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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

Catecholaminergic polymorphic ventricular tachycardia is caused by mutation-linked defective conformational regulation of the ryanodine receptor.

RATIONALE: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by a single point mutation in a well-defined region of the cardiac type 2 ryanodine receptor (RyR)2. However, the underlying mechanism by which a single mutation in such a large molecule produces drastic effects on channel function remains unresolved. OBJECTIVE: Using a knock-in (KI) mouse model with a human CPVT-associated RyR2 mutation (R2474S), we investigated the molecular mechanism by which CPVT is induced by a single point mutation within the RyR2. METHODS AND RESULTS: The R2474S/+ KI mice showed no apparent structural or histological abnormalities in the heart, but they showed clear indications of other abnormalities. Bidirectional or polymorphic ventricular tachycardia was induced after exercise on a treadmill. The interaction between the N-terminal (amino acids 1 to 600) and central (amino acids 2000 to 2500) domains of the RyR2 (an intrinsic mechanism to close Ca(2+) channels) was weakened (domain unzipping). On protein kinase A-mediated phosphorylation of the RyR2, this domain unzipping further increased, resulting in a significant increase in the frequency of spontaneous Ca(2+) transients. cAMP-induced aberrant Ca(2+) release events (Ca(2+) sparks/waves) occurred at much lower sarcoplasmic reticulum Ca(2+) content as compared to the wild type. Addition of a domain-unzipping peptide, DPc10 (amino acids 2460 to 2495), to the wild type reproduced the aforementioned abnormalities that are characteristic of the R2474S/+ KI mice. Addition of DPc10 to the (cAMP-treated) KI cardiomyocytes produced no further effect. CONCLUSIONS: A single point mutation within the RyR2 sensitizes the channel to agonists and reduces the threshold of luminal [Ca(2+)] for activation, primarily mediated by defective interdomain interaction within the RyR2.

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.

Effects of aldosterone on Cx43 gap junction expression in neonatal rat cultured cardiomyocytes.

BACKGROUND: The renin-angiotensin-aldosterone system affects cellular morphology and function in the heart under a variety of pathologic conditions. In the present study the effects of aldosterone on the expression of connexin (Cx) 43 gap junctions in cardiomyocytes were investigated. METHODS AND RESULTS: Cultured rat ventricular myocytes were exposed to aldosterone for 24 h. The protein and mRNA expression of Cx43 was estimated. Propagation of excitation was visualized by a multiple electrode array system. Treatment of the myocytes with 10(-8) mol/L aldosterone resulted in a significant upregulation of Cx43 (by approximately 1.5-fold in protein and by approximately 1.2-fold in mRNA). The immunoreactive signal of Cx43 was also increased. Conduction velocity (CV) was increased by approximately 24%. Treatment of the myocytes with aldosterone at higher concentrations (10(-6)-10(-4) mol/L) caused a significant downregulation of Cx43 protein (by approximately 0.3-fold) without affecting Cx43 mRNA levels, and decreased the CV by ~23%. The Cx43 upregulation and CV acceleration at 10(-8) mol/L aldosterone were prevented by pretreatment with eplerenone, but unaffected by mifepristone. Pretreatment of the myocytes with eplerenone or mifepristone did not prevent the Cx43 downregulation by aldosterone at 10(-6)-10(-4) mol/L. CONCLUSIONS: Aldosterone may be involved in arrhythmogenic gap junction remodeling through its dual effects on the expression of Cx43.

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.

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.

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.

Defective regulation of interdomain interactions within the ryanodine receptor plays a key role in the pathogenesis of heart failure.

BACKGROUND: According to our hypothesis, 2 domains within the ryanodine receptor (RyR) of sarcoplasmic reticulum (SR) (N-terminal [0 to 600] and central [2000 to 2500] domains), where many mutations have been found in patients with polymorphic ventricular tachycardia, interact with each other as a regulatory switch for channel gating. Here, we investigated whether the defective FKBP12.6-mediated stabilization of RyR in heart failure is produced by an abnormal interdomain interaction. METHODS AND RESULTS: SR vesicles were isolated from dog left ventricular muscles, and then the RyR moiety of the SR was fluorescently labeled with methylcoumarin acetate (MCA) using DPc10, a synthetic peptide corresponding to Gly2460-Pro2495 of RyR (one of the mutable domains in polymorphic ventricular tachycardia), as a site-directing carrier; the carrier was removed from the RyR after MCA labeling. Addition of DPc10 induced an unzipped state of the interacting N-terminal and central domains, as evidenced by an increase in the accessibility of the RyR-bound MCA fluorescence to a large fluorescence quencher. Domain unzipping resulted in Ca2+ leak through the RyR and facilitated cAMP-dependent hyperphosphorylation of RyR and FKBP12.6 dissociation from RyR. When DPc10 was introduced into the isolated myocytes, the magnitude of intracellular Ca2+ transient decreased, and its decay time was prolonged. In the SR isolated from pacing-induced dog failing hearts, the domain unzipping has already occurred, together with FKBP12.6 dissociation and Ca2+ leak. CONCLUSIONS: The specific domain interaction within the RyR regulates the channel gating property, and the defectiveness in the mode of the interdomain interaction seems to be the initial critical step of the pathogenesis of heart failure.

Correction of defective interdomain interaction within ryanodine receptor by antioxidant is a new therapeutic strategy against heart failure.

BACKGROUND: Defective interdomain interaction within the ryanodine receptor (RyR2) seems to play a key role in the pathogenesis of heart failure, as shown in recent studies. In the present study we investigated the effect of oxidative stress on the interdomain interaction, its outcome in the cardiac function in heart failure, and the possibility of preventing the problem with antioxidants. METHODS AND RESULTS: Sarcoplasmic reticulum (SR) vesicles were isolated from dog left ventricular (LV) muscle (normal or rapid ventricular pacing for 4 weeks with or without the antioxidant edaravone). In the edaravone-treated paced dogs (EV+), but not in the untreated paced dogs (EV-), normal cardiac function was restored almost completely. In the SR vesicles isolated from the EV-, oxidative stress of the RyR2 (reduction in the number of free thiols) was severe, but it was negligible in EV+. The oxidative stress of the RyR2 destabilized interdomain interactions within the RyR2 (EV-), but its effect was reversed in EV+. Abnormal Ca2+ leak through the RyR2 was found in EV- but not in EV+. The amount of the RyR2-bound FKBP12.6 was less in EV- than in normal dogs, whereas it was restored almost to a normal amount in EV+. The NO donor 3-morpholinosydnonimine (SIN-1) reproduced, in normal SR, several abnormal features seen in failing SR, such as defective interdomain interaction and abnormal Ca2+ leak. Both cell shortening and Ca2+ transients were impaired by SIN-1 in isolated normal myocytes, mimicking the pathophysiological conditions in failing myocytes. Incubation of failing myocytes with edaravone restored the normal properties. CONCLUSIONS: During the development of heart failure, edaravone ameliorated the defective interdomain interaction of the RyR2. This prevented Ca2+ leak and LV remodeling, leading to an improvement of cardiac function and an attenuation of LV remodeling.

High ambient pressure produces hypertrophy and up-regulates cardiac sarcoplasmic reticulum Ca2+ regulatory proteins in cultured rat cardiomyocytes.

Previously, we demonstrated in vivo that the nature of the alterations in sarcoplasmic reticulum (SR) function and SR Ca2+ regulatory proteins depends both on the type of mechanical overload imposed and on the duration of the heart disorder. The purpose of the present study was to determine in vitro whether an extrinsic mechanical overload (in the form of high ambient pressure) would cause an up-regulation of ryanodine receptor (RyR) and Ca2+-ATPase, as we previously reported mildly pressure-overloaded, hypertrophied rat hearts. Primary cultures of neonatal rat cardiomyocytes were prepared and high ambient pressure was produced using an incubator and pressure-overloading apparatus. Cells were exposed to one of two conditions for 72 h: atmospheric pressure conditions (APC) or high pressure conditions (HPC; HPC=APC+200 mmHg). The expression levels of RyR and Ca2+-ATPase were quantified and functional characteristics were monitored. The cell area was significantly greater under HPC. After 6 h exposure, the physiological properties of cardiomyocytes were impaired, but they returned to the baseline level within 24 h. After 24 h exposure, the expression level of RyR was significantly higher under HPC, and for Ca2+-ATPase, the expression level was significantly higher under HPC after 6 h exposure. HPC caused hypertrophy and up-regulated the expression of Ca2+ regulatory proteins and their genes. We suggest that this in vitro pressure-overloading model may prove useful, as is a stretch-overloading model, for investigation of the intracellular Ca2+ regulatory pathways responsible for the development of cardiac hypertrophy.

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% (