Therefore, we propose that efficient removal of cardiac tissue at the 4HNE level by both augmenting ALDH2 activation mediated 4HNE detoxification, along with decreasing hyperglycemia-mediated 4HNE production, will be beneficial in ameliorating diabetes-associated HFpEF, which can be tested in other HFpEF models where oxidative stress ensues. The gene discussed is ALDH2; the disease is diabetes mellitus.