European Heart Journal Advance Access originally published online on January 17, 2008
European Heart Journal 2008 29(3):290-292; doi:10.1093/eurheartj/ehm593
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Neurohormones in valvular heart disease: what can they tell us?
Adult Congenital and Valvular Heart Disease Center (EMAH-Zentrum), University Hospital Muenster, Albert-Schweitzer-Str. 33, D-48149 Muenster, Germany
* Corresponding author. Tel: +49 251 83 46110, Fax +49 51 46109. Email: helmut.baumgartner{at}ukmuenster.de
This editorial refers to ‘Elevated B-type natriuretic peptide despite normal left ventricular function on rest and exercise stress echocardiography in mitral regurgitation’ by A.J. Kerr et al.,
on page 363
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
Management of valvular heart disease has dramatically changed over the last decades. Although valve surgery has been shown to be capable of reducing or even eliminating symptoms, it has also been recognized that outcome is unsatisfactory when intervention occurs too late. Already irreversible damage of the myocardium and/or pulmonary vasculature causes ongoing morbidity and increased mortality. Thus, long-term preservation of ventricular function has become one of the major goals in the management of valvular heart disease.1 With respect to this, early surgery has been proposed to protect the myocardium from irreversible damage. However, surgery itself bears some risk and, particularly when prosthetic heart valves are used, long-term morbidity caused by surgery itself must be taken into account. Thus, risk must be carefully weighed against benefit, and surgery should be performed early enough to preserve left ventricular (LV) function but not earlier than really necessary to achieve this goal. Therefore, optimal timing of surgery in valvular heart disease certainly remains a challenge. It is clear that we should not wait until symptoms become severe. The onset of symptoms indicates surgery in aortic stenosis (AS) as well as in aortic and mitral regurgitation (MR).1 However, symptoms typically develop slowly in valvular heart disease, and the early symptomatic state is more difficult to define than one might think. More importantly, even still asymptomatic patients may already have developed irreversible myocardial damage, particularly in MR. Although a lot of effort has been put into better evaluation of myocardial function and early detection of functional deterioration, we must still rely on the assessment of ventricular size (diameter and volume) and ejection fraction where cut-offs have been established that indicate surgery in asymptomatic patients.1 In addition to intrinsic limitations of these variables such as load dependence, current techniques used for their measurement are demanding and not really precise. Thus, better variables—possibly easy to obtain and to repeat—are desirable for the detection of early myocardial damage and optimal timing of surgical intervention.
Previous studies have shown that elevated plasma levels of neurohormones such as natriuretic peptides may indicate early states of myocardial deterioration in various diseases.2,3 In patients with congestive heart failure, plasma levels of neurohormones have been shown not only to predict worsening of disease and outcome, but also to correlate with haemodynamic variables, and with the severity of symptoms as stratified by the New York Heart Association classification.4 Such findings raised the hope that neurohormones may also detect early myocardial damage in valvular heart disease and may therefore help to optimize timing of surgery.
Kerr et al.5 demonstrate in a group of asymptomatic or mildly symptomatic patients with moderate to severe or severe MR and normal systolic LV function that an increase in brain-type natriuretic peptide (BNP) levels is associated with higher pulmonary artery pressure at rest and on exercise, and with left atrial enlargement. However, they could not find any correlation with LV dimensions and ejection fraction or with MR severity. Does that mean that BNP measurements are less helpful than hoped and cannot be used to detect early myocardial damage in MR?
There are several studies published previously that have reported a statistically significant association between plasma levels of BNP and MR severity, symptoms and LV function, particularly end-systolic dimensions, as well as adverse clinical events during follow-up.6–8 The association between the presence and severity of symptoms and increase in plasma levels of BNP found in previous studies is indeed consistent with the strong correlation between BNP and functional capacity described in the present study. At first sight, these findings may appear less important since one might argue that there are easier and cheaper ways to find out about a patient's symptomatic state. However, early symptoms are indeed frequently difficult to assess. With the slow development of symptoms, patients frequently unconsciously avoid exercise in order to avoid symptoms and then declare themselves to be still asymptomatic. In addition, we are frequently faced with equivocal symptoms, particularly in elderly patients, and there may be other possible explanations for limited exercise capacity and shortness of breath in an individual patient. Thus, it would indeed be highly desirable to have a more objective measure than just asking the patient about his or her symptoms and a simpler and more specific test than regular exercise testing.
With regard to ventricular function, the results of the present study seem to disagree with previous reports. However, it is likely that this is primarily a matter of patient selection. The present study included only patients with normal LV function defined as ejection fraction >60% and not severely dilated ventricles. It remains unclear whether and how frequently early LV dysfunction was actually present in this patient group. On the other hand, previous data demonstrating that BNP correlates with LV function when studying patient groups including individuals with definitely impaired LV function do not necessarily indicate that BNP measurements can indeed identify patients with early myocardial damage who are still asymptomatic and do not yet have clear sings of LV dysfunction by echo criteria. The present study indeed included the right patients, but to answer the critical questions longer follow-up would be necessary to study prospectively how BNP levels are related to further development of LV dilation and deteriorating function as well as to development of symptoms, arrhythmias, and other events. As a matter of fact, BNP may be less closely related to ventricular function than expected but still be a potent predictor of outcome with regard to both natural history and surgical outcome. In this context, the finding of the present study that BNP levels are associated with higher pulmonary artery pressure at rest and on exercise appears important. Both variables are assumed to predict outcome, and their elevation beyond certain cut-offs indicates surgery for MR in current practice guidelines.1 It is likely that BNP elevation in the patients with higher pulmonary artery pressure was caused by right ventricular pressure overload, although no association between BNP and measures of right ventricular function (which is difficult to assess anyway) was found in the present study. It is well known from aortic stenosis that patients may present with markedly elevated neurohormones despite normal ventricular function and even though they are still asymptomatic without any signs of heart failure.9 In aortic stenosis, BNP plasma levels have been shown to correlate with the ejection fraction, but this is a weak correlation and it is again no longer present when only looking at patients with a normal ejection fraction.9 In AS patients, BNP levels have also been shown to be significantly related to LV filling pressure, end-diastolic volume, mass, systolic wall stress, and diastolic wall stress.10,11 Regulation of BNP expression and production is complex and it cannot be expected that BNP levels reflect directly one myocardial or haemodynamic feature. Nevertheless, in AS, besides a possible role for increased LV mass or systolic load, diastolic stretch load is likely to be the key mechanical stimulus triggering on-and-off BNP expression and production.10,11 BNP appears to predict the actual haemodynamic state of an individual patient and to reflect non-invasively the transition from a compensated to decompensated state.10 From a clinical point of view, it is even more important that plasma BNP levels in AS have been shown to predict symptom-free survival9 and that pre-operative BNP levels predict post-operative outcome with regard to survival, post-operative symptomatic status, and post-operative LV function [9]. Although more data are required for definite recommendations, these findings strongly suggest that BNP measurements may become a valuable tool to guide optimal time of intervention in AS. Although MR differs with regard to pathophysiology, not allowing the experience in AS to be directly applied, and although far fewer data are currently available compared with AS, the present study adds an important piece of information and encourages further studies in this direction.
In summary, neurohormones may gain increasing importance for the management of valvular heart disease, in particular with regard to optimal surgical intervention. Although increasing plasma levels of BNP do not necessarily indicate the onset of LV dysfunction in these patients, their measurement may help to define better the transition from the asymptomatic to the symptomatic phase of disease and to evaluate patients with equivocal symptoms. In AS, BNP plasma levels appear to predict symptom-free survival and post-operative morbidity and mortality. In MR, they increase in asymptomatic patients with increasing pulmonary artery pressure at rest and on exercise. Future research must focus on the definition and prospective testing of cut-offs for neurohormone plasma levels that can be used for management decisions. It appears realistic that a low range can be defined which supports watchful waiting in an individual patient who has not reached other currently accepted indications for surgical interventions at this point. On the other hand, high values beyond a certain upper limit that still needs to be better defined may support early surgery. It must also be expected that there will remain a considerable grey zone where measurements do not give a clear answer but closer follow-up may be necessary.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehm553 
References
- Vahanian A, Baumgartner H, Bax J, Butchart E, Dion R, Filippatos G, Flachskampf F, Hall R, Iung B, Kasprzak J, Nataf P, Tornos P, Torracca L, Wenink A. Guidelines on the management of valvular heart disease. Eur Heart J (2007) 28:230–268.
[Free Full Text] - Dickstein K, Larsen AI, Bonarjee V, Thoresen M, Aarsland T, Hall C. Plasma proatrial natriuretic factor is predictive of clinical status in patients with congestive heart failure. Am J Cardiol (1995) 76:679–683.[CrossRef][Web of Science][Medline]
- Davidson NC, Naas AA, Hanson JK, Kennedy NS, Coutie WJ, Struthers AD. Comparison of atrial natriuretic peptide, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptide as indicators of left ventricular systolic dysfunction. Am J Cardiol (1996) 77:828–831.[CrossRef][Web of Science][Medline]
- Pacher R, Stanek B, Hülsmann M, Koller-Strametz J, Berger R, Schuller M, Hartter E, Ogris E, Frey B, Heinz G, Maurer G. Prognostic impact of big endothelin-1 plasma concentrations as compared to invasive hemodynamic evaluation in severe heart failure. J Am Coll Cardiol (1996) 27:633–641.[Abstract]
- Kerr AJ, Raffel OC, Whalley GA, Zeng I, Stewart RA. Elevated B-type natriuretic peptide despite normal left ventricular function on rest and exercise stress echocardiography in mitral regurgitation. Eur Heart J (2008) 29:363–370. doi:10.1093/eurheartj/ehm553.
[Abstract/Free Full Text] - Sutton TM, Stewart RA, Gerber IL, West TM, Richards AM, Yandle TG, Kerr AJ. Plasma natriuretic peptide levels increase with symptoms and severity of mitral regurgitation. J Am Coll Cardiol (2003) 41:2280–2287.
[Abstract/Free Full Text] - Detaint D, Messika-Zeitoun D, Avierinos JF, Scott C, Chen H, Burnett JC Jr, Enriquez-Sarano M. B-type natriuretic peptide in organic mitral regurgitation: determinants and impact on outcome. Circulation (2005) 111:2391–2397.
[Abstract/Free Full Text] - Detaint D, Messika-Zeitoun D, Chen HH, Rossi A, Avierinos JF, Scott C, Burnett JC Jr, Enriquez-Sarano M. Association of B-type natriuretic peptide activation to left ventricular end-systolic remodeling in organic and functional mitral regurgitation. Am J Cardiol (2006) 97:1029–1034.[CrossRef][Web of Science][Medline]
- Bergler-Klein J, Klaar U, Heger M, Rosenhek R, Mundigler G, Gabriel H, Binder T, Pacher R, Maurer G, Baumgartner H. Natriuretic peptides predict symptom-free survival and postoperative outcome in severe aortic stenosis. Circulation (2004) 109:2302–2308.
[Abstract/Free Full Text] - Vanderheyden M, Goethals M, Verstreken S, De Bruyne B, Muller K, Van Schuerbeeck E, Bartunek J. Wall stress modulates brain natriuretic peptide production in pressure overload cardiomyopathy. J Am Coll Cardiol (2004) 44:2349–2354.
[Abstract/Free Full Text] - Iwanaga Y, Nishi I, Furuichi S, Noguchi T, Sase K, Kihara Y, Goto Y, Nonogi H. B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: comparison between systolic and diastolic heart failure. J Am Coll Cardiol (2006) 47:742.
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
Related articles in EHJ:
- Elevated B-type natriuretic peptide despite normal left ventricular function on rest and exercise stress echocardiography in mitral regurgitation
- Andrew J. Kerr, O. Christopher Raffel, Gillian A. Whalley, Irene Zeng, and Ralph A. Stewart
EHJ 2008 29: 363-370.[Abstract] [FREE Full Text]
This article has been cited by other articles:
|
|
 |
|
  D. T. Hsu and G. D. Pearson Heart Failure in Children: Part I: History, Etiology, and Pathophysiology Circ Heart Fail, January 1, 2009; 2(1): 63 - 70. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||