Autonomic denervation, myocardial hypoperfusion and fibrosis may predict ventricular arrhythmia in the early stages of Chagas cardiomyopathy.

BACKGROUND: Sudden cardiac death (SCD) can be the first clinical event of Chagas heart disease (CHD). However, current guidelines contain no clear recommendation for early cardioverter-defibrillator implantation. Using imaging modalities, we evaluated associations among autonomic denervation, myocardial hypoperfusion, fibrosis and ventricular arrhythmia in CHD. METHODS AND RESULTS: Twenty-nine patients with CHD and preserved left ventricular function underwent 123I-metaiodobenzylguanidine (MIBG) scintigraphy, 99mTc-methoxyisobutylisonitrile (MIBI) myocardial perfusion and cardiac magnetic resonance imaging (MRI). They were divided into arrhythmic (≥ 6 ventricular premature complexes/h and/or non-sustained ventricular tachycardia on 24-hour Holter, n = 15) and non-arrhythmic (< 6 ventricular premature complexes/h and no ventricular tachycardia; n = 14) groups. The arrhythmic group had higher denervation scores from MIBG imaging (23.2 ± 18.7 vs 5.6 ± 4.9; P < .01), hypoperfusion scores from MIBI SPECT (4.7 ± 6.8 vs 0.29 ± 0.6: P = .02), innervation/perfusion mismatch scores (18.5 ± 17.5 vs 5.4 ± 4.8; P = .01) and fibrosis by late gadolinium enhancement on MRI (14.3% ± 13.5% vs 4.0% ± 2.9%; P = .04) than the non-arrhythmic group. CONCLUSION: These imaging parameters were associated with ventricular arrhythmia in early CHD and may enable risk stratification and the implementation of primary preventive strategies for SCD.

Renal Denervation Exacerbates LPS- and Antibody-induced Acute Kidney Injury, but Protects from Pyelonephritis in Mice.

BACKGROUND: Renal denervation (RDN) is an invasive intervention to treat drug-resistant arterial hypertension. Its therapeutic value is contentious. Here we examined the effects of RDN on inflammatory and infectious kidney disease models in mice. METHODS: Mice were unilaterally or bilaterally denervated, or sham operated, then three disease models were induced: nephrotoxic nephritis (NTN, a model for crescentic GN), pyelonephritis, and acute endotoxemic kidney injury (as a model for septic kidney injury). Analytical methods included measurement of renal glomerular filtration, proteinuria, flow cytometry of renal immune cells, immunofluorescence microscopy, and three-dimensional imaging of optically cleared kidney tissue by light-sheet fluorescence microscopy followed by algorithmic analysis. RESULTS: Unilateral RDN increased glomerular filtration in denervated kidneys, but decreased it in the contralateral kidneys. In the NTN model, more nephritogenic antibodies were deposited in glomeruli of denervated kidneys, resulting in stronger inflammation and injury in denervated compared with contralateral nondenervated kidneys. Also, intravenously injected LPS increased neutrophil influx and inflammation in the denervated kidneys, both after unilateral and bilateral RDN. When we induced pyelonephritis in bilaterally denervated mice, both kidneys contained less bacteria and neutrophils. In unilaterally denervated mice, pyelonephritis was attenuated and intrarenal neutrophil numbers were lower in the denervated kidneys. The nondenervated contralateral kidneys harbored more bacteria, even compared with sham-operated mice, and showed the strongest influx of neutrophils. CONCLUSIONS: Our data suggest that the increased perfusion and filtration in denervated kidneys can profoundly influence concomitant inflammatory diseases. Renal deposition of circulating nephritic material is higher, and hence antibody- and endotoxin-induced kidney injury was aggravated in mice. Pyelonephritis was attenuated in denervated murine kidneys, because the higher glomerular filtration facilitated better flushing of bacteria with the urine, at the expense of contralateral, nondenervated kidneys after unilateral denervation.

Improvements in Nerve Dissection Surgery Methodology for Spasmodic Torticollis Treatment.

Spasmodic torticollis is the most common focal dystonia and is characterized by aberrant involuntary contraction of muscles of the neck and shoulders, which greatly affects patients' quality of life. Consequently, patients with this condition often desire treatment to alleviate their symptoms. The common clinical treatments for spasmodic torticollis include interventions such as drug therapy, botulinum toxin injections, and surgery. Surgical treatment is feasible for patients who do not respond well to other treatments or who are resistant to drugs. The gradual improvement of surgeons' understanding of anatomy and the ongoing developments in surgical techniques since their advent in the 1640s have resulted in many innovative surgical approaches that have led to improvements in the treatment of spasmodic torticollis. Previously used surgical treatments that result in uncertain outcomes, various postoperative complications, and serious damage to motor functions of the head and neck have gradually been discontinued. Nerve dissection surgery is the most common surgical treatment for spasmodic torticollis. This article reviews existing research on nerve dissection surgery for the treatment of spasmodic torticollis and the history of its development, along with the advantages and disadvantages of various surgical improvements. This article aims to provide clinicians with practical advice.

Electrical storm: Prognosis and management.

Electrical storm is present when a cluster of ventricular arrhythmias (VAs) occurs within a short time frame. The most widely accepted definition is 3 or more episodes of VA within a 24-h period, although prognostic risk begins to rise when 2 or more events occur within 3months. Electrical storm often presents as a medical emergency in the form of recurrent implantable cardiac defibrillator (ICD) shocks, recurrent syncope in patients with no ICD or low cardiac output symptoms. Management often requires a multimodality approach including ICD management, pharmacologic therapy, catheter ablation and modulations of the autonomic nervous system. In this article, we review the definition, prognosis and management of electrical storm.

Effect of renal denervation on long-term outcomes in patients with resistant hypertension.

Increasing studies strongly prove that renal denervation, a minimally invasive surgery, is a promising new non-drug treatment method that can effectively control blood pressure in patients with resistant hypertension, but the evaluation of the long-term blood pressure control effect of renal denervation for resistant hypertension is still lacking. Here, we critically review current long-term follow-up data about the use of renal denervation for RH to comprehensively evaluate the effectiveness of renal denervation for RH, and to provide practical guidance for practitioners who are establishing a renal denervation service. Limited by the current research, many problems need to be solved before renal denervation is applied to RH. In addition, ambulatory blood pressure should be the first choice for the evaluation of blood pressure. Finally, the continuous antihypertensive effect of renal denervation in different renal denervation systems also needs to be strictly compared.

Surgical Treatment of Atrial Fibrillation.

The surgical treatment of atrial fibrillation (AF) has evolved significantly over the last 20 years and even more so in the last 5 years. There are now many clinically successful surgical procedures focused on eliminating AF and AF-related stroke. This review discusses the current types of surgical AF procedures, including minimally invasive and hybrid, and may assist clinicians in understanding the various surgical AF options available to patients today.

Renal denervation prevents myocardial structural remodeling and arrhythmogenicity in a chronic kidney disease rabbit model.

BACKGROUND: The electrophysiological (EP) effects and safety of renal artery denervation (RDN) in chronic kidney disease (CKD) are unclear. OBJECTIVE: The purpose of this study was to investigate the arrhythmogenicity of RDN in a rabbit model of CKD. METHODS: Eighteen New Zealand white rabbits were randomized to control (n = 6), CKD (n = 6), and CKD-RDN (n = 6) groups. A 5/6 nephrectomy was selected for the CKD model. RDN was applied in the CKD-RDN group. All rabbits underwent cardiac EP studies for evaluation. Immunohistochemistry, myocardial fibrosis, and renal catecholamine levels were evaluated. RESULTS: The CKD group (34.8% ± 9.2%) had a significantly higher ventricular arrhythmia (VA) inducibility than the control (8.6% ± 3.8%; P <.01) and CKD-RDN (19.5% ± 6.3%; P = .01) groups. In the CKD-RDN group, ventricular fibrosis was significantly decreased compared to the CKD group (7.4% ± 2.0 % vs 10.4% ± 3.7%; P = .02). Sympathetic innervation in the CKD group was significantly increased compared to the control and CKD-RDN groups [left ventricle: 4.1 ± 1.8 vs 0.8 ± 0.5 (102 µm2/mm2), P <.01; 4.1 ± 1.8 vs 0.9± 0.6 (102 µm2/mm2), P <.01; right ventricle: 3.6 ± 1.0 vs 1.0 ± 0.4 (102 µm2/mm2), P <.01; 3.6 ± 1.0 vs 1.0 ± 0.5 (102 µm2/mm2), P <.01]. CONCLUSION: Neuromodulation by RDN demonstrated protective effects with less structural and electrical remodeling, leading to attenuated VAs. In a rabbit model of CKD, RDN plays a therapeutic role by lowering the risk of VA caused by autonomic dysfunction.

Neuroscientific therapies for atrial fibrillation.

The cardiac autonomic nervous system (ANS) plays an integral role in normal cardiac physiology as well as in disease states that cause cardiac arrhythmias. The cardiac ANS, comprised of a complex neural hierarchy in a nested series of interacting feedback loops, regulates atrial electrophysiology and is itself susceptible to remodelling by atrial rhythm. In light of the challenges of treating atrial fibrillation (AF) with conventional pharmacologic and myoablative techniques, increasingly interest has begun to focus on targeting the cardiac neuraxis for AF. Strong evidence from animal models and clinical patients demonstrates that parasympathetic and sympathetic activity within this neuraxis may trigger AF, and the ANS may either induce atrial remodelling or undergo remodelling itself to serve as a substrate for AF. Multiple nexus points within the cardiac neuraxis are therapeutic targets, and neuroablative and neuromodulatory therapies for AF include ganglionated plexus ablation, epicardial botulinum toxin injection, vagal nerve (tragus) stimulation, renal denervation, stellate ganglion block/resection, baroreceptor activation therapy, and spinal cord stimulation. Pre-clinical and clinical studies on these modalities have had promising results and are reviewed here.

Advanced Therapies for Ventricular Arrhythmias in Patients With Chagasic Cardiomyopathy: JACC State-of-the-Art Review.

Chagas disease is caused by infection from the protozoan parasite Trypanosoma cruzi. Although it is endemic to Latin America, global migration has led to an increased incidence of Chagas in Europe, Asia, Australia, and North America. Following acute infection, up to 30% of patients will develop chronic Chagas disease, with most patients developing Chagasic cardiomyopathy. Chronic Chagas cardiomyopathy is highly arrhythmogenic, with estimated annual rates of appropriate implantable cardioverter-defibrillator therapies and electrical storm of 25% and 9.1%, respectively. Managing arrhythmias in patients with Chagasic cardiomyopathy is a major challenge for the clinical electrophysiologist, requiring intimate knowledge of cardiac anatomy, advanced training, and expertise. Endocardial-epicardial mapping and ablation strategy is needed to treat arrhythmias in this patient population, owing to the suboptimal long-term success rate of endocardial mapping and ablation alone. We also describe innovative approaches to improve acute and long-term clinical outcomes in patients with refractory ventricular arrhythmias following catheter ablation, such as bilateral cervicothoracic sympathectomy and bilateral renal denervation, among others.

Cutaneous sensory and autonomic denervation in progressive supranuclear palsy.

AIM: Progressive Supranuclear Palsy (PSP) is a progressive neurodegenerative tauopathy characterised by motor, behavioural and cognitive dysfunction. While in the last decade, sensory and autonomic disturbances as well as peripheral nerve involvement are well-recognised in Parkinson's Disease (PD), little is known in this regard for PSP. Herein, we aim to assess peripheral sensory and autonomic nerve involvement in PSP and to characterise possible differences in morpho-functional pattern compared to PD patients. METHODS: We studied 27 PSP and 33 PD patients without electrophysiological signs of neuropathy, and 33 healthy controls (HC). In addition to motor impairment, evaluated by means of UPDRS-III and the PSP rating scale, all patients underwent clinical, functional and morphological assessment of sensory-autonomic nerves through dedicated questionnaires, sympathetic skin response, dynamic sweat test and skin biopsies. The analysis of cutaneous sensory and autonomic innervation was performed using indirect immunofluorescence and confocal microscopy. RESULTS: PSP patients displayed a length-dependent loss of sensory and autonomic nerve fibres associated with functional impairment compared to HC and, overall, a more severe picture than in PD patients. The disease severity correlated with the loss of intraepidermal nerve fibre density in the leg of PSP patients (p < 0.05). CONCLUSION: We demonstrated a length-dependent small fibre pathology in PSP, more severe compared to PD, and paralleling disease severity. Our findings suggest the morphological and functional study of cutaneous nerves as possible biomarkers to monitor disease progression and response to new treatments.

Changes in sympathetic nervous system activity after renal denervation: results from the randomised Oslo RDN study.

PURPOSE: Sympathetic nervous system (SNS) over-activity is associated with essential hypertension. Renal sympathetic denervation (RDN) possibly lowers office- and ambulatory blood pressure (BP) in patients with treatment-resistant hypertension (TRH). We aimed to assess the effect of RDN compared to drug adjustment on SNS activity among patients with TRH by measuring plasma catecholamines and heart rate variability (HRV) during stress tests. MATERIALS AND METHODS: Patients with TRH were randomised to RDN (n = 9) or Drug Adjustment (DA) (n = 10). We measured continuous HRV and beat-to-beat-BP using FinaPres® and obtained plasma catecholamines during standardised orthostatic- and cold-pressor stress tests (CPT) before- and six months after randomisation. RESULTS: CPT revealed no differences between groups at baseline in peak adrenaline concentration (69.3 pg/mL in the DA group vs. 70.0 pg/mL in the RDN group, p = 0.38) or adrenaline reactivity (Δ23.1 pg/mL in the DA group vs. Δ29.3 pg/mL in the RDN group, p = 0.40). After six months, adrenaline concentrations were statistically different between groups after one minute (66.9 pg/mL in the DA group vs. 55.3 pg/mL in the RDN group, p = 0.03), and six minutes (62.4 pg/mL in the DA group vs. 50.1 pg/mL in the RDN group, p = 0.03). There was a tendency of reduction in adrenaline reactivity after six months in the RDN group (Δ26.3 pg/mL at baseline vs. Δ12.8 pg/ml after six months, p = 0.08), while it increased in the DA group (Δ13.6 pg/mL at baseline vs. Δ19.9 pg/mL after six months, p = 0.53). We also found a difference in the Low Frequency band at baseline following the CPT (667µs2 in the DA group vs. 1628µs2 in the RDN group, p = 0.03) with a clear tendency of reduction in the RDN group to 743µs2 after six months (p = 0.07), compared to no change in the DA group (1052µs2,p = 0.39). CONCLUSION: Our data suggest that RDN reduces SNS activity after six months. This finding warrants investigation in a larger study. Clinical Trial Number registered at www.clinicaltrials.gov: NCT01673516.

Calcium-Induced Autonomic Denervation in Patients With Post-Operative Atrial Fibrillation.

BACKGROUND: Post-operative atrial fibrillation (POAF) is associated with worse long-term cardiovascular outcomes. OBJECTIVES: This study hypothesized that injecting calcium chloride (CaCl2) into the major atrial ganglionated plexi (GPs) during isolated coronary artery bypass grafting (CABG) can reduce the incidence of POAF by calcium-induced autonomic neurotoxicity. METHODS: This proof-of-concept study randomized 200 patients undergoing isolated, off-pump CABG to CaCl2 (n = 100) or sodium chloride (sham, n = 100) injection. Two milliliters of CaCl2 (5%) or sodium chloride (0.9%) was injected into the 4 major atrial GPs during CABG. All patients received 7-day continuous telemetry and Holter monitoring. The primary outcome was incidence of POAF (≥30 s) in 7 days. Secondary outcomes included length of hospitalization, POAF burden, average ventricular rate during AF, plasma level of inflammatory markers, and actionable antiarrhythmic therapy to treat POAF. RESULTS: The POAF incidence was reduced from 36% to 15% (hazard ratio: 0.366; 95% confidence interval: 0.211 to 0.635; p = 0.001). Length of hospitalization did not differ between the 2 groups. POAF burden (first 7 post-operative days), the use of amiodarone or esmolol, and the incidence of atrial couplets and nonsustained atrial tachyarrhythmias were significantly reduced in the CaCl2 group. Heart rate variability data showed a decrease in both high-frequency and low-frequency power in the CaCl2 group with a preserved low-frequency/high-frequency ratio, suggesting that the sympathetic/parasympathetic balance was not perturbed by CaCl2 injection. CONCLUSIONS: Injection of CaCl2 into the 4 major atrial GPs reduced the POAF hazard by 63%. Inhibition of GP function by Ca-mediated neurotoxicity may underlie the therapeutic effect. (Calcium Autonomic Denervation Prevents Postoperative Atrial Fibrillation; ChiCTR1800019276).

Cancer-Associated Neurogenesis and Nerve-Cancer Cross-talk.

In this review, we highlight recent discoveries regarding mechanisms contributing to nerve-cancer cross-talk and the effects of nerve-cancer cross-talk on tumor progression and dissemination. High intratumoral nerve density correlates with poor prognosis and high recurrence across multiple solid tumor types. Recent research has shown that cancer cells express neurotrophic markers such as nerve growth factor, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor and release axon-guidance molecules such as ephrin B1 to promote axonogenesis. Tumor cells recruit new neural progenitors to the tumor milieu and facilitate their maturation into adrenergic infiltrating nerves. Tumors also rewire established nerves to adrenergic phenotypes via exosome-induced neural reprogramming by p53-deficient tumors. In turn, infiltrating sympathetic nerves facilitate cancer progression. Intratumoral adrenergic nerves release noradrenaline to stimulate angiogenesis via VEGF signaling and enhance the rate of tumor growth. Intratumoral parasympathetic nerves may have a dichotomous role in cancer progression and may induce Wnt-ß-catenin signals that expand cancer stem cells. Importantly, infiltrating nerves not only influence the tumor cells themselves but also impact other cells of the tumor stroma. This leads to enhanced sympathetic signaling and glucocorticoid production, which influences neutrophil and macrophage differentiation, lymphocyte phenotype, and potentially lymphocyte function. Although much remains unexplored within this field, fundamental discoveries underscore the importance of nerve-cancer cross-talk to tumor progression and may provide the foundation for developing effective targets for the inhibition of tumor-induced neurogenesis and tumor progression.

Atrial fibrillation in obstructive sleep apnea: Neural mechanisms and emerging therapies.

Obstructive sleep apnea (OSA) has been reproducibly identified as a risk factor for initiation and progression of atrial fibrillation (AF) and reduces the efficacy of antiarrhythmic drugs, electrical cardioversion, and catheter ablation in AF. It is still controversial whether continuous positive airway pressure ventilation (CPAP) could improve the successful rate of AF treatment in OSA patients. Besides, CPAP has shown relative low compliance in patients with OSA. Therefore, novel optional therapies might be needed to improve the control of AF associated with OSA. A growing body of evidence suggests that autonomic activation contributes to the pathogenesis of AF in OSA. Acute apneic episodes result in sympathovagal co-activation, shortening atrial refractoriness and promoting the initiation of AF. Chronic OSA-induced sympathetic activation plays a crucial role in atrial autonomic, structural, and electrical remodeling, thus providing substrates for AF maintenance and recurrence. Therefore, the autonomic nervous system may be a promising therapeutic target for OSA and AF. Autonomic modulation as a treatment for OSA-associated AF has been well established in several preclinical studies. Further clinical studies are needed to provide a more precise definition of the role of autonomic modulation in the treatment of AF in OSA.

Stimulation Mapping of the Pulmonary Artery for Denervation Procedures: an Experimental Study.

Transcatheter pulmonary artery denervation (PADN) has been developed for the correction of pulmonary hypertension. We investigated pulmonary artery stimulation mapping and its role in PADN procedures. Artery stimulation was performed in 17 Landrace pigs. Low-frequency stimulation defined areas of ventricular and atrial capture. High-frequency stimulation evoked the following responses: sinus rhythm slowing and/or atrial rhythm acceleration in 59% of animals, phrenic nerve capture in 100%, and laryngeal recurrent nerve capture in 23%. The sites with evoked heart rate responses were marked by discrete radiofrequency ablations (RFA). An autopsy showed nerves in the adventitia and perivascular fat under the RFA sites, and the lack of muscarinic-1, tyrosine hydroxylase, and dopamine-5 receptors' expression. During PADN, areas adjacent to the course of phrenic and recurrent laryngeal nerves should be avoided. RFA at points with heart rate responses leads to the non-reproducibility of evoked reactions and the disappearance of neural markers' expression. Graphical abstract.

Pallidal Deep Brain Stimulation in Patients with Prior Bilateral Pallidotomy and Selective Peripheral Denervation for Treatment of Dystonia.

INTRODUCTION: Deep brain stimulation (DBS) of the globus pallidus internus has become an accepted treatment for severe isolated idiopathic and inherited dystonia. Patients who had other forms of surgery earlier, such as radiofrequency lesioning or selective peripheral denervation, however, usually are not considered candidates for DBS. OBJECTIVE: The aim of this study was to evaluate the long-term outcome of pallidal DBS in a rare subgroup of patients who had undergone both pallidotomy and selective peripheral denervation previously with a waning effect over the years. METHODS: Pallidal DBS was performed according to a prospective study protocol in 2 patients with isolated idiopathic dystonia, and patients were followed for a period of at least 6 years. RESULTS: Both patients benefitted from long-lasting amelioration of dystonia after pallidal DBS, which was comparable to that of patients who did not have previous surgeries. In a 62-year-old female with cervical dystonia both the Burke-Fahn-Marsden (BFM) and the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) motor scores were improved at follow-up 8 years after surgery (50 and 39%). In a 32-year-old male with generalized dystonia, the BFM motor and disability scores showed marked improvement at 6.5 years of follow-up (82 and 66%). CONCLUSIONS: Pallidal DBS can yield marked and long-lasting improvement in patients who underwent both pallidotomy and selective peripheral denervation earlier. Therefore, such patients, in general, should not be excluded from DBS.

TRPC6 participates in the development of blood pressure variability increase in sino-aortic denervated rats.

Increased blood pressure variability (BPV) has been proved to be associated with cardiovascular morbidity and mortality. It is of great significance to elucidate the mechanism of BPV increase. The cation channel transient receptor potential canonical 6 (TRPC6) is involved in a series of cardiovascular disease. Our experiment aimed to explore the role of TRPC6 in the development of BPV increase. Sino-aortic denervation (SAD) operation was applied to establish the model of BPV increase in rats. The BPV was presented as the standard deviation to the mean of systolic or diastolic blood pressure every 1 h during 12 h of the light period. SAD was performed in male Sprague Dawley (SD) rats at the age of 10 weeks. At 8 weeks after SAD operation, the hemodynamic parameters were determined non-invasively via a Rodent Blood Pressure Analysis System. The TRPC6 expressions in myocardial and thoracic aortic tissue was determined utilizing Western Blot, immunofluorescence and quantitative RT-PCR. The expression of TRPC3 was detected as well. To investigate whether TRPC6 was a causative factor of BPV increase in SAD rats, TRPC6 activator and inhibitor with three progressively increasing doses were intraperitoneally injected to the SAD rats. We found that SAD rats presented significant augmentation of systolic and diastolic BPV with no change of BP level and heart rate. The mRNA and protein expression levels of TRPC6 in myocardial and thoracic aortic tissue in SAD rats were substantially increased, but there was no obvious change in TRPC3 expression. The systolic and diastolic BPV increase were dose-dependently exacerbated after TRPC6 activation with GSK1702934A but were dose-dependently attenuated after TRPC6 inhibition with SAR7334. In Conclusion, the TRPC6 (but not TRPC3) expressions in myocardial and thoracic aortic tissue were substantially increased in SAD rats, and TRPC6 probably played an important role in the development of BPV elevation.