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

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