VULNERABLE PATIENT SYMPOSIUM SCA Risk Factors: What are the triggers?

VULNERABLE PATIENT SYMPOSIUMSCA Risk Factors:What are the triggers?

SOBERING STATS • 30-50% SCD that are due to CAD occur as first cardiac event • 1/3 SCD occur in pts with known CAD or risk markers but power insufficient to be useful marker • Only a small % have well established risk markers (ICD trials) • Therefore, >2/3 unable to predict Zipes and Wellens Circ 1998; 98:2334; Myerburg JCE 2002; 13:709;

PROBLEMS WITH RISK FACTORS • LACK OF SPECIFICITY, SENSITIVITY, PREDICTIVE ACCURACY • ABLE TO IDENTIFY POPULATIONS AT RISK BUT NOT INDIVIDUAL • Present risk factors identify risk of developing SHD rather than proximate precipitator • Need individual-specific predisposition: single patient probabilities, not population predictions • Lack insight into mechanisms of SCD Zipes and Wellens Circ 1998; 98:2334; Myerburg JCE 2002; 13:709;

Previous Sudden Cardiac Arrest Event or Prior Episode of Ventricular Tachyarrhythmia (VT) Decreased LVEF and heart failure Previous Myocardial Infarction (MI)/Coronary Artery Disease (CAD) Ventricular Ectopy in Chronic Ischemic Heart Disease; PVCs during recovery from TME EP/ECG parameters: QTc. QRSd, HRV, BRS, EPS, TWA, SAECG, QT dispersion Atrial fibrillation Smoking Obesity, DM Inactivity Fatty acid metabolism: mitochondrial defects Serum biomarkers: cytokines, other proteins Inflammation: (CRP), troponin Molecular markers: beta receptor subtypes Genetics: control of substrate, thrombosis precipitators, inherited arrhythmias Single nucleotide polymorphisms (SNPs): ion channels, other Temperature Perfusion patterns: MRI Heart rate turbulence Risk Factors for SCA NEW STANDARD

Time Dependence of Mortality Risk Post-MI: MADIT-II % Mortality Time from MI (n = 296) (n = 284) (n = 290) (n = 289) Hazard Ratio 1.08 (p = 0.81) 0.56 (p < 0.001) 0.56 (p< 0.001) 0.56 (p < 0.001) David J. Wilber MD, NASPE 2003. Abstract ID. 100865

Time Dependence of Mortality Risk Post-MI Maastricht Circulatory Arrest Registry: • In 224 SCA victims, only 4% were due to an acute MI. • The median time from MI to SCA was 9 years in 92 patients (41% of total). Gorgels PMA. European Heart Journal. 2003;24:1204-1209.

WHAT TRIGGERS SUDDEN CARDIAC DEATH?“Why Did He Die On Tuesday and Not On Monday? Or On Wednesday?” Adapted from an editorial (Zipes DP Less heart is more. Circulation 107:2531, 2003) for a paper on ventricular remodeling by Pfeffer and Braunwald

ANATOMIC/FUNCTIONALSUBSTRATE TRANSIENT INITIATINGEVENTS Coronary artery disease Cardiomyopathy Dilated Hypertrophic Right ventricular dysplasia Valvular Congenital Primary electrophysiological Neurohumeral Developmental Inflammatory, infiltrative, neoplastic, degenerative, toxic Neuro/endocrine Drugs Electrolytes, pH, pO2 Ischemia/reperfusion Hemodynamic Stretch Arising/Stress/Sleep ALCOHOL EMD Asystole VT VF Reentry Automaticity Triggered activity Block/cell-to-cell uncoupling Zipes, Wellens Sudden Cardiac Death Circulation 1998 ARRHYTHMIA MECHANISMS Zipes and Wellens Circ 1998; 98:2334

40 yo man developed incessant SVT after second MI and development of RBBB Rate 74 bpm Rate 81 bpm Spontaneous onset SVT Prystowsky, Heger, Jackman, Naccarelli and Zipes AHJ 103:426-30, 1982

Atrial pre-excitation when His is refractory established presence of a concealed accessory pathway Early A AHJ 103:426-30, 1982

HV interval 50 ms: AP refractory REMODELING REMODELING THAT ALTERS CONDUCTION BY A FEW MSEC CAN PRECIPITATE TACHYCARDIA IN A SUBSTRATE PRESENT BUT DORMANT FOR YEARS 74 bpm 81 bpm HV interval 90 ms post RBBB: AP conducts and SVT is initiated. AHJ 103:426-30, 1982

WHY DO SOME PVCs INDUCE VT BUT OTHERS DO NOT?EPICARDIUM IS MORE SENSITIVE TO THE EFFECTS OF ISCHEMIA THAN IS THE ENDOCARDIUM. Transmural Reentry Triggered by Epicardial Stimulation during Acute Ischemia in Canine Ventricular Muscle Wu J, Zipes DP American Journal of Physiology 283: H2004-11, 2002

OPTICALMAPPING Di-4-Anepps and cytochalasin D

Asymmetrical conduction initiated by epi- & endocardial stimulation during acute ischemia

“WINDOWS OF OPPORTUNITY DURING ISCHEMIA” TIMING IS CRITICAL FOR DEVELOPMENT OF REENTRANT VT v. NONE EPICARDIAL v. ENDOCARDIAL PVCS Heterogeneity precludes safe and effective pharmacotherapy but supports benefits of ICDs

Optical Mapping of the Functional Reentrant Circuit ofVentricular Tachycardia in Acute Myocardial Infarction Jianyi Wu, MD Tamana Takahashi, MD Pascal van Dessel, MD, PhD William Groh, MD John Miller, MD Douglas P. Zipes, MD SUBMITTED FOR PUBLICATION

Therefore, timing and activation sequence determine whether or not VT/VF will occur after MI.But, can ischemia predispose to VT/VF via other mechanisms?

Prior ischemia enhances arrhythmogenicity in isolated canine ventricular wedge model of Long QT 3 Norihiro Ueda, Douglas P. Zipes, Jiashin Wu Krannert Institute of Cardiology, Indiana Univ. Sch. of Medicine IN PRESS CARDIOVASCULAR RESEARCH

Conclusions A prior episode of acute ischemia, even after apparent electrophysiologic recovery, enhances the arrhythmogenicity of ATX II (LQT3 model) through the development of EADs and reentry. CAN ISCHEMA “SENSITIZE” PATIENTS WITH LQTS, OR OTHER DISEASE STATES, TO DEVELOPING SCD?

TRIGGERS • MYOCARDIAL EP PROCESSES PROBABLY DETERMINE ONSET/LACK OF VT/VF/SCD • DIFFICULT TO MEASURE CLINICALLY; INDIRECT EP SURROGATES • MUST CONTINUE TO RELY ON OTHER INDIRECT RISK FACTORS FOR NOW • BUT MUST HAVE AED DEPLOYMENT FOR IMMEDIATE RESPONSE TO SAVE LIVES IN THE FORSEEABLE FUTURE

VULNERABLE PATIENT SYMPOSIUM SCA Risk Factors: What are the triggers?