Lilei Yu1, Benjamin S Scherlag2, Kenneth Dormer3, Isaac Rutel4, Bing Huang1, Xiaoya Zhou1, Aneetta E Kuriakose5, Kytai K Nguyen5, Sunny Po6. 1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Wuhan University, Wuhan, China. 2. Section of Cardiovascular Diseases and Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. 3. Integrative Physiology and Pharmacology Department, College of Osteopathic Medicine, Liberty University, Lynchburg, Virginia. 4. Department of Radiological Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. 5. Department of Bioengineering, the University of Texas at Arlington, Arlington, Texas. 6. Section of Cardiovascular Diseases and Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Electronic address: sunny-po@ouhsc.edu.
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.
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.
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