A ‘2-Hit’ model of HFpEF has been described where mice received both a metabolic insult from a 60% high-fat diet (HFD) and a haemodynamic insult from the endothelial nitric oxide synthase (eNOS) inhibitor L-NAME to induce hypertension.144 This 2-Hit mouse model results in diastolic dysfunction, as evidenced by the elevated E/E′ ratio, with preserved EF.144 Importantly, a study from Tong et al.150 employed this HFpEF protocol in mice and found an impaired cardiac fatty acid oxidation associated with hyperacetylation of enzymes in the fatty acid oxidation pathway. The gene discussed is NOS3; the disease is Hypertension.