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New Paradigm of Defibrillation: Towards Painless Therapy

ProQuest Dissertations and Theses, 2011
Dissertation
Author: Wenwen Li
Abstract:
Sudden cardiac death (SCD) causes approximately 300,000-400,000 deaths a year in the United States. It usually starts as ventricular tachycardia (VT) and then degenerates into ventricular fibrillation (VF). Implantable cardioverter defibrillator (ICD) therapy is the only reliable treatment of VT/VF and has been shown to effectively reduce mortality by many clinical trials. However, high-voltage ICD shocks could result in myocardial dysfunction and damage. The majority of patients receiving ICD therapy have a history of coronary disease; their hearts develop myocardium infarction, which could provide a substrate for reentrant tachy-arrhythmias. Other than lethal ventricular tachycardia, atrial fibrillation (AF) became the most common arrhythmia by affecting 2.2 to 5.6 millions of Americans. The complications of AF include an increased rate of mortality, heart failure, stroke, etc. In this dissertation, we explore mechanisms of sustained ventricular and atrial tachyarrhythmias and the mechanisms of defibrillation using the conventional high-voltage single shock. Through the use of novel fluorescent optical mapping techniques and several animal models of ventricular and atrial arrhythmias, we develop and validate several novel low-voltage defibrillation therapies for atrial and ventricular arrhythmias. Several important previous studies on mechanisms of arrhythmia maintenance and termination using mathematical and experimental models are overviewed in Chapter 2. A study on multiple monophasic shocks improving electrotherapy of ventricular tachycardia in rabbit model of chronic infarction is presented in Chapter 3. Ventricular arrhythmias and low-voltage defibrillation therapy are studied in a more clinically-relevent in vivo canine model of healing myocardial infarction in Chapter 4. Finally, Chapter 5 presents a novel multi-stage low-energy defibrillation therapy for atrial fibrillation in in vivo canine hearts.

5 
 Table of Contents

ABSTRACT
OF
THE
DISS ERTATION ................................ ................................ .................... 2 
 Acknowledgements ................................ ................................ ................................ ................. 4 
 1 
 Introduction ................................ ................................ ................................ ........................ 7 
 1.1 
 Ventricular
Arrhythmia ................................ ................................ ................................ ....... 7 
 1.2 
 ICD
Therapy
for
Ventricular
Arrhythmias ................................ ................................ .... 9 
 1.3 
 Atrial
Arrhythmia ................................ ................................ ................................ ................ 11 
 1.4 
 Defibrillation
Waveforms ................................ ................................ ................................ . 13 
 1.5 
 Scope
and
Procedure
of
the
Dissertation ................................ ................................ .... 16 
 2
 
 Defibrillation
Therapy
towards
Lower
Energy ................................ ................... 17 
 2.1 
 Virtual
Electrode
Polarization
Theory ................................ ................................ ......... 17 
 2.2 
 A
Mathematical
Model
of
VEP
Unpinning
Theory ................................ ..................... 23 
 2.3 
 Mechanisms
of
Termination
of
Ventricular
Tachycardia
in
an
 in
vitro 
Acute
 Model
of
Infarction
Border
Zone ................................ ................................ ............................... 25 
 2.4 
 Mechanis ms
of
Termination
of
Ventricular
Tachycardia
in
Rabbit
Heart
with
 Chronic
Infarction ................................ ................................ ................................ .......................... 28 
 3
 
 Multiple
Monophasic
Shocks
Improve
Electrotherapy
of
Ventricular
 Tachycardia
in
a
Rabbit
Model
of
Chronic
Infarction ................................ ............... 34 
 3.1 
 Abstract ................................ ................................ ................................ ................................ ... 34 
 3.2 
 Keywords ................................ ................................ ................................ ................................ 35 
 3.3 
 Introduction ................................ ................................ ................................ .......................... 35 
 3.4 
 Materials
and
Methods ................................ ................................ ................................ ...... 37 
 3.4.1


Survival
Surgery ................................ ................................ ................................ .............................. 37 
 3.4.2


Heart
Preparation ................................ ................................ ................................ ........................... 38 
 3.4.3


Acute
Experimental
Protocol ................................ ................................ ................................ ..... 38 
 3.4.4


Data
Analysis ................................ ................................ ................................ ................................ .... 39 
 3.5 
 Results ................................ ................................ ................................ ................................ ..... 40 
 3.5.1


Initiation
of
sustained
ventricular 
arrhythmias ................................ ................................ 40 
 3.5.2


Mechanism
of
sustained
ventricular
arrhythmia
in
CMI ................................ ............... 43 
 3.5.3


Efficacy
of
Antitachycardia
Pacing
(ATP) ................................ ................................ ............. 44 
 3.5.4


Termination
of
sustained
VT
by
a
singl e
biphasic
shock ................................ ............... 45 
 3.5.5


Termination
of
sustained
VT
by
five
monophasic
and
five
biphasic
shocks ......... 51 
 3.6 
 Discussion ................................ ................................ ................................ .............................. 55 
 3.6 
 Study
Limitations ................................ ................................ ................................ ................. 59 
 4
 
 Lo w
Voltage
Multiple
Shock
Therapy
of
VT
in
Canine
Hearts
with
Healing
 Infarction ................................ ................................ ................................ ................................ . 61 
 4.1 
 Abstract: ................................ ................................ ................................ ................................ .. 61 
 4.2
 



 Key
Terms ................................ ................................ ................................ .............................. 63 
 4.3 
 Introduction ................................ ................................ ................................ .......................... 63 
 4.4 
 Methods ................................ ................................ ................................ ................................ ... 65 
 4.4.1


Surgical
Procedures ................................ ................................ ................................ ....................... 65 
 4.4.2


Electrode
Configuration ................................ ................................ ................................ ............... 66 
 4.4.3


Induction
of
Ventricular
Tachycardia ................................ ................................ .................... 67 
 4.4.4


Defibrillation
Wa veforms ................................ ................................ ................................ ............ 68 
 4.4.5 


 Data
Analysis ................................ ................................ ................................ ................................ .... 70 
 4.5 
 Results ................................ ................................ ................................ ................................ ..... 71 


6 
 4.5.1 


 VT
in
Canine
Hearts
with
4 ‐ day
Infarct ................................ ................................ ................. 71 
 4.5.2


Anti ‐ tachycardia
Pacing
(ATP) ................................ ................................ ................................ .. 73 
 4.5.3


Ventricular
Shock
Excitation
Threshold ................................ ................................ ............... 73 
 4.5.4


Cardioversion
Thresholds
of
a
Single
Monophasic
Shock ................................ ............. 73 
 4.5.5


Cardioversion
Thresholds
of
Multiple
Shock
Therapies ................................ ................ 77 
 4.6 


 

 Discussion ................................ ................................ ................................ .............................. 80 
 4.7

 
 

 Conclusions ................................ ................................ ................................ ............................ 84 
 5 
 Low
Energy
Multi ­ stage
Atrial
Defibrillation
Therapy ................................ ...... 85 
 5.1 
 Abstract ................................ ................................ ................................ ................................ ... 85 
 5.2 
 Key
Words ................................ ................................ ................................ .............................. 86 
 5.3 
 Introduction ................................ ................................ ................................ .......................... 86 
 5.4 
 Methods ................................ ................................ ................................ ................................ ... 89 
 5.4.1 


 Surgical
Procedures ................................ ................................ ................................ ....................... 89 
 5.4.2


Electrode
Placement ................................ ................................ ................................ ...................... 90 
 5.4.3


 Atrial
Fibrillation
Induction
and
Definitions ................................ ................................ ...... 90 
 5.4.4


Defibrillation
Vectors
and
Waveforms ................................ ................................ .................. 92 
 5.4.5


Statistical
Analysis ................................ ................................ ................................ .......................... 94 
 5.5 
 Results ................................ ................................ ................................ ................................ ..... 95 
 5.5.1


Atrial
Fibrillation
Model ................................ ................................ ................................ .............. 95 
 5.5.2


Shock
Excitation
Threshold ................................ ................................ ................................ ........ 96 
 5.5.3


Testing
MP
versus
BP
and
single
versus
multiple
shocks ................................ ............. 99 
 5.5.4


Development
of
a
low
energy
m ultiple
stage
defibrillation
therapy ...................... 101 
 5.5.5


The
relationship
of
shock
vector
to
atrial
DFT ................................ ................................ 102 
 5.5.6


Safety
considerations ................................ ................................ ................................ .................. 104 
 5.6 
 Discussion ................................ ................................ ................................ ........................... 104 
 5. 7 
 Conclusions ................................ ................................ ................................ ......................... 110 
 5.8 
 Sources
of
Funding ................................ ................................ ................................ ........... 111 
 5.9 
 Disclosures ................................ ................................ ................................ .......................... 111 
 6 
 Conclusions
and
Future
Directions ................................ ................................ ........ 112 
 6.1 
 
 Concluding
Remarks ................................ ................................ ................................ ....... 112 
 6.2
 
 Future
Directions ................................ ................................ ................................ ............. 118 
 6.2.1 
 Mechanisms
of
Defibrillation
using
Multi ‐ stage
Therapy
for
AF ........................... 118 
 6.2.2 
 Low ‐ voltage
Defibrillation
therapy
for
VT
in
canine
model
of
healing
infarct 120 
 6.2.3 
 Implantable
Low ‐ voltage
Atrial
Defibrillation
Therapy
in
canine
hearts .......... 121 
 Appendix
A ................................ ................................ ................................ ............................ 123 
 A.1 
 Multi ­ Stage
Defibrillation
Therapy ................................ ................................ ............ 123 
 A.1.1
 

 Hardwar e ................................ ................................ ................................ ................................ ......... 123 
 A.1.2
 

 Three ‐ stage
therapy
LabVIEW ................................ ................................ ................................ 125 
 A.1.3
 

 Data
analysis
software
LabVIEW ................................ ................................ ........................... 126 
 A.2
 
 Rotating ­ field
Defibrillation
Therapy ................................ ................................ ...... 127 
 A.2.1
 

 Hardware ................................ ................................ ................................ ................................ ......... 1 27 
 A.2.2
 

 Rotating ‐ field
Therapy
LabVIEW ................................ ................................ ........................... 128 
 References ................................ ................................ ................................ ............................. 130 
 


7 
 1

Introduction


 
 
 1.1

Ventricular Arrhythmia


 
 Sudden cardiac death (SCD) caused by ventricular tachyarrhythmias (VT and VF) is the most prevalent immediate cause of mortality, which counts for 300,000 - 400,000 deaths per year in the United States

1 .

SC D most often occurs in patients with heart disease. In 90 percent of adult victims of SCD, two or more major coronary arteries are narrowed by fatty buildups. Scarring from a prior heart attack is found in two - thirds of victims. Patients diagnosed with congestive heart failure are also at a high risk for SCD.

Three mechanisms underlie the initiation and maintenance of VT: automaticity, triggered activity, and reentry. Abnormal automaticity causes a region of ventricular cells to depolarize at an accelerated rate, which overrides sinus rhythm. Triggered activity refers to action potential generation when oscillations in transmembrane resting potential reach activation th reshold. There are two forms of t riggered activity : early or delayed afterdepolarization. Reentrant VT requires specific electrophysiological substrates, including unidirectional conduction, functional or structural conduction block, and a region of “slow

8 
 conduction .” Reentrant VTs are often seen in structurally abnormal hearts due to ischemic or non - ischemic heart diseases . Ventricular scars consist of regions of dense fibrosis with collagen and fibroblast s.

There are also surviving myocyte bundles overlyi ng on the scars , which are called infarction boarder zone

2 . The dense fibrosis creates conduction block for the formation of reentry circuit

3 . The surviving myocytes form a common pathway or isthmus with slowed conduction though the scar. Therefore, functional or structural slowed conduction and conduction block set the stage f or sustained reentry VT. Most scar - related reentrant VT is monomorphic since the reenty circuit is stable and pin to the infarction border zone of the scar. Although a single sc ar can support several different reentrant circuits, a patient with myocardial infarction can have different morphologies of monomorphic VT

4 .

Without cardioversion in time, VT will quickly degenerate to VF, which is driven by many turbulent wavelets and has a very dynamic and complex pattern of wave propagation. Transition from VT to VF is due to the increased heterogeneity in refractoriness of the cardiac tissue induced by acute ischemia or other chronic heart diseases. Several mechanisms have been proposed to explain the underlying dynamics of VF. One widely studied mechanism is multiple wavelets

VF and is characterized by the presence of multiple self - sustained electrical wavelets. Another well - established hypothesis is mother rotor VF, in which VF is deemed to be driven by one pre dominant fa st source of excitation 5 , 6 . Preexisting tissue heterogeneity plays an important role in both hypotheses.

9 
 Although VF is likely responsible for an overwhelming majority o f SCDs, recent studies from ICD patients indicate that up to 90% of detected spontaneous episodes of ventricular arrhythmias are either VT or fast VT (FVT)

7 . Therefo re, in most instances, ICD therapy can be targeted to treat VT before it degenerates to VF.


 1.2

ICD Therap y for Ventricular Arrhythmias

Over the past two decades, implantable cardioverter defibrillators (ICD) have become the standard of care for patien ts at risk for SCD. Multiple multicenter trials have demonstrated that ICD implantation is the most effective therapy for SCD 8 - 11 . Despite the proven efficacy of IC Ds in saving lives, at least three complications have been associated with high voltage shocks. Firstly, high voltage shocks produce substantial pain, which is often associated with anxiety, fear and depression, reduced quality of life 12 . Secondly, while the majority of ICD shocks are appropriate, studies estimate that approximately 20 percent of patients with ICDs may experience inappropriate shocks within about three years of implant in response to a non - lethal arrhythmia or electrical noise within the device system 13 , 14 . Finally, we have shown that ICD shocks could induce myocardial damage via electroporation 15 evident from post - shock RV endocardial electrograms, which were linked with increased risk of heart failure and death 16 . Sweeney et al

10 
 demonstrated that ICD shocked patients have substantially higher ventricular arrhythmia episode burden and poorer survival compared with anti - tachycardia paced - only patients 17 . These results indic ate that exclusive reliance on high voltage shocks could degrade ICD survival benefit. Therefore, lower energy strategies have been promoted to improve survival and quality of life in ICD patients. Recent adoption of shock - reduction programming strategie s, includ e

lengthening the number of intervals to detect VF, using more sensitiv e supraventricular tachycardia (SVT) discriminators, and employing ATP reduced shocks by 17 to 28% 18 . However, these efforts to prevent the delivery of shocks with increased programming have not fully eliminated the need for high energy shocks to terminate VF or the problems of inappropriate shock delivery for SVTs. In addition, ICD malfunction has been problematic in the cardiac rhythm management field. According a recent meta - analysis of industrial reports of implantable device malfunctions to the FDA from 1990 - 2002, ICD malfunction replacement rate is significantly higher than for pacemakers . A detailed breakdown of causes of malfunctions shows that high - voltage components, connectors, and circuits are mostly to blame for malfunctions: battery/capacitor (31.7%), charge circuit (17.4%), connector/header (9.3%), mi scellaneous electri cal (24.9%). The difference in reliability between pacemakers and ICDs appears to come primarily from hi gh - voltage hardware components

19 . Thus an unmet need for low energy electrotherapy challenges current high - energy shock paradigm.

11 
 Treatments, depending on the severity of symptoms and degree of structural heart disease, usually combine medications, device implantation, and catheter ablation. Antiarrhythmic drugs have been disappointing. Catheter ablation is used for treatment of VT/VF associated with cardiomyo pathy as well as idiopathic VT in structurally normal heart. Focal sources of ventricular arrhythmogenesis are particularly targeted by ablative therapy. However, ablation is typically adopted as an adjunct to ICD therapy, because ablation often fails due to anatomically complex multiple reentrant circuits, harbored within midmyocardium.

1.3

Atrial Arrhythmia


 
 Besides lethal ventricular arrhythmias, atrial fibrillation (AF) is the most common arrhythmias encountered in clinical medicine. In 1999, AF affects

approximately 2.2 million adults in the United States 20

and is the most common sustained heart rhythm disturbance observed in clinical practice. In the same year, a total of 66,875 deaths with AF as a contributing cause occurred, and a total of 1,765,304 hospi talizations (137.1 per 1,000 Medicare enrollees) were reported among persons with AF in the Medicare population.

12 
 The mechanism of paroxysmal AF is a single or multiple ectopic foci localized usually around pulmonary veins

21 . This type of AF could be cure d by catheter ablation. However, in chronic AF, the prevailing theory for its mechanism is that multiple random wavelets of activation coexist to create a

dis organized atrial excitation pattern

22 . There is also a hypothesis that AF may be induced and maintained by several stable, self - sustained rotors generating exceedingly high frequency excitation, wit h fibrillation tissue conducti on in atria

23 . Moreover, after onset of AF, atrial electrophysiological properties changed with time and the threshold of inducing and sustaining the arrhythmia was lowered . Th is process explained AF progression by a process known as electrical remodeling. Other than electrical remodeling, AF also cause s contractile remodeling and irreversible structural remodeling. Mechanical remodeling manifests as decreased atrial contractili ty , which

stimulates the structural remodeling due to the remo deled enlarged atria

24 . The remodeled atrium then becomes an e lectro - anatomical substrate to sustain AF by allowing more wavelets with smal l er reentrant circuits with

shorter wavelength due to shortening of refractor iness, slowing of conduction, and an increase in heterogeneity of atrial tissue properties . Different from ventricular tachy - arrhythmias, the autonomic nervous system has an impor tant and crucial role in the genesis, maintenance and abruption of AF

25 .

This has been attributed to the heterogeneous distribution of vagal innervation throughout the atria, which increases spatial dispersion of refractory periods.

Although many people live with AF for years, chronic atrial fibrillation is associated with an increased risk of death. AF can decrease the heart's pumping

13 
 ability by as much as 20 to 25 percent. Combined with a fast heart rate over a long period of time, AF can result in congestive heart failure and tachycardia - related cardiomyopathy. It is also a major cardiac cause of stroke

26 . AF requires pharmacological and/or electrical s hocks to restore sinus rhythm. However, medication for this arrhythmia has limited effect, and has the potential for serious side - effects, including promoting ventricular arrhythmias. The external transthoracic cardioversion for AF involves high - volta ge el ectric shocks, thus requiring costly hospitalization and anesthesia . I mplantable atrial defibrillator s

have been previously developed but are not accepted by patients because

the technology employed at that time required high voltage shocks, which exceeded

the patients’ pain threshold .


 
 1.4

Defibrillation Waveforms

In 1899, two physiologists Prevost and Batelli at University of Geneva discovered that they could defibrillate the heart by applying appropriate high current AC or DC shocks directly to the su rface of the myocardium

27 . In 1947, Claud e Beck successfully performed the first case human internal defibrillation on a pulseless 14 - year old boy with exposed chest during surgery. His defibrillator used AC current directly from the wall socket in operating rooms

28 . I n 1939, Gurvich and Yuniev suggested using a single discharge from a capacitor to defibrillate VF

in Soviet Union , thus first introduced DC shock for the purposes of defibrillation

29 .

14 
 In the West,

scientists and clinicians had been used AC sh ock for defibrillation until 1960s. I n the United States, in 1962, Lown et al. reported their success in terminating VT with a single DC monophasic shock in nine patients

30 .

Gurvich was the first person who demonstrate d the superiority of the biphasic waveform over the monophasic in dogs in 1967

31 , while, John Schuder is the first per son who studied and compared the monophasic and biphasic defibri llation waveforms in the West in 1980

32 . Mirowski and his co lleagues produce d the first ICD which then was implanted in a patient at John Hopkins Hospital. Soon after, ATP was added to the device therapy. Later, Schude r 33

together with Ideker’ s 34

continuous work on optimization of biphasic waveform ma d e the contemporary miniature ICD possible.

Current state - of - the - art ICD therapy is based on low energy ATP followed by a high - energy shock with biphasic truncated exponential waveform. Initial biphasic waveform design was based on the Gurvich waveform 35 , 36 , which was generated by an inductor - capacitor - resistor (LCR) circuit resulting in a damped sinusoidal waveform. The Gurvich waveform is widely used in transthoracic defibrilla tors, which can accommodate large inductors. However, implantable device size constraints led to adoption of truncated exponential waveforms with different characteristics 37 . The truncated exponential waveform is generated by a capacitor and high - voltage switch (resistor - capacitor (RC) circuit). Both damped

15 
 sinusoidal and truncated exponential waveforms have been optimized by empirical stud ies varying characteristics of the first and second phases such as duration: the rise - time and decay of each phase, energy ratio and time delay between the two phases, etc. Properly optimized biphasic waveforms of both designs have been shown to significan tly decrease the defibrillation threshold 38 . However, truncated exponential waveform is the dominant approach in ICD therapy due to the size of capacitors and reliability with which a large amount of energy can be transferred from a battery to a capacitor and then to the heart. Capacitor - based design allows a reasonably sized device for implantation in the body.

However, it appears that the existing waveforms were inspired primarily by the circuit designers, without detailed understanding of the biophysical m echanisms of defibrillation. From a physiologic standpoint, it is rather clear that the truncated exponential waveform is not the most efficient way to stimulate cardiac tissue. For example replacing truncated exponential descending waveform with an ascend ing waveform improves DFT by ~15 - 20% 39 , 40 . S uch an improvement is incremental but still not enough to justify s ignificant increase in complexity of the high - energy circuit, which is likely to contribute to malfunctions.

16 
 1. 5

Scope and Procedure of the Dissertation

In this dissertation, we explore mechanisms of sustained ventricular and atrial tachyarrhythmias a nd the mechanisms of defibrillation using the conventional high - voltage single shock . Through the use of novel fluorescent optical mapping techniques and several animal models of ventricular and atrial arrhyt hmias, we develop and validate several novel low - voltage

defibrillation therapies f or atrial and ventricular

arrhythmias. Chapter 2 will first overview several important pre vious studies by several groups on mechanisms of arrhythmia maintenance and termination using mathematical and experimental models.

A study on multiple monophasic shocks improving electrotherapy of ventricular tachycardia in rabbit model of chronic infarction is presented in Chapter 3. Ventricular arrhythmias and low - voltage defibrillation therapy are studied in a more clinically - rele vent in vivo canine model of healing myocardial infarction in Chapter 4. Finally, Chapter 5 discusses a novel multi - stage low - energy defibrillation therapy for atrial fibrillation in in vivo canine hearts.

17 
 2

Defibrillation Therapy towards Lower Energ y


 


2. 1

Virtual Electrode Polarization Theory

When myocardium is exposed to electric field, t ransmembrane voltage of myocytes could be altered during the electric stimulus. Some area of the myocardium is depolarized, where the action potential duration and refractory period is prolonged; some area of the myocardium is hyperpolarized, where the action potential and the refractory period is shortened; while the transmembrane voltage of other area remains the same during shock. The depolarization effect is caused by virtual cathode. And the virtual anode leads to hyperpolarization.

Electric stimuli affect the cardiac tissue through the mechanism of virtual electrode polarization ( VEP ).

VEP

pattern s

induced by

a single monophasic and a single biphasic shock were measured

and compared by

Efimov

41 . He discovered

that a monophasic shock induced post - shock epicardial transmembrane polarization with a highly nonuniform pol arity - dependent pattern. D epolarization (virtual cathode)

occurred around the cathode electrode and

18 
 hyper polarization (virtual anode) appeared close to the anode electrode

41 , 42 . Figure 2.1 shows the three types of tissue responses through the VEP effect produced by the electric shock

43 .


 Figure
 2.1 .
 Three
 types
 of
 tissue
 responses
 to
 virtual
 electrode
 polarization:
 de ‐ e.Kcitation.
prolongation,
and
re ‐ excitation.
Maps
 of
shock ‐ induced
polarization
and
 representative
traces
superimposed
with
control
action
potentials
are
shown.
Shock
 was
 applied
 from
 a
 1 ‐ cm
 electrode
 placed
 in
 the
 left
 ventricular
 cavity.
 Electrical
 activity
 was
 mapped
 from
 the
 left
 ventricular
 epicardiu m.
 At
 the
 end
 of
 a
 +200 ‐ V
 monoplumic
 shock
 (upper
 map),
 negative
 polarization
 produces
 shortening
 of
 action
 potential
 duration
 (upper
 blue
 trace),
 while
 positive
 polarization
 produced
 its
prolongation
(red
trace).
A
stronger
shock
(+300
V)
resulted
in
stro nger
negative
 polarization
 with
.subsequent
 re ‐ excitation
 following
 shock
 withdrawal
 (green
 trace). 
 (From
 Efimov
 et
 al,
 J
 Cardiovasc
 Electrophysiol,
 Vol.
 J
 I,
 pp.
 339 ­ 353, 
 March
 2000) 


19 
 


Figure
2. 2 
 The
spatial
pattern
of
polarization
at
the
end
of
the
shoc k
produced
by
a
 monophasic
 shock
 (+100
 V,
 7th
 ms
 of
 an
 8 ‐ ms
 shock),
 optimal
 biphasic
 shock
 (+100/ ‐ 50
V,
15th
ms
of
16 ‐ ms
shock),
and
nonoptimal
biphasic
shock
(+100/ ‐ 200
 V,
15th
ms
of
16 ‐ ms
shock).
The
area
of
recordings
(11.5
mm311.5
mm)
is
shown
by
 the
 r ed
 box.
 Values
 of
 polarization
 are
 shown
 relative
 to
 the
 preshock
 transmembrane
voltage,
with
red
assigned
to
positive
polarization,
blue
to
negative
 polarization,
and
white
to
areas
of
no
polarization.
RA
and
LA
indicate
right
and
left
 atrium,
 respectivel y;
 BE,
 bipolar
 electrode.
 ( From
 Efimov
 et
 al,
 Circ.
 Res.
 1998;82;918 ­ 925 ) 
 


Then he varied the leading voltage of the second phase of the biphasic shocks from 0% to 200% that of the first phase

44 . The VEP pattern created by b iphasic shocks with a second phase at below 20%

leading - edge voltage of the first phase produced was similar to that of a monophasic shock . The VEP pattern produced by b iphasic shocks with a s econd phase at above 70%

leading - edge voltage of the first phase was similar to that of a monophasic shock with an opposite polarity.

20 
 Post - shock arrhythmias were induced by both of these waveforms . However, when the amplitudes of the second - phase were from 20% to 70% that of first - phase, the biphasic shocks produce d uniform VEP s around zero. This is because the second phase of the biphasic shock reverses the VEP pattern produced by the

first phase of the shock . Examples of transmembrane voltages maps at the end of a monophasic shock and two biphasic shocks with different ratios of

leading edge voltage of first phase to that of second phase are shown in Figure 2. 2 .

The transmembrane voltage of myocardium can be represented in terms of phase. On the phase ma p, phase equals to + π where the upstroke of an action potential is being initiated, while phase equals to - π where the myocardium is fully repolarized, and the phase is ranged from - π to + π during an action potential. A phase singularity is defined as a po int on the phase map that is surrounded by a region of activated area, a region of refractory area, and a region of excitable area. Efimov et al showed that shock - induced phase singularity as a mechanism of initiation of reentrant activity, thus a mechanis m of defibrillation failure

44 . The new waveform (‘Re - excitation’) could be generated at the boundary between a virtual cathode and a virtual anode when the trans membrane voltage gradient in these two regions are strong enough and the virtual anode is strong enough to fully restore the excitability of the myocardium, which is called ‘de - excitation’ effect of the shock

45 . New reentrant circuit could be initiated by the post - shock waveform, which leads to failure of defibrillation. VEP theory of defibrillation is the first theory of defibrillation

that counts the de - excitation

21 
 effect of the shock into the mechanism of defibrillation success and failure.

Figure
 2. 3 
 Creation
 of
 a
 shock ‐ in duced
 phase
 singularity.
 Electrical
 activity
 was
 recorded
 from
 the
 area
 shown
 in
 Figure
 1
 by
 the
 red
 box.
 The
 upper
 left
 panel
 shows
 the
 polarization
 pattern
 at
 the
 end
 of
 a
 1100/2200 ‐ V
 biphasic
 shock
 (15th
 millisecond
 of
 16 ‐ ms
 shock),
 which
 resulted
 in
 a
 single
 extra
 beat.
 The
 scale
 is
 shown
in
millivolts,
calibrated
in
the
same
manner
described
in
Figure
1.
The
point
 of
phase
singularity
is
shown
with
the
black
circle.
The
upper
middle
panel
shows
a
 5 ‐ ms
 isochronal
 map,
 which
 depicts
 the
 initiation
 of
 the 
 postshock
 spread
 of
 activation.
The
map
starts
at
the
onset
of
the
8 ‐ ms
second
phase
of
the
shock
(phase
 reversal).
 The
 lower
 left
 and
 lower
 right
 panels
 show
 optical
 recordings
 from
 several
 recording
 sites
 used
 to
 reconstruct
 the
 activation
 maps:
 the
 eig ht
 sites
 marked
 with
 a
 red
 arrow
 correspond
 to
 the
 lower
 left
 panel,
 and
 the
 16
 sites


22 
 marked
 with
 a
 blue
 arrow
 correspond
 to
 the
 lower
 right
 panel.
 The
 upper
 right
 panel
shows
a
continuation
of
the
reentrant
activation
that
follows
the
middle
panel.
 Reentr ant
 activity
 then
 self ‐ terminated,
 after
 encountering
 refractory
 tissue
 in
 the
 lower
right
corner
of
the
field
of
view
(see
lower
right
panel
traces).
( From
Efimov
et
 al,
 Circ.
Res.
 1998;82;918 ­ 925 ) 


Figure 2. 3 shows a phase singularity that was created b y a shock and a new post - shock waveform was generated at the boundary of a virtual cathode and a virtual anode where has the largest spatial gradient of transmembrane potentials. Based on the phase singularity mechanism, the o ptimal defibrillation waveform s should

produce uniform VEPs over the whole heart. And this explains why the conventional biphasic waveform is superior compared to the monophasic waveform in defibrillation of VF.

As we mentioned earlier, deexcitation effect of the shock could generate new wave front propagating from the depolarized area to the excitable area. On the other hand, the stronger the virtual anode, the more hyperpolarized the myocardium, which means more sodium channels are available to be activated. The larger the number of

recovered sodium channels, the faster the conduction velocity is in the area. Therefore, when the excitable region is activated by the new post - shock wave front generated by the VEP effect, strong deexcitation effect of the shock could cause fast conductio n through the virtual anode region, where

23 
 the excitable gap in the new reentrant circuit is. Therefore, the excitable gap is quickly el iminated by the new wave front. The wave front will hit the refractory region ahead of the excitable gap then vanish, whi ch leads to the success of defibrillation . From the discussion above , we conclude that we could use t he VEP theory of defibrillation to

Full document contains 144 pages
Abstract: Sudden cardiac death (SCD) causes approximately 300,000-400,000 deaths a year in the United States. It usually starts as ventricular tachycardia (VT) and then degenerates into ventricular fibrillation (VF). Implantable cardioverter defibrillator (ICD) therapy is the only reliable treatment of VT/VF and has been shown to effectively reduce mortality by many clinical trials. However, high-voltage ICD shocks could result in myocardial dysfunction and damage. The majority of patients receiving ICD therapy have a history of coronary disease; their hearts develop myocardium infarction, which could provide a substrate for reentrant tachy-arrhythmias. Other than lethal ventricular tachycardia, atrial fibrillation (AF) became the most common arrhythmia by affecting 2.2 to 5.6 millions of Americans. The complications of AF include an increased rate of mortality, heart failure, stroke, etc. In this dissertation, we explore mechanisms of sustained ventricular and atrial tachyarrhythmias and the mechanisms of defibrillation using the conventional high-voltage single shock. Through the use of novel fluorescent optical mapping techniques and several animal models of ventricular and atrial arrhythmias, we develop and validate several novel low-voltage defibrillation therapies for atrial and ventricular arrhythmias. Several important previous studies on mechanisms of arrhythmia maintenance and termination using mathematical and experimental models are overviewed in Chapter 2. A study on multiple monophasic shocks improving electrotherapy of ventricular tachycardia in rabbit model of chronic infarction is presented in Chapter 3. Ventricular arrhythmias and low-voltage defibrillation therapy are studied in a more clinically-relevent in vivo canine model of healing myocardial infarction in Chapter 4. Finally, Chapter 5 presents a novel multi-stage low-energy defibrillation therapy for atrial fibrillation in in vivo canine hearts.