Michela Casella

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Ventricular Arrhythmias Due to a Transient of 
Correctable Cause in MADIT-II Patients: 
Prevalence and Clinical Relevance 
Michela Casella et al.* 
Cardiac Arrhythmia Research Centre,  
Centro Cardiologico Monzino IRCCS, Milan, 
Italy 
1. Introduction 
Post-infarction patients with severe left ventricular dysfunction are at high risk of sudden 
cardiac death. Antiarrhythmic therapy does not improve survival in such patients and, 
therefore, implantable cardioverter defibrillators (ICD) emerged as treatment of choice for 
both primary and secondary prevention of mortality after myocardial infarction (MI). The 
MADIT (Multicenter Automatic Defibrillator Implantation Trial) (1), and MUSTT 
(Multicenter Unsustained Tachycardia Trial) trials (2) were the first primary prevention ICD 
trials documenting a substantial reduction in mortality with an ICD in postinfarction 
patients with depressed ejection fraction, nonsustained ventricular tachycardia, and 
inducible sustained ventricular tachycardia. The MADIT II trial broadened the indications 
for prophylactic ICD use in post-infarction patients with ejection fraction of 30% or less 
without a requirement for additional risk stratification (3). The benefit from ICD therapy in 
patients with low ejection fraction was recently confirmed by results from the SCD-HeFT 
(Sudden Cardiac Death in Heart Failure) (4) and COMPANION (Comparison of Medical 
Therapy, Pacing, and Defibrillation in Heart Failure) trials (5). 
2. Triggers of ventricular arrhythmias 
Most investigations failed to reveal a transient cause for the development of ventricular 
arrhythmias in the majority of patients with severe left ventricular dysfunction. Singh et al. 
showed that among a comprehensive list of baseline clinical, echocardiographic, and 
electrophysiological variables in the MADIT-II study, more symptomatic patients (NYHA 
functional class >II) with blood urea nitrogen (BUN)>25 mg/dl, and no beta-blocker use are 
                                                 
* Pasquale Santangeli, Ghaliah Al-Mohani1, Antonio Dello Russo1, Francesco Perna2, Stefano Bartoletti1, 
Joseph Gallinghouse, Luigi Di Biase, Andrea Natale and Claudio Tondo1 
Texas Cardiac Arrhythmia Institute at St David’s Medical Center, Austin, TX, USA  
1Cardiac Arrhythmia Research Centre, Centro Cardiologico Monzino IRCCS, Milan, 
2Catholic University of the Sacred Heart, Rome, 
Italy 
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Cardiac Defibrillation  
– Prediction, Prevention and Management of Cardiovascular Arrhythmic Events 
 
150 
at a higher risk for first appropriate ICD therapy and death (6). Several data suggest that 
transient triggers (ischemia, heart failure, hypokalemia) may cause such events in a 
substantial proportion of patients. Ventricular premature Beats (VPB) have been found to 
trigger ventricular tachycardia (VT) especially in the setting of structural heart disease (7). 
Psychological stress may also be an important trigger. The impact of sympathetic activity on 
electrical instability is corroborated by the finding of a decreased baroreflex sensitivity in 
patients with clinical VT (8,9). In this chapter, we report the prevalence and clinical 
relevance of ventricular arrhythmias due to a transient arrhythmia triggers in patients with 
ischemic dilated cardiomyopathy undergoing primary prevention ICD implantation. 
3. Methods 
We collected data of 31 patients with ischemic cardiomyopathy (age 73±8 years, 25 males) 
who experienced the first arrhythmic event, defined as appropriate ICD intervention on 
sustained VT or fibrillation (VF), after the implantation of an ICD according to MADIT-II 
criteria (i.e. LVEF ≤ 30%). Patients were enrolled in our Institution between 2006 and 2008. 
All ICDs were uniformly programmed. Stored electrograms and ICD data disks from the 
included patients were reviewed by two expert electrophysiologists. Episodes of 
spontaneous sustained VT that were terminated by anti-tachycardia pacing or direct-current 
cardioversion were identified. VF was defined as a rapid, disorganized rhythm with 
variable cycle length, morphology, and amplitude of the electrogram with difficulty in 
precisely identifying all activation complexes. Polymorphic VT was diagnosed when 
electrograms displayed a ventricular tachycardia with almost constant amplitude but with 
variability in the cycle length and/or morphology of the electrograms. Monomorphic VT 
was defined as a ventricular tachycardia with a uniform beat-to-beat cycle length and 
electrogram morphology. 
Transient arrhythmia triggers were assessed at the time of the arrhythmic event by means of 
a complete clinical and laboratory evaluation, including serum electrolyte assessment, 
echocardiography and coronary angiography in all patients. Patients whose VT/VF was 
associated with a transient or correctable cause were classified by two independent and 
blinded investigators into: acute myocardial ischemic event (including myocardial infarction 
or unstable angina), proarrhythmic drug reaction, worsening of heart failure, electrolyte 
imbalance (hypokalemia or hypomagnesemia) or other causes. 
Continuous variables are presented as mean ± standard deviation, whereas categorical 
variables are presented as number and percentages. Comparisons between groups were 
performed with the two-tailed t test for continuous variables and chi-square test for discrete 
variables. A probability (p) value <0.05 was considered statistically significant. Analyses 
were performed with the PASW 18.1 statistical software (SPSS Inc.). 
4. Results 
Baseline characteristics of the patients included in the study are summarized in Table 1. All 
patients had ischemic cardiomyopathy and the mean left ventricular ejection fraction was 
28% ± 5%. Overall, 19 (61%) patients had ICD shock, either on VT (10/19, 53%) or on VF 
(9/19, 47%). The remaining 12 (39%) patients experienced effective ATP on VT. The mean 
time from ICD implantation to the ICD intervention was 23 ± 16 months.  
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Characteristics  
Total number 31 
Age, years 73 ± 8 
Sex, males 25 (81) 
Age at implant, years 70 ± 8 
Type of ICD, n (%)  
Dual-chamber 25 (81) 
Single-chamber 6 (19) 
Sinus Rhythm, n (%) 23 (74) 
Atrial Fibrillation, n (%) 8 (26) 
Risk factors, n (%)  
Smoke 6 (19) 
Hypertension 8 (26) 
Diabetes 10 (32) 
Hypercholesterolemia 12 (39) 
Drug Therapy, n (%)  
Beta blockers 30 (97) 
ACE-Inhibitors 31 (100) 
Diuretics 17 (55) 
Statins 28 (90) 
Left ventricular EF, % 28 ± 5 
NYHA functional class 2.4 ± 0.7 
Creatinine, mg/dL 1.4 ± 0.4 
Table 1. Baseline clinical characteristics of the study patients. 
The mean time from ICD implantation to the first arrhythmic event was 24±16 months. The 
first arrhythmic event consisted of VF in 9 (29%) and sustained VT in 22 (71%) patients, of 
which 10 treated with an ICD shock and 12 with effective anti-tachycardia pacing. No 
significant differences in baseline characteristics were found between patients with different 
types of ICD intervention. A transient or correctable trigger for the arrhythmic event was 
identifiable in 9 (29%) patients and consisted of worsening heart failure in 5 (16%), clinical 
and angiographic evidence of acute ischemia in 3 (10%) and electrolyte abnormalities (i.e. 
hypokalemia) in 1 (3%). Ventricular fibrillation was more often associated with a transient 
trigger compared with sustained VT (67% vs. 14%, respectively, p=0.007). Interestingly, all 
three patients with acute ischemia as a trigger had VF as arrhythmic event. 
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Cardiac Defibrillation  
– Prediction, Prevention and Management of Cardiovascular Arrhythmic Events 
 
152 
5. Discussion 
A number of well-known precipitating factors significantly increase the electrical instability 
of the heart. Among them, exacerbation of heart failure is one of the most important trigger 
factor suggesting that arrhythmia may simply be a marker of already-worsening HF. In our 
study worsening heart failure constituted 16% of cases. Previous analysis of the SCD-HeFT 
data (10) showed findings similar to those of the MADIT-II study. In the SCD-HeFT study, 
33% of HF patients received an ICD shock, and among those patients, the most common 
cause of death was progressive HF (10,11). Myocardial ischemia is important factor. In this 
study, there were three patients in whom myocardial ischemia was proven to be the trigger 
for electrical instability and presented with VF as arrhythmic event. VF and myocardial 
ischemia are inseparable. Presence of one precipitates and perpetuates the other. Transmural 
heterogeneities in myocardial action potential and ionic currents produce transmural 
asymmetry in conduction during acute ischemia. Acute transmural ischemia depresses the 
excitability and velocity of conduction more rapidly in the epicardium than in the 
endocardium leading to increased dispersion. The occurrence of potentially lethal 
arrhythmia is the end result of a cascade of pathophysiological abnormalities (12-14). Other 
triggering factors include the development of electrolyte disturbances such as profound 
hypokalemia, which was demonstrated in one of our patients. Electrical instability is 
enhanced upon patients in whom drug treatment for congestive heart failure often acts to 
further increase electrolyte disturbances. 
6. Clinical implication 
The ICD has become the therapy of first choice to prevent sudden cardiac death in high-risk 
patients. Our study also supports the well-understood clinical notion that continued clinical 
vigilance toward preventing heart failure exacerbations and coronary events might decrease 
the risk of sudden cardiac death and ICD therapy in these patients. Interestingly importance 
of heart failure deterioration  (i.e.,worsening of clinical status) suggests that this subset of 
patients have a wider margin to deteriorate and have additional predictive value as a 
determinant of ICD therapy. This also supports the evidence that in sicker heart failure 
subjects, the cause of death is more likely owing to pump failure. These results are 
corroborated by recent studies that show that preventing progression of heart failure with 
cardiac resynchronization therapy reduces the incidence of arrhythmic events (15,16). 
Acute myocardial ischemia in high risk patients is arrhythmogenic, often leading to fatal 
outcome in the clinical setting. The arrhythmic outcome of an event between trigger and 
substrate differs. Genetic predisposition and governing responses of ion channels to 
myocardial ischemia might have a greater role than what is known at present. Efforts to 
understand these arrhythmias better can do early identification of patients with myocardial 
ischemia prone to arrhythmias. One of the most important aspects of the current study 
relates to potential prognostic implications of triggers. At present, there is a paucity of 
information on this clinically important issue. 
Finally, in interpreting our results, it must be recognized that not all triggers causing 
arrhythmias appropriate ICD shocks for VT/VF would have been detected, and further 
identification of clinical triggers may help us to higher surveillance and vigilance of possible 
triggers to avoid primary shock that further deteriorate mortality and heart failure 
progression, increase in sympathetic tone that may give rise to proarrhythmic side effects of 
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Ventricular Arrhythmias in MADIT-II Patients 
 
153 
antiarrhythmic drugs may also constitute a precipitating factor for recurrent ventricular 
tachycardia or fibrillation.  
7. Conclusion 
Due to the increasing number of patients with severe left ventricular dysfunction, further 
studies are needed to optimize priority of such patients for ICD therapy. Optimal 
pharmacologic and anti-ischemic (CABG, percutaneous transluminal coronary angioplasty) 
therapy, accurate and rapid correction of electrolytes disturbances are essential for proper 
prevention of shock and mortality in addition to ICD therapy. 
8. References 
[1] Moss AJ, Hall WJ, Cannom DS, et al.: Improved survival with an implanted defibrillator 
in patients with coronary disease at high risk for ventricular arrhythmia. 
Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 
1996, 335:1933–1940. 
[2] Buxton AE, Lee KL, Fisher JD, et al.: A randomized study of the prevention of sudden 
death in patients with coronary artery disease. Multicenter Unsustained 
Tachycardia Trial Investigators. N Engl J Med 1999, 341:1882–1890. 
[3] Moss AJ, Zareba W, Hall WJ, et al.: The Multicenter Automatic Defibrillator 
Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in 
patients with myocardial infarction and reduced ejection fraction. N Engl J Med 
2002, 346:877–883. 
[4] Sudden Cardiac Death in Heart Failure Trial: (SDC-HeFT). Available at: 
http://www.sicr.org. Accessed July 26, 2004. Recent (as yet unpublished) study 
finalizing debate regarding usage of amiodarone for primary prevention of 
mortality in postinfarction patients with low EF and providing evidence for a 
beneficial effect of ICD therapy in both ischemic and nonischemic cardiomyopathy 
patients. 
[5] Bristow MR, Saxon LA, Boehmer J, et al.: Cardiac-resynchronization therapy with or 
without an implantable defibrillator in advanced chronic heart failure. N Engl J 
Med 2004, 350:2140–2150. 
[6] C. Israel and S. Barold, Electrical storm in patients with an implanted defibrillator: a 
matter of definition, Ann Noninvas Electrocardiogr 12 (2007), pp. 375–382. 
[7] Rosman J, Hanon S, Shapiro M, Evans SJ, Schweitzer P. Triggers of sustained 
monomorphic ventricular tachycardia differ among patients with varying 
etiologies of left ventricular dysfunction. Ann Noninvasive Electrocardiol 11: 113-
117, 2006.  
[8] Credner SC, Klingenheben T, Mauss O, et al. Electrical storm in patients with 
transvenous implantable cardioverter-defibrillators: Incidence, management and 
prognostic implications. J Am Coll Cardiol 1998;32:1909–1915. 
[9] Nademanee K, Taylor R, Bailey WE, et al. Treating electrical storm: Sympathetic 
blockade versus advanced cardiac life support-guided therapy. Circulation 
2000;102:742–747. 
[10] Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator 
shocks in patients with heart failure. N Engl J Med 2008;359:1009 –17. 
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Cardiac Defibrillation  
– Prediction, Prevention and Management of Cardiovascular Arrhythmic Events 
 
154 
[11] Moss AJ, Greenberg H, Case RB, et al. Long-term clinical course of patients after 
termination of ventricular tachyarrhythmia by an implanted defibrillator. 
Circulation 2004;110:3760 –5. 
[12] Janse MJ, Wit AL. Electrophysiological mechanisms of ventricular arrhythmias 
resulting from myocardial ischemia and infarction. Phys Rev 1989;69:1049–169. 
[13] Carmeliet E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. 
Phys Rev 1999;79:917–1017. 
[14] Casciol WE, Johnson TA, Gettes LS. Electrophysiologic changes in ischemic ventricular 
myocardium: I. Influence of ionic, metabolic and energetic changes. J Cardiovasc 
Electrophysiol 1995;l6:1039–62. 
[15] Higgins SL, Hummel JD, Niazi IK, et al. Cardiac resynchronization therapy for the 
treatment of heart failure in patients with intraventricular conduction delay and 
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[16] Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or 
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Cardiac Defibrillation - Prediction, Prevention and Management of
Cardiovascular Arrhythmic Events
Edited by Dr. Joyelle Harris
ISBN 978-953-307-692-8
Hard cover, 176 pages
Publisher InTech
Published online 14, November, 2011
Published in print edition November, 2011
InTech Europe
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Slavka Krautzeka 83/A 
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Phone: +86-21-62489820 
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Millions of people throughout the world currently depend on appropriate, timely shocks from implantable
cardioverter defibrillators (ICDs) to avoid sudden death due to cardiovascular malfunctions. Therefore,
information regarding the use, applications, and clinical relevance of ICDs is imperative for expanding the body
of knowledge used to prevent and manage fatal cardiovascular behavior. As such, the apt and timely research
contained in this book will prove both relevant to current ICD usage and valuable in helping advance ICD
technology. This book is divided into three comprehensive sections in order to cover several areas of ICD
research. The first section introduces defibrillator technology, discusses determinants for successful
defibrillation, and explores assessments of patients who receive defibrillation. The next section talks about
predicting, preventing, and managing near catastrophic cardiovascular events, and research presented in the
final section examine special cases in ICD patients and explore information that can be learned through clinical
trial examinations of patients with defibrillators. Each chapter of this book will help answer critical questions
about ICDs.
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Michela Casella, Pasquale Santangeli, Ghaliah Al-Mohani, Antonio Dello Russo, Francesco Perna, Stefano
Bartoletti, Joseph Gallinghouse, Luigi Di Biase, Andrea Natale and Claudio Tondo (2011). Ventricular
Arrhythmias Due to a Transient of Correctable Cause in MADIT-II Patients: Prevalence and Clinical Relevance,
Cardiac Defibrillation - Prediction, Prevention and Management of Cardiovascular Arrhythmic Events, Dr.
Joyelle Harris (Ed.), ISBN: 978-953-307-692-8, InTech, Available from:
http://www.intechopen.com/books/cardiac-defibrillation-prediction-prevention-and-management-of-
cardiovascular-arrhythmic-events/ventricular-arrhythmias-due-to-a-transient-of-correctable-cause-in-madit-ii-
patients-prevalence-and-
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Ventricular Arrhythmias Due to a Transient of Correctable Cause in MADIT-II Patients: Prevalence and Clinical Relevance

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Ventricular Arrhythmias Due to a Transient of Correctable Cause in MADIT-II Patients: Prevalence and Clinical Relevance

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