American Heart Journal
Volume 148, Issue 5 , Pages 743-746, November 2004

Expanding indications for natriuretic peptides: Importance of Better New (research) Protocols

  • Ramachandran S. Vasan, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Ramachandran S. Vasan, MD, Boston University School of Medicine & The Framingham Heart Study, 73 Mt. Wayte Avenue, Suite 2, Framingham, MA 01702-5827, USA

Boston University School of Medicine and the Framingham Heart Study, Framingham, MassUSA

Article Outline

 

B-type natriuretic peptide (BNP) and its propeptide (pro-BNP) have emerged as key biomarkers for the diagnosis, evaluation and management of heart failure (CHF).1, 2 The critical role of natriuretic peptide (NP) testing for the diagnosis of CHF in the emergency room has been established by well-designed large studies.3, 4, 5 Given the initial success associated with these easily measured and relatively inexpensive biomarkers, investigators have sought to expand the role of NP for other purposes, such as for screening for left ventricular (LV) dysfunction,6, 7 for prognostication and management of CHF,8 and for risk stratification in acute ischemic syndromes.9 Still larger studies are in progress to refine the indications for NP testing for the management of patients with CHF.2 The growing indications for NP testing have generated a debate among experts, with divergent opinions being articulated.8, 10

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BNP for the diagnosis of elevated LV filling pressures 

In this context, the article by Mak et al in this issue of the Journal assumes importance. The investigators examine the cross-sectional relations of plasma BNP to select echocardiographic tissue Doppler imaging (TDI) indices that provide information regarding LV diastolic relaxation and LV filling pressures in a sample of patients referred for echocardiography. It is noteworthy that women were underrepresented in this sample, which consisted of predominantly male veterans. Investigators performing echocardiography were blinded to plasma BNP levels. The authors observed that plasma BNP levels were not correlated with the E′ wave, a relatively load-independent indicator of LV relaxation. They demonstrated a modest correlation between plasma BNP and the ratio of the E/E′, a marker of elevated LV filling pressures. The positive association was especially striking in patients with LV diastolic dysfunction. Additionally, the investigators identified a plasma BNP threshold of 173 pg/mL that identified an E/E′ of >15 with acceptable accuracy. The authors conclude that plasma BNP can reliably identify LV filling pressures in this heterogeneous patient group.

The association of elevated plasma NP with higher LV filling pressures and exertional capacity has been well documented in the setting of CHF.11, 12 The positive relations of plasma BNP to select TDI indices in patients with systolic CHF also have been reported recently.13 In the present investigation, the authors test the hypothesis that BNP may identify elevated LV filling pressure in a more diverse group of patients referred for echocardiography. Identification of elevated filling pressures may aid the diagnosis of CHF in ambulatory patients who complain of breathlessness, but in whom the clinical diagnosis is equivocal. Knowledge of LV filling pressures also may be of prognostic importance in acute ischemic syndromes.

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BNP and E/E′ on TDI: Methodological issues 

The importance of the research question notwithstanding, several methodological issues must be considered carefully while interpreting the findings reported by Mak et al.

First, the study setting, design, and sample merits comment. The authors use a convenience sample of patients (some inpatients, others ambulatory) undergoing echocardiography. The modest numbers of patients with an E/E′ >15 (n = 16) precludes exploratory analyses to test the internal validity of the results (such as testing of split halves of the sample and analyses excluding patients with known CHF). While the specific indications for echocardiography are not reported, the generalizability (external validity) of the findings would be limited to such a sample. Performances of diagnostic tests frequently change in “validation samples” compared to that observed in the initial “training” samples. Therefore, diagnostic tests are best evaluated in a patient population representative of the one on whom the test would be performed ultimately.14 It is unclear if LV filling pressures should be routinely assessed in all cardiac patients in the absence of unexplained symptoms or clear-cut indications. If the focused question is to assess LV filling pressures via plasma NP testing in ambulatory patients with suspected chronic or mild heart failure, the research should be targeted at such a sample.

Second, it is uncertain if NP testing would yield additional information if there is a clear-cut clinical indication for echocardiography, such as for the patients in the present study. Echocardiography provides specific and comprehensive information regarding LV wall thickness and chamber dimensions, LV function, LA size, and valve function. Further, an E/E′ ratio on TDI could be obtained instead of plasma NP, given that it is simple to obtain, quite reproducible, easy to interpret, and less likely to be influenced by factors affecting BNP levels (see below). NP testing may be an initial screening alternative when access to echocardiography is limited or may complement echocardiographic information when TDI is not performed routinely.15, 16 Additional studies would be needed to investigate these possibilities.

Third, the choice of the gold standard used deserves scrutiny. While an E/E′ >15 has been reported to have high specificity and positive predictive value for elevated LV filling pressures, its sensitivity has been modest (0.40–0.50), and is especially low in patients with a normal LV systolic function.17, 18 In other words, a considerable proportion of patients with an E/E′ <15 may have elevated LV filling pressures. Thus, when the reference standard (in this case E/E′) is imperfect, it is difficult to assess the performance of NP testing for identifying elevated LV filling pressures. Since the appropriate gold standard, in this case cardiac catheterization, is invasive, the investigators could have used an alternative approach of tandem testing.19 Measurement of LV filling pressures in a subset of patients in whom the 2 tests (plasma NP and E/E′) yielded concordant results and in a subset of patients in whom they provided discordant results would shed light on how well the 2 tests actually perform. The observation of a mean plasma BNP value of about 100 pg/mL in patients with E/E′ <8 and who are presumed to have normal LV filling pressures raises additional questions regarding the reference standard. Interestingly, the authors conclude that a combination of NP and TDI may better predict LV filling pressures than either alone. Such a premise merits further study.

Fourth, there are other methodological issues related to the E/E′ measurements that should be noted. The authors used the medial mitral annulus to make their measurements. Given that a large proportion of their patients had coronary disease, the lateral mitral annulus may be preferable for TDI because wall motion abnormalities more often influence the medial mitral annular measurements.20 Also, a recent report that used cardiac catheterization as the gold standard suggested varying E/E′ cutoff points for identifying elevated LV filling pressures with optimal sensitivity and specificity when medial mitral annular measurements are used; thresholds varied from 12 for patients with normal LV systolic function to 20 for those with impaired LV systolic function.21 The correlations of E/E′ with LV filling pressures were also more modest in that study, especially in patients with normal LV systolic function, and were higher for lateral mitral annular measurements.21 Further, while the E′ wave is typically not sensitive to preload in patients with impaired LV relaxation, it does change with loading conditions in healthier individuals.22 Thus, the case mix of individuals with normal and with varying degrees of impairment of LV relaxation may affect the ability of the E/E′ ratio to predict LV filling pressures in a given sample.

Fifth, while the identification of select plasma NP thresholds as markers of increased LV filling pressures (based on bivariate analyses relating them to TDI indices) is a simple and easily understood approach, numerous clinical factors influence plasma NP levels.23, 24, 25 That is why some experts caution that “BNP measurements should not be used in isolation from the clinical context”26 and others maintain that “the concept of a single diagnostic level for BNP has effectively disappeared—at least for identification of chronic CHF.”10 Performance of multivariable analyses relating plasma BNP to the E/E′ ratio may provide additional valuable insights in the present study.

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Tracking of NP with LV filling pressures: Parallelism and dissociation 

Plasma NP levels may not adequately reflect LV filling pressures for several reasons (Table I). Plasma BNP levels may appear elevated (exceeding the 100 pg/mL threshold most often used for diagnosis of CHF) relative to normal LV filling pressures in the very elderly, in women, and in the presence of renal dysfunction.23, 24, 25 Additional conditions associated with an “NP-LV filling pressure dissociation” include acute pulmonary embolism,27 RV systolic dysfunction or chronic RV pressure overload (with preserved LV systolic function),13 ischemia,28 and LV hypertrophy.29 Indeed, both elevated plasma NP and altered DTI may antedate LV hypertrophy in patients with hypertrophic cardiomyopathy, serving as markers of early myocardial alterations at a stage when LV filling pressures are likely normal.30, 31 Patients with acute CHF who are treated adequately with diuretics may demonstrate a phase during recovery when normalization of NP levels lags behind the restoration of LV filling pressures.11 Cardioactive medications, such as beta-blocking agents, may variably influence plasma NP levels.32

Table I. Causes of NP–filling pressure dissociation
High NP*, normal filling pressuresNP below diagnostic threshold in CHF patients†
Elderly23, 24, 25Well-compensated CHF34, 35
Women23, 24, 25Drug effects such as diuretics34
Renal dysfunction37Diastolic CHF35 and milder degrees of diastolic dysfunction36
Increased LV mass, LV dilation33End-stage cardiomyopathy10
Hypertension33
Pulmonary embolism27
RV dysfunction13
Ischemia; prior MI33
Lag phase after treatment of CHF11

* >100 pg/mL (for BNP) or exceeding age- and sex-specific 95th percentile of reference limits (for pro-BNP).

† These patients have a history of elevated LV filling pressures, a fundamental feature for the diagnosis of CHF.

In summary, multiple factors influence plasma NP levels and a careful consideration of these factors is essential for the appropriate interpretation of NP tests. In a recent pooled analysis of 3051 participants from 3 epidemiological studies, McDonagh et al used plasma pro-BNP values exceeding the age- and sex-specific 95th percentile to identify elevated levels.33 Elevated plasma pro-BNP levels could be attributed to LV dysfunction or CHF in only a third of patients; a prior myocardial infarction or angina was a possible reason in another 25%, LV hypertrophy and hypertension accounted for another 20%, with no identifiable cause observed in 6%.33 These findings emphasize a relative lack of specificity of high plasma NP levels, such as values in the range 100 to 400 pg/mL for plasma BNP.

On a parallel note, plasma NP levels may be normal in patients with chronic CHF. It has been reported that about 20% of symptomatic CHF patients may have plasma BNP levels less than 100 pg/mL.34 Other situations for which plasma NP levels may be normal in patients with CHF include well-compensated patients,35 patients using diuretics, and those with milder degrees of diastolic dysfunction manifesting with exertional dyspnea.36 It has also been postulated that patients with end-stage cardiomyopathy also may have normal NP levels due to “myocardial exhaustion.”10

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Expanding indications for NP testing: The road ahead 

The above caveats notwithstanding, the study by Mak et al is a step in the right direction. There is a need for performing well-designed studies to evolve evidence-based guidelines for NP testing for purposes beyond their approved use for the diagnosis of acute CHF. Clinical trials are in progress (Rapid Assessment of Bedside BNP in Treatment of congestive heart failure [RABBIT], BNP-Assisted Treatment to LEssen Serial CARdiac Readmission [BATTLE-SCARRED], Suivi du traitement dans insuffisance cardiaque systolique [STARS]) to determine if plasma NP levels can be used as biochemical surrogates for monitoring and titrating treatment of chronic CHF patients and for determining appropriate therapeutic target levels for NP in such patients.2 Definitive answers to several other research questions need to be sought: Does knowledge of the appropriateness of higher NP levels for a given age, sex and level of renal function increase the clinical certainty of a diagnosis of CHF in ambulatory patients with unexplained breathlessness? Does measurement of NP in such a situation alter clinical decision making (including therapy) and/or provide prognostic information? Do NP levels provide incremental information to a comprehensive echocardiogram (with TDI) in patients with a clinical indication for echocardiography? Do NP levels identify diastolic dysfunction with sufficient specificity in patients with suspected diastolic CHF to be part of the diagnostic criteria for the latter? Among the NP (BNP vs pro-BNP), does one perform better than another in specific clinical situations?

As noted above, several investigations that currently are in progress will likely provide the evidence base for the expanding indications for clinical NP testing. In the interim, the principal indication for NP testing is to aid the diagnosis of CHF in patients presenting to the emergency room with acute breathlessness.

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References 

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PII: S0002-8703(04)00323-0

doi:10.1016/j.ahj.2004.04.044

American Heart Journal
Volume 148, Issue 5 , Pages 743-746, November 2004

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