Previous studies have demonstrated elevated B-type natriuretic peptide (BNP) level indicates a poor outcome in patients with heart failure (HF). However, some patients with end-stage HF presented with low BNP level and the impact of the nearly “normal” BNP level on long-term outcome is not well understood. Our study aimed to evaluate the association of BNP level with long-term outcome in 218 consecutive patients with dilated cardiomyopathy and end-stage HF. Sixty-two patients (28%) presented with admission BNP level ≤400 pg/ml. During a median follow-up period of 20 months (4 to 26 months), the all-cause mortality rate in patients with BNP ≤400 pg/ml was higher than in patients with BNP >400 pg/ml (76% vs 48%, p <0.001). Patients were then divided into 5 groups according to the BNP level (≤400, 401 to 1,000, 1,001 to 2,000, 2,001 to 3,000, and >3,000 pg/ml), the all-cause mortality were 76%, 41%, 40%, 49%, and 75%, respectively (p <0.001). After multivariate adjustment, both BNP ≤400 and >3,000 pg/ml were independently associated with increased risk of all-cause mortality (hazard ratios 1.87, 95% CI 1.02 to 3.42, p = 0.043 and hazard ratio 2.31, 95% CI 1.16 to 4.60, p = 0.018, respectively). In conclusion, our present study demonstrated a “U-like” shape between BNP level and all-cause mortality in end-stage HF, and the seemingly “normal” BNP level might also be a risk factor for poor outcome. Low BNP level may be a reflection of impaired neurohormonal response or altered metabolism of BNP and is associated with increased risk of poor outcome.
Heart failure (HF) is a global pandemic affecting an estimated 26 million people worldwide. Although death rates from cardiovascular disease as a whole have decreased, the incidence of HF is considered to be increasing with aging, and the long-term prognosis associated with HF is poor. B-type natriuretic peptide (BNP) is an important biomarker for diagnostic and prognostic evaluation of HF, and it has been demonstrated BNP level was positively associated with poor long-term outcome. However, it was also found some patients with end-stage HF presented with relatively low BNP level (≤400 pg/ml). We hypothesized that the prognosis of these patients was no better than those with modestly elevated BNP level. The aim of present study was to analyze the BNP level in patients with end-stage HF due to dilated cardiomyopathy (DC), a common etiology of HF in China, and to evaluate the impact of admission BNP level on the long-term outcome.
Methods
From February 2011 to September 2014, a total of 244 consecutive patients with DC with end-stage HF were recruited. Among the inclusion criteria were a New York Heart Association class III to IV with end-stage HF, left ventricular end-diastolic diameter >55 mm, left ventricular ejection fraction (LVEF) <40%, and/or a fractional shortening <25% confirmed by echocardiography in the absence of abnormal loading conditions (hypertension and valve disease) or coronary artery disease confirmed by coronary angiography that were sufficient to cause global systolic impairment. End-stage HF is defined as New York Heart Association class III to IV despite optimal medical and device therapy, intolerance or withdrawal of evidence-based HF medications such as beta blockers, angiotensin-converting enzyme inhibitors (ACEIs) due to hypotension, diuretic-refractory volume overload, or need for intravenous inotrope. Study protocols were approved by the appropriate Institutional Review Boards of the First Affiliated hospital of Chongqing Medical University and complied with the Declaration of Helsinki. All subjects were provided with written informed consent.
Baseline characteristics were collected at admission according to the predesigned case report form. Data of laboratory examination and echocardiographic parameters were obtained. At admission, 5 ml of venous blood was collected into tubes containing potassium ethylenediaminetetraacetic acid. The tubes were then centrifuged for 10 minutes (2,500 ×0 g ), and the plasma was separated. Measurement of BNP was performed within 2 hours after the blood samples were collected using a fluorescence immunoassay kit (Triage; Biosite, SanDiego, CA) according to the protocols provided by the manufacturer, and the measurable range of the BNP assays was 5.0 to 5000.0 pg/ml. BNP assays were done in the clinical laboratory with strict quality control system, and the interassay and intraassay coefficients of variability were 4.0% to 5.8% and 2.8% to 4.5%, respectively.
Follow-up was carried out every 3 to 6 months after enrollment by telephone. The primary end point was all-cause mortality during follow-up period. Secondary end points were stroke, bleeding, occurrence of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF), and the major adverse cardiovascular events (MACE; combined all-cause mortality, stroke, bleeding, and occurrence of sustained VT/VF).
Because patients in this cohort were confirmedly diagnosed with HF and usually had BNP level above the diagnostic threshold (>400 pg/ml), patients were divided into 2 groups according to the admission BNP level ≤400 and >400 pg/ml. Baseline characteristics and outcome were compared between the 2 groups. The association of different BNP level (≤400, 401 to 1,000, 1,001 to 2,000, 2,001 to 3,000, >3,000 pg/ml) with long-term outcome was also analyzed.
The baseline characteristics of the patients were presented with mean ± SD or interquartile range for continuous variables and compared by the Student t tests if the data were normally distributed, otherwise Wilcoxon signed-rank test was used. Categorical variables presented as number and percentage were compared by the Pearson’s chi-square test. Survival curves were constructed using the Kaplan–Meier method and were compared by log-rank tests. Multivariate Cox proportional hazard regression models were performed to identify the association between BNP level and the follow-up outcome, and the models were corrected for age, gender, body mass index, systolic blood pressure (SBP), heart rate, troponin I (TnI), D-dimer, left ventricular end-diastolic diameter, LVEF, and main medications. The adjusted hazard ratios (HRs) with their respective 95% CIs were calculated. All statistical tests were 2-tailed, and p <0.05 was considered to be statistically significant. All statistical analyses were carried out using the SPSS statistical software, version 20.0 (SPSS Inc., Chicago, Illinois).
Results
The median follow-up period was 20 months (4 to 26 months). Of 244 consecutive patients with DC, 16 patients were lost to follow-up, and 10 patients had incomplete data. Therefore, data of 218 remaining patients were analyzed; of which, 62 patients (28%) had admission BNP level ≤400 pg/ml.
Table 1 summarizes the baseline characteristics in patients with admission BNP level ≤400 and >400 pg/ml. Compared with patients with BNP >400 pg/ml, patients with BNP ≤400 pg/ml were older, had a lower body mass index, presented with relatively lower SBP and LVEF but had higher heart rate and TnI level (all p <0.05). Moreover, aldosterone receptor antagonist and amiodarone were less likely to be administered to patients with BNP ≤400 pg/ml (all p <0.05).
| Variable | BNP (pg/mL) | p Value | |
|---|---|---|---|
| ≤400 (n = 62) | >400 (n = 156) | ||
| Age (years) | 58±12 | 54±11 | 0.03 |
| Men | 39 (63%) | 119 (76%) | 0.06 |
| Body mass index (kg/m 2 ) | 20±3 | 21±4 | 0.02 |
| Coronary atherosclerosis | 6 (10%) | 12 (8%) | 0.60 |
| Hypertension | 6 (10%) | 21 (14%) | 0.50 |
| Diabetes mellitus | 32 (52%) | 71 (46%) | 0.45 |
| Atrial fibrillation | 46 (74 %) | 107 (69%) | 0.51 |
| Chronic obstructive pulmonary disease | 7 (11%) | 8 (5%) | 0.14 |
| Previous or current smoking | 30 (48%) | 94 (60%) | 0.13 |
| Previous or current alcohol use | 25 (40%) | 60 (39%) | 0.88 |
| Admission vital signs | |||
| Systolic blood pressure (mmHg) | 91±11 | 98±16 | 0.01 |
| Diastolic blood pressure (mmHg) | 65±8 | 65±9 | 0.78 |
| Heart rate (bmp) | 93±16 | 87±18 | 0.04 |
| Lab examination | |||
| BNP (pg/mL) | 299 (239-362) | 1863 (1222-2675) | <0.001 |
| Troponin I (ug/L) | 0.4 (0.1-1.1) | 0.05 (0.04-0.1) | <0.001 |
| D-dimer (mg/L) | 0.9 (0.6-1.5) | 0.8 (0.6-1.4) | 0.83 |
| Serum creatinine (umol/L) | 99 (71-169) | 102 (82-125) | 0.18 |
| Left ventricular end diastolic diameter (mm) | 75±8 | 74±10 | 0.30 |
| Left ventricular ejection fraction (%) | 33±5 | 35±5 | <0.001 |
| Therapy | |||
| Diuretics | 61 (98%) | 151 (97%) | 0.68 |
| Beta blockers | 16 (26%) | 44 (29%) | 0.87 |
| Angiotensin-converting enzyme inhibitors (or angiotensin receptors blockers) | 22 (36%) | 64 (41%) | 0.54 |
| Aldosterone receptor antagonist | 44 (71%) | 144 (92%) | <0.001 |
| Digoxin | 49 (79%) | 116 (74%) | 0.60 |
| Warfarin | 8 (13%) | 32 (21%) | 0.25 |
| Aspirin | 34 (55%) | 64 (41%) | 0.07 |
| Clopidogrel | 22 (36%) | 66 (42%) | 0.44 |
| Amiodarone | 5 (8%) | 30 (19%) | 0.04 |
| Dual or single chamber pacemaker implantation | 2 (3%) | 13 (8%) | 0.24 |
| Cardiac resynchronization therapy | 8 (13%) | 14 (9%) | 0.46 |
Figure 1 shows the follow-up outcome. The all-cause mortality in patients with BNP ≤400 pg/ml was significantly higher than in patients with BNP >400 pg/ml (76% vs 48%, p <0.001). The incidence of VT/VF and MACE in patients with BNP ≤400 pg/ml were also significantly higher than in patients with BNP >400 pg/ml (all p <0.05). However, the incidence of stroke and bleeding were comparable between the 2 groups.
We found patients with low BNP level (≤400 pg/ml) had higher all-cause mortality, and therefore, we subdivided patients into 5 groups according to the BNP level (≤400, 401 to 1,000, 1,001 to 2,000, 2,001 to 3,000, and >3,000 pg/ml), and the association of BNP level and all-cause mortality was reanalyzed. Figure 2 shows the all-cause mortality among groups. A “U-like” shape was found between BNP level and all-cause mortality. Mortality in BNP ≤400 pg/ml group (76%) and in BNP >3,000 pg/ml group (75%) were significantly higher than in other 3 groups (41%, 40%, and 49%, respectively; p <0.001).
Both low BNP level (≤400 pg/ml) and high BNP level (>3,000 pg/ml) were associated with high all-cause mortality, and the baseline characteristics and management of the 2 groups were then compared ( Table 2 ). Patients with low BNP level (≤400 pg/ml) were more likely to be older, presented with lower SBP and TnI level, whereas patients with high BNP level (>3,000 pg/ml) tended to be men, have lower LVEF, and more often treated with aldosterone receptor antagonist (all p <0.05).
| Variable | BNP (pg/mL) | p Value | |
|---|---|---|---|
| ≤400 (n = 62) | >3000 (n = 28) | ||
| Age (years) | 58±12 | 52±11 | 0.04 |
| Men | 39 (63%) | 25 (89%) | 0.01 |
| Body mass index (kg/m 2 ) | 20±3 | 20±5 | 0.64 |
| Hypertension | 6 (10%) | 4 (14%) | 0.50 |
| Diabetes mellitus | 32 (52%) | 15 (54%) | 1.000 |
| Atrial fibrillation | 46 (74%) | 21 (75%) | 1.00 |
| Systolic blood pressure (mmHg) | 92±11 | 98±13 | 0.03 |
| Heart rate (bmp) | 93±16 | 90±18 | 0.49 |
| Troponin I (ug/L) | 0.4 (0.1-1.1) | 0.7 (0.2-1.8) | <0.001 |
| Left ventricular end diastolic diameter (mm) | 75±8 | 78±11 | 0.18 |
| Left ventricular ejection fraction (%) | 33±5 | 30±4 | 0.01 |
| Diuretics | 61 (98%) | 26 (93%) | 0.23 |
| Beta blockers | 16 (26%) | 4 (14%) | 0.28 |
| Angiotensin-converting enzyme inhibitors or angiotensin receptors blockers | 22 (36%) | 9 (32%) | 0.82 |
| Aldosterone receptor antagonist | 44 (71%) | 27 (96%) | 0.01 |
| Digoxin | 49 (79%) | 23 (82%) | 1.00 |
Figure 3 displays the Kaplan–Meier curves survival and MACE stratified by admission BNP level. When divided into 2 groups (BNP ≤400 and >400 pg/ml), patients with BNP ≤400 pg/ml had significantly higher cumulative mortality and MACE than patients with BNP >400 pg/ml (log-rank p <0.001 and p = 0.005, respectively). When divided into 5 groups, patients with BNP ≤400 and >3,000 pg/ml had significantly higher cumulative mortality and MACE as compared with other 3 groups (both log-rank p <0.001).
The association of admission BNP level with all-cause mortality and MACE were analyzed by multivariate Cox model ( Table 3 ). Two models were constructed. In the first model, BNP was categorized as ≤400 and >400 pg/ml (reference) and in the second model, BNP was categorized as ≤400, 401 to 1,000 (reference), 1,001 to 2,000, 2,001 to 3,000, and >3,000 pg/ml. After multivariate adjustment, in the first model, BNP ≤400 pg/ml was associated with nearly 1.5-fold increased risk of all-cause mortality (HR 1.48, 95% CI 1.02 to 2.16, p = 0.041); in the second model, both BNP ≤400 pg/ml and >3,000 pg/ml were independently associated with increased risk of all-cause mortality (HR 1.87, 95% CI 1.02 to 3.42, p = 0.043 and HR 2.31, 95% CI 1.16 to 4.60, p = 0.018, respectively). Other factors included admission SBP, LVEF, D-dimer level, and beta blockers use. However, admission BNP level was not independently associated with MACE. Factors associated with MACE included admission SBP (HR 0.98, 95% CI 0.97 to 0.99, p = 0.006), D-dimer level (HR 1.26, 95% CI 1.02 to 1.57, p = 0.036), ACEIs/angiotensin receptors blockers (ARBs) use (HR 0.64, 95% CI 0.45 to 0.89, p = 0.009), and occurrence of VT/VF (HR 3.39, 95% CI 2.31 to 4.98, p <0.001).
