What is the metabolic cost of starting exercise in individuals across the spectrum of functional limitation, including heart failure with preserved ejection fraction (HFpEF)?
In this cohort study of 3047 individuals from the Framingham Heart Study (an observational cohort study) and 184 individuals with HFpEF using comprehensive cardiopulmonary exercise testing, metabolic cost (in watts) of unloaded exercise (internal work) was determined. Obesity was associated with internal work across both the Framingham Heart Study and HFpEF cohorts; in patients with HFpEF, greater internal work was associated with more significant hemodynamic alterations in unloaded exercise.
A greater energetic cost of exercise initiation is associated with obesity and greater excursions in filling pressures early in exercise, suggesting that exercise initiation (before imposing an external load on the cardiovascular system) may represent and important locus of functional limitation in HFpEF.
Heart failure with preserved ejection fraction (HFpEF) is a joint metabolic and cardiovascular disorder with significant noncardiac contributions.
To define and quantify the metabolic cost of initiating exercise in individuals with and without HFpEF and its functional consequences.
Design, Setting, and Participants
This prospective cohort study included individuals with hemodynamically confirmed HFpEF from the Massachusetts General Hospital Exercise Study (MGH-ExS) and community-dwelling participants from the Framingham Heart Study (FHS). Analysis began April 2016 and ended November 2020.
Internal work (IW), a measure of work equivalents required to initiate movement.
Main Outcomes and Measures
Using breath-by-breath oxygen uptake (V̇o2) measurements and V̇o2-work rate associations, cost of initiating exercise (IW) in patients with HFpEF (MGH-ExS) and in community-dwelling individuals (FHS) was quantified. Linear regression was used to estimate associations between IW and clinical/hemodynamic measures.
Of 3231 patients, 184 (5.7%) had HFpEF and were from MGH-ExS, and 3047 (94.3%) were community-dwelling individuals from FHS. In the MGH-ExS cohort, 86 (47%) were women, the median (interquartile range) age was 63 (53-72) years, and the median (interquartile range) peak V̇o2 level was 13.33 (11.77-15.62) mL/kg/min. In the FHS cohort, 1620 (53%) were women, the median (interquartile range) age was 54 (48-60) years, and the median (interquartile range) peak V̇o2 level was 22.2 (17.85-27.35) mL/kg/min. IW was higher in patients with HFpEF and accounted for 27% (interquartile range, 21%-39%) of the total work (IW + measured external workload on the cycle), compared with 15% (interquartile range, 12%-20%) of that in FHS participants. Body mass index accounted for greatest explained variance in patients with HFpEF from MGH-ExS and FHS participants (22% and 18%, respectively), while resting cardiac output and biventricular filling pressures were not significantly associated with variance in IW in patients with HFpEF. A higher IW in patients with HFpEF was associated with a greater increase in left- and right-sided cardiac filing pressure during unloaded exercise, despite similar resting hemodynamic measures across IW.
Conclusions and Relevance
This study found that internal work, a new body mass index–related measure reflecting the metabolic cost of initiating movement, is higher in individuals with HFpEF compared with middle-aged adults in the community and is associated with steep, early increases in cardiac filling pressures. These findings highlight the importance of quantifying heterogeneous responses to exercise initiation when evaluating functional intolerance in individuals at risk for or with HFpEF.
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Corresponding Author: Gregory D. Lewis, MD, Division of Cardiology, GRB 800, Department of Medicine, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114 (email@example.com).
Accepted for Publication: January 28, 2020.
Published Online: March 17, 2021. doi:10.1001/jamacardio.2021.0292
Author Contributions: Drs Shah and Lewis 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 Shah and Armengol de la Hoz and Mr Schoenike contributed equally.
Concept and design: Schoenike, Armengol de la Hoz, Blodgett, Kowal, Malhotra, Vasan, Lewis.
Acquisition, analysis, or interpretation of data: Shah, Schoenike, Armengol de la Hoz, Cunningham, Tanguay, Sbarbaro, Nayor, Rouvina, Houstis, Baggish, Ho, Hardin, Malhotra, Larson, Vasan, Lewis.
Drafting of the manuscript: Shah, Schoenike, Armengol de la Hoz, Cunningham, Sbarbaro, Rouvina, Kowal, Vasan, Lewis.
Critical revision of the manuscript for important intellectual content: Shah, Schoenike, Blodgett, Tanguay, Nayor, Houstis, Baggish, Ho, Hardin, Malhotra, Larson, Vasan.
Statistical analysis: Shah, Schoenike, Armengol de la Hoz, Cunningham, Sbarbaro, Malhotra.
Obtained funding: Shah, Vasan, Lewis.
Administrative, technical, or material support: Schoenike, Blodgett, Tanguay, Rouvina, Kowal, Houstis, Hardin, Vasan.
Supervision: Nayor, Ho, Hardin, Vasan.
Conflict of Interest Disclosures: Dr Shah reported grants from National Institutes of Health (NIH) and American Heart Association during the conduct of the study; personal fees from MyoKardia and Best Doctors; grants from Amgen; stocks in Pfizer and Gilead Sciences outside the submitted work; and has patent for extracellular RNAs and cardiac remodeling issued. Dr Ho reported grants from NIH during the conduct of the study; grants from Gilead Sciences and Bayer; and research supplies from EcoNugenics outside the submitted work. Dr Malhotra reported consulting fees from MyoKardia and Third Pole Therapeutics and ownership interest from Patch outside the submitted work. Dr Vasan reported grants from NIH during the conduct of the study and is supported in part by the Evans Medical Foundation and the Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine. Dr Lewis reported grants from NIH, American Heart Association, Amgen, Cytokinetics, Applied Therapeutics, Cyclerion Therapeutics, SoniVie, and AstraZeneca; personal fees from AstraZeneca, Pfizer, Boehringer Ingelheim, Novartis, Edios, American Regent, and UpToDate; and has served as a scientific advisor for Merck and Relypsa outside the submitted work. No other disclosures were reported.
Funding/Support: This work was supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (contracts N01-HC-25195, HHSN268201500001I, and 75N92019D00031), the National Institutes of Health (grants K23-HL138260 [Dr Nayor], R01HL134893 [Dr Ho], R01HL140224 [Dr Ho], 1R01HL131029 [Drs Vasan and Lewis], R01HL151841 [Drs Lewis and Shah]), American Heart Association (grant 15GPSGC24800006 [Dr Lewis]), and Amgen (Dr Lewis).
Role of the Funder/Sponsor: The funders 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; and decision to submit the manuscript for publication.
Additional Contributions: We acknowledge the dedication of the Framingham Heart Study participants and Massachusetts General Hospital Exercise Study participants without whom this research would not be possible.
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