Effects of atorvastatin on renal function in patients with dyslipidemia and chronic kidney disease: assessment of clinical usefulness in CKD patients with atorvastatin (ASUCA) trial.

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.

Diuretic Action of Sodium-Glucose Cotransporter 2 Inhibitors and Its Importance in the Management of Heart Failure.

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 ß-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).

[Nocturnal hypertension and cardio-renal association].

Circadian rhythm of blood pressure (BP) is closely linked with sodium balance. With positive sodium balance the nocturnal BP is elevated, resulting in non-dipper pattern. Nocturnal BP elevation plays an important role in the cardio-renal association to cause the cardiovascular events. It is vey important, therefore, how to lower nocturnal hypertension especially in CKD.

Kidney-protective effects of azelnidipine versus a diuretic in combination with olmesartan in hypertensive patients with diabetes and albuminuria: a randomized study.

BACKGROUND: A thiazide diuretic used in combination with benazepril is superior to amlodipine plus benazepril in reducing albuminuria in hypertensive patients with diabetes. However, calcium channel blockers have diverse characteristics. Thus, we investigated whether combining an angiotensin receptor blocker with either azelnidipine or a thiazide diuretic produced similar reductions in albuminuria in hypertensive diabetic patients for the same levels of blood pressure achieved. METHODS: Hypertensive patients with type 2 diabetes and albuminuria (30-600 mg/g creatinine) under antihypertensive treatment (mean age 67.0±7.6 years) were instructed to stop all antihypertensive treatment and take a combination of olmesartan (20 mg/day) and amlodipine (5 mg/day) for 3 months (run-in period). Then, patients were randomly assigned to receive either olmesartan plus azelnidipine (16 mg/day; n=71) or olmesartan plus trichlormethiazide (1 mg/day; n=72) for an additional 6 months. The primary end point was urinary excretion of albumin at 6 months after randomization. RESULTS: At the time of randomization, urinary albumin was 116.0 and 107.8 mg/g creatinine (geometric mean) in the azelnidipine and diuretic arms, respectively, and was reduced to a similar extent [79.8 (95% confidence interval 66.4-96.0) and 89.7 (74.6-107.7) mg/g creatinine, respectively, after adjustment for baseline values]. Blood pressure did not differ between the two groups throughout the study period. CONCLUSIONS: Azelnidipine is equally effective as a thiazide diuretic in reducing urinary albumin when used in combination with olmesartan.

Relationship between effective arterial elastance, total vascular resistance, and augmentation index at the ascending aorta and left ventricular diastolic function in older women.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is frequently observed in older women. Increased arterial stiffness in this population may be a cause of HFpEF. METHODS AND RESULTS: In 75 patients who underwent cardiac catheterization and who had no significant coronary artery stenosis or left ventricular (LV) wall motion abnormalities, the LV relaxation time constant (Tp) was calculated. The LVEF was obtained from left ventriculography, and plasma brain natriuretic peptide (BNP) level was measured. From the pressure waveforms at the ascending aorta, the augmentation index (AIx) was calculated. Effective arterial elastance (Ea) and total vascular resistance (TVR) were also determined. No significant differences were found between genders for age, heart rate, central blood pressure, or LVEF. Ea, TVR, AIx, and BNP level were significantly greater in women than in men, but only AIx was significantly correlated with Tp (r=0.25, P=0.04) and BNP level (r=0.33, P=0.005). CONCLUSIONS: The arterial system is stiffer in women than in men of the same age. Among the parameters of arterial stiffness, only AIx is related to abnormal LV relaxation and increased BNP level. Elevated AIx is a factor that causes LV diastolic dysfunction and may be associated with the development of HFpEF in this gender.

Effects of atorvastatin on renal function in patients with dyslipidemia and chronic kidney disease: rationale and design of the ASsessment of clinical Usefulness in CKD patients with Atorvastatin (ASUCA) trial.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Effects of ezetimibe on visceral fat in the metabolic syndrome: a randomised controlled study.

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 cm(2) to 148·4 ± 52·7 cm(2) (P < 0·05), and adiponectin was increased 7·7%, from 3·61 ± 3·10 µg/mL to 3·86 ± 3·62 µg/mL (P < 0·05), after ezetimibe therapy; these beneficial effects were not observed in the control group. The increase in the adiponectin level was correlated with the reduction in visceral fat after ezetimibe treatment. Furthermore, ezetimibe reduced fasting insulin levels (P < 0·05) and improved the homoeostasis model assessment of insulin resistance (HOMA-IR) (P < 0·05). CONCLUSIONS: Ezetimibe reduces visceral fat with beneficial effects on adiponectin and insulin resistance in patients with metabolic syndrome, suggesting a new therapeutic approach in such patients.

Cardiac ß-adrenergic receptor density and myocardial systolic function in the remote noninfarcted region after prior myocardial infarction with left ventricular remodelling.

PURPOSE: 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 (ß-AR), we hypothesized that a reduction in ß-AR density may be manifested in the remote noninfarcted region and such reduction may be related to myocardial systolic dysfunction. Accordingly, we assessed ß-AR density with a focus on the remote noninfarcted region. METHODS: Cardiac PET was performed in 15 patients with a prior MI and 10 age-matched healthy controls using (11)C-CGP 12177, a radioligand for ß-receptors. The maximum number of available specific (11)C-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. RESULTS: The LV end-diastolic volume index was significantly larger in patients than in controls (67.8 ± 16.9 vs. 49.1 ± 12.3 ml/m(2), p < 0.01). Significant differences in ß-AR density were observed among three areas: the apical area in controls (where the lowest ß-AR density was observed), the remote noninfarcted region of patients and LVEF ≥ 55 %, and the remote noninfarcted region of patients and LVEF <55 % (5.8 ± 2.1 vs. 4.2 ± 0.7 vs. 3.3 ± 0.7 pmol/ml, p < 0.01, ANOVA). Peak systolic myocardial strain was significantly reduced in the remote noninfarcted LV wall in patients with a prior anterior wall MI compared with that in the corresponding wall in controls (-15.5 ± 2.5 vs. -20.1 ± 2.2 %, p < 0.001). A similar finding was also observed in patients with a prior inferior wall MI. CONCLUSION: In the remote noninfarcted region in patients, ß-AR downregulation was observed, which was related to deterioration of local myocardial systolic function.

Salt sensitivity and nondippers in chronic kidney disease.

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.

Plasma N-terminal pro-brain natriuretic peptide levels identifying left ventricular diastolic dysfunction in patients with preserved ejection fraction.

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 <48 ms). Patients were also classified into another 2 groups: those with IF (≥0.5 mmHg) and those without (<0.5 mmHg). Plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥56.5 pg/ml had a sensitivity of 100%, specificity of 52.5%, and negative predictive value of 100% for identifying impaired LV relaxation. NT-proBNP ≥244.5 pg/ml had a sensitivity of 62.5% and specificity of 93.9% for detecting lack of IF. CONCLUSIONS: NT-proBNP level <56.5 pg/ml could be used as a value to sensitively identify patients with preserved LV systolic and diastolic function among those with coronary artery disease. NT-proBNP level ≥244.5 pg/ml is able to specifically detect a lack of IF and has potential for specifically diagnosing LV isolated diastolic dysfunction.

Circadian rhythm of urinary potassium excretion in patients with CKD.

AIMS: We previously reported in patients with chronic kidney disease (CKD) that the circadian rhythms of blood pressure (BP) and urinary sodium excretion were both impaired into non-dipper pattern as renal function deteriorated. However, the circadian rhythm of urinary potassium excretion has not been studied in relation to renal dysfunction. METHODS: BP and urinary excretion rates of sodium (UNaV) and potassium (UKV) were evaluated for daytime and nighttime to estimate their circadian rhythms in 83 subjects with CKD. RESULTS: As renal function deteriorated, night/day ratios of UNaV and UKV were both increased. Night/day ratio of UKV was positively correlated with night/day ratio of UNaV (r = 0.60, p < 0.0001). Multiple regression analysis (R2 = 0.37, p < 0.0001) revealed that night/day ratio of UKV was determined independently by the night/day ratio of UNaV (r = -0.55, p < 0.0001), rather than renal function or night/day ratio of BP. CONCLUSIONS: Circadian rhythm of natriuresis was regulated by renal function and night/day ratio of BP. On the other hand, the circadian rhythm of urinary potassium excretion was primarily determined by neither renal function nor BP, but was correlated with that of urinary sodium excretion.

Low birth weight and end-stage renal disease: demographic analysis by region in Japan.

UNLABELLED: BACKGROUND We have previously shown regional differences in the incidence of end-stage renal disease (ESRD)within Japan, which is ethnically homogenous, suggesting that non-genetic factors may contribute to the differences.We examined regional distribution in the incidence of low birth weight (LBW), a surrogate for low nephron number,in our search for an explanation. METHODS: Each year, the Ministry of Health, Labour and Welfare of Japan and the Japanese Society for Dialysis Therapy report the number of LBW babies and patients initiating maintenance dialysis in each prefecture of Japan,respectively. In this study, we calculated the annual incidences of LBW and ESRD in 11 regions of Japan over a 24-year period from 1984 to 2007. RESULTS: There were distinct regional differences in the annual incidences of both LBW and ESRD (p<0.0001).These regional distributions persisted despite consistent increases (p<0.0001) in incidences of both LBW and ESRD during the study period. Compared with the reference group consisting of 3 regions with the lowest LBW incidence, the odds ratios for ESRD (95% confidence interval) of the 5 regions with intermediate LBW incidence and the 3 regions with the highest LBW incidence are 1.09(1.05­1.14) and 1.29 (1.22­1.35), respectively. The annual incidence of LBW was positively correlated with annual incidence of ESRD in their regional distribution across 11 regions (r = 0.66, p = 0.03). CONCLUSIONS: The present study, relating regional distribution between LBW and ESRD dynamics in a nationwide population of Japan, revealed that the marked regional differences in the incidence of ESRD within Japan could be explained by a similar regional distribution in the incidence of LBW.

Angiotensin receptor blockers shift the circadian rhythm of blood pressure by suppressing tubular sodium reabsorption.

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; U(Na)V) 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 U(Na)V were decreased. The decrease in the night/day ratio of BP correlated with the increase in the daytime U(Na)V (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 U(Na)V 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.

Uric acid levels predict future development of chronic kidney disease.

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 m(2)) 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 <60 ml/min/1.73 m(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.

B-type natriuretic peptide levels and cardiovascular risk in patients with diastolic dysfunction on chronic haemodialysis: cross-sectional and observational studies.

BACKGROUND: Elevated B-type natriuretic peptide (BNP) levels are predictive of cardiovascular events in patients on chronic maintenance haemodialysis, even in those without apparent cardiovascular disorders when they start dialysis. In the present study, we tested the hypothesis that left ventricular diastolic dysfunction increases BNP levels and can predict cardiovascular events in patients on chronic haemodialysis without apparent cardiac disease. METHODS: Patients on chronic maintenance haemodialysis in a stable condition and with normal systolic function were enrolled (n=98). BNP concentrations were measured, and left ventricular diastolic function was assessed using echocardiography after the first dialysis session of the week. Then, they were followed up for 2 years with the end point being the incidence of cardiovascular events. RESULTS: At baseline, left ventricular diastolic dysfunction was detected in 39 of 98 patients. After adjustment for known risk factors, multivariable regression analysis demonstrated that diastolic dysfunction was a significant predictor of increased BNP levels (P<0.05). During the follow-up period, 17 patients experienced cardiovascular events. Kaplan-Meier analysis demonstrated that the incidence of cardiovascular events was higher in patients with (28.2%) than without (10.2%) left ventricular diastolic dysfunction (log-rank, P<0.01). Univariate Cox proportional hazards regression analysis indicated that diastolic dysfunction and BNP were significant predictors of cardiovascular events (hazard ratio 3.63 and 4.87, respectively; P<0.05). CONCLUSIONS: Left ventricular diastolic dysfunction is associated with increased BNP levels and an increased risk of cardiovascular events in patients on haemodialysis.

Reduced renal function is associated with combined increases in ventricular-systolic stiffness and arterial load in patients undergoing cardiac catheterization for coronary artery disease.

Although mildly reduced renal function is associated with increased risk for heart failure in patients with coronary artery disease (CAD), mechanisms underlying the association remain unclear. We tested the hypothesis that abnormal ventricular-arterial interaction may occur in mildly reduced renal function. We examined the relationships of the estimated glomerular filtration rate (eGFR) with various indices reflecting ventricular-arterial coupling [effective arterial elastance (the ratio of left ventricular (LV) end-systolic pressure to stroke volume, E (a)], LV end-systolic elastance (the ratio of LV end-systolic pressure to end-systolic volume, E (es)), and the total arterial compliance (the ratio of stroke volume to aortic pulse pressure)] and those of LV systolic and diastolic function [peak systolic and diastolic mitral annular velocities (S' and E') and the ratio of peak early diastolic mitral inflow to annular velocity (E/E')] in 320 consecutive patients who underwent cardiac catheterization for CAD and had normal (≥ 0.50) ejection fractions (EF). As eGFR decreased, E (a) and E (es) increased and total arterial compliance and E' decreased. eGFR did not correlate with E (a)/E (es), S', or E/E'. After adjusting for potential confounders, the findings were generally similar, but the correlation of eGFR with E' did not remain significant. In conclusion, reduced renal function may be associated with combined increases in ventricular-systolic stiffness and arterial load in known or suspected CAD patients with normal EF.

Geographic differences in the increasing ESRD rate have disappeared in Japan.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: The increasing ESRD rate is slowing in Japan, and its geographic differences, previously observed, have disappeared.

Pulmonary venous occlusion and death in pulmonary arterial hypertension: survival analyses using radiographic surrogates.

BACKGROUND: Recent studies find that a considerable number of patients with pulmonary arterial hypertension (PAH) develop fibrous obstruction of the pulmonary veins. Such obstruction more commonly accompanies connective tissue disorder (CTD)-associated PAH than idiopathic PAH. However, few researchers have gauged the risk of death involving obstruction of the pulmonary veins. METHODS: Thirty-seven patients with PAH were enrolled (18 patients, idiopathic PAH; 19 patients, CTD-associated PAH). The patients were 49 ± 18 years and had a World Health Organization functional class of 3.2 ± 0.6. Thickening of the interlobular septa, centrilobular ground-glass attenuation, and mediastinal adenopathy were surrogates for obstruction of the pulmonary veins, and were detected by a 16-row multidetector computed tomography scanner. RESULTS: The follow-up period was 714 ± 552 days. Fifteen deaths occurred. Thickening of the interlobular septa, centrilobular ground-glass attenuation, and mediastinal adenopathy were found in 37.8%, 24.3%, and 16.2% of patients, respectively. Cox proportional hazard analysis revealed an increased risk of death with each radiographic surrogate (mediastinal adenopathy: p < 0.0001, hazard ratio = 13.9; thickening of interlobular septa: p < 0.001, hazard ratio = 12.0; ground-glass attenuation: p = 0.02, hazard ratio = 3.7). The statistical significance of these relationships was independent of the cause of PAH and plasma concentration of brain natriuretic peptide. CONCLUSIONS: The results of this study imply that obstruction of the pulmonary veins is associated with an increased risk of death in patients with PAH.

[Merit and demerit of fixed dose combination therapy between ARB and diuretics in hypertension].

When RAS inhibitors are prescribed as the first-line agent in hypertension, the combination of diuretics on them exerts several preferable effects in both blood pressure lowering and organ protection. As far as low-dose of diuretics, the unfavorable side effects such as hypokalemia and insulin resistance can be minimized by RAS inhibitors. Therefore, unless the compelling indication for Ca channel blockers exists, diuretics should be added on RAS inhibitors.