Long Term CardiotoxicEffects of Sarin

Mariana Morris

Wright State University

Dayton, Ohio

ACKNOLWLEDGEMENTS• Swapnil Shewale• Mike Horenziak• James Lucot• Brent Izu• Mary Key• Mark Anstadt• Vera Farah • Teresa Garrett

Appendix A Presentation 6 - Morris

RAC-GWVI Meeting Minutes March 1-2, 2010 Page 86 of 124

Demolition of bunkers at Khamisiyah, 4 March 1991.CIA, 1997; http://www.fas.org/irp/gulf/cia/970409/cia_wp.html

HISTORICAL PERSPECTIVE THE USE OF SARIN GULF WAR 1991

Plume Models for the Demolition of Bunkers at Khamisiyah, 12 March 1991.CIA, 1997; https://www.cia.gov/library/reports/general-reports-1/gulfwar/555/425055597.html

HISTORICAL PERSPECTIVE USE OF SARIN GULF WAR 1991

Appendix A Presentation 6 - Morris

RAC-GWVI Meeting Minutes March 1-2, 2010 Page 87 of 124

Plume Models for the Demolition of Bunkers at Khamisiyah, 12 March 1991.CIA, 1997; https://www.cia.gov/library/reports/general-reports-1/gulfwar/555/425055597.html

POTENTIAL EXPOSURE OF 100,000 PERSONS

Quantitative magnetic resonance brain imaging in US army veterans of the 1991 Gulf War potentially exposed to sarin and cyclosarin

Kristin J. Heaton, Carole L. Palumbo, Susan P. Proctor,Ronald J. Killiany, Deborah A. Yurgelun-Todd, Roberta F. White

Neurotoxicology 28: 2007

Reduced white matterEnlarged left cerebral ventriclePersistent CNS pathologies

Appendix A Presentation 6 - Morris

RAC-GWVI Meeting Minutes March 1-2, 2010 Page 88 of 124

Case Report: Long term cognitive sequelae of sarin exposure

Loh et al., Neurotoxicology, 2010

Recent exposure Army captainMunition disposal Sustained neurocognitive deficits

OBJECTIVE 1:Autonomic Cardiovascular

Effects of Low Dose Sarin

• Radiotelemetry• Sarin sc

0.4 LD50• Spectral analysis -

autoregressive method

• Blood and brain AChE

Appendix A Presentation 6 - Morris

RAC-GWVI Meeting Minutes March 1-2, 2010 Page 89 of 124

Spectral Analysis for Characterization of Autonomic Balance

Statistical method for characterization of variability. Spectra of variability are composed of 2 oscillatory components; low frequency 0.1-1 Hz) and high frequency (1-5.0 Hz). Spectra are associated with autonomic balance, sympathetic and parasympathetic

400

800

1200

iRR

400

800

1200

iRR

400

800

1200

iRR

Signal Analysis

Appendix A Presentation 6 - Morris

RAC-GWVI Meeting Minutes March 1-2, 2010 Page 90 of 124

Low Dose Sarin Blood Pressure and Heart Rate

Mean Arterial Pressure

mm

Hg

0

40

80

120

Basal 1 7

Heart Rate

bpm

0

200

400

600

Basal 1 7

Week After Exposure Week After Exposure

Variance Low Freq High Freq

0

40

*

*

ms2

20

Control Sarin

Effect of Sarin on Heart Rate Variance and Frequency Domains

Farah et al., Autonomic Neuroscience: Clinical and Basic, 2007

Appendix A Presentation 6 - Morris

RAC-GWVI Meeting Minutes March 1-2, 2010 Page 91 of 124

CLINICAL IMPLICATIONS OF LOW HR VARIABILITY

LaRovere et al. 2003

Low Dose Sarin on Brainstem Catecholamine Systems

Appendix A Presentation 6 - Morris

RAC-GWVI Meeting Minutes March 1-2, 2010 Page 92 of 124

OBJECTIVE 2:

To identify the long term effects of low dose sarin on cardiac structure and function in mice

Appendix A Presentation 6 - Morris

RAC-GWVI Meeting Minutes March 1-2, 2010 Page 93 of 124

CV DATA 10, 12, 18 WEEKS AGE

TIME COURSE PROTOCOL

SARIN (0.4 LD50)8 WEEKS AGE

SACRIFICE 18 WEEKS AGE

ECHOCARDIOGRAPHY (ECHO)ELECTROCARDIOGRAM (ECG)CV STRESS TESTCARDIAC MARKERS HEART AND CELL SIZE

CV DATA 10, 12, 18 WEEKS AGE

METHODS PROTOCOL

SARIN (0.4 LD50) 8 WEEKS AGE

CV DATA 10, 12, 18 WEEKS AGE

SACRIFICE 18 WEEKS AGE

2D and M mode ECHO were used to measure left ventricular structure and performance at baseline and after dobutamine stress test at 2, 4, and 10 wks after sarin.ECG tracings were recorded at the 10 week point, baseline and after dobutamine. Histological and immunochemical parameters (i.e., natriuretic peptides) were measured upon sacrifice

Appendix A Presentation 6 - Morris

RAC-GWVI Meeting Minutes March 1-2, 2010 Page 94 of 124

• Piezoelectric crystals convert electrical current into sound waves

• Tissues of varying impedence create reflected sound waves

• Reflected sound waves produce electrical currents that are processed into images

Echocardiography

PosteriorWall

EndSystolicDiameter

EndDiastolicDiameter

M-MODE ECHO

ECHO RECORDING UNDER ANESTHESIA

Appendix A Presentation 6 - Morris

RAC-GWVI Meeting Minutes March 1-2, 2010 Page 95 of 124

Right Atrium

LeftVentricle

PapillaryMuscle

SeptalWall

Parasternal Long Axis (PLAX) 2-D ECHO

Right Atrium

LeftVentricle

PapillaryMuscle

SeptalWall

Parasternal Long Axis (PLAX) 2-D ECHO

Appendix A Presentation 6 - Morris

RAC-GWVI Meeting Minutes March 1-2, 2010 Page 96 of 124

CARDIOTOXICITY AND SARIN

Appendix A Presentation 6 - Morris

RAC-GWVI Meeting Minutes March 1-2, 2010 Page 97 of 124