[Relationship between carotid atherosclerotic plaque characteristics in magnetic resonance imaging and perioperative hemodynamic instability].

Objective: To analyze the relationship between carotid atherosclerotic plaque characteristics in magnetic resonance imaging (MRI) and perioperative hemodynamic instability in patients with severe carotid artery stenosis undergoing carotid artery stenting (CAS). Methods: A total of 89 patients with carotid artery stenosis who underwent CAS treatment at Beijing Tsinghua Changgung Hospital affiliated to Tsinghua University from January 1, 2017, to December 31, 2021, were prospectively included. Among them, 74 were male and 15 were female, with an age range of 43 to 87 years (mean age: 67.8±8.2 years). Preoperative examinations included carotid artery MRI vessel wall imaging to analyze the existence of large lipid-rich necrotic core (LRNC), intraplaque hemorrhage (IPH), and fibrous cap rupture in carotid artery plaques. Plaques without the above-mentioned risk factors were defined as stable plaque group (34 cases), while those with such risk factors were defined as vulnerable plaque group (55 cases). The number of risk factors present in each plaque was also calculated. Intraoperative changes in blood pressure and heart rate were recorded, and the use of dopamine postoperatively was noted. Using the risk factors that the plaque has as independent variables and the clinical outcomes as dependent variables, the RR values were calculated, and the differences in clinical outcomes of patients with different risk factors were compared. Results: The incidence rates of hypotension and bradycardia were higher in patients with vulnerable plaques than those with stable plaques (60.0% (33/55) vs 14.7%(5/34) and 38.2%(21/55) vs 14.7%(5/34), respectively; both P<0.05). Based on MRI imaging features, the large LRNC was present in 45 cases, with RR values for hypotension and bradycardia of 3.15 (1.69-5.87) and 2.20 (1.07-4.53), respectively; IPH was present in 37 cases, with RR values for hypotension and bradycardia of 2.70 (1.61-4.55) and 2.25 (1.15-4.39), respectively; and fibrous cap rupture was present in 29 cases, with RR values for hypotension and bradycardia of 1.50 (0.94-2.40) and 1.29 (0.67-2.49), respectively. The higher the number of risk factors in vulnerable plaques, the higher the incidence of intraoperative blood pressure and heart rate decrease: when the number of risk factors ranged from 0 to 3, the incidence of blood pressure decrease was 14.7% (5/34), 9/18, 11/18, and 13/19, respectively (P<0.001), and the incidence of heart rate decrease was 14.7% (5/34), 6/18, 7/18, and 8/19, respectively (P=0.022). There was no significant difference in the number of cases of dopamine use between the two groups (P>0.05). Conclusion: Patients with a higher number of risk factors for vulnerable carotid plaques, as indicated by carotid artery MRI vessel wall imaging, are at a higher risk of experiencing blood pressure and heart rate decrease during CAS surgery.

Vertebral artery dissection induced lateral medullary syndrome characterized with severe bradycardia: a case report and review of the literature.

BACKGROUND: Lateral medullary syndrome is the most common type of brainstem infarction. Lateral medullary syndrome results in damage to the corresponding cranial nerve nuclei and the nucleus tractus solitarius, with vertigo, ipsilateral ataxia, crossed sensory disturbances, Horner's sign, bulbar palsy, and other underlying symptoms or signs. However, cases with cardiac arrhythmia and other autonomic dysfunctions as the primary manifestations are less common. Clinically, sudden death occasionally occurs in patients with lateral medullary syndrome, which may be associated with severe cardiac arrhythmia. These patients may suffer in life-threatening arrhythmia and even cardiac arrest, and vital signs should be closely monitored to prevent sudden death. In younger patients, vertebral artery dissection is the most common cause. CASE DESCRIPTION: Here, we present a case of lateral medullary syndrome caused by vertebral artery dissection with severe bradycardia. The patient was a 49-year-old man who was admitted with "sudden onset of numbness in the left limbs and right side of the face for 1 hour". Electrocardiogram (ECG) monitoring showed a repeated heart rate decrease to as low as 23 beats/min, followed by a gradual increase in heart rate to 35-55 beats/min after 2-3 seconds. Head magnetic resonance imaging (MRI) examination revealed right dorsolateral cerebral infarction of the medulla oblongata. Digital subtraction angiography (DSA) revealed a right vertebral artery dissecting aneurysm. We performed an emergency placement of a temporary pacemaker, followed by conservative treatment with platelet aggregation inhibitors, vascular softening agents and improved collateral circulation. Elective spring coil embolization of the vertebral artery dissecting aneurysm and stent implantation were performed. At outpatient follow-up, the patient had a good prognosis. CONCLUSIONS: Clinical management of patients with lateral medullary syndrome should be prioritized, with close cardiac monitoring at the early stages of observation and pacemaker placement and tracheal intubation as required to prevent adverse events.

Thiazoline-related innate fear stimuli orchestrate hypothermia and anti-hypoxia via sensory TRPA1 activation.

Thiazoline-related innate fear-eliciting compounds (tFOs) orchestrate hypothermia, hypometabolism, and anti-hypoxia, which enable survival in lethal hypoxic conditions. Here, we show that most of these effects are severely attenuated in transient receptor potential ankyrin 1 (Trpa1) knockout mice. TFO-induced hypothermia involves the Trpa1-mediated trigeminal/vagal pathways and non-Trpa1 olfactory pathway. TFOs activate Trpa1-positive sensory pathways projecting from trigeminal and vagal ganglia to the spinal trigeminal nucleus (Sp5) and nucleus of the solitary tract (NTS), and their artificial activation induces hypothermia. TFO presentation activates the NTS-Parabrachial nucleus pathway to induce hypothermia and hypometabolism; this activation was suppressed in Trpa1 knockout mice. TRPA1 activation is insufficient to trigger tFO-mediated anti-hypoxic effects; Sp5/NTS activation is also necessary. Accordingly, we find a novel molecule that enables mice to survive in a lethal hypoxic condition ten times longer than known tFOs. Combinations of appropriate tFOs and TRPA1 command intrinsic physiological responses relevant to survival fate.

Short-term hypoxia does not promote arrhythmia during voluntary apnea.

The presence of bradycardic arrhythmias during volitional apnea at altitude may be caused by chemoreflex activation/sensitization. We investigated whether bradyarrhythmic episodes became prevalent in apnea following short-term hypoxia exposure. Electrocardiograms (ECG; lead II) were collected from 22 low-altitude residents (F = 12; age=25 ± 5 years) at 671 m. Participants were exposed to normobaric hypoxia (SpO2 ~79 ± 3%) over a 5-h period. ECG rhythms were assessed during both free-breathing and maximal volitional end-expiratory and end-inspiratory apnea at baseline during normoxia and hypoxia exposure (20 min [AHX]; 5 h [HX5]). Free-breathing HR became elevated at AHX (78 ± 10 bpm; p < 0.0001) and HX5 (80 ± 12 bpm; p < 0.0001) compared to normoxia (68 ± 10 bpm), whereas apnea caused significant bradycardia at AHX (nadir end-expiratory -17 ± 14 bpm; p < 0.001) and HX5 (nadir end-expiratory -19 ± 15 bpm; p < 0.001), but not during normoxia (nadir end-expiratory -4 ± 13 bpm), with no difference in bradycardia responses between apneas at AHX and HX5. Conduction abnormalities were noted in five participants during normoxia (Premature Ventricular Contraction, Sinus Pause, Junctional Rhythm, Atrial Foci), which remained unchanged during apnea at AHX and HX5 (Premature Ventricular Contraction, Premature Atrial Contraction, Sinus Pause). End-inspiratory apneas were overall longer across conditions (normoxia p < 0.05; AHX p < 0.01; HX5 p < 0.001), with comparable HR responses to end-expiratory and fewer occurrences of arrhythmia. While short-term hypoxia is sufficient to elicit bradycardia during apnea, the occurrence of arrhythmias in response to apnea was not affected. These findings indicate that previously observed bradyarrhythmic events in untrained individuals at altitude only become prevalent following chronic hypoxia specificlly.

Thyroid Hormone Receptor α Mutations Cause Heart Defects in Zebrafish.

Background: Mutations of thyroid hormone receptor α1 (TRα1) cause resistance to thyroid hormone (RTHα). Patients exhibit growth retardation, delayed bone development, anemia, and bradycardia. By using mouse models of RTHα, much has been learned about the molecular actions of TRα1 mutants that underlie these abnormalities in adults. Using zebrafish models of RTHα that we have recently created, we aimed to understand how TRα1 mutants affect the heart function during this period. Methods: In contrast to human and mice, the thra gene is duplicated, thraa and thrab, in zebrafish. Using CRISPR/Cas9-mediated targeted mutagenesis, we created C-terminal mutations in each of two duplicated thra genes in zebrafish (thraa 8-bp insertion or thrab 1-bp insertion mutations). We recently showed that these mutant fish faithfully recapitulated growth retardation as found in patients and thra mutant mice. In the present study, we used histological analysis, gene expression profiles, confocal fluorescence, and transmission electron microscopy (TEM) to comprehensively analyze the phenotypic characteristics of mutant fish heart during development. Results: We found both a dilated atrium and an abnormally shaped ventricle in adult mutant fish. The retention of red blood cells in the two abnormal heart chambers, and the decreased circulating blood speed and reduced expression of contractile genes indicated weakened contractility in the heart of mutant fish. These abnormalities were detected in mutant fish as early as 35 days postfertilization (juveniles). Furthermore, the expression of genes associated with the sarcomere assembly was suppressed in the heart of mutant fish, resulting in abnormalities of sarcomere organization as revealed by TEM, suggesting that the abnormal sarcomere organization could underlie the bradycardia exhibited in mutant fish. Conclusions: Using a zebrafish model of RTHα, the present study demonstrated for the first time that TRα1 mutants could act to cause abnormal heart structure, weaken contractility, and disrupt sarcomere organization that affect heart functions. These findings provide new insights into the bradycardia found in RTHα patients.

cAMP-dependent regulation of HCN4 controls the tonic entrainment process in sinoatrial node pacemaker cells.

It is highly debated how cyclic adenosine monophosphate-dependent regulation (CDR) of the major pacemaker channel HCN4 in the sinoatrial node (SAN) is involved in heart rate regulation by the autonomic nervous system. We addressed this question using a knockin mouse line expressing cyclic adenosine monophosphate-insensitive HCN4 channels. This mouse line displayed a complex cardiac phenotype characterized by sinus dysrhythmia, severe sinus bradycardia, sinus pauses and chronotropic incompetence. Furthermore, the absence of CDR leads to inappropriately enhanced heart rate responses of the SAN to vagal nerve activity in vivo. The mechanism underlying these symptoms can be explained by the presence of nonfiring pacemaker cells. We provide evidence that a tonic and mutual interaction process (tonic entrainment) between firing and nonfiring cells slows down the overall rhythm of the SAN. Most importantly, we show that the proportion of firing cells can be increased by CDR of HCN4 to efficiently oppose enhanced responses to vagal activity. In conclusion, we provide evidence for a novel role of CDR of HCN4 for the central pacemaker process in the sinoatrial node.

Mitochondrial thioredoxin-2 maintains HCN4 expression and prevents oxidative stress-mediated sick sinus syndrome.

OBJECTIVE: Sick sinus syndrome (SSS) is associated with loss of HCN4 (hyperpolarization-activated cyclic nucleotide-gated potassium channel 4) function in the cardiac conduction system. The underlying mechanism for SSS remains elusive. This study is to investigate how mitochondrial oxidative stress induces HCN4 downregulation associated with in sick sinus syndrome. METHODS AND RESULTS: Trx2lox/lox mice were crossed with α-myosin heavy chain (α-Mhc)-Cre and Hcn4-CreERT2 deleter mice to generate Trx2 deletion mice in the whole heart (Trx2cKO) and in the conduction system (Trx2ccsKO), respectively. Echocardiography was applied to measure hemodynamics and heart rhythm. Histological analyses, gene profiling and chromatin immunoprecipitation were performed to define the mechanism by which thioredoxin-2 (Trx2) regulates HCN4 expression and cardiac function. Trx2cKO mice displayed dilated cardiomyopathy, low heart rate, and atrial ventricular block (AVB) phenotypes. Immunofluorescence revealed that HCN4 expression was specifically reduced within the sinoatrial node in Trx2cKO mice. Interestingly, Trx2ccsKO mice displayed low heart rate and AVB without dilated cardiomyopathy. Both mRNA and protein levels of HCN4 were reduced in the sinoatrial node, suggesting transcriptional HCN4 regulation upon Trx2 deletion. ChIP indicated that the binding of MEF2 to the HCN4 enhancer was not altered by Trx2 deletion; however, histone 3 acetylation at the MEF2 binding site was decreased, and expression of histone deacetylase 4 (HDAC4) was elevated following Trx2 deletion. Moreover, HDAC4 binding to the HCN4 enhancer was mediated by MEF2. Mitochondrial ROS were increased by Trx2 deletion and importantly, mitochondria-specific ROS scavenger MitoTEMPO suppressed HDAC4 elevation, HCN4 reduction, and sinus bradycardia in Trx2ccsKO mice. CONCLUSION: In the conduction system, Trx2 is critical for maintaining HCN4-mediated normal heart rate. Loss of Trx2 reduces HCN4 expression via a mitochondrial ROS-HDAC4-MEF2C pathway and subsequently induces sick sinus syndrome in mice.

Mutant KCNJ3 and KCNJ5 Potassium Channels as Novel Molecular Targets in Bradyarrhythmias and Atrial Fibrillation.

BACKGROUND: Bradyarrhythmia is a common clinical manifestation. Although the majority of cases are acquired, genetic analysis of families with bradyarrhythmia has identified a growing number of causative gene mutations. Because the only ultimate treatment for symptomatic bradyarrhythmia has been invasive surgical implantation of a pacemaker, the discovery of novel therapeutic molecular targets is necessary to improve prognosis and quality of life. METHODS: We investigated a family containing 7 individuals with autosomal dominant bradyarrhythmias of sinus node dysfunction, atrial fibrillation with slow ventricular response, and atrioventricular block. To identify the causative mutation, we conducted the family-based whole exome sequencing and genome-wide linkage analysis. We characterized the mutation-related mechanisms based on the pathophysiology in vitro. After generating a transgenic animal model to confirm the human phenotypes of bradyarrhythmia, we also evaluated the efficacy of a newly identified molecular-targeted compound to upregulate heart rate in bradyarrhythmias by using the animal model. RESULTS: We identified one heterozygous mutation, KCNJ3 c.247A>C, p.N83H, as a novel cause of hereditary bradyarrhythmias in this family. KCNJ3 encodes the inwardly rectifying potassium channel Kir3.1, which combines with Kir3.4 (encoded by KCNJ5) to form the acetylcholine-activated potassium channel ( IKACh channel) with specific expression in the atrium. An additional study using a genome cohort of 2185 patients with sporadic atrial fibrillation revealed another 5 rare mutations in KCNJ3 and KCNJ5, suggesting the relevance of both genes to these arrhythmias. Cellular electrophysiological studies revealed that the KCNJ3 p.N83H mutation caused a gain of IKACh channel function by increasing the basal current, even in the absence of m2 muscarinic receptor stimulation. We generated transgenic zebrafish expressing mutant human KCNJ3 in the atrium specifically. It is interesting to note that the selective IKACh channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish. CONCLUSIONS: The IKACh channel is associated with the pathophysiology of bradyarrhythmia and atrial fibrillation, and the mutant IKACh channel ( KCNJ3 p.N83H) can be effectively inhibited by NIP-151, a selective IKACh channel blocker. Thus, the IKACh channel might be considered to be a suitable pharmacological target for patients who have bradyarrhythmia with a gain-of-function mutation in the IKACh channel.

Impact of Physiologic Pacing Versus Right Ventricular Pacing Among Patients With Left Ventricular Ejection Fraction Greater Than 35%: A Systematic Review for the 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.

BACKGROUND: It is unclear whether physiologic pacing by either cardiac biventricular pacing (BiVP) or His bundle pacing (HisBP) may prevent adverse structural and functional consequences known to occur among some patients who receive right ventricular pacing (RVP). AIM: Our analysis sought to review existing literature to determine if BiVP and/or HisBP might prevent adverse remodeling and be associated with structural, functional, and clinical advantages compared with RVP among patients without severe left ventricular dysfunction (>35%) who required permanent pacing because of heart block. METHODS: A literature search was conducted using MEDLINE (through PubMed) and Embase to identify randomized trials and observational studies comparing the effects of BiVP or HisBP versus RVP on measurements of left ventricular dimensions, left ventricular ejection fraction (LVEF), heart failure functional classification, quality of life, 6-minute walk, hospitalizations, and mortality. Data from studies that met the appropriate population, intervention, comparator, and outcomes of interest were abstracted for meta-analysis. Studies that reported pooled outcomes among patients with LVEF both above and below 35% could not be included in the meta-analysis because of strict relationships with industry procedures that preclude retrieval of industry-retained unpublished data on the subset of patients with preserved left ventricular function. RESULTS: Evidence from 8 studies, including a total of 679 patients meeting the prespecified criteria for inclusion, was identified. Results were compared for BiVP versus RVP, HisBP versus RVP, and BiVP+HisBP versus RVP. Among patients who received physiologic pacing with either BiVP or HisBP, the LV end-diastolic and end-systolic volumes were significantly lower (mean duration of follow-up: 1.64 years; -2.77 mL [95% CI -4.37 to -1.1 mL]; P=0.001; and -7.09 mL [95% CI -11.27 to -2.91; P=0.0009) and LVEF remained preserved or increased (mean duration of follow-up: 1.57 years; 5.328% [95% CI: 2.86%-7.8%; P<0.0001). Data on clinical impact such as functional status and quality of life were not definitive. Data on hospitalizations were unavailable. There was no effect on mortality. Several studies stratified results by LVEF and found that patients with LVEF >35% but ≤52% were more likely to receive benefit from physiologic pacing. Patients with chronic atrial fibrillation who underwent atrioventricular node ablation and pacemaker implant demonstrated clear improvement in LVEF with BiVP or HisBP versus RVP. CONCLUSION: Among patients with LVEF >35%, the LVEF remained preserved or increased with either BiVP or HisBP compared with RVP. However, patient-centered clinical outcome improvement appears to be limited primarily to patients who have chronic atrial fibrillation with rapid ventricular response rates and have undergone atrioventricular node ablation.

Biological therapies targeting arrhythmias: are cells and genes the answer?

INTRODUCTION: Arrhythmias can cause symptoms ranging from simple dizziness to life-threatening circulatory collapse. Current management includes medical therapy and procedures such as catheter ablation or device implantation. However, these strategies still pose a risk of serious side effects, and some patients remain symptomatic. Advancement in our understanding of how arrhythmias develop on the cellular level has made more targeted approaches possible. In addition, contemporary studies have found that several genes are involved in the pathogenesis of arrhythmias. AREAS COVERED: In the present review, the authors explore the cellular and genetic mechanisms leading to arrhythmias as well as the progress that has been made in using both gene and cell therapy to treat tachy- and bradyarrhythmias. They also consider why gene and cell therapy has resulted into a few clinical trials with promising results, however still not applicable in routine clinical practice. EXPERT OPINION: The question currently is whether such biological therapies could replace current established approaches. The contemporary evidence suggests that despite recent advances in this field, it will need more work in experimental models before this is applied into clinical practice. Gene and cell studies targeting conduction and repolarization are promising, but still not ready for use in the clinical setting.

[Metabolic Characteristics of Lethal Bradycardia Induced by Myocardial Ischemia].

OBJECTIVES: To explore the metabolic characteristics of lethal bradycardia induced by myocardial ischemia in rat's serum. METHODS: A rat myocardial ischemia-bradycardia-sudden cardiac death （MI-B-SCD） model was established, which was compared with the sham-operation group. The metabolic profile of postmortem serum was analyzed by gas chromatography-mass spectrometry （GC-MS）, coupled with the analysis of serum metabolic characteristics using metabolomics strategies. RESULTS: The serum metabolic profiles were significantly different between the MI-B-SCD rats and the control rats. Compared to the control rats, the MI-B-SCD rats had significantly higher levels of lysine, ornithine, purine, serine, alanine, urea and lactic acid; and significantly lower levels of succinate, hexadecanoic acid, 2-ketoadipic acid, glyceraldehyde, hexendioic acid and octanedioic acid in the serum. There were some correlations among different metabolites. CONCLUSIONS: There is obvious metabolic alterations in the serum of MI-B-SCD rat. Both lysine and purine have a high value in diagnosing MI-B-SCD. The results are expected to provide references for forensic and clinical applications of prevention and control of sudden cardiac death.

Newly divided eosinophils limit ozone-induced airway hyperreactivity in nonsensitized guinea pigs.

Ozone causes vagally mediated airway hyperreactivity and recruits inflammatory cells, including eosinophils, to lungs, where they mediate ozone-induced hyperreactivity 1 day after exposure but are paradoxically protective 3 days later. We aimed to test the role of newly divided eosinophils in ozone-induced airway hyperreactivity in sensitized and nonsensitized guinea pigs. Nonsensitized and sensitized guinea pigs were treated with 5-bromo-2-deoxyuridine (BrdU) to label newly divided cells and were exposed to air or ozone for 4 h. Later (1 or 3 days later), vagally induced bronchoconstriction was measured, and inflammatory cells were harvested from bone marrow, blood, and bronchoalveolar lavage. Ozone induced eosinophil hematopoiesis. One day after ozone, mature eosinophils dominate the inflammatory response and potentiate vagally induced bronchoconstriction. However, by 3 days, newly divided eosinophils have reached the lungs, where they inhibit ozone-induced airway hyperreactivity because depleting them with antibody to IL-5 or a TNF-α antagonist worsened vagally induced bronchoconstriction. In sensitized guinea pigs, both ozone-induced eosinophil hematopoiesis and subsequent recruitment of newly divided eosinophils to lungs 3 days later failed to occur. Thus mature eosinophils dominated the ozone-induced inflammatory response in sensitized guinea pigs. Depleting these mature eosinophils prevented ozone-induced airway hyperreactivity in sensitized animals. Ozone induces eosinophil hematopoiesis and recruitment to lungs, where 3 days later, newly divided eosinophils attenuate vagally mediated hyperreactivity. Ozone-induced hematopoiesis of beneficial eosinophils is blocked by a TNF-α antagonist or by prior sensitization. In these animals, mature eosinophils are associated with hyperreactivity. Thus interventions targeting eosinophils, although beneficial in atopic individuals, may delay resolution of airway hyperreactivity in nonatopic individuals.

Cardiovascular dysfunction associated with neurodegeneration in an experimental model of Parkinson's disease.

Patients with Parkinson's disease (PD) exhibit both motor and non-motor symptoms. Among the non-motor symptoms, cardiovascular autonomic dysfunction is frequently observed. Here, we evaluated baroreflex function, vascular reactivity and neuroanatomical changes in brainstem regions involved in the neural control of circulation in the 6-hydroxydopamine (6-OHDA) model of PD. Male Wistar rats received a bilateral injection of 6-OHDA or vehicle into the striatum. After 61days, baroreflex function and vascular reactivity were assessed. The 6-OHDA and vehicle groups showed similar increases in mean arterial pressure (MAP) in response to phenylephrine (PE). However, the bradycardia observed in the vehicle group was blunted in the 6-OHDA-treated rats. Injection of sodium nitroprusside (SNP) decreased hypotension, tachycardia and vascular relaxation in 6-OHDA-treated rats. Bilateral intrastriatal 6-OHDA led to massive degeneration of tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra and to reductions in the numbers of A1/C1 and A5 catecholaminergic neurons while sparing A2 neurons within the nucleus of the solitary tract (NTS). 6-OHDA-treated rats also showed decreases in Phox2b-expressing neurons in the NTS and in choline acetyltransferase (ChAT) immunoreactivity in the nucleus ambiguus. Altogether, our data suggest that this model of PD includes neuroanatomical and functional changes that lead to cardiovascular impairment.

Primary blast causes mild, moderate, severe and lethal TBI with increasing blast overpressures: Experimental rat injury model.

Injury severity in blast induced Traumatic Brain Injury (bTBI) increases with blast overpressure (BOP) and impulse in dose-dependent manner. Pure primary blast waves were simulated in compressed gas shock-tubes in discrete increments. Present work demonstrates 24 hour survival of rats in 0-450 kPa (0-800 Pa∙s impulse) range at 10 discrete levels (60, 100, 130, 160, 190, 230, 250, 290, 350 and 420 kPa) and determines the mortality rate as a non-linear function of BOP. Using logistic regression model, predicted mortality rate (PMR) function was calculated, and used to establish TBI severities. We determined a BOP of 145 kPa as upper mild TBI threshold (5% PMR). Also we determined 146-220 kPa and 221-290 kPa levels as moderate and severe TBI based on 35%, and 70% PMR, respectively, while BOP above 290 kPa is lethal. Since there are no standards for animal bTBI injury severity, these thresholds need further refinements using histopathology, immunohistochemistry and behavior. Further, we specifically investigated mild TBI range (0-145 kPa) using physiological (heart rate), pathological (lung injury), immuno-histochemical (oxidative/nitrosative and blood-brain barrier markers) as well as blood borne biomarkers. With these additional data, we conclude that mild bTBI occurs in rats when the BOP is in the range of 85-145 kPa.

Hypovolemic hemorrhage induces Fos expression in the rat hypothalamus: Evidence for involvement of the lateral hypothalamus in the decompensatory phase of hemorrhage.

This study tested the hypothesis that the hypothalamus participates in the decompensatory phase of hemorrhage by measuring Fos immunoreactivity and by inhibiting neuronal activity in selected hypothalamic nuclei with lidocaine or cobalt chloride. Previously, we reported that inactivation of the arcuate nucleus inhibited, but did not fully prevent, the fall in arterial pressure evoked by hypotensive hemorrhage. Here, we report that hemorrhage (2.2 ml/100g body weight over 20 min) induced Fos expression in a high percentage of cells in the paraventricular, supraoptic and arcuate nuclei of the hypothalamus as shown previously. Lower densities of Fos immunoreactive cells were also found in the medial preoptic area (mPOA), anterior hypothalamus, lateral hypothalamus (LH), dorsomedial hypothalamus, ventromedial hypothalamus (VMH) and posterior hypothalamus. Bilateral injection of lidocaine (2%; 0.1 µl or 0.3 µl) or cobalt chloride (5mM; 0.3 µl) into the tuberal portion of the LH immediately before hemorrhage was initiated reduced the magnitude of hemorrhagic hypotension and bradycardia significantly. Lidocaine injection into the VMH also attenuated the fall in arterial pressure and heart rate evoked by hemorrhage although inactivation of the mPOA or rostral LH was ineffective. These findings indicate that hemorrhage activates neurons throughout much of the hypothalamus and that a relatively broad area of the hypothalamus, extending from the arcuate nucleus laterally through the caudal VMH and tuberal LH, plays an important role in the decompensatory phase of hemorrhage.

Cardiovascular toxicity with levetiracetam overdose.

OBJECTIVE: To describe the cardiovascular toxicity and pharmacokinetics of levetiracetam in overdose. CASE REPORT: A 43-year-old female presented 8 h post ingestion of 60-80 g of levetiracetam with mild central nervous system depression, bradycardia, hypotension and oliguria. Her cardiovascular toxicity transiently responded to atropine and intravenous fluids. A bedside echocardiogram demonstrated normal left and right ventricular contractility. Despite her cardiovascular toxicity and oliguria, she had normal serial venous lactates and renal function; and made a complete recovery over 48 h. Her levetiracetam concentration was 463 mcg/ml 8 h post ingestion (therapeutic range 10-40 mcg/ml) and her concentration-time data best fitted a one-compartment model with first-order input and an elimination half-life of 10.4 h. DISCUSSION: Levetiracetam in large ingestions appears to cause bradycardia and hypotension that is potentially responsive to atropine and intravenous fluids. Based on a normal echocardiogram, the mechanism for this effect may be levetiracetam acting at muscarinic receptors at high concentration. The pharmacokinetics of levetiracetam in overdose appeared to be similar to therapeutic levetiracetam dosing.

Time-course effects of aerobic exercise training on cardiovascular and renal parameters in 2K1C renovascular hypertensive rats

Exercise training (Ex) has been recommended for its beneficial effects in hypertensive states. The present study evaluated the time-course effects of Ex without workload on mean arterial pressure (MAP), reflex bradycardia, cardiac and renal histology, and oxidative stress in two-kidney, one-clip (2K1C) hypertensive rats. Male Fischer rats (10 weeks old; 150–180 g) underwent surgery (2K1C or SHAM) and were subsequently divided into a sedentary (SED) group and Ex group (swimming 1 h/day, 5 days/week for 2, 4, 6, 8, or 10 weeks). Until week 4, Ex decreased MAP, increased reflex bradycardia, prevented concentric hypertrophy, reduced collagen deposition in the myocardium and kidneys, decreased the level of thiobarbituric acid-reactive substances (TBARS) in the left ventricle, and increased the catalase (CAT) activity in the left ventricle and both kidneys. From week 6 to week 10, however, MAP and reflex bradycardia in 2K1C Ex rats became similar to those in 2K1C SED rats. Ex effectively reduced heart rate and prevented collagen deposition in the heart and both kidneys up to week 10, and restored the level of TBARS in the left ventricle and clipped kidney and the CAT activity in both kidneys until week 8. Ex without workload for 10 weeks in 2K1C rats provided distinct beneficial effects. The early effects of Ex on cardiovascular function included reversing MAP and reflex bradycardia. The later effects of Ex included preventing structural alterations in the heart and kidney by decreasing oxidative stress and reducing injuries in these organs during hypertension.

Time-course effects of aerobic exercise training on cardiovascular and renal parameters in 2K1C renovascular hypertensive rats.

Exercise training (Ex) has been recommended for its beneficial effects in hypertensive states. The present study evaluated the time-course effects of Ex without workload on mean arterial pressure (MAP), reflex bradycardia, cardiac and renal histology, and oxidative stress in two-kidney, one-clip (2K1C) hypertensive rats. Male Fischer rats (10 weeks old; 150-180 g) underwent surgery (2K1C or SHAM) and were subsequently divided into a sedentary (SED) group and Ex group (swimming 1 h/day, 5 days/week for 2, 4, 6, 8, or 10 weeks). Until week 4, Ex decreased MAP, increased reflex bradycardia, prevented concentric hypertrophy, reduced collagen deposition in the myocardium and kidneys, decreased the level of thiobarbituric acid-reactive substances (TBARS) in the left ventricle, and increased the catalase (CAT) activity in the left ventricle and both kidneys. From week 6 to week 10, however, MAP and reflex bradycardia in 2K1C Ex rats became similar to those in 2K1C SED rats. Ex effectively reduced heart rate and prevented collagen deposition in the heart and both kidneys up to week 10, and restored the level of TBARS in the left ventricle and clipped kidney and the CAT activity in both kidneys until week 8. Ex without workload for 10 weeks in 2K1C rats provided distinct beneficial effects. The early effects of Ex on cardiovascular function included reversing MAP and reflex bradycardia. The later effects of Ex included preventing structural alterations in the heart and kidney by decreasing oxidative stress and reducing injuries in these organs during hypertension.