Characteristics of sleep-disordered breathing in children with down syndrome - A comparison with typically developing children.

Background: Compared with typically developing control children (CC), children with Down syndrome (DS) frequently exhibit sleep-disordered breathing (SDB) and unusual sleep postures (USPs). No studies have directly compared SDB-related signs and symptoms, SDB-related parameters, and USPs between children with DS and CC. This study aimed to evaluate the prevalences of SDB and USPs in children with DS and CC. Methods: We analyzed SDB-related parameters measured via overnight pulse oximetry and questionnaires administered to parents on SDB-related signs and symptoms, including sleeping postures. Estimated SDB was defined as a 3% oxygen desaturation index (ODI) ≥5 dips/h. Results: Fifty-one children with DS (4-5 years: N = 12, 6-10 years: N = 23, 11-15 years: N = 16) and sixty-three CC (4-5 years: N = 18, 6-10 years: N = 27, 11-15 years: N = 18) were included. The prevalence of estimated SDB and observed USPs was higher in children with DS than in CC (p < 0.0001). Among children aged 11-15 years old, but not those aged 4-5 and 6-10 years old, frequency of arousal and apnea (p = 0.045 and p = 0.01, respectively) were higher in children with DS than in CC. Multivariate analyses showed that DS was associated with SDB-related signs and symptoms, estimated SDB, 3% ODI, average oxygen saturation (SpO2), and nadir SpO2, while USPs were associated only with higher values of SpO2 <90%. Conclusions: Estimated SDB tended to increase in children with DS but decreased in CC with growth. USPs were more frequent in children with DS than in CC, especially in older children. USPs might indicate severe hypoxemia due to SDB in DS.

Peripartum Management of Pregnant Women With Congenital Heart Disease.

BACKGROUND: The average maternal age at delivery, and thus the associated maternal risk are increasing including in women with congenital heart disease (CHD). A comprehensive management approach is therefore required for pregnant women with CHD. The present study aimed to investigate the factors determining peripartum safety in women with CHD.Methods and Results:We retrospectively collected multicenter data for 217 pregnant women with CHD (age at delivery: 31.4±5.6 years; NYHA classifications I and II: 88.9% and 7.4%, respectively). CHD severity was classified according to the American College of Cardiology/American Heart Association guidelines as simple (n=116), moderate complexity (n=69), or great complexity (n=32). Cardiovascular (CV) events (heart failure: n=24, arrhythmia: n=9) occurred in 30 women during the peripartum period. Moderate or great complexity CHD was associated with more CV events during gestation than simple CHD. CV events occurred earlier in women with moderate or great complexity compared with simple CHD. Number of deliveries (multiparity), NYHA functional class, and severity of CHD were predictors of CV events. CONCLUSIONS: This study identified not only the severity of CHD according to the ACC/AHA and NYHA classifications, but also the number of deliveries, as important predictive factors of CV events in women with CHD. This information should be made available to women with CHD and medical personnel to promote safe deliveries.

Effects of recombinant canine interferon-γ injected before general anesthesia with propofol and isoflurane on natural killer cytotoxic activity during anesthesia in dogs.

We aimed to determine whether subcutaneous injection of recombinant canine interferon-γ (rCaIFN-γ) 1h before general anesthesia with a combination of propofol and isoflurane (P-I) changes the cytotoxic activity of natural killer (NK) cells during anesthesia in dogs. Nine clinically healthy beagles were assigned to one of two groups: rCaIFN-γ-treated group (n=5) and control group (no treatment, n=4). One hour before P-I anesthesia, rCaIFN-γ was subcutaneously injected at a dose of 1×104U/kg body weight for the test group and physiologic saline was subcutaneously injected for the control group. Blood samples were collected 1h before P-I anesthesia (immediately before rCaIFN-γ injection) and 1 and 3h after anesthesia induction. NK cytotoxic activity was measured using the Rose Bengal assay, using canine thyroid adenocarcinoma cells as target cells. In the control group, NK cytotoxic activity decreased significantly over time (P<0.05). On the other hand, in the rCaIFN-γ group, the activity increased for the first hour after anesthesia induction without a significant difference from the level before anesthesia; furthermore, the activity at 3h after anesthesia induction was comparable with that before anesthesia. NK cytotoxic activity at 1 and 3h after anesthesia induction was significantly higher in the rCaIFNγ group than in the control group (P<0.05). Subcutaneous injection of rCaIFN-γ 1h before P-I general anesthesia not only maintained but also enhanced NK cytotoxic activity up to 3h after anesthesia induction in dogs. In conclusion, subcutaneous injection of rCaIFN-γ before cancer resection in cancer-bearing dogs might be effective for preventing intraoperative dissemination of cancer cells and postoperative cancer recurrence and metastasis.

Three nights leg thermal therapy could improve sleep quality in patients with chronic heart failure.

Sleep quality is often impaired in patients with chronic heart failure (HF), which may worsen their quality of life and even prognosis. Leg thermal therapy (LTT), topical leg warming, has been shown to improve endothelial function, oxidative stress, and cardiac function in patients with HF. However, its short-term influence to sleep quality has not been evaluated in HF patients. Eighteen of 23 patients with stable HF received LTT (15 min of warming at 45 °C and 30 min of insulation) at bedtime for 3 consecutive nights and 5 patients served as control. Subjective sleep quality was evaluated by St. Mary's Hospital Sleep Questionnaire, Oguri-Shirakawa-Azumi Sleep Inventory, and Epworth sleepiness scale, and also objectively evaluated by polysomnography. LTT significantly improved subjective sleep quality indicated by depth of sleep (p < 0.01), sleep duration (p < 0.05), number of awaking (p < 0.01), nap duration (p < 0.01), sleep quality (p < 0.05), and sleep satisfaction (p < 0.05). It was also objectively affirmed by a slight but significant decrease of sleep stage N1 (p < 0.01), and increase in sleep stage N2 (p < 0.05). No significant changes occurred in the controls. Hence, the short-term LTT could improve subjective and objective sleep quality in patients with HF. LTT can be a complimentary therapy to improve sleep quality in these patients.

Effects of chemotherapy on the health-related quality of life of Japanese lower rectal cancer patients after sphincter-saving surgery.

We examined the effects of adjuvant chemotherapy on the health-related quality of life (HRQOL) of lower rectal cancer patients receiving sphincter-saving surgery (SSS). In all, 109 patients completed a questionnaire before surgery and 1, 6, and 12 months afterwards. In the chemotherapy group, physical and social functioning scores were significantly lower 12 months after surgery compared with the nonchemotherapy group. These effects of adjuvant chemotherapy suggest that a different clinical approach might more effectively improve physical and social functioning in lower-rectal cancer patients undergoing chemotherapy. Healthcare providers should be alert for adverse events in patients with lower-rectal cancer and promptly address such conditions.

Effect of water bath temperature on physiological parameters and subjective sensation in older people.

AIM: In Japan, the incidence of water bathing-related cardiopulmonary accidents among older people is high in winter. The purpose of the present study was to investigate alterations in physiological characteristics and subjective thermal sensations of older people when bathing in a cool environment. METHODS: We assessed the skin temperature, rectal temperature, blood pressure, pulse rate, body fluid loss (sweat and urine), and subjective thermal responses of 11 older healthy male and 10 young male volunteers throughout 42°C and 39°C bathing in a room at 20°C with 50% humidity. RESULTS: At 42°C bathing, the rectal temperature during bathing and in the post-bathing period were significantly lower in the older men than in the young men, and skin temperature during the post-bathing period decreased gradually in the older men. Systolic blood pressure and pulse rate immediately increased just after entering 42°C water and decreased during bathing in the older men. With the activities of dressing, systolic blood pressure increased followed by a decrease during the post-bathing period. Thus, double product (pulse rate × systolic blood pressure) increased during the bathing period. Although there was no significant difference in body fluid loss between the older and younger men in 42°C water, the older men produced significantly less sweat. The older men also reported feeling less warm after 42°C bathing, and feeling less cold during the post-bathing period after 39°C bathing. CONCLUSIONS: These results suggest that hot water bathing during cold seasons might induce more serious physiological changes in older people. Geriatr Gerontol Int 2017; 17: 2164-2170.

Cardiac and respiratory effects of deep regional hyperthermia using an 8 MHz radiofrequency-capacitive device on patients with cancer.

PURPOSE: Hyperthermia (HT), an adjuvant therapy for variable cancers, may cause physiological changes in the patients, which may lead to cardiovascular problems. Among various HT treatments, the physiological effects of deep regional HT are still unclear. We examined the physiological alterations throughout deep regional HT to improve the HT safety. MATERIALS AND METHODS: Thirty-one patients (age: 61 ± 12 years) with cancer received HT in the thoracic or upper abdominal regions using an 8-MHz radiofrequency-capacitive-device for 50 min. Rectal temperature (Trec), systolic and diastolic blood pressures (SBP and DBP), pulse rate (PR), respiratory rate (RR), percutaneous oxygen saturation (SpO2) and sweating volume were evaluated throughout HT. RESULTS: At 50 min after starting HT, Trec, PR and RR were significantly increased compared with the baseline values (Trec: 38.2 ± 1.4 vs. 36.3 ± 0.8 °C, p < 0.001, PR: 104 ± 15 vs. 85 ± 16 bpm, p < 0.05, RR: 23 ± 3 vs. 21 ± 3/min, p < 0.05). Although the average SBP and DBP were both stable during HT in a recumbent position, these values dropped significantly in a standing position (SBP: 113 ± 16 vs. 127 ± 18 mmHg, p < 0.001, DBP: 70 ± 12 vs. 75 ± 13 mmHg, p < 0.01). The total amount of sweating was 356 ± 173 g/m2 on average. CONCLUSIONS: Deep regional HT increased the deep body temperature and resulted in an increase of sweating with peripheral vasodilatation. Consequently, a significant reduction in BP would be induced on standing after HT. Careful attention is needed for patients receiving HT, especially when standing after HT.

Seasonal ambient changes influence inpatient falls.

Background: falls by inpatients often result in serious injuries and deterioration in a patient's physical abilities and quality of life, especially among older individuals. Although various factors have been found to be associated with falls, the combined effects of behavioural and ambient factors are not fully evaluated. Objective: we investigated the influence of both behavioural and ambient factors on inpatient falls, focusing on seasonal and diurnal variations. Design: retrospective study. Methods: we surveyed the incident reports related to falls from April 2010 to March 2014 and examined the relationship between the incidents and seasonal and diurnal variations in behavioural and ambient factors, including the sunrise time, the night-time length and temperature. Results: we identified 464 fallers from 3,037 incident reports. The average fall-rate of the study population was 1.4 ± 0.5/1,000 occupied bed-days. The seasonal and diurnal variations in falls were compared. The number of falls around dawn in October-February was higher than that in April-September. Toileting was the behaviour most frequently related to the falls (56.9%, n = 264), and 57.1% of the falls occurred at night. A multivariate analysis showed that the night-time length was significantly related to an increase in night-time falls (P = 0.047). Conclusion: these results suggested that the inpatient falls increased in the early morning from November to March and tended to be related to toileting activities. Considering these results, additional attention and support during the higher risk hours and seasons, especially in relation to toileting activities, might help to reduce the incidence of falls. Clinical trial name, URL and registration number: N/A (Because of retrospective nature).

Radial forces of stents used in thoracic endovascular aortic repair and bare self-expanding nitinol stents measured ex vivo - Rapid rescue for obstruction of the innominate artery using bare self-expanding nitinol stents.

Purpose Our objective was to compare the radial forces of several stents ex vivo to identify stents suitable for rescue of the unexpected coverage of aortic arch branches in thoracic endovascular aortic repair. Methods We measured the radial forces of two types of self-expanding bare nitinol stents (E-luminexx and Epic) used singly or as double-walled pairs, and of three endoprostheses used in thoracic endovascular aortic repair (TEVAR, Gore c-TAG, Relay, and Valiant) by compressing the stent using an MTS Instron universal testing machine (model #5582). We also examined the compressive effects of the TEVAR endoprostheses and the bare nitinol stents on each other. Results The radial force was greater in the center than at the edge of each stent. In all stents tested, the radial force decreased incrementally with increasing stent diameter. The radial force at the center was two times greater when using two stents than with a single stent. In the compression test, only E-luminexx used as a pair was not compressed after compressing a Relay endoprosthesis by 12 mm. Conclusion Two E-luminexx stents are appropriate to restore the blood flow if a TEVAR endoprosthesis covers the innominate artery following innominate-carotid-left subclavian arterial bypass.

Evaluation of water content around airway in obstructive sleep apnea patients using peripharyngeal mucosal T2 magnetic resonance imaging.

INTRODUCTION: Obstructive sleep apnea (OSA) is common sleep disorder characterized by repetitive episodes of airway closure which usually occurs in the retropalatal region of the oropharynx. It has been known that upper airway mucosa in OSA patients is described as edematous, but not fully clarified. OBJECTIVES: This study aimed to investigate and establish magnetic resonance imaging (MRI) parameter to estimate tissue water content at retropalatal level and its relationship with sleep parameters in OSA patients. METHODS: Forty-eight subjects with OSA underwent overnight polysomnography and cervical MRI with 1.5-tesla [mean (SD) age 55 (14) years and apnea-hypopnea index (AHI) 45.2 (26.1) events/hour, 79.2% male]. On the axial T2-weighted images from epipharynx to oropharynx, the signal intensities of masseter muscle and peripharyngeal mucosa [T2 mucous-to-masseter intensity ratio (T2MMIR)], was used as water content estimation in the retropalatal region. Partial correlation analysis was performed to examine the correlation between T2MMIR and polysomnography parameters. RESULTS: We found that there were strong and positive correlations between the T2MMIR and AHI (r = 0.545, P < 0.05), supine AHI (r = 0.553, P < 0.05) and REM AHI (r = 0.640, P < 0.01) by partial correlation analysis. Besides, in patients with less efficient sleep who had more stage 1 sleep, significantly higher T2MMIR was noted (r = 0.357, P < 0.05). CONCLUSIONS: This study confirmed that peripharyngeal T2MMIR can be a simple parameter representing peripharyngeal tissue water contents related to severe OSA.

BubR1 Insufficiency Impairs Liver Regeneration in Aged Mice after Hepatectomy through Intercalated Disc Abnormality.

A delay in liver regeneration after partial hepatectomy (PHx) leads to acute liver injury, and such delays are frequently observed in aged patients. BubR1 (budding uninhibited by benzimidazole-related 1) controls chromosome mitotic segregation through the spindle assembly checkpoint, and BubR1 down-regulation promotes aging-associated phenotypes. In this study we investigated the effects of BubR1 insufficiency on liver regeneration in mice. Low-BubR1-expressing mutant (BubR1(L/L)) mice had a delayed recovery of the liver weight-to-body weight ratio and increased liver deviation enzyme levels after PHx. Microscopic observation of BubR1(L/L) mouse liver showed an increased number of necrotic hepatocytes and intercalated disc anomalies, resulting in widened inter-hepatocyte and perisinusoidal spaces, smaller hepatocytes and early-stage microvilli atrophy. Up-regulation of desmocollin-1 (DSC1) was observed in wild-type, but not BubR1(L/L), mice after PHx. In addition, knockdown of BubR1 expression caused down-regulation of DSC1 in a human keratinocyte cell line. BubR1 insufficiency results in the impaired liver regeneration through weakened microstructural adaptation against PHx, enhanced transient liver failure and delayed hepatocyte proliferation. Thus, our data suggest that a reduction in BubR1 levels causes failure of liver regeneration through the DSC1 abnormality.

Left Ventricular Ejection Fraction Predicts Severity of Posttraumatic Stress Disorder in Patients With Implantable Cardioverter-Defibrillators.

BACKGROUND: Implantable cardioverter-defibrillators (ICD) have provided effective therapy for fatal arrhythmia. However, ICD patients are known to develop psychological problems, such as posttraumatic stress disorder (PTSD), if they have experienced potentially fatal arrhythmia and ICD shocks. Little is known about the factors influencing PTSD in ICD patients. HYPOTHESIS: Echocardiographic cardiac-function parameters might relate to psychological problems, especially PTSD, in ICD patients. METHODS: A total of 128 outpatients with ICD implantation completed the Impact of Event Scale Revised (IES-R) questionnaire as a measurement of PTSD. Demographic and clinical characteristic data were collected from medical records. RESULTS: The mean age of the ICD patients was 59 ± 16 years; 103 were male; and the mean left ventricular ejection fraction (LVEF) by echocardiography was 52.4% ± 18.3%. In the ICD patients, female sex and impaired LVEF were related to lower IES-R scores or led to PTSD (P = 0.01 and P = 0.03, respectively). Impaired LVEF also worsened 2 symptoms of PTSD, intrusion (P = 0.02) and hyperarousal (P = 0.03). In patients with LVEF <35%, there was a significant negative correlation between LVEF level and IES-R score (P = 0.045). CONCLUSIONS: This study showed that LVEF was related to the severity of PTSD, especially in the ICD patients with LVEF of <35%. We should pay more attention to ICD patients with severely impaired left ventricular function to prevent psychological problems.

Influence of primary and secondary prevention indications on anxiety about the implantable cardioverter-defibrillator.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) have been established for primary and secondary prevention of fatal arrhythmias. However, little is known about the influence of ICD indications on quality of life (QOL) and psychological disturbances. This study aimed to examine whether there were differences in QOL and psychological distress in patients that have an ICD for primary or secondary prevention of fatal arrhythmias. METHODS: A multicenter survey of 179 consecutive outpatients (29.1% primary prevention) with ICD implantations completed the Short Form-8 (SF-8), Beck Depression Inventory (BDI), Impact of Event Scale-Revised (IES-R), State-Trait Anxiety Inventory (STAI), and Worries about ICD (WAICD). RESULTS: Patients with an ICD for primary prevention had a higher trait anxiety score and worries about ICD score than patients with an ICD for secondary prevention (41.7±12.4 vs. 34.7±12.3, p=0.001 and 39.6±18.0 vs. 30.0±18.9, p=0.002, respectively), even after adjusting for demographic and clinical characteristics. In multivariable analysis of variance, primary prevention ICD recipients reported a poorer QOL on the vitality subscale of the SF-8. CONCLUSIONS: In our study population, which mostly consisted of New York Heart Association (NYHA) class I and II subjects, primary prevention ICD recipients were more prone to experience worries about their ICD, anxiety, and a poorer QOL compared to secondary prevention ICD recipients. In clinical practice, primary prevention ICD patients should be closely monitored. If warranted, they should be offered psychological intervention, as anxiety and low QOL were predictors of mortality.

Radial force measurement of endovascular stents: Influence of stent design and diameter.

BACKGROUND AND PURPOSE: Angioplasty and endovascular stent placement is used in case to rescue the coverage of main branches to supply blood to brain from aortic arch in thoracic endovascular aortic repair. This study assessed mechanical properties, especially differences in radial force, of different endovascular and thoracic stents. MATERIAL AND METHODS: We analyzed the radial force of three stent models (Epic, E-Luminexx and SMART) stents using radial force-tester method in single or overlapping conditions. We also analyzed radial force in three thoracic stents using Mylar film testing method: conformable Gore-TAG, Relay, and Valiant Thoracic Stent Graft. RESULTS: Overlapping SMART stents had greater radial force than overlapping Epic or Luminexx stents (P < 0.01). The radial force of the thoracic stents was greater than that of all three endovascular stents (P < 0.01). CONCLUSIONS: Differences in radial force depend on types of stents, site of deployment, and layer characteristics. In clinical settings, an understanding of the mechanical characteristics, including radial force, is important in choosing a stent for each patient.

Cumulative Hypoxemia During Sleep Predicts Vascular Endothelial Dysfunction in Patients With Sleep-Disordered Breathing.

BACKGROUND: Sleep-disordered breathing (SDB) is associated with repeated intermittent hypoxemia, and it is known as one of the risk factors for cardiovascular diseases. Previous studies assessing the effects of frequency and depth of hypoxemia on cardiovascular diseases have shown conflicting results. The aim of the current study was to clarify what SDB-related parameters most predict endothelial dysfunction to better understand the pathogenesis of endothelial dysfunction in patients with SDB. METHODS: We conducted polysomnography (PSG) and measured flow-mediated vasodilation response (%FMD) in 50 outpatients suspected of SDB. Evaluated indices included: apnea-hypopnea index (AHI), 3% oxygen desaturation index (3%ODI), averaged arterial oxygen saturation (averaged SpO2), lowest arterial oxygen saturation (lowest SpO2), ratio of arterial oxygen saturation <90% (

Obstructive sleep apnea-related symptoms in Japanese people with Down syndrome.

This study evaluated the prevalence of obstructive sleep apnea-related symptoms and assessed the relationship with obesity or unusual sleep postures in Down syndrome patients in Japan. We obtained the demographic characteristics, sleep postures, and obstructive sleep apnea-related symptoms experienced by 90 people as reported by their caregivers. Although 71% reported snoring and 59% arousals, obstructive sleep apnea-related symptoms were not significantly different between obese and non-obese participants. The youngest age group had the fewest obstructive sleep apnea-related symptoms, especially symptoms of snoring. The odds for arousal, nocturia, and apnea tended to be higher in the unusual sleep-postures group. Unusual sleep postures were most frequent in the group 6-15 years of age. People with Down syndrome might sleep in unusual postures to avoid upper airway obstruction caused by other anatomical factors. For nurses and other health professionals working in mainstream service, it is important to screen all persons with Down syndrome for symptoms suggestive of obstructive sleep apnea, particularly those six years of age and older, and to refer them for further evaluation for sleep disorders.

A nationwide cross-sectional study on congenital heart diseases and symptoms of sleep-disordered breathing among Japanese Down's syndrome people.

OBJECTIVE: It is well known that people with Down's syndrome (DS) frequently complicate with congenital heart diseases (CHDs). Patients with heart diseases often have sleep-disordered breathing as a co-morbidity (SDB) which worsens the heart diseases. However, the relationship between SDB and CHDs in DS people has not yet been fully elucidated. The aim of this study was to establish the association between SDB and CHDs in DS people using data from a large nationwide questionnaire survey in Japan. METHODS: We conducted a cross-sectional questionnaire survey of a randomly selected sample of 2,000 DS people and their caregivers throughout Japan to examine the associations between observed signs of SDB and CHDs in DS people. The questionnaire included the presence of SDB symptoms (snoring, apnea, arousal, nocturia, and napping) and CHDs (the presence and types of CHDs). RESULTS: Of the 1,222 replies received from the caregivers, 650 reported complications of some type of CHDs. The observed apnea tended to be higher among DS people with CHDs than those without CHDs (OR=1.28, 95% CI=0.97-1.70, p=0.09). DS people with tetralogy of Fallot reported significantly more frequent apnea than those without CHDs (OR=3.10, 95% CI=1.36-7.05, p<0.01). CONCLUSION: SDB prevailed among DS people with severe CHDs, such as tetralogy of Fallot. Careful attention to the signs of SDB in such patients may lead to earlier clinical intervention removing the vicious cycle between SDB and CHDs.

A longitudinal study of gender differences in quality of life among Japanese patients with lower rectal cancer treated with sphincter-saving surgery: a 1-year follow-up.

BACKGROUND: Up to 80% of patients with rectal cancer undergo sphincter-saving surgery, and almost 90% of them experience subsequent physical changes. The number of studies on gender differences in response to this surgery has increased, and the connection between gender and symptoms and patient outcomes has generated increasing interest. Nevertheless, little is known about the gender differences in quality of life and cancer-related symptoms. We examined gender differences and quality of life changes over a 1-year period among patients with lower rectal cancer who were treated with sphincter-saving surgery. METHODS: Patients (men = 42; women = 33) completed a self-administered questionnaire on their quality of life and related factors before surgery and 1, 6, and 12 months afterwards. The questionnaire was developed by the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30/CR-38). RESULTS: Scores on physical, role, and social functioning and global health status/quality of life decreased 1 month after surgery, improved after 6 months, and returned to baseline within 12 months, with the exception of social functioning in men. Factors related to quality of life changed after surgery and differed between men and women. Women's global health status/quality of life was affected by fatigue, weight loss, defecation problems, and future perspective, while that of men was affected by fatigue, weight loss, future perspective, and role functioning, which was affected by pain, defecation problems, and financial difficulties. CONCLUSIONS: Gender differences should be considered when predicting the quality of life of cancer patients undergoing surgery. Identifying gender differences will help health care providers anticipate the unique needs of patients undergoing surgery for rectal cancer.

Rapid electrical stimulation causes alterations in cardiac intercellular junction proteins of cardiomyocytes.

The intercellular junctions contain two complexes, adhesion junctions (AJ) and connexin (Cx) gap junctions (GJs). GJs provide the pathway for intercellular current flow. AJs mediate normal mechanical coupling and play an important role in the stability of GJs. We investigated the effects of rapid electrical stimulation (RES) on cardiac intercellular junctions, especially ß-catenin and Cx43 alterations. We also studied the effects of ANG II receptor blockade on intercellular junction remodeling. Neonatal rats were euthanized by decapitation, and cardiomyocytes were prepared, cultured, and subjected to RES. We used real-time PCR, western blot analysis, and immunohistochemical methods. Conduction properties were examined by an extracellular potential mapping system. Cx43 protein expression in cardiomyocytes was significantly increased after 60 min. ß-Catenin expression in the total cell fraction was significantly increased after 30 min. The expression level of ß-catenin in the nucleus, which functions as a T cell factor/lymphocyte enhancer binding factor transcriptional activator of Cx43 with its degradation regulated by glycogen synthase kinase-3ß, was dramatically increased after 10 min. Conduction velocity was increased significantly by RES for 60 min. Olmesartan prevented most these effects of RES. We showed an increase of phosphorylated glycogen synthase kinase-3ß, which is phosphorylated by activated MAPKs and inhibits ß-catenin degradation, was attenuated by olmesartan. The changes in ß-catenin precede Cx43 GJ remodeling and might play an important role in the formation and stability of GJs. Olmesartan might be a new upstream arrhythmia therapy by modulating intercellular junction remodeling through the ß-catenin signaling pathway.

Alterations in adhesion junction precede gap junction remodelling during the development of heart failure in cardiomyopathic hamsters.

AIMS: The intercalated disc (ID) contains two complexes, the adhesion junction (AJ) and the gap junction (GJ). We studied ID remodelling and its potential role in arrhythmogenesis and investigated the effects of olmesartan on ID remodelling during development of heart failure (HF) in UM-X7.1 cardiomyopathic hamsters. METHODS AND RESULTS: The UM-X7.1 hamsters showed left ventricular (LV) hypertrophy by the age of 10-15 weeks and a moderate impairment in LV contractility at 20 weeks. At age 10-15 weeks, 10-20% of the hamsters died suddenly without HF, and ventricular tachycardia (VT)/ventricular fibrillation (VF) was induced in ∼30% of hamsters. Electron microscopy showed that density linking cell-to-cell adhesion was irregular and unclearly defined, and filamentous structures attached to electron-dense components were arranged in disorder. Western blotting showed that the total cellular expression level of ß-catenin was decreased, and expression of nuclear ß-catenin, which functions as a T-cell factor/lymphocyte enhancer binding factor transcriptional activator, was also remarkably decreased. At age 20 weeks, LV connexin43 expression showed a remarkable decrease, and the VT/VF induction rate was ∼90%. In UM-X7.1 hamsters, olmesartan improved abnormal ID ultrastructural changes, attenuated the decrease of total cellular and nuclear ß-catenin expression, decreased VT/VF induction, and improved survival rate. CONCLUSION: These results suggest that changes in AJ protein precede connexin43 GJ alterations, and ID remodelling might contribute to arrhythmogenesis during the development of HF. Angiotensin receptor blockade might be a new therapy for lethal ventricular arrhythmia by modulating both AJ and GJ remodelling.