Abstract 14918: Invalidation Of Trpm4 Channel In Mouse Induces Slowed Cardiac Conduction, Arrhythmias And Hyperplasia
Background: TRPM4 channel is selective for Na+ and K+, activated by intracellular Ca2+ and blocked by intracellular ATP. It was recently demonstrated to be involved in human cardiac rhythm defects when TRPM4 is over expressed while its physiological role in the heart is unclear, in particular in electrical conduction and rhythm control.
Method: We used a knock-out mouse model for Trpm4 gene (Trpm4-/-). Electrophysiologic explorations (electrocardiogram in vigil mice and intracardiac exploration), echocardiographic analyses, frozen hearts cryosections, qPCR and cellular electrophysiology were performed for in vivo and in vitro analyses.
Results: Electrical conduction was lengthened in absence of the TRPM4 channel (PR and QRS intervals were 39±0.5 vs. 42.3±0.3; and 16.8±0.5 vs. 19.4±0.4. ms; for Trpm4+/+ (n=13) and Trpm4-/- (n=18) mice). Both the suprahisian (AH) and infrahisian (HV) conduction times were increased in Trpm4-/- mice compared to Trpm4+/+ (n=6). Trpm4-/- mice also exhibited a high incidence of atrioventricular blocks exclusively after a progressive prolongation of the few PR intervals preceding the blocks. Trpm4-/- mice developed frequent ectopic atrial activities not observed in Trpm4+/+ mice. We then investigated the cardiac morphology and function. The Trpm4-/- mice exhibited increased left ventricular (LV) mass (2.62±0.17 vs. 3.14±0.16 mg/g, n=11 for Trpm4+/+ and 14 Trpm4-/- mice) and LV dilation (0.85±0.03 in Trpm4+/+ vs. 0.96±0.03 10-1 mm/g in Trpm4-/-). By different techniques, we excluded the hypothesis of pro-fribotic phenotype or increased LV cardiomyocytes size. We thus assessed the hyperplasic status of cardiomyocytes during cardiomyogenesis by staining of phospho-histone H3 (P-H3), a mitosis marker, in heart cryosections one day after birth. P-H3 staining was increased 3-fold throughout the heart of Trpm4-/-.
Conclusion: Taken together, all these data suggest that TRPM4 invalidation is associated with pathophysiological phenotype characterized by conduction disorders, arrhythmias and hypertrophy due to neonate hyperplasia.
- © 2011 by American Heart Association, Inc.