Author + information
- Received August 10, 2017
- Accepted August 18, 2017
- Published online October 30, 2017.
- aDivision of Cardiology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California
- bAhmanson-UCLA Cardiomyopathy Center, University of California Los Angeles Medical Center, Los Angeles, California
- ↵∗Address for correspondence:
Dr. Gregg C. Fonarow, Ahmanson-UCLA Cardiomyopathy Center, Ronald Reagan UCLA Medical Center, 10833 LeConte Avenue, Room A2-237 CHS, Los Angeles, California 90095-1679.
- heart failure with borderline ejection fraction (HFbEF)
- heart failure with mid-range ejection fraction (HFmrEF)
- heart failure with preserved ejection fraction (HFpEF)
The complex clinical syndrome of heart failure (HF) is associated with a wide spectrum of left ventricular functional abnormalities (1). These range from preserved left ventricular ejection fraction (EF) and normal left ventricular size to severely reduced EF and marked dilation of the left ventricle. Although for many decades, HF was considered to be synonymous with diminished contractility of the left ventricle, in the early 2000s there was a growing appreciation for the fact that a substantial portion of patients with HF had relatively normal EF, frequently characterized as diastolic HF or diastolic dysfunctional HF. When carefully assessed, there is evidence for the presence of both systolic and diastolic functional abnormalities in most patients with HF (1). Dr. Milton Packer was one of the early proponents of using an EF-based classification for HF patients, suggesting that the term of diastolic HF be avoided and stating that “a less presumptuous approach is to refer to these patients as having HF with a normal ejection fraction, a descriptive approach that makes no assumptions about our knowledge about the pathophysiology of this disorder” (2). Since the 2005 American College of Cardiology/American Heart Association HF Guidelines adopted this approach (HF with reduced EF [HFrEF] and HF with preserved EF [HFpEF]), EF has been considered essential in the classification of patients with HF.
There have been extensive studies demonstrating that the demographics, causes, comorbidities, prognoses, and, most importantly, responses to therapy differ among HF patients based on EF classification (3). Differences among the evidence bases for therapies is, in and of itself, a compelling enough rationale for EF-based classification. Furthermore, to date, no measurement or marker other than EF has demonstrated utility in distinguishing which patient populations will or will not derive benefit from each guideline-directed therapy. Nevertheless, use of EF is not without limitations because it is dependent on the imaging technique used, the analysis methods, the operators, and the variability up to 5% (3). However, the use of EF is nearly ubiquitous in characterizing patients with HF in clinical practice and research, as well as being used as an indispensable component of the enrollment criteria in nearly every randomized clinical trial. Ejection fraction has proven to be of such substantial clinical and research value in the assessment and management of HF patients, there is a Class I level recommendation for EF measurement in every national and international HF guideline (1,4).
Despite the widespread adoption of EF-based classification of HF, the actual definitions of patients with hearts with reduced and preserved EFs have varied. HFrEF has been variably defined as EF values of ≤35%, <40%, and ≤40% (1). HFpEF has been classified as EF values of >40%, ≥45%, >45%, ≥50%, >50%, and ≥55% (1). In studies which explored the optimal cutpoint(s) for defining EF groups, data emerged suggesting there was an intermediate group of patients with EF in the range of 41% to 49% (3). These patients have a clinical profile and prognosis that are intermediate but closer to those of HFpEF patients defined by EF of ≥50% than those of HFrEF defined by EF of ≤40%, with certain exceptions. In addition, the large scale randomized controlled outcome trials in patients with HF have largely enrolled patients with EF values of ≤35% and ≤40%. It has been only in these HF patients that angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, angiotensin receptor neprilysin inhibitors, beta-blockers, aldosterone antagonists, and device therapies have demonstrated benefits of reduced mortality (1). Clinical trials to date in HF patients with an EF value of >40%, ≥45%, or ≥50% testing various therapies have not been successful (1). Furthermore, registry-based studies have with few exceptions not observed benefits associated with the use of neurohormonal antagonists once the EF is >40% (3). Thus, there is not a sufficient evidence base and no current guideline recommendations to extend the use of therapies proven in patients with EF of ≤35% or ≤40% to those expressly with EF of >40% as a treatment for HF (1,4).
Based on the totality of available data, EF-based classification of HF was further refined, and an intermediate EF group, HF with borderline EF (HFbEF), was added to the 2013 the American College of Cardiology/American Heart Association HF guidelines. This group was defined by the presence of the typical symptoms of HF and EF of 41% to 49% (1). Following suit in 2016, the European Society of Cardiology specified HF with mid-range EF (HFmrEF) of 40% to 49% (4). It has also been recognized that there is a cohort of patients who present with HF with EF of ≤40%, whose EF subsequently improves. These patients with improved or recovered EF appear to be clinically distinct from patients with persistently reduced, borderline, or preserved EF and have a much better prognosis (1). A distinct classification was provided for these patients in the 2013 guidelines as well (1). Since these guidelines have been published, there has been ongoing debate as to whether these refined EF classifications are helpful or merely creating arbitrary distinctions. This debate notwithstanding, these refined classifications have fostered new studies that are improving the understanding of the causes, phenotypes, pathophysiologies, and prognoses in these patients. For example, a recent study of biomarker profiles analyzing 37 biomarkers from different pathophysiologic domains (myocardial stretch, inflammation, angiogenesis, oxidative stress, and hematopoiesis) found that patients with HFmrEF had an intermediate biomarker profile with interactions between both cardiac stretch and inflammation makers, whereas HFrEF profiles were mainly related to stretch and HFpEF to inflammation (5). These findings suggested that patients with HFmrEF may be a mixture of HFrEF and HFpEF patients (5). Biomarker-based profiling could potentially be used to identify the subset of patients who, despite having EF of >40%, could benefit from those therapies that benefit HFrEF patients.
There are certainly limitations to an HF classification system based on EF alone, and more detailed phenotyping may help to better characterize patients; provide greater prognostic discrimination; allow for more precise targeting of therapies to patients who will derive benefit; and facilitate the discovery of new, more effective treatments. Further research may establish the fact that there is a subset of patients with HF with EF of 41% to 49% who will benefit from therapies demonstrated to improve outcomes in patients with HF with EF of ≤40% (3). Whether this refined EF classification approach adopted in recent versions of the guidelines best serves the needs of patients, helps to advance the field, or needs to be further updated remains to be determined. However, the enduring value of EF for classifying and managing HF is something that physicians, no matter what their specialty, should be able to appreciate.
Dr. Fonarow’s research is supported by U.S. National Institute of Health; and he consults for Amgen, Janssen, Medtronic, Novartis, and St. Jude Medical.
- Received August 10, 2017.
- Accepted August 18, 2017.
- 2017 American College of Cardiology Foundation
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