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CASE REPORT
Frequent Premature Ventricular Contractions in an
Orbital Spaceflight Participant
Richard T. Jennings, Jan P. Stepanek, Luis R. Scott,
and Yury I. Voronkov
JENNINGS RT, STEPANEK JP, SCOTT LR, VORONKOV YI. Frequent preor in flight. The certification process for Soyuz flights to
mature ventricular contractions in an orbital spaceflight participant.
the ISS begins with a medical prescreening examination
Aviat Space Environ Med 2010; 81:597–601.
followed by 2 wk of medical testing at the Gagarin CosBackground: Commercial spaceflight participants on orbital flights
monaut Training Center (GCTC) and Institute for Biotypically are older than career astronauts and they often have medical
conditions that have not been studied at high g or in microgravity. This is
medical Problems in Russia. Training cannot begin unless
a case report of a 56-yr-old orbital spaceflight participant with essential
the spaceflight participant is medically approved by the
tremor and frequent premature ventricular contractions that occurred at
Russian Medical Commission. Prior to flight to the ISS,
rates up to 7000 per day. Before training and spaceflight, he was required
International Partners’ Multilateral Space Medicine Board
to complete extensive clinical investigations to demonstrate normal cardiac
Delivered
by Ingenta
to: ?medically approve the spaceflight participant.
structures and the absence of cardiac pathology. The evaluation
included
must also
5.10.31.211 exercise
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May
2017 20:33:34
signal averaged ECG, transthoracic stress IP:
echocardiography,
The following
case describes a spaceflight participant
tolerance tests, electrophysiological studies, cardiac MRI, electron beam
with
frequent
premature
ventricular contractions (PVCs)
CT, Holter monitoring, and overnight oximetry. While no cardiac patholand essential tremor, and illustrates some of the medical
ogy was demonstrated, the Russian medical team required that the PVCs
be treated prior to training and spaceflight. For the initial flight, a selecand ethical issues that confront aerospace medicine spetive beta-1 receptor beta blocker was used and for the second a calcium
cialists who evaluate, certify, treat, and monitor individchannel blocker was used in combination with a nonselective beta
uals for short-duration orbital spaceflight.
blocker for tremor control. Analogue environment testing assured that
this combination of medications was compatible. Conclusion: The spaceCASE STUDY
flight participant’s PVCs were incompletely suppressed with a low-dose
selective beta-1 blocker, but were well suppressed by a calcium channel
Clinical Summary
blocker. He tolerated in-flight periodic use of a nonselective beta blocker
in combination with a calcium channel blocker. In-flight ECG and blood
Flight 1: A 56-yr-old male spaceflight participant
pressure monitoring results were normal, and an ECG obtained midwas
prescreened in January 2005 for a potential shortmission and on landing day showed successful PVC suppression. He did
duration orbital spaceflight. He was an experienced jet
not have any cardiac difficulty with launch, on-orbit operations, entry, or
recovery
pilot and held a current Class III FAA medical certificate.
Keywords: premature ventricular contractions, PVCs, spaceflight particiHe received excellent preventive medical services and
pant, ventricular ectopy, orbital spaceflight. Copyright: Aerospace Medical Association
C
LINICAL EXPERIENCE with medical conditions
during spaceflight is limited and often requires
decision making without medical precedent for flight
certification, treatment, and in-flight care. The advent of
private spaceflight participants for orbital and suborbital
flights results in crewmembers that are typically older,
with higher prevalence of clinical problems than career
astronauts or cosmonauts. The medical certification for
current short-duration orbital spaceflight participant candidates is arduous because the examination and certification process evolved from testing employed for selecting
long-duration career astronauts.
Before initiating training, the spaceflight participant
must meet the medical standards for the Russian medical team and subsequently meet the new spaceflight
participant standards of the International Space Station
(ISS) International Partner Multilateral Space Medicine
Board (1). The examinations often uncover medical problems that are asymptomatic, but may cause problems
during the medical approval process, during training,
Aviation, Space, and Environmental Medicine x Vol. 81, No. 6 x June 2010
annual examinations from his personal physician. He
exercised regularly and participated in daily workouts
under the guidance of a personal trainer. His father died
at age 86 of non-cardiovascular problems and his mother,
who was in her 80s, suffered from no cardiovascular disease. At the time of the prescreening evaluation, he had
not committed to a flight but was strongly considering
an orbital flight.
During the prescreen examination, there were two
pertinent clinical findings noted. These included familial
or essential tremor confined to the upper extremities and
From the University of Texas Medical Branch, Galveston, TX; Mayo
Clinic in Arizona, Scottsdale, AZ; and the Institute for Biomedical
Problems, Moscow, Russia.
This manuscript was received for review in January 2010. It was accepted for publication in February 2010.
Address correspondence and reprint requests to: Richard T. Jennings,
M.D., Preventive Medicine and Community Health, University of
Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-1110;
[email protected].
Reprint & Copyright © by the Aerospace Medical Association,
Alexandria, VA.
DOI: 10.3357/ASEM.2742.2010
597
PVCS IN A SPACEFLIGHT PARTICIPANT—JENNINGS ET AL.
frequent asymptomatic PVCs with occasional bigeminy.
improve the essential tremor, but the Russian medical
He was normotensive and the resting ECG was normal;
team was familiar with this medication and preferred its
however, a 24-h Holter monitor tracing showed 1289
use in space. Bisoprolol may be used at dosages from
PVCs in 24 h with brief periods of bigeminy. There were
2.5–40 mg z d21. Launch to the ISS occurred in early 2007
no couplets, triplets, or sustained tachycardia. The Exerand landing in Kazakhstan was completed 14 d later. On
cise Tolerance Test (ETT) showed no evidence of ischemia
launch day, continuous ECG monitoring showed brief
and the pilot completed 12:21 min of the Bruce protocol
episodes of bigeminy. There were no cardiac complicastudy with a maximum heart rate of 171 bpm, double
tions during the flight and a 5-min ECG tracing downproduct 26,334, and 13.7 METS. There were frequent PVCs
linked mid-mission showed occasional unifocal PVCs.
noted during recovery. An echocardiogram revealed
The postflight period was uneventful, but PVCs did pernormal cardiac structures, motion, and ejection fraction.
sist. A 7-h Holter tracing obtained immediately after landPulmonary function studies with arterial blood gases were
ing showed 33,000 beats and 395 PVCs.
normal as were the serum electrolytes. Lipids showed a
Flight 2: The spaceflight participant was seen by his
total cholesterol of 187 mg z dl21, LDL 106 mg z dl21, HDL
personal physician in December 2007. The lipids remained
47 mg z dl21, Trig 171 mg z dl21, CRP , 0.4, and potasfavorable, but the 24-h Holter tracing showed 7740 PVCs
sium 4.4 mmol z L21.
(7.2%) and occasional bigeminy. This time there was a
Prior to committing to the flight program, the pilot
single couplet, but no ventricular runs. In September
requested a Soyuz entry profile trial in a centrifuge and
2008, an unexpected spaceflight opportunity opened for
this was attempted in January 2006. During the prerun
March 2008, and the pilot considered a second Soyuz/
medical monitoring, the candidate had frequent PVCs
ISS flight since this flight was thought to be the last Soyuz/
and runs of bigeminy. Since the original cardiac workup
ISS opportunity for a spaceflight participant. Due to the
was completed a year earlier, the centrifuge operators
increased frequency of the PVCs, his personal physician
Delivered
to:therapy
?
requested a current evaluation prior to proceeding.
Onby Ingenta
initiated
with long-acting propranolol (Inderal
IP: 5.10.31.211 On: Sat, 06 May 2017 20:33:34
January 30, 2006, a cardiology consultation and cardioLA) at 60 mg z d21. The strategy was to address the esvascular workup directed by a cardiac electrophysiolosential tremor and PVCs with a nonselective beta blocker.
gist was completed. The Holter monitor tracing showed
The lowest dose available of propranolol LA is 60 mg.
a total of 1599 PVCs in 24 h with a maximum of 356 venThe spaceflight participant presented for evaluation
tricular ectopic beats in 1 h. He averaged 66 PVCs per
by the Russian medical team in October 2008. Due to the
hour. A stress echocardiogram was normal with mild inpilot’s compressed schedule and other travel requireferior wall hypokinesis that was unchanged with exercise.
ments, there was no opportunity to titrate the propranoThere was no motion-based or electrical evidence of stresslol LA to a PVC-suppressing level. In order to begin
induced ischemia and the ejection fraction with exercise
required training for the rapidly approaching flight, the
was 70%. During the study, he reached Bruce stage 5,
Russian flight medical certification needed to be comexercised for 12:27 min, and reached a maximum heart
pleted by early December 2008. There were no major
rate of 193 bpm. Monomorphic PVCs were noted and
changes from the certification workup from 2006 except
bigeminy occurred early in the ETT and suppressed at
that the 20-h Holter monitor tracing showed 6527 PVCs
peak exercise. PVCs and bigeminy recurred during recovwith a maximum of 523 per hour. The tracing also reery. There were no couplets, triplets, or
ventricular
runs.
vealed several
runs of bigeminy, and three ventricular
Copyright:
Aerospace
Medical
Association
Laboratory for electrolytes, lipids, TSH, Free T4, and
couplets (Fig. 1). Even though the spaceflight particiCRP (, 0.4) were again normal. Following the cardiovaspant had flown successfully 2 yr earlier, the Russian
cular evaluation, in March 2006, he completed monitored
medical team was uncomfortable with the increase in
centrifuge runs to 6.7 1Gx and 5.0 1Gz and experienced
PVCs/couplets and requested a new cardiac evaluation
only isolated unifocal PVCs that did not increase under
that included electrophysiological (EP) studies, investiacceleration. An electron beam computed tomography
gation to rule out myocarditis, and repeat Holter monidone on June 6, 2006, showed zero coronary artery
toring. Due to the short time span available, he returned
calcium.
to the United States for evaluation and initiation of
All the prescreen data were transferred to the Russian
treatment.
medical team and in June 2006 the certification medical
Cardiology consultation was performed, and the initesting began at GCTC and the Institute for Biomedical
tial clinical impression was right ventricular outflow tract
Problems. Most of the previous tests were repeated with(RVOT) PVCs. His ECG was normal, and the initial 20-h
out interval changes. The 21-h Holter tracing obtained
and 34-min Holter monitor tracing showed sinus rhythm
on June 20, 2006, showed 794 PVCs with a maximum of
with a heart rate of 57 to 92 bpm and 3309 ventricular
38 per hour. Based on the medical commission deliberaectopic beats (165 per hour). The PVCs were mostly isotion, he was approved for specialized training, but required
lated with the exception of two ventricular couplets. There
to complete periodic Holter monitor tracings throughwas no ventricular tachycardia or any changes in the ST
out the training period. Due to continued PVCs that ofsegment analysis. Signal averaged ECG testing showed
ten numbered 1500 per day, the Russian medical team
no evidence of late potentials. Additional ancillary tests
elected to treat the ectopy preflight and in flight with the
for assessment of structural heart disease included tranbeta-1 selective adrenergic blocker bisoprolol 2.5 mg every
sthoracic echocardiography, which revealed normal left
12 h. As a beta-1 selective agent, the bisoprolol did not
ventricular size and systolic function (EF 65%), with no
598
Aviation, Space, and Environmental Medicine x Vol. 81, No. 6 x June 2010
PVCS IN A SPACEFLIGHT PARTICIPANT—JENNINGS ET AL.
subject with a structurally normal heart. Drug testing
with verapamil was used to assess the response of the
ventricular ectopy. Following i.v. infusion of 5 mg of verapamil, the PVCs were suppressed. Oral verapamil (80 mg
every 6 h) was initiated and Holter monitoring was repeated in the first 24 h. During a 16-h Holter study, only
287 PVC were noted (average of 19 per hour), with no
couplets, triplets, or ventricular tachycardia seen. He was
then started by the electrophysiologist on long-acting
(sustained release) verapamil 240 mg z d21.
Following return to Russia, the spaceflight participant
completed four required extreme environment studies
at GCTC. These included a 12-min velo-ergometer study
(similar to a Bruce Protocol ETT), altitude chamber exFig. 1. Holter monitor tracing from October 2008, showing ventricular
posures on air at 5000 m (16,404 ft) for 30 min and on
couplet.
100% oxygen at 10,000 m (32,808 ft) for 15 min, and a
9 1Gx ballistic Soyuz entry centrifuge run. The initial
12-min velo-ergometer run was terminated due to
regional wall motion abnormality, and normal right
bigeminy and subsequently the verapamil SR dosage
ventricular size and function. With the exception of minwas briefly increased to 360 mg z d21 and the veloimal aortic valve sclerosis, all valves were structurally and
ergometer
workload minimally reduced. Following a
functionally normal. Atrial size and volumes were
successful
velo-ergometer study, he completed the altiwithin normal limits. A cardiac MRI showed normal
to: ?
tude chamber
and centrifuge requirements without difcardiac morphology and wall motion; specifiDelivered
cally thereby Ingenta
IP: 5.10.31.211 On: Sat, 06 May 2017 20:33:34
ficulty. The Russian medical commission approved him
was no change suggestive of arrhythmogenic right venfor specialized training and subsequently for flight with
tricular dysplasia.
the requirement that he take verapamil SR 240 mg z d21. In
The spaceflight participant underwent overnight oxiJanuary while taking verapamil, a 24-h Holter monitor
metry to rule out sleep disordered breathing that could
study showed a single PVC. The downside of this therapy
play a role in his frequent premature ventricular contracchoice is that it did not help the essential tremor and
tions. This study was normal. Noninvasive assessment
20 mg of oral propranolol was used for occasions when
of central vascular pressures with radial tonometry was
the tremor might affect operations or be noticeable during
within normal limits. Radial tonometry allows for the
public events. In order to assess the combined effect of a
noninvasive assessment of central vascular pressure and
low-dose beta blocker with verapamil, he was monitored
indices of vascular stiffness based on a recording of the
during 30-min operational tilt table exposures. During
peripheral radial pressure waveform and concomitant
this exposure, his tilt was altered between head down
recording of brachial pressure. The inference from pe(15°, 30°, and 45°) and head up (50°). His cardiovascular
ripheral to central vascular pressures is based on an FDA
status was stable throughout this exposure. He also
approved transfer function. Coronary calcium testing retolerated
15-min rotating chair sessions that included
vealed no evidence of coronary artery
calcifiedAerospace
plaque. Medical
Copyright:
Association
continuous head motion.
An invasive EP study revealed normal sinus node, atria,
The second Soyuz launched from the Baikonur CosAV node, and His-Purkinje functions. There was no evimodrome in March 2009 and landed in Kazakhstan 13 d
dence of a bypass tract. Isolated monomorphic premalater. There were no symptoms from PVCs and a 5-min
ture ventricular contractions were noted at baseline with
ECG downlinked mid-mission revealed no PVCs. The
a left bundle, right-inferior axis morphology, suggesting
blood pressure taken by the Russian commander was
origin in the right ventricular outflow tract. These PVCs
consistent with his normal blood pressure. The medical
had typical behavior of a triggered-activity PVC, with
team elected to decrease the verapamil SR dosage to 120
increased frequency while on isoproterenol and supmg on landing day to reduce the risk of postflight orthopression with verapamil. Rapid atrial pacing rates (by
static intolerance. The flight, landing, and postflight reinducing higher intracellular calcium concentration)
covery were uneventful, and he remained on verapamil
also increased the frequency of the PVCs. Ventricular
during the recovery period. A 12-lead ECG on landing
function testing during EP testing included programmed
day was normal and showed no PVCs. A 13-h Holter
ventricular stimulation in two different sites, using two
tracing on R10 also showed no PVCs in 53,800 beats.
different paced cycle lengths with up to three ventricular
extrastimuli, until refractoriness was noted. The ventricDISCUSSION
ular stimulation was performed on and off isoprotereFrequent PVCs may be clinically important since the
nol. Ventricular burst pacing up to cycle lengths of 280
cause may be ischemia, myocarditis, cardiomyopathy,
ms (215 bpm) was accomplished and no sustained orgaelectrolyte disturbances, thyroid problems, medications,
nized ventricular tachycardia was noted. Ventricular
chemicals, and cardiac structural problems. The military
fibrillation was induced once during programmed venbranches and the FAA require cardiac evaluations if PVCs
tricular stimulation with triple ventricular extrastimulaoccur frequently (such as more than two on a resting
tion. This was considered a nonspecific finding in this
Aviation, Space, and Environmental Medicine x Vol. 81, No. 6 x June 2010
599
PVCS IN A SPACEFLIGHT PARTICIPANT—JENNINGS ET AL.
adrenergic discharge was expected during his flight, which
ECG, greater than 1% of total beats on a Holter monitor
could lead to an increased frequency of this arrhythmia.
or greater than five occurring per minute) or are multiThe PVC suppression was successful in the second flight
form. Contractions that originate in the right or left venwith the use of a calcium channel blocker (verapamil).
tricle are also associated with some transient decrease in
Verapamil was chosen because of its beneficial effect
cardiac output. In this case, a pilot with asymptomatic
noted during invasive EP testing and following minimal
RVOT PVCs and a normal cardiovascular evaluation
PVC suppression with the previous use of two different
that included invasive EP studies and cardiac MRI had
low-dose beta blockers. There were no important arrhyththe PVCs electively suppressed by the medical team.
mias before, during, or after the second flight and the
The clinical significance of PVCs generally depends on
spaceflight participant remained asymptomatic. It remains
the presence of underlying cardiac disease and, for this
a question whether this strategy is the most appropriate
pilot, the repeated normal evaluations were reassuring.
one, or whether it reduces the risk for cardiovascular
It is estimated that 10% of patients presenting with ventricular arrhythmias (VA) have no obvious structural
events.
In individuals with structural heart disease, particuheart disease (10). RVOT PVCs, RVOT ventricular tachylarly coronary artery disease or cardiomyopathy, PVCs
cardia (VT), left ventricular outflow VT, idiopathic left
have been implicated in increased risk of sudden cardiac
ventricular VT, and propranolol-sensitive VT are types of
death (9,11,16). However, in a large multicenter trial,
VT commonly called “idiopathic VAs,” and they are gentheir suppression with certain antiarrhythmic agents inerally not associated with underlying structural heart discreased the risk of death and sudden cardiac death (7).
ease (14). RVOT monomorphic PVCs and RVOT VT are
This risk is not applicable to patients with normal hearts
the most common forms of idiopathic VA and are differwhen the agents being considered are beta blockers and
ent manifestations of the same syndrome. They are typicalcium channel blockers, such as was the case in this
cally characterized by a left bundle branch block
Delivered
subjectto:(5?,6). When membrane-active antiarrhythmic
morphology with the QRS axis directed inferiorly.
Theby Ingenta
IP: 5.10.31.211 On: Sat, 06 May 2017 20:33:34
drugs are being considered, the risk/benefit ratio alelectrocardiogram in these patients is generally normal
ways has to be carefully analyzed and it is usually acand these VA comprise 70% of the idiopathic VA (14).
cepted that these agents should not be used in completely
They usually present in the fourth or fifth decade of life
asymptomatic patients. This question takes on added imand, when symptomatic, may present with palpitations/
portance in commercial spaceflight because these inditachycardia, presyncope, or syncope. Exercise, emotional,
viduals are often older, when PVCs are more common,
and/or physical distress may facilitate this arrhythmia.
even in the absence of disease. While PVCs could indiThe two common presentations of RVOT PVC/VT are the
cate increased risk in individuals with structural heart
so-called non-sustained, repetitive monomorphic VT and
disease, cardiomyopathy, ischemia, or electrolyte disturthe sustained, exercise-induced VT (2). The mechanism of
bances, that was not the case with this aviator. In the
RVOT PVC/VT is triggered activity mediated by cateabsence of a myocardial infarction or left ventricular
cholamine-induced delay after depolarizations. These are
dysfunction, PVCs, even complex PVCs, are rarely assooscillations of membrane potential that occur after or durciated with malignant rhythms or sudden cardiac death.
ing the action potential. When an after depolarization
However, the Paris Prospective Study I did show a slightly
reaches enough amplitude, a full action potential may be
increased
risk of cardiac death in asymptomatic middletriggered. The delayed after depolarization-induced
trigCopyright: Aerospace Medical
Association
aged men who had exercise-induced PVCs. Bothersome
gered arrhythmias are usually facilitated by conditions or
symptoms are the most common indication for pharmadrugs that increase intracellular calcium, leading to incologic suppression with beta blockers or calcium channel
creased inward current (13). Cyclic adenosine monophosblockers, but symptoms were not an important factor
phate (cAMP) plays a significant role in regulating
for this aviator. We probably did increase his risk for
intracellular calcium. When the concentration of cAMP is
postflight orthostatic intolerance.
increased, intracellular calcium levels are high. Adenosine
Since many of the PVCs in individuals without heart
is effective in terminating RVOT VT due its anticholinergic
disease originate in the right ventricular outflow tract,
effect and its inhibition of delayed after depolarization.
many are now treated by radiofrequency ablation of the
Beta-blockers may be effective because of their inhibition
arrhythmogenic focus. That could not be done in this
of adenylate cyclase, which leads to a decrease of cAMP.
case since ablation would have resulted in a 6-mo waiting
Verapamil inhibits L-type calcium channels, which deperiod before initiating at-risk training and that would
creases the concentration of intracellular calcium (13).
have cost the participant any chance for the last potenLong-term management of RVOT VT/PVC includes
tial spaceflight participant flight.
clinical observation for asymptomatic or minimally sympAnother important consideration is the concern regardtomatic patients. Medical therapy usually includes beta
ing any deleterious effect on the PVCs from the training
blockers and, in certain cases, membrane-active antiaror flight environment, specifically 1Gx exposure and
rhythmic drugs such as sotalol, amiodarone, and others
(3). Catheter ablation is an effective option for the treatmicrogravity. The acceleration environment and particment of symptomatic patients, with a success rate of 90%
ularly 1Gx exposure can cause increase in arrhythmias
(13).
(15,17), but this did not occur in the several training and
In this case, it was opted to prophylactically treat the
certification ballistic and nominal entry centrifuge expopilot prior to his training and orbital flight. Increased
sures experienced by this participant. A NASA study of
600
Aviation, Space, and Environmental Medicine x Vol. 81, No. 6 x June 2010
PVCS IN A SPACEFLIGHT PARTICIPANT—JENNINGS ET AL.
five subjects wearing a Holter monitor on short-duration
tive that the spaceflight participant allowed this data to
flights reported no increase in arrhythmias and other
be released to help those that follow into space.
studies comparing EVA ECG tracings preflight and in
ACKNOWLEDGMENTS
flight also showed no important change in arrhythmias
Authors and affiliations: Richard T. Jennings, M.D., M.S., Preventive
during short-duration spaceflight (4).
Medicine and Community Health, University of Texas Medical Branch,
The ideal medication for a pilot with essential tremor
Galveston, TX; Jan P. Stepanek, M.D., M.P.H., and Luis R. Scott, M.D.,
Mayo Clinic in Arizona, Scottsdale, AZ; and Yury I. Voronkov, M.D.,
and PVCs would be a nonselective beta blocker. UnforInstitute for Biomedical Problems, Moscow, Russia.
tunately, the low-dose bisoprolol he used in the first flight
and the low-dose propranolol he used before the second
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