Author + information
- Milton Packer, MD∗ ()
- ↵∗Address for correspondence:
Dr. Milton Packer, Baylor Heart and Vascular Institute, Baylor University Medical Center, 621 North Hall Street, Dallas, Texas 75226.
Have you ever wondered who invented the idea of measuring the ejection fraction? The calculation was first proposed by Dr. Stuart Bartle at the American College of Cardiology meeting in 1965 (1). In a subsequent paper, he coined the term “ejected fraction” (Online Appendix A). Interestingly, Dr. Bartle was a respected psychiatrist who practiced in Manhattan at Mount Sinai Hospital, where I spent my early years. He was a gentle and self-effacing physician, well known for his humanitarian efforts. When I asked him about his work on ejection fraction, Dr. Bartle rolled his eyes: it was a silly idea, he told me with a twinkle; when cardiologists embraced it, he knew it was time to specialize in psychiatry.
Glorification of Ejection Fraction by Cardiologists
Over the past 5 decades, cardiologists have become obsessed with the ejection fraction. The term can be found in the abstracts of more than 52,000 papers; 10s of 1,000s of additional papers refer to it in their texts. The measurement yields important prognostic information in patients without heart failure, yet the field of heart failure has been particularly consumed by its assessment. We rarely find a paper about heart failure that does not mention it, guidelines mandate its evaluation in all patients, and it has been an entry criterion for every heart failure trial over the past 30 years. Its importance seems odd, however, because ejection fraction is not related to or associated with any specific clinical feature or pathophysiological abnormality of heart failure.
Nevertheless, heart failure specialists have placed the ejection fraction on a pedestal. If the measured ejection fraction is <40% (or so), we conclude that the disease is related to a loss of contractile function, typically accompanied by chamber dilation, fluid retention, and neurohormonal activation, pathophysiological factors that are important targets for treatment. However, if the ejection fraction is >40%, we waffle. We ingenuously categorize such patients as having heart failure with a preserved ejection fraction. The term is purely descriptive and provides no mechanistic insights; we use it because it offends no one.
Does Ejection Fraction Identify a Physiological Tipping Point?
Some physicians believe that an ejection fraction of 40% differentiates patients with “systolic heart failure” from those with “diastolic heart failure,” but these phrases imply a distinction that does not exist. Systolic function is impaired in most patients with heart failure with an ejection fraction of >40%. Admittedly, a value of 45% is not “normal,” yet even heart failure patients with ejection fractions of >50% have diminished contractility. Conversely, those with heart failure and a reduced ejection fraction typically exhibit marked abnormalities in diastolic filling. Therefore, the measurement of ejection fraction does not distinguish hearts with “systolic dysfunction” from those with “diastolic dysfunction.”
We might assume that patients with heart failure and a preserved heart ejection fraction have pathognomonic pathophysiological features, but do they? Dozens of different disorders can present clinically in this manner (Online Appendix B). Some patients previously had a reduced ejection fraction that improved spontaneously or following treatment (so-called “recovered” ejection fraction). Young or middle-aged patients often have small hypertrophic ventricles that exhibit an impairment of pressure–volume relationships in diastole. Myocardial inflammation and fibrosis have been identified in some circumstances but have not been shown to play a causal role. Most patients have evidence of ventricular overfilling due to an identifiable structural abnormality (e.g., arteriovenous fistula or aortic regurgitation), a metabolic derangement (e.g., hyperthyroidism, beriberi, or severe anemia), volume expansion (e.g., due to renal impairment), or a spatial or temporal redistribution of circulating blood volume (e.g., due to obesity or changes in peripheral vascular function). The fact that diuretic therapy is the cornerstone of treatment underscores the importance of ventricular overfilling in most patients, as diuretics would be expected to exert deleterious effects if the ventricles in this disorder were routinely small and noncompliant (2).
Therefore, we deceive ourselves when we imagine that grouping patients with heart failure based on the ejection fraction implies mechanistic insights. The critical pathophysiological abnormalities of heart failure (i.e., ventricular overfilling and neurohormonal activation) are identifiable, whether the ejection fraction is >40% or <40%. Furthermore, diuretics and neurohormonal antagonists (angiotensin-converting enzyme inhibitors, beta-blockers, and mineralocorticoid receptor antagonists) are routinely used both in patients with a reduced ejection fraction and in those with a preserved ejection fraction. We avoid the use of positive inotropic agents, whether we think contractility is impaired or preserved. It is true that comorbidities play a critical role in patients with an ejection fraction of >40%, but these also contribute importantly to the clinical course of patients with lower ejection fractions. The totality of evidence simply does not support the premise that a value of 40% represents a pathophysiological or therapeutic tipping point.
An Ejection Fraction Threshold of 40% Is Not Evidence-Based
The inability to support an ejection fraction of 40% as a tipping point is not surprising; that value is based solely on the capriciousness of the entry criteria of clinical trials. However, even here, there is confusion. The major clinical trials in patients with reduced ejection fraction have used eligibility thresholds ranging from as low as 25% to as high as 45%. Notably, patients with ejection fractions of 40% to 45% have been regularly enrolled in large-scale trials of digitalis, inhibitors of the renin-angiotensin system, beta-blockers, mineralocorticoid receptor antagonists, and hydralazine-isosorbide dinitrate (Online Appendix C). In these studies, the therapeutic responses of patients with an ejection fraction of 40% to 45% were indistinguishable from those seen in their counterparts with lower values. It is therefore difficult to understand why guidelines have used a threshold of <40% (instead of 45%) to define patients with a reduced ejection fraction.
The Illusion of Heart Failure With a Mid-Range Ejection Fraction
Recently, our confusion about ejection fraction has been exacerbated by the decision of the guideline committee of the European Society of Cardiology to designate patients with an ejection fraction of 40% to 49% as an identifiable group, distinct from other patients, and labeled “heart failure with a mid-range ejection fraction” (3). Miraculously, this grouping has not been adopted by U.S. heart failure guidelines. The stated rationale for creating this new subgroup was to encourage further study; it is not clear that the European committee intended to define a brand new disorder. Nevertheless, its action has been widely misconstrued as a declaration of the existence of a newly discovered malady (Online Appendix D). Dozens of papers have been written with the hope of characterizing the distinct features of heart failure with mid-range ejection fraction (4,5). However, this is not a clinical disorder with distinguishable features; it is the artifact of the arbitrary compartmentalization of the numerical values of a very poor biomarker (3).
Do you believe that heart failure with mid-range ejection fraction is a distinct disorder that warrants attention? After you see your next patient with an ejection fraction of 40% to 49%, wait a week and order a second evaluation measured by the same or a different imaging test. Assume that the first measurement was 45%, and remember that repeated calculations in the same patient routinely vary by up to 7 points or more. It is highly likely that the values of the second assessment will cause the patient to be reclassified. This thought experiment might provoke several questions. Has the patient’s disease changed in 7 days? Should the treatment strategy developed after the first calculation be modified after the second value is obtained? Clearly, these questions serve little purpose. If we try to answer them, we are naïvely exploiting the variability in the measurement of ejection fraction to justify our fondness for creating new illnesses or, at a minimum, to cause unnecessary searches for a nonexistent truth. Physicians always excel in taking themselves too seriously.
The embrace of ejection fraction by heart failure specialists has been problematic. Its calculation represents a vain effort to rely on an unstable measurement to pretend that we understand a complex disease. Patients who by happenstance exhibit a mid-range ejection fraction on a particular day do not have a newly discovered disease; the estimate of 40% to 49% merely represents the inadequate characterization of a clinical phenotype. The holding of hands by two “children” (representing those with preserved and reduced ejection fractions) does not give birth to a third sibling (4). The last thing patients with heart failure need is a new identity crisis. If physicians are the genesis of this parental dysfunction, we will require the assistance of yet another psychiatrist.
Dr. Packer serves on the Executive Committee for the EMPEROR trials; and is a consultant for Admittance, Amgen, Bayer, Boehringer Ingelheim, Cardiorentis, Celyad, Daiichi Sankyo, Ferring, Novartis, Relypsa, Sanofi, Takeda, and ZS Pharma.
- Received July 18, 2017.
- Accepted August 10, 2017.
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