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Adverse remodeling of cardiac cholinergic innervation and pacemaker dysfunction in Gαq overexpressing mice
Author(s) -
Hoover Donald B.,
Hoard Jennifer L.,
Mabe Abigail M.,
Hancock John C.,
Cormaci Gianfrancesco,
Kaludercic Nina,
Feng Ning,
Dorn Gerald W.,
Paolocci Nazareno
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1263-c
Subject(s) - chronotropic , medicine , cholinergic , bradycardia , endocrinology , stimulation , atropine , cardiac pacemaker , heart rate , heart failure , blood pressure
Cardiac‐selective overexpression of Gαq leads first to cardiac hypertrophy and then to marked systolic dysfunction and blunted β‐adrenergic response. Unlike clinical heart failure, Gαq overexpressors also exhibit a reduced heart rate. To address this discrepancy, we evaluated cardiac cholinergic innervation in Gαq overexpressors at 6 months of age. Resting HR, chronotropic response to right vagal stimulation (VS) and effect of atropine (5 mg/kg, i.p.) were determined by EKG analysis in mice anesthetized with 2% isoflurane. Compared to control mice, overexpressors had a lower resting HR and shorter PR interval (25±3 vs 65±11 ms, n=6‐7, P<0.01). VS caused a robust, frequency‐dependent bradycardia in control mice with 20Hz stimuli reducing HR by 81±2% to 84±19 bpm. Chronotropic response to VS was absent or blunted in transgenic mice. Transgenic responders exhibited a higher threshold for stimulation‐evoked bradycardia and smaller responses. Stimulation at 20Hz decreased HR by 20±4% to 132±12 bpm (n=4). Atropine increased heart rate by 114±23 bpm in control mice but did not affect HR significantly in overexpressors. Immunohistochemical analysis of atrial tissue sections revealed a much lower density of cholinergic nerves in Gαq mice compared to nontransgenic controls. We conclude that chronic Gαq overexpression by cardiac myocytes produces an intrinsic pacemaker defect and causes adverse remodeling of cardiac cholinergic neurons. Supported by grants from AHA and HL075265.