Cardiac Atrophy and the
Consequences for Long Duration
Spaceflight
Michael W. Bungo, MD, FACC, FACP, CPE
Professor of Medicine in Cardiology
The University of Texas Health Science Center
Houston – April 22, 2008
Pathophysiology of Syncope
Cerebral
Autoregulation
HR too slow
Heart
Rate
MAP
HR too fast
Stroke
Volume
LVESV too high
LVEDV
too low
Total
Peripheral
Resistance
TPR too low
“Puffy face – bird legs syndrome”
HR Increases During Standing
After Bedrest or Spaceflight
140
140
Supine
Standing (5 min)
100
120
Heart Rate
Heart Rate
120
NASA Data (SLS,D2)
Bedrest Data
80
60
100
80
60
40
40
20
20
0
0
Pre Bedrest
Post Bedrest
From Levine et al, Circulation 1997
Supine
Standing (5 min)
Pre Spaceflt Post Spaceflt
From Buckey et al, J Appl Physiol 1996
Heart Rate Response Is Augmented
HR (bpm)
L - 60
L - 15
R+0
100
100
100
90
90
90
80
80
80
70
70
70
60
60
60
50
50
50
40
0
40
0
tilt
BL
5’
Levine et al, J Physiol 2002
10’
tilt
BL
5’
10’
40
0
tilt
BL
5’
10’
Charles & Lathers; J Clin Pharmacol 1991; 31; 1010
CID = ΔHR - (ΔSBP - ΔDBP)
Δ = postflight - preflight
Charles & Lathers; J Clin Pharmacol 1991; 31; 1010
Vascular Resistance Does
NOT Rise Enough in Fainters
Systemic Vascular Resistance
Supine
Standing
Finishers (n=5)
Non Finishers (n=9)
30
30
*
20
20
10
10
0
0
Pre
Post
Buckey et al., J Appl.Physiol.,81:7,1996
Pre
Post
Pre Spaceflight
Post Spaceflight
Supine
units
Supine
0
10
20
30
40
0
10
20
30
40
time (sec)
time (sec)
Tilt
units
Tilt
0
10
20
30
time (sec)
Levine et al J Physiol 2002; 538; 331-340
40
0
10
20
30
time (sec)
40
Levine et al J Physiol 2002; 538; 331-340
MSNA (burst/min)
L-60
R+0
60
60
50
50
40
40
30
30
20
20
10
10
0
0
BL
supine
60 upright
tilt
BL
supine
60 upright
tilt
MSNA is Calibrated to Stroke Volume
55
50
*
Burst/min
45
40
35
30
pre spaceflight
post spaceflight
25
*
20
15
0
0 40 50 60 70 80 90 100 110 120 130 140
Stroke Volume (ml)
Levine et al, J Physiol 2002
Norepinephrine Does Not
Rise Enough in Fainters
Supine
Standing
Plasma NE (Pg/ml)
Finishers (n=21)
800
800
600
600
400
400
200
200
0
0
Pre
Post
Fritsch-Yelle et al, J Appl.Physiol, 81:2134, 1996
Non Finishers (n=8)
*
Pre
Post
Insert: Ertl et al, J Physiol, 538:321, 2002
Intra-Arterial Phenylephrine
120
90
60
30
0
150
Resistance (Flow/mmHg)
Resistance (Flow/mmHg)
150
Arm
Pre bed rest
Post bed rest
0.
0.
Ba
0
0
0
0
se 025 050 .100 .200 .400 .800
Leg
* *
120
*
*
90
60
30
0
Ba
0
0
0
0
0.
0.
80
40
se .025 .050 .100 .20
0
0
0
Infusion Rate ( μg/100ml/min)-1
Pawelczyk and Levine, J Appl.Physiol. 2002
Muscle Sympathetic
nerve activity
Arterial Pressure R-R interval (ms)
(mmHg)
Pre Flight
Phase 1
Late mission
Phase 4
Phase 2
Phase 3
Cox et. al. J Physiol (2002) 338.1 p309-320
Time (seconds)
Average Sympathetic & Vagal Responses as
Function of Blood Pressure Changes
Sympathetic Baroreflex Gain
Vagal Baroreflex Gain
The two left panels depict responses to straining and the right panel depicts responses after release of straining.
Cox et al, J Physiol, 538:309-320, 2002
Mechanism Proposed for Baroreflex
Changes in Space
Normal resting position (operational point) indicated by open circles;
microgravity shifts subjects leftward.
Cox et al, J Physiol, 538:309-320, 2002
Iwasaki K, et al. Am J Physiol 279: R2189-R2199, 2000
[Above] Mean changes (SE) in normalized
power of R-R interval variability at low
frequency (NormLF: 0.05–0.15Hz) and high
frequency (NormHF: 0.15–0.25Hz).
[Right] Mean changes (SE) in gains of
transfer function between blood pressure
and R-R interval at low frequency (GainLF)
and high frequency (GainHF).
A: after 2wk of head-down-tilt bedrest,
*P=0.05 compared with pre-bedrest (n9). B:
2h after administration of furosemide (n5),
*P=0.05 compared with pre-administration.
There were no significant differences for
the baseline data between head-down-tilt
bedrest and the acute hypovolemia (n5,
ANOVA).
Furosemide
induced
hypovolemia
produces
baroreflex
changes similar
to bedrest
Skylab4 – the first U.S. experience
84 day mission (data pre & post flight)
Left Ventricular End
Diastolic Volume
Stroke Volume
Down 15% in two crew; persisted
11 days; normal 31 days. Down
only 7% in one crewmember.
Down 20%; still reduced on R+11;
normal on R+31
LV Mass
Decreased 8% post flight; still
reduced at R+11; normal at R+31
LV Function Assessment LVEDV vs. SV
No change in slope
Henry et. at. Biomedical Results of Skylab. eds. Johnston & Dietlein 1977; Chapter 35 pp 366-371
Cumulative Data
Charles et. al. J Clin Pharmacol 1991; 31:1010-1023
Short vs. Long Duration Flight
(coordinated, equivalent ground based data is collected)
Short Flights
Long Flights
(Shuttle, n=13)
(Mir, n=4)
Systolic Volume
Decreased
Increased
Stroke Volume
Decreased
Greater decrease
Ejection Fraction
No significant
change
Decreased with a
possible increased
E/A ratio
Cardiac Mass
Unchanged or
decreased on
landing with quick
recovery
Larger decrease on
landing with
incomplete recovery
during short follow up
Martin et. al. Aviat Space Environ Med 2002;73:532-6
HEMODYNAMIC ADAPTATION TO HEAD DOWN TILT
STROKE VOLUME
STROKE VOLUME (ML)
150
150
130
Bed Rest
Spaceflight
Headdown
110
24 Hours
Supine
130
110
1 Week
6 Hours
90
90
48 Hours
Supine
70
70
“Set Point” for Central Blood
Volume Regulation
Upright
50
50
0
2
4
6
60
120 180
240 300 360
30°
TIME (HRS)
From Levine et al, Circ 1997; and Buckey et al, JAP 1996
HEMODYNAMIC ADAPTATION TO HEAD DOWN TILT
Stroke Volume (ml)
150
150
120
Head Down
120
5 WEEKS
Supine
2 WEEKS
Supine
Supine
90
9 WEEKS
Supine
*
3 WEEKS
Supine
60
Upright
7 WEEKS
Supine
90
60
10 WEEKS
Supine
0
0
0
10
20
30
40
450
Time (Hrs)
900
1350
1800
Stroke Volume Is Too Low In the
Upright Position
Supine
Standing (5 min)
Stroke Volume
100
Bedrest Data
100
80
80
60
60
40
40
20
20
0
Pre Bedrest
Post Bedrest
From Levine et al, Circulation 1997
0
NASA Data (SLS, D2)
Pre SpaceflightPost Spaceflight
From Buckey et al, J Appl Physiol 1996
Sine Qua Non of CV Adaptation to Space:
A Low SV in the Upright Position
SV (ml)
L - 60
L - 15
R+0
140
140
140
120
120
120
100
100
100
80
80
80
60
60
60
40
40
40
tilt
tilt
0
tilt
0
0
BL
5’
Levine et al, J Physiol 2002
10’
BL
5’
10’
BL
5’
10’
Stroke Volume (ml)
Ventricular Performance is Impaired
After
Bedrest
120
105
90
PRE BEDREST
POST BEDREST
75
60
45
4
From Levine et al, Circulation 1997
8
12
16
PCW (mmHg)
20
Pressure Volume Curves
P = -Sln[(Vm - V)/(Vm - Vo)]
Pulmonary Capillary Wedge
Pressure (mmHg)
Bedrest
Lasix
24
24
20
20
16
16
baseline
post
12
baseline
post
12
8
baseline
pre
4
baseline
pre
8
4
*
0
0
0 VO
40 VO 80
From Levine et al, Circulation 1997
120
160
0
LVEDV (ml)
40 VOVO 80
120
160
From Perhonen et al, Circulation 2001
Change in Diastolic Suction
after Bed Rest
*
100
V0
*
ESV
Volume (ml)
80
60
40
20
0
PRE
From Levine et al, Circulation 1997
k:\BRCM\Presentations\Nasa2001\Dias_su.JNB
POST
Heart Rate Increases
Stroke Volume Increases To Match Stroke Volume Relative Work Rate:
More in Athletes
A Matter of CV Control
200
200
200
*
150
*
*
150
100
*
100
*
HR ( bpm)
HR (bpm)
SV (ml)
150
100
50
50
Athletes
50
Sedentary
0
10 20 30 40 50
VO (ml/kg/min)
2
Athletes
0
0
0
Sedentary
Sedentary
Athletes
0
10 20 30 40 50
VO 2 (ml/kg/min)
0
40
80
%VO 2max (%)
12
Trans-Mural Pressure (mmHg)
Sedentary Aging Leads to Cardiac Stiffening
Exercise Training: The Fountain of Youth
6
4
2
Sedentary
Athletes
Young
0
50
75
100
125
150
Left Ventricular End Diastolic Volume (ml)
From Zadeh et al, Circulation 2004
Doppler Assessment of Myocardial Relaxation
LVP
Aortic Pressure
relaxation
LV volume
suction
compliance
Atrial contraction
LAP
Echocardiography parameters:
IVRT IVPG
E, E’
A
Prasad et al. Am J Cardiol 2007
Diastolic
Dysfunction
Delayed Relaxation
Restriction
This ambiguity
between the
normal and
pseudonormal
filling pattern is a
manifestation of
preload
compensation. As
diastolic
dysfunction
begins
(manifested
initially by slowed
ventricular
relaxation), E/A
ratio falls; later,
as dysfunction
worsens further,
left atrial
pressure rises in a
compensatory
attempt to
preserve stroke
volume. With this
rise in preload,
E/A ratio rises,
producing a Ushaped curve,
common to many
flow-based
parameters.
Old and New Modalities to Assess Diastolic Dysfunction
Typical transmitral, pulmonary venous, tissue Doppler, and color M-mode patterns in
various stages of diastolic dysfunction. TDE, tissue Doppler echocardiography; CMM,
color M-mode; Vp, velocity of transmitral flow propagation.
E
E’
Vp
Pacini et al, JACC 2007
Echocardiographic evaluation of E, E’, and Vp with variation in PCWP
Tissue Doppler
Velocity & Strain Rate
Strain Rate
TVI
Expand
SR1
v2
v1
v1
SR2
v2
SR2
SR1
[m/s]
No deformation
Contract
[1/s]
New Techniques
Tissue Velocity Image (TVI):
Velocity!
•Measures the tissue velocities
longitudinally
•Evaluates systolic and diastolic
global function
Tissue Tracking (TT):
Distance!
•Measures the segmental
displacement myocardium
longitudinally
•Evaluates systolic function
Strain Imaging:
Deformation!
•Measures the myocardial
compression (deformation) between
two points
•NOT influenced by adjacent
segments!
•Evaluates ischemic heart disease
Tissue Synchronization (TSI):
Time to Peak!
•Green = Synchrony
•Red = Dysynchrony
50
degrees/sec
endocardium
midwall
epicardium
-20
0
-50
-100
frame interval
100
Dorfman et al, JAP 2007
Post-bedrest
50
-30
degrees/sec
Pre-bedrest
max untwisting rates (degrees/sec)
100
-40
-50
-60
0
-50
-70
-80
-100
pre bed rest
post bed rest
frame interval
endocardium
midwall
epicardium
End Diastolic Volume Mean Wall Thickness
*
145
#
1.55
1.50
LVEDV (ml)
135
1.45
130
125
1.40
120
1.35
115
0
0.00
Base
2 wks
From Perhonen et al, JAP 2001
6 wks
Base
2 wks
6 wks
Mean Wall Thickness (cm)
*
140
*
Cardiac Atrophy with Bedrest
*
LV mass (gm)
280
260
240
220
0
Baseline
K:\Ben\Atrophy\B edR est.ppt
From
Perhonen et al, JAP 2001
2 w eeks
6 w eeks
LV Mass Continues to Decrease
Over 12 Weeks of Bedrest
325
300
LV Mass (gm)
275
250
225
200
175
0
From Perhonen et al, JAP 2001
BL
2 Wks
6 Wks 12 Wks
LV Mass (g)
200
Cardiac Atrophy After
Spaceflight [D2 Mission]
180
160
140
From Perhonen et al, JAP 2001
0
Pre
Post
Laplace’s Law
h
R
P
.R
P
Wall stress ≈
2h
Index = “mass/volume ratio”
Acute microgravity
h
h↑
R↓
Chronic
remodeling
R
P
P↓
P↓ . R ↓ ∴ wall stress↓↓
h↑ (→) and mass/volume ratio↑
Atrophy will
continue until m/v
ratio is normalized
Maximal Cross-Sectional Changes
% Baseline LV Mass Index
140
75 % Range!
130
Longitudinal Changes
37.5 % Range
120
12mo
110
100
9mo
short
flight
90
6mo
3mo
2wk
6wk
80
12wk
0
Spinal cord Bed rest
Injury
(from deGroot et al, unpublished observations)
Base
Training
Elite
Runners
(from Milliken et al, Am J Cardiol 1998)
0.14
0.12
11.5%
0.1
0.08
0.06
0.04
2.2%
0.02
0.6%
0
MA
JH
BT
McGavock et al Circulation 2007
Myocardial Triglyceride (F/W %)
1 .4
1 .2
1 .0
0 .8
0 .6
0 .4
0 .2
0 .0
Masters
Athlete
Sedentary- Sedentary SedentaryVigorous Moderate
No
Training Training Training
NEJM March 2008
Nitric Oxide & cGMP
up regulated resulting
in vascular & cardiac
hyporeactivity
BIOLOGICAL MODEL OF SUDDEN
CARDIAC DEATH
Structure
Function
• Myocardial
Infarction
(coronary lesion)
• Ischemia or
Reperfusion
– Acute
– Chronic
•Cardiomyopathy
– Hypertrophic
– Dilated
• Electrical
Abnormality
Circulatory
Collapse
• Systemic
Factors
• Neurohumoral
Effects
As Adapted from
Am J Cardiology 89
Myerburg et al
RDT 10/96
Ventricular Tachycardia on Mir
Fritsch-Yelle et al, Am J Cardio 1998
Categorizing VT/VF
¾ Normal Heart
– Outflow Tract VT
– Idiopathic Left VT
– Idiopathic VF
¾ Genetic Arrhythmia
Syndromes
– Hereditary Long QT
Syndrome
– Brugada Syndrome
– Hypertrophic and
Arrhythmogenic RV
Cardiomyopathie
¾ Environmental
– Drug-induced LQTS
– Hypokalemia
– Hyperkalemia
¾ LV Dysfunction
– Ischemic CMP
– Non-ischemic CMP
¾ Spaceflight
– ???
The SCD Risk Paradox
Myerberg
% Risk of SCD / year
Actual Numbers with SCD
General Population
High CAD Risk
Hx CAD Event
Primary prevention:
SCD-HeFT, MADIT 2
EF <30, CHF
Secondary prevention:
AVID
Arrest Survivors
High Risk
post MI
1° Prev: MADIT, MUSTT
30
20 10 5 2 1
100K
200K
300K
Predictors of SCD Risk
¾ LV dysfunction (strongest predictor)
– LVEF < 40%: substantial risk increase
– LVEF <30%: most robust single marker
¾ Complex Ectopy in post-MI patients.
– >10 PVCs/hr
– Non-sustained VT
¾ Prior Cardiac Arrest
¾ CAD risk factors
¾ T wave alternans
¾ Late potentials (from Signal Averaged ECG)
¾ QT variability, dispersion, and T wave
morphology
The Cardiac Action Potential
Depolarization
Repolarization
Ito
Ikr
ICa
Inward
Current
INa
Iks
Outward
Current
-80mV
QRS
T wave
ST
Schneider 1996
Nearing 2003
Starc & Schlegel J Electrocardiol 2006
~ 1/1000 NPV
Ikeda et al, JACC 2006
Risk Matrix
1 in 100,000 yr
2
1
1
Low
First Aid or minor injury
Med
4
5
Consequence
Risk
High
3
2
Adapted from: Doug Hamilton - USRA Aerospace Medicine Grand Rounds May 22, 2007
Loss of Life or Mission
1 in 10,000 yr
3
Permanent or serious
injury impairment
1 in 1000 yr
4
Long-term or missionimpact injury impairment
DQ
1 in 100 yr
L
I
K
E
L
I
H
O
O
D
5
Short-term injury, illness,
or impairment DNIF
1 in 10 yr
The ICV Study
The
C.A.R.D.I.A.C.
“Integrated CardioVascular”
Study: E 377
Cardiac Atrophy and Diastolic
Dysfunction During and After Long
Duration Spaceflight: Functional
Consequences for Orthostatic
Intolerance, Exercise Capacity, and
Risk of Cardiac Arrhythmias
Cardiac
Abnormalities in
Rhythm and
Diastolic function due to
Inactivity,
Atrophy and
Confinement
Clinical Implications of Cardiac Atrophy for
health and safety during long duration
spaceflight
1 ? magnitude, rate of change, and plateau over
time in flight
more severe
2 ? does more severe atrophy
orthostatic intolerance
3 ? what are the implications for systolic and
diastolic performance
4 ? does atrophy occur by apoptosis, and could
this pre-dispose to ventricular arrhythmias
Objectives
Objective 1a: To determine the magnitude of left and right ventricular atrophy associated
with long duration space flight, and to relate this atrophy to measures of physical activity
and cardiac work in-flight. Magnetic resonance imaging (MRI) will be performed pre- and
postflight as the most accurate means of measuring cardiac mass, including sufficient
repetitions to document recovery.
Objective 1b: To determine the time course and pattern of progression of cardiac atrophy
in-flight using cardiac ultrasound.
Objectives
Objective 1a: To determine the magnitude of left and right ventricular atrophy associated
with long duration space flight, and to relate this atrophy to measures of physical activity and
cardiac work in-flight. Magnetic resonance imaging (MRI) will be performed pre- and
postflight as the most accurate means of measuring cardiac mass, including sufficient
repetitions to document recovery.
Objective 1b: To determine the time course and pattern of progression of cardiac atrophy inflight using cardiac ultrasound.
Objective 2: To determine the functional importance of cardiac atrophy for cardiac diastolic
function and the regulation of stroke volume during gravitational transitions, by using
innovative, non-invasive imaging techniques to measure the dynamic component of diastole:
a) Strain Rate and Tissue Doppler Imaging (TDI) to quantify ventricular wall motion;
b) Color Doppler M-mode echocardiography to quantify intraventricular pressure gradients
and assess the magnitude of diastolic suction; and
c) MRI with myocardial tagging to quantify the rate of untwisting.
Objectives
Objective 1a: To determine the magnitude of left and right ventricular atrophy associated
with long duration space flight, and to relate this atrophy to measures of physical activity and
cardiac work in-flight. Magnetic resonance imaging (MRI) will be performed pre- and
postflight as the most accurate means of measuring cardiac mass, including sufficient
repetitions to document recovery.
Objective 1b: To determine the time course and pattern of progression of cardiac atrophy inflight using cardiac ultrasound.
Objective 2: To determine the functional importance of cardiac atrophy for cardiac diastolic
function and the regulation of stroke volume during gravitational transitions, by using
innovative, non-invasive imaging techniques to measure the dynamic component of diastole:
a) Strain Rate and Tissue Doppler Imaging (TDI) to quantify ventricular wall motion;
b) Color Doppler M-mode echocardiography to quantify intraventricular pressure gradients
and assess the magnitude of diastolic suction; and
c) MRI with myocardial tagging to quantify the rate of untwisting.
Objective 3: To identify changes in ventricular conduction, depolarization and repolarization
during and after long duration spaceflight, and relate these to changes in cardiac mass and
morphology (presence of fibrosis from late gadolinium enhancement and/or fat accumulation
from MR spectroscopy). The goal of this objective is to combine the best currently available
non-invasive tests of arrhythmia risk with high negative predictive value to demonstrate
convincingly the absence of risk for like threaten arrhythmias. These tests will quantify:
1) Arrhythmia burden;
2) Delayed conduction via the signal averaged electrocardiogram (ECG) (SAECG);
3) Dispersion of refractoriness from QT dispersion (QTD), QT variability and T-loop
morphology; and
4) Microvolt T-wave alternans (TWA) during daily activity including routine exercise.
"There is a place in your brain, I
think, reserved for the melancholy
of relationships past.
It grows and prospers as life
progresses, forcing you finally,
against your grain, to listen to
country music."
(K.B. Mullis et. al., eds., The Polymerase Chain Reaction,
Birkhauser: Boston, 1995, p. 427)
Slide compliments of Neal Pellis from NASA JSC
Many thanks to my co-principal
investigator, Ben Levine, from whom I
adapted numerous slides and/or material.