Narine Sarvazyan, Ph.D.Pharmacology and Physiology Dept, The George Washington University Medical Center

Arrhythmias

Wave PROPAGATION disturbances

Normal rhythm Reentry

inlet 1 inlet 2 outlet

stainless

steel holder

coverslip

inlet 1

inlet 2

outlet

A. CROSS SECTION

B. BOTTOM VIEW

I - Zone

Peltier-

controllered

mount

Plastic

holder

* *

25 mm

pacing electrodes

+ =cells

chamber

Time (sec)210 215 220 225 230 235

80

100

120

140

A.U

.F. (F

luo-4

)

D

A200 m

218.554 218.773 219.100

control zone

I-zone

B

C

0

660

msec

200 m

* * ** * *

200 m

Time (sec)210 215 220 225 230 235

80

100

120

140

A.U

.F. (F

luo-4

)

D

A200 m

218.554 218.773 219.100

control zone

I-zone

B

C

0

660

msec

200 m

* * ** * *

200 m

I. Cellular Origins of Ectopic Arrhythmias

Ectopic

Wave INITIATION disturbances

Time/sec550 600 650

A.U

.F. (

Flu

o-4

) A

B

80

100

120

140

575 625

I-zone

controlzone

C

2

4

6

8

[Ca

++],

nM

/s

P < 0.01

*

200 m

In silico

In vitro

I

IIIV

I - synchronized activity II - propagationIII - propagation failureIV - individual ectopicsV - local ectopic wavesVI - spreading ectopic waves

V

Ectopic excitability

Cell-to-cell coupling highlow

highlow

VI

transition curve

III

0.00

0.04

0.08

0.12

0.16

Diffusion coefficient, Dx10-4 ( cm2/s)

<

>

1 2 3 4 50

BOUNDARY ACTIVITY in 3D: computer simulations

Micro-reentriesEctopic beats

II. Stems cells & cardiac regeneration

A B

C D

Contracting cells of cardiac lineage are fluorescent within attached embryoid body. Phase-contrast picture of attached embryoid body and its fluorescent image.

embryoid body α-MHC-GFPconstruct

III. Cardiotoxicity of anthracyclines

Doxo

rubicin

,

040

80120

160

Mean fluorescence intensity

0 25 50

Myocytes load

ed w

ith D

FDA

Control m

yocytes

515530

610

Wavele

ngth

, n

m

500

550

600

650

DIC

HLO

RO

FLU

OR

ESC

EIN

AD

RIA

MYC

INC

H1

CH

2C

hannel 1

AD

BCC

hannel 2

Adria

mycin

,

040

80

120

160

0 25

50

Myocyte

s lo

aded w

ith D

CFH

Contro

l myocyte

s

DCF intensity

phospholipidsphospholipid

hydroperoxides oxidized fatty acids

DOX

ROS PLA2

_+

GPX/GSH,otherantioxidants

HPGPX

Reduction of oxidized fatty acids/lysophospholipids,and membrane remodeling

+ +

+

+_

promote

inhibit

phospholipidsphospholipid

hydroperoxides oxidized fatty acids

DOX

ROS PLA2

_+

GPX/GSH,otherantioxidants

HPGPX

Reduction of oxidized fatty acids/lysophospholipids,and membrane remodeling

+ +

+

+_

promote

inhibit

Acknowledgement of financial support: NIH and American Heart Association

Other areas of interest:

doxorubicin induced oxidative stress

Phospholipase A2 inhibition