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(Chest. 2005;128:2604-2610.)
© 2005 American College of Chest Physicians

Amino-Terminal Pro-Brain Natriuretic Peptide Predicts Ventricular Arrhythmogenesis in Patients With Ischemic Cardiomyopathy and Implantable Cardioverter-Defibrillators*

Emmanuel G. Manios, MD; Eleftherios M. Kallergis, MD; Emmanuel M. Kanoupakis, MD; Hercules E. Mavrakis, MD; Despina C. Kambouraki, MD; Dimitris A. Arfanakis, MD and Panos E. Vardas, MD, PhD

* From the Department of Cardiology, University Hospital of Heraklion, Crete, Greece.

Correspondence to: Emmanuel Manios, MD, Department of Cardiology, Heraklion University Hospital, 71000, Voutes, Heraklion-Crete, Greece; e-mail: mman{at}med.uoc.gr


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Study objectives: Even in high-risk population groups, not all patients have the same risk of sudden cardiac death (SCD). Given the emerging data about the amino-terminal fragment of the brain natriuretic peptide prohormone (NT-proBNP) value in heart failure, we planned to evaluate the importance of NT-proBNP levels in predicting the occurrence of malignant arrhythmias in patients with ischemic cardiomyopathy and implantable cardioverter-defibrillators (ICDs).

Design: Prospective study.

Setting: Tertiary referral center.

Patients: Thirty five ambulatory patients with previous myocardial infarction, left ventricular ejection fraction < 35%, and ICDs for primary prevention of SCD according to Multicenter Automatic Defibrillator Implantation Trial I criteria.

Interventions: Venous blood samples for plasma NT-proBNP measurement were obtained after 30 min of supine rest from all patients at the beginning of the study. Patients were evaluated every 2 months, or sooner in cases of device discharges, during a 1-year follow-up period. Data concerning arrhythmias and device therapy were stored at the time of device interrogation on each follow-up visit.

Measurements and results: During 1-year follow-up, 11 of 35 patients (31.4%) received 18 antiarrhythmic device therapies for ventricular tachyarrhythmia (VT). Patients who experienced such arrhythmias had NT-proBNP levels of 997.27 ± 335.14 pmol/L (mean ± SD), whereas those without VT had NT-proBNP levels of 654.87 ± 237.87 pmol/L (p = 0.001). An NT-proBNP cutoff value of 880 pmol/L had a sensitivity of 73%, a specificity of 88%, a positive predictive value of 80%, and a negative predictive value of 88% for the prediction of occurrence-sustained VT events.

Conclusion: To achieve the maximum benefit by ICD therapy, more precise risk stratification is required, even in high-risk, post-myocardial infarction patients. Plasma NT-proBNP levels comprise a promising method that could help in the better identification of a patient group with an even higher risk of sudden death.

Key Words: ischemic cardiomyopathy • natriuretic peptides • risk stratification • sudden cardiac death • ventricular arrhythmogenesis


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Prediction of sudden cardiac death (SCD) is still a challenge, since it remains a major public health problem despite advances in our understanding of its pathophysiologic mechanisms and in the effectiveness of implantable cardioverter defibrillators (ICDs).123 To achieve the maximum benefit from ICD therapy, individual risk prediction is required in order to identify patients at increased risk for SCD and patients with negligible risk who would be exposed to potential adverse effects without benefit.123

Brain natriuretic peptide (BNP) and the amino-terminal fragment of the BNP prohormone (NT-proBNP) are neurohormones that are secreted mainly in the cardiac ventricles in response to ventricular stretch attributable to volume and pressure overload.4 Previous studies45678 have demonstrated that these peptides are powerful markers for diagnosis, prognosis, and risk stratification in heart failure (HF) patients. Studies9101112 have suggested that elevated plasma BNP and NT-proBNP levels are associated with an increased risk of total and cardiac death in patients with acute coronary syndromes. Although BNP and NT-proBNP levels are similar in normal subjects, the proportional and absolute increment above normal levels of the NT-proBNP exceeds that for BNP in cardiac impairment, suggesting that NT-proBNP may be a more discerning prognostic marker compared to BNP.13 Since a relationship between B-type natriuretic peptides and arrhythmogenesis has been suggested,514151617 we planned to evaluate the importance of NT-proBNP levels in predicting the occurrence of malignant arrhythmias in patients with ischemic cardiomyopathy and ICDs.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Patient Selection
The Ethics Committee of our institution approved the study. This investigation conforms to the principles outlined in the Declaration of Helsinki. Signed informed written consent was obtained from all subjects before their participation in the study.

The study population consisted of 35 ambulatory patients with a history of myocardial infarction (MI), a left ventricular ejection fraction (LVEF) < 35%, a documented nonsustained ventricular tachycardia (VT) on Holter monitoring, and inducible sustained ventricular tachyarrhythmia during programmed ventricular stimulation, in whom an ICD had been implanted for primary prevention of SCD according to the Multicenter Automatic Defibrillator Implantation Trial (MADIT) I criteria (suppressibility by procainamide was not tested).18 Our purpose was to investigate whether baseline plasma NT-proBNP levels could predict the future occurrence of sustained ventricular arrhythmias in such a high-risk population.

All patients were 44 to 75 years of age and were clinically stable during the 4 weeks preceding the beginning of our study. Exclusion criteria were infection, chronic inflammatory disease, malignancy, renal failure, and any disease associated with a life expectancy < 1 year. Patients who had an acute coronary syndrome or decompensated heart failure during the previous 4 weeks were also excluded.

Study Design
Follow-up and Data Collection:
A complete evaluation of device function was performed at entry into the study. A VT detection zone with antitachycardia pacing therapy was programmed in all patients followed by shocks if necessary. Above 200 beats/min, only shock therapies were programmed.

Patients were evaluated every 2 months, or sooner in cases of device discharges, during a 1-year follow-up period. On each visit, an appropriate clinical and laboratory evaluation that included serum cardiac markers, cardiac troponins, plasma potassium, and thyroid hormones to exclude factors potentially triggering arrhythmias was carried out. Medication use was also recorded, and the defibrillator was interrogated.

Data concerning arrhythmias and device therapy were obtained and stored at the time of device interrogation on each follow-up visit. The incidence and the type of arrhythmias and the incidence of appropriate and inappropriate defibrillator therapies were determined by reviewing stored electrograms. Events were classified by an agreement of two reviewing electrophysiologists blinded to the study. VTs were categorized as VT or ventricular fibrillation (VF) on the basis of rate and morphology and by the type of device therapy (antitachycardia pacing or shock) that terminated the tachyarrhythmia. Appropriate antitachycardia pacing or shock was defined as any ICD therapy that occurred in response to VT or VF, whereas such an event was classified as inappropriate when it was triggered by supraventricular tachycardias, T-wave oversensing, or when it was secondary to electrode dysfunction.

Blood Sampling and Plasma BNP Assay:
Peripheral blood samples for plasma NT-proBNP measurement were obtained from all patients at the beginning of the study by direct puncture of an antecubital vein after 30 min of supine rest. Blood samples were immediately placed on ice and centrifuged within 1 h. Plasma samples were stored at – 70°C until analysis. Commercially available assay kits (Biomedica; Wien, Austria) were used for determination of NT-proBNP (enzyme-linked immonosorbent assay). Venous blood samples for the determination of serum cardiac markers, cardiac troponins, plasma potassium, and thyroid hormones were also obtained at each scheduled or unscheduled visit.

Statistical Analysis
Data are presented as mean ± SD. The statistical differences of paired data were evaluated by one-way, repeated-measures analysis of variance followed by contrasts for mean values comparison. Logistic regression model was used to determine if NT-pro BNP could predict VTs; p < 0.05 was considered significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Patients
The baseline clinical and demographic features of the patients are shown in Table 1 . The patient population included 34 men and 1 woman aged 44 to 75 years (mean, 64 ± 8 years) who fulfilled the MADIT I criteria and had received an ICD in our department during the last 7 years prior to their enrollment in the study. All patients had a previous MI, a mean LVEF of 27.9 ± 3.7%, and were in New York Heart Association (NYHA) functional class I, II, or III. Eighteen patients had a history of an anterior MI, while the remaining 17 patients had a history of inferior or both inferior and lateral MI. Coronary artery bypass had been performed in 57% of the patients, and 42% of the study population had undergone coronary angioplasty with stent implantation in one or more coronary arteries. Most of our patients (60%) were in NYHA functional class II, 20% in were in class I, and the remainder were in class III.


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  		Table 1. Baseline Clinical and Demographic Characteristics of the Patient Population*

 
Patients were receiving optimal medical therapy for ischemic cardiomyopathy, which included ß-blockers, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers, aspirin, and lipid-lowering agents unless there was any contraindication or patient intolerance. The doses of ACE inhibitors and ß-blockers were either in accordance with the recommended levels for patients with ischemic cardiomyopathy or were the highest doses tolerated. Digoxin and diuretics were used when necessary to manage clinical symptoms.

Clinical Outcome and NT-proBNP Levels
Follow-up was available in all patients, and no one died during the study period. Of the 35 patients with an ICD, 11 patients received one or more successful device therapies during the 1-year follow-up period. The initial arrhythmia triggering defibrillator activity was monomorphic VT in eight patients, polymorphic VT in one patient, and VT in one patient. One patient had both monomorphic VT and VF. Among those 11 patients, 6 patients had one tachyarrhythmic event and the remaining 5 patients had two or three episodes.

Among 18 spontaneous sustained VTs, 14 were monomorphic VTs, 2 were classified as VF, and 2 were polymorphic VTs. The mean cycle length of VT was 307 ± 27 ms. No VT had a cycle length > 390 ms.

Although a VT detection zone with antitachycardia pacing therapy was programmed in all patients, most (12 of 14 patients) sustained monomorphic VTs and required at least one shock. Apart from the 11 patients who experienced appropriate device therapies, 1 patient experienced an inappropriate ICD discharge due to atrial fibrillation.

The clinical characteristics of patients who experienced sustained VTs (VT/VF) and received device therapies compared to those who did not are showed in Table 2 . Age, gender, LVEF, NYHA class, and medications did not differ between these two groups. However, baseline NT-proBNP levels were significantly higher in patients with sustained VTs than in those without (997.27 ± 335.14 pmol/L vs 654.87 ± 237.87 pmol/L, respectively; p = 0.001) [Fig 1 ]. Additionally, an NT-proBNP cutoff value of 880 pmol/L was found to be adequately sensitive (73%) and specific (88%) for the prediction of sustained tachyarrhythmic events. NT-proBNP levels < 880 pmol/L had a negative predictive value of 88%, while the positive predictive value of NT-proBNP values > 880 pmol/L was 80% for the occurrence of VT.


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  		Table 2. Clinical Characteristics and NT-proBNP Values in Patients With and Without Sustained VT*

 


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  		Figure 1. Box plots showing median levels of NT-proBNP measured at the beginning of the study in patients with and without sustained VT (VT/VF). Boxes show ranges, and bars represent highest and lowest values.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
ICDs are the treatment of choice for patients who are at high risk for potentially fatal ventricular arrhythmias.12319202122232425 It has been increasingly recognized that ICDs are superior to antiarrhythmic drugs in survivors of cardiac arrest or unstable VT192021 and that they are more beneficial than drug therapy for primary prevention of SCD in certain high-risk groups.22232425 This is particularly true for patients with severe ischemic cardiomyopathy, the population of our study.

Despite the established efficacy of ICDs for terminating ventricular arrhythmias, their utilization is not without problems. Approximately one third of patients will experience some adverse effect, including inappropriate shocks, lead problems, infection, and adverse psychosocial effects.26 This is particularly important for ICD recipients who will have no benefit from ICD implantation. In addition, it has become clear that, even in high-risk groups, a significant number of patients will obtain no advantages from ICDs.12627 Thus, a better identification of patients with depressed ventricular function who could benefit from an ICD or, perhaps more importantly, those who are unlikely to benefit would help in their management.

In a population with ischemic cardiomyopathy, in whom SCD is the main cause of death, we found that NT-proBNP is an independent predictor for sustained ventricular arrhythmias. Moreover, our results underline that NT-proBNP levels could help to refine the identification of patients who might benefit from prophylactic implantation of an ICD and could specify a patient subgroup with an even higher risk of ventricular arrhythmogenesis.

The current evidence indicates that ICDs prolong life in certain high-risk patients who are susceptible to SCD.12319202122232425 These devices do not prevent ventricular arrhythmias, but they effectively terminate them when they occur. However, ICD use is associated with some possible adverse events that could affect the patient’s quality of life.1262728 These complications may occur early after implantation and be associated with the procedure itself, or they may be related to alterations in lifestyle, including emotional problems and driving restrictions.1262728 The ICD is often associated with adverse psychosocial effects. Anxiety and depression resulting from the fear of device discharge or failure, a decrease in physical activity, and negative lifestyle changes (such as the inability to drive or to return to work) are common.1262728 Some patients have severe psychiatric problems after receiving appropriate or inappropriate shocks. The sudden occurrence of multiple painful electrical shocks may result in acute stress and panic.1262728 In addition, ICDs are an invasive and expensive therapy.1262728 Therefore, more precise risk stratification is necessary to identify patients at the highest risk of occurrence of SCD who would most benefit from an ICD. It is also of particular importance to recognize patients who are not going to obtain any advantage from such therapy while still experiencing adverse effects.

Actually, even in high-risk population groups (such as patients with ischemic cardiomyopathy), not all patients have the same risk of SCD. Although a number of clinical features have been evaluated as possible risk factors for the development of fatal arrhythmias, the sensitivity and specificity of any single test for predicting major arrhythmic events is limited.123 Several tests have been developed to identify patients at high risk for fatal arrhythmias. Spontaneous ventricular premature beats and nonsustained VT documented on 24-h ambulatory monitoring, late potentials on a signal-averaged ECG, T-wave alternans, reduced heart rate variability assessed by ambulatory monitoring, and VT induced by electrophysiologic study are common arrhythmia risk variables that have been evaluated in predicting the occurrence of SCD among post-MI patients.123 Despite the fact that each of these tests may have some prognostic value, essentially they are generally unable to predict who will experience VT or VF.123 In other words, none of the aforementioned invasive and noninvasive risk variables has adequate sensitivity and specificity for predicting SCD at the level of the individual.

However, studies456789101112 have shown that both BNP and NT-proBNP may be powerful markers for prognosis and risk stratification in the setting of HF and coronary artery disease. Berger and colleagues5 found that BNP was the single independent predictor of SCD among HF patients during a mean follow-up period of 592 days. Additionally, natriuretic peptides have been shown to be strong predictors of total and cardiac mortality after MI.101112 Furthermore, Tapanainen and colleagues9 confirmed that natriuretic peptides maintain their prognostic value, even in the ß-blocking era, among survivors of acute MI and that elevated BNP provides useful information about the risk of subsequent SCD, independent of clinical variables and LVEF.

NT-proBNP is also a powerful indicator of long-term mortality in patients with acute coronary syndromes and provides prognostic information above and beyond conventional risk markers.101112 In addition NT-proBNP may be more useful prognostic marker than BNP in post-MI patients, as was suggested by Richards and colleagues.29

Similarly, we found that in post-MI patients with moderate-to-severe reduced LVEF, elevated NT-proBNP levels are associated with the occurrence of sustained VTs. Therefore, increased circulating levels of NT-proBNP could predict the appearance of sustained VT/VF and may serve as an additional criterion, defining patients at high risk for SCD.

NT-proBNP Production and Arrhythmogenesis
B-type or BNP is a natriuretic hormone released as pre-BNP prohormone and then enzymatically cleaved to the NT-proBNP.430 It was initially identified in the brain but is also present in the heart.430 The major source of plasma BNP and NT-proBNP is the cardiac ventricles, suggesting that these peptides may be a more sensitive and specific indicator of ventricular disorders than other natriuretic peptides.430 It has been established that circulating NT-proBNP levels are elevated in patients with chronic HF in proportion to the severity of the disease and that the NT-proBNP assay can facilitate the diagnosis of HF.430 The most important stimulus for its synthesis and release is an increase in ventricular wall stretch due to ventricular pressure or volume overload.430

Both acute and chronic mechanical stretch of myocardial tissue cause immediate and chronic responses that lead to significant changes in cardiac electrophysiologic properties via the activation of mechanosensitive or stretch-activated ion channels.1415161731 Ventricular stretch enhances refractoriness, slows conduction, and triggers ventricular ectopic beats and after depolarizations.1415161731 This phenomenon, called mechanoelectric feedback, is thought to contribute to arrhythmogenesis and SCD in patients with impaired ventricular function and elevated filling pressures.1415161731 It is of interest that the stimuli of NT-proBNP production also cause various electrophysiologic abnormalities, predisposing to the onset and perpetuation of life-threatening arrhythmias. Thereby, NT-proBNP may be an indirect marker of ventricular remodeling that favors arrhythmogenesis in the failing heart.

Study Limitations and Clinical Implications
Obviously, each of the ICD discharges for VT, in our study, does not represent prevention of a lethal event, as a number of VT episodes would probably have terminated spontaneously. However, two patients received successful electrical therapy for VF, while some of the VT episodes could potentially have progressed to VF, suggesting that at least some interventions were lifesaving. In addition, it seems reasonable that termination of VT early in its clinical course may prevent VF occurrence in susceptible patients. Therefore, since SCD is caused by the onset of a rapid monomorphic VT that degenerates into VF,2 or directly by polymorphic VT/VF,2 in the vast majority of cases, NT-proBNP predicting the occurrence of such events may be a useful prognostic marker for risk stratification among post-MI patients.

Despite the significant success of current medical treatment in reducing both total and SCD mortality, many post-MI patients remain at increased risk for SCD.32 Therefore, the identification of those high-risk patients is of particular importance in light of the benefit on mortality resulting from the prophylactic use of ICDs. It is also true that a number of post-MI patients who have received an ICD do not obtain any benefit from it, while still being exposed to unnecessary risks.126273334 In addition, ICD implantation is an invasive and expensive therapy that imposes a considerable burden on society.26272834 The number of patients needed to treat to prevent one premature death in 2 years, as calculated by Ezekowitz et al,35 was 18 patients for MADIT II and closer to 4 patients for MADIT I and the Multicenter Unsustained Tachycardia Trial.222325 Thus, the ICD is implanted in a noteworthy number of patients unnecessarily (17 of 18 patients, 3 of 4 patients, and 3 of 4 patients in MADIT II, MADIT I, and the Multicenter Unsustained Tachycardia Trial, respectively). In fact, even in survivors of SCD, in view of the 40% recurrence rate3436 of lethal, arrhythmic events, 60 of 100 patients receive an ICD without need.34 Hence, there is a clear need to identify not only patients who require but also those who do not require an ICD. NT-proBNP measurement is a simple blood test that could aid in the risk stratification and management of post-MI patients. It is a simple method that, in combination with clinical and functional variables that are routinely measured in everyday clinical practice, could help in the better management of post-MI patients. Identification of high-risk patients with high levels of NT-proBNP might be helpful in the selection of more intense pharmacologic or interventional treatment.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Despite the established effectiveness of ICDs in reducing SCD mortality, their utilization is not without complications. Their optimal use requires more precise risk stratification. NT-proBNP could help to identify those patients most likely to benefit from ICD therapy. The measurement of the NT-proBNP concentration in blood appears to be a sensitive and specific test for identification of patients who are most likely to experience sustained VTs among those with ischemic cardiomyopathy. However, further investigation and randomized trials are needed to evaluate the clinical use of NT-proBNP as an arrhythmia risk marker in different subgroups of patients and in general population.


   Footnotes
 
Abbreviations: ACE = angiotensin-converting enzyme; BNP = brain natriuretic peptide; HF = heart failure; ICD = implantable cardioverter defibrillator; LVEF = left ventricular ejection fraction; MADIT = Multicenter Automatic Defibrillator Implantation Trial; MI = myocardial infarction; NT-proBNP = amino terminal fragment of the brain natriuretic peptide prohormone; NYHA = New York Heart Association; SCD = sudden cardiac death; VF = ventricular fibrillation; VT = ventricular tachycardia

Received for publication April 3, 2005. Accepted for publication May 16, 2005.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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