Schiattarella and colleagues recently formulated a ‘two‐hit’ hypothesis, inducing HFpEF in mice by metabolic stress (feeding of a high fat diet) and mechanical stress (hypertension induced by blocking eNOS activity) as second stressor. However, another animal model, developing HFpEF owing to diabetes and hypertension, is the ZSF1 (Zucker fatty and spontaneously hypertensive) rat. The gene discussed is NOS3; the disease is Hypertension.