Responsiveness of α2-adrenoceptor/I1-imidazoline receptor in the rostral ventrolateral medulla to cardiovascular regulation is enhanced in conscious spontaneously hypertensive rat.

Stimulation of α2-adrenoceptor/I1-imidazoline receptors in the rostral ventrolateral medulla decreases the blood pressure via sympathoinhibition. However, alteration of receptor responses in genetically hypertensive rats remains unclear. We examined cardiovascular responses of α2-adrenoceptor/I1-imidazoline receptor agonist and antagonists microinjected into the rostral ventrolateral medulla of conscious spontaneously hypertensive rats and normotensive Wistar Kyoto rats. Injection of 2-nmol clonidine-an α2-adrenoceptor/I1-imidazoline receptor agonist-unilaterally into the rostral ventrolateral medulla decreased the blood pressure, heart rate, and renal sympathetic nerve activity; the responses were significantly enhanced in spontaneously hypertensive rats than in Wistar Kyoto rats. Co-injection of 2-nmol 2-methoxyidazoxan (a selective α2-adrenoceptor antagonist) or 2-nmol efaroxan (an I1-receptor antagonist) with 2 nmol of clonidine attenuated the hypotensive and bradycardic effects of clonidine-only injection. Injection of 2-methoxyidazoxan alone increased the blood pressure and heart rate in spontaneously hypertensive rats, but not in Wistar Kyoto rats. These results suggest enhanced responsiveness of α2-adrenoceptor/I1-imidazoline receptors in the rostral ventrolateral medulla of spontaneously hypertensive rats.

Differences in 24-h blood pressure profile of Japanese hypertensive patients under ARB treatment.

Blood pressure (BP) control throughout the entire day is recommended for cardiovascular protection. Angiotensin-II receptor blockers (ARBs) are widely used in hypertensive patients because of beneficial class effects. It is uncertain, however, whether are there any differences in 24-h BP profiles among ARBs. We examined ambulatory blood pressure monitoring (ABPM) among 211 Japanese hypertensive patients (age, 69.4 ± 9.6 years; female, 59.2%) under treatment with five different ARBs. Patients were divided into five groups according to ARBs prescribed. Patient backgrounds were almost identical in all the groups and there were no differences in office, 24-h and daytime BP; however, nighttime BP with olmesartan was significantly lower than with other ARBs. Office BPs with candesartan and telmisartan, but not other ARBs, correlated well with 24-h BP (p < 0.01). Also, there were higher correlations between daytime and nighttime BP with candesartan and telmisartan. In all patients, pulse pressure with office BP was significantly correlated with ambulatory arterial stiffness index (p = 0.001) and fluctuation of systolic BP on ABPM (p = 0.002). In conclusion, different ARB treatments produced meaningful differences in 24-h profiles.

A randomised controlled trial for the evaluation of risk for type 2 diabetes in hypertensive patients receiving thiazide diuretics: Diuretics In the Management of Essential hypertension (DIME) study.

OBJECTIVES: Thiazide diuretics are one of the first choice antihypertensives but not optimally utilised because of concerns regarding their adverse effects on glucose metabolism. The Diuretics In the Management of Essential hypertension (DIME) study was designed, for the first time, to assess the risk for type 2 diabetes mellitus in patients with essential hypertension during antihypertensive treatment with low-dose thiazide diuretics compared to those not treated with diuretics. DESIGN: Multicentre, unblinded, pragmatic, randomised, controlled trial with blinded assessment of end points and intention-to-treat analysis that was started in 2004 and finished in 2012. SETTING: Hypertension clinics at 106 sites in Japan, including general practitioners' offices and teaching hospitals. PARTICIPANTS: Non-diabetic patients with essential hypertension. INTERVENTIONS: Antihypertensive treatment with low-dose thiazide diuretics at 12.5 mg/day of hydrochlorothiazide or equivalent (Diuretics group) or that without thiazide diuretics (No-diuretics group). MAIN OUTCOME: The primary outcome was new onset of type 2 diabetes diagnosed according to WHO criteria and the criteria of Japanese Society of Diabetes. RESULTS: 1130 patients were allocated to Diuretics (n=544) or No-diuretics group (n=586). Complete end point information was collected for 1049 participants after a median follow-up of 4.4 years. Diabetes developed in 25 (4.6%) participants in the Diuretics group, as compared with 29 (4.9%) in the No-diuretics group (HR 0.93; 95% CI 0.55 to 1.58; p=0.800). CONCLUSIONS: Antihypertensive treatment with thiazide diuretics at low doses may not be associated with an increased risk for new onset of type 2 diabetes. This result might suggest safety of use of low doses of thiazide diuretics. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00131846.

Combinations of olmesartan and a calcium channel blocker or a diuretic in elderly hypertensive patients: a randomized, controlled trial.

OBJECTIVE: The aim of the present study was to compare the cardiovascular effects of olmesartan, an angiotensin II receptor blocker, combined with a calcium channel blocker (CCB) or a diuretic, in a prospective, randomized, open-label, blinded endpoint trial. METHODS: Japanese hypertensive patients aged at least 65 to less than 85 years with SBP at least 140 mmHg and/or DBP at least 90 mmHg with antihypertensive treatment, or SBP at least 160 mmHg and/or DBP at least 100 mmHg without antihypertensive treatment were randomized to receive olmesartan with either a dihydropyridine CCB or a low-dose diuretic. If SBP and/or DBP remained at least 140 and/or at least 90 mmHg, the other antihypertensive drug was added. The primary endpoint was a composite of fatal and nonfatal cardiovascular events. The median follow-up time was 3.3 years. RESULTS: Blood pressure decreased similarly in both groups. The primary endpoint occurred in 116/2568 patients (4.5%) in the olmesartan plus CCB group and in 135/2573 patients (5.3%) in the olmesartan plus diuretic group [hazard ratio 0.83, 95% confidence interval (CI) 0.65-1.07, P = 0.16]. Rates of all-cause death and cardiovascular deaths were similar. Among patients aged at least 75 years, the incidence of stroke tended to be lower in the olmesartan plus CCB group than in the olmesartan plus diuretic group (hazard ratio 0.63, 95% CI 0.38-1.02, P = 0.059, interaction P = 0.019). Fewer patients in the olmesartan plus CCB group (8.2%, 211/2568) than in the olmesartan plus diuretic group (9.8%, 253/2573; P = 0.046) experienced serious adverse events. CONCLUSION: Despite no significant difference in cardiovascular events, the different safety profiles suggest that the combination of olmesartan and CCB may be preferable to that of olmesartan and diuretic.

Diuretics enhance effects of increased dose of candesartan on ambulatory blood pressure reduction in Japanese patients with uncontrolled hypertension treated with medium-dose angiotensin II receptor blockers.

Abstract Although blockade of the renin-angiotensin system by increasing the dose of angiotensin II receptor blockers (ARBs) is recommended to achieve clinical benefits in terms of blood pressure (BP) control and cardiovascular and renal outcomes, the effect of this increased dose on ambulatory BP monitoring has not been evaluated completely in Japanese patients with uncontrolled hypertension undergoing medium-dose ARB therapy. The primary objective of this study was to examine the effect of the relatively high dose of the ARB candesartan (12 mg/day) on 24-h systolic BP and the attainment of target BP levels in uncontrolled hypertension treated with a medium dose of ARBs. A total of 146 hypertensive patients (age: 69.9 ± 9.3 years; females: 65.8%) completed the study. After switching to candesartan at 12 mg/day, all these BP measurements decreased significantly (p<0.001). Attainment of the target office BP (p=0.0014) and 24-h BP levels (p=0.0296) also improved significantly. Subgroup analysis indicated that the reduction of 24-h systolic BP was larger in patients treated with diuretics than those without (p=0.0206). Multivariate analysis revealed a significant correlation between the combined ARB and diuretic therapy, and the change in 24-h systolic BP irrespective of preceding ARBs. In conclusion, the switching therapy to increased dose of candesartan caused significant reductions in office and ambulatory BP levels, and improved the attainment of target BP levels in patients with uncontrolled hypertension treated with a medium dose of ARBs. Combination with diuretics enhanced this effect.

Target blood pressure for treatment of isolated systolic hypertension in the elderly: valsartan in elderly isolated systolic hypertension study.

In this prospective, randomized, open-label, blinded end point study, we aimed to establish whether strict blood pressure control (<140 mm Hg) is superior to moderate blood pressure control (> or =140 mm Hg to <150 mm Hg) in reducing cardiovascular mortality and morbidity in elderly patients with isolated systolic hypertension. We divided 3260 patients aged 70 to 84 years with isolated systolic hypertension (sitting blood pressure 160 to 199 mm Hg) into 2 groups, according to strict or moderate blood pressure treatment. A composite of cardiovascular events was evaluated for > or =2 years. The strict control (1545 patients) and moderate control (1534 patients) groups were well matched (mean age: 76.1 years; mean blood pressure: 169.5/81.5 mm Hg). Median follow-up was 3.07 years. At 3 years, blood pressure reached 136.6/74.8 mm Hg and 142.0/76.5 mm Hg, respectively. The blood pressure difference between the 2 groups was 5.4/1.7 mm Hg. The overall rate of the primary composite end point was 10.6 per 1000 patient-years in the strict control group and 12.0 per 1000 patient-years in the moderate control group (hazard ratio: 0.89; [95% CI: 0.60 to 1.34]; P=0.38). In summary, blood pressure targets of <140 mm Hg are safely achievable in relatively healthy patients > or = 70 years of age with isolated systolic hypertension, although our trial was underpowered to definitively determine whether strict control was superior to less stringent blood pressure targets.

Penicillin G-induced hemorrhagic cystitis with hydronephrosis.

Irritable urological symptoms with gross hematuria and bilateral lumbar pain developed when the patient received penicillin G for endocarditis. These symptoms were followed by renal insufficiency. A contrast-enhanced abdominal computed tomography (CT) scan revealed a thickened bladder wall, bilateral hydroureter and hydronephrosis, suggesting hemorrhagic cystitis complicated with urinary tract obstruction. Urine culture was negative. After discontinuation of penicillin G, all symptoms subsided and renal function recovered; hence, penicillin G seems to have been associated with hemorrhagic cystitis and acute kidney injury. Positive findings in the drug lymphocyte stimulation test (DLST) for penicillin G were consistent with this diagnosis.

Effect of heart rate on the risk of developing metabolic syndrome.

High heart rate and metabolic syndrome are risk factors for cardiovascular morbidity and mortality. The relationship between heart rate and risk of developing metabolic syndrome has not been studied in a large cohort. We examined the relationship between heart rate and the risk of developing metabolic syndrome in individuals who participated in a health evaluation program from 1997 to 2002. Among the 7958 individuals who participated in the program, 1677 were excluded from our study because they were being treated for heart disease or had been diagnosed with metabolic syndrome at baseline examination. A total of 6281 individuals (3789 men and 2492 women, 20-89 years of age) were evaluated. They were categorized according to their baseline heart rate and were followed up for a mean of 47+/-16 months (range: 7-71 months). Over the 5-year period, 619 individuals (9.9%) developed metabolic syndrome. Men with elevated baseline heart rates were more likely to experience metabolic syndrome than were those with normal heart rates. This was not true for female patients. The odds ratio (95% confidence interval) of developing metabolic syndrome among men in the highest quartile for heart rate was 1.725 (1.282-2.320) compared with those in the lowest quartile. Each increase in the heart rate category led to an approximately 1.2-fold increase in the risk of developing metabolic syndrome for men only, even after adjusting for age and lifestyle. Elevated heart rate is a risk factor for developing metabolic syndrome in men.

Improvement of cardiac function after granulocyte-colony stimulating factor-mobilized peripheral blood mononuclear cell implantation in a patient with non-ischemic dilated cardiomyopathy associated with thromboangiitis obliterans.

Cardiac involvement is a rare complication with thromboangiitis obliterans (TAO). We report a 29-year-old man with TAO accompanied with non-ischemic dilated cardiomyopathy. He had no history of heart disease, but echocardiogram demonstrated diffuse hypokinesis and dilated left ventricle. Coronary angiography revealed no organic stenotic lesion. For limb salvage, he was treated with granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cell (PBMNC) implantation on his right leg. Not only ischemic leg symptoms, but also plasma level of BNP and (123)I-metaiodobenzylguanidine scintigraphic parameters improved after 24 weeks. G-CSF-mobilized PBMNC implantation could be an effective approach to treating non-ischemic cardiomyopathy.

Prevalence of anemia according to stage of chronic kidney disease in a large screening cohort of Japanese.

BACKGROUND: The prevalence of chronic kidney disease (CKD) is high in developed countries, including Japan. However, little is known about the prevalence of anemia according to the estimated glomerular filtration rate (eGFR) among Japanese. METHODS: We studied screenees on the Okinawa General Health Maintenance Association (OGHMA) registry in 1993 (N = 94,602; 54,848 women and 39,754 men) who had both serum creatinine and hematocrit data. Anemia was defined as follows: hematocrit level <40% in men, <32% in women aged <50 years, and <35% in women aged >or=50 years. GFR was estimated using a new Japanese equation: eGFR (ml/min per 1.73 m(2)) = 194 x serum creatinine(1.094) x age(0.287) x 0.739 (if female). RESULTS: The prevalence of anemia clearly increased as CKD progressed below an eGFR of 60 ml/min per 1.73 m(2) in both genders. Logistic analysis adjusted with body mass index and older age (>or=70 years) revealed that the odds ratio for complications of anemia was significantly increased below an eGFR of 45 ml/min per 1.73 m(2) in women and 90 ml/min per 1.73 m(2) in men. The association of lower kidney function with anemia was found to be more prevalent: adjusted odds ratio >or=2.0, from approximately 50 ml/min per 1.73 m(2). CONCLUSION: The present study suggested that there might be as many as 1,000,000 people with CKD stage 3-5 complicated with anemia in Japan.

Heart rate as a risk factor for developing chronic kidney disease: longitudinal analysis of a screened cohort.

BACKGROUND: High heart rate and chronic kidney disease (CKD) are both risk factors for cardiovascular morbidity and mortality. The relationship between heart rate and the risk of developing CKD, however, has not been studied in a large screened cohort. METHODS AND RESULTS: We examined the relationship between heart rate and the risk of developing CKD in participants in a health evaluation program. CKD was diagnosed as glomerular filtration rate of less than 60 mL/min/1.73 m(2), calculated using the Modification of Diet in Renal Disease (MDRD) study equation or dipstick proteinuria. Among 7,958 subjects, 1,199 subjects diagnosed with CKD or with arrhythmia at baseline examination were excluded. A total of 6,759 subjects (4,268 men, 2,491 women, 20-84 years of age) were evaluated. The subjects were quadrisected according to baseline heart rate. The subjects were followed up for a mean of 47 +/- 16 months (range 7-71 months). Seven hundred and thirty-four subjects developed CKD over the 5-year follow-up period. Subjects with a high heart rate had greater magnitude of decreasing glomerular filtration rate (eGFR) and higher odds ratio of developing proteinuria. Cox analysis indicated that each heart rate category increment led to approximately 1.1 times increase in the risk of developing CKD, eGFR less than 60 mL/min/1.73 m(2), and 1.2 times increase of the risk of developing proteinuria in middle-aged or older subjects. CONCLUSIONS: High heart rate is a risk factor for developing CKD in middle-aged or older subjects.

Rationale, study design and implementation of the COLM study: the combination of OLMesartan and calcium channel blocker or diuretic in high-risk elderly hypertensive patients.

The COLM study is an investigator-initiated trial comparing the combination therapy using an angiotensin II receptor blocker (ARB), olmesartan, and a calcium channel blocker (CCB) with that using an ARB and a diuretic in high-risk elderly hypertensive patients. Here we describe the rationale and study design. Olmesartan was administered concomitantly with a long-acting dihydropyridine CCB (ARB/CCB group) or with a low-dose diuretic (ARB/diuretic group) to elderly hypertensive patients with a history of or risk factors for cardiovascular disease. Cardiovascular morbidity and mortality as a primary end point were compared between the two groups, with the target blood pressure (BP) being <140 mm Hg for systolic BP and <90 mm Hg for diastolic BP. Safety and tolerability will also be investigated. A total of more than 4000 patients were recruited and will be followed up for at least 3 years.

Role of HCN4 channel in preventing ventricular arrhythmia.

Bradycardia is a trigger of ventricular arrhythmias in patients with arrhythmia including Brugada syndrome and long QT syndrome. The HCN4 channel controls the heart rate, and its mutations predispose to inherited sick sinus syndrome and long QT syndrome associated with bradycardia. We found a 4 base-insertion at the splice donor site of the HCN4 gene in a patient with idiopathic ventricular tachycardia, which was supposed to generate a truncated channel. To investigate the role of the HCN4 channel in ventricular arrhythmia, we introduced a ventricular action potential of I(f) channel produced by HCN4 in a computer simulation model and found that the I(f) channel generated a leaky outward current during the plateau phase of ventricular action potential. Currents through the I(f) channel were suggested to contribute to the shortening of the action potential duration and the prevention of early after-depolarization in bradycardia. These observations suggested that the HCN4 channel played a preventive role in triggering bradycardia-induced ventricular arrhythmias.

Decreased body mass index as an independent risk factor for developing chronic kidney disease.

BACKGROUND: Obesity and metabolic syndrome are risk factors for the development of chronic kidney disease (CKD). Few studies have examined the effect of change in body mass index (DeltaBMI) on CKD incidence in a general screening setting. METHODS: Subjects of this study were screenees that participated in the screening program of the Okinawa General Health Maintenance Association in 1993 and 2003 in Okinawa, Japan. Using identification number, birth date, sex, and other recorded identifiers, we identified 33,389 subjects among the 1993 screening participants (N = 143,948) who also participated in the 2003 screening. CKD was defined as estimated glomerular filtration rate <60 ml/min/1.73 m(2), according to the modification of diet in renal disease study equation. Obesity was defined as BMI > or = 25 kg/m(2). RESULTS: CKD prevalence was 13.8% in 1993 and 22.4% in 2003. The incidence of developing CKD in 10 years was 15.5%. The effect of DeltaBMI on CKD incidence was evaluated after considering other confounding factors such as age, sex, blood pressure, BMI, fasting plasma glucose, and proteinuria. Median DeltaBMI was 1.0%. The adjusted odds ratio (95% CI) for the effect of DeltaBMI on CKD incidence was 1.111 (1.026-1.204, P < 0.01; entire study population), 1.271 (1.116-1.448, P = 0.0030; men), and 1.030 (0.931-1.139, NS; women), when DeltaBMI > or = 1% was taken as a reference. DeltaBMI was an independent predictor of CKD incidence. CONCLUSIONS: The present results suggest that there was an inverse relationship between DeltaBMI and CKD incidence among screened subjects. The reasons for this observation are not clear, but careful follow-up for DeltaBMI is necessary, particularly in obese men with proteinuria.

Dietary intervention with Okinawan vegetables increased circulating endothelial progenitor cells in healthy young women.

OBJECTIVE: Circulating endothelial progenitor cells (EPCs) play a critical role in maintaining the integrity of vascular vessels. The number of EPCs inversely correlates with the number of atherosclerotic risk factors. Although nonpharmacological treatment represents the first approach to the primary prevention of atherosclerotic diseases, little is known about the effects of diet on EPCs. We investigated the effect of a dietary intervention with vegetables that are commonly eaten in Okinawa on the number of EPCs. METHODS AND RESULTS: Forty-five healthy young women were employed and randomized to a dietary intervention group (n=24) or a control group (n=21). Subjects in the intervention group received typical Okinawan vegetables through home-parcel delivery for 2 weeks. After the dietary intervention, urinary potassium and magnesium excretion increased only in the intervention group and changes were greater than in the control group (p=0.007, 0.010, respectively). The consumption of total vegetables correlated with changes in both urinary potassium and magnesium excretion. Serum folic acid increased and plasma homocysteine decreased in both groups but the change was significant only in the intervention group. The EPCs number significantly increased in the intervention group but did not in the control group. An inverse correlation was observed between EPC number and plasma homocysteine level (r=-0.272, p=0.016). Changes in the EPC number inversely correlated with changes in both serum total cholesterol and low-density lipoprotein cholesterol level (r=-0.555, p=0.0002; r=-0.626, p<0.0001, respectively). CONCLUSIONS: The consumption of vegetables increased the number of circulating EPCs; this change might be associated with a homocysteine-lowering effect.

Proteinuria and decreased body mass index as a significant risk factor in developing end-stage renal disease.

BACKGROUND: Body mass index (BMI) is a significant predictor of developing end-stage renal disease (ESRD). The relation between a change in BMI (DeltaBMI) and the incidence of ESRD has not been examined in any large epidemiologic studies. METHODS: We determined the DeltaBMI in subjects who participated in the Okinawa General Health Maintenance Association (OGHMA) screenings in 1983 and again in 1993. Screenees were free of ESRD at the 1993 screening and were then monitored until the end of 2000 to determine whether they developed ESRD. Participants were identified using ID numbers, birthdates, and other identifiers. Details of every ESRD patient treated in Okinawa are maintained in an independent community-based dialysis registry. Multivariate logistic analyses were performed to determine the significance of a DeltaBMI on the incidence of ESRD using SAS. The ethics committee of the OGHMA approved the study protocol. Only coded data were used for this study. RESULTS: Among the 92,364 subjects aged 30-89 years screened in 1983, 29,011 (31.4%) returned for the 1993 screening. The median DeltaBMI was 2.1%, and the subjects were divided into two groups: DeltaBMI < 2.1% (G1) and DeltaBMI > or = 2.1% (G2). The cumulative incidence of ESRD was 0.31% in G1 (ESRD in 44) and 0.14% in G2 (ESRD in 21). The odds ratio (95% confidence interval) of developing ESRD based on a DeltaBMI was 2.268 (1.284-4.000, P < 0.01) after adjusting for age, sex, systolic blood pressure, BMI in 1983, and proteinuria. CONCLUSION: The findings of the present study suggest that a DeltaBMI is an independent risk factor for the incidence of ESRD, especially for those with proteinuria. The reasons for the BMI change were not recorded in this study. Unintentional weight loss, however, might warrant evaluation for the presence or progression of chronic kidney disease.

Pioglitazone, a thiazolidinedione derivative, attenuates left ventricular hypertrophy and fibrosis in salt-sensitive hypertension.

Thiazolidinediones, which stimulate peroxisome proliferator-activated receptor gamma, have been shown to prevent cardiovascular injury. However, little is known about their effects on salt-sensitive hypertension. We thus investigated whether or not pioglitazone affects left ventricular (LV) hypertrophy in Dahl salt-sensitive rats, then compared its effects to those of an angiotensin II receptor blocker, candesartan. Rats were used at 16 weeks of age after they had been fed either a low-salt (0.3%; DSL) or high-salt (8%; DSH) diet for 10 weeks; some of the DSH rats were treated with pioglitazone (10 mg/kg/day) or candesartan (4 mg/kg/day). Both drugs decreased the elevated blood pressure in DSH rats, although it was still higher than in DSL rats. Both drugs decreased plasma insulin levels, but neither affected plasma glucose levels. The thiobarbituric acid reactive substance level in the LV was decreased by both drugs. LV hypertrophy evaluated by echocardiography in DSH rats was nearly normalized by both drugs, whereas only candesartan decreased LV diameter. In histological analysis, both drugs ameliorated LV fibrosis and myocardial cell hypertrophy. Both drugs decreased elevated gene expression levels of transforming growth factor-beta1 and collagen type I, although the pioglitazone action was slightly modest. The metalloproteinase activity was increased in DSH rats, but both drugs decreased this level. Taken together, these findings indicate that pioglitazone reduced LV hypertrophy and fibrosis in salt-sensitive hypertension. Improvement in blood pressure, insulin level, and oxidative stress may be associated with this beneficial action of pioglitazone.

Association between heart rate and multiple risk factor syndrome: cross-sectional analysis of a screened cohort in Okinawa, Japan.

BACKGROUND: Increased heart rate (HR) and metabolic syndrome are risk factors for cardiovascular morbidity and mortality, but their relationship has not been studied in a large, screened cohort. METHODS AND RESULTS: The association between HR and multiple risk factor syndrome, resembling metabolic syndrome, was examined in participants of a health evaluation program in 1997. Of the 8,432 subjects (5,223 males, 3,209 females, 18-89 years of age), 1,502 (1,185 males, 317 females) were diagnosed with multiple risk factor syndrome and these subjects had higher HR than those without the syndrome (p<0.0001); subjects with a higher number of risk factors had higher HR than those with fewer risk factors (males, p<0.0001; females, p<0.0001). After adjusting for age, sex, and lifestyle factors, subjects within the highest HR quartile had a 2.5-fold higher risk for multiple risk factor syndrome than those in the lowest quartile (p<0.0001). An increase of 10 beats/min was associated with an approximately 30% increase in the risk for multiple risk factor syndrome. CONCLUSIONS: A higher HR is closely associated with multiple risk factor syndrome.

rHuEPO dose inversely correlated with the number of circulating CD34+ cells in maintenance hemodialysis patients.

BACKGROUND: A decreased number of endothelial progenitor cells (EPCs) as well as anemia have been reported to be associated with cardiovascular disease. Maintenance hemodialysis (MHD) patients who require higher doses of recombinant human erythropoietin (rHuEPO) have higher cardiovascular mortality. However, it has not been examined whether there is correlation between the numbers of CD34+ cells, including EPCs and erythroid progenitor cells, and the dose of rHuEPO in MHD patients. METHODS: We measured the number of circulating CD34+ cells by flow cytometry and examined the clinical characteristics in 35 MHD patients (50% male). RESULTS: A significant negative correlation was discovered between the number of circulating CD34+ cells and the dose of rHuEPO (r = -0.441, p = 0.013). We performed multivariate regression analysis to determine whether the number of CD34+ cells was associated with age, gender, diabetes, serum albumin, C-reactive protein, ferritin, statin, and dose of rHuEPO. The dose of rHuEPO, diabetes, and statin were independent predictors of the number of circulating CD34+ cells. A reciprocal analysis that divided these patients into two groups according to mean value of CD34+ cells also demonstrated the significant relationship between rHuEPO dose level and the number of CD34+ cells. CONCLUSION: These findings suggested that the requirement of a higher dose of rHuEPO to maintain target hemoglobin was associated with a decrease in the number of CD34+ cells. This relationship may be partly responsible for the higher cardiovascular mortality of this group among MHD patients.