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