Right ventricular cardiomyocyte expansion accompanies cardiac regeneration in newborn mice after large left ventricular infarcts
Tianyuan Hu, Mona Malek Mohammadi, Fabian Ebach, Michael Hesse, Michael I. Kotlikoff, Bernd K. Fleischmann
Tianyuan Hu, Mona Malek Mohammadi, Fabian Ebach, Michael Hesse, Michael I. Kotlikoff, Bernd K. Fleischmann
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Research Article Cardiology

Right ventricular cardiomyocyte expansion accompanies cardiac regeneration in newborn mice after large left ventricular infarcts

Abstract

Cauterization of the root of the left coronary artery (LCA) in the neonatal heart on postnatal day 1 (P1) resulted in large, reproducible lesions of the left ventricle (LV), and an attendant marked adaptive response in the right ventricle (RV). The response of both chambers to LV myocardial infarction involved enhanced cardiomyocyte (CM) division and binucleation, as well as LV revascularization, leading to restored heart function within 7 days post surgery (7 dps). By contrast, infarction of P3 mice resulted in cardiac scarring without a significant regenerative and adaptive response of the LV and the RV, leading to subsequent heart failure and death within 7 dps. The prominent RV myocyte expansion in P1 mice involved an acute increase in pulmonary arterial pressure and a unique gene regulatory response, leading to an increase in RV mass and preserved heart function. Thus, distinct adaptive mechanisms in the RV, such as CM proliferation and RV expansion, enable marked cardiac regeneration of the infarcted LV at P1 and full functional recovery.

Authors

Tianyuan Hu, Mona Malek Mohammadi, Fabian Ebach, Michael Hesse, Michael I. Kotlikoff, Bernd K. Fleischmann

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Figure 1

Cauterization of the root of the LCA results in opposite outcomes in P1 and P3 MI mice.

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Cauterization of the root of the LCA results in opposite outcomes in P1 ...
(A) P1 MI hearts and heart sections at 2, 7, and 21 days post surgery (dps). Visualization of scar areas (marked with dashed lines) with TNNI3 and DAPI or Sirius red and Fast Green costaining. Scale bars: 1 mm. (B) Quantitation of infarct size (percentage of the LV). (C) Ejection fraction (EF) measured with echocardiography in P1. (D) P3 MI hearts and heart sections, visualization of scar area (marked with dashed lines) with TNNI3 and DAPI or Sirius red and Fast Green costaining. Scale bars: 1 mm. (E) Quantitation of infarct size. (F) EF measured with echocardiography. (G) Kaplan-Meier survival curve of mice after P1 MI and P3 MI. (H) Echocardiographic short-axis view of MI and sham hearts; dashed lines mark endocardial and epicardial regions. Scale bar: 1 mm. (I) Echocardiographic measurements of LV wall thickness in MI and sham hearts. (J) Echocardiographic long-axis view of MI and sham hearts; red lines mark the endocardium of the LV at the end of diastole. Scale bar: 1 mm. (K) Echocardiographic quantitation of the LV end diastolic area (LVEDA) in MI and sham hearts. (L) Quantitation of LV cardiomyocyte (CM) cross-sectional area in MI and sham hearts. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by unpaired, 2-tailed Student’s t test (E) or 1-way ANOVA with Holm-Šidák post hoc test (B, C, F, I, K, and L). Data in G were evaluated with the log-rank test: P = 0.0006. NS, no significance.