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Lack of activation of molecular forms of the BNP system in human grade 1 hypertension and relationship to cardiac hypertrophy

¹Department of Medicine, University of Catania, Catania, Italy; and ²Cardiorenal Research Laboratory, Mayo Clinic, Rochester, Minnesota

Submitted 30 January 2006 ; accepted in final form 18 April 2006

	ABSTRACT

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We evaluated relationships among two circulating molecular forms of brain natriuretic peptide (BNP32 and NT-proBNP), severity of hypertension (HTN), and cardiac hypertrophy in subjects with mild, moderate, and severe HTN. We prospectively studied 78 patients (43 males; mean age 51.4 ± 11 yr) with essential HTN and 28 age- and sex-matched controls. BNP32 and NT-proBNP were measured by radioimmunoassay. In grade 1 HTN, BNP32 was not elevated and NT-proBNP was reduced (P = 0.030) compared with controls. However, log-transformed values of BNP32 and NT-proBNP were both increased with severity of HTN from grade 1 to 3 (P <0.0001 and P = 0.003, respectively). By multivariate analysis, log BNP32 was independently predicted by age ( = 0.210, P = 0.026) and HTN grade ( = 0.274, P = 0.004), whereas log NT-proBNP was independently predicted by sex ( = 0.235, P = 0.012) and HTN grade ( = 0.218, P = 0.0023). Two forms of BNP were measured in normal subjects and patients with essential HTN. In grade 1 HTN, BNP32 was unchanged and NT-proBNP was significantly reduced compared with controls. As severity increased in humans with grade 1 to 3 HTN, both BNP32 and NT-proBNP levels were increased while not being affected by the presence of left ventricular hypertrophy. The lack of activation of BNP32 together with the reduction of NT-proBNP in grade 1 HTN may represent an impaired response of the BNP system in the early phase of HTN. The later activation of both forms of BNP may be a late compensatory effect, because it correlates with severity of HTN rather than cardiac hypertrophy/remodeling.

natriuretic peptide; brain natriuretic peptide; amino-terminal pro-brain natriuretic peptide; left ventricular hypertrophy

In congestive heart failure (CHF) as well as in hypertension (HTN), ventricular cardiomyocytes are progressively recruited to synthesize BNP (24). Whereas initially a successful defensive endocrine response by the heart to preserve cardiorenal homeostasis might occur, a hyporesponsiveness to cardiac peptides, which might contribute in turn to the progression of hypertension, could follow later. Although BNP32 has emerged as an important diagnostic and prognostic biomarker of CHF (1, 12, 37), its levels are markedly variable in HTN. Therefore, its biological and prognostic significance in HTN remains to be elucidated. In addition, NT-proBNP has been proposed as an emerging biomarker of cardiovascular disease with prognostic potential in both HTN and CHF as well as in the general population, as recently shown by Costello-Boerrigter et al. (13) and others (21, 30, 31, 36).

Although several reports have demonstrated that plasma BNP is elevated in patients with HTN, especially in those with left ventricular hypertrophy (LVH), there is limited information available on the relationship between circulating molecular forms of BNP and the hypertensive phenotype. We hypothesized that early stages of HTN are characterized by a lack of compensatory activation of BNP system, which is partially reversed in more severe stages of HTN. The objective of the current study was to evaluate changes in circulating BNP32 and NT-proBNP in subjects with early stage HTN. Specifically, in human subjects with essential HTN, we evaluated the relationship among circulating BNP32 and NT-proBNP, cardiac remodeling assessed with echocardiography, blood pressure levels, and the severity of HTN.

	METHODS

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The study was approved by the Ethical Committee of the Department of Medicine of Catania and the Cardiovascular Research Committee and Mayo Institutional Review Board. We prospectively recruited 78 HTN patients (43 males; mean age 51.4 ± 4 yr) and 28 age- and sex-matched controls. Each subject provided informed consent. Patients were classified as belonging to three grades of HTN targeted according to office systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) and in accordance with the 2003 European Society of Hypertension-European Society of Cardiology guidelines, grades 1 to 3 (19). Blood pressure was measured three times at 5-min intervals at an outpatient clinic, and a complete cardiovascular evaluation, including ambulatory blood pressure monitoring (ABPM) and echocardiogram, was performed the day of the study. Blood pressure levels, assessed by ABPM, were used for the multivariate analysis in HTN subjects only. Echocardiography was carried out in accordance with the recommendations of the American Society of Echocardiography (32). Left ventricular mass (LVM) was calculated using the regression equation described by Devereux and Reichek (14) and indexed for body surface. Upper normal limits for LVM were considered 135 and 110 g/m² for males and females, respectively. Cardiac remodeling was defined as concentric pattern if relative wall thickness (RWT) was >0.45 and as eccentric if RWT was 0.45. To limit the confounding effect on plasma BNP concentrations, patients with systolic (ejection fraction <50%) and/or diastolic (E < A) dysfunction or hepatic, metabolic, and renal diseases (serum creatinine > 1.5 mg/dl) were excluded. Blood samples were collected from an antecubital vein in the morning (8:00 to 9:00 AM) after patients had fasted overnight and rested supine for 30 min. Blood was placed in chilled EDTA (1 mg/ml) and aprotinin (500 U/ml) tubes. Blood was then centrifuged at 4°C, and plasma was frozen and stored at –80°C until assayed.

Radioimmunoassay. Biologically active BNP32 (Shionogi) and NT-proBNP (Roche) levels were measured at the Mayo Clinic Cardiorenal Research Laboratory (Rochester, MN) with commercially available radioimmunoassays carried out as previously described (2, 7, 9, 18). BNP32 level was determined using the Shionogi assay, which is highly specific for the mature 32-amino acid BNP peptide with recognition sites to both the 17-amino acid ring and the COOH terminus. In unpublished studies from our laboratory, we have determined that the Shionogi assay does not recognize NT-proBNP_(1–76). No information exists regarding recognition of proBNP_(1–108); however, we speculate that under normal physiological conditions, proBNP_(1–108) does not circulate but rather is fully processed to NT-proBNP_(1–76) and the mature BNP32. The Roche NT-proBNP_(1–76) radioimmunoassay is highly specific for this linear processed form of BNP, which lacks any disulfide ring structure. Again, unpublished studies by our laboratory have determined that the Roche NT-proBNP assay does not detect BNP32. Furthermore, Roche's description of the assay states there is <0.001 cross-reaction with BNP32. No information has been published regarding its ability to detect proBNP_(1–108), but we again speculate that proBNP_(1–108) may not circulate under normal physiological conditions, and studies are required to determine whether this is the case in hypertension and especially heart failure with more advanced technologies. Thus these assays are highly specific for NT-proBNP_(1–76) (Roche) and BNP32 (Shionogi).

Statistical analysis. Summary statistics are presented as frequencies (percentages) for categorical variables, as means ± SD for the normal variables, and as median and first and third quartiles for the skewed variables. Categorical variables were compared by ²-test and continuous variables by t-test or Mann-Whitney test as appropriate. ANOVA testing for linear trend among all study groups was performed using log-transformed values of BNP32 (log BNP32) and NT-proBNP (log NT-proBNP). Multiple linear regression analysis was performed to assess which variables were independent predictors of log BNP32 and log NT-proBNP values. The variables for the multiple linear regression model were selected among the variables with P < 0.10 at univariate analysis and included age and sex. All tests were two-sided, and for all analyses P < 0.05 was considered statistically significant. Data were analyzed with SPSS 13.0 for Windows.

	RESULTS

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The clinical and biochemical characteristics of the patient population are shown in Table 1. According to blood pressure level, subjects were divided into three groups, from grade 1 to grade 3 HTN. There were no differences among groups in age, sex, and serum creatinine level. HTN drugs (angiotensin-converting enzyme inhibitor, calcium channel blocker, -blocker, diuretic, blocker of angiotensin II receptor type IA, ₁-receptor antagonist, ₂-receptor partial agonist) used to treat patients increased from grade 1 to grade 3 of HTN from a minimum of one drug to a maximum of five drugs. The overall prevalence of LVH in our study was 35%, equally distributed in all three grades of HTN (Table 1). BNP32 concentration was slightly, but not significantly, higher in females [9.1 (4–32) pg/ml] than in males [8.3 (4–14) pg/ml] (P = 0.06). NT-proBNP was significantly higher in females [55.7 (31–122) pg/ml] than males [27.2 (14–58) pg/ml] (P = 0.001). Median values of BNP32 and NT-proBNP in controls and HTN subjects are summarized in Table 2. As shown in Fig. 1, A and B, log BNP32 and log NT-proBNP levels in grades 2 and 3 HTN were significantly higher than in grade 1 HTN. Importantly, although BNP32 was not different in subjects with grade 1 HTN compared with controls (P = 0.63), NT-proBNP was reduced in these subjects compared with controls (P = 0.03) (Fig. 2, A and B). In patients with HTN, BNP32 was not elevated in the subjects with LVH compared with those without LVH (Fig. 3A). In contrast, NT-proBNP was significantly higher in subjects with LVH compared with subjects without LVH (P = 0.02) (Fig. 3B).

View larger version (12K): [in this window] [in a new window]   Fig. 1. Mean log-transformed values of brain natriuretic peptide level (log BNP; A) and amino-terminal proBNP (log NT-proBNP; B) in controls and patients with grades 1 to 3 hypertension (HTN). Data are means ± SD. Significance is referred to test for trend.

View larger version (8K): [in this window] [in a new window]   Fig. 2. A: BNP32 level in subjects with grade 1 HTN [median 4 (Q1-Q2 4–11) pg/ml] and in controls [4.75 (4–10) pg/ml] (P = 0.63) by Mann-Whitney test. B: NT-proBNP level in subjects with grade 1 HTN [16.3 (9–54) pg/ml] and in controls [34.8 (25–48) pg/ml] (P = 0.03) by Mann-Whitney test. Error bars indicate the range of distribution, columns show the 25th (Q1) and 75th (Q2) percentiles, and the horizontal line within each column represents the median.

View larger version (8K): [in this window] [in a new window]   Fig. 3. A: BNP32 in subjects with HTN and left ventricular hypertrophy (LVH) [median 9 (Q1-Q2 4–18) pg/ml] and in subjects with HTN without LVH [13 (8–26) pg/ml] (P = 0.07 by Mann-Whitney test). B: NT-proBNP in subjects with HTN and LVH [66.2 (33–114) pg/ml] and in subjects with HTN without LVH [32.2 (12–83) pg/ml] (P = 0.02 by Mann-Whitney test). Error bars indicate the range of distribution, columns show the Q1 and Q2 percentiles, and the horizontal line within each column represents the median.

	DISCUSSION

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BNP is an endogenous peptide produced and is released from the heart under physiological and pathological conditions. Like atrial natriuretic peptide (ANP) (7), BNP is highly increased in CHF, mainly because of left ventricular dysfunction. Indeed, in the last decade it has been well established that BNP is a biomarker of diagnostic and prognostic importance in CHF. Although BNP is involved in blood pressure regulation, clinical studies have provided conflicting results on its concentration in patients with essential HTN. Some reports indicate that patients with HTN have plasma natriuretic peptides levels higher than normal subjects (6), whereas others have demonstrated a different pattern (16, 34). Although elevated levels of both forms of BNP in HTN often have been attributed to the presence of LVH (17, 23, 35), no clear relationship between plasma BNP levels and blood pressure has been reported so far in patients with essential HTN.

In our study we simultaneously evaluated plasma BNP32 and NT-proBNP levels in an unselected cohort of patients with essential HTN and compared them with those of age- and sex-matched normal subjects to assess their association with HTN grade, cardiac remodeling, and LVH and cardiac volumes. Indeed, in grade 1 HTN, BNP32 concentration was not different from that of normal subjects, and a slight, yet significant, increase was observed in grades 2 and 3 HTN. We observed that both forms were higher than controls in grades 2 and 3 of HTN (Table 3), and the relationship between natriuretic peptides and HTN grades also was confirmed using multivariate analysis. Furthermore, in HTN subjects, NT-proBNP was independently predicted by 24-h SBP levels (Table 4). Moreover, the association between peptide concentrations and HTN was further strengthened by results of logistic regression, particularly for BNP32, with the HTN phenotype almost two times more frequent for any increase of 10 pg/ml BNP32. Of interest, the lack of activation or even a reduction of BNP (BNP32 and NT-proBNP) concentration in subjects with grade 1 HTN compared with controls might indicate the presence of an impaired response of this cardioprotective system in mild HTN. In addition, the relationship between both forms of BNP and blood pressure levels may be under a certain threshold for a stimulation of BNP system in grade 1 HTN. An alternative possible explanation of these findings may relate to a decrease in degradation by neutral endopeptidase, or clearance by the natriuretic peptide type C receptor (NPR-C) could attenuate the reduction in BNP32 concentration, whereas the decrease in NT-proBNP in grade 1 HTN may reflect a decrease in whole BNP secretion and/or production.

Importantly, our data show that the relationship between both BNP32 and NT-proBNP and HTN grades is independent of LVH. Ultimately, in subjects with HTN, no differences in plasma levels of BNP32 were observed between subjects with and without LVH, whereas NT-proBNP was elevated in the presence of LVH (Fig. 3, A and B). The lack of increase in concentrations of BNP32 in subjects with essential HTN and LVH compared with HTN subjects without LVH is certainly one of the most controversial finding of the current study. As to the relationship between natriuretic peptides and cardiac remodeling in patients with HTN, Nishikimi et al. (29) showed that plasma ANP and BNP levels increased with LVH and that plasma BNP levels were specifically higher in concentric cardiac hypertrophy compared with eccentric hypertrophy, despite comparable blood pressure and left ventricular mass values. Indeed, several other authors have hypothesized that the increased level of BNP in subjects with HTN is mainly due to LVH, and the lack of relationship at multivariate analysis between both forms of BNP and LVH and geometry in the current study is somehow surprising. One possible explanation of these findings may rely on the inclusion criteria adopted in our study. In fact, in our cohort, the grades of HTN were equally distributed and LVH had the same rather low prevalence (35%) in all three HTN grades. It is likely that in a cohort with a higher prevalence of severe HTN and LVH, the relationship between this cardiac hormone and cardiac hypertrophy/remodeling might become more evident. The present study therefore emphasizes that the relationship between BNP and cardiac remodeling/hypertrophy is rather weak when the prevalence of cardiac damage is low, therefore underscoring the weak utility of plasma BNP for LVH screening previously shown by others in a large survey (28). Moreover, considering that the presence of LVH was similar across the groups (Table 1), one could propose that chronic drug treatment in these groups was more effective for cardiac remodeling than it was for underlying vessel disease, thus contributing to the lack of relationship between BNP peptide levels and LVH. However, we do not have conclusive evidence that treatment of HTN could have affected underlying vessel disease more than cardiac remodeling.

Finally, to date, it is not yet clear whether BNP is circulating in a biologically active form and/or whether NT-proBNP possesses biological activities. However, it is common opinion that the physiological process that leads to the production of mature active BNP starts from the precursor proBNP_(1–108) that is cleaved by the enzyme corin in two distinct fragments: BNP32, which contains the ring structure, and the linear 76-amino acid fragment NT-proBNP. Our group (20) previously reported the lack of mature BNP32 in some patients with overt heart failure, suggesting that an altered processing of proBNP_(1–108) may occur in heart failure. However, it remains unclear whether altered processing occurs in hypertensive patients, as well, and, if it is so, at which stage of HTN it occurs. Furthermore, it is not yet known whether the altered processing of proBNP_(1–108) occurs early in the natural history of the cardiovascular disease or if it is a late phenomenon. In this regard, it should be noted that Dries et al. (15) recently reported that the presence of corin gene allele defined by two missense mutations is associated with high blood pressure and HTN, making reasonable the hypothesis that an altered processing pathway also occurs in HTN. However, it is tempting to hypothesize that an initial insufficient production, processing, and/or release of BNP may take place in mild HTN and is followed by a later increase of BNP production (grades 2 and 3 HTN). If this hypothesis is proven to be true, subjects with mild HTN may be candidates for exogenous chronic administration of active forms of BNP. In this regard, our laboratory (10) recently reported a new technology that makes oral BNP administration feasible in animals.

There are limitations to these findings. First, this is an observational hypothesis generating study with a limited number of subjects enrolled that warrants further confirmation. Second, in this study we used common available radioimmunoassay methodology to determine concentration of BNP32 and NT-proBNP; although this technique may have a lower sensitivity and specificity compared with more advanced methodologies such as mass spectrometry, it is largely used and has high clinical relevance.

In conclusion, plasma levels of the two cardiac hormones BNP32 and NT-proBNP were for the first time measured concurrently in normal subjects and in patients with grades 1 to 3 essential HTN. Although both forms are not activated in mild HTN, with NT-proBNP levels even lower than in controls, their concentrations are increased in more advanced stages of HTN (grades 2 and 3), with no relationship to cardiac remodeling and/or hypertrophy. These findings could provide a better understanding of the biology of the BNP system in essential HTN.

	GRANTS

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A. Cataliotti was the recipient of an Italian Society of Hypertension scholarship and American Heart Association Beginning Grant in Aid Award 0365411Z. This work was also supported by National Institutes of Health Grants HL-36634 and P01-HL-76611.

	FOOTNOTES

 

Address for reprint requests and other correspondence: A. Cataliotti, Cardiorenal Research Laboratory, 200 First St., SW, Rochester, MN 55905 (e-mail: cataliotti.alessandro{at}mayo.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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