Patients with heart failure are commonly divided into those with reduced ejection fraction (EF<40%) and those with preserved ejection fraction (HFpEF; EF>50%). For heart failure with reduced EF, a number of therapies have been found to improve patient morbidity and mortality, and treatment is guideline based. However for patients with HFpEF, no treatment has been found to have clinical benefit. To objectively assess treatments for HFpEF, a comprehensive PubMed literature search was performed using the terms HFpEF, heart failure, smooth muscle, myosin, myosin phosphatase, and PKG (up to December 31, 2017), with an unbiased focus on pathophysiology, cell signaling, and therapy. This review provides evidence that could explain the lack of clinical benefit in treating patients with HFpEF with sildenafil and long-acting nitrates. Furthermore, the review highlights the vascular abnormalities present in patients with HFpEF, and these abnormalities of the vasculature could potentially contribute to the pathophysiology of HFpEF. Thus, focusing on HFpEF as a vascular disease could result in the development of novel and effective treatment paradigms.
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