Ventricular tachycardia in coronary artery disease Zahra Emkanjoo, M.D. Rajaie Cardiovascular, Medical and Research Centre Tehran, IRAN Zahra Emkanjoo, M.D. Rajaie Cardiovascular, Medical and Research Centre Tehran, IRAN

The most common anatomic substrate for all these arrhythmia is chronic coronary artery disease,usually associated with prior infarction

The pathologic substrate for patients with VT associated with CAD is usually a prior MI resulting in wall motion abnormalities. The pathologic substrate for patients with VT associated with CAD is usually a prior MI resulting in wall motion abnormalities. The greater the wall motion abnormalities,the higher the incidence of aneurysm formation, and the lower the EF, the more likely is the development of a sustained uniform VT. The greater the wall motion abnormalities,the higher the incidence of aneurysm formation, and the lower the EF, the more likely is the development of a sustained uniform VT.

Patients presented with cardiac arrest fall into two groups: Patients presented with cardiac arrest fall into two groups: Most commonly, those with prior infarction,usually with less wall motion abnormality and depression of myocardial function than patients with SMVT Most commonly, those with prior infarction,usually with less wall motion abnormality and depression of myocardial function than patients with SMVT Those with severe CAD and relatively normal ventricular function,in this cardiac arrest is most likely due to acute ischemia. Those with severe CAD and relatively normal ventricular function,in this cardiac arrest is most likely due to acute ischemia.

Patients with uniform VT have the lowest EF(27%),while those with cardiac arrest and NSVT have higher EF(35% and 39%) Patients with uniform VT have the lowest EF(27%),while those with cardiac arrest and NSVT have higher EF(35% and 39%)

The extent of infarction,and location involving the septum, may be the two important prognostic factors associated with the malignant sustained ventricular arrhythmia The extent of infarction,and location involving the septum, may be the two important prognostic factors associated with the malignant sustained ventricular arrhythmia

Most VTs that are associated with structural heart disease are due to reentry involving regions of infarction or ventricular scar. 8% are due to reentry or automaticity involving the Purkinje system. A smaller number have a focal origin in regions of abnormal myocardium.

Infarct-related VT circuits Magnification of the subendocardial region emphasizing the interdigitation of fibrous sheathes between surviving muscle bundles.

(A) A simple circuit consisting of a single loop around a region of block. If the loop is broad,ablation in the loop (dotted black line) may increase the re-entry path but fail to interrupt re- entry. (B) A figure-of-eight type of re-entry circuit defined by wave fronts propagating around 2 regions of block and sharing a common isthmus. (C) A complex circuit with several regions of conduction block along a valve annulus that creates multiple potential channels

Infarct-related VT circuits Patients with scar-related VTs often have multiple potential reentry circuits, giving rise to more than one morphology of inducible monomorphic VT. In most patients, three or four different VTs are inducible The majority of patients have one or more VTs that are unstable and not amenable to extensive mapping, due to poor hemodynamic tolerance, frequent changes to other VT morphologies during attempted mapping, or inconsistent inducibility

Electectrophysiologic studies are the most useful in patients with CAD. Electectrophysiologic studies are the most useful in patients with CAD.

Clinical presentation In the setting of CAD,VT results in a wide spectrum of clinical presentation,raging from incidental detection to rapid hemodynamic collapse. In the setting of CAD,VT results in a wide spectrum of clinical presentation,raging from incidental detection to rapid hemodynamic collapse. The key determinant of hemodynamic tolerance of a VT episode is the tachycardia rate. The key determinant of hemodynamic tolerance of a VT episode is the tachycardia rate.

The highest incidence of cardiac arrest occurred in the first 6-12 months following infarction. The highest incidence of cardiac arrest occurred in the first 6-12 months following infarction. After the first year,the incidence of cardiac arrest decreased rapidely,such that within 3 years the incidence is low. After the first year,the incidence of cardiac arrest decreased rapidely,such that within 3 years the incidence is low. In patients who present with SMVT,onset of the arrhythmia appears later. In patients who present with SMVT,onset of the arrhythmia appears later.

Electrophysiologic substrate The clinically measurable electrophysiologic consequence of infarction that are potentially arrhythmogenic include: The clinically measurable electrophysiologic consequence of infarction that are potentially arrhythmogenic include: Abnormalities of conduction and refractoriness Abnormalities of conduction and refractoriness Heterogenity of conduction and refractoriness Heterogenity of conduction and refractoriness Enhanced automaticity Enhanced automaticity Ereas of inexcitability Ereas of inexcitability

The criteria for normal and abnormal electrogram Normal electrogram characterized by: Normal electrogram characterized by: Sharp,biphasic,or triphasic spikes with amplitude> 3 mV,duration of Sharp,biphasic,or triphasic spikes with amplitude> 3 mV,duration of Fractionated electrogram characterized by: Fractionated electrogram characterized by: Amplitude 133msec, amplitude/duration ratio 133msec, amplitude/duration ratio<0.005

Signal-Averaged ECG “Late potentials” are surface representation of areas of slow conduction in ventricular myocardium “Late potentials” are surface representation of areas of slow conduction in ventricular myocardium Slow conduction, which may be due to myocardial scar or ischemia, has been correlated with ventricular reentry, one mechanism of VT Slow conduction, which may be due to myocardial scar or ischemia, has been correlated with ventricular reentry, one mechanism of VT

In post-MI patients, SAECG may be helpful in stratifying risk In post-MI patients, SAECG may be helpful in stratifying risk Computer-generated ECG looks for presence or absence of “late potentials” which are enhanced and unmasked by digital filtering techniques Computer-generated ECG looks for presence or absence of “late potentials” which are enhanced and unmasked by digital filtering techniques

Normal Conducti on Abnormal Conduction Normal SAECG Abnormal SAECG Courtesy of Arrhythmia Research Technology, Inc. (Formerly Corazonix Corp.)

Normal Signal-Averaged ECG SAECG with Late Potentials

The incidence of positive SAECG is highest in patients with sustained uniform VT(85%) The incidence of positive SAECG is highest in patients with sustained uniform VT(85%) And is lower for patients presenting with cardiac arrest(55%) and NSVT(50%) And is lower for patients presenting with cardiac arrest(55%) and NSVT(50%)

The natural history of these conduction abnormalities in CAD is uncertain,although they appear to develop,3 days to 2 weeks following infarction. The natural history of these conduction abnormalities in CAD is uncertain,although they appear to develop,3 days to 2 weeks following infarction.

Mechanisms of VT Potential mechanisms of VT include: Potential mechanisms of VT include: Reentry Reentry Normal and abnormal automaticity Normal and abnormal automaticity Triggered activity Triggered activity

Characteristics of VT in CAD with reentrant mechanism Reproducible induction and termination with programmed stimulation Reproducible induction and termination with programmed stimulation Absence of a consistent effect of isoproternole on inducibility Absence of a consistent effect of isoproternole on inducibility Site specificity of induction Site specificity of induction Indirect relationship of coupling interval and the interval to the first tachycardia CL Indirect relationship of coupling interval and the interval to the first tachycardia CL Evidence of slow conduction (electrogram abnormalitie,continious activity) Evidence of slow conduction (electrogram abnormalitie,continious activity) Response of tachycardia to extrastimuli(resetting and entrainment) Response of tachycardia to extrastimuli(resetting and entrainment) Data from high density intra-operative mapping techniques Data from high density intra-operative mapping techniques

Arrhythmic risk stratification of post–myocardial infarction patients Arrhythmic risk stratification (ARS) of post– acute myocardial infarction (AMI) patients is intended to identify subgroups of patients with different risks of sudden death, using clinical parameters and data derived from noninvasive risk stratification (NIRS) or invasive procedures. Furthermore, ARS is obtained to identify the best therapeutic strategy for these patients.

ICD Clinical Trials in Post-MI Patients MADIT Multicenter Automatic Defibrillator Implantation Trial Multicenter Automatic Defibrillator Implantation Trial Moss AJ. N Engl J Med 1996:335: MUSTT Multicenter Unsustained Tachycardia Trial Multicenter Unsustained Tachycardia Trial Buxton AE. N Engl J Med. 1999;341: MADIT-II Multicenter Automatic Defibrillator Implantation Trial- II Multicenter Automatic Defibrillator Implantation Trial- II Moss AJ. N Engl J Med. 2002;346:

1 Moss AJ. N Engl J Med. 1996;335: Buxton AE. N Engl J Med. 1999;341: Moss AF. N Engl J Med. 2002;346: Moss AJ. Presented before ACC 51st Annual Scientific Sessions, Late Breaking Clinical Trials, March 19, The AVID Investigators. N Engl J Med. 1997;337: , 4 54% 75% 55% 73% 31% 61% Post-MI ICD Trials vs. AVID 27 Months 39 Months20 Months % Mortality Reduction w/ ICD Rx 31% 56% 5 24 Months

MADIT/MUSTT/MADIT-II Study Criteria Comparison Inclusion Criteria MADIT 1 (196 patients) MUSTT 2 (704 patients) MADIT- II 3 (1232 patients) CAD/Post-MI LV Dysfunction (<35%) (<40%) (<30%) NSVT Inducible VT on EPS Inducible, non- suppressible VT on EPS

MADIT-II Survival Results Moss AJ. N Engl J Med. 2002;346: Defibrillator Conventional P = Probability of Survival Year No. At Risk Defibrillator (0.91)274 (0.94)110 (0.78)9 Conventional (0.90)170 (0.78) 65 (0.69)3

MADIT-II: Mortality Events Moss AJ. Presented at ACC Latebreaking Clinical Trials, March % relative risk reduction 31% relative risk reduction

Post-MI ICD Trials Conclusions Post-MI patients with LV dysfunction are at an increased risk of SCA. Post-MI patients with LV dysfunction are at an increased risk of SCA. ICD therapy in these patients results in significant reductions in overall mortality (31- 55%) over antiarrhythmics or conventional therapy. ICD therapy in these patients results in significant reductions in overall mortality (31- 55%) over antiarrhythmics or conventional therapy.

ICD mortality reductions in post-MI trials (primary prevention) are equal to or greater than the mortality reductions achieved in VT/VF trials (secondary prevention, e.g., AVID). ICD mortality reductions in post-MI trials (primary prevention) are equal to or greater than the mortality reductions achieved in VT/VF trials (secondary prevention, e.g., AVID). ICD therapy in MADIT-II patients provided significant survival benefit in patients who were on optimal drug therapies. ICD therapy in MADIT-II patients provided significant survival benefit in patients who were on optimal drug therapies. Post-MI ICD Trials Conclusions

Risk stratification for VT Will one test work for all? Will one test work for all? Mechanism of sudden death vary Mechanism of sudden death vary Dependence on anatomic substrates Dependence on anatomic substrates Coronary anatomy and MI location Coronary anatomy and MI location Ventricular size,systolic function,hypertrophy Ventricular size,systolic function,hypertrophy Non-coronary disease Non-coronary disease Dilated Cardiomyopathy Dilated Cardiomyopathy HOCM HOCM

Risk stratification for Sudden Death Will one test work forever? Will one test work forever?  Time dependence  Disease evolves  Ventricular remodeling  Hypertrophy  Dilatation  CHF

Requirements to develop effective tests for Risk Stratification Prospective testing for tests Prospective testing for tests 1. ability to discriminate between patients who will or will not experience events 1. ability to discriminate between patients who will or will not experience events 2. ability of treat based on test to alter outcome 2. ability of treat based on test to alter outcome

Today the most important problem is to identify patients best suited for the treatment that will be more effective in the primary prevention of sudden death. Today the most important problem is to identify patients best suited for the treatment that will be more effective in the primary prevention of sudden death. Furthermore,it should be identify patients,both at high risk of future arrhythmia events or SD who are at the same time,at low risk of nonarrhythmic mortality. Furthermore,it should be identify patients,both at high risk of future arrhythmia events or SD who are at the same time,at low risk of nonarrhythmic mortality.

Identification of patients at risk How to recognize? How to recognize? Substrate Substrate EPS EPS SAECG SAECG T wave alternance T wave alternance EF EF Triggers Triggers ECG monitoring-VPDs,NSVT ECG monitoring-VPDs,NSVT Autonomic Nervous System Autonomic Nervous System Heart Rate variability Heart Rate variability Baroreflex sensivity Baroreflex sensivity

Types of screening tests General General Tests that identify populations at risk of all cause mortality Tests that identify populations at risk of all cause mortality Specific Specific Tests that identify patients whose risk for sudden death is increased out of proportion to total mortality Tests that identify patients whose risk for sudden death is increased out of proportion to total mortality

“Reduced left ventricular ejection fraction (LVEF) remains the single most important risk factor for overall mortality and sudden cardiac death.” 1 1 Prior SG, Aliot E, Blonstrom-Lundqvist C, et al. Task Force on Sudden Cardiac Death of the European Society of Cardiology. Eur Heart J, Vol. 22; 16; August 2001.

Type of Death and LVEF Yap GY. Heart. 2000;83,Supplement 1:85. LVEF % Death 23.1% 17.5% 6.8% 9.4% 7.7% 3.2% 10.6% 6.3% 2.2% # Patients

Ventricular arrhythmia Frequent PVB represent an independent prognostic factor for cardiac and arrhythmic mortality. Frequent PVB represent an independent prognostic factor for cardiac and arrhythmic mortality. PVB are frequently documented in patients with reduced EF(31.8% of patients with EF <35%) PVB are frequently documented in patients with reduced EF(31.8% of patients with EF <35%) A two-to threefold increase in the mortality rate is observed in this subgroup 6 months after AMI. A two-to threefold increase in the mortality rate is observed in this subgroup 6 months after AMI. Data from GISSI study Data from GISSI study

Table 1. Relationship between percent ejection fraction and premature ventricular beats in the Multicenter Investigation for Limitation of Infarct Size study (MILIS)

NSVT is observed in 11% to 15% post MI patients. NSVT is observed in 11% to 15% post MI patients. The presence of NSVT is associated with a 21% mortality(34% in patients with reduced EF) in comparison with 8% in patients without NSVT. The presence of NSVT is associated with a 21% mortality(34% in patients with reduced EF) in comparison with 8% in patients without NSVT.

Today, a more comprehensive approach includes EPS after the risk stratification has been completed by using EF% and ambient ventricular arrhythmia identification or other NIRS parameters. Using this approach, two studies (MADIT II and BEST AICD) have been recently proposed

SAECG Late potentials have been documented in % of patients 1-4 weeks after MI. Late potentials have been documented in % of patients 1-4 weeks after MI. They are predictive of spontaneous or inducible ventricular arrhythmia or SD. They are predictive of spontaneous or inducible ventricular arrhythmia or SD. They have been more frequently documented in patients with reduced EF and their prognostic significance is independent of the EF itself. They have been more frequently documented in patients with reduced EF and their prognostic significance is independent of the EF itself. A very high number of false-positive results have been observed. A very high number of false-positive results have been observed.

Neurovegetative tone measurement In the Multicenter Postinfarction Study (MPS), a strong correlation has been found between reduced HRV and total post-AMI mortality. The observed mortality was independent of other prognostic factors, and a fivefold increase in mortality has been observed in patients exhibiting an HRV of less than 50 ms. The change in HRV can be observed soon after an AMI and can be almost completely reversed 6 to 12 weeks after the episode, with some exceptions due to age and sex. The prognostic value of reduced HRV is more evident in the subgroup of patients with an EF% of less than 30%

Baroreflex sensivity A linear relation has been proved between an increase in blood pressure and changes in the RR interval. This relation can be changed and decreased after an AMI: its decrease correlates with an increase in the number of arrhythmic events and makes ventricular tachycardia episodes more easily inducible at EPS.

Conclusion We have yet to find the ideal test We have yet to find the ideal test No single test is likely to be appropriate for any patient No single test is likely to be appropriate for any patient We will need combination of tests We will need combination of tests We will need to repeat tests periodically We will need to repeat tests periodically When is the ideal time to test? When is the ideal time to test?