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Targeted Ganglionated Plexi Denervation Using Magnetic Nanoparticles Carrying Calcium Chloride Payload.

ABSTRACT: OBJECTIVES:This study sought to develop a novel targeted delivery therapy to ablate the major atrial ganglionated plexi (GP) using magnetic nanoparticles carrying a CaCl2 payload. BACKGROUND:Prior studies indicated the role of hyperactivity of the cardiac autonomic nervous system in the genesis of atrial fibrillation. METHODS:Twenty-eight male mongrel dogs underwent a bilateral thoracotomy. CaCl2-encapsulated magnetic nanoparticles (Ca-MNP) included magnetite in a sphere of biocompatible, biodegradable poly(lactic-co-glycolic acid). A custom external electromagnet focusing the magnetic field gradient (2,600 G) on the epicardial surface of the targeted GP was used to pull Ca-MNP into and release CaCl2 within the GP. The ventricular rate slowing response to high frequency stimulation (20 Hz, 0.1 ms) of the GP was used to assess the GP function. RESULTS:The minimal effective concentration of CaCl2 to inhibit the GP function was 0.5 mmol/l. Three weeks after CaCl2 (0.5 mmol/l, n = 18 GP) or saline (n = 18 GP) microinjection into GP, the increased GP function, neural activity, and atrial fibrillation inducibility, as well as shortened effective refractory period in response to 6 h of rapid atrial pacing (1,200 beats/min) were suppressed by CaCl2 microinjection. After intracoronary infusion of Ca-MNP, the external electromagnet pulled Ca-MNP to the targeted GP and suppressed the GP function (n = 6 GP) within 15 min. CONCLUSIONS:Ca-MNP can be magnetically targeted to suppress GP function by calcium-mediated neurotoxicity. This novel approach may be used to treat arrhythmias related to hyperactivity of the cardiac autonomic nervous system, such as early stage of atrial fibrillation, with minimal myocardial injury.

SUBMITTER: Yu L

PROVIDER: S-EPMC6598434 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Targeted Ganglionated Plexi Denervation Using Magnetic Nanoparticles Carrying Calcium Chloride Payload.

Yu Lilei L Scherlag Benjamin S BS Dormer Kenneth K Rutel Isaac I Huang Bing B Zhou Xiaoya X Kuriakose Aneetta E AE Nguyen Kytai K KK Po Sunny S

JACC. Clinical electrophysiology 20180829 10

<h4>Objectives</h4>This study sought to develop a novel targeted delivery therapy to ablate the major atrial ganglionated plexi (GP) using magnetic nanoparticles carrying a CaCl<sub>2</sub> payload.<h4>Background</h4>Prior studies indicated the role of hyperactivity of the cardiac autonomic nervous system in the genesis of atrial fibrillation.<h4>Methods</h4>Twenty-eight male mongrel dogs underwent a bilateral thoracotomy. CaCl<sub>2</sub>-encapsulated magnetic nanoparticles (Ca-MNP) included ma ...[more]

PMID: 30336881

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Project description:Background The autonomic nervous system response to apnea and its mechanistic connection to atrial fibrillation (AF) are unclear. We hypothesize that sensory neurons within the ganglionated plexi (GP) play a role. We aimed to delineate the autonomic response to apnea and to test the effects of ablation of cardiac sensory neurons with resiniferatoxin (RTX), a neurotoxic TRPV1 (transient receptor potential vanilloid 1) agonist. Methods Sixteen dogs were anesthetized and ventilated. Apnea was induced by stopping ventilation until oxygen saturations decreased to 80%. Nerve recordings from bilateral vagal nerves, left stellate ganglion, and anterior right GP were obtained before and during apnea, before and after RTX injection in the anterior right GP (protocol 1, n=7). Atrial effective refractory period and AF inducibility on single extrastimulation were assessed before and during apnea, and before and after intrapericardial RTX administration (protocol 2, n=9). GPs underwent immunohistochemical staining for TRPV1. Results Apnea increased anterior right GP activity, followed by clustered crescendo vagal bursts synchronized with heart rate and blood pressure oscillations. On further oxygen desaturation, a tonic increase in stellate ganglion activity and blood pressure ensued. Apnea-induced effective refractory period shortening from 110.20±31.3 ms to 90.6±29.1 ms ( P<0.001), and AF induction in 9/9 dogs versus 0/9 at baseline. After RTX administration, increases in GP and stellate ganglion activity and blood pressure during apnea were abolished, effective refractory period increased to 126.7±26.9 ms ( P=0.0001), and AF was not induced. Vagal bursts remained unchanged. GP cells showed cytoplasmic microvacuolization and apoptosis. Conclusions Apnea increases GP activity, followed by vagal bursts and tonic stellate ganglion firing. RTX decreases sympathetic and GP nerve activity, abolishes apnea's electrophysiological response, and AF inducibility. Sensory neurons play a role in apnea-induced AF.

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Targeted Ganglionated Plexi Denervation Using Magnetic Nanoparticles Carrying Calcium Chloride Payload.

Publications

Targeted Ganglionated Plexi Denervation Using Magnetic Nanoparticles Carrying Calcium Chloride Payload.

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