Risks of occupational mental disorders in Korean civil servants (2009-18).

BACKGROUND: Previous studies have suggested that firefighters, police officers and civil servants in the education sector, particularly in Western countries, are vulnerable to mental stress and disorders; however, evidence for this association in South Korea is lacking. AIMS: This study aimed to identify whether firefighters, police officers and teachers are at a higher risk for occupational mental health disorders. METHODS: We used workers' compensation claims from civil servants (2009-18). Our target population comprised 46 209 civil servants (9009 civil servants in administrative and technical positions, 23 107 police officers, 4417 firefighters and 8676 civil servants in the educational sector). Occupational and environmental medicine physicians and medical doctors defined and confirmed mental disorders. We conducted Cox proportional hazards regression analyses to evaluate civil servants' risk of occupational mental health disorders. RESULTS: Compared with the civil servants in administrative and technical positions, civil servants in the education sector (hazard ratio [HR] = 2.16; 95% confidence interval [CI]:1.65-2.84) showed a statistically significant increased risk of mental disorders; conversely, firefighters did not (HR = 0.80; 95% CI 0.51-1.27). Police officers had a significantly decreased mental disorder risk compared with civil servants in administrative and technical positions (HR = 0.17; 95% CI 0.11-0.25). CONCLUSIONS: The risk of occupational mental health disorders was higher in civil servants in the education sector but lower in police officers and firefighters than civil servants in administrative and technical positions. Further studies on civil servants' mental health awareness are required to confirm our results.

Analysis of predisposing factors in unilateral maxillary sinus fungal ball: the predictive role of odontogenic and anatomical factors.

BACKGROUND: The pathogenesis of maxillary sinus fungal ball (MSFB) is explained by aerogenic and odontogenic factors. We evaluated the predisposing factors, including intranasal anatomical and dental factors for increased diagnostic accuracy. METHODOLOGY: In this study, 117 patients who underwent endoscopic sinus surgery for unilateral MSFB were included. Preoperative computed tomography (CT) scans were used to analyze the presence of anatomical variations (anterior and posterior nasal septal deviation (NSD), concha bullosa (CB), infraorbital cell (haller cell), paradoxical middle turbinate, everted uncinate process and MS size). Dental factors including history of dental procedures and findings on CT scans were reviewed. RESULTS: Anterior and posterior NSD toward non-affected side were significantly associated with the presence of FB. The presence of CB and infraorbital cell was higher in the non-affected side rather than in the lesion side. Compared to non-affected MS, FB-presence MS was shallower and had a larger height to depth ratio. The presence of dental history was significantly higher on FB-presence MS than non-affected MS. In multivariable analysis, posterior NSD toward non-affected side, dental history increased the aOR of MSFB, while the presence of CB and infraorbital cell decreased the aOR of MSFB. CONCLUSIONS: The occurrence of MSFB seems to be associated with ipsilateral odontogenic factors, followed by anatomic variations including posterior NSD toward non-affected side and absence of CB and infraorbital cell.

Recent metformin adherence and the risk of hypoglycaemia in the year following intensification with a sulfonylurea.

AIM: To evaluate whether recent low adherence to metformin monotherapy is associated with hypoglycaemia after addition of a sulfonylurea. METHODS: We assembled a retrospective cohort of veterans who filled a new prescription for metformin between 2001 and 2011 and intensified treatment with a sulfonylurea after ≥1 year of metformin use. We calculated metformin adherence from pharmacy data using the proportion of days covered in the 180-day period before intensification. The primary outcome was hypoglycaemia, defined as a hospitalization or emergency department visit for hypoglycaemia or an outpatient blood glucose measurement <3.3 mmol/l in the year following intensification. Cox proportional hazards models were used to compare the risk of hypoglycaemia between participants with low (<80%) and high (≥80%) adherence. Adherence was also modelled as a continuous variable using restricted cubic splines. RESULTS: Of 187 267 participants who initiated metformin monotherapy, 49 424 added a sulfonylurea after ≥1 year. The median (interquartile range) rate of treatment adherence was 87 (50-100)% and 43% had adherence <80%. Hypoglycaemia rates per 1000 person-years were 23.1 (95% CI 21.1-25.4) and 24.5 (95% CI 22.7-26.4) in participants with low and high adherence, respectively (adjusted hazard ratio 0.95, 95% CI 0.84-1.08). The risk of hypoglycaemia was similar across all levels of adherence when adherence was modelled as a continuous variable. CONCLUSIONS: We found no evidence that past low adherence to metformin monotherapy was associated with hypoglycaemia after intensification with a sulfonylurea.

Effect of goal-directed haemodynamic therapy in free flap reconstruction for head and neck cancer.

BACKGROUND: In free flap reconstruction for head and neck cancer, achieving a haemodynamic target using excessive fluid infusion is associated with decreased flap survival rates and extended hospital stays. We hypothesized that goal-directed haemodynamic therapy would improve flap survival rates and shorten hospitalization periods. METHODS: Patients scheduled for free flap reconstruction were randomly assigned to a goal-directed haemodynamic therapy group (n = 31) or a conventional haemodynamic therapy control group (n = 31). The control group received extra bolus fluid and ephedrine or norepinephrine to maintain a mean arterial pressure ≥ 65 mmHg. The goal-directed haemodynamic therapy group received a colloid solution as the extra bolus fluid to maintain a stroke volume variation < 12%; dobutamine, ephedrine, or norepinephrine was administered to maintain a cardiac index ≥ 2.5 l/min/m2 and mean arterial pressure ≥ 65 mmHg. Enhanced recovery after surgery protocols were not used except for fluid therapy. An otolaryngologist blinded to group assignments assessed flap outcomes and classified them as 'survival,' 'at risk' or 'failure.' RESULTS: The hospitalization period was not significantly different between the groups. The goal-directed haemodynamic therapy group had significantly shorter intensive care unit stays and a higher flap survival rate. The crystalloid volume was significantly lower in goal-directed haemodynamic therapy group. Reoperation rates, post-operative complications, and laboratory data including inflammatory markers were similar between the groups. CONCLUSION: Compared to conventional haemodynamic therapy, goal-directed haemodynamic therapy does not reduce hospitalization periods; it may, however, reduce the length of intensive care unit stays and increase flap survival rates. Further studies including multi-centre trials with larger sample sizes are warranted.

Abdominal adiposity intensifies the negative effects of ambient air pollution on lung function in Korean men.

BACKGROUND: Some studies have provided the possibility that adipose tissue may mediate air pollution-induced lung dysfunction. Studies using quantified fat mass data are needed to understand the biological mechanisms between adipocyte and air pollution in lung function. We aimed to investigate whether abdominal adiposity measured by computed tomography (CT) modifies the effects of air pollution on lung function in Korean men. METHODS: A total of 1876 men who visited one of two health checkup centers were recruited for this study. Adiposity traits such as visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and total adipose tissue (TAT) areas were measured by CT. We used the annual mean concentrations of ambient air pollutants including nitrogen dioxide (NO2) and particulate matter with an aerodynamic diameter ⩽10 µm (PM10). RESULTS: Interquartile range (IQR) increase in annual mean concentration of NO2 was significantly associated with a 2.5% lower forced expiratory volume in 1 s (FEV1) and 2.9% lower forced vital capacity (FVC) (both P<0.05). The decrease in lung function was more strongly associated with adiposity traits than with body mass index. In a stratified analysis of adiposity, compared with subjects with low-VAT area (VAT⩽200 cm2), those with high-VAT area (VAT>200 cm2) showed a rapid decrease in FEV1 with each IQR increase in PM10 (ß=-0.0812; 95% confidence interval (CI) =-0.1590, -0.0035) and NO2 (ß=-0.0979; 95% CI=-0.1611, -0.0346). In the high-VAT group, each IQR increase in NO2 content was significantly associated with a 10.6% decrease (ß=-0.1056; 95% CI=-0.1770, -0.0343) in FVC. SAT and TAT areas showed similar patterns. CONCLUSIONS: We report the first finding that abdominal adiposity intensifies the inverse relationship between air pollution and lung function.

PAI-1 gain-of-function genotype, factors increasing PAI-1 levels, and airway obstruction: The GALA II Cohort.

BACKGROUND: PAI-1 gain-of-function variants promote airway fibrosis and are associated with asthma and with worse lung function in subjects with asthma. OBJECTIVE: We sought to determine whether the association of a gain-of-function polymorphism in plasminogen activator inhibitor-1 (PAI-1) with airway obstruction is modified by asthma status, and whether any genotype effect persists after accounting for common exposures that increase PAI-1 level. METHODS: We studied 2070 Latino children (8-21y) with genotypic and pulmonary function data from the GALA II cohort. We estimated the relationship of the PAI-1 risk allele with FEV1/FVC by multivariate linear regression, stratified by asthma status. We examined the association of the polymorphism with asthma and airway obstruction within asthmatics via multivariate logistic regression. We replicated associations in the SAPPHIRE cohort of African Americans (n=1056). Secondary analysis included the effect of the at-risk polymorphism on postbronchodilator lung function. RESULTS: There was an interaction between asthma status and the PAI-1 polymorphism on FEV1 /FVC (P=.03). The gain-of-function variants, genotypes (AA/AG), were associated with lower FEV1 /FVC in subjects with asthma (ß=-1.25, CI: -2.14,-0.35, P=.006), but not in controls. Subjects with asthma and the AA/AG genotypes had a 5% decrease in FEV1 /FVC (P<.001). In asthmatics, the risk genotype (AA/AG) was associated with a 39% increase in risk of clinically relevant airway obstruction (OR=1.39, CI: 1.01, 1.92, P=.04). These associations persisted after exclusion of factors that increase PAI-1 including tobacco exposure and obesity. CONCLUSIONS AND CLINICAL RELEVANCE: The decrease in the FEV1 /FVC ratio associated with the risk genotype was modified by asthma status. The genotype increased the odds of airway obstruction by 75% within asthmatics only. As exposures known to increase PAI-1 levels did not mitigate this association, PAI-1 may contribute to airway obstruction in the context of chronic asthmatic airway inflammation.

Adequate interval for the monitoring of vital signs during endotracheal intubation.

BACKGROUND: In the perioperative period, it may be inappropriate to monitor vital signs during endotracheal intubation using the same interval as during a hemodynamically stable period. The aim of the present study was to determine whether it is appropriate to use the same intervals used during the endotracheal intubation and stable periods to monitor vital signs of patients under general anesthesia. METHODS: The mean arterial pressure (MAP) and heart rate (HR) were continuously measured during endotracheal intubation (15 min after intubation) and hemodynamically stable (15 min before skin incision) periods in 24 general anesthesia patients. Data was considered "unrecognized" when continuously measured values were 30% more or less than the monitored value measured at 5- or 2.5-min intervals. The incidence of unrecognized data during endotracheal intubation was compared to that during the hemodynamically stable period. RESULT: There were significantly more unrecognized MAP data measured at 5-min intervals during endotracheal intubation than during the hemodynamically stable period (p value <0.05). However, there was no difference in the incidence of unrecognized MAP data at 2.5 min intervals or HR data at 5 or 2.5 min intervals between during the endotracheal intubation and hemodynamically stable periods. CONCLUSION: A 5-min interval throughout the operation period was not appropriate for monitoring vital signs. Therefore, , a 2.5-min interval is recommended for monitoring the MAP during endotracheal intubation.

Relation of serum vitamin A levels to all-cause and cause-specific mortality among older adults in the NHANES III population.

AIMS: Although studies have suggested that vitamin A is associated with cardiovascular events and mortality, it remains unclear whether low doses or high doses of vitamin A have harmful effects on the cardiovascular system. This study investigated whether serum vitamin A levels are associated with all-cause and cause-specific mortality in US older adults. DATA SYNTHESIS: We analyzed the mortality information for 6069 participants aged 50 years or older who had serum vitamin A data available from the baseline examination. The participants were categorized as having deficient (<30 µg/dL), normal (30-80 µg/dL), or excessive (>80 µg/dL) levels of serum vitamin A, and a multivariate Cox proportional hazards regression analysis was performed on mortality. We found a U-shaped association between serum vitamin A levels and death from all-cause and cause-specific mortality among US adults. Comparing the normal range of serum vitamin A, the hazard ratio with deficient serum vitamin A was 2.9 (95% CI 2.0-4.3) for all-cause mortality, 2.1 (95% CI 1.1-4.1) for cardiovascular-related mortality and 2.5 (95% CI 1.2-5.3) for coronary artery disease-related mortality. Excessive serum vitamin A was associated with a 1.2-fold (95% CI 1.1-1.4) increased risk of all-cause mortality, a 1.4-fold (95% CI 1.2-1.8) increased risk of cardiovascular-related mortality, and a 1.5-fold (95% CI 1.2-2.0) increased risk of coronary artery disease-related mortality compared with the reference group. CONCLUSION: The finding suggests that serum vitamin A levels less than 30 µg/dL or greater than 80 µg/dL levels may indicate a high risk of subsequent mortality.

A randomised comparison of the i-gel™ and the Laryngeal Mask Airway Classic™ in infants.

We performed a randomised comparison of the i-gel™ and the Laryngeal Mask Airway (LMA) Classic™ in children aged less than a year who were undergoing general anaesthesia for elective surgery. Fifty-four infants were randomly allocated to either the i-gel or the LMA Classic. We measured performance characteristics, fibreoptic views through the device and complications. Success rate at first insertion attempt was 100% (27/27) in the i-gel group compared with 88% (23/26) in the LMA Classic group. Insertion of the device was considered easy in 26/27 (96%) patients in the i-gel group compared with 18/26 (69%) patients in the LMA Classic group (p = 0.009). There were no differences between the groups in insertion times, fibreoptic views through the device, airway leak pressures or complications. We conclude that the i-gel was considered easier to insert than the LMA Classic in infants.

Assisted reproductive techniques and subsequent risk of asthma and allergic rhinitis in offspring: a nationwide birth cohort study in South Korea.

OBJECTIVE: The relationship between assisted reproductive techniques (ART) and the risk of asthma and allergic rhinitis (AR) is controversial. Thus, we aimed to investigate the relationship between ART and the risk of asthma and AR in a nationwide, large-scale birth cohort. PATIENTS AND METHODS: This study utilized the National Health Insurance Service data in South Korea to conduct a nationwide, large-scale, population-based birth cohort. We included all infants born between 2017 and 2018. AR, asthma, food allergies, and atopic dermatitis were defined using the International Classification of Diseases tenth edition codes. Asthma was classified as allergic or non-allergic based on accompanying allergic diseases (AR, food allergy, or atopic dermatitis). Using 1:10 propensity score matching, we compared infants conceived through ART with those conceived naturally (non-ART). After matching, logistic regression was used to compare the hazard ratio for asthma and AR between the two groups. RESULTS: We included 543,178 infants [male infants, 280,194 (51.38%)]. After matching, 8,925 and 74,229 infants were selected for the ART and non-ART groups, respectively. The ART group showed a decreased risk of asthma in the offspring [adjusted hazard ratio (aHR), 0.45; 95% confidence interval (CI), 0.41-0.48]. Similarly, for AR, being conceived by ART was associated with a decreased risk of AR (aHR, 0.25; 95% CI, 0.12-0.37). ART offspring showed a decreased risk of asthma and AR in offspring compared to that observed in non-ART offspring. CONCLUSIONS: Our study offers important insights for clinicians, researchers, and parents regarding the health outcomes of ART-conceived infants and enhances our understanding of ART's impact on respiratory health.

Relationship between chewing ability and depressive symptoms.

OBJECTIVE: Depression, as one of the most common mental health problems, has many related factors. Recent studies have suggested chewing difficulties as a risk factor for depression in the elderly. This study seeks to investigate whether chewing ability is associated with depressive symptoms in a Korean population. METHODS: This study used data from the Fifth Korean National Health and Nutrition Examination Survey (KNHANES V) conducted in 2010. Self-reported questionnaires assessed depressive symptoms and chewing ability for the purposes of this study. A total of 6,255 subjects aged over 19 years were included for this study (2,704 males and 3,551 females). RESULTS: Comparing depressive symptoms with chewing ability (i.e., very poor, poor, moderate, good, and very good), the adjusted odds ratios (ORs) and confidence intervals (CI) were 1.05 (95% CI: 0.84-1.32) for good vs. very good (as a reference), 1.31 (95% CI: 1.00-1.73) for moderate vs. very good, 1.41 (95% CI: 1.12-1.78) for poor vs. very good, and 1.76 (95% CI: 1.16-2.76) for very poor vs. very good. CONCLUSION: This study suggests that subjects with reduced chewing ability were more susceptible to having depressive symptoms.

Evaluation of inferior turbinate outfracture outcomes using computed tomography.

BACKGROUND: Outfracture of the inferior turbinate (IT) presents numerous advantages, but it is generally believed that the lateralized IT will resume its original position. The purpose of this study was to evaluate the outcome of IT outfracture objectively using computed tomography (CT). METHODOLOGY: Fifteen patients who underwent bilateral IT outfracture for the removal of pituitary adenomas by the endonasal approach were enrolled. The angles between the lateral wall of the nasal cavity (NC) and IT on both sides were measured from CT scans before and at least 6 months after operation. In addition, we evaluated the effects of variables including age, thickness of IT attachment site and width of the nasal floor, on the angles. RESULTS: Regardless of the side where a Hardy retractor was placed, the angle between the lateral wall of the NC and IT decreased significantly within 6 months after the outfracture compared to preoperative values on both sides. Other variables showed no significant correlations with the angle between the IT and the lateral wall of the NC. CONCLUSION: The outfracture procedure effectively lateralized the IT and it maintained that position for at least 6 months after the operation.

A prospective study of work stressors and the common cold.

BACKGROUND: Psychological stress is a risk factor for infectious diseases. Although psychological stress at work is considered an important problem for many workers, there is little evidence for the effect of work-related stress on infectious diseases. AIMS: To investigate whether work-related stress affected the occurrence of the common cold in South Korean workers in small- to medium-sized manufacturing companies. METHODS: We conducted a prospective study, involving 1241 workers. At the outset, we collected information regarding sociodemographic and work characteristics. At follow-up after 6 months, we asked subjects whether they had experienced common cold symptoms during the preceding 4 months. RESULTS: Male subjects experiencing stress at the outset were more likely to report having experienced the common cold at follow-up (odds ratios: high job demand group 1.74; 95% CI: 1.28-2.36; insufficient job control 1.42; 95% CI: 1.05-1.93; inadequate social support 1.40; 95% CI: 1.03-1.91). For females, no significant association between work stress and occurrence of the common cold was detected. CONCLUSIONS: Males experiencing work stress in job demand, job control and social support reported an increased occurrence of the common cold at follow-up but this association was not seen in females.

In-utero development of the fetal anal sphincter.

OBJECTIVE: To investigate the in-utero development of the fetal anal sphincter using transabdominal ultrasound. METHODS: This was a cross-sectional study in which the diameter of the fetal anal sphincter was measured sonographically once in 631 well-dated, non-anomalous fetuses scanned between 19 and 38 weeks of gestation. Visualization rates were determined. Regression analysis was used to assess the relationship between the diameter of the fetal anal sphincter and gestational age (GA), and reference values including the mean and 95% reference interval were calculated for each GA. RESULTS: The sonographic visualization rate of the fetal anal sphincter increased with gestational age, plateauing at 90-100% between 23-34 weeks of gestation. There was a significant positive relationship between fetal anal sphincter diameter and GA, which was best described by the equation: anal sphincter diameter (mm) = - 0.014 x GA(2) + 1.107 x GA - 11.664 (R(2) = 0.62). CONCLUSION: We have provided reference values for the in-utero development of the fetal anal sphincter throughout gestation.

Anatomical analysis to establish the optimal positioning of an osteotomy for genioglossal advancement: a trial in cadavers.

Genioglossal advancement, which is one of the treatments for obstructive sleep apnoea, can be effective only if it contains enough genial tubercle for an osteotomy. The aim of this study was to establish the position of the genial tubercle and of the optimal osteotomy during genioglossal advancement. Twenty-four adult cadavers with intact bony mandibular structures were included. Five variables were measured: the width and height of the genial tubercle (GTW); the distance from its inferior border to the inferior border of the mandible (IGT-IBM); the distance from the superior border of the genial tubercle to the inferior border of the mandible (SGT-IBM); and the width of the intermental foramen (IMFW). The following mean (SD) (range) measurements were obtained: GTW 7.38 (1.43) (4.5-10.0); GTH 7.94 (1.45) (5.0-10.0); IGT-IBM 7.96 (2.29) (4.0-12.0); SGT-IBM 15.90 (2.29) (12.0-20.0); and IMFW 56.65 (6.44) (43.0-67.0) mm. Of the 24 cadavers, 22 showed evidence of optimal positioning when the osteotomy was placed 2mm higher than the SGT-IBM measured on the inner table. This suggests that an optimal osteotomy, which includes the genial tubercle, may be possible in most patients when the osteotomy is positioned 2mm higher at the SGT-IBM.

Tuberculosis infection via the emergency department among inpatients in South Korea: a propensity score matched analysis of the National Inpatient Sample.

BACKGROUND: Emergency departments (EDs) carry a high risk of infectious disease transmission and have also been implicated in tuberculosis (TB) outbreaks. AIM: To determine if patients who visit EDs have an increased risk of TB infection. Using South Korean inpatient sample data (2012), the risk of TB occurrence during 90 days after hospitalization for patients admitted via EDs was compared with that for patients admitted via outpatient clinics. METHODS: The data of the 2012 Health Insurance Review and Assessment Service - National Inpatient Sample were used. TB diagnosis was based on International Classification of Diseases Version 10 [all TB (A15-A19), pulmonary TB (A15-A16) and extrapulmonary TB (A17-A18)]. FINDINGS: After propensity score matching using the demographic and clinical characteristics of the patients, 191,997 patients (64,017 patients admitted via EDs and 127,908 patients admitted via outpatient clinics) were included in this study. There was no significant difference in baseline patient characteristics between the two groups. The percentage of patients with TB admitted via EDs was higher than that of patients admitted via outpatient clinics. The likelihood of active TB occurrence was 30% higher for all TB [hazard ratio (HR) 1.30; 95% confidence interval (CI) 1.12-1.52] and pulmonary TB (HR 1.30; 95% CI 1.10-1.53) in patients admitted via EDs compared with patients admitted via outpatient clinics; this difference was significant. However, no difference in the occurrence of extrapulmonary TB was observed between the two groups. CONCLUSIONS: The likelihood of TB infection was greater in patients admitted via EDs than in patients admitted via outpatient clinics.

Serum anti-amyloid-beta antibodies and Alzheimer's disease in elderly Korean patients.

Alzheimer's disease (AD) is characterized by the deposition of senile plaques and neurofibrillary tangles in the brain. The presence of the amyloid-beta (Abeta) peptide in senile plaques seems to play a central role in the neuropathology of AD. Diagnosis of AD involves neuropsychological examinations or magnetic resonance imaging and, to date, a specific diagnostic marker indicating AD has not been found. This study analysed anti-Abeta antibodies from the serum of 153 patients with AD using an enzyme-linked immunosorbent assay method. The levels of anti-Abeta antibody from patients in the control group (n=193) were compared with those of patients with AD. Our results showed a significantly lower anti-Abeta antibody level in patients with AD than in the control group. These results showed that the anti-Abeta antibody level in serum could potentially be used to diagnose the presence of AD.

CD14 receptor gene promoter polymorphism: awakening maternal immunity during pregnancy.

We investigated whether monocyte CD14 receptor gene promoter polymorphisms were associated with the development and severity of pre-eclampsia. We genotyped the CD14 -260 C/T polymorphism in 36 pre-eclamptic patients and 52 healthy pregnant controls. A total of 30.6% and 69.4% of pre-eclamptic patients had the C and T alleles, respectively, and 48.0% and 52.0% of the controls, respectively. More pre-eclamptic patients were TT homozygotes compared with controls (50.0% versus 13.5%). In pre-eclamptic patients, the TT homozygotes exhibited a significantly higher mean systolic blood pressure compared with the non-TT homozygotes (173 +/- 28 mmHg versus 153 +/- 22 mmHg). We also noted a tendency towards increased proteinuria and placental abruption in the TT homozygotes compared with the non-TT homozygotes. We conclude that CD14 gene promoter polymorphisms appear to be a risk factor for pre-eclampsia. With further research, these findings might form the basis of a prognostic tool for pre-eclampsia.

Effects of the calcium channel antagonist mibefradil on haemodynamic parameters and myocardial Ca(2+)-handling in infarct-induced heart failure in rats.

OBJECTIVE: Abnormal intracellular Ca(2+)-handling has been implicated in the pathogenesis of contractile dysfunction and arrhythmias in failing hearts. Calcium channel antagonists (CCA) have been proposed for the prevention of cardiac events after myocardial infarction (MI). Recent studies suggest that the blockade of T-type Ca(2+)-channels induced a heart rate reduction without negative inotropic effects. We investigated the effects of the preferentially T-channel blocking CCA, mibefradil, on haemodynamic parameters and intramyocardial Ca(2+)-handling and contractility in the early and late period after MI. METHODS: MI was induced by permanent ligation of the left coronary artery in male normotensive Wistar rats. Animals were divided in sham-operated and placebo- or mibefradil-treated MI rats. Placebo or Mibefradil treatment (10 mg/kg/d via gastric gavage) was started 7 days prior to MI-induction. Haemodynamic and intramyocardial Ca2+ measurements were performed 1, 3, 7 and 42 days after surgery. At these time points, mean arterial blood pressure (MAP), heart rate (HR), left ventricular enddiastolic pressure (LVEDP) and cardiac contractility (dP/dtmax) were measured in conscious rats. After haemodynamic measurements, the left ventricular papillary muscle was separated to determine developed tension (DT), time to peak tension (TPT) and systolic and diastolic free intracellular Ca2+ concentrations ([Ca2+]i) using the Ca2+ indicator aequorin. Dose-response curves after extracellular isoproterenol- or Ca(2+)-stimulation were recorded. RESULTS: In the early (1-3 days) period after MI, MAP and dP/dtmax were decreased and LVEDP and HR were increased in placebo-treated MI rats. Mibefradil treatment increased MAP and dP/dtmax and decreased LVEDP and HR in infarcted rats. In the papillary muscle of placebo-treated rats, MI induced a decrease in DT and an increase in TPT and in diastolic and systolic [Ca2+]i. DT of placebo-treated MI rats showed a reduced reactivity after isoproterenol- or Ca(2+)-stimulation. After mibefradil treatment DT was increased and TPT was reduced in the late period (7-42 days) after MI, and diastolic and systolic [Ca2+]i were decreased in the early period after MI (1-3 days). The inotropic response to beta-adrenergic or extracellular Ca(2+)-stimulation was markedly improved by mibefradil 7 and 42 days after MI. CONCLUSION: We conclude, that mibefradil improves cardiac function, protects the myocardium against ischemia-induced Ca(2+)-overload and increases beta-adrenergic responsiveness in chronically failing rat hearts.

Dantrolene sodium improves the force-frequency relationship and beta-adregenic responsiveness in failing human myocardium.

BACKGROUND: Failing human myocardium is characterized by a negative force-frequency relationship and impaired beta-adrenergic responsiveness which have been related to alterations of the intracellular Ca2+ homeostasis. Dantrolene sodium is a clinically used drug that modulates myocardial [Ca2+]i handling in animal models. This study investigated the effects of dantrolene sodium on intracellular Ca2+ handling and contractile function in failing human myocardium. METHODS AND RESULTS: Twenty-three muscle strips from human left ventricular trabeculae were obtained from patients undergoing heart transplantation for end-stage heart failure caused by idiopathic dilated cardiomyopathy (n = 15). Isometric contraction and intracellular Ca2+ transients (Ca2+ indicator: aequorin) were recorded simultaneously. The experiments were performed in three separate groups exposed to control condition (n = 8), addition of dantrolene (10 micromol/l; n = 8), or addition of verapamil (1 micromol/l; n = 7). Isoproterenol induced a moderate positive inotropic effect in the control group with a maximal increase of developed tension from 10.8 +/- 2.9 to 23.4 +/- 4.7 mN/mm2 and a parallel rise in peak systolic [Ca2+]i to a maximum of 1.36 +/- 0.20 micromol/l. Dantrolene significantly improved (10.2 +/- 3.8 to 32.4 +/- 0.9 mN/mm2) and verapamil blunted (8.3 +/- 2.8 to 17.1 +/- 4.3 mN/mm2) the inotropic response to isoproterenol. The diastolic and systolic [Ca2+]i during isoproterenol stimulation were slightly lower in the dantrolene group but significantly depressed in the verapamil group as compared to the control group. Similarly, analyses of force-frequency relationships revealed an improvement of developed tension in dantrolene-treated as compared to control preparations whereas the peak systolic [Ca2+]i was almost identical. CONCLUSION: Dantrolene improves the negative force-frequency relationship and beta-adrenergic responsiveness in failing human myocardium. These effects are not accompanied by an additional increase in intracellular [Ca2+]i but might be related to modifications of the diastolic [Ca2+]i homeostasis.