Heart failure with preserved ejection fraction (HFpEF) is defined by increased left ventricular (LV) chamber pressures at rest or with exertion. Cardiac chamber pressures are referenced to atmospheric pressure and reflect a combination of both myocardial compliance and external constraining forces from the pericardium, the lung, and the chest wall. Exposure to weightlessness experimentally removes the influence of chest wall and lung weight. When healthy adults were exposed to zero gravity (0G) during spaceflight, central venous pressure unexpectedly decreased to near 0 mm Hg, despite an increase in LV volume resulting in a downward and rightward shift in the end-diastolic pressure-volume relationship (EDPVR). This case series study aimed to determine the effect of external constraint on LV filling pressures in patients with obesity and HFpEF. Pulmonary artery systolic, diastolic, and mean pressures (PASP, PADP, and PAMP, respectively) were measured in 2 patients during transient 0G conditions in parabolic flight. It was hypothesized that 0G would acutely reduce PADP compared to normal gravity (1G) due to a reduction in external constraint.
Detailed methods are available in the eMethods in Supplement 1. Briefly, 2 participants with HFpEF, obesity, and previously implanted CardioMems sensors (Abbott) underwent PASP, PADP, and PAMP measurements in the supine position during parabolic flight at 0G, 1G, and hypergravity (1.8G) (Figure, A). Participants provided written informed consent.
Participant characteristics are shown in the Table. Participant 1 (aged 62 years, female) had mean out-of-clinic PA pressures (PASP/PADP [PAMP]) of 51/31 (40) mm Hg, and participant 2 (aged 72 years, male) had mean out-of-clinic PA pressures of 36/18 (25) mm Hg. Pulmonary pressures for 1G and mean (SD) pressures for 0G and 1.8G during flight are shown in the Figure, B and C, and as follows: participant 1 (1.8G: 61/36 [46]; 1G: 59 [4]/34 [3] [45 (3)]; 0G: 52 [3]/26 [1] [37 (2)] mm Hg) and participant 2 (1.8G: 41/27 [32]; 1G: 38/24 [30]; 0G: 29 [1]/15 [1] [21 (1)] mm Hg). For participants 1 and 2, the changes in PADP from 1G to 0G were -8 mm Hg and -9 mm Hg, respectively (Figure, B), and the differences in PADP between 0G and 1.8G were -10 mm Hg and -12 mm Hg, respectively.
Zero gravity reduced PADP in patients with obesity and HFpEF. A defining feature of HFpEF is an exaggerated increase in LV filling pressures when venous return is increased (eg, during exercise) due to a relatively steep EDPVR curve. While we were not able to define LV volumes during this experiment, it is almost certain that venous return increased during 0G; in prior studies of space flight, CVP decreased and cardiac chamber size increased in 0G. The observed decrease in PADP in this study's participants during 0G suggests an acute change in chamber compliance and a shift in the LV EDPVR. Because 0G is unlikely to have a transient effect on myocardial compliance, the most likely explanation is decreased external constraint on the heart, a key mechanism of the obese phenotype of HFpEF. A dose response occurred with highest PADP at 1.8G, albeit with a lesser magnitude than 0G to 1G, possibly due to protective rigidity of the rib cage or nonlinear influence of external constraint. The small sample size and number of measurements limit definitive conclusions from these data, but the PADP responses that were collected are high resolution, consistent, and in line with prior studies of healthy adults. We are unable to differentiate potential sources of external constraint, including paracardial fat, chest wall or lung weight, and combined pericardial effects. In this case series study, acute weightlessness decreased PADP in patients with the obese phenotype of HFpEF indicating that external constraint, including weight of the lung or chest wall, contributes to cardiac hemodynamics in HFpEF. The alleviation of elevated filling pressures may be why weight loss was effective at improving symptoms and functional capacity in the obese phenotype of HFpEF. Further study into the hemodynamic consequences of weight loss in HFpEF are needed.
Corresponding Author: Benjamin D. Levine, MD, Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Dallas, 7232 Greenville Ave, Dallas, TX 75231 (benjaminlevine@texashealth.org).
Author Contributions: Drs MacNamara and Levine had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs MacNamara and Hearon contributed equally.
Concept and design: MacNamara, Hearon, Manferdelli, Tayon, Sarma, Levine.
Acquisition, analysis, or interpretation of data: MacNamara, Hearon, Manferdelli, Shah, Pandey, Sarma, Levine.
Drafting of the manuscript: MacNamara, Hearon, Tayon.
Critical review of the manuscript for important intellectual content: MacNamara, Hearon, Manferdelli, Shah, Tayon, Pandey, Sarma, Levine.
Administrative, technical, or material support: MacNamara, Shah, Tayon, Sarma, Levine.
Supervision: MacNamara, Hearon, Sarma, Levine.
Conflict of Interest Disclosures: Dr Shah reported consultant fees from Abbott outside the submitted work. Dr Pandey reported receiving research support from the US National Institute of Health; grant funding from Applied Therapeutics and Gilead Sciences; honoraria from serving as an advisor or consultant from Axon Therapies, Bayer, Cytokinetics, Edwards Lifesciences, Emmi Solutions, Lilly, Medtronic, Merck, Novo Nordisk, Rivus, Roche Diagnostics, Sarfex Pharmaceuticals, and Tricog Health outside the submitted work; receiving nonfinancial support from Merck and Pfizer; and serving as a consultant with stock compensation for Palomarin. No other disclosures were reported.
Funding/Support: Funding provided by the Jesse and Milo Kirk Center of Cardiac Excellence Endowment at Texas Health Presbyterian Dallas.
Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 2.
Additional Contributions: The authors thank the crew of the ZeroG flight for a safe flight for the team and patients, and the authors would like to acknowledge the patients for their commitment and sense of adventure. The authors thank the patients for granting permission to publish this information.