Spaceflight:
Understanding the impact on
vascular function
Christian M. Westby, Ph.D.
JSC Cardiovascular Laboratory
University Space Research Association
Houston, TX, United States
Outline
• Gender differences in venous
function following 60-days headdown bedrest
• Radiation induced CVD: should we
be worried.
Orthostatic Intolerance
Orthostatic hypotension - the inability to
maintain standing blood pressure.
– Presyncope (lightheadedness, loss of
peripheral vision)
–Syncope
This is a potential threat to both crew and
vehicle.
Postflight Orthostatic Hypotension
The incidence and severity of postflight
orthostatic hypotension has a complex,
interrelated set of contributing factors,
including:
–
–
–
–
–
–
–
Dehydration
Direct Cardiac effects
Changes in blood vessel responses
Loss of neural control of blood pressure
Duration of flight
Individual preflight characteristics
Gender
Tilt tolerance after space flight
Survival Analysis
1.0
Survival
0.8
0.6
0.4
Pre-flight
Shuttle R+0
Long Duration R+0
0.2
0.0
0
2
4
6
Time(minutes)
8
10
Reduced Post-Flight Orthostatic Tolerance
Flight Program
Mercury-Atlas 9
(34 hrs of orbital flight)
Gemini
(3-14 day missions)
Post-Flight
Orthostatic
Tolerance
Moderate orthostatic
hypotension
Reduced orthostatic tolerance:
↑heart rate, pulse pressure,
↑venous pooling
Orthostatic
Challenge
Tilt Table
Hoffler GW, Johnson RL. Chapter 4: Apollo
Flight Crew Cardiovascular Evaluations in
Biomedical Results of Apollo, Johnston RS,
Dietlein LF, and Berry CA, Eds. NASA SP-368,
1975.
Tilt Table
(70 upright tilt)
Hoffler GW, Johnson RL. Chapter 4: Apollo
Flight Crew Cardiovascular Evaluations in
Biomedical Results of Apollo, Johnston RS,
Dietlein LF, and Berry CA, Eds. NASA SP-368,
1975.
Lower Body
Negative Pressure
and Static Stand Test
Hoffler GW, Johnson RL. Chapter 4: Apollo
Flight Crew Cardiovascular Evaluations in
Biomedical Results of Apollo, Johnston RS,
Dietlein LF, and Berry CA, Eds. NASA SP-368,
1975.
(Symptoms persisted up to 50 hours
after splashdown)
Apollo
(6-13 day missions)
Reduced orthostatic tolerance:
↑heart rate, pulse pressure,
stroke volume, body weight
(Symptoms persisted for 7 to 19
hours after landing)
Skylab
(28, 59, and 84 day
missions)
EDOMP
(4-14 day missions)
Reduced orthostatic tolerance:
↑heart rate, pulse pressure,
Lower Body
Negative Pressure
Johnson RL, Hoffler GW, Nicogossian AE, et al.
Chapter 29: Lower Body Negative Pressure: Third
Manned Skylab Mission in Biomedical Results
from Skylab, Johnston RS and Dietlein LF eds.,
NASA SP-377, 1977.
Monitoring during
first stand after
landing, Static stand
test, Lower Body
Negative Pressure
Charles JB, Fritsch-Yelle JM, Whitson PA, et al.
Chapter 1: Cardiovascular Deconditioning in
Extended Duration Orbiter Medical Project: Final
Report 1989-1995. Sawin SF, Taylor GR, Smith
WL, eds. NASA SP-1999-534.
(No detailed recovery time but
stated as longer than Apollo)
Reduced orthostatic tolerance:
↑heart rate, pulse pressure,
(Symptoms persisted up to 2 days)
References
Volume Distribution in Humans
• 70 % of blood volume is below
heart
• 19x more blood in capacitance
vessels than resistance vessels
• Up to 1 liter of blood resides in
gut and legs
• Without a gravitational field,
blood redistributes, shifts head
ward
Loring B. Rowell, 1986
Example of cephalad fluid shift
Pre-flight press briefing
Day-2 in flight
Gender Differences
There is great individual variability
in susceptibility to postflight
orthostatic hypotension. The
primary separating characteristic
between presyncopal and nonpresyncopal astronauts is gender
Orthostatic Tolerance
Females
~20%
~80%
Presyncopal
Males
~20%
~80%
Non-presyncopal
Gender Differences in
Venous Function
Rat suspended hind limb model
Zhang, LF. 1996
Arterial Remodeling
Zhang LF et. al. J Gravit Physiol. 1996;3(2):5-8
Arterial Function
Zhang LF et. al. J Gravit Physiol. 1996;3(2):5-8
Specific Aims
To compare venous responses
before and after bed rest:
1. between the hand and foot
2. between men and women
Subject Characteristics
Variable (pre bedrest)
Male
(n=16)
Female
(n=10)
Age, yr
34 ± 2
37 ± 2
Body mass, kg
79.8 ± 2.4
61.3 ± 3.1*
BMI, kg/m2
26.6 ± 0.5
23.8 ± 0.9*
Systolic BP, mmHg
122 ± 2
104 ± 2*
Diastolic BP, mmHg
80 ± 2
67 ± 2*
29.5 ± 1.9
24.7 ± 1.6
•
VO2max, ml/kg/min
Mean ± SEM; *p < 0.05
Ultrasound Images
Venous Compliance (hand)
7.0
7.0
Pre
Post
6.0
5.0
5.0
2
Area (mm )
6.0
2
Area (mm )
Pre
Post
4.0
3.0
4.0
3.0
2.0
2.0
1.0
1.0
Male
Female
0.0
0.0
20
30
Pressure (mmHg)
40
20
30
Pressure (mmHg)
40
Venous Compliance (foot)
3.0
3.0
Pre
Post
Pre
Post
*
2.5
2.5
*
2.0
*
2
Area (mm )
2
Area (mm )
2.0
1.5
1.5
1.0
1.0
0.5
0.5
0.0
0.0
20
30
Pressure (mmHg)
40
20
30
Pressure (mmHg)
40
ACh Mediated Dilation
2
Change in area (mm )
1.0
*
Pre
Post
1.0
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0.0
0.0
-0.2
-0.2
Male
Pre
Post
Female
-0.4
-0.4
0.10
0.316
1.00
Acetylcholine (mmol)
3.16
0.10
0.316
1.00
Acetylcholine (mmol)
3.16
Venoconstriction
0.6
Male
Female
0.5
2
Area (mm )
0.4
0.3
0.2
0.1
0.0
Pre
Post
Phenylephrine
Smooth Muscle Function
1.4
Male
Female
1.2
Area (mm2)
1.0
0.8
0.6
0.4
0.2
0.0
Pre
Post
Nitorglycerine
Nitric Oxide
5
5
Saline
LNMMA
4
2
Area (mm )
2
Area (mm )
4
Saline
LNMMA
3
2
1
3
2
1
0
0
Pre
Post
Acetylcholine
Pre
Post
Acetylcholine
Shear
Stress
Acetylcholine
Bradykinin
R
L-NMMA
-
NOS
L-ARGININE
ENDOTHELIUM
PGI
L-citrulline
Nitric Oxide
Nitric Oxide
Guanylate
cyclase (inactive)
Guanylate
cyclase (active)
cGMP
SMOOTH
MUSCLE
Relaxation
GTP
2
Prostaglandins
5
5
Saline
PGI2
4
Area (mm2)
Area (mm2)
4
Saline
PGI2
3
2
1
3
2
1
0
0
Pre
Post
Prostaglandin Inhibition
Pre
Post
Prostaglandin Inhibition
Shear
Stress
Acetylcholine
Bradykinin
R
L-NMMA
-
NOS
EDHF
L-ARGININE
ENDOTHELIUM
PGI
L-citrulline
Nitric Oxide
Nitric Oxide
Guanylate
cyclase (inactive)
Guanylate
cyclase (active)
cGMP
SMOOTH
MUSCLE
Relaxation
GTP
2
Conclusion
• Males:
– decrease venous compliance
– Differences in vasodilator response
• Females:
– do not change venous compliance
– EDHF or central reset
Venous Compliance (foot)
3.0
3.0
Pre
Post
Pre
Post
*
2.5
2.5
*
2.0
*
2
Area (mm )
2
Area (mm )
2.0
1.5
1.5
1.0
1.0
0.5
0.5
0.0
0.0
20
30
Pressure (mmHg)
40
20
30
Pressure (mmHg)
40
Survival Analysis
100
Survival (%)
80
60
40
20
Male
Female
0
0
3
6
9
Time (min)
12
15
Future Research
Future Directions/Areas of Interest
1. Gender differences in orthostatic
hypotension and venous tone
regulation
2. Space-like radiation and CVD risk
Space Exploration and CVD Risk
• Astronauts outside the protection of the
earth’s magnetic field will be continuously
exposed to low levels of space radiation.
– Increased risk for the development of certain
diseases such as cancer
• The same evidence used for cancer risk
prediction suggests that exposure to low-dose
radiation may also contribute to an increased
risk for cardiovascular disease (CVD).
The Vascular Endothelium
Endothelial Cells
Connective Tissue
Smooth Muscle Cells
Atherosclerosis Timeline
Foam
Cells
Fatty Intermediate
Streak
Lesion
Atheroma
From First
Decade
Complicated
Lesion/
Fibrous
Rupture
Plaque
Endothelial Dysfunction
From Third
Decade
From Fourth
Decade
Adapted from Pepine CJ. Am J Cardiol. 1998;82 suppl 10A
Epidemiological Support
• Patients who received
radiotherapy as part of their
treatment for a peptic ulcer
– CVD-related mortality was ~24%
higher compared to non-irradiated
patients.
Experimental Support
Datta et al. demonstrated that in
mice irradiated with 56Fe there was
a significant increase in ROS and
the pro-inflammatory cytokines IL-6
and TNF- , compared with gamma
irradiation
Experimental Support
Factors associated with
vascular dysfunction
Luscher T F et al. Circulation 2000;102:2434-2440
Effects of Space-like Radiation on the
Vessel Wall?
Inflammation/Oxidation
Cell Adhesion/Migration
↑ Cytokines
• TNF-α, CRP
↑ Oxidative stress
• oxLDL, superoxide
monocyte adherence
CAM expression
chemotaxis
Lumen
Coagulation/Fibrinolysis
fibrinogen
factors VII, X
PAI-1
Endothelial Vasoregulation
Study 1 General Hypothesis
Exposure to space-like radiation will
impair endothelial vasodilator
function and that this will be
mediated by an increase in oxidative
stress and associated with
increased systemic inflammation.
Study 1 Specific Aims
1.
2.
3.
To determine if endothelial vasodilator function is
decreased in rats exposed to low-fluence high
energy particle radiation and whether the effects
extend across different radiation ion types.
To determine if the radiation-related decrease in
endothelial vasodilator function is due to
increased oxidative stress and if so, whether this
is due to an increase in superoxide formation
regulated at the level of NADPH oxidase.
To determine if the radiation-related decrease in
endothelial vasodilator function is associated
with increased systemic inflammation.
Study 1 Design
Infusion Protocol
Study 2 General Hypothesis
Long-term exposure to fractionated
low-dose space-like radiation in the
presence of modeled microgravity
will have a synergistic deleterious
effect on endothelial vasodilator
function.
Endothelial Cell
eNOS
(uncoupled)
NADPH oxidase
O2-
ONOO-
COX
eNOS
Vasodilator
prostanoids
NO
Vasoconstrictor
prostanoids
NADPH oxidase
ONOOO2
O2-
O2NO
ONOOiNOS
(uncoupled)
Nucleus
Vascular Smooth Muscle Cell
NF-κB
Study 2 Specific Aims
• To determine if the vascular effects of long-term
exposure to fractionated space-like radiation
combined with modeled microgravity differ from
the vascular effects following exposure to
radiation or modeled microgravity alone.
• To determine if the expression, release and
availability of nitric oxide differs in animals
exposed to radiation compared to modeled
microgravity alone.
• To identify differences in transcriptional control of
nitric oxide dependent, atheroprotective pathways
between groups.
Study 2 Design
SHAM
Vascular function
HLU
56Fe 1000 MeV/u
Regulation and expression of
nitric oxide
60
120
HLU
+
56Fe 1000 MeV/u
240
Changes in NO-mediated
pathways
associated with vascular
endothelial atheroprotective
processes
Contributions
• Does exposure to space-like radiation
(at low doses) contribute to an increase
risk for CVD
• Is the type of radiation important in
explaining changes in vascular function
and CVD risk?
• What is the effect of exposure to
microgravity combined with
fractionated low-dose radiation
Acknowledgments
Steve Platts, Ph.D.
Mike Stenger, Ph.D.
Shang-Jin Shi, M.D. Ph.D.
Stuart Lee
Natalia Arzeno
Susan Bourbonais
Angie Brown
Tim Cain
Sondra Freeman-Perez
David Martin
Tim Matz
Tiffany Phillips
Chris Ribeiro
Donna South
Sydney Stein
Michael Willig