Europace Advance Access originally published online on April 16, 2007
Europace 2007 9(6):385-390; doi:10.1093/europace/eum050
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SUDDEN DEATH
Prediction of sudden death in heart failure patients: a novel perspective from the assessment of the peak ectopy rate
1 Biophysics Institute, CNR, Genova, Italy; 2 Department of Biomedical Engineering, S. Maugeri Foundation, IRCCS, Montescano, Italy; 3 Department of Cardiology, S. Maugeri Foundation, IRCCS, Montescano, Italy; 4 Department of Cardiology, San Martino Hospital, Genova, Italy
Manuscript submitted 23 October 2006. Accepted after revision 3 March 2007.
* Corresponding author. Tel: +39 0385 247277; fax: +39 0385 61386. E-mail address: rmaestri{at}fsm.it
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Abstract |
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Aims: In patients with heart failure (HF), the association between sudden death and arrhythmic pattern at 24-h Holter monitoring [number of ventricular premature contractions per hour (VPCs/h) and presence of non-sustained ventricular tachycardia (NSVT)] has previously been investigated with conflicting results. Since both VPCs/h and NSVT disregard the time course of arrhythmic events, we developed a new index based on the short-term peak rate of ectopies and investigated its prognostic power in HF patients.
Methods and results: We studied 200 HF patients in sinus rhythm {age: [median (interquartile range)] 54 years [47–58], left ventricular ejection fraction (LVEF): 23% [19–28], New York Heart Association (NYHA) class II–III: 88%}. For each patient, the Holter recording was automatically scanned shifting a 30 beat window one beat at a time, and the maximum number of ectopic beats found in a window was named peak ectopy rate (PEAK_ER). The association between PEAK_ER and sudden death was assessed by Cox proportional hazards regression analysis. Survival analysis was also carried out adjusting for NYHA class, aetiology, LVEF, left ventricular end diastolic diameter, blood urea nitrogen, amiodarone, Digoxin, beta-blockers, NSVT, VPCs/h, and the standard deviation of all normal-to-normal beats. During a 5-year follow-up [31 (12–60) months], 23 patients died of sudden death. Out of the arrhythmic markers, PEAK_ER but not VPCs/h and NSVT was significantly associated with sudden death in univariable analysis (RR: 1.08, 95% CI: 1.02–1.14, P = 0.005) and after adjustment for covariates (RR: 1.09, 95% CI: 1.03–1.15, P = 0.004).
Conclusions: The investigation of the time course of arrhythmic events provides independent information in the identification of patients at increased risk of sudden death and may therefore be considered in the development of treatment strategies in HF patients.
Key Words: Heart failure, Sudden death, Ectopic activity
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Introduction |
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Sudden death accounts for one-fourth to one-half of all deaths in patients with heart failure (HF).1
Prophylactic implantable cardioverter defibrillator (ICD) therapy has been shown to improve overall survival in patients with symptomatic HF and reduced left ventricular ejection fraction (LVEF) resulting from coronary as well as non-coronary disease.2,3 However, the identification of patients at risk solely on the basis of ejection fraction still remains a controversial issue,4 supporting the need for further attempts to improve the identification process. Indeed, the most marked ICD survival benefits have been demonstrated in trials that required runs of non-sustained ventricular tachycardia (NSVT) in addition to a reduced ejection fraction as risk factors for mortality.5,6 Although many studies in the 1970s reported that the presence of frequent ventricular premature contractions (VPCs) and left ventricular systolic dysfunction carried an increased risk for sudden cardiac death among post-myocardial infarction patients, counting VPCs from Holter recordings has gained less popularity in the setting of HF because of conflicting results. While in some studies7,8 the frequency of VPCs showed a significant association with sudden death or major arrhythmic events only in univariable analysis, an independent predictive value was demonstrated in other investigations.9 We reasoned that a possible explanation for this inconsistency in results could be that the way ambient ventricular arrhythmias in Holter recordings are taken into consideration disregards important aspects of the phenomenon. As a matter of fact, NSVT considers only runs of tachycardic events, and the VPCs/h parameter provided by Holter systems gives only an average rate of occurrence of arrhythmic events during the 24h, being the same in patients in whom a given number of ectopies occur scattered over time and in patients in whom the occurrence is concentrated within short periods of time. No indices related to the time course of arrhythmic events have been proposed so far. We hypothesized that this information would be relevant in determining the risk of sudden death in HF patients.
To test this hypothesis, we developed a new index based on the measurement of the peak rate of ectopies occurring in a Holter recording, and investigated its prognostic power in a population of mild-to-moderate HF patients.
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Methods |
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Subjects
In this study, we considered 200 mild-to-moderate HF patients in sinus rhythm admitted to the Heart Failure Unit of the Scientific Institute of Montescano between 1992 and 1996 for evaluation and therapy of HF, including heart transplantation. Inclusion criteria were stable clinical condition (no changes in signs, symptoms or therapy in the 2 weeks preceding the study), absence of pulmonary or neurological diseases, including insulin-dependent diabetes or any other disease that limits survival, no recent myocardial infarction or cardiac surgery (within the previous 6 months), 24h Holter recording analysable for at least half of the night-time (00:00–05:00 h) and half of the daytime (09:00–19:00 h).
These patients were part of a larger, prospectively collected data-base of 443 patients: 106 were excluded because of atrial fibrillation or pacemaker implantation, a further 63 were excluded for clinical reasons (mainly for clinical instability or presence of pulmonary or neurological diseases), and other 74 were not included because of missing or poor quality Holter recordings.
The study was approved by the local Ethics Committee and all patients gave their informed consent.
Clinical evaluation, laboratory testing, and follow-up
All patients underwent standard clinical and laboratory examinations within 1 week from the Holter recording. NSVT was defined as three or more consecutive ventricular premature beats at a rate >100 bpm that were not sustained for more than 30 s.
During follow-up, patients were periodically re-evaluated and hospitalized if clinically unstable. The date and mode of death and information regarding transplantation were accurately investigated. The majority of deaths occurred in hospitals and the pertaining documentation was obtained, while information about the events that occurred at home was obtained from careful chart review and/or telephone interviews of the referring physician and relatives.
The mode of death was classified as sudden if it occurred within 1 h of onset of symptoms in a previously clinically stable patient, during sleep or while unobserved within 1 h of the patient last being seen alive, if circumstantial evidence pointed to death from cardiovascular causes in the absence of clinical or post-mortem evidence of acute myocardial infarction or increasing HF.
Holter recordings and computation of the peak ectopy rate parameter
Holter recordings were performed using a two-channel recorder and processed using a Synetec System (ElaMedical, S.p.A., Segrate/Milano, Italy). Each beat was first automatically labelled as normal or aberrant by the Holter analysis software and then carefully edited by an expert analyst.
Using an automated procedure, the 24h recording was entirely scanned shifting a 30-beat window one beat at a time. In each window, the number of ventricular ectopic beats was computed and the maximum value found in the overall recording was taken as the parameter representative of that patient. This parameter was named peak ectopy rate (PEAK_ER).
To investigate the presence of circadian rhythms in PEAK_ER, the same computational procedure was repeated for daytime (PEAK_ER_d, from 9:00 a.m. to 7:00 p.m.) and nighttime (PEAK_ER_n, from 0:00 a.m. to 5:00 a.m.).
Statistical analysis
Because of a marked skewness in several variables, non-parametric statistical tests were used. Day-time and night-time values were compared by the Wilcoxon signed-rank test. The association between PEAK_ER and categorical variables was assessed by the Mann–Whitney U test, while the association with continuous variables was assessed by the Spearman correlation coefficient. All hypothesis tests were performed using a significance level of 0.05.
Primary endpoint of survival analysis was sudden death according to previous definition, while secondary endpoint was total cardiac death. The survival function was estimated by the Kaplan–Meier method. Survival curves from different subgroups of patients were compared by the log-rank test.
The univariable association between PEAK_ER and the event was assessed by Cox proportional hazards regression analysis. To test whether its predictive value, if any, was independent of clinical and functional variables, survival analysis was also carried out adjusting for a set of variables which had shown a predictive value in previous studies on similar populations:9–11 New York Heart Association (NYHA) class, aetiology, LVEF, left ventricular end diastolic diameter (LVEDD), blood urea nitrogen (BUN), amiodarone, Digoxin, beta-blockers and a set of parameters from 24h Holter recordings comprising NSVT, VPCs/h, and the standard deviation of all normal-to-normal beats (SDNN).
Spectral parameters such as the power in the low frequency band (0.04–0.15 Hz) of the RR time series have consistently been shown to carry independent prognostic value in HF patients,9,10,12 but their measurability is affected by the presence of ectopic beats.9 Moreover, we observed in a previous study that cardiac mortality was higher in those patients in whom spectral indices could not be measured due to a high ectopy rate.13 Hence, in this study, we disregarded spectral indices and focused on the new index specifically derived from the occurrence of ectopic beats.
Multivariable model building was carried out by a backward elimination procedure using P = 0.10 as significance level for removing a variable from the model.
To assess the ability of PEAK_ER to discriminate between patients who did and did not experience the primary study outcome at 2 years, we computed the area under the curve (AUC) [i.e. the area under the receiver operating characteristic (ROC) curve], after exclusion of patients with censored follow-up at <2 years. An AUC value of 0.5 indicates no predictive discrimination, while a value of 1 indicates perfect separation of patients with different outcomes. Two years was chosen as a tradeoff between a value close to the median follow-up of the patients and the need for keeping the number of observations as high as possible. AUCs were compared by the Hanley–McNeil test.
Descriptive statistics are reported as median and 25th and 75th percentiles.
All statistical analyses were carried out using the SAS/STAT statistical package, release 8.02 (SAS Institute Inc., Cary, NC, USA).
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Results |
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Follow-up data
During a 5-year follow-up (median: 31 months, interquartile range: 12–60), 94 patients (47%) died of cardiac death, of whom 23 died of sudden death. Only six patients were lost to follow-up (follow-up duration ranging from 28 to 55 months).
Demographic and clinical characteristics of the study patients are given in Table 1.
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Clinical correlates of PEAK_ER and circadian rhythms
As shown in Table 2, PEAK_ER was lower in patients with ischaemic compared with idiopathic cardiomyopathy, (P = 0.03) while no difference was found in relation to NYHA class (P = 0.44). As expected, PEAK_ER was significantly higher in patients with NSVT and with VPCs/h >30 (P < 0.0001 both). A moderate correlation was found between PEAK_ER and VPCs/h (continuous variable), with a Spearman correlation coefficient
= 0.58 (P < 0.0001).
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A significant difference (P = 0.0005) was observed between PEAK_ER_d (median: 4, interquartile range: 2–8), and PEAK_ER_n (median: 5, interquartile range: 2–7).
Survival analysis
Figure 1 shows the survival curves for PEAK_ER dichotomized according to upper tertile (cut-off value: 10) for sudden death. It is noted that mortality was significantly higher in patients with high PEAK_ER when compared with patients with low PEAK_ER.
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Neither VPCs/h nor NSVT were associated with sudden death (P = 0.5 and P = 0.9, respectively), while PEAK_ER (as continuous variable) showed a highly significant association with sudden death in univariable analysis (RR: 1.08, 95% CI: 1.023–1.137, P = 0.005). Therefore, a unitary increase in the maximum number of ectopic beats occurring in a 30-beat window would cause an 8% increase in the risk of sudden death. Significance was confirmed after adjustment for covariates (RR: 1.086, 95% CI: 1.027–1.147, P = 0.004). LVEF was the only covariate remaining in the multivariable model (Table 3). This result is consistent with the recommendations of having a maximum number of explanatory variables equal to one-tenth of the events, in order to obtain a reliable multivariable model.14
We also computed the contingency table relating PEAK_ER dichotomized according to the upper tertile to sudden death in patients with and without NSVT. We found that in patients without NSVT, the rate of mortality was significantly higher in those with high (>upper tertile) PEAK_ER, passing from 8 to 29% (P = 0.004), while there was no significant difference in patients with NSVT (from 7 to 14%, P = 0.34).
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In Figure 2, we have superimposed the ROC curves of PEAK_ER and VPCs/h for a 2-year outcome event. The AUC ± SE were 0.69 ± 0.04 and 0.60 ± 0.05 for PEAK_ER and VPCs/h, respectively (P = 0.08). Even though the difference in AUC did not reach statistical significance (the comparison is performed on total areas), in the overall region of best trade-off between sensitivity and false positive rate, PEAK_ER shows a better predictive discrimination compared with VPCs/h.
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PEAK_ER was also found to be a significant predictor of total cardiac mortality (RR: 1.039, 95% CI: 1.009–1.071, P = 0.01), and significance was confirmed after adjustment for NYHA class, LVEF, SDNN, and beta-blockers (RR: 1.036, 95% CI: 1.005–1.068, P = 0.02).
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Discussion |
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Despite a large number of studies have developed several prognostic models for assessing individual risk in HF, the identification of patients who could benefit from more aggressive treatment, including the ICD, is still a challenging task. In this study, we have proposed a novel index measuring the maximum rate of ectopies occurring in a 30 s window during a 24h Holter recording, and have investigated its prognostic power in relation to sudden death in a population of mild-to-moderate HF patients. Our results add to known risk factors indicating that this parameter is a powerful predictor of sudden death, independently of clinical and functional variables with known predictive value. The specific background from which we derived the rationale to set up the present methodological study led us to focus on sudden death, but PEAK_ER was also found to be significantly and independently associated with total cardiac mortality.
In the context of a damaged myocardium, spontaneous arrhythmias have aetiologically been linked to sudden cardiac death by either triggering fatal arrhythmias or serving as markers of an electrically unstable myocardium at risk of forming the substrate for ventricular dysrhythmias. Quantifying spontaneous arrhythmias only through the parameters that are commonly derived from Holter recordings (number of ‘simple’ and ‘complex’ arrhythmias) is likely to be too simplistic to exploit all the available information, which might explain why in several previous studies these parameters failed to provide useful prognostic information. For instance, in the Beta-blocker Heart Attack Trial,15 418 out of 1640 patients were defined at risk on the basis of VPCs 
10/h, or runs of NSVT. Thirty-three of these patients died suddenly. However, 43 of the remaining 1222 patients with ‘normal’ Holter recording according to ‘classical’ criteria also died suddenly. It may be speculated that at least some of these patients could have manifested a peculiar concentration of their limited number of VPCs providing an increased PEAK_ER.
Even though PEAK_ER looks at the arrhythmic pattern from a new point of view, a certain amount of association with VPCs/h and NSVT was obviously expected. Indeed, a significant association with VPCs/h was found, but the value of the correlation coefficient was moderate. This finding confirms that these two parameters investigate the same phenomenon from a different perspective: the latter considers only the average amount of ectopies occurring during 24 h, completely disregarding their distribution over time, which, on the contrary, is the focus of PEAK_ER. Our results suggest that the occurrence of (possibly occasional) bursts of ectopic beats is associated with a risk of sudden death higher than simply having a high average number of VPCs.
A significant association was found between PEAK_ER and NSVT, the former being higher in patients with NSVT. Even this result was largely expected since runs of ventricular tachycardia are likely to contribute to a high PEAK_ER, and could account for the predictive power shown by NSVT in several studies.16 An interesting finding was the way these two parameters interacted in relation to sudden death. We found that in patients without NSVT, the rate of mortality was significantly higher in subjects with high PEAK_ER, while no significant difference in mortality rate between patients with low and high PEAK_ER was found in patients with NSVT. Hence, the role of PEAK_ER in the identification of patients at risk for sudden death is mainly played in those patients who are classified at low risk according to NSVT.
The pathophysiological link between PEAK_ER and increased risk of sudden cardiac death remains speculative. A tenable hypothesis relies on the ‘VPCs hypothesis’ itself. Ambulatory recordings in patients experiencing spontaneous life-threatening arrhythmias show a tendency to increase VPCs frequency prior to ventricular fibrillation.17–19 This supports the concept that an increased ‘density’ of ventricular ectopies may establish the pathophysiological conditions for potentially fatal arrhythmias. The possibility to recognize and quantify this unstable condition likely explains the observed superiority of PEAK_ER against other Holter patterns as marker of increased risk.
It is worth to point out that the final model we obtained consisted of PEAK_ER (a variable easily computable from Holter recordings), plus LVEF, a parameter routinely collected in the evaluation of patients with advanced HF. Moreover, both these variables do not suffer from limitations as regards measurability, an aspect which, although often disregarded, can jeopardize the use of some parameters in patients with high ectopy rate.13
Limitations
The present study has some limitations that deserve to be addressed. The first limitation is the relatively small sample size of the study (200 patients with only 23 sudden deaths) and the peculiar clinical and demographic characteristics of our population. Even though the practical implication is that our results should be taken as exploratory and potentially linked to the population studied, this study provides a novel perspective in the identification of patients who are at higher risk of sudden death proposing a methodological approach extremely simple and with a clear link to pathophysiology.
The other critical point is the low portion of patients treated with beta-blockers (13%). Even though the prognostic power of peak ectopy rate should be validated in a fresh sample of patients treated according to current guidelines, we look optimistically to the confirmation of our results in HF patients of current ‘beta-blocking era’. Indeed, in a previous study,9 carried out on two samples of patients with a five-fold difference in the percentage of beta-blockers and with clinical and demographical characteristics close to the population considered in the present study, we found that the univariable association of PVCs with sudden death was borderline in the group with lower portion of treated patients but became significant in the group with the higher percentage of patients taking beta-blocking medications. Therefore, it is likely that even PEAK_ER may exhibit the same prognostic behaviour.
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Conclusions |
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The results of this study indicate that the quantification of the time course of arrhythmic events provides independent information in the identification of patients at increased risk of sudden death.
In particular, short-term ectopy rate adds to the prognostic power of reduced LVEF, which has been used as a criterion for implanting ICD.20 This finding integrates well in the debate on the results of the MADIT-II trial, where a more detailed exploration of risk stratification was advocated to improve the decision process.21
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References |
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