title: Particulate matter induces cardiac arrhythmias via dysregulation of carotid body sensitivity and cardiac sodium channels.
abstract: The mechanistic links between exposure to airborne particulate matter (PM) pollution and the associated increases in cardiovascular morbidity and mortality, particularly in people with congestive heart failure (CHF), have not been identified. To advance understanding of this issue, genetically engineered mice (CREB(A133)) exhibiting severe dilated cardiomyopathic changes were exposed to ambient PM collected in Baltimore. CREB(A133) mice, which display aberrant cardiac physiology and anatomy reminiscent of human CHF, displayed evidence of basal autonomic aberrancies (compared with wild-type mice) with PM exposure via aspiration, producing significantly reduced heart rate variability, respiratory dysynchrony, and increased ventricular arrhythmias. Carotid body afferent nerve responses to hypoxia and hyperoxia-induced respiratory depression were pronounced in PM-challenged CREB(A133) mice, and denervation of the carotid bodies significantly reduced PM-mediated cardiac arrhythmias. Genome-wide expression analyses of CREB(A133) left ventricular tissues demonstrated prominent Na(+) and K(+) channel pathway gene dysregulation. Subsequent PM challenge increased tyrosine phosphorylation and nitration of the voltage-gated type V cardiac muscle α-subunit of the Na(+) channel encoded by SCN5A. Ranolazine, a Na(+) channel modulator that reduces late cardiac Na(+) channel currents, attenuated PM-mediated cardiac arrhythmias and shortened PM-elongated QT intervals in vivo. These observations provide mechanistic insights into the epidemiologic findings in susceptibility of human CHF populations to PM exposure. Our results suggest a multiorgan pathobiology inherent to the CHF phenotype that is exaggerated by PM exposure via heightened carotid body sensitivity and cardiac Na(+) channel dysfunction.
authors: Section of Pulmonary, Critical Care, Sleep & Allergy, Department of Medicine, University of Illinois at Chicago, Illinois, USA.
authors: Ting
authors: T
authors: Wang
authors: Gabriel D
authors: GD
authors: Lang
authors: Liliana
authors: L
authors: Moreno-Vinasco
authors: Yong
authors: Y
authors: Huang
authors: Sascha N
authors: SN
authors: Goonewardena
authors: Ying-Jie
authors: YJ
authors: Peng
authors: Eric C
authors: EC
authors: Svensson
authors: Viswanathan
authors: V
authors: Natarajan
authors: Roberto M
authors: RM
authors: Lang
authors: Jered D
authors: JD
authors: Linares
authors: Patrick N
authors: PN
authors: Breysse
authors: Alison S
authors: AS
authors: Geyh
authors: Jonathan M
authors: JM
authors: Samet
authors: Yves A
authors: YA
authors: Lussier
authors: Samuel
authors: S
authors: Dudley
authors: Nanduri R
authors: NR
authors: Prabhakar
authors: Joe G N
authors: JG
authors: Garcia
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D015142:Baltimore; D001919:Bradycardia / Q000139:chemically induced; D002344:Carotid Body / Q000187:drug effects* / Q000503:physiopathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000209:etiology; D006352:Heart Ventricles / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D062554:NAV1.5 Voltage-Gated Sodium Channel; D052638:Particulate Matter / Q000633:toxicity*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D000393:Air Pollutants; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D062554:NAV1.5 Voltage-Gated Sodium Channel; D052638:Particulate Matter; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels