The left ventricle undergoes biomechanical and gene expression changes in response to increased right ventricular pressure overload

Figures

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  Figure 1. (a) Overall study design, timeline, and analysis; (b and c) Short axis cardiac MRI of a Sham mouse at (b) end‐diastole and (c) end‐systole. (d) Histology with collagen staining shown in blue for a randomly selected Sham mouse. (e, f) Short axis cardiac MRI of a PAB mouse at (e) end‐diastole and (f) end‐systole, respectively. (g) Histology with collagen staining in the LV of a randomly selected PAB mouse. Arrows show visible regions of fibrosis

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  Figure 2. Pulmonary arterial banding results in significant changes to RV systolic function and gene expression. (a) Slope graphs showing longitudinal changes in RV ejection fraction for PAB and Sham mice. The plot shows a significant decrease in RV EF 1‐week after PAB. (b) RV stroke is significantly increased in mice after 7‐weeks of PAB, relative to the Sham animals. (c) Example ventricular pressure‐volume loops in Sham and PAB mice use to compute ventricular stroke work. (d) Principal component analysis biplot of the first 2 principal components, showing Sham and PAB animals cluster based on 5 genes. (e) RV myocardium shows significantly increased β‐MHC expression at 7‐weeks after PAB. In the box plots shown, the central mark indicates the mean, with bottom and top edges showing the 25th and 75th percentiles, respectively. The symbol: * indicates statistical significance of the Wilcox rand sum test (p 2‐tailed < .05)

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  Figure 3. An acute pressure‐overload insult to the RV leads to biomechanical and functional changes in the LV. (a, b) LV ejection fraction and torsion rate compared longitudinally using slope graphs and between control and PAB mice. LV ejection fraction (LVEF) is significantly decreased 1‐week after PAB and remains decreased for the duration of the experiment. (b) LV torsion rate (TR) during systole is significantly decreased 1‐week after PAB and remains decreased for the duration of the experiment. (c) LV stroke work is significantly decreased at week 7 after PAB, relative to Sham mice. (d) LV and septal weight normalized by mouse body weight ((LV + S)/BW)) is significantly decreased in mice at 7‐weeks after PAB. (e) Multivariate linear regression model between declining LV systolic function/mechanics ‐measured by maximum LV torsion rate and LV ejection fraction ‐ and declining RV ejection fraction. Red and black dots represent PAB and Sham animals, respectively. In the box plots shown, the central mark indicates the mean, with bottom and top edges showing the 25th and 75th percentiles, respectively. The symbol: * indicates statistical significance of the Wilcox rand sum test (p 2‐tailed…

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  Figure 4. Gene expression is altered in the LV of mice after PAB surgery, and changes in expression are correlated to changes in contractile mechanics. (a) Principal component biplot shows that LV gene and protein expression in the LV stratify PAB and Sham mice along PC2. (b, c) β‐MHC expression in the LV is significantly increased after PAB surgery and ATP2A2 ‐which governs myocardial calcium dynamics‐ in the LV is significantly decreased. (d, e) Downregulation of miR‐130a and let‐7b – respectively‐ in the LV are correlated with a decrease in maximum LV torsion during systole. (f) Stepwise linear regression with interaction reveals a multivariate model of gene expression (including genes coding for contractile proteins) in the LV described 99% of the variability in maximum LV torsion. (g) An increase in β‐MHC expression in the LV is correlated with a decrease in LV torsion rate. In the box plots shown, the central mark indicates the mean, with bottom and top edges showing the 25th and 75th percentiles, respectively. The symbol: * indicates statistical significance of the Wilcox rand sum test (p 2‐tailed < .05)