|
| HOME | SUBSCRIPTIONS | CURRENT ISSUE | PAST ISSUES | CARDIOSOURCE | SEARCH | HELP | FEEDBACK |
|
|
|
|||||||||
|
|||||||||||
|
J Am Coll Cardiol, 2006; 47:749-751, doi:10.1016/j.jacc.2005.11.031
(Published online 6 February 2006). © 2006 by the American College of Cardiology Foundation |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts.
* Reprint requests and correspondence: Dr. Anju Nohria, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. (Email: anohria{at}partners.org).
B-type natriuretic peptide is constitutively synthesized and secreted by cardiac tissue; however, extracardiac sources, including the lungs, kidneys, and adrenal glands, also secrete BNP, although at significantly lower levels. Whereas BNP messenger ribonucleic acid is more abundant in the human atria than in the ventricles, given the total ventricular mass 70% of all cardiac BNP is derived from the ventricles under normal conditions and 88% under pathophysiologic conditions (4). Proximal elements of the BNP promoter are responsive to growth and proinflammatory stimuli, resulting in increased BNP synthesis and secretion under conditions such as hypertrophy, ischemic injury, and oxidative stress. More distal elements respond to mechanical stretch and thyroid hormone stimulation, resulting in up-regulation of BNP with increased wall stress as well as during exercise (4).
There is important biologic variability in BNP. B-type natriuretic peptide is continuously released from the heart, and plasma levels in normal individuals increase with age and female gender (5). In addition, BNP is metabolized by adipose tissue, and levels decrease with obesity (6). In 1990, Mukoyama et al. (7) first reported elevated BNP levels in patients with heart failure, and subsequent catheterization laboratory-based studies demonstrated cardiac release in vivo (8). Plasma BNP has since emerged as a sensitive and cost-effective test for the diagnosis of heart failure in patients presenting with dyspnea of unclear etiology (9). Relevant to patient management, BNP correlates with severity of symptoms and has been shown to predict prognosis (9).
Studies in patients with advanced heart failure have demonstrated that BNP levels correlate modestly with left ventricular filling pressures (10,11), although the diagnostic accuracy of BNP for predicting wedge pressure of >15 mm Hg is limited by the high number of false negative tests (11). Others have shown that BNP levels decrease in concert with a reduction in filling pressures during acute diuretic and vasoactive therapy, and discharge BNP has emerged as a powerful independent predictor of subsequent events (12,13). However, in clinical practice, BNP levels can vary substantially between individuals with the same degree of left ventricular dysfunction and similar elevation in filling pressures. Therefore, the stimuli for BNP secretion in patients with heart failure remain unclear. In this issue of the Journal, Iwanaga et al. (14) provide further insight into potential determinants of BNP secretion that may explain the observed heterogeneity in BNP levels between individuals with heart failure.
In 160 consecutive patients hospitalized with systolic or diastolic heart failure, Iwanaga et al. (14) measured plasma BNP levels before discharge. They correlated the BNP measurements with hemodynamic and echocardiographic parameters of diastolic and systolic load and showed that BNP correlated better with end-diastolic wall stress (r2 = 0.89) than with any other parameter, including left ventricular end-diastolic pressure (r2 = 0.33). B-type natriuretic peptide did not show a significant correlation with left ventricular mass index in their study. In addition, they demonstrated that despite equivalent end-diastolic filling pressures, patients with systolic heart failure had higher end-diastolic wall stress. They suggest that this correlation with wall stress might explain why patients with systolic heart failure have higher BNP levels than patients with diastolic heart failure, despite equivalent filling pressures. These findings are consistent with those in patients with aortic stenosis, where end-diastolic wall stress has also been shown to correlate well with BNP (15).
Chronic elevations in BNP levels are seen with sustained pressure or volume overload and neuroendocrine stimulation, such as that seen with long-standing hypertension or chronic heart failure. These situations are characterized by activation of cardiac fetal genes that accompany hypertrophy, including re-expression of BNP (16). Left ventricular dilation is a compensatory response to maintain stroke volume in heart failure and is directly related to wall stress by LaPlace’s law. Diastolic overstretch has previously been shown to promote angiotensin II production, which in turn initiates the early hypertrophic gene response (17). Furthermore, in isolated papillary muscles, continuous diastolic overstretch induces BNP expression which is reversed by treatment with angiotensin-receptor blockade (18). Thus, in vitro data suggests that diastolic overstretch results in changes associated with hypertrophy, including increased BNP secretion. The findings of Iwanaga et al. (14) support the notion that left ventricular dilation, via its effects on wall stress, may be an important mechanical factor stimulating BNP release in humans with heart failure. In fact, their data demonstrates that among other echocardiographic parameters, left ventricular end-diastolic diameter and left ventricular end-diastolic volume index were significantly higher in patients with systolic dysfunction and greater elevations in BNP.
These findings have important implications for clinical practice and future research. First, they suggest that left ventricular end-diastolic wall stress, and perhaps left ventricular dilation may be important stimuli for BNP secretion, and thus BNP may be a marker of ventricular remodeling. Although the relationship between end-diastolic wall stress and outcomes has not been examined, end-systolic wall stress has previously been shown to predict prognosis in patients with dilated cardiomyopathy (19). Iwanaga et al. (14) found that although both end-systolic and end-diastolic wall stress correlated with BNP levels, the relationship between end-diastolic wall stress and BNP was more robust. Thus, it is possible that end-diastolic wall stress is also an important predictor of prognosis in heart failure.
Researchers from the Framingham Heart Study have shown that some of the variability in plasma BNP is attributable to genetic effects (20). A recent study evaluating first-degree relatives of patients with idiopathic dilated cardiomyopathy suggests that approximately 10% of asymptomatic relatives with echocardiographic evidence of left ventricular enlargement progress to dilated cardiomyopathy (21). One could speculate that genetic variation in BNP may contribute to the progression of disease or that elevated BNP levels may identify those individuals with left ventricular dilation who are likely to develop symptomatic disease.
Second, disease-modifying therapy for heart failure, such as angiotensin-converting enzyme inhibitors, may exert beneficial effects by decreasing diastolic wall stress (22). Besides conventional medical treatments, there are several novel therapies such as the Myocor Myosplint (23) and CorCap cardiac support device (24) that are aimed at limiting ventricular remodeling and thus reducing end-diastolic dimensions and wall stress. Other surgical interventions, including left ventricular reconstructive procedures (e.g., aneurysmectomy and surgical ventricular restoration) and mitral valve repair, also limit symptoms by reducing diastolic wall stress (25). Even mechanical cardiac assist has been shown to decrease wall stress, reverse cardiac hypertrophy, and normalize natriuretic peptide levels (26). Given the tight correlation between plasma BNP levels and end-diastolic wall stress, it is possible that BNP levels could be used to monitor the efficacy of these therapies.
Lastly, there is increasing enthusiasm to use BNP to guide therapy in the outpatient setting. However, target BNP levels remain unclear. Some studies (RABBIT and STARBRITE) suggest using discharge BNP levels as therapeutic targets, because they represent the optimized state, and additional elevations are felt to reflect increased filling pressures. Other studies (27) aim to intensify therapy to an absolute target proBNP level of <200 pg/ml, because this value is associated with a good prognosis in patients with known left ventricular dysfunction (12). The results of this study suggest that in patients with long-standing left ventricular dysfunction and remodeling, left ventricular dilation and increased end-diastolic wall stress may be an irreversible stimulus for BNP secretion. Thus therapy targeted to individual patient levels, or targeting a percentage reduction from baseline, may be more reasonable than absolute population-based targets. Alternatively, novel biomarkers of myocardial stress (e.g., ST2) (28) may emerge as more powerful prognostic indicators or more sensitive and specific targets for therapy.
Iwanaga et al. (14) have added to the available literature on stimuli for BNP release in patients with heart failure. By demonstrating that BNP correlates well with left ventricular end-diastolic wall stress they have shown that although lowering filling pressures may help reduce wall stress and thus BNP, ventricular dilation, by its effects on increasing end-diastolic wall stress, may be an independent stimulus that is more difficult to modify with therapy. These results help explain the persistently elevated and highly variable BNP levels seen in patients with long-standing ventricular dysfunction and lend support to the notion that BNP may serve better as a diagnostic and prognostic tool than as a guide for therapy. However, these results make BNP an attractive marker to monitor novel therapies aimed specifically at limiting ventricular remodeling and reducing end-diastolic wall stress.
 |
Footnotes |
|---|
|
References |
|---|
 Top References |
|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | SUBSCRIPTIONS | CURRENT ISSUE | PAST ISSUES | CARDIOSOURCE | SEARCH | HELP | FEEDBACK |
