Preventing Right Heart Failure in Pressure-Overload Hypertrophy through Transplantation of Autologous Mitochondria

Objectives: We have previously shown that a key event in the progression of right ventricular hypertrophy (RVH) to failure (RVF) is cardiomyocyte apoptosis due to mitochondrial dysfunction. With transplantation of respiration-competent mitochondria available, the aim of this study was to determine whether localized intramyocardial injection of autologous mitochondria could prevent heart failure.

Methods: An RVH/RVF model was created by banding of the pulmonary artery (PAB) by 50% (gradient =15–20 mm Hg) in immature piglets (n = 6/group). Sham-operated animals served as control (Ctr). Animals were followed up for 8 weeks by echocardiography (RV free-wall thickness, TAPSE). Four weeks after surgery, banded animals were either treated with autologous mitochondria (PAB-mito), or vehicle (PAB-V) through injection into the RV free wall. At euthanasia, tissue was analyzed histologically for cardiomyocyte hypertrophy, fibrosis (H&E, Masson’s trichrome, desmin), and apoptosis by TUNEL. Invasive PV loop measurements (Ved, Dp/Dt max, Pdev) were obtained at baseline and euthanasia.

Results: All animals survived until study end point. One month after surgery, banded animals showed hypertrophy signs with a significantly thicker RV free wall (cm) compared with Ctr (0.27 ± 0.03 vs. 0.4 ± 0.02; p < 0.01). RV wall thickness further increased until study end point in the PAB-mito animals, whereas PAB-V hearts were already severely dilated (0.5 ± 0.04 vs. 0.28 ± 0.08; p < 0.01). Total heart weight (g) (Ctr: 100.6 ± 11.4, PAB-V: 132.4 ± 31.9, PAB-mito: 141.5 ± 31.4; p < 0.05) and histological hypertrophy calculations (desmin/nuclei ratio: Ctr: 0.17 ± 0.02, PAB-V: 0.45 ± 0.01, PAB-mito: 0.42; p < 0.05) corresponded with these findings. There was no apoptotic cardiomyocyte loss in Ctr and PAB-mito hearts but 3 ± 1/total nuclei in the PAB-V hearts. Dp/Dtmax (mm Hg/s) significantly increased from 831.9 ± 170.5 in all groups at baseline to 1,006 ± 178.2 in PAB-mito compared with a decline in PAB-V (501.2 ± 158.9) and remained unchanged in Ctr (843.5 ± 27.6) at euthanasia (p < 0.05). TAPSE (mm) at baseline (10.3 ± 1.7) significantly decreased in PAB-V (6.5 ± 0.6) compared with a significant improvement in PAB-mito (12.3 ± 1; p < 0.01).

Conclusion: Mitochondrial transplantation maintained hypertrophic adaptation of the RV and preserved contractile function. Addressing the myocardial dysfunction directly by targeting mitochondrial dysfunction will allow us to offer treatment for patients with pulmonary disease affecting right heart function.