Electrophysiological and Structural Remodeling of the Atria in a Mouse Model of Troponin-I Mutation Linked Hypertrophic Cardiomyopathy: Implications for Atrial Fibrillation

Figures

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  Figure 1. Action potential durations (APD) at 20% (APD20), 50% (APD50), and 90% (APD90) repolarization are reduced in both young and aged hypertrophic cardiomyopathy (HCM) atria. Young HCM mice atria demonstrated reduced APD20, APD50, and APD90 compared to control mice across all pacing cycle lengths tested. Similarly, aged HCM mice also showed reduced APD20, APD50, and APD90 compared to controls across all pacing cycle lengths tested. * p < 0.001.

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  Figure 2. Electrophysiological changes in the HCM left atria (LA). ((A), left) Young HCM mice demonstrate unchanged effective refractory period (ERP), whereas aged mice (right) exhibit increased ERP across all pacing cycle lengths. ((B), left) Young HCM mice demonstrate unchanged conduction velocity (CV), whereas aged mice (right) exhibit decreased CV across all pacing cycle lengths. (C) Both young (left) and aged (right) HCM mice demonstrate increased conduction heterogeneity index (CHI) as compared to controls across all pacing cycle lengths. (D) Representative LA time maps and corresponding phase histograms of mice at 30 weeks and 50 weeks at 200 ms pacing. Phase histograms depict the number of episodes on the y-axis and the largest phase difference within each quadruplet of electrodes on the x-axis. Young HCM mice demonstrate unchanged total activation time but increased conduction heterogeneity progressing to slowed heterogeneous conduction in aged mice. Isochrones (black lines) are constructed at 1 ms intervals. Red indicates the start of the electrical impulse activation and pink represents the longest activation time with intermediate values color coded according to the time scale…

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  Figure 3. HCM mouse atria demonstrates myocyte hypertrophy, elevated inflammatory cell infiltrates, and interstitial fibrosis. (A) Representative photomicrographs of transverse sections of the LA stained with hematoxylin and eosin (H&E; top) and Masson’s trichrome (MT; bottom) in young and aged HCM mice demonstrated increased inflammatory cell infiltration (black arrowheads) and interstitial fibrosis (stained blue; red arrowheads) in the atrial myocardium as compared to controls. Scale = 50 µm. (B) Pooled data on LA cardiomyocyte diameter, (C) inflammatory cell infiltrate, and (D) atrial fibrosis across six independent animals per group. No significant age differences were observed. * p < 0.05, ** p < 0.01 and *** p < 0.001.

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  Figure 4. HCM mouse atria demonstrates altered connexin 43 (Cx43) expression, increased macrophage infiltration, and changes in extracellular matrix remodeling. (A) Representative photomicrographs of transverse sections of the LA stained for Cx43, ionized calcium binding adaptor molecule 1 (Iba-1) macrophage, matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase 1 (TIMP-1), transforming growth factor beta 1 (TGFβ1) expression. Red arrowheads indicate Iba-1+ve macrophages. Scale = 25 µm. Cumulative data on Cx43 (B), Iba-1 (C), MMP-2 (D), TIMP-1 (E), and TGFβ1 (F) expressed as a percentage of total myocardium area in six independent samples per group. * p < 0.05, ** p < 0.01 and *** p < 0.001.

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  Figure 5. Circulating plasma biomarkers of extracellular matrix and inflammation. (A) Plasma levels of extracellular matrix biomarkers MMP-2, -3, pro-MMP-9, TIMP-1, and TGFβ1 in young and aged HCM mice compared to controls. (B) Plasma levels of inflammatory biomarkers tumor necrosis factor alpha (TNFα), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) in both young and aged HCM mice compared to controls. * p < 0.05 and *** p < 0.001.

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  Figure 6. Summary of atrial conduction, histological, and circulating biomarker alterations in the troponin I (TnI) mutant mouse model of HCM. Created with BioRender.com on 17 June 2021.