Identification of Mineralocorticoid Receptors, Aldosterone, and Its Processing Enzyme CYP11B2 on Parasympathetic and Sympathetic Neurons in Rat Intracardiac Ganglia

Recent interest has focused on the mineralocorticoid receptor (MR) and its impact on the myocardium and the performance of the heart. However, there is a lack of evidence about MR expression and its endogenous ligand aldosterone synthesis with specific regard to the intrinsic cardiac nervous system. Therefore, we looked for evidence of MR and aldosterone in sympathetic and parasympathetic neurons of intracardiac ganglia. Tissue samples from rat heart atria were subjected to conventional reverse-transcriptase polymerase chain reaction (PCR), Western blot, and double immunofluorescence confocal analysis of MR, corticosterone-inactivating enzyme 11β-hydroxysteroid-dehydrogenase-2 (11β-HSD2), aldosterone, and its processing enzyme CYP11B2 together with the neuronal markers vesicular acetylcholine transporter (VAChT) and tyrosine hydroxylase (TH). Our results demonstrated MR, 11β-HSD2, and CYP11B2 specific mRNA and protein bands in rat heart atria. Double immunofluorescence labeling revealed coexpression of MR immunoreactivity with VAChT in large diameter parasympathetic principal neurons. In addition, MR immunoreactivity was identified in TH-immunoreactive small intensely fluorescent (SIF) cells and in nearby VAChT- and TH-immunoreactive nerve terminals. Interestingly, the aldosterone and its synthesizing enzyme CYP11B2 and 11β-HSD2 colocalized in MR– immunoreactive neurons of intracardiac ganglia. Overall, this study provides first evidence for the existence of not only local expression of MR, but also of 11β-HSD2 and aldosterone with its processing enzyme CYP11B2 in the neurons of the cardiac autonomic nervous system, suggesting a possible modulatory role of the mineralocorticoid system on the endogenous neuronal activity on heart performance.

Inappropriate sinus tachycardia in post-COVID-19 syndrome

Inappropriate sinus tachycardia (IST) is a common observation in patients with post-COVID-19 syndrome (PCS) but has not yet been fully described to date. To investigate the prevalence and the mechanisms underlying IST in a prospective population of PCS patients. Consecutive patients admitted to the PCS Unit between June and December 2020 with a resting sinus rhythm rate ≥ 100 bpm were prospectively enrolled in this study and further examined by an orthostatic test, 2D echocardiography, 24-h ECG monitoring (heart rate variability was a surrogate for cardiac autonomic activity), quality-of-life and exercise capacity testing, and blood sampling. To assess cardiac autonomic function, a 2:1:1 comparative sub-analysis was conducted against both fully recovered patients with previous SARS-CoV-2 infection and individuals without prior SARS-CoV-2 infection. Among 200 PCS patients, 40 (20%) fulfilled the diagnostic criteria for IST (average age of 40.1 ± 10 years, 85% women, 83% mild COVID-19). No underlying structural heart disease, pro-inflammatory state, myocyte injury, or hypoxia were identified. IST was accompanied by a decrease in most heart rate variability parameters, especially those related to cardiovagal tone: pNN50 (cases 3.2 ± 3 vs. recovered 10.5 ± 8 vs. non-infected 17.3 ± 10; p < 0.001) and HF band (246 ± 179 vs. 463 ± 295 vs. 1048 ± 570, respectively; p < 0.001). IST is prevalent condition among PCS patients. Cardiac autonomic nervous system imbalance with decreased parasympathetic activity may explain this phenomenon.

Differences in the Asymmetry of Beat-to-Beat Fetal Heart Rate Accelerations and Decelerations at Preterm and Term Active Labor

The fetal autonomic nervous system responds to uterine contractions during active labor as identified by changes in the accelerations and decelerations of fetal heart rate (FHR). Thus, this exploratory study aimed to characterize the asymmetry differences of beat-to-beat FHR accelerations and decelerations in preterm and term fetuses during active labor. In an observational study, we analyzed 10 min of fetal R-R series collected from women during active preterm labor (32–36 weeks of pregnancy, n = 17) and active term labor (38–40 weeks or pregnancy, n = 27). These data were used to calculate the Deceleration Reserve (DR), which is a novel parameter that quantifies the asymmetry of the average acceleration and deceleration capacity of the heart. In addition, relevant multiscale asymmetric indices of FHR were also computed. Lower values of DR, calculated with the input parameters of T = 50 and s = 10, were associated with labor occurring at the preterm condition (p = 0.0131). Multiscale asymmetry indices also confirmed significant (p < 0.05) differences in the asymmetry of FHR. Fetuses during moderate premature labor may experience more decaying R-R trends and a lower magnitude of decelerations compared to term fetuses. These differences of FHR dynamics might be related to the immaturity of the fetal cardiac autonomic nervous system as identified by this system response to the intense uterine activity at active labor.

Assessment of cardiac autonomic function in patients with permanent and paroxysmal atrial fibrillation

Background Atrial fibrillation (AF) is the commonest abnormal heart rhythm with significant related morbidity and mortality. There is increasing evidence that abnormalities of the cardiac autonomic nervous system (ANS) are involved in the pathogenesis of AF. Exploring the ANS is possible through heart rate variability (HRV) evaluation. Purpose To investigate whether HRV is more abnormal in patients with permanent AF compared to paroxysmal AF. Design In a cross-sectional comparison, we studied two patient groups: permanent AF (n=30) and paroxysmal AF (n=31). Time-domain, frequency-domain and non-linear measures of HRV were determined using eMotion Faros ECG sensor. Participant's breathing was controlled with a metronome set at 12 breaths per minute. Data was analysed using SPSS software. Results Time-domain and non-linear indices of HRV were significant higher in permanent AF group compared to paroxysmal AF (table 1). Permanent AF was the only independent predictor of HRV on multivariable analysis in this cohort of patients (p=0.006) Conclusions First study investigating autonomic function in patients with permanent AF and paroxysmal AF. HRV indices were significantly higher in permanent AF compared to paroxysmal AF which may suggest pronounced cardiac autonomic influence in the pathophysiology of permanent AF. FUNDunding Acknowledgement Type of funding sources: None.

A review of cardiac autonomics: from pathophysiology to therapy

The effective management of cardiovascular diseases requires knowledge of intrinsic and extrinsic innervation of the heart and an understanding of how perturbations of said components affect cardiac function. The innate cardiac conduction system, which begins with cardiac pacemaker cells and terminates with subendocardial Purkinje fibers, is modulated by said systems. The intrinsic component of the cardiac autonomic nervous system, which remains incompletely elucidated, consists of intracardiac ganglia and interconnecting neurons that tightly regulate cardiac electrical activity. Extrinsic components of the autonomic nervous system, such as carotid baroreceptors and renin-angiotensin-aldosterone system, modulate sympathetic input to the heart through the stellate ganglion and parasympathetic input via the vagus nerve. There remains a need for additional therapies to treat conditions, such as advanced heart failure and refractory arrhythmias, and a better understanding of autonomics may be key to their development.

Asymmetry and Heterogeneity: Part and Parcel in Cardiac Autonomic Innervation and Function

The cardiac autonomic nervous system (cANS) regulates cardiac adaptation to different demands. The heart is an asymmetrical organ, and in the selection of adequate treatment of cardiac diseases it may be relevant to take into account that the cANS also has sidedness as well as regional differences in anatomical, functional, and molecular characteristics. The left and right ventricles respond differently to adrenergic stimulation. Isoforms of nitric oxide synthase, which plays an important role in parasympathetic function, are also distributed asymmetrically across the heart. Treatment of cardiac disease heavily relies on affecting left-sided heart targets which are thought to apply to the right ventricle as well. Functional studies of the right ventricle have often been neglected. In addition, many principles have only been investigated in animals and not in humans. Anatomical and functional heterogeneity of the cANS in human tissue or subjects is highly valuable for understanding left- and right-sided cardiac pathology and for identifying novel treatment targets and modalities. Within this perspective, we aim to provide an overview and synthesis of anatomical and functional heterogeneity of the cANS in tissue or subjects, focusing on the human heart.

Exploring the Effect of Long Naps on Handball Performance and Heart Rate Variability

This study explored the effect of long naps on handball-related performance and assessed the role of the cardiac autonomic nervous system in this process. Eleven male collegiate handball players performed a repeated sequential trial consisting of a 20-m consecutive turnaround run, 10-m run with a load, and shooting the ball into a target. Participants were allocated randomly and sequentially to have a short (20 minutes) nap, long (60 minutes) nap, or no nap. The Pittsburgh Sleep Quality Index was used to assess regular sleep quality. Subjective sleepiness before and after napping was measured using the Karolinska Sleepiness Scale. Heart rate variability was recorded to assess cardiac autonomic nervous function during napping. The Pittsburgh Sleep Quality Index score was correlated with shot accuracy only after long naps (ρ=0.636, r=0.048). A negative correlation was observed between the root mean square of successive differences and average load run time (ρ=−0.929, p<0.001). Long napping was associated with a significant benefit on performance in athletes with poor sleep quality, implying a role of the autonomic nervous system in this regard. Our findings indicate the effect of sleep quality on the endurance and resistance of handball players.

Strong Early Phase Parasympathetic Inhibition Followed by Sympathetic Withdrawal During Propofol Induction: Temporal Response Assessed by Wavelet-Based Spectral Analysis and Photoplethysmography

Background: Induction of anesthesia with propofol is associated with a disturbance in hemodynamics, in part due to its effects on parasympathetic and sympathetic tone. The impact of propofol on autonomic function is unclear. In this study, we investigated in detail the changes in the cardiac autonomic nervous system (ANS) and peripheral sympathetic outflow that occur during the induction of anesthesia.Methods: Electrocardiography and pulse photoplethysmography (PPG) signals were recorded and analyzed from 30 s before to 120 s after propofol induction. The spectrogram was derived by continuous wavelet transform with the power of instantaneous high-frequency (HFi) and low-frequency (LFi) bands extracted at 1-s intervals. The wavelet-based parameters were then divided into the following segments: (1) baseline (30 s before administration of propofol), (2) early phase (first minute after administration of propofol), and (3) late phase (second minute after administration of propofol) and compared with the same time intervals of the Fourier-based spectrum [high-frequency (HF) and low-frequency (LF) bands]. Time-dependent effects were explored using fractional polynomials and repeated-measures analysis of variance.Results: Administration of propofol resulted in reductions in HFi and LFi and increases in the LFi/HFi ratio and PPG amplitude, which had a significant non-linear relationship. Significant between-group differences were found in the HFi, LFi, and LFi/HFi ratio and Fourier-based HF and LF after dividing the segments into baseline and early/late phases. On post hoc analysis, changes in HFi, LFi, and the LFi/HFi ratio were significant starting from the early phase. The corresponding effect size (partial eta squared) was &gt; 0.3, achieving power over 90%; however, significant decreases in HF and LF were observed only in the late phase. The PPG amplitude was increased significantly in both the early and late phases.Conclusion: Propofol induction results in significant immediate changes in ANS activity that include temporally relative elevation of cardiac sympathovagal balance and reduced sympathetic activity.Clinical Trial Registration: The study was approved by the Institutional Review Board of Taipei Veterans General Hospital (No. 2017-07-009CC) and is registered at ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03613961).

Neurohumoral Cardiac Regulation: Optogenetics Gets Into the Groove

The cardiac autonomic nervous system (ANS) is the main modulator of heart function, adapting contraction force, and rate to the continuous variations of intrinsic and extrinsic environmental conditions. While the parasympathetic branch dominates during rest-and-digest sympathetic neuron (SN) activation ensures the rapid, efficient, and repeatable increase of heart performance, e.g., during the “fight-or-flight response.” Although the key role of the nervous system in cardiac homeostasis was evident to the eyes of physiologists and cardiologists, the degree of cardiac innervation, and the complexity of its circuits has remained underestimated for too long. In addition, the mechanisms allowing elevated efficiency and precision of neurogenic control of heart function have somehow lingered in the dark. This can be ascribed to the absence of methods adequate to study complex cardiac electric circuits in the unceasingly moving heart. An increasing number of studies adds to the scenario the evidence of an intracardiac neuron system, which, together with the autonomic components, define a little brain inside the heart, in fervent dialogue with the central nervous system (CNS). The advent of optogenetics, allowing control the activity of excitable cells with cell specificity, spatial selectivity, and temporal resolution, has allowed to shed light on basic neuro-cardiology. This review describes how optogenetics, which has extensively been used to interrogate the circuits of the CNS, has been applied to untangle the knots of heart innervation, unveiling the cellular mechanisms of neurogenic control of heart function, in physiology and pathology, as well as those participating to brain–heart communication, back and forth. We discuss existing literature, providing a comprehensive view of the advancement in the understanding of the mechanisms of neurogenic heart control. In addition, we weigh the limits and potential of optogenetics in basic and applied research in neuro-cardiology.