The Value of Natriuretic Peptides for the Management of Heart Failure: Current State of Play (2001)

The discovery by Adolfo deBold of the endocrine function of the heart in 1980 is of relevance both for diagnosis and therapy of heart failure 1. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have biological effects (diuresis, vasodilatation, renin-angiotensin inhibition, inhibition of smooth muscle growth) that are potentially advantageous for treatment of hypertension and heart failure. Drugs exploiting these mechanisms are currently in clinical trials 2. In the area of diagnosis the natriuretic peptides or the N-terminal part of their propeptides (Nt-proANP, Nt-proBNP) have been investigated as markers of cardiac function. At the National Hospital in Oslo, measurement of plasma Nt-proANP has been routinely offered to general practitioners since 1993. During the last 15 years we have seen a steady accumulation of documentation regarding the utility of these measurements. Commercial immunoassays are now coming to the market and an increased use of these measurements in the clinical routine is expected. The plasma concentration of natriuretic peptides or their propeptides is primarily determined by the secretion from the heart. Changes in the clearance from plasma, as in the case of advanced renal failure, will also influence the plasma concentration. Cardiac secretion is primarily regulated by myocyte stretch, i.e. wall stress. Since increases in wall stress is a common phenomenon in many cardiac diseases, natriuretic peptide plasma concentration can provide information with regard to the presence of cardiac disease as well as its severity. According to the guidelines of the European Society of Cardiology the diagnosis of heart failure requires objective evidence of cardiac dysfunction 3. The current standard method for the objective diagnosis of left ventricular dysfunction is echocardiography with systolic dysfunction defined as left ventricular ejection fraction below a cutoff point (usually 40%). The diagnosis of diastolic dysfunction is less standardized and more controversial. Natriuretic peptides are increased both in systolic and diastolic dysfunction, although the degree of correlation to echocardiographic parameters is variable in different studies. Since diagnosis of heart failure in general practice is accompanied by a high frequency of false-positive diagnoses, especially in women, the use of natriuretic peptide measurement has been recommended for increasing the diagnostic performance through ruling out the presence of heart failure 4. In the case of a high natriuretic peptide level the patient is in need of further investigations into the cause of peptide elevation. The progressive nature of heart failure and the relation of natriuretic peptide levels to the degree of cardiac pump impairment form the basis for the finding that the natriuretic peptides are strong indicators of long-term morbidity and mortality. Natriuretic peptides are among the strongest known prognostic indicators in patients with established heart failure, after myocardial infarction, in hospitalized patients, in the elderly and in populations from general practice. The value of this prognostic information is, however, unknown since studies examining its utility are lacking. Nevertheless, many doctors having access to natriuretic peptide plasma concentration measurements report that they give priority to patients with high natriuretic peptide levels during follow-up. Drugs acting to change the wall stress of the heart will influence the concentration of natriuretic peptides in plasma. Loop diuretics, aldosterone antagonists and to some degree, also ACE and A-II antagonists are known to lower peptide levels. With regard to beta-blocking agents, the situation is currently unclear, although these drugs may lead to an elevation followed by reduction of peptide levels. The drug effects imply that normal peptide levels do not necessarily mean a healthy heart if the patient is being treated with these substances. On the other hand, repeated measurements might be used as a tool for monitoring drug effects. It has been speculated that it might be possible to adjust therapy according to peptide levels with the aim of normalizing peptide concentration and thereby improve the prognosis. A recently published study from New Zealand indicates that this in fact is possible, although larger studies are necessary to clarify the question 5. Repeated measurements may also be of use in the diagnostic setting. In patients with chronic heart disease experiencing a worsening of symptoms, repeated peptide measurements may assist the doctor in assessing whether there is a cardiac cause of worsening. A final clinical area in which natriuretic peptide measurements might be of use is to serve as an indication for treatment. Since the peptide levels have a very strong prognostic impact, it would seem logical to employ them as a tool for selection of high-risk patients for specific treatment. Such use would require that the peptides should be included into inclusion criteria for randomized trials. No trials as of yet have currently been using this criterion. The natriuretic peptides are synthesized and stored in the cardiac myocytes in the form of prohormones proANP and proBNP. After release they can be found in plasma as the active hormones ANP and BNP and also as the remaining part of the prohormones Nt-proANP and Nt-proBNP. Data indicate that proBNP may also circulate as an intact prohormone. Which of these peptides should be measured? With regard to the A-type peptides Nt-proANP has clearly been shown to perform better as a marker than ANP, possibly because of its longer half-life and better in vitro stability. With regard to the B-type peptides, the situation is not that clear. Nt-proBNP seems to have somewhat longer half-life and also possibly better in vitro stability than BNP. However, in studies where the two peptides have been compared, they have been found to perform equally well as markers. Should we measure A- or B-type peptide? In studies where the peptides have been compared with regard to diagnosis and prognosis, a peptide of the B-type usually comes out better. This may be explained by findings indicating that while ANP and Nt-proANP are produced in cardiac atriae, BNP and Nt-proBNP are produced both in atriae and ventricles (although not solely in ventricles, as is often said). The B-type peptides are thereby more directly tied up with wall stress of the left ventricle, while the A-type peptide is a more indirect reflector of this. Since the two-peptide types are partly produced in different cardiac regions, it is possible that in some clinical states, e.g. aortic stenosis and hypertension it may be useful to measure both A- and B-type peptides. Early, after the introduction of the natriuretic peptide measurement, the question was asked whether they would make other diagnostic examinations superfluous. The answer to this is certainly no. A clinical–chemical parameter will not be able to replace cardiac imaging or exercise testing. Peptide measurements will, however, provide a new and hitherto not traveled road to information about cardiac function which is characterized by simplicity, easy access and relatively low cost. Especially in situations where cardiac imaging is not available, e.g. in the general practice situation, peptide measurements will improve diagnostic performance over what is achieved on clinical grounds alone. Natriuretic peptide plasma concentrations are not perfectly correlated to the current echocardiogaphic diagnostic gold standard of heart failure. Importantly, they therefore, represent a source of new information supplementing rather than replacing current methods. This is illustrated in the case of prognostic evaluation where the peptides add important information on top of echocardiographic measurement 6.