Cardiac Nerve Research Articles

Blood norepinephrine/epinephrine/dopamine measurements in 108 patients with takotsubo syndrome from the world literature: pathophysiological implications

Objectives Release of norepinephrine (NE) from neuronal cardiac nerve endings and/or blood-borne catecholamines (CATs), mainly epinephrine (EPI), may mediate TTS. The aim of this study was to document the levels of NE, EPI, and dopamine (DA) in patients with TTS. Materials and methods A qualitative/quantitative meta-analysis of CATs and their relationship to age, gender, and triggers, was carried out, employing the world literature on TTS, published in PubMed. Results NE/EPI/DA in108 patients with TTS, 65.2 ± 16.4 years old, 89 (82.4%) women, revealed that: NE was measured more frequently than EPI, and EPI than DA; the timing of the measurements was variable; CATs were reported variably (qualitatively/quantitatively/with/without upper limits of normal); NE/EPI or NE/EPI/DA rose to the same degree; CATs were normal, or mildly/moderately elevated, with only 6 patients showing markedly elevated NE/EP/DA; NE, EPI, and DA were similar in patients with physical triggers and NE was similar in patients with physical, emotional, or no triggers (p = 0.47); EPI was higher than NE in patients with emotional triggers and EPI was higher in patients with emotional than physical triggers (p = 0.012); NE, EPI, and DA rose to the same proportion in men and women; types of TTS triggers were distributed proportionally in men and women. Conclusion NE, EPI, and DA rise proportionally in patients with TTS; CATs are mildly/moderately, and rarely markedly elevated; measurements of CATs should become more systematised; although CATs may not be essential for TTS diagnosis, they may contribute to prognosis and elucidation of the pathophysiology of TTS.

Multiple Primary Cardiac Malignant Peripheral Nerve Sheath Tumors in the Left Atrium

Malignant peripheral nerve sheath tumors are rare sarcomas of the heart. Herein, we report the case of a 24-year-old man who complained of dyspnea, cough, and upper left back pain. He was found to have multiple primary heart tumors obstructing the right superior pulmonary vein in the left atrium, which were diagnosed as malignant peripheral nerve sheath tumors. The patient underwent successful resection of the tumors and immunohistochemistry was utilized for diagnosis.

Abstract 16157: Catheter Ablation Induces an Increase in Heart Rate With Discordant With a Decrease in Sympathetic Nerve Activity in Patients With Paroxysmal Atrial Fibrillation

Background/Introduction: Paroxysmal atrial fibrillation (PAF) is the most common arrhythmia and catheter ablation (CA) is selected with the aim of rhythm control. CA was reported to increase heart rate (HR), which explains the modulation on the cardiac autonomic nervous system. However, little is known about the relationship between heart rate, sympathetic nerve activity and parasympathetic nerve activity in patient with PAF. Purpose: The purpose of this study was to evaluate the effect of CA on direct recording of muscle sympathetic nerve activity (MSNA) and heart rate variability (HRV), and these influences on HR. Methods: This study was conducted as a prospective, observational study. Patients with PAF who were scheduled for CA were enrolled. We measured blood pressure, HR, body weight, brain natriuretic peptide (BNP), echocardiogram parameters, high frequency component as cardiac parasympathetic nerve activity and low frequency component as cardiac sympathetic nerve activity in HRV, and MSNA before and 12 weeks after CA. Results: 21 PAF patients participated in this study. After CA, E/e’ and Ln BNP were significantly reduced(10.6±2.9 to 9.2±2.6, p<0.05. 3.8±1.3 to 3.3±1.6 log/pg/ml, p<0.05, respectively) while no significant changes were observed in EF, SV, left atrial diameter, left ventricular end diastolic and systolic diameters. HR was significantly increased (61.3±7.8 to 71.1±7.6 beats/min, p<0.05, respectively). However, the MSNA burst incidence and frequency were significantly decreased (65.4±12.6 to 41.3±13.4 bursts/100beats, p<0.01, n=21. 39.8±8.8 to 28.1±9.6 bursts/min, p<0.01, n=21. respectively). Also, the reduction in MSNA burst frequency was correlated with the increase in HR (r=0.57, 95%CI 0.183-0.804, p=0.00702). Ln Low frequency component in HRV was significantly decreased (5.72±1.75 to 3.85±2.13 log/ms 2 , p<0.05, n=12), but Ln high frequency (HF) component was not changed . No significant relationship observed between increased HR and HF component. Conclusion: CA induced paradoxical increasing heart rate with the reduction in sympathetic nerve activity in patient with PAF. These findings suggest that CA might modulate autonomic interaction between sinus nodes and in left atrium with denervated in ganglionated plexi.

Cholinergic nerve regulation of heart regeneration

Abstract Background Cardiac nerves regulate many important physiological functions of the heart such as heart rate and contractility. The emerging role of cardiac nerves during tissue homeostasis and regeneration is beginning to be appreciated. We discovered that neonatal mice are capable of regenerating their hearts following injury within a brief period after birth by proliferation of the pre-existing cardiomyocytes. Furthermore, we have demonstrated that cholinergic nerves play an important role in guiding the neonatal heart regenerative response. However, the adult mammalian heart, including the human heart, is incapable of regeneration following injury. Thus, there is great excitement about understanding the evolutionarily conserved mechanisms of endogenous cardiac regeneration, so that we can explore potential avenues to reawaken this process in adult humans. Purpose Our overarching goal is to define the mechanisms by which cholinergic nerves regulate heart regeneration following ischemic injury by using the neonatal mouse heart regeneration model. These studies will uncover novel pathways by which cholinergic signaling promotes cardiomyocyte proliferation and heart regeneration, which holds significant therapeutic potential for treatment of adult heart disease. Methods In this project, we employed genetically engineered mouse models of the critical receptors for cholinergic signaling in the heart to define the mechanisms of cholinergic nerve regulation of heart regeneration. First, we generated a cardiomyocyte-specific deletion of the muscarinic receptor (M2), the most predominant muscarinic receptor subtype present in the heart. In addition, we utilized the α7 nicotinic receptor (Chrna7) knockout mice to study the role of Chrna7 in endogenous immune cells, which is the main mediator of the cholinergic anti-inflammatory pathway. These mouse models will address how cholinergic nerves regulate heart regeneration via the M2 muscarinic receptor signaling and the inflammatory response following injury. Results Our results demonstrate that inhibition of two different cholinergic receptors (muscarinic and nicotinic) results in a reduction in cardiomyocyte proliferation and inhibition of the neonatal cardiac regenerative response following injury. More importantly, we demonstrate that cholinergic signaling mediates the cardiac regenerative response mainly through suppression of pro-inflammatory cytokines via the cholinergic anti-inflammatory pathway. Conclusions Cholinergic nerve signaling plays an important role in mounting a robust cardiac regenerative response following injury. These results have significant therapeutic potential, which will forge new paradigms with respect to the role of cardiac nerves during mammalian cardiac regeneration and reveal potential mechanisms regarding the benefits of nerve stimulation following cardiac injury in humans. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): American Heart Association, Wisconsin Partnership Program

Novel Neuromodulation Approach to Improve Left Ventricular Contractility in Heart Failure: A First-in-Human Proof-of-Concept Study.

Morbidity and mortality outcomes for patients admitted for acute decompensated heart failure are poor and have not significantly changed in decades. Current therapies are focused on symptom relief by addressing signs and symptoms of congestion. The objective of this study was to test a novel neuromodulation therapy of stimulation of epicardial cardiac nerves passing along the posterior surface of the right pulmonary artery. Fifteen subjects admitted for defibrillator implantation and ejection fraction ≤35% on standard heart failure medications were enrolled. Through femoral arterial access, high fidelity pressure catheters were placed in the left ventricle and aortic root. After electro anatomic rendering of the pulmonary artery and branches, either a circular or basket electrophysiology catheter was placed in the right pulmonary artery to allow electrical intravascular stimulation at 20 Hz, 4 ms pulse width, and ≤20 mA. Changes in maximum positive dP/dt (dP/dtMax) indicated changes in ventricular contractility. Of 15 enrolled subjects, 5 were not studied due to equipment failure or abnormal pulmonary arterial anatomy. In the remaining subjects, dP/dtMax increased significantly by 22.6%. There was also a significant increase in maximum negative dP/dt (dP/dtMin), mean arterial pressure, systolic pressure, diastolic pressure, and left ventricular systolic pressure. There was no significant change in heart rate or left ventricular diastolic pressure. In this first-in-human study, we demonstrated that in humans with stable heart failure, left ventricular contractility could be accentuated without an increase in heart rate or left ventricular filling pressures. This benign increase in contractility may benefit patients admitted for acute decompensated heart failure.

Cauterization as a Simple Method for Regeneration Studies in the Zebrafish Heart.

In the last two decades, the zebrafish has emerged as an important model species for heart regeneration studies. Various approaches to model loss of cardiac myocytes and myocardial infarction in the zebrafish have been devised, and have included resection, genetic ablation, and cryoinjury. However, to date, the response of the zebrafish ventricle to cautery injury has not been reported. Here, we describe a simple and reproducible method using cautery injury via a modified nichrome inoculating needle as a probe to model myocardial infarction in the zebrafish ventricle. Using light and electron microscopy, we show that cardiac cautery injury is attended by significant inflammatory cell infiltration, accumulation of collagen in the injured area, and the reconstitution of the ventricular myocardium. Additionally, we document the ablation of cardiac nerve fibers, and report that the re-innervation of the injured zebrafish ventricle is protracted, compared to other repair processes that accompany the regeneration of the cauterized ventricle. Taken together, our study demonstrates that cautery injury is a simple and effective means for generating necrotic tissue and eliciting a remodeling and regenerative response in the zebrafish heart. This approach may serve as an important tool in the methods toolbox for regeneration studies in the zebrafish.

MALIGNANT PERIPHERAL NERVE SHEATH TUMOR SPREAD TO THE THORACIC CAVITY CAUSING OBSTRUCTIVE SHOCK

SESSION TITLE: Medical Student/Resident Lung Pathology SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Malignant peripheral nerve sheath tumor (MPNST) is a rare and aggressive subtype of sarcoma, which originates from peripheral nerves. MPNST can present sporadically or in association with neurofibromatosis type 1 (NF1). In this case we describe a patient with a rare spread of MPNST to her thoracic cavity resulting in a combination of obstructive and septic shock leading to death. CASE PRESENTATION: A 30 year old female with NF1 and MPNST presented with right flank pain of 5 days duration. The patient was found to have leukocytosis in the setting of hydronephrosis and was subsequently admitted. She quickly decompensated, becoming tachycardic and hypotensive. Computed tomography angiography of the abdomen and pelvis revealed severe hydronephrosis secondary to large abdominal mass effect and intrathoracic mass extending into the right middle lobe of the lung with invasion of the right and left atrium. Subsequently, she was transferred to the medical intensive care unit for mixed obstructive and septic shock requiring intubation and vasopressor support. Transthoracic echocardiogram revealed a small left ventricle cavity and an echogenic density 1.96 x 2.75 cm compressing the left atrium which appeared to be mass effect from the intrathoracic sarcoma. While awaiting hospice placement, she became bradycardic and was unable to be resuscitated, and ultimately succumbed to her condition. DISCUSSION: MPNST is defined as malignant tumors arising from peripheral nerves or as benign neurogenic tumors converted into malignant tumors. Although MPNST primarily affects extremities, it can rarely also occur in the thoracic cavity. The majority of MPNST occur on the right side of the heart, in close proximity to the interatrial septum, likely because of the origin of MPNST from cardiac branches of the vagus nerve and cardiac plexus. However, the presence of MPNST on the left side has also been reported. As with this patient, patients with Neurofibromatosis type I carry an increased risk for MPNST between 8-13%. In this case, the significant and severe spread of this patient’s MPNST caused multiple obstructions in the urinary system as well as within the heart, ultimately leading to the mixed shock. The most effective treatment for MPNST is complete excision, which unfortunately is not always possible in advanced stages. CONCLUSIONS: MPNST can be very difficult to treat due to its aggressive nature leading to terrible complications including obstruction and early death. In this case, the patient not only had MPNST, but also an even rarer spread to the thoracic cavity ultimately leading to her death. It is important to recognize that this disease process can escalate to a shock state and must be treated accordingly. Whenever possible, palliative care should be involved in patient care early to establish goals of care. Reference #1: Evans DG, Baser ME, McGaughran J, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet 2002; 39:311. Reference #2: Li S, Qiu Y, Yu J, Liang C, Peng L. Cardiac malignant peripheral nerve sheath tumor on computed tomography and magnetic resonance imaging: A case report. Medicine (Baltimore). 2019;98(44):e17463. doi:10.1097/MD.0000000000017463 Reference #3: Prifti E, Baboci A, Ikonomi M. A giant cardiac malignant peripheral nerve sheath tumor presenting with total obstruction of the superior vena cava. Ann Thorac Surg. 2014;97(1):e7-e9. doi:10.1016/j.athoracsur.2013.08.044 DISCLOSURES: No relevant relationships by Christopher Izzo, source=Web Response No relevant relationships by Nimeh Najjar, source=Web Response No relevant relationships by Spencer Streit, source=Web Response

Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial

BackgroundProtection from lethal ventricular arrhythmias leading to sudden cardiac death (SCD) is a crucial challenge after acute myocardial infarction (AMI). Cardiac sympathetic and parasympathetic activity can be noninvasively assessed using heart rate variability (HRV) and heart rate turbulence (HRT). The EMBODY trial was designed to determine whether the Sodium–glucose cotransporter 2 (SGLT2) inhibitor improves cardiac nerve activity.MethodsThis prospective, multicenter, randomized, double-blind, placebo-controlled trial included patients with AMI and type 2 diabetes mellitus (T2DM) in Japan; 105 patients were randomized (1:1) to receive once-daily 10-mg empagliflozin or placebo. The primary endpoints were changes in HRV, e.g., the standard deviation of all 5-min mean normal RR intervals (SDANN) and the low-frequency–to–high-frequency (LF/HF) ratio from baseline to 24 weeks. Secondary endpoints were changes in other sudden cardiac death (SCD) surrogate markers such as HRT.ResultsOverall, 96 patients were included (46, empagliflozin group; 50, placebo group). The changes in SDANN were + 11.6 and + 9.1 ms in the empagliflozin (P = 0.02) and placebo groups (P = 0.06), respectively. Change in LF/HF ratio was – 0.57 and – 0.17 in the empagliflozin (P = 0.01) and placebo groups (P = 0.43), respectively. Significant improvement was noted in HRT only in the empagliflozin group (P = 0.01). Whereas intergroup comparison on HRV and HRT showed no significant difference between the empagliflozin and placebo groups. Compared with the placebo group, the empagliflozin group showed significant decreases in body weight, systolic blood pressure, and uric acid. In the empagliflozin group, no adverse events were observed.ConclusionsThis is the first randomized clinical data to evaluate the effect of empagliflozin on cardiac sympathetic and parasympathetic activity in patients with T2DM and AMI. Early SGLT2 inhibitor administration in AMI patients with T2DM might be effective in improving cardiac nerve activity without any adverse events.Trial Registration: The EMBODY trial was registered by the UMIN in November 2017 (ID: 000030158). UMIN000030158; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034442.

Vascular supply of the anterior interventricular epicardial nerves and ventricular Purkinje fibers in the porcine hearts.

The aim of this study was to perform a pilot histological and quantitative analysis of the blood vessels accompanying the epicardial nerves (vasa nervorum) in the porcine hearts. Twenty healthy porcine hearts were used in this study. The blood vessels were analyzed by light microscopy using four different staining techniques in transverse sections taken from the upper, middle, and lower segments of the anterior part of the interventricular region and the adjacent parts of the right and left ventricles containing epicardial nerves and the endocardial peripheral parts of the Purkinje fibers. In total, 317 epicardial nerves were detected. The vasa nervorum were present in 75.7% of these nerves. The vasa nervorum resembled arterioles and postcapillary and collecting venules. One hundred and forty nine epicardial nerves were perivascular, located in the adventitia of the anterior interventricular artery and vein. The remaining 168 nerves ran freely through the epicardial interstitium. The presence of the vasa nervorum was not related to topographical location or nerve diameter. Additionally, from a total of 33 analyzed ventricular complexes of Purkinje fibers small blood vessels located in their proximity were identified in only two cases. It can be concluded that the majority of the anterior epicardial nerves of porcine heart possess well-developed vasa nervorum. In contrast, similar blood vessels are rarely present in the vicinity of the Purkinje fibers. The data obtained contribute to a better understanding of the nutrition of the cardiac nerves.

Identification of Cardiac Expression Pattern of Transient Receptor Potential Vanilloid Type 1 (TRPV1) Receptor using a Transgenic Reporter Mouse Model

Transient receptor potential vanilloid type 1 (TRPV1) channels are structurally related, non-selective cation channels that exhibit a high permeability to calcium. Sensory nerve endings expressing TRPV1 channels play a prominent role in regulating the cardiac sympathetic afferent reflex and contribute to cardiac remodeling and dysfunction in chronic heart failure. However, the precise expression of TRPV1 channels in cardiomyocytes vs. non-cardiomyocytes remains debated. Here we utilized a tdTomato-GFP reporter mouse crossed with a mouse line expressing Cre recombinase under the control of the TRPV1 promoter to map the TRPV1 expression pattern in heart. In this model, TRPV1-negative cells express tdTomato protein (red), whereas TRPV1-positive cells express GFP protein (green). As we expected, substantial GFP expression was found in many small and medium diameter dorsal root ganglia neurons in heterozygous TRPV1-Cre +/-, tdTomato flox/flox +/- male mice, suggesting that this heterozygous model is sufficient for labeling TRPV1-positive cells. Furthermore, these results showed that GFP green staining was not detectable in cardiomyocytes. Instead, we found strong GFP green staining in cardiac blood vessels—thought to be arterioles—in the heart. We also observed strong GFP signals on PGP9.5-positive cardiac nerve endings in the epicardium. In summary, this study does not support the concept that TRPV1 channels are strongly expressed in mouse cardiomyocytes. We conclude that TRPV1 channels in mouse heart are mostly expressed on non-cardiomyocyte cells including cardiac nerve endings and vessels. These data have important implications for the modulations of cardiogenic reflexes.

A specialized population of Periostin-expressing cardiac fibroblasts contributes to postnatal cardiomyocyte maturation and innervation

During the postnatal period in mammals, the cardiac muscle transitions from hyperplasic to hypertrophic growth, the extracellular matrix (ECM) undergoes remodeling, and the heart loses regenerative capacity. While ECM maturation and crosstalk between cardiac fibroblasts (CFs) and cardiomyocytes (CMs) have been implicated in neonatal heart development, not much is known about specialized fibroblast heterogeneity and function in the early postnatal period. In order to better understand CF functions in heart maturation and postnatal cardiomyocyte cell-cycle arrest, we have performed gene expression profiling and ablation of postnatal CF populations. Fibroblast lineages expressing Tcf21 or Periostin were traced in transgenic GFP reporter mice, and their biological functions and transitions during the postnatal period were examined in sorted cells using RNA sequencing. Highly proliferative Periostin (Postn)+ lineage CFs were found from postnatal day 1 (P1) to P11 but were not detected at P30, due to a repression of Postn gene expression. This population was less abundant and transcriptionally different from Tcf21+ resident CFs. The specialized Postn+ population preferentially expresses genes related to cell proliferation and neuronal development, while Tcf21+ CFs differentially express genes related to ECM maturation at P7 and immune crosstalk at P30. Ablation of the Postn+ CFs from P0 to P6 led to altered cardiac sympathetic nerve patterning and a reduction in binucleation and hypertrophic growth with increased fetal troponin (TroponinI1) expression in CM. Thus, postnatal CFs are heterogeneous and include a transient proliferative Postn+ population required for cardiac nerve development and cardiomyocyte maturation soon after birth.

Anatomical evidence of non-parasympathetic cardiac nitrergic nerve fibres in rat.

Neuronal nitric oxide synthase (nNOS)-derived nitric oxide (NO) plays a major role in the neural control of circulation and in many cardiovascular diseases. However, the exact mechanism of how NO regulates these processes is still not fully understood. This study was designed to determine the possible sources of nitrergic nerve fibres supplying the heart attempting to imply their role in the cardiac neural control. Sections of medulla oblongata, vagal nerve, its rootlets and nodose ganglia, vagal cardiac branches, Th1 -Th5 spinal cord segments, dorsal root ganglia of C8 -Th5 spinal nerves, and stellate ganglia from 28 Wistar rats were examined applying double immunohistochemical staining for nNOS combined with choline acetyltransferase (ChAT), peripherin, substance P, calcitonin gene-related peptide, tyrosine hydroxylase or myelin basic protein. Our findings show that the most abundant population of purely nNOS-immunoreactive (IR) neuronal somata (NS) was observed in the nodose ganglia (37.4±1.3%). A high number of nitrergic NFs spread along the vagal nerve and entered its cardiac branches. All nitrergic neuronal somata (NS) in the nucleus ambiguus were simultaneously immunoreactive (IR) to ChAT and composed only a small subset of neurons (6%). In the dorsal nucleus of vagal nerve, biphenotypic nNOS-IR/ChAT-IR neurons composed 7.0±1.0%, while small purely nNOS-IR neurons were scarce. Nitrergic NS were plentifully distributed within the nuclei of solitary tract. In the examined dorsal root and stellate ganglia, a few nitrergic NS were sporadically present. The majority of sympathetic NS in the intermediolateral nucleus were simultaneously immunoreactive for nNOS and ChAT. In conclusion, an abundant population of nitrergic NS in the nodose ganglion implies that neuronal NO is involved in afferent cardiac innervation. Nevertheless, nNOS-IR neurons identified within vagal nuclei may play a role in the transmission of preganglionic parasympathetic nerve impulses.

Fetal topography of branches of the cervical and thoracic divisions of the vagus nerves

The study of age and individual anatomical variability of vagus nerves and their branches in different age periods of human ontogenesis causes interest among both morphologists and doctors of different specialties.The aim of the study. To find out the topography of the cervical and thoracic divisions of the vagus nerves in human fetuses aged from 4th to 10th gestational months.Materials and methods. The research was conducted on 75 preparations of human fetuses ranging from 81.0 to375.0 mm in parietal-coccygeal length (PCL) using methods of macro-microscopic dissection and morphometry.Results. In human fetuses, the left vagus nerve is placed anteriorly to the left subclavian artery, then on the lateral surface of the Botallo’s arterial duct and the aortic arch. In the neck region, the superior cardiac branch departs from the left vagus nerve and goes to the anterior surface of the left common carotid artery.In the inferior part of the left common carotid artery, the superior cardiac branch gives off two branches: the middle one reaches the aortic arch wall, and the lateral one runs along the anterior surface of the left common carotid artery. The left recurrent laryngeal nerve departs from the left vagus nerve at the level of the inferior border of the aortic arch. The right vagus nerve passes from the right subclavian artery anteriorly and gives rise to the right recurrent laryngeal nerve, which continues inferiorly and posteriorly around the subclavian artery. The superior cardiac branch originates from the right vagus nerve at the level of the inferior border of the thyroid gland. The inferior cardiac branch departs inferiorly and medially from the right laryngeal nerve and is located on the right anterolateral surface of the trachea.Conclusions. During the fetal period of human ontogenesis, age and individual anatomical variations of the branches of the cervical and thoracic vagus nerves is observed, which is manifested by the variability of the structure, asymmetry of the topography of the recurrent laryngeal nerves, bronchial, esophageal and cardiac branches. The left recurrent laryngeal nerve departs from the left vagus nerve at the level of the inferior border of the aortic arch, the right recurrent laryngeal nerve departs from the right vagus nerve at the level of the right subclavian artery. The esophageal nervous plexus is formed by esophageal branches of the vagus nerves, which then forms mainly the posterior vagal trunk. The anterior vagal trunk is a direct continuation of the left vagus nerve branches. The innervation of the aortic arch involves the common cardiac trunk, which is formed by the superior cardiac branch and the superior cardiac nerve and also anastomoses both with vagus nerve and with recurrent laryngeal nerves.

Effect of music therapy on heart rate variability in generalized anxiety disorder: A poincaré analysis

Background: Poincare plot analysis of heart rate variability (HRV) is a complex nonlinear method for assessing cardiac autonomic nerve function (CANF) in generalized anxiety disorder (GAD).
 Objective: This study aimed to observe the effect of music therapy on HRV by poincaré plot analysis in GAD patients.
 Methods: This prospective Interventional study was done in 2019 on 60 newly diagnosed GAD patients aged 20- 40 years, both male and female. Among them, 30 patients were under music therapy with Raga Bhairabi based Rabindra Sangeet for 3 months and 30 patients were without music therapy and both patient groups were studied over three months. Healthy controls, who were enrolled in this study, were Age, sex and BMI matched. Poincaré plot (non linear measure) of HRV of all GAD patients and control were recorded at baseline and after three months of follow up. HRV were recorded by Power Lab 8/ 35. For statistical analysis Bonferroni’s Post Hoc test and paired sample ‘t’ test were done.
 Results:Standard deviation of the points perpendicular to the axis of line of identity(SD1), standard deviation of the points along the axis of line of identity (SD2) SD and SD1/SD2 were significantly lower in all GAD patients compared to healthy control at baseline. After 3 months of music therapy, significant increment of these parameters occurred in GAD patients, whereas no changes of these except SD1 were noted in patients without music therapy after 3 months. Moreover, these parameters were not significantly different in patients under music therapy compared to control at the end of three months.
 Conclusion: This study concluded that music therapy can improve cardiac autonomic dysfunction in GAD patients.
 J Bangladesh Soc Physiol. 2020, June; 15(1): 39-45

Human adult cardiac autonomic innervation: Controversies in anatomical knowledge and relevance for cardiac neuromodulation.

Cardiac sympathetic blockade is a therapeutic approach for arrhythmias and heart failure and may be a beneficial effect of high thoracic epidural anesthesia. These treatments require detailed knowledge of the spatial location and distribution of cardiac autonomic nerves, however, there are controversies on this subject in humans. To provide a systematic overview of current knowledge on human anatomy of the cardiac autonomic nervous system. In contrast to the often claimed assumption that human preganglionic sympathetic cardiac neurons originate mainly from thoracic spinal segments T1-T4 or T5, there is ample evidence indicating involvement of cervical spinal segment C8 and thoracic spinal segments below T5. Whether cervical ganglia besides the stellate ganglion play a role in transmission of cardiac sympathetic signals is unclear. Similarly, there is debate on the origin of cardiac nerves from different thoracic ganglia. Most human studies report thoracic cardiac nerves emerging from the first to fourth thoracic paravertebral ganglia; others report contributions from the fifth, sixth and even the seventh thoracic ganglia. There is no agreement on the precise composition of nerve plexuses at the cardiac level. After years of debate, it is generally accepted that the vagal nerve contributes to ventricular innervation. Vagal distribution appears higher in atria, whereas adrenergic fibers exceed the number of vagal fibers in the ventricles. Anatomy of the human cardiac autonomic nervous system is highly variable and likely extends beyond generally assumed boundaries. This information is relevant for thoracic epidural anesthesia and procedures targeting neuronal modulation of cardiac sympathetic innervation.

Impact of Heart Rate Fragmentation on the Assessment of Heart Rate Variability

Heart rate fragmentation (HRF) is a type of sinoatrial instability characterized by frequent (often every beat) appearance of inflection in the R-R interval time series, despite the electrocardiograms appearing to be sinus rhythm. Because the assessment of parasympathetic function by heart rate variability (HRV) analysis depends on the assumption that the high-frequency component (HF, 0.15–0.4 Hz) of HRV is mediated solely by the cardiac parasympathetic nerve, HRF that is measured as a part of HF power confounds the parasympathetic functional assessment by HRV. In this study, we analyzed HRF in a 24-h electrocardiogram big data and investigated the changes in HRF with age and sex and its influence on the assessment of HRV. We observed that HRF is often observed during childhoods (0–20 year) and increased after 75 year, but it has a large impact on individual differences in HF power at ages 60–90.

Electroacupuncture at "Neiguan"(PC6) decreased cardiac sympathetic hyperactivity and improved cardiac function in chronic myocardial ischemia model rats

To investigate the autonomic nervous mechanism of acupuncture therapy in the treatment of ischemic cardiomyopathy by observing the influence of electroacupuncture (EA) at "Neiguan"(PC6) on the superior cervical cardiac nerve activity and cardiac function in chronic myocardial ischemia (CMI) rats. Male SD rats were randomly divided into control, model and EA groups (n＝8 in each group). The CMI model was established by ligating the anterior descending branch of the left coronary artery. EA (15 Hz, 1.5 mA) was applied to bilateral PC6 for 20 min, once a day for 28 consecutive days. Cardiac sympathetic nerve electrical activities (CSNEA), electrocardiogram (ECG) of the standard limb lead Ⅱ and ultrasonic cardiogram (UCG) were recorded for observing changes of ST segment height, left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS)．. The CSNEA was significantly increased(P<0.001), and the hight of ECG-STⅡ， LVEF and LVFS were considerably decreased in the model group relevant to the control group (P<0.01, P<0.001), while after the intervention, modeling induced increase of CSNEA and decrease of ECG-STⅡ， LVEF and LVFS were obviously suppressed in the EA group in comparison with the model group (P<0.01, P<0.05, P<0.001). EA of PC6 can improve cardiac function and myocardial ischemia in CMI rats, which is possibly related to its effect in decreasing cardiac sympathetic hyperactivity.

Conceptual Considerations for Device-Based Therapy in Acute Decompensated Heart Failure: DRI2P2S.

Acute decompensated heart failure remains the most common cause of hospitalization in older adults, and studies of pharmacological therapies have yielded limited progress in improving outcomes for these patients. This has prompted the development of novel device-based interventions, classified mechanistically based on the way in which they intend to improve central hemodynamics, increase renal perfusion, remove salt and water from the body, and result in clinically meaningful degrees of decongestion. In this review, we provide an overview of the pathophysiology of acute decompensated heart failure, current management strategies, and failed pharmacological therapies. We provide an in depth description of seven investigational device classes designed to target one or more of the pathophysiologic derangements in acute decompensated heart failure, denoted by the acronym DRI2P2S. Dilators decrease central pressures by increasing venous capacitance through splanchnic nerve modulation. Removers remove excess fluid through peritoneal dialysis, aquaphoresis, or hemodialysis. Inotropes directly modulate the cardiac nerve plexus to enhance ventricular contractility. Interstitial devices enhance volume removal through lymphatic duct decompression. Pushers are novel descending aorta rotary pumps that directly increase renal artery pressure. Pullers reduce central venous pressures or renal venous pressures to increase renal perfusion. Selective intrarenal artery catheters facilitate direct delivery of short acting vasodilator therapy. We also discuss challenges posed in clinical trial design for these novel device-based strategies including optimal patient selection and appropriate end points to establish efficacy.

Cardiac Neuroanatomy and Chronotropic Modulation of the Adult Giant Danio Heart

Studies in non‐mammalian models species have contributed significantly to our understanding of the biology and the nature of innervation in the heart. The giant danio (D. malabaricus) is a teleost fish species closely related to zebrafish, that is also capable of heart regeneration. We previously described the development and maturation of the giant danio (GD) heart. However, little is known about its innervation. We hypothesized that the pattern of innervation in the GD heart is anatomically and physiologically complex, and that the heart is responsive to physiological modulation similar to that seen in cyprinid fish and mammals. Using various neuronal markers and electron microcopy, we described the presence, distribution, and nature of nerves in the GD heart. Our study shows first that fine intrinsic cardiac nerve fibers are present throughout the heart chambers. Second, nerve soma and ganglia are highly concentrated at nerve plexuses located near the sinoatrial (SA) and atrioventricular (AV) junctions. However, the volume density of axonal processes_ projecting from ganglia located over the ventral aorta_ is highest over the corpus of the bulbus arteriosus. Third, using an ex vivo GD heart preparation, we found that the GD heart responded to both adrenergic and cholinergic agonists, in a manner that mirrors mammalian and teleost hearts. Taken together, our studies show that the GD heart displays complex patterns of innervation, and conserved cardiac physiological responses, and strongly suggest that the GD could be used as a viable model for investigating cardiac biology.Support or Funding Information• NIH R15 HD084262‐01, Martha C. Rieth Faculty Fellowship, Buehler Family Foundation

Tragus Nerve Stimulation Suppresses Post-Infarction Ventricular Arrhythmia by Modulating Autonomic Activity and Heterogeneities of Cardiac Receptor Distribution.

BackgroundImbalanced cardiac autonomic control and cardiac receptors redistribution contribute to the arrhythmogenic substrate under the myocardial infarction (MI) condition. Stimulating the auricular branch of vagus nerve (AB-VNS) has been proven to reduce post-infarction ventricular arrhythmia (VAs), but its potential mechanisms were largely unknown.This study aimed to investigate whether long-term intermittent low-intensity AB-VNS could produce a protective effect on modulating autonomic activities and abnormal redistribution of autonomic nerve efferent receptors in a MI canine model.Material/MethodsTwelve healthy beagle dogs underwent ligation of the left anterior descending coronary artery to establish a MI model and were randomized into 2 groups: an AB-VNS group, (AB-VNS for 4 weeks) and a control group (sham stimulation for 4 weeks). Dynamic electrocardiogram recording, neural recording, catecholamine concentration, and histological studies were conducted subsequently.ResultsCompared to the control group, the AB-VNS group had significantly suppressed post-infarction VAs, reduced low frequency (LF) power and increased high frequency (HF) power. In the AB-VNS group, with the progression of reduced cardiac sympathetic activities and augmented cardiac parasympathetic activities, the catecholamine concentration in heart tissue declined in the peripheral infarction area and right ventricle (RV); tyrosine hydroxylase (TH)-positive neurons decreased in the inferior cardiac sympathetic nerve, and choline acetyltransferase (ChAT)-positive neurons increased in the cervical vagus nerve. Expression of TrkA and P75NGFR were reduced in the peripheral MI (peri-MI) and non-MI area with AB-VNS. The mRNA expression of adrenergic and nicotinic receptors (β1-AR, β3-AR, and CHRNA7) significantly declined in the peri-MI and non-MI area of the AB-VNS group.ConclusionsChronic intermittent low-intensity AB-VNS effectively suppressed post-infarction VAs by potentially rebalancing extracardiac intrathoracic autonomic activities, reducing excessive cardiac sympathetic denervation, and attenuating the heterogeneities of cardiac efferent nerve receptors distribution.