Long-Term Cognitive and Behavioral Outcomes following Resolution of Sleep Disordered Breathing in Preschool Children

This study aimed to determine the long term effects of resolution of SDB in preschool children, either following treatment or spontaneous recovery, on cognition and behavior. Children diagnosed with SDB at 3-5y (N = 35) and non-snoring controls (N = 25), underwent repeat polysomnography (PSG) and cognitive and behavioral assessment 3 years following a baseline study. At follow-up, children with SDB were grouped into Resolved and Unresolved. Resolution was defined as: obstructive apnea hypopnea index (OAHI) ≤1 event/h; no snoring detected on PSG; and no parental report of habitual snoring. 57% (20/35) of children with SDB received treatment, with SDB resolving in 60% (12/20). 43% (15/35) were untreated, of whom 40% (6/15) had spontaneous resolution of SDB. Cognitive reduced between baseline and follow-up, however this was not related to persistent disease, with no difference in cognitive outcomes between Resolved, Unresolved or Control groups. Behavioral functioning remained significantly worse in children originally diagnosed with SDB compared to control children, regardless of resolution. Change in OAHI did not predict cognitive or behavioral outcomes, however a reduction in nocturnal arousals, irrespective of full resolution, was associated with improvement in attention and aggressive behavior. These results suggest that resolution of SDB in preschool children has little effect on cognitive or behavioral outcomes over the long term. The association between sleep fragmentation and behavior appears independent of SDB, however may be moderated by concomitant SDB. This challenges the assumption that treatment of SDB will ameliorate associated cognitive and behavioural deficits and supports the possibility of a SDB phenotype.     

Gentamicin-Induced Chronotoxicity: Use of Body Temperature as a Orcadian Marker Rhythm

Aminoglycoside antibiotics produce varying degrees of ototoxicity, dependent on dosage time, in animals synchronized for rhythm study. Herein, we illustrate the use of an economical and reliable system to telemeter body temperature of laboratory animals as an endogenous marker rhythm for gentamicin-induxed ototoxicity. Two groups of 3 male Sprague-Dawley rats (250–400 gm) were housed in separate cages in a temperature-controlled room programmed with a 12:12 LD schedule and monitored for hearing thresholds at the frequencies of 8kHz, 16kHz, 24kHz and 32kHz at 2-week intervals. Each rat was dosed with 100 mg/kg/day gentamicin subcutaneously for a duration of 28 days. The animals from one group were dosed at their daily temperature maximum, while the animals of the other group were dosed at their daily temperature minimum. Both after 14 and 28 days of gentamicin treatment there was no important changes in auditory thresholds from baseline values when treatment was timed daily to the circadian peak of body temperature. Animals dosed daily at the trough of the circadian temperature rhythm evidenced an auditory threshold shift of between 5 and 25 dB after 14 days of treatment and a total hearing loss (80–90 dB) after 28 days of such treatment. These results document a dramatically greater level of hearing loss induced in those animals dosed with gentamicin at the body temperature trough (diurnal rest span) as compared to those dosed at the acrophase (nocturnal activity span). The findings indicate that the peak and trough of the circadian pattern of body temperature serve as meaningful markers of the resistance and susceptibility, respectively, of gentamicin-induced ototoxicity in rodent models.     

Gentamicin-Induced Chronotoxicity: Use of Body Temperature as a Orcadian Marker Rhythm

Aminoglycoside antibiotics produce varying degrees of ototoxicity, dependent on dosage time, in animals synchronized for rhythm study. Herein, we illustrate the use of an economical and reliable system to telemeter body temperature of laboratory animals as an endogenous marker rhythm for gentamicin-induxed ototoxicity. Two groups of 3 male Sprague-Dawley rats (250-400 gm) were housed in separate cages in a temperature-controlled room programmed with a 12:12 LD schedule and monitored for hearing thresholds at the frequencies of 8kHz, 16kHz, 24kHz and 32kHz at 2-week intervals. Each rat was dosed with 100 mg/kg/day gentamicin subcutaneously for a duration of 28 days. The animals from one group were dosed at their daily temperature maximum, while the animals of the other group were dosed at their daily temperature minimum. Both after 14 and 28 days of gentamicin treatment there was no important changes in auditory thresholds from baseline values when treatment was timed daily to the circadian peak of body temperature. Animals dosed daily at the trough of the circadian temperature rhythm evidenced an auditory threshold shift of between 5 and 25 dB after 14 days of treatment and a total hearing loss (80-90 dB) after 28 days of such treatment. These results document a dramatically greater level of hearing loss induced in those animals dosed with gentamicin at the body temperature trough (diurnal rest span) as compared to those dosed at the acrophase (nocturnal activity span). The findings indicate that the peak and trough of the circadian pattern of body temperature serve as meaningful markers of the resistance and susceptibility, respectively, of gentamicin-induced ototoxicity in rodent models.     

Application of Chaos Theory in Analyzing the Cardiac Rhythm in Healthy Subjects at Different Sleep Stages

The changes in the chaotic element of the cardiac rhythm (CR) were quantitated at different sleep stages by calculating the correlation dimension (D2) in 26 healthy subjects of both sexes (mean age 29.2 years), including 7 trained and 19 untrained subjects. Three untrained subjects took part in tests with autonomic nervous system blockers (atropine and propranolol). The study demonstrated a correlation between the changes in D2 at different sleep stages and the level of the autonomic regulation of CR. As the influence of the parasympathetic system on CR increased from one stage of slow wave sleep to another, D2 increased; during rapid eye movement (REM) sleep, this influence weakened and D2 decreased. The character of changes differed in the trained and untrained subjects and depended on the initial level of the autonomic regulation of CR. In the trained subjects, characterized by predominance of the parasympathetic regulation of CR, the initial and subsequent D2 values were higher than in the untrained subjects. Both during wakefulness and at all stages of sleep, D2 increased when the sympathetic regulation of CR was blocked, decreased when the parasympathetic regulation was blocked, and reached the lowest level when both of them were blocked. This showed that the chaotic element of CR, expressed numerically by D2, depends on the regulating effects of the autonomic nervous system.     

Longitudinal Change in Sleep and Daytime Sleepiness in Postpartum Women

Sleep disruption strongly influences daytime functioning; resultant sleepiness is recognised as a contributing risk-factor for individuals performing critical and dangerous tasks. While the relationship between sleep and sleepiness has been heavily investigated in the vulnerable sub-populations of shift workers and patients with sleep disorders, postpartum women have been comparatively overlooked. Thirty-three healthy, postpartum women recorded every episode of sleep and wake each day during postpartum weeks 6, 12 and 18. Although repeated measures analysis revealed there was no significant difference in the amount of nocturnal sleep and frequency of night-time wakings, there was a significant reduction in sleep disruption, due to fewer minutes of wake after sleep onset. Subjective sleepiness was measured each day using the Karolinska Sleepiness Scale; at the two earlier time points this was significantly correlated with sleep quality but not to sleep quantity. Epworth Sleepiness Scores significantly reduced over time; however, during week 18 over 50% of participants were still experiencing excessive daytime sleepiness (Epworth Sleepiness Score ≥12). Results have implications for health care providers and policy makers. Health care providers designing interventions to address sleepiness in new mothers should take into account the dynamic changes to sleep and sleepiness during this initial postpartum period. Policy makers developing regulations for parental leave entitlements should take into consideration the high prevalence of excessive daytime sleepiness experienced by new mothers, ensuring enough opportunity for daytime sleepiness to diminish to a manageable level prior to reengagement in the workforce.     

Delta Neutrophil Index as a Promising Prognostic Marker in Out of Hospital Cardiac Arrest

Background

The post-resuscitation phase after out-of-hospital cardiac arrest (OHCA) is characterised by a systemic inflammatory response (e.g., severe sepsis), for which the immature granulocyte count is a diagnostic marker. In this study we evaluated the prognostic significance of the delta neutrophil index (DNI), which is the difference in leukocyte subfractions as assessed by an automated blood cell analyser, for early mortality after OHCA.

Materials and Methods

OHCA records from the emergency department cardiac arrest registry were retrospectively analysed. Patients who survived at least 24 h after return of spontaneous circulation were included in the analysis. We evaluated mortality and cerebral performance category scores at 30 days.

Results

A total of 83 patients with OHCA were included in the study. Our results showed that DNI >8.4% on day 1 (hazard ratio [HR], 3.227; 95% CI, 1.485–6.967; p = 0.001) and DNI >10.5% on day 2 (HR, 3.292; 95% CI, 1.662–6.519; p<0.001) were associated with increased 30-day mortality in patients with OHCA. Additionally, DNI >8.4% on day 1 (HR, 2.718; 95% CI, 1.508–4.899; p<0.001) and DNI >10.5% on day 2 (HR, 1.709; 95% CI, 1.051–2.778; p = 0.02) were associated with worse neurologic outcomes 30 days after OHCA.

Conclusion

A higher DNI is a promising prognostic marker for 30-day mortality and neurologic outcomes after OHCA. Our findings indicate that patients with elevated DNI values after OHCA might be closely monitored so that appropriate treatment strategies can be implemented.     

Paradoxical Cardiac Rhythm in Rat Pups as a Possible Analog of the Sick Sinus Syndrome

Experiments with simultaneous recordings of ECG, electrogram of myocardial fibers of the right ventricle and neurogram of the right branch of vagus or sympathetic nerves were carried out on 3–18-day old rat pups. The electric activity recordings were performed under both in vivo and in situ conditions at unilateral or bilateral pneumothorax. It is established that the change in the cholinergic system activation level produced prior to pneumothorax decelerates the rhythm of cardiac contractions (CC) and induces periods of more frequent CC. After pneumothorax, this syndrome becomes more pronounced. The periods of alternation of the slow and fast rhythms may last for up to 1–2 min. The development of the pathological process leads to development of the sino-auricular and atrio-ventricular blocks. There appears a pattern of CC changes and complexes of the ventricular electric potentials that occur in decasecond and then in minute rhythms and are separated by periods of total asystole or preserved potentials of atrial excitation. When the electrograms of myocardium were recorded in rat pups under conditions of bilateral pneumothorax without any pharmacological intervention, it was possible to see a distortion of the sinus rhythm of CC developing for 2–2.5 h after respiration arrest and similar to the above-described distortion. The appearance and development of the phenomenon of the atypical cardiac rhythm is not directly related to the firing patterns of vagus and sympathetic nerves. At the same time, a correlation is clearly seen between the amplitude–frequency modulation of CC and discharges of vagus. A contraction of groups of respiratory muscles lasts for up to 30 min after pneumothorax, with occasional discharges seen in neurogram even after the complete immobilization of the animal. The development of the pathological process reveals a certain similarity with the phenomenon described in literature as the sinus node syndrome (tachy–bradycardia syndrome, TBS). Based on analysis of the cardiac rhythm transformation, it is suggested that the clinical TBS is a consequence of recapitulation, i.e., a successive release of ancient rhythms of excitation due to an impair of regulatory mechanisms.     

Heart Rate Orcadian Rhythm as a Biological Marker of Desynchronization in Major Depression: A Methodological and Preliminary Report

Heart rate (HR) was continuously monitored during successive 24-hr periods in 19 healthy subjects and 26 major depressed patients (DSM III-R). Recordings were performed after a 2-week wash-out period and the morningness or eveningness typology of each subject was determined. The chronobiological parameters and rhythm percentage (RP) were calculated by the single cosinor method from the smoothed HR curves of each subject. In normal subjects, HR follows a circadian rhythm (RP > 65%) with the lowest values at night. Morning type subjects have an earlier peak time (13:30) than evening type subjects (17:30). Major depressive patients were split into two groups; in the first one HR circadian rhythm was still present (RP > 63%) with a decrease in amplitude (24%) while in the second group, no circadian rhythm of HR could be detected (RP < 25%, decrease in amplitude > 70%). In the group of patients with a persisting HK circadian rhythm, no veritable phase advance was observed. Our results suggest that circadian HR rhythm, which can be easily studied with non-invasive methods, might represent a chronobiological marker of some depressions. Given the lag that exists between the rhythms of morning type and evening type subjects, our study also stresses the importance of taking into account this behavioural trait in chronobiological studies.     

Melatonin Treatment Effects on Adolescent Students' Sleep Timing and Sleepiness in a Placebo-Controlled Crossover Study

During the last few decades, the incidence of sleep-onset insomnia, due to delay of circadian phase, has increased substantially among adolescents all over the world. We wanted to investigate whether a small dose of melatonin given daily, administered in the afternoon, could advance the sleep timing in teenagers. Twenty-one students, aged 14–19 yrs, with sleep-onset difficulties during school weeks were recruited. The study was a randomized, double blind, placebo (PL)-controlled crossover trial, lasting 5 wks. During the first 6 d in wks 2 and 4, the students received either PL or melatonin (1 mg) capsules between 16:30 and 18:00 h. During the first 6 d of wk 5, all students received melatonin. Wks 1 and 3 were capsule-free. In the last evening of each week and the following morning, the students produced saliva samples at home for later melatonin analysis. The samples were produced the same time each week, as late as possible in the evening and as early as possible in the morning. Both the student and one parent received automatic mobile text messages 15 min before saliva sampling times and capsule intake at agreed times. Diaries with registration of presumed sleep, subjective sleepiness during the day (Karolinska Sleepiness Scale, KSS) and times for capsule intake and saliva samplings were completed each day. Primary analysis over 5 wks gave significant results for melatonin, sleep and KSS. Post hoc analysis showed that reported sleep-onset times were advanced after melatonin school weeks compared with PL school weeks (p < .005) and that sleep length was longer (p < .05). After the last melatonin school week, the students fell asleep 68 min earlier and slept 62 min longer each night compared with the baseline week. Morning melatonin values in saliva diminished compared with PL (p < .001) and evening values increased (p < .001), indicating a possible sleep phase advance. Compared with PL school weeks, the students reported less wake up (p < .05), less school daytime sleepiness (p < .05) and increased evening sleepiness (p < .005) during melatonin weeks. We conclude that a small dose of melatonin given daily, administered in the afternoon, could advance the sleep timing and make the students more alert during school days even if they continued their often irregular sleep habits during weekends. (Author correspondence: arne.lowden@stress.su.se)     

Characterization of Sleep Breathing Pattern in Patients with Type 2 Diabetes: Sweet Sleep Study

Background

Although sleep apnea-hypopnea syndrome (SAHS) is highly prevalent in patients with type 2 diabetes (T2D), it is unknown whether or not subjects with and without T2D share the same sleep breathing pattern.

Methodology/Principal findings

A cross-sectional study in patients with SAHS according to the presence (n = 132) or not (n = 264) of T2D. Both groups were matched by age, gender, BMI, and waist and neck circumferences. A subgroup of 125 subjects was also matched by AHI. The exclusion criteria included chronic respiratory disease, alcohol abuse, use of sedatives, and heart failure. A higher apnea hypopnea index (AHI) was observed in T2D patients [32.2 (10.2–114.0) vs. 25.6 (10.2–123.4) events/hours; p = 0.002). When sleep events were evaluated separately, patients with T2D showed a significant increase in apnea events [8.4 (0.1–87.7) vs. 6.3 (0.0–105.6) e/h; p = 0.044), as well as a two-fold increase in the percentage of time spent with oxygen saturation <90% [15.7 (0.0–97.0) vs. 7.9 (0.0–95.6) %; <0.001)], higher rates of oxygen desaturation events, and also higher daily sleepiness [7.0 (0.0–21.0) vs. 5.0 (0.0–21.0); p = 0.006)] than subjects without T2D. Significant positive correlations between fasting plasma glucose and AHI, the apnea events, and CT90 were observed. Finally, multiple linear regression analyses showed that T2D was independently associated with AHI (R² = 0.217), the apnea index (R² = 0.194), CT90 (R² = 0.222), and desaturation events.

Conclusions/significance

T2D patients present a different pattern of sleep breathing than subject without diabetes. The most important differences are the severity of hypoxemia and the number of apneas whereas the incidence of hypopnea episodes is similar.     

Salivary Melatonin Rhythm as a Marker of the Circadian System in Healthy Children and Those With Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood. Problems with sleep structure, efficiency, and timing have been reported in some, but not all, studies on ADHD children. As the sleep-wake cycle belongs to circadian rhythms, the timekeeping circadian system might be involved in ADHD. To assess whether the circadian system of ADHD children differs from that of controls, the rhythm of the pineal hormone melatonin was used as a reliable marker of the system. Saliva from 34 ADHD and 43 control 6- to 12-yr-old children was sampled at 2-h intervals throughout the entire 24-h cycle, and the melatonin profiles of the ADHD and control children were compared. The nocturnal melatonin peaks of the ADHD and control group did not differ significantly. The high nocturnal interindividual variability of the peaks seen in adulthood was present already in the studied children. The 24-h melatonin profiles of all the ADHD subjects did not differ significantly from those of the control subjects. Categorization of subjects according to age, into groups of 6- to 7-yr-old (9 ADHD, 5 control), 8- to 9-yr-old (16 ADHD, 26 control), and 10- to 12-yr-old (9 ADHD, 12 control) children, revealed significant differences between the ADHD and control group in the melatonin rhythm waveform, but not in nocturnal melatonin peaks; the peaks were about the same in both groups and did not change significantly with increasing age. In the oldest, but not in the younger, children, the melatonin signal duration in the ADHD group was shorter than in the control group. The difference might be due to the fact that whereas in the control group both the evening melatonin onset and the morning offset phase delayed in the oldest children relative to those in the youngest children, in the ADHD group only the onset, but not the offset, phase delayed with increasing age. The data may indicate subtle differences between the circadian system of ADHD and control children during development. (Author correspondence: sumova@biomed.cas.cz)     

Lifestyle Regularity Measured by The Social Rhythm Metric in Parkinson's Disease

Parkinson's disease (PD) is a chronic progressive motor disorder that may present with a spectrum of symptoms and disease severity. Therapy is frequently associated with motor fluctuations and dyskinesias; therefore, monitoring of motor fluctuations and daily abilities is important for adequate management. The Social Rhythm Metric (SRM) is a diary‐like questionnaire that quantifies the extent to which a person's life is regular vs. irregular on a daily basis with respect to event timing. Lifestyle regularity has been assessed by the SRM in other clinical situations. The aim of this study was to evaluate lifestyle regularity in a population with PD using the SRM and its relationship to clinical and therapeutic factors. Twenty‐eight consecutive patients with PD and 14 control subjects were studied. Severity of motor dysfunction was evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS). Depressive symptoms were assessed with the Montgomery Asberg Depressive Rating Scale (MADRS), sleep quality with the Pittsburgh Sleep Quality Index (PSQI), and subjective daytime sleepiness with the Epworth sleepiness scale. Daily lifestyle regularity was assessed by the SRM for 2 weeks. Patients with PD had lower SRM scores than controls, and those with motor fluctuations had even lower scores (p=0.04). Patients with motor fluctuations showed more clinical disability (p=0.01), a worse quality of sleep (p=0.02), and more depressive symptoms (p=0.02). SRM results were correlated with PSQI values (p=0.016). Our findings show that the regularity of daily activities as measured by the SRM is disorganized in patients with PD and that this irregularity is related to sleep quality.     

Autonomic Cardiac Rhythm Regulation and Temperament in Infancy

The specific features of the cardiac rhythm (CR) and temperament were studied in 92 children aged from 15 to 31 months. The average cardiac interval in a recumbent position and its variability (standard deviation) were determined. The parasympathetic tone (PT) was determined by analyzing the CR wave structure according to CR spectrum power within the range of 0.2 to 1.2 Hz. The sympathetic tone was measured by subtracting the PT contribution from the spectrum power within the range of 0 to 0.2 Hz by means of regression. The children's temperament was measured using their parents' questionnaires. Repeated examination showed the stability of the CR characteristics. The PT was shown to correlate with the children's motor activity (0.52), approaching a new subject (0.39), distraction (–0.34), and the age of entering a nursery (–0.35). The results evidenced a relationship between the parasympathetic tone and the behavioral activity during the first years of life and the role of the parasympathetic tone in physiological regulation of approach/avoidance responses and sustained attention.     

Prevalence and Correlates of Poor Sleep Quality and Daytime Sleepiness in Belgian Truck Drivers

Sleepiness and sleep complaints are common among professional drivers. Sleepiness is a considerable problem not only because it affects the drivers' well-being, but also because of the consequences for performance and safety. Assessment of the (self-reported) prevalence and research into the risk factors are thus an important health issue and are also indispensable to prevent productivity loss and work-related accidents and injuries. Therefore, the aim of this study was to describe sleeping, driving, and health characteristics of Belgian truck drivers and to determine occupational and individual factors associated with poor sleep quality and daytime sleepiness. Cross-sectional data were collected using a self-administered questionnaire that included the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and Berlin Questionnaire (BQ). The mean (SD) age of the 476 studied truck drivers was 42.7 (10.2) yrs and the mean (SD) body mass index was 27.3 (5.1) kg/m². Approximately 47% declared that they drove >50 h/wk and found their work schedule unrealistic. The mean (SD) PSQI score was 4.45 (2.7); poor quality of sleep (PSQI >5) was found in 27.2%. The mean (SD) ESS score was 6.79 (4.17); 18% had a score >10. The BQ indicated that 21.5% had a higher risk on obstructive sleep apnea. In multiple logistic regression analysis, low educational level (odds ratio [OR] 1.86), current smoking (OR 1.75), unrealistic work schedule (OR 1.75), and risk for obstructive sleep apnea (OR 2.97) were found to be independent correlates of daytime sleepiness. Poor sleep quality was significantly associated with poor self-perceived health (OR 1.95), unrealistic work schedule (OR 2.85), low job satisfaction (OR 1.91), and less driving experience (OR 1.73). These results show that poor sleep quality and daytime sleepiness were prevalent in Belgian truck drivers. Taking into account that several significant correlates with respect to these sleep problems were identified both at the individual and the occupational level, comprehensive countermeasures to improve working conditions and organization are needed, as well as health promotion interventions, to ensure the safety and well-being of truck drivers. (Author correspondence: lutgart.braeckman@ugent.be)     

Sleep,Sleepiness, Fatigue,and Performance of 12-Hour-Shift Nurses

Nurses working 12-h shifts complain of fatigue and insufficient/poor-quality sleep. Objectively measured sleep times have not been often reported. This study describes sleep, sleepiness, fatigue, and neurobehavioral performance over three consecutive 12-h (day and night) shifts for hospital registered nurses. Sleep (actigraphy), sleepiness (Karolinska Sleepiness Scale [KSS]), and vigilance (Performance Vigilance Task [PVT]), were measured serially in 80 registered nurses (RNs). Occupational fatigue (Occupational Fatigue Exhaustion Recovery Scale [OFER]) was assessed at baseline. Sleep was short (mean 5.5?h) between shifts, with little difference between day shift (5.7?h) and night shift (5.4?h). Sleepiness scores were low overall (3 on a 1–9 scale, with higher score indicating greater sleepiness), with 45% of nurses having high level of sleepiness (score ?>?7) on at least one shift. Nurses were progressively sleepier each shift, and night nurses were sleepier toward the end of the shift compared to the beginning. There was extensive caffeine use, presumably to preserve or improve alertness. Fatigue was high in one-third of nurses, with intershift fatigue (not feeling recovered from previous shift at the start of the next shift) being most prominent. There were no statistically significant differences in mean reaction time between day/night shift, consecutive work shift, and time into shift. Lapsing was traitlike, with rare (39% of sample), moderate (53%), and frequent (8%) lapsers. Nurses accrue a considerable sleep debt while working successive 12-h shifts with accompanying fatigue and sleepiness. Certain nurses appear more vulnerable to sleep loss than others, as measured by attention lapses. (Author correspondence: jgeiger@son.umaryland.edu)     

Polyvinyl Alcohol as a Water-Soluble Marker

The usefulness of partially hydrolyzed polyvinyl alcohol (PVA ${\displaystyle \overline{\text{P}}}$ =500) was examined by the absorption and excretion from the gastro-intestinal tract of adult rat. About 86% of orally injected PVA was excreted in feces in 48 hr, but no excretion was observed in urine. More than 50% of PVA injected into heart was excreted in urine in 12 hr, but no fecal PVA was observed. About 100% of orally injected PVA was recovered in the gastro-intestinal tract killed 5.5 hr after injection, but no PVA was observed in blood from the killed rats.     

Senescence Marker Protein 30 Has a Cardio-Protective Role in Doxorubicin-Induced Cardiac Dysfunction

Background

Senescence marker protein 30 (SMP30), which was originally identified as an aging marker protein, is assumed to act as a novel anti-aging factor in the liver, lungs and brain. We hypothesized that SMP30 has cardio-protective function due to its anti-aging and anti-oxidant effects on doxorubicin (DOX)-induced cardiac dysfunction.

Methods and Results

SMP30 knockout (SMP30 KO) mice, SMP30 transgenic (SMP30 TG) mice with cardiac-specific overexpression of SMP30 gene and wild-type (WT) littermate mice at 12–14 weeks of age were given intra-peritoneal injection of DOX (20 mg/kg) or saline. Five days after DOX injection, echocardiography revealed that left ventricular ejection fraction was more severely reduced in the DOX-treated SMP30 KO mice than in the DOX-treated WT mice, but was preserved in the DOX-treated SMP30 TG mice. Generation of reactive oxygen species and oxidative DNA damage in the myocardium were greater in the DOX-treated SMP30 KO mice than in the DOX-treated WT mice, but much less in the SMP30 TG mice. The numbers of deoxynucleotidyltransferase-mediated dUTP nick end-labeling positive nuclei in the myocardium, apoptotic signaling pathways such as caspase-3 activity, Bax/Bcl-2 ratio and phosphorylation activity of c-Jun N-terminal kinase were increased in SMP30 KO mice and decreased in SMP30 TG mice compared with WT mice after DOX injection.

Conclusions

SMP30 has a cardio-protective role by anti-oxidative and anti-apoptotic effects in DOX-induced cardiotoxicity, and can be a new therapeutic target to prevent DOX-induced heart failure.