Heart Failure with Preserved Ejection Fraction

Pathophysiology, Diagnosis, and Treatment

Barry A. Borlaug; Walter J. Paulus


Eur Heart J. 2011;32(6):670-679. 

In This Article

Abstract and Introduction


Half of patients with heart failure (HF) have a preserved left ventricular ejection fraction (HFpEF). Morbidity and mortality in HFpEF are similar to values observed in patients with HF and reduced EF, yet no effective treatment has been identified. While early research focused on the importance of diastolic dysfunction in the pathophysiology of HFpEF, recent studies have revealed that multiple non-diastolic abnormalities in cardiovascular function also contribute. Diagnosis of HFpEF is frequently challenging and relies upon careful clinical evaluation, echo-Doppler cardiography, and invasive haemodynamic assessment. In this review, the principal mechanisms, diagnostic approaches, and clinical trials are reviewed, along with a discussion of novel treatment strategies that are currently under investigation or hold promise for the future.


Clinical interest in heart failure (HF) with preserved ejection fraction (HFpEF) emerged from the confluence of two research areas dealing, respectively, with diastolic left ventricular (LV) dysfunction in hypertrophied hearts and with LV remodelling after small myocardial infarctions. In the late seventies, the first studies appeared that showed diastolic LV dysfunction to importantly contribute to HF in hypertrophic cardiomyopathy,[1,2] aortic stenosis,[2,3] and hypertensive heart disease.[4] Shortly after this inroad from the small niche of diastolic LV dysfunction in hypertrophied hearts, HFpEF was also identified and addressed in studies, which were a 'by-product' of the large HF trials investigating the use of angiotensin converting enzyme inhibitors (ACEIs) in HF with reduced EF (HFrEF) and in post-infarct LV remodelling.[5–7] The HFpEF populations derived from the latter studies were, however, clearly different, as they consisted of patients with limited myocardial infarction at risk for unfavourable eccentric LV remodelling. This ambiguous origin of HFpEF contributed to the confusion surrounding HFpEF as a distinct diagnosis[8–10] and the neutral outcome of many large HFpEF trials.[11,12]

Cardiac hypertrophy indeed has little in common with limited myocardial infarction, and in both conditions, mechanisms driving LV remodelling are likely to be dissimilar and react differently to pharmacological treatment. Recently, stringent criteria have been proposed for the diagnosis of HFpEF consisting not only of signs or symptoms of fluid overload and a preserved LVEF but also of evidence of diastolic LV dysfunction.[13,14] This caused most HFpEF patients to currently present with a concentrically remodelled left ventricle because of arterial hypertension, obesity, and diabetes, without evidence of coronary artery disease. A low prevalence of coronary artery disease has indeed recently been proposed as a measure for correct patient enrolment in HFpEF trials.[15]

In the past, HFpEF was frequently referred to as 'diastolic' HF (DHF) in opposition to 'systolic' HF (SHF), which corresponded with HFrEF. Because diastolic LV dysfunction was not unique to HFpEF but also observed in patients with HFrEF, the term DHF was abandoned and replaced by HFpEF[16,17] or by HF with normal LVEF (HFnEF).[17] The terms HFpEF and HFnEF, however, also have their shortcomings. The notion of a preserved LVEF implies knowledge of a pre-existing EF, which is almost always absent, and the exact range of a 'normal' LVEF is hard to define.[18,19] It is not established whether HFpEF and HFrEF represent distinct forms of HF or exist as part of one 'HF spectrum',[13] although the distinct patterns of chamber and myocellular remodelling observed coupled with disparate responses to medical therapies would all suggest that they are two discrete disease processes. Heart failure with preserved ejection fraction is currently observed in 50% of HF patients, and outcomes are similar to those seen in HFrEF.[20] The dismal prognosis is likely a reflection of the complex multisystem involvement characteristic of all HF, regardless of EF—including skeletal muscle and vascular dysfunction, pulmonary hypertension, renal failure, anaemia, and atrial fibrillation.[21] The prevalence of HFpEF relative to HFrEF is rising at an alarming rate of ~1% per year, thereby rapidly turning HFpEF into the most prevalent HF phenotype over the next decennium; yet in contrast to HFrEF, no improvements in outcome have been realized over the past two decades.[20] Despite these worrisome epidemiological trends, pathophysiological mechanisms underlying HFpEF and diagnostic or therapeutic strategies remain uncertain[21,22] and will therefore be addressed in the current review, which spans transatlantic views on this subject as part of the Frontiers in Cardiovascular Medicine Series of the European Heart Journal.