Download Cardiac Arrhythmias: From Simple Models to the Clinic

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