Loss of Hepatic ALDH2 Contributes to Metabolic Stress Mediated Heart Failure

Recent studies report an increased incidence of cardiovascular diseases (CVDs) in patients with metabolic-dysfunction-associated steatotic liver disease (MASLD). Liver pathology resulting from increased metabolic stress has been linked to the development of heart failure (HF), but the pathophysiology remains unclear. Our research demonstrates that metabolic stress leads to elevated production of reactive oxygen species (ROS), causing increased lipid peroxidation and the production of 4-hydroxy-2-nonenal (4-HNE), a toxic aldehyde. The enzyme aldehyde dehydrogenase (ALDH2) primarily detoxifies harmful aldehydes like 4-HNE, thus protecting tissues including the liver and heart. Therefore, we hypothesized that low hepatic ALDH2 plays a significant role in metabolic stress-mediated hepatic damage and resultant HF progression. To test this hypothesis, we employed ALDH2hepatic-/- knockout (KO) mice with low hepatic ALDH2 and wild-type (WT) mice and subjected them to a high-fat diet (HFD) (60% kcal from fat) for 4 weeks. After this period, we assessed hepatic 4-HNE adduct levels and ALDH2 enzyme activity. We also measured hepatic oxidative stress, inflammation, fibrosis, and associated cell signaling changes using histopathology and immunoblotting. Additionally, we measured cardiac function using echocardiography. The results showed increased 4-HNE adducts in ALDH2hepatic-/- KO mice compared to WT mice after metabolic stress (p=0.0286). We found exacerbated liver inflammation and fibrosis in ALDH2hepatic-/- KO mice compared to WT mice. Most importantly, we found augmented cardiac dysfunction in ALDH2hepatic-/- KO mice with HFD compared to WT mice with HFD (p<0.05). These findings indicate that a decrease in hepatic ALDH2 exacerbates the progression of HF following metabolic stress-mediated liver damage due to increased reactive aldehydes. In conclusion, we postulate that decreasing hepatic ROS-mediated reactive aldehydes in MASLD-like metabolic conditions by activating ALDH2 will attenuate hepatic damage-mediated HF progression. Henry Ford Health System A10249 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.