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: Ting Wang, Gabriel D Lang, Liliana Moreno-Vinasco, Yong Huang, Sascha N Goonewardena, Ying-Jie Peng, Eric C Svensson, Viswanathan Natarajan, Roberto M Lang, Jered D Linares, Patrick N Breysse, Alison S Geyh, Jonathan M Samet, Yves A Lussier, Samuel Dudley, Nanduri R Prabhakar, Joe G N Garcia
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 46 Issue 4 Pg. 524-31 (Apr 2012) ISSN: 1535-4989 [Electronic] United States
• PMID: 22108299 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Air Pollutants
• Creb1 protein, mouse
• Cyclic AMP Response Element-Binding Protein
• NAV1.5 Voltage-Gated Sodium Channel
• Particulate Matter
• SCN5A protein, human
• Scn5a protein, mouse
• Sodium Channels

Topics

• Air Pollutants (toxicity)
• Animals
• Arrhythmias, Cardiac (chemically induced)
• Baltimore
• Bradycardia (chemically induced)
• Carotid Body (drug effects, physiopathology)
• Cyclic AMP Response Element-Binding Protein (genetics)
• Disease Models, Animal
• Gene Expression Regulation
• Heart Failure (etiology)
• Heart Ventricles (drug effects)
• Mice
• Mice, Inbred Strains
• Mice, Mutant Strains
• NAV1.5 Voltage-Gated Sodium Channel
• Particulate Matter (toxicity)
• Sodium Channels (genetics, metabolism)