Randomized Controlled Trial

. 2023 Aug;11(8 Pt 2):1103-1117.

doi: 10.1016/j.jchf.2023.01.030. Epub 2023 Mar 20.

Exercise-Induced Left Atrial Hypertension in Heart Failure With Preserved Ejection Fraction

Sheldon E Litwin¹, Jan Komtebedde², Mo Hu³, Daniel Burkhoff⁴, Gerd Hasenfuß⁵, Barry A Borlaug⁶, Scott D Solomon⁷, Michael R Zile⁸, Rajeev C Mohan⁹, Rami Khawash¹⁰, Aaron L Sverdlov¹¹, Peter Fail¹², Eugene S Chung¹³, David M Kaye¹⁴, John Blair¹⁵, Jean-Christophe Eicher¹⁶, Scott L Hummel¹⁷, Andreas Zirlik¹⁸, Ralf Westenfeld¹⁹, Christopher Hayward²⁰, Thomas M Gorter²¹, Catherine Demers²², Ranjith Shetty²³, Gregory Lewis²⁴, Randall C Starling²⁵, Sanjay Patel²⁶, Deepak K Gupta²⁷, Hakim Morsli²⁸, Martin Penicka²⁹, Maja Cikes³⁰, Finn Gustafsson³¹, Frank E Silvestry³², Ethan J Rowin³³, Donald E Cutlip³⁴, Martin B Leon⁴, Dalane W Kitzman³⁵, Franz X Kleber³⁶, Sanjiv J Shah³; REDUCE LAP-HF Investigators and Research Staff

Affiliations

¹ Medical University of South Carolina, Charleston, South Carolina, USA; Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, USA. Electronic address: litwins@musc.edu.
² Corvia Medical Inc, Tewksbury, Massachusetts, USA.
³ Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
⁴ Cardiovascular Research Foundation, New York City, New York, USA.
⁵ University of Göttingen, Göttingen, Germany.
⁶ Mayo Clinic, Rochester, Minnesota, USA.
⁷ Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁸ Medical University of South Carolina, Charleston, South Carolina, USA; Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, USA.
⁹ Scripps Health, La Jolla, California, USA.
¹⁰ The Ohio State University, Columbus, Ohio, USA.
¹¹ John Hunter Hospital, New Castle, New South Wales, Australia; University of Newcastle, New Castle, New South Wales, Australia.
¹² Cardiovascular Institute of the South, Houma, Louisiana, USA.
¹³ Christ Hospital, Cincinnati, Ohio, USA.
¹⁴ Alfred Hospital, Melbourne, Australia.
¹⁵ University of Chicago, Chicago, Illinois, USA.
¹⁶ Centre Hospitalier Universitaire de Dijon-Hôpital Bocage Central, Dijon, France.
¹⁷ University of Michigan Health Systems, Ann Arbor, Michigan, USA; Veterans Affairs Ann Arbor, Ann Arbor, Michigan, USA.
¹⁸ University of Graz, Graz, Austria.
¹⁹ Division of Cardiology, Pulmonology, and Vascular Medicine Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
²⁰ St Vincent Hospital Sydney, Sydney, Australia.
²¹ University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
²² McMaster University and Hamilton Health Sciences, Hamilton, Canada.
²³ University of Arizona, Arizona, USA.
²⁴ Massachusetts General Hospital, Boston, Massachusetts, USA.
²⁵ Cleveland Clinic, Cleveland, Ohio, USA.
²⁶ Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; Sydney Medical School, The University of Sydney, New South Wales, Australia; The Heart Research Institute, Sydney, New South Wales, Australia.
²⁷ Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²⁸ Sarasota Memorial Hospital, Sarasota, Florida, USA.
²⁹ Onze Lieve Vrouwen Ziekenhuis, Aalst, Belgium.
³⁰ Department of Cardiovascular Diseases, University of Zagreb School of Medicine and University Hospital Center, Zagreb, Croatia.
³¹ Rigshospitalet Copenhagen, Copenhagen, Denmark.
³² University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³³ Tufts University, Boston, Massachusetts, USA.
³⁴ Baim Clinical Research Institute, Boston, Massachusetts, USA.
³⁵ Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
³⁶ Martin-Luther-University, Halle-Wittenberg, Germany.

PMID: 36939661
PMCID: PMC11185159
DOI: 10.1016/j.jchf.2023.01.030

Randomized Controlled Trial

Exercise-Induced Left Atrial Hypertension in Heart Failure With Preserved Ejection Fraction

Sheldon E Litwin et al. JACC Heart Fail. 2023 Aug.

. 2023 Aug;11(8 Pt 2):1103-1117.

doi: 10.1016/j.jchf.2023.01.030. Epub 2023 Mar 20.

Authors

Affiliations

¹ Medical University of South Carolina, Charleston, South Carolina, USA; Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, USA. Electronic address: litwins@musc.edu.
² Corvia Medical Inc, Tewksbury, Massachusetts, USA.
³ Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
⁴ Cardiovascular Research Foundation, New York City, New York, USA.
⁵ University of Göttingen, Göttingen, Germany.
⁶ Mayo Clinic, Rochester, Minnesota, USA.
⁷ Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁸ Medical University of South Carolina, Charleston, South Carolina, USA; Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, USA.
⁹ Scripps Health, La Jolla, California, USA.
¹⁰ The Ohio State University, Columbus, Ohio, USA.
¹¹ John Hunter Hospital, New Castle, New South Wales, Australia; University of Newcastle, New Castle, New South Wales, Australia.
¹² Cardiovascular Institute of the South, Houma, Louisiana, USA.
¹³ Christ Hospital, Cincinnati, Ohio, USA.
¹⁴ Alfred Hospital, Melbourne, Australia.
¹⁵ University of Chicago, Chicago, Illinois, USA.
¹⁶ Centre Hospitalier Universitaire de Dijon-Hôpital Bocage Central, Dijon, France.
¹⁷ University of Michigan Health Systems, Ann Arbor, Michigan, USA; Veterans Affairs Ann Arbor, Ann Arbor, Michigan, USA.
¹⁸ University of Graz, Graz, Austria.
¹⁹ Division of Cardiology, Pulmonology, and Vascular Medicine Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
²⁰ St Vincent Hospital Sydney, Sydney, Australia.
²¹ University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
²² McMaster University and Hamilton Health Sciences, Hamilton, Canada.
²³ University of Arizona, Arizona, USA.
²⁴ Massachusetts General Hospital, Boston, Massachusetts, USA.
²⁵ Cleveland Clinic, Cleveland, Ohio, USA.
²⁶ Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; Sydney Medical School, The University of Sydney, New South Wales, Australia; The Heart Research Institute, Sydney, New South Wales, Australia.
²⁷ Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²⁸ Sarasota Memorial Hospital, Sarasota, Florida, USA.
²⁹ Onze Lieve Vrouwen Ziekenhuis, Aalst, Belgium.
³⁰ Department of Cardiovascular Diseases, University of Zagreb School of Medicine and University Hospital Center, Zagreb, Croatia.
³¹ Rigshospitalet Copenhagen, Copenhagen, Denmark.
³² University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³³ Tufts University, Boston, Massachusetts, USA.
³⁴ Baim Clinical Research Institute, Boston, Massachusetts, USA.
³⁵ Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
³⁶ Martin-Luther-University, Halle-Wittenberg, Germany.

PMID: 36939661
PMCID: PMC11185159
DOI: 10.1016/j.jchf.2023.01.030

Abstract

Background: Many patients with heart failure and preserved ejection fraction have no overt volume overload and normal resting left atrial (LA) pressure.

Objectives: This study sought to characterize patients with normal resting LA pressure (pulmonary capillary wedge pressure [PCWP] <15 mm Hg) but exercise-induced left atrial hypertension (EILAH).

Methods: The REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc. IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) trial randomized 626 patients with ejection fraction ≥40% and exercise PCWP ≥25 mm Hg to atrial shunt or sham procedure. The primary trial outcome, a hierarchical composite of death, heart failure hospitalization, intensification of diuretics, and change in health status was compared between patients with EILAH and those with heart failure and resting left atrial hypertension (RELAH).

Results: Patients with EILAH (29%) had similar symptom severity, but lower natriuretic peptide levels, higher 6-minute walk distance, less atrial fibrillation, lower left ventricular mass, smaller LA volumes, lower E/e', and better LA strain. PCWP was lower at rest, but had a larger increase with exercise in EILAH. Neither group as a whole had a significant effect from shunt therapy vs sham. Patients with EILAH were more likely to have characteristics associated with atrial shunt responsiveness (peak exercise pulmonary vascular resistance <1.74 WU) and no pacemaker (63% vs 46%; P < 0.001). The win ratio for the primary outcome was 1.56 (P = 0.08) in patients with EILAH and 1.51 (P = 0.04) in those with RELAH when responder characteristics were present.

Conclusions: Patients with EILAH had similar symptom severity but less advanced myocardial and pulmonary vascular disease. This important subgroup may be difficult to diagnose without invasive exercise hemodynamics, but it has characteristics associated with favorable response to atrial shunt therapy. (A Study to Evaluate the Corvia Medical, Inc. IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure [REDUCE LAP-HF TRIAL II]; NCT03088033).

Keywords: exercise capacity; exercise hemodynamics; heart failure with preserved ejection fraction; pulmonary capillary wedge pressure; randomized controlled trial.

PubMed Disclaimer

Conflict of interest statement

Funding Support and Author Disclosures This study was sponsored by Corvia Medical Inc. Dr Litwin has received research funding from the department of Veterans Affairs, Corvia, AstraZeneca, V-Wave, Axon Therapeutics, and Eli Lilly all paid to the institution; has received consulting fees from CVRx, Axon Therapeutics, Occlutech, Eli Lilly, and Rivus Pharmaceuticals; and has received travel grants, speaker fees, and advisory board honoraria from NovoNordisk and Roche. Dr Komtebedde is employed by Corvia. Dr Burkhoff has consulted for Corvia. Dr Hasenfuß has consulted for AstraZeneca, Boehringer Ingelheim, Corvia, Impulse Dynamics, Novartis, Servier, Vifor; has received honoraria for lectures from AstraZeneca, Bayer, Impulse Dynamics, Novartis, Pfizer, Servier, and Vifor; and is a co-principal investigator to Impulse Dynamics. Dr Borlaug has received research grants from Corvia, AstraZeneca, Medtronic, GlaxoSmithKline, Mesoblast, Novartis, and Tenax Therapeutics; and has received consulting fees from Actelion, Amgen, Aria, Axon Therapies, Boehringer Ingelheim, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, and VADovations. Dr Solomon has received research grants from Alnylam, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Cytokinetics, Eidos, GlaxoSmithKline, Ionis, Lilly, MyoKardia, the National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, DiNAQOR, Tremeau, CellProthera, Moderna, American Regent, Sarepta, Lexicon, AnaCardio, and Akros. Dr Mohan has received research support from Corvia and V-Wave paid to the institution. Dr Kahwash has served as a consultant for Medtronic, Impulse Dynamics, and Cardionomic. Dr Sverdlov has received research grants from the National Heart Foundation of Australia (Future Leader Fellowships 101918 and 106025), Department of Health and Aged Care (Australia): Medical Research Future Fund (MRF2017053), New South Wales Health (Australia), Novartis Australia, Biotronik, RACE Oncology, Bristol Myers Squibb, Roche Diagnostics, and Vifor Pharma; and has received personal fees from Novartis, Bayer, Bristol Myers Squibb, AstraZeneca, Corvia, and Boehringer Ingelheim. Dr Fail has received research support paid to the institution from Corvia and Alleviant. Dr Chung has served as a consultant to Intershunt. Dr Kaye has received research support from Corvia. Dr Hummel has received research grant funding from National Institutes of Health, Veterans Affairs, American Heart Association, Novartis, Pfizer, AstraZeneca, Corvia, and Axon Therapies. Dr Zirlik has received personal consulting fees and honoraria for lectures from Abbott, Abiomed, AstraZeneca, Amarin, Amgen, Bayer Healthcare, Biotronik, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimensions, Cardiorentis, Corvia, Daichi Sankyo, Edwards Lifesciences, Eli Lilly, Janssen, Merck, Neucomed, Novo Nordisk, Novartis, Rigel, and Stealth Peptides. Dr Hayward has received research support from Corvia, Medtronic, Abbott, Roche, and Procyrion. Dr Lewis has received research funding from the National Institutes of Health (R01-HL 151841, R01-HL131029, R01-HL159514), American Heart Association (15GPSGC-24800006), Amgen, Cytokinetics, Applied Therapeutics, AstraZeneca, and SoniVie; has received honoraria for advisory boards outside of the current study from Pfizer, Merck, Boehringer Ingelheim, NXT, American Regent, Cyclerion, Cytokinetics, and Amgen; and has received royalties from UpToDate for scientific content authorship related to exercise physiology. Dr Gupta has received research support from the National Institutes of Health, Imara, Corvia, and Astellas Pharma. Dr Cikes has received institutional research grants from Abbott, Novartis, and Pfizer; has received travel grants, speaker fees, and advisory board honoraria from Abbott, Abiomed, Amicus, AstraZeneca, Bayer, Boehringer Ingelheim, GE Healthcare, Krka Pharma, LivaNova, Medtronic, Novartis, Orion Corporation, Pfizer, Sanofi, Swixx BioPharma, and Teva Pharmaceutical Industries, all outside of the present study; and has received research support from Corvia. Dr Gustafsson has received honoraria outside the present study as a consultant for Abbott, Pfizer, Ionis Pharmaceuticals, Bayer, AstraZeneca, and Alnylam; has received speaker fees from Novartis and Orion Pharma; and has received research support from Corvia. Dr Silvestry has received research support from Corvia. Dr Rowin has received research support from Corvia; and has served as a consultant for Cardiovascular Clinical Sciences. Dr Cutlip has received research support from Corvia paid to the institution. Dr Kitzman has received honoraria outside the present study as a consultant for Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Rivus, Keyto, and Novartis; has received grant funding outside the present study from Novartis, Bayer, Novo Nordisk, and AstraZeneca; owns stock in Gilead Sciences; and has received research support from Corvia. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received personal fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, Intellia Therapeutics, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Shifamed, Tenax, Tenaya, and United Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

**FIGURE 1**
Relationship Between Resting and Peak Exercise PCWP Patients with resting pulmonary capillary wedge pressure (PCWP) <15 mm Hg (exercise-induced left atrial hypertension) are shown in **blue** and those with resting PCWP ≥15 mm Hg (resting left atrial hypertension) in **red**. The mean PCWP at peak exercise was lower in the exercise-induced left atrial hypertension group.

**FIGURE 2**
Relationship Between Resting PCWP and Peak Exercise PVR Patients with resting PCWP <15 mm Hg (exercise-induced left atrial hypertension) are shown in **blue** and those with resting PCWP ≥15 mm Hg (resting left atrial hypertension) in **red**. The mean pulmonary vascular resistance (PVR) at peak exercise was lower in the exercise-induced left atrial hypertension group (1.1 vs 1.4 WU). Patients with peak exercise PVR <1.74 WU have previously been identified as a group with beneficial response to atrial shunt therapy. Abbreviation as in Figure 1.

**FIGURE 3**
Kaplan-Meier Curves for HF Events Broken Down by EILAH and RELAH and Sham or Atrial Shunt Therapy Kaplan-Meier curves for heart failure (HF) events broken down by the classification of resting PCWP <15 mm Hg (exercise-induced left atrial hypertension [EILAH], shown in **blue**) and resting PCWP ≥15 mm Hg (resting left atrial hypertension [RELAH], shown in **red**) and randomization to sham or atrial shunt therapy. Patients with EILAH had fewer HF events overall, regardless of therapy. The overall log rank score indicates differences between the 4 groups. However, for the entire EILAH and RELAH groups HF events were not different in the sham or treatment groups. The trend toward lower events in the patients with EILAH who were randomized to treatment is likely related to lower peak pulmonary vascular resistance and fewer subjects with pacemakers in this group. Abbreviations as in Figure 1

**FIGURE 4**
Changes in Hemodynamics From Baseline to Peak Exercise in the EILAH and RELAH Groups Changes in hemodynamics from baseline to peak exercise in the patients with resting PCWP <15 mm Hg (EILAH, shown in **blue**) and resting PCWP ≥15 mm Hg (RELAH, shown in **red**). **Dots** represent median values for each group. Patients with EILAH had lower right atrial (RA) pressure, lower PCWP, and lower PCWP-RA pressure gradient at rest. RA pressure increased comparably at peak exercise in both groups, whereas PCWP increased more in the EILAH groups. This resulted in nearly equivalent PCWP-RA pressure gradient at peak exertion in both groups. The peak PCWP is likely a major driver of symptoms, whereas the PCWP-RA pressure gradient is the main driver of left-to-right shunting. Abbreviations as in Figures 1 and 3.

**CENTRAL ILLUSTRATION**
Dyspnea on Exertion Is the Most Common Symptom in HFpEF and Is Due in Part to Elevation of LA Pressure During Exertion Some patients have normal left atrial (LA) pressure at rest, but have exercise-induced left atrial hypertension (EILAH). Compared to those with resting left atrial hypertension (RELAH), the group with EILAH had fewer comorbidities, lower natriuretic peptide levels, less cardiac remodeling, and better 6-minute walk distance (6MWD). They were more likely to have characteristics associated with favorable response to atrial shunt therapy (lower exercise pulmonary vascular resistance [PVR] and fewer implanted pacemakers). Hemodynamics at rest and with exertion suggest that patients with EILAH may have less left-to-right shunting at rest, but equivalent shunting (LA decompression) during exercise. BNP = B-type natriuretic peptide; DOE = dyspnea on exertion; HFpEF = heart failure with preserved ejection fraction; KCCQ = Kansas City Cardiomyopathy Questionnaire; LV = left ventricle.

See this image and copyright information in PMC

Comment in

Difficult Diagnoses Are Often Undertreated: The Case of HFpEF With Exercise-Induced Left Atrial Hypertension.
Maurer MS, Rosenblum HR. Maurer MS, et al. JACC Heart Fail. 2023 Aug;11(8 Pt 2):1118-1120. doi: 10.1016/j.jchf.2023.02.010. Epub 2023 Mar 20. JACC Heart Fail. 2023. PMID: 37038879 No abstract available.

References

1. Pandey A, Khera R, Park B, et al. Relative impairments in hemodynamic exercise reserve parameters in heart failure with preserved ejection fraction: a study-level pooled analysis. J Am Coll Cardiol HF. 2018;6(2):117–126. - PMC - PubMed
1. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail. 2010;3(5):588–595. - PMC - PubMed
1. Berry N, Mauri L, Feldman T, et al. Transcatheter interatrial shunt device for the treatment of heart failure: rationale and design of the pivotal randomized trial to REDUCE Elevated Left Atrial Pressure in Patients with Heart Failure II (REDUCE LAP-HF II). Am Heart J. 2020;226:222–231. - PubMed
1. Griffin JM, Borlaug BA, Komtebedde J, et al. Impact of interatrial shunts on invasive hemodynamics and exercise tolerance in patients with heart failure. J Am Heart Assoc. 2020;9(17):e016760. - PMC - PubMed
1. Feldman T, Mauri L, Kahwash R, et al. Transcatheter interatrial shunt device for the treatment of heart failure with preserved ejection fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With Heart Failure]): a phase 2, randomized, sham-controlled trial. Circulation. 2018;137(4):364–375. - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Exercise-Induced Left Atrial Hypertension in Heart Failure With Preserved Ejection Fraction

Affiliations

Exercise-Induced Left Atrial Hypertension in Heart Failure With Preserved Ejection Fraction

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous