Cardiac Sympathetic Nervous System Research Articles

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.

Targeted ablation of the left middle cervical ganglion prevents ventricular arrhythmias and cardiac injury induced by AMI.

Cardiac sympathetic overactivation is a critical driver in the progression of acute myocardial infarction (AMI). The left middle cervical ganglion (LMCG) is an important extracardiac sympathetic ganglion. However, the regulatory effects of LMCG on AMI have not yet been fully documented. In the present study, we detected that the LMCG was innervated by abundant sympathetic components and exerted an excitatory effect on the cardiac sympathetic nervous system in response to stimulation. In canine models of AMI, targeted ablation of LMCG reduced the sympathetic indexes of heart rate variability and serum norepinephrine, resulting in suppressed cardiac sympathetic activity. Moreover, LMCG ablation could improve ventricular electrophysiological stability, evidenced by the prolonged ventricular effective refractory period, elevated action potential duration, increased ventricular fibrillation threshold, and enhanced connexin43 expression, consequently showing antiarrhythmic effects. Additionally, compared with the control group, myocardial infarction size, circulating cardiac troponin I, and myocardial apoptosis were significantly reduced, accompanied by preserved cardiac function in canines subjected to LMCG ablation. Finally, we performed the left stellate ganglion (LSG) ablation and compared its effects with LMCG destruction. The results indicated that LMCG ablation prevented ventricular electrophysiological instability, cardiac sympathetic activation, and AMI-induced ventricular arrhythmias with similar efficiency as LSG denervation. In conclusion, this study demonstrated that LMCG ablation suppressed cardiac sympathetic activity, stabilized ventricular electrophysiological properties and mitigated cardiomyocyte death, resultantly preventing ischemia-induced ventricular arrhythmias, myocardial injury, and cardiac dysfunction. Neuromodulation therapytargeting LMCG represented a promising strategy for the treatment of AMI.

Remote ischemic peri-conditioning suppressed the activation of cardiac sympathetic nervous system in patients with acute myocardial infarction: a randomized controlled trial

Abstract Background The activation of cardiac sympathetic nervous system is associated with poor prognosis in patients with acute myocardial infarction (AMI). Remote ischemic peri-conditioning (RIPC) is reported to improve clinical outcome in patients with AMI. However, there is not fully clarified whether RIPC could have an effect on cardiac sympathetic activity. Purpose The purpose of this study is to investigate the effect of RIPC on cardiac sympathetic activity in patients with AMI. Methods We randomly assigned 157 patients with suspected AMI undergoing emergent percutaneous coronary intervention to receive transient limb ischemia (by inflating a cuff at 200 mmHg for 4×5 minutes: RIPC group, n=77) or no procedure (control group, n=80) upon arrival to the cardiac catheterization laboratory. After excluding inappropriate patients such as those who were diagnosed with other than AMI, we analyzed 122 patients (62 patients in RIPC and 60 in control group). The primary endpoint was cardiac sympathetic activity assessed by the cardiac MIBG imaging washout rate (WR) at discharge and 1 year after discharge. WR and late heart-to-mediastinum ratio (HMR) in cardiac MIBG was calculated from the chest anterior view images obtained at 20 and 200 min after isotope injection. Results Patients in RIPC and control group had similar demographic and clinical characteristics at baseline. There was no significant difference in WR between two groups at discharge. Although WR was significantly decreased 1 year after the discharge in both groups, patients in RIPC group showed significantly lower WR than those in control group (22.0 [15.1-30.6]% and 26.5 [18.4-34.4]%, p=0.0269) 1 year after the discharge. Late HMR significantly decreased during 1-year follow-up in patients only in RIPC group (p=0.0133) and patients in RIPC group tended to show higher late HMR compared to those in control group (2.01 [1.79-2.25] and 1.92 [1.72-2.11], p=0.0581) 1 year after the discharge. Conclusion(s) Remote ischemic peri-conditioning could suppress the augmented cardiac sympathetic activity in patients with acute myocardial infarction during 1-year follow-up.

Role of ventrolateral part of ventromedial hypothalamus in post-myocardial infarction cardiac dysfunction induced by sympathetic nervous system

Psychological stress has been recognized as a contributing factor to worsened prognosis in patients with cardiac failure following myocardial infarction (MI). Although the ventrolateral part of the ventromedial hypothalamus (VMHVL) has been implicated in emotional distress, its involvement in post-MI cardiac dysfunction remains largely unexplored. This study was designed to investigate the effect of the VMHVL activation in the MI rat model and its underlying mechanisms. Our findings demonstrate that activation of VMHVL neurons enhances the activity of the cardiac sympathetic nervous system through the paraventricular nucleus (PVN) and superior cervical ganglion (SCG). This activation leads to an elevation in catecholamine levels, which subsequently modulates myosin function and triggers the release of anti-inflammatory factors, to exacerbate the post-MI cardiac prognosis. The denervation of the superior cervical ganglion (SGN) effectively blocked the cardiac sympathetic effects induced by the VMHVL activation, and ameliorated the cardia fibrosis and dysfunction. Therefore, our study identified the role of the “VMHVL-PVN-SCG” sympathetic pathway in the post-MI heart, and proposed SGN as a promising strategy in mitigating cardiac prognosis in stressful rats.

Nuclear Imaging Data-Driven Classification of Parkinson's Disease.

Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder characterized by motor and nonmotor symptoms. Several features have prognostic importance and have been used as key indicators for identifying clinical subtypes. However, the symptom-based classification approach has limitations with respect to the stability of the obtained subtypes. The purpose of this study was to identify subtypes of PD using nuclear imaging biomarkers targeting the cardiac sympathetic nervous and nigro-striatal systems and to compare patterns of cortical morphological change among obtained subtypes. We performed unbiased hierarchical cluster analysis using 123 I-metaiodobenzylguanidine cardiac scintigraphy and 123 I-N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane single photon emission computed tomography data for 56 patients with PD. We compared clinical characteristics and the patterns of cortical atrophy in the obtained clusters. Three clusters were identified and showed distinct characteristics in onset ages and dopamine-replacement therapy and deep brain stimulation requirements. According to the characteristics, clusters were classified into two subtypes, namely, "cardio-cortical impairment (CC)" and "dopaminergic-dominant dysfunction (DD)" subtype. The three clusters were named according to subtype and time since onset in which 14 patients were classified as "early DD," 25 as "advanced DD," and 17 as "early CC." Compared with the early DD subtype, the early CC subtype showed parietal-dominant diffuse cortical atrophy and the advanced DD subtype showed left-side predominant mild cortical atrophy. Nuclear imaging biomarker-based classification can be used to identify clinically and pathologically relevant PD subtypes with distinct disease trajectories. © 2023 International Parkinson and Movement Disorder Society.

Effects of low-to-moderate doses of X-rays on the cardiac rhythm via the sympathetic nervous system in female mice

Radiotherapy is one of the common therapeutic approaches in the treatment of breast cancer, with the heart inevitably being exposed to ionizing radiation which may cause late cardiac pathologies. Our recent study revealed that right atrium irradiation of right-sided breast cancer patients is associated with the development of cardiac diseases such as heart failure, arrhythmias, and conduction disorders. The aim of this project is to examine the effect of low to moderate doses of X-rays on the development of late cardiac pathologies. We specifically studied the alterations in the cardiac sympathetic nervous system which is located in potentially arrhythmogenic structures of the sinoatrial and atrioventricular nodes. Female C57Bl/6J mice were exposed to X-rays irradiation targeted to top, bottom or whole heart, such that different cardiac nodes were exposed. To examine the presence of a threshold in a dose-response for cardiac rhythm pathology, as assessed by ultrasound examinations, mice were exposed to doses ranging from 0.25 to 2 Gy. Molecular and cellular mechanisms involved in these cardiac disorders at early (24-hours) and late (60-weeks) time points post-irradiation were studied. At the functional level, our Doppler echography data show the presence of an alteration of cardiac function with the occurrence of arrhythmic events at 60-weeks post-irradiation in all irradiated animals, specifically in top heart irradiation. To confirm these results, we will also use transesophageal atrial stimulation (10 Hz during 3 sec) to assess supraventricular arrhythmias. At the molecular level, we focused on proteins involved in cardiac conduction system and in sympathetic innervation patterning 24-hours post-irradiation. Our Western Blot results show a significant increase of Connexin 40 (P = 0.02), Connexin 43 (P = 0.02), Tyrosine Hydroxylase (P = 0.04), and b3-Tubulin (P = 0.03) protein levels in whole heart irradiated animals. Altogether, our preliminary results showed modifications of cardiac function 60-weeks post-irradiation with the development of cardiac rhythm disorders and molecular alterations of cardiac conduction and sympathetic nervous system already present 24-hours post-irradiation.

MP-453081-9 CARDIAC SYMPATHOEXCITATION MONITORING DURING PULMONARY VEIN ISOLATION BY PSYCHOGENIC SWEATING: POSSIBILITY OF REPRESENTING CARDIAC SYMPATHETIC NEUROMODULATION

Vagal responses during pulmonary vein isolation (PVI) have been reported, suggesting cardiac neuromodulation in atrial fibrillation (AF) patients. The cardiac sympathetic nervous system also innervates the left atrium (LA) and its nerve fibers are reported to be greatly distributed around the PV antrum. However, the sympathetic nervous system’s response during PVI is unclear and the precise method to evaluate the cardiac sympathetic reflex is still not established. Psychogenic sweating (skin potential response; SPR) occurs during sympathetic excitation and may be useful to represent cardiac sympathoexcitation during PVI. We investigated whether the SPR could represent a cardiac sympathetic response during a balloon-based PVI and considered its clinical implications in persistent AF patients. Eighty persistent AF patients (Hot-balloon;45pt, Cryoballoon;35pt) were enrolled and the SPR was monitored during balloon-based ablation of each PV. The SPR was measured by the difference in two skin potentials recorded from skin electrodes (Figure top row). The reduction in the activation recovery interval (ARI), suggesting sympathetic excitation, was examined from the ventricle unipolar electrogram of the great cardiac vein recorded from an electrode catheter placed inside the coronal sinus (Figure bottom row). An ROC analysis was used to determine a valid reduction in the SPR, with a reduction cut-off value of 3.5mV in the heart rate (HR) increase due to sympathoexcitation (sensitivity 73%, specificity 97%). SPRs occurred in 41% of the PVs (LSPV=41%, RSPV=38%, LIPV=28%, RIPV=20%). The SPR was related to a significant increase in the blood pressure and HR, and a reduction in the ARI (p<0.01, Table). A total of 18 patients (20%) had AF recurrences within the 1-year follow-up. The number of SPRs within the 4PVs was 1.08PV in non-recurrence patients and 1.83PV in AF recurrent patients (p=0.07). The patients that had early recurrences but recovered sinus rhythm (SR) within 3 months, had more frequent SPRs than the other recurrent patients (2.80 vs. 0.63PV, p<0.01). The SPR was strongly related to cardiac sympathoexcitation during PVI. The SPR was suggested to represent the cardiac sympathetic reflex during PV antrum ablation, which may lead to an investigation of the cardiac sympathetic neuromodulation during PVI. Frequent SPRs were related to SR recovery after early AF recurrences and a cardiac sympathetic response may have an important role in the outcome of the PVI.

Dysregulation of hypoxia-inducible factor 1α in the sympathetic nervous system accelerates diabetic cardiomyopathy

BackgroundAn altered sympathetic nervous system is implicated in many cardiac pathologies, ranging from sudden infant death syndrome to common diseases of adulthood such as hypertension, myocardial ischemia, cardiac arrhythmias, myocardial infarction, and heart failure. Although the mechanisms responsible for disruption of this well-organized system are the subject of intensive investigations, the exact processes controlling the cardiac sympathetic nervous system are still not fully understood. A conditional knockout of the Hif1a gene was reported to affect the development of sympathetic ganglia and sympathetic innervation of the heart. This study characterized how the combination of HIF-1α deficiency and streptozotocin (STZ)-induced diabetes affects the cardiac sympathetic nervous system and heart function of adult animals.MethodsMolecular characteristics of Hif1a deficient sympathetic neurons were identified by RNA sequencing. Diabetes was induced in Hif1a knockout and control mice by low doses of STZ treatment. Heart function was assessed by echocardiography. Mechanisms involved in adverse structural remodeling of the myocardium, i.e. advanced glycation end products, fibrosis, cell death, and inflammation, was assessed by immunohistological analyses.ResultsWe demonstrated that the deletion of Hif1a alters the transcriptome of sympathetic neurons, and that diabetic mice with the Hif1a-deficient sympathetic system have significant systolic dysfunction, worsened cardiac sympathetic innervation, and structural remodeling of the myocardium.ConclusionsWe provide evidence that the combination of diabetes and the Hif1a deficient sympathetic nervous system results in compromised cardiac performance and accelerated adverse myocardial remodeling, associated with the progression of diabetic cardiomyopathy.

Autonomic Nervous System Regulation of Epicardial Adipose Tissue: Potential Roles for Regulator of G Protein Signaling-4.

The epicardial adipose tissue (EAT) or epicardial fat is a visceral fat depot in the heart that contains intrinsic adrenergic and cholinergic nerves, through which it interacts with the cardiac sympathetic (adrenergic) and parasympathetic (cholinergic) nervous systems. These EAT nerves represent a significant source of several adipokines and other bioactive molecules, including norepinephrine, epinephrine, and free fatty acids. The production of these molecules is biologically relevant for the heart, since abnormalities in EAT secretion are implicated in the development of pathological conditions, including coronary atherosclerosis, atrial fibrillation, and heart failure. Sympathetic hyperactivity and parasympathetic (cholinergic) derangement are associated with EAT dysfunction, leading to a variety of adverse cardiac conditions, such as heart failure, diastolic dysfunction, atrial fibrillation, etc.; therefore, several studies have focused on exploring the autonomic regulation of EAT as it pertains to heart disease pathogenesis and progression. In addition, Regulator of G protein Signaling (RGS)-4 is a protein with significant regulatory roles in both adrenergic and muscarinic receptor signaling in the heart. In this review, we provide an overview of the autonomic regulation of EAT, with a specific focus on cardiac RGS4 and the potential roles this protein plays in this regulation.

Stellate Ganglia and Cardiac Sympathetic Overactivation in Heart Failure.

Heart failure (HF) is a major public health problem worldwide, especially coronary heart disease (myocardial infarction)-induced HF with reduced ejection fraction (HFrEF), which accounts for over 50% of all HF cases. An estimated 6 million American adults have HF. As a major feature of HF, cardiac sympathetic overactivation triggers arrhythmias and sudden cardiac death, which accounts for nearly 50-60% of mortality in HF patients. Regulation of cardiac sympathetic activation is highly integrated by the regulatory circuitry at multiple levels, including afferent, central, and efferent components of the sympathetic nervous system. Much evidence, from other investigators and us, has confirmed the afferent and central neural mechanisms causing sympathoexcitation in HF. The stellate ganglion is a peripheral sympathetic ganglion formed by the fusion of the 7th cervical and 1st thoracic sympathetic ganglion. As the efferent component of the sympathetic nervous system, cardiac postganglionic sympathetic neurons located in stellate ganglia provide local neural coordination independent of higher brain centers. Structural and functional impairments of cardiac postganglionic sympathetic neurons can be involved in cardiac sympathetic overactivation in HF because normally, many effects of the cardiac sympathetic nervous system on cardiac function are mediated via neurotransmitters (e.g., norepinephrine) released from cardiac postganglionic sympathetic neurons innervating the heart. This review provides an overview of cardiac sympathetic remodeling in stellate ganglia and potential mechanisms and the role of cardiac sympathetic remodeling in cardiac sympathetic overactivation and arrhythmias in HF. Targeting cardiac sympathetic remodeling in stellate ganglia could be a therapeutic strategy against malignant cardiac arrhythmias in HF.

Metabolism regulator adiponectin prevents cardiac remodeling and ventricular arrhythmias via sympathetic modulation in a myocardial infarction model.

The stellate ganglia play an important role in cardiac remodeling after myocardial infarction (MI). This study aimed to investigate whether adiponectin (APN), an adipokine mainly secreted by adipose tissue, could modulate the left stellate ganglion (LSG) and exert cardioprotective effects through the sympathetic nervous system (SNS) in a canine model of MI. APN microinjection and APN overexpression with recombinant adeno-associated virus vector in the LSG were performed in acute and chronic MI models, respectively. The results showed that acute APN microinjection decreased LSG function and neural activity, and suppressed ischemia-induced ventricular arrhythmia. Chronic MI led to a decrease in the effective refractory period and action potential duration at 90% and deterioration in echocardiography performance, all of which was blunted by APN overexpression. Moreover, APN gene transfer resulted in favorable heart rate variability alteration, and decreased cardiac SNS activity, serum noradrenaline and neuropeptide Y, which were augmented after MI. APN overexpression also decreased the expression of nerve growth factor and growth associated protein 43 in the LSG and peri-infarct myocardium, respectively. Furthermore, RNA sequencing of LSG indicated that 4-week MI up-regulated the mRNA levels of macrophage/microglia activation marker Iba1, chemokine ligands (CXCL10, CCL20), chemokine receptor CCR5andpro-inflammatory cytokine IL6, and downregulated IL1RN and IL10 mRNA, which were reversed by APN overexpression. Our results reveal that APN inhibits cardiac sympathetic remodeling and mitigates cardiac remodeling after MI. APN-mediated gene therapy may provide a potential therapeutic strategy for the treatment of MI.

Reclassification of Heart Failure with Preserved Ejection Fraction Following Cardiac Sympathetic Nervous System Activation: A New Cutoff Value of 58.

Heart failure (HF) with preserved left ventricular ejection fraction (LVEF) is a heterogeneous syndrome. An LVEF of 50% is widely used to categorize patients with HF; however, this is controversial. Previously, we have reported that patients with an LVEF of ≥ 58% have good prognoses. Further, cardiac sympathetic nervous system (SNS) activation is a feature of HF. In this retrospective, observational study, the cardiac SNS activity of HF patients (n = 63, age: 78.4 ± 9.6 years; male 49.2%) with LVEF ≥ 58% (n = 15) and LVEF < 58% (n = 48) were compared using 123I-metaiodobenzylguanidine scintigraphy. During the follow-up period (median, 3.0 years), 18 all-cause deaths occurred. The delayed heart/mediastinum (H/M) ratio was significantly higher in the LVEF ≥ 58% group than in the LVEF < 58% group (2.1 ± 0.3 vs. 1.7 ± 0.4, p = 0.004), and all-cause mortality was significantly lower in patients in the former than those in the latter group (log-rank, p = 0.04). However, when these patients were divided into LVEF ≥ 50% (n = 22) and LVEF < 50% (n = 41) groups, no significant differences were found in the delayed H/M ratio, and the all-cause mortality did not differ between the groups (log-rank, p = 0.09). In conclusion, an LVEF of 58% is suitable for reclassifying patients with HF according to cardiac SNS activity.

Does quantification of [11C]meta-hydroxyephedrine and [13N]ammonia kinetics improve risk stratification in ischemic cardiomyopathy

BackgroundIn ischemic cardiomyopathy patients, cardiac sympathetic nervous system dysfunction is a predictor of sudden cardiac arrest (SCA). This study compared abnormal innervation and perfusion measured by [11C]meta-hydroxyephedrine (HED) vs [13N]ammonia (NH3), conventional uptake vs parametric tracer analysis, and their SCA risk discrimination. MethodsThis is a sub-study analysis of the prospective PAREPET trial, which followed ischemic cardiomyopathy patients with reduced left ventricular ejection fraction (LVEF ≤ 35%) for events of SCA. Using n = 174 paired dynamic HED and NH3 positron emission tomography (PET) scans, regional defect scores (%LV extent × severity) were calculated using HED and NH3 uptake, as well as HED distribution volume and NH3 myocardial blood flow by kinetic modeling. ResultsDuring 4.1 years follow-up, there were 27 SCA events. HED defects were larger than NH3, especially in the lowest tertile of perfusion abnormality (P < .001). Parametric defects were larger than their respective tracer uptake defects (P < .001). SCA risk discrimination was not significantly improved with parametric or uptake mismatch (AUC = 0.73 or 0.70) compared to HED uptake defect scores (AUC = 0.67). ConclusionQuantification of HED distribution volume and NH3 myocardial blood flow produced larger defects than their respective measures of tracer uptake, but did not lead to improved SCA risk stratification vs HED uptake alone.

Characterization of Cardiac Sympathetic Nervous System and Inflammatory Activation in HFpEF Patients

We have shown that systemic and cardiac sympathetic activation is present in heart failure with preserved ejection fraction (HFpEF) patients. Conversely, whereas systemic inflammatory activation was also detected in HFpEF, we did not detect local myocardial release of inflammatory cytokines. Activation of the sympathetic system correlated with both hemodynamic and demographic factors that characteristically cluster together in HFpEF. Together these data suggest that there may be a role for antiadrenergic therapies in certain HFpEF patients. The study does not implicate locally derived cytokines in the myocardial biology of HFpEF, although systemic sources may contribute to the global pathophysiology of HFpEF.

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.

Molecular Imaging-Derived Biomarker of Cardiac Nerve Integrity — Introducing High NET Affinity PET Probe 18F-AF78

Background: Radiolabeled agents that are substrates for the norepinephrine transporter (NET) can be used to quantify cardiac sympathetic nervous conditions and have been demonstrated to identify high-risk congestive heart failure (HF) patients prone to arrhythmic events. We aimed to fully characterize the kinetic profile of the novel 18F-labeled NET probe AF78 for PET imaging of the cardiac sympathetic nervous system (SNS) among various species.Methods: 18F-AF78 was compared to norepinephrine (NE) and established SNS radiotracers by employing in vitro cell assays, followed by an in vivo PET imaging approach with healthy rats, rabbits and nonhuman primates (NHPs). Additionally, chase protocols were performed in NHPs with NET inhibitor desipramine (DMI) and the NE releasing stimulator tyramine (TYR) to investigate retention kinetics in cardiac SNS.Results: Relative to other SNS radiotracers, 18F-AF78 showed higher transport affinity via NET in a cell-based competitive uptake assay (IC50 0.42 ± 0.14 µM), almost identical to that of NE (IC50, 0.50 ± 0.16 µM, n.s.). In rabbits and NHPs, initial cardiac uptake was significantly reduced by NET inhibition. Furthermore, cardiac tracer retention was not affected by a DMI chase protocol but was markedly reduced by intermittent TYR chase, thereby suggesting that 18F-AF78 is stored and can be released via the synaptic vesicular turnover process. Computational modeling hypothesized the formation of a T-shaped π-π stacking at the binding site, suggesting a rationale for the high affinity of 18F-AF78.Conclusion: 18F-AF78 demonstrated high in vitro NET affinity and advantageous in vivo radiotracer kinetics across various species, indicating that 18F-AF78 is an SNS imaging agent with strong potential to guide specific interventions in cardiovascular medicine.

The Gut Microbial-Derived Metabolite Trimethylamine N-Oxide and Atrial Fibrillation: Relationships, Mechanisms, and Therapeutic Strategies.

Accumulating evidence has demonstrated that gut microbial-derived metabolite trimethylamine N-oxide (TMAO) plays a crucial role in the pathogenesis of many diseases and can be served as a prognostic biomarker for several cardiovascular disorders, including arrhythmia. Recently, some studies have documented that TMAO was associated with the occurrence, progression, recurrence, and embolism risk of atrial fibrillation (AF). The activation of related inflammatory signal pathways and the cardiac sympathetic nervous system (CSNS) caused by elevated TAMO may be the underlying mechanism. It is worth noting that intervention in the metabolic pathway of TMAO may be an underlying therapeutic target of AF. In addition, standardized and individualized treatment strategies in clinical practice may be of great significance for AF patients, particularly those with high serum TMAO concentrations. However, there are also contradictions in the current research on TMAO and AF. Moreover, notwithstanding the positive preclinical and clinical findings, data supporting a direct association between TMAO and AF is a paucity. Thus, conclusive evidence from preclinical studies and multi-center randomized controlled trials to reveal the essential relationship between TMAO and AF is needy. In this review, we have attempted to summarize recent studies on TMAO and AF, highlighted the potential therapeutic strategies for AF patients, followed by a discussion on directions for future research in this field.

Cardiac Sympathetic Positron Emission Tomography Imaging with Meta-[18F]Fluorobenzylguanidine is Sensitive to Uptake-1 in Rats.

Dysfunction of the cardiac sympathetic nervous system contributes to the development of cardiovascular diseases including ischemia, heart failure, and arrhythmias. Molecular imaging probes such as meta-[123I]iodobenzylguanidine have demonstrated the utility of assessing neuronal integrity by targeting norepinephrine transporter (NET, uptake-1). However, current radiotracers can report only on innervation due to suboptimal kinetics and lack sensitivity to NET in rodents, precluding mechanistic studies in these species. The objective of this work was to characterize myocardial sympathetic neuronal uptake mechanisms and kinetics of the positron emission tomography (PET) radiotracer meta-[18F]fluorobenzylguanidine ([18F]mFBG) in rats. Automated synthesis using spirocyclic iodonium(III) ylide radiofluorination produces [18F]mFBG in 24 ± 1% isolated radiochemical yield and 30-95 GBq/μmol molar activity. PET imaging in healthy rats delineated the left ventricle, with monoexponential washout kinetics (kmono = 0.027 ± 0.0026 min-1, Amono = 3.08 ± 0.33 SUV). Ex vivo biodistribution studies revealed tracer retention in the myocardium, while pharmacological treatment with selective NET inhibitor desipramine, nonselective neuronal and extraneuronal uptake-2 inhibitor phenoxybenzamine, and neuronal ablation with neurotoxin 6-hydroxydopamine reduced myocardial retention by 33, 76, and 36%, respectively. Clearance of [18F]mFBG from the myocardium was unaffected by treatment with uptake-1 and uptake-2 inhibitors following peak myocardial activity. These results suggest that myocardial distribution of [18F]mFBG in rats is dependent on both NET and extraneuronal transporters and that limited reuptake to the myocardium occurs. [18F]mFBG may therefore prove useful for imaging intraneuronal dysfunction in small animals.

Cardiac Sympathetic Activity and Rhythm Control Following Pulmonary Vein Isolation in Patients with Paroxysmal Atrial Fibrillation-A Prospective 123I-mIBG-SPECT/CT Imaging Study.

Background: Pulmonary vein isolation (PVI) and antiarrhythmic drug therapy are established treatment strategies to preserve sinus rhythm in atrial fibrillation (AF). However, the efficacy of both interventional and pharmaceutical therapy is still limited. Solid evidence suggests an important role of the cardiac sympathetic nervous system in AF. In this blinded, prospective observational study, we studied left ventricular cardiac sympathetic activity in patients treated with PVI and with antiarrhythmic drugs. Prospectively, Iodine-123-benzyl-guanidine single photon emission computer tomography (123I-mIBG-SPECT) was performed in a total of 23 patients with paroxysmal AF, who underwent PVI (n = 20) or received antiarrhythmic drug therapy only (n = 3), respectively. 123I-mIBG planar and SPECT/CT scans were performed before and 4 to 8 weeks after PVI (or initiation of drug therapy, respectively). For semiquantitative SPECT image analysis, attenuation-corrected early/late images were analyzed. Quantitative SPECT analysis was performed using the AHA 17-segment model of the left ventricle. Results: PVI with point-by-point radiofrequency ablation led to a significantly (p < 0.05) higher visual sympathetic innervation defect score when comparing pre-and post PVI. Newly emerging innervation deficits post PVI were localized predominantly in the inferior lateral wall. These findings were corroborated by semiquantitative SPECT analysis identifying inferolateral segments with a reduced tracer uptake in comparison to SPECT before PVI. Following PVI, patients with an AF relapse showed a different sympathetic innervation pattern compared to patients with sufficient rhythm control. Conclusions: PVI results in novel defects of cardiac sympathetic innervation. Differences in cardiac sympathetic innervation remodelling following PVI suggest an important role of the cardiac autonomous nervous system in the maintenance of sinus rhythm following PVI.

Indirect autonomic nervous system activity assessment in patients with myocardial infarction

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Abnormalities in the cardiac sympathetic nervous system have been documented in myocardial infarction (MI) and have been directly implicated in pathogenesis and progression of MI. Assessment of the autonomic nervous system activity in acute stage of MI allowed us to identify groups of high-risk patients. Purpose To investigate the sympathetic nervous system activity in patients with MI by assessing the condition of beta-adrenergic reactivity of erythrocytes. To analyze ADRB1 Arg389Gly associations with the state of beta-adrenergic reactivity of erythrocytes in patients with MI. Methods During the study period, 62 patients were enrolled. The patients were divided into 2 groups. The first group consisted of 11 patients (nine women and two men, median age of 54.0 [49.0;61.0] years) with normal beta-adrenergic reactivity of erythrocytes, the second group consisted of 51 patients (40 women and 11 man, median age of 61.0 [48.0;72.0] years) with abnormal beta-adrenergic reactivity of erythrocytes. The research of beta-adrenergic reactivity of erythrocytes was conducted by analysis of changing erythrocyte osmoresistance under the influence of beta blocker in the first 6 hours from the onset of the heart attack. The genetic research was conducted by PСR method in real time. Results Groups of patients were comparable in main clinical indicators (anamnesis of ischemic heart disease and chronic heart failure, frequency of beta blockers administration before and during of MI, electrocardiography features: elevation of ST-segment, Q-wave and etc.). The second group presented with a higher occurrence of acute left ventricular failure (33.3% vs 0%, p = 0.026) and arterial hypertension (90.2% vs 63.6%, p = 0.044). Parameters of myocardial damage were significantly higher in the second group than the first group. Primarily, this manifested in the presence of a greater number of hypokinesis zones on echocardiography (p = 0.015). In addition, patients of the second group had a lower ejection fraction according to echocardiography (51.0 [46.5;59.0]% vs 58.0 [52.0;63.0]%, p = 0.042). Levels of blood necrosis biomarkers were significantly higher in the second group, e.g. Troponin I (24.1 [9.9;68.0] ng/ml vs 1.3 [0.2;1.8] ng/ml, p = 0.001). At the same time statistically significant distinctions of the severity of coronary atherosclerosis in groups were not revealed. The analysis of ADRB1 Arg389Gly demonstrated association of CC-genotype with abnormal beta-adrenergic reactivity of erythrocytes [OR 5.9, 95% СI 1.16-30.25, p = 0.043]. Conclusion Patients with an abnormal beta-adrenergic reactivity were characterized by a greater volume of damage to the heart muscle. Moreover, association of CC-genotype of gene ADRB1 Arg389Gly with abnormal beta-adrenergic reactivity of erythrocytes was identified.