Although N-terminal pro-brain natriuretic peptide (NT-proBNP) is a useful screening test of impaired right ventricular (RV) function in conditions affecting the right-sided cardiac muscle, the role of NT-proBNP remains unclear in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). This study was designed to clarify the relation between the plasma NT-proBNP level and the RV function evaluated by cardiovascular magnetic resonance (CMR) imaging. We selected 56 patients with confirmed ARVC only when their blood specimens for NT-proBNP measurements were collected within 48 hours of a CMR scan. The NT-proBNP level was significantly higher in patients with RV dysfunction than in patients without RV dysfunction (median of 655.3 [interquartile range 556.4 to 870.0] vs 347.0 [interquartile range 308.0 to 456.2] pmol/L, p <0.001). The NT-proBNP levels were positively correlated with RV end-diastolic and end-systolic volume indices (r = 0.49 and 0.70, respectively) and negatively correlated with RV ejection fraction (r = −0.76, all p <0.001), which remained significant after adjustment for age, gender, and body mass index. The area under the receiver-operating characteristic curve for NT-proBNP was 0.91 (95% confidence interval 0.80 to 0.97, p <0.001). The cut-off value of NT-proBNP (458 pmol/L) was associated with sensitivity, specificity, and positive and negative predictive values of 91%, 89%, 67%, and 98%, respectively. In conclusion, NT-proBNP is a useful marker for the detection of RV dysfunction and associated with extent of RV dilatation and dysfunction determined by CMR in patients with ARVC.
Highlights
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Cardiovascular magnetic resonance was the main imaging method for assessing patients with suspected or known arrhythmogenic right ventricular (RV) cardiomyopathy.
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The role of N-terminal pro-brain natriuretic peptide (NT-proBNP) is unclear in patients with arrhythmogenic RV cardiomyopathy.
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NT-proBNP was correlated with RV remodeling and function determined by cardiovascular magnetic resonance imaging.
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NT-proBNP is a useful marker for the detection of RV dysfunction.
N-terminal pro-brain natriuretic peptide (NT-proBNP) is primarily secreted from the cardiomyocytes in response to myocardial wall stress and volume overload, predominantly in the left ventricle (LV) and to a lesser degree from the right ventricle (RV). Previous studies have demonstrated that NT-proBNP level is a useful screening test of impaired RV function in conditions affecting the right-sided cardiac muscle. However, relatively little research relevant to NT-proBNP and RV function is conducted in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). The purpose of this study was to clarify the relation between the plasma NT-proBNP level and the RV function evaluated by cardiovascular magnetic resonance (CMR) imaging and identify the best cut-off value of NT-proBNP for prediction of RV dysfunction in patients with ARVC.
Methods
We retrospectively reviewed patients with suspected ARVC referred for a CMR scan between October 2006 and December 2013 from Fuwai Hospital. Clinical, laboratory, basal 12-lead electrocardiography (ECG), and 24-hour Holter monitoring data were extracted from the medical archives. The study was reviewed and approved by the committee on human research at Fuwai hospital. The diagnoses of ARVC were confirmed according to the revised task force criteria (TFC), if the patients either had 2 major criteria, 1 major and 2 minor criteria, or 4 minor criteria. The patients with confirmed ARVC were selected only when their blood specimens for NT-proBNP measurements were collected within 48 hours of a CMR scan. Patients with one or more of the following conditions were further excluded: any cardiac surgery in the past, history of cardioversion, presence of atrial fibrillation, LV ejection fraction (EF) <55% on CMR, mean pulmonary artery pressure ≥25 mm Hg at rest on echocardiography, and renal impairment (creatinine >130 μmol/L). The patients with ARVC were divided into 2 groups based on the presence of RV dysfunction. The RV dysfunction was defined as RVEF ≤45% measured by CMR, based on the value proposed by the modified TFC for the identification of RV dysfunction in ARVC.
All CMR examinations were performed on a 1.5-T MR scanner (Siemens Avanto, Erlangen, Germany). Scout transverse and sagittal images were acquired followed by a half-Fourier acquisition single-shot turbo spin echo sequence. Image parameters for half-Fourier acquisition single-shot turbo spin echo sequence were as follows: repetition time 1 R-R interval, echo time 42 ms, slice thickness 6 mm, imaging matrix 111 × 256, and field of view 34 cm. True imaging with steady-stage precession sequence was chosen for cine scan in the axial and short-axis planes. Image parameters for true imaging with steady-stage precession sequence were as follows: repetition time 2.3 ms, echo time 1.4 ms, slice thickness 6 mm, image matrix 256 × 192, field of view 34 cm, and flip angle 60°.
All CMR images were transferred to workstation (Siemens Medical Systems, Erlangen, Germany) for analysis. The biventricular volumes and EF were obtained using Argus analytical software (version VE36 A) and indexed by body surface area. Endocardial borders of the LV and RV were traced manually on end-diastolic and end-systolic images, in each of the contiguous short-axis slice. End-diastolic and end-systolic frames were defined on the basis of the respective image frames demonstrating the largest and smallest cavity size. Global and regional wall motion abnormalities of the RV were subjectively assessed. Localized aneurysms were defined as akinetic regions of the RV wall showing bulging in diastole and systole. All CMR images were analyzed by a single experienced radiologist (M.L.) who was blinded regarding the results of clinical and NT-proBNP investigations. The interobserver variability for RV volumes and function has been reported in our previous study for ARVC.
Peripheral venous blood samples were obtained from all patients after they had rested for at least 30 minutes. NT-proBNP levels were determined by quantitative enzyme immunoassay (Biomedica medizinprodukte GmbH and Co KG, Wien, Austria) according to the manufacturers’ instructions. The standard ranges were from 0 to 6,400 pmol/L. The intra-assay coefficients of variation were 6% and 8%, respectively. The interassay coefficients of variation were 6% and 7%, respectively. The normal range of NT-proBNP value for the laboratory was <400 pmol/L.
The normal distribution variables were tested by the Kolmogorov-Smirnov test. Continuous data were compared using the Student unpaired t test or Mann-Whitney U test. Categorical data were analyzed by chi-square test or Fisher’s exact test. NT-proBNP values underwent logarithmic transformation to normalize data for analyses. Correlation analyses were performed using the Pearson or Spearman correlation test. A linear regression model was used to evaluate the relation between NT-proBNP values and CMR parameters adjusted for age, gender, and body mass index (BMI). Receiver-operating characteristic curve was used to test the diagnostic accuracy of NT-proBNP for RV dysfunction in patients with ARVC. The statistical analyses were performed using statistical software package SPSS, version 16.0 (SPSS, Chicago, Illinois). All statistical tests were 2 sided, and a p value of <0.05 was considered statistically significant.
Results
The study population consisted of 56 patients with ARVC, matching the earlier mentioned enrollment criteria ( Figure 1 ). The diagnostic details of modified TFC for ARVC are listed in Table 1 . Baseline characteristics of the patient population are listed in Table 2 . The mean age at inclusion was 39.6 ± 13.8 years. There were 6 patients (11%) with family history. A first-degree relative with confirmed ARVC were in 4 patients (7%) on the basis of current TFC. Premature sudden death (<35 years) because of suspected ARVC in a first-degree relative was in 2 patients (4%). On the standard ECG, 37 patients (66%) showed a T-wave inversion in right precordial leads (V1, V2, and V3) or beyond in absence of complete right bundle branch block (BBB), and epsilon wave was present in 7 patients (13%; Figure 2 ). Ventricular arrhythmias presented in 46 patients (82%) on 24-hour Holter ECG, including ventricular premature contraction in 19 patients (34%), nonsustained and sustained ventricular tachycardia with left BBB morphology with superior axis in 25 patients (45%), and nonsustained ventricular tachycardia of left BBB morphology with inferior axis in 2 patients (4%).
| Revised task force criteria | Value | |
|---|---|---|
| Global or regional dysfunction and structural alterations (cardiovascular magnetic resonance imaging) | Major (RVEF) | 33 (59%) |
| Minor (RVEF) | 12 (21%) | |
| Major (RVEDVI) | 28 (50%) | |
| Minor (RVEDVI) | 7 (13%) | |
| Repolarization abnormalities | Major | 37 (66%) |
| Minor | 7 (13%) | |
| Depolarization/conduction abnormalities | Major | 7 (13%) |
| Minor | 7 (13%) | |
| Arrhythmias | Major | 25 (45%) |
| Minor | 21 (38%) | |
| Family history | Major | 4 (7%) |
| Minor | 2 (4%) |
| Variable | Value |
|---|---|
| Age (years) | 39.6 ± 13.8 |
| Men | 39 (70%) |
| Palpitations | 39 (70%) |
| Chest pain/discomfort | 5 (9%) |
| Presyncope | 6 (11%) |
| Syncope | 9 (16%) |
| Medication | |
| Beta-blocker | 29 (52%) |
| Amiodarone | 10 (18%) |
| Calcium-channel blocker | 6 (11%) |
| Other antiarrhythmics | 5 (9%) |
Morphofunctional RV abnormalities, either global or regional, were observed at CMR in 47 patients (84%), including RV regional aneurysm in 15 patients (27%; Figure 3 ). The CMR characteristics and biomarkers of patients according to RVEF level were compared in Table 3 . The NT-proBNP levels were significantly higher in patients with RV dysfunction than in patients without RV dysfunction (median of 655.3 [interquartile range 556.4 to 870.0] vs 347.0 [interquartile range 308.0 to 456.2] pmol/L, p <0.001; Figure 4 ). There were no differences between patients with RV dysfunction and without dysfunction in age, gender, BMI, creatinine, LVEF, and LV end-diastolic volume index (EDVI) and end-systolic volume index (ESVI).
| Variable | Right ventricular dysfunction | p value | |
|---|---|---|---|
| Yes (n = 45) | No (n = 11) | ||
| Men | 30 (67%) | 9 (82%) | 0.473 |
| Age (years) | 40.5 ± 14.6 | 35.7 ± 9.6 | 0.309 |
| Body mass index (kg/m 2 ) | 23.0 ± 3.3 | 23.4 ± 6.7 | 0.710 |
| Left ventricular ejection fraction (%) | 60.3 ± 4.6 | 61.3 ± 4.9 | 0.518 |
| Left ventricular end-diastolic volume index (ml/m 2 ) | 62.1 ± 12.2 | 63.1 ± 13.2 | 0.800 |
| Left ventricular end-systolic volume index (ml/m 2 ) | 24.7 ± 6.3 | 24.8 ± 7.9 | 0.994 |
| Right ventricular ejection fraction (%) | 34.3 ± 8.2 | 50.5 ± 5.0 | <0.001 |
| Right ventricular end-diastolic volume index (ml/m 2 ) | 116 ± 30.0 | 95.7 ± 8.2 | <0.001 |
| Right ventricular end-systolic volume index (ml/m 2 ) | 77.7 ± 8.2 | 47.4 ± 6.1 | <0.001 |
| Global right ventricular dilatation | 20 (44%) | 0 | 0.005 |
| Global right ventricular hypokinesia | 26 (58%) | 0 | <0.001 |
| Right ventricular regional wall motion abnormalities | 19 (42%) | 2 (18%) | 0.179 |
| Right ventricular regional aneurysm | 15 (33%) | 0 | 0.026 |
| Creatinine (μmol/L) | 79.3 ± 16.1 | 75.5 ± 12.9 | 0.474 |
| NT-proBNP (pmol/L) | 655 (556-870) | 347 (308-456) | <0.001 |
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