Mitochondria in right heart failure – potential for therapeutic strategies

• Applicants: Dr. Anna Klinke, Ph.D.; Dr. Marion Müller
• Subject Area: Cardiology, Angiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 532901429

Despite the fact that right ventricular (RV) dysfunction (RVD) significantly impairs patients’ prognosis, no specific treatment options for RVD or right heart failure (RHF) are available. Approved left heart failure (LHF) drugs are ineffective or even harmful in RVD or RHF. The understanding of RHF pathomechanisms and in particular of interventricular differences in heart failure pathophysiology is insufficient. To develop specific treatment options, it is inevitable to advance translational research focusing on RHF and to decipher molecular mechanisms of the disease. A number of data point towards mitochondrial oxidative stress (mitoROS) to play a role in RHF pathogenesis. In a recent project we observed that in a murine model of RV pressure overload, oxidative stress was associated with the development of RHF, mitochondrial antioxidative therapy alleviated RHF symptoms and oxidative damage was associated with RVD in patients’ RV tissue. However, the functionally relevant subcellular targets in the RV, that are affected by mitoROS are unknown, and mitochondrial antioxidants have not yet been tested for RVD or RHF in clinical trials. With the project outlined here, we intend to unravel subcellular mechanisms driving the development of RHF with a particular focus on mitoROS, to identify a pharmacological strategy to prevent and reverse RHF and to review translation of our findings to patients. We hypothesize, that mitochondrial and sarcomere dysfunction is importantly involved in the functional deterioration of the RV. To achieve our aims, we will use murine models of RV pressure and volume overload and will deepen and specify the phenotypic identification of RHF in these models. Moreover, we will conduct extensive studies of relevant subcellular mechanisms that may be responsible for the transition from RVD to RHF using the mouse models and additionally using isolated cardiomyocytes and Langendorff-perfused hearts. These investigations will particularly focus on mitochondrial and sarcomere integrity. In addition, we will test the two antioxidative molecules nitro-oleic acid and SS-31, that have been tested in phase 2 clinical trials for other disorders, as potential preventive and therapeutic agents. Finally, we will conduct a comprehensive clinical evaluation of patients with pulmonary arterial hypertension (PAH) and patients with tricuspid regurgitation (TR) undergoing transcatheter tricuspid valve intervention, both with severe RVD or RHF. By taking RV biopsies, we will test for enhanced oxidative damage and its potential correlation with their clinical phenotype. With the proposed project, we aim to significantly advance the understanding of RHF and disclose, whether a targeted and effective antioxidative therapy could possibly be aimed at for a specific patient population, be it PAH patients to prevent RHF decompensation or TR patients, to stabilize their RV function in preparation for a clinical intervention.

• DFG Programme: Research Grants
• Co-Investigators: Dr. Daniel Dumitrescu; Dr. Dragan Opacic, Ph.D.