Jennifer Hadley

THE ROLE OF TISSUE STRUCTURE AND INTERCELLULAR ELECTRICAL COUPLING VIA CONNEXIN43 IN ARRHYTHMOGENESIS IN A TRANSGENIC RABBIT MODEL OF HEART FAILURE. Jennifer Hadley¹, Crystal Ripplinger¹, Igor Efimov¹, Department of Biomedical Engineering, Washington University, St. Louis, MO¹.

According to the American Heart Association, over 5 million Americans have been diagnosed with Heart Failure (HF), for which there is no available treatment. Sudden Cardiac Death (SCD) is one of the main causes of death associated with Heart Failure. One common cause of familial HF in humans is a mutation in the gene encoding sarcomeric heavy chain myosin. Humans express mostly β-myosin heavy chain (β-MyHC), while mice express mostly α-MyHC, making them a poor model for SCD studies. Rabbits, however, express β-MyHC, which allowed us to characterize the tissue structure and intercellular electrical coupling via connexin43 (Cx43) of a specific transgenic rabbit model of HCM.

Methods: Hearts from transgenic (TG) rabbits (n=6) with a point mutation in the β-MyHC chain gene (R403Q) were investigated and results were compared to non-transgenic (NTG) age- and weight-matched controls (n=6). The transmural fiber angle shift was measured using optical coherence tomography (OCT) from the anterior left ventricle, and compared to values obtained using Diffusion-Tensor-MRI (DTMRI). The Cx43 distribution throughout the left ventricle was quantified using immunohistochemistry on sections parallel to the epicardium and analyzed using confocal microscopy.

Results: OCT revealed that the sub-epicardial transmural fiber angle shift was significantly higher in the TG group compared to the NTG controls: 34.4° ± 17.6° versus 3.75° ± 3.17° (mean ± STD, p=0.04), with distinct jumps in fiber angle visible in 2 of the 3 TG hearts. These results agreed with DTMRI data where the change in fiber angle across the LV wall was found to be 106.2° ± 1.5° in the TG hearts versus 83.8° ± 9.8° in the NTG controls. Cx43 distribution in sub-epicardial sections also showed a significant difference between the TG group and NTG controls: 0.0490 ± 0.00028 versus 0.0415 ± 0.00016 (mean ± variance, p=0.0001).

Conclusions: The increase in Cx43 density of the transgenic model suggests an increase in intercellular coupling, possibly including disorganized cellular communication via lateralized gap junctions. The increased transmural fiber angle shows that there are also changes in the structural properties of the transgenic rabbit model. Both the molecular and structural differences may be behind the increased risk of arrhythmias and SCD experienced by these animals.