Outcomes for heart failure (HF) patients remain suboptimal. No known therapy improves mortality in acute HF and HF with preserved ejection fraction; the most recent HF trial results have been negative or neutral. Improvement in surrogate markers has not necessarily translated into better outcomes. To translate breakthroughs with potential therapies into clinical benefit, a better understanding of the pathophysiology establishing the foundation of benefit is necessary. Vascular function plays a central role in the development and progression of HF. Endothelial function and nitric oxide availability affect myocardial function, systemic and pulmonary hemodynamics, and coronary and renal circulation. Arterial stiffness modulates ventricular loading conditions and diastolic function, key components of HF with preserved ejection. Endothelial function and arterial stiffness may therefore serve as important physiological targets for new HF therapies and facilitate patient selection for improved application of existing agents.

The burden of heart failure with preserved ejection fraction (HFpEF) is considerable and is projected to worsen. To date, there are no approved therapies available for reducing mortality or hospitalizations for these patients. The pathophysiology of HFpEF is complex and includes alterations in cardiac structure and function, systemic and pulmonary vascular abnormalities, end-organ involvement, and comorbidities. There remain major gaps in our understanding of HFpEF pathophysiology. To facilitate a discussion of how to proceed effectively in future with development of therapies for HFpEF, a meeting was facilitated by the FDA and included representatives from academia, industry and regulatory agencies. This document summarizes the proceedings from this meeting.

The number of annual hospitalizations for heart failure (HF) and the mortality rates among patients hospitalized for HF remains unacceptably high. The search continues for safe and effective agents that improve outcomes when added to standard therapy. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway serves an important physiologic role in both vascular and non-vascular tissues, including regulation of myocardial and renal function, and is disrupted in the setting of HF, leading to decreased protection against myocardial injury, ventricular remodeling, and the cardio-renal syndrome. The impaired NO-sGC-cGMP pathway signaling in HF is secondary to reduced NO bioavailability and an alteration in the redox state of sGC, making it unresponsive to NO. Accordingly, increasing directly the activity of sGC is an attractive pharmacologic strategy. With the development of two novel classes of drugs, sGC stimulators and sGC activators, the hypothesis that restoration of NO-sGC-cGMP signaling is beneficial in HF patients can now be tested. Characterization of these agents in pre-clinical and clinical studies has begun with investigations suggesting both hemodynamic effects and organ-protective properties independent of hemodynamic changes. The latter could prove valuable in long-term low-dose therapy in HF patients. This review will explain the role of the NO-sGC-cGMP pathway in HF pathophysiology and outcomes, data obtained with sGC stimulators and sGC activators in pre-clinical and clinical studies, and a plan for the further clinical development to study these agents as HF therapy.

Background Simultaneous adherence with multiple self-care instructions among heart failure (HF) patients is not well described. Methods Patient-reported adherence to eight recommendations related to exercise, alcohol, medications, smoking, diet, weight, and symptoms was assessed among 308 HF patients using the Medical Outcomes Study Specific Adherence Scale questionnaire (0=‘never’, 5=‘always’; maximum score=40). A baseline cumulative score of ≥32/40 (average ≥80%) defined good adherence. Clinical events (death/transplantation/ventricular assist device), resource utilization, functional capacity (6-minute walk distance), and health status (Kansas City Cardiomyopathy Questionnaire [KCCQ]) were compared among patients with and without good adherence. Results Mean follow-up 2.0±1.0 years. Adherence ranged from 26.3% (exercise) to 89.9% (medications). A cumulative score indicating good adherence was reported by 35.7%, whereas good adherence with every behavior was reported by 9.1% of patients. Good adherence was associated with fewer hospitalizations (all-cause 87.8 vs. 107.6; P=0.018; HF 29.6 vs. 43.8; P=0.007), and hospitalized days (all-cause 422 vs. 465; P=0.015; HF 228 vs. 282; P<0.001) per 100 person-years; and better health status (KCCQ overall score 70.1±24.6 vs. 63.8±22.8; P=0.011). Adherence was not associated with clinical events or functional capacity. Conclusions Patient-reported adherence with HF self-care recommendations is alarmingly low and selective. Good adherence was associated with lower resource utilization and better health status.