Death
H.V. HUIKURI
Introduction
Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are vasoactive peptide hormones with natriuretic, diuretic, and vasodilator activity [1–3]. They have emerged as important candidates in the develop- ment of diagnostic and prognostic tools for cardiovascular diseases [3, 4]. An association between elevated levels of natriuretic peptides (NP) and increased mortality has been established in patients with heart failure [5, 6]
as well as in patients with acute coronary syndromes [7, 8]. Moreover, previ- ous studies have further extended the role of BNP measurements to risk stratification of the general population [9–11].
Prediction of sudden cardiac death (SCD) after an acute myocardial infarction (AMI) is still a challenge. Several methods of prediction have been proposed [12–20], but none of them, except the measurement of left ventric- ular systolic function, is in routine clinical use in screening patients for can- didac y for ant i-ar rhy thmic therapy such as implantat ion of a cardioverter–defibrillator [17]. New methods of risk stratification are there- fore urgently needed.
BNP and Sudden Cardiac Death
At least two studies have assessed the role of BNP in predicting SCD [18, 19].
A study among patients with chronic heart failure specifically addressed the value of BNP measurement in the prediction of SCD [18]. Berger et al. [18]
Division of Cardiology, Department of Internal Medicine, University of Oulu, Finland
studied 452 patients with a left ventricular ejection fraction of less than 35%.
Forty-four patients suffered sudden death during a mean follow-up time of 592 ± 387 days. Univariate risk factors of sudden death were log BNP level (P = 0.006), log N-terminal ANP level (P = 0.003), left ventricular ejection fraction (LVEF; P = 0.005), log N-terminal BNP level (P = 0.006), systolic blood pressure (P = 0.01), high endothelin level (P = 0.03), and NYHA class (P = 0.04). In the multivariate model, log BNP level was the only inde- pendent predictor of sudden death (P = 0.0006). Using a cutoff point of log BNP < 2.11 (130 pg/ml), Kaplan–Meier sudden-death-free survival rates were significantly higher in patients below (99%) compared with patients above (81%) this cutoff point (P = 0.0001).
Tapanainen et al. [19] studied 521 patients with a recent AMI. During a mean follow-up of 43 ± 13 months 16 patients (3.1%) suffered SCD. On uni- variate analysis, high levels of all measured peptides and low EF predicted the occurrence of non-sudden cardiac death (P < 0.001 for all). Peptides and EF also predicted the occurrence of SCD (P < 0.05), with elevated BNP (> 23.0 pmol/1) being the most powerful predictor of SCD [hazard ratio (HR) 4.4, 95% confidence interval (CI), 1.4 to 13.8, P = 0.01]. After adjusting for clini- cal variables, only elevated BNP (HR 3.9, 95% CI, 1.2 to 12.3, P = 0.02) and low EF (< 0.40%; P = 0.03) remained as significant predictors of SCD.
The main implication of these studies is that the measurement of BNP can be used to identify the ‘low risk’ patients who may not need further risk stratification and may not benefit from prophylactic cardioverter-
Fig. 1.Kaplan–Meier survival curves:
sudden-death-free survival among patients after acute myocardial infarc- tion (post-AMI patients) in relation to plasma brain natriuretic peptide (BNP) level (by quartile)
defibrillator implantation despite depressed left ventricular function. For example, in the re-analysis of the study by Tapanainen et al. there were no SCDs among the patients with the lowest BNP quartile even when they had an EF of less than 35% (Figs. 1–3). Elevated BNP also had a predictive power among patients with preserved left ventricular function (EF > 40%) (relative
Fig. 2.Kaplan–Meier survival curves:
non-sudden-cardiac-death-free sur- vival among post-AMI patients in rela- tion to plasma brain natriuretic pep- tide (BNP) level (by quartile)
Fig. 3.Kaplan–Meier survival curves:
sudden-death-free survival among post-AMI patients with an ejection fraction (EF) less than 35% (highest quartile only)
risk 3.9, 95% CI, 1.0–16.5, P = 0.05). Patients with an EF below 40% also accounted for the highest cumulative number of SCD events. Prediction and prevention of SCD among the large number of survivors of AMI who have preserved left ventricular function will be important in future efforts aimed at reducing the overall burden of premature SCD. Measurement of BNP may have clinical value in this respect.
Prediction of SCD After AMI
Several risk markers, such as autonomic markers, the signal-averaged elec- trocardiogram (ECG), and T-wave alternans, have been extensively studied as predictors of SCD after AMI [12–14, 19–21]. Most of the studies have sug- gested that these variables provide information on the risk of subsequent SCD and arrhythmia events [12–14, 21]. However, the majority of these observational studies were performed in the era before optimised medical therapy. For example, in the Autonomic Tone and Reflexes After Myocardial Infarction (ATRAMI) study, which showed that autonomic markers predict sudden death, only around 20% of patients were receiving β-blocking thera- py [12]. Similarly, in studies showing that T-wave alternans after AMI pre- dicts SCD, only 13% of patients were receiving β-blocking medication [14, 21]. Our previous analyses of the same population as in the present study suggested that arrhythmia risk variables such as autonomic markers, signal- averaged ECG, and T wave alternans lose some of their predictive power among post-AMI patients with optimised β-blocking therapy [19, 20]. In the light of these findings, the present observations suggest that elevated BNP may have some potential value in the prediction of SCD among current post- AMI populations.
Elevated BNP and Risk of SCD
There may be several reasons why BNP provides more specific information on the risk of SCD than do the other peptides or even the measurement of LV systolic function. Both ANP and N-terminal ANP are more closely related to atrial volume loading, whereas BNP secretion from the ventricles is increased during progressive HF [22, 23] and is released from the ventricles in response to increased pressure, stretch, and hypertrophy [24]. Ventricular stretch, hypertrophy, and fibrosis can have significant influences on the elec- trophysiological properties of the heart via mechano-electrical feedback [25–28]. Thus, BNP may be an indirect marker of the mechanical factors pre- disposing a person to the onset and perpetuation of life-threatening arrhyth- mias. This is also supported by an observation that BNP specifically predict-
ed the occurrence of SCD late after the index event. It is possible that elevat- ed BNP is a marker of LV remodelling occurring late after AMI, which then predisposes to sudden arrhythmic death.
Clinical Implications
A significant proportion of post-AMI patients, even with adequate treat- ment, are still at high risk of dying during the first few years after the AMI.
The prediction and prevention of SCD is of particular importance, because recent large-scale randomised trials have documented the mortality benefit from prophylactic cardioverter-defibrillator implantation in certain high- risk subgroups of patients [17]. The data from two studies suggest that BNP level should be included as one of the risk variables in future studies com- paring the various indexes as predictors of SCD.
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