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Predicting the Risk of Sudden Cardiac Death Leon Glass Isadore Rosenfeld Chair in Cardiology, McGill University, Montreal, Quebec • Disclosure – Licensing and research contract with Medtronic Histogram of ΔRR Intervals during AF Data from www.physionet.org Patents describing algorithm are licensed to Medtronic • Medtronic Reveal XT™ ICM Offers Important Insights into Patients’ Irregular Heart Rhythms, Including Atrial Fibrillation • MINNEAPOLIS – Feb. 11, 2009 – Medtronic, Inc. (NYSE: MDT) today announced the commercial availability of its Reveal XT™ Insertable Cardiac Monitor (ICM) in the United States, along with the nation’s first implant of the new device. The revolutionary Reveal LINQ™ Insertable Cardiac Monitoring System is designed to help your doctor quickly diagnose and treat irregular heartbeats that may be related to unexplained fainting. • “Given the desirability of accurate risk stratification [for sudden cardiac death] and the long history of research in this area, it is important to understand why the field is not further advanced.” Jeffrey Goldberger et al. Circulation 2011 Key Questions • Laboratory: Understand complex rhythms and transitions between rhythms in model cardiac systems? • Clinical: What therapies are available? • Clinical: Who is at high risk for tachyarrhythmic sudden cardiac death? Dynamics in chick heart cells – transitions to reentrant dynamics Thanks to my colleague Alvin Shrier A Resetting Experiment (in chicken heart) Chaos in periodically stimulated heart cells Predict chaos based on 1D circle maps determined from resetting experiments. Resetting depends on phase of stimulus. (Guevara, Glass, Shrier Science ,1981) Reentrant arrhythmias: period of oscillation is set by a reentrant circuit NOT a pacemaker ) Macroscope for Studying Dynamics in Tissue Culture Bub, Hodge,Shrier Dynamics in a Ring of Cardiac Cells Pacemaker Nagai, Gonzalez, Shrier, Glass, PRL (2000) Reentry Cardiac Ballet FitzHugh-Nagumo Model of Propagation Spiral waves in cardiac tissue role in atrial and ventricular tachycardias? • Theoretical predictions – Wiener and Rosenblueth, Krinski, Winfree et al. • Experimental observations – Jalife, Witkowski and many others subsequently Bursting Rhythms in Cardiac 2D Tissue Culture Bub, Glass, Publicover, Shrier, PNAS (1998) periodic periodic periodic burst burst high burst mid density irreg.burst irregular irregular low 0 mm 5 mm (Bub, Glass, Shrier, PRL 2005) 10 mm a glycyrrhetinic acid Cellular automata model – pacemakers, heterogeneity, fatigue, connectivity R=3, q=0.35 R=1.8, q=0.35 Target patterns (‘periodic’) bursting Universal organization: Fatigue vs Coupling (Bub, Glass, Shrier, PRL 2005) Spiral formation in tissue culture with a central obstacle Quail et al., Physical Review Letters 2014 Role of asymmetry in determining chirality of spirals Quail et al., unpublished 2014 Key Questions • Laboratory: Understand complex rhythms in model cardiac systems? • Clinical: What therapies are available? • Clinical: Who is at high risk for tachyarrhythmic sudden cardiac death? Implantable Cardioverter Defibrillators (ICD) reduce the incidence of sudden death due to rapid arrhythmias But it is difficult to assess which patients will benefit from an ICD Cheney's change-out: Vice president's ICD replaced July 30, 2007 Steve Stiles Washington, DC - Vice President Dick Cheney's implantable cardioverter-defibrillator (ICD) was replaced Saturday at George Washington University Hospital, news outlets reported over the weekend, citing a statement made by his deputy press secretary Megan McGinn. There were no complications, and the vice president emerged from the hospital about four hours after he entered, according to the reports. The procedure had been scheduled after a check of the device during the vice president's annual physical last month showed the battery was nearing the end of its lifetime. The device was implanted in 2001 and, according to the vice president's office, on no occasion did it deliver a shock. The lead system wasn't replaced. Cheney's cardiovascular health history is one of the world's most publicly documented. As reported over the years by heartwire and news outlets virtually everywhere, it includes four heart attacks before he became vice president, a CABG, two PCIs, and an episode of deep venous thrombosis on a recent international tour. From the internet Re: Cost of ICD Last year when I was in the hospital, I was told it would cost $30,000 for the ICD and the procedure. We lost count at $100,000 for the complete hospitalization. I am thankful I was able to pay my insurance premiums. Key Questions • Laboratory: Understand complex rhythms in model cardiac systems? • Clinical: What therapies are available? • Clinical: Who is at high risk for tachyarrhythmic sudden cardiac death? Sudden death. Why did this 82 yr old woman die at 19:13:53 and not at 16:05:55 ? www.physionet.org Most sudden cardiac death occurs in people few risk factors (Myerburg et al., 1997) CARISMA (Huikuri et al. EHJ 2009) More PVCs increase the risk of death Kostis et al. 1987 Cardiac Arrhythmia Suppression Trial (CAST). NEJM 321:406 (1989); 324:781 (1991) Analysis of arrhythmias in people • Risk stratification for sudden cardiac death • First analyze mechanisms of arrhythmia in individual patients (this is NOT commonly done now) Dynamics of PVCs What is the mechanism of this rhythm? 16 year old boy who had an atrial septal defect corrected at a young age who fainted on the lunch line in a school cafeteria. Does he have a high risk for SCD? Pure Parasystole Rules of Pure Parasystole Count the number of sinus beats between PVCs beats. In this sequence: (1) there are 3 integers; (2) one is odd; (3) the sum of the two smaller is one less than the largest. Glass, Goldberger, Belair (1986) Stochastic Model of Parasystole Heartprint of a Patient Other mechanisms than parasystole PhysioBank’s Sudden Cardiac Death Database Heartprint from a patient who had sudden cardiac death - Record 47 - Potassium channel defects • Long QT due to repolarization defects • Possibility for early afterdepolarizations leading to PVCs and inducing tachycardia • Rule of “bigeminy” – bigeminal patterns tend to perpetuate. Possible reason – following a PVC there is a compensatory pause leading to a longer recovery time and long QT with a PVC New Indices for Risk Assessment • The coupling interval (short versus long) • The maximum value of the NIB • Examine data from the CARISMA study – (data from patients who have had a heart attack and who have poor cardiac function) (Lerma, Ghanem, Gorelick, Glass, Huikuri, 2013) Kaplan-Meier plots for CARISMA Data • “Given the desirability of accurate risk stratification [for sudden cardiac death] and the long history of research in this area, it is important to understand why the field is not further advanced.” Jeffrey GOLDBERGER et al. Circulation 2011 • Possible Reasons : (i) impossible; (ii) the wrong people are studying the problem; (iii) the data concerning arrhythmias is not good enough; (iv) new strategy needed – mechanisms in individual patients. Acknowledgments Collaborators: Michael Guevara, Alvin Shrier, Glen Ward, Ary Goldberger, Jacques Bélair, Hiroyuki Ito, Verena SchulteFrohlinde, Taishin Nomura, Eugene Stanley, Plamen Ivanov, Gil Bub, Hortensia González, Yoshihiko Nagai, Katsumi Tateno, Kevin Hall, Jacques Billette, David Christini, Claudia Lerma, Chiu Fan Lee, Ben Steinberg, Alex Hodge, Min-Young Kim, Bart Borek, Alex Gorelick, Raja Ghanem, Heikki Huikuri, TK Shajahan, Thomas Quail, Manli Marquez Funding Sources: NSERC, CIHR, MITACS, NIH (National Resource for Complex Physiologic Signals), Canadian Heart and Stroke Foundation, Medtronic