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VIEWPOINT

Treatment of Heart Failure With Normal Ejection Fraction

An Inconvenient Truth!

Institute for Cardiovascular Research Vrije Universiteit, VU University Medical Center Amsterdam, Amsterdam, the Netherlands

Manuscript received April 28, 2009; revised manuscript received June 12, 2009, accepted June 15, 2009.

^_* Reprint requests and correspondence: Dr. Walter J. Paulus, Institute for Cardiovascular Research VU, VU University Medical Center Amsterdam, Van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands (Email: wj.paulus{at}vumc.nl).

Despite use of similar drugs, outcomes of recent heart failure (HF) trials were frequently neutral in heart failure with normal left ventricular ejection fraction (HFNEF) and positive in heart failure with reduced left ventricular ejection fraction (HFREF). The neutral outcomes of HFNEF trials were often attributed to deficient HFNEF patient recruitment with inclusion of many HFREF or noncardiac patients. Patient recruitment criteria of 21 HFNEF trials were therefore reviewed in reference to diagnostic guidelines for HFNEF. In the 4 published sets of guidelines, a definite diagnosis of HFNEF required the simultaneous and obligatory presence of signs and/or symptoms of HF and evidence of normal systolic left ventricular (LV) function and of diastolic LV dysfunction. In 3 of 4 sets of guidelines, normal systolic LV function comprised both a left ventricular ejection fraction (LVEF) >50% and an absence of LV dilation. Among the 21 HFNEF trials, LVEF cutoff values ranged from 35% to 50%, with only 8 trials adhering to an LVEF >50%. Furthermore, only 1 trial specified a normal LV end-diastolic dimension as an enrollment criterion and only 7 trials required evidence of diastolic LV dysfunction. Nonadherence to diagnostic guidelines induced excessive enrollment into HFNEF trials of HF patients with eccentric LV remodeling and ischemic heart disease compared with HF patients with concentric LV remodeling and arterial hypertension. Nonadherence to guidelines also led to underpowered HFNEF trials with a low incidence of outcome events such as death or HF hospitalizations. Future HFNEF trials should therefore adhere to diagnostic guidelines for HFNEF.

Key Words: heart failure • diastole • hemodynamics • ejection fraction

Abbreviations and Acronyms   ACEI = angiotensin-converting enzyme inhibitor   AGE = advanced glycation end product   ARB = angiotensin II receptor blocker   cGMP = guanosine 3',5'-cyclic monophosphate   HF = heart failure   HFNEF = heart failure with normal left ventricular ejection fraction   HFREF = heart failure with reduced left ventricular ejection fraction   LA = left atrial   LBBB = left bundle branch block   LV = left ventricle/ventricular   LVEDP = left ventricular end-diastolic pressure   LVEDVI = left ventricular end-diastolic volume index   LVEF = left ventricular ejection fraction   MMP = matrix metalloproteinase   NP = natriuretic peptide   PCWP = pulmonary capillary wedge pressure   PDE5 = phosphodiesterase-5   PFR = peak filling rate   PKG = protein kinase G   TDI = tissue Doppler imaging   TIMP = tissue inhibitors of matrix metalloproteinase

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