The ICV Study

“Integrated CardioVascular”

Benjamin D. Levine, M.D. Michael W. Bungo, M.D.

Co-Is: Jim Thomas, MD, Rick Page, MD, Jeff Goldberger, MD, Steve Platts, PhD,

Smith Johnston, MD, Doug Hamilton, MD, Jeff Hastings, MD

Ventricular Tachycardia on Mir

Fritsch-Yelle et al, Am J Cardio 1998

Cardiac Abnormalities in Rhythm and Diastolic function due to Inactivity, Atrophy and Confinement

Buckey et al, JAP 1996

UT Southwestern Medical Center Spacelab Life Sciences - 1

Pre Post

Le

ft V

en

tric

ula

r M

as

s (

g)

0

140

160

180

200

Perhonen et al, JAP 2001

Cardiac Atrophy After Spaceflight

Base 2 Wks 6 Wks 12 Wks

Le

ft V

en

tric

ula

r M

as

s (

gm

)

0

175

200

225

250

275

300

325

~ 1%/week

over many studies

LV Mass Continues to Decrease

Over 12 Weeks of Bedrest

Pre Post

Le

ft V

en

tric

ula

r M

as

s (

g)

0

140

160

180

200

Perhonen et al, JAP 2001

Cardiac Atrophy After Spaceflight

Base 2 Wks 6 Wks 12 Wks

Le

ft V

en

tric

ula

r M

as

s (

gm

)

0

175

200

225

250

275

300

325

~ 1%/week

over many studies

LV Mass Continues to Decrease

Over 12 Weeks of Bedrest

Fritsch-Yelle et al, Am J Cardiol 1998

Earth Orbit

Mars Orbit

Piloted Trajectories

Stay on Mars Surface

4

1

3

2

2014 Mars Design Reference Mission Scenario (typical)

Earth Arrival

June 26, 2016

Mars Arrival

June 30,

2014

Mars Departure

Jan. 24, 2016

Earth

Departure

Jan. 20, 2014

Mars Perihelion

January 22, 2013

December 10, 2014

Flight Profile Transit out: 161 days

Mars surface stay: 573 days

Return: 154 days

LV

ED

V (

ml)

0

60

80

100

120

140

160

180

80o 41o 22o 22o 0o 0o

LV Volume Decreases With Tilt Angle

But Remains Above Upright On Mars

After Landing

FD30 FDR-15

Tis

su

e D

op

ple

r E

' (m

ean

)

0

2

4

6

8

10

12

14

16

80o 41o 22o

22o 0o

0o

Tissue Doppler Velocity Decreases With Tilt Angle

But Is Minimally Affected on Landing Day

FD30 FDR-15

Stacked image

For mass and volume

Comprehensive

Cardiac MRI for

LV/RV Structure

And Function

Delayed Enhancement

To detect scar

Tagged image

For untwisting

Stacked image

For mass and volume

Tagged image

For untwisting

Comprehensive

Cardiac MRI for

LV/RV Structure

And Function

Delayed Enhancement

To detect scar

Pre-flight Post-flight

50

100

150

200

250

Pre-flight Post-flight

LVEDV (ml)

25

45

65

85

Pre-flight Post-flight

LVESV (ml)

50

70

90

110

130

150

Pre-flight Post-flight

SV (ml)

55

60

65

70

75

Pre-flight Post-flight

LVEF (%)

No Change in LV Morphology

No Change in Left Ventricular Mass

55

75

95

115

135

155

175

Pre-flight Post-flight

LV mass (g)

108[90-134] 109[98-145]

No Change in RV Morphology

50

100

150

200

250

Pre-flight Post-flight

RVEDV (ml)

25

45

65

85

105

125

Pre-flight Post-flight

RVESV (ml)

45

50

55

60

65

70

75

Pre-flight Post-flight

RVEF (%)

15

20

25

30

35

40

Pre-flight Post-flight

RV mass (g)

No Change in Right Ventricular Mass

Pre-flight Post-flight

One Astronaut (very fit before flight)

Myocardial Tagging

LV mass/volume

stack

LVEDV: 165mL

LV Mass: 178 g

LVEDV: 149 mL

LV Mass: 158 g

LV Untwisting Velocity: -41.5 deg/sec

LV Untwisting Velocity: -46.5 deg/sec

JW_pre_mid_slice.mpg

Post-flight #2

LVEDV: 168 mL

LV Mass: 176 g

Pre-flight Post-flight

Another Astronaut (less fit)

Myocardial

Tagging

Structural

Imaging

LV mass 74 gm

LVEDV 78 ml

LV mass 87 gm

LVEDV 90 ml

Peak untwist

-46 deg/sec

Peak untwist

-51 deg/sec

Cardiac Mass

Is Determined by Cardiac Work

Heart Rate

57

58

59

60

61

62

63

64

65

90 95 100 105 110 115 120

Time (s)

HR

(B

PM

)

Stroke Volume

96

98

100

102

104

106

108

110

90 95 100 105 110 115 120 Time (s)

SV (

mL)

During evening (stable blood pressure)

L-55

During exercise

During sleep

During day time (stable blood pressure)

During exercise

During night time (sleep)

R-15

12 PM 6 PM 12 AM 6 AM 0 2000000 4000000 6000000 8000000 10000000 12000000 14000000

0

1000

2000 Pre-Flight

Actiwatch (Hip)

Cardiac Work Actiwatch (Ankle)

Sleep

Drink Coffee

Walk to Building S4 Robotic Training

Walk a Dog Elliptical Machine (Exercise)

Cardiac Work (mmHg*ml)Activity

0 0

2000000 4000000 6000000 8000000 10000000 12000000 14000000

1000

2000 FD R-15

Sleep

Cevis Exercise

12 PM 6 PM 12 AM 6 AM Red: Information from Flight Diary

Cardiac Work (mmHg*ml) Activity

Change in LV Mass with Spaceflight

Is Proportional to Changes in Volume Work

y = 0.56x + 4.1

R² = 0.644

-15

-10

-5

5

10

15

20

-30 -20 -10 10

% C

han

ge o

f LV

Mass

% Change of Stroke work

POTS: young women whose hearts are “two sizes too small”

Adabag, A. S. et al. J Am Coll Cardiol 2008;51:1369-1374

Presence of Delayed Enhancement In Patients Identifies High Risk For Ventricular Arrhythmias

HR = Heart Rate

No Focal Delayed Enhancement After Spaceflight

Pre Post

T1 Mapping with MOLLI sequence

T1 post-contrast:494 ms Normal T1 pre-constrast: 1166+/-60ms ( Piechnik, SK et al. J Cardiovasc Mag Reson. 2010;12:69).

T1 pre-contrast: 1172 ms

T1 post-contrast: 444 ms

T1 pre-contrast: 1168ms

PRE-FLIGHT POST-FLIGHT

G inflight

C preflight C inflight

A inflight M preflight

Lots of Arrhythmias Observed –

Both Pre And During Spaceflight

Pre2

Pre1

FD14FD30

FD75

FD135R-15 R0

Ve

ntr

icu

lar

Ec

top

ic B

eats

in 4

8 h

ou

r s

am

ple

, b

eats

0.1

1

10

100

1000

10000A

B

C

D

E

F

G

H

I

J

K

L

M

Col 25

No Consistent Changes in

Ventricular Ectopy

< 1

Pre2

Pre1

FD14FD30

FD75

FD135R-15 R0

Su

pra

ven

tric

ula

r E

cto

pic

Beats

in 4

8 h

ou

r s

am

ple

, b

eats

0

1000

2000

3000

4000

5000

6000A

B

C

D

E

F

G

H

I

J

K

L

M

No Consistent Changes in

Supraventricular Ectopy

Inward Current

Outward Current

Depolarization Repolarization Ito

Ikr

Iks

INa

ICa

-80mV

QRS

ST

T wave

The Heart’s Electrical Activity Coordinates

the Heart Beat

Raw ECG

Signal-

averaged

ECG

Collaboration with Jeff Goldberger, MD and Jason Ng PhD from Northwestern

12-lead

ECG

Inverse

Dower

Transform

Frank-lead

ECG

40 Hz

Bidirectional

Highpass

Filter

Filtered and

amplified

Frank-lead

ECG

Magnitude

QRSd: QRS duration (late potentials: >114 ms)

RMS = Root-mean-square voltage in last 40 ms (late potentials: <20uV)

LAS = Low-amplitude (<40 µV) signal duration in terminal QRS

(late potentials: >38 ms)

Astronaut H SAECG

50 100 150 200 2500

20

40

60

80

100

Time (ms)

Am

plit

ud

e (

uV

)fQRSd = 66 ms

RMS = 105.1038 uV

LAS = 17 ms

FD135

FD14 FD30

FD75

Pre1

R-15

Signal-Averaged ECG Subject H

50 100 150 200 2500

20

40

60

80

100

Time (ms)

Am

plit

ud

e (

uV

)

fQRSd = 66 ms

RMS = 105.1038 uV

LAS = 17 ms

50 100 150 200 2500

20

40

60

80

100

Time (ms)

Am

plit

ud

e (

uV

)

fQRSd = 68 ms

RMS = 125.2844 uV

LAS = 16 ms

50 100 150 200 2500

20

40

60

80

100

Time (ms)

Am

plit

ud

e (

uV

)

fQRSd = 66 ms

RMS = 115.7917 uV

LAS = 16 ms

50 100 150 200 2500

20

40

60

80

100

Time (ms)

Am

plit

ud

e (

uV

)

fQRSd = 96 ms

RMS = 23.173 uV

LAS = 30 ms

50 100 150 200 2500

20

40

60

80

100

Time (ms)

Am

plit

ud

e (

uV

)

fQRSd = 101 ms

RMS = 21.0425 uV

LAS = 33 ms

50 100 150 200 2500

20

40

60

80

100

Time (ms)

Am

plit

ud

e (

uV

)

fQRSd = 67 ms

RMS = 125.849 uV

LAS = 15 ms

Pre2

Pre1

FD14FD30

FD75

FD135R-15 R0

QR

SD

,msec

0

20

40

60

80

100

120A

B

C

D

E

F

G

H

I

J

K

L

M

Col 24

Pre2

Pre1

FD14FD30

FD75

FD135R-15 R0

RM

S,

mV

0

20

40

60

80

100

120

140

160A

B

C

D

E

F

G

H

I

J

K

L

M

Col 24

Pre2

Pre1

FD14FD30

FD75

FD135R-15 R0

LA

S,

msec

0

10

20

30

40A

B

C

D

E

F

G

H

I

J

K

L

M

Col 24

No Clear Trends for

Changes in SAECG

Measures of Conduction

Pre1 Pre2

FD15 FD30 FD75

R

TW Alternans

Astronaut B

Lead V5 (MMA)

Slight Increase in Resting TWA in Any Lead

But Not Changed in V5 (most clinical data)

Pre3

Pre2

Pre1

FD14FD30

FD75

FD135R-15 R0

No

rmalized

Max R

est

TW

A,

V

0.0

0.2

0.4

0.6

0.8

1.0

1.2A

B

C

D

E

F

G

H

I

J

K

L

M

Col 26

Pre3

Pre2

Pre1

FD14FD30

FD75

FD135R-15 R0

No

rmalized

V5 R

est

TW

A,

V

0.0

0.2

0.4

0.6

0.8A

B

C

D

E

F

G

H

I

J

K

L

M

Summary Conclusions from ICV

1). Given current training programs, and ground based

interventions, cardiac morphology (right and left ventricular

mass and volume) and function (EF and untwisting) are

preserved after 6 months of spaceflight.

When landing on Mars after a 6 month flight, cardio-

vascular function is highly likely to be sufficient to allow

exploration activities, and there is little risk of orthostatic

intolerance;

2). This cardiac adaptation to long duration spaceflight

depends on the relative change in cardiac work between

pre-flight and post-flight levels;

Summary Conclusions from ICV

3). In some individuals, a subtle change in cardiac ultra-

structure may occur, that is suggestive of myocardial fibrosis.

Whether this is an idiosyncratic response in a rare astronaut

(e.g., subclinical myocarditis), or a more common direct

response to the hemodynamics of spaceflight (pregnancy

analogy) is unknown.

4). In general, long duration spaceflight does not appear to

increase the risk for cardiac arrhythmias, and there are no

microgravity specific changes in electrophysiology.

* However, there may be some astronauts who acquire a

risk for potentially serious arrhythmias (and their secondary

manifestations), either as a result of an infection, or an

atypical response to microgravity.

So Many People To Thank!

1). The amazing technical support from the JSC

Cardiovascular lab: Chris Ribreiro, David Martin, Stuart Lee, Mike

Stenger and the rest of their team;

2). Outstanding project support from our Wylie team: Kelly

Norwood, Matt Roper, Gwen Sandoz, Cathy Modica, et al;

3). Extraordinary flight surgeons; Doug Hamilton,

Smith Johnston, and all the individual astronaut flight surgeons;

4). NASA Science Management: Peter Norsk, John Charles,

Clarence Sams, Chuck Sawin, Victor Schneider and many others;

5). Many colleagues who helped with data analysis: Jason Ng,

Jamie Kowal, James Daniels, Shuaib Abdullah, Shigeki Shibata, Qi

Fu.