Cardiorespiratory anomalies and increased brainstem microglia in a rat model of neonatal opioid withdrawal syndrome.

Infants born with neonatal opioid withdrawal syndrome (NOWS) can display abnormal cardiorespiratory patterns including tachypnea, tachycardia, and impaired ventilatory responses to hypoxia (HVR) and hypercapnia (HCVR). Chronic morphine exposure is associated with increased midbrain microglial expression. Using a rat model of pre- and post-natal morphine exposure, we assessed cardiorespiratory features of NOWS (resting tachycardia and tachypnea) including the attenuated HVR and HCVR and whether they are associated with increased brainstem microglia expression. Pregnant rats (dams) received twice-daily subcutaneous injections of morphine (5 mg/kg) during the third (last) week of pregnancy to simulate 3rd trimester in utero opioid exposure. Offspring then received once-daily subcutaneous injections of morphine (0.5 mg/kg) until postnatal (P) day P10 days of age to simulate postnatal morphine therapy. Cardiorespiratory responses were assessed 24 h later (P11 days) following spontaneous withdrawal. Compared to saline-treated pups, morphine-exposed offspring exhibited tachycardia and tachypnea as well as an attenuated HVR and HCVR. Microglial cell counts were increased in the nucleus tractus solitarius (nTS), dorsal motor nucleus of the vagus (DMNV) and nucleus ambiguous (NAamb), but not the retrapezoid nucleus (RTN) or the non-cardiorespriatory region, the cuneate nucleus (CN). These data suggest that the cardiorespiratory features and autonomic dysregulation in NOWS infants may be associated with altered microglial function in specific brainstem cardiorespiratory control regions.

Case of multisystem inflammatory syndrome in children presenting as fever and abdominal pain.

This case aims to remind all providers to scrutinise for atypical presentations of multisystem inflammatory syndrome in children (MIS-C) which may mimic a more routine diagnosis. In the absence of mucocutaneous symptoms, the diagnosis of MIS-C can be missed. Given the potential for rapid deterioration of patients with MIS-C, early treatment and inpatient interventions are necessary.

Critical inflammatory mechanisms underlying arrhythmias.

During the past few decades, cardiovascular research has increasingly focused on systemic inflammatory mechanisms, particularly in the field of atherosclerosis but also in association with cardiac arrhythmogenesis. Objective inflammatory markers including C­reactive protein and cytokines, also called "biomarkers," seem to serve as predictors of onset and prognosis of cardiac arrhythmias. This review gives an overview of potential mechanisms underlying inflammatory processes and arrhythmias, especially atrial fibrillation, which is the most common sustained arrhythmia in daily clinical routine. The association between inflammatory pathways and cardiac arrhythmia is highly complex and includes direct as well as indirect pathways. While past research into arrhythmia focused on fibrosis, altered action potential properties, and ischemia, novel concepts include coagulation and inflammation in cardiac tissue. The underlying mechanisms are altered electrophysiological properties, including ion channel disturbance, early and late afterdepolarizations, as well as enhanced fibrosis and structural remodeling in cardiomyopathies. These pathophysiological factors favor the occurrence of ectopic pacemakers as well as re-entry tachycardia. Further studies are essential to better understand the main inflammatory signal cascades and the exact proarrhythmic effect of interacting key mediators. This will facilitate the evaluation of future anti-inflammatory therapeutic approaches for arrhythmias, analogous to recent developments in atherosclerosis.

Toll-like receptor 9 plays a key role in the autonomic cardiac and baroreflex control of arterial pressure.

The crosstalk between the immune and the autonomic nervous system may impact the cardiovascular function. Toll-like receptors are components of the innate immune system and play developmental and physiological roles. Toll-like receptor 9 (TLR9) is involved in the pathogenesis of cardiovascular diseases, such as hypertension and heart failure. Since such diseases are commonly accompanied by autonomic imbalance and lower baroreflex sensitivity, we hypothesized that TLR9 modulates cardiac autonomic and baroreflex control of arterial pressure (AP). Toll-like receptor 9 knockout (TLR9 KO) and wild-type (WT) mice were implanted with catheters into carotid artery and jugular vein and allowed to recover for 3 days. After basal recording of AP, mice received methyl-atropine or propranolol. AP and pulse interval (PI) variability were evaluated in the time and frequency domain (spectral analysis), as well as by multiscale entropy. Spontaneous baroreflex was studied by sequence technique. Behavioral and cardiovascular responses to fear-conditioning stress were also evaluated. AP was similar between groups, but TLR9 KO mice exhibited lower basal heart rate (HR). AP variability was not different, but PI variability was increased in TLR9 KO mice. The total entropy was higher in TLR9 KO mice. Moreover, baroreflex function was found higher in TLR9 KO mice. Atropine-induced tachycardia was increased in TLR9 KO mice, whereas the propranolol-induced bradycardia was similar to WT mice. TLR9 KO mice exhibit increased behavioral and decreased tachycardia responses to fear-conditioning stress. In conclusion, our findings suggest that TLR9 may negatively modulate cardiac vagal tone and baroreflex in mice.

Prolonged TSH receptor A subunit immunization of female mice leads to a long-term model of Graves' disease, tachycardia, and cardiac hypertrophy.

A transient model for human Graves' disease was successfully established in mice using up to 3 immunizations with recombinant adenovirus expressing the extracellular A-subunit of the human TSH receptor (TSHR) (Ad-TSHR). We studied extension of adenovirally induced TSHR A-subunit immunization in mice by using a novel protocol of long-term 3- and 4-weekly injections. Generation of TSHR binding stimulatory antibodies (capacity to stimulate cAMP activity in TSHR-expressing test cells), goiter, and histological thyroid alterations were maintained for at least 9 months in all Ad-TSHR-immunized mice. In response to injection of 10(10) plaque-forming units of Ad-TSHR, also elevated mean serum T4 levels were observed throughout the study. Moreover, cardiac organ involvement (tachycardia and hypertrophy) were consistently observed in these mice. Higher doses of Ad-TSHR (10(11) plaque-forming units) did not produce consistent elevation of T4 and were not associated with a clear increase in heart rate vs controls, probably because these high doses provoked an immune response-induced tachycardia on their own. In summary, a long-term model of Graves' disease induced by a relatively simple protocol of continuing monthly immunizations should allow to investigate long-term disease mechanisms and may possibly obviate the need for more complicated disease models. Moreover, the clinical outcome predictor of tachycardia and cardiac involvement was reliably detected in the model.

Heart rate after cardiac transplantation-lessons from the tortoise and the shrew.

There is a striking consistency in the total number of heart beats accrued over a lifetime across a range of animal species despite vast differences in size. Moreover, an inverse relationship is observed between heart rate and lifespan, leading to speculation that elevated heart rate could significantly affect longevity. It is the aim of this review to analyze heart rate as a contributing factor in defining the functional lifespan of the transplanted human heart, which may unavoidably determine the longevity of the recipient. Sinus tachycardia occurs as a result of sympathetic/parasympathetic denervation, an unavoidable consequence of transplantation. The effect of elevated heart rate in this cohort has been scarcely reported. We highlight herein multitudinous mechanisms whereby elevated heart rate accelerates the deterioration in cardiac function and arterial elasticity due to injury and stress accumulation. Additionally, we propose a significant role for heart rate in confounding the alloimmune response. Tachycardia exacerbates injurious episodes of myocardial ischemia and significantly increases the production of reactive oxygen species via increased metabolism. These factors promote immune infiltration and activation, contributing to acute and chronic rejection. Further research is required to assess the potential therapeutic benefits of heart rate reduction.

Invited Article: Autonomic ganglia: target and novel therapeutic tool.

Nicotinic acetylcholine receptors (AChR) are ligand-gated cation channels that are present throughout the nervous system. The muscle AChR mediates transmission at the neuromuscular junction; antibodies against the muscle AChR are the cause of myasthenia gravis. The ganglionic (alpha 3-type) neuronal AChR mediates fast synaptic transmission in sympathetic, parasympathetic, and enteric autonomic ganglia. Impaired cholinergic ganglionic synaptic transmission is one important cause of autonomic failure. Pharmacologic enhancement of ganglionic synaptic transmission may be a novel way to improve autonomic function. Ganglionic AChR antibodies are found in patients with autoimmune autonomic ganglionopathy (AAG). Patients with AAG typically present with rapid onset of severe autonomic failure. Major clinical features include orthostatic hypotension, gastrointestinal dysmotility, anhidrosis, bladder dysfunction, and sicca symptoms. Impaired pupillary light reflex is often seen. Like myasthenia, AAG is an antibody-mediated neurologic disorder. The disease can be reproduced in experimental animals by active immunization or passive antibody transfer. The patient may improve with plasma exchange treatment or other immunomodulatory treatment. Antibodies from patients with AAG inhibit ganglionic AChR currents. Other phenotypes of AAG are now recognized based on the results of antibody testing. These other presentations are generally associated with lower levels of ganglionic AChR antibodies. A chronic progressive form of AAG may resemble pure autonomic failure. Milder forms of dysautonomia, such as postural tachycardia syndrome, are associated with ganglionic AChR in 10-15% of cases. Since ganglionic synaptic transmission is a common pathway for all autonomic traffic, enhancement of autonomic function through inhibition of acetylcholinesterase is a potential specific therapeutic strategy for autonomic disorders. Increasing the strength of ganglionic transmission can ameliorate neurogenic orthostatic hypotension without aggravating supine hypertension. Recent evidence also suggests a potential role for acetylcholinesterase inhibitors in the treatment of postural tachycardia syndrome.

[Spectral parameters of heart rate variability and frequency of detection of autoantibodies to beta(1)-adrenoreceptors in patients with tachyarrhythmias: idiopathic and at the background of primary myocardial diseases].

In order to assess parameters of heart rate variability (HRV) and prevalence of autoantibodies against the beta(1)-adrenoreceptors in patients with cardiac arrhythmias we studied 42 patients with arrhythmias and 20 healthy control subjects. Thirty one patients with idiopathic arrhythmias were included in group I: with paroxysmal atrial fibrillation or flutter (n=13), paroxysmal atrial tachycardia (n=2) and paroxysmal ventricular tachycardia (n=16). Group II was formed of 11 patients with paroxysmal ventricular tachycardia and dilated cardiomyopathy or chronic myocarditis. ab1-AR were determined in blood serum by direct immunoassay. Synthetic fragment containing 26 amino acids of ab1-AR second loop was used as antigen. Groups I (54.8%) and II (63.6%) showed similar prevalence of ab1-AR, which was significantly higher than in control subjects (10%) (p<0.005). HRV parameters in I group were lower in ab1-AR-positive compared with ab1-AR-negative patients. At the same time HRV parameters in ab1-AR-positive patients were significantly different from those in controls (p<0.05). In group II HRV parameters of ab1-AR-positive and ab1-AR-negative patients were significantly lower than in control subjects (p<0.05). We suppose, that ab1-AR could participate in dysfunction of chronotropic heart regulation and contribute to development of arrhythmias in patients with structurally normal hearts.

Muscle relaxants and histamine release.

Many anaesthetic drugs and adjuvants can cause the release of histamine by chemical (anaphylactoid) or immunologic (anaphylactic) mechanisms. While both types of reactions can be clinically indistinguishable, they are mechanistically different. In anaphylactoid reactions, only preformed mediators are released, of which histamine may be the most clinically important. In true immunologic reactions, mast cell degranulation occurs, and many vasoactive substances (including histamine) are released. Clinical signs and symptoms of both classes of reactions include hypotension (most common), tachycardia, bronchospasm, or cutaneous manifestations. Anaphylactoid reactions may occur commonly under anaesthesia in response to many drugs, including induction agents, some opiates, plasma expanders, and curariform relaxants. Anaphylactic reactions are far less common than anaphylactoid reactions, but they nevertheless represent more than half of the life-threatening reactions that occur in anaesthetic practice. Muscle relaxants are the most frequently implicated class of drugs; suxamethonium is the most common agent implicated in anaphylactic reactions during anaesthesia, but even drugs without apparent chemical histamine release (i.e., vecuronium) are frequently implicated in anaphylactic reactions.

[Fetal arrhythmias--new immunologic studies and results]. / Fetale Arrhythmien--Neue Immunologische Untersuchungen und Ergebnisse.

The etiology of fetal arrhythmias is still unknown. We therefore did a research for immunologic causes: antimyolemmal antibodies (AMLA) in mothers and umbilical cord serum resulting from secondary immunopathogenesis caused by myocarditis of the mother. Is there a correlation between immunological and clinical findings giving a possible explanation for fetal arrhythmias? In 21 cases mothers and umbilical cord serum was investigated for AMLA; 16 with fetal atrial premature beats, 4 with fetal tachycardia and 1 with fetal bradyarrhythmia. From 16 mothers with fetal atrial premature beats had 12 AMLA, from these were in 4 cases in the umbilical cord serum AMLA. In 4 cases of fetal tachycardia we found in 1 case AMLA in mothers and umbilical cord serum. In the other 3 cases accessory pathways have been the cause for tachycardia. From 19 healthy persons were found in 3 cases AMLA in mothers serum, umbilical cord serum was negative.

[Laser irradiation of the blood in patients with refractory tachyarrhythmias]. / Lazerne oprominennia krovi khvorykh z refrakternymy takhiarytmiiamy.

A study of 108 with paradoxic tachyarrhythmias including 80 with tachyarrhythmias refractory to antiarrhythmic drugs revealed that a major role is played by the structural functional changes of the membranes and in humoral chain of the immune response that is accompanied by functional disorder of the cell receptor apparatus. Laser blood irradiation effecting neurohumoral regulation promotes normalization of barrier and receptor functional of myocardium cell membranes and overcoming refractivity of tachyarrhythmias to antiarrhythmic agents.

Lethal myocarditis with atrioventricular block and ventricular tachycardia--a case report.

This case report details the acute clinical course and the follow-up of a 42-year-old woman with active recurring myocarditis, the main electrical features of which were atrioventricular block and ventricular tachycardia. It also focuses on immunohistological and serological parameters of autoreactivity that might explain the chronic clinical course over a period of 10 years.

Ventricular arrhythmias and left ventricular dysfunction in familial cardiomyopathy.

In familial cardiomyopathy (CM), different forms of myocardial abnormalities including asymmetric and symmetric hypertrophy and dilated left ventricles are presented, mostly showing varying hereditary penetrance. This study presents a family with CM including three major clinical manifestations: severe ventricular arrhythmias, repolarization abnormalities and left ventricular hypertrophy. This triad was strikingly consistent in the two generations examined. The familial pattern with an autosomal dominant inheritance did not show any linkage to the HLA region.

Congenital prolongation of Q-T interval: a family study of three generations.

Three generations of a family with the Romano-Ward syndrome are described. Of all the affected members, only 1 was symptomatic, experiencing episodes of syncope proven to be due to polymorphous ventricular tachycardia (PMVT) induced by chlorimipramine treatment for depression. During treatment of an episode of PMVT with lidocaine, the patient developed the 'torsade de pointes' variant of ventricular tachycardia, which progressed to ventricular fibrillation and was successfully treated with electroversion. The hazards of treating these patients with commonly used drugs, the possible etiologies for the Romano-Ward syndrome and its mode of inheritance are discussed.