Europace Advance Access originally published online on May 24, 2007
Europace 2007 9(9):724-729; doi:10.1093/europace/eum102
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IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS
Serum BNP, hs-C-reactive protein, procollagen to assess the risk of ventricular tachycardia in ICD recipients after myocardial infarction
1 Département de Cardiologie, CHU de Nancy, Hôpital de Brabois, Rue du Morvan, 54511 Vandoeuvre-lès-Nancy, France; 2 Centre d'Investigations Cliniques INSERM-CHU, Nancy, France; 3 Laboratoire Central de Biochimie, CHU de Nancy, France; 4 Unité mixte UHP-INSERM U684, CHU de Nancy, France
Manuscript submitted 1 March 2007. Accepted after revision 21 April 2007.
* Corresponding author. Tel: +33 3 83 15 42 82; fax: +33 3 83 85 43 82. E-mail address: h.blangy{at}chu-nancy.fr
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Abstract |
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Aims Ventricular arrhythmia is the main cause of sudden cardiac death. Intracardiac strain, myocardial and extracellular matrix remodelling, and subsequent myocardial fibrosis are involved in arrhythmia pathogenesis. The present study investigates the relationship between cardiac fibrosis [procollagen type I aminoterminal peptide (PINP), procollagen type III aminoterminal peptide (PIIINP), TIMP1, membrane metalloproteinase I], pressure overload [brain natriuretic peptide (BNP)] inflammation [high sensitivity (hs)-C-reactive protein] serum markers, and the incidence of ventricular tachycardia (VT) in implantable cardioverter–defibrillators (ICD) recipients.
Methods and results Serum markers were collected in 121 patients implanted for spontaneous sustained VT and a prior history of myocardial infarction. VT incidence was obtained during ICD interrogation. Over a 1 year period, 38 patients (31%) experienced at least 1 VT. In a multivariate analysis, a left ventricular ejection fraction <0.35 (OR = 2.19, 95%CI 1.00–4.79, P = 0.049), an increased serum BNP (OR = 3.75, 95%CI 1.46–9.67, P = 0.014), an increased hs-C-reactive protein (OR = 3.2, 95%CI 1.26–8.10, P = 0.006), an increased PINP (OR = 3.71, 95%CI 1.40–9.88, P = 0.009), and a decreased PIIINP (OR = 0.21, 95%CI 0.08–0.59, P = 0.003) were associated with a higher VT incidence.
Conclusion In coronary artery disease patients: (1) BNP is not only a marker of left ventricular dysfunction, but also a marker of VT; (2) combined ‘high PINP and low PIIINP’ is a strong VT marker; and 3) inflammatory process is involved in VT pathogenesis.
Key Words: Procollagen, BNP, C-reactive protein, Extracellular matrix, Ventricular tachycardia, Coronary artery disease
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Introduction |
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Ventricular arrhythmia is the predominant cause of sudden cardiac death. Each year, at least 450 000 subjects die from unexpected cardiac arrest in the United States. About 50% of them have a history of coronary artery disease (CAD).1
In CAD patients, the arrhythmic risk stratification use several non-invasive electrophysiological tests. Unfortunately, these tests have a poor predictive value.
In the post-myocardial infarction (MI) heart, there is a time-dependent damage to myocytes, non-myocytes, and extracellular matrix (ECM) in the infarct zone, followed by gradual reparation with fibrosis. The non-infarct zone exhibits reactive hypertrophy, interstitial fibrosis, and increased collagen, leading to cardiac dysfunction and progressive dilation.2 Therefore, in such pathological conditions, ECM remodelling may lead to myocardial fibrosis and has deleterious effects on pumping capacity and diastolic function. In addition, cardiac fibrosis may provide electrical heterogeneity, which is the substrate for arrhythmogenicity, thus potentially contributing to the occurrence of ventricular arrhythmia and subsequent sudden cardiac death.
Myocytes and fibroblasts are supported by the ECM, which consists of a macromolecular network of fibres. Collagen is the principal structural protein. Its synthesis and degradation result from a balance between ischaemia, stretch, inflammation, and biochemical mediators. Collagen types I and III are the most abundant in the myocardium. Type I has a poor specificity but represents the majority (85%) and confers tensile strength and resistance to stretch and deformation. Type III, more specific, confers resilience.2
Serological markers of the collagen turnover have been used to provide information on the prognosis in patients with symptomatic heart failure,3 idiopathic- or ischaemic-dilated cardiomyopathies,4 and after acute MI.5
The purpose of this study was to assess the association between serological markers for cardiac ECM turnover and ventricular tachycardia (VT) occurrence, in a cohort of CAD patients implanted with an implantable cardioverter–defibrillator (ICD) for secondary prevention.
In addition, serum brain natriuretic peptide (BNP) and high sensitivity (hs)-C-reactive protein were both measured for a better understanding of the mechanisms leading to VT occurrence. BNP is a natriuretic peptide largely released from the ventricles, in response to increases in intraventricular pressure and myocardial stretch. Changes in ventricular pressure and geometry may cause electrophysiological damages and subsequent enhanced arrhythmogenesis.6 The role of inflammation in the appearance of ventricular arrhythmias has never been clearly investigated.
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Patients and study design
This prospective observational study included 121 patients. All the patients had a stable coronary heart disease with a prior MI, and all of them had experienced spontaneous VT for which an ICD was implanted. Hospitalizations for acute congestive heart failure or acute myocardial ischaemia during the last year or during the study period were the exclusion criteria.
Written informed consent was duly obtained at baseline from each study participant prior the inclusion. The study duration was of 1 year. Data were collected at enrolment and at follow-up visits scheduled at 6 months and at 12 months.
Clinical data were collected at enrolment. They consisted of sociodemographic (age, sex, MI date, ICD first implantation date, weight, and height) and chronic degenerative comorbidity (bone or joint diseases, such as rheumatoid arthritis, arthropathy, osteoporosis and multiple myeloma, and other fibrotic diseases such as cancer, renal failure, pulmonary fibrosis, liver disease, and diabetes mellitus).
Blood sample, haemodynamic data [New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), hypertension, atrial fibrillation (AF) or sinus rhythm], and current medications [angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, digitalis, amiodarone, other anti-arrhythmic drugs, angiotensin II (ATII) inhibitors, aldosterone antagonists, statins] were drawn at 6 months follow-up.
The endpoint of the study was VT occurrence. Cardioverter–defibrillators were interrogated at baseline, 6 months follow-up, and 12 months follow-up in order to collect all the VT episodes during this 1 year period. VT episodes were stated on the basis of electrogram analysis.
Laboratory analysis
Serum samples were stored at –20°C until assay. All samples were analysed at once. Using a radioimmunoassay from commercially available kits (Orion Diagnostica, Espoo, Finland), two ECM synthesis serum markers [intact procollagen type I aminoterminal peptide (PINP) and intact procollagen type III aminoterminal peptide (PIIINP)] were measured.
We evaluated two ECM degradation serum markers: total membrane metalloproteinase I (MMP1) by ELISA (R&D systems, Mineapolis, MN, USA) and collagen I carboxytelopeptide (ICTP) by radioimmunoassay (Orion Diagnostica).
In addition, measurement of plasma BNP, which reflects the left ventricular stretch and pressure overload, was performed using immunoradiometric assay (Shionoria BNP, Cis-Bio International, Gif-sur-Yvette, France). Measurements of serum hs-C-reactive protein and serum creatinine were also performed in each patient.
Interassay and intra-assay variations ranged from 3 to 13% for all variables. The sensitivity (lowest concentration different from zero) was 2 µg/L for PINP, 0.3 µg/ L for PIIINP, 0.7 µg/ L for ICTP, 0.095 µg/ L for MMP1, 2 ng/ L for BNP, and 0.2 mg/ L for hs-C-reactive protein.
Statistical analysis
Statistical analysis consisted of a descriptive analysis and a study of association between serum markers and VT occurrence during the study period. Patients were classified into two groups: group I included patients who experienced at least one VT during the study period and group II included patients without VT during the study period. Data are presented as mean ± SD for continuous variables and proportions for categorical variables.
VT prevalence in both groups was compared using a Pearson 
2 test or a Fisher's exact test (when 2 was not applicable), and the mean values of continuous variables were compared using a Mann–Whitney test. The association between patients' clinical and biological characteristics and VT occurrence was tested using a multivariable logistic regression (stepwise selection method). Covariates included gender, age, body mass index, LVEF, hypertension, diabetes, AF, comorbidity, aldosterone antagonists, amiodarone, digitalis, ACE inhibitor, beta-blocker, statin, ATII inhibitor, other anti-arrhythmic drugs, ICTP, PINP, PIIINP, MMP1, BNP, hs-C-reactive protein, and serum creatinine. Associations between markers and VT occurrence were analysed in two different ways: first using markers as continuous variables and then using them as binary variables with medians as cutoff value.
Data management and analysis were performed by using the SAS© software. For all tests, a P-value <0.05 was required for statistical significance.
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Out of the 121 patients included in the study, 38 (31%, group I) experienced at least one VT episode during the 1 year period [total = 510; range = 1–128; 12 patients experienced 10 VTs or more (Figure 1)]. The mean LVEF was 0.36 ± 0.11, LVEF was 0.35 or less in 45% of the patients, and 78% of the patients were in NYHA class II. Patients' characteristics and treatments are detailed in Table 1.
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In the entire population, serum markers levels (mean ± SD) were 42.1 ± 25.9 µg/L for PINP, 4.8 ± 1.8 µg/L for PIIINP, 17.4 ± 13.8 µg/L for MMP1, 4.9 ± 2.3 µg/L for ICTP, 146 ± 235 ng/L for BNP, and 0.8 ± 1.7 mg/dL for hs-C-reactive protein.
hs-C-reactive protein was significantly higher in patients who experienced VT (1.3 ± 2.8 vs. 0.6 ± 0.8, P = 0.016). The multivariate analysis revealed no difference in the mean serum markers levels between group I and group II. Nevertheless, 68% of group I patients had a serum BNP above median (64 ng/L) vs. only 48% of group II patients (P = 0.038).
Excluding serum markers from the multivariate analysis, only decreased LVEF (<0.35) was found associated with VT occurrence (OR = 2.19, 95%CI 1.00–4.79, P = 0.049). When adding the serum markers in the model, hs-C-reactive protein, PINP, and BNP above median appeared to be independent factors associated with a higher risk of VT occurrence, whereas PIIINP above median was associated with a lower risk of VT occurrence (Table 2, Figure 2). Combination of both PINP above median and PIIINP below median was highly associated with a risk of VT, as shown in Table 3. Collagen degradation serum markers were not significant (ICTP, MMP1). Serum markers as continuous variables were not significant. Interestingly, LVEF and BNP were significantly correlated (r = –0.324, P = 0.0003), whereas PINP, PIIINP, and hs-C-reactive protein were not correlated with LVEF (r = –0.010, P = 0.91; r = –0.097, P = 0.29; r = –0.060, P = 0.51, respectively).
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Discussion |
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The three main findings of this study are the following: (1) BNP is not only a useful marker of left ventricular dysfunction, but also a marker of ventricular arrhythmia. (2) An increased level of serum PINP and/or decreased level of serum PIIINP are associated with a higher risk of VT occurrence in CAD patients. Combined ‘High PIIINP and low PINP’ is a strong VT marker in our study. (3) hs-C-reactive protein is a non-specific marker of ventricular arrhythmia, supporting the potential role of inflammation in VT pathogenesis.
Our sample of patients reflects the current clinical practice. CAD patients were around 60- to 70-year-old and had been implanted with an ICD for secondary prevention after spontaneous episodes of ventricular arrhythmia, occurring after a prior MI. Their mean LVEF was 
0.35, resulting in moderate heart failure symptoms (NYHA class II), and patients were in a steady state during the entire study period. Three-quarters of the patients were receiving beta-blockers (75%) and 83% were on ACE inhibitors (83%), whereas approximately one-third of the patients were receiving amiodarone, most often to prevent supraventricular tachycardia.
Interactions between serum markers, left ventricular ejection fraction, and ventricular tachycardia occurrence
In agreement with previous studies, we found that collagen serum markers were not correlated with LVEF,3 whereas BNP was significantly correlated with LVEF.7,8 Omitting serum markers from the multivariate analysis, LVEF was the only VT marker. Association between decreased LVEF and ventricular arrhythmia, especially in ischaemic heart disease, is now well established.9,10 However, LVEF predictive value disappeared when entering the serum markers in the model, suggesting that due to their power in predicting VT occurrence and due to the underlying relationship between BNP and LVEF, their association with VT outweighed that of LVEF alone.
Serum markers, including collagen synthesis serum markers (PINP, PIINP), pressure overload serum marker (BNP), and inflammatory serum marker (hs-C-reactive protein) exhibit a strong independent association with the risk of VT occurrence. Serum markers are only significant as binary variables, suggesting the existence of a threshold effect.
Brain natriuretic peptide as a ventricular tachycardia marker
Usually, the risk of sudden cardiac death in CAD patients is evaluated with the use of several non-invasive electrophysiological markers, such as non-sustained VT, QT dispersion, heart rate variability, or signal averaged ECG. The predictive value of these electrophysiological tests remains still debated. Therefore, risk stratification takes into account primarily the LVEF value.10 Indeed, the MADIT II trial has shown that high-risk CAD patients (LVEF< 0.3) should be implanted with an ICD. In the present study also, LVEF< 0.35 was significantly associated with a higher risk of VT. However, when LVEF is >0.3, risk stratification needs other non-invasive markers to better identify patients who may benefit from ICD implantation. Several previous studies have shown that serum BNP, a marker of congestive heart failure, should be used as a predictor of sudden cardiac death. Berger et al.11 found that serum BNP level was a strong independent predictor of sudden cardiac death in patients with ischaemic or non-ischaemic severe heart failure. Tapanainen et al.12 showed that elevated serum BNP provided information on the risk of arrhythmic death among the survivors of acute MI, independently of LVEF, and should hence be used as an additive marker to determine which patient may benefit the most from ICD implantation. In another study, a single pre-implantation determination of BNP concentration was independently predictive of the appropriate ICD therapies in both primary- and secondary-prevention indications.13 In the present study, serum BNP above median was also an independent predictor of ventricular arrhythmia in patients with a prior MI, mild-to-moderate heart failure, and spontaneous VT episodes. Elevated serum BNP may provide arguments in favour of ICD implantation, in addition to other non-invasive electrophysiological markers.
Collagen serum markers and the risk of ventricular tachycardia
On the basis of the interaction between cardiac fibrosis and electrical heterogeneity in ventricular arrhythmia pathogenesis, we tested the hypothesis that ECM turnover serum markers could provide information on the risk of ventricular arrhythmia occurrence in CAD patients. In a substudy from the RALES trial,14 our group reported a significant lower sudden cardiac death rate in patients receiving spironolactone when compared with those receiving placebo (P = 0.02). The benefit from spironolactone therapy in congestive heart failure patients might be due partially to the limitation of the excessive ECM turnover.3 In the same way, in the EPHESUS trial,15 sudden cardiac death occurrence was lower in acute MI survivors receiving eplerenone when compared with those receiving placebo (P = 0.03).
In this study, factors involved in collagen degradation (ICTP, MMP1) were not associated with an increased risk of VT. ECM turnover in ischaemic heart disease would be more directed to a higher synthesis rate than to altered collagen degradation, as observed in the RALES population.3
Despite the small size of the subgroups leading to quite large 95% confidence interval, the combined ‘PIIINP below median and PINP above median’ was the most significant marker of the risk of VT in the multivariate analysis, whereas the combined ‘PIIINP above median and PINP below median’ was associated with the lowest risk of VT (Figure 3).
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The myocardial collagen network mainly consists of type I and type III collagen, which have different physical properties. Type I collagen is predominant in tissues characterized by strength and stiffness (such as tendon) and type III collagen is predominant in tissues characterized by their elasticity (such as skin). In the myocardium, the type I/III ratio results in a balance between rigidity and elasticity, contributing to optimize systolic and diastolic functions. It has been shown that an increased type I/III ratio, due to differential increase of collagen I and collagen III, is usually observed in both dilated16
,17 and post-MI cardiomyopathies,18 resulting in systolic and diastolic dysfunction. Moreover, the present study shows that collagen I accumulation may also have electrophysiological consequences.
hs-C-reactive protein as a VT marker
Experimental and clinical evidence indicate that inflammation plays a major role in atherothrombosis.19,20 Measurement of hs-C-reactive protein may detect individuals at high risk of plaque rupture among apparently healthy subjects. Elevated hs-C-reactive protein is also observed in patients who experience non-post-operative AF and may be related to AF burden and type.21 Thus, the use of lipid-lowering drugs with known antioxidant and anti-inflammatory effects in patients with reduced LVEF is associated with a reduction in the prevalence of AF, independent of the lipid profile and other known arrhythmia risk factors.22
Therefore, despite a poor specificity, hs-C-reactive protein is a strong independent predictor of future myocardial infarction, stroke, peripheral arterial disease, cardiovascular death in both primary23–25 and secondary prevention,26 and AF recurrence after successful electrical cardioversion.27
In this study, patients were in a steady state regarding their ischaemic heart disease, and they experienced VT that are commonly not related to acute ischaemia, differing from ventricular fibrillation. Nevertheless, patients who experienced VT had a significantly higher serum hs-C-reactive protein level when compared with those who did not. Albert et al. demonstrated in a previous study that hs-C-reactive protein was a useful indicator of long-term risk of sudden death in apparently healthy men. They reported that sudden cardiac death was mainly related to an acute coronary event, but in some autopsy cases, in which no macroscopic cause of death could be found, isolated areas of myocardial fibrosis were often seen. The authors hypothesized that these areas might provide a substrate for re-entry and subsequent lethal arrhythmia.25
Independently from CAD, inflammation may be involved in ventricular arrhythmia pathogenesis. Of interest, statin use in patients implanted with an ICD in both the MADIT II trial28 and the AVID trial29 was associated with a reduction of ventricular arrhythmia incidence. The unclear mechanism by which statins reduce ventricular arrhythmia incidence may relate indirectly to their anti-inflammatory or antioxidant properties.28
hs-C-reactive protein may not only be a predictor of plaque rupture and potentially subsequent fatal MI, but also a predictor of arrhythmic death.
Study limitations
Only patients implanted with an ICD for secondary prevention were included in this study. All the patients were clinically stable without angina. However, we cannot rule out asymptomatic myocardial ischaemia in some patients during the study period. Therefore, we cannot exclude myocardial ischaemia as a possible confounding factor, contributing partially to elevated levels of biomarkers. In primary prevention, the population would be more homogenous, but the relatively low VT occurrence rate would have needed a larger sample of patients with a longer follow-up and repetitive serum markers' measurements. Our analysis was based on a single determination of each serum marker, which did not allow assessing for the potential changes in these markers over time.
Another limitation of this study is the treatment received by the patients, including anti-arrhythmic drugs, which have minimized VT occurrence in some of the patients.
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Conclusion |
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This study identifies some serum markers that are strongly associated with a higher risk of VT in CAD patients implanted with an ICD for secondary prevention. Elevated BNP, hs-C-reactive protein, and a combined "low PIIINP and high PINP" are the indirect serum markers of the mechanical and physiopathological conditions predisposing to VT occurrence in such patients. Our results confirm the role of cardiac fibrosis in ventricular arrhythmia pathogenesis and furthermore show that fibrosis composition and inflammation are some of the parameters involved in the constitution of an arrhythmogenic substrate in ischaemic heart disease. Because these markers have a poor specificity, they should be considered as additive non-invasive variables that the clinician can easily obtain for arrhythmic risk stratification. Further prospective studies are needed to determine their positive and negative predictive accuracy and to investigate their predictive ability when compared with previously defined non-invasive electrophysiological tests, especially in primary prevention.
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The authors thank the association ARISC (Association de Recherche et Information Scientifique en Cardiologie, CHU de Nancy) for financial support.
Conflict of interest: none declared.
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