Myocardial Ischemia: An Underrated Cause of Sudden Cardiac Death? William T. Abraham, MD, FACP, FACC, FAHA Professor of Medicine, Physiology, and Cell Biology Chair of Excellence in Cardiovascular Medicine Chief, Division of Cardiovascular Medicine Deputy Director, Davis Heart & Lung Research Institute The Ohio State University Columbus, Ohio

Disclosures - Dr. Abraham has received research grants and/or consulting fees from Biotronik, Medtronic, and St. Jude Medical

Ohio State University Sudden Cardiac Death (SCD) Research Center

Underlying Arrhythmias of SCD 83% Are Ventricular Tachyarrhythmias Bradycardia 17% VT 62% Primary VF 8% Torsades de Pointes 13% Adapted from Bayés de Luna A. Am Heart J. 1989;117:151-159.

80% Coronary Artery Disease Underlying Causes of Fatal Arrhythmias Coronary Artery Disease is Most Common 80% Coronary Artery Disease 15% Cardiomyopathy 5% Other* *ion-channel abnormalities, valvular or congenital heart disease, other causes Adapted from Heikki et al. N Engl J Med, Vol. 345, No. 20, 2001.

Mechanisms of VT/VF in Acute Ischemia Dispersion of refractoriness Potassium current Alteration of conduction velocity and propagation Sodium current Enhanced abnormal automaticity Calcium current

Dispersion of Refractoriness Alteration of potassium handling alters local action potential duration/refractoriness Regional increase in interstitial concentration related to cell lysis Accumulation of ADP in ischemic tissue directly alters cellular potassium current

Altered Conduction Velocity Lack of mitochondrial function/ATP results in loss of sodium/calcium current Slowed and differential conduction Spontaneous multifocal ventricular ectopy Abnormal automaticity related to altered calcium current

VT/VF in Acute Ischemia Multifactorial Mechanisms Altered handling of sodium, potassium and calcium current Dispersion of refractoriness/ areas of functional block Differential conduction propagation/velocity Multifocal automatic discharges Promotes local reentry and prompt degeneration into PMVT/VF Thus if a patient presents with monomorphic VT it rarely is related to acute ischemia

VT in Chronic Ischemic Heart Disease Scar from Prior MI Establishes a zone of slow conduction Tissue within the infarct that is viable but not healthy Conduction is slow…essential substrate to establish reentry Random ventricular ectopy that otherwise would be benign becomes malignant in setting of scar and slow conduction Reentry

ACC/AHA/HRS Guidelines: Indications for ICDs Class III Indication: Ventricular tachyarrhythmias due to a transient or reversible disorder (e.g., acute MI, electrolyte imbalance, drugs, or trauma) when correction of the disorder is considered feasible and likely to substantially reduce the risk of recurrent arrhythmias. Level of evidence: B.

How Reversible Are Reversible Causes (e.g., Ischemia) of SCD? In every ICD clinical trial: Patients with sustained VT or VF due to an identifiable transient or correctable cause have been excluded Presumption that these patients are at low risk for recurrent malignant ventricular arrhythmias, thus little benefit for ICD No clinical trials to support this approach

AVID Trial: Amiodarone Versus ICD for Secondary Prevention VT/VF, EF < 40% Registry of all patients screened Excluded patients with transient or correctable cause of VT/VF Wyse et al, JACC 2001: Assessed mortality of patients screened but excluded from AVID due to correctable cause versus patients enrolled in AVID for secondary prevention of VT/VF and who received an ICD

Transient/Reversible Causes Determined by the AVID principal investigator at each site Classified as New Q-wave MI New non Q-wave MI Other ischemic event Proarrhythmic drug reaction Electrolyte imbalance (hypo-K/-Mg) Other

Transient or Correctable Causes of VT/VF (n = 278) Ischemic events New MI Non-Q-wave Q-wave Transient ischemia, no MI Other or unknown* Electrolyte imbalance Antiarrhythmic drug reaction n 183 161 83 78 22 50 27 18 % 65.8% 57.9% 29.9% 28.0% 7.9% 17.9% 9.7% 6.5% *Cocaine, or illicit drug use, sepsis, hypoxia, electrocution, drowning and other Wyse, et al. J Am Coll Cardiol 2001;38:1718-1724

Patients with Primary VT/VF versus VT/VF due to Transient/Correctable Cause n Age (yrs) LVEF Men CAD Cardiomyoapthy Prior history VF VT Atrial fibrillation MI CHF Diabetes CABG/PTCA AAD Primary 2,013 63.4 ± 12.3 0.35 ± 0.15 76.6% 74.9% 3.1% 4.3% 15.0% 22.3% 57.5% 38.4% 17.8% 26.2% 13.1% Transient Correctable Cause 278 61.0 ± 12.7 0.41 ± 0.15 72.3% 82.0% 2.9% 9.7% 18.7% 44.2% 21.6% 15.8% 13.7% p Value 0.004 < 0.001 0.132 0.851 0.206 0.007 0.148 0.406 0.003 0.783 Transient Cause: Younger, Better EF with Less HF, Less MI …but with More CAD and Less Revascularization Wyse, et al. J Am Coll Cardiol 2001;38:1718-1724

After adjustment for differences in patient variables Survival Curves of Primary VT/VF vs Transient/Correctable Cause for VT/VF After adjustment for differences in patient variables 100 – 90 – 80 – 70 – 60 – 50 – Primary VT/VF Cumulative Survival Transient VT/VF p = 0.008 182 364 546 728 910 1092 Days No. at Risk Primary VT/VF Transient VT/VF 2013 278 1722 238 1067 187 508 82 Wyse, et al. J Am Coll Cardiol 2001;38:1718-1724

Survival Curves for Non Q wave MI, Q wave MI, and Ischemia Without MI Patients with a transient/correctable cause for VT/VF 1.0 – 0.9 – 0.8 – 0.7 – 0.6 – 0.5 – Non Q wave MI, n=83 Cumulative Survival Q wave MI, n=78 p = NS Ischemia w/o MI, n=22 182 364 546 728 910 1092 Days Wyse, et al. J Am Coll Cardiol 2001;38:1718-1724

VT/VF in Setting of Acute Ischemia and Preserved EF (No Scar) Often Exercise related Considered low risk for recurrent VT/VF after successful management of ischemia How many pts have only 1 Ischemic event? Compliance with medical therapy Reversibility of contributing features: DM, HTN, Hyperlipidemia Few trials

VT/VF in Setting of Acute Ischemia and Depressed EF/Prior Scar due to Prior MI Is VT/VF due to transient ischemia or due to scar-mediated VT or multifactorial? Will revascularization prevent further episodes of SCD? What is the impact of revascularization on scar? Will revascularization manage a reentrant VT circuit?

Impact of CABG on SCD Natale et al 1994 J Cardiovasc Electrophysiol Retrospective review of 58 pts with SCD and CABG with ICD placement EP testing before and after CABG Mean EF 31%; F/U of 4.6 years 22/58 (38%) with appropriate ICD therapies EP testing was not predictive Including post CABG EP testing

Impact of CABG on SCD Daoud et al, 1995 Am Heart J 23 pts survived SCD + noninducible at EP testing + ischemia on stress testing CABG + ICD Mean EF 28%; F/U 3.1 years 10/23 (43%) with ICD shocks No clinical differences between pt with vs without ICD shocks Conclusion: CABG not protective; no variables predicted ICD therapy

Conclusion: Transient (Acute) Ischemic Causes of VT/VF Limited research…presumed not to be at increased risk for recurrent arrhythmias It is sometimes difficult to ascertain with confidence that the VT/VF is reversible Approach must be individualized for the patient and clinical scenario Accomplish 3 goals: Correctly identify all contributing features; and, Fully correct the reversible cause(s); and, High degree of confidence that reversible cause(s) will not recur