From Kaufman Center for Heart Failure, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio
Since its approval as a diagnostic test in the United States in 2001, plasma B-type natriuretic peptide (BNP) has been used extensively to diagnose heart failure in the clinical setting. Studies have repeatedly demonstrated the unsurpassed success of plasma BNP and its N-terminal counterpart, NT-proBNP, to accurately diagnose congestive heart failure in patients presenting with acute dyspnea or edema.1 Meanwhile, the consistent demonstration of the prognostic value of plasma BNP and NT-proBNP measurements has led to the widespread belief that the rise in BNP or NT-proBNP levels represents the corresponding ventricular response to additional pressure or volume overload, thus directly corresponding to disease progression in heart failure.
While it is true, for the most part, that plasma BNP levels do relate to clinical heart failure, there remains the fundamental question of why there are patients presenting with comparable clinical profiles of heart failure who display a wide range of plasma BNP values. Over the years, we have observed that there is a cohort of patients with chronic heart failure symptoms who have plasma BNP levels lower than what would be considered “diagnostic” for heart failure. We therefore conducted a retrospective analysis of the heart failure patients in our outpatient clinic to determine the prevalence and clinical characteristics of this subset.
Patients and methods
We performed a retrospective cross-sectional chart analysis. The patient cohort, who were seen as outpatients between November 2001 and February 2003 and who underwent plasma BNP testing, consisted of consecutive patients with a clinical diagnosis of chronic heart failure (longer than 3-month duration, on a stable medical regimen, and with left ventricular ejection fraction less than 50% by two-dimensional echocardiography). Excluded from the study were patients with a history of congenital heart disease, cardiac transplantation, primary valvular disease, or active ischemia requiring urgent revascularization. We performed a standardized chart re-view via our electronic medical records to extract clinical, demographic, and laboratory data at the time of plasma BNP testing. A plasma BNP level of less than 100 pg/mL was considered to be in the “normal” diagnostic range.
Among 662 consecutive patients in the cohort, 104 were excluded. There were 109 asymptomatic patients (New York Heart Associa-
tion [NYHA] functional class I) with plasma BNP levels ranging from 5 to 572 pg/mL (median 87 pg/mL). One hundred six patients of the remaining 449 symptomatic patients (NYHA functional class II—III) had plasma BNP levels less than 100 pg/mL (in the normal range). Patients who demonstrated normal plasma BNP levels were more likely to be younger and female, and to have a nonischemic pathogenesis, less depressed left ventricular ejection fraction, lower serum creatinine levels, and less atrial fibrillation (table). Age, cardiac and renal functions, and heart failure etiology were all independent predictors for normal plasma BNP levels.
The main finding in our study was that a substantial proportion of stable, ambulatory patients with chronic systolic heart failure have plasma BNP levels within the range that is typically considered to be normal, despite the presence of chronic symptoms and underlying left ventricular systolic dysfunction. This finding, however, does not contradict the usually reliable diagnostic role of plasma BNP levels in the presence of acute dyspnea, or the consistently observed prognostic value of BNP.1
It is reasonable to believe that patients with heart failure and relatively low plasma BNP levels represent a subgroup of patients who simply respond well to optimal therapy despite having persistent symptoms. What the data in our study point out, however, is the importance of interpreting plasma BNP levels in the appropriate clinical context. There is also the question of whether there is a subgroup of patients that may have symptomatic heart failure and relatively low plasma BNP levels. Indeed, we observed that patients with a nonischemic etiology tend to present with relatively lower plasma BNP levels.
Because BNP is produced by cardiac myocytes (and, to some extent, surrounding fibroblasts), it is plausible that the underlying cause of myocyte dysfunction can in some ways affect the trigger, synthesis, release, or even clearance of BNP. Such a hypothesis should be tested in future mechanistic studies, as these processes may greatly affect the interpretation of plasma BNP levels in a clinical setting.
There have also been recent reports of potential genetic heterogeneity in BNP production.2 We have always assumed, based on previous animal studies, that a direct correlation exists between ventricular loading and myocardial or plasma BNP production.3 While this load-dependent mechanism is likely, we should begin to explore other potential load-independent mechanisms that may regulate BNP release, or even different sites of plasma BNP production, in order to explain this somewhat unexpected observation.
While there may be many underlying factors that determine the plasma BNP levels measured in our study cohort, our observations have identified what is true to all diagnostic tests—that results of the test can only be an adjunct to clinical judgment in making the diagnosis. A plasma BNP level less than 100 pg/mL or a plasma NT-proBNP level less than 125 pg/mL, therefore, may not necessarily exclude heart failure or left ventricular systolic dysfunction. While a low plasma BNP level may help to rule out heart failure as the underlying cause of acute symptoms, low plasma BNP levels in the case of chronic and stable symptomatic heart failure may not be as useful. Such variability also complicates use of a “cutoff” plasma BNP level to initiate or titrate medical therapies in order to lower plasma BNP levels.
As we continue to enthusiastically embrace BNP and NT-proBNP levels as important new parameters in the diagnosis and management of heart failure, we must also strive to better understand how to interpret these values in the context of a general clinical setting as well as in specific patient populations.