Nocturnal Hypertension and Left Ventricular Diastolic Dysfunction in Patients With Diabetes With the Absence of Heart Failure: Prospective Cohort HSCAA Study.

BACKGROUND: Diabetes is an important risk factor for heart failure (HF) and is associated with left ventricular (LV) diastolic dysfunction. However, diabetic comorbid conditions, such as nocturnal hypertension, as predictors of diastolic dysfunction are not known in the absence of an HF period. The present study was conducted as the longitudinal examination of the predictive value of nocturnal hypertension profiles on the progression of LV diastolic dysfunction in patients with and without diabetes without HF. METHODS: The subjects (154 diabetes and 268 nondiabetes) in the absence of HF were followed for 36.8±18.2 months. The relationships among the patterns of nocturnal hypertension and the outcome of LV diastolic dysfunction, defined as an increase in E/e'>14, were investigated in the patients with and without diabetes. RESULTS: The interaction effect of the diabetes status and the patterns of nocturnal hypertension on the hazard rate of the occurrence of E/e'>14 was statistically significant (P=0.017). Kaplan-Meier analysis results revealed that patients with diabetes with nondipper (P=0.021 versus dipper) and riser (P=0.006 versus dipper) had a greater risk for a diastolic dysfunction event. Furthermore, multivariable Cox proportional hazards analysis revealed that nondipper (hazard ratio, 4.56 [95% CI, 1.49-13.96]; P=0.007) and riser (hazard ratio, 3.89 [95% CI, 1.31-11.57]; P=0.014) patterns were associated with elevated risk of the outcome of LV diastolic dysfunction. In contrast, no similar significant associations were found in patients without diabetes. CONCLUSIONS: During the absence of HF periods, nocturnal hypertension is an important predictor for the progression of LV diastolic dysfunction in patients with diabetes.

Excessive daytime napping independently associated with decreased insulin sensitivity in cross-sectional study - Hyogo Sleep Cardio-Autonomic Atherosclerosis cohort study.

Background: Although excessive daytime napping has been shown to be involved in diabetes occurrence, its impact on insulin secretion and sensitivity has not been elucidated. It is speculated that excessive napping disrupts the sleep-wake rhythm and increases sympathetic nerve activity during the day, resulting in decreased insulin sensitivity, which may be a mechanism leading to development of diabetes. We previously conducted a cross-sectional study that showed an association of autonomic dysfunction with decreased insulin sensitivity, though involvement of autonomic function in the association between napping and insulin sensitivity remained unclear. Furthermore, the effects of napping used to supplement to short nighttime sleep on insulin secretion and sensitivity are also unknown. In the present cross-sectional study, we examined the relationships of daytime nap duration and autonomic function with insulin secretion and sensitivity in 436 subjects enrolled in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) Cohort Study who underwent a 75-g oral glucose tolerance test (75-g OGTT), after excluding those already diagnosed with diabetes. Methods: Daytime nap duration was objectively measured using actigraphy, with the subjects divided into the short (≤1 hour) and long (>1 hour) nap groups. Insulin secretion and sensitivity were determined using 75-g OGTT findings. Standard deviation of normal to normal R-R interval (SDNN), a measure of autonomic function, was also determined based on heart rate variability. Subgroup analysis was performed for the associations of napping with insulin secretion and sensitivity, with the results stratified by nighttime sleep duration of less or greater than six hours. Results: Subjects in the long nap group exhibited lower insulin sensitivity parameters (QUICKI: ß=-0.135, p<0.01; Matsuda index: ß=-0.119, p<0.05) independent of other clinical factors. In contrast, no associations with insulin secretion were found in either group. Furthermore, the association of long nap duration with insulin sensitivity was not confounded by SDNN. Specific subgroup analyses revealed more prominent associations of long nap habit with lower insulin sensitivity in subjects with a short nighttime sleep time (ß=-0.137, p<0.05). Conclusion: Long daytime nap duration may be a potential risk factor for decreased insulin sensitivity.

Syndrome of inappropriate antidiuretic hormone with recurrent giant cabergoline-resistant prolactinoma.

A macro pituitary tumour or giant pituitary tumour is regarded as a rare causal factor in syndrome of inappropriate antidiuretic hormone (SIADH) cases. Previous reports have presented findings showing that blood flow insufficiency related to stress caused by an obstructive mass may lead to inappropriate secretion of arginine vasopressin. On the other hand, prolactin is known to influence water metabolism, and several cases of a macroprolactinoma or giant prolactinoma (PRLoma) in patients with SIADH have been reported. Nevertheless, few studies have examined such a relationship with SIADH and discussion of pathophysiological factors has been limited. The present report provides details of an elderly patient with SIADH in a chronic giant PRLoma. Of note, exacerbation of prolactin level accompanied the occurrence of SIADH. Findings obtained in this case suggest the possibility of development of SIADH in PRLoma cases due to more than only the effect of the mass.

Cardiac Hypertrophy and Related Dysfunctions in Cushing Syndrome Patients-Literature Review.

The survival rate of adrenal Cushing syndrome patients has been greatly increased because of the availability of appropriate surgical and pharmacological treatments. Nevertheless, increased possibility of a heart attack induced by a cardiovascular event remains a major risk factor for the survival of affected patients. In experimental studies, hypercortisolemia has been found to cause cardiomyocyte hypertrophy via glucocorticoid receptor activation, including the possibility of cross talk among several hypertrophy signals related to cardiomyocytes and tissue-dependent regulation of 11ß-hydroxysteroid dehydrogenase type 1. However, the factors are more complex in clinical cases, as both geometric and functional impairments leading to heart failure have been revealed, and their associations with a wide range of factors such as hypertension are crucial. In addition, knowledge regarding such alterations in autonomous cortisol secretion, which has a high risk of leading to heart attack as well as overt Cushing syndrome, is quite limited. When considering the effects of treatment, partial improvement of structural alterations is expected, while functional disorders are controversial. Therefore, whether the normalization of excess cortisol attenuates the risk related to cardiac hypertrophy has yet to be fully elucidated.

Non-autoimmune acute-onset type 1 diabetes mellitus newly developed in an elderly patient presenting elevation of serum pancreatic exocrine enzymes.

An 82 year-old female patient not suffering from diabetes was transported to our hospital with hyperglycemia (HbA1c 8.2%, blood glucose 584 mg/dL) and mildly increased levels of pancreatic exocrine enzymes (amylase 543 IU/L, lipase 59 U/L, elastase-1 479 ng/dL), while there were no findings indicating pancreatitis. Under a diagnosis of new-onset diabetes, she was discharged with oral hypoglycemic agents, as retention of insulin secretion function [blood glucose 117 mg/dL, serum connecting peptide immunoreactivity (CPR) 1.63 ng/mL] with normalization of the enzymes was confirmed following administration. However, at 73 days after the hospitalization, she returned with diabetic ketoacidosis (blood glucose 910 mg/dL, pH in blood gas analysis 7.15, total blood ketone bodies > 7000 µmol/L) with a transient repeated increase of the enzymes (amylase 382 IU/L, lipase 82 U/L, elastase-1 569 ng/dL) and without pancreatitis. Notably, depletion of insulin secretion (6.1 µg/day in urine, 0.36 ng/mL in serum CPR with no response in glucagon-loading test) was revealed, and serum CPR level remained low after discharge. Together with negative findings for islet-related autoantibodies, the patient was diagnosed with acute-onset type 1B diabetes (T1BD). In the present patient with acute-onset T1BD, a mild increase in pancreatic exocrine enzymes was repeatedly observed, which may mimic fulminant type and raise questions for us about the commonly accepted pathophysiology of T1D. These findings may help to clarify issues related to newly developed T1D in elderly individuals.

Correction to: Non-autoimmune acute-onset type 1 diabetes mellitus newly developed in an elderly patient presenting elevation of serum pancreatic exocrine enzymes.

[This corrects the article DOI: 10.1007/s13340-021-00535-0.].

White esophagus accompanying multiple circumferential duodenal erosions extending to upper jejunum.

Although white esophagus is an extremely rare disease, careful diagnosis and intensive treatment are required because of a relationship with black esophagus. Further case accumulation including duodenal and jejunum lesion is needed.

Severe tardive dyskinesia induced by domperidone in presenile and non-dementia type 2 diabetes man with alcohol misuse showing albuminocytological dissociation and white matter hyperintensity.

Domperidone has difficulty passing the blood-brain barrier, thus rarely causes tardive dyskinesia. Furthermore, its symptoms in adults are generally mild. Although both alcohol and diabetes are thought to increase the risk of development of tardive dyskinesia, their impact remains controversial, especially diabetes, and factors related to worsened tardive dyskinesia have not been clearly elucidated. A 59-year-old man with type 2 diabetes and history of alcohol misuse, who had been chronically prescribed domperidone at 15 mg/day, showed severe tardive dyskinesia, which was remitted within several days by stopping the drug. In our case, albuminocytological dissociation and white matter hyperintensity on MRI were confirmed, which were thought to be related to blood-brain barrier dysfunction. This present findings indicate that alcohol misuse and type 2 diabetes, as well as albuminocytological dissociation and white matter hyperintensity may result in severe tardive dyskinesia, even in individuals receiving domperidone.

Fever of unknown origin following parathyroidectomy prior to onset of typical polymyalgia rheumatica symptoms: a case report.

Polymyalgia rheumatica (PMR) is a disease commonly seen in elderly individuals, however, the etiology has not been reported. Typical clinical features include bilateral shoulder pain and morning stiffness, while serologic autoantibody test findings are negative. Approximately 40%-50% of affected patients present with low-grade fever, fatigue, and appetite loss, which we often experience in the field of general medicine, and thus, the condition should not be given low priority. However, knowledge regarding such constitutional manifestations is also limited. We encountered an elderly woman with a fever of unknown origin that developed following a parathyroidectomy for a single parathyroid adenoma, after which severe shoulder pain and morning stiffness emerged, leading to a diagnosis of PMR. The fever developed several days prior to appearance of severe pain, which is an uncommon presentation in PMR cases. Our patient had low-grade inflammation without pyrexia prior to the surgery, which might have been an important reason for the accelerated immoderate immune activation leading to PMR induced by surgery in this case. Furthermore, she was infected with the influenza A virus 3 weeks before coming to us. Some reports have suggested a relationship between the influenza virus or vaccine and PMR. It is difficult to conclude regarding the definite trigger in our patient, though the details of this case should be helpful for a better understanding of the disease.

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.

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.

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 (ß = -0.179) and awake physical activity (ß = 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 (ß = -0.336) and awake physical activity (ß = 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.

Extension of recovery time from fatigue by repeated rest with short-term sleep during continuous fatigue load: Development of chronic fatigue model.

Homeostasis is known to be involved in maintaining the optimal internal environment, helping to achieve the best performance of biological functions. At the same time, a deviation from optimal conditions often attenuates the performance of biological functions, and such restricted performance could be considered as individual fatigue, including physical and mental fatigue. The present study seeks to develop an animal model of chronic or subacute fatigue in which the recovery time is extended through the gradual disruption of homeostasis. We show that repeated short-term rest periods with certain lengths of sleep during continuous fatigue loading extend recovery from spontaneous nighttime activity but not physical performance in comparison with a continuous fatigue-loading procedure. Furthermore, the immobility time in a forced swimming test was extended by repeated short-term rests. These results suggest that repeated short-term rest with certain lengths of sleep during continuous fatigue loading is able to extend the recovery from mental fatigue but not from physical fatigue and that this effect might occur via the disruption of a homeostatic mechanism that is involved in restoring the optimal internal environment.

Plasma leptin level is associated with cardiac autonomic dysfunction in patients with type 2 diabetes: HSCAA study.

BACKGROUND: It has been shown that visceral fat accumulation is associated with autonomic dysfunction, though the precise mechanism remains unclear. A recent basic study found that leptin can directly modulate autonomic function through the dorsomedial hypothalamus in relation to obesity. Here, we investigated the mutual relationships among plasma leptin, visceral fat accumulation, and cardiac autonomic dysfunction in patients with type 2 diabetes. METHODS: This cross-sectional study included 100 diabetic patients, and 100 age- and gender-matched non-diabetic patients with cardiovascular risk factors. Plasma leptin and soluble leptin receptor levels, visceral fat area (VFA), and heart rate variability (HRV) were determined in addition to classical cardiovascular risk factors. RESULTS: In the type 2 diabetic patients, VFA was significantly (p < 0.05) and inversely associated with HRV parameters (SDNN: r = -0.243; SDANN5: r = -0.238), while the plasma level of leptin, but not soluble leptin receptor, was also significantly (p < 0.05) and inversely associated with HRV parameters (SDNN: r = -0.243; SDANN5: r = -0.231). Multiple regression analysis showed that plasma leptin was significantly associated with SDNN and SDANN5 independent of other factors, including age, gender, presence of hypertension and dyslipidemia, duration of diabetes, HbA1c, and eGFR. Furthermore, the relationship of leptin with SDNN and SDANN5 (ß = -0.279 and -0.254, respectively) remained significant (p < 0.05) after adjustment for VFA. In patients without diabetes, no significant associations were observed between leptin and any of the HRV parameters. CONCLUSIONS: Hyperleptinemia may be involved in cardiac autonomic dysfunction in patients with type 2 diabetes and visceral obesity.

Sleep, cardiac autonomic function, and carotid atherosclerosis in patients with cardiovascular risks: HSCAA study.

OBJECTIVES: Behavioral and psychosocial factors have been gaining increased attention in regard to cardiovascular diseases. We evaluated sleep conditions, cardiac autonomic function, and carotid atherosclerosis in subjects who participated in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) Study. METHODS: This cross-sectional study included 330 serial patients registered in the HSCAA study who were free from past cardiovascular diseases, and prescribing α- or ß-blockers. In addition to clinical background and classical cardiovascular risk factors, sleep efficiency, apnea hypopnea index (AHI), awake physical activity, heart rate variability (HRV), carotid intima-media thickness (IMT), presence of plaque and plaque score were determined. RESULTS: Sleep efficiency (r = -0.183) and all HRV parameters (SDNN: r = -0.202; rMSSD: r = -0.234; pNN50: r = -0.277) were significantly (p < 0.01) and negatively associated with IMT, while AHI (r = 0.220, p < 0.001) was positively associated with IMT. Similarly, sleep efficiency (r = -0.129), HRV parameters (SDNN: r = -0.170; rMSSD: r = -0.217; pNN50: r = -0.260) and AHI (r = 0.184) were also significantly (p < 0.05) associated with plaque scores. Multivariate logistic regression analyses showed that rMSSD, but not sleep efficiency or AHI, was significantly associated with carotid plaque (OR 0.74, 95% CI 0.56-0.98, p = 0.037), independent of classical risk factors. The association of rMSSD with carotid plaque remained significant even after adjustment for sleep efficiency or AHI. A comparison of risk factors in specific subgroups showed that the association of lower HRV with carotid plaque was more prominent in patients with cardiovascular risk factors including male gender, hypertension, dyslipidemia and diabetes mellitus. CONCLUSION: Cardiac autonomic nervous dysfunction was independently associated with carotid atherosclerosis, independent of sleep condition. Moreover, that association was more prominent in specific subgroups with cardiovascular risk factors.

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.