High Coronary Heart Disease Risk in Hemodialysis Patients with Central Sleep Apnea: A Pilot Study.

BACKGROUND: The high prevalence of sleep apnea is reported in hemodialysis patients despite the low prevalence of obesity. The present study compared the occurrence of central sleep apnea (CSA) in hemodialysis patients with that in non-hemodialysis patients, and its association with new-onset coronary heart disease (CHD) events. METHODS: Seventy-three hemodialysis and 444 non-hemodialysis patients were examined for CSA and obstructive sleep apnea (OSA) occurrence using polysomnography. Hemodialysis patients were monitored for the occurrence of new-onset CHD events. RESULTS: Hemodialysis patients had a significantly higher central apnea-hypopnea index (AHI; 0.7, range 0.2-3.1) than age-, sex- and obstructive AHI-matched non-hemodialysis patients (0.1, range 0-1.0; p < 0.001), in contrast with an insignificant difference for obstructive AHI. Furthermore, the prevalence of CSA was significantly higher in the hemodialysis (21.9%) than in the non-hemodialysis group (9.7%; p = 0.004). A significant and negative association existed between log (central AHI + 1) and Kt/V in hemodialysis patients. In the Kaplan-Meier analysis, hemodialysis patients with CSA had a significantly higher rate of new-onset CHD events than those without CSA. Cox proportional-hazards regression analysis identified CSA prevalence as an independent risk factor for the development of a new-onset CHD event, independent of OSA. CONCLUSIONS: The present study demonstrated that hemodialysis patients had a significantly higher CSA prevalence than non-hemodialysis patients despite similar obstructive AHI, and that hemodialysis patients with CSA had a significantly higher risk for new-onset CHD events than those without CSA independent of obstructive AHI, suggesting CSA as a potential CHD risk specifically in hemodialysis patients.

Teriparatide Therapy Reduces Serum Phosphate and Intima-Media Thickness at the Carotid Wall Artery in Patients with Osteoporosis.

Although cross-sectional and longitudinal studies report a relationship between osteoporosis and cardiovascular disorders (known as the bone-cardiovascular axis), the benefits of osteoporosis treatment on atherosclerosis are largely unclear. Teriparatide is a bone-forming agent that increases urinary phosphate excretion. Because elevated serum phosphate is associated with the development of atherosclerosis, the purpose of our study was to examine the relationship among lumbar spine bone mineral density (LS-BMD), intima-media thickness at the carotid artery (CA-IMT), and phosphate metabolism in response to daily teriparatide therapy. Osteoporotic patients (n = 28) with low LS-BMD (T-score < -2.5) and/or at least one vertebral fracture were treated with teriparatide (20 µg/day) for 12 months. Metabolic bone markers, LS-BMD, and CA-IMT were measured over the course of treatment. The LS-BMD significantly increased by 0.046 ± 0.038 g/cm(2) over the 12-month period (P < 0.001). CA-IMT decreased from 0.701 mm (interquartile range: 0.655-0.774 mm) at baseline to 0.525 mm (0.477-0.670 mm) at 12 months (P < 0.05); however, CA-IMT change was not significantly associated with LS-BMD change. Serum phosphate decreased after 1 month of teriparatide administration, and the change in serum phosphate at 1 months was associated with the change in CA-IMT at 12 months (ρ = 0.431, P = 0.025). Teriparatide improved LS-BMD and CA-IMT, suggesting the existence of the bone-cardiovascular axis. The association between serum phosphate and CA-IMT suggests that the teriparatide decreased CA-IMT in part by reducing serum phosphate, a well-known vascular toxin, in addition to the improvement of bone-cardiovascular axis.

REM sleep latency as an independent risk for cardiovascular events in hemodialysis patients.

BACKGROUND: Clinical significance of objectively measured poor sleep quality (SQ) as a risk for cardiovascular disease (CVD) events is not well known in hemodialysis (HD) patients, independently of sleep-related breathing disorders (SRBDs) and sleep-related metabolic abnormality. METHODS: The present study investigated baseline levels of objective sleep architecture together with obstructive sleep apnea (OSA) and central sleep apnea (CSA) using polysomnography in 88 HD study participants (M/F, 56/32; age 68.4 ± 9.3). Then, HD study participants were monitored for the occurrence of new-onset CVD events with a median (range) follow-up period of 33 (1-64) months. RESULTS: Among various measures of SQ, log (REM sleep latency [REM-SL]) (interval between sleep-onset and the first REM period) alone correlated in negative manners with triglycerides and non-HDL-C in all study participants and with fasting plasma glucose and HbA1c in study participants with type-2 diabetes mellitus. In the Kaplan-Meier analysis, HD study participants with shorter REM-SL had a significantly higher rate of new-onset CVD events than those with longer REM-SL. Stepwise logistic regression analysis and multivariate Cox proportional hazard regression analysis identified shorter REM-SL as an independent risk factor for the development of a new-onset CVD events, independent of mean oxygen saturation, log (AHI+1), log (central AHI+1), diabetes mellitus, CVD history, systolic blood pressure, statins use, and non-HDL-C. CONCLUSIONS: The present study demonstrated that reduction of REM-SL is independently associated with a higher rate of new-onset of CVD events, independent of SRBDs (OSA and CSA) and diabetes mellitus, non-HDL-C in HD study participants, suggesting impaired SQ as a potential CVD risk factor, and thus a definite treatment target to protect against CVD specifically in HD study participants. REM-SL might be a new risk factor of CVD events in HD patients with SRBDs.

Positive association of plasma leptin with sleep quality in obese type 2 diabetes patients.

AIMS/INTRODUCTION: Poor sleep quality is associated with obesity and diabetes. The adipocyte-derived hormone, leptin, was recently shown to underlie the link between abnormal sleep and obesity. We aimed to investigate the association between leptin and sleep quality in type 2 diabetes patients. MATERIALS AND METHODS: In the present cross-sectional study, we studied 182 type 2 diabetes patients, among whom 113 were diagnosed with obesity (body mass index ≥25 kg/m2 ). Fasting plasma leptin levels were measured, and sleep architecture was assessed using single-channel electroencephalography. RESULTS: Using unadjusted analyses, the obese type 2 diabetes patients, but not their non-obese counterparts, showed a positive correlation between plasma leptin levels and a parameter for deep sleep assessed by delta power during the first sleep cycle. Multivariate analysis showed that plasma leptin levels were positively associated with delta power, but not with the total sleep time, after adjusting for potential confounders including age, body mass index and the apnea-hypopnea index, in the obesity group. However, neither delta power nor total sleep time was associated with leptin in the non-obesity group. CONCLUSIONS: Plasma leptin levels are independently associated with sleep quality in obese, but not in non-obese, type 2 diabetes patients. The present study indicates a favorable relationship between leptin and sleep quality in obese type 2 diabetes patients.

Association of Erythropoietin Resistance with Fatigue in Hemodialysis Patients: A Cross-Sectional Study.

BACKGROUND/AIMS: Fatigue is a common symptom in patients receiving hemodialysis (HD) and is generally associated with anemia. However, it can be difficult to resolve, even when anemia has been treated using erythropoiesis-stimulating agents and iron replacement therapy. In the present study, we examined the associations of anemia, the erythropoietin resistance index (ERI) and iron deficiency with fatigue during HD. METHODS: In this cross-sectional study, fatigue score was calculated on the basis of questionnaire responses in HD patients. Participants were divided into 3 groups according to their hemoglobin (Hb) levels (low, normal and high). Iron deficiency was assessed as a transferrin saturation (TSAT) of <20%. RESULTS: We included 571 HD patients (men/women 368/203; mean age 62.2 ± 10.8 years). Among the 3 groups, fatigue scores increased significantly with decreasing Hb levels. HD patients with low Hb levels (<90 g/l) had significantly higher fatigue scores than those with higher Hb levels (≥120 g/l). In the multiple regression analysis, we showed that a high ERI (ß = 0.208) and a low TSAT (ß = -0.155), but not the Hb level, were significantly associated with increased fatigue score. Moreover, this was independent of age, gender and modifiable confounders linked to anemia. Even after restricting patients to those without iron deficiency (TSAT ≥20%), the ERI (ß = 0.258) retained a significant and independent association with the fatigue score. CONCLUSION: Iron deficiency and a high ERI despite iron sufficiency may cause fatigue in HD patients.

Association of Nocturnal Hypertension With Disease Activity in Rheumatoid Arthritis.

OBJECTIVES: Both nocturnal hypertension (HT) and systemic inflammation underlying rheumatoid arthritis (RA) have been shown to be independent predictors of cardiovascular disease (CVD), although little is known on the relationship between nocturnal blood pressure (BP) and disease activity in RA patients. METHODS: We performed 24-hour ambulatory BP monitoring (ABPM) in 71 RA patients to examine the relationship of nocturnal fall in BP and RA disease activity based on a disease activity score of 28 joint counts with C-reactive protein (CRP, 28-joint disease activity score (DAS28)-CRP). Among them, 25 RA patients whose consent obtained were reexamined by ABPM to assess the improvement of nocturnal fall in BP after RA therapeutic intervention. RESULTS: The mean DAS28-CRP level was 4.8±1.6 in 71 RA patients. The mean nocturnal fall in BP was 5.6±8.9%. DAS28-CRP was associated significantly and independently in a negative manner with the nocturnal fall in BP (ß = -0.388, P = 0.004). In 25 RA patients, DAS28-CRP improved from 5.4±1.1 to 3.5±0.8 (P < 0.0001) and the nocturnal fall in BP increased significantly from 4.5±9.2% to 10.6±5.8% (P = 0.002) with the significant decrease of nighttime systolic BP (SBP) from 121.2±22.5mm Hg to 112.5±18.8mm Hg (P = 0.02) in spite of no change in daytime BP after 4 weeks of RA treatment. CONCLUSIONS: The present study observed that higher RA activity was associated with lower nocturnal fall in BP, but not daytime BP, in RA patients.

Association between poor glycemic control, impaired sleep quality, and increased arterial thickening in type 2 diabetic patients.

OBJECTIVE: Poor sleep quality is an independent predictor of cardiovascular events. However, little is known about the association between glycemic control and objective sleep architecture and its influence on arteriosclerosis in patients with type-2 diabetes mellitus (DM). The present study examined the association of objective sleep architecture with both glycemic control and arteriosclerosis in type-2 DM patients. DESIGN: Cross-sectional study in vascular laboratory. METHODS: The subjects were 63 type-2 DM inpatients (M/F, 32/31; age, 57.5±13.1) without taking any sleeping promoting drug and chronic kidney disease. We examined objective sleep architecture by single-channel electroencephalography and arteriosclerosis by carotid-artery intima-media thickness (CA-IMT). RESULTS: HbA1c was associated significantly in a negative manner with REM sleep latency (interval between sleep-onset and the first REM period) (ß=-0.280, p=0.033), but not with other measurements of sleep quality. REM sleep latency associated significantly in a positive manner with log delta power (the marker of deep sleep) during that period (ß=0.544, p=0.001). In the model including variables univariately correlated with CA-IMT (REM sleep latency, age, DM duration, systolic blood pressure, and HbA1c) as independent variables, REM sleep latency (ß=-0.232, p=0.038), but not HbA1c were significantly associated with CA-IMT. When log delta power was included in place of REM sleep latency, log delta power (ß=-0.257, p=0.023) emerged as a significant factor associated with CA-IMT. CONCLUSIONS: In type-2 DM patients, poor glycemic control was independently associated with poor quality of sleep as represented by decrease of REM sleep latency which might be responsible for increased CA-IMT, a relevant marker for arterial wall thickening.

Association between glycemic control and morning blood pressure surge with vascular endothelial dysfunction in type 2 diabetic patients.

OBJECTIVE: Morning blood pressure surge (MBPS) is an independent predictor of cardiovascular events. However, little is known about the association between glycemic control and MBPS, and its effect on vascular injury in patients with type 2 diabetes mellitus (T2DM). The current study examined the association between glycemic control and MBPS, and the involvement of MBPS in the development of vascular dysfunction in T2DM patients. RESEARCH DESIGN AND METHODS: We examined MBPS in T2DM patients (25 male patients/25 female patients; mean age, 60.1 ± 13.2 years; n = 50) using 24-h ambulatory blood pressure monitoring, and assessed vascular function by brachial artery flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD). RESULTS: HbA1c (ρ = 0.373, P = 0.009) and triglyceride (TG) (ρ = 0.375, P = 0.009) levels correlated significantly and positively with MBPS. In multiple regression analysis, including TG and HbA1c levels in addition to age and 24-h systolic blood pressure (SBP) as independent variables, HbA1c (ß = 0.328, P = 0.016) and TG (ß = 0.358, P = 0.014) were associated significantly in a positive manner with MBPS. In a noninsulin user, when homeostasis model assessment ratio (HOMA-R) was included in place of TG, HOMA-R emerged as a significant factor. MBPS (ρ = -0.289, P = 0.043) and HbA1c (ρ = -0.301, P = 0.035) correlated significantly and negatively with FMD, whereas 24-h SBP correlated with both FMD (ρ = -0.359, P = 0.012) and NMD (ρ = -0.478, P = 0.004). In multiple regression analysis, including age, gender, 24-h SBP, MBPS, LDL cholesterol, and HbA1c, MBPS (ß = -0.284, P = 0.044) alone associated significantly in a negative manner with FMD, but not with NMD. CONCLUSIONS: The current study demonstrated that poor glycemic control and insulin resistance are independently associated with the occurrence of MBPS in T2DM patients, which might be significantly associated with endothelial dysfunction.

Increased soluble IL-2 receptor levels in serum from a patient with painless thyroiditis.

CONTEXT: Serum concentration of soluble interleukin-2 receptor (sIL-2R) has been established as a reliable marker of T-lymphocyte activation. However, there have been no reports describing the relationship between serum sIL-2R and painless thyroiditis. OBJECTIVE: We report a case of a 76-yr-old female with a significant and temporary increase of sIL-2R concomitant with painless thyroiditis. CASE ILLUSTRATION: The patient was diagnosed with malignant lymphoma at the age of 73. After 6 cycles of CHOP-R complete remission was induced and no recurrence was observed up to 3.5 years. At 76 years of age, she exhibited hyperthyroidism and was diagnosed with painless thyroiditis based upon US examination and 99mTc-Thyroid scintigraphy. Her AST and ALT were mildly elevated, and her serum level of sIL-2R increased up to 2230 U/mL from the approximately 540 U/mL, which had been stable for 3 years before.These abnormal data normalized without requiring any treatment. The time-course of the reduction in sIL-2R did not correlate with FT4 or FT3, but was very similar to that of AST and ALT. CONCLUSION: There was no evidence of relapse of the malignant lymphoma. We conclude that the increase of sIL-2R was associated with painless thyroiditis. Considering the similar time-course between the reduction of serum sIL-2R and those of AST and ALT, which are often accompanied by autoimmune processes in painless thyroiditis during the development of hyperthyroidism, it was suggested that the increase of serum sIL-2R in this case resulted from activation of an autoimmune process.

Thyroid heterogeneity, as indicated by the CV of ultrasonographic intensities, correlates with anti-thyroid peroxidase antibodies in euthyroid Hashimoto's thyroiditis.

OBJECTIVE: To prospectively evaluate the heterogeneous appearance of the thyroid gland, reflecting inflammation and destruction in euthyroid Hashimoto's thyroiditis (HT), we investigated the clinical utilities of the heterogeneity index (HI) [the coefficient of variance (CV) of the ultrasonographic (US) intensities], focusing on anti-thyroid peroxidase antibodies (TPO-Ab), which represent not only disease activity but also subsequent thyroid destruction of HT. METHODS: Forty-four consecutive patients with euthyroid HT [60.5 ± 2.7 years old (mean ± SE)] and 30 age-matched normal controls were studied. HI was calculated as the CV (SD/mean) of US intensities of either four points per lobe of the thyroid gland along a horizontal line at the depth of the right common carotid artery. Evaluation included serum levels of free thyroxine (FT4), free triiodothyronine (FT3), thyroid stimulating hormone (TSH), anti-thyroid peroxidase antibodies (TPO-Ab), anti-thyroglobulin antibodies (Tg-Ab), thyroglobulin and thyroid volume. RESULTS: While no differences were observed for TSH, FT4 and FT3, thyroglobulin and thyroid volume between the two groups, HI exhibited a tendency towards a significant difference (3.59 ± 0.20% in HT patients vs 3.23 ± 0.19% in normal group, p = 0.089). In HT patients, there was a significant and positive correlation of HI with TPO-Ab (r = 0.396, p = 0.034), whereas such a correlation was absent in normal controls. In both groups, there were no significant correlations of HI with Tg-Ab, FT3, FT4 or TSH. CONCLUSIONS: This is the first report of the close relation between heterogeneity of US of the thyroid gland and TPO-Ab in euthyroid HT patients before the heterogeneity becomes distinguishable from normal thyroid glands. Furthermore, at this stage, subsequent thyroid destruction in HT might be already be predicted through the heterogeniety of the thyroid tissue.

Poor muscle quality as a predictor of high mortality independent of diabetes in hemodialysis patients.

BACKGROUND: Poor muscle quality provides a clinically relevant measure for mortality in general population, particularly in the elderly people. Our previous reports indicating poorer muscle quality in diabetes mellitus (DM) hemodialysis patients than in non-DM counterparts prompted us to examine the association between two parameters in hemodialysis patients, independent of DM prevalence. METHODS: The study was performed from 1997 to 2005. Grip dynamometry and dual-energy X-ray absorptiometry (DXA) were used to measure handgrip strength (HGS) and arm lean mass (ALM), respectively, with the muscle quality defined as the ratio of HGS to ALM. RESULTS: During the mean follow-up period of 77 months, 90 out of 272 patients died. The patients were divided into higher and lower groups based on the values of muscle quality. In Kaplan-Meier analysis, the higher group revealed lower mortality than the lower group. Cox regression hazards analysis identified higher muscle quality as a significant independent predictor for better survival in hemodialysis patients (HR; 0.889, 95% CI 0.814-0.971; P<0.05), after adjustment for age, sex and the prevalence of DM. Since DM prevalence is a major factor for poorer muscle quality, another analysis was performed after restriction of the subjects to non-DM patients. The result also indicated that muscle quality provides a relevant measure independent of the presence of DM to predict the mortality in hemodialysis patients (HR; 0.849, 95% CI 0.759-0.950; P<0.05). CONCLUSION: The study suggested that muscle quality provides a good marker for survival in hemodialysis patients, independently of the presence DM, age and serum albumin.

Impaired response of FGF-23 to oral phosphate in patients with type 2 diabetes: a possible mechanism of atherosclerosis.

BACKGROUND: Fibroblast growth factor (FGF)-23, secreted from osteocytes/osteoblasts, plays major roles in phosphate (Pi)-mediated stimulation of PTH secretion and consequently in regulation of serum Pi. Osteocyte/osteoblast dysfunction develops in patients with type 2 diabetes mellitus (DM). OBJECTIVE: Our objective was to examine whether increases in serum FGF-23 and PTH after oral Pi stimulation are impaired in type 2 DM. DESIGN AND METHODS: The subjects were 10 DM and 10 non-DM patients without chronic kidney disease stage 3-5. Serum FGF-23, intact PTH (iPTH), and Pi were measured serially after oral Pi administration at a daily dose of 2.0 g. RESULTS: Pi administration caused significant increases of FGF-23 by 2 h and iPTH by 4 h in non-DM patients. These increases were attenuated in DM patients. After 2 d of Pi stimulation, serum FGF-23 and iPTH remained elevated in non-DM patients but not in DM. In all subjects, initial changes of serum FGF-23 (0-2 h) and iPTH (0-4 h) were positively correlated (r = 0.528) and showed significant negative correlations with later changes in serum Pi (2-4 h) (r = -0.457 and r = -0.673, respectively). Serum Pi (2-4 h) significantly increased in DM patients, consistent with the lack of change in serum FGF-23 and iPTH, whereas serum Pi did not change significantly in non-DM patients. CONCLUSION: These results show that increases of serum FGF-23 and PTH in response to Pi stimulation are impaired in type 2 DM and that serum Pi is significantly increased thereafter. This may be a mechanism underlying advanced atherosclerosis in type 2 DM.