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J Am Coll Cardiol, 2004; 44:2349-2354, doi:10.1016/j.jacc.2004.09.038
© 2004 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: HEART FAILURE

Wall stress modulates brain natriuretic peptide production in pressure overload cardiomyopathy

Marc Vanderheyden, MD*,*, Marc Goethals, MD*, Sofie Verstreken, MD*, Bernard De Bruyne, MD*, Kristin Muller, RN{dagger}, Eddy Van Schuerbeeck, RN* and Jozef Bartunek, MD*

* Cardiovascular Center, Onze Lieve Vrouw Ziekenhuis, Aalst, Belgium
{dagger} Cardiovascular Center, Imelda Ziekenhuis, Bonheiden, Belgium

Manuscript received May 11, 2004; accepted September 13, 2004.

* Reprint requests and correspondence: Dr. Marc Vanderheyden, Cardiovascular Center, Onze Lieve Vrouwziekenhuis, Moorselbaan 164, 9400 Aalst, Belgium (Email: Marc.Vanderheyden{at}olvz-aalst.be).


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: We postulated that both diastolic and systolic load modulate B-type natriuretic peptide (BNP) production in human pressure overload hypertrophy/failure.

BACKGROUND: In isolated myocytes, diastolic stretch induces BNP messenger ribonucleic acid expression. However, the mechanism of the BNP release in human hypertrophy remains controversial.

METHODS: In 40 patients with symptomatic aortic stenosis (AS), left ventricular (LV) performance and systolic and diastolic wall stress were calculated from combined invasive and echocardiographic data. Plasma BNP was determined by the rapid point-of-care bedside analyzer (Biosite Triage, Biosite Diagnostics Inc., San Diego, California).

RESULTS: A significant relationship was observed between plasma BNP and pulmonary capillary wedge pressure (p < 0.001), fractional shortening (p = 0.001), and aortic valve area (p = 0.006). Furthermore, a significant correlation was noted between BNP and LV mass index (p = 0.005) as well as between BNP and markers of diastolic load such as LV end-diastolic wall stress (p = 0.011), indexed LV end-diastolic volume (p < 0.001), and isovolumic relaxation time (p = 0.02). Preoperative BNP levels were elevated in patients with AS compared with patients without AS. Plasma BNP was higher in AS patients with impaired versus normal preload reserve (297 ± 56 pg/ml vs. 168 ± 44 pg/ml; p = 0.017) and in AS patients with clinical deterioration after valve replacement compared with those without (399 ± 82 pg/ml vs. 124 ± 41 pg/ml; p = 0.011).

CONCLUSIONS: In patients with AS, BNP appears to be regulated not only by systolic but also by diastolic load. This supports the hypothesis that myocardial stretch modulates BNP production in human pressure overload hypertrophy/failure.

Abbreviations and Acronyms
  AS = aortic stenosis
  BNP = B-type natriuretic peptide
  LV = left ventricle/ventricular
  PCWP = pulmonary capillary wedge pressure

Brain or B-type natriuretic peptide (BNP), a 32-amino-acid peptide, is continuously released from the heart in response to ventricular volume expansion and pressure overload (1,2) and acts both as a natriuretic and diuretic peptide (3). Assessment of plasma BNP is a highly sensitive and cost-effective method for detecting heart failure; BNP levels are elevated in patients with left ventricular (LV) dysfunction (4) proportional to New York Heart Association functional class and filling pressures (5) and bear prognostic information (6). In patients admitted with decompensated congestive heart failure, treatment-related changes in BNP levels predict mortality and early readmission (7).

The BNP gene is a fetal gene whose expression is up-regulated in the failing myocardium (8). However, mechanisms regulating BNP gene expression are not clear (2). Whereas in the isolated papillary muscle (9) or in animal models (10) diastolic wall stress modulates BNP gene expression, earlier human data indicate that in aortic stenosis (AS) with compensated hypertrophy, systolic load acts as stimulus for production of natriuretic peptides (11). This suggests that changes in wall stress might play a role in the synthesis and secretion of BNP and that changes in BNP could reflect the transition from compensated to decompensated heart failure. To test this hypothesis, we investigated the relationship between plasma levels of BNP and hemodynamic parameters of LV contractile performance in symptomatic patients with pressure overload cardiomyopathy due to aortic valve stenosis and normal LV systolic function.


   Methods
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Results
 Discussion
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Patients.   Between January and November 2003, 40 consecutive symptomatic patients with aortic valve stenosis (age 70 ± 1 years , range 27 to 81 years) with a peak aortic valve velocity of ≥2.5 m/s referred for elective diagnostic left-right heart catheterization were included. All patients presented either with heart failure, angina, and/or exertional presyncope or syncope due to AS. Patients with primary cardiomyopathy, ischemic cardiomyopathy, atrial fibrillation, or renal insufficiency defined by a serum plasma creatinine level >0.16 mmol/l were excluded. At time of investigation, 10 patients were treated with digoxin and 13 patients received angiotensin-converting enzyme inhibitors and diuretics. No patient was taking beta-blockers at the time of the study. Because of ethical considerations, medical therapy remained unchanged at the time of study. Clinical postoperative in-hospital follow-up was obtained in all patients. Ten age- and gender-matched subjects free of angina, heart failure, renal failure, or other cardiorenal symptoms served as controls. All patients gave oral informed consent, and the study was approved by the local ethical committee.

Left-right heart catheterization.   Catheterization of the left and right sides of the heart was performed from the right femoral artery and vein. Pulmonary capillary wedge pressure (PCWP) was measured by use of a Swan-Ganz catheter (Baxter Edwards, Deerfield, Illinois), whereas LV pressure was recorded with a catheter positioned in the LV cavity. Left ventricular angiograms were obtained in the right anterior oblique coronary artery and left anterior oblique coronary artery positions. Left ventricular volumes and ejection fractions were derived from the single-plane angiogram using the area-length method. An impaired preload reserve was defined by the presence of LV end-diastolic pressure ≥16 mm Hg (12), whereas afterload mismatch was assessed by the ratio of systolic wall stress over ejection fraction (13,14).

Doppler echocardiography.   Echo-Doppler study was performed immediately before cardiac catheterization according to the guidelines of the American Society of Echocardiography (15). The pressure gradient across the aortic valve was estimated from peak flow velocity detected by continuous-wave Doppler echocardiography with the simplified Bernouilli equation. The mean aortic valve gradient was obtained by tracing the continuous-wave flow velocity signal across the aortic valve. The aortic valve area was calculated using the continuity equation (16). Left ventricular end-diastolic and end-systolic meridional wall stress (WS) were calculated from M-mode data in combination with pressure data, using the following formula: WS = 0.334 x P x LVID/(PWT x [1 + PWT/LVID]), where P = LV pressure, LVID = LV internal diameter, and PWT = posterior wall thickness. End-systolic wall stress was calculated using systolic LV pressure, PWT, and LVID at end-systole, whereas end-diastolic wall stress was calculated using LV pressure, PWT, and LVID at end-diastole (17,18). Left ventricular mass was calculated by the equation of Devereux et al. (19): LV mass = 1.04 ([LVDD + IVSD + PWD]3 – LVDD3) – 14 and normalized to body surface area (LVMI), where LVDD = LV end-diastolic diameter, IVSD = interventricular thickness at end-diastole, and PWD = posterior wall thickness at end-diastole. Measurements were done by two experienced observers unaware of the clinical data.

Measurement of BNP plasma levels.   Before diagnostic catheterization, when the patient was in a stable hemodynamic condition, 5 ml of whole blood was drawn from the femoral vein for subsequent BNP measurements. B-type natriuretic peptide was measured using the rapid, point-of-care Triage B-type Natriuretic Peptide test (Biosite Diagnostics Inc., San Diego, California). As previously described, the Triage BNP test is a fluorescence immunoassay for the quantitative determination of BNP in whole blood or plasma specimens. The measurable range of the Triage BNP test is from 5 to 1,300 pg/ml with a within-assay coefficient of variation of 5.2%. Using this system, BNP levels in controls ranged from 22 to 92 pg/ml (mean 62 ± 12 pg/ml).

Statistical analysis.   All results are given as mean values ± SEM. Comparisons between groups for continuous variables were made using t tests or one-way analysis of variance where appropriate. Pearson's correlation coefficient was used to assess the association between BNP levels and hemodynamic variables. Because the distribution of the BNP levels was positively skewed, the natural log transformation was used, and all analyses used log-transformed values unless otherwise specified. Statistical significance was set at a two-tailed probability level of <0.05.


   Results
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Discussion
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Clinical characteristics and plasma levels of BNP.   Table 1 summarizes baseline hemodynamic and clinical characteristics of patients with AS. Aortic valve area ranged from 0.20 to 1.20 cm2, mean 0.69 ± 0.05 cm2, whereas the mean gradient across the aortic valve was 59 ± 4 mm Hg. The cause of the AS was degenerative calcification in 38 patients and rheumatic in 2 patients.


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  		Table 1. Characteristics of Patients With Aortic Valve Stenosis
 
Patients with AS were divided into two groups: group A consisted of 20 patients with normal preload reserve characterized by LV end-diastolic pressure <16 mm Hg; group B consisted of 20 patients with impaired preload reserve defined by an LV end-diastolic pressure ≥16 mm Hg. Hemodynamic data of both groups are summarized in Table 2. As expected, AS patients with impaired preload reserve were characterized by lower ejection fraction and fractional shortening and higher end-diastolic and end-systolic wall stress, PCWP, and indexed LV end-diastolic volume as well as by a more severe degree of afterload mismatch assessed by the ratio of end-systolic WS over ejection fraction. No differences in age, aortic valve area, mean transvalvular aortic pressure gradient, or LV mass index were noted between groups.


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  		Table 2. BNP and Hemodynamic Parameters in AS Patients With and Without Impaired Preload Reserve
 
In the entire study population, BNP levels ranged from 7 to 934 pg/ml, mean 201 ± 31 pg/ml. As shown in Figure 1, plasma BNP levels were significantly higher in patients with AS compared with patients without AS. Of note, despite similar aortic valve area and LV mass index, AS patients with impaired preload reserve had significantly higher BNP levels compared with AS patients with normal preload reserve (Table 2, Fig. 1).



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  		Figure 1 Serum B-type natriuretic peptide (BNP) levels in age-matched controls (NI), aortic stenosis patients with normal (group A) and with impaired preload reserve (group B).

 
Relationship between plasma levels of BNP and hemodynamics.   In the entire study population, a positive relationship was noted between BNP and PCWP (r = 0.558; p < 0.001) and an inverse correlation was noted between BNP and fractional shortening (r = –0.525; p = 0.001), and aortic valve area (r = –0.449; p = 0.006) (Fig. 2). Note that plasma BNP was also directly related to the extent of cardiac hypertrophy as assessed from the LV mass index (Fig. 2). Furthermore, a significant positive relationship was noted between BNP and markers of diastolic wall stress (Fig. 3), such as LV end-diastolic wall stress (r = 0.437; p = 0.011) and LV end-diastolic volume index (r = 0.570; p < 0.001). Finally, plasma BNP was inversely related to the isovolumic relaxation time (r = –0.412; p = 0.02).



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  		Figure 2 Correlations between log-transformed (Ln) B-type natriuretic peptide (BNP) and parameters of contractile function. FS = fractional shortening; LV = left ventricular; PCWP = pulmonary capillary wedge pressure.

 


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  		Figure 3 Correlations between log-transformed (Ln) B-type natriuretic peptide (BNP) and parameters of diastolic load. IVRT = isovolumic relaxation time; LVEDVI = indexed left ventricular end-diastolic volume.

 
In-hospital course and clinical follow-up.   All patients underwent aortic valve replacement 23 ± 8 days after diagnostic heart catheterization (Table 3). No patient died immediately or late after aortic valve replacement. Seventeen patients experienced clinical deterioration, with symptoms of left-sided heart failure in eight patients, right-sided heart failure in eight patients, and hypotension in one patient. Patients with clinical deterioration were characterized by significantly higher baseline preoperative BNP levels, end-diastolic wall stress, PCWP, and length of hospital stay, as compared with those without clinical events. Ejection fraction, fractional shortening, aortic valve area, systolic wall stress, and mean gradient were similar in both groups (Table 3).


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  		Table 3. Preoperative BNP and Hemodynamic Parameters in AS Patients With and Without Clinical Deterioration After Aortic Valve Replacement
 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The present study investigated the relationship between circulating BNP levels and hemodynamic indexes of diastolic and systolic load in a pressure overload heart failure model. The results can be summarized as follows: 1) BNP levels are elevated in patients with pressure overload cardiomyopathy irrespective of the presence of overt LV systolic dysfunction; 2) plasma BNP levels are related to both diastolic and systolic indexes of hemodynamic load; 3) plasma BNP levels were higher in AS patients with elevated filling pressures despite relatively preserved LV ejection fraction; and 4) patients with clinical deterioration postoperatively were characterized by significantly higher baseline BNP levels.

BNP and heart failure.   B-type natriuretic peptide is a cardiac-specific peptide whose synthesis appears to correlate well with circulating BNP levels (20). The detection of BNP has emerged recently as a highly sensitive and accurate method for the detection of LV systolic (21) and diastolic dysfunction (22). In addition, elevated levels of BNP have been reported in AS (11,23,24), during ischemia (25,26), and in hypertrophic cardiomyopathy (27). The present study corroborates these data by finding elevated levels of BNP in patients with symptomatic aortic valve stenosis. Nevertheless, in the present study, even those without overt LV systolic dysfunction had significantly higher BNP levels compared with the normals. Similar observations were reported by Talwar et al. (28) who described elevated levels of N-terminal BNP and cardiotrophin-1 in AS patients without major wall motion abnormalities on echocardiography.

Regulation of BNP production.   A variety of mechanisms might be responsible for this BNP generation. First, elevated BNP levels have been attributed to myocardial ischemia (29,30) and myocardial infarction (31). In our study population, ischemia seems unlikely because no patient had a transient increase in troponin levels or cardiac enzyme markers at the time of the exam, and patients with overt coronary artery disease were excluded. Second, mRNA of BNP is considered as a molecular marker of LV hypertrophy (9). Consistent with these experimental postulates and with previous clinical and experimental studies (32,33), plasma BNP levels were directly related to LV mass in our cohort of patients with AS, suggesting that BNP levels may reflect the extent of hypertrophic growth. Finally, several studies have demonstrated that alterations in the LV wall stress are fundamental in regulating cardiac plasticity. Previous studies in patients with AS indicated that LV systolic load may be related to BNP production. In our study, BNP was, indeed, related inversely to fractional shortening and appeared to be proportional also to the degree of AS severity. However, in contrast with the study by Ikeda et al. (11), no relation between BNP levels and systolic wall stress was observed. This could be related to the patient selection because our study included mostly patients with preserved LV systolic function. Alternatively, elevated LV diastolic wall stress has previously been shown to promote myocardial gene expression and production of neurohormones (34), cytokines (35), stress proteins (36), and growth factors. Similar to up-regulation of transcription factors such as early growth response factor-1 and cellular myelocytomatosis oncogene (37), BNP appears to be an early responsive gene (2,10) that is up-regulated at the early stage of pressure overload, well before the development of LV hypertrophy (38,39). Therefore, it is attractive to hypothesize that BNP is regulated primarily by changes in wall stress and that its up-regulation is one of the early steps in the induction cascade of cardiac growth. Corroborating this hypothesis, Langenickel et al. (40) demonstrated in a pacing dog heart failure model that cardiac BNP messenger ribonucleic acid expression will only selectively be up-regulated in overt heart failure when ventricular stretch is high. This is in apparent contrast with ventricular atrial natriuretic peptide expression that is up-regulated in congestive LV dysfunction, regardless of the loading conditions (40). In addition, in an isolated papillary muscle preparation, continuous diastolic overstretch induces BNP gene expression and release (9). Our clinical data corroborate these experimental observations by demonstrating a significant relationship between end-diastolic wall stress and BNP generation. Taken together, our data strongly suggest that, in human pressure overload hypertrophy, regulation of BNP expression and production is complex, and, besides a possible role of increased cardiac mass or systolic load, diastolic stretch load is likely to be the key mechanical stimulus triggering on-and-off BNP expression and production.

Clinical implications and conclusions.   Our data indicate that BNP may be an excellent screening tool for LV diastolic dysfunction in patients with pressure overload cardiomyopathy and normal LV systolic function. We noticed a broad range of BNP levels even in patients with apparently normal LV ejection fractions. However, whenever hypertrophy is inadequate to return systolic wall stress to normal levels, afterload mismatch will occur and will trigger transition from compensated hypertrophy to failure with preload impairment. In our study, these patients were characterized by higher BNP levels. These elevated BNP levels could not be purely explained by marked LV hypertrophy. In contrast, elevated BNP levels increased in parallel with increases in end-diastolic wall stress, LV dilation, and filling pressures. On one hand, this has pathophysiologic implications corroborating that overstretch and LV dilation are important mechanical factors responsible for the induction and subsequent secretion of BNP. On the other hand, it may have clinical implications, because plasma BNP appears to predict the actual hemodynamic state of an individual patient and reflects noninvasively the transition from compensated to decompensated heart failure. Thus, BNP assessment may represent an important adjunct for the early and adequate recognition of LV dysfunction in this patient cohort. It is also of note that patients with higher in-hospital morbidity after valve replacement had elevated preoperative BNP as compared with patients with an uncomplicated postoperative course. This suggests that preoperative BNP assessment may also bear prognostic information and identify a high-risk subgroup of AS patients with worse outcome after aortic valve replacement. Nevertheless, the design of the study did not allow us to address the value of BNP for clinical decision-making in patients with asymptomatic moderate or severe AS. Prospective follow-up studies are needed to further elucidate these issues.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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A. Hirashiki, H. Izawa, F. Somura, K. Obata, T. Kato, T. Nishizawa, A. Yamada, H. Asano, S. Ohshima, A. Noda, et al.
Prognostic Value of Pacing-Induced Mechanical Alternans in Patients With Mild-to-Moderate Idiopathic Dilated Cardiomyopathy in Sinus Rhythm
J. Am. Coll. Cardiol., April 4, 2006; 47(7): 1382 - 1389.
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 Eur Heart JHome page
S. Watanabe, J. Shite, H. Takaoka, T. Shinke, Y. Imuro, T. Ozawa, H. Otake, D. Matsumoto, D. Ogasawara, O. L. Paredes, et al.
Myocardial stiffness is an important determinant of the plasma brain natriuretic peptide concentration in patients with both diastolic and systolic heart failure
Eur. Heart J., April 1, 2006; 27(7): 832 - 838.
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 J Am Coll CardiolHome page
Y. Iwanaga, I. Nishi, S. Furuichi, T. Noguchi, K. Sase, Y. Kihara, Y. Goto, and H. Nonogi
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., February 21, 2006; 47(4): 742 - 748.
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A. Nohria and M. M. Givertz
B-Type Natriuretic Peptide and the Stressed Heart
J. Am. Coll. Cardiol., February 21, 2006; 47(4): 749 - 751.
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S. H. Rahimtoola
The Year in Valvular Heart Disease
J. Am. Coll. Cardiol., January 17, 2006; 47(2): 427 - 439.
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 Clin. Chem.Home page
T. Mueller, A. Gegenhuber, B. Dieplinger, W. Poelz, and M. Haltmayer
Capability of B-Type Natriuretic Peptide (BNP) and Amino-Terminal proBNP as Indicators of Cardiac Structural Disease in Asymptomatic Patients with Systemic Arterial Hypertension
Clin. Chem., December 1, 2005; 51(12): 2245 - 2251.
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