Author + information
- ↵*Reprint requests and correspondence:
Dr. Barry M. Massie, Cardiology (111C), VA Hospital, 4150 Clement Street, San Francisco, California 94121, USA.
The study by Maisel et al. (1)on the use of B-type natriuretic peptide (BNP) in the diagnosis of heart failure (HF) in this issue of the Journalprovides additional data and analyses from the previously published Breathing Not Properly trial (2). The most important of these, and the focus of this editorial comment, deal with the 37% of patients (165 of 452 patients) adjudicated to have HF and who had ejection fractions >45%. Before discussing these results and their implications, it is important to provide some background about this group of patients, who are variously referred to as having “HF with preserved systolic function” (HFPSF) or “nonsystolic HF” but who for the most part have HF due to diastolic dysfunction.
Importance of HFPSF
The occurrence of HF in patients without apparent systolic dysfunction, in the absence of specific conditions such as valvular abnormalities, infiltrative diseases, or high output states, initially surprised and continues to confound many clinicians. When noninvasive cardiac imaging first became available, this syndrome was considered an oddity. Only recently has the high prevalence of HFPSF (a designation that has been loosely applied to patients with ejection fractions >45% or 50%) been fully appreciated. Various studies have found 40% to 50% of HF patients to have normal ejection fractions (3–5). Indeed, in the Cardiovascular Health Study, a community-based longitudinal evaluation of individuals ≥65 years, only a relatively small minority of patients with heart failure at baseline or who develop HF during follow-up had ejection fractions <40%, a value that is often considered a threshold for causing chronic systolic HF (6).
Characteristics of patients with HFPSF
Who are these patients with heart failure in the absence of systolic dysfunction? Compared to patients with HF and reduced ejection fractions, they tend to be older, more frequently women, and to have a history of hypertension that persists even after HF develops (3–5,7). Coronary disease and other manifestations of arteriosclerosis are common, but fewer have prior myocardial infarctions. Nonetheless, there is considerable overlap with systolic HF. Thus, demographic characteristics and accompanying conditions cannot distinguish the underlying physiology in individual patients with HF.
The clinical presentation of patients with HFPSF and systolic HF may differ in some aspects, but overlap is again considerable; HFPSF tends to be more episodic and quickly responsive to therapy (especially diuretics and treatment of hypertension and ischemia, if present). When HF is chronic and relatively severe, systolic dysfunction is more likely. Aside from persistent and sometimes severe hypertension in patients with HFPSF, the physical examination also does not provide discriminating information, with both groups often having signs of left- and, sometimes, right-sided failure. Thus, direct measurement of systolic function has been the only way to differentiate these groups.
Mechanism of HFPSF
What is the cause of nonsystolic HF? In the absence of the type of conditions previously mentioned (valvular heart disease, high output states), the mechanism in most cases is diastolic dysfunction (8). Figure 1schematically illustrates some of the processes that lead to diastolic dysfunction and failure. The left ventricle undergoes structural and functional changes as a result of the increased vascular load presented by hypertension and loss of vascular compliance and elasticity due to arteriosclerosis, aging, and endothelial dysfunction. In addition, cardiac aging and, in some patients, episodic ischemia have direct effects on myocardial structure and function. These processes result in myocardial hypertrophy and fibrosis, with loss of myocardial compliance and, in some cases, impaired relaxation. Chronically or intermittently elevated left ventricular diastolic pressures then cause the symptoms and signs of HF.
Unfortunately, direct measurements of diastolic function are invasive and difficult to perform, so they are rarely available in HF patients. Alternatively, physicians use indirect measurements, based on transvalvular flow patterns measured by Doppler echocardiography (such as mitral valve flow velocities and relaxation times), Doppler-derived indices of cardiac motion, or radionuclide indices of ventricular filling (9). Although noninvasive and readily available, these techniques have important limitations. Measurements are often rate- and load-dependent, and they vary with age even in healthy populations (10). Thus, except when the abnormalities are severe, substantial overlap exists between older patients with clinical evidence of diastolic HF and asymptomatic subjects. Typically, patients with systolic HF also have diastolic dysfunction, so these measurements themselves do not distinguish these abnormal physiologies.
The clinical dilemma
When first learning that their patient with presumed HF has a normal or near normal ejection fraction, clinicians should ask themselves several questions. First, is the ejection fraction correct? All measurement techniques, whether quantitative or qualitative, are fallible, especially when the data are suboptimal. The distinction between 50% and 39% is not always obvious, but it is useful because of the demonstrated benefits that medications such as angiotensin-converting enzyme (ACE) inhibitors and beta-blockers have been in systolic dysfunction.
Second, was the diagnosis of HF correct? In the past, clinicians often, but in many cases incorrectly, excluded the diagnosis when informed that left ventricular function was normal. But there are many potentially confounding causes for the symptoms and signs of HF. Some of these are listed in Table 1. The answer to this question is important in determining whether additional diagnostic testing is required, and it also has therapeutic implications.
Third, was HF precipitated by a transient condition that may have impaired systolic function that has now resolved, such as myocardial ischemia, an arrhythmia, or episodic hypertension? Is further evaluation required?
A simple diagnostic test is needed
In this setting, great need exists for a simple, readily available, reliable, and cost-effective diagnostic test. Ideally, the test could answer three questions: 1) In a patient with symptoms and signs attributable to HF, whether systolic or diastolic in origin, will the test be abnormal? In other words, does it have high sensitivity? 2) Conversely, does an abnormal test in a symptomatic patient exclude other causes for the clinical presentation? For example, does the test have high specificity for the diagnosis? 3) Can the same test distinguish systolic HF from diastolic HF? A test with these characteristics would not only facilitate appropriate management but might also obviate an extensive and expensive evaluation that often includes repeating previously performed tests and invasive procedures.
The test most frequently employed to address these questions is echocardiography with Doppler-flow measurements (echo-Doppler) (9). How well does it fill the need? Although echo-Doppler is noninvasive and widely available, it often is not available “on demand,” and it is relatively expensive. If a technically adequate study can be obtained, echo-Doppler has high sensitivity. With regard to sensitivity, a completely normal study, showing normal chamber size, function, and structure, with normal mitral flow velocities excludes HF with a high degree of certainty. However, echo-Doppler is less specific for the diagnosis of HF. Patients with no evidence of HF may have abnormalities of cardiac function or structure (reduced systolic function, chamber enlargement or hypertrophy, valvular abnormalities, and abnormal diastolic flow patterns), and patients with these findings may have symptoms and signs consistent with HF owing to a noncardiac etiology. And with regard to the third need, echo-Doppler is the test clinicians depend upon to distinguish systolic HF from HFPSF. In this regard, it is the ejection fraction measurement, not measurements of diastolic function, that drives this classification. Many patients with HFPSF do not have clear-cut evidence of diastolic dysfunction.
It should also be noted that the value of echo-Doppler is not limited to its ability to diagnose or exclude HF. It provides additional invaluable information on the etiology of HF. Furthermore, many of the findings that may result in a false-positive diagnosis of HF are clearly pathological and may be clinically important, leading to effective interventions (such as ACE inhibitors or beta-blockers for asymptomatic systolic dysfunction, more rigorous treatment of hypertension, or even valve repair or replacement).
The role of natriuretic peptide measurements in the diagnosis of HF
Early results have suggested that natriuretic peptide measurements may fulfill some of these needs (11,12). Atrial natriuretic peptide (ANP), BNP, and the N-terminal portion of BNP (NT-BNP) levels are all increased in patients with elevated left ventricular diastolic pressures, and the latter two are now available commercially as diagnostic tests for HF. Natriuretic peptides have been shown to be elevated in patients with HFPSF and in patients with evidence of diastolic dysfunction (13,14).
The Breathing Not Properly trial provides the largest multicenter experience with the use of natriuretic peptide measurements for the diagnosis of HF in 1,586 patients presenting to an emergency room with a primary complaint of dyspnea (2). The emergency room physicians made a clinical determination as to whether the dyspnea was due to HF or not, and a blood sample was collected for later determination of BNP levels. The final diagnosis, adjudicated by two independent cardiologists unaware of either the clinical diagnosis or the BNP measurements, was dyspnea due to HF in 744 patients (47%), dyspnea due to other causes in a patient with a history of left ventricular dysfunction in 72 (5%), and no finding of HF in 770 patients (49%). Using a cut point of 100 pg/ml, the BNP had a sensitivity of 90%, a specificity of 76%, and an accuracy of 83% for differentiating HF from other causes of dyspnea. The BNP was more accurate than any historical or physical examination variable. Among those with a completed emergency room diagnosis, the accuracy for the diagnosis of HF for BNP was 81%, which was superior to that of the treating clinician (74%) (15).
The performance of BNP in the diagnosis of HFPSF
The accompanying study by Maisel et al. (1)provides the first information from the Breathing Not Properly trial about patients with HFPSF. Using an ejection fraction of >45% to define this group (their mean EF was 59%), patients with HFPSF constituted 165 (36.5%) of the 452 subjects with an adjudicated diagnosis of HF who had echocardiograms within 30 days of the emergency room visit. The median BNP of the HFPSF patients was 413 pg/ml, compared to 34 pg/ml in the patients without HF (p < 0.001) and 821 pg/ml in patients with systolic HF (also p < 0.001). Thus, BNP appears to be a helpful test in patients with HFPSF.
However, a closer look at the data indicates important limitations exist to the use of BNP to diagnose HFPSF. Considerable overlap occurs in BNP levels in HFPSF patients and those without HF. The sensitivity of BNP at a threshold of 100 pg/ml remained acceptable at 85%; nonetheless, 15% of HFPSF patients were missed—a figure substantially higher than in systolic HF. The larger problem, however, is specificity, and this is driven by the higher BNP levels exhibited in older patients, and particularly in older women, whose median BNP without HF was above the 100 pg/ml cut point. Indeed, no significant difference was seen in BNP levels between women adjudicated to have HFPSF and those who did not have HF. This problem is further compounded by the fact that older women constitute the largest proportion of patients with HFPSF (16,17). Finally, BNP levels did not separate patients with systolic HF from those with HFPSF, although the former group tended to have higher levels.
The poorer performance of BNP in diagnosing HFPSF is, in fact, not surprising. With regard to its inability to distinguish systolic from nonsystolic HF, this should be expected because the symptoms in both conditions relate to elevated ventricular filling pressures, the mechanism responsible for rising BNP levels. The trend to higher measurements in systolic HF probably relate to the generally greater chronicity and severity of systolic HF. If this distinction is to be made, a measure of ejection fraction is required.
The higher BNP levels in older women and, to a lesser extent, older men probably reflect underlying diastolic dysfunction in these groups and may well represent the equivalent of asymptomatic left ventricular systolic dysfunction; the levels probably identify patients at risk for developing diastolic HF (16,18–20). Indeed, the same phenomenon is responsible for the relatively poor specificity of Doppler-derived indices of diastolic filling for the diagnosis of HFPSF. The use of age and gender-specific “normal” values would improve the specificity of the test, but with a loss of sensitivity, which is already lower for HFPSF and systolic HF. Rather, clinicians will continue to have to use a Bayesian approach to the diagnosis of HFPSF, carefully considering the likelihood that the patient has HF and using elevated natriuretic peptide levels as corroborative evidence.
Natriuretic peptides are becoming an important adjunct to the diagnosis of HF. They are highly accurate for the diagnosis of systolic HF, but unfortunately perform less well for HFPSF. It is important to recognize that natriuretic peptide levels increase with age, especially in women, probably as a result of the changes in cardiac structure and diastolic function with aging in industrialized societies. Thus, a higher rate of false-positive results is to be expected. An elevated BNP measurement in these demographic groups should be interpreted in light of the clinical presentation, and an echocardiogram may be necessary to clarify the diagnosis. Unfortunately, natriuretic peptides cannot differentiate systolic from diastolic HF, thus, a measurement of ejection fraction is still required to guide the management, if not necessarily the diagnosis, of this syndrome.
↵* Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
- American College of Cardiology Foundation
- ↵Maisel AS, McCord J, Nowak RM, et al. Bedside B-type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction: results from the Breathing Not Properly (BNP) multinational study. J Am Coll Cardiol 2003;41:2010–7
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