EDITORIAL COMMENT
B-Type Natriuretic Peptide and Echocardiography in the Surveillance of Severe Mitral Regurgitation Prior to Valve Surgery*
Peter A. McCullough, MD, MPH ,* and
George S. Hanzel, MD
Department of Medicine, Division of Nutrition and Preventive Medicine, William Beaumont Hospital, Royal Oak, Michigan
Department of Cardiology, William Beaumont Hospital, Royal Oak, Michigan
* Reprint requests and correspondence: Dr. Peter A. McCullough, Division of Nutrition and Preventive Medicine, William Beaumont Hospital, 4949 Coolidge, Royal Oak, Michigan 48073 (Email: peteramccullough{at}gmail.com).
Key Words: mitral regurgitation • left ventricular dysfunction • creatinine • B-type natriuretic peptide • mitral valve repair • mitral valve replacement
Primary mitral regurgitation (MR) should be a recognizable precursor to left ventricular (LV) failure and death. The challenge for practicing clinicians is to identify the disease process and provide a surveillance program that will allow the detection of a change in status sensed by the left ventricle and left atrium heralding decompensation in the months and years that follow. Such a surveillance program would allow for avoidance of surgery in those patients who are stable and optimal timing of valve surgery prior to irreversible cardiac structural changes or the occurrence of any clinical consequence, including atrial fibrillation, the development of heart failure, or cardiac death. Traditionally, this surveillance approach has been grounded in the clinical examination and echocardiography. The American College of Cardiology/American Heart Association (ACC/AHA) guidelines advise that asymptomatic patients with severe MR should be followed up with a history, physical examination, and echocardiography every 6 to 12 months to assess symptoms or transition to asymptomatic LV dysfunction (1). Exercise stress testing may be used to add objective evidence of a change in physiologic consequences of severe MR (1). The ACC/AHA guidelines and the European Society of Cardiology (ESC) guidelines recommend mitral valve surgery in asymptomatic patients with LV systolic dysfunction or enlargement, pulmonary hypertension, or new-onset atrial fibrillation (1,2). Additionally, the ACC/AHA guidelines suggest early surgery in the absence of these findings if mitral valve repair rate is estimated to be >90% (Class IIa) (1). This last recommendation is controversial and is not addressed in the ESC guidelines. Two studies suggest reduced cardiac events, including death, with early surgical intervention in asymptomatic patients with severe MR (3,4). However, a third study reports no difference in mortality in patients treated with early surgery compared with those who undergo surgery only with the development of symptoms, LV dysfunction or enlargement, atrial fibrillation, or pulmonary hypertension (5). These divergent studies confound clinical decision-making, particularly since the mitral valve repair rate is only 50% in the U.S. (6). Thus, it is desirable to develop novel predictors of decompensation to efficiently target the optimal patient for early surgery.
In this issue of the Journal, Pizarro et al. (7) report on the addition of baseline blood B-type natriuretic peptide (BNP) in the clinical assessment of patients with asymptomatic severe MR. We anticipate that both atrial and ventricular cardiomyocytes produce BNP primarily in response to end-diastolic wall stress as shown in Figure 1
(8,9). Importantly, data were prospectively collected, blinded, and then split into derivation and validation sets for analysis. Baseline BNP  105 pg/ml (highest quartile), just above the approved normal cutpoint of 100 pg/ml, and a more prominent change in BNP at 1 year ( 25 pg/ml increase for those with BNP <105 pg/ml), predicted the composite outcome of a clinical consequence of severe MR. Baseline BNP >105 pg/ml identified a subset of patients at high risk for developing symptoms, LV systolic dysfunction, or death at 48 months (derivation set: 76% vs. 5.4%, p < 0.001, and validation set: 66% vs. 4%, p < 0.001). Importantly, optimal timing of surgery occurred before any clinical events in only 25 of 76 patients (33%). This implies that improved surveillance with BNP could have potentially allowed for better timing of surgery in up to two-thirds of cases with the avoidance of complications, including hospitalizations for heart failure, arrhythmias, and death. Given the observation that up to 90% of patients with severe MR, especially with those that develop a flail leaflet, will die untreated in 10 years, one could make the case that more frequent surveillance (every 3 or 6 months) with a readily available, inexpensive blood test could complement annual or semiannual echocardiographic assessments. Conversely, 2 other studies suggest mortality rates of <10% at 7 to 8 years in patients monitored by "watchful waiting," implying that with the right clinical assessment, a group appropriate for prolonged observation can be identified.
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Figure 1 BNP Release
Pathophysiology of B-type natriuretic peptide (BNP) release in the setting of mitral regurgitation in which both left atrial and left ventricular increases in wall tension are expected to trigger the up-regulation of the BNP gene and production of this cardiac hormone.
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The key messages from this paper are that baseline BNP 105 pg/ml, very severe mitral regurgitation (effective regurgitant orifice area [EROA] >55 mm2), and LV dilation (end-systolic diameter indexed to body surface area >22 mm/m2) all had significant, independent odds ratios (range 3.4 to 4.6) for the combined end point. Other studies have found that BNP, as a reflection of wall tension and myocardial performance, is relatively independent of MR severity, jet size, or regurgitant fraction (10–12). This intimates that in an asymptomatic patient with severe MR and a normal ejection fraction, any 1 of these 3 findings (elevation of BNP, worsening EROA beyond 40 mm2, LV dilation) should raise a red flag for a complication over the next 2 to 3 years and potentially should prompt referral for mitral valve surgery despite good exercise tolerance (9 metabolic equivalents of work) (4).
We anticipate that future research will guide the frequency of BNP measurement needed and clarify the changes within the normal range that signal LV decompensation in the months to come. It appears that a change in BNP is probably the first clinical signal, prior to any measure on echocardiography or the development of symptoms, that can inform both the physician and the patient of trouble ahead as a consequence of severe MR (12). In these patients, it is expected that mitral valve surgery offers the opportunity for a reduction in clinical events, including mortality.
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Footnotes
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Dr. Hanzel served as a proctor for the Helex PFO/ASD Closure Device for W. L. Gore.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease) J Am Coll Cardiol 2008;52:e1-e142.[Free Full Text]2. Vahanian A, Baumgartner H, Bax J, et al. Guidelines on the management of valvular heart disease: the Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology Eur Heart J 2007;28:230-268.[Free Full Text] 3. Kang D-H, Kim JK, Rim JH, et al. Comparison of early surgery versus conventional treatment in asymptomatic severe mitral regurgitation Circulation 2009;119:797-804.[Abstract/Free Full Text] 4. Enriquez-Sarano M, Avierinos JF, Messika-Zeitoun D, et al. Quantitative determinants of the outcome of asymptomatic mitral regurgitation N Engl J Med 2005;352:875-883.[CrossRef][Web of Science][Medline] 5. Rosenhek R, Rader F, Klaar U, et al. Outcome of watchful waiting in asymptomatic mitral regurgitation Circulation 2006;113:2238-2244.[Abstract/Free Full Text] 6. Savage EB, Ferguson TB, DiSesa VJ. Use of mitral valve repair: analysis of contemporary United States experience reported to the Society of Thoracic Surgeons National Cardiac Database Ann Thorac Surg 2003;75:820-825.[Abstract/Free Full Text] 7. Pizarro R, Bazzino OO, Oberti PF, et al. Prospective validation of the prognostic usefulness of brain natriuretic peptide in asymptomatic patients with chronic severe mitral regurgitation J Am Coll Cardiol 2009;54:1099-1106.[Abstract/Free Full Text] 8. McGrath MF, de Bold AJ. Determinants of natriuretic peptide gene expression Peptides 2005;26:933-943.[CrossRef][Web of Science][Medline] 9. Iwanaga Y, Nishi I, Furuichi S, et al. 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;47:742-748.[Abstract/Free Full Text] 10. Sayar N, Lütfullah Orhan A, Cakmak N, et al. Correlation of the myocardial performance index with plasma B-type natriuretic peptide levels in patients with mitral regurgitation Int J Cardiovasc Imaging 2008;24:151-157.[CrossRef][Web of Science][Medline] 11. Hellgren L, Landelius J, Stridsberg M, Kvidal P, Ståhle E, Bjerner T. Severe mitral regurgitation-relations between magnetic resonance imaging, echocardiography and natriuretic peptides Scand Cardiovasc J 2008;42:48-55.[CrossRef][Web of Science][Medline] 12. 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.[Abstract/Free Full Text]
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