Effect of Intracoronary Administration of AAV1/SERCA2a on Ventricular Remodelling in Patients with Advanced Systolic Heart Failure: Results from the Agent-Hf Randomized Phase 2 Trial
Open accessAbstract
Aims: Restoration of sarco/endoplasmic reticulum Ca2+ATPase (SERCA2a) activity through gene transfer improved cardiac function in experimental and pilot studies in humans with heart failure. The AGENT-HF (NCT01966887) trial investigated the impact of adeno-associated virus (AAV1)/SERCA2a on ventricular remodelling using multimodality non-invasive cardiac imaging. Methods and results: AGENT-HF was a single centre, randomized, double-blind, placebo-controlled trial in adult patients with NYHA class III–IV ischaemic or non-ischaemic heart failure and left ventricular ejection fraction ≤35%. Eligible patients were randomized to receive a single intracoronary infusion of either 1 × 1013DNase-resistant particles of AAV1/SERCA2a or placebo. The primary endpoint was change in left ventricular end-systolic volume (LVESV), measured by cardiac computed tomography at 6 month follow-up. We planned to include 40 patients but the trial was terminated prematurely as the sponsor suspended further enrolment following neutral results of the CUPID-2 outcome trial. At the time of termination, nine patients were randomized with five patients infused with AAV1/SERCA2a and four with placebo. At 6 months, LVESV was increased in both groups compared with baseline: median (interquartile range) in AAV1/SERCA2a vs. placebo: 13 (13;14) mL vs. 3.5 (−36;36) mL, P = 0.74, with a mean difference between groups of 11.4 mL in favour of placebo. No safety issues were noted. Conclusion: AGENT-HF failed to demonstrate any improvement in ventricular remodelling in response to AAV1/SERCA2a at the dose studied. However, because of premature termination, the study was underpowered to demonstrate an effect of AAV1/SERCA2a and these data should be interpreted with caution.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
CUPID-2 confirmed the safety of AAV1-SERCA2a but showed no effect on the primary outcome of HF hospitalization or decompensated HF.
“A larger Phase 2 study (CUPID-2), testing a higher dose (10 13 viral genome particles of AAV1-SERCA2a per patient), confirmed the safety of this approach, 61,62 but showed no effect on the primary outcome of HF hospitalization or decompensated HF.”
From Reversal of contractile defects by mediating calcium homeostasis in human mini-heart models of heart failure with preserved ejection fraction (HFpEF) leads to first-in-human gene therapy clinical trial (2024) · cites this paper as [61]
The Discussion (page unavailable) says AAV1/SERCA2a caused no untoward effects in AGENT-HF and that this was consistent with the CUPID studies. The Introduction and Results describe CUPID-2 as having no clinical benefit or neutral results, but our copy does not identify HF hospitalization or decompensated HF as its primary outcome. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Lang, R. M., Badano, L. P., Mor‐Avi, V., Afilalo, J., Armstrong, A. D. C., Ernande, L., Flachskampf, F. A., Foster, E., Goldstein, S. A., Kuznetsova, T., et al. (2015) · European Heart Journal - Cardiovascular Imaging · doi:10.1093/ehjci/jev014 · Cited by 8,449 · see citing works
Heart Disease and Stroke Statistics—2012 Update: A Report From the American Heart Association
Writing Group Members, Roger, V. L., Go, A. S., Lloyd-Jones, D. M., Benjamin, E. J., Berry, J. D., Borden, W. B., Bravata, D. M., Dai, S., Ford, E. S., et al. (2012) · Circulation · doi:10.1161/cir.0b013e31823ac046 · Cited by 7,333 · see citing works
Calcium cycling and signaling in cardiac myocytes.
Bers, D. (2008) · Annual Review of Physiology · doi:10.1146/annurev.physiol.70.113006.100455 · Cited by 1,386 · see citing works
Maggioni, A. P., Dahlström, U., Filippatos, G. S., Chioncel, O., Leiro, M. C., Dróżdż, J., Fruhwald, F. M., Gullestad, L. L., Logeart, D., Fabbri, G., et al. (2013) · European Journal of Heart Failure · doi:10.1093/eurjhf/hft050 · Cited by 804 · see citing works
Self-citationJessup, M., Greenberg, B., Mancini, D., Cappola, T., Pauly, D. F., Jaski, B., Yaroshinsky, A., Zsebo, K. M., Dittrich, H., & Hajjar, R. J. (2011) · Circulation · doi:10.1161/circulationaha.111.022889 · Cited by 760 · see citing works
Self-citationGreenberg, B., Butler, J., Felker, G. M., Ponikowski, P., Voors, A. A., Desai, A. S., Barnard, D., Bouchard, A., Jaski, B., Lyon, A. R., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(16)00082-9 · Cited by 525 · see citing works
Calcium Cycling in Congestive Heart Failure
Hasenfuss, G. P., & Pieske, B. M. (2002) · Journal of Molecular and Cellular Cardiology · doi:10.1006/jmcc.2002.2037 · Cited by 412 · see citing works
del Monte, F., Williams, E., Lebeche, D., Schmidt, U., Rosenzweig, A., Gwathmey, J. K., Lewandowski, E. D., & Hajjar, R. J. (2001) · Circulation · doi:10.1161/hc3601.095574 · Cited by 382 · see citing works
Self-citationOvercoming Preexisting Humoral Immunity to AAV Using Capsid Decoys
Mingozzi, F., Anguela, X. M., Pavani, G., Chen, Y., Davidson, R. J., Hui, D. J., Yazicioglu, M., Elkouby, L., Hinderer, C. J., Faella, A., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005795 · Cited by 355 · see citing works
Kawase, Y., Ly, H. Q., Prunier, F., Lebeche, D., Shi, Y., Jin, H., Hadri, L., Yoneyama, R., Hoshino, K., Takewa, Y., et al. (2008) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2007.12.014 · Cited by 343 · see citing works
Self-citationZsebo, K., Yaroshinsky, A., Rudy, J. J., Wagner, K., Greenberg, B., Jessup, M., & Hajjar, R. J. (2014) · Circulation Research · doi:10.1161/circresaha.113.302421 · Cited by 315 · see citing works
Self-citationAltered sarcoplasmic reticulum calcium cycling—targets for heart failure therapy
Kho, C., Lee, A., & Hajjar, R. J. (2012) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2012.145 · Cited by 177 · see citing works
Self-citationGene therapy for the treatment of heart failure: promise postponed
Hulot, J.-S., Ishikawa, K., & Hajjar, R. J. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehw019 · Cited by 150 · see citing works
Self-citationGreenberg, B., Butler, J., Felker, G. M., Ponikowski, P. P., Voors, A. A., Pogoda, J. M., Provost, R., Guerrero, J., Hajjar, R. J., & Zsebo, K. M. (2015) · Gene Therapy · doi:10.1038/gt.2015.109 · Cited by 113 · see citing works
Self-citationBiosafety of recombinant adeno-associated virus vectors.
Dismuke, D., Tenenbaum, L., & Samulski, R. (2014) · Current Gene Therapy · doi:10.2174/15665232113136660007 · Cited by 83 · see citing works
Karakikes, I., Hadri, L., Rapti, K., Ladage, D., Ishikawa, K., Tilemann, L. M., Yi, G., Morel, C., Gwathmey, J. K., Zsebo, K. M., et al. (2012) · Molecular Therapy · doi:10.1038/mt.2011.268 · Cited by 44 · see citing works
Self-citationRole of cardiac CTA in estimating left ventricular volumes and ejection fraction
Singh, R. (2014) · World Journal of Radiology · doi:10.4329/wjr.v6.i9.669 · Cited by 27 · see citing works
Assessment of cardiac volumes by multidetector computed tomography
Lin, F. Y.-H., & Min, J. K. (2008) · Journal of cardiovascular computed tomography · doi:10.1016/j.jcct.2008.05.144 · Cited by 17 · see citing works
Salem, J., Aïssaoui, N., Paluszkiewicz, L., et al. (2014) · Critical Care Medicine · doi:10.1097/ccm.0000000000000513 · Cited by 11 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Consideration of clinical translation of cardiac AAV gene therapy
Yamada, K. P., Tharakan, S., & Ishikawa, K. (2020) · Cell and Gene Therapy Insights · doi:10.18609/cgti.2020.073 · Cited by 13 · see citing works
Costa, K. D., Wong, A. O. T., Mak, S. Y., Roberts, E. G., Keung, W., Correia, C., Walentinsson, A., Christoffersson, J., Cheung, A., Lieu, D. K., et al. (2024) · bioRxiv · doi:10.1101/2024.08.27.609034 · Cited by 5 · see citing works
Self-citation
- Authors
- Hulot, J.-S., Salem, J.-E., Redheuil, A., Collet, J.-P., Varnous, S., Jourdain, P., Logeart, D., Gandjbakhch, E., Bernard, C., Hatem, S. N., Isnard, R., Cluzel, P., Le Feuvre, C., Leprince, P., Hammoudi, N., Lemoine, F. M., Klatzmann, D., Vicaut, E., Komajda, M., Montalescot, G., Lompré, A.-M., & Hajjar, R. J.
- Affiliations
- Assistance Publique – Hôpitaux de Paris (FR)
- Sorbonne Universités, UPMC Univ Paris 06, AP-HP, CIC Paris-Est 1421, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital , F-75013, Paris ,
- Centre Hospitalier Pontoise
- Sorbonne Université (FR)
- Sorbonne Universités, UPMC Univ Paris 06, AP-HP, Clinical Investigation Center for Biotherapies and Inflammation-Immunopathology-Biotherapy Department , F-75013, Paris ,
- ACTION Study Group, Unité de Recherche Clinique, Lariboisière , Paris ,
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Hulot, Jean-Sébastien
- ORCID
- Venue
- European Journal of Heart Failure
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-04-10
- Volume
- 19
- Issue
- 11
- Pages
- 1534-1541
- ISSN
- 1388-9842 (ISSN-L)
- 1879-0844
- OpenAlex
- W2606688972
- Cited by
- 113
- References
- 19
- Citations by year
- 2026: 13 · 2025: 14 · 2024: 14 · 2023: 13 · 2022: 13 · 2021: 9 · 2020: 13 · 2019: 9 · 2018: 11 · 2017: 4
- FWCI
- 6.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Heart Failure (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- French Ministry of Health ((PHRC-N, AOM09191))
- Celladon Corporation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Keywords
- adeno-associated virus gene therapy, ventricular remodeling, heart failure with reduced ejection fraction, left ventricular end-systolic volume, cardiac CT, early trial termination, ischemic heart failure, non-ischemic heart failure
- MeSH terms
- Aged, Coronary Vessels, Double-Blind Method, Female, Humans, Infusions, Intra-Arterial, Male, Middle Aged, Genetic Therapy, Treatment Outcome, Ventricular Remodeling, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Heart Failure, Systolic
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
