Cardiac Sympathetic Nerve Activity Research Articles

Sympathetic transduction of cardiac sympathetic nerve activity in healthy, conscious sheep.

Sympathetic transduction is the study of how impulses of sympathetic nerve activity (SNA) affect end-organ function. Recently, the transduction of resting bursts of muscle SNA (MSNA) has been investigated and shown to have a role in the maintenance of blood pressure through changes in vascular tone in humans. In the present study, we investigate whether directly recorded resting cardiac SNA (CSNA) regulates heart rate (HR), coronary blood flow (CoBF), coronary vascular conductance (CVC), cardiac output (CO) and mean arterial pressure. Instrumentation was undertaken to record CSNA and relevant vascular variables in conscious sheep. Recordings were performed at baseline, as well as after the infusion of a β-adrenoceptor blocker (propranolol) to determine the role of β-adrenergic signalling in sympathetic transduction in the heart. The results show that after every burst of CSNA, there was a significant effect of time on HR (n=10, ∆: +2.1±1.4 beatsmin-1 , P=0.002) and CO (n=8, ∆: +100±150mLmin-1 , P=0.002) was elevated, followed by an increase in CoBF (n=9, ∆: +0.76mLmin-1 , P=0.001) and CVC (n=8, ∆: +0.0038mLmin-1 mmHg-1 , P=0.0028). The changes in HR were graded depending on the size and pattern of CSNA bursts. The HR response was significantly attenuated after the infusion of propranolol. Our study is the first to explore resting sympathetic transduction in the heart, suggesting that CSNA can dynamically change HR mediated by an action on β-adrenoceptors. KEY POINTS: Sympathetic transduction is the study of how impulses of sympathetic nerve activity (SNA) affect end-organ function. Previous studies have examined sympathetic transduction primarily in the skeletal muscle and shown that bursts of muscle SNA alter blood flow to skeletal muscle and mean arterial pressure, although this has not been examined in the heart. We investigated sympathetic transduction in the heart and show that, in the conscious condition, the size of bursts of SNA to the heart can result in incremental increases in heart rate and coronary blood flow mediated by β-adrenoceptors. The pattern of bursts of SNA to the heart also resulted in incremental increases in heart rate mediated by β-adrenoceptors. This is the first study to explore the transduction of bursts of SNA to the heart.

Chronic Expression of Interleukin-10 Transgene Modulates Cardiac Sympathetic Ganglion Resulting in Reduced Ventricular Arrhythmia.

The cardiac autonomic nervous system (CANS) is intimately connected to the regulation of electrophysiology and arrhythmogenesis in cardiac systems. This work aimed at investigating whether interleukin-10 (IL-10) could effectively modulate CANS and suppress ischemia-induced ventricular arrhythmia (VA) through chronically acting on the cardiac sympathetic ganglion (CSG). Using an adeno-associated virus (AAV), we achieved local chronic overproduction of IL-10 in the CSG, left stellate ganglion (LSG). As a result, in the IL-10 group, we observed a decreased number of tyrosine hydroxylase-positive (TH+) cells in the LSG. IL-10 markedly downregulated the nerve growth factor, synaptophysin, as well as growth-associated protein 43 expression. In vivo, results from ambulatory electrocardiography showed that IL-10 overexpression significantly inhibited the cardiac sympathetic nervous system activity and improved heart rate variability. Meanwhile, we observed decreased LSG function as well as prolonged ventricular effective refractory period and suppressed VA after myocardial infarction (MI) in the IL-10 group. In addition, IL-10 overexpression attenuated inflammation and decreased norepinephrine levels in the myocardium after acute MI. In conclusion, our data suggest that chronic IL-10 overexpression modulates cardiac sympathetic nerve remodeling and suppresses VA induced by MI. Neuromodulation through AAV-mediated IL-10 overexpression may have the characteristics of and advantages as a potential neuroimmunotherapy for preventing MI-induced VAs.

Neuroimmune modulation mediated by IL-6: A potential target for the treatment of ischemia-induced ventricular arrhythmias

BackgroundNeural remodeling in the left stellate ganglion (LSG), as mediated by neuroimmune reactions, promotes cardiac sympathetic nerve activity (SNA) and thus increases the incidence of ventricular arrhythmias (VAs). Interleukin-6 (IL-6) is an important factor of the neuroimmune interaction. ObjectiveThe present study explored the effects of IL-6 on LSG hyperactivity and the incidence of VAs. MethodsEighteen beagles were randomly allocated to a control group (saline with myocardial infarction [MI], n = 6), adeno-associated virus (AAV) group (AAV with MI, n = 6), and IL-6 group (overexpression of IL-6 via AAV vector with MI, n = 6). Ambulatory electrocardiography was performed before and 30 days after AAV microinjection into the LSG. LSG function and ventricular electrophysiology were assessed at 31 days after surgery, and a canine MI model was established. Samples of the LSG were collected for immunofluorescence staining and molecular biological evaluation. Blood samples and 24-hour Holter data were obtained from 24 patients with acute MI on the day after they underwent percutaneous coronary intervention to assess the correlation between IL-6 levels and SNA. ResultsIL-6 overexpression increased cardiac SNA and worsened postinfarction VAs. Furthermore, sustained IL-6 overexpression enhanced LSG function, promoted expression of nerve growth factor, c-fos, and fos B in the LSG, and activated the signal transducer and activator of transcription 3/regulator of G protein signalling 4 signaling pathway. Clinical sample analysis revealed a correlation between serum IL-6 levels and heart rate variability frequency domain index as well as T-wave alternans. ConclusionIL-6 levels are correlated with cardiac SNA. Chronic overexpression of IL-6 mediates LSG neural remodeling through the signal transducer and activator of transcription 3/regulator of G protein signalling 4 signaling pathway, elevating the risk of VA after MI.

Machine learning based hybrid anomaly detection technique for automatic diagnosis of cardiovascular diseases using cardiac sympathetic nerve activity and electrocardiogram.

Coronary artery diseases (CADs) are the leading cause of death worldwide and early diagnosis is crucial for timely treatment. To address this, our study presents a novel automated Artificial Intelligence (AI)-based Hybrid Anomaly Detection (AIHAD) technique that combines various signal processing, feature extraction, supervised, and unsupervised machine learning methods. By jointly and simultaneously analyzing 12-lead cardiac sympathetic nerve activity (CSNA) and electrocardiogram (ECG) data, the automated AIHAD technique performs fast, early, and accurate diagnosis of CADs. In order to develop and evaluate the proposed automated AIHAD technique, we utilized the fully labeled STAFF III and PTBD databases, which contain the 12-lead wideband raw recordings non-invasively acquired from 260 subjects. Using these wideband raw recordings, we developed a signal processing technique that simultaneously detects the 12-lead CSNA and ECG signals of all subjects. Using the pre-processed 12-lead CSNA and ECG signals, we developed a time-domain feature extraction technique that extracts the statistical CSNA and ECG features critical for the reliable diagnosis of CADs. Using the extracted discriminative features, we developed a supervised classification technique based on Artificial Neural Networks (ANNs) that simultaneously detects anomalies in the 12-lead CSNA and ECG data. Furthermore, we developed an unsupervised clustering technique based on Gaussian mixture models (GMMs) and Neyman-Pearson criterion, which robustly detects outliers corresponding to CADs. Using the automated AIHAD technique, we have, for the first time, demonstrated a significant association between the increase in CSNA signals and anomalies in ECG signals during CADs. The AIHAD technique achieved highly reliable detection of CADs with a sensitivity of 98.48 %, specificity of 97.73 %, accuracy of 98.11 %, positive predictive value of 97.74 %, negative predictive value of 98.47 %, and F1-score of 98.11 %. Hence, the automated AIHAD technique demonstrates superior performance compared to the gold standard diagnostic test ECG in the diagnosis of CADs. Additionally, it outperforms other techniques developed in this study that separately utilize either only CSNA data or only ECG data. Therefore, it significantly increases the detection performance of CADs by taking advantage of the diversity in different data types and leveraging their strengths. Furthermore, its performance is comparatively better than that of most previously proposed machine and deep learning methods that exclusively used ECG data to diagnose or classify CADs. Additionally, it has a very low implementation time, which is highly desirable for real-time detection of CADs. The proposed automated AIHAD technique may serve as an efficient decision-support system to increase physicians' success in fast, early, and accurate diagnosis of CADs. It may be highly beneficial and valuable, particularly for asymptomatic patients, for whom the diagnostic information provided by ECG alone is not sufficient to reliably diagnose the disease. Hence, it may significantly improve patient outcomes by enabling timely treatments and considerably reducing the mortality of cardiovascular diseases (CVDs).

Autonomic Nerve Activity Features According to Dry Eye Type.

The purpose of this study was to investigate the association between autonomic nerve activity and symptom intensity according to the type of dry eye (DE). This prospective, cross-sectional, comparative study included 25 eyes of 25 patients with short tear break-up time DE (sBUTDE; mean age = 57.4 ± 11.4 years, range = 30-74 years) and 24 eyes of 24 patients with aqueous tear-deficient DE (ADDE; mean age = 62.3 ± 10.7 years, range = 29-76 years) were studied. Autonomic nerve activity was examined, and the Japanese version of the Ocular Surface Disease Index (J-OSDI) and a stress check questionnaire were administered. Autonomic nerve activity was continuously measured for 10 minutes. The parameters were low-frequency (LF) and high-frequency (HF) components of heart rate variability, reflecting cardiac sympathetic and parasympathetic nerve activity, and parasympathetic nerve activity alone, respectively; and the coefficient of variation of R wave-to-R wave (RR) interval (cvRR), component coefficient of variation of LF (ccvLF), and component coefficient of variation of HF (ccvHF), reflecting fluctuation of RR interval, LF, and HF, respectively. Higher J-OSDI scores were associated with higher HF, ccvHF, and subjective stress in sBUTDE, showing a significant correlation (r = 0.53, P < 0.01; r = 0.55, P = 0.01; and r = -0.66, P = 0.01); no correlations were observed between the J-OSDI score and autonomic parameters and stress in ADDE. DE symptoms were significantly associated with the magnitude and fluctuation of parasympathetic activity in sBUTDE. Thus, among the autonomic parameters, parasympathetic activity is involved in the development of symptoms in sBUTDE, whereas the involvement of the autonomic nervous system may be minimal in ADDE.

Pulmonary Artery Denervation Inhibits Left Stellate Ganglion Stimulation-Induced Ventricular Arrhythmias Originating From the RVOT

BackgroundElectrical stimulation of the left stellate ganglion (LSG) can evoke ventricular arrhythmias (VAs) that originate from the right ventricular outflow tract (RVOT). The involvement of pulmonary artery innervation is unclear. ObjectivesThis study investigated the effects of selective pulmonary artery denervation (PADN) on blood pressure (BP), sympathetic activity, ventricular effective refractory period (ERP), and the incidence of VAs induced by LSG stimulation in canines. MethodsRadiofrequency ablation with basic anesthetic monitoring was used to induce PADN in canines. In Protocol 1 (n = 11), heart rate variability, serum norepinephrine and angiotensin-II levels, BP changes and ventricular ERP in response to LSG stimulation were measured before and after PADN. In Protocol 2 (n = 8), the incidence of VAs induced by LSG stimulation was calculated before and after PADN in a canine model of complete atrioventricular block. In addition, sympathetic nerves in the excised pulmonary arteries were immunohistochemically stained with tyrosine hydroxylase. ResultsThe low-frequency components of heart rate variability, serum norepinephrine and angiotensin-II levels were remarkably decreased post-PADN. Systolic BP elevation and RVOT ERP shortening induced by LSG stimulation were mitigated by PADN. The number of RVOT-premature ventricular contractions as well as RVOT tachycardia episodes and duration induced by LSG stimulation were significantly reduced after PADN. In addition, a large number of tyrosine hydroxylase-immunoreactive nerve fibers were located in the anterior wall of the pulmonary artery. ConclusionsPADN ameliorated RVOT ERP shortening, and RVOT-VAs induced by LSG stimulation by inhibiting cardiac sympathetic nerve activity.

PC6 electroacupuncture reduces stress-induced autonomic and neuroendocrine responses in rats

Stress can trigger cardiovascular disease. Both imbalance of autonomic nervous activity and increase of neurohormonal output are core aspects of stress responses and can lead to cardiovascular disease. PC6 as a very important acupoint is used to prevent and treat cardiovascular disease and to improve stress-related activities. We examined the influence of electroacupuncture (EA) at PC6 on stress-induced imbalance of autonomic nervous activity and increase of neurohormonal output. EA at PC6 relieved increased cardiac sympathetic nervous activity and decreased cardiac vagal nervous activity induced by immobilization stress. Also, EA at PC6 reduced immobilization stress-induced increases of plasma norepinephrine (NE) and adrenaline (E) released from sympatho-adrenal-medullary axis. Finally, EA at PC6 reduced immobilization stress-induced increases of corticotropin-releasing hormone (CRH) in paraventricular hypothalamic nucleus and plasma cortisol (CORT) released from hypothalamic-pituitary-adrenal axis. However, EA at tail had no significant effect on the stress-induced autonomic and neuroendocrine responses. The results demonstrate the role of EA at PC6 regulating the autonomic and neuroendocrine responses induced by stress and provide insight into the prevention and treatment of EA at PC6 for stress-induced cardiovascular disease by targeting autonomic and neuroendocrine systems.

Early Effect of Transcatheter Mitral Valve Repair on Cardiac Sympathetic Nerve Activity

BackgroundCardiac sympathetic nerve activity (SNA) is overactivated in heart failure patients and associated with clinical outcomes. The aim of this study is to investigate the early effect of MitraClip repair on cardiac SNA. MethodsWe evaluated the change of cardiac SNA by 123I- meta-iodobenzylguanidine (MIBG) scintigraphy in patients who underwent MitraClip repair from March 2019 to June 2020 in our hospital. Patients without acute procedural success were excluded, including patients who died or underwent mitral valve surgery before discharge. MIBG scintigraphy was performed at baseline and 1 ​month after MitraClip repair. ResultsWe analyzed 48 patients (mean age 78.6 ± 10 years; 52.1% male; 37 secondary mitral regurgitation [SMR]/11 primary mitral regurgitation [PMR]). MR severity and New York Heart Association functional class significantly improved from baseline to 1 ​month after MitraClip repair (both p < 0.001). Overall, delay heart-mediastinum ratio (H/M) had no significant change, and washout rate (WR) showed a decreasing trend (delay H/M; pre 2.07 ± 0.46, post 2.05 ± 0.49, paired p = 0.348, WR; pre 36.1 ± 11.6%, post 33.6 ± 11.7%, paired p = 0.061). In PMR patients, WR was significantly decreased, however, delay H/M was not (delay H/M; pre 2.15 ± 0.50, post 2.10 ± 0.57, paired p = 0.019, WR; pre 34.6 ± 10.5%, post 26.7 ± 13.8%, paired p = 0.568). In contrast, in SMR patients, neither delay H/M nor WR were significantly changed (delay H/M; pre 2.05 ± 0.45, post 2.03 ± 0.47, paired p = 0.474, WR; pre 36.6 ± 11.9%, post 35.7 ± 10.4%, paired p = 0.523). ConclusionsOur study demonstrates that MitraClip repair could significantly decrease cardiac SNA of WR in PMR patients during 1-month follow-up, however, in SMR patients, the significant change of MIBG parameters was not observed.

LL-VNS attenuates SK2 expression and incidence of arrhythmias following acute myocardial infarction in rats.

Our previous study has demonstrated that low-level vagus nerve stimulation (LL-VNS) protects the heart against ventricular arrhythmias (VAs) induced by acute myocardial infarction (AMI). However, the potential mechanisms by which it influences ventricular electrophysiology remain unknown. Forty-five rats were divided into three groups: a Control group (sham AMI followed by sham LL-VNS, n = 15), an AMI group (AMI followed by sham LL-VSN for 60 mins, n = 15), and an AMI + LL-VNS group (AMI followed by LL-VSN for 60 mins, n = 15). Heart rate variability (HRV), ventricular effective refractory period (ERP), ventricular fibrillation threshold (VFT), and left stellate ganglion (LSG) activity were measured at baseline and during AMI. Finally, myocardial tissues were collected for tissue analysis. AMI directly induced hyperactivity in the LSG and reduced vagal tone as indexed by HRV. AMI also decreased VFT, and shortened ERP but increased ERP dispersion. AMI resulted in an increase in expression of ventricular small-conductance Ca2+-activated K+ (SK2). However, LL-VNS significantly mitigated or eliminated the effects of AMI. LL-VNS altered the electrophysiological properties of the ventricles through inhibition of cardiac sympathetic nervous activity and reduction in SK2 expression.

Assessment of the changes in cardiac sympathetic nervous activity using the pupil size changes measured in seated patients whose stellate ganglion is blocked by interscalene brachial plexus block.

As a side effect of interscalene brachial plexus block (ISBPB), stellate ganglion block (SGB) causes reductions in pupil size (Horner's syndrome) and cardiac sympathetic nervous activity (CSNA). Reduced CSNA is associated with hemodynamic instability when patients are seated. Therefore, instantaneous measurements of CSNA are important in seated patients presenting with Horner's syndrome. However, there are no effective tools to measure real-time CSNA intraoperatively. To evaluate the usefulness of pupillometry in measuring CSNA, we investigated the relationship between pupil size and CSNA. Forty-two patients undergoing right arthroscopic shoulder surgery under ISBPB were analyzed. Pupil diameters were measured at 30 Hz for 2 s using a portable pupillometer. Bilateral pupil diameters and CSNA (natural-log-transformed low-frequency power [0.04-0.15 Hz] of heart rate variability [lnLF]) were measured before ISBPB (pre-ISBPB) and 15 min after transition to the sitting position following ISBPB (post-sitting). Changes in the pupil diameter ([right pupil diameter for post-sitting - left pupil diameter for post-sitting] - [right pupil diameter for pre-ISBPB - left pupil diameter for pre-ISBPB]) and CSNA (lnLF for post-sitting - lnLF for pre-ISBPB) were calculated. Forty-one patients (97.6%) developed Horner's syndrome. Right pupil diameter and lnLF significantly decreased upon transition to sitting after ISBPB. In the linear regression model (R2 =0.242, P=0.001), a one-unit decrease (1 mm) in the extent of changes in the pupil diameter reduced the extent of changes in lnLF by 0.659 ln(ms2/Hz) (95% CI [0.090, 1.228]). Pupillometry is a useful tool to measure changes in CSNA after the transition to sitting following ISBPB.

Effects of mineralocorticoid receptor antagonist eplerenone on cardiac sympathetic nerve activity and left ventricular remodeling after reperfusion therapy in patients with first ST-segment elevation myocardial infarction

PurposeThe activation of the renin-angiotensin-aldosterone system prevents the uptake of norepinephrine and promotes structural remodeling of the heart. The mineralocorticoid receptor antagonist (MRA) eplerenone prevents left ventricular (LV) remodeling in patients with acute myocardial infarction, but its influence on cardiac sympathetic nerve activity (CSNA) has not been determined. MethodsWe retrospectively evaluated the first ST-segment elevation myocardial infarction (STEMI) patients in our database who underwent 123I-metaiodobenzylguanidine (MIBG) scintigraphy 3 weeks after admission. Eighty-four STEMI patients after primary coronary angioplasty were selected, and used propensity score matching to compare patients who treated with MRA (N = 42), and those who did not (N = 42). The LV end-diastolic volume, end-systolic volume, and ejection fraction were determined by echocardiography, and plasma procollagen type III amino terminal peptide (PIIINP) was measured before and 3 weeks after treatment. The delayed total defect score (TDS), delayed heart/mediastinum count (H/M) ratio, and washout rate (WR) were determined using 123I-MIBG scintigraphy after 3 weeks. ResultsFollowing primary angioplasty, age, gender, risk factors, culprit coronary artery, peak serum creatine phosphokinase concentration, and recanalization time were similar in the two groups. However, the MRA group showed significantly lower TDS and WR values (TDS: 22.8 ± 8.1 vs 32.2 ± 11.5, P < 0.005; WR: 31.1 ± 9.0% vs 42.7 ± 9.9%, P < 0.001) and a significantly higher H/M ratio (2.23 ± 0.41 vs 2.03 ± 0.36, P < 0.05) than the non-MRA group. The degree of change in LV parameters, and PIIINP were more favorable in the MRA group than in the non-MRA group. Moreover, multiple linear regression analyses revealed that both WR and not MRA treatment were significant predictor for LV remodeling, along with PIIINP concentrations. ConclusionAdministration of eplerenone improves CSNA and prevents LV remodeling in patients with a first STEMI.

Carotid Artery Revascularization Improves Cardiac Sympathetic Nerve Activity in Patients With Carotid Artery Stenosis.

The carotid sinus baroreceptor reflex controls the neural regulation of blood pressure. Baroreceptor disorders due to carotid sinus atherosclerosis have detrimental cardiovascular effects. This study investigated the medium-term effects of carotid artery revascularization (CAR) on sympathetic and cardiac function and systemic blood pressure variability in patients with carotid artery stenosis. This study included 21 consecutive patients (median age 70 years, 18 men) with carotid artery stenosis scheduled for CAR. 123I metaiodobenzylguanidine (MIBG) scintigraphy, echocardiography, brain natriuretic peptide levels, 24-h Holter electrocardiography (ECG), and ambulatory blood pressure monitoring assessed approximately 3 months postoperatively were compared to preoperative data. All 21 enrolled patients underwent CAR. Carotid artery stenting was done in three patients with cardiovascular risk or anatomical difficult for carotid endarterectomy. The mean common carotid artery end-diastolic velocity improved significantly (P < 0.01) by 1.6-fold, from 10.8 ± 3.2 to 16.1 ± 7.1 cm/s. In 123I-MIBG scintigraphy, the heart-to-mediastinum (H/M) count ratio was significantly higher than preoperatively (from 2.66 ± 0.48 to 2.86 ± 0.56, P = 0.03). Holter ECG analysis revealed a significant decrease in the low-frequency/high-frequency (LF/HF) ratio compared to preoperatively (from 2.17 ± 1.20 to 1.62 ± 0.68, P = 0.04). These findings suggest decreased myocardial sympathetic activation. In echocardiography, the tissue Doppler-derived e' increased, and E/e' decreased significantly (P < 0.05) from 11.7 ± 5.1 to 10.1 ± 4.0, suggesting an improved left ventricular diastolic capacity. The mean 24-h and nighttime blood pressures were unchanged. CAR in patients with carotid stenosis may provide medium-term improvement in cardiac sympathetic nerve activity and left ventricular diastolic dysfunction.

Abstract P1091: Granulocyte-Macrophage Colony-Stimulating Factor Signaling Pathway And Antiarrhythmic Effect Of Renal Denervation In Chronic Heart Failure

Renal denervation (RDN) is widely investigated in multiple studies of sympathetically driven cardiovascular diseases. While the therapeutic potential of RDN for ventricular arrhythmia has been reported, the mechanisms responsible for the antiarrhythmic effect of RDN are poorly understood. Our recent study showed that macrophage expansion-induced neuroinflammation in the stellate ganglion (SG) was a critical factor for cardiac sympathetic overactivation and ventricular arrhythmogenesis in chronic heart failure (CHF). This study aims to investigate if and how RDN decreases ventricular arrhythmias through attenuating neuroinflammation in cardiac sympathetic postganglionic (CSP) neurons in CHF. CHF was induced by acute surgical ligation of the left coronary artery in rats. Completed bilateral RDN was achieved by surgically cutting all the visible renal nerves around the renal artery and vein and followed by application of 70% ethanol around the vessels. Using immunofluorescence staining and Western blot analysis, we found that expression of granulocyte-macrophage colony-stimulating factor receptor-α subunit (GM-CSFRα), and Iba1 (an activated macrophage marker) in macrophages from the SG were increased in 16-week CHF rats, compared with age matched sham rats. In the ELISA experiment, we observed high levels of GM-CSF in kidney, serum, and SG in CHF rats, which were markedly reduced at 3 weeks after RDN. CHF-elevated macrophage activation and expression of GM-CSFRα in the SG were decreased by RDN. Flow cytometry data confirmed that CHF-increased percentage of macrophages in the SG was reduced at 3 weeks after RDN. Patch-clamp data found that RDN reduced the N-type Ca 2+ currents in CSP neurons from CHF rats (50.5+3.3 pA/pF in CHF rats vs. 28.6+2.2 pA/pF in CHF+RDN rats, P&lt;0.05). RDN attenuated CHF-enhanced cardiac sympathetic nerve activity. ECG data from 24-hour continuous telemetry recording in conscious rats revealed that RDN decreased the incidence and duration of spontaneous ventricular tachyarrhythmias in CHF rats. Based on these data, we confirm that RDN inhibits cardiac sympathetic overactivation and ventricular arrhythmogenesis through GM-CSF-macrophage activation-neuroinflammation-N-type Ca 2+ channel signaling axis in CHF.

The Mechanism of Cardiac Sympathetic Activity Assessment Methods: Current Knowledge.

This review has summarized the methods currently available for cardiac sympathetic assessment in clinical or under research, with emphasis on the principles behind these methodologies. Heart rate variability (HRV) and other methods based on heart rate pattern analysis can reflect the dominance of sympathetic nerve to sinoatrial node function and indirectly show the average activity level of cardiac sympathetic nerve in a period of time. Sympathetic neurotransmitters play a key role of signal transduction after sympathetic nerve discharges. Plasma or local sympathetic neurotransmitter detection can mediately display sympathetic nerve activity. Given cardiac sympathetic nerve innervation, i.e., the distribution of stellate ganglion and its nerve fibers, stellate ganglion activity can be recorded either directly or subcutaneously, or through the surface of the skin using a neurophysiological approach. Stellate ganglion nerve activity (SGNA), subcutaneous nerve activity (SCNA), and skin sympathetic nerve activity (SKNA) can reflect immediate stellate ganglion discharge activity, i.e., cardiac sympathetic nerve activity. These cardiac sympathetic activity assessment methods are all based on the anatomy and physiology of the heart, especially the sympathetic innervation and the sympathetic regulation of the heart. Technological advances, discipline overlapping, and more understanding of the sympathetic innervation and sympathetic regulation of the heart will promote the development of cardiac sympathetic activity assessment methods.

Sleep apnea and atrial fibrillation: the spell of Groundhog Day.

Sleep apnea and atrial fibrillation: the spell of Groundhog Day.

Optical Activation of the Dorsal Horn of the Thoracic Spinal Cord Prevents Ventricular Arrhythmias in Acute Myocardial Ischemia-Reperfusion Rats.

Background and ObjectivesSpinal cord stimulation can prevent myocardial ischemia and reperfusion arrhythmias, but the relevant neurons and mechanisms remain unknown. Thus, this study applied optogenetic techniques to selectively activate glutamatergic neurons at the thoracic spinal cord (T1 segment) for examining the anti-arrhythmia effects during acute myocardial ischemic-reperfusion.MethodsAdeno-associated viruses (AAVs) carrying channelrhodopsin-2 (ChR2, a blue-light sensitive ion channel) CaMKIIα-hChR2(H134R) or empty vector were injected into the dorsal horn of the T1 spinal cord. Four weeks later, optogenetic stimulation with a 473-nm blue laser was applied for 30 min. Then, the myocardial ischemia-reperfusion model was created by occlusion of the anterior descending coronary artery for ischemia (15 min) and reperfusion (30 min). Cardiac electrical activity and sympathetic nerve activity were assessed continuously.ResultsCaMKIIα-hChR2 viral transfection is primarily expressed in glutamatergic neurons in the spinal cord. Selective optical stimulation of the T1 dorsal horn in the ChR2 rat reduced the ventricular arrhythmia and arrhythmia score during myocardial ischemia-reperfusion, preventing the over-activation of cardiac sympathetic nerve activity. Additionally, optical stimulation also reduced the action potential duration at the 90% level (APD90) and APD dispersion.ConclusionSelective optical stimulation T1 glutamatergic neurons of dorsal horn prevent ischemia-reperfusion arrhythmias. The mechanism may be associated with inhibiting sympathetic nervous system overexcitation and increasing APD dispersion during myocardial ischemia-reperfusion.

Blood Pressure Regulation by the Carotid Sinus Nerve: Clinical Implications for Carotid Body Neuromodulation.

Chronic carotid sinus nerve (CSN) electrical modulation through kilohertz frequency alternating current improves metabolic control in rat models of type 2 diabetes, underpinning the potential of bioelectronic modulation of the CSN as a therapeutic modality for metabolic diseases in humans. The CSN carries sensory information from the carotid bodies, peripheral chemoreceptor organs that respond to changes in blood biochemical modifications such as hypoxia, hypercapnia, acidosis, and hyperinsulinemia. In addition, the CSN also delivers information from carotid sinus baroreceptors—mechanoreceptor sensory neurons directly involved in the control of blood pressure—to the central nervous system. The interaction between these powerful reflex systems—chemoreflex and baroreflex—whose sensory receptors are in anatomical proximity, may be regarded as a drawback to the development of selective bioelectronic tools to modulate the CSN. Herein we aimed to disclose CSN influence on cardiovascular regulation, particularly under hypoxic conditions, and we tested the hypothesis that neuromodulation of the CSN, either by electrical stimuli or surgical means, does not significantly impact blood pressure. Experiments were performed in Wistar rats aged 10–12 weeks. No significant effects of acute hypoxia were observed in systolic or diastolic blood pressure or heart rate although there was a significant activation of the cardiac sympathetic nervous system. We conclude that chemoreceptor activation by hypoxia leads to an expected increase in sympathetic activity accompanied by compensatory regional mechanisms that assure blood flow to regional beds and maintenance of hemodynamic homeostasis. Upon surgical denervation or electrical block of the CSN, the increase in cardiac sympathetic nervous system activity in response to hypoxia was lost, and there were no significant changes in blood pressure in comparison to control animals. We conclude that the responses to hypoxia and vasomotor control short-term regulation of blood pressure are dissociated in terms of hypoxic response but integrated to generate an effector response to a given change in arterial pressure.

Proteomic Sequencing of Stellate Ganglions in Rabbits With Myocardial Infarction.

The stellate ganglion (SG) of the autonomic nervous system plays important role in cardiovascular diseases (CDs). Myocardial infarction (MI) is associated with sustained increasing cardiac sympathetic nerve activity. Expressions and functions of proteins in SG tissue after MI are remaining unclear. This study is to explore the expression characteristics of proteins in SGs associated with MI. Japanese big-ear white rabbits (n = 22) were randomly assigned to the control group and MI group. The MI model was established by left anterior descending coronary artery ligation and confirmed by serum myocardial enzymes increasing 2,3,5-triphenyltetrazolium (TTC) staining and echocardiography. The expressions of proteins in rabbit SGs after MI were detected using tandem mass tags (TMT) quantitative proteomic sequencing. There were 3,043 credible proteins were predicted in rabbit SG tissues and 383 differentially expressed proteins (DEPs) including 143 upregulated and 240 downregulated proteins. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the DEPs involved in adrenergic signaling in cardiomyocytes, positive regulation of ERK1 and ERK2 cascade, and other biological processes. Three kinds of proteins directly correlated to CDs were selected to be validated by the subsequent western blot experiment. This study first identified the characterization of proteins in rabbit SG after MI, which laid a solid foundation for revealing the mechanism of roles of SG on the MI process.

Abstract 9177: Prognostic Value of Chronic Kidney Disease and Cardiac Sympathetic Dysfunction Assessed by 123 I-metaiodobenzylguanidine Scintigraphy for Lethal Arrhythmic Events in Chronic Heart Failure

Introduction: Clinical implication of chronic kidney disease (CKD) and cardiac sympathetic nerve activity (CSNA) for lethal arrhythmic events has not been fully elucidated in patients with chronic heart failure (CHF). Hypothesis: The combination of CKD and abnormal CSNA, assessed by 123 I-metaiodobenzylguanidine ( 123 I-MIBG) scintigraphy, may provide useful prognostic information for the incidence of lethal arrhythmic events. Methods: We studied 165 consecutive hospitalized CHF patients without dialysis. In a clinically stable condition, cardiac 123 I-MIBG scintigraphy was performed. CKD was defined as estimated glomerular filtration rate (eGFR) &lt;60 ml/min/1.73m 2 , and abnormal CSNA was defined as late heart to mediastinum ratio &lt;1.6. We then investigated the incidence of lethal arrhythmic events (sustained ventricular arrhythmia, appropriate implantable cardioverter-defibrillator therapy, or sudden cardiac death). Results: During a median follow-up of 5.3 years, lethal arrhythmic events were observed in 40 patients (24.2%). The patients were divided into 4 groups according to the presence of CKD and CSNA abnormality: non-CKD/ normal CSNA ( n = 52), CKD/ normal CSNA ( n = 39), non-CKD/ abnormal CSNA ( n = 33), and CKD/ abnormal CSNA ( n = 41).The Kaplan-Meier analysis showed that CKD/ abnormal CSNA had the highest event rate (log-rank p = 0.004). In addition, the multivariable Cox proportional hazard analysis after the adjustment of multiple confounders showed that CKD/ abnormal CSNA was an independent predictor for lethal arrhythmic events compared to non-CKD/ normal CSNA (HR, 4.667, p = 0.006). However, the other two groups did not show significant differences compared to non-CKD/ normal CSNA. Conclusions: The combination of CKD and abnormal CSNA, assessed by cardiac 123 I-MIBG scintigraphy, had a significant prognostic value for the incidence of lethal arrhythmic events in patients with CHF.

Factors Influencing Cardiac Sympathetic Nervous Function in Patients With Severe Aortic Stenosis: Assessment by 123I-Metaiodobenzylguanidine Myocardial Scintigraphy

Numerous studies have shown that 123I-metaiodobenzylguanidine (MIBG) scintigraphy, an index of cardiac sympathetic nervous (CSN) activity, is useful for predicting prognosis in patients with heart failure. However, the factors influencing the CSN activity of patients with severe aortic stenosis (AS) remain unclear. We enrolled 91 patients with severe AS who underwent 123I-MIBG scintigraphy, coronary computed tomography (CCT), and transthoracic echocardiography. When CCT angiography (CCTA) showed an obstructive epicardial artery, invasive coronary angiography was performed within 1 week of CCTA. There were 21 male and 70 female patients with a mean age of 84±5 years. Eighty-five (85) patients (93%) had hypertension and 13 patients (14%) had diabetes. Two (2) patients (2%) had previous myocardial infarction and eight (9%) had a previous coronary intervention. All patients had severe AS: aortic valve area was 0.63±0.18 cm2 and the mean pressure gradient was 56±19 mmHg. Regarding 123I-MIBG parameters, early heart-to-mediastinum (H/M) ratio was 3.1±0.5, delayed H/M ratio was 2.8±0.6, and the washout rate (WR) was 35%±13%. Multivariable linear regression analysis showed that coronary artery disease (β=-0.30, p=0.002) was an independent predictor of delayed H/M ratio, and that aortic valve area (β=-0.20, p=0.048) was an independent predictor of WR. Our findings suggest that coronary artery disease is an independent predictor of delayed H/M ratio, and aortic valve area is an independent predictor of WR in patients with severe AS.