To determine whether cardiac sympathetic nervous dysfunction is present, in this single center prospective, non-randomized trial non-invasive SPECT/CT imaging using the radiotracer 123I-metaiodobenzylguanidine was performed in 33 recovered COVID-19 patients without pre-existing cardiac conditions. Increased cardiac sympathetic activity, as indicated by late HMR, was observed in 67.7% of patients. At 6-8 months, 82% of these subjects (27/33) received follow-up, and cardiac sympathetic innervation abnormalities were still present in 70.4% (19/27). Additionally, at 12-15 months post-diagnosis, persistently abnormal HMRs were found in 9 individuals who initially had abnormal sympathetic innervation. Further follow-up is needed to investigate potential long-term cardiovascular consequences of COVID-19.

Although the neurocardiac axis is central to cardiovascular homeostasis, its dysregulation drives heart failure and cardiometabolic diseases. This review examines the bidirectional interplay between the autonomic nervous system and the heart, highlighting the role of this interplay in disease progression and its therapeutic potential. The autonomic nervous system modulates cardiac function and vascular tone through its sympathetic and parasympathetic branches. However, in heart failure, chronic sympathetic overdrive and parasympathetic withdrawal exacerbate myocardial remodeling and metabolic dysfunction, both of which are exacerbated by cardiometabolic conditions such as obesity and diabetes. These conditions are increasingly recognized to impair neurocardiac regulation, thereby promoting inflammation and adverse outcomes. An important emerging area concerns neuroimmune control, in which the brain orchestrates systemic inflammation through circuits involving the bone marrow, spleen, and other organs, thereby amplifying cardiovascular damage. This neuroimmune axis integrates peripheral signals to influence immune responses that contribute to disease progression. Lifestyle factors, such as stress, sleep, exercise, and diet, affect autonomic and immune balance and, thus, cardiovascular disease. Therapeutically, targeting neurocardiac and neuroimmune pathways pharmacologically or via neuromodulation (eg, vagal or splenic nerve stimulation) offers promise although the clinical translation of the latter remains challenging. In this review, we synthesize preclinical and clinical data to highlight the neurocardiac axis as a critical nexus in heart failure and cardiometabolic disease. Harnessing neuroimmune and neurocardiac interactions may inform precision approaches to reduce the burden of these conditions.

Cardiac autonomic dysfunction is associated with heart failure (HF). Reduced heart rate recovery (HRR) indicates impaired parasympathetic reactivation after physical activity. Heart rate recovery 60 seconds after peak effort (HRR60) is linked to autonomic dysfunction, but data on its relevance across HF phenotypes are scarce. This study aimed to identify clinical determinants of HRR60 in an HF cohort and assess its relationship with clinical outcomes.

Data from the MyoVasc study (NCT04064450; N=3289) were analyzed. Participants underwent standardized clinical phenotyping including cardiopulmonary exercise testing. HRR60 was defined as the heart rate decline 60 seconds after exercise termination. Clinical determinants of HRR60 were evaluated using multivariate regression, whereas Cox regression analyses assessed all-cause death and worsening of HF.

The analysis sample comprised 1289 individuals (median age, 66.0 [interquartile range {IQR}, 58.0-73.0] years, 30.4% women) ranging from stage B to stage C/D according to the universal definition of HF. Age, sex, smoking, obesity, peripheral artery disease, and chronic kidney disease were identified as determinants of HRR60. HRR60 showed a strong association with all-cause death (hazard ratio [HR]HRR60 [10 bpm], 1.56 [95% CI, 1.32-1.85]; P<0.0001) and worsening of HF (HRHRR60 [10 bpm], 1.36 [95% CI, 1.10-1.69]; P=0.0052) independent of age, sex, and clinical profile. Sensitivity analysis showed a stronger association with worsening HF in HF with preserved left ventricular ejection fraction (Pinteraction=0.027).

HRR60 was associated with clinical outcome in chronic HF. Because it showed a stronger association with outcomes in HF with preserved ejection fraction, future research should consider phenotype-specific differences.

Autonomic nerves are crucial in cardiac function and pathology. However, data on the distribution of cholinergic and noradrenergic nerves in normal and pathologic human hearts is lacking. Nonfailing donor hearts were pressure-perfusion fixed, imaged, and dissected. Left ventricular cardiomyopathy samples were also obtained. Fixed frozen sections were immunostained for nerves, and adjacent tissue underwent clearing for 3D visualization. Cholinergic and noradrenergic nerves were evenly abundant in both atria, except the sinoatrial node, where vesicular acetylcholine transporter (VAChT) nerves were dominant. Noradrenergic consistently outnumbered cholinergic nerves in right (RV) and left ventricular (LV) regions. Noradrenergic innervation of LV regions varied between donors. Cholinergic innervation was higher in RV compared to LV samples, which generally had reduced VAChT nerves. Marked neural remodeling occurred in three cardiomyopathy cases. Tyrosine hydroxylase (TH) nerve density was increased in the right atrial appendage, and all nerves showed a trend to decrease in the left atrial appendage. Cholinergic innervation was reduced in the LV, and TH innervation was heterogeneous. Noradrenergic nerves were present in granulation tissue but absent in regions of dense scar. Some border zone regions had reduced TH innervation but no hyperinnervation. Dual innervation of most atrial regions supports balanced regulation of atrial function. Higher cholinergic input to the sinoatrial node favors vagal dominance in heart rate regulation. Innervation patterns support a significant role of noradrenergic input to the ventricle, especially on the left. Both atrial and ventricular nerves remodel in cardiomyopathy, providing a foundation for asymmetric neural input and dysregulation of cardiac electromechanical function.

Electrical stimulation (ES) has been established as a reliable and beneficial approach in therapeutic rehabilitation, exhibiting negligible side effects. Nevertheless, research focusing on the application of ES for cardiac hypertrophy remains limited, as it fails to provide an enduring remedy for chronic diseases. In this investigation, vagal ES, characterized by its wireless, battery-free, and fully implantable nature, was utilized to treat cardiac hypertrophy. The vagus nerve at the stimulation site was carefully embedded within an envelope, sealed securely using multiple bioabsorbable sutures. Subsequently, a cardiac hypertrophy model was induced in rats via abdominal aortic coarctation for four weeks. The findings of this investigation demonstrated that ES markedly attenuated cardiac hypertrophy. Metabolomic analysis revealed a notable reduction in lactate levels within myocardial tissue following ES. Proteomic analysis of myocardial tissues indicated a substantial decrease in the expression of autophagy and mitophagy-related proteins after ES. Additionally, ChIP-seq result revealed a specific binding interaction between H3K18 lactylation (H3K18la) and BCL2 interacting protein 3 (Bnip3), while luciferase reporter assays demonstrated that H3K18la directly governed Bnip3 transcriptional activation, exploring its role in modulating mitophagy. Mechanistically, it was shown that ES reduced lactate accumulation through the upregulation of monocarboxylate transporter 4 (MCT4) by decreasing norepinephrine (NE) levels. Furthermore, ES reversed cardiac hypertrophy by diminishing H3K18la levels, thus inhibiting Bnip3 protein expression. This pathway assists in diminishing cardiac hypertrophy, emphasizing the critical involvement of the afferent vagal pathway in regulating cardiac hypertrophy.

Maximal oxygen uptake/consumption is an important variable determining exercise performance. It is generally considered to be limited largely, but not exclusively, by maximal cardiac output (CO), which limits the ability of heart to pump oxygen-rich arterial blood to working muscles. Cardiac output is a product of heart rate and stroke volume, which is the amount of blood ejected from the heart by one heart beat. Exercise training, especially of the endurance type, can increase maximal CO substantially. A straightforward way for the heart to increase maximal CO would be to increase maximal heart rate, but this does not happen; instead, maximal heart rate tends to be reduced after training. This is because heart rate is the most important determinant of myocardial oxygen consumption, and ventricular filling and myocardial blood flow (MBF) would be compromised by further increases in heart rate, given that MBF is blunted by contractions and occurs principally during diastole. Myocardial oxygen extraction is already high at rest and is increased further in endurance-trained athletes, making their hearts even more dependent on increases in MBF. The trained heart therefore also shows reduced MBF, enhanced blood mean transit time and higher myocardial vascular resistance at rest and during submaximal exercise, although MBF reserve is not improved. It follows logically that MBF is an important determinant of myocardial performance, and it is proposed in this review that cardiac afferent sensory nerves might contribute to controlling and limiting heart rate, hence maximal CO, in order to protect the heart from ischaemia.

The role of the autonomic nervous system in cardiovascular diseases has increasingly attracted the attention of researchers. This study aims to review research on the autonomic nervous system in arrhythmias from 2004 to 2024, with a focus on understanding the development trends in this field. Data for this study were sourced from the Web of Science Core Collection. We constructed and analyzed bibliometric visualizations related to publication trends, countries/regions, institutions, journals, research categories, themes, references, and keywords. Over the past two decades, academic output related to the autonomic nervous system's role in arrhythmias has grown, although global research distribution remains uneven. The United States leads in publication volume and is home to many high-output institutions, providing it with significant academic influence and fostering international collaboration. By summarizing high-citation literature, clustering keywords, and performing a "burst detection" analysis of keywords, we identified that the mechanisms and assessment methods for autonomic nervous system regulation are major research focuses. Recent hotspots include the psychopathology related to the autonomic nervous system and autonomic regulation therapies. As the biomedical field shifts toward precision medicine, future research trends are likely to focus on identifying precise biomarkers for assessing autonomic nervous system function and developing novel strategies to regulate it. These strategies may include correcting immune dysfunction, psychological interventions, and surgical treatments. This study suggests that ganglionated plexi ablation may represent the most transformative intervention strategy for the Autonomic Nervous System currently available, and highlights electrodermal activity as an evaluation index with considerable potential for widespread application.

Malignant ventricular arrhythmias (VAs), such as ventricular tachycardia and ventricular fibrillation, are the cause of approximately half a million deaths per year in the United States, which is a common lethal event in heart disease, such as hypertension, catecholaminergic polymorphic ventricular tachycardia, takotsubo cardiomyopathy, long-QT syndrome, and progressing into advanced heart failure. A common characteristic of these heart diseases, and the subsequent development of VAs, is the overactivation of the sympathetic nervous system. Current treatments for VAs in these heart diseases, such as β-adrenergic receptor blockers and cardiac sympathetic ablation, aim at inhibiting cardiac sympathetic overactivation. However, these treatments do not translate into becoming efficacious as long-term suppressors of ventricular tachycardia/ventricular fibrillation events. As a key regulatory component in the heart, cardiac postganglionic sympathetic neurons residing in the stellate ganglia (SGs) release neurotransmitters (such as norepinephrine and NPY [neuropeptide Y]) to perform their regulatory role in dictating cardiac function. Growing evidence from animal experiments and clinical studies has demonstrated that the remodeling of the SG may be intimately involved in malignant arrhythmogenesis. This identifies the SG as a key potential therapeutic target for the treatment of malignant VAs in heart disease. Therefore, this review summarizes the role of SG in ventricular arrhythmogenesis and updates the novel targeting of SG for clinical treatment of VAs in heart disease.

Activity of cardiac-projecting neurons in the dorsal motor nucleus of the vagus (CVNDMV) is vital in cardiac reflexes contributing to maintaining cardiovascular health. However, how this population adapts to metabolic challenges, such as high-fat diet (HFD), is unclear. This study aimed to identify neuroplasticity changes induced by HFD in CVNDMV. Using whole-cell patch-clamp electrophysiology, we found that 15-day HFD feeding increased tonic, but not phasic, gamma-aminobutyric acid type A (GABAA) inhibitory neurotransmission, exclusive to CVNDMV. Single-cell quantitative reverse-transcription PCR (scRT-qPCR) analysis revealed a higher number of CVNDMV expressing GABAA receptor δ-subunit (GABAA(δ)R) in HFD compared to normal fat diet (NFD). Deletion of GABAA(δ)R in ChAT-positive motor neurons abolished HFD-induced increased tonic GABAA neurotransmission in CVNDMV. Altogether, this evidence suggests that CVNDMV exhibits early onset HFD-induced increased GABAergic neurotransmission, likely mediated by GABAA(δ)R. This increased inhibitory tone could explain previously reported reduced cardiac vagal motor output, thus contributing to poor cardiometabolic health after HFD.

Cardiac autonomic dysfunction (CADF), mainly characterized by increased heart rate, decreased heart rate variability, and loss of vagal modulation, has been extensively described in patients with schizophrenia (SCZ) and their healthy first-degree relatives. As such, it represents an apparent physiological link that contributes to the increased cardiovascular mortality in these patients. Common genetic variation is a putative underlying mechanism, along with lifestyle factors and antipsychotic medications. However, the extent to which CADF is associated with genetic factors for SCZ is unknown. A sample of 83 drug-naive SCZ patients and 96 healthy controls, all of European origin, underwent a 30-minute autonomic assessment under resting conditions. We incorporated parameters from several domains into our model, including time and frequency domains (mean heart rate, low/high frequency ratio) and compression entropy, each of which provides different insights into the dynamics of cardiac autonomic function. These parameters were used as outcome variables in linear regression models with polygenic risk scores (PRS) for SCZ as predictors and age, sex, BMI, smoking status, principal components of ancestry and diagnosis as covariates. Of the three CADF parameters, SCZ PRS was significantly associated with mean heart rate in the combined case/control sample. However, this association was was no longer significant after including diagnosis as a covariate (p = 0.29). In contrast, diagnostic status is statistically significant for all three CADF parameters, accounting for a significantly greater proportion of the variance in mean heart rate compared to SCZ PRS (approximately 16% vs. 4%). Despite evidence for a common genetic basis of CADF and SCZ, we were unable to provide further support for an association between the polygenic burden of SCZ and cardiac autonomic function beyond the diagnostic state. This suggests that there are other important characteristics associated with SCZ that lead to CADF that are not captured by SCZ PRS.

Takotsubo syndrome (TTS) is an acute cardiac syndrome characterized by transient left ventricular dysfunction. Although the wall motion abnormality resolves completely, the prognosis is poor. Defect of 123I-metaiodobenzylguanidine uptake, interpreted as sympathetic impairment, persisted in TTS patients, but the mechanism is not fully understood. We aimed to elucidate morphological sympathetic nerve change in a TTS model mouse using three-dimensional imaging techniques, with a particular focus on the role of factors in these alterations. The TTS model was induced by a single intraperitoneal injection of 2.0 mg/kg adrenaline to C57BL/6 mice, resulting in transient akinesis localized to the inferior apical region of the heart. Three-dimensional morphological assessment revealed that sympathetic nerve length within the inferior apical area of TTS mice reduced during the chronic phase compared with the sham mice. Notably, the study observed a pattern of denervation during the acute phase, followed by re-innervation and subsequent denervation in the chronic phase. The neurotrophic factors expressions changed in a time-dependent manner, corresponding to the phase-specific damage both to cardiomyocytes and sympathetic neurons. The bimodal change in sympathetic nerves and altered neurotrophic factors in TTS mice provide novel insights into the pathophysiological mechanism of TTS to establish therapeutic strategies for TTS.

Acute myocardial ischemia (AMI)-triggered ventricular arrhythmias are closely linked to maladaptive sympathetic hyperactivity mediated via the left stellate ganglion (LSG). Although M-type potassium channels regulate neuronal excitability and hold therapeutic potential for neurological disorders, their role in intrinsic LSG neurons during ischemia remains unexplored. We investigated whether pharmacological M-channel activation in the LSG mitigates sympathetic overdrive and arrhythmogenesis in AMI.

Twenty-four beagles underwent LSG microinjection of either vehicle (n=12) or retigabine (M-channel activator, 50 μM; n=12) 30 minutes before AMI induction. We assessed (1) neural parameters (LSG electrophysiology, plasma norepinephrine levels, and c-fos+/tyrosine hydroxylase+ neuron expression); (2) cardiac electrophysiological parameters (beat-to-beat repolarization variability, spatial dispersion of effective refractory period and action potential duration, ventricular fibrillation threshold, and spontaneous ventricular arrhythmias incidence); and (3) autonomic and hemodynamic measures (heart rate variability and blood pressure). Retigabine pretreatment significantly suppressed ischemia-induced LSG hyperactivity and reduced sympathetic activation markers compared with controls. Treated animals exhibited attenuated repolarization variability and reduced electrophysiological heterogeneity in ischemic myocardium. The retigabine group demonstrated a higher ventricular fibrillation threshold (26.67±2.61 versus 12.33±1.76 voltage (V), P=0.0008) and a lower incidence of ventricular arrhythmias during AMI, with only negligible effects on baseline cardiac repolarization duration or LSG function before ischemia induction.

Targeted activation of LSG M-channels with retigabine stabilizes ischemia-induced sympathetic hyperactivity, promotes cardiac autonomic balance, preserves repolarization homogeneity, and ultimately mitigates arrhythmic susceptibility. These findings highlight ganglionic M-channel modulation as a translatable strategy to suppress neurogenic arrhythmogenesis in AMI.

Stellate ganglia (SG) provide sympathetic innervation to the heart and may predispose the myocardial conducting system to arrhythmias. However, little is known about age-related changes in the electrophysiology of murine SG. We investigated alterations in the electrophysiological properties of SG with aging. The loose patch clamp technique was adapted to SG tissue to investigate the voltage-gated ionic currents in its neuronal cells. We compared SG and ventricular cells from young (4 months) and aged (13 months) C57BL/6J mice to explore age-related alterations in their voltage-gated ionic currents (n > 30 patches, eight mice in each group). We observed that the voltage-gated inward sodium current (peak INa(Max)) was significantly decreased with aging in the SG, but not in the ventricle. Additionally, Scn8a gene expression, which encodes the Nav 1.6 channel, was decreased with aging in the SG. Application of loose patch clamp electrophysiology thus suggests that ionic current alterations with age in murine SG could contribute to cardiac autonomic dysregulation in geriatric conditions.

The intricate role of the autonomic nervous system (ANS) in regulating cardiac physiology has long been recognized. Aberrant function of the ANS is central to the pathophysiology of cardiovascular diseases. It stands to reason, therefore, that neuroscience-based cardiovascular therapeutics hold great promise in the treatment of cardiovascular diseases in humans. A decade after the inaugural edition, this White Paper reviews the current state of understanding of human cardiac neuroanatomy, neurophysiology and pathophysiology in specific disease conditions, autonomic testing, risk stratification, and neuromodulatory strategies to mitigate the progression of cardiovascular diseases.

This paper updates and builds on a previous White Paper in this journal that some of us contributed to concerning the molecular and cellular basis of cardiac neurobiology of heart disease. Here we focus on recent findings that underpin cardiac autonomic development, novel intracellular pathways and neuroplasticity. Throughout we highlight unanswered questions and areas of controversy. Whilst some neurochemical pathways are already demonstrating prognostic viability in patients with heart failure, we also discuss the opportunity to better understand sympathetic impairment by using patient specific stem cells that provides pathophysiological contextualization to study 'disease in a dish'. Novel imaging techniques and spatial transcriptomics are also facilitating a road map for target discovery of molecular pathways that may form a therapeutic opportunity to treat cardiac dysautonomia.

Spatially selective vagus nerve stimulation (sVNS) offers a promising approach for addressing heart disease with enhanced precision. Despite its therapeutic potential, VNS is limited by off-target effects and the need for time-consuming titration. Our research aimed to determine the spatial organization of cardiac afferent and efferent fibres within the vagus nerve of pigs to achieve targeted neuromodulation. Using trial-and-error sVNS in vivo and ex vivo micro-computed tomography fascicle tracing, we found significant spatial separation between cardiac afferent and cardiac efferent fibres at the mid-cervical level and they were localized on average on opposite sides of the nerve cross-section. This was consistent between both in vivo and ex vivo methods. Specifically, cardiac afferent fibres were located near pulmonary fibres, consistent with findings of cardiopulmonary convergent circuits and, notably, cardiac efferent fascicles were exclusive. These cardiac efferent regions were located in close proximity to the recurrent laryngeal regions. This is consistent with the roughly equitable spread across the nerve of the afferent and efferent fibres. Our study demonstrated that targeted neuromodulation via sVNS could achieve scalable heart rate decreases without eliciting cardiac afferent-related reflexes; this is desirable for reducing sympathetic overactivation associated with heart disease. These findings indicate that understanding the spatial organization of cardiac-related fibres within the vagus nerve can lead to more precise and effective VNS therapy, minimizing off-target effects and potentially mitigating the need for titration. KEY POINTS: Spatially selective vagus nerve stimulation (sVNS) presents a promising approach for addressing chronic heart disease with enhanced precision. Our study reveals significant spatial separation between cardiac afferent and efferent fibres in the vagus nerve, particularly at the mid-cervical level. Utilizing trial-and-error sVNS in vivo and micro-computed tomography fascicle tracing, we demonstrate the potential for targeted neuromodulation, achieving therapeutic effects such as scalable heart rate decrease without stimulating cardiac afferent-related reflexes. This spatial understanding opens avenues for more effective VNS therapy, minimizing off-target effects and potentially eliminating the need for titration, thereby expediting therapeutic outcomes in myocardial infarction and related conditions.

The sympathetic nervous system modulates cardiac contractile and electrophysiological function and contributes to adverse remodelling following myocardial infarction (MI). Axonal modulation therapy (AMT), directed at the sympathetic chain, blocks efferent sympathetic outflow to the heart and is a strategy to transiently and controllably mitigate chronic MI-associated sympatho-excitation. In porcine models, we evaluated scalable AMT, directed at the paravertebral chain, in blocking reflex-mediated pacing-induced sympatho-excitation post-MI. The level of sympatho-excitation was assessed by dynamic interstitial measurement of noradrenaline (NA) and neuropeptide Y (NPY). In anaesthetized normal (n = 5) and age-matched pigs 6 weeks post-MI induction (n = 10), we electrically stimulated the right sympathetic chain and determined levels of direct current block applied at the T1-T2 level sufficient to reduce the evoked changes in heart rate and/or contractility by 25-75%. Reflex-mediated neural release of NA and NPY into the interstitial space during programmed pacing (PP) was assessed using fast-scanning cyclic voltammetry and capacitive immunoprobes. Normal animals demonstrated homogeneous NA and NPY release profiles during PP. In contrast, for MI animals PP evoked differential NA and NPY release in remote and MI border zones of the left ventricle. Right-sided AMT mitigated NA and NPY pacing-induced release in the remote left ventricle with a positive correlation to increasing AMT levels. Pacing-induced NA and NPY release in the MI border zone was not mitigated by AMT. Differential effects of AMT on NA and NPY may underlie the anti-arrhythmic effects of partial stellate ganglion block in the setting of chronic MI. KEY POINTS: Programmed cardiac pacing evokes homogeneous noradrenaline (NA) and neuropeptide Y (NPY) release in equivalent areas (e.g. medial and lateral aspects) of the normal left ventricle. Programmed cardiac pacing evokes differential NA and NPY release in remote and border zones of the infarcted left ventricle. Axonal modulation therapy (AMT), using a graded direct current block applied to the stellate ganglia, can proportionally modulate cardiac sympathetic reflexes. Unilateral AMT mitigates NA and NPY release in remote left ventricular tissue, with release negatively correlated to increasing AMT levels. Heterogeneities in NA and NPY between the border and remote tissues are reduced by progressive AMT.

Sudden cardiac death (SCD) is generally associated with life-threatening ventricular arrhythmias. Supraventricular arrhythmias are an accepted cause of SCD in Wolff-Parkinson-White syndrome and complex congenital heart disease. However, the role of atrial tachyarrhythmias (ATAs) in SCD in patients with structurally normal hearts is unclear.

The goal of this study was to present data on resuscitated patients without structural heart disease (SHD), experiencing recurrent implantable cardioverter-defibrillator (ICD) shocks, who share common clinical and electrical features suggesting that ATAs can cause SCD.

We describe the clinical characteristics and ICD analysis of syncopal events terminated with shock delivery in 5 young SCD survivors without SHD. Details on the follow-up after ablation of the arrhythmia causing the syncopal episode are also reported.

In all patients (4 male, 1 female; median age 23 years; age range 15-47 years), a surface electrocardiogram recording in the resuscitation setting suggested ventricular fibrillation. After the index event, all patients exhibited recurrent arrhythmic syncopal episodes in a setting of elevated adrenergic tone, treated with ICD shocks. ICD interrogation suggested ATAs (atrial fibrillation in 4 patients, atrial tachycardia in 1 patient), conducting to the ventricles at rates approaching 300 beats/min, as the underlying arrhythmia leading to the syncopal events. ATA ablation abolished episodes of arrhythmic syncope and shock delivery in all patients after a median follow-up of 34 months. No patient died suddenly during follow-up.

Common clinical and electrical features define a distinct entity of SCD caused by ATAs with ultra-rapid ventricular response in otherwise healthy patients. Catheter ablation of the ATA is an effective treatment in these patients.

The standard conception of cardiac conduction is based on the cable theory of nerve conduction, which treats cardiac tissue as a continuous syncytium described by the Hodgkin-Huxley equations. However, cardiac tissue is composed of discretized cells with microscopic and macroscopic heterogeneities and discontinuities, such as subcellular localizations of sodium channels and connexins. In addition to this, there are heterogeneities in the distribution of sympathetic and parasympathetic nerves, which powerfully regulate impulse propagation. In the continuous models, the ultrastructural details, i.e. the microscopic heterogeneities and discontinuities, are ignored by 'coarse graining' or 'smoothing'. However, these ultrastructural components may play crucial roles in cardiac conduction and arrhythmogenesis, particularly in disease states. We discuss the current progress of modelling the effects of ultrastructural components on electrical conduction, the issues and challenges faced by the cardiac modelling community, and how to scale up conduction properties at the subcellular (microscopic) scale to the tissue and whole-heart (macroscopic) scale in future modelling and experimental studies, i.e. how to link the ultrastructure at different scales to impulse conduction and arrhythmogenesis in the heart.

In our original white paper published in the The Journal of Physiology in 2016, we set out our knowledge of the structural and functional organization of cardiac autonomic control, how it remodels during disease, and approaches to exploit such knowledge for autonomic regulation therapy. The aim of this update is to build on this original blueprint, highlighting the significant progress which has been made in the field since and major challenges and opportunities that exist with regard to translation. Imbalances in autonomic responses, while beneficial in the short term, ultimately contribute to the evolution of cardiac pathology. As our understanding emerges of where and how to target in terms of actuators (including the heart and intracardiac nervous system (ICNS), stellate ganglia, dorsal root ganglia (DRG), vagus nerve, brainstem, and even higher centres), there is also a need to develop sensor technology to respond to appropriate biomarkers (electrophysiological, mechanical, and molecular) such that closed-loop autonomic regulation therapies can evolve. The goal is to work with endogenous control systems, rather than in opposition to them, to improve outcomes.

The evolution of stem cell-based heart models from cells and tissues to organoids and assembloids and recently synthetic embryology gastruloids, is poised to revolutionize our understanding of cardiac development, congenital to adult diseases, and patient customized therapies. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have already been integrated into transplantable patches and are in preclinical efforts to reverse fibrotic scarring from myocardial infarctions. To inform on the complexity of heart diseases, multi-tissue morphogenic heart models are needed that replicate fundamental components of heart function to heart organogenesis in vitro and which require a deep understanding of heart development. Organoid and assembloid models capture selected multicellular cardiac processes, such as chamber formation and priming events for vascularization. Gastruloid heart models offer deeper insights as synthetic embryology to mimic multi-staged developmental events of in vivo heart organogenesis including established heart fields, crescent formation and heart tube development along with vascular systemic foundation and even further steps. The human Elongating Multi-Lineage Organized Cardiac (EMLOC) gastruloid model captures these stages and additional events including chamber genesis, patterned vascularization, and extrinsic central and intrinsic cardiac nervous system (CNS-ICNS) integration guided by spatiotemporal and morphogenic processes with neural crest cells. Gastruloid synthetic embryology heart models offer new insights into previously hidden processes of development and provide powerful platforms for addressing heart disease that extends beyond cardiomyocytes, such as arrhythmogenic diseases, congenital defects, and systemic injury interactions, as in spinal cord injuries. The holistic view that is emerging will reveal heart development and disease in unprecedented detail to drive transformative state-of-the-art innovative applications for heart health.

Background: In recent years, sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated significant cardiovascular and renal benefits in patients with heart failure (HF), in addition to their established antidiabetic effects. However, their role in arrhythmia prevention remains unclear. This study aimed to assess the effect of SGLT2 inhibitors on the incidence of supraventricular tachycardia (SVT) and ventricular tachycardia (VT) in patients with HF with reduced ejection fraction (HFrEF) during an extended follow-up period. Methods: This retrospective cohort study was conducted between January 2019 and November 2024 at the Ulm University Heart Center. All patients exhibited severely reduced left ventricular function and underwent primary prophylactic implantable cardioverter-defibrillator (ICD) implantation. Half of the cohort initiated SGLT2 inhibitor therapy alongside optimal medical HF treatment (the SGLT2 group). Patients were followed for approximately three years (846.2 ± 520.0 days) and the incidence of SVT and VT was analyzed using intracardiac Holter records of the ICD. Results: The study population consisted of 78 patients with a mean age of 66.6 ± 12.9 years. Over the follow-up period, a significant prolongation in the time to first occurrence of SVT was observed in the SGLT2 group (Log-Rank p = 0.03), suggesting a potential protective effect of SGLT2 inhibitors. However, regarding VT, additional SGLT2 inhibitor therapy did not show an additional benefit to optimal medical HF treatment. Conclusions: This study suggests that SGLT2 inhibitors may play a beneficial role in reducing the incidence of SVT in patients with HFrEF. These results highlight the importance of further investigating the antiarrhythmic potential of SGLT2 inhibitors through large-scale, prospective studies to better understand their clinical implications and mechanisms of action.

Autonomic regulation of cardiovascular function is often disrupted following a spinal cord injury (SCI). A systematic review was undertaken to evaluate the effect of non-invasive, non-pharmacological (NINP) interventions on cardiovascular autonomic biomarkers in adults with SCI. AMED, CENTRAL, CINAHL EMBASE, and MEDLINE were searched from inception to May 17, 2024. Randomized controlled trials (RCTs) of NINP interventions for cardiovascular autonomic biomarkers (heart rate variability [HRV], systolic blood pressure variability [SBPV], or baroreflex gain) in adults (≥18 years of age) with SCI (>3 months) were included. Primary outcomes included HRV (low-frequency power [HRV-LF], high-frequency power [HRV-HF], root mean square of successive differences [RMSSD]), SBPV (low-frequency power [SBPV-LF]), and baroreflex sensitivity. The quality and certainty of the evidence were assessed using version 2 of the Cochrane risk of bias tool and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis tool, respectively. Of 2651 records identified, six RCTs were included (participants, n = 123). HRV-LF (four studies; participants, n = 69) and HRV-HF (five studies; participants, n = 93) showed no to small changes in favor of NINP interventions ([g = 0.25; 95% confidence interval [CI] = -0.23, 0.73; p = 0.31; I2 = 0%], [g = 0.00; 95% CI = -0.41, 0.42; p = 0.98; I2 = 0%], respectively). Limited evidence was available for RMSSD, SBPV-LF, and baroreflex gain. This review found that the evidence is inconclusive regarding the effect of NINP interventions on the included HRV, BPV, and BRS parameters in adults with SCI. Further research with strong methodological rigor is needed to provide greater insights in this area.

Cardiovascular disease has remained the top contributor to global mortality for decades, necessitating research into the most effective methods of its prevention and treatment. Simultaneous with an immense amount of discovery and innovation in the field of cardiology, certain therapies with traditional Chinese origins have become progressively more popular in the West in recent decades. Specifically, ancient meditative mind-body practices such as Qigong and Tai Chi may lower cardiovascular disease risk and severity through a focus on movement and meditation. Such practices are generally low-cost and modifiable, with few adverse effects. Studies have shown higher quality of life in patients with coronary artery disease and heart failure after participation in Tai Chi, as well as a positive impact on cardiovascular risk factors such as hypertension and waist circumference. Most studies in the field have various limitations, such as small sample size, lack of randomization, and inadequate control; however, these practices show potential as an adjunct in the prevention and treatment of cardiovascular disease. Patients unable or unwilling to partake in traditionally aerobic activities may benefit greatly from such mind-body therapies. Nonetheless, more studies are warranted for more definitive answers to the question of Tai Chi and Qigong's effectiveness. In this narrative review, we discuss the current evidence surrounding the effects of Qigong and Tai Chi on cardiovascular disease, in addition to the limitations and difficulties in conducting such studies.

Ventricular arrhythmias increase cardiovascular morbidity and mortality. Recurrent PVCs and IVT are generally considered benign in the absence of structural heart abnormalities. Artificial intelligence is a rapidly growing field. In recent years, medical professionals have shown great interest in the potential use of ML, an integral part of AI, in various disciplines, including diagnostic applications, decision-making, prognostic stratification, and solving complex pathophysiological aspects of diseases from these data at extraordinary complexity, scale, and acquisition rate. The aim of this study was to design an ML model to predict the probability of PVC and IVT recurrence after RF ablation. Data of patients were collected and manipulated using traditional analysis and various artificial intelligence models, namely MLP, Gradient Boosting Machines, Random Forest, and Logistic Regression. Hypertension, male sex, and the use of non-irrigate catheters were associated with less freedom from arrhythmia. All these results were obtained through traditional analytic methods, and according to AI, none of the variables had a clear effect on the recurrence of arrhythmia. Each AI model presents unique strengths and weaknesses, and further optimization and fine-tuning of these models are necessary to increase their clinical utility. By expanding the dataset, improved predictions can be fostered to ultimately increase the clinical utility of AI in predicting PVC erosion outcomes.

About 26 million people worldwide live with heart failure (HF), and hypertension is the primary cause in 25% of these cases. Autonomic dysfunction and sympathetic hyperactivity accompany cardiovascular diseases, including HF. However, changes in cardiac sympathetic innervation in HF are not well understood. We hypothesized that cardiac sympathetic innervation is disrupted in hypertension-induced HF. Male and female C57BL6/J mice were infused with angiotensin II (ANG II) for 4 wk to generate hypertension leading to HF; controls were infused with saline. ANG II-treated mice displayed HF phenotype, including reduced cardiac function, hypertrophy, and fibrosis. ANG II-treated mice also had significantly reduced sympathetic nerve density in the left ventricle, intraventricular septum, and right ventricle. In the left ventricle, the subepicardium remained normally innervated, whereas the subendocardium was almost devoid of sympathetic nerves. Loss of sympathetic fibers led to loss of norepinephrine content in the left ventricle. Several potential triggers for axon degeneration were tested and ruled out. ANG II-treated mice had increased premature ventricular contractions after isoproterenol and caffeine injection. Although HF can induce a cholinergic phenotype and neuronal hypertrophy in stellate ganglia, ANG II treatment did not induce a cholinergic phenotype or activation of trophic factors in this study. Cardiac neurons in the left stellate ganglion were significantly smaller in ANG II-treated mice, whereas neurons in the right stellate were unchanged. Our findings show that ANG II-induced HF disrupts sympathetic innervation, particularly in the left ventricle. Further investigations are imperative to unveil the mechanisms of denervation in HF and to develop neuromodulatory therapies for patients with autonomic imbalance.NEW & NOTEWORTHY Angiotensin II (ANG II)-induced hypertension leads to a heart failure phenotype and cardiac sympathetic denervation with the endocardial region of the left ventricle being the most affected. Denervation is accompanied by loss of norepinephrine content in the left ventricle and increased premature ventricular contractions (PVCs) after isoproterenol and caffeine injection. ANG II treatment also causes morphological changes in cardiac-projecting left stellate ganglion neurons.

Increased sympathetic and reduced parasympathetic nerve activity is associated with disease progression and poor outcomes in patients with chronic heart failure. The demonstration that markers of autonomic imbalance and vagal dysfunction, such as reduced heart rate variability and baroreflex sensitivity, hold prognostic value in patients with chronic heart failure despite modern therapies encourages the research for neuromodulation strategies targeting the vagus nerve. However, the approaches tested so far have yielded inconclusive results. This review aims to summarize the current knowledge about the role of the parasympathetic nervous system in chronic heart failure, describing the pathophysiological background, the methods of assessment, and the rationale, limits, and future perspectives of parasympathetic stimulation either by drugs or bioelectronic devices.

The mechanisms linking acute psychological stress to cardiovascular disease (CVD) mortality are incompletely understood. We studied the relationship of electrocardiographic measures of autonomic dysfunction during acute mental stress provocation and CVD death.

In a pooled cohort of 765 participants with stable CVD from two related studies, we collected Holter data during standardized laboratory-based mental stress testing with a speech task and followed them for events. We assessed autonomic function using low-frequency (LF) heart rate variability (HRV) in 5-min intervals before, during, and after stress induction, and specifically examined changes from rest to stress. We employed cause-specific survival models to examine its association with CVD and all-cause mortality, controlling for demographic and CVD risk factors. The mean (SD) age was 58 (10) years, 35% were women, and 44% self-identified as Black. After a median follow-up of 5.6 years, 37 (5%) died from CVD causes. A stress-induced LF HRV decrease (67% of sample), vs. increase, was associated with a hazard ratio (HR) of 3.48 (95% confidence interval-3.25, 3.73) for CVD mortality. Low rest LF HRV (bottom quartile) was also independently associated with CVD mortality, HR = 1.75 (1.58, 1.94), vs. normal rest LF HRV (upper three quartiles). The combination of stress-induced LF HRV decrease and low rest LF HRV was associated with HR = 5.73 (5.33, 6.15) vs. the normal stress/rest LF HRV reference. We found similar results with HF HRV.

Stress-induced LF HRV decrease and low rest LF HRV are both independently and additively associated with a higher CVD mortality risk. Additional research is needed to assess whether targeting autonomic dysfunction may improve CVD outcomes.

Heart failure and chronic kidney disease are common and clinically important conditions that regularly coexist. Electrophysiologic changes of advanced heart failure often result in abnormal conduction, causing dyssynchronous contraction, and development of ventricular arrhythmias, which can lead to sudden cardiac arrest. In the last 2 decades, implantable cardioverter-defibrillator and cardiac resynchronization therapy devices have been developed to address these complications. However, when the coexisting chronic kidney disease is advanced, the associated pathophysiologic cardiovascular changes can alter the efficacy and safety of those interventions and complicate the management. This review explores the impact of comorbid advanced heart failure and advanced chronic kidney disease on the efficacy and safety of implantable cardioverter-defibrillator and cardiac resynchronization therapy, the currently available evidence, and potential future directions.

Diabetes mellitus (DM) confers an increased risk of sudden cardiac death (SCD) independent of its associated cardiovascular comorbidities. DM induces adverse structural, electrophysiologic, and autonomic cardiac remodeling that can increase one's risk of ventricular arrhythmias and SCD. Although glycemic control and prevention of microvascular and macrovascular complications are cornerstones in the management of DM, they are not adequate for the prevention of SCD. In this narrative review, we describe the contribution of DM to the pathophysiologic mechanism of SCD beyond its role in atherosclerotic cardiovascular disease and heart failure. On the basis of this pathophysiologic framework, we outline potential preventive and therapeutic strategies to mitigate the risk of SCD in this population of high-risk patients.

This study evaluated the effects of cessation of both conventional low-frequency (50 Hz) and high-frequency (10 kHz) spinal cord stimulation (SCS) on the cardiospinal neural network activity in pigs with myocardial infarction (MI). The objective is to provide an insight into the memory effect of SCS.

In nine Yorkshire pigs, chronic MI was created by delivering microspheres to the left circumflex coronary artery. Five weeks after MI, anesthetized pigs underwent sternotomy to expose the heart for performing acute ischemia intervention, and laminectomy to expose the T1-T4 spinal regions for extracellular in vivo neural recording and SCS. Cardiac ischemic-sensitive neurons were identified by selective responsiveness to left anterior descending (LAD) coronary artery occlusion. SCS episodes were delivered in a random order between low- (50 Hz) and high- (10 kHz) frequency, for 1 minute, at 90% of the motor threshold current. Neural firing and synchrony of ischemic-sensitive spinal neurons were evaluated before vs after SCS.

Using a 64-channel microelectrode array, 2711 spinal neurons were recorded extracellularly. LAD ischemia excited 228 neurons that were labeled as ischemic-responsive neurons. The cessation of 50-Hz SCS caused a higher activation than did inhibition of ischemic-responsive neurons (41 activated vs 19 inhibited), whereas the cessation of 10-kHz SCS caused an opposite response with higher inhibition (11 activated vs 28 inhibited, p < 0.01 vs 50 Hz). Termination of low-frequency SCS caused an increase in ischemic-responsive neuronal firing rate compared with high-frequency SCS (50 Hz: 0.39 Hz ± 0.16 Hz, 10 kHz: -0.11 Hz ± 0.057 Hz, p < 0.01). In addition, SCS delivered at 50 Hz increased the number of synchronized pairs of neurons by 205 pairs, whereas high-frequency SCS decreased the number of synchronized pairs by 345 pairs (p < 0.01).

High-frequency (10 kHz) stimulation provides persistent suppression of the ischemia-sensitive neurons after termination of SCS. In contrast, the spinal neural network reverted to excitatory state after termination of low-frequency (50 Hz) stimulation.

Communication between sympathetic nerves and the immune system is a crucial and active process during myocardial ischemia (MI), as myocardial damage and inflammatory stimuli concurrently occur. Sympathetic nerves undergo structural and functional changes after MI, leading to adverse left ventricular (LV) remodeling and heart failure (HF). The complex inflammatory response to MI, including local myocardial anti-inflammatory repair and systemic immune reactions, plays a key role in adverse LV remodeling. Here, we review the progressive structural and electrophysiological remodeling of the LV and the involvement of sympathetic tone in complex and dynamic processes that are susceptible to MI pathological conditions. Acupuncture has been reported to effectively improve cardiac function, eliminate arrhythmia, and mitigate adverse LV remodeling via somatosensory regulation after MI. Moreover, acupuncture has an anti-inflammatory effect on the pathological process of myocardial ischemia. In this Review, we aim to summarize the involvement of sympathetic nerve activation in the neuro-immune modulation of structural and functional cardiac changes after MI. As a noninvasive method for sympathetic regulation, acupuncture is an ideal option because of its anti-ischemic efficacy. A better understanding of the neural circuitry that regulates cardiac function and immune responses following MI could reveal novel targets for acupuncture treatment.

The neurocardiac axis constitutes the neuronal circuits between the arteries, heart, brain, and immune organs (including thymus, spleen, lymph nodes, and mucosal associated lymphoid tissue) that together form the cardiovascular brain circuit. This network allows the individual to maintain homeostasis in a variety of environmental situations. However, in dysfunctional states, such as exposure to environments with chronic stressors and sympathetic activation, this axis can also contribute to the development of atherosclerotic vascular disease as well as other cardiovascular pathologies and it is increasingly being recognized as an integral part of the pathogenesis of cardiovascular disease. This review article focuses on 1) the normal functioning of the neurocardiac axis; 2) pathophysiology of the neurocardiac axis; 3) clinical implications of this axis in hypertension, atherosclerotic disease, and heart failure with an update on treatments under investigation; and 4) quantification methods in research and clinical practice to measure components of the axis and future research areas.