Neurohormonal activation is prevalent in adults with congenital heart disease, but its relation to outcome remains unknown. B-type natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) were measured prospectively in 49 patients with adult congenital heart disease, who were followed up for a median of 7.9 years (interquartile range 7.7 to 8.2). Cox proportional hazards regression analysis was used to determine the relation of BNP and ANP concentrations to all-cause mortality. The mean age at baseline was 33.9 ± 11.3 years, and 46.9% of patients were men. Most patients (77.5%) were symptomatic (20.4% had New York Heart Association class III), 10 (20.4%) were cyanotic, and 28 (57.1%) had systemic ventricular dysfunction (moderate or severe in 18.4%). The median concentration of BNP was 52.7 pg/ml (interquartile range 39.1 to 115.4) and of ANP was 47.4 pg/ml (interquartile range 19.7 to 112.8). Of the 49 patients, 11 (22.4%) died during the follow-up period. Both BNP and ANP were strong predictors of mortality (hazard ratio per 100-pg/ml increase 1.80, 95% confidence interval 1.38 to 2.34, p <0.0001; and hazard ratio per 100-pg/ml increase 1.21, 95% confidence interval 1.12 to 1.32, p <0.0001, respectively). A BNP value >78 pg/ml predicted death with a sensitivity of 100% and specificity of 76.3% (area under the curve 0.91, p = 0.0001). An ANP value of >146 pg/ml predicted death with a sensitivity of 72.7% and specificity 94.7% (area under the curve 0.89, p = 0.0001). No patients with a BNP level <78 pg/ml died during the follow-up period. In conclusion, the BNP and ANP levels strongly predicted death in symptomatic ambulatory patients with adult congenital heart disease during mid-term follow-up and could be used as a simple clinical marker for risk stratification in this population.
Elevated B-type natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) levels have been reported across a wide spectrum of congenital lesions, correlating with a worsening New York Heart Association (NYHA) functional class and systemic ventricular dysfunction. As adult patients with congenital heart disease (ACHD) age, the prevalence of heart failure and its complications increase, resulting in greater morbidity and mortality. Risk prediction is a prerequisite for the appropriate selection of treatment strategies, including medical therapy, additional surgical or catheter intervention, and heart transplantation. Identification of a widely available biomarker of disease severity with strong prognostic information is, therefore, highly desirable. The present study assessed the prognostic power of BNP and ANP plasma concentrations in an ambulatory ACHD population and defined cutoff values for these natriuretic peptides that can best predict the clinical outcomes in this population.
Methods
A total of 49 consecutive patients with stable ACHD were prospectively recruited from the ACHD outpatient clinic of the Royal Brompton Hospital from September 2000 to April 2001. No patients with clinically decompensated cardiac disease or evidence of concurrent systemic infection or malignancy were included in the present study. No patients with advanced chronic renal failure (serum creatinine >200 μmol/L or 2.26 mg/dl) or evidence of significant hepatic dysfunction (aspartate transaminase 2 or more times the upper limit of normal) were included. Cyanosis was defined as oxygen saturation of ≤90% in room air, by pulse oximetry, after ≥2 minutes of complete rest. Systolic ventricular function was recorded by echocardiography at blood sampling, using the following semiquantitative classification: 1, normal; 2, mildly impaired; and 3, moderately to severely impaired.
Follow-up data were obtained through the National Health Service computer system, which is linked to a national database of patient survival held by the Office for National Statistics (London, United Kingdom). The major end point was all-cause mortality. Death was defined as sudden when occurring within 1 hour of acute symptoms. Death was classified as secondary to heart failure when occurring after progressive worsening heart failure with evidence of at least one of the following: orthopnea, nocturnal dyspnea, pulmonary edema, increasing peripheral edema, renal hypoperfusion (worsening renal function), or radiologic signs of congestive heart failure. Deaths were classified as perioperative when occurring within 30 days of surgery or before hospital discharge. All participants provided written informed consent, and the local ethics committee approved the study.
Peripheral venous blood samples were obtained from all participants at baseline after they had rested for ≥20 minutes. Blood was collected into tubes containing ethylenediaminetetraacetic acid and aprotinin (50 kIU/ml of blood). The samples were centrifuged at 3,000 rpm for 15 minutes at 4°C. The plasma and serum aliquots were stored at −75°C until analysis. ANP and BNP were determined using immunoradiometric assays from ethylenediaminetetraacetic acid/aprotinin plasma (Shionogi, Osaka, Japan). For all subjects, the full blood count, renal function, and liver function were determined using routine laboratory methods.
Continuous variables are expressed as the mean ± SD or median (interquartile range, ie, twenty-fifth to seventy-fifth percentile). The groups were compared using the Wilcoxon rank sum test. The Kruskal-Wallis one-way analysis of variance was used to compare BNP values across ACHD patient groups according to NYHA class and systemic ventricular function categories. Cox regression analysis was used to assess the relation between natriuretic peptide levels, treated as continuous variables, and outcome. Receiver operating characteristic curves were used to determine the cutoff values for BNP and ANP that would best predict all-cause mortality. Kaplan-Meier curves were plotted according to the identified BNP and ANP cutoff values, and differences in survival were compared using the log-rank test. A 2-sided p value <0.05 was considered indicative of statistical significance. R, version 2.7.0 (R Development Core Team, [2008] R: A language and environment for statistical computing; R Foundation for Statistical Computing, Vienna, Austria, available at www.R-project.org ) was used for statistical analysis.
Results
The mean age at baseline was 33.9 ± 11.3 years, and 46.9% of the patients were men ( Table 1 ). Of the 49 patients, 18 (36.7%) had tetralogy of Fallot, 15 (30.6%) had univentricular circulation, 6 (12.2%) had a systemic right ventricle (transposition of the great arteries after an atrial switch operation or congenitally corrected transposition of the great arteries), and 10 (20.4%) had other lesions. Most (77.5%) patients were symptomatic (20.4% with NYHA class III). Ten patients (20.4%) were cyanotic at rest. Systemic ventricular dysfunction was present in 57.1%, and it was moderate or severe in 18.4%. Almost 1/3 received treatment with diuretics, and only a few patients were receiving conventional heart failure medical treatment, reflecting the uncertainty regarding the efficacy of traditional heart failure treatments in the ACHD population, especially in the setting of subpulmonary ventricular dysfunction.
| Characteristic | Value |
|---|---|
| Age (years) | 34 ± 11 |
| Men | 23 (47%) |
| Body mass index (kg/m 2 ) | 22 ± 5 |
| Ventricular morphology | |
| Left | 42 (86%) |
| Right | 7 (14%) |
| New York Heart Association class | |
| I | 11 (22%) |
| II | 28 (57%) |
| III | 10 (20%) |
| Cyanosis at rest | 10 (20%) |
| Systolic blood pressure (mm Hg) | 117 ± 16 |
| Diastolic blood pressure (mm Hg) | 68 ± 12 |
| Heart rate (beats/min) | 74 ± 12 |
| Medications | |
| Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers | 14 (29%) |
| β Blockers | 4 (8%) |
| Digoxin | 3 (6%) |
| Diuretics | 15 (31%) |
| Spironolactone | 6 (12%) |
| Blood test results | |
| Sodium (mmol/L) | 137 ± 1 |
| Creatinine (μmol/L) | 82 ± 20 |
| Hemoglobin (g/dl) | 15 ± 2 |
| Platelet count (10 9 /L) | 200 ± 59 |
| Cardiothoracic ratio (%) | 58 ± 9 |
| Echocardiographic variables | |
| Systemic ventricular function | |
| Normal | 21 (43%) |
| Mildly impaired | 19 (39%) |
| Moderate to severely impaired | 9 (18%) |
| Right atrial volume (cm 3 ) | 88 (54–155) |
| Left atrial volume (cm 3 ) | 69 (45–96) |
The median BNP concentration was 52.7 pg/ml (interquartile range 39.1 to 115.4), and the median ANP concentration was 47.4 pg/ml (interquartile range 19.7 to 112.8). The BNP values did not differ according to gender (p = 0.32), type of systemic ventricle (morphologically right vs left, p = 0.69), or the presence of cyanosis (p = 0.21). A significant stepwise increase was found in the BNP concentrations with increasing disease severity (as expressed by NYHA class, p = 0.01) and systemic ventricular function (p = 0.05).
During a median follow-up of 7.9 years (interquartile range 7.7 to 8.2 years), 11 patients (22.4%) died (mortality rate of 3.3%/year, 95% confidence interval 1.7 to 6.0). The median age at death was 30.8 years (range 22.1 to 56.1). Of the patients who died, 4 had tetralogy of Fallot, 4 had univentricular circulation, 1 had a systemic right ventricle, and 2 had other lesions. Six patients died from progressive heart failure, 4 patients died suddenly, and 1 patient died perioperatively (during conversion of atriopulmonary Fontan to total cavopulmonary connection).
Both BNP and ANP were strong predictors of mortality (hazard ratio per 100-pg/ml increase 1.80, 95% confidence interval 1.38 to 2.34, p <0.0001 and hazard ratio per 100-pg/ml increase 1.21, 95% confidence interval 1.12 to 1.32, p <0.0001 respectively). A BNP value >78 pg/ml predicted death with a sensitivity of 100% and a specificity of 76.3% (area under then curve 0.91, p = 0.0001), and an ANP value >146 pg/ml predicted death with a sensitivity of 72.7% and a specificity of 94.7% (area under the curve 0.89, p = 0.0001). No patients with BNP <78 pg/ml died during follow-up ( Figure 1 ), and all but 2 patients with ANP >146 pg/ml (n = 7) died within 3 years of follow-up ( Figure 2 ). A linear association was observed for both BNP and ANP levels and the hazard of death, with no evidence of thresholds ( Figure 3 ).
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