Depressed Heart Rate Research Articles

Exercise-induced neuroplasticity in autonomic nuclei restores the cardiac vagal tone and baroreflex dysfunction in aged hypertensive rats.

Aging is accompanied by considerable deterioration of homeostatic systems, such as autonomic imbalance characterized by heightened sympathetic activity, lower parasympathetic tone, and depressed heart rate (HR) variability, which are aggravated by hypertension. Here, we hypothesized that these age-related deficits in aged hypertensive rats can be ameliorated by exercise training, with benefits to the cardiovascular system. Therefore, male 22-mo-old spontaneously hypertensive rats (SHRs) and age-matched Wistar Kyoto (WKY) submitted to moderate-intensity exercise training (T) or kept sedentary (S) for 8 wk were evaluated for hemodynamic/autonomic parameters, baroreflex sensitivity, cardiac sympathetic/parasympathetic tone and analysis of dopamine β-hydroxylase (DBH+) and oxytocin (OT+) pathways of autonomic brain nuclei. Aged SHR-S versus WKY-S exhibited elevated mean arterial pressure (MAP: +51%) and HR (+20%), augmented pressure/HR variability, no cardiac vagal tone, and depressed reflex control of the heart (HR range, -28%; gain, -49%). SHR-T exhibited a lower resting HR, a partial reduction in the MAP (-14%), in the pressure/HR variabilities, and restored parasympathetic modulation, with improvement of baroreceptor reflex control when compared with SHR-S. Exercise training increased the ascending DBH+ projections conveying peripheral information to the paraventricular nucleus of hypothalamus (PVN), augmented the expression of OT+ neurons, and reduced the density of DBH+ neurons in the rostral ventrolateral medulla (RVLM) of SHR-T. Data indicate that exercise training induces beneficial neuroplasticity in brain autonomic circuitry, and it is highly effective to restore the parasympathetic tone, and attenuation of age-related autonomic imbalance and baroreflex dysfunction, thus conferring long-term benefits for cardiovascular control in aged hypertensive individuals.NEW & NOTEWORTHY Exercise training reduces high blood pressure and cardiovascular autonomic modulation in aged hypertensive rats. The dysfunction in the baroreflex sensitivity and impaired parasympathetic tone to the heart of aged hypertensive rats are restored by exercise training. Exercise induces beneficial neuroplasticity in the brain nuclei involved with autonomic control of cardiovascular function of aged hypertensive rats.

A Dual Beta Blocker and Calcium Channel Blocker Overdose in a Patient with Substance Abuse

Aim: Nearly 25% of hospital admissions have related adverse drug events with 6-7% of these related to beta blockers (BB) or calcium channel blockers (CCB). Introduction: In some cases, patients do not report their noncompliance at home as well as their illicit substance use leading to worsened outcomes. We present a case of BB and CCB toxicity with concomitant substance abuse, its treatment and general outcome. Case: A 49-year-old woman with history of diabetes mellitus, stroke, and hypertension presented with flu-like symptoms including fever, nausea, vomiting, diarrhea and dysuria. She was admitted for treatment of urinary tract infection and possible left lower lobar pneumonia with guideline-directed antibiotic and IV fluids for acute kidney injury. She was elusive about her substance use history and endorsed compliance with her cardiac and other medications. Unfortunately, after administration of her morning medications, she had cardiac decline including hypotension and bradycardia with a subsequent hypoglycemia and left sided deficits leading to further investigation into her medication adherence and substance use history. History evolved that she was noncompliant with her high dose cardiac medications and a urine drug screen was positive for amphetamines, barbiturates, and nonprescription benzodiazepines. Treatment: The patient’s shock was treated with resuscitative fluids, glucagon, and calcium infusion as well as a short round of vasopressor. She was transferred to a higher acuity center for large vessel occlusion at the distal portion of the left vertebral artery as seen on stroke imaging. Her blood and urine cultures ultimately grew extended spectrum beta lactamase bacteria, meanwhile her shock was deemed medication-induced hypovolemic shock with a depressed heart rate response given a normal transthoracic echocardiogram and quick resolution after reversal agent. Despite the severity and progression of the hospitalization the patient elected to leave against medical advice (AMA) prior to neurosurgical evaluation and completion of antibiotics. She has since been seen well in follow up by her outpatient provider. Discussion: Cardiac medications are associated with adverse cardiac effects and should be prescribed carefully in patients with substance abuse. Further elucidation of substance abuse led to improved treatment outcomes in this patient with polysubstance and alcohol abuse.

Sophoridine manifests as a leading compound for anti-arrhythmia with multiple ion-channel blocking effects

BackgroundSophoridine (SR) has shown the potential to be an antiarrhythmic agent. However, SR's electrophysiological properties and druggability research are relatively inadequate, which limits the development of SR as an antiarrhythmic candidate. PurposeTo facilitate the development process of SR as an antiarrhythmic candidate, we performed integrated studies on the electrophysiological properties of SR in vitro and ex vivo to gain more comprehensive insights into the multi-ion channel blocking effects of SR, which provided the foundation for the further drugability studies in antiarrhythmic and safety studies. Firstly, SR's electrophysiological properties and antiarrhythmic potentials were recorded and assessed at the cell and tissue levels by comprehensively integrating the patch clamp with the Electrical and Optical Mapping systems. Subsequently, the antiarrhythmic effects of SR were validated by aconitine and ouabain-induced arrhythmia in vivo. Finally, the safety of SR as an antiarrhythmic candidate compound was evaluated based on the guidelines of the Comprehensive in Vitro Proarrhythmia Assay (CiPA). Study designThe antiarrhythmic effect of SR was evaluated at the in vitro, ex vivo, and in vivo levels. MethodsIsolated primary cardiomyocytes and stable cell lines were prepared to explore the electrophysiologic properties of being a multiple ion-channel blocker in vitro by whole-cell patch clamp. Using electrical and optical mapping, the negative chronotropic effect of SR was determined in langendorff-perfused rat or guinea-pig hearts.The antiarrhythmic activity of SR was assessed by the ex vivo tachyarrhythmia models induced by left coronary artery ligation (LCAL) and isoproterenol (ISO). Canonical models of aconitine and ouabain-induced arrhythmia were used to verify the antiarrhythmic effects in vivo. Finally, the pro-arrhythmic risk of SR was detected in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hSCCMs) using a Microelectrode array (MEA). ResultsSingle-cell patch assay validated the multiple ion-channel blockers of SR in transient outward current potassium currents (Ito), l-type calcium currents (ICa-l), and rapid activation delayed rectifier potassium currents (IKr). SR ex vivo depressed heart rates (HR) and ventricular conduction velocity (CV) and prolonged Q-T intervals in a concentration-dependent manner. Consistent with the changes in HRs, SR extended the active time of hearts and increased the action potential duration measured at 90% repolarization (APD90). SR could also significantly lengthen the onset time and curtail the duration of spontaneous ventricular tachycardia (VT) in the ex vivo arrhythmic model induced by LCAL. Meanwhile, SR could also significantly upregulate the programmed electrical stimulation (PES) frequency after the ISO challenge in forming electrical alternans and re-entrant excitation. Furthermore, SR exerted antiarrhythmic effects in the tachyarrhythmia models induced by aconitine and ouabain in vivo. Notably, the pro-arrhythmic risk of SR was shallow for a moderate inhibition of the human ether-à-go-go-related gene (hERG) channel. Moreover, SR prolonged field potential duration (FPDc) of hSCCMs in a concentration-dependent manner without early after depolarization (EAD) and arrhythmia occurrence. ConclusionOur results indicated that SR manifested as a multiple ion-channel blocker in the electrophysiological properties and exerts antiarrhythmic effects ex vivo and in vivo. Meanwhile, due to the low pro-arrhythmic risk in the hERG inhibition assay and the induction of EAD, SR has great potential as a leading candidate in the treatment of ventricular tachyarrhythmia.

Olfactory receptor 78 modulates renin but not baseline blood pressure.

Olfactory receptor 78 (Olfr78) is a G protein‐coupled receptor (GPCR) that is expressed in the juxtaglomerular apparatus (JGA) of the kidney as well as the peripheral vasculature, and is activated by gut microbial metabolites. We previously reported that Olfr78 plays a role in renin secretion in isolated glomeruli, and that Olfr78 knockout (KO) mice have lower plasma renin activity. We also noted that in anesthetized mice, Olfr78KO appeared to be hypotensive. In this study, we used radiotelemetry to determine the role of Olfr78 in chronic blood pressure regulation. We found that the blood pressure of Olfr78KO mice is not significantly different than that of their WT counterparts at baseline, or on high‐ or low‐salt diets. However, Olfr78KO mice have depressed heart rates on high‐salt diets. We also report that Olfr78KO mice have lower renin protein levels associated with glomeruli. Finally, we developed a mouse where Olfr78 was selectively knocked out in the JGA, which phenocopied the lower renin association findings. In sum, these experiments suggest that Olfr78 modulates renin, but does not play an active role in blood pressure regulation at baseline, and is more likely activated by high levels of short chain fatty acids or hypotensive events. This study provides important context to our knowledge of Olfr78 in BP regulation.

Predicting efficacy of combined assessment with fragmented QRS and severely depressed heart rate variability on outcome of patients with acute myocardial infarction

The association between fragmented QRS (fQRS) and autonomic nervous dysfunction, and major adverse cardiovascular events (MACE) is not fully clear in patients with acute myocardial infarction (AMI). This study aimed to observe whether combined assessment with fQRS and cardiac autonomic nervous function could enhance the predicting efficacy on outcome in AMI patients. A total of 153 consecutive hospitalized AMI patients were included in this retrospective study. Patients were divided into non-fQRS (nfQRS) group and fQRS group according to 12-lead electrocardiogram, into sHRV [severely depressed heart rate variability (HRV): standard deviation of NN intervals (SDNN) < 100 ms and very low frequency (VLF) < 26.7 ms] group and nsHRV (non-severely depressed HRV) group according to 24 h Holter monitoring, and into non-MACE (nMACE) group and MACE group according to 12 months’ follow-up results. The incidence of sHRV was significantly higher in the fQRS group than in the nfQRS group (71.9 vs. 39.3%, p < 0.05). The incidences of MACE were 7.4, 22.2, 25.7 and 56.5%, respectively, in nsHRV + nfQRS group, nsHRV + fQRS group, sHRV + nfQRS group and sHRV + fQRS group (p < 0.05). Multivariable Cox regression analysis showed that patients in the sHRV + fQRS group had a sixfold higher risk of MACE compared to patients in the nsHRV + nfQRS group (HR = 6.228, 95% CI 1.849–20.984, p = 0.003). The predicting sensitivity and specificity on MACE were 81.4 and 58.2% by sHRV, 69.8 and 69.1% by fQRS in these AMI patients. The specificity (81.8%) was the highest with the combination of sHRV and fQRS. Adding sHRV and fQRS to clinical data offered incremental prognostic value. Present results indicate that fQRS is closely related to sHRV, suggesting significant impairment of sympathetic nerve function in AMI patients with fQRS. Combined assessment with fQRS and sHRV enhances the predicting efficacy on outcome in AMI patients.

Characterization of brain-wide somatosensory BOLD fMRI in mice under dexmedetomidine/isoflurane and ketamine/xylazine.

Mouse fMRI under anesthesia has become increasingly popular due to improvement in obtaining brain-wide BOLD response. Medetomidine with isoflurane has become well-accepted for resting-state fMRI, but whether this combination allows for stable, expected, and robust brain-wide evoked response in mice has yet to be validated. We thus utilized intravenous infusion of dexmedetomidine with inhaled isoflurane and intravenous infusion of ketamine/xylazine to elucidate whether stable mouse physiology and BOLD response are obtainable in response to simultaneous forepaw and whisker-pad stimulation throughout 8 h. We found both anesthetics result in hypercapnia with depressed heart rate and respiration due to self-breathing, but these values were stable throughout 8 h. Regardless of the mouse condition, brain-wide, robust, and stable BOLD response throughout the somatosensory axis was observed with differences in sensitivity and dynamics. Dexmedetomidine/isoflurane resulted in fast, boxcar-like, BOLD response with consistent hemodynamic shapes throughout the brain. Ketamine/xylazine response showed higher sensitivity, prolonged BOLD response, and evidence for cortical disinhibition as significant bilateral cortical response was observed. In addition, differing hemodynamic shapes were observed between cortical and subcortical areas. Overall, we found both anesthetics are applicable for evoked mouse fMRI studies.

Comparative toxicological effects of planktonic Microcystis and benthic Oscillatoria on zebrafish embryonic development: Implications for cyanobacteria risk assessment.

Planktonic and benthic cyanobacteria blooms are increasing in frequency in recent years. Although many studies have focused on the effects of purified toxins or cyanobacteria extracts on fish developments, the more complex impacts of cyanobacteria cells on fish populations are still considered insufficient. This study compared the toxicological effects of harmful planktonic Microcystis and benthic Oscillatoria on zebrafish (Danio rerio) early stages of development. Zebrafish embryos, at 1-2h post fertilization (hpf), were exposed to 5, 10, and 20×105cells/mL Microcystis (producing microcystins) or Oscillatoria (producing cylindrospermopsins) until 96 hpf. The results indicated that the effects of benthic Oscillatoria on embryonic development of zebrafish were different from those of planktonic Microcystis. Reduced hatching rates, increased mortality, depressed heart rates and elevated malformation rates were observed following exposures to increased concentrations of Microcystis, whilst Oscillatoria exposures only caused yolk sac edemas. Exposure to a high concentration of Microcystis induced severe oxidative damage, growth inhibition and transcriptional downregulations of genes (GH, GHR1, IGF1, IGF1rb) associated with the growth hormone/insulin-like growth factor (GH/IGF) axis. Although Oscillatoria exposure did not affect the body growth, it obviously enhanced the antioxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) and up-regulated the expressions of several oxidative stress-related genes. Discrepancies in the developmental toxicity caused by Microcystis and Oscillatoria may not only attributed to the different secondary metabolites they secrete, but also to the different adhesion behaviors of algal cells on embryonic chorion. These results suggested that harmful cyanobacteria cells could influence the successful recruitment of fish, while the effects of benthic cyanobacteria should not be ignored. It also highlighted that the necessity for further investigating the ecotoxicity of intact cyanobacterial samples when assessing the risk of cyanobacterial blooms.

Early rehabilitation after stroke: relationship between the heart rate variability and functional outcome.

AimsImpaired autonomic nervous system regulation is frequently observed in patients with stroke. The aim of this prospective study was to evaluate the impact of cardiac autonomic tone on functional outcome after the early post‐stroke rehabilitation.Methods and resultsOne hundred and three consecutive patients (67 ± 11 years, body mass index (BMI) 27.1 ± 5.4 kg/m2, 64% men) with ischaemic (84% of patients) and haemorrhagic stroke were studied. Depressed heart rate variability (HRV), as a surrogate marker of increased sympathetic tone, was defined by the standard deviation of NN intervals < 100 ms and HRV triangular index ≤ 20 assessed from a 24 h Holter electrocardiogram at admission to rehabilitation (23 ± 16 days after stroke). Twenty‐two per cent of patients had depressed HRV at baseline and were comparable with patients with normal HRV with regard to their functional [Barthel Index (BI), modified Rankin Scale (mRS), and Rivermead Motor Assessment (RMA)] and biochemical status. After a 4‐week follow‐up, 70% of patients with depressed HRV showed a cumulative functional disability, defined by mRS ≥ 4, BI ≤ 70, and RMA ≤ 5, in contrast to patients with normal HRV (35%, P = 0.003). Patients with depressed HRV showed a worse functional status by BI (−16%, P < 0.001), RMA (−12%, P < 0.05), and mRS (+16%, P < 0.01), compared with patients with normal HRV. Cumulative functional disability was associated with depressed HRV (odds ratio 4.25, 95% confidence interval 1.56–11.54, P < 0.005) after adjustment for age, sex, and body mass index (odds ratio 4.6, 95% confidence interval 1.42–14.97, P < 0.05).ConclusionsThe presence of autonomic cardiovascular dysregulation in patients with subacute stroke was associated with adverse functional outcome after the early post‐stroke rehabilitation.

Thermal sensitivity of lizard embryos indicates a mismatch between oxygen supply and demand at near-lethal temperatures.

Aspects of global change create stressful thermal environments that threaten biodiversity. Oviparous, non-avian reptiles have received considerable attention because eggs are left to develop under prevailing conditions, leaving developing embryos vulnerable to increases in temperature. Though many studies assess embryo responses to long-term (i.e., chronic), constant incubation temperatures, few assess responses to acute exposures which are more relevant for many species. We subjected brown anole (Anolis sagrei) eggs to heat shocks, thermal ramps, and extreme diurnal fluctuations to determine the lethal temperature of embryos, measure the thermal sensitivity of embryo heart rate and metabolism, and quantify the effects of sublethal but stressful temperatures on development and hatchling phenotypes and survival. Most embryos died at heat shocks of 45°C or 46°C, which is ~12°C warmer than the highest constant temperatures suitable for successful development. Heart rate and O2 consumption increased with temperature; however, as embryos approached the lethal temperature, heart rate and CO2 production continued rising while O2 consumption plateaued. These data indicate a mismatch between oxygen supply and demand at high temperatures. Exposure to extreme, diurnal fluctuations depressed embryo developmental rates and heart rates, and resulted in hatchlings with smaller body size, reduced growth rates, and lower survival in the laboratory. Thus, even brief exposure to extreme temperatures can have important effects on embryo development, and our study highlights the role of both immediate and cumulative effects of high temperatures on egg survival. Such effects must be considered to predict how populations will respond to global change.

The Role of Heart Rate Variability and Fragmented QRS for Determination of Subclinical Cardiac Involvement in Beta-Thalassemia Major

Background: Iron accumulation leads to increased susceptibility to cardiovascular diseases in thalassemia major (TM) patients. Depressed heart rate variability (HRV) and development of arrhythmia are among the manifestations of subclinical cardiac involvement in TM cases. Determination of subclinical cardiac involvement is essential for preventive measures. Thus, we aimed to evaluate the best method for identification of subclinical cardiac dysfunction in TM cases. Materials and Methods: In this prospective study, 45 TM and 45 non-TM cases, who were referred for cardiac evaluation, were enrolled. Exclusion criteria included non-sinus rhythm and overt cardiac disease. TM cases underwent cardiac MRI, electrocardiography (ECG), and Holter monitoring. TM cases were divided into two groups of normal versus iron overload with a cardiac T2* of more or less than 20 ms, respectively. The non-TM cases underwent only ECG and Holter monitoring. Results: We observed no significant difference regarding HRV between normal versus iron overload TM and non-TM cases. Higher rates of premature atrial complex, low limb voltage, low atrial rhythm, as well as minimum and average HR with lower QRS duration and PR interval were detected in TM versus non-TM cases (p value <0.05). Conclusions: We observed a higher prevalence of low limb voltage and low atrial rhythm in TM cases versus non-TM cases. Indeed, the role of fragmented QRS (fQRS) for subclinical detection of cardiac disease in TM cases is still so controversial and needs more evaluation. Application of HRV and fQRS in this regard may need to be performed at the right time point after initiation of blood transfusion, but this needs to be determined.

Low intensity, continuous wave focused ultrasound reversibly depresses heart rate in anesthetized mice

Focused ultrasound (FUS) can noninvasively and reversibly modulate brain activity. Observed motor activity or behavioral changes are commonly used to infer neuromodulatory effects. Changes in autonomic nervous system regulation such as heart and respiratory function can potentially be used for studying the effects of FUS neuromodulation that do not produce outwardly observable motor or behavioral activity. In this study, low pressure (850 kPa), long duration (120 s) continuous-wave (CW) FUS at 2 MHz was targeted such that the focus spanned the visual cortex, hippocampus, and thalamus. These parameters were shown to reversibly depress heart rate in in vivo mice anesthetized with sodium pentobarbital by an average of 8.1 ± 3.7%. Following stimulus offset, heart rate either increased or varied in trend. Higher pressure (2 MPa), short duration (0.3 s) pulses at the same frequency resulted in either small, transient increases in heart rate or no change. Thermocouple measurements show the peak temperature elevation in the dura to be approximately 2 °C. Thermal simulations predict a peak temperature increase in the brain of 2.3 °C. These results indicate that CW FUS can alter autonomic nervous system regulation through very low heating and show that cardiorespiratory responses can be altered as a result of FUS neuromodulation.

Assessment and clinical relevance of the dynamic parameters of ventricular repolarization in patients with grade I left ventricular diastolic dysfunction 1.

Imbalance in ventricular repolarization parameters are related to increased risk of severe arrhythmia and sudden cardiac death. There is limited research regarding markers to detect patients at risk in this early stage. We aimed to assess the influence of grade I left ventricular diastolic dysfunction on repolarization parameters in asymptomatic patients. Ambulatory patients with grade I left ventricular diastolic dysfunction were studied and compared with a control group. We assessed the QT dispersion circadian variation, heart rate variability in the time and frequency domains, and dynamics of QT using a 12-lead Holter. In the diastolic dysfunction group, 8 (30%) patients had QT dispersion > 80 ms. One (3.8%) patient presented premature ventricular complex > 10/h. The comparison between the 2 groups showed that the difference between the standard deviation of normal-to-normal intervals and low frequency power in both groups was statistically significant. We therefore conclude that increased parameters of ventricular repolarization and depressed heart rate variability reflect an imbalance in autonomic responses in patients with grade I left ventricular diastolic dysfunction without cardiovascular symptoms, enabling the identification of patients that are at a higher risk for cardiovascular events.

Chinese older people's subjective and physiological responses to moderate cold and warm temperature steps

Older people are very likely to experience transitions among spaces with different temperatures in daily life. But little has been known about their thermal comfort and physiological responses to these temperature steps. This study investigated 18 healthy older people's thermal perceptions and physiological parameters under cold and warm exposures with 3/5/6 °C temperature steps. The results showed that subjects' thermal sensation was sensitive to all moderate temperature steps, but their thermal comfort perception could only distinguish temperature changes greater than 5 °C. Thermal unacceptability was only observed when subjects' tympanic temperature reached at 37.08 °C. Also, we found older people need more than 50 min time to get their mean skin temperature steady after cold stimuli, while they only need <24 min after warm ones. Cold stimuli could significantly boost subjects' blood pressure, respiratory rate, blood oxygen saturation, and depress heart rate. To predict older people's transient thermal sensation after temperature steps, we proposed two regression models for cold and warm exposures respectively. Based on the above observations, we suggest older people should try their best to avoid large step temperature changes, especially for cold side steps.

Differential Toxicity of mDia Formin-Directed Functional Agonists and Antagonists in Developing Zebrafish

The mammalian Diaphanous-related (mDia) formins are cytoskeletal regulators that assemble and, in some cases, bundle filamentous actin (F-actin), as well as stabilize microtubules. The development of small molecule antagonists and agonists that interrogate mDia formin function has allowed us to investigate the roles of formins in disease states. A small molecule inhibitor of FH2 domain (SMIFH2) inhibits mDia-dependent actin dynamics and abrogates tumor cell migration and cell division in vitro and ex vivo tissue explants. mDia formin activation with small molecule intramimics IMM01/02 and mDia2-DAD peptides inhibited glioblastoma motility and invasion in vitro and ex vivo rat brain slices. However, SMIFH2, IMMs, and mDia2 DAD efficacy in vivo remains largely unexplored and potential toxicity across a range of developmental phenotypes has not been thoroughly characterized. In this study, we performed an in vivo screen of early life-stage toxicity in Danio rerio zebrafish embryos 2 days post-fertilization (dpf) in response to SMIFH2, IMM01/02, and mDia2 DAD. SMIFH2 at concentrations ≥5–10 μM induced significant defects in developing zebrafish, including shorter body lengths, tail curvature and defective tail cellularity, craniofacial malformations, pericardial edema, absent and/or compromised vasculature function and flow, depressed heart rates and increased mortality. Conversely, IMM and mDia2 DAD peptides were minimally toxic at concentrations up to 10–20 and 50 μM, respectively. SMIFH2's therapeutic potential may therefore be limited by its substantial in vivo toxicity at functional concentrations. mDia formin agonism with IMMs and mDia2 DADs may therefore be a more effective and less toxic anti-invasive therapeutic approach.

Stochastic Pacing Inhibits Spatially Discordant Cardiac Alternans

Depressed heart rate variability is a well-established risk factor for sudden cardiac death in survivors of acute myocardial infarction and for those with congestive heart failure. Although measurements of heart rate variability provide a valuable prognostic tool, it is unclear whether reduced heart rate variability itself is proarrhythmic or if it simply correlates with the severity of autonomic nervous system dysfunction. In this work, we investigate a possible mechanism by which heart rate variability could protect against cardiac arrhythmia. Specifically, in numerical simulations, we observe an inverse relationship between the variance of stochastic pacing and the occurrence of spatially discordant alternans, an arrhythmia that is widely believed to facilitate the development of cardiac fibrillation. By analyzing the effects of conduction velocity restitution, cellular dynamics, electrotonic coupling, and stochastic pacing on the nodal dynamics of spatially discordant alternans, we provide intuition for this observed behavior and propose control strategies to inhibit discordant alternans.

Effects of Microcystis on development of early life stage Japanese medaka (Oryzias latipes): Comparative toxicity of natural blooms, cultured Microcystis and microcystin-LR

Freshwater cyanobacterial harmful algal blooms (CyanoHABs) caused by algae in the genus Microcystis have been increasing in frequency and severity in recent decades. Microcystis blooms threaten aquatic organisms through effects associated with the rapid increase of biomass and the production of the hepatotoxin microcystin (MC) by toxic strains. Among fish, effects of blooms are likely to be more severe for early life stages, and physiological impacts on this life stage could significantly impact recruitment and fish populations. This study explores the effects of Microcystis blooms on the development of fish using the model organism, the Japanese medaka (Oryzias latipes), under realistic exposure conditions. Medaka embryos were exposed to natural blooms collected from New York City (USA) lakes, lab cultures of Microcystis, and MC-LR solutions. Field collected samples were more toxic than lab cultures (even when compared at the same algal density or MC concentration), causing decreased survival, premature time to hatch, reduced body length, yolk sac edema, and decreased heart rate, while lab culture exposures only resulted in bradycardia. Heart rate was the most sensitive endpoint measured, being depressed in embryos exposed to both lab cultures and field collected blooms. Generalized linear model analysis indicated bradycardia was statistically associated with both cell densities of blooms and MC concentrations, while single factor analysis indicated that MC concentrations had a stronger correlation compared to cell densities. However, MC exposure could not fully explain the effects observed, as exposures to MC-LR solutions alone were not able to reduce heart rate as severely as algal exposures. Collectively, these experiments indicate that factors beyond exposure to MC or even isolated Microcystis strains influence heart rate of fish exposed to Microcystis blooms. Enhanced mortality, depressed heart rate, and abnormal development observed in response to environmentally realistic exposures of Microcystis blooms could affect success of fish at both individual or population levels.

Mitochondrial DNA Damage Initiates Acute Lung Injury and Multi-Organ System Failure Evoked in Rats by Intra-Tracheal Pseudomonas Aeruginosa.

Although studies in rat cultured pulmonary artery endothelial cells, perfused lungs, and intact mice support the concept that oxidative mitochondrial (mt) DNA damage triggers acute lung injury (ALI), it has not yet been determined whether enhanced mtDNA repair forestalls development of ALI and its progression to multiple organ system failure (MOSF). Accordingly, here we examined the effect of a fusion protein construct targeting the DNA glycosylase, Ogg1, to mitochondria in a rat model intra-tracheal Pseudomonas aeruginosa (strain 103; PA103)-induced ALI and MOSF. Relative to controls, animals given PA103 displayed increases in lung vascular filtration coefficient accompanied by transient lung tissue oxidative mtDNA damage and variable changes in mtDNA copy number without evidence of nuclear DNA damage. The approximate 40% of animals surviving 24 h after bacterial administration exhibited multiple organ dysfunction, manifest as increased serum and tissue-specific indices of kidney and liver failure, along with depressed heart rate and blood pressure. While administration of mt-targeted Ogg1 to control animals was innocuous, the active fusion protein, but not a DNA repair-deficient mutant, prevented bacteria-induced increases in lung tissue oxidative mtDNA damage, failed to alter mtDNA copy number, and attenuated lung endothelial barrier degradation. These changes were associated with suppression of liver, kidney, and cardiovascular dysfunction and with decreased 24 h mortality. Collectively, the present findings indicate that oxidative mtDNA damage to lung tissue initiates PA103-induced ALI and MOSF in rats.

Pattern of brain injury and depressed heart rate variability in newborns with hypoxic ischemic encephalopathy.

BackgroundDecreased heart rate variability (HRV) is a measure of autonomic dysfunction and brain injury in newborns with hypoxic ischemic encephalopathy (HIE). This study aimed to characterize the relationship between HRV and brain injury pattern by MRI in newborns with HIE undergoing therapeutic hypothermia.MethodsHRV metrics were quantified in the time domain (αS, αL, and root mean square at short [RMSS] and long [RMSL] time scales) and frequency domain (relative low-[LF] and high-frequency [HF] power) during the time period 24–27 hours of life. Brain injury pattern by MRI was classified as no injury, pure cortical/white matter injury, mixed watershed/mild basal nuclei injury, predominant basal nuclei or global injury, and died. HRV metrics were compared across brain injury pattern groups using a random effects mixed model.ResultsData from 74 infants were analyzed. Brain injury pattern was significantly associated with degree of HRV suppression. Specifically, negative associations were observed between pattern of brain injury and RMSS (estimate −0.224, SE 0.082, p=0.006), RMSL (estimate −0.189, SE 0.082, p=0.021), and LF power (estimate −0.044, SE 0.016, p=0.006).ConclusionDegree of HRV depression is related to pattern of brain injury. HRV monitoring may provide insights into pattern of brain injury at the bedside.

Psychological and Physiological Markers of Stress in Concussed Athletes Across Recovery Milestones.

Sport-related concussions are associated with a range of physical, cognitive, and behavioral disturbances that are highly variable across individuals. Much remains unknown about the effects of sport concussion, and changes in markers of psychological and physiological stress over the recovery timeline. To examine psychological (mood, stress, sleep quality, and symptoms) and physiological (heart rate variability and salivary cortisol) measures in concussed athletes over clinical recovery milestones. University athletic program, sport medicine clinic, Canada. A sample of 52 interuniversity athletes (32 male and 20 female), 26 with concussion and 26 healthy controls. Case-control repeated measures study at 3 time points of the clinical recovery process. Measures were administered to a matched control sample of uninjured athletes as well. Physiological measures were heart rate variability and salivary cortisol; psychological measures were mood, perceived stress, and quality of sleep. Psychological measures were significantly worse for concussed athletes relative to controls at the symptomatic phase (acute injury), but significantly better at return-to-play (RTP). Multivariate analysis of heart rate variability identified main effects of sex and concussion, with reduced high-frequency heart rate variability for females and concussed athletes extending into the post-RTP phase. An interaction effect was also observed, showing the cardiac response of female athletes was more sensitive to concussion compared with males. Conversely, male athletes showed greater suppression of low-frequency heart rate variability associated with mood disturbances. This integrated study of psychological and physiological markers in concussed athletes confirmed the resolution of mood disturbances, symptoms, and sleep quality by RTP, but identified autonomic nervous system disturbances, as measured by depressed heart rate variability beyond RTP.

Assay for the developmental toxicity of safflower (Carthamus tinctorius L.) to zebrafish embryos/larvae

ObjectiveTo explore the developmental toxicity and the potential toxicological mechanism of safflower (Carthamus tinctorius L.) on zebrafish embryos/larvae. MethodsMortality, malformations and increased apoptosis induced by safflower were assessed in zebrafish embryos from 6 to 96 hours post-fertilization. Enzymes and genes in the anti-oxidative and apoptotic pathways were also assayed. ResultsThe lethal concentration 50 of safflower to zebrafish embryos was 345.6 mg/L. Hatching inhibition, abnormal spontaneous movement, depressed heart rate, pericardial edema, yolk sac edema, abnormal head-trunk angle, inhibition of melanin release, enlarged yolk, and short body length were observed in safflower-treated zebrafish. Additional apoptotic cells mainly appeared around the heart. Safflower exposure changed the activities of defense enzymes (SOD↑, CAT↑, MDA↑, GPX without trend), increased MDA content, decreased caspase-3 activity, and altered mRNA levels of related genes (ogg1↓, p53↓, Cu/Zn-sod↑, Mn-sod↓, cat↓, gpx↑). ConclusionSafflower exhibits developmental toxicity for zebrafish embryos/larvae. The developing heart was speculated as the target organ of toxicity. Oxidative stress and increased apoptosis have roles in the developmental toxicity of safflower. This article provides a novel method to research the teratogenicity and possible mechanisms of toxicity of traditional Chinese medicines that are prohibited or contraindicated in pregnant women.