Heart failure (HF) is an important cause of mortality and morbidity in the population worldwide (1). It may be associated with a wide spectrum of left ventricular (LV) functional abnormalities, which may range from patients with normal LV size and preserved ejection fraction (EF) to those with severe dilatation and/or markedly reduced systolic function (2). Approximately 40%-50% of HF patients have diastolic HF with preserved left ventricular systolic function (3). Brain natriuretic peptide (BNP) is a cardiac neurohormone, secreted from ventricular myocytes in response to increased end-diastolic pressure or volume (4,5). Several clinical and epidemiological studies have demonstrated a direct relationship between increasing plasma concentrations of natriuretic peptides and decreasing cardiac, especially left ventricular functions (6,7). Recent heart failure guidelines recommend that BNP can be used in the diagnosis of HF (2,8), however it’s role in the diagnosis of diastolic heart failure is contentious. In this review paper we discuss the diagnostic value of BNP in diastolic HF.
Definition of diastolic heart failure
According to the 2005 Heart Failure Guideline from European Society of Cardiology (8), a diagnosis of primary diastolic HF requires three conditions to be simultaneously satisfied: (i) presence of signs or symptoms of heart failure, (ii) evidence of abnormal left ventricular relaxation, diastolic distensibility, or diastolic stiffness and (iii) preserved left ventricular systolic function.
The components of left ventricular diastolic dysfunction include impaired relaxation and decreased diastolic compliance. Left ventricular catheterization (obtaining pressure/volume relationship and measuring left ventricular filling pressures) is the gold standard tool in the diagnosis of left ventricular dysfunction, but it is an invasive method and it is not practical in clinical routine. Instead, different noninvasive diagnostic tools are applied for the assessment of diastolic function. Echocardiography is the most frequently used method for the evaluation of diastolic dysfunction. The transmitral and pulmonary venous flow velocities obtained by pulsed wave Doppler echocardiography and mitral annular velocities by tissue Doppler imaging are the most useful parameters used for the assessment of diastolic dysfunction (9-11). Three abnormal filling patterns have been described in patients with diastolic dysfunction (12,13). An early stage of diastolic dysfunction is impaired myocardial relaxation, an advanced stage of diastolic dysfunction is called restrictive filling pattern and an intermediate pattern between impaired relaxation and restrictive filling patterns is defined as pseudonormalized filling pattern. The three filling patterns impaired relaxation, pseudonormalized filling and restrictive filling represent mild, moderate, and severe diastolic dysfunction respectively.
The heart secretes natriuretic peptides as a homeostatic signal to maintain stable blood pressure and plasma volume, and to prevent excess salt and water retention. Atrial natriuretic peptide (ANP) was initially identified from the atrial myocardium of rats (14). In 1988 a compound was isolated from pig brain that caused natriuretic and diuretic responses similar to ANP (15). Although this peptide was called brain natriuretic peptide, the primary site of BNP synthesis is ventricular myocardium (16,17). Cardiac myocytes secrete a BNP precursor that is synthesized into proBNP, which consists of 108 amino acids. After it is secreted into the ventricles, proBNP is cleaved into the biologically active C-terminal portion (32 aminoacid active hormone-BNP) and the biologically inactive N-terminal portion Š76 aminoacid N-terminal proBNP (NT-proBNP)Ć. BNP gene expression can increase very rapidly in response to an appropriate stimulus (18). Three natriuretic peptide receptors have been identified (NPR-A, NPR-B, and NPR-C) (19). Binding of natriuretic peptides to the A and B receptors on the surface of target cells leads to generation of the second messenger cGMP (cyclic guanosine monophosphate), which mediates most of the biological effects of the natriuretic peptides (19). BNP binds preferentially to NPR-A receptors. NPR-C is a clearance receptor for BNP. Lower affinity of NPR-C for BNP contributes to a longer plasma half-life of BNP compared with ANP in human beings (19). Natriuretic peptides are also inactivated by neutral endopeptidase, a zinc metallopeptidase that is present on the surface of endothelial cells, smooth-muscle cells, cardiac myocytes, renal epithelium, and fibroblasts (20).
Natriuretic peptides have several actions:
- down-regulating the sympathetic nervous system (SNS) (21) and the renin angiotensin-aldosterone (RAAS) system (22,23);
- facilitating natriuresis and diuresis through the afferent and efferent hemodynamic mechanisms of the kidney and distal tubules (24);
- decreasing peripheral vascular resistance (25); and
- increasing smooth muscle relaxation (25);
- direct lusitropic (relaxing) properties in the myocardium (26);
- antiproliferative and antifibrotic effects in vascular tissues (27,28), therefore inhibiting cardiac growth and hypertrophy, counteracting the mitogenesis that causes ventricular remodelling.
BNP and diastolic heart failure
Neurohormonal contributions to the development of clinical manifestations of diastolic dysfunction are complex. The difference between clinical stability and decompensation is a balancing act between the actions of the RAAS axis, SNS activity, endothelin, and arginine vasopressin regulatory systems, and the counterregulatory hormones ANP, BNP, and C-type natriuretic peptide (29). ANP and BNP are considered counter-regulatory to the RAAS through their actions of vasodilation and natriuresis. BNP found in high concentrations in the ventricles, has been studied extensively as a serologic marker of volume overload and increased LV pressures (30).
Accumulating recent data showed that BNP levels were increased in heart failure and it is especially important in the differential diagnosis of dyspnea. Maisel et al (31) assessed value of rapid bedside measurements of plasma BNP in distinguishing between heart failure and a pulmonary a cause of dyspnea in 1586 patients presenting with acute dyspnea. A cut-off plasma BNP value of 100 pg /mL diagnosed heart failure with a sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of 90%, 76%, 79%, 89% and 83%, respectively. BNP was especially useful for ruling out heart failure; at a BNP threshold of 50 pg/mL, the negative predictive value was 96%.
The degree of BNP increase was examined in different types of the heart failure in some studies. Left ventricular systolic and diastolic dysfunction increase plasma BNP concentrations to a different extent. Wei et al (32) investigated BNP levels in 149 heart failure patients and they showed that left ventricular systolic dysfunction is associated with a higher level of plasma BNP than left ventricular diastolic dysfunction (mean BNP level in left ventricular diastolic dysfunction was 115 ± 80 pg/mL; in left ventricular systolic dysfunction was 516 ± 445 pg/ml (P < 0.05). In another study (33), the concentrations of BNP are higher in patients with systolic dysfunction than in those with isolated diastolic dysfunction, and highest in those with both systolic and diastolic dysfunction.
In a meta-analysis of 20 studies where the diagnostic accuracy of natriuretic peptides for heart failure was evaluated, the use of a cut-off value for BNP or NT-proBNP of 15 pmol/L (52 pg/mL and 127 pg/mL, respectively) achieves high sensitivity, and BNP values below this exclude heart failure in patients in whom disease is suspected (34). Two of the studies in this meta-analysis that measured BNP against echocardiographic criteria for both systolic and diastolic heart failure, the diagnostic odd ratio (DOR) (37.7; 95% CI = 5.9-237.2) was greater than in studies that measured only systolic function (34).
The role of BNP in the diagnosis of isolated diastolic heart failure has been examined in several studies. Lubien et al (35) showed that BNP levels could predict diastolic abnormalities in patients with normal systolic function. In this study the patients diagnosed with abnormal diastolic function had a mean BNP concentration of 286 ± 31 pg/mL, whereas the control subjects had a mean BNP concentration of 33 ± 3 pg/mL. A BNP value of 62 pg/mL had a sensitivity of 85%, a specificity of 83%, and an accuracy of 84% for detecting diastolic dysfunction. In a meta-analysis, three studies that measured BNP in diastolic heart failure had 28.8; (95 % CI = 2.66-300.5) DOR (34).
Differences of BNP concentration according to stage of diastolic dysfunction
Lubien et al (35) revealed that BNP concentrations were different in subgroups of diastolic dysfunction but all subgroups had higher BNP levels than control subjects. Patients with restrictive filling patterns on echocardiography had the highest BNP levels (408 ± 66 pg/mL). Yu et al (36) showed that BNP concentrations were increased in patients with pseudonormalized or restrictive filling pattern. These studies revealed that patients with the pseudonormalized filling pattern had higher BNP concentrations than patients with impaired relaxation. BNP concentrations increase according to the stage/type of diastolic dysfunction. In the early stage of diastolic dysfunction, impaired myocardial relaxation, BNP levels mildly increase; in an intermediate stage, pseudonormalized filling pattern, moderately increased BNP concentrations are noted; and in an advanced stage of diastolic dysfunction, restrictive filling pattern, BNP concentrations are markedly increased.
Patients with symptoms had higher BNP levels in all diastolic filling patterns. As a group, patients with diastolic dysfunction and symptoms had higher BNP levels than those patients with asymptomatic diastolic dysfunction (35). Although BNP correlate with LV volume, size and EF in systolic heart failure, it is not associated with LV size, volume and mass in diastolic heart failure with preserved left ventricular EF. Yamaguchi and coauthors (37) found that, despite a similar distribution of LV mass and size, concentrations of BNP were higher in patients with diastolic HF than in the controls (149 ± 38 vs. 31 ± 5 pg/mL, P < 0.01). They stated that an elevation of BNP may be a hallmark of patients with or at risk of diastolic HF among subjects with preserved systolic function independent of LV hypertrophy. It has been shown that BNP levels in patients with normal left ventricular systolic function are not affected by left ventricular mass, cardiac output, or cardiac index (37,38).
Occasionally BNP levels might be in normal range in patients with diastolic dysfunction. It can be normal in asymptomatic patients with a mild degree of diastolic dysfunction, impaired relaxation. Mottram and colleagues (38) have demonstrated that BNP concentrations are higher in patients having diastolic dysfunction than they are in those with normal diastolic function. In that study, the authors also found that BNP concentrations were higher in patients with pseudonormalized pattern than they were in those with abnormal relaxation pattern. In our study we evaluated BNP levels and functional capacity determined by cardiopulmonary exercise test in patients with isolated diastolic dysfunction. We detected a correlation between BNP concentrations and functional capacity (39). However, since our patients had mostly mild diastolic dysfunction, impaired relaxation pattern, the mean BNP concentrations were in normal range.
In a review article, Dahlstörm (40) stated that natriuretic peptides are not activated in patients having diastolic dysfunction in the form of delayed relaxation. Thus, it seems not appropriate to measure BNP or NT-proBNP level in clinical routine to detect patients with mild relaxation abnormalities.
The optimal cut-off value for a diastolic heart failure diagnosis is unclear. The BNP has a role in detecting patients with diastolic dysfunction especially in those patients having a restrictive or pseudonormalized filling pattern. Patients with relaxation abnormalities and mild symptoms or who are asymptomatic may have normal BNP levels, indicating normal or only slightly elevated left ventricular filling pressures. Thus, low levels cannot be used to rule out diagnosis of diastolic dysfunction. However, if there are high concentrations of the BNP, there is a need for further investigation with echocardiography to verify the diagnosis of abnormal cardiac function.
NT-proBNP (N-Terminal pro B-type natriuretic peptide)
NT-proBNP is a biologically inactive fragment. NT-proBNP is released predominantly by the ventricles in response to stretch, similar to BNP. NT-proBNP circulated at higher plasma concentrations and has a longer half-life compared with BNP (41). It may be used for the diagnosis of heart failure as BNP (42). NT-proBNP was found to be high in isolated diastolic dysfunction and it could be useful for the detection of all degrees of diastolic dysfunction (43). NT-proBNP levels are increased significantly according to the severity of overall diastolic dysfunction, displaying a pattern similar to BNP (43). In a meta-analysis the pooled estimates of sensitivity and specificity were the same for the BNP studies as for the NT-proBNP studies. BNP and NT-proBNP have very similar diagnostic performance characteristics and can be used to rule out heart failure. However, there is no easily identifiable optimum cut point value for each peptide (44). The other meta-analysis both BNP and NT-proBNP assays have a high degree of diagnostic accuracy and clinical relevance for both acute and chronic heart failure (45).
Influences on BNP and NT-proBNP concentrations
The optimal cut-off value of BNP and NT-ProBNP for the diagnosis of diastolic heart failure is unclear. It may relate some factors. The most important factors the cut-off values of BNP and NT-proBNP are method-dependent. Hammerer- Lercher et al (46) pointed out that the performance of BNP for the diagnosis of systolic or diastolic left ventricular dysfunction is not affected by the assay used, whereas the performance of NT-proBNP for the diagnosis of isolated diastolic left ventricular dysfunction is assay dependent (46). They found that both BNP assays (Triage and Shionoria) and both NT-proBNP assays (Biomedica and Roche) performed equally well for the diagnosis of systolic left ventricle dysfunction despite the poor agreement between NT-proBNP assays (46). In patients with isolated diastolic left ventricular dysfunction, the diagnostic performance of the Triage BNP was significantly better than that of Biomedica NT-proBNP. Furthermore, the performance of the Biomedica NT-proBNP assay was significantly worse than that of the Roche NT-proBNP assay for diagnosis of isolated diastolic left ventricular dysfunction. In other studies the Triage BNP assay when compared to the Shionoria assay gives consistently higher values and the magnitude of difference increases with concentration (and severity of heart failure) of peptide (46,47). The Biomedica method shows considerably higher values compared to the Elecsys method (Roche) suggesting that higher cut-off values are needed to be comparable (46, 48).
Other factors in determining a cut point value for the diagnosis of HF were demonstrated by Raymond et al (49). They found that female sex, age, increasing dyspnea, diabetes mellitus, valvular heart disease, low heart rate, left ventricular ejection fraction < 45%, abnormal ECG, high plasma creatinine, low plasma HbA1c, and high urine albumin were each independently associated with a high plasma NT-proBNP level.
Some medications used to treat heart failure might affect natriuretic concentrations. Diuretics such as spironolactone, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers reduce natriuretic peptide concentrations (50). Therefore, many patients with chronic stable heart failure will have BNP levels in the normal diagnostic range. However, digoxin and some beta blockers appear to increase natriuretic peptide concentrations (50-52).
Exercise causes a slight increase in BNP levels which are detectable at short-term (one hour after exercise) (53) (i.e., increase of 0.9 percent in patients without heart failure, 3.8 percent in patients with New York Heart Association [NYHA] class I or II heart failure, and 15 percent in patients with NYHA class III to IV heart failure) (54).
No circadian variation has been reported when BNP is measured every three hours for 24 hours (55) and there is less hourly variation with BNP than with ANP (56).
BNP concentrations increase in diastolic HF but it is typically lower than that in systolic HF. BNP concentrations correlate with the stage of diastolic dysfunction. Concentrations might be raised among patients with evidence of impaired relaxation and highest among those with a restrictive filling pattern. BNP concentrations increase in patients with diastolic dysfunction as they become symptomatic. Sometimes in impaired relaxation groups it might be in normal range. Therefore low levels should not be used as a rule out the diagnosis of diastolic dysfunction. However, if there are high concentrations of the BNP there is a need for further investigation to verify the diagnosis of abnormal cardiac function. The optimal cut-off value for the diagnosis of diastolic heart failure is not defined accurately because of the performance of BNP and NT-proBNP for the diagnosis of isolated diastolic left ventricular dysfunction is assay dependent.