Manabu Kadoya

Plasma brain-derived neurotrophic factor and reverse dipping pattern of nocturnal blood pressure in patients with cardiovascular risk factors.

Context Basic studies have shown that brain-derived neurotrophic factor (BDNF) has critical roles in the survival, growth, maintenance, and death of central and peripheral neurons, while it is also involved in regulation of the autonomic nervous system. Furthermore, recent clinical studies have suggested potential role of plasma BDNF in the circulatory system. Objective We investigated the mutual relationships among plasma BDNF, patterns of nocturnal blood pressure changes (dippers, non-dippers, extra-dippers, and reverse-dippers), and cardiac autonomic function as determined by heart rate variability (HRV). Design This was a cross-sectional study of patients registered in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) Study from October 2010 to November 2012. Patients Two-hundred fifty patients with 1 or more cardiovascular risk factor(s) (obesity, smoking, presence of cardiovascular event history, hypertension, dyslipidemia, diabetes mellitus, chronic kidney disease) were enrolled. Results Plasma BDNF levels (natural logarithm transformed) were significantly (p = 0.001) lower in reverse-dipper patients (7.18±0.69 pg/ml, mean ± SD, n = 36) as compared to dippers (7.86±0.86 pg/ml, n = 100). Multiple logistic regression analysis showed that BDNF (odds ratios: 0.417, 95% confidence interval: 0.228–0.762, P = 0.004) was the sole factor significantly and independently associated with the reverse-dippers as compared with dippers. Furthermore, plasma BDNF level was significantly and positively correlated with the time-domain (SDNN, SDANN5, CVRR) and frequency-domain (LF) of HRV parameters. Finally, multiple logistic regression analyses showed that the relationship between plasma BDNF and the reverse-dippers was weakened, yet remained significant or borderline significant even after adjusting for HRV parameters. Conclusions Low plasma BDNF was independently associated with patients showing a reverse-dipper pattern of nocturnal blood pressure, in which an imbalance of cardiac autonomic function may be partly involved.

Serum Macro TSH Level is Associated with Sleep Quality in Patients with Cardiovascular Risks – HSCAA Study

Macro thyroid-stimulating hormone (TSH) has been reported to be associated with seasonality and regulated by changes in day length in rodents, different from free TSH. In the present study, we investigated structural differences between macro TSH and free TSH levels in human serum, as well as the association of macro TSH with sleep quality. We enrolled 314 patients registered in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) study. Sleep quality shown by actigraphy, sleep physical activity, and percent sleep in all and TSH closely matched subjects were significantly associated with high macro TSH levels. Macro and free TSH were similarly increased following thyrotropin-releasing hormone (TRH) stimulation, while circadian changes associated with those were distinct. To further analyze the structure of macro TSH, serum samples were separated by gel filtration chromatography. Although treatment with glycosidase did not affect morbidity, the macro TSH fraction had a markedly low affinity to the Con A column as compared with free TSH, indicating a distinct glycosylation structure. In conclusion, an increase in serum macro TSH is associated with low sleep quality and regulated in a manner distinct from free TSH, potentially due to an altered glycosylation structure.

Associations of Sleep Quality and Awake Physical Activity with Fluctuations in Nocturnal Blood Pressure in Patients with Cardiovascular Risk Factors

Background Sleep quality and awake physical activity are important behavioral factors involved in the occurrence of cardiovascular diseases, potentially through nocturnal blood pressure (BP) changes. However, the impacts of quantitatively measured sleep quality and awake physical activity on BP fluctuation, and their relationships with several candidate causal factors for nocturnal hypertension are not well elucidated. Methods This cross-sectional study included 303 patients registered in the HSCAA study. Measurements included quantitatively determined sleep quality parameters and awake physical activity obtained by actigraph, nocturnal systolic BP (SBP) fall [100 × (1- sleep SBP/awake SBP ratio)], apnea hypopnea index, urinary sodium and cortisol secretion, plasma aldosterone concentration and renin activity, insulin resistance index, parameters of heart rate variability (HRV), and plasma brain-derived neurotrophic factor (BDNF). Results Simple regression analysis showed that time awake after sleep onset (r = -0.150), a parameter of sleep quality, and awake physical activity (r = 0.164) were significantly correlated with nocturnal SBP fall. Among those, time awake after sleep onset (β = -0.179) and awake physical activity (β = 0.190) were significantly and independently associated with nocturnal SBP fall in multiple regression analysis. In a subgroup of patients without taking anti-hypertensive medications, both time awake after sleep onset (β = -0.336) and awake physical activity (β = 0.489) were more strongly and independently associated with nocturnal SBP falls. Conclusion Sleep quality and awake physical activity were found to be significantly associated with nocturnal SBP fall, and that relationship was not necessarily confounded by candidate causal factors for nocturnal hypertension.

Plasma leptin concentration is associated with fatigue severity in patients with cardiovascular risk factors – HSCAA study

Fatigue induced by complex dysfunctions of the central nervous system is frequently complained by patients with cardiovascular risk factors. Although leptin is considered to regulate the central nervous system, there are no reports regarding its association with fatigue in those patients. This cross-sectional study included 347 patients with cardiovascular risk factors. Fatigue score and plasma leptin concentration were measured. In addition, abdominal fat accumulation, systemic inflammation, sleep condition, and functions of hypothalamus-pituitary axis and autonomic system were estimated. Plasma leptin concentration (natural logarithm transformed) was significantly and positively (r=0.222, p<0.001) associated with fatigue score, and significantly (p<0.001) higher in the moderately-fatigued group (2.32±0.75ng/ml, mean±SD, n=52) than in the normally-fatigued group (1.85±1.02ng/ml, mean±SD, n=295). Multiple logistic regression analysis showed that plasma leptin concentration was significantly and independently associated with a moderately-fatigued condition independent of other factors, including age, gender, presence of diabetes, hypertension, dyslipidemia, alcohol consumption habit, urinary free cortisol, serum high-sensitive CRP concentration, visceral and subcutaneous fat area, apnea/hypopnea index, sleep efficiency, and heart rate variability. Hyperleptinemia may contribute to fatigue severity in patients with cardiovascular risk factors.

Plasma brain-derived neurotrophic factor concentration is a predictor of chronic kidney disease in patients with cardiovascular risk factors – Hyogo Sleep Cardio-Autonomic Atherosclerosis study

Background Brain-derived neurotrophic factor (BDNF) has been shown to have protective effects against cardiovascular diseases and death through neural and non-neural pathways via tropomyosin-related kinase B signaling. However, it is not known whether plasma BDNF concentration is a predictor of chronic kidney disease (CKD). Design This study was conducted as a prospective cohort study as part of the Hyogo Sleep Cardio-Autonomic Atherosclerosis. Methods We measured plasma BDNF concentration in 324 patients without CKD, defined as an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73m2, and with cardiovascular risk factors. As potential confounders, sleep condition, nocturnal hypertension, and autonomic function were quantitatively examined. The patients were followed for a median 37 months (range 2–59 months) and occurrence of CKD was noted. Results Plasma BDNF concentration was significantly and independently associated with CKD development, which occurred in 38 patients (11.7%). Kaplan-Meier analysis revealed that patients with reduced plasma BDNF concentration exhibited a significantly (p = 0.029) greater number of CKD events as compared to those with a higher concentration. Moreover, comparisons of key subgroups showed that the risk of CKD in association with low plasma BDNF concentration was more prominent in patients with a greater reduction of nocturnal systolic blood pressure, better movement index, higher standard deviations of the NN(RR) interval or average NN(RR) interval for each 5-minute period, and without past cardiovascular disease events, smoking habit, or albuminuria. Conclusions Plasma BDNF concentration is an independent predictor for development of CKD in patients with cardiovascular risk factors.

Nonpharmacological Management of Gout and Hyperuricemia: Hints for Better Lifestyle

We reviewed lifestyle factors that influence serum uric acid levels and risk of gout flare, and how to improve their deleterious effects. Since obesity increases uric acid and weight gain increases gout risk, weight reduction by daily exercise and limiting intake of excess calories is recommended. However, strenuous exercise, which causes adenine nucleotide degradation; starvation, which decreases uric acid excretion; and dehydration may raise the level of uric acid in serum and trigger gout. Increased intake of purine-rich foods, such as meat and seafood, raise the level of uric acid in serum and is associated with increased risk of gout, whereas dairy products, especially low-fat types, are associated with a lower risk of gout. Also, heavy alcohol drinking raises the uric acid level and increases the risk of gout through adenine nucleotide degradation and lactate production. Sweet fruits and soft drinks containing fructose should be moderated, since fructose may raise uric acid and increase gout risk through uric acid production and/or decreased excretion. On the other hand, the Mediterranean diet is recommended for gout patients, since it may also help prevent hyperuricemia. Furthermore, coffee and vitamin C supplementation could be considered as preventive measures, as those can lower serum uric acid levels as well as the risk of gout.

Low sleep quality is associated with progression of arterial stiffness in patients with cardiovascular risk factors: HSCAA study

BACKGROUND AND AIMS Improvement in sleep quality is considered to be a viable target for prevention and treatment of cardiovascular diseases. To gain insight into its underlying mechanisms, we evaluated the significance of objectively measured sleep quality in patients with regard to progression of arterial stiffness over a 3-year follow-up period. METHODS This prospective cohort study included 306 serial patients registered in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) study. In addition to classical cardiovascular risk factors (body mass index, current smoking, past history of cardiovascular disease, dyslipidemia, diabetes mellitus), the participants were examined for ambulatory blood pressure (BP), apnea-hypopnea index (AHI), standard deviation of the NN (RR) interval (SDNN) for heart rate variability (HRV), and objective sleep quality using actigraphy findings. Brachial-ankle pulse wave velocity (baPWV) was measured at both baseline and follow-up (36.6 ± 6.8 months) as a parameter of arterial stiffness. RESULTS Increases in PWV (%) were greater (p = 0.03) in the low sleep quality (LSQ) group (5.75 ± 1.15%) as compared to the normal sleep quality group (2.69 ± 0.85%). Patients with the greatest increase (≥20%) from baseline exhibited a significantly (p < 0.05) larger percentage of LSQ (75% vs. 49.6%) as compared to those without PWV progression (<0%), with the association still significant (odds ratio 3.62, 95% confidence interval 1.04-12.55, p = 0.04) even after adjustment for other clinical risk factors. For all subjects, univariate logistic regression analyses showed that diabetes and LSQ were significantly associated with the greatest increase of PWV. Comparisons of characteristics among specific subgroups showed more prominent associations of LSQ with the greatest increase of PWV in patients with greater age, dyslipidemia, and higher AHI. CONCLUSIONS LSQ was associated with progression of arterial stiffness over a 3-year period, independent of cardiovascular risk factors such as BP, AHI, and HRV.

Familial Carney complex with biatrial cardiac myxoma

We report a case of Carney complex (CNC) with biatrial cardiac myxoma. The patient had left and right atrial myxomas which were resected in a surgery. She showed bilateral adrenal tumors and multiple mammary tumors. She had pigmentation on her lower lip. Previously, her daughter was also diagnosed with CNC with cardiac myxoma. Both of them showed mutations in the PRKAR1A gene. <Learning objective: Carney complex is a syndrome with skin pigmentation, myxomas, and endocrine abnormalities. It is an autosomal dominant disease and shows PRKAR1A gene mutation. We experienced a rare case of familial Carney complex with biatrial cardiac myoxomas found by echocardiography and treated surgically.>