The cGMP Signaling Pathway as a Therapeutic Target in Heart Failure With Preserved Ejection Fraction

H eart failure with preserved ejection fraction (HFpEF) is agrowing public health problem that accounts for approximately half of all prevalent heart failure (HF).1,2 Once believed to carry a favorable prognosis compared with HF and reduced ejection fraction (HFrEF), contemporary data suggest that both groups face similar outcomes in the community setting.1,3 Although survival rates for patients with chronic HFrEF have improved in the last 2 decades with advances in drug and device-based therapies, there has been no such parallel progress in HFpEF management,4 and treatment remains largely limited to the active recognition and treat-ment of comorbidities and the use of diuretics. The prevalence of HFpEF relative to HFrEF continues to rise at 1 % per year, projecting it to be the more common form of HF over the next decade.5,6 HFpEF is particularly common in the elderly and is associated with a significant risk of death, hospitalization and suboptimal quality of life. Thus, there remains an enormous unmet need for effective therapy for this group of patients.7,8 Augmentation of cyclic guanosine monophosphate (cGMP) signaling is recognized as a potential therapeutic strategy in HFpEF based on several preclinical and clinical studies that have investigated various mechanisms and effects of cGMP enhancement.7,9–14 However, the recent neutral result of the