Heart Failure With Normal Ejection Fraction

A Growing Pandemic

Satnam Singh; Michael Frenneaux


Future Cardiol. 2012;8(3):383-392. 

In This Article

Management of HFNEF

Due to the paucity of randomized clinical trials on HFNEF, management of HFNEF has been largely empiric with the main focus on managing patient symptoms, arterial blood pressure control, optimizing volume status, optimizing myocardial filling in diastole by maintaining sinus rhythm. Current guidance recommends the use of diuretics and nitrates to alleviate signs and symptoms of congestion and avoid unnecessary hypotension.

Treatment of HFNEF is focused on three targets:

  • Symptom control

  • Manage the diseases causing HFNEF

  • Treat the underlying pathophysiological process

We will briefly discuss the variety of therapies used to treat this dynamic entity.

Management options are outlined in the following sections.


These agents are the mainstay of symptomatic treatment in patients with HFNEF. In general, loop diuretics are preferred as they are more potent compared with thiazides. Diuretics should be initiated at lower doses and gradually up-titrated to maintenance doses. However, patients with HFNEF are typically very sensitive to relatively small changes in blood volume and care must be taken to avoid hypotension.

Renin–angiotensin–aldosterone Modulators

Hypertension is present in the majority of patients with HFNEF and reduction of blood pressure reduces pulmonary congestion, symptoms of ischemia and results in regression of LVH. Despite these theoretical benefits, none of the recent trials revealed any significant benefit in HFNEF patients. The PEP-CHF trial studied the role of the angiotensin-converting enzyme inhibitor (perindopril) in HFNEF patients but the results were disappointing with no difference in mortality or HF-related hospitalizations.[1]

The CHARM preserved trial was among the first trials to use the angiotensin receptor blocker (candesartan) in HFNEF, but again failed to show any significant effect on cardiovascular death, although it did show a trend towards less frequent hospitalizations in the treatment cohort.[1] Results of larger trials like I-PRESERVE (irbesartan) also showed no difference in CVS mortality or hospitalization rates (the primary end point was all-cause mortality or prespecified cardiovascular hospitalizations for nonfatal myocardial infarction, stroke, HF, unstable angina or arrhythmias).[1] HFNEF patients treated with aldosterone antagonists, such as spironolactone, show a favorable trend in improvements in diastolic dysfunction based on Echo findings (E/E') and improved exercise capacity.[32]


In the DIG trial registry, a small subgroup of patients with LVEF >45% did not show any benefit in the primary end point of HF mortality or HF hospitalizations. Although there was a small reduction in hospitalization from worsening HF but that was negated by increased hospitalization due to angina.[33]

β-adrenergic Receptor Blockers

The rationale behind the use of β-blockers is to increase diastolic filling time; however, since the increase in the rate of LV active relaxation on exercise is sympathetically mediated, β-blockers may be anticipated to impair this physiological response. The Optimize-HF trial assessed long-term use of β-blockers in HFNEF after discharge from the hospital. Unfortunately, there was no benefit seen in the HFNEF patients when followed for up to 1 year compared with heart failure with reduced ejection fraction patients who benefitted the most. This was in accordance with the findings of Flather et al..[34] The primary end points of the OPTIMIZE study were time to death, time to first re-hospitalization and time to death or first re-hospitalization within 1 year after hospital discharge. The SENIORS trial (nebivolol) demonstrated a benefit regardless of the EF in HF patients. The primary outcome (all-cause mortality or hospital admission for cardiovascular events) was significantly reduced by 14%. The cutoff point for LVEF was 35% and most of the patients with EF >35% were males. We believe that this was an atypical population as most patients with HFNEF are postmenopausal women. As there are no therapies proven to treat HFNEF available, there has been a trend to develop novel therapies by targeting metabolic pathways.

Calcium Channel Blockers

Calcium channel blockers are negatively inotropic agents and their use has been proposed in the management of HFNEF based on the assumption that rate lowering and prolongation of diastole results in better LV filling and output.[35] They have been demonstrated to improve exercise capacity in HFNEF patients and directly improve diastolic LV function by decreasing cardiomyocyte cytoplasmic calcium concentration.[36] It was demonstrated that verapamil produces significant improvements in exercise time, HF score and peak LV filling rate in a randomized, placebo-controlled, cross-over trial involving 22 men (mean age: 65 years) with clinical HFNEF.[37]

Metabolic Modulators

Modulation of cardiac metabolism can be achieved by targeting substrate utilization, oxidative phosphorylation and manipulating phosphate metabolites.

Agents such as perhexiline and trimetazidine, are a promising new avenue for the treatment of HF by altering the substrate utilization as they inhibit fatty acid oxidation and promote glucose utilization. There is growing evidence that these agents improve patients' symptoms, LV function and improve VO2 max in HF.[27]

Currently, there are ongoing trials to examine their role in diastolic HF but recent trials carried out by Abozguia et al. have been encouraging.[38]

Zile et al. demonstrated that MCC 135 improves diastolic dysfunction by inhibiting sodium–potassium exchange and by enhancing calcium uptake by the sarcoplasmic reticulum.[39] Agents such as perhexiline (a carnitine palmitoyle transferase 1 inhibitor that causes a shift from free fatty acids to glucose utilization), which showed very promising results in systolic HF and in hypertrophic cardiomyopathy, should be evaluated in HFNEF.[38,40]

Cyclic GMP Modulator

Cyclic GMP modulators, such as sildenafil, nitric oxide and natriuretic peptides, are currently being tested owing to their favorable response in cardiovascular physiology (Figure 2). Phosphodiesterase (PDE)5 inhibitors like sildenafil, block the catabolism of cyclic GMP, thereby increasing its levels.[41] The RELAX trial, which is currently underway, will evaluate the effects of PDE5 inhibitors on exercise capacity, functional status and ventricular function.[102] Natriuretic peptides and nitric oxide both increase cyclic GMP synthesis and have favorable effects on ventricular stiffness and function. A small study conducted by Guazzi et al.[42] on 44 patients with HFNEF syndrome suffering from pulmonary hypertension, demonstrated that sildenafil was associated with decreased mean pulmonary artery and reduced right atrial pressure and improved right ventricular function, improved alveolar–capillary gas conductance, as well as an improved measure of left-sided systolic and diastolic cardiac function.[43]

Figure 2.

Physiological effects of cyclic GMP activation on the heart and vessels.

Other Potential Therapeutic Options

Another novel agent that has emerged over the past few years is alagebrium (ALT-711), a thiazolium derivative, which acts by nonenzymatically breaking glucose crosslinks that develop between advanced glycation end products on proteins such as collagen and elastin.[44] It improves arterial compliance and left ventricular distensibility, reduces LV mass, improves E' on tissue Doppler analysis and improves patient quality of life.

Fukuta et al. and Zile et al. independently demonstrated the benefits of using statins in decreasing LV mass, myocardial fibrosis and an improvement in arterial compliance independent of lipid-lowering effect.[45,46] These studies, in contrast to the CORONA trial (a neutral trial), showed mortality benefit in HFNEF patients.[47]

Other novel agents currently being studied are: ranolazine, ivabradine, TGF-β neutralizing antibody, CRT, carotid sinus stimulation.


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