Cardiac Sympathetic Nerve Research Articles

NADPH oxidase 2 inhibitor GSK2795039 prevents doxorubicin-induced cardiac atrophy by attenuating cardiac sympathetic nerve terminal abnormalities and myocyte autophagy

Doxorubicin is widely used for the treatment of human cancer, but its clinical use is limited by a cumulative dose-dependent cardiotoxicity. However, the mechanism of doxorubicin-induced cardiac atrophy and failure remains to be fully understood. In this study, we tested whether the specific NADPH oxidase 2 (Nox2) inhibitor GSK2795039 attenuates cardiac sympathetic nerve terminal abnormalities and myocyte autophagy, leading to the amelioration of cardiac atrophy and dysfunction in chronic doxorubicin-induced cardiomyopathy. Mice were randomized to receive saline, doxorubicin (2.5 mg/kg, every other day, 6 times) or doxorubicin plus GSK2795039 (2.5 mg/kg, twice a day, 9 weeks). Left ventricular (LV) total wall thickness and LV ejection fraction were decreased in doxorubicin-treated mice compared with saline-treated mice and the decreases were prevented by the treatment of the specific Nox2 inhibitor GSK2795039. The ratio of total heart weight to tibia length and myocyte cross-sectional area were decreased in doxorubicin-treated mice, and the decreases were attenuated by the GSK2795039 treatment. In doxorubicin-treated mice, myocardial Nox2 and 4-hydroxynonenal levels were increased, myocardial expression of GAP43, tyrosine hydroxylase and norepinephrine transporter, markers of sympathetic nerve terminals, was decreased, and these changes were prevented by the GSK2795039 treatment. The ratio of LC3 II/I, a marker of autophagy, and Atg5, Atg12 and Atg12-Atg5 conjugate proteins were increased in doxorubicin-treated mice, and the increases were attenuated by the GSK2795039 treatment. These findings suggest that inhibition of Nox2 by GSK2795039 attenuates cardiac sympathetic nerve terminal abnormalities and myocyte autophagy, thereby ameliorating cardiac atrophy and dysfunction after chronic doxorubicin treatment.

The New Trends in Physiological and Pathological Actions of Ghrelin (Brain-Heart Axis) on the Heart and Cardiovascular System

Background: Ghrelin increased significantly the Left Ventriculus Eject Fraction and end-systolic volume after 30 minutes of intra-venous injection and without alterations heart rate and blood pressure. Ghrelin was discovered in 1999 as an only one 28 amino acid peptides (with octanoyl serine group) located on the short arm of chromosome 3 (position 3p25-26) having six exons, two are noncoding and four introns and encodes a 511 bp mRNA. Ghrelin is synthesized by the endocrine X/A-like cells located from the gastric fundus mucosa through the whole mucosa of the medium right vertical side of the stomach until to the 1 inch before anatomical pylorus. These cells are responsible to produced 80% of the whole ghrelin produced in the human body. Furthermore, other place of this production occurs at the hypothalamus, the pituitary, second portion of duodenum, pancreas, heart and other tissues. Bibliographic references also demonstrate the importance of ghrelin’s action in the main cardiovascular activities. Related to cardiovascular activities, ghrelin plays multitudinous beneficial and thereby help during cardiovascular diseases. Several studies demonstrated that ghrelin cause an anti-inflammatory activity by the inhibition of proinflammatory cytokines which can diminish inflammatory diseases in the heart, pericardium and specific innervations, for instance, vagus nerve and inhibited sympathetic nerves. Outcomes of this review emphasize these important actions of ghrelin. Methods: A systematic review of ghrelin activities over the heart and cardiovascular system with the inclusion of papers in review involved the physiological and physio pathological activities of ghrelin in vivo and in vitro studies. Results: Ghrelin is a natural tide with the growth hormone secretagogue (GHS) receptor (GHS-R) which cloned in 1996. The processes which generate this peptide and ghrelin-related peptides are transcriptional, translational and posttranslational. Homo and heterodimers of GHS-R and other yet unidentified receptors mediate the biological actions of acyl ghrelin and desacyl ghrelin. However, the main biological functions of ghrelin involve the secretion of growth hormone, stimulation of appetite and food intake at the hypothalamus, modulate acid secretion and motility, endocrine and exocrine pancreas secretion, blockaded insulin activity, heart functions and cardiovascular responses and other. Conclusion: One of the main occurrences in acute heart infarction is an increase activation of cardiac sympathetic nerve activity (CSNA) which is one of the causes of chronic cardiac dysfunction (CCD). Ghrelin is an effective for obtain a better cardiac function and by the suppression of renal sympathetic nerve activity which also have an important benefit to the acute myocardial infarction. Therefore, the physiological effects of ghrelin are very important to the body homeostasis even in the grave heart and cardiovascular diseases and in the immunological system.

Cardiac Sympathetic Nerve Function in Patients with Severe Aortic Stenosis Prior and After Transcatheter Aortic Valve Implantation

Cardiac Sympathetic Nerve Function in Patients with Severe Aortic Stenosis Prior and After Transcatheter Aortic Valve Implantation

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.

AIEgen-Based Covalent Organic Frameworks for Preventing Malignant Ventricular Arrhythmias Via Local Hyperthermia Therapy.

The engineering of aggregation-induced emission luminogens (AIEgen) based covalent organic frameworks (COFs), TDTA-COF, BTDTA-COF, and BTDBETA-COF are reported, as hyperthermia agents for inhibiting the occurrence of malignant ventricular arrhythmias (VAs). These AIE COFs exhibit dual functionality, as they not only directly modulate the function and neural activity of stellate ganglion (SG) through local hyperthermia therapy (LHT) but also induce the browning of white fat and improve the neuroinflammation peri-SG microenvironment, which is favorable for inhibiting ischemia-induced VAs. In vivo studies have confirmed that BTDBETA-COF-mediated LHT enhances thermogenesis and browning-related gene expression, thereby serving a synergistic role in combating VAs. Transcriptome analysis of peri-SG adipose tissue reveals a substantial downregulation of inflammatory cytokines, highlighting the potency of BTDBETA-COF-mediated LHT in ameliorating the neuroinflammation peri-SG microenvironment and offering myocardial and arrhythmia protection. The work on AIE COF-based hyperthermia agent for VAs inhibition provides a new avenue for mitigating cardiac sympathetic nerve hyperactivity.

Exercise capacity of the patients after cardiac surgery with special reference to left atrium incision

Abstract Background Chronotropic incompetence (CI) is sometimes observed during exercise in patients who underwent cardiac surgery, however, little is known which factors affect to the incidence of CI and exercise capacity of those patients. Purpose We hypothesized that the incidence of CI is higher in patients with left atrium incision (LAI) as compared with those without LAI, which is caused by impairment of cardiac sympathetic nerves by LAI. The purpose of this study is to elucidate whether LAI causes CI, and if so, to analyze which factor determine the exercise capacity of the patients with LAI. Methods We performed cardiopulmonary exercise testing in total 157 patients who had undergone elective cardiac operation (46 patients with LAI, 111 patients without LAI). We analyzed chronotropic response index (CRI), parameters of exercise capacity, echocardiography, and blood hemoglobin concentration (Hb). Results The value of CRI was significantly reduced in the patients with LAI as compared with those without LAI (0.24±0.22 vs. 0.45±0.17, respectively, p<0.001). Exercise capacity such as peak oxygen uptake (peak VO2), anaerobic threshold showed no significant difference between two groups. In patients with LAI, peak VO2 showed significant correlations between peak oxygen pulse (peak VO2/HR; r=0.34, p<0.05), Hb (r=0.43, p<0.005) and left atrium dimension (LAD) measured by echocardiography (r=-0.56, p<0.001). Conclusions The present study demonstrated that higher incidence of CI was observed in patients with LAI as compared with those without LAI. Moreover, peak VO2 of patients with LAI showed significant correlations with peak VO2/HR, Hb and LAD. These results suggest that 1) LAI may impairs cardiac sympathetic nerves and causes CI, 2) peak VO2/HR and its component Hb are important factors which determine exercise capacity of patients with CI, 3) LAD which indicates left atrial function may also affect exercise capacity of patients with CI.

Abstract 17680: MIBG Myocardial Scintigraphy is Useful for Predicting CTRCD Caused by Trastuzumab

Introduction: Trastuzumab is known to reduce the mortality rate, recurrence rate, and metastasis rate in Human epidermal growth factor receptor type 2 (HER2)-positive breast cancer patients, and it is recommended to administer it for 12 months to all early-stage HER2-positive breast cancer patients. However, trastuzumab administration can lead to Cancer Therapeutics-Related Cardiac Dysfunction (CTRCD). The guidelines suggest that regular echocardiography every 3 months is useful for early detection of CTRCD, but there are no tests available to predict it before its onset.The purpose of this study is to determine whether cardiac sympathetic nerve evaluation using MIBG myocardial scintigraphy before trastuzumab administration can predict the development of CTRCD three months after administration. Methods: MIBG myocardial scintigraphy was performed before trastuzumab administration in 35 HER2-positive breast cancer patients, and cardiac function assessment was conducted using echocardiography before administration, at 1 month, and at 3 months. Simultaneously, NT-proBNP and troponin levels were measured. CTRCD was defined as a decrease in global longitudinal strain (GLS) of 10% or more from before administration at the 3-month follow-up. Results: Anthracycline and trastuzumab regimens were used in 21 patients (60%). CTRCD occurred in 17 patients at the 3-month follow-up. There were no significant differences in age or previous medication between the CTRCD group and the non-CTRCD group, but the early H/M ratio in MIBG myocardial scintigraphy was significantly lower in the CTRCD group (2.77±0.36) compared to the non-CTRCD group (3.10±0.36) (p<0.01). There were no significant differences in the delay H/M ratio or washout rate. None of the echocardiographic parameters, NT-proBNP levels, or troponin levels showed significant differences and did not become predictive factors. Conclusions: MIBG myocardial scintigraphy is useful for predicting CTRCD caused by trastuzumab. Preclinical studies have suggested that HER2 transactivation from β-adrenergic receptors in the myocardium confers cardioprotection. Suppression of HER2 signaling during cardiac sympathetic nerve dysfunction potentially contributes to the development of CTRCD.

Unlocking the Potential of Left Cardiac Sympathetic Denervation: A Scoping Review of a Promising Approach for Long QT Syndrome.

Left cardiac sympathetic denervation (LCSD) has emerged as an alternative therapy for individuals diagnosed with long QT syndrome (LQTS), a genetic disorder characterized by abnormal electrical activity in the heart and sudden cardiac death (SCD). This review examines the history and rationale behind LCSD in LQTS treatment, as well as the procedure, its efficacy, and indications along with the adverse effects that may be associated with it. LQTS presents with prolonged QT intervals on an electrocardiogram and can manifest asseizures, fainting, and SCD. Beta-blockers are the primary treatment for LQTS but some patients do not respond well to these medications or experience side effects. Additionally, implantable cardioverter-defibrillators (ICDs) are not always effective in preventing arrhythmias and can lead to complications. LCSD might offer an alternative approach by disrupting sympathetic activity in the heart. In humans, LCSD reduces the release of norepinephrine, normalizes the QT interval, and decreases the likelihood of life-threatening heart rhythms. The procedure does not impair heart rate or cardiac function due to the compensatory effects of the right cardiac sympathetic nerves. The surgical procedure for LCSD involves the removal of the lower half of the stellate ganglion and thoracic ganglia. Complete denervation is essential for optimal outcomes, while incomplete procedures are considered unacceptable. Traditional and minimally invasive approaches, such as video-assisted thoracic surgery (VATS), are available, with VATS offering shorter hospital stays and fewer complications. In conclusion, LCSD provides a viable treatment option for individuals with LQTS who do not respond well to beta-blockers or require additional protection beyond medication or ICDs. Further research and clinical experience are needed to enhance its acceptance and implementation in routine practice.

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.

Chronotropic incompetence and exercise capacity after cardiac surgery with left atrium incision

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Chronotropic incompetence (CI) is sometimes observed during exercise training of cardiac rehabilitation in patients who underwent cardiac surgery, however, little is known which factors affect to the incidence of CI and exercise capacity of those patients. Purpose Because the possibility exists that cardiac sympathetic nerves might be impaired by surgical procedure, moreover CI is sometimes observed in patients after mitral valve surgery, we hypothesized that the incidence of CI was higher in patients with left atrium incision (LAI) during surgical operation as compared with those without LAI. And if so, which factor determines the exercise capacity of patients after cardiac surgery with LAI. We thus aimed this study to elucidate the hypothesis with cardiopulmonary exercise testing (CPX). Methods We performed CPX in total 153 patients who had undergone elective cardiac operation (45 patients with LAI, age 60.5±11.0; 108 patients without LAI, age 62.0±11.7). We analyzed chronotropic response index (CRI), peak oxygen uptake (peak VO2/W), anaerobic threshold (AT), and peak oxygen pulse (peak VO2/HR) with CPX, echocardiography, and blood hemoglobin concentration (Hb). Results The value of CRI was significantly reduced in the patients with LAI as compared with those without LAI (with LAI 0.24±0.22 vs. without LAI; 0.44±0.18, p&amp;lt;0.001). Exercise capacity such as peak oxygen uptake (peak VO2), anaerobic threshold showed no significant difference between two groups. In patients with LAI, peak VO2 showed significant correlations between peak oxygen pulse (peak VO2/HR; r=0.36, p&amp;lt;0.05), Hb (r=0.40, p&amp;lt;0.01) and left atrium dimension (LAD) measured by echocardiography (r=-0.54, p&amp;lt;0.001). Conclusions The present study demonstrated that higher incidence of CI was shown in patients with LAI as compared with those without LAI. Moreover peak VO2 of patients with LAI showed significant correlations with peak VO2/HR, Hb and LAD. These results suggest that 1) left atrium incision impairs cardiac sympathetic nerves and causes CI, 2) peak VO2/HR and Hb which is essential element of oxygen pulse are important factors for exercise capacity in patients after LAI with CI. Left atrium enlargement may indicates pre-operative damages of left atrium, 3) LAD which may indicate left atrium function, also is an important factor of exercise capacity in those patients.

Thoracic epidural analgesia prolongs postoperative QT interval on electrocardiogram in major non-cardiac surgery: a randomized comparison and a prospective cohort analysis.

Introduction: Prolongation of QT interval on electrocardiogram can be associated with perioperative lethal arrhythmia. Epidural analgesia is a commonly used modality to relieve surgical pain by blocking sensory nerves, which also blocks the autonomic nervous system and can affect QT interval. Since patient monitoring becomes much less frequent after surgery than intraoperative period, we investigated the effects of epidural analgesia on postoperative QT interval with a randomized clinical trial and a prospective cohort study. Methods: In a randomized study, we assigned 60 patients undergoing thoracic epidural analgesia to an epidural analgesia or no-epidural analgesia group, in which 3ml/h of 0.25% epidural levobupivacaine (7.5mg/h) was administered only in the epidural analgesia group during surgery. The primary outcome was the postoperative heart rate-corrected QT interval. In a prospective cohort study, patients were assigned to receive 5ml/h epidural levobupivacaine (12.5mg/h). The plasma concentration of levobupivacaine was measured using liquid chromatography-mass spectrometry. Results: The median postoperative corrected QT interval interval with 3ml/h epidural levobupivacaine was significantly longer than that without epidural analgesia. Using multiple regression analysis for the factors known to affect postoperative corrected QT interval interval, epidural analgesia was found to be an independent variable for prolongation, and the mean difference of the corrected QT interval interval with or without epidural analgesia was 23ms after adjustment. The median plasma concentration of levobupivacaine at the end of surgery was 164ng/ml with 3ml/h epidural levobupivacaine, and the correlation coefficient to the postoperative corrected QT interval interval was 0.14, showing a not significant correlation. A prospective cohort study showed that 5ml/h epidural levobupivacaine significantly prolonged postoperative corrected QT interval interval compared to preoperative baseline. The median plasma concentration of levobupivacaine was 166ng/ml with 5ml/h, the correlation coefficient of which showed no significant correlation. Conclusion: Thoracic epidural analgesia could enhance postoperative corrected QT interval prolongation after general anesthesia. The mechanism is possibly caused by blocking neighboring or part of the cardiac sympathetic nerves, rather than by systemic effects of epidurally administered levobupivacaine. Clinical trial number: UMIN000013347 for the randomized study and UMIN000041518 for the prospective cohort study, which were registered at University hospital Medical Information Network Center.

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.

Innervation of the heart: Anatomical study with application to better understanding pathologies of the cardiac autonomics.

Current advances in management of the cardiac neuroaxis in different cardiovascular diseases require a deeper knowledge of cardiac neuroanatomy. The aim of the study was to increase knowledge of the human fetal extrinsic cardiac nervous system. We achieved this by systematizing the origin and formation of the cardiac nerves, branches, and ganglia and their sympathetic/parasympathetic connections. Thirty human fetuses (60 sides) were subjected to detailed sub-macroscopic dissection of the cervical and thoracic regions. Cardiac accessory ganglia lying on a cardiac nerve or in conjunction with two or more (up to four) nerves before entering the mediastinal cardiac plexus were observed in 13 sides. Except for the superior cardiac nerve, the sympathetic cardiac nerves were individually variable and inconstant. In contrast, the cardiac branches of the vagus nerve appeared grossly more constant and invariable, although the individual cardiac branches varied in number and position of origin. Each cervical cardiac nerve or cardiac branch of the vagus nerve could be singular or multiple (up to six) and originated from the sympathetic trunk or the vagus nerve by one, two, or three roots. Sympathetic nerves arose from the cervical-thoracic ganglia or the interganglionic segment of the sympathetic trunk. Connections were found outside the cardiac plexus. Some cardiac nerves were connected to non-cardiac nerves, while others were connected to each other. Common sympathetic/parasympathetic cardiac nerve trunks were more frequent on right (70%) versus left sides (20%). The origin, frequency, and connections of the cardiac nerves and branches are highly variable in the fetus. Detailed knowledge of the normal neuroanatomy of the heart could be useful during cardiac neuromodulation procedures and in better understanding nervous pathologies of the heart.

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.

Imperatorin Improves Obesity-Induced Cardiac Sympathetic Nerve Injury Mediated by P2X4 Receptor in Stellate Sympathetic Ganglion

Obesity can activate the inflammatory signal pathway, induce in the body a state of chronic inflammation, and increase the excitability of the sympathetic nervous system, which may induce sympathetic neuropathic injury. The stellate sympathetic ganglia (SG) can express the P2X4 receptor, and the abnormal expression of the P2X4 receptor is related to inflammation. Imperatorin (IMP) is a kind of furan coumarin plant which has anti-inflammatory effects. This project aimed to investigate whether IMP can affect the expression of P2X4 receptors in the SG of obese rats to display a protective effect from high-fat-triggered cardiac sympathetic neuropathic injury. Molecular docking through homology modelling revealed that IMP had good affinity for the P2X4 receptor. Our results showed that compared with the normal group, the administration of IMP or P2X4 shRNA decreased sympathetic excitement; reduced the serum levels of triglyceride, total cholesterol, and lactate dehydrogenase; downregulated the expression of P2X4 receptors in SG; and inhibited the expression of inflammatory factors in the SG and serum of obese rats significantly. In addition, the expression of factors associated with the cell pyroptosis GSDMD, caspase-1, NLRP-3, and IL-18 in obese rats were significantly higher than those of the normal rats, and such effects were decreased after treatment with IMP or P2X4 shRNA. Furthermore, IMP significantly reduced the ATP-activated currents in HEK293 cells transfected with P2X4 receptor. Thus, the P2X4 receptor may be a key target for the treatment of obesity-induced cardiac sympathetic excitement. IMP can improve obesity-induced cardiac sympathetic excitement, and its mechanism of action may be related to the inhibition of P2X4 receptor expression and activity in the SG, suppression of cellular pyroptosis in the SG, and reduction of inflammatory factor levels.

Abstract 10134: Role of Cardiac Sympathetic Nerves in Mediating the Central Nervous System Cardioprotective Effects of Leptin After Ischemia/Reperfusion Injury

We previously demonstrated that central nervous system (CNS) administration of leptin improves left ventricular (LV) function after myocardial infarction through mechanisms that are poorly understood. Increased cardiac sympathetic activity is an important compensatory mechanism to maintain cardiac output after ischemic injury, and previous studies showed that centrally-administered leptin increases sympathetic outflow to various tissues. In the present study, we tested the hypothesis that leptin’s CNS-mediated cardioprotective effects are mediated via cardiac sympathetic nerves. Male and female Wistar rats (~8 weeks of age) were submitted to cervical ganglia denervation (CGx) and instrumented with an intracerebroventricular (ICV) cannula in the brain lateral ventricle. After recovery and baseline assessment of cardiac function by echocardiography (ECHO) and an exercise performance test (Vmax), myocardial ischemia/reperfusion (I/R) was induced by temporary (60 min) ligation of the left anterior descending coronary artery. Vehicle (saline, 0.5 μL/hr) or leptin (0.62 μg/hr) was infused chronically for 28 days starting 20 min after reperfusion using osmotic pumps implanted subcutaneously in the scapular region and connected to the ICV cannula. Cardiac function was assessed weekly by ECHO. At the end of week 4, a final Vmax was performed and +dP/dt max was accessed by LV catheterization using a Millar catheter. Despite ~70% reduction in cardiac tyrosine hydroxylase positive fibers compared to sham, CGx did not prevent leptin’s CNS-mediated cardioprotective effects as indicated by improved ejection fraction (55±1 vs. 29±3 %), global longitudinal strain (-19±2 vs. -3±2 %), +dP/dt max (10214±614 vs. 7174±716 mmHg/s) and exercise performance (1.3±14 vs. -46.3±14 Δ% compared to baseline before I/R) when compared with CGx vehicle-treated animals. CGx also did not prevent the effect of ICV leptin to reduce septal collagen deposition and heart weight/tibia length post-I/R. These results suggests that leptin, via its CNS actions, improves cardiac function and remodeling after I/R injury independent of cardiac sympathetic innervation.

Upregulation of neuropeptide Y in cardiac sympathetic nerves induces stress (Takotsubo) cardiomyopathy.

Substantial emotional or physical stress may lead to an imbalance in the brain, resulting in stress cardiomyopathy (SC) and transient left ventricular (LV) apical ballooning. Even though these conditions are severe, their precise underlying mechanisms remain unclear. Appropriate animal models are needed to elucidate the precise mechanisms. In this study, we established a new animal model of epilepsy-induced SC. The SC model showed an increased expression of the acute phase reaction protein, c-Fos, in the paraventricular hypothalamic nucleus (PVN), which is the sympathetic nerve center of the brain. Furthermore, we observed a significant upregulation of neuropeptide Y (NPY) expression in the left stellate ganglion (SG) and cardiac sympathetic nerves. NPY showed neither positive nor negative inotropic and chronotropic effects. On the contrary, NPY could interrupt β-adrenergic signaling in cardiomyocytes when exposure to NPY precedes exposure to noradrenaline. Moreover, its elimination in the left SG via siRNA treatment tended to reduce the incidence of SC. Thus, our results indicated that upstream sympathetic activation induced significant upregulation of NPY in the left SG and cardiac sympathetic nerves, resulting in cardiac dysfunctions like SC.

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.

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.