was increased in patients with greater declines in eGFR during the study period of 2 years, although baseline eGFR did not correlate with the incidence of cardiovascular events. These findings have implications for therapeutic strategies in treating hypertension with regard to renal protection and cardiovascular events in elderly hypertensive patients.

Aims: Increased uric acid levels are associated with kidney dysfunction. We tested the hypothesis that uric acid level predicts future development of chronic kidney disease (CKD) in the general population. Methods: For this study, we enrolled 7,078 consecutive subjects with normal estimated glomerular filtration rates (eGFR; ≧60 ml/min/1.73 m2) who visited our hospital for a yearly health checkup (age: 52.8 ± 10.7 years; female: 35.8%). Subjects underwent a routine physical examination and laboratory assessment of cardiovascular disease risk factors at enrollment, and were followed up for 1,694 days (median) with the endpoint being the development of CKD (eGFR 2). The impact of uric acid and other cardiovascular risk factors at baseline on the future development of CKD were assessed. Results: During the follow-up period, 417 male (9.2%) and 151 female subjects (6.0%) developed CKD. Univariate logistic regression analysis revealed a significant association between the onset of CKD and age, male gender, body mass index, blood pressure, fasting plasma glucose, dyslipidemia and uric acid. Multiple logistic regression analysis revealed that new-onset CKD was independently correlated with the baseline uric acid level after adjustment for possible factors. Subanalysis showed similar results in subjects with normal uric acid levels (male: ≤7.0 mg/dl; female: ≤6.0 mg/dl; n = 6,223). Conclusion: Uric acid is an independent predictor of future development of CKD. Whether preventing an increase in uric acid levels reduces the incidence of CKD must be clarified by prospective follow-up studies.

Some cardiovascular disorders disturb circadian variation of endothelial function. We investigated whether deterioration of renal function alters circadian variation of endothelial function in patients with hypertension. Endothelial function was assessed by the peak forearm blood flow (FBF) response to reactive hyperemia, and 24-hour ambulatory blood pressure monitoring was performed in 25 patients with essential hypertension (61 ± 17 years). Relationships among renal function, 24-hour blood pressure, and endothelial function were analyzed. The ratio of nighttime to daytime mean arterial pressure was inversely correlated with estimated glomerular filtration rate (eGFR) ( r = −0.43, P = .03). The FBF response to reactive hyperemia examined at 21:00, but not at 6:30 or 11:30, was significantly correlated with eGFR ( r = 0.44, P = .03). Furthermore, the ratio of FBF response measured at 21:00 to that measured at 6:30 was independently correlated with eGFR (β = 0.47, P = .02). Renal dysfunction is associated with the derangement of circadian variation of both endothelial function and blood pressure. Nocturnal blood pressure is elevated, and evening endothelial function deteriorates in parallel with a decline in renal function in hypertensive patients.

OBJECTIVES Effective blood pressure (BP) control is difficult to achieve in diabetic patients. This study investigated factors that exacerbate resistance to antihypertensive medication in patients with diabetes. METHODS Hypertensive patients with type 2 diabetes (n = 108, 67 ± 9 years) were subjected to a step-wise upward titration of medication (step 1, routine dose of angiotensin receptor blocker; step 2, routine doses of angiotensin receptor blocker and calcium channel blocker; step 3, step 1 + double dose of calcium channel blocker; step 4, double doses of angiotensin receptor blocker and calcium channel blocker; step 5, step 4 + routine dose of diuretic; step 6, step 5 + routine dose of β-blocker; step 7, step 6 + routine dose of α-blocker; step 8, step 6 + double dose of α-blocker) implemented with a target home BP of below 130/80 mmHg. The step number at which target BP was achieved was considered the amount of antihypertensive medications needed for BP control. RESULTS All patients reached the target BP at step 4.0 ± 1.5. Multivariate regression analysis identified estimated glomerular filtration rate, but not measures of glycemic control, as an independent predictor of the number of drugs needed for BP control (P < 0.0001). CONCLUSION The number of antihypertensive medications needed for BP control in patients with diabetes mellitus is largely dependent on estimated glomerular filtration rate. Impaired kidney function could produce resistance to antihypertensive therapy in diabetic patients.

In this prospective, randomized, open-label, blinded end point study, we aimed to establish whether strict blood pressure control (P =0.38). In summary, blood pressure targets of

It is acknowledged that expansion of the remote normal region of the left ventricle causes remodeling after myocardial infarction (MI). However, the characteristics of that region have not been fully elucidated. We studied 13 patients with atypical chest pain (controls) and 15 patients with a prior anterior MI who underwent cardiac catheterization. With Doppler strain imaging, we measured the peak radial myocardial systolic strain and peak radial early diastolic strain rate at the posterior wall of the left ventricle. None of the patients with atypical chest pain exhibited significant stenosis of the three major coronary arteries or left ventricular (LV) wall motion abnormality in cardiac catheterization. The patients with a prior anterior MI had single anterior descending artery disease without wall motion abnormality in the LV inferoposterior wall. LV ejection fraction and the LV relaxation time constant were also measured. The LV ejection fraction was significantly smaller in patients with a prior MI compared to controls. The peak radial systolic strain in the LV posterior wall was not significantly different between the patients with a prior MI and controls (125 ± 49 vs. 122 ± 29%). In contrast, the peak radial early diastolic strain rate in the same area was significantly lower in the patients with a prior MI than in controls (−7.4 ± 2.7 vs. −13.2 ± 4.0 s−1, p

In healthy subjects, blood pressure (BP) drops by 10-20% during the night. Conversely, in patients with the salt-sensitive type of hypertension or chronic kidney disease, nighttime BP does not fall, resulting in an atypical pattern of circadian BP rhythm that does not dip. This pattern is referred to as the 'non-dipper' pattern. Loss of renal functional reserve, due to either reduced ultrafiltration capacity or enhanced tubular sodium reabsorption, induces the salt-sensitive type of hypertension. When salt intake is excessive in patients with salt-sensitive hypertension, the defect in sodium excretory capability becomes evident, resulting in elevated BP during the night. This nocturnal hypertension compensates for diminished natriuresis during the daytime and enhances pressure natriuresis during the night. Nocturnal hypertension and the non-dipper pattern of circadian BP rhythm cause cardiovascular events. When excess salt intake is loaded in patients who are in a salt-sensitive state, glomerular capillary pressure is also elevated, resulting in glomerular sclerosis and eventual renal failure. In this way, salt sensitivity and excess salt intake contribute to both cardiovascular and renal damage at the same time. We propose that salt sensitivity of BP and excess salt intake have important roles in the genesis of the cardiorenal connection. Salt sensitivity and circadian rhythm of BP are the keys to understanding the connections between cardiovascular and renal complications.

Aim: Peroxisome proliferator-activated receptor (PPAR) α is a nuclear receptor that through sensing fatty acid metabolites as ligands regulates genes involved in lipid transport and metabolism (Atherosclerosis 205: 413, 2009). Disruption of the PPARα gene, however, may not lead to apparent changes in phenotypes, perhaps due to compensation by other members of the nuclear receptor superfamily. We characterized cholesterol homeostasis in PPARα-null mice on a C57BL/6 background with a focus on HDL metabolism.Methods and Results: PPARα-null mice gained weight significantly more than wild-type mice, with more prominence in females, without changing the HDL-apoprotein clearance rate. Clearance of plasma HDL-cholesteryl ester was retarded, more prominently in females. Uptake of HDL-cholesteryl ester by the adrenal glands and ovaries was found to be decreased in female mutant mice. The ATP binding cassette transporter A1 (ABCA1), liver X receptor α and PPARδ mRNAs were decreased in the liver, and that encoding scavenger receptor B1 (SR-B1) decreased in the adrenal glands of these mice. Although the plasma lipoprotein profile did not show major differences, some subtle changes were found in the mutants, including HDL properties being consistent with its slow turnover. Cholesterol content in the organs was not significantly influenced except for a paradoxical increase in gonad glands.Conclusions: We conclude that the plasma HDL turnover rate is retarded in PPARα-null mice, perhaps more prominently in females.

Background: Although left ventricular (LV) diastolic dysfunction is associated with increased risk for incident heart failure in patients with coronary artery disease (CAD), no specific treatment for diastolic abnormalities has been established. Animal and small human studies have shown that an acute increase in LV afterload adversely impacts on LV early diastolic relaxation, but little is known about its chronic effect on diastolic function. Methods and Results: The relationships of various components of arterial load (arterial compliance, total vascular resistance index, and augmentation index [AI] in the ascending aorta) with LV diastolic function indices determined on cardiac catheterization (relaxation time constant [Tau] and end-diastolic pressure [EDP]) and those on tissue Doppler echocardiography (early diastolic mitral annular velocity [E'] and the ratio of early diastolic mitral inflow to annular velocities [E/E']) were investigated in 303 consecutive patients undergoing cardiac catheterization for CAD. All components of arterial load correlated with diastolic function indices, with AI, an index reflecting late-systolic load, having the strongest correlations with diastolic function indices. After adjustment for potential confounders, AI correlated with Tau (standardized β=0.25, P

Tako-tsubo cardiomyopathy, also called transient left ventricular apical ballooning, is a clinical entity first described in Japan. This syndrome is triggered by emotional or physical stress and mimics an acute coronary syndrome, although the coronary arteries are essentially normal. Recently, several reports have described variant forms of tako-tsubo cardiomyopathy, such as inverted tako-tsubo and mid-ventricular ballooning cardiomyopathy. We describe a case herein of an 87-year-old woman who presented a variant form of tako-tsubo cardiomyopathy complicated by syncope. Our findings may contribute to an elucidation of the mechanism underlying tako-tsubo cardiomyopathy.

We report a rare case of Holter monitoring documenting the onset of tako-tsubo cardiomyopathy in a 70-year-old woman. The patient experienced sudden chest discomfort after a quarrel in her hospital stay. Follow-up echocardiography on day 22 revealed a marked improvement of left ventricular apical akinesis. Angiographic examination at discharge showed neither coronary artery disease nor left ventricular asynergy.

Left ventricular (LV) remodeling occurs in the remote normal region in the LVs after myocardial infarction (MI) and is closely involved in heart failure. We assessed myocardial oxygen consumption using a clearance rate constant K mono for the time activity curves of 11C-acetate in 15 patients with a prior anterior wall MI, 8 with a prior inferior wall MI, and 10 age-matched normal control subjects. LV end-systolic volume index (ESVI) was determined by echocardiography. The LVESVI was significantly greater in patients with an anterior and inferior MI than in control subjects. The heart rate systolic pressure product did not differ among the groups. K mono in the remote normal region in patients with an anterior MI was significantly less than that in the corresponding area in control subjects (0.055 ± 0.005 vs 0.065 ± 0.008 min−1, P

Although higher red cell distribution width (RDW) has recently been reported to be associated with increased mortality independent of anemia in patients with heart failure and those with coronary artery disease (CAD), the mechanism underlying this association is unknown. We hypothesized that higher RDW may reflect neurohumoral activation and a chronic inflammatory state that each contribute to adverse clinical outcomes in these populations. We measured RDW and plasma levels of B-type natriuretic peptide (BNP) and high-sensitive C-reactive protein (hs-CRP) in 226 consecutive patients undergoing cardiac catheterization for CAD (age, 67 +/- 8 years; males, 77%; RDW, 45.8 +/- 3.3 fL; hemoglobin, 13.2 +/- 1.4 g/dL; BNP, median [interquartile range], 26.0 [9.0-58.4] pg/mL; hs-CRP, 679 [345-1920] ng/mL). Plasma BNP (r = 0.21, P0.01) but not hs-CRP (r = 0.04, P0.1) levels correlated with RDW. After adjustment for potential confounders including age, gender, body mass index, glomerular filtration rate, hemoglobin, and known hemodynamic determinants of BNP, including elevated left ventricular end-diastolic pressure and volume and slow left ventricular relaxation, RDW was independently predicted by BNP (r(2) = 0.058, P0.001). In conclusion, elevated BNP levels are independently associated with higher RDW in patients with CAD. Neurohumoral activation may be a mechanistic link between increased RDW and adverse clinical outcomes in this population.

The plasma concentration of B-type natriuretic peptide (BNP) in outpatients is hard to interpret because of the lack of knowledge of the natural within-person variation of BNP. In this study, we estimated the safety range of within-person variation in the plasma concentration of BNP in outpatients with stable heart failure.In a prospective historical cohort study, 6 consecutive measurements of the plasma concentration of BNP were made at 4-week intervals in 131 consecutive patients with strictly stable heart failure. The reference change values at the 95% CI and the 95% limits of agreement of the peptide concentration were calculated with a log-normal approach, and the results were back-transformed to a normal scale.The within-person distribution of BNP was right-skewed, and a Gaussian distribution was achieved by log transformation. In all of 15 combinations of paired measurements randomly selected from 6 measurements, the correlations were significant (P.001) with correlation coefficients ranging from 0.615 to 0.835. The up and down reference change values at the 95% confidence level for all measurements were 240.4% and -70.6% of the geometric means, respectively, and the median values of the upper and lower 95% limits of agreements were 219.7% and -71.8% of the geometric mean, respectively.The plasma concentration of BNP may triple or fall by one third without a change in the status of heart failure. In monitoring of patients with heart failure, BNP should be interpreted in the context of the skewed within-person distribution.

SummaryChronic kidney disease (CKD) is a serious clinical condition that is associated with a high incidence of cardiovascular disease and end-stage renal disease. Although CKD has been recognised as a risk factor for myocardial infarction (MI), genetic factors for predisposition to MI in individuals with CKD have remained largely unknown. The purpose of the present study was to identify genetic variants that confer susceptibility to MI in Japanese individuals with CKD. The study subjects comprised 1,339 Japanese individuals with CKD, including 496 subjects with MI and 843 controls. The genotypes for 248 polymorphisms of 181 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. An initial screen of allele frequencies by the chi-square test revealed that the 11496G→A (Arg353Gln) polymorphism of F7 (rs6046) was significantly (false discovery rate

We have postulated that the diminished renal capacity to excrete sodium causes nocturnal blood pressure (BP) elevation, which enhances pressure natriuresis in compensation for impaired daytime natriuresis. If such a mechanism holds, high BP during sleep at night may continue until excess sodium is sufficiently excreted into urine. This study examined whether the duration, defined as “dipping time,” until nocturnal mean arterial pressure began to fall to cr ; ρ=−0.61; P P P cr (mean arterial pressure: r =−0.58, P r =−0.69, P cr (mL/min), hazard ratios of nocturnal BP dip adjusted for age, gender, and body mass index were 0.37 (95% CI: 0.17 to 0.79; P =0.01) for the second tertile (C cr : 50 to 90) and 0.20 (95% CI: 0.08 to 0.55; P =0.002) for the third tertile (C cr : 5 to 41) compared with the first tertile (C cr : 91 to 164). These findings demonstrate that patients with renal dysfunction require a longer duration until BP falls during the night. The prolonged duration until BP dip during sleep seems an essential component of the nondipper pattern of the circadian BP rhythm.

Nifedipine has been shown to improve endothelial function. Recent studies have indicated that endothelial function is correlated with the number of circulating endothelial progenitor cells (EPCs), but it is unclear whether nifedipine affects the number and function of EPCs. The aims of this study were to determine the effects of nifedipine on the number and function of EPCs and to investigate the relationship between improvement of endothelial function and EPC numbers in patients with hypertension. Stage 1 hypertensive men (n=37) were randomly divided into the nifedipine group and the control untreated group. The nifedipine group was administered slow-release nifedipine (20 mg) once daily. At baseline and after 4 weeks, flow-mediated dilation, blood pressure, biochemical data, and number of circulating CD34+CD133+ progenitor cells and EPCs were measured. The direct effects of nifedipine on EPC number and function were assessed in vitro. In the nifedipine group, flow-mediated dilation and the number s of circulating CD34+CD133+ progenitor cells and EPCs were increased, along with a decrease of serum malondialdehyde low-density lipoprotein. The improvement of flow-mediated dilation by nifedipine was correlated with the increase of circulating CD34+CD133+ progenitor cells. Nifedipine also improved angiogenesis-related functions of EPCs (differentiation, migration, and resistance to oxidative stress) in vitro. Thus, nifedipine improved endothelial function and EPC function in stage 1 hypertensive subjects. The latter action may be mediated by reduction of oxidative stress and suppression of EPC apoptosis. These results demonstrate that nifedipine preserves endothelial integrity in patients with hypertension, at least partly, by enhancing EPC numbers and activity.

Each component of the metabolic syndrome is not necessarily clustered coincidentally. Thus, subjects who have obesity, dyslipidemia or impaired glucose tolerance may be at high risk for the development of hypertension. We studied the predictive value of the following for the development of hypertension: obesity (body mass indexor =25.0 kg/m2), dyslipidemia (high-density lipoprotein-cholesterol40 mg/dL, triglycerideor =150 mg/dL, or use of anti-dyslipidemic drugs), high normal blood pressure (130 mmHgor = systolic140 mmHg, or 85 mmHgor = diastolic90 mmHg), and impaired glucose tolerance (fasting plasma glucoseor =110 mg/dL or use of anti-diabetic agents). This observational study included 5,785 subjects without hypertension recruited from participants in our health checkup program. They were followed up for 1,097+/-365 d, with the endpoint being the development of hypertension. During the follow-up, hypertension developed in 1,168 subjects (74.1 per 1,000 person-years). The incidence of hypertension was higher in subjects who had obesity (106.2 vs. 67.8), dyslipidemia (96.1 vs. 69.0), high normal blood pressure (166.0 vs. 40.1), or impaired glucose tolerance (130.5 vs. 65.3 per 1,000 person-years) than in those without these disorders at baseline. The risk of hypertension was increased as the number of metabolic disorders in an individual increased. Multiple regression analysis indicated that obesity, high normal blood pressure, and impaired glucose tolerance remained independent predictors of the onset of hypertension. Thus, the presence of individual components of the metabolic syndrome predicts the development of hypertension. Prediction of the development of hypertension may lead to effective prevention of both hypertension and resulting cardiovascular diseases.

We have shown that as renal function deteriorated, night-time fall in both blood pressure and urinary sodium excretion were diminished. We have also reported that sodium intake restriction and diuretics both normalized circadian blood pressure rhythm from nondipper to dipper patterns. In this study, we investigated whether an angiotensin II receptor blocker, olmesartan, could restore night-time blood pressure fall.Twenty patients with chronic kidney disease (13 men, seven women; mean age 44.8 +/- 18.1 years; BMI 22.9 +/- 3.5 kg/m2) were studied. At baseline and 8 weeks after the treatment with olmesartan medoxomil (10-40 mg/day), 24-h blood pressure monitoring and urinary sampling for both daytime (0600-2100 h) and night-time (2100-0600 h) were repeated to compare the circadian rhythms of blood pressure and urinary sodium excretion.The 24-h mean arterial pressure was lowered by olmesartan, while urinary sodium excretion remained unchanged. On the other hand, daytime urinary sodium excretion was increased from 4.8 +/- 2.2 to 5.7 +/- 2.1 mmol/h, while night-time urinary sodium excretion tended to be reduced from 3.9 +/- 1.7 to 3.4 +/- 1.6 mmol/h. Night/day ratios of mean arterial pressure (0.98 +/- 0.1 to 0.91 +/- 0.08; P = 0.01) and urinary sodium excretion (0.93 +/- 0.5 to 0.68 +/- 0.4; P = 0.0006) were both decreased. Olmesartan enhanced night-time falls more in mean arterial pressure (r = 0.77; r2 = 0.59; P0.0001) and urinary sodium excretion (r = 0.59; r2 = 0.34; P = 0.007), especially in patients whose baseline night-time falls were more diminished.These findings demonstrated that olmesartan could restore night-time blood pressure fall, as seen with diuretics and sodium restriction, possibly by enhancing daytime sodium excretion. Since nocturnal blood pressure is a strong predictor of cardiovascular events, olmesartan could relieve cardiorenal load through normalization of circadian blood pressure rhythm besides having powerful ability to block the renin-angiotensin system.

Elevated plasma B-type natriuretic peptide (BNP) predicts future cardiovascular events in dialyzed patients without heart failure. We investigated whether carvedilol reduces the elevated BNP in these patients. Asymptomatic patients on chronic hemodialysis with elevated BNP but without clinical signs of heart failure were randomly assigned to receive either carvedilol (n = 10) or nothing (control group, n = 10). BNP and malondialdehyde-low density lipoprotein (MDA-LDL) were measured, and ultrasound cardiography was performed at baseline and at 3 months. Carvedilol reduced the concentrations of BNP (551 +/- 90 to 237 +/- 174 ng/L, P < 0.01) and MDA-LDL (174 +/- 63 to 85 +/- 23 U/L, P < 0.01) and increased the velocity ratio of E to A waves of the transmitral flow (E/A: 0.59 +/- 0.04 to 0.71 +/- 0.05, P < 0.05), while no such alterations were observed in the control group. The reduction in BNP concentration was correlated with that in MAD-LDL and the increase in the E/A. There was a significant correlation between the increase in the E/A and the reduction in MDA-LDL concentration. Thus, carvedilol reduces the elevated BNP by improving left ventricular diastolic function in dialyzed patients without heart failure, which may be attributable to the antioxidant property of the beta-blocker. Administering carvedilol may improve the prognosis in this population.

Recent studies have shown that metabolic syndrome is associated with an increased risk for chronic kidney disease. We recently found that the prevalence of sodium-sensitive hypertension in patients with metabolic syndrome was significantly higher than that in patients with essential hypertension but without metabolic syndrome. We therefore assessed the effects of benidipine, a long-acting calcium channel blocker, on the sodium sensitivity of blood pressure and renal hemodymamics in 5 patients with metabolic syndrome. Glomerular hemodynamics were assessed using pressure-natriuresis curves, which were constructed by plotting the urinary excretion of sodium as a function of the mean arterial pressure, which was calculated as the mean of 48 values based on 24-h monitoring, during the intake of low (3 g NaCl daily) and relatively high (10 g NaCl daily) sodium diets. Under the relatively high sodium diet condition, benidipine significantly lowered systolic and diastolic blood pressure. The pressure-natriuresis curve was steeper after the administration of benidipine. Benidipine lowered glomerular capillary hydraulic pressure (P(GC)) levels (from 54.4+/-7.5 to 47.0+/-7.0 mmHg, p=0.0152) and reduced both the resistance of the afferent arterioles (from 10,338+/-2,618 to 9,026+/-2,627 dyn.s/cm5, p=0.047) and the resistance of the efferent arterioles (from 4,649+/-2,039 to 2,419+/-2,081 dyn.s/cm(5), p=0.003). The urinary albumin excretion rate also decreased after the administration of benidipine. These findings indicated that benidipine may be effective for reducing the risk of developing chronic kidney disease in patients with metabolic syndrome.

Background Although there is a close relationship between dietary sodium and hypertension, the concept that persons with relatively high dietary sodium are at increased risk of developing hypertension compared with those with relatively low dietary sodium has not been studied intensively in a cohort. Methods and Results We conducted an observational study to investigate whether dietary sodium intake predicts future blood pressure and the onset of hypertension in the general population. Individual sodium intake was estimated by calculating 24‐hour urinary sodium excretion from spot urine in 4523 normotensive participants who visited our hospital for a health checkup. After a baseline examination, they were followed for a median of 1143 days, with the end point being development of hypertension. During the follow‐up period, hypertension developed in 1027 participants (22.7%). The risk of developing hypertension was higher in those with higher rather than lower sodium intake (hazard ratio 1.25, 95% CI 1.04 to 1.50). In multivariate Cox proportional hazards regression analysis, baseline sodium intake and the yearly change in sodium intake during the follow‐up period (as continuous variables) correlated with the incidence of hypertension. Furthermore, both the yearly increase in sodium intake and baseline sodium intake showed significant correlations with the yearly increase in systolic blood pressure in multivariate regression analysis after adjustment for possible risk factors. Conclusions Both relatively high levels of dietary sodium intake and gradual increases in dietary sodium are associated with future increases in blood pressure and the incidence of hypertension in the Japanese general population.

ObjectivesWe investigated whether a lack of inertia force of late systolic aortic flow and/or apical asynergy provoke early diastolic dysfunction in patients with coronary artery disease (CAD).BackgroundLeft ventricular (LV) isolated diastolic dysfunction is a well-recognized cause of heart failure.MethodsWe evaluated LV apical wall motion and obtained left ventricular ejection fraction (LVEF) by left ventriculography in 101 patients who underwent cardiac catheterization to assess CAD. We also computed the LV relaxation time constant (Tp) and the inertia force of late systolic aortic flow from the LV pressure (P)–first derivative of left ventricular pressure (dP/dt) relation. Using color Doppler echocardiography, we measured the propagation velocity of LV early diastolic filling flow (Vp). Patients with LVEF ≥50% (preserved systolic function [PSF], n = 83) were divided into 2 subgroups: patients with inertia force (n = 53) and without inertia force (n = 30). No patient with systolic dysfunction (SDF) (LVEF

Patients with infective endocarditis (IE) often have renal complications which may include infarcts, abscesses and glomerulonephritis (GN). Furthermore, it is generally accepted that there is an association between IE and anti-neutrophil cytoplasmic antibody (ANCA). Here, we report the case of a 24-year-old man who developed rapidly progressive GN in the course of IE due to infection with alpha-streptococcus. The initial clinical manifestation of the condition was severe sacroiliitis without fever. Sandwich ELISA showed that the patient was positive for PR3-ANCA at low titer, and the classical complement pathway was also activated. Renal biopsy demonstrated several lesions: focal embolic GN, GN with immune deposits and focal and segmental crescentic necrotizing GN. Treatment with antibiotics and steroids led to eradication of the infection, and resolution of the renal disease was accompanied by immediate disappearance of PR3-ANCA and hypocomplementemia. During a 4-year follow-up period, no recurrence was observed. There have only been 7 case reports of GN associated with IE and PR3-ANCA in which the renal pathology has been described, and the current report is the first to document renal pathology in a patient with isolated pulmonic valve IE and PR3-ANCA. Moreover, this report is the first to show a change in renal biopsy findings in response to treatment. A review of the 7 literature cases and that of our patient showed that none involved pauci-immune GN. Hence, further studies are needed to clarify the prevalence of pauci-immune GN in ANCA-positive IE patients.

Objective To assess whether an association between sodium-sensitive hypertension and metabolic syndrome exists; and whether, in patients with metabolic syndrome, the nocturnal fall of blood pressure decreases and salt restriction affects the circadian blood pressure rhythm. Methods Japanese patients with essential hypertension, who were treated without any antihypertensive agent, were maintained on a high-sodium diet and a low-sodium diet for 1 week each. On the last day of each diet, the 24-h blood pressures were measured. A diagnosis of metabolic syndrome was made according to the International Diabetes Foundation definition Results Among the 56 patients with essential hypertension, 15 patients were complicated with metabolic syndrome while 41 patients were not. The nocturnal blood pressure fall was significant in patients without metabolic syndrome, while it was not so in patients with metabolic syndrome. Only in patients with metabolic syndrome was the nocturnal blood pressure fall enhanced by sodium restriction. The prevalence of sodium-sensitive hypertension in patients with metabolic syndrome was significantly higher than in those without metabolic syndrome (70.6 versus 36.0%, respectively; P = 0.017). A multiple logistic regression analysis revealed central obesity to be an independent risk factor for sodium-sensitive hypertension (odds ratio, 1.41; 95% confidence interval, 1.04-1.91). Conclusions In patients with essential hypertension, an inter-relationship exists among metabolic syndrome, enhanced sodium sensitivity of the blood pressure and non-dipping. The elevated risk of cardiovascular diseases in patients with metabolic syndrome may be related to sodium-sensitive hypertension and non-dipping.

Background. Nocturnal polyuria has been well known in renal insufficiency. Recently, we found that as renal function deteriorated in chronic kidney disease (CKD), natriuresis was enhanced during the night with nocturnal blood pressure elevation. In the present study, we investigated whether nocturnal polyuria in CKD was due to the inability to concentrate urine, as previously proposed, or based on osmotic diuresis mainly by natriuresis. Methods. In 27 CKD patients, circadian rhythms of urinary sodium, potassium, urea and osmolar excretion rates (UNaV, UKV, UureaV, UosmV) as well as of urinary volume (V) and free-water clearance ðC H2O Þ were estimated during both daytime (6:00 to 21:00) and nighttime (21:00 to 6:00). Then, the night/day ratios of these parameters were analysed in relation to creatinine clearance (Ccr) as a marker of glomerular filtration rate. Results. Ccr had significantly negative relationships with night/day ratios of V (R ¼� 0.69; P < 0.0001), UosmV (R ¼� 0.54; P ¼ 0.004) and UNaV (R ¼� 0.63; P ¼ 0.0005), but no correlation with night/day ratios of CH2O (R ¼� 0.33; P ¼ 0.1), UKV (R ¼� 0.29; P ¼ 0.1) or UureaV (R ¼� 0.31; P ¼ 0.1). Linear and multiple regression analysis identified nocturnal natriuresis rather than urea excretion as an independent determinant of nocturia. Conclusion. As renal function deteriorated, nocturnal polyuria was seen, being consistent with classical recognition. Furthermore, this increase in nocturnal urine volume seemed related to osmotic diuresis mainly by natriuresis rather than to water diuresis or urea excretion.

Remarkable regional differences in the annual incidence of endstage renal disease (ESRD) was found within Japan, which has a relatively homogeneous ethnic composition. In addition, there existed no regional difference in the incidence of ESRD due to polycystic kidney disease, the major genetic disorder of the kidneys. These findings suggest that the presence of factors other than genetic disposition contribute to the differences. On the other hand, there were similar regional variations in the incidences of ESRD between two causes of ESRD: chronic glomerulonephritis and diabetic nephropathy. Because it is unlikely that the regional distribution of underlying disease incidence and the disease-specific progression rate would be similar for two different causes, this observation suggests that factors governing the progression rate, which operate commonly for all causes of ESRD but differ among regions, may play an important role in generating the regional differences. Finally, we examined regional differences in the amounts of inhibitors of the renin-angiotensin system used, especially angiotensin-converting enzyme (ACE) inhibitors, in our search for an explanation of the regional differences in ESRD dynamics. Among antihypertensive agents examined, only ACE inhibitors were negatively correlated with the annual incidence of ESRD. The renal protective effects of ACE inhibitors have been established by results with animal models of progressive nephropathy and by large-scale clinical trials. Our epidemiological results for Japan as a whole show the same protective effects still more convincingly from a different approach. It is not completely clear yet at present, however, how regional variations in the incidence of ESRD are generated. If we could identify in future the factors that contribute to the regional differences, strategies for the treatment of renal disease will become available from different angles. Thus, much effort will be encouraged for the further analysis of regional differences in ESRD dynamics.

SUMMARY: Background: We recently showed that there were clear regional differences in the dynamics of end-stage renal disease (ESRD) within Japan, which has an ethnically homogenous population. We speculate on the reason for these regional differences by correlating the regional distributions in the incidence of ESRD due to each of the following individual causes of ESRD: chronic glomerulonephritis (CGN), diabetic nephropathy (DMN) and polycystic kidney disease (PKD). Methods: The number of ESRD patients entering maintenance dialysis therapy due to individual causes of renal disease in each prefecture was reported annually for a 6-year period by the Japanese Society for Dialysis Therapy. After combining data from several prefectures into 11 geopolitical regions in Japan, the mean annual incidence of ESRD across the 11 regions was correlated among the three causes of ESRD. Results There were significant regional differences in the incidence of ESRD due to CGN (P

Myocardial characteristics of remote normal regions in patients with myocardial infarction (MI) and left ventricular (LV) remodeling have not been fully elucidated. Thus, we investigated this issue from the viewpoint of myocardial Tl-201 dynamics.In 14 patients with prior anterior MI, 10 with inferior MI, and 14 age-matched patients with atypical chest pain served as controls; exercise stress Tl-201 SPECT and cardiac catheterization were performed. Tl-201 washout rate was calculated for 8 myocardial segments, and LV end-diastolic volume index was obtained as a parameter of LV remodeling. LV end-diastolic volume index was greater in anterior MI patients than in control patients; in contrast, no significant difference was observed between inferior MI patients and control patients. The washout rate in remote normal regions was significantly less in anterior MI patients than in the corresponding segments in control patients (39.8% +/- 8.7% vs 48.4% +/- 4.4%, P.01). There was no significant difference between inferior MI patients and control patients (43.6% +/- 6.9% vs 47.8% +/- 4.5%).Reduced Tl-201 washout rates in remote normal regions are found in patients with anterior MI and LV remodeling. Subclinical myocardial ischemia during exercise in remote normal regions exists and may be related to the pathologic condition of such LV walls.