MECHANISMS OF VENTRICULAR ARRHYTHMIAS · • Ischaemic Heart Disease – Acute ischaemia/infarction...
Transcript of MECHANISMS OF VENTRICULAR ARRHYTHMIAS · • Ischaemic Heart Disease – Acute ischaemia/infarction...
MECHANISMS OF VENTRICULAR ARRHYTHMIAS
Nicholas S PetersProfessor of Cardiac Electrophysiology
St. Mary’s Hospital, Imperial College London
HRC 2009
Overview
• Ischaemic Heart Disease– Acute ischaemia/infarction– Reperfusion– Late Post-Infarction
• Dilated Cardiomyopathy• ARVC• Structurally “Normal” Hearts
– RVOT VT– Brugada– Long QT– CPVT
From: Shah, M. et al. Circulation 2005
Basic Concept of Arrhythmogensis
Genetic Predisposition
AcquiredStressors
MyocardialRemodelling
ExtrinsicPrecipitants
Overview
• Ischaemic Heart Disease– Acute ischaemia/infarction– Reperfusion– Late Post-Infarction
• Dilated Cardiomyopathy• ARVC• Structurally “Normal” Hearts
– RVOT VT– Brugada– Long QT– CPVT
de Groot, J. R et al. Cardiovasc Res 2004
Ventricular Arrhythmias in Acute Ischaemia
Ion Channel Changes in Acute Ischaemia
Changes in Action Potential in Acute Ischaemia
Pro-Arrhythmic Changes Acute Ischaemia
• Changes in Action Potential– Relative depolarization of resting potential– Slowing of upstroke– Reduced amplitude– Reduced AP duration
• Increase in Triggers– Calcium Overload
• Acute Cellular Uncoupling
Pro-Arrhythmic Changes Acute Ischaemia
• Changes in Action Potential– Relative depolarization of resting potential– Slowing of upstroke– Reduced amplitude– Reduced AP duration
• Increase in Triggers– Calcium Overload
• Acute Cellular Uncoupling
Pro-Arrhythmic Changes Acute Ischaemia
• Changes in Action Potential– Relative depolarization of resting potential– Slowing of upstroke– Reduced amplitude– Reduced AP duration
• Increase in Triggers– Calcium Overload
• Acute Cellular Uncoupling– Enhanced Inhomogeneity
Pro-Arrhythmic Changes Acute Ischaemia
• Changes in Action Potential– Relative depolarization of resting potential– Slowing of upstroke– Reduced amplitude– Reduced AP duration
• Increase in Triggers– Calcium Overload
• Acute Cellular Uncoupling– Enhanced Inhomogeneity– Conduction Slowing
Shaw, R. M. et al. Circ Res 1997
Changes in Conduction Velocity in Acute Ischaemia
Reperfusion Arrhythmias
Modulation of Gap Junctional Coupling as an Anti-Arrhythmic Strategy to Reduce the Incidence of
Reperfusion Arrhythmias
Fu Siong Ng, et al
Oral Abstract (Young Investigator)Tuesday 20th October, 2pm, Churchill/Gladstone Room
Intermediate Phase Post-MI (hours-weeks)
Nattel 2007
90% repolarization
0
50
100
150
200
250
normal 1 day 5 days 2 weeks 2 month
AP
D (m
s)
normal
1 day
5 days
2 weeks
2 monthCANINE: Ursell et al 1985
Changes in AP duration post MI
Changes in Electrogram post-MI
myocardium
V=0.8 m/s
V= 0.07 m/s
Non-infarcted
5-day-old infarct
2-week-old infarct
2-month-old infarct
fibrosis
273
313
283
Human Ventricular Tachycardia
VT
SR VF
Functional Determinants of Conduction
Infarct border zone
Changes in Gap Junction Distribution Post-MI
Canine 5-day LAD ligation
VT 5-days Post MICanine 5-day LAD ligation
Canine 5-day MILAD ligation
X O
Non-infarcted
5-day-old infarct
2-week-old infarct
2-month-old infarct
Arrhythmogenic Conduction Post-MI
myocardium
V=0.8 m/s
V= 0.07 m/s
DISRUPTEDCONNECTIVITY
From: Shah, M. et al. Circulation 2005
Basic Concept of Arrhythmogensis
Genetic Predisposition
AcquiredStressors
MyocardialRemodelling
ExtrinsicPrecipitants
Dilated CardiomyopathyEpidemiology
• 40/10,000• 5-year mortality 15-50%
– 30% deaths sudden (arrhythmic)• NSVT in 60%
– Independent predictor of SCD• 25% familial
– Heterogeneous• Auto Dom (+) commonest• Auto Rec & X-linked rare
Dilated CardiomyopathyGenetics
Dilated CardiomyopathyGenetics
“All three fundamental mechanisms:
TRIGGERED ACTIVITY, AUTOMATICITY and RE-ENTRY
may play a role but exact contribution of each is unclear.”
1. Roberts AJC 1987; 2. Olshausen BHJ 1984; 3. Olshausen AJC 1988;2. 4. Doval Circ 1996; 5. De Maria AJC 1992
Dilated CardiomyopathyArrhythmia Mechanisms
Afterdepolarisations are facilitated by conditions causing:• intracellular Ca overload• decreased extracellular K and Mg levels• increased circulating catecholamines• ventricular wall stretch
Myocytes show changes in resting membrane potential• enhancement of both normal and abnormal automaticity• increased catecholamine levels• downregulation of β-adrenoceptors
Dilated CardiomyopathyEvidence for Triggered Activity & Automaticity
Greatest body of evidence for mechanism of ventricular arrhythmia in DCM
Sustained monomorphic VTanatomically anchoreddefined by fixed and functional blocrelatively uncommon in DCM
Non-sustained and polymorphic VTsuggestive of variable (functional) blocksubstrate related to myocardial fibrosis
subendo- and subepicardium
Dilated CardiomyopathyEvidence for Reentry
Human DCMVoltage Mapping
Hsia et al 2003
88% VTs from low-voltage area
Myocardial FibrosisLate-gadolinium enhanced CMR
Assomull et al 2006
Myocardial FibrosisLate-gadolinium enhanced CMR
Wu et al 2008
Mechanisms of Ventricular Arrhythmia
• Heterogeneity of action potential duration• Heterogeneity of conduction velocity• Heterogeneity of gap-junctional coupling
• Likely dependent on functional morphology of conduction– Scar– Gap-junctional coupling
• Very poorly understood in DCM
Research Group
• Richard Schilling• Anthony Chow• Oliver Segal • Pipin Kodjojojo• Fu Siong Ng• Wajid Hussain• Riyaz Kaba• Pravina Patel• Prapa Kanagaratnam• Tom Wong• Vias Markides• Julian Jarman• Michael Koa-Wing• Phang Boon Lim• Alex Lyon• Andy Kontogeorgis
• Hetal Patel• Rasheda Chowdhury• Yasmina Martins• YuLing Ma• Emmanuel Dupont
• Nicholas Severs• Wyn Davies• Christopher Fry• Rosaire Gray• Sian Harding
New York• Andrew Wit• Michael Rosen• Ed Ciaccio• David Gutstein• Glen Fishman
Modulators of Remodelling in the Arrhythmogenic Heart
StretchHypertrophyAltered electrical activation
Pacing in Canine Ventricle
membrane
Vm
+
reference
preamplifier
d
STRUCTURAL REMODELLINGLVH: connectivity, conductivity & conduction
Hussain et al. Circ in press
LVH↑ Cx43 per cell↑ cell-to-cell contacts↑ intercalated disks per cellno change end-to-end vs side-to-side
HUMAN UNCOUPLING STUDIESCarbenoxolone 100mg
Before CARB After CARB30
50
70
90
110
130
Vent
ricu
lar
WPV
(cm
/s)
0
100
200
300
AER
P (m
s)
RVA RVOT
Pre - Post -
p=0.2451.5 ± 5.255.3 ± 8.1Longitudinal CV
p=0.00728.7 ± 2.535.4 ± 5.4Transverse CV
StretchBaseline
DOG Stretch in Canine Ventricle
14%
Cx43
Mechanisms of Ventricular Arrhythmia
• Heterogeneity of action potential duration• Heterogeneity of conduction velocity• Heterogeneity of gap-junctional coupling
• Likely dependent on functional morphology of conduction– Scar– Gap-junctional coupling
• Very poorly understood in DCM
Research Group
• Richard Schilling• Anthony Chow• Oliver Segal • Pipin Kodjojojo• Fu Siong Ng• Wajid Hussain• Riyaz Kaba• Pravina Patel• Prapa Kanagaratnam• Tom Wong• Vias Markides• Julian Jarman• Michael Koa-Wing• Phang Boon Lim• Alex Lyon• Andy Kontogeorgis
• Hetal Patel• Rasheda Chowdhury• Yasmina Martins• YuLing Ma• Emmanuel Dupont
• Nicholas Severs• Wyn Davies• Christopher Fry• Rosaire Gray• Sian Harding
New York• Andrew Wit• Michael Rosen• Ed Ciaccio• David Gutstein• Glen Fishman
Can arrhythmogenic remodeling be detected without an
arrhythmia?
Carbenoxoloneex vivo
membrane
Vm
+
reference
preamplifier
d
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0 100 200 300 400 500 600 700
(a/ θ2)*106, cm -1.s-2
Ri, ž.cm
A
LV
LV+carb
LA+carb
LA
RA+carb
RA
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0 100 200 300 400 500 600
NO
(a/ θ2)*106, cm -1.s-2
Rj, ž.cm
B
RA+carb
LARA
LV
LV+carb
LA+carb
Mapping in Sinus Rhythm
SR• Latest
• Rayhigh regression coeffsteep activation gd(slowest / most uniform)
• Boundarylong Egs (>15ms longer)
Actual (VT) vs Estimated (SR) DPTemplate matching
Ciaccio et al Heart Rhythm 2008
Anatomical arrhythmia mappingLOCALISATION OF CIRCUIT
170ms
1
1530
607590
105
0
1020
3040
10
50
3045
45
APEX
LAD
5.3μm/mm
0
D E F
63ms
1
1226μm
0.1
A B C
6250μm
50
Ciaccio et al Heart Rhythm 2008
VT SR IBZ THICKNESS
THICKNESS GRADIENT CVc,max THRESHOLD
ARRHYTHMOGENIC VENTRICULAR REMODELLING
Conclusions• Scar necessary for arrhythmogenicity
• Remodelling of the functional morphology of the border zone myocardium that determines arrhythmogenesis