Clinical significance and therapeutic potential of BNP

By Nadezhda Glezeva PhD

Clinical significance of BNP

Synthesis, processing and release of BNP (Brain natriuretic peptide) occur at low levels under normal physiological conditions when the hormone is released from the heart into the circulation to regulate fluid balance. However, under pathophysiological conditions as in the event of increased myocyte tension due to elevated blood pressure or venous volume, BNP levels are dramatically increased. This increase is the result of the augmented secretion of BNP from the heart and also from the slow clearance rates of the peptide from the circulation, which further exaggerate the elevation of plasma BNP levels in HF patients. BNP levels were shown to increase rapidly and reach manifold higher concentrations in response to appropriate stimuli. Plasma hormone levels were massively amplified in CHF and MI patients [1].

In CHF, plasma BNP was increased approximately 100- to 300-fold with normal plasma concentrations of about 1 pmol/l compared to average BNP concentrations of 100 pmol/l in the patient plasma. MI boosted plasma BNP levels approximately 70-fold [2]. The large difference in BNP values between healthy individuals and HF patients give a strong argument in favour of the use of BNP as a reliable prognostic and diagnostic marker for cardiac disorders.
Indeed, during the last few years the advantages from the use of BNP in the clinical setting were recognized and the peptide is currently utilized both as a therapeutic agent and perhaps more importantly as a diagnostic and prognostic marker for HF.

Diagnostic use of BNP

One important clinical benefit of BNP is its use as a diagnostic tool for HF. Common causes for the acute onset of heart failure include hypertensive heart disease (HHD), AMI, ischemic heart disease, valvular heart disease and cardiomyopathies (reviewed in [3]). While it may be “relatively easy” to predict a HF outcome from such acute heart events which gives the clinician the chance to administer the appropriate for the patient therapy, it is much harder to assign a diagnosis of HF to a patient presenting with common symptoms to the emergency department (ED) or hospital.

Since HF occurs predominantly in the elderly, its presentation is often complicated by numerous co-morbidities common for this age group, such as dyspnea, fatigue, peripheral oedema, and obesity which unfortunately are the most common presentations of HF. These conditions are unspecific and insensitive for the prediction of HF. Therefore, HF is often undiagnosed due to the lack of officially agreed guidelines for the interpretation of the occurring symptoms and signs, and also due to the lack of accurate diagnostic tests. This explains the relatively high mortality rates observed in the slow-progressing or chronic HF patient population.

It is obviously of vital importance to improve the diagnostics for HF, which is where natriuretic peptides step in. Unlike other routinely performed blood tests including renal-, liver- and thyroid-function tests, electrolyte and C-reactive protein (CRP) testing,
measurement of the blood concentrations of BNP has proven to be quite accurate and helpful for the diagnosis of HF [4].

BNP can be used to differentiate the cause of dyspnea

In the emergency department, BNP is especially useful to differentiate between causes of dyspnea due to HF from other common causes such as chronic pulmonary disease, pericardial abnormalities, etc. [120] The cause-effect relationship between dyspnea, HF and BNP levels has been extensively studied and a BNP consensus algorithm with cut-off points to “rule-in” or “rule-out” the diagnosis of HF in the acute dyspnea patient has been calculated and clinically implemented [5]. According to the algorithm, a diagnosis of HF is ruled-out in dyspnoeic patients presenting to the ED with BNP <100 pg/ml, and plasma BNP >400 pg/ml is suggestive of heart inconsistency. However, while a low BNP level is enough to exclude HF, a definitive HF diagnosis cannot be given solely on the ground of high BNP since it is also released in considerable amounts in conditions like acute coronary syndrome, primary pulmonary hypertension, flash pulmonary oedema and renal failure, which cause blood pressure and volume elevation as well.

Additionally levels of  Brain natriuretic peptide are known to vary with respect to age (increase proportionate to age), sex (higher in women), and obesity (decrease as the body mass index rises) [6]. All of the above aspects should be taken into consideration when attributing a patient to a low-HF or high-HF risk group relative to the measured plasma BNP. In addition, when using the 2-cut-off-point algorithm, one does have an intermediate range of BNP values [5]. Generally, concentrations of 100-400 pg/ml lie in the “grey zone” where a final diagnosis could be agreed only after additional clinical tests such as electrocardiography (ECG), (Doppler-) echocardiography and hemodynamic assessment of heart function.

BNP a quantitative marker for HF

BNP is currently referred to as “the quantitative marker” for HF and BNP levels are not only helpful in HF diagnosis but also in risk stratification and improvement of the accuracy of physician decision-making. One can judge for many different aspects of cardiac function by the level of BNP. Elevated blood BNP concentrations correlate with amelioration in heart function and can be used to quantify the severity of HF reflecting LV systolic and diastolic dysfunction, valvular dysfunction and right-ventricular (RV) dysfunction. Such assessment is of primary importance as it will determine the direction of the treatment – palliative or aggressive, with or without a need for surgical intervention.

One important application for BNP is the assessment of the degree of diastolic dysfunction – a condition reflecting the left-sided performance of the heart. Increased BNP and NTproBNP values correlate significantly with the severity of DD, which mirrors heart functionality [6]. Generally, diagnosing DD is difficult, especially in its early stages when the condition is mostly asymptomatic. Identification of the disease in its early phase is however of primary importance, since it would allow the initiation of effective treatment, which could then slow down cardiac remodelling which leads to hypertrophy and heart failure. With HF being the most common cause of death and LVDD its main predecessor, a correct assessment of the degree of DD could significantly reduce the risk of acute HF and hold back progression of chronic HF, which will have a positive socioeconomic impact.

The use of BNP for diagnosing DD in the asymptomatic or minimally symptomatic cohort is currently examined with major effort put to define specific cut-off point values relative to the age, gender and weight characteristics of each examined individual.

BNP for prognostic assessment

In patients with CHF, high BNP values correlate with increased cardiovascular and all-cause mortality rates, independent on age, NYHA class, history of MI, or LVEF. High BNP values are also strongly associated with sudden cardiac death, early decompensation, (re)hospitalization for HF, and future HF outcomes after presentation to the emergency ED with dyspnea [7]. BNP has a prognostic value also in diseases other than HF. After AMI, BNP correctly identifies patients at risk for adverse cardiac remodelling, LVDD, HF and cardiac death, and in patients with unstable angina raised plasma levels correlate with risk of death.

 

Therapeutic potential

Therapeutically, BNP’s potential for the treatment of HHD, CHF and renal failure became known from studies on nesiritide, the purified recombinant form of human BNP [8]. Nesiritide (trade name Natrecor) is identical in structure and function to the peptide found in human plasma. Upon application in the acute heart failure setting, nesiritide was shown to cause significant arterial and venous vasodilatation, elevated diuresis and natriuresis rates, and decreased synthesis and release of norepinephrine, aldosterone, and endothelin-1 [8]. The net effects from the treatment were reduction in ventricular filling pressure, blood volume and total peripheral resistance, and reversal of HF symptoms including dyspnea.

Following its approval for the treatment of acutely decompensated HF by the Food and Drug Association in 2001, nesiritide has been extensively used to treat HF patients with little regard to underlying symptoms, complications and disease aetiology. This was however brought to the clinicians’ attention and severely criticised following significant increases in the risk of renal dysfunction and mortality observed in the patients undergoing BNP treatment [ 9]. Therefore, BNP therapy for HF is now implemented only after precise evaluation of the risk and benefits for such therapy on an individual basis and large randomised clinical trials are under way to assess the effects of nesiritide on major adverse clinical outcomes and to define more accurately specific criteria and guidelines for its use as a therapeutic agent.

 

References

  1. Hama, N., et al., Rapid ventricular induction of brain natriuretic peptide gene expression in experimental acute myocardial infarction. Circulation, 1995. 92(6): p. 1558-64.Sengenes, C., et al., Involvement of a cGMP-dependent pathway in the natriuretic peptide-mediated hormone-sensitive lipase phosphorylation in human adipocytes. J Biol Chem, 2003. 278(49): p. 48617-26.
  2. McMurray, J.J. and M.A. Pfeffer, Heart failure. Lancet, 2005. 365(9474): p. 1877-89.
  3. Cowie, M.R., et al., Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet, 1997. 350(9088): p. 1349-53.
  4. Brenden, C.K., et al., Gray zone BNP levels in heart failure patients in the emergency department: results from the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT) multicenter study. Am Heart J, 2006. 151(5): p. 1006-11.
  5. Redfield, M.M., et al., Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol, 2002. 40(5): p. 976-82.
  6. Maisel, A.S., 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 Multinational Study. J Am Coll Cardiol, 2003. 41(11): p. 2010-7.
  7. Berger, R., et al., B-type natriuretic peptide predicts sudden death in patients with chronic heart failure. Circulation, 2002. 105(20): p. 2392-7.
  8. Fonarow, G.C., B-type natriuretic peptide: spectrum of application. Nesiritide (recombinant BNP) for heart failure. Heart Fail Rev, 2003. 8(4): p. 321-5.Sackner-Bernstein, J.D., H.A. Skopicki, and K.D. Aaronson, Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation, 2005. 111(12): p. 1487-91.

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