Increased levels of B-type natriuretic peptide (BNP) are associated with prolongation of the action potential in ventricular myocardium. We investigated the relation of a BNP increase, QT interval, and sudden cardiac death (SCD) in the presence of heart failure (HF). We enrolled 398 patients with HF, New York Heart Association class III or IV, and left ventricular ejection fraction <40%. At baseline and after 3 months, we measured BNP and the QT interval. A BNP increase was defined as a change in BNP of ≥+10%. The QTc interval was calculated using the Bazett formula. QTc interval prolongation was defined as a change in QTc of ≥+10%. The patients were followed up for 1 year. During a 3-month period, BNP increased significantly in 53% of the patients (group 1) and did not in 47% (group 2). During the same period, the QTc interval was more prolonged in group 1 (+44 ± 12 ms) than in group 2 (+7 ± 6 ms; p = 0.01). During 1 year of follow-up, 20 patients died suddenly (SCD), 16 from pump failure. Although the SCD rates did not differ between the 2 groups (5.7% in group 1 vs 4.2% in group 2, p = 0.53), they were significantly greater in the patients in group 1 with QTc interval prolongation ≥+10% (13.8%, p <0.001). The Kaplan-Meier–derived SCD-free survival rates were 2.9 times greater in patients without QTc interval prolongation than in those with prolonged QTc (p <0.001). QTc interval prolongation was an independent correlate of SCD (p = 0.006), but BNP increase was not (p = 0.32). In conclusion, a BNP increase in patients with HF was associated with an increased risk of SCD only in patients with QTc interval prolongation.
Despite the clinical evidence suggesting a relation between high B-type natriuretic peptide (BNP) levels and sudden cardiac death (SCD), the underlying mechanisms and the benefit of BNP testing, in addition to other risk stratification tests, remains unclear. Previously, we have demonstrated that increased BNP levels can be used, together with a prolonged QT interval, to predict mortality in patients with advanced chronic heart failure (HF). Because the QT interval is mainly affected by changes in ventricular repolarization, patients with greater BNP levels might have an increased duration of their ventricular action potential and a longer QT interval on the surface electrocardiogram (ECG). Thus, the aim of the present study was to investigate the relation among BNP levels, QT interval, and risk of SCD in patients with advanced chronic HF.
Methods
The study design was based on a prospective study conducted at the Advanced Heart Failure and Transplantation Center at University Medical Center Ljubljana in collaboration with Stanford University. All patients with HF referred to the Advanced Heart Failure and Transplantation Center at the University Medical Center Ljubljana from January 1, 2008 to June 1, 2008 were considered for inclusion in the present study. The inclusion criteria consisted of age >18 years, optimal medical management for ≥6 months, left ventricular ejection fraction <40%, and New York Heart Association functional class III or IV for ≥3 months before referral. Patients with pacemakers or implantable cardioverter-defibrillators (AICDs) and patients with atrial fibrillation were not included. All patients provided written informed consent before participation in the present study, and the national medical ethics committee approved the study protocol.
In all patients, we performed a standard clinical evaluation and echocardiography and measured the plasma BNP and QT interval duration on a standard surface ECG at baseline and again after 3 months (phase 1). Thereafter, we followed up the patients for 1 year for the occurrence of SCD (phase 2).
Blood samples for BNP measurement were collected into an ethylenediaminetetraacetic acid-coated tube containing aprotinin, immediately placed on ice for ≤4 hours, and then centrifuged at 4500 rpm for 15 minutes at 0°C. The serum was extracted and stored at −80°C until BNP assay. All BNP assays were performed with a commercially available kit (Triage BNP Test, Biosite Diagnostics, San Diego, California). A BNP increase was defined as a change in the BNP level at 3 months ≥+10% from baseline.
In all patients 12-lead ECGs at rest were recorded at a paper speed of 25 mm/s on a Marquette Resting ECG machine (Marquette Electronics, Milwaukee, Wisconsin). Two independent observers who were unaware of the clinical and survival data determined the QT interval duration. The QT interval duration was recorded for 3 consecutive beats through leads II and V 4 . Using calipers on the printed ECGs, each QT interval was measured from the beginning of the QRS complex to the visual return of the T wave to the isoelectric line. When the T wave was interrupted by the U wave, the end of the T wave was defined as the nadir between the T and U waves. When the nadir was not clearly visible or the maximal T-wave amplitude in leads II or V 4 did not exceed 0.25 mV, the patient was excluded from the study. Also excluded were patients with electrocardiographic evidence of arrhythmias or pacemaker rhythms. Heart rate correction was done using the Bazett formula, and the QTc interval duration was defined as the mean duration of all QTc intervals measured. QTc interval prolongation was defined as a change in the QTc interval at 3 months of ≥+10% from baseline.
The echocardiographic data were recorded and analyzed by an independent echocardiographer who was unaware of the timing of both recordings. The left ventricular ejection fraction was estimated using Simpson’s biplane method, and the left ventricular end-diastolic dimension was measured in the parasternal long-axis view by side by side comparison. Both the left ventricular ejection fraction and the left ventricular end-diastolic dimension were averaged for 5 cycles.
The patients were followed up for a 1-year period after the second measurement (15 months from baseline). The primary end point was SCD, defined as either witnessed cardiac arrest or death within 1 hour after the onset of acute symptoms or an unexpected death of a patient known to have been well within the previous 24 hours. The secondary end point was pump failure death, defined as death resulting from multiorgan failure caused by HF progression.
Continuous variables are expressed as the mean ± SD. Differences between patients with and without a BNP increase in phase 1 were analyzed using 1-factor analysis of variance followed by Tukey’s test for continuous variables. Categorical variables were compared using a chi-square test. Univariate and multivariate stepwise Cox proportional hazard regression analyses were performed to identify the independent predictors of SCD in phase 2. The probability value for entering and staying in the model was set at 0.05. The Kaplan-Meier method was used to analyze and compare survival in patients with and without QTc interval prolongation. A value of p <0.05 was considered significant.
Results
Of the 512 patients eligible for the present study, we excluded 92 patients (18%) because of electrocardiographic abnormalities, including atrial fibrillation in 74, pacemaker rhythm in 14, and low T-wave amplitude or an inadequate definition of T-wave offset in 4. Of the 420 patients entering phase 1, 7 patients died (2%) and 15 (4%) were lost to follow-up ( Figure 1 ).
In phase 1, BNP increased by ≥10% in 212 of 398 patients (53%, group 1). In 186 patients (47%, group 2), we found no significant increase in BNP during the 3-month period. The 2 groups did not differ with regard to the baseline BNP levels (1,012 ± 567 pg/ml in group 1 vs 988 ± 612 pg/ml in group 2, p = 0.72) or QTc interval ( Figure 2 ). During the 3-month period, the QTc interval was more prolonged in group 1 than in group 2, with ≥10% prolongation present in 38% of patients in group 1 versus 25% of patients in group 2 (p = 0.01).
Of the 398 patients enrolled in phase 2, 39 died and 5 underwent transplantation during the 1-year follow-up period. Deaths were attributed to SCD in 20 (51%), pump failure in 16 (41%), and noncardiac causes in 3 (8%). The characteristics of the patients enrolled in phase 2 are listed in Table 1 according to the 1-year clinical outcomes.
| Variable | All (n = 398) | Survivors (n = 354) | Deaths | |
|---|---|---|---|---|
| SCD (n = 20) | Non-SCD (n = 19) | |||
| Age (yrs) | 65 ± 12 | 64 ± 13 | 65 ± 15 | 66 ± 12 |
| Gender | ||||
| Male | 262 (66%) | 236 (67%) | 13 (65%) | 13 (68%) |
| Female | 136 (34%) | 118 (33%) | 7 (35%) | 6 (32%) |
| Etiology | ||||
| Ischemic | 267 (67%) | 240 (68%) | 14 (70%) | 12 (63%) |
| Nonischemic | 131 (33%) | 114 (32%) | 6 (30%) | 7 (37%) |
| Heart rate (beats/min) | 85 ± 12 | 83 ± 13 | 86 ± 10 | 86 ± 14 |
| Blood pressure (mm Hg) | ||||
| Systolic | 110 ± 18 | 115 ± 22 | 111 ± 10 | 108 ± 14 |
| Diastolic | 65 ± 15 | 69 ± 7 | 70 ± 10 | 60 ± 12 |
| Left ventricular ejection fraction (%) | 28 ± 10 | 29 ± 11 | 28 ± 14 | 26 ± 5 |
| Left ventricular end-diastolic dimension (cm) | 6.2 ± 1.2 | 6.0 ± 1.1 | 6.1 ± 0.9 | 6.3 ± 1.3 |
| Sodium (mmol/L) | 135 ± 8 | 137 ± 7 | 135 ± 8 | 133 ± 6 |
| Creatinine (mg/dl) | 1.42 ± 0.65 | 1.37 ± 0.59 | 1.40 ± 0.77 | 1.44 ± 0.5 |
| Therapy | ||||
| Loop diuretics | 358 (90%) | 300 (85%) | 18 (90%) | 18 (95%) |
| Spironolactone | 78 (20%) | 67 (19%) | 3 (15%) | 4 (21%) |
| Digoxin | 135 (34%) | 110 (31%) | 6 (30%) | 7 (37%) |
| Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers | 370 (93%) | 322 (91%) | 19 (95%) | 17 (89%) |
| β Blockers | 330 (83%) | 291 (82%) | 17 (85%) | 15 (79%) |
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