EDITORIAL COMMENT
Holter Electrocardiogram Parameters in Risk Stratification of Arrhythmic Events in Idiopathic Dilated Cardiomyopathy
More Studies Are Needed*
Wojciech Zareba, MD, PhD, FACC*
Cardiology Division, University of Rochester Medical Center, Rochester, New York.
* Reprint requests and correspondence: Dr. Wojciech Zareba, Heart Research Follow-up Program, Cardiology Division, University of Rochester Medical Center, 601 Elmwood Avenue, Box 653, Rochester, New York 14642. (Email: wojciech_zareba{at}urmc.rochester.edu).
Recent advancements in the management of patients with acute coronary syndromes and chronic coronary artery disease have contributed to a decreasing number of ischemic patients developing advanced left ventricular dysfunction and heart failure. Trends in clinical practices using device therapy in patients with heart failure and left ventricular dysfunction indicate that the incidence of nonischemic or idiopathic dilated cardiomyopathy (DCM) is increasing. Current guidelines for the primary prevention of cardiac mortality with implantable cardioverter-defibrillators (ICDs) in DCM patients are based on the landmark DEFINITE (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation) trial (1) and the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) (1,2). The DEFINITE trial enrolled DCM patients with ejection fraction 
35% and a history of symptomatic heart failure and the presence of ambient arrhythmias (1). The SCD-HeFT (2) used low ejection fraction and presence of symptomatic heart failure (New York Heart Association [NYHA] functional class II or III) as entry criteria. Both trials showed a marked improvement in survival with ICD therapy; however, in both trials the majority of patients (even those assigned to conventional therapy) remained asymptomatic during follow-up. This high proportion of patients without cardiac events raises the question of whether we are able to identify high- and low-risk subsets of patients with DCM to optimize ICD and other therapies. However, effective and clinically useful risk stratification in DCM patients remains a challenge. Low ejection fraction and advanced NYHA functional class are proven as important risk factors, but they seem too unspecific for identifying patients at risk for arrhythmic events. Moreover, preserved left ventricular function is increasingly seen in heart failure patients, and there are no data regarding risk stratification in that population.
In this issue of the Journal, Iacoviello et al. (3) described a comprehensive risk-stratification study aiming to identify clinical and electrocardiogram (ECG) parameters that could be useful in the risk stratification for arrhythmic events in patients with idiopathic DCM. The main study population consisted of 179 patients with DCM and left ventricular ejection fraction of 34 ± 10% (42% of patients had ejection fraction >35%). During 39 ± 22 months follow-up, there were 24 arrhythmic events identified, including 9 sudden deaths. There were a total of 15 deaths, regardless of causes. Both mortality rates and arrhythmic event rates were relatively low in the studied population, most likely due to a high proportion of patients with relatively preserved ejection fraction and possibly due to the relatively young age of studied patients: 49 years on average.
In comparison, the DEFINITE trial enrolled patients with mean ejection fraction of 31% and mean age of 58 years (1). Despite these relatively low overall rates of cardiac events reported by Iacoviello et al. (3), the authors demonstrated that within studied population there is a cohort of patients at significantly increased risk of arrhythmic events. This cohort could be identified by adding electrocardiographic parameters to standard risk stratification based on ejection fraction dichotomized at 35%.
Detection of nonsustained ventricular tachycardia (NSVT) on Holter recordings (hazard ratio [HR] 2.96, p = 0.022) significantly improved risk stratification in patients studied by Iacoviello et al. (3). In the study by Iacoviello et al. (3), NSVT was found in over 30% of patients, similar to rates observed by Grimm et al. (4) in 343 patients from the Marburg Cardiomyopathy study. However, in the Grimm et al. (4) study, NSVT on Holter was associated with only a trend toward higher arrhythmia risk (HR 1.7, p = 0.11), despite the fact that clinical characteristics of these 2 studied populations were quite similar. Another recent study by Baker and Koelling (5) in 355 DCM patients showed that NSVT was associated with decreased survival (HR 1.63, p = 0.02). Zecchin et al. (6) evaluated 554 DCM patients with much longer follow-up of 81 months on average, and found that the presence or absence of NSVT at baseline did not differentiate patients with versus without cardiac events. However, they demonstrated that the presence of frequent NSVT episodes (
3 runs/day) was associated with an increased risk for total mortality (HR 1.68, p = 0.041) and major ventricular arrhythmias (HR 2.11, p = 0.037), but only in the subgroup of patients with severe left ventricular impairment. Therefore, a controversy still exists regarding the prognostic significance of NSVT in DCM patients, and further studies are needed to document this association in patients with well-documented arrhythmic events by interrogated implantable devices.
Another important contribution of the study by Iacoviello et al. (3) is the analysis of QT/RR slopes in DCM patients. This is the first study evaluating the prognostic significance of QT dynamics in DCM population. The QT/RR slope was found to be predictive for arrhythmic events after adjustment for clinical covariates and presence of NSVT in the model. Patients with arrhythmic events had significantly steeper QT/RR slope in comparison with arrhythmia-free patients. Increased QT/RR slope (>0.19) was able to identify high-risk subset of DCM patients with ejection fraction 35%. Patients with low ejection fraction but with less steep slope (QT/RR slope 0.19) had much lower event rates. These findings indicate that evaluating QT dynamics might provide clinically useful information when considering ICD therapy. The observations by Iacoviello et al. (3) correspond to a similar analysis conducted by Chevalier et al. (7) in postinfarction patients, where increased slope (>0.18) also identified a high-risk subset of patients. Facilitation of re-entry by shortening of the refractory period might be considered as a potential mechanism behind this phenomenon (8).
Patients with ejection fraction >35% in the study by Iacoviello et al. (3) were few in number and experienced very few events. As a result, there was limited statistical power to determine the prognostic usefulness of studied ECG parameters in this subgroup of patients. It is possible that DCM patients with relatively preserved ejection fraction might benefit from ECG-based risk stratification and optimization of therapy, but no studies have addressed this group of patients so far.
The study by Iacoviello et al. (3) also provides insight into a comprehensive approach for risk stratification combining clinical, echocardiographic, ECG, and Holter-based parameters. This approach reflects clinical practice and utilizes standard and broadly accessible technologies. We have learned from this study that QRS duration, QTc duration, or heart rate variability was not predictive for arrhythmic events in studied DCM patients. Instead, the authors propose a risk-stratification algorithm based on a combination of 3 parameters: low ejection fraction, NSVT, and QT/RR slope, each reflecting different mechanistic pathways that could lead to arrhythmic events. This algorithm requires further testing in prospective cohorts to enable validation of the concept.
It is worth stressing that there are several other risk-stratification methods utilizing the ECG including T-wave alternans (9), QT variability (10,11), and heart rate turbulence (12,13). A direct comparison of these methods may provide us with clinically useful information to further improve clinical management of DCM patients. These ECG methods will, in the future, be complemented by imaging techniques like magnetic resonance imaging, allowing a more precise assessment of myocardial changes and their propensity for major cardiac events.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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- Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter defibrillator for congestive heart failure N Engl J Med 2005;352:225-237.[Abstract/Free Full Text]
- Iacoviello M, Forleo C, Guida P, et al. Ventricular repolarization dynamicity provides independent prognostic information toward major arrhythmic events in patients with idiopathic dilated cardiomyopathy J Am Coll Cardiol 2007;50:225-231.[Abstract/Free Full Text]
- Grimm W, Christ M, Bach J, Muller HH, Maisch B. Noninvasive arrhythmia risk stratification in idiopathic dilated cardiomyopathy: results of the Marburg Cardiomyopathy study Circulation 2003;108:2883-2891.[Abstract/Free Full Text]
- Baker RL, Koelling TM. Prognostic value of ambulatory electrocardiography monitoring in patients with dilated cardiomyopathy J Electrocardiol 2005;38:64-68.[ISI][Medline]
- Zecchin M, Di Lenarda A, Gregori D, et al. Prognostic role of non-sustained ventricular tachycardia in a large cohort of patients with idiopathic dilated cardiomyopathy Ital Heart J 2005;6:721-727.[Medline]
- Chevalier P, Burri H, Adeleine P, et al. QT dynamicity and sudden death after myocardial infarction: results of a long-term follow-up study J Cardiovasc Electrophysiol 2003;14:227-233.[ISI][Medline]
- Zareba W, Bayes de Luna A. QT dynamics and variability Ann Noninvasive Electrocardiol 2005;10:256-262.[CrossRef][ISI][Medline]
- Hohnloser SH, Klingenheben T, Bloomfield D, Dabbous O, Cohen RJ. Usefulness of microvolt T-wave alternans for prediction of ventricular tachyarrhythmic events in patients with dilated cardiomyopathy: results from a prospective observational study J Am Coll Cardiol 2003;41:2220-2224.[Abstract/Free Full Text]
- Berger RD, Kasper EK, Baughman KL, Marban E, Calkins H, Tomaselli GF. Beat-to-beat QT interval variabilityNovel evidence for repolarization lability in ischemic and nonischemic dilated cardiomyopthy. Circulation 1997;96:1557-1565.[Abstract/Free Full Text]
- Haigney MC, Zareba W, Gentlesk PJ, et al. Multicenter Automatic Defibrillator Implantation Trial II Investigators QT interval variability and spontaneous ventricular tachycardia or fibrillation in the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II patients J Am Coll Cardiol 2004;44:1481-1487.[Abstract/Free Full Text]
- Francis J, Watanabe MA, Schmidt G. Heart rate turbulence: a new predictor for risk of sudden cardiac death Ann Noninvasive Electrocardiol 2005;10:102-109.[CrossRef][ISI][Medline]
- Cygankiewicz I, Zareba W. Heart rate turbulence—an overview of methods and applications Folia Cardiologica 2006;13:359-368.
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References