“Once a photograph of the Earth, taken from outside, is available… a new idea as powerful as any in history will be let loose.”

Fifty years ago, Apollo 8 orbited the Moon. Instead of only discovering the moon on that voyage, however, the astronauts turned their camera back toward the Earth and took the first photograph of our planet, essentially proving Sir Fred Hoyle’s quote from two decades earlier. This photograph profoundly altered forever our understanding of what was always right in front of us. Since then, more than 500 astronauts have been in orbit and most have experienced a cognitive shift in their understanding of their home planet. This recognition of the Earth (as seen from afar) as a tiny, fragile blue ball of life racing through space but appearing to be suspended in a void, nourished by a paper-thin atmosphere, is termed the “overview effect.” A similar photograph of the heart that serves to shift our understanding of myocardial performance has yet to be taken. Instead, we continue to measure and report various portions of this phenomenally complex organ that, like the Earth, is composed of uniquely developed, geographically separate, and operationally diverse regions working in unison to stay alive . We often question the importance of the contributions from ‘lesser’ regions and focus our attention on an aspect of performance we think we understand, only to dismiss our results when they are not in keeping with our expectations.

The draw of space seems to be as uniform as intellectual curiosity. Negishi et al. used tilt-table testing to study astronauts and to assess the effects of various levels of preload on measures of left ventricular (LV) filling and function (mimicking the effects of altering gravity), as reported in this issue of the JASE. This work provides an important assessment of LV performance in different loading conditions, and represents another important step along this profound journey toward better understanding the important contribution of regional myocardial deformation to global myocardial performance. It raises new questions, but enticingly emphasizes our need to continue to accumulate a greater understanding of the gravity of the situation. It demonstrates that there are many contributing factors, even body position, that may alter what we currently refer to as global longitudinal strain (GLS). It is obvious that NASA would have a vested interest in the effects of gravity on cardiovascular performance. For simplification, however, the authors studied the heart using a tilt table to create acute changes in preload in an effort to mimic different gravitational forces. How these findings compare to the actual impact of zero-gravity or more prolonged changes in gravitational forces remains to be demonstrated.

Two-dimensional (2D) strain measures are often touted as less load-dependent; however, the authors reported an acute 5% absolute and 25% relative worsening (less negative) in GLS in an upright versus a supine position, suggesting a clinically significant load dependent nature of GLS. In their study, an acutely decreased preload decreased the GLS. Is this simply a modern reflection of the Frank-Starling mechanism where nearly two centuries ago it was demonstrated that the heart is able to change its force of contraction in response to changes in preload? Or does this represent a previously unreported impact from changes in posture yet to be identified? Regardless, one clinical scenario, as highlighted by the authors, is very relevant. Given the high interest in the serial evaluation of patients undergoing chemotherapy, the American Society of Echocardiography recently published an Expert Consensus document stating that “GLS is the optimal parameter of deformation for the early detection of subclinical LV dysfunction” and a “relative… reduction … > 15% from baseline [is] very likely abnormal.” If the findings in this report remain valid in clinical patients and the relative value of GLS can be acutely worsened to this degree simply by acute changes in preload, then the volume status of these serially monitored patients will need to be taken into consideration. Once again, considering the early work from Otto Frank and Ernest Starling, there is a different Frank-Starling curve that is unique to the population studied and varies according to the existing conditions of afterload and contractile forces. This finding reiterates the need to study the impact of loading conditions on myocardial deformation assessment in various pathologies and differing hemodynamic settings.

As we address this thought-provoking study, let us consider the applicability of the reported research subjects (e.g., astronauts) to the typical clinical population. Astronauts are extraordinary people, meshing physical ability, scientific curiosity, and a drive to boldly go where few have gone before. However, from a fitness perspective, these study subjects have more in common with physically fit age- and gender-matched controls (i.e., weekend warriors) rather than elite athletes. The average maximal V.O ₂ of the study group was ∼39 +/− 6 mL/kg/min and coincides well with the reported maximal V.O ₂ of astronauts (∼41 mL/kg/min). This is well above the average for a typical cardiovascular disease patient, but not to the level of elite athletes (especially elite endurance athletes in whom maximal V.O ₂ often approaches 70-80 mL/kg/min), and is more analogous to the exercise performance of an active, healthy adult. Furthermore, the supine ventricular volumes, ejection fractions, E/A ratios, and LA dimensions are in the normal (or upper normal) ranges. The classic cardiac remodeling pattern associated with elite athletic training is not seen, and it is likely that these results would be applicable to at least some of our more physically active patients.

This work demonstrates a positional impact to at least one aspect of myocardial mechanics. It remains to be seen if there is a chronic difference in myocardial deformation parameters seen in supine versus upright exercise activities. Or if there is a “gravitational component” to rest and relaxation that may have been under appreciated with regards to long-term cardiovascular health. This study highlights the need for better understanding of the diagnostic imaging tools we use to study these questions. An improved understanding of which hemodynamic parameters are load-dependent and load-independent is essential. For example, utilization of load-dependent echocardiographic parameters to study patients during supine bike vs upright treadmill adds a confounder that would be difficult to overcome.

Where does this study lie in our current understanding of LV hemodynamics and the relative impact of different loading conditions? It is fairly consistent with previously reported studies using more conventional 2D and Doppler echocardiographic parameters which are also known to be load dependent. Specifically, end diastolic and end systolic left ventricular volumes as well as left atrial volumes decreased with increasing the tilt table angle, likely due to decreased venous return. Doppler parameters of ventricular filling in diastole (both E and A wave) also decreased with increasing the tilt table angle. Ejection fraction did not change with different loading conditions in this study, but the authors attribute this to being underpowered to detect this difference.

This study raises important considerations for the clinical investigation of other cardiovascular variables. Importantly, the ventriculo-arterial coupling equation is built on assumptions validated in resting conditions, and the impact of altering acute loading conditions is not well known. End systolic elastance (Ees) is considered to be a load-independent measure of intrinsic cardiac contractility, and the single heart beat acquisition used in this study supported that conclusion. Effective arterial elastance (Ea) is influenced by volume loading with secondary sympathetic activation and an increase in systemic vascular resistance, decrease in arterial compliance, and an increase in Ea. This was observed in this study as well. This load-dependent increase in the Ea/Ees ratio (worsening ventriculo-arterial coupling) may have important clinical implications in diseased hearts, where small changes in volume (or even body position) may have a major clinical impact.

Given the potential wide-spread clinical implications of the reported findings, it is prudent to highlight some specific concerns. Despite being a relatively large cohort of astronauts, this remains a very small study. However, we suspect that if this investigation had simply been a report on 13 normal volunteers rather than 13 astronauts, it would not have the same gravitas. Given that the authors’ stated purpose of the study was to expand our understanding of the impact of loading conditions on strain, strain rate, and cardiac energetics, this study should be considered adequately powered directly due to the excellent interobserver reproducibility of the strain measures. While adequately powered to assess the primary strain assessments, it is underpowered to interpret all of the different variables reported comprehensively. Therefore, this study does not completely alter our understanding of the impact of loading conditions on these different echocardiographic parameters, and we await further validation. This was highlighted with the reported ejection fraction findings, where the study results differed from previous reports and was dismissed as a beta (type II) error.

The reader should take note that some of the reported data used validated, but less commonly applied, equations either to acquire data (e.g. single heart beat estimation of Ees) or to supplement missing data (LA volume index). The demonstrated rigor with which the study was conducted, the reported reproducibility, the consistency of the data, and the reasonable conclusions drawn by the authors should help to reassure the reader of the internal validity of the study.

Next, there are important logistical challenges in imaging upright patients compared with supine patients. This may especially be true for angle dependent measures such as pulsed wave Doppler. Small errors in these measures may be carried through to different aspects of the study (e.g. stroke volume estimates and Ees). Even routine measures of 2D volumes are susceptible to foreshortening and likely unavoidable. As demonstrated in Negishi’s Figure 2, the endocardial border of the LV apex is apparent between 3.0 cm and 3.5 cm depth from the probe at 0 and 22 degrees, but increases to more than 4.0 cm and 5.0 cm at 41 and 80 degrees, respectively. Not surprisingly, the overall image quality was notably worse at higher tilting angles and this likely contributed to at least some of the reported differences (e.g. smaller LV volumes at 80 degrees which, notably, was the tilt angle at which the 3D volumes were most consistent with the 2D volumes).

The assessment of LV deformation by 2D speckle-tracking holds promise for the assessment of myocardial diseases and the detection of subclinical heart disease. Major challenges remain beyond the rapid pace of technological growth and incomplete standardization, and importantly include a lack of fully understanding how the various measures are pieced together. The term “global longitudinal (or circumferential or radial) strain” refers to the average of all longitudinal (or circumferential or radial) segmental strain components from regional myocardial segments throughout the entire myocardium. Most investigators have focused on GLS or GCS as a means to ‘ignore’ the regional variations of segmental strain and this approach has certainly been justified as it has been shown to correlate with important clinical outcomes. Other investigators have reported on rotational deformation using twist and torsion. However, as our skills at regional assessment improve, regional strain assessment will likely become an important parameter that justly reflects a myocardium that is indeed not very homogenous. Using tagged and cine DENSE cardiac MRI sequences, this is certainly known to be the case.

Although it is true that speckle tracking 2D strain imaging is angle-independent, apical foreshortening would likely impact the size and reproducible tissue positioning of the segmental myocardial strain regions as compared to the supine images. Even though the individual segments were not reported, they are necessary to derive the averaged “global” results. Whether this factor contributed to the reported findings is not known. A discrepancy exists between longitudinal strain (reduced) and radial strain (preserved) early in coronary artery disease which primarily impacts the endocardium. Once again, in isolation, these separate reports provide only a portion of the true ‘cardiac photograph’. To continue along this puzzle, the base-to-apex and endocardial-to-epicardial gradients and influences of loading conditions will need to be better understood. Eventually, our understanding of the heart will become vastly improved. Until then, caution should be given to any report that does not consider the heart as a whole and it would be prudent for us to continue to search for more pixels to complete this “overview” photograph of the heart.

Given these findings, in addition to considering the inter-dependent and compensatory effects of the entire heart, the impact of loading conditions, both acute and chronic, must clearly be taken into consideration in subsequent clinical investigations of myocardial mechanics. It may no longer be appropriate to simply highlight that one component of myocardial deformation is abnormal in aortic valve regurgitation or stenosis and normalizes after valve replacement. The inter-relationship between GLS, which is reduced in many preclinical diseases, and GCS or LV twist, which may be increased in many of these same patients, likely contributes to the preserved LVEF.

Subclinical LV systolic dysfunction is common in chronic MR. It has been demonstrated that the peak untwisting velocity remains normal but correlates negatively with end-systolic dimension and regurgitant volume, suggesting that this parameter depends on the stage of the disease. With our increased understanding on the impact of changes in loading conditions, one should question the impact of acute versus chronic MR in myocardial deformation assessment. Only by stepping back did we develop our current understanding that the “normal LVEF” in severe MR is significantly higher than the “normal LVEF” for patients without severe MR. Similarly, an E>A mitral inflow pattern, on its own merits, is woefully inaccurate at separating normal from abnormal ventricular filling dynamics. Our understanding of myocardial mechanics is in its infancy, and as our technological capabilities improve, so must our comprehensive perspective.

Although a small study, the report by Negishi et al. highlights the load-dependent nature of measuring 2D strain (and more load-independence of SR) as well as the impact of loading conditions on cardiac energetics and the presumed subsequent implications for LV stroke work. The more load-independence of SR is worth reflection. Using current echo software, SR is actually measured after tracking the speckles and strain is then derived from this data using drift compensation to force the strain to a zero value at the R wave. A very recent investigation in premature infants documented higher SR in association with higher HR and unchanged preload, but no relationship with LV strain and HR. These authors concluded that SR (not strain) possessed a positive force-frequency relationship and represents myocardial contractility, rather than adverse loading conditions, indicating preservation of the Frank-Starling phenomenon. Like most expeditions, the journey for the truth is still ongoing, and the joys of discovering new horizons is not limited to just those about to hurtle through space.

As we continue to develop more focused approaches to understanding the heart, it may be equally important that we step back and take a photograph of the entire cardiovascular apparatus. Given the complexity of design and the profound interrelationship of the atria and ventricles, ventricles with each other and the vasculature, and the impact of chamber shape and loading conditions, what we currently interpret as “normal” or “abnormal” function will likely require many corrections. Compensatory alterations in myocardial deformation, not to mention the ability of the hibernating myocardium to jettison its contractile function as a final means to preserve life, are just beginning to be understood. Before we conclude that a reduction in one aspect of myocardial performance represents impairment of the heart, we need to consider the entire cardiovascular environment from preload, to afterload, to inter-dependence of its whole parts.

Beyond even this degree of complexity, layers within the ventricular myocardium contribute to the performance of adjacent layers at different depths. Recent thought-provoking findings using 3T cardiac MRI offered new insight into this complex myofiber relationship by demonstrating that the contraction of the endocardial layer imposes cross-myocyte shortening on the simultaneously contracting subepicardial layer. In this study, the authors found that myocardial layers (so-called “sheetlets”) alter their angulations and reorient as a direct result of individual fiber thickening and contraction of more superficial or deeper myocytes in the same vicinity.

Only when our technology advances sufficiently to allow the reporting of robust global and segmental myocardial strain and strain rate (SR), inclusive of both systolic and diastolic values, will we finally have our cardiovascular snapshot to rival the impact obtained from photographing the Earth from afar. This may or may not develop into the ability to measure fiber strain, but it will likely include 3D strain. Given the rate of technological advancement, however, predicting what this 3D strain will look like is an act of futility. Maybe then we will recognize the heart for what it is and have our own profound “overview effect” of the complexities currently still hidden within all components of myocardial mechanics.

Finally, the natural progression of this line of research leads to questions about the impact of prolonged exposure to microgravity on both acute and chronic changes in LV hemodynamics and remodeling. Does prolonged microgravity increase LV volumes due to persistent improvement in venous return? Does prolonged microgravity blunt some of the sympathetic stimulation that is seen to increase effective arterial elastance? Would this better optimize ventriculo-arterial coupling? Can these acute changes be used as a potential therapeutic target for some patients? Again, these demonstrated acute changes were seen in a healthy population. What are the effects on diseased hearts or even healthy older hearts? Wouldn’t it have been interesting if one of these study subjects was 77 years old (thank you John Glenn for your amazing service as the oldest person to fly into space)?

As pointed out by the authors, acute preload alterations result in important changes in cardiovascular physiology. It will be fascinating to monitor the cardiovascular impact of returning to Earth’s gravity after a prolonged period in space. How quickly will these changes take place? Which components of cardiovascular physiology change–and in what direction – as the heart compensates for the environment of space? Can we eventually create imaging tools to study real-time changes that provide instantaneous feedback for a greater understanding of lift-off, orbit, and re-entry? If so, it will be critical that we do not make assumptions regarding which portion of the cardiac performance should be assessed. Only in the totality of these changes will we begin to create a better understanding of the heart as a whole.

“Space isn’t remote at all. It’s only an hour’s drive away if your car could go straight upwards.” As Sir Fred Hoyle states, the mystery of myocardial deformation assessment is also not very remote, if only our eyes can focus and our brains digest what’s right in front of us. It is our responsibility to use the strengths and weaknesses of these separate reports to creep one step closer to this global understanding.

Like the Earth seen from outer space, the heart is one coherent system still waiting for the overview effect of a cosmic perspective. Like our evolution of understanding the Earth as a planet soaring through space, our evolution of understanding the Heart more comprehensively, held in balance by the hemodynamic environment it keeps, is ongoing. From afar, the fragility of the Earth is easy to understand as you bear witness to the paper-thin atmosphere required to maintain all life within. The recent burden of massive fires, catastrophic earthquakes, and repeated occurrence of once-in-a-lifetime major hurricanes serves to substantiate this delicateness. Similarly, the Heart is dependent upon many variables each working in unison to maintain life. An image of this fragility of the Heart may one day come from this line of research.