By contrast, the result that the DCM circadian distribution is polynomial rather than harmonic, may suggest a different underlying mechanism at the basis of VT initiation. The observation that almost all VT occur during the day-light and almost none during the night, might lead to the hypothesis that sympathetic tone could be involved. In fact, Pogwizd described that a cardiac preserved beta-receptor responsiveness might likely facilitate early and delayed after-depolarizations, and, consequently, a triggered activity [Pogwizd et al.

Such considerations might lead to speculate that sympatho-vagal tone changings could facilitate a reentry in the CAD group, while a higher sympathetic tone could determine a

It is noteworthy that the three different initiation patterns of VT episodes also show

VT initiated with PM pattern are better described, in both DCM and CAD patients, by a polynomial model. Distribution is almost uniform during the observed 24 hours in the DCM group , while it is mostly focused during the night in the CAD group. Although the number of VT is small (7 PM-onset in CAD and 13 in DCM), the result in the CAD population may be consistent with a lower heart rate occurring during the night, promoting a greater antibradycardia pacing intervention . It is less obvious to explain the finding in DCM, because the PM-onset occurs almost uniformly during the whole day. An increased prevalence of post-extrasystolic pauses distributed during the whole day, determining a frequent pacing

Circadian distribution of SLS patterns are well described by a harmonic models in both CAD (R2 = 0.92 vs 0.77 for polynomial model) and DCM (R2 = 0.91 vs 0.68 for polynomial model) with VT initiation especially between 9 a.m. to 6 p.m. in CAD, while it is evident a

Finally, the distribution of the PVC patterns is better described by a polynomial regression in the DCM group (R2=0.86 vs. 0.78 for harmonic regression) with a peak in the middle of the day and no VT during the night (hour range: 0-6 a.m. ); a different behavior is observed in the CAD group where a harmonic model fits slightly better (R2=0.84 vs. 0.83 for polynomial model ), with distribution showing small peaks between 9 a.m. and 12 a.m. and

The main limitations of this registry lie in the small number of patients and in the lack of endomyocardial biopsy in the DCM group. In addition, only single chamber ICDs were considered: they may present increased risk of PM-onset vs dual and three-chamber ICDs [Sweeney et al. 2007]. About the pharmacological treatment, the only detailed information was referred to implant date: eventual changes, during the follow-up period, were not

Moreover, to examine the basal heart rhythm before the VT initiation, a good quality EGM at 250 Hz was obtained. As a consequence, for technical reasons, the ICD diagnostic parameters were programmed to store at the most three VT episodes. This setting, however, could have caused a lack of some episodes. For instance, in a DCM patient with some VT storms, successfully treated with the anti-tachycardia pacing, it was not possible to analyze

immediate PVCs (denominated extrasystolic onset) and VT with sudden onset, showing that extrasystolic onset was the most common pattern of VT initiation and was associated with lower ejection fraction. Sudden-onset initiation was more common with better preserved systolic function. Non sudden onset episodes required higher levels of shock energy and more frequent multiple shock achievements than sudden onset episodes [Gorenek et al. 2006].

In the present study the analysis of the modes of VT-onset indicated that 12% of VT initiate immediately after a paced beat, which may suggest a proarrhythmic effect of pacing in some patients [Sweeney et al. 2007, Himmrich et al. 2003]. These results are consistent with recent findings: Sweeney et al [Sweeney et al. 2007] found a 9.4% rate of VT initiated immediately after anti-bradycardia pacing in patients with a single chamber ICD, such as those used in our study. In our study the prevalence of VT with PM-onset was higher in DCM (15%) than CAD (9%), but statistical analysis with chi-square test shows that this difference is not significant (p<0.28). On the contrary, a statistically significant difference between CAD and DCM populations is obtained from the analysis of the number of initiation pattern indicating a more heterogeneous VT-onset in DCM patients (see Table 2). In particular, in 3 DCM patients all the three initiation patterns are present, while most of CAD initiated their VT always with the same mode.

Results in Table 3 indicate EGM features do not allow discriminating differences between CAD and DCM, suggesting that EGM features do not correlate with the cardiac disease substrate. However, in each group, significantly higher prematurity index and median heart cycle PreVT were observed in VT with PM-onset with respect to other VT initiation modes. The HC\_PreVT can be explained by observing that anti-bradycardia pacing is a consequence of a low spontaneous heart rate. The significantly higher PI of PM-onset episodes, observed both in CAD and DCM patients, deserves further investigation.

#### **4.2 Circadian distribution**

In the literature the circadian distributions of VT episodes in the CAD population has been studied and a non-uniform distribution with clear peaks in the morning and afternoon has been observed [Englund et al. 1999, Eksik et al. 2007]. Results are controversial in the case of non-ischemic patients. While in some papers [Englund et al. 1999, Anand et al. 2007] nonischemic disease presents circadian distribution similar to ischemic patients, in other studies [Carson et al. 2000, Taneda et al. 2001] non-ischemic patients do not have the morning peak and circadian distribution is almost uniformly distributed during daylight hours. The present study shows the presence of the two peaks in CAD patients, and a more uniformly distribution during daylight hours in DCM patients (see Fig. 4). This conclusion is further supported by our observation that the timing of VT-onset in CAD and DCM populations are described by structurally different statistical models, with harmonic and polynomial regression providing the best fitting function in CAD and DCM, respectively. The finding that the circadian distribution of VT in CAD patients is better described by a harmonic function (such as a bimodal activity) may suggest that the underlying arrhythmogenic mechanism could be oscillating during the 24-hour period, as is the case of the autonomic sympathetic-vagal balance. This hypothesis is supported by Taneda et al. who described a much higher peak of VT in the morning in patients not taking beta-blockers vs. patients who did [Figure 2 in Taneda et al. 2001]. Similarly, Dorian suggested that sympathetic activation can lead to a distributed shortening or, in some cases, prolonged action potential in the substrate, increasing the risk for reentrant arrhythmia [Dorian 2005].

By contrast, the result that the DCM circadian distribution is polynomial rather than harmonic, may suggest a different underlying mechanism at the basis of VT initiation. The observation that almost all VT occur during the day-light and almost none during the night, might lead to the hypothesis that sympathetic tone could be involved. In fact, Pogwizd described that a cardiac preserved beta-receptor responsiveness might likely facilitate early and delayed after-depolarizations, and, consequently, a triggered activity [Pogwizd et al. 2001, Pogwizd et al. 2004].

Such considerations might lead to speculate that sympatho-vagal tone changings could facilitate a reentry in the CAD group, while a higher sympathetic tone could determine a dangerous triggered activity in the DCM one.

It is noteworthy that the three different initiation patterns of VT episodes also show differences in the circadian distribution. (Figure 5 and Table 4).

VT initiated with PM pattern are better described, in both DCM and CAD patients, by a polynomial model. Distribution is almost uniform during the observed 24 hours in the DCM group , while it is mostly focused during the night in the CAD group. Although the number of VT is small (7 PM-onset in CAD and 13 in DCM), the result in the CAD population may be consistent with a lower heart rate occurring during the night, promoting a greater antibradycardia pacing intervention . It is less obvious to explain the finding in DCM, because the PM-onset occurs almost uniformly during the whole day. An increased prevalence of post-extrasystolic pauses distributed during the whole day, determining a frequent pacing escape, is more likely.

Circadian distribution of SLS patterns are well described by a harmonic models in both CAD (R2 = 0.92 vs 0.77 for polynomial model) and DCM (R2 = 0.91 vs 0.68 for polynomial model) with VT initiation especially between 9 a.m. to 6 p.m. in CAD, while it is evident a very strong peak between 3 p.m. to 6 p.m. in DCM patients.

Finally, the distribution of the PVC patterns is better described by a polynomial regression in the DCM group (R2=0.86 vs. 0.78 for harmonic regression) with a peak in the middle of the day and no VT during the night (hour range: 0-6 a.m. ); a different behavior is observed in the CAD group where a harmonic model fits slightly better (R2=0.84 vs. 0.83 for polynomial model ), with distribution showing small peaks between 9 a.m. and 12 a.m. and 3 p.m. to 6 p.m.

#### **4.3 Limitations**

Cardiac Defibrillation

62 – Prediction, Prevention and Management of Cardiovascular Arrhythmic Events

immediate PVCs (denominated extrasystolic onset) and VT with sudden onset, showing that extrasystolic onset was the most common pattern of VT initiation and was associated with lower ejection fraction. Sudden-onset initiation was more common with better preserved systolic function. Non sudden onset episodes required higher levels of shock energy and more frequent multiple shock achievements than sudden onset episodes [Gorenek et al.

In the present study the analysis of the modes of VT-onset indicated that 12% of VT initiate immediately after a paced beat, which may suggest a proarrhythmic effect of pacing in some patients [Sweeney et al. 2007, Himmrich et al. 2003]. These results are consistent with recent findings: Sweeney et al [Sweeney et al. 2007] found a 9.4% rate of VT initiated immediately after anti-bradycardia pacing in patients with a single chamber ICD, such as those used in our study. In our study the prevalence of VT with PM-onset was higher in DCM (15%) than CAD (9%), but statistical analysis with chi-square test shows that this difference is not significant (p<0.28). On the contrary, a statistically significant difference between CAD and DCM populations is obtained from the analysis of the number of initiation pattern indicating a more heterogeneous VT-onset in DCM patients (see Table 2). In particular, in 3 DCM patients all the three initiation patterns are present, while most of CAD initiated their

Results in Table 3 indicate EGM features do not allow discriminating differences between CAD and DCM, suggesting that EGM features do not correlate with the cardiac disease substrate. However, in each group, significantly higher prematurity index and median heart cycle PreVT were observed in VT with PM-onset with respect to other VT initiation modes. The HC\_PreVT can be explained by observing that anti-bradycardia pacing is a consequence of a low spontaneous heart rate. The significantly higher PI of PM-onset episodes, observed

In the literature the circadian distributions of VT episodes in the CAD population has been studied and a non-uniform distribution with clear peaks in the morning and afternoon has been observed [Englund et al. 1999, Eksik et al. 2007]. Results are controversial in the case of non-ischemic patients. While in some papers [Englund et al. 1999, Anand et al. 2007] nonischemic disease presents circadian distribution similar to ischemic patients, in other studies [Carson et al. 2000, Taneda et al. 2001] non-ischemic patients do not have the morning peak and circadian distribution is almost uniformly distributed during daylight hours. The present study shows the presence of the two peaks in CAD patients, and a more uniformly distribution during daylight hours in DCM patients (see Fig. 4). This conclusion is further supported by our observation that the timing of VT-onset in CAD and DCM populations are described by structurally different statistical models, with harmonic and polynomial regression providing the best fitting function in CAD and DCM, respectively. The finding that the circadian distribution of VT in CAD patients is better described by a harmonic function (such as a bimodal activity) may suggest that the underlying arrhythmogenic mechanism could be oscillating during the 24-hour period, as is the case of the autonomic sympathetic-vagal balance. This hypothesis is supported by Taneda et al. who described a much higher peak of VT in the morning in patients not taking beta-blockers vs. patients who did [Figure 2 in Taneda et al. 2001]. Similarly, Dorian suggested that sympathetic activation

both in CAD and DCM patients, deserves further investigation.

2006].

VT always with the same mode.

**4.2 Circadian distribution**

The main limitations of this registry lie in the small number of patients and in the lack of endomyocardial biopsy in the DCM group. In addition, only single chamber ICDs were considered: they may present increased risk of PM-onset vs dual and three-chamber ICDs [Sweeney et al. 2007]. About the pharmacological treatment, the only detailed information was referred to implant date: eventual changes, during the follow-up period, were not collected.

Moreover, to examine the basal heart rhythm before the VT initiation, a good quality EGM at 250 Hz was obtained. As a consequence, for technical reasons, the ICD diagnostic parameters were programmed to store at the most three VT episodes. This setting, however, could have caused a lack of some episodes. For instance, in a DCM patient with some VT storms, successfully treated with the anti-tachycardia pacing, it was not possible to analyze

Ventricular Tachyarrhythmias in Implantable Cardioverter

29:48-52.

50:614-622.

Defibrillator Recipients: Differences Between Ischemic and Dilated Cardiomyopathies 65

Eksik A, Akyol A, Norgaz T, Aksu H, Erdinler I, Cakmak N et al. (2007) Circadian pattern of

El-Sherif N, Caref EB, Chinushi M, Restivo M. (1999) Mechanism of Arrhythmogenicity of

Englund A, Behrens S, Wegscheider K, Rowland E, for the European 7219 Jewel

Gorenek B, Kudaiberdieva G, Birdane A, Cavusoglu Y, Goktekin O, Unalir A et al. (2006)

Henkel DM, Witt BJ. (2006) Ventricular arrhythmias after acute myocardial infarction: A 20-

Himmrich E, Przibille O, Zellerhoff C, Liebrich A, Rosocha S, Andreas K et al. (2003)

Jayaraj P, Monahan KM. (2005) Sudden cardiac death and the role of device therapy in

Pogwizd SM, Schlotthaurer K, Li L, et al. (2001). Arrhythmogenesis and contractile

Pogwizd SM and Bers DM. (2004) Cellular Basis of Triggered Arrhythmias in Heart Failure.

Pogwizd SM, McKenzie JP, Cain ME. (1998) Mechanisms underlying spontaneous and

Saeed M, Link MS, Mahapatra S, Mouded M, Tzeng D, Jung V et al. (2000) Analysis of

Sweeney MO, Ruetz LL, Belk P, Mullen TJ, Johnson JW, Sheldon T. (2007) Bradycardia

Taneda K, Aizawa Y on behalf of the Japanese ICD study group. (2001) Absence of a

induced ventricular arrhythmias in patients with idiopathic dilated

intracardiac electrograms showing monomorphic ventricular tachycardia in patients with implantable cardioverter-defibrillators. Am J Cardiol 85:580-587. Sarter BH, Callans DJ, Gottlieb CD, Schwartzman DS, Marchlinski FE. (1998) Implantable

Defibrillator Diagnostic Storage Capabilities: Evolution, Current Status and Future

pacing-induced short-long-short sequences at the onset of ventricular tachyarrhythmias: a possible mechanism of proarrhythmia? J Am Coll Cardiol

Morning Peak in Ventricular Tachycardia and Fibrillation Events in Nonischemic Heart Disease: Analysis of Therapies by Implantable Cardioverter Defibrillators.

cardioverter defibrillators. Med Sci Monit 13:CR412-416.

the Long QT Syndrome. J Am Coll Cardiol 33:1415–1423

Defibrillator Implantation. J Am Coll Cardiol; 34:1560-1568.

year community study. Am Heart J; 151:806-812.

Cardioverter-Defibrillators Circulation 108:192-197.

dysfunction in heart failure. Circ Res 88: 1159– 1167.

Utilization. Pacing Clin Electrophysiol 21:1287-1298.

Trends Cardiovasc Med 14:61–66.

cardiomyopathy. Circulation 98:2404-2414.

Pacing Clin Electrophysiol 24:1602-1606.

dilated cardiomyopathy. Curr Heart Fail Rep 2:124-127.

spontaneous ventricular tachyarrhythmias in patients with implantable

the Short–Long Cardiac Sequence That Precedes Ventricular Tachyarrhythmias in

Investigators. (1999) Circadian Variation of Malignant Ventricular Arrhythmias in Patients With Ischemic and Nonischemic Heart Disease After Cardioverter

Importance of initiation pattern of polymorphic ventricular tachycardia in patients with implantable cardioverter defibrillators. Pacing Clin Electrophysiol;

Proarrhythmic Effect of Pacemaker stimulation in Patients With Implanted

all the episodes, but only the latest ones. In order to limit these drawbacks, the same settings were used for CAD and DCM groups and the follow-up was performed periodically, (minimum of 3 to maximum 6 months) unless the ICD delivered a shock. In that case, the patient was invited to contact the hospital for a visit as soon as possible and data were retrieved by the ICD. It is authors' opinion that the frequent follow-up could be sufficient to minimize the number of undetected VT episodes.

### **5. Conclusion**

This study examines the differences between CAD and non-ischemic DCM patients with ICD. Our results show that patients with DCM exhibit a significantly higher prevalence of VT episodes (p<0.02) and a significantly greater variability in the VT initiation pattern (p<0.01). The circadian distribution (in a 3 –hour period analysis) of the VT-onset is also different in the two groups: CAD patients exhibit a morning peak: between 9 and 12 a.m. and an afternoon peak (around 6 p.m.), whereas DCM patients show a more uniform distribution during waking hours and very few episodes during the night.

Eventually, no significant differences between CAD and DCM are observed from the analysis of VT-rate, coupling interval, prematurity index. Likewise, the analysis of the EGM signal during the 20 seconds immediately preceding VT onset show no significant differences in the heart-cycle, prevalence of PVC, nor prevalence of paced beats.

This study (based on characterization of EGM, VT-onset and VT circadian distribution) does not define a relationship between observed CAD-DCM differences and underlying CAD-DCM electrogenetic-mechanisms. Nevertheless, our findings suggest different foundations of VT initiation in patients with ischemic versus idiopathic dilated cardiomyopathy.

#### **6. References**

64 – Prediction, Prevention and Management of Cardiovascular Arrhythmic Events

all the episodes, but only the latest ones. In order to limit these drawbacks, the same settings were used for CAD and DCM groups and the follow-up was performed periodically, (minimum of 3 to maximum 6 months) unless the ICD delivered a shock. In that case, the patient was invited to contact the hospital for a visit as soon as possible and data were retrieved by the ICD. It is authors' opinion that the frequent follow-up could be sufficient to

This study examines the differences between CAD and non-ischemic DCM patients with ICD. Our results show that patients with DCM exhibit a significantly higher prevalence of VT episodes (p<0.02) and a significantly greater variability in the VT initiation pattern (p<0.01). The circadian distribution (in a 3 –hour period analysis) of the VT-onset is also different in the two groups: CAD patients exhibit a morning peak: between 9 and 12 a.m. and an afternoon peak (around 6 p.m.), whereas DCM patients show a more uniform

Eventually, no significant differences between CAD and DCM are observed from the analysis of VT-rate, coupling interval, prematurity index. Likewise, the analysis of the EGM signal during the 20 seconds immediately preceding VT onset show no significant

This study (based on characterization of EGM, VT-onset and VT circadian distribution) does not define a relationship between observed CAD-DCM differences and underlying CAD-DCM electrogenetic-mechanisms. Nevertheless, our findings suggest different foundations

Anand K, Aryana A, Cloutier D. (2007) Circadian, daily, and seasonal distributions of

Carson PA, O'Connor CM, Miller AB, Anderson S, Belkin R, Neuberg GW et al. (2000)

Randomized Amlodipine Survival Trial. J Am Coll Cardiol; 36:541-546. Casaleggio A, Rossi P, V Malavasi V, Musso G, Oltrona L. (2008) "Differences between

Dilated Cardiomyopathy." Computers in Cardiology 2008, 35:913-916. Casaleggio A, Rossi P, Faini A, Guidotto T, Malavasi V, Musso G et al. (2006) Analysis of

Electrical Activity Characterization. Med Biol Eng Comput; 44:45-53. Chung MK, Pogwizd SM, Miller DP, Cain ME. (1997) Three-Dimensional Mapping of

ventricular tachyarrhythmias in patients with implantable cardioverter-

Circadian Rhythm and Sudden Death in Heart Failure. Results from Prospective

Ventricular Tachyarrhythmias for Patients with Coronary Artery Disease and

Implantable Cardioverter Defibrillator Signals for Non Conventional Cardiac

Initiation of Nonsustained Ventricular tachycardia in the Human Heart.

Dorian P. Antiarrhythmic Action of β-Blockers: Potential Mechanisms. (2005) J Cardiovasc

distribution during waking hours and very few episodes during the night.

defibrillators. Am J Cardiol; 100:1134-1138.

Pharmacol Therapeut 10(Supplement I):S15–S22.

Circulation; 95: 2517-2527.

differences in the heart-cycle, prevalence of PVC, nor prevalence of paced beats.

of VT initiation in patients with ischemic versus idiopathic dilated cardiomyopathy.

minimize the number of undetected VT episodes.

**5. Conclusion**

**6. References**

**Part 2**

**Prediction, Prevention, and Management**

**of Cardiovascular Events**

### **Part 2**

### **Prediction, Prevention, and Management of Cardiovascular Events**

Cardiac Defibrillation

66 – Prediction, Prevention and Management of Cardiovascular Arrhythmic Events

Taylor E, Berger R, Hummel JD, Dinerman JL, Kenknight B, Arria AM et al. (2000) Analysis

Vlay LC, Vlay SC. (1997) Pacing induced ventricular fibrillation in internal cardioverter

implantable defibrillators. J Cardiovasc. Electrophysiol 11:719-726.

20:132-133

of the pattern of initiation of sustained ventricular arrhythmias in patients with

defibrillator patients: a new form of proarrhythmia. Pacing Clin Electrophysiol

**5**

*Norway*

**Prediction of Ventricular Arrhythmias in**

*Oslo University Hospital, Rikshospitalet, Oslo and University of Oslo,*

K.H. Haugaa, J.P. Amlie and T. Edvardsen

**Patients at Risk of Sudden Cardiac Death**

Sudden cardiac deaths remain the major cause of mortality in the western world. Ventricular arrhythmia due to ischemic heart disease is the most frequent cause of sudden cardiac death. In patients >35 years of age, ischemic heart disease is the most frequent cause of ventricular arrhythmias. In patients <35 years of age, inherited cardiac diseases play a significant role in sudden cardiac death. Prediction of who will experience a life-threatening

An implantable cardioverter defibrillator (ICD) provides efficient preventive treatment for ventricular arrhythmias and sudden death and is implanted in patients at risk. However, risk stratification of ventricular arrhythmias is insufficient and the majority of patients dying

Patients after myocardial infarction are at high risk for cardiac arrhythmic events and sudden cardiac death (Zipes, 2006). Currently, LV ejection fraction (EF) is the primary parameter used to select patients for ICD therapy after a myocardial infarction. Impaired EF is shown to be a marker of increased cardiovascular mortality and sudden cardiac death. However, EF has relatively low sensitivity to detect arrhythmic risk (Buxton, 2007). A number of other diagnostic tests have been proposed to improve the accuracy for selection of patients for ICD therapy. Currently available data, however, are not adequate to routinely recommend additional risk-stratification methods for selection of patients for ICD therapy (Passman, 2007). The presence of myocardial scar forms the substrate for malignant arrhythmias (Zipes, 1998). Heterogeneity in scar tissue may create areas of slow conduction that generate the substrate for ventricular arrhythmia post-myocardial infarction (Verma, 2005). Electrical dispersion, including both activation time and refractoriness, in infarcted tissue is a known arrhythmogenic factor, (Endresen, 1987; Han, 1964; Janse, 1989; Vassallo, 1988). Electrical abnormalities may lead to distorted myocardial function (Nagueh, 2008). Therefore, regional differences in electrical properties may cause heterogeneity of myocardial contraction which

In this report, a novel echocardiographic method will be presented in order to evaluate the cardiac contractility pattern in patients at increased risk of life-threatening arrhythmias.

Better echocardiographic tools for more accurate assessment of ventricular function have been developed during the last 2 decades. Minor degrees of myocardial contraction

ventricular arrhythmia is a major challenge in current cardiology.

suddenly have not been evaluated for ICD therapy.

can be recognized as myocardial dyssynchrony (Yu, 2003).

**2. Modern echocardiographic modalities**

**1. Introduction**

### **Prediction of Ventricular Arrhythmias in Patients at Risk of Sudden Cardiac Death**

K.H. Haugaa, J.P. Amlie and T. Edvardsen *Oslo University Hospital, Rikshospitalet, Oslo and University of Oslo, Norway*

#### **1. Introduction**

Sudden cardiac deaths remain the major cause of mortality in the western world. Ventricular arrhythmia due to ischemic heart disease is the most frequent cause of sudden cardiac death. In patients >35 years of age, ischemic heart disease is the most frequent cause of ventricular arrhythmias. In patients <35 years of age, inherited cardiac diseases play a significant role in sudden cardiac death. Prediction of who will experience a life-threatening ventricular arrhythmia is a major challenge in current cardiology.

An implantable cardioverter defibrillator (ICD) provides efficient preventive treatment for ventricular arrhythmias and sudden death and is implanted in patients at risk. However, risk stratification of ventricular arrhythmias is insufficient and the majority of patients dying suddenly have not been evaluated for ICD therapy.

Patients after myocardial infarction are at high risk for cardiac arrhythmic events and sudden cardiac death (Zipes, 2006). Currently, LV ejection fraction (EF) is the primary parameter used to select patients for ICD therapy after a myocardial infarction. Impaired EF is shown to be a marker of increased cardiovascular mortality and sudden cardiac death. However, EF has relatively low sensitivity to detect arrhythmic risk (Buxton, 2007). A number of other diagnostic tests have been proposed to improve the accuracy for selection of patients for ICD therapy. Currently available data, however, are not adequate to routinely recommend additional risk-stratification methods for selection of patients for ICD therapy (Passman, 2007). The presence of myocardial scar forms the substrate for malignant arrhythmias (Zipes, 1998). Heterogeneity in scar tissue may create areas of slow conduction that generate the substrate for ventricular arrhythmia post-myocardial infarction (Verma, 2005). Electrical dispersion, including both activation time and refractoriness, in infarcted tissue is a known arrhythmogenic factor, (Endresen, 1987; Han, 1964; Janse, 1989; Vassallo, 1988). Electrical abnormalities may lead to distorted myocardial function (Nagueh, 2008). Therefore, regional differences in electrical properties may cause heterogeneity of myocardial contraction which can be recognized as myocardial dyssynchrony (Yu, 2003).

In this report, a novel echocardiographic method will be presented in order to evaluate the cardiac contractility pattern in patients at increased risk of life-threatening arrhythmias.

#### **2. Modern echocardiographic modalities**

Better echocardiographic tools for more accurate assessment of ventricular function have been developed during the last 2 decades. Minor degrees of myocardial contraction

Prediction of Ventricular Arrhythmias in Patients at Risk of Sudden Cardiac Death 71

arrhythmias that required appropriate anti tachycardia pacing or shock from the ICD, were recorded. During 2.3 years of follow up, 45% of the ICD patients experienced one or more episodes with sustained ventricular tachycardia or ventricular fibrillation requiring appropriate ICD therapy (anti tachycardia pacing or shock) while 55% had no sustained

Speckle tracking technique by strain echocardiography was used to assess the contraction duration in each of the 16 left ventricular segments (Figure 1). Mechanical dispersion was calculated as the standard deviation from contraction durations the 16 left ventricular segments. Global left ventricular strain was obtained by averaging all segmental values for

Fig. 1. Speckle tracking longitudinal strain curves from 6 segments in apical 4 chamber view from a healthy individual with synchronous ECG recording below. Segment contraction (shortening) starts during QRS and reaches a maximum myocardial shortening (white vertical arrow) at the end of the ECG T-wave. (Modified from *JACC Cardiovasc Imaging* 2010

The study showed that mechanical dispersion was significantly more pronounced in those with arrhythmias compared to those without (Fig 2). Furthermore, mechanical dispersion

Survival analyses showed that ICD patients with mechanical dispersion > 70ms showed

was a strong and independent predictor of arrhythmias requiring ICD therapy.

more frequent arrhythmic events than ICD patients with dispersion < 70ms (Fig 3).

arrhythmia during follow up.

March;**3**(3):247-56).

maximum shortening in a 16 segment model.

heterogeneity and contraction dyssynchrony can be demonstrated by these modern echocardiographic techniques (Reisner, 2004; Yu, 2007). One way to discover subtle wall motion abnormalities caused by electrical heterogeneity would be to use strain echocardiography (Edvardsen, 2002b). The introduction of strain echocardiography has made it possible to accurately perform quantitative and objective measures of regional ventricular function by measuring regional contraction by strain. Strain can accurately quantify timing and deformation of regional myocardial function (Edvardsen, 2002a; Reisner, 2004; Voigt, 2003).

Currently, visual assessment of regional myocardial function from 2-D image is the standard echocardiographic method to assess ventricular function in daily clinical practice. Visual assessment has had that position since the introduction of 2-D echocardiography. This method has also been established as a clinically important tool in detecting regional ventricular function, but has limited ability to detect more subtle changes in function and changes in timing of myocardial motion throughout systole and diastole. Strain echocardiographic technique may be used to accurately assess timing and function of myocardial contraction in patients with increased risk of ventricular arrhythmias. The hypotheses that echocardiography can contribute to arrhythmic risk assessment is based on the assumption that arrhythmogenic electrical abnormalities will lead to mechanical alterations which can be assessed by strain echocardiography.

#### **2.1 Use of strain echocardiography for prediction of ventricular arrhythmias**

We have recently reported that strain echocardiography can be used as a novel risk predictor of ventricular arrhythmias in patients with the long QT syndrome (Haugaa, 2009; Haugaa, 2010a). The long QT syndrome has traditionally been regarded as a purely electrical disease. Sporadic reports have indicated, however, that the electrical alterations may lead to mechanical consequences (De Ferrari, 2009; Nador, 1991). In our publications, we could show by modern echocardiographic techniques that subtle contraction heterogeneity was present in patients with the long QT syndrome, possibly due to electrical abnormalities. Therefore, these echocardiographic techniques were able to detect subtle changes in myocardial function. Furthermore, we could associate mechanical dispersion to ventricular arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy (Sarvari, 2011). Contraction heterogeneity defined as mechanical dispersion was a marker of arrhythmias in these patients and could help risk stratification of arrhythmias in so far asymptomatic mutation carriers. In a recent paper, we investigated if contraction heterogeneity due to fibrosis in infarcted myocardial tissue leads to mechanical dispersion in patients after myocardial infarction (Haugaa, 2010b). These results are briefly presented below. We presumed that the mechanical dispersion reflected electrical heterogeneity. We investigated if mechanical dispersion can predict ventricular arrhythmias in patients with risk of ventricular arrhythmias. Furthermore, we investigated if global strain by echocardiography is a better marker of arrhythmias than EF in patients after myocardial infarction.

#### **3. Study of 85 post MI patients with an ICD**

We prospectively investigated 85 post-MI patients fulfilling indications for ICD therapy. All patients had prior myocardial infarction and indication for ICD therapy according to primary or secondary prevention criteria. Arrhythmic events, defined as ventricular

70 – Prediction, Prevention and Management of Cardiovascular Arrhythmic Events

heterogeneity and contraction dyssynchrony can be demonstrated by these modern echocardiographic techniques (Reisner, 2004; Yu, 2007). One way to discover subtle wall motion abnormalities caused by electrical heterogeneity would be to use strain echocardiography (Edvardsen, 2002b). The introduction of strain echocardiography has made it possible to accurately perform quantitative and objective measures of regional ventricular function by measuring regional contraction by strain. Strain can accurately quantify timing and deformation of regional myocardial function (Edvardsen, 2002a;

Currently, visual assessment of regional myocardial function from 2-D image is the standard echocardiographic method to assess ventricular function in daily clinical practice. Visual assessment has had that position since the introduction of 2-D echocardiography. This method has also been established as a clinically important tool in detecting regional ventricular function, but has limited ability to detect more subtle changes in function and changes in timing of myocardial motion throughout systole and diastole. Strain echocardiographic technique may be used to accurately assess timing and function of myocardial contraction in patients with increased risk of ventricular arrhythmias. The hypotheses that echocardiography can contribute to arrhythmic risk assessment is based on the assumption that arrhythmogenic electrical abnormalities will lead to mechanical

alterations which can be assessed by strain echocardiography.

**3. Study of 85 post MI patients with an ICD**

**2.1 Use of strain echocardiography for prediction of ventricular arrhythmias**

We have recently reported that strain echocardiography can be used as a novel risk predictor of ventricular arrhythmias in patients with the long QT syndrome (Haugaa, 2009; Haugaa, 2010a). The long QT syndrome has traditionally been regarded as a purely electrical disease. Sporadic reports have indicated, however, that the electrical alterations may lead to mechanical consequences (De Ferrari, 2009; Nador, 1991). In our publications, we could show by modern echocardiographic techniques that subtle contraction heterogeneity was present in patients with the long QT syndrome, possibly due to electrical abnormalities. Therefore, these echocardiographic techniques were able to detect subtle changes in myocardial function. Furthermore, we could associate mechanical dispersion to ventricular arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy (Sarvari, 2011). Contraction heterogeneity defined as mechanical dispersion was a marker of arrhythmias in these patients and could help risk stratification of arrhythmias in so far asymptomatic mutation carriers. In a recent paper, we investigated if contraction heterogeneity due to fibrosis in infarcted myocardial tissue leads to mechanical dispersion in patients after myocardial infarction (Haugaa, 2010b). These results are briefly presented below. We presumed that the mechanical dispersion reflected electrical heterogeneity. We investigated if mechanical dispersion can predict ventricular arrhythmias in patients with risk of ventricular arrhythmias. Furthermore, we investigated if global strain by echocardiography is a better marker of arrhythmias than EF in patients after myocardial

We prospectively investigated 85 post-MI patients fulfilling indications for ICD therapy. All patients had prior myocardial infarction and indication for ICD therapy according to primary or secondary prevention criteria. Arrhythmic events, defined as ventricular

Reisner, 2004; Voigt, 2003).

infarction.

arrhythmias that required appropriate anti tachycardia pacing or shock from the ICD, were recorded. During 2.3 years of follow up, 45% of the ICD patients experienced one or more episodes with sustained ventricular tachycardia or ventricular fibrillation requiring appropriate ICD therapy (anti tachycardia pacing or shock) while 55% had no sustained arrhythmia during follow up.

Speckle tracking technique by strain echocardiography was used to assess the contraction duration in each of the 16 left ventricular segments (Figure 1). Mechanical dispersion was calculated as the standard deviation from contraction durations the 16 left ventricular segments. Global left ventricular strain was obtained by averaging all segmental values for maximum shortening in a 16 segment model.

Fig. 1. Speckle tracking longitudinal strain curves from 6 segments in apical 4 chamber view from a healthy individual with synchronous ECG recording below. Segment contraction (shortening) starts during QRS and reaches a maximum myocardial shortening (white vertical arrow) at the end of the ECG T-wave. (Modified from *JACC Cardiovasc Imaging* 2010 March;**3**(3):247-56).

The study showed that mechanical dispersion was significantly more pronounced in those with arrhythmias compared to those without (Fig 2). Furthermore, mechanical dispersion was a strong and independent predictor of arrhythmias requiring ICD therapy. Survival analyses showed that ICD patients with mechanical dispersion > 70ms showed more frequent arrhythmic events than ICD patients with dispersion < 70ms (Fig 3).

Prediction of Ventricular Arrhythmias in Patients at Risk of Sudden Cardiac Death 73

In ICD patients with EF > 35%, mechanical dispersion was more pronounced in those who experienced arrhythmia compared to those without. Global strain showed better left

The results of the study showed that increased heterogeneity of myocardial contraction measured by strain echocardiography predicted cardiac arrhythmias better than current risk stratification tools. This novel method may improve risk stratification of cardiac arrhythmias

There is ample evidence from different cardiac disease models, including heart failure (Tomaselli, 2004), ischemia (Han, 1964) and infarction (Spragg, 2005; Vassallo, 1988) that increases in dispersion of conduction velocity result in susceptibility to arrhythmias (Spragg, 2005; Tomaselli, 2004). These electrical abnormalities will presumptively lead to changes in myocardial function. Assessing the extent of electrical dispersion in the individual patient has so far been difficult (Tomaselli, 2004). These findings support the idea that tissue heterogeneity in and around scarred myocardium lead to a dispersed myocardial

Earlier echocardiographic studies have observed that an EF of 40% serves as the threshold for identifying high-risk individuals (Bigger, Jr., 1984; Greenberg, 1984). However, EF has reduced sensitivity in predicting sudden death (Buxton, 2007; Stecker, 2006). Speckle based strain has shown to be a robust technique for assessment of LV function and a recent study has demonstrated that speckle tracking strain is superior to EF for assessment of myocardial function post-myocardial infarction (Gjesdal, 2008). Global strain discriminated between those with and without arrhythmic events in post-MI patients with EF > 35%. This finding suggests that global strain might become a useful tool for risk stratification in postmyocardial infarction patients with relatively preserved LV function. Future trials should investigate if mechanical dispersion and global strain can be used to select additional patients for ICD therapy among the majority of patients after myocardial infarction with

Arrhythmogenic right ventricular cardiomyopathy is an inheritable, chronic and progressive cardiomyopathy and is one of the leading causes of sudden unexpected cardiac death in previously healthy young individuals (Sen-Chowdhry, 2010a; Thiene, 1988).

Recent molecular genetic reports have revealed arrhythmogenic right ventricular cardiomyopathy as mainly a desmosomal disease (Xu, 2010). Mutations in one of the 5 desmosomal or 3 extra desmosomal genes so far identified, lead to progressive loss of myocytes, followed by fibro-fatty replacement. Penetrance is age and gender dependent and

Four clinical stages have been documented: An early concealed phase, overt electrical disorder, isolated right heart failure (Fig 4a), and biventricular pump failure (Fig 4b) (Basso, 1996; Sen-Chowdhry, 2007; Sen-Chowdhry, 2010a). Importantly, life-threatening arrhythmias can occur with only discrete or even absent myocardial structural changes (Sen-

ventricular function in those without recorded arrhythmias, while EF did not differ.

and help the clinician to select patients for ICD therapy.

contraction and is associated with risk of arrhythmic events.

relatively preserved EF in whom current ICD indications fail.

**arrhythmogenic right ventricular cardiomyopathy**

the progressive clinical picture is highly variable (Dalal, 2006).

**5. Risk assessment of ventricular arrhythmias in patients with**

Prevalence has been estimated to be at least 1 in 1000 (Sen-Chowdhry, 2010a).

**4. Electromechanical interactions**

Fig. 2. Strain curves from a healthy individual (left panel), a post MI patient with arrhythmias (mid panel) and a post MI patient with recurrent arrhythmias (right panel). White arrows indicate timing of maximum myocardial shortening. The post MI patient with recurrent arrhythmias (right panel) has the most dispersed timing in myocardial contraction and thereby most pronounced mechanical dispersion. (Modified from *JACC Cardiovasc Imaging* 2010 March;**3**(3):247-56).

Fig. 3. Kaplan Meier analyses of 85 patients after myocardial infarction with ICD. Patients with mechanical dispersion > 70 ms have higher rate of arrhythmic events during follow up compared to patients with mechanical dispersion < 70 ms. (Modified from *JACC Cardiovasc Imaging* 2010 March;**3**(3):247-56).

In ICD patients with EF > 35%, mechanical dispersion was more pronounced in those who experienced arrhythmia compared to those without. Global strain showed better left ventricular function in those without recorded arrhythmias, while EF did not differ.

The results of the study showed that increased heterogeneity of myocardial contraction measured by strain echocardiography predicted cardiac arrhythmias better than current risk stratification tools. This novel method may improve risk stratification of cardiac arrhythmias and help the clinician to select patients for ICD therapy.

#### **4. Electromechanical interactions**

Cardiac Defibrillation

72 – Prediction, Prevention and Management of Cardiovascular Arrhythmic Events

Fig. 2. Strain curves from a healthy individual (left panel), a post MI patient with arrhythmias (mid panel) and a post MI patient with recurrent arrhythmias (right panel). White arrows indicate timing of maximum myocardial shortening. The post MI patient with recurrent arrhythmias (right panel) has the most dispersed timing in myocardial contraction and thereby most pronounced mechanical dispersion. (Modified from *JACC Cardiovasc*

Fig. 3. Kaplan Meier analyses of 85 patients after myocardial infarction with ICD.

*Cardiovasc Imaging* 2010 March;**3**(3):247-56).

Patients with mechanical dispersion > 70 ms have higher rate of arrhythmic events during follow up compared to patients with mechanical dispersion < 70 ms. (Modified from *JACC*

*Imaging* 2010 March;**3**(3):247-56).

There is ample evidence from different cardiac disease models, including heart failure (Tomaselli, 2004), ischemia (Han, 1964) and infarction (Spragg, 2005; Vassallo, 1988) that increases in dispersion of conduction velocity result in susceptibility to arrhythmias (Spragg, 2005; Tomaselli, 2004). These electrical abnormalities will presumptively lead to changes in myocardial function. Assessing the extent of electrical dispersion in the individual patient has so far been difficult (Tomaselli, 2004). These findings support the idea that tissue heterogeneity in and around scarred myocardium lead to a dispersed myocardial contraction and is associated with risk of arrhythmic events.

Earlier echocardiographic studies have observed that an EF of 40% serves as the threshold for identifying high-risk individuals (Bigger, Jr., 1984; Greenberg, 1984). However, EF has reduced sensitivity in predicting sudden death (Buxton, 2007; Stecker, 2006). Speckle based strain has shown to be a robust technique for assessment of LV function and a recent study has demonstrated that speckle tracking strain is superior to EF for assessment of myocardial function post-myocardial infarction (Gjesdal, 2008). Global strain discriminated between those with and without arrhythmic events in post-MI patients with EF > 35%. This finding suggests that global strain might become a useful tool for risk stratification in postmyocardial infarction patients with relatively preserved LV function. Future trials should investigate if mechanical dispersion and global strain can be used to select additional patients for ICD therapy among the majority of patients after myocardial infarction with relatively preserved EF in whom current ICD indications fail.

#### **5. Risk assessment of ventricular arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy**

Arrhythmogenic right ventricular cardiomyopathy is an inheritable, chronic and progressive cardiomyopathy and is one of the leading causes of sudden unexpected cardiac death in previously healthy young individuals (Sen-Chowdhry, 2010a; Thiene, 1988). Prevalence has been estimated to be at least 1 in 1000 (Sen-Chowdhry, 2010a).

Recent molecular genetic reports have revealed arrhythmogenic right ventricular cardiomyopathy as mainly a desmosomal disease (Xu, 2010). Mutations in one of the 5 desmosomal or 3 extra desmosomal genes so far identified, lead to progressive loss of myocytes, followed by fibro-fatty replacement. Penetrance is age and gender dependent and the progressive clinical picture is highly variable (Dalal, 2006).

Four clinical stages have been documented: An early concealed phase, overt electrical disorder, isolated right heart failure (Fig 4a), and biventricular pump failure (Fig 4b) (Basso, 1996; Sen-Chowdhry, 2007; Sen-Chowdhry, 2010a). Importantly, life-threatening arrhythmias can occur with only discrete or even absent myocardial structural changes (Sen-

Prediction of Ventricular Arrhythmias in Patients at Risk of Sudden Cardiac Death 75

(Sarvari, 2011). Furthermore, we investigated if mechanical dispersion was present in arrhythmogenic right ventricular cardiomyopathy mutation carriers in early stages of the

Mechanical dispersion and strain in right and left ventricle were assessed in 36 arrhythmogenic right ventricular cardiomyopathy patients, in 23 asymptomatic arrhythmogenic right ventricular cardiomyopathy mutation carriers and in 30 healthy individuals. All 36 arrhythmogenic right ventricular cardiomyopathy patients had experienced ventricular arrhythmias either as aborted cardiac arrest or as documented sustained ventricular tachycardia and fulfilled 2010 International Task Force criteria (Marcus, 2010). They were treated with ICD in addition to medical anti arrhythmic therapy. The 23 asymptomatic mutation carriers were family members of the arrhythmogenic right ventricular cardiomyopathy patients and were diagnosed by cascade genetic screening. Peak systolic myocardial strain by 2D speckle tracking echocardiography was assessed in 16 left ventricular segments and averaged to left ventricular global longitudinal strain in arrhythmogenic right ventricular cardiomyopathy patients. Additionally, peak systolic strain from 3 right ventricular free wall segments was averaged as a measure of right ventricular function (RV strain) (Fig 5). Contraction duration was measured as time from onset R on ECG to maximum LV and right ventricular shortening by strain. Standard deviation of contraction duration was calculated as mechanical dispersion, in a 16 left

Fig. 5. Strain curves in an patient with arrhythmogenic right ventricular cardiomyopathy. Strain curves from a dilated right ventricle from apical 4 chamber view. Vertical arrows indicate the timing of maximum myocardial shortening in each right ventricular segment

and are consistent with pronounced right ventricular mechanical dispersion.

disease where no structural alterations were visible.

ventricular segments and a 6 right ventricular segments model.

Chowdhry, 2010b). Risk stratification of ventricular arrhythmias and sudden cardiac death is therefore challenging.

Fig. 4. Echocardiographic pictures of 2 patients with arrhythmogenic right ventricular cardiomyopathy.

A) left panel: classical right sided affection with dilatation (5 cm diameter, white arrow) and wall thinning of the right ventricle. The ICD lead is visible in the right ventricle. B) right panel: Affection of both right and left ventricle in a patient with arrhythmogenic right ventricular cardiomyopathy. The right ventricle is dilated and with visible ICD lead. Furthermore, the left ventricle is dilated and shows apical affection of the myocardial wall (arrow).

Mechanisms of arrhythmias in early stages of arrhythmogenic right ventricular cardiomyopathy are probably due to dysfunction of desmosomal proteins and disturbed cell to cell coupling (Saffitz, 2009). In later stages of arrhythmogenic right ventricular cardiomyopathy when structural abnormalities in the myocardium have developed, reentrant ventricular arrhythmias can occur in tissue with fibro fatty replacement. Therefore, electrical conduction delay with consequent electrical dispersion has been suggested as an important mechanism of ventricular arrhythmias (Amlie, 1997; Turrini, 2001).

In a recent study we investigated if arrhythmogenic right ventricular cardiomyopathy patients had cardiac contraction heterogeneity assessed as mechanical dispersion and if contraction heterogeneity was associated with susceptibility to ventricular arrhythmias

74 – Prediction, Prevention and Management of Cardiovascular Arrhythmic Events

Chowdhry, 2010b). Risk stratification of ventricular arrhythmias and sudden cardiac death

Fig. 4. Echocardiographic pictures of 2 patients with arrhythmogenic right ventricular

wall thinning of the right ventricle. The ICD lead is visible in the right ventricle.

important mechanism of ventricular arrhythmias (Amlie, 1997; Turrini, 2001).

A) left panel: classical right sided affection with dilatation (5 cm diameter, white arrow) and

Mechanisms of arrhythmias in early stages of arrhythmogenic right ventricular cardiomyopathy are probably due to dysfunction of desmosomal proteins and disturbed cell to cell coupling (Saffitz, 2009). In later stages of arrhythmogenic right ventricular cardiomyopathy when structural abnormalities in the myocardium have developed, reentrant ventricular arrhythmias can occur in tissue with fibro fatty replacement. Therefore, electrical conduction delay with consequent electrical dispersion has been suggested as an

In a recent study we investigated if arrhythmogenic right ventricular cardiomyopathy patients had cardiac contraction heterogeneity assessed as mechanical dispersion and if contraction heterogeneity was associated with susceptibility to ventricular arrhythmias

B) right panel: Affection of both right and left ventricle in a patient with arrhythmogenic right ventricular cardiomyopathy. The right ventricle is dilated and with visible ICD lead. Furthermore, the left ventricle is dilated and shows apical affection of the myocardial wall

is therefore challenging.

cardiomyopathy.

(arrow).

(Sarvari, 2011). Furthermore, we investigated if mechanical dispersion was present in arrhythmogenic right ventricular cardiomyopathy mutation carriers in early stages of the disease where no structural alterations were visible.

Mechanical dispersion and strain in right and left ventricle were assessed in 36 arrhythmogenic right ventricular cardiomyopathy patients, in 23 asymptomatic arrhythmogenic right ventricular cardiomyopathy mutation carriers and in 30 healthy individuals. All 36 arrhythmogenic right ventricular cardiomyopathy patients had experienced ventricular arrhythmias either as aborted cardiac arrest or as documented sustained ventricular tachycardia and fulfilled 2010 International Task Force criteria (Marcus, 2010). They were treated with ICD in addition to medical anti arrhythmic therapy. The 23 asymptomatic mutation carriers were family members of the arrhythmogenic right ventricular cardiomyopathy patients and were diagnosed by cascade genetic screening.

Peak systolic myocardial strain by 2D speckle tracking echocardiography was assessed in 16 left ventricular segments and averaged to left ventricular global longitudinal strain in arrhythmogenic right ventricular cardiomyopathy patients. Additionally, peak systolic strain from 3 right ventricular free wall segments was averaged as a measure of right ventricular function (RV strain) (Fig 5). Contraction duration was measured as time from onset R on ECG to maximum LV and right ventricular shortening by strain. Standard deviation of contraction duration was calculated as mechanical dispersion, in a 16 left ventricular segments and a 6 right ventricular segments model.

Fig. 5. Strain curves in an patient with arrhythmogenic right ventricular cardiomyopathy. Strain curves from a dilated right ventricle from apical 4 chamber view. Vertical arrows indicate the timing of maximum myocardial shortening in each right ventricular segment and are consistent with pronounced right ventricular mechanical dispersion.

Prediction of Ventricular Arrhythmias in Patients at Risk of Sudden Cardiac Death 77

cardiomyopathy mutation carriers. Mechanical dispersion and myocardial strains demonstrated subclinical myocardial involvement in these individuals. Longitudinal follow up studies are required to assess if these methods can provide added value in arrhythmia risk stratification in asymptomatic arrhythmogenic right ventricular

Furthermore, this paper demonstrated frequent and early left ventricular involvement in arrhythmogenic right ventricular cardiomyopathy which supported recent reports of arrhythmogenic right ventricular cardiomyopathy as a biventricular disease (Kjaergaard, 2007). Biventricular impairment is probably a result of biventricular arrhythmogenic right ventricular cardiomyopathy affection, but mutual dependency of right and left ventricular hemodynamics may be considered. In patients with overt arrhythmogenic right ventricular cardiomyopathy, strain echocardiography may be a useful tool for quantification of right

**6. Comparisons of mechanical dispersion in patients after myocardial**

Mechanical dispersion has been demonstrated in arrhythmogenic right ventricular cardiomyopathy patients and in post-myocardial infarction patients and has been shown to be a marker of recurrent ventricular arrhythmias in both conditions. The mechanisms for arrhythmias in arrhythmogenic right ventricular cardiomyopathy and in infarcted myocardial tissue are different, but have similarities regarding electrical dispersion. In arrhythmogenic right ventricular cardiomyopathy patients, mechanisms of arrhythmias are probably stage dependent, but electrical dispersion has been considered to be of importance in early and later stages of the disease (Amlie, 1997; Turrini, 2001). In post-MI patients delayed start of ventricular activation in scarred myocardium leads to a dispersed recovery of excitability (Vassallo, 1988), finally resulting in dispersed electrical repolarization. One might therefore speculate that electrical dispersion may be regarded as the final common

The extent of mechanical dispersion appeared most pronounced in post-myocardial infarction patients. This difference was probably a result of the concomitant contractile impairment in infarcted tissue which was more pronounced compared to presence of fibrosis in arrhythmogenic right ventricular cardiomyopathy. Myocardial function was significantly impaired in post-myocardial infarction patients compared to arrhythmogenic right ventricular cardiomyopathy patients. Contractile impairment will pronounce mechanical dispersion. The ranges and values of mechanical dispersion which are related to increased arrhythmic risk will therefore not necessarily be interchangeable between

**7. Future risk assessment of ventricular arrhythmias and additional patient**

The most important patient group for further risk assessment of ventricular arrhythmias are patients after myocardial infarction representing the largest cohort of individuals at risk. Future trials should investigate if mechanical dispersion and global strain can be used to select additional patients for ICD therapy among the majority of post-myocardial infarction

**infarction and in patients with arrhythmogenic right ventricular**

cardiomyopathy mutation carriers.

and left sided myocardial dysfunction.

pathway of arrhythmia mechanism in both conditions.

different myocardial diseases.

**entities**

**cardiomyopathy**

Mechanical dispersion was more pronounced in arrhythmogenic right ventricular cardiomyopathy patients with arrhythmias in right and left ventricle compared to asymptomatic mutation carriers and healthy individuals (Table 1). Importantly, mechanical dispersion was more pronounced in asymptomatic mutation carriers compared to healthy individuals in both right and left ventricle, indicating sub clinical ventricular involvement. Right and left ventricular strains were reduced in arrhythmogenic right ventricular cardiomyopathy patients compared to asymptomatic mutation carriers and healthy individuals (Table 1). Reduced right and left ventricular strains were significantly correlated in arrhythmogenic right ventricular cardiomyopathy patients, indicating biventricular disease. Right and left ventricular function in asymptomatic mutation carriers were within normal range, but significantly reduced compared to healthy individuals.

Table 1. Echocardiographic results in 36 ARVC patients, 23 asymptomatic ARVC mutation carriers and 30 healthy individuals.

Mean±SD. Right column shows P-values for ANOVA test. Flags for significance are obtained from the post hoc pair-wise comparison using the Bonferroni correction. \*p<0.05 compared with healthy individuals. \*\*p<0.01 compared with asymptomatic mutation carriers. ANOVA, analysis of variance; EF, ejection fraction; RV, right ventricular; LV, left ventricular.

Risk stratification of ventricular arrhythmias in so far asymptomatic arrhythmogenic right ventricular cardiomyopathy mutation carriers is difficult. This report demonstrated that mechanical dispersion was closely related to ventricular arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy. Increased mechanical dispersion in both ventricles was present in asymptomatic mutation carriers, indicating sub clinical myocardial alterations. Importantly, pronounced mechanical dispersion was also present in individuals who had experienced arrhythmias in the early stages of arrhythmogenic right ventricular cardiomyopathy and in whom no structural alterations assessed by conventional echocardiography and magnetic resonance imaging could be assessed. These findings suggest that mechanical dispersion may be a marker of arrhythmic events and help risk stratification in so far asymptomatic arrhythmogenic right ventricular

P

ARVC patients with arrhythmias (n=36)

76 – Prediction, Prevention and Management of Cardiovascular Arrhythmic Events

Mechanical dispersion was more pronounced in arrhythmogenic right ventricular cardiomyopathy patients with arrhythmias in right and left ventricle compared to asymptomatic mutation carriers and healthy individuals (Table 1). Importantly, mechanical dispersion was more pronounced in asymptomatic mutation carriers compared to healthy individuals in both right and left ventricle, indicating sub clinical ventricular involvement. Right and left ventricular strains were reduced in arrhythmogenic right ventricular cardiomyopathy patients compared to asymptomatic mutation carriers and healthy individuals (Table 1). Reduced right and left ventricular strains were significantly correlated in arrhythmogenic right ventricular cardiomyopathy patients, indicating biventricular disease. Right and left ventricular function in asymptomatic mutation carriers were within normal range, but significantly reduced

> Asymptomatic mutation carriers (n=23)

EF (%) 64±5 63±4 57±14\* <0.01

LV strain (%) -23±2 -20±2\* -16±5\*·\*\* <0.001

RV strain (%) -28±5 -24±5\* -19±7\*·\*\* <0.001

Table 1. Echocardiographic results in 36 ARVC patients, 23 asymptomatic ARVC mutation

Risk stratification of ventricular arrhythmias in so far asymptomatic arrhythmogenic right ventricular cardiomyopathy mutation carriers is difficult. This report demonstrated that mechanical dispersion was closely related to ventricular arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy. Increased mechanical dispersion in both ventricles was present in asymptomatic mutation carriers, indicating sub clinical myocardial alterations. Importantly, pronounced mechanical dispersion was also present in individuals who had experienced arrhythmias in the early stages of arrhythmogenic right ventricular cardiomyopathy and in whom no structural alterations assessed by conventional echocardiography and magnetic resonance imaging could be assessed. These findings suggest that mechanical dispersion may be a marker of arrhythmic events and help risk stratification in so far asymptomatic arrhythmogenic right ventricular

Mean±SD. Right column shows P-values for ANOVA test. Flags for significance are obtained from the post hoc pair-wise comparison using the Bonferroni correction. \*p<0.05 compared with healthy individuals. \*\*p<0.01 compared with asymptomatic mutation carriers. ANOVA, analysis of variance; EF, ejection fraction; RV, right ventricular; LV, left

22±8 42±13\* 64±25\*·\*\* <0.001

15±8 33±20\* 53±25\*·\*\* <0.001

compared to healthy individuals.

Healthy

carriers and 30 healthy individuals.

LV Dispersion

RV Dispersion

(ms)

(ms)

ventricular.

individuals (n=30)

cardiomyopathy mutation carriers. Mechanical dispersion and myocardial strains demonstrated subclinical myocardial involvement in these individuals. Longitudinal follow up studies are required to assess if these methods can provide added value in arrhythmia risk stratification in asymptomatic arrhythmogenic right ventricular cardiomyopathy mutation carriers.

Furthermore, this paper demonstrated frequent and early left ventricular involvement in arrhythmogenic right ventricular cardiomyopathy which supported recent reports of arrhythmogenic right ventricular cardiomyopathy as a biventricular disease (Kjaergaard, 2007). Biventricular impairment is probably a result of biventricular arrhythmogenic right ventricular cardiomyopathy affection, but mutual dependency of right and left ventricular hemodynamics may be considered. In patients with overt arrhythmogenic right ventricular cardiomyopathy, strain echocardiography may be a useful tool for quantification of right and left sided myocardial dysfunction.

#### **6. Comparisons of mechanical dispersion in patients after myocardial infarction and in patients with arrhythmogenic right ventricular cardiomyopathy**

Mechanical dispersion has been demonstrated in arrhythmogenic right ventricular cardiomyopathy patients and in post-myocardial infarction patients and has been shown to be a marker of recurrent ventricular arrhythmias in both conditions. The mechanisms for arrhythmias in arrhythmogenic right ventricular cardiomyopathy and in infarcted myocardial tissue are different, but have similarities regarding electrical dispersion. In arrhythmogenic right ventricular cardiomyopathy patients, mechanisms of arrhythmias are probably stage dependent, but electrical dispersion has been considered to be of importance in early and later stages of the disease (Amlie, 1997; Turrini, 2001). In post-MI patients delayed start of ventricular activation in scarred myocardium leads to a dispersed recovery of excitability (Vassallo, 1988), finally resulting in dispersed electrical repolarization. One might therefore speculate that electrical dispersion may be regarded as the final common pathway of arrhythmia mechanism in both conditions.

The extent of mechanical dispersion appeared most pronounced in post-myocardial infarction patients. This difference was probably a result of the concomitant contractile impairment in infarcted tissue which was more pronounced compared to presence of fibrosis in arrhythmogenic right ventricular cardiomyopathy. Myocardial function was significantly impaired in post-myocardial infarction patients compared to arrhythmogenic right ventricular cardiomyopathy patients. Contractile impairment will pronounce mechanical dispersion. The ranges and values of mechanical dispersion which are related to increased arrhythmic risk will therefore not necessarily be interchangeable between different myocardial diseases.

#### **7. Future risk assessment of ventricular arrhythmias and additional patient entities**

The most important patient group for further risk assessment of ventricular arrhythmias are patients after myocardial infarction representing the largest cohort of individuals at risk. Future trials should investigate if mechanical dispersion and global strain can be used to select additional patients for ICD therapy among the majority of post-myocardial infarction

Prediction of Ventricular Arrhythmias in Patients at Risk of Sudden Cardiac Death 79

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patients with relatively preserved EF in whom current ICD indications fail. Furthermore, there are several large groups of patients who are at risk of ventricular arrhythmias on a non-ischemic basis, i.e. patients with idiopathic dilated cardiomyopathies, other cardiomyopathies and patients with congenital heart disease. It is of great concern that EF is currently the only parameter to select patients with idiopathic dilated cardiomyopathy for ICD therapy. There is emerging awareness of the insufficiency of EF to predict ventricular arrhythmias in these patients and further risk stratification tools are urgently needed. Mechanical dispersion may reflect the electrical dispersion and represent a fundamental arrhythmogenic factor. Furthermore, mechanical dispersion has been shown to predict arrhythmias independently of EF. Mechanical dispersion may therefore have the potential to be introduced as an additional tool in arrhythmic risk stratification in other groups of patients.

#### **8. Conclusion**

In summary, mechanical dispersion has been shown to predict ventricular arrhythmias in post-myocardial infarction patients and in patients with arrhythmogenic right ventricular cardiomyopathy and the long QT syndrome. This principle may therefore be a valuable supplement in evaluating patients at risk independently of EF. Mechanical dispersion and global strain may be useful for including more patients for ICD therapy after myocardial infarction.

#### **9. References**

78 – Prediction, Prevention and Management of Cardiovascular Arrhythmic Events

patients with relatively preserved EF in whom current ICD indications fail. Furthermore, there are several large groups of patients who are at risk of ventricular arrhythmias on a non-ischemic basis, i.e. patients with idiopathic dilated cardiomyopathies, other cardiomyopathies and patients with congenital heart disease. It is of great concern that EF is currently the only parameter to select patients with idiopathic dilated cardiomyopathy for ICD therapy. There is emerging awareness of the insufficiency of EF to predict ventricular arrhythmias in these patients and further risk stratification tools are urgently needed. Mechanical dispersion may reflect the electrical dispersion and represent a fundamental arrhythmogenic factor. Furthermore, mechanical dispersion has been shown to predict arrhythmias independently of EF. Mechanical dispersion may therefore have the potential to be introduced as an additional tool in arrhythmic risk stratification in other groups of

In summary, mechanical dispersion has been shown to predict ventricular arrhythmias in post-myocardial infarction patients and in patients with arrhythmogenic right ventricular cardiomyopathy and the long QT syndrome. This principle may therefore be a valuable supplement in evaluating patients at risk independently of EF. Mechanical dispersion and global strain may be useful for including more patients for ICD therapy after myocardial

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**9. References**

1157.

**8. Conclusion**

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Prediction of Ventricular Arrhythmias in Patients at Risk of Sudden Cardiac Death 81

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Yu, CM, Sanderson, JE, Marwick, TH, & Oh, JK. (2007). Tissue Doppler imaging a new

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*Cardiovascular Electrophysiology,* Vol. 16, No. 5, pp. 465-471.

inducible ischemia*. Circulation,* Vol. 107, No. 16, pp. 2120-2126.

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Nonuniform recovery of excitability in the left ventricle*. Circulation,* Vol. 78, No. 6,

A, Bhargava, M, Burkhardt, JD, Kilicaslan, F, Martin, DO, & Natale, A. (2005). Relationship between successful ablation sites and the scar border zone defined by substrate mapping for ventricular tachycardia post-myocardial infarction*. Journal of*

Platsch, G, Kuwert, T, Daniel, WG, & Flachskampf, FA. (2003). Strain-rate imaging during dobutamine stress echocardiography provides objective evidence of

Kravitz, J, Zareba, W, Danieli, GA, Lorenzon, A, Nava, A, Bauce, B, Thiene, G, Basso, C, Calkins, H, Gear, K, Marcus, F, & Towbin, JA. (2010). Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy*. Journal of the American College of Cardiology,* Vol. 55, No. 6, pp. 587-

systolic and diastolic asynchrony in patients with congestive heart failure and

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Klein, G, Moss, AJ, Myerburg, RJ, Priori, SG, Quinones, MA, Roden, DM, Silka, MJ, Tracy, C, Smith, SC, Jr., Jacobs, AK, Adams, CD, Antman, EM, Anderson, JL, Hunt, SA, Halperin, JL, Nishimura, R, Ornato, JP, Page, RL, Riegel, B, Priori, SG, Blanc, JJ, Budaj, A, Camm, AJ, Dean, V, Deckers, JW, Despres, C, Dickstein, K, Lekakis, J, McGregor, K, Metra, M, Morais, J, Osterspey, A, Tamargo, JL, & Zamorano, JL. (2006). ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management

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80 – Prediction, Prevention and Management of Cardiovascular Arrhythmic Events

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**6**

*1,2,3Italy 3USA*

**Prevention of Sudden Death –**

Alfredo Zuppiroli2 and Gian Franco Gensini1 *1Heart and Vessels Department AOU Careggi, Florence*

*2Cardiology Department ASL 10, Florence*

*3MIT (USA), Finbest, Florence*

**Implantable Cardioverter Defibrillator**

Andrea Colella1, Marzia Giaccardi2, Antonella Sabatini3,

**and/or Ventricular Radiofrequency Ablation**

Sudden cardiac death (SCD) is defined as death from cardiac causes occurring unexpectedly within 1 hour of onset of symptoms. About 80% of SCDs are due to ventricular tachyarrhythmia that is, ventricular tachycardia and ventricular fibrillation. The remaining 20% consists of a number of conditions, including cardiomyopathies (10–15%), other structural heart defects (less than 5%) and bradycardia. SCD is responsible for more deaths than cancer, stroke, and AIDS combined (CDC, 2002). The overall incidence of SCD in the United States and Europe is 1 to 2 per 1000 people (0.1% to 0.2%) annually. Almost 80% of all SCDs occur at home. The 10%-25% survival rate is low and has not been improved by the automatic external defibrillator in patients with moderate risk (de Vreede-Swagemakers, 1997; Bardy, 2008; Myerburg, 2001). On the other hand, several clinical trials showed that the implantable cardioverter defibrillator (ICD) could prevent SCD and reduce overall mortality in some patients with severe left ventrocular dysfunction. For these reasons, ICD therapy has become the first choice strategy to prevent SCD from malignant ventricular tachyarrhythmia in high-risk patients. However, there are numerous well-recognized limitations to ICD therapy. These include the effects and the result of appropriate and inappropriate ICD shocks, the cost of the devices, complications related both to the implantation procedure and to subsequent device function, device malfunction, and restricted efficacy despite normal device function in presence of significant concomitant disease and in particular in presence of severe left ventricular disfunction. Several possible solutions have been proposed in the clinical practice, these include better patients' selection for ICD implantation, better ICD programmation, better medical therapy and arrhythmic substrate ablation. The role of catheter ablation of ventricular tachycardia in patients with structural heart disease has been increasing in the last 2 decades. The mechanisms of ventricular tachycardia are now clearer, and the electroanatomic mapping systems have made precise activation and substrate mapping more feasible; therefore, the potential for doing catheter ablation of ventricular tachycardia has increased dramatically in the past

**1. Introduction**

of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death)*. Journal of the American College of Cardiology,* Vol. 48, No. 5, pp. e247-e346.

Zipes, DP,Wellens, HJ. (1998). Sudden cardiac death*. Circulation,* Vol. 98, No. 21, pp. 2334- 2351.

### **Prevention of Sudden Death – Implantable Cardioverter Defibrillator and/or Ventricular Radiofrequency Ablation**

Andrea Colella1, Marzia Giaccardi2, Antonella Sabatini3, Alfredo Zuppiroli2 and Gian Franco Gensini1 *1Heart and Vessels Department AOU Careggi, Florence 2Cardiology Department ASL 10, Florence 3MIT (USA), Finbest, Florence 1,2,3Italy 3USA*

#### **1. Introduction**

Cardiac Defibrillation

82 – Prediction, Prevention and Management of Cardiovascular Arrhythmic Events

Zipes, DP,Wellens, HJ. (1998). Sudden cardiac death*. Circulation,* Vol. 98, No. 21, pp. 2334-

2351.

of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death)*. Journal of the American College of Cardiology,* Vol. 48, No. 5, pp. e247-e346.

> Sudden cardiac death (SCD) is defined as death from cardiac causes occurring unexpectedly within 1 hour of onset of symptoms. About 80% of SCDs are due to ventricular tachyarrhythmia that is, ventricular tachycardia and ventricular fibrillation. The remaining 20% consists of a number of conditions, including cardiomyopathies (10–15%), other structural heart defects (less than 5%) and bradycardia. SCD is responsible for more deaths than cancer, stroke, and AIDS combined (CDC, 2002). The overall incidence of SCD in the United States and Europe is 1 to 2 per 1000 people (0.1% to 0.2%) annually. Almost 80% of all SCDs occur at home. The 10%-25% survival rate is low and has not been improved by the automatic external defibrillator in patients with moderate risk (de Vreede-Swagemakers, 1997; Bardy, 2008; Myerburg, 2001). On the other hand, several clinical trials showed that the implantable cardioverter defibrillator (ICD) could prevent SCD and reduce overall mortality in some patients with severe left ventrocular dysfunction. For these reasons, ICD therapy has become the first choice strategy to prevent SCD from malignant ventricular tachyarrhythmia in high-risk patients. However, there are numerous well-recognized limitations to ICD therapy. These include the effects and the result of appropriate and inappropriate ICD shocks, the cost of the devices, complications related both to the implantation procedure and to subsequent device function, device malfunction, and restricted efficacy despite normal device function in presence of significant concomitant disease and in particular in presence of severe left ventricular disfunction. Several possible solutions have been proposed in the clinical practice, these include better patients' selection for ICD implantation, better ICD programmation, better medical therapy and arrhythmic substrate ablation. The role of catheter ablation of ventricular tachycardia in patients with structural heart disease has been increasing in the last 2 decades. The mechanisms of ventricular tachycardia are now clearer, and the electroanatomic mapping systems have made precise activation and substrate mapping more feasible; therefore, the potential for doing catheter ablation of ventricular tachycardia has increased dramatically in the past

Prevention of Sudden Death – Implantable Cardioverter

associated with increased mortality (Credner, 1998; Arya, 2006).

function (Hallas, 2010).

**2.2 Electrical storm**

**2.3 Mortality in patients with ICD**

Defibrillator and/or Ventricular Radiofrequency Ablation 85

family members as well (Luderitz, 1994). Anxiety after ICD shocks remains elevated for an unknown amount of time, and then begins to return to normal levels as long as no further shocks take place (Fricchione, 1989). The level of anxiety, depression, and poor quality of life is comparable in incidence to patients resuscitated from cardiac arrest and cardiopulmonary bypass surgery (Bostwick, 2007). In addition, ICD implantation is associated with neuropsychological impairment that significantly affects acute and long-term cognitive

Another significant problem is the electrical storm, which is defined as having more than three shocks in a 24-hours period, occurring in 10% to 20% of patients during the first 2 years after ICD implantation (Exner, 2001; Dunbar, 1999). An electrical storm establishes an adverse conditioned response including avoidance of activities that may have been associated with the shocks, leading to heightened self-monitoring of bodily functions, increased anxiety, uncertainty, and increased dependence. In some ICD patients, this condition leads to a reactive depression, helplessness, and post-traumatic stress disorder. In addition, an electrical storm is

Inappropriate ICD shocks may not only have adverse psychological consequences but also adverse medical consequences, such as a higher mortality than patients who did not suffer inappropriate shocks, with a hazard ratio of 2.29 (p=0.025) (Daubert & Zareba, 2008). Similarly, patients with appropriate shocks also had an increased overall mortality with a hazard ratio between 3 and 4. The higher hazard ratio arises in patients who had both appropriate and inappropriate shocks. In a multivariate analysis, predictors of inappropriate shocks included age > 70 years (hazard ratio 1.9, 95% CI 1.3-2.5; p=0.01) and history of atrial fibrillation (hazard ratio 2.0, 95% CI 1.5-2.7; p<0.01). The occurrence of only one inappropriate shock showed an all-cause mortality hazard ratio of 1.6 (95% CI 1.1-2.3; p=0.01), adjusted for history of atrial fibrillation, age, NYHA functional class, renal function, QRS duration, and beta-blockers use. Each additional inappropriate shock corresponded to a hazard ratio of 1.4 (95% CI 1.2-1.7; p=0.01), such that the risk was more than triple after a total of five such shocks (Johannes, 2011). It is interesting to investigate the causality between ICD shocks and an increased risk of death. It is especially reasonable to postulate that patients with progressive heart failure, and therefore increased mortality, might be more likely to develop atrial fibrillation and to suffer inappropriate ICD shocks. These same patients may also be more likely to exhibit ventricular tachycardia or ventricular fibrillation induced by progressive congestive heart failure and to undergo appropriate ICD shocks before dying of congestive heart failure. Depending on the ventricular rate and ICD programming, atrial fibrillation and sinus tachycardia can lead to antitachycardia pacing instead of ICD shocks. If rapid atrial fibrillation and sinus tachycardia were markers for increased mortality, then one would expect inappropriate antitachycardia pacing to be associated with increased mortality as well. In contrast to this expectation, in the MADIT II population, although both appropriate and inappropriate shocks were associated with an increased total mortality, appropriate and inappropriate antitachycardia pacing was not. In fact, having only antitachycardia pacing episodes and no shocks was associated with a trend toward lower mortality. Various likely contributions of ICD shocks to increased total mortality might subsist. Several possible explanations are debated. The first explanation is a

several years. Now, multiple and/or unstable ventricular tachycardias, polymorphic ventricular tachycardias, and ventricular fibrillation in selected cases can be targeted by different ablation strategies (Raymond, 2009). General recommendations for the use of catheter ablation are well documented; at this time, an open question remains, namely, whether catheter ablation can replace ICD in patients with structural heart disease.

#### **2. Implantable cardioverter defibrillator**

In 1980 Mirowski and colleagues (Mirowski, 1980) implanted the first ICD in a young female with recurrent ventricular fibrillation and provided an innovative approach to aborted SCD. This milestone event started a prolific period of research in SCD prevention and therapy. Although the ICD was considered a treatment of last resort during that incipient stage, subsequent years have witnessed expansion of indications for ICD implantation. (Epstein, 2008). Several large-scale clinical trials have demonstred its efficacy for both primary and secondary prevention of SCD in patients with ischemic and nonischemic cardiomyopathy. The advent of transvenous ICD technology and their potential effects in prevention of SCD elicited also several trials to compare the ICD with conventional antiarrhythmic drug therapy alone. In such high-risk patients, ICD therapy has been shown to improve survival rate compared with a neutral or harmful effect of chronic pharmacological therapy (Dimarco, 2003; Reiffel, 2005). In light of these excellent results, the number of ICD implantations has increased significantly in the last decade, with a simultaneous reduction of the use of stand-alone antiarrhythmic drugs for ventricular indications. (Al-Khatib, 2003; Hine, 1989; Zhan, 2008).

#### **2.1 ICD-related complications**

Because of the growing number of ICD patients, ICD-related problems are increasingly encountered and patients undergoing one or multiple shocks are today frequently seen in emergency departments, hospital wards, or ICD clinics.

Therefore, personnel working in these environments should have specific knowledge concerning the management of ICD-related problems. Typically, patients who receive ICDs are at high risk for recurrent arrhythmia; hence, most patients receive one or more ICD treatments for spontaneous arrhythmias after implantation (Dimarco, 2003). Despite the technological evolution of ICD systems, more than 20% of shocks are triggered by supraventricular arrhythmia; thus, they are inappropriate (Dorian, 2004; Nanthakumar, 2000; Rosenqvist, 1998).

The most common cause of inappropriate ICD shocks was atrial fibrillation (44%), followed by other supraventricular tachycardias, including sinus tachycardia (36%), and abnormal sensing (20%) (Daubert, 2008). If appropriate ICD shocks save lives, it may emerge that a few inappropriate shocks are a small price to pay (Raitt, 2008). Inappropriate shocks have a downside. There is a growing medical literature on the adverse psychological consequences of ICD shocks, whether appropriate or not. The ICD shocks are perceived as awfully painful. After an ICD shock, the patient may become immobilized, fearing that any movement or activity might activate another shock. Multiple shocks are the most frightening for patients, causing them to wonder if the device is really working or if it might even kill them. Those individuals who experience an ICD shock exhibit higher levels of psychological distress, anxiety, anger, and depression than those who do not. (Ahmad, 2000; Dunbar, 1993; Dougherty, 1995). The ICD shocks lead to greater psychological distress for family members as well (Luderitz, 1994). Anxiety after ICD shocks remains elevated for an unknown amount of time, and then begins to return to normal levels as long as no further shocks take place (Fricchione, 1989). The level of anxiety, depression, and poor quality of life is comparable in incidence to patients resuscitated from cardiac arrest and cardiopulmonary bypass surgery (Bostwick, 2007). In addition, ICD implantation is associated with neuropsychological impairment that significantly affects acute and long-term cognitive function (Hallas, 2010).

#### **2.2 Electrical storm**

Cardiac Defibrillation

84 – Prediction, Prevention and Management of Cardiovascular Arrhythmic Events

several years. Now, multiple and/or unstable ventricular tachycardias, polymorphic ventricular tachycardias, and ventricular fibrillation in selected cases can be targeted by different ablation strategies (Raymond, 2009). General recommendations for the use of catheter ablation are well documented; at this time, an open question remains, namely,

In 1980 Mirowski and colleagues (Mirowski, 1980) implanted the first ICD in a young female with recurrent ventricular fibrillation and provided an innovative approach to aborted SCD. This milestone event started a prolific period of research in SCD prevention and therapy. Although the ICD was considered a treatment of last resort during that incipient stage, subsequent years have witnessed expansion of indications for ICD implantation. (Epstein, 2008). Several large-scale clinical trials have demonstred its efficacy for both primary and secondary prevention of SCD in patients with ischemic and nonischemic cardiomyopathy. The advent of transvenous ICD technology and their potential effects in prevention of SCD elicited also several trials to compare the ICD with conventional antiarrhythmic drug therapy alone. In such high-risk patients, ICD therapy has been shown to improve survival rate compared with a neutral or harmful effect of chronic pharmacological therapy (Dimarco, 2003; Reiffel, 2005). In light of these excellent results, the number of ICD implantations has increased significantly in the last decade, with a simultaneous reduction of the use of stand-alone antiarrhythmic drugs for ventricular indications. (Al-Khatib, 2003;

Because of the growing number of ICD patients, ICD-related problems are increasingly encountered and patients undergoing one or multiple shocks are today frequently seen in

Therefore, personnel working in these environments should have specific knowledge concerning the management of ICD-related problems. Typically, patients who receive ICDs are at high risk for recurrent arrhythmia; hence, most patients receive one or more ICD treatments for spontaneous arrhythmias after implantation (Dimarco, 2003). Despite the technological evolution of ICD systems, more than 20% of shocks are triggered by supraventricular arrhythmia; thus, they are inappropriate (Dorian, 2004; Nanthakumar,

The most common cause of inappropriate ICD shocks was atrial fibrillation (44%), followed by other supraventricular tachycardias, including sinus tachycardia (36%), and abnormal sensing (20%) (Daubert, 2008). If appropriate ICD shocks save lives, it may emerge that a few inappropriate shocks are a small price to pay (Raitt, 2008). Inappropriate shocks have a downside. There is a growing medical literature on the adverse psychological consequences of ICD shocks, whether appropriate or not. The ICD shocks are perceived as awfully painful. After an ICD shock, the patient may become immobilized, fearing that any movement or activity might activate another shock. Multiple shocks are the most frightening for patients, causing them to wonder if the device is really working or if it might even kill them. Those individuals who experience an ICD shock exhibit higher levels of psychological distress, anxiety, anger, and depression than those who do not. (Ahmad, 2000; Dunbar, 1993; Dougherty, 1995). The ICD shocks lead to greater psychological distress for

whether catheter ablation can replace ICD in patients with structural heart disease.

**2. Implantable cardioverter defibrillator**

Hine, 1989; Zhan, 2008).

2000; Rosenqvist, 1998).

**2.1 ICD-related complications**

emergency departments, hospital wards, or ICD clinics.

Another significant problem is the electrical storm, which is defined as having more than three shocks in a 24-hours period, occurring in 10% to 20% of patients during the first 2 years after ICD implantation (Exner, 2001; Dunbar, 1999). An electrical storm establishes an adverse conditioned response including avoidance of activities that may have been associated with the shocks, leading to heightened self-monitoring of bodily functions, increased anxiety, uncertainty, and increased dependence. In some ICD patients, this condition leads to a reactive depression, helplessness, and post-traumatic stress disorder. In addition, an electrical storm is associated with increased mortality (Credner, 1998; Arya, 2006).

#### **2.3 Mortality in patients with ICD**

Inappropriate ICD shocks may not only have adverse psychological consequences but also adverse medical consequences, such as a higher mortality than patients who did not suffer inappropriate shocks, with a hazard ratio of 2.29 (p=0.025) (Daubert & Zareba, 2008). Similarly, patients with appropriate shocks also had an increased overall mortality with a hazard ratio between 3 and 4. The higher hazard ratio arises in patients who had both appropriate and inappropriate shocks. In a multivariate analysis, predictors of inappropriate shocks included age > 70 years (hazard ratio 1.9, 95% CI 1.3-2.5; p=0.01) and history of atrial fibrillation (hazard ratio 2.0, 95% CI 1.5-2.7; p<0.01). The occurrence of only one inappropriate shock showed an all-cause mortality hazard ratio of 1.6 (95% CI 1.1-2.3; p=0.01), adjusted for history of atrial fibrillation, age, NYHA functional class, renal function, QRS duration, and beta-blockers use. Each additional inappropriate shock corresponded to a hazard ratio of 1.4 (95% CI 1.2-1.7; p=0.01), such that the risk was more than triple after a total of five such shocks (Johannes, 2011). It is interesting to investigate the causality between ICD shocks and an increased risk of death. It is especially reasonable to postulate that patients with progressive heart failure, and therefore increased mortality, might be more likely to develop atrial fibrillation and to suffer inappropriate ICD shocks. These same patients may also be more likely to exhibit ventricular tachycardia or ventricular fibrillation induced by progressive congestive heart failure and to undergo appropriate ICD shocks before dying of congestive heart failure. Depending on the ventricular rate and ICD programming, atrial fibrillation and sinus tachycardia can lead to antitachycardia pacing instead of ICD shocks. If rapid atrial fibrillation and sinus tachycardia were markers for increased mortality, then one would expect inappropriate antitachycardia pacing to be associated with increased mortality as well. In contrast to this expectation, in the MADIT II population, although both appropriate and inappropriate shocks were associated with an increased total mortality, appropriate and inappropriate antitachycardia pacing was not. In fact, having only antitachycardia pacing episodes and no shocks was associated with a trend toward lower mortality. Various likely contributions of ICD shocks to increased total mortality might subsist. Several possible explanations are debated. The first explanation is a

Prevention of Sudden Death – Implantable Cardioverter

is acceptable if a procedure has no demonstrated benefit.

**2.4.1 Patients selection**

**2.4.2 ICD programmation**

be used whenever possible (Raitt, 2008).

**2.4.3 Medical therapy**

Defibrillator and/or Ventricular Radiofrequency Ablation 87

There are different approaches to reduce the incidence of appropriate and inappropriate shocks. The first line of defense is good patients' selection for ICD implantation. There is a well-documented increased complication rate for non-guideline-based ICD implantation. In particular, there was an excess of 4 deaths per 1000 ICD implants when the device was implanted outside the guidelines. (Kadish, 2011). The age at implant of patients is very important. Indeed in elderly patients, pooled analysis of the 3 trials considered most relevant to current use of ICDs for primary prevention (MADIT-II, DEFINITE, and SCD-HeFT) showed that prophylactic ICD therapy was associated with a nonsignificant reduction in all-cause mortality compared with medical therapy (HR, 0.81 [95% CI, 0.62 to 1.05]; *P* =0.11). Analyses that included the 2 studies of early enrolled post-acute myocardial infarction patients (DINAMIT and IRIS), also showed no statistically significant decrease in mortality with prophylactic ICD therapy (HR, 0.97 [CI, 0.78 to 1.19]; *P=*0.75) (Santangeli, 2010). Patients who received a non**–**evidence-based ICD had significantly more comorbidities than patients who received an evidence-based device and were at a higher risk of postprocedural complications (including death). The increased prevalence of comorbidities in recipients of non–evidence based ICDs is unquestionably associated with an increased risk of competing causes of death (Al-Khatib, 2011). While a small risk of complications is acceptable when a procedure has been shown to improve outcomes, no risk

The second line of defense is ICD programming. In the MADIT II trial, AF was the most common cause of inappropriate shocks. The patients provided with the stability detection algorithm programmed on in their ICDs, which is designed to prevent shocks for atrial fibrillation, were less likely to have inappropriate shocks (Daubert, 2008). Other detection algorithms are available on many ICDs that evaluate the morphology of tachycardias or the timing and frequency of atrial and ventricular activation. They prevent inappropriate shocks for supraventricular rhythms such as atrial fibrillation and sinus tachycardia. These algorithms help to prevent inappropriate shocks. The next step in reducing ICD shocks is programming the devices to use antitachycardia pacing instead of shocks whenever possible. Currently, many electrophysiologists do not routinely program antitachycardia pacing in patients with ICDs. By protocol, antitachycardia pacing was not enabled in the SCD-HeFT (Bardy, 2005). Arguing in favor of the usefulness and efficacy of antitachycardia pacing is the Pain Free II study, which showed that aggressive use of antitachycardia pacing, even for very fast episodes of ventricular tachycardia, was effective and reduced the risk of shocks (Wathen, 2004). Some physicians are concerned that an ineffective antitachycardia pacing will delay tachycardia termination. In response to this concern, one ICD manufacturer has introduced a characteristic in which antitachycardia pacing is used to try to terminate ventricular arrhythmias while the capacitor is charging in preparation for an ICD shock. If the antitachycardia pacing works, the shock is aborted; otherwise, the shock delivery is not delayed. Given the adverse psychological effects of ICD shocks and the possibility that shocks may increase mortality, these programming features should probably

It is less clear whether medical therapy can reduce the risk of ICD shocks. If, in fact, exacerbation of congestive heart failure leads to ICD shocks, perhaps, more aggressive

direct damage on the myocardium. Animal models have demonstrated a vast array of potentially deleterious effects of DC shocks including alterations in cellular morphology, biochemical function, electrophysiologic function, and hemodynamic function (Tedeschi, 1954; Van Vleet, 1977; Babbs, 1980; Jones, 1980; Wilson, 1988; Trouton, 1992).

Many of the morphologic, biochemical, electrophysiologic and hemodynamic adverse effects of high-intensity DC shocks reported in animals models have also been noted, although with lower frequency, in patients who have received DC shocks of clinically significant intensities. As in animal models, many of these functional changes have been demonstrated to last for minutes to hours as opposed to seconds. The immediacy of postshock electromechanical dissociation suggests that necrosis is not the cause of the phenomenon. Instead, it is likely that an instantaneous functional abnormality is accountable for electromechanical dissociation. This probability is supported by reports of severe hemodynamic deterioration after internal DC shocks during ICD implantation procedures (Avitall, 1990; Steinbeck, 1994). A severe manifestation of this phenomenon could be expressed as sudden death due to electromechanical dissociation that is the most common mechanism of sudden death in patients with a functioning ICD in place and is associated with high-energy shocks in patients with advanced congestive heart failure. (Mitchell, 2002). The protection afforded by the ICD against sudden arrhythmic death is not absolute, being the rate of sudden death among patients with ICD approximately 5%. If the majority of patients receiving ICDs is similar to those patients included in randomized clinical trials, then ICDs can be expected to be 60 to 70% effective in reducing SCD. This may be more effective than any other available therapy and is thought to be additive to reduction of SCD due to other therapies such as beta-blockers and angiotensin converting enzyme inhibitors. On the other hand, it should serve as a reminder to physicians of the importance of optimization of ICD programming and medical therapy and to patients with regard to compliance with medications and recommended life-style modifications as these measures will reduce their risk (Anderson, 2005).

The second explanation is a possible non-direct damage on the myocardium for the adverse effects of ICD shocks that could direct to increased mortality. We have already outlined the adverse psychological effects of ICD shocks, anxiety and depression, that can set off a cascade of events, including poor compliance to medical therapy, that culminates in an increased risk of death in patients with congestive heart failure. Whether or not there is a causal relationship between ICD shocks and the associated increase in mortality, the psychological effects of shocks alone are reason to do everything possible to reduce the incidence of appropriate and inappropriate shocks (Raitt, 2008).

The extensive implementation of ICD therapy has changed the natural history of ventricular tachycardia (Mason, 1993; Connolly, 2000; AVID Investigators, 1997).

#### **2.4 Approaches to reduce ICD therapy**

CDs effectively terminate ventricular arrhythmias through either antitachycardia pacing or shocks and comprise the standard of care for patients at high risk for ventricular arrhythmias. However, ICDs do not prevent the occurrence of ventricular arrhythmias. Patients who, formerly, would have suffered sudden death, now survive to experience recurrent ventricular tachycardia and ICD therapy; thus, shock delivery is administered in a large proportion to patients who have experienced at least one ventricular arrhythmia (Connolly, 2006; Credner, 1998).

#### **2.4.1 Patients selection**

Cardiac Defibrillation

86 – Prediction, Prevention and Management of Cardiovascular Arrhythmic Events

direct damage on the myocardium. Animal models have demonstrated a vast array of potentially deleterious effects of DC shocks including alterations in cellular morphology, biochemical function, electrophysiologic function, and hemodynamic function (Tedeschi,

Many of the morphologic, biochemical, electrophysiologic and hemodynamic adverse effects of high-intensity DC shocks reported in animals models have also been noted, although with lower frequency, in patients who have received DC shocks of clinically significant intensities. As in animal models, many of these functional changes have been demonstrated to last for minutes to hours as opposed to seconds. The immediacy of postshock electromechanical dissociation suggests that necrosis is not the cause of the phenomenon. Instead, it is likely that an instantaneous functional abnormality is accountable for electromechanical dissociation. This probability is supported by reports of severe hemodynamic deterioration after internal DC shocks during ICD implantation procedures (Avitall, 1990; Steinbeck, 1994). A severe manifestation of this phenomenon could be expressed as sudden death due to electromechanical dissociation that is the most common mechanism of sudden death in patients with a functioning ICD in place and is associated with high-energy shocks in patients with advanced congestive heart failure. (Mitchell, 2002). The protection afforded by the ICD against sudden arrhythmic death is not absolute, being the rate of sudden death among patients with ICD approximately 5%. If the majority of patients receiving ICDs is similar to those patients included in randomized clinical trials, then ICDs can be expected to be 60 to 70% effective in reducing SCD. This may be more effective than any other available therapy and is thought to be additive to reduction of SCD due to other therapies such as beta-blockers and angiotensin converting enzyme inhibitors. On the other hand, it should serve as a reminder to physicians of the importance of optimization of ICD programming and medical therapy and to patients with regard to compliance with medications and recommended life-style modifications as these measures

The second explanation is a possible non-direct damage on the myocardium for the adverse effects of ICD shocks that could direct to increased mortality. We have already outlined the adverse psychological effects of ICD shocks, anxiety and depression, that can set off a cascade of events, including poor compliance to medical therapy, that culminates in an increased risk of death in patients with congestive heart failure. Whether or not there is a causal relationship between ICD shocks and the associated increase in mortality, the psychological effects of shocks alone are reason to do everything possible to reduce the

The extensive implementation of ICD therapy has changed the natural history of ventricular

CDs effectively terminate ventricular arrhythmias through either antitachycardia pacing or shocks and comprise the standard of care for patients at high risk for ventricular arrhythmias. However, ICDs do not prevent the occurrence of ventricular arrhythmias. Patients who, formerly, would have suffered sudden death, now survive to experience recurrent ventricular tachycardia and ICD therapy; thus, shock delivery is administered in a large proportion to patients who have experienced at least one ventricular arrhythmia

1954; Van Vleet, 1977; Babbs, 1980; Jones, 1980; Wilson, 1988; Trouton, 1992).

will reduce their risk (Anderson, 2005).

**2.4 Approaches to reduce ICD therapy**

(Connolly, 2006; Credner, 1998).

incidence of appropriate and inappropriate shocks (Raitt, 2008).

tachycardia (Mason, 1993; Connolly, 2000; AVID Investigators, 1997).

There are different approaches to reduce the incidence of appropriate and inappropriate shocks. The first line of defense is good patients' selection for ICD implantation. There is a well-documented increased complication rate for non-guideline-based ICD implantation. In particular, there was an excess of 4 deaths per 1000 ICD implants when the device was implanted outside the guidelines. (Kadish, 2011). The age at implant of patients is very important. Indeed in elderly patients, pooled analysis of the 3 trials considered most relevant to current use of ICDs for primary prevention (MADIT-II, DEFINITE, and SCD-HeFT) showed that prophylactic ICD therapy was associated with a nonsignificant reduction in all-cause mortality compared with medical therapy (HR, 0.81 [95% CI, 0.62 to 1.05]; *P* =0.11). Analyses that included the 2 studies of early enrolled post-acute myocardial infarction patients (DINAMIT and IRIS), also showed no statistically significant decrease in mortality with prophylactic ICD therapy (HR, 0.97 [CI, 0.78 to 1.19]; *P=*0.75) (Santangeli, 2010). Patients who received a non**–**evidence-based ICD had significantly more comorbidities than patients who received an evidence-based device and were at a higher risk of postprocedural complications (including death). The increased prevalence of comorbidities in recipients of non–evidence based ICDs is unquestionably associated with an increased risk of competing causes of death (Al-Khatib, 2011). While a small risk of complications is acceptable when a procedure has been shown to improve outcomes, no risk is acceptable if a procedure has no demonstrated benefit.

#### **2.4.2 ICD programmation**

The second line of defense is ICD programming. In the MADIT II trial, AF was the most common cause of inappropriate shocks. The patients provided with the stability detection algorithm programmed on in their ICDs, which is designed to prevent shocks for atrial fibrillation, were less likely to have inappropriate shocks (Daubert, 2008). Other detection algorithms are available on many ICDs that evaluate the morphology of tachycardias or the timing and frequency of atrial and ventricular activation. They prevent inappropriate shocks for supraventricular rhythms such as atrial fibrillation and sinus tachycardia. These algorithms help to prevent inappropriate shocks. The next step in reducing ICD shocks is programming the devices to use antitachycardia pacing instead of shocks whenever possible. Currently, many electrophysiologists do not routinely program antitachycardia pacing in patients with ICDs. By protocol, antitachycardia pacing was not enabled in the SCD-HeFT (Bardy, 2005). Arguing in favor of the usefulness and efficacy of antitachycardia pacing is the Pain Free II study, which showed that aggressive use of antitachycardia pacing, even for very fast episodes of ventricular tachycardia, was effective and reduced the risk of shocks (Wathen, 2004). Some physicians are concerned that an ineffective antitachycardia pacing will delay tachycardia termination. In response to this concern, one ICD manufacturer has introduced a characteristic in which antitachycardia pacing is used to try to terminate ventricular arrhythmias while the capacitor is charging in preparation for an ICD shock. If the antitachycardia pacing works, the shock is aborted; otherwise, the shock delivery is not delayed. Given the adverse psychological effects of ICD shocks and the possibility that shocks may increase mortality, these programming features should probably be used whenever possible (Raitt, 2008).

#### **2.4.3 Medical therapy**

It is less clear whether medical therapy can reduce the risk of ICD shocks. If, in fact, exacerbation of congestive heart failure leads to ICD shocks, perhaps, more aggressive

Prevention of Sudden Death – Implantable Cardioverter

**3.1 Electroanatomic systems and substrate mapping**

event (Bogun, 2006; de Chillou, 2002).

ventricular tachycardia (Figure 1).

Defibrillator and/or Ventricular Radiofrequency Ablation 89

stable ventricular tachycardia could be treated, for which an ECG of the spontaneous ventricular tachycardia had been obtained and mapping could be performed during such

The introduction of the electroanatomic mapping system allowed creation of ventricular geometry and displayed low-voltage areas of scar or infarction (Marchlinski, 2000). Mapping during stable sinus or paced rhythm to identify targets for ventricular tachycardia, the so-called substrate mapping (Reddy, 2003; Volkmer, 2006), allows performing catheter ablation in patients with unstable, hemodynamically nontolerated ventricular tachycardia, in patients with multiple ventricular tachycardias, or in patients without inducible

Fig. 1. A and B show the substrate respectively, in the posterior and inferior view in a patient with ischemic dilated cardiomiopathy. In substrate mapping the scar region (grey

myocardium (purple area) was defined as areas with a bipolar local electrogram ≥1.5 mV.

Today, most patients with recurrent ventricular tachycardia have an ICD that promptly terminates ventricular tachycardia, so its hemodynamic impact and ECG morphology are often unknown. Thus, substrate mapping is often the only method to perform catheter ablation in patients with an ICD (Kuck, 2009). By selecting catheter ablation for an individual patient, risks and benefits that are determined by patient characteristics, as well

area) was defined as areas with bipolar local electrogram ≤0.5 mV and the normal

The white dots represent the ablation lesions.

congestive heart failure treatment in patients with ICDs, and use of congestive heart failure monitoring protocols built into some ICDs might prevent some appropriate and inappropriate shocks. It is less clear whether empiric antiarrhythmic therapy prevents ICD shocks; in addition, such therapy cannot be recommended at this time because of the risk of proarrhythmia and the cardiac and noncardiac side effects of antiarrhythmic medications (Raitt, 2008). Beyond aggressive treatment of ischemia and heart failure, preventive treatments for inhibition of ventricular tachycardia are limited. Three agents have been demonstrated in randomized clinical trials to reduce ICD therapies. Amiodarone resulted in a substantial decline in ICD shocks compared with beta-blockers in patients who had experienced prior ventricular arrhythmias. Sotalol moderately reduced shocks (after a 3 week blanking period) in the same population and increased shock-free survival in a placebo-controlled trial (Raitt, 2008). Azimilide has been found to reduce all-cause shocks and symptomatic ventricular tachycardia in a placebo-controlled study (Dorian, 2004). Unfortunately, each of these agents carries significant risk of harmful side-effects. The proarrhythmic mortality risk of sotalol (Waldo, 1996) may be both attenuated in ICD patients, and may be increased in presence of heart failure, diuretic use and older age – all common features of patients with ischemic cardiomyopathy and ventricular tachycardia. Amiodarone use is also associated with a high incidence of adverse effects (Brendorp, 2002), which are moderate at low doses (Vorperian, 1997); on the other hand, they increase with dose and duration such that, in long-term use, side-effects or recurrent arrhythmia are seen very frequently (Bokhari, 2004). Amiodarone use, nephropathy, low left ventricular ejection fraction, and supraventricular tachycardia are independent predictors of cardiac death (Worck, 2007). One can speculate that proarrhythmia and/or increased defibrillation thresholds could play a role in the association with increased mortality (Khalighi, 1997; Zhou, 1998). In addition, amiodarone harmfully affected survival in NYHA III patients in the SCD-HeFT (Bardy, 2005). Azimilide has not demonstrated a change in mortality and is associated with a relatively low rate of torsades de pointes (Camm, 2004; Pratt, 2006), but has not been made available for clinical use. Dronedarone has been associated with higher mortality in the situation of heart failure. Other antiarrhythmic drugs, including dronedarone and dofetilide, have been disappointing, hence, nonpharmacologic alternatives are needed. (Echt, 1991; The CAST Investigators, 1989; DIAMOND studies, 1997; Torp-Pedersen, 1999; Kober, 2008). A good therapeutic alternative to reduce risk of ICD shocks is catheter ablation of ventricular tachycardias.

#### **3. Catheter ablation**

In 1987, catheter ablation of ventricular tachycardia was a newly emerging field. The primary therapy for drug refractory ventricular tachycardia was surgical ablation, which was successful in controlling this arrhythmia in 80% to 90% of selected patients, but yielded an operative mortality of 5% to 15% (Cox, 1989). Over the subsequent two decades, significant developments in ablation and mapping technology contributed to improved outcomes: catheter ablation, first, using direct-current energy and radiofrequency current, later. The initial acute success rates using radiofrequency current were on average 75%, with a recurrence rate of 21% over a follow-up time average of 21 months (Gu¨rsoy, 1993; Stevenson, 1993; Gonska, 1994; Kim, 1994; Wilber, 1995; Stevenson, 1998). The limitation of catheter ablation at this time was 2-fold. First, only conventional radiofrequency current (non-irrigated) was available; secondly, only patients with hemodynamically tolerated and

88 – Prediction, Prevention and Management of Cardiovascular Arrhythmic Events

congestive heart failure treatment in patients with ICDs, and use of congestive heart failure monitoring protocols built into some ICDs might prevent some appropriate and inappropriate shocks. It is less clear whether empiric antiarrhythmic therapy prevents ICD shocks; in addition, such therapy cannot be recommended at this time because of the risk of proarrhythmia and the cardiac and noncardiac side effects of antiarrhythmic medications (Raitt, 2008). Beyond aggressive treatment of ischemia and heart failure, preventive treatments for inhibition of ventricular tachycardia are limited. Three agents have been demonstrated in randomized clinical trials to reduce ICD therapies. Amiodarone resulted in a substantial decline in ICD shocks compared with beta-blockers in patients who had experienced prior ventricular arrhythmias. Sotalol moderately reduced shocks (after a 3 week blanking period) in the same population and increased shock-free survival in a placebo-controlled trial (Raitt, 2008). Azimilide has been found to reduce all-cause shocks and symptomatic ventricular tachycardia in a placebo-controlled study (Dorian, 2004). Unfortunately, each of these agents carries significant risk of harmful side-effects. The proarrhythmic mortality risk of sotalol (Waldo, 1996) may be both attenuated in ICD patients, and may be increased in presence of heart failure, diuretic use and older age – all common features of patients with ischemic cardiomyopathy and ventricular tachycardia. Amiodarone use is also associated with a high incidence of adverse effects (Brendorp, 2002), which are moderate at low doses (Vorperian, 1997); on the other hand, they increase with dose and duration such that, in long-term use, side-effects or recurrent arrhythmia are seen very frequently (Bokhari, 2004). Amiodarone use, nephropathy, low left ventricular ejection fraction, and supraventricular tachycardia are independent predictors of cardiac death (Worck, 2007). One can speculate that proarrhythmia and/or increased defibrillation thresholds could play a role in the association with increased mortality (Khalighi, 1997; Zhou, 1998). In addition, amiodarone harmfully affected survival in NYHA III patients in the SCD-HeFT (Bardy, 2005). Azimilide has not demonstrated a change in mortality and is associated with a relatively low rate of torsades de pointes (Camm, 2004; Pratt, 2006), but has not been made available for clinical use. Dronedarone has been associated with higher mortality in the situation of heart failure. Other antiarrhythmic drugs, including dronedarone and dofetilide, have been disappointing, hence, nonpharmacologic alternatives are needed. (Echt, 1991; The CAST Investigators, 1989; DIAMOND studies, 1997; Torp-Pedersen, 1999; Kober, 2008). A good therapeutic alternative to reduce risk of ICD shocks is