Rational Approach to Improving Cardiac Arrhythmia Therapy€¦ · ANDERSON JL et al, NEJM 305 :473-477, 1981 Odds ratio for total mortality 1-48 hr post-MI MACMAHON S et al, JAMA

Stanley Nattel, MD

Rational Approach to Improving

Cardiac Arrhythmia Therapy

SN.2003

Rational Approach to Improving

Cardiac Arrhythmia Therapy

Stanley Nattel, MD

DEDICATED TO THE MASTER OF RATIONAL THERAPEUTICS

SENAC:Cinchona bark for palpitations (1749)

FREY: On atrial fibrillation in humansand Its Elimination by Quinidine (1918)

Ventricular fibrillation as an electrical accident

WIGGERS CJ, Am Heart J 20:399-412, 1940

A B

C

Lidocaine to treat ventricular ectopy post-MI

GIANELLY R et al, NEJM 277:1215-1219, 1967

PVC's

20 sec. POST-LIDOCAINE

PRE-LIDOCAINE

VT

LIDOCAINE IV

Total suppression of ventricular arrhythmiasby encainide

RODEN DM et al, NEJM 302 :877-882, 1980

Oral flecainide acetate for the treatmentof ventricular arrhythmias

ANDERSON JL et al, NEJM 305 :473-477, 1981

Odds ratio for total mortality 1-48 hr post-MI

MACMAHON S et al,JAMA 260:1910-1916, 1988

Effects of class 1C antiarrhythmiason post-MI mortality

NEJM 321:406-412, 1989

CAST

CAST II Investigators, NEJM 327 :227-233, 1992


NEJM 321:406-412, 1989

CAST CAST II

CAST II Investigators, NEJM 327 :227-233, 1992


NEJM 321:406-412, 1989

CAST CAST II

Meta-analysis of quinidine effects on mortalityin AF patients

COPLEN et al, Circulation 82 :1106-1116, 1990

OK, Class I drugs are bad. Class III is the future.

LAZZARA R, AJC 78(4A):28-33, 1996

From first class to third class: recent upheaval in antiarrhythmictherapy – lessons from clinical trials.

Lazzara R.

Effects of a pure class III drugon post-MI mortality

WALDO AL et al, Lancet 348:7-12, 1996

Something doesn’t fit!

Something doesn’t fit!

Look for the finding that doesn’t fit. THAT

is the clue to great discoveries!!

Focus on a specific arrhythmia

Age-RelatedPrevalence of AF

181614121086420

Prev

alen

ce %

FraminghamCHSRochesterWestern Australia

Age40 50 60 70 80 90

FEINBERG WM ET AL, Arch Intern Med 1995; 155:469-473

Novel ion channel targets

New antiarrhythmic drug development approaches for AF

Problem of ventricular proarrhythmia

DESSERTENNE, Arch. des Mal.du Cœur 1966; 59:263-272

Agrandissement des 3 dérivations synchrones

montrant en D III les torsades de pointes.

Atrium

Ventricle

IK1

IK1

INa

Ito

Ito ICa

ICa

IKs

IKs

IKr

IK1

IK1

IKur

IKACh

IKACh

INa

IKr

………. and strategy of atrial-selective therapies




Atrium

Ventricle

IK1

IK1

INa

INa

Ito

Ito ICa

ICa

IKs

IKs

IKr

IKr

IK1

IK1

IKur

IKACh

IKACh

K+ channel blockers with atrial selectivity

Atrial-selective therapiesIKur




Atrium

Ventricle

IK1

IK1

INa

INa

Ito

Ito ICa

ICa

IKs

IKs

IKr

IKr

IK1

IK1

IKur

IKACh

IKACh

XX

IKur (ultrarapid delayed rectifier) is Atrial-specific in Man

LI ET AL, Circ Res. 1996; 78:689-696

Ventricular cellAtrial cell

IKur (ultrarapid delayed rectifier) is Atrial-specific in Man

LI ET AL, Circ Res. 1996; 78:689-696

Ventricular cellAtrial cell

Control

50 m

V100 ms

3 µM XEN-D0101

1 µM XEN-D0101

HUMAN ATRIAL MUSCLE

50 m

V

100 ms

Control

1 µM XEN-D0101

3 µM XEN-D0101

HUMAN VENTRICULAR MUSCLE

VARRO ET AL, 2007

0

50

100

150

200

Base

line

Base

line

Base

line

0.3m

g/kg

1mg/

kg

3mg/

kg

ERP 300 (ms)

0

50

100

150

200

Base

line

Base

line

Base

line

1mg/

kg

3mg/

kg

ERP 500 (ms)

0.3m

g/kg

RV

*

Baseline

Post drug

40

60

80

100

120

100 200 300 400

ERP (ms)

BCL (ms)

40

60

80

100

120

100 200 300 400

ERP (ms)

BCL (ms)

40

60

80

100

120

100 200 300 400

ERP (ms)

BCL (ms)

RA

A

0.3mg/kg 1mg/kg 3mg/kg

** *

*********

Efficacy of an IKur blocker (Xen-D0101) on atrial and ventricular ERPs in AT-remodeled dogs

Shiroshita-Takeshita et al,Heart Rhythm 3: S183, 2006.

Efficacy of an IKur blocker (Xen-D0101) on AF in dogs with atrial tachycardia remodeling

0.3m

g/kg

0

200

400

600

800

1000

1200

Base

line

1mg/

kg

3mg/

kg

Base

line

Base

line

DAF (s)

***

0

20

40

60

80

100

Base

line

0.3m

g/kg

Base

line

1mg/

kg

Base

line

3mg/

kg

AF vulnerability(%)

****

*:p<0.05, **:p<0.01vs baseline Shiroshita-Takeshita et al,Heart Rhythm 3: S183, 2006.

Targeting the substrate


Substrate

Determinants of Arrhythmia Mechanisms in AF:Role of Remodeling

Atrial Fibrillation

Trigger Ectopicactivity

Reentry

Remodeling

Substrate

Determinants of Arrhythmia Mechanisms in AF:Prevention of Remodeling

Atrial Fibrillation

Trigger Ectopicactivity

Reentry

Remodeling

XX XX

Effects of electrically maintained AF on spontaneous AF maintenance when stimulation stopped

WIJFFELS MCEF, Kirchhof CJHJ, Dorland R, et al. Circulation 1995; 92:1954-1968

Atrial Myocyte Adaptation to Ca2+ Loading

SN.2002

Sinus rhythm(60/min)

AF(400-600/min)

10-fold rateincrease

CellularCa2+ loading

Threat tocell viability


SN.2002


AF(400-600/min)


minutes



ICa inactivation

ICa


SN.2002


AF(400-600/min)


minutes

hours - days



ICa mRNA

ICa proteinICa inactivation

ICa ICa


SN.2002


AF(400-600/min)


minutes

hours - days



ICa mRNA

ICa protein

RPAPD

ICa inactivation

ICa ICa

+

ICa

Superiority of Amiodarone in AF

SN.2003 KOCHIADAKIS et al, Heart 2000; 84: 251-257ROY et al, N Engl J Med 2000; 342: 913-920

100

80

60

40

20

00 100 200 300 400 500 600

Pat

ient

s w

ithou

tRec

urre

nce

(%)

Days of Follow-up

Amiodarone (n = 201)

Propafenone (n = 101)

Sotalol (n = 101)

Effects of Antiarrhythmic Drugs on AF

0200400600800

100012001400

0200400600800

100012001400

CTL Amio A+ Amio/A+

AF

dura

tion

(s)

*

CTL Dof A+ Dof/A+

*

**

CTL Fle A+ Fle/A+

* *

CTL Fle A+ Fle/A+

**

**

CTL Dof A+ Dof/A+

**

*

0

25

50

75

100

0

25

50

75

100

CTL Amio A+ Amio/A+

Vul

nera

bilit

y (%

)

**

* P<0.05, ** P<0.01 vs CTL

0200400600800

100012001400

0200400600800

100012001400

0

25

50

75

100

0

25

50

75

100

0200400600800

100012001400

0200400600800

100012001400

0

25

50

75

100

0

25

50

75

100

SHINAGAWA et al, Circulation, 107: 1440-1446, 2003

AF duration

AF vulnerability

SN.2003


0200400600800

100012001400

0200400600800

100012001400

CTL Amio A+ Amio/A+

AF

dura

tion

(s)

*

CTL Dof A+ Dof/A+

*

**

CTL Fle A+ Fle/A+

* *

CTL Fle A+ Fle/A+

**

**

CTL Dof A+ Dof/A+

**

*

0

25

50

75

100

0

25

50

75

100

CTL Amio A+ Amio/A+

Vul

nera

bilit

y (%

)

**

* P<0.05, ** P<0.01 vs CTL

0200400600800

100012001400

0200400600800

100012001400

0

25

50

75

100

0

25

50

75

100

0200400600800

100012001400

0200400600800

100012001400

0

25

50

75

100

0

25

50

75

100


AF duration

AF vulnerability

SN.2003


0200400600800

100012001400

0200400600800

100012001400

CTL Amio A+ Amio/A+

AF

dura

tion

(s)

*

CTL Dof A+ Dof/A+

*

**

CTL Fle A+ Fle/A+

* *

CTL Fle A+ Fle/A+

**

**

CTL Dof A+ Dof/A+

**

*

0

25

50

75

100

0

25

50

75

100

CTL Amio A+ Amio/A+

Vul

nera

bilit

y (%

)

**

* P<0.05, ** P<0.01 vs CTL

0200400600800

100012001400

0200400600800

100012001400

0

25

50

75

100

0

25

50

75

100

0200400600800

100012001400

0200400600800

100012001400

0

25

50

75

100

0

25

50

75

100


AF duration

AF vulnerability

SN.2003

Effects of Remodeling on α1c Subunit Expression

Control Pace

Control Amio Amio + Pace

Control Flec Flec + Pace

Control Dof Dof + Pace


A

B

D

C

ND A F D0.0

0.2

0.4

0.6

0.8

1.0

1.2

Control Pacing

NS NS NS

***

******

NS

Are

a x

OD

nor

mal

ized

ND = no drug A = amiodaroneF = flecainide D = dofetilide

ND A F D

E


Control Pace





A

B

D

C

ND A F D0.0

0.2

0.4

0.6

0.8

1.0

1.2

Control Pacing

NS NS NS

***

******

NS

Are

a x

OD

nor

mal

ized


ND A F D

E


Control Pace





A

B

D

C

ND A F D0.0

0.2

0.4

0.6

0.8

1.0

1.2

Control Pacing

NS NS NS

***

******

NS

Are

a x

OD

nor

mal

ized


ND A F D

E

Effects of Various Agents on Cav1.2 Expression

Cav 1.2

GAPDH

NPATP

OXYVitC

VitC&E

SIM PRO

NP ATP SIM OXY PRO VitCVitC&E0

0.5

1.0

1.5(AU)

** *

*:p<0.05 vs ATP, **:p<0.01 vs ATP

Effects of Various Agents on Cav1.2 Expression

Cav 1.2

GAPDH

NPATP

OXYVitC

VitC&E

SIM PRO

NP ATP SIM OXY PRO VitCVitC&E0

0.5

1.0

1.5(AU)

** *

*:p<0.05 vs ATP, **:p<0.01 vs ATP

Can we identify new antiarrhythmic approaches thatwork by preventing atrial-tachycardia remodeling?

DAF (s)

1

10

100

1000

3000

NP ATP

** *

0

50

100

NP ATP

AF vulnerability(%)

**

Shiroshita-Takeshita et al, Circulation 2004;110: 2313-2319.

SIM SIM

Can we identify new antiarrhythmic approaches thatwork by preventing atrial-tachycardia remodeling?

DAF (s)

1

10

100

1000

3000

NP ATP SIM

** *

0

50

100

NP ATP SIM

AF vulnerability(%)

**

Sinus rhythm maintenance

Siu et al, Am J Cardiol 2003;92:1343-1345Shiroshita-Takeshita et al, Circulation 2004;110: 2313-2319.

Remodeling Induces Two Clinically Relevant AF Substrates:Atrial-tachycardia Remodeling and Structural Remodeling

Atrial tachycardia remodeling CHF-induced remodeling

LI et al, Circulation 1999; 100:87-95

AF-induced remodeling Heart disease-induced remodelingFENG et al, Circ Res. 1997;80:572-579

CHF produces a structural substrate for AF

Epicardial maps

CHFControl

Histology

LI et al, Circulation 1999; 100:87-95

Can Inhibiting Ang-II Formation Prevent Development of the Substrate for AF?

% Connective tissue

AF duration(s)

CH

F+H

I0

100

200

300

400

500

600

700

800

900

CTL

CH

F

CH

F+E

****

* #

LI D et al, Circulation 104: 2608-2614, 2001E = enalapril; HI=hydralazine/isosorbide

CHF induces fibrosis and increases AF duration


% Connective tissue

CH

F+H

I


Enalapril attenuates fibrosis and AF duration increases

AF duration(s)

0

100

200

300

400

500

600

700

800

900

CTL

CH

F

CH

F+E

****

* #


% Connective tissue

AF duration(s)

CH

F+H

I0

100

200

300

400

500

600

700

800

900

CTL

CH

F

CH

F+E

****

* #


Vasodilator therapy does not mimic enalapril effects

ACE antagonism and clinical AF in LV dysfunction

enalapril

placebo

AF in SOLVD patients

Vermes et al, Circulation 2003; 107: 2926-2931

AF in post-MI patients with LVD

Pedersen et al, Circulation 1999; 100: 376-380

AF occurrence

SR maintenance

Substrate-selective ion channels


Atrial tachycardia remodeling: AF Begets AF

Wijffels MCEF, Kirchhof CJHJ, Dorland R, et al. Circulation 1995; 92:1954-1968SN.2001

Normal AP

AT AP

↓ICa

Atrial tachycardia remodeling: AF Begets AF

Wijffels MCEF, Kirchhof CJHJ, Dorland R, et al. Circulation 1995; 92:1954-1968SN.2001

Normal AP

AT AP

↓ICa

? Changes in outward currents

Constitutive IKACh that is enhanced by atrial tachycardiaCONTROL AT

Pre-TQ

Tertiapin-Q(Specific IKACh

blocker)

TQ-sens

Cha TJ et al, Circulation. 2006;113:1730-7.

CONTROL AT

Effects of IKACh block on APD and tachyarrhythmia


CONTROL AT

Effects of IKACh block on APD and tachyarrhythmia





Atrium

Ventricle

IK1

IK1

INa

INa

Ito

Ito ICa

ICa

IKs

IKs

IKr

IKr

IK1

IK1

IKur

IKACh

IKACh

Atrial-selective therapiesIKACh

XXNO. Time plasma conc.

terminated sec (ng/ml)vehicle 1/12 - - 0/1

2 2/3 830 13 -NIP-151 5 4/5 525±25 22±6 1/4

10 5/5 372±38 106±4 4/53 1/3 558 n.d 0/110 0/3 - - -dofetilide

dose(μg/kg/min)

AF terminationcompound

prevention ofAF reinduction

NO. Timeterminated sec

vehicle 0/3 -

0.01 0/3 -0.03 2/3 670.1 3/3 610.3 3/3 55

compound

NIP-151

dose(mg/kg)

AF termination

Effects of an IKACh-selective blocker (NIP 151) on AF in two canine models

Vagal AF

Aconitine-induced AFHashimoto N et al.

Circulation. 2005;112:II-191.

NO. Time plasma conc.terminated sec (ng/ml)

vehicle 1/12 - - 0/1

2 2/3 830 13 -NIP-151 5 4/5 525±25 22±6 1/4

10 5/5 372±38 106±4 4/53 1/3 558 n.d 0/110 0/3 - - -dofetilide

dose(μg/kg/min)

AF terminationcompound

prevention ofAF reinduction

NO. Timeterminated sec

vehicle 0/3 -

0.01 0/3 -0.03 2/3 670.1 3/3 610.3 3/3 55

compound

NIP-151

dose(mg/kg)

AF termination

Effects of an IKACh-selective blocker (NIP 151) on AF in two canine models

Vagal AF

Aconitine-induced AFHashimoto N et al.

Circulation. 2005;112:II-191.

Collateral effects on extra-atrial (SAN) and extracardiac (GI and GU systems) need to be avoided

We have come a long way…

We have come a long way…

…There is still a considerable way to go…

…But we do hope to get there!

Control

50 m

V

3 µM XEN-D01011 µM XEN-D0101

HUMAN ATRIAL MUSCLE

50 m

V

100 ms

Control

1 µM XEN-D0101

3 µM XEN-D0101

HUMAN VENTRICULAR MUSCLE

VARRO ET AL, 2007

0100200300400500600700800900

CTL

CH

F

CH

F +E

****

* #

CH

F+H

/I

McGillMGH

St. Paul’s Dalhousie

McGill

Thank You

MGH

St. Paul’s Dalhousie

Documents

Rational Approach to Improving Cardiac Arrhythmia Therapy€¦ · ANDERSON JL et al, NEJM 305 :473-477, 1981 Odds ratio for total mortality 1-48 hr post-MI MACMAHON S et al, JAMA