Is the Breadth of the Cited Literature Sufficient?
The literature cited and reviewed covers the breadth of the topic and it is current.
Is the Expertise of the Authors Sufficient to Fully Cover the Scope of the Given Risk? Is Input from Additional Disciplines Needed?
Overall, the expertise of the authors is sufficient, but including an expert in muscle physiology, especially one interested in the bone/muscle interface, would have been useful. Although the report reflects the input of the bone-focused metabolic, epidemiologic, and imaging disciplines well, input from muscle physiologists and nutritionists might be worthwhile to include.
Has the Evidence Report Addressed Previous Recommendations Made by the IOM in the 2008 Letter Report?
Many of the recommendations made and the issues raised in the 2008 report have not been incorporated into the current report. Examples include the lack of using appropriate ground-based models, such as models of chronic spinal cord injuries. Similarly, the issues of the heterogeneity of individuals regarding bone loss and recovery were mentioned in the 2008 report, but no further study of these biological responses has been made. Developing better monitoring in flight for bone loss was recommended, but the evidence report does not discuss progress on this issue. Further consideration of nutritional, metabolic (hormonal), and stress factors on bone loss was mentioned in the 2008 report, but no apparent progress or even consideration of these factors was obvious in the current evidence report.
The NASA evidence report Risk of Cardiac Rhythm Problems During Spaceflight was first published in 2009. The risk of cardiac rhythm problems has been identified by NASA for at least 4 decades and was included in the IOM’s 2008 review as “Cardiac Rhythm Problems.” The
committee’s analysis of the current evidence report (Lee et al., 2017) recapitulates and expands on many of the conclusions made in the 2008 review. The committee had workshop presentations (see Appendix A) from three practicing cardiologists who provided extensive commentary to supplement the committee’s analysis.
Cardiac arrhythmias are a normal part of life. They occur throughout the day in most individuals. Thus, the presence of cardiac arrhythmias during spaceflight should not be seen as different from the arrhythmias dealt with in contemporary cardiovascular medicine, which makes clear distinctions between significant and non-significant arrhythmias.
Generally speaking, cardiac arrhythmias are categorized according to their potential substrates:
- Changes in automaticity. There is no evidence that this occurs in space.
- The triggering of depolarizations in cardiac myocytes (e.g., after-depolarizations). These are generally of no physiological consequence, even when they are coupled to form brief, but spontaneously terminating, runs of arrhythmic beats (e.g., ventricular tachycardia).
- Reentry phenomena that lead to sustained cardiac rhythm disturbances. The substrate for these arrhythmias is an anatomical or functional boundary with an area of absolute refractoriness, such as focal scarring (i.e., tissue fibrosis).
Since its inception, this evidence report has relied on the “biological model” of sudden cardiac death (Myerburg et al., 1989), where structural abnormalities interact with functional alterations, such as electrolyte disturbances or neuro-humoral modulation, to generate an environment that increases the likelihood that arrhythmias will be initiated or sustained, or both. This model serves as a justification for considering both the substrate and the trigger for arrhythmias that might pose an increased risk of sudden death.
In patients with coronary artery disease, the arrhythmogenic substrate is clear: a myocardial infarction or scar leading to focal areas of delayed conduction—a necessary condition for a reentry current. For patients with apparently normal ventricular function, reentry is often not the mechanism of arrhythmia development. Rather, arrhythmias in these patients are more often caused by delayed after-depolarizations, and the triggered activity may be mediated via catecholamines (Lerman et al.,
1996). Indeed, this observation supports the suggestion that sustained, life-threatening arrhythmia is strongly associated with underlying cardiovascular disease, and that NASA should abandon arrhythmia as a driver of astronauts’ cardiovascular risk profile.
Thus, contemporary clinical decision making considers arrhythmia to be a “fact of life,” stratifies the need to consider clinical intervention when hemodynamic function may be compromised (e.g., sustained ventricular tachycardia, ventricular fibrillation, severe bradyarrhythmias, or pulseless electrical activity), and embraces a more holistic approach to screening for cardiovascular risk and disease with an emphasis on primary prevention.
Does the Evidence Report Provide Sufficient Evidence, as Well as Sufficient Risk Context, That the Risk Is of Concern for Long-Term Space Missions?
There is sufficient evidence to conclude that arrhythmia will occur prior to spaceflight and during most, if not all, phases of spaceflight and extraterrestrial exploration. The available evidence supports the conclusion that these arrhythmias are neither life threatening nor any different from what would occur in the general population of healthy people (Convertino and Cooke, 2005).
The available evidence does not support the conclusion that spaceflight is, or enables, a unique arrhythmogenic substrate. The report provides no definitive evidence that spaceflight is associated with increased frequency or complexity of cardiac arrhythmias either during or after flight. In fact, two flight investigations cited in the report indicated that the frequencies of arrhythmias during either intravehicular or extravehicular operations were virtually the same as the frequencies measured before flight.
While there is sufficient evidence that preexisting cardiovascular disease poses a risk to the health and safety of astronauts that increases with mission duration, there is insufficient evidence to conclude that the risk of arrhythmia is amplified by long-term space missions. It is also acknowledged that cardiovascular events can be of great concern during space exploration because the continuity of care is affected by communication time and distance from Earth.
Does the Evidence Report Provide Evidence That the Named Gaps Are the Most Critical Presented?
The risk is poorly contextualized, with disproportionate weight given to clinically minor observations. Benign, non-sustained, and infrequent arrhythmias are an expected part of spaceflight. Other gaps are not named. There is a significant gap in evidence in the failure to provide any association of the existence of post-flight arrhythmias with occurrence during flight. And most importantly, there is a gap in associating arrhythmia risk with preexisting cardiovascular disease, not acquired arrhythmias in space.
Are There Any Additional Gaps or Aspects to Existing Gaps That Are Not Addressed for This Specific Risk?
Less consideration is given to the overall cardiovascular risk profile of astronauts and flight crews, which can be improved with primary prevention (screening) that includes cardiac imaging, coronary artery calcium scanning, an assessment of valve function, and Holter monitoring. Furthermore, tissue fibrosis can be gauged with cardiac MRI. A greater emphasis in the evidence report on the risk of atrial fibrillation is supported by contemporary experience in cardiology, cardiac electrophysiology, and epidemiology, particularly by the substantial and growing prevalence of atrial fibrillation in the middle-aged general population. Furthermore, medical management strategies for atrial fibrillation that occurs during long-duration spaceflight need to be explored. The lack of data from missions of exploration-class duration is notable, but this situation should improve as the ISS experimental manifest is completed. A consideration of non-ischemic changes in cardiac health (e.g., atrial fibrillation, stress cardiomyopathy) as a component of primary prevention could be included as a research gap. Finally, greater consideration should be given to post-flight assessment and long-term follow-up.
Does the Evidence Report Address Relevant Interactions Among Risks?
The evidence report adequately presents human and animal spaceflight and ground-based experimental data in an attempt to link relevant interactions of arrhythmia factors, such as age, gender, fluid shifts, decreased cardiac mass (remodeling), QT interval prolongation, electrolyte
disturbances, elevated sympatho-adrenal activity, oxidative stress, preexisting cardiovascular disease, and genetic abnormalities, in cardiac excitation–contraction coupling. In addition, the report includes routine physical stressors, such as exercise, lower-body negative pressure, and extravehicular activity, as possible confounding factors that might increase the occurrence of arrhythmias. Nevertheless, the evidence does not support the hypothesis that these potential interactions contribute to a clinically important change in cardiovascular risk.
What Is the Overall Readability and Quality?
The overall readability and quality of the report are good. The readability could be improved by including a specific section that enumerates the gaps in knowledge. The current report places the burden on the reader to extract gaps.
Is the Breadth of the Cited Literature Sufficient?
The bibliography appears to include a thorough description of published literature documenting non-threatening arrhythmias during spaceflight. However, it appears to lack sources from the literature on the difference between benign and life-threatening arrhythmias and the rapidly expanding role of prevention in modern cardiovascular medicine.
The report makes extensive reference to a recent paper by Delp and colleagues (2016) that reviewed mortality in Apollo astronauts. This paper has been the subject of considerable controversy because of its retrospective nature, lack of hypothesis, small sample size, and questionable epidemiological technique. While the risk of accelerated cardiovascular disease from high LET (linear energy transfer) ionizing radiation may be of concern, it is difficult to accept this paper as definitive “evidence.” In fact, NASA has invested considerable resources in its space radiation program to determine whether in fact there are any cardiac risks associated with space radiation exposure since this is considered uncertain at space-relevant doses at this time. The background for this work is summarized in the NASA evidence report Risk of Cardiovascular Disease and Other Degenerative Tissue Effects from Radiation Exposure (Patel et al., 2016).
Thus, in view of the current lack of evidence that arrhythmia occurrence during spaceflight is a particularly significant clinical problem, a more holistic approach to cardiovascular risk (which would incorporate a discussion of arrhythmia) might be considered.