Development of the cardiac pacemaker.

The sinoatrial node (SAN) is the dominant pacemaker of the heart. Abnormalities in SAN formation and function can cause sinus arrhythmia, including sick sinus syndrome and sudden death. A better understanding of genes and signaling pathways that regulate SAN development and function is essential to develop more effective treatment to sinus arrhythmia, including biological pacemakers. In this review, we briefly summarize the key processes of SAN morphogenesis during development, and focus on the transcriptional network that drives SAN development.

High-fat diet increases vulnerability to atrial arrhythmia by conduction disturbance via miR-27b.

BACKGROUND: Lifestyle-related diseases, such as obesity and dyslipidemia are important risk factors for atrial fibrillation (AF). However, the underlying mechanism linking these diseases and AF has not been fully investigated. METHODS: Adult male mice were fed a high-fat diet (HFD) or vehicle (NC) for 2 months. Electrocardiography and in vivo electrophysiological study were performed. Mice were then sacrificed for quantification of mRNA, microRNA, and protein in atria, in addition to histological analysis. Conduction velocity (CV) in right atrium was measured by optical mapping in Langendorff perfused hearts. Cultured atrial cardiomyocytes were treated with palmitate with or without a specific microRNA inhibitor. Twelve hours after stimulation, cells were lysed, and subjected to analysis with qPCR and Western blotting. RESULTS: HFD mice showed prolonged P wave duration, increased inducibility of sustained atrial tachycardia, and reduced atrial CV than NC mice. HFD mice also showed increased expression in inflammatory cytokines, whereas fibrotic area and signals relating fibrosis were not changed. HFD mice demonstrated reduced expression of Cx40 in mRNA and protein levels, and its lateralized expression in atria. MicroRNA array analysis revealed that miR-27b expression was up-regulated in HFD mice, and luciferase assay confirmed the direct interaction between miR-27b and Cx40 3'UTR. In palmitate-stimulated atrial cardiomyocytes, miR-27b up-regulation and Cx40 down-regulation were observed, while expression of inflammatory cytokines was not altered. Inhibition of miR-27b with antisense oligonucleotides reversed the alteration caused by palmitate stimulation. CONCLUSION: HFD may increase the vulnerability to atrial arrhythmia by down-regulation of Cx40 via miR-27b, rather than fibrosis, which is independent of inflammation.

Noncompaction cardiomyopathy: a substrate for a thromboembolic event.

BACKGROUND: Noncompaction cardiomyopathy (NCC) is a rare genetic cardiomyopathy characterized by a thin, compacted epicardial layer and an extensive noncompacted endocardial layer. The clinical manifestations of this disease include ventricular arrhythmia, heart failure, and systemic thromboembolism. CASE PRESENTATION: A 43-year-old male was anticoagulated by pulmonary thromboembolism for 1 year when he developed progressive dyspnea. Cardiovascular magnetic resonance imaging showed severe biventricular trabeculation with an ejection fraction of 15%, ratio of maximum noncompacted/compacted diastolic myocardial thickness of 3.2 and the presence of exuberant biventricular apical thrombus. CONCLUSION: Still under discussion is the issue of which patients and when they should be anticoagulated. It is generally recommended to those presenting ventricular systolic dysfunction, antecedent of systemic embolism, presence of cardiac thrombus and atrial fibrillation. In clinical practice the patients with NCC and ventricular dysfunction have been given oral anticoagulation, although there are no clinical trials showing the real safety and benefit of this treatment.

Cerebrovascular accident under anesthesia during dental surgery.

Stroke, or cerebrovascular accident (CVA), is a medical emergency that may lead to permanent neurological damage, complications, and death. The rapid loss of brain function due to disruption of the blood supply to the brain is caused by blockage (thrombosis, arterial embolism) or hemorrhage. The incidence of CVA during anesthesia for noncardiac nonvascular surgery is as high as 1% depending on risk factors. Comprehensive preoperative assessment and good perioperative management may prevent a CVA. However, should an ischemic event occur, appropriate and rapid management is necessary to minimize the deleterious effects caused to the patient. This case report describes a patient who had an ischemic CVA while under general anesthesia for dental alveolar surgery and discusses the anesthesia management.

Poverty, problem behavior, and promise: differential susceptibility among infants reared in poverty.

Do infants reared in poverty exhibit certain physiological traits that make them susceptible to the positive and negative features of their caregiving environment? Guided by theories of differential susceptibility and biological sensitivity to context, we evaluated whether high baseline respiratory sinus arrhythmia (RSA) operates as a susceptibility factor among infants reared in poverty (N = 73). Baseline RSA at 5 months, the quality of the attachment relationship at 17 months, and the interaction of these two factors were included in our models as predictors of problem behavior at 17 months. Consistent with theory, results showed no significant differences in problem behavior among infants with low baseline RSA; however, infants with high baseline RSA exhibited the lowest levels of problem behavior if reared in an environment that fostered security, and they exhibited the highest levels of problem behavior if reared in an environment that fostered disorganization. These results have important implications for the psychological health of infants living in poverty.

Cardiovascular impairment in a patient with acute myelitis.

STUDY DESIGN: Case report. OBJECTIVE: to report and discuss the development of sudden symptomatic sinus bradycardia in a 35-year-old woman with acute myelitis. CASE REPORT: A 35-year-old woman presented rapidly progressive weakness and hypoesthesia in the left hemibody. Five days after symptom onset, she developed symptomatic sinus bradycardia up to 30 b.p.m. Bradycardia was completely resolved ∼36 h after its onset. RESULTS: Cervical spine magnetic resonance imaging showed a focal T2-hyperintense intramedullary lesion at C2 level, with moderate cord swelling. The lesion involved bilaterally dorsal funiculi, and left lateral and ventral funiculi. Cardiac I-123 metaiodobenzylguanidine (MIBG) scintigraphy showed a decreased cardiac MIBG uptake suggesting sympathetic denervation. CONCLUSION: The most likely explanation for bradycardia in our patient is the myelitis-related disruption of descending vasomotor pathways, resulting in sympathetic hypoactivity. Our case extends the spectrum of the clinical presentations of cervical myelitis and emphasizes the importance of careful cardiac monitoring in acute phase of cervical myelitis.

Incoherent oscillations of respiratory sinus arrhythmia during acute mental stress in humans.

Respiratory sinus arrhythmia (RSA) has been widely used as a measure of the cardiac vagal control in response to stress. However, RSA seems not to be a generalized indicator because of its dependency on respiratory parameter and individual variations of RSA amplitude (A(RSA)). We hypothesized that phase-lag variations between RSA and respiration may serve as a normalized index of the degree of mental stress. Twenty healthy volunteers performed mental arithmetic task (ART) after 5 min of resting control followed by 5 min of recovery. Breathing pattern, beat-to-beat R-R intervals, and blood pressure (BP) were determined using inductance plethysmography, electrocardiography, and a Finapres device, respectively. The analytic signals of breathing and RSA were obtained by Hilbert transform and the degree of phase synchronization (λ) was quantified. With the use of spectral analysis, heart rate variability (HRV) was estimated for the low-frequency (LF) and high-frequency (HF) bands. A steady-state 3-min resting period (REST), the first 3 min (ART1), and the last 3 min (ART2) of the ART period (ranged from 6- to 19 min) and the last 3 min of the recovery period (RCV) were analyzed separately. Heart rate, systolic BP, and breathing frequency (f(R)) increased and λ, A(RSA), and HF power decreased from REST to ART (P < 0.01). The λ was correlated with normalized A(RSA) and the HF power. The decrease in λ could not be explained solely by the increase in f(R). We conclude that mental stress exerts an influence on RSA oscillations, inducing incoherent phase lag with respect to breathing, in addition to a decrease in RSA.

Trajectories of children's internalizing symptoms: the role of maternal internalizing symptoms, respiratory sinus arrhythmia and child sex.

BACKGROUND: We assessed trajectories of children's internalizing symptoms as predicted by interactions among maternal internalizing symptoms, respiratory sinus arrhythmia (RSA) and child sex. METHOD: An ethnically and socioeconomically diverse sample of children (n = 251) participated during three study waves. Children's mean ages were 8.23 years (SD = 0.72) at T1, 9.31 years (SD = 0.79) at T2 and 10.28 years (SD = 0.99) at T3. RESULTS: Multiple-indicator multilevel latent growth analyses showed maternal internalizing symptoms interacted with child RSA and sex to predict children's internalizing symptoms. Girls with higher RSA whose mothers had lower levels of internalizing symptoms showed the steepest decline in internalizing symptoms across time. Girls with lower RSA whose mothers had higher levels of internalizing symptoms showed the highest levels of internalizing symptoms at T3, whereas boys with higher RSA whose mothers had higher levels of internalizing symptoms showed the highest levels of internalizing symptoms at T3. CONCLUSIONS: Findings build on this scant literature and support the importance of individual differences in children's physiological regulation in the prediction of psychopathology otherwise associated with familial risk.

Onset of atrial arrhythmias elicited by autonomic modulation of rabbit sinoatrial node activity: a modeling study.

Neuronal modulation of the sinoatrial node (SAN) plays a crucial role in the initiation and maintenance of atrial arrhythmias (AF), although the exact mechanisms remain unclear. We used a computer model of a rabbit right atrium (RA) with a heterogeneous SAN and detailed ionic current descriptions for atrial and SAN myocytes to explore reentry initiation associated with autonomic activity. Heterogeneous acetylcholine (ACh)-dependent ionic responses along with L-type Ca current (I(Ca,L)) upregulation were incorporated in the SAN only. During control, activation was typical with the leading pacemaker site located close to the superior vena cava or the intercaval region. With cholinergic stimulation, activation patterns frequently included caudal shifts of the leading pacemaker site and occasional double breakouts. The model became increasingly arrhythmogenic for the ACh concentration >20 nM and for large I(Ca,L) conductance. Reentries obtained included counterclockwise rotors in the free wall, clockwise reentry circulating between the SAN and free wall, and typical flutter. The SAN was the cause of reentry with a common leading sequence of events: a bradycardic beat with shifting in the caudal direction, followed by a premature beat or unidirectional block within the SAN. Electrotonic loading, and not just overdrive pacing, squelches competing pacemaker sites in the SAN. Cholinergic stimulation concomitant with I(Ca,L) upregulation shifts leading pacemaker site and can lead to reentry. A heterogeneous response to autonomic innervation, a large myocardial load, and an extensive SAN in the intercaval region are required for neurally induced SAN-triggered reentry.

Reduced autonomic flexibility as a predictor for future anxiety in girls from the general population: The TRAILS study.

The present study investigated whether autonomic flexibility predicted future anxiety levels in adolescent boys and girls. This study is part of the TRacking Adolescents' Individual Lives Survey (TRAILS), a prospective cohort study of Dutch adolescents. The current study included a subsample of 965 individuals. Measures of autonomic flexibility, i.e., heart rate (HR) and respiratory sinus arrhythmia (RSA), were determined during the first assessment wave (T1: participants 10-12 years old). Self-reported anxiety was assessed at the first and second assessment wave (T2: participants 12-14 years old). Possible gender differences and co-occurring depressive problems were examined. In girls, low RSA predicted anxiety levels 2 years later. In boys, no associations between HR and RSA and future anxiety were found. We conclude that in adolescent girls from the general population, signs of reduced autonomic flexibility (i.e., low RSA) predict future anxiety levels. Since the effect size was small, at this point, RSA reactivity alone cannot be used to identify individuals at risk for anxiety, but should be regarded as one factor within a large group of risk factors. However, if the present findings are replicated in clinical studies, intervention programmes - in the future - aimed at normalising autonomic functioning may be helpful.

Vagus nerve stimulation induces changes in respiratory sinus arrhythmia of epileptic children during sleep.

PURPOSE: This study analyzed the direct short-term effect of vagus nerve stimulation (VNS) on respiratory sinus arrhythmia (RSA) in children with pharmacoresistant epilepsy. METHODS: RSA magnitude is calculated as the ratio between maximum and minimum heart rate for each respiratory cycle-before, during, and after the actual VNS period. In 10 children, changes in RSA magnitude were evaluated on polysomnographic recordings, including electrocardiography (ECG), electroencephalography (EEG), thoracoabdominal distension, nasal airflow, and VNS artifacts. Measurements during stimulation were compared with those at baseline, immediately preceding the VNS periods and individually for each patient. RESULT: During VNS, respiratory frequency increased and respiratory amplitude decreased with a variable effect on cardiac activity. The coupling between heart rate and respiratory rate was disturbed and RSA magnitude decreased significantly in 6 of 10 children during VNS. These changes in RSA magnitude varied from one child to another. The observed changes for respiratory and cardiac activity were concomitant with changes in RSA but were not correlated. CONCLUSION: Together with disorders of respiration, cardiac activity, and oxygen saturation (SaO(2)) described previously. VNS also modifies synchronization between cardiac and respiratory activity, resulting in poor optimization of oxygen delivery to tissues that can be regarded as an additive side effect, which should be considered in patients with already altered brain function. This interaction between the effects of VNS and potential autonomic nervous system (ANS) dysfunction already reported in epileptic patients should be considered to be potentially life-threatening. In addition, evaluation of changes in respiratory parameters can also provide reliable markers for further evaluation of the effectiveness of VNS.

Respiratory sinus arrhythmia is reduced in adolescent major depressive disorder.

OBJECTIVE: Although the emotion regulatory difficulties in patients with major depressive disorder (MDD) are predicted to associate with impaired cardiovascular autonomic regulation, the changes of cardiac vagal regulation MDD are incompletely understood. The aim of the study was to evaluate the respiratory sinus arrhythmia (as an index of cardiac vagal regulation) using the spectral analysis in high frequency band of the heart rate variability and the indices of deep breathing test in adolescent patients with major depressive disorder. MATERIAL AND METHOD: Twenty-eight adolescent girls were examined - 14 patients with major depressive disorder without pharmacological treatment (average age: 16.4 +/- 0.2 yr) and 14 healthy probands (control group) matched for age and gender. The respiratory sinus arrhythmia was evaluated using the spectral analysis in high frequency band of the heart rate variability (HF-HRV) and the parameters of deep breathing test (I-E, I/E). In addition, mean R-R interval was calculated. RESULTS: The adolescent patients with MDD has significantly reduced spectral activity in the HF-HRV and lower I/E, I-E parameters compared to marched health subjects (P<0.05). CONCLUSIONS: We conclude that the adolescents girls with MDD have reduced respiratory sinus arrhythmia indicating cardiac vagal dysregulation. Since impaired cardiac vagal regulation is associated with increased risk of cardiovascular morbidity, this finding underscores the importance of impaired autonomic neuro-cardiac integrity already in adolescents with major depressive disorder without pharmacological treatment.

Symbiotic cardiac pacemaker.

Self-powered implantable medical electronic devices that harvest biomechanical energy from cardiac motion, respiratory movement and blood flow are part of a paradigm shift that is on the horizon. Here, we demonstrate a fully implanted symbiotic pacemaker based on an implantable triboelectric nanogenerator, which achieves energy harvesting and storage as well as cardiac pacing on a large-animal scale. The symbiotic pacemaker successfully corrects sinus arrhythmia and prevents deterioration. The open circuit voltage of an implantable triboelectric nanogenerator reaches up to 65.2 V. The energy harvested from each cardiac motion cycle is 0.495 µJ, which is higher than the required endocardial pacing threshold energy (0.377 µJ). Implantable triboelectric nanogenerators for implantable medical devices offer advantages of excellent output performance, high power density, and good durability, and are expected to find application in fields of treatment and diagnosis as in vivo symbiotic bioelectronics.

Social isolation disrupts autonomic regulation of the heart and influences negative affective behaviors.

BACKGROUND: There is a documented association between affective disorders (e.g., depression and anxiety) and cardiovascular disease in humans. Chronic social stressors may play a mechanistic role in the development of behavioral and cardiac dysregulation. The current study investigated behavioral, cardiac, and autonomic responses to a chronic social stressor in prairie voles, a rodent species that displays social behaviors similar to humans. METHODS: Female prairie voles were exposed to 4 weeks of social isolation (n = 8) or pairing (control conditions; n = 7). Electrocardiographic parameters were recorded continuously during isolation, and behavioral tests were conducted during and following this period. RESULTS: Isolation induced a significant increase in resting heart rate, reduction in heart rate variability (standard deviation of normal-to-normal intervals and amplitude of respiratory sinus arrhythmia), and exaggerated cardiac responses during an acute resident-intruder paradigm. Isolation led also to both depression-like and anxiety-like behaviors in validated operational tests. These changes in response to social isolation showed predictable interrelations and were mediated by a disruption of autonomic balance including both sympathetic and parasympathetic (vagal) mechanisms. CONCLUSIONS: These findings indicate that social isolation induces behavioral, cardiac, and autonomic alterations related to those seen after other stressors and which are relevant to cardiovascular disease and affective disorders. This model may provide insight into the mechanisms that underlie these co-occurring conditions.

[The ictal bradycardia syndrome: a case report and review of the literature]. / Le syndrome de bradycardie comitiale: cas clinique et revue de la littérature.

Epilepsy is a rare cause of sinus node dysfunction which should be recognised. The authors report the case of a 55 year old woman with refractory epilepsy who had sinus arrest during her epileptic fits. After excluding a possible interaction by long-term Carbamazepine treatment, the diagnosis of the Ictal bradycardia syndrome was made in view of the simultaneous occurrence of severe bradycardia and epileptic activity recorded on electro-encephalography. Sudden death being more common in epilepsy, effective treatment of conductive cardiac abnormalities is essential. The refractory nature of the epileptic fits led to the implantation of a permanent pacemaker in this case.

Anesthetic management of the trigeminocardiac reflex during mesiodens removal-a case report.

We describe a case in which reflection of a palatal flap for removal of a mesiodens is presented as the triggering factor for bradycardia caused by stimulation of the trigeminocardiac reflex. The management of the case, as well as the reflex arc, is discussed.

[Occupational diseases-related autonomic system cardioneuropathy in Chelyabinsk region].

Cardiovascular diseases appear to be the most frequent complication and death cause in patients with various forms of occupational diseases. Autonomous nervous system could play significant role in genesis of those complications.

Stability of pacing indices and need for pacing in cardiac transplant patients over 1 year of follow-up.

BACKGROUND: A significant minority of cardiac transplant patients require permanent pacemaker (PPM) implant, primarily for sinus node dysfunction. The stability of pacing indices has not been determined in this unique patient population, and data regarding ongoing need for pacing are limited. METHODS: Pacing indices (sensing, threshold, and impedance) as well as the percentage of time patients required pacing were recorded, from 30 cardiac transplant patients that underwent PPM implant, over 1 year of follow-up. Repeated measure ANOVA (analysis of variance) was used to compare pacing indices and the percentage of time patients required pacing in each cardiac chamber (right atrium (RA) and right ventricle (RV)) and at different time points. RESULTS: There was no difference in sensing among the follow-up time points (p = 0.9). Thresholds at 3 months were significantly higher compared to the day of implant (p = 0.005) and the day after implant (p = 0.03). Impedances at implant were significantly higher compared to day 1 (p < 0.001), 3 months (p < 0.003), and 12 months (p < 0.001) post-implant. The mean percentage of RA pacing was 85 ± 6% the day after implant, 74 ± 6% at 3 months, and 80 ± 6% at 1 year (p = 0.17). CONCLUSION: In cardiac transplant patients, pacing impedances decrease and thresholds trend up in short-term follow-up, but subsequent sensing, threshold, and impedance remain stable at 1 year. This is comparable to the pattern observed among noncardiac transplant PPM recipients. The atrial pacing percentage was stable over 1 year, suggesting continued relative sinus node dysfunction.

Sinus Bradycardia in Habitual Cocaine Users.

Common physiological manifestations of cocaine are related to its adrenergic effects, due to inhibition of dopamine and norepinephrine uptake at the postsynaptic terminal. Few studies have documented bradycardia secondary to cocaine use, representing the antithesis of its adrenergic effects. We assessed the prevalence of sinus bradycardia (SB) in habitual cocaine users and postulated a mechanism for this effect. One hundred sixty-two patients with a history of cocaine use were analyzed and compared with age- and gender-matched controls. SB was defined as a rate of <60 beats/min and habitual cocaine use as 2 or more documented uses >30 days apart. Propensity score-matching analysis was applied to balance covariates between cocaine users and nonusers and reduce selection bias. Patients with a history of bradycardia, hypothyroidism, or concomitant beta-blocker use were excluded. Mean age of study patients was 44 ± 8 years. SB was observed in 43 of 162 (27%) cocaine users and in 9 of 149 (6%) nonusers (p = 0.0001). Propensity score-matching analysis matched 218 patients from both groups. Among matched patients SB was observed in 25 of 109 (23%) cocaine users and in 5 of 109 (5%) nonusers (p = 0.0001). Habitual cocaine use was an independent predictor of SB and associated with a sevenfold increase in the risk of SB (95% CI 2.52 to 19.74, p = 0.0002). In conclusion, habitual cocaine use is a strong predictor of SB and was unrelated to recency of use. A potential mechanism for SB may be related to cocaine-induced desensitization of the beta-adrenergic receptor secondary to continuous exposure. Symptomatic SB was not observed; thus, pacemaker therapy was not indicated.