ISOPTWPO Today

AUGUST 2015, N O 19

ISOPTWPO Today

Editorial Dear Reader It is my pleasure to introduce the ISOPTWPO. ISOPTWPO(International Space Flight & Operations - Personnel Recruitment, Training, Welfare, Protocol Programs Office) is part of ISA, which support research on Human Space Flight and its complications.

The International Space Agency (ISA) was founded by Mr. Rick Dobson, Jr., a U.S. Navy Veteran, and established as a non-profit corporation for the purpose of advancing Man’s visionary quest to journey to other planets and the stars.

ISOPTWPO will research on NASA’S Human Research Roadmap. It will also research on long duration spaceflight and publish special issues on one year mission at ISS and twin study.

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Mr. Martin Cabaniss

Director Mr. Martin Cabaniss ISOPTWPO – International Space Agency(ISA) http: // www. international-space-agency. us/ Email:martin.cabaniss@international-space-agency.us

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IN THIS EDITION Page No. 3-7

Article Name Evidence Based Review: Risk of Cardiac Rhythm Problems during Space Flight

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A Simple In-flight Method to Test the Risk of Fainting on Return to Earth After Long-Duration Space Flights

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Impairment of Cerebral Blood Flow Regulation in Astronauts With Orthostatic Intolerance After Flight

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DID YOU KNOW ? PREVENTION OF SUDDEN CARDIAC DEATH

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Reduced heart rate variability during sleep in longduration spaceflight

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DID YOU KNOW ? OUABAIN :ANTI-ARRHYTHMIA AGENTS; CARDIOTONIC AGENTS; ENZYME INHIBITORS

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Cardiovascular regulation during long-duration spaceflights to the International Space Station

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DID YOU KNOW ? Heart Rate and Daily Physical Activity with Long-Duration Habitation of the ISS

Risk of Cardiac Rhythm Problems

Evidence Based Review: Risk of Cardiac Rhythm Problems during Space Flight Heart rhythm disturbances have been seen among astronauts. Most of these have been related to cardiovascular disease, but it is not clear whether this was due to pre-existing conditions or effects of space flight. It is hoped that advanced screening for coronary disease has greatly mitigated this risk. Other heart rhythm problems, such as atrial fibrillation, can develop over time, necessitating periodic screening of crewmembers’ heart rhythms.

Beyond these terrestrial heart risks, some concern exists that prolonged exposure to microgravity may lead to heart rhythm disturbances.

At present, there is little evidence suggesting that cardiovascular adaptation to microgravity or space flight increases susceptibility to life threatening arrhythmias in astronauts. From a clinical perspective, according to the "biological model" of sudden cardiac death, both the substrate and the trigger for arrhythmias should be considered to determine whether long-term space flight could lead to an increased risk of sudden death.

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In this model, structural abnormalities interact with functional alterations, such as exercise, electrolyte disturbances, or neurohumoral modulation, to create an environment in which arrhythmias can be initiated and/or sustained. In patients with coronary artery disease, the substrate is clear: a myocardial infarction (MI) and/or scar leading to focal areas of slowed conduction, a necessary condition for re-entry.

For patients with apparently normal ventricular function, the potential substrate is less certain. In fact, reentry often is not the mechanism of arrhythmia development in these clinical cases: the arrhythmias may be caused by delayed after-depolarizations, and the triggered activity may be mediated via catecholamines. The published report of non-sustained ventricular tachycardia during prolonged space flight supports this hypothesis, in that initiation of tachycardia by a late diastolic premature ventricular contraction (PVC) is more consistent with triggered activity than it is with re-entry.

While there are no definitive data showing that long-duration space flight is associated with cardiac arrhythmias, there are observational data that have been documented over many years that are suggestive of cardiac electrical changes during long flights. For example, during Skylab, all 9 American crewmembers exhibited some form of rhythm disturbance.

Most of these rhythm disturbances consisted of single PVCs and were clinically insignificant. However, one crewmember experienced a 5-beat run of ventricular tachycardia during a lower-body negative pressure protocol, and another had periods of "wandering supraventricular pacemaker" during rest and following exercise.

More recently, it has been shown that the corrected QT interval (QTc), a marker of ventricular repolarization, was prolonged slightly in a small number of astronauts after long-duration space flight. In-flight Holter monitoring was not performed during these space flights. Thus, it is not known whether this prolongation was associated with any known arrhythmias. In-flight Holter monitoring was undertaken in the early Space Shuttle era.

Virtually no changes in arrhythmias were documented in flights of 4 to 16 days during either intravehicular or extravehicular operations compared to preflight measurements. Indeed, in these studies, the frequency of arrhythmias may actually have been reduced in flight, though the day-to-day variability of these arrhythmias, which is known to be quite wide, was not quantified. However, aboard the Mir space station, PVCs were detected that were not present before flight and a 14-beat run of ventricular tachycardia was documented More recently, several conditions that may predispose crewmembers to arrhythmias have been identified. DAunno et al. found that after long-duration missions QTc intervals are slightly prolonged in crewmembers who did not have prolonged QTc intervals after their short-duration Space Shuttle flights, and several investigators have found decreases in left ventricular mass following space flight.

All of these findings raise the concern that cardiac rhythm disturbances may become an issue during the long in-flight tours of duty planned for ISS and interplanetary missions. The degree to which space flight and its many variables can be considered arrhythmogenic is not clear, but the possibility that serious cardiac rhythm disturbances might occur during space flight is a concern to NASA.

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Evidence Space Flight There have been no systematic studies of the arrhythmogenic potential of long-duration space flight, and only two studies of short-duration space flight. There have been, however, a number of published reports detailing in-flight arrhythmias. Table 1 includes a summary of some of these reports.

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Leguay and Seigneuric also compiled some of the reports from the pre-Shuttle era of manned space flight. Several of these reports are briefly described below.

One crewmember during Apollo 15 experienced a 22-beat nodal bigeminal rhythm, which was followed by premature atrial beats. This crewmember reported extreme fatigue during the incident, but only when questioned about it by crew surgeons; thus, it was not severe enough to impact the mission. Twenty-one months later the crew member suffered from coronary artery disease and a cardiac infarction without suggestive ECG changes.

In the Skylab missions, several instances of ventricular PVCs, supraventricular PVCs, and nodal arrhythmia were recorded. The arrhythmias occurred during effort tests, extravehicular activities (EVAs), lower body negative pressure sessions, and throughout the entire mission. These included two consecutive PVCs in one astronaut during exercise and an episode of atrioventricular dissociation preceded by sinus bradycardia in two astronauts.

In addition, an isolated incident of a non-sustained 14-beat ventricular tachycardia (Figure 1), with a maximum heart rate of 215 beats per minute, was recorded using in-flight Holter monitoring abroad thr Mir. Although not part of a systematic scientific study, this case provides additional evidence of arrhythmias during during long-duration spaceflight.

Systematic studies of cardiac rhythm disturbances have been performed during short-duration space flight.

These studies were conducted in response to medical reports of arrhythmias occuring in 9 of 14 Space Shuttle EVA astronauts between 1983 and 1985. Rossum et al. used 24-hour Holter recordings acquired during and after high altitude chamber activity, 30 days before launch,during,and after each EVA activity performed ,and on return to Earth.

The investigators observed no change in the number of premature ventricular contractions or premature atrial contractions per hour during flight compared to preflight or postflight(Figure 2). Likewise,arrhythmias were not observed by Fritsch-Yelle et al. in 12 astronauts studied before, during,and after 6 Space Shuttle missions.

It is unknown whether long-duration exposure to microgravity itself may precipitate cardiac arrhythmias. Based on observations and clinical judgment, medical operations personnel have suggested that some of these incidents may have been related to pre-existing, undiagnosed coronary artery disease. Additional pre-selection crew screening tests, including calcium scoring, have been added to reduce such occurrences in the future.

Contributing Factors Left Ventricular Mass Recent evidence suggests that the development of apoptosis, or "programmed cell death" in response to pathological, physiologic, and/or genetic signals, may be a key developmental factor in causing cardiac arrhythmias.

For example, apoptosis associated with atrophy and fibrofatty replacement of right ventricular tissue has been identified as the likely mechanism for arrhythmia development in arrhythmogenic right ventricular dysplasia, a condition that may lead to sudden death in otherwise healthy young individuals.

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Risk of Cardiac Rhythm Problems

Two publications have reported decreases in left ventricular mass after shortduration space flight.

In one of these publications, cardiac MRI was used and showed a reduction in left ventricular mass on landing day; however, extended recovery data were not obtained (Figure 3). In the other publication, echocardiography was used and showed a similar decrease in mass on landing day with full recovery 3 days after landing.

Unpublished data (also measured with ultrasound) show decreases in left ventricular mass after 6-month missions aboard the ISS. These decreases are double those observed after short flights and do not fully recover by the third day after landing (Figure 5).

There is some disagreement over the mechanism of the decrease in mass, especially after short duration missions. While there is evidence to support the idea that tissue dehydration contributes to the loss in mass after short-duration space flights, there are data from bed rest studies showing that the decrease in mass can be prevented with exercise and/or nutritional countermeasures. However, there is agreement that the greater loss of mass with long-duration flight is most likely due to atrophy.

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Risk of Cardiac Rhythm Problems

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QT Prolongation The QT interval is a measure of the combined duration of ventricular depolarization (QRS) and repolarization (T-wave). The QRS complex is usually of fixed duration in healthy individuals and does not change during longduration space flight. Thus, changes in QT duration represent alterations in ventricular repolarization.

The QT interval of the surface ECG is a spatial and temporal summation of all cardiac cellular action potentials. Not all cells within the heart share identical action potentials; therefore, a certain degree of variability, or inhomogeneity, in their repolarization time exists. The degree of inhomogeneity during repolarization directly correlates with the overall morphology of the QT waveform (primarily the T-wave) and in most cases with the QT interval duration. A clear association between the magnitude of inhomogeneity of repolarization and the risk for the development of ventricular arrhythmias has been established.

The QT interval is often corrected for heart rate and is shown as QTc. Some conditions that can prolong the QTc interval are ischemic heart disease, autonomic dysfunction, bradycardia, electrolyte abnormalities, cardiac remodeling, and dehydration medications that interfere with the cardiac potassium ion channels.

Which of these factors are seen in long-duration astronauts?

• Astronauts develop changes in the autonomic nervous system.

• On long-duration flights, astronauts have a relative bradycardia compared to astronauts on short-duration flights.

• There is evidence of cardiac remodeling after long-duration flight as seen in Figure 5.

• There are medications available to astronauts aboard the ISS that prolong QTc interval, including ciprofloxacin, haldol, inderal, verapamil, zithromax, Zoloft, and nortriptyline.

The environment created by the combination of factors listed above might cause or exacerbate the prolongation of the QT interval.

Prolongation of QTc interval does not itself guarantee an increase in ventricular arrhythmias. For example, sleep, hypothyroidism, and use of the anti-arrhythmic drug amiodarone all prolong QTc without increasing the incidence of ventricular arrhythmias. It is possible that space flight presents a similar situation. However, at this time, that determination cannot be made due to lack of data. Therefore, the data must be collected.

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A Simple In-flight Method to Test the Risk of Fainting on Return to Earth After Long-Duration Space Flights

NASA Image: ISS035E022356 - Chris Hadfield, during increment 35, is instrumented to perform BP Reg on-orbit. Chris has the LACS installed on his thighs, and the CBPD on his left hand Space flight affects blood pressure functioning in a way that causes astronauts to be more likely to faint when they return to Earth. A sensitive test has been developed to identify whether astronauts need countermeasures to prevent them from fainting on return to Earth. This research will verify the accuracy of this test.

Direct measures of venous pressure or use of multiple Doppler ultrasound probes to quantify blood flow requires considerable operator expertise and multiple pieces of equipment. The proposed method for quantifying indicators of overall cardiovascular regulation from the finger blood pressure waveform will represent an interesting alternative non-invasive measurement.

Dizziness with the risk of fainting (orthostatic intolerance) remains a critical problem for the return of astronauts to the gravitational forces of Earth, especially after long-duration space flight. Mechanisms contributing to this orthostatic intolerance on return to Earth have not yet been fully identified.

Evidence points to an important role for reductions in cardiac output contributing to the fall in blood pressure due to some combination of reduced blood volume, reduced cardiac muscle mass, and impaired venous properties that reduce return of blood to the heart. Mechanisms may include a reduction in total circulating blood volume, however orthostatic intolerance has been seen when blood volume has been maintained or restored and after short- or long-duration space flights even when saline loading was administered as a countermeasure .

There is definitely impairment of the rapid parasympathetic nervous system-mediated heart rate component of the arterial baroreflex . Various results have been found with regard to changes in the activity of the sympathetic nervous system after bed rest and space flight, although for those individuals who failed a stand test after space flight impaired vasoconstriction clearly implied reduced sympathetic vasoconstrictor responses . Because of these different observations and the lack of conclusive evidence, there are different opinions about the most likely mechanism for orthostatic intolerance.

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Recent research demonstrates the feasibility of a simple noninvasive measurement of cardiovascular function and the benefits to be gained from quantification of the venous return (VR), stroke volume (SV), heart rate (HR), cardiac output (Q) and total peripheral vascular resistance (TPR) responses to leg cuff deflation in-flight. The continuous blood pressure device (CBPD) is a non-invasive finger blood pressure cuff that provides continuous, real-time estimates of arterial blood pressure. With the finger cuff it is possible to monitor changes in the arterial blood waveform as if there were a needle placed directly in the artery.

To gain insight into the effectiveness of current coun-termeasures for the maintenance of cardiovascular health during long-duration spaceflight, the Canadian Space Agency (CSA) has supported three experiments: Cardiovascular and Cerebrovascular control on return from the International Space Station (CCISS); Cardiovascular Health Consequences of Long-duration Spaceflight (Vascular) and Blood Pressure Regulation and Risk of Fainting on Return from Space (BP Reg).

The CCISS experiment examined cardiovascular health in 7 astronauts (1 woman). Flight durations averaged 147 Âą49 days, with 3 astronauts landing at Kennedy Space Center, 1 at Dryden Flight Research Center, and 3 in Kazakhstan with return to Star City outside Moscow. The CSA experiment Vascular is in progress but has studied 7 astronauts (3 women), all of whom have landed in Kazakhstan after 176 Âą13 days on ISS followed by return to Star City (n=1) or direct return to Johnson Space Center and testing on the next day (R+1). The BP Reg experiment has started and 4 astronauts have all returned to Johnson Space Center for testing on R+1.

Heart rate during activities of daily living The first reports during long-duration spaceflight of simultaneous monitoring of physical activity from the Actiwatch placed on each of the ankle and wrist, in combination with heart rate from 24-h Holter recording were published with the CCISS experiments (Fig. 1).

Ankle activity counts recorded in activities of daily living were significantly reduced during spaceflight, as was the asso-ciated transient increase in HR during these activities . The marked reduction in ankle activity counts during spaceflight is clear from this example and could be taken as a reflection of an extreme sedentary lifestyle as often described with aging .

The only stimulus to the heart for maintenance of cardiovascular fitness occurred during the planned daily exercise sessions. While astronauts are allocated 2.5-h per day for exercise, the time spent in actual exercise is considerably less than this. Indeed, the CCISS astronauts completed aerobic exercises 4-8 times per week with average duration of 22-48 min per session, and conducted resistance exercises 4-6 times per week Indicators of cardiac health Heart rate variability (HRV) provides an overall indicator of cardiovascular health as reflected by the changes in autonomic nervous system balance in the regulation of cardiovascular control. Head-down bed rest, an analog of spaceflight, causes reduced HRV. Aging and disease also cause reduced HRV but physical training can maintain HRV in older individuals . The CCISS experiment revealed that high frequency (>0.15 Hz) HRV was reduced during spontaneous breathing at rest and during sleep. In contrast with the ground-based studies of head-down bed rest, resting HR was not significantly changed.

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In space, smaller variations in stroke volume and pulse pressure occurred at the respiratory (high) frequency, reducing the impact on the arterial baroreflex to modulate parasympathetic nervous activity to the sinoatrial node within a respiratory cycle. Post-flight there were reductions in HRV at low and high frequencies while there was a trend to reduction in post-flight RR-interval (P=0.07) suggesting that an overall reduction in parasympathetic nervous activity contributed to the decrease in HRV. Considerable differences between individuals were observed with large reductions in post-flight resting RR-interval associated with greater reductions in HRV. Arterial baroreflex The CCISS experiments measured the arterial baroreflex before, during and after long-duration spaceflight from the sequence method that related to spontaneous changes in RR-interval with finger arterial blood pressure measured in space with the continuous blood pressure device (CBPD).

Pre- and post-flight, astronauts were studied in supine and seated postures. The arterial baroreflex slope was not different inflight compared to pre-flight baseline in either the supine or seated postures . Post-flight, a significant reduction was observed only in paced breathing (10 breaths/min).

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Large changes in baroreflex slope were observed in individuals who did the most aerobic exercise sessions while on ISS. While this observation seems contrary to expectations, it is probable that the individuals who did the most aerobic exercise while on ISS were also the same astronauts who incorporated large quantities of aerobic exercise into their pre-flight routines. That is, they had the lowest heart rate prior to spaceflight due to high parasympathetic tone, but were unable to maintain their high aerobic fitness on ISS due to lack of loading of the treadmill device . These astronauts also reported frequent dizziness that might have been related to post-flight orthostatic hypotension.

Arterial stiffness Increased arterial stiffness, normally observed with aging , has recently been observed during and after spaceflight including long-duration ISS missions as well as short-duration shuttle flights. Baevsky et al. [2] measured the pulse wave transit time from the R-wave of the ECG to the arrival of the finger pressure wave.

The observations of faster transit time from pre- to post-flight in the Vascular experiment (P=0.07) were almost identical to previous data. However, preliminary new data from the first 6 astronauts in the Vascular study revealed reductions in carotid artery distensibility after approximately 6 months in space.

Given the observations in older sedentary individuals that 3 months of walking or jogging for 40 min/day reduced carotid and peripheral artery stiffness, possibly through enhanced bioavailability of nitric oxide , authors investigated whether astronauts who maintained physical fitness would have less change in pulse wave transit time to the finger. There was no relationship between the change in pulse wave transit time and the change in heart rate at a fixed work rate (mean pre-flight heart rate approximately 145Âą17 bpm) as shown in Fig. 2.

It is established that multiple factors could contribute to increased arterial stiffness with aging including increased vasoconstrictor or reduced vasodilator factors, structural breakdown of elastin, accumulation of collagen, Vascular smooth muscle cell proliferation and increased cross-linking in the extracellular matrix . The possible roles of these factors related to the increased arterial stiffness with spaceflight have not been investigated. The animal model of hindlimb suspension, used as an analog of spaceflight, revealed cellular hypertrophy in the middle cerebral artery with a potential role for activation of Vascular wall renin-angiotensin system.

Other experiments with a similar animal model suggested increased cross-linkage in the major elastic arteries.

The Vascular experiment provides data to test these mechanisms. It is not clear from the cosmonaut data of Baevsky et al. whether the increased stiffness is an acute or long-term effect of spaceflight.

Life long increased arterial stiffness in aging has important health consequences associated with increased systolic arterial blood pressure that can lead to target organ damage such as increased cerebrovascular resistance with a reduction in brain blood flow in otherwise healthy elderly individuals.

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Developing individual countermeasures The CCISS and Vascular studies have revealed a range of individual responses to long-duration spaceflight. It is not possible from current data to determine how genetic variations versus exercise regimes might have resulted in the various outcomes although this is a logical question based on studies showing heritability of training responses .

Research is required to identify astronauts who are in greater need for countermeasures to prevent cardiovascular deconditioning during long-duration spaceflights and in future exploration missions.

Changes of structure and/or function in different physiological systems can have different health consequences. Sensitive biomarkers should be developed to monitor during spaceflight and a "healthy range" should be defined. Beyond this, specific "thresholds" should be established for application of more intensive countermeasures.

It has been assumed that inflight exercise testing can provide a sensitive biomarker of physical fitness. Adjustments of exercise routines are based on the outcomes to maintain aerobic fitness and strength. However, the variability observed in heart rate at a fixed work rate in Vascular requires greater probing of the links between exercise routines and other daily stressors that might affect the heart rate response. Periodization of training could be used to adjust the stress on the astronaut while considering the time available and important resources such as food and water.

The current experiment BP Reg is attempting to focus on one aspect of cardiovascular health; that is, regulation of arterial blood pressure (BP) on return to upright posture on Earth. The experiment monitors BP during a challenge that is similar to standing up on Earth while still in space. The experiment inflates large cuffs (Leg Arm Cuff System, LACS) about the upper legs to a pressure above systolic BP for 3-min then rapidly deflates the cuffs while BP is monitored with the continuous blood pressure device (CBPD).

On Earth, the BP response during transition to standing and supine leg cuff deflation was similar (Fig. 3).

It is anticipated that astronauts who have the greatest change in the BP response to leg cuff deflation comparing the inflight response with the pre-flight baseline will be those who have a greater drop in BP on standing after flight. Results from this biomarker test could be used to apply countermeasures that will mimic the effects of gravity on the cardiovascular system such as lower body negative pressure or centrifuge if these devices are available on ISS. For the general population, dizziness and fainting (syncope) are major health problems accounting for 1-3% of visits to hospital emergency rooms. These problems become especially important for elderly, where falling is a major contributor to bone fracture. A better understanding of the mechanisms responsible for fainting could reduce risk of injury. Astronauts returning from space flights risk experiencing dizziness or fainting when they stand immediately after returning to Earth.

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Impairment of Cerebral Blood Flow Regulation in Astronauts With Orthostatic Intolerance After Flight

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In this study authors investigated the possible importance of cerebral autoregulation on orthostatic intolerance after space flight in a sample that contained presyncopal astronauts on landing day. Authors hypothesized that autoregulation would be negatively affected by space flight in those astronauts who did not complete a 10-minute stand test (nonfinishers) when compared to those did (finishers).

Twenty-seven astronauts from shuttle missions lasting 8 to 16 days underwent a 10minute stand test: 10 days before flight, 1 to 2 hours and 3 days after landing. Mean blood flow velocity of the middle cerebral artery (MCA) was measured using transcranial Doppler; Mean arterial pressure was measured using a Finapres (Ohmeda, Englewood, CO) and was adjusted to the level of the MCA (BPM CA ). Cross-spectral power, gain, phase, and coherence were determined for the relation between BPM CA and the cerebrovascular resistance index mean blood flow velocity/BPM CA .

This protocol was approved by the Johnson Space Center Human Research Policy and Procedures Committee. Data before and after flights were recorded from astronauts who took part in shuttle missions lasting 8 to 16 days. Data were collected 10 days before launch (baseline, before flight), on landing day (1 to 2 hours after landing), and 3 days after landing (after flight).

Cerebral blood flow in the M1 segment of the middle cerebral artery (MCA) was measured using transcranial Doppler ultrasound and blood pressure via noninvasive finger photoplethysmography. The dynamic autoregulatory gain was determined using the noninvasive transfer function method. Astronauts were classified as finishers (completed the 10-minute stand test) or as nonfinishers (presyncopal during the stand test).

Results Of the 27 astronauts (20 male, 7 female) who were analyzed in this study, 19 (17 male) were classified as finishers and 8 (5 female) were classified as nonfinishers. Mean arterial pressure at the level of the MCA (BPM CA ) was significantly reduced by the stand test (P<0.001). This was combined with differences between finishers and nonfinishers (P=0.011) and over test days (P=0.004). On landing day, finishers had a higher BPM CA than those before flight and the nonfinishers (Figure 1). Three days after landing, the finishers had returned to preflight values whereas the nonfinishers had elevated supine BPM CA .

Mean cerebral blood flow velocity (MFV) was affected by test day(P<0.001) and by the stand test (P<0.01).Preflight nonfinishers had higher MFV than finishers. Compared to the preflight group, the supine MFV of the finisher group was elevated on landing day, whereas in the nonfinisher group MFV was unchanged.

Unlike preflight MFV, on landing day both finishers and nonfinishers had a reduction in MFV with standing.

Only the nonfinishers had MFV reduced lower than preflight values. Three days after landing, both supine and stand MFV were not different from preflight values for the finishers but were significantly elevated in the nonfinishers.

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Cerebrovascular conductance was affected by stand (P<0.001) and by group (P<0.001), and it was different between finishers and nonfinishers during stand and over test days (P<0.01). Before flight, conductance increased with the stand test; however, nonfinishers had higher conductance than finishers (Figure 1, bottom).

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On landing day, supine conductance was unchanged from preflight values, but the response to standing was different. On standing, conductance did not change in the finishers and decreased in the nonfinishers to a value lower than that before flight. Three days after flight, supine conductance was again higher in the nonfinishers compared to the finishers, but it did not increase on standing.

There were significant gender effects with BPM CA (P=0.035), MFV (P=0.044), and conductance (P=0.041), which are represented in Figure 1. Female astronauts had an increase in supine BPM CA 3 days after flight and in overall MFV 3 days after flight compared to preflight values.

In general, the largest change in conductance occurred in females 3 days after flight, when cerebral conductance was greater than preflight.

The effects of space flight on blood pressure at head level and cerebral blood flow velocity can be seen readily in the beat-by-beat tracing of a nonfinisher astronaut (Figure 2). Although the blood pressures in the supine and early standing conditions were similar, MFV was drastically lower. In the expanded view of presyncope, beat-by-beat differences can be seen in signals from preflight to 2 hours after landing.

To further explore impairment of autoregulation on landing day, authors plotted the average MFV against average BPM CA (Figure 3) in each of the groups. The large decline of MFV on landing day in the nonfinishers is visible, and this decrease occurred within the same blood pressure range seen before flight in both finishers and nonfinishers. A standardized autoregulation curve with arbitrary upper and lower limits was superimposed over the preflight data with the supine and standing data on the plateau of the curve (Figure 3, dashed lines).

The curve was adjusted to the landing day results through a simple increase in the slope (slope, curved arrow, Figure 3) of the plateau region. The data from 3 days after flight also could be represented by a simple upward shift (plateau, vertical arrow, Figure 3) of the preflight autoregulation curve. The same pattern of increased slope of the plateau on landing day and upward shift of the curve 3 days after flight also could be observed in the group of nonfinishers but with larger changes in slope on landing day and upward shift (plateau) 3 days after flight.

Before flight, the change in MFV as a function of BPM CA (slope of solid lines, Figure 4) was not different between males (0.16±0.22 cms−1 mm Hg−1 ) and females (0.01±0.51 cms−1 mm Hg−1 ; P=0.76); however, it was greater in females on landing day (1.10±0.35 cms−1 mm Hg−1 ) when compared to preflight values (P=0.048) and compared to males on landing day (0.19±0.21 cms−1 mm Hg−1 ; P=0.06).

BPM CA and Cerebrovascular Resistance Index Autospectral Data Differences in BPM CA low-frequency (LF) (0.07-0.20 Hz) power were observed between finishers and nonfinishers during the stand tests (Figure 5). On average, nonfinishers had elevated (P<0.001) LF power (3.07±0.31 mm Hg 2 Hz −1 ) compared to finishers (1.49±0.18 mm Hg 2 Hz −1 ). There was also a significant overall difference between the finishers and nonfinishers with respect to the stand test (interaction, P<0.001).

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There was a significant effect of test day on the cerebrovascular resistance index (CVRi) very-low-frequency (VLF) power between the finishers and nonfinishers (P=0.04); the nonfinishers had significantly higher CVRi VLF power 3 days after flight (Figure 5).

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BPM CA and CVRi Cross-Spectral Data Gain and Phase In the VLF region, there was a significant 3-way interaction (day, stand, presyncope; P=0.0037). The finisher group was characterized by constant autoregulation gain in the VLF region over all test conditions (Figure 6). Preflight, the nonfinisher group had a greater supine VLF gain than did the finisher group, which decreased on standing.

On landing day, the supine VLF gain of the nonfinisher group was not different from that of the finishers; however, during the stand portion the gain was greater than that of the finishers. Significant main effects were observed for the gain in the LF region of cerebral autoregulation. Overall, supine gain was higher than stand gain (0.043±0.002 CVRu mm Hg−1 , 0.032±0.002 CVRu mm Hg−1 , respectively; P=0.0004). An interaction was found between test day and astronaut presyncope (P=0.005).

Astronauts who could finish the 10-minute stand test had a significant reduction in their LF gain from preflight to landing and 3 days after landing; however, the nonfinishers had a significant increase in LF gain on landing day that was greater than the finisher group.

In the VLF range, females had an overall larger gain (0.039±0.004 CVRu mm Hg−1 ) than males (0.022±0.002 CVRu mm Hg−1 ; P=0.03). Preflight, females had a larger supine VLF gain than males; on landing day, females had a higher VLF gain while standing compared to males (Figure 6). Males had a reduction in LF gain from preflight to landing and 3 days after landing. Males had lower LF gain than female astronauts on landing day and 3 days after landing (Figure 6). Both male and female astronauts had a significant main effect of a decrease in LF gain from supine to stand (P=0.036); however, visual inspection of the data (Figure 6) would suggest that this was not the case on landing day.

Results confirm previous space flight data by Iwasaki et al, who showed that astronauts who do not exhibit orthostatic intolerance after flight have normal cerebral autoregulation on landing day; however, there was a severe impairment of cerebral blood flow velocity regulation in astronauts with orthostatic intolerance after flight.

Preflight, nonfinishers were operating at a higher resting cerebral blood flow velocity and similar mean supine blood pressure compared to finishers (Figure 1). On landing day, nonfinishers exhibited a large decrease in MFV associated with the same decline in BPM CA with standing as exhibited preflight. These results suggest that the cause of presyncope in astronauts may be linked with the loss of cardiovascular control of blood pressure and also may be related to a change in ability to autoregulate cerebral blood flow within the preflight blood pressure range.

Preflight data (Figure 1) suggest that autoregulation characteristics of nonfinishers and finishers were different.

MFV and conductance were much higher in the nonfinisher group in both the supine and standing positions.

This could indicate that the nonfinishers were operating at a higher cerebral vasodilation for a given blood pressure. Although preflight BPM CA decreased from supine to stand, both finishers and nonfinishers had an increase in conductance, an appropriate response of a functional cerebral autoregulation system, and did not become presyncopal.

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Finishers had neither an increase nor a decrease in conductance with stand on landing day. The finishers also had an increase in supine MFV compared to preflight values but without an increase in conductance, which is a strong indication that this was driven by the increase in BPM CA (Figure 1) after flight and that autoregulation was operating at a new set point. The lack of increase in conductance with the decline in BPM CA with standing also suggests some impairment in autoregulatory function before flight, although this was not serious enough to precipitate symptoms of presyncope.

In the nonfinishers, the decrease of landing day MFV with standing (Figure 1) was much greater than that of the finishers and those preflight. These data indicate that the nonfinishers were more severely challenged in terms of cerebral blood flow during stand than the finishers. This would indicate a severe impairment of cerebral autoregulation and may have precipitated presyncope in these astronauts. This can be seen in the sample landing day data from a nonfinisher (Figure 2); prolonged cerebral hypoperfusion attributable to loss of vasodilatory response (reduced blood flow) may be an important factor in the development of presyncope.

A decrease in MCA conductance could be related to an increase in vascular stiffness, as seen in cerebral vessels after hind limb suspension in rats, or it could be that the cerebral vessels were close to maximal dilation and the decrease in MFV was directly attributable to the decline in blood pressure during standing.

Although it has been suggested that vasoconstriction, rather than vasodilation, could occur during presyncope because of increased sympathetic cerebral vasoconstriction, this mechanism may not play a role in the presyn-

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Risk of Cardiac Rhythm Problems copal astronauts because this group has been shown to have a less effective sympathetic response to standing.

An increase of cerebral blood volume, caused by vasodilatation, could result in intracranial pressure elevation, which is positively correlated with cerebral blood flow velocity latency.

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Using data, however, authors are unable to speculate on this. The current data on cardiac output and blood pressure in these astronauts indicate hypovolemia and, therefore, a decrease in cerebral volume during standing.

However, with respect to space flight, it has been speculated that the head ward fluid shift causes vasodilation in the cerebral vessels, which may cause similar velocity latency on landing day.

Results indicate that female astronauts have different autoregulation characteristics, and on landing day females had reduced autoregulation compared to males. Astronaut gender may also play a role in susceptibility to orthostatic intolerance after flight. In this data set, 5 of 8 nonfinishers were female, whereas 17 of 19 finishers were male. A compilation of statistics (25 female, 140 male) on incidence of presyncope after short-duration space flight (5-16 days) showed a similar effect, with presyncope occurring in 28% of the females and in 7% of the males.

The majority of cerebral autoregulation characteristics are similar between males and females; however, there are a few characteristics that are different and that may predispose females to orthostatic intolerance. These include differences in cerebral blood flow velocity and cerebrovascular reactivity.

In this study, authors did observe higher cerebral blood flow velocity in females 3 days after flight, but not during preflight or on landing day (Figure 1). However, preflight VLF gain was double that of males (Figure 6) and reduced on landing day. This may indicate a reduction in autoregulation on landing day compared to that of males. Pavy Le-Trao4 showed no major impairment of cerebral autoregulation with HDBR in females; however, there was a slower response in vasodilation to a sudden decline in blood pressure in participants who were orthostatic-intolerant.

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D ID YOU KNOW ?

P REVENTION OF S UDDEN C ARDIAC D EATH

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Microvolt T-wave Alternans (MTWA)

Despite recent advances in the prevention and treatment of cardiovascular disease, sudden cardiac death (SCD) still accounts for â&#x2030;&#x2C6; 50% of all cardiovascular deaths in developed countries, thus accounting for a significant proportion of annual death worldwide. Now, thanks to NASA technology, Cambridge Heart Inc. has produced the only U.S. FDA - approved tool to identify individuals with a high risk of SCD. The Microvolt T-Wave Alternans Test measures heartbeat patterns too small to be detected by an electrocardiogram. This technology originally was developed to determine whether spaceflight increases the risk of heart arrhythmias.

Microvolt T-wave alternans (MTWA) testing is a robust predictor of ventricular tachyarrhythmias and sudden cardiac death (SCD) in at risk patients.

The first major study of MTWA was published in the New England Journal of Medicine in 1994 and concluded that MTWA was an independent marker of arrhythmic vulnerability equivalent to invasive electrophysiology testing. Since that time, several largescale studies have confirmed the predictive value of MTWA in various patient groups including those with left ventricular dysfunction, ischemic cardiomyopathy, non-ischemic cardiomyopathy and history of myocardial infarction.

A 2009 meta-analysis of 13 studies (â&#x2030;&#x2C6;6,000 pts) showed that patients with an abnormal MTWA result are up to 14 times more likely to experience sudden cardiac arrest than those with a normal test result. This analysis also concluded that a negative MTWA test confers an extremely low risk of experiencing SCA in the next 12-18 months (<0.3%).

Microvolt T-Wave Alternans T-wave alternans describes beat-to-beat fluctuations in T-wave morphology, which have been anecdotally associated with the onset of ventricular fibrillation (VF).

Experimental work has suggested that T-wave alternans is caused by cellular repolarization alternans, which can cause dynamic instability in cardiac repolarization and predispose to VF. In initial clinical studies, MTWA during atrial pacing was associated with an increased risk of ventricular arrhythmia. MTWA testing is now performed during submaximal exercise, using a commercially available system (CH2000 or HearTwave II, Cambridge Heart, Bedford, Mass). A series of beats recorded at a stable heart rate

Risk of Cardiac Rhythm Problems are aligned and the amplitude of each T-wave at the same time with respect to the QRS complex is plotted.

These data then undergo spectral analysis, which determines the magnitude of T-wave fluctuation occurring on alternate beats. If sufficient alternans is sustained at heart rates <110 bpm, the test is positive.

Absence of alternans at 110 bpm constitutes a negative test. A test satisfying neither set of criteria is classified as indeterminate. The system presents the data, along with an automated classification, as shown in the Figure. Atrial fibrillation (AF) precludes MTWA testing by this method as unequal R-R intervals confound the frequency analysis. MTWA can also be determined with time-domain methods, which are applicable to Holter data and AF. Although this technology has been evaluated during pacing,16 no prospective data are available regarding the prognostic value of Holter-based MTWA testing.

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Reference:

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Bloomfield, D.M., et al., Microvolt T-wave alternans and the risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction. J Am Coll Cardiol, 2006. 47(2): p. 456-63.

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Chow, T., et al., Prognostic utility of microvolt T-wave alternans in risk stratification of patients with ischemic cardiomyopathy. J Am Coll Cardiol, 2006. 47(9): p. 1820-7.

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Salerno-Uriarte, J.A., et al., Prognostic Value of T-Wave Alternans in Patients With Heart Failure Due to Nonischemic Cardiomyopathy: Results of the ALPHA Study. J Am Coll Cardiol, 2007. 50(19): p. 1896-1904.

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Ikeda, T., et al., Predictive value of microvolt T-wave alternans for sudden cardiac death in patients with preserved cardiac function after acute myocardial infarction: results of a collaborative cohort study. J Am Coll Cardiol, 2006. 48(11): p. 2268-74.

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Kaufman, E.S., et al., "Indeterminate" microvolt T-wave alternans tests predict high risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction. J Am Coll Cardiol, 2006. 48(7): p.

1399-404.

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Chan, P.S., et al., Prognostic implication of redefining indeterminate microvolt T-wave alternans studies as abnormal or normal. Am Heart J, 2007. 153(4): p. 523-9.

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Reduced heart rate variability during sleep in long-duration spaceflight Limited data are available to describe the regulation of heart rate (HR) during sleep in spaceflight. Sleep provides a stable supine baseline during preflight Earth recordings for comparison of heart rate variability (HRV) over a wide range of frequencies using both linear, complexity, and fractal indicators.

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Several investigators have reported that compared with preflight values, there was no change in the sleep time HR during spaceflight, and one study reported no change in the long-term scaling (fractal) behavior of HR (HRV) compared with healthy controls. However, another study reported lengthening of the R-R interval by about 100 ms, and no change or an increase in high-frequency HRV.

The current study investigated the effect of longduration spaceflight on HR and HRV during sleep in seven astronauts aboard the International Space Station up to 6 months. Measurements included electrocardiographic waveforms from Holter monitors and simultaneous movement records from accelerometers before, during, and after the flights.

Seven astronauts (1 female, age 47±4.6 years, height 176 ± 5.0 cm, weight 81± 9.6 kg) who participated in space missions aboard the ISS (52-199; 144 ± 49 days) were studied. Each subject was given full verbal and written details of the experiment and signed a consent form. The experiment protocol conformed to the guidelines in the Declaration of Helsinki and was approved by the Office of Research Ethics at the University of Waterloo, and the Committee for the Protection of Human Subjects at Johnson Space Center.

Measurements were obtained in four test sessions for each subject: 41±30 days (minimum 18 days) before flight (preflight); 2-3 wk after launch (early inflight); 2-3 wk before landing (late inflight); and 1 day (n=5), 2 days (n=1), or 3 days (n=1) after return to Earth (postflight). Preflight tests were performed at the Johnson Space Center, Houston, TX (n=4) and the Gagarin Cosmonaut Training Center, Star City, Russia (n=3). Postflight tests were completed at the Kennedy Space Center, Cape Canaveral, FL (n=3), the Johnson Space Center (n=1, landed at the Dryden Flight Research Center), and the Gagarin Cosmonaut Training Center (n=3).

In each test session, subjects were asked to wear Holter monitors [for the first two subjects and the early inflight session of the third subject these were designated as HM1 (Digicorder Model 483; Del Mar Reynolds Medical, Irvine, CA); for all other sessions these were designated as HM2 (H12+ Holter; Mortara Instrument, Milwaukee, WI)] for at least 24 h to collect the electrocardiographic (ECG) waveforms. Simultaneously, movements were recorded by accelerometers Actiwatch-L AW-7; MiniMitter, Bend, OR) placed on subjects’ ankle and wrist of the dominant arm. The Actiwatch captured the highest activity or movement amplitude in each second and output the summation of counts every 15 s. The inflight raw data were downlinked and preprocessed by support personnel at Johnson Space Center.

Data collected during sleep were analyzed in this study. Data for mean HR and activity patterns at different times of the day have been described for these same subjects . The sleep period in each session was manually identified on the basis of markedly reduced activity level in that period. Then, a segment of steady data was take from the sleep period for subsequent analysis (see Fig. 1). For each subject, the data length used for analysis was the same for all four test sessions (i.e., the shortest segment identified among the sessions) to diminish the influence of data length on HRV indices (48a). In this way, the data length varied between 1.5 and 4 h.

Results Inflight vs. preflight Inflight, mean HR was maintained at the preflight level as summarized along with all other data in Table 1.

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On the other hand, inflight HRV indices in time domain (SDRR, SDARR, and RMSSD) were reduced from preflight values by 33-42% on average. The reductions were significant except for SDARR during late inflight.

Consistent with their time domain counterparts, inflight spectral powers were lower than the preflight values by 49-67% on average, although the ULF, VLF, and LF power reductions showed no statistical significance, likely due to large intersubject variations. Normalization of spectral powers, as expected, attenuated the standard deviations and revealed significant decrements in HRV in all frequency bands. No significant difference was found in LF/HF ratio, SampEn, or α-DFA from preflight to inflight.

Ankle movement was much lower during flight, whereas wrist movement remained unchanged compared with preflight values. The resulting inflight overall movement counts were significantly lower than those at the preflight level.

Postflight vs. preflight and inflight Postflight HR was greater than both preflight and inflight values by ≈ 5 bpm (Table 1).SDRR and SDARR recovered toward preflight levels upon return to Earth (P > 0.05 vs. preflight; P < 0.05 vs. inflight), whereas postflight RMSSD remained lower (P < 0.01 vs. preflight). The frequency domain postflight HRV indices showed similar patterns of recovery toward preflight values except for P_HF and NP_HF (P < 0.05 vs. preflight). The LF/HF ratio was slightly but not significantly elevated. SampEn and α-DFA postflight were not significantly different from either preflight or inflight values. Upon return to Earth, the movement counts were higher than inflight values (P < 0.01). The wrist and overall movement levels after landing also exceeded preflight values (P < 0.05).

Movement and HRV Figure 2A illustrates time series of R-R interval and overall movements for preflight and inflight recordings from one astronaut and the R-R interval power spectra. Reductions in inflight HRV from preflight in all four frequency bands were noticeable. Figure 2A further reveals temporal agreement of events when movement counts increased and R-R interval decreased. Figure 2B shows the linear regression between movement power and HRV in ULF and VLF bands. Quantitatively, the regression analysis revealed moderate but significant correlation between movement power and HRV in both ULF (r = 0.63; P = 0.003) and VLF (r = 0.40; P = 0.03) bands, indicating a reasonable contribution of movement to slow fluctuations in HR. Short-term HRV Table 2 summarizes the short-term HRV indices derived from the median value of the 5-min data segments from each subject by power spectral analysis and sample entropy method.Although there were differences in 20

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the absolute values when comparing the short-term HRV values in Table 2 with the long-term HRV values in Table 1.

The novel finding of the current study was the marked reduction in time and frequency domain indicators of HRV while sleeping during spaceflight even though there was no change in mean HR. These results contrast with our hypothesis and with a previous investigation of cosmonauts sleeping on the Mir station when HR was lower but there was no change or a small increase in HF HRV .

The results also differ from the recent report of no change in HR or HRV in volunteers confined for 105 days in a spaceflight simulation .The reductions in HRV power at ultralow and very low frequencies could be explained in part by parallel reductions in the patterns of movement during sleep at these same frequencies.

In the low and high frequency bands for HRV the reductions in power during sleep were unlikely to be associated with movement; rather, other mechanisms associated with cardiovascular regulation need to be considered. Interestingly, the complexity and fractal dynamics of HR were unaltered by spaceflight. The spectral power indices in the low and high frequency bands and the SampEn results were further confirmed by short-term HRV analysis (see Tables 1 and 2).

Mean HR Mean HR in sleep was not different from preflight values during both early and late inflight testing. This was consistent with some previous research but it contrasts with the prolongation of R-R interval in Mir cosmonauts.

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Risk of Cardiac Rhythm Problems Postflight (1-3 days after landing), HR during sleep was elevated by â&#x2030;Ą5 bpm, suggesting that gravitational stimuli may affect the autonomic control system and invoke a tachycardic response even without orthostatic stress.

More specifically, blood volume is reduced in space and might not have recovered, whereas redistribution of blood flow occurs upon return to Earth even in a supine position (i.e., shift toward one side of the body).

Either of these factors could have contributed to baroreceptor stimulation, reducing parasympathetic and/or enhancing sympathetic nerve activity to increase HR. The overall reduction in movement during sleep was not sufficient to alter the mean HR. Inflight HRV in LF and HF Limited data during sleep in spaceflight have provided evidence of unchanged or a small increase in highfrequency HRV . Also, recent data indicated no change in sleep time HRV during simulated spaceflight in the Mars 500 pilot study . The HF component of HRV is considered to be related to parasympathetic nervous control on HR, whereas the LF variability is modulated by both sympathetic and parasympathetic nervous systems.

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During sleep, vagal activity is dominant in healthy humans. In the present study, inflight mean HR was maintained at the preflight level. Thus the marked reduction of inflight HRV at LF and HF was more likely to reflect smaller fluctuations in HR regulatory systems rather than a resetting of tonic autonomic modulation level. The reduced and more evenly distributed blood volume in space is likely to cause smaller fluctuations in venous return and cardiac filling, and the resulting attenuation in blood pressure variability was translated into reduced HRV by the baroreflex regulatory system.

In these same astronauts studied under controlled conditions while they were awake, there was a significant reduction in HF HRV with no change in LF HRV. Coincident with the change in HF HRV were significant reductions in HF power for the estimated stroke volume and arterial pulse pressure, as well as nonsignificant reductions in LF power for these same variables.

It is possible that during sleep similar changes in stroke volume and pulse pressure contributed to the reductions in both LF and HF HRV, but this cannot be confirmed because blood pressure was not measured. HR fluctuations in LF and HF bands are also modulated by respiration. Higher respiratory rate and smaller tidal volume are associated with decreased HRV in LF and HF with unchanged mean HR due to the kinetics of sinoatrial node responses to acetylcholine .

In the current study, inflight respiratory frequency was slightly but significantly higher than that at preflight (Table 1), which was consistent with previous observations of astronauts during sleep. Therefore, reduction of inflight HRV may also be attributed to higher respiratory rate. Indeed, linear regression analysis between respiratory rate and normalized HRV powers showed significant correlations in VLF (r = - 0.46; P = 0.01), LF (r = - 0.50; P = 0.007), and HF (r = - 0.49; P = 0.008) bands. Although measurement or estimate of tidal volume was not available, recent studies have shown similar or reduced tidal volume in space compared with the preflight value measured in supine posture.

Postflight HRV in LF and HF In the first days after landing, LF and HF HRV powers during sleep tended to recover, but there was still a 19% reduction in LF and a 40% reduction in HF compared with preflight. The tendency of postflight recovery in LF and HF powers could be a result of combined effects from 1) restoring blood volume, 2) gravitational stimuli, 3) sustained higher respiratory rate (Table 1), and 4) possibly decreased postflight baroreflex sensitivity .

The postflight elevation in mean HR indicated a shift in the balance between parasympathetic and sympathetic activation that affected HRV, which was not detected as a significant increase in postflight LF/HF ratio due to large intersubject variance. Indeed, the postflight LF/HF ratio was much larger than the preflight values in three subjects, marginally increased in two subjects, and lower in two subjects.

HRV in ULF and VLF Mechanisms causing ULF and VLF components in HRV are incompletely understood . VLF HRV is mainly effected by modulation of parasympathetic activity and this is reflected by the dramatic reduction in HRV in these frequency bands by atropine . Variation in the mean level of parasympathetic activity is unlikely in the current study given the unchanged inflight HR. Additional mechanisms inducing HRV in the ULF and VLF bands are suggested to include renin-angiotensinaldosterone system , thermoregulation , and physical activity . Elevated levels of the renin-angiotensin-aldosterone system during spaceflight might be associated with reduced HRV in the VLF frequency band in the current study.

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Risk of Cardiac Rhythm Problems It is unlikely that thermoregulatory effects contributed during the 1.5 - 4 h data segments.

Physical activity affects long-term fluctuations in HR under daily routines . Although movement was limited during sleep, our results revealed moderate correlations between overall movements and HRV in both ULF and VLF. Complexity and fractal dynamics of HRV The finding of no difference in Îą-DFA between preflight and inflight values was similar to the observation by Ivanov et al. who compared healthy subjects during sleep on Earth with astronauts during sleep in orbit . There was also no significant difference in the SampEn with spaceflight. The overall observations in the current study suggest that the complexity and fractal properties of HRV were not changed by spaceflight in contrast to the observed changes in the linear components.

These results are consistent with the hypothesis presented by Yamamoto and colleagues that the linear and fractal mechanisms regulating HRV are distinct . Postflight, SampEn and Îą-DFA were almost identical to their preflight values, indicating stability in this aspect of cardiovascular control, even though there were small but significant increases in HR and reduced HF HRV compared with preflight.

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The effects of long-duration spaceflight on the cardiovascular regulatory systems were assessed in terms of HR and HRV. The current results showed that unequivocal alterations occurred in the linear, but not the complexity and fractal, indicators of cardiac rhythm control mechanisms during sleep in astronauts living on the ISS up to 6 months.

The wide-scale impact on linear HRV from the ULF to the HF regions of the power spectrum compared with data on Earth suggest multiple rhythms are altered by spaceflight, including altered sleep pattern affecting movements, oscillations in the renin-angiotensin- aldosterone system, and gravitational effects on blood volume distribution in the body and within a respiratory cycle.

These results provide new insights into the adaptations of the human cardiovascular regulatory system under microgravity and suggest that future studies need to include quantitative measurements of sleep stage and detailed investigations of mechanisms proposed for the alterations in HRV. One major limitation of the study was the lack of polysomnography recordings. Sleep structure has been documented to change during spaceflight. Authors noted reduced inflight movements during sleep that might be associated with reduced sleep-disordered breathing. Reported impairment of sleep quality during spaceflight could be associated with factors such as variable light-dark cycle, altered circadian rhythm, microgravity, confinement, and workload.

The potential of better sleep on the basis of observations of reduced movement and HRV in the current study could be linked to regular exercise as a countermeasure that facilitates the adaptation of circadian rhythmicity. Nevertheless, without polysomnography it is likely that our data crossed sleep stages, which could alter HRV. To test for potential impact of sleep phase, the same time and frequency domain analysis methods were applied on the first 1.5 h of data during sleep (presumably within the first sleep cycle). The resulting HR and HRV indices were similar to those in Table 1 (results not shown), suggesting that the effect of microgravity on HRV was probably predominant over that of different sleep stages. However, incorporating polysomnography into studies of sleep structure effect on HRV during spaceflight is warranted in future studies.

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D ID YOU KNOW ?

O UABAIN :A NTI -A RRHYTHMIA A GENTS ; C ARDIOTONIC A GENTS ; E NZYME I NHIBITORS

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A cardioactive glycoside consisting of rhamnose and ouabagenin, obtained from the seeds of Strophanthus gratus and other plants of the Apocynaceae; used like DIGITALIS. It is commonly used in cell biological studies as an inhibitor of the NA(+)-K(+)-EXCHANGING ATPASE. Seeds of Strophanthus gratus are very toxic and have been used extensively in the preparation of arrow poison throughout its distribution area. The seeds are mostly ground with the sticky plant juice and the arrow tip is dipped into the mixture. In the rainforest area of Central Africa, the stem bark or roots are used similarly; they are often mixed with other plant products, especially the latex of Periploca nigrescens Afzel., but also of Rauvolfia spp. Game wounded by a poisoned arrow dies quickly, and the flesh can be eaten without problem, although the flesh immediately surrounding the wound is discarded. The seeds are also used as fish poison. In southern Nigeria Strophanthus gratus is cultivated by hunters for the seeds.

In medicine, ouabain is used as a remedy for congestive heart failure, like digitalis glycosides. Congestive heart failure is a disease characterized by impaired blood circulation, due to a decrease in the force with which the heart muscle contracts. Cardiac glycosides such as ouabain have a direct cardiotonic action on the myocardium, resulting in an increase in the force of contraction. The increased contractility is caused by inhibition of the membrane-bound enzyme Na+K+ATPase, leading to an increase in the intracellular stores of calcium. When the cardiac glycoside is given to a patient suffering from congestive heart failure, the stroke volume of the heart is increased, causing a more effective emptying of the ventricles, and a lowering of the diastolic pressure. In higher doses, cardiac glycosides have a direct inhibiting action on atrioventricular conduction together with a decrease of the heart rate, and are especially employed in the treatment of atrial flutter and atrial fibrillation.

The effects of cardiac glycosides are particularly dramatic in patients suffering from a combination of congestive heart failure and atrial fibrillation. When ouabain is applied, its actions are of rapid onset, but of short duration; furthermore, there is little risk of accumulation. It is mainly administered by injection, because it is poorly absorbed orally, contrary to digitalis glycosides.

Its major disadvantage is its narrow therapeutic range, which is the margin between the therapeutically effective and toxic doses. Toxic effects include vomiting and convulsions, while larger doses lead to cardiac arrest and death, which explains its success as arrow poison. Ouabain has recently been identified as a steroid hormone in mammals. A remarkable interaction occurs between ouabain and reserpine obtained from Rauvolfia spp. Pretreatment with reserpine reduces the toxicity of ouabain, while simultaneous treatment increases it.

This may well explain the success of the mixture in hunting poisons.

PHARMACOLOGY: Cardiac glycosides inhibit the sodium-potassium ATPase pump. The increase in intracellular sodium leads to increased activity of the sodium-calcium exchanger, which elevates intracellular calcium and improves cardiac contractility. Cardiac glycosides also increase cardiac vagal tone which decreases cardiac sympathetic activity.

TOXICOLOGY: The effects in overdose are an extension of the therapeutic effects. Increased intracellular calcium leads to early afterdepolarization, cardiac irritability, and dysrhythmias. Increased vagal and decreased sympathetic tones lead to bradycardia and heart block. Inhibition of the sodium-potassium ATPase pump causes hyperkalemia.

EPIDEMIOLOGY: Cardiac glycoside toxicity is uncommon,but severe toxicity and deaths may occur. Most cases are due to exposure to pharmaceuticals, but occasionally patients will develop symptoms after ingestion of plant or animal products containing cardiac glycosides.

Risk of Cardiac Rhythm Problems WITH POISONING/EXPOSURE • MILD TO MODERATE TOXICITY: Toxicity from cardiac glycosides can be acute (from a single overdose due to accidental ingestion by a child or due to a self-harm attempt by an adult) or chronic toxicity (due to increased dosing or decreased drug clearance). The manifestations and treatment are slightly different.

The most common symptoms following acute ingestion are nausea, vomiting, abdominal pain, lethargy, and bradycardia. With chronic toxicity, patients often present with bradycardia, malaise, nausea, anorexia, delirium, and vision changes.

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• SEVERE TOXICITY: Patients with acute poisoning may develop severe bradycardia, heart block, vomiting, and shock. Hyperkalemia is a marker of severe acute toxicity and serum potassium is the best predictor of cardiac glycoside toxicity after acute overdose. Severe chronic toxicity causes ventricular dysrhythmias and varying degrees of heart block, but hyperkalemia is uncommon.

REPRODUCTIVE HAZARDS Digoxin has been classified as FDA pregnancy category C. There are no adequate and well-controlled studies of digoxin in pregnant women. Animal studies have not been conducted. Congenital anomalies and perinatal problems have not been linked with cardiac glycoside use during pregnancy. Digoxin can be used in pregnancy, but may require dosage adjustments due to increased plasma volume, decreased protein binding, and increased renal excretion in the pregnant patient. Digoxin has been used in pregnant women without apparent harm to the mother or fetus. The fetus is able to metabolize digoxin and excretes it in the bile. Low birth weight has been observed in infants of mothers receiving digitalis glycosides, presumably due to decreased gestational age and not due to intrauterine growth retardation. In addition, adverse effects to the fetus have been found when the mother develops digitalis toxicity. As it is unknown whether digoxin causes fetal harm when administered during pregnancy, it is recommended that the drug be administered in pregnant women only if clearly necessary.

Reference:

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Beentje, H.J., 2006. Strophanthus gratus (Wall. & Hook.) Baill. In: Schmelzer, G.H. & Gurib-Fakim, A. (Editors). Prota 11(1): Medicinal plants/Plantes médicinales 1. [CD-Rom]. PROTA, Wageningen, Netherlands.

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Ouabain,Compound Summary for CID 439501,National Center for Biotechnology Information, U.S. National Library of Medicine .http://pubchem.ncbi.nlm.nih.gov/compound/ouabain#section=Top

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TOXNET,HSDB: OUABAIN CASRN: 630-60-4. http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@rn+@rel+630-60-4

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Fürstenwerth H. Ouabain - the insulin of the heart. Int J Clin Pract. 2010 Nov;64(12):1591-4. doi: 10.1111/j.17421241.2010.02395.x. PubMed PMID: 20946265.

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Cardiovascular regulation during long-duration spaceflights to the International Space Station Astronauts participating in spaceflights of <2-week duration might have an initial increase in vagally mediated carotid baroreceptor (arterial) baroreflex responses during spaceflight, but this is followed by reductions in-flight and on return to Earth . This change in baroreflex response might contribute to poor cardiovascular responses to upright posture after spaceflight. Overall, the cardiovascular system adapts rapidly to the microgravity environment.

In addition to observations of arterial baroreflex, there are many reports of generally small increases or no changes in heart rate (HR) for short-duration missions , but there are reports of reduced HR during in-flight experimental sessions and during 24-h recordings . There are fewer reports of arterial blood pressure (BP) during short-duration spaceflight. One study reports a transient increase in systolic BP (SBP) on day 1 of spaceflight followed by a reduction to preflight at rest in the seated upright position .

Other studies indicate no change in mean arterial pressure (MAP) or a reduction in diastolic BP (DBP) with no change in SBP. Stroke volume (SV) and cardiac output (CO) were found to increase with short-duration flights , suggesting that systemic vascular resistance (SVR) was reduced to maintain MAP.

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There is little information on the cardiovascular responses to long-duration spaceflight, especially in the era of the International Space Station (ISS). Early data from the Russian Mir space station suggest that the overall cardiovascular system adapted well to the microgravity environment, with minimal changes in HR and MAP. However, limited observations suggest that the arterial baroreflex response was reduced in-flight.

Two recent publications provide the first information on cardiovascular responses on the ISS. Baevsky et al. observed significant reductions in SBP and DBP from preflight to month 5 on the ISS but found that resting HR was not different. Verheyden et al. reported no changes in BP or HR in-flight. These latter investigators also examined the baroreflex response and observed, in contrast to several investigations of short-duration spaceflight , no change in baroreflex response slope during 6 mo in-flight. With the exception of the marked reduction in baroreflex response slope following 9 mo on Mir , there are no reports of the baroreflex on return to Earth after long-duration spaceflight.

The current study investigated cardiovascular regulation before, during, and after long-duration spaceflights.

Finger arterial BP was measured during spontaneous and paced breathing to examine the arterial baroreflex, and the pulse waveform was further analyzed to derive indicators of cardiac function and arterial vascular responses. On the basis of the available literature when the study was initiated in 2001 , it was hypothesized that the arterial baroreflex would be reduced during and after long-duration spaceflight. Furthermore, it was hypothesized that postflight HR would be elevated and that indicators of vascular function derived from the finger pulse pressure (PP) waveform would reflect reductions in SV and impaired vasoconstrictor responses.

Six male astronauts (41-55 yr old, 175.7 ±5.0 cm height, 81.0 ± 9.6 kg body wt) volunteered to participate in the study after receiving full verbal and written details of the experiment. Each astronaut signed a consent form approved by the Office of Research Ethics at the University of the Waterloo and the Committee for the Protection of Human Subjects at Johnson Space Center. The experiment conformed to the guidelines in the Declaration of Helsinki.

Three of the astronauts launched and landed on the space shuttle. The durations of their missions to the ISS were 153, 120, and 52 days. The other three astronauts travelled to and from the ISS on the Russian Soyuz.

Their mission durations were 175, 199, and 180 days. Preflight tests were conducted ≈30 days before flight; in-flight tests were conducted ≈ 2-3 wk after launch (In-flight-1), which was close to the time of data collection in some previous short-duration flights, and ≈2-3 wk before returning to Earth (In-flight-2); postflight tests were conducted on the day after landing (R+1) for four of the six astronauts, on R+2 for one, and on R+3 for the other, according to their schedule for return to the test site after landing. All testing was completed between May 2007 and December 2009.

RESULTS Cardiovascular Variables Pre- and postflight supine and seated Pre- and postflight supine and seated. During the spontaneous breathing component of the protocol preflight, the RR interval was longer in the supine than seated position, although the absolute difference was small (Tables 1 and 2). HR tended to be lower and the standard deviation (SD) of the RR interval tended to be larger

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in the supine than seated position. SV was greater in the supine position, and CO tended to be higher. The estimate of LVETi from the finger pulse wave was significantly longer in the supine than seated posture. Arterial baroreflex slope during spontaneous breathing was 14.8±6.5 and 13.6 ± 7.4 ms/mmHg in supine and seated positions, respectively; this difference was not significant (Fig. 1). During paced breathing, the slope was 13.4± 6.8 ms/mmHg.

After spaceflight, there was a trend for HR to be lower in the supine than seated position, and again estimated LVETi was longer in the supine than seated position (Tables 1 and 2). Arterial baroreflex slopes, 10.6 ± 4.5 and 8.0 ± 2.1 ms/mmHg while supine and seated, respectively, were not different from each other, but the postflight supine value was less than the preflight supine value (Fig. 1; P < 0.05).

On-ground and in-flight From preflight to in-flight, there were no differences in any cardiovascular variable measured during spontaneous paced breathing, with the exceptions of the estimates of LVETi, which were increased in-flight (Table 1), and SV (Fig. 2) and CO, which was significantly increased only In-flight-2, and SVR, which was decreased only In-flight-2 during paced breathing (Table 1).

Preflight arterial baroreflex slope was not different from In-flight-1 (11.0± 3.7 and 12.3± 5.3 ms/mmHg during spontaneous and paced breathing, respectively, respectively) or In-flight-2 (11.8± 5.3 and 14.4± 6.4 ms/mmHg, respectively; Fig. 1).

Postflight measurements revealed several differences with respect to preflight or in-flight (Table 1). The postflight estimate of LVETi was reduced compared with the two in-flight measurements. With the repeated-measures ANOVA, only CO was increased postflight compared with preflight during spontaneous and paced breathing, and total SVR was significantly lower postflight during paced breathing (Table 1).

Arterial baroreflex slope tended to be reduced (P = 0.058) postflight compared with preflight (8.0± 2.1 ms/mmHg, 75.1± 40.1% of preflight) during spontaneous breathing and was significantly reduced during paced breathing postflight (7.1± 2.4 ms/mmHg, 66.1± 33.1% of preflight) compared with preflight, In-flight-1, and In-flight-2 (Fig. 1).

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Postflight comparisons were also made directly with preflight by paired t-tests. HR was ≈5-6 beats/min higher postflight, the RR interval tended to be smaller, and the SD of the RR interval was reduced postflight (Table 1).

Spectral Analysis Pre- and postflight supine and seated. In the preflight comparisons of RR interval spectral power in the seated (Table 3) and supine (Table 4) postures, only HF and total spectral powers tended to be different (P < 0.1). There were no significant differences in any of the other spectral power indicators between supine and seated preflight measurements.

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In the postflight comparisons of supine and seated postures, HF and total RR interval spectral powers were greater in the supine posture. In the postflight comparisons, the HF spectral power of SBP and the HF spectral power of PP were significantly greater in the supine than seated posture.

On-ground and in-flight HF spectral power for the RR interval and for arterial PP was significantly reduced in-flight compared with preflight in the seated posture during spontaneous breathing (Table 3). The spontaneous breathing frequency determined from the peak frequency in the HF band shifted to lower frequencies in-flight but was not significantly changed from preflight (0.237 ±0.037 Hz) to In-flight-1 (0.193 ± 0.026 Hz) and In-flight-2 (0.188 ± 0.054 Hz).

During paced breathing, PP LF power was less than preflight. LF, HF, and total RR interval spectral power were reduced postflight during spontaneous breathing compared with preflight (Table 3), but breathing frequency was unchanged postflight (0.223 ± 0.032 Hz). LF and total RR interval power were also less postflight than In-flight-1 and In-flight-2, while HF RR interval power was less In-flight-2 (Table 3).

During spontaneous breathing, the HF power of arterial PP postflight was greater than in-flight but was not different from preflight, and SV HF power was greater than In-flight-1. Under the paced breathing conditions of postflight testing, there were no differences in spectral power compared with in-flight or preflight (Table 3).

Changes in Spontaneous Baroreflex Slope The data for each individual astronaut relating the slope of the spontaneous baroreflex with the RR interval recorded at that specific time point are shown in Fig. 3.

In general, the RR interval decreased the supine to the seated position preflight and to postflight, and simultaneously the slope of the spontaneous baroreflex was reduced. Three of the six subjects portrayed in Fig. 3 had significant correlation coefficients for the reduction in baroreflex slope relative to the reduction in RR interval.

The estimates of the baroreflex gain calculated from the spontaneous beat sequence method and from the cross-correlation between systolic arterial pressure and RR interval were highly correlated during spontaneous breathing in the HF (r = 0.87) and LF (r = 0.78) ranges and during paced breathing in the LF range (r = 0.97).

Furthermore, the mean values obtained by the two methods did not differ, so only data from the sequence analysis are included in Figs. 1 and 3.

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This study provides the first data on cardiovascular stability and control from the arterial baroreflex response slope and indicators of cardiac function derived from the finger pulse wave during and after long-duration missions to the ISS. In-flight cardiovascular function was similar to that observed evidence of cardiovascular deconditioning postflight, suggesting that the in-flight countermeasures were reasonably effective in these astronauts.

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Reduced baroreflex response slopes during the paced breathing phase of postflight testing were consistent with the hypothesis; however, the magnitude of change was less than anticipated. Similarly, the 5-6 beat/min increase in HR during the postflight testing was significant but of very small magnitude.

Despite the small change in HR postflight, there was a marked reduction in LF, HF, and total RR interval spectral power during spontaneous breathing compared with preflight and in-flight. Previous data from short-duration spaceflights combined with early research of long-duration astronauts on the Russian Mir station provided the rationale for expecting a marked change in arterial baroreflex of astronauts living up to 6 mo on the ISS.

In-flight data showing essentially unchanged baroreflex responses contrast with these early observations, but they are in line with the recent observations of Verheyden et al. during 6-month sojourns to the ISS. Our data, which are the first reported after long-duration flight, reflect considerably less cardiovascular deconditioning than in two cosmonauts who spent 9 month on Mir.

For some astronauts, the individual changes in baroreflex response slope were correlated with changes in RR interval, suggesting a mechanism related to the overall reduction in parasympathetic activity to the heart. The current study also provided new insight into cardiovascular stability from analysis of the finger pulse waveform.

In contrast to the hypothesis, SV was maintained during and after spaceflight when referenced to the preflight upright seated position. The LVETi was longer in-flight without a change in SV, in contrast with simultaneous changes on Earth.

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Risk of Cardiac Rhythm Problems

A consequence of the late spaceflight and postflight time points of maintained or slightly increased SV, along with small increases in HR, was that the estimate of CO was significantly elevated compared with preflight baseline, while SVR was reduced to maintain MAP. The reductions in HF RR interval power in-flight and postflight in HF, LF, and total RR interval power might reflect reduced parasympathetic modulatory effects on HR . However, when the in-flight results are viewed along with significant reductions in HF power of PP and SV, it might suggest that the within-breath modulatory influence of the respiratory pump on venous return and cardiac filling was reduced in-flight, even though overall SV and MAP were maintained.

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D ID YOU KNOW ?

Heart Rate and Daily Physical Activity with Long-Duration Habitation of the ISS

Long-term habitation in the microgravity environment of the International Space Station (ISS) dramatically changes the demands of everyday tasks with the cardiovascular system no longer loaded by gravity. Previous measurements of HR during daily life in space have suggested that it might be elevated , unchanged, or reduced.

While these studies excluded periods of physical exercise from the analysis and stated that in-flight activity approximated that on Earth, there was no means to quantify the level of physical activity.

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The only previous observations of the HR responses to daily living during long-duration spaceflights are from studies of cosmonauts on the Mir space station. Baevsky et al. found that in two individuals HR was elevated in flight (3 bpm in one and 19 bpm in the other), and was also considerably higher (≈27 bpm) upon return to Earth when compared to preflight.

Other researchers have observed no change in cosmonauts’ HR while on the Mir space station, and postflight HR that was unchanged or differed only from an early in-flight value but not from preflight. Data collected in the quiet resting phases of controlled experiments in space have suggested that, over long-duration missions on the ISS, resting HR was not significantly changed from preflight supine values , but was significantly reduced (≈ 14 bpm) from prefl ight standing.

Authors investigated the pattern of activity and heart rate (HR) during daily living on the International Space Station (ISS) compared to on Earth in 7 long-duration astronauts to test the hypotheses that the HR responses on the ISS would be similar to preflight values, although the pattern of activity would shift to a dominance of arm activity, and postflight HR would be elevated compared to preflight during similar levels of activity.

Methods Authors studied seven long-duration astronauts (one woman, six men) during missions aboard the ISS between May 2007 and December 2009 (age 47.0 ± 4.6 yr, weight 81.0 ± 9.6 kg, height 175.7 ± 5.0 cm; means 6 SD).

Participation was voluntary after receiving full verbal and written details of the experiment. This study was approved in advance by the Office of Research Ethics at the University of Waterloo, and the Committee for the Protection of Human Subjects at Johnson Space Center and each person provided written, informed consent before participating. The experiment conformed to the guidelines in the Declaration of Helsinki.

Four of the astronauts launched and landed using the space shuttle while the other three traveled on the Russian Soyuz. The duration of the shuttle missions were 153, 132, 120, and 52 d, while the length of the Soyuz missions were 175, 199, and 180 d. The average number of days on orbit for all seven astronauts was 144 ± 49 d.

HR and activity were collected for 24-h periods. During this time, the astronauts were asked to maintain their normal daily routines including consumption of caffeinated beverages. Preflight collections took place 41 ± 30 d before flight at the Johnson Space Center (Houston, TX) for shuttle astronauts and at the Gagarin Cosmonaut Training Center (Star City, Russia) for Soyuz astronauts. Collections on the ISS were 2-3 wk after launch (inflight-1) and 2-3 wk before return to Earth (in-flight-2).

Two astronauts provided additional inflight data that contributed to analysis of exercise patterns. Before going into orbit, the astronauts were trained to perform the in-flight measurements themselves. Inflight collections were downlinked to Johnson Space Center for processing. Postflight collections were conducted the day after landing (R + 1) for five astronauts,R + 2 for one astronaut, and R + 3 for the other, depending on the testing schedule for the landing site. Of the four shuttle astronauts, three completed postflight testing at Kennedy Space Center (Cape Canaveral, FL) while the other was tested at Johnson Space Center. All three astronauts that traveled on the Russian Soyuz were tested postflight at the Gagarin Cosmonaut Training Center.

While on orbit, each astronaut was allocated up to 2.5 h/d for exercise, which included the time needed for

Risk of Cardiac Rhythm Problems set-up, exercise, and clean-up. The exercise equipment available included the treadmill with vibration isolation and stabilization (TVIS), the cycle ergometer with vibration isolation and stabilization (CEVIS), and two resistive devices (interim and advanced resistive exercise device, IRED, ARED). Two astronauts used the IRED for their whole mission while four had access to the ARED. One astronaut initially used the IRED but then used the ARED once it arrived on the ISS. The main benefit of the ARED is its increased loading capabilities compared to the IRED. The combination of aerobic and resistance exercise represents the only countermeasure engaged in by the astronauts while on the ISS. Immediately before returning to Earth, the astronauts used a fluid loading protocol that likely had limited effects on HR since all 24-h monitoring periods began on at least R+1.

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Results Consistent with the hypotheses, HR during daily activities on the ISS was unchanged compared to preflight; activity patterns shifted to predominantly arm in space. Contrary to the hypothesis, only night time HR was elevated postflight, although this was very small (+4±3 bpm compared to preflight). A trend was found for higher postflight HR in the afternoon (+10 ±10 bpm) while ankle activity level was not changed (99 ± 48, 106 ± 52 counts pre- to postflight, respectively). Astronauts engaged in aerobic exercise 4-8 times/week, 30-50 min/session, on a cycle ergometer and treadmill. Resistance exercise sessions were completed 4-6 times/week for 58 ± 14 min/session.

Consistent with hypothesis, the physical activity counts from the wrist and ankle provide clear evidence of a shift away from leg plus arm activities on Earth to predominantly arm activity in flight. This change in pattern was anticipated as the activities of daily life in space, including movement through the space station, are performed by the arms with the legs tending to be used simply to anchor the body during certain work tasks.

Consistent with this finding, mechanical loading measured at the feet during daily activities in space has been found to be greatly reduced or nonexistent.

Postflight HR and activity indicators were not significantly different from preflight with the exception of a small increase in nighttime HR (4 ± 3 bpm) and afternoon HR that tended to be higher (10 ± 10 bpm). These data contrast with the marked elevation noted by Baevsky et al. after prolonged flights. In-flight exercise sessions elevated the ankle activity counts and HR, possibly contributing to the level of physical fitness and HR during daily activities.

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Baevsky RM, Bennett BS, Bungo MW, Charles JB, Goldberger AL, Nikulina GA . Adaptive responses of the cardiovascular system to prolonged spacefl ight conditions: assessment with Holter monitoring . J Cardiovasc Diagn Proced 1997;14:53-7 .

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Ad Astra ! To The Stars! In Peace For All Mankind !

Mr. Rick R. Dobson, Jr. (Veteran U.S Navy)

Image Credit: NASA

Image Credit: NASA

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