Evolution of a Geriatric Syndrome: Pathophysiology and Treatment of Heart Failure With Preserved Ejection Fraction

Bharathi Upadhya, MD; Barbara Pisani, MD; Dalane W. Kitzman, MD


J Am Geriatr Soc. 2017;65(11):2431-2440. 

In This Article

Pharmacological Therapies

Supplemental Table S2 summarizes the pharmacological therapies tested to date in individuals with HFpEF.

Targeting Renin-angiotensin-aldosterone System Signaling

For a variety of reasons, the renin-angiotensin-aldosterone system (RAAS) was the most obvious target for potential HFpEF therapies because RAAS antagonists are highly beneficial for HFrEF and hypertension, but of the three large randomized trials of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARBs) performed in individuals with HFpEF, only the Candesartan Cilexetil in Heart Failure Assessment of Reduction in Mortality and Morbidity study found nominal benefit from candesartan in reducing HF hospitalizations over 3 years of follow-up.[87–89] The aldosterone antagonist trials also showed no definite benefit,[10,90,91] although a post hoc geographical analysis from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial indicated that the cohort from the Americas most closely matched characteristics observed in other randomized trials and also appeared most responsive to spironolactone.[92] Despite these mixed results, given the lack of alternatives and the relatively low cost and moderate rate of side effects of low-dose spironolactone, some have suggested this agent for the purpose of reducing hospitalizations.

Targeting Beta-adrenergic Signaling and HR

Slowing the HR should result in an increase in the diastolic filling period in an abnormally stiff left ventricle, potentially allowing greater end diastolic volume and stroke volume, but none of the beta-blocker trials had encouraging effects on their primary outcomes in individuals with HFpEF (Supplemental Table S2). The findings from beta-blocker trials are consistent with those from multiple exercise physiology studies that have shown that individuals with HFpEF have a high rate of intrinsic chronotropic incompetence and that this is a significant contributor to their low exercise capacity.[31–33,93]

Targeting Defective Cyclic Guanosine Monophosphate Signaling

As discussed in the Pathophysiology Section, according to the new HFpEF paradigm, endothelial inflammation results in low NO bioavailability and production of peroxynitrite, which reduces soluble guanylate cyclase activity, cyclic guanosine monophosphate (cGMP) content, and its effector kinase PKG activity. Thus, targeting defective cGMP-PKG signaling could be a novel therapy for HFpEF treatment. Sildenafil is an inhibitor of phosphodiesterase-5 that increases cGMP levels, augmenting PKG activity in multiple organs relevant to HF. In the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction trial, sildenafil did not improve 6-minute walk distance or quality of life and was associated with modest worsening of renal function and increases in neurohormone levels.[94] Other pharmacological trials targeting cGMP-PKG signaling are summarized in Supplemental Table S2.

Targeting Natriuretic Peptide-cGMP Signaling

Neprilysin is a zinc-dependent metalloprotease that degrades biologically active natriuretic peptides and does not affect the biologically inactive NT-proBNP.[95] LCZ696 is a new combination drug of the type 1 ARB valsartan and the neprilysin inhibitor prodrug AHU377. It has been shown to decrease mortality in individuals with HFrEF. In the Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion trial, LCZ696 significantly lowered NT-proBNP levels and, at 36 weeks, decreased LA size and showed a trend toward better functional class.[95] This Phase 2 study led to an ongoing, large, multicenter trial (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients with Preserved Ejection Fraction) in individuals with HFpEF with the primary composite outcome of CV death or first hospitalization for HF (ClinicalTrials.gov NCT01920711).