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Original Article

CD4+ T Cells Promote the Transition From Hypertrophy to Heart Failure During Chronic Pressure OverloadCLINICAL PERSPECTIVE

Fanny Laroumanie, Victorine Douin-Echinard, Joffrey Pozzo, Olivier Lairez, Florence Tortosa, Claire Vinel, Christine Delage, Denis Calise, Marianne Dutaur, Angelo Parini, Nathalie Pizzinat
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https://doi.org/10.1161/CIRCULATIONAHA.113.007101
Circulation. 2014;129:2111-2124
Originally published March 21, 2014
Fanny Laroumanie
From the Institut National de la Santé et de la Recherche Médicale UMR1048 (INSERM), Institute of Cardiovascular and Metabolic Diseases (I2MC), Rangueil, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Toulouse III University, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Department of Cardiology, University Hospital of Rangueil, Toulouse, France (J.P., O.L.); and INSERM-UMS 006-Microsurgery Facility, Toulouse, France (C.D., D.C.).
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Victorine Douin-Echinard
From the Institut National de la Santé et de la Recherche Médicale UMR1048 (INSERM), Institute of Cardiovascular and Metabolic Diseases (I2MC), Rangueil, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Toulouse III University, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Department of Cardiology, University Hospital of Rangueil, Toulouse, France (J.P., O.L.); and INSERM-UMS 006-Microsurgery Facility, Toulouse, France (C.D., D.C.).
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Joffrey Pozzo
From the Institut National de la Santé et de la Recherche Médicale UMR1048 (INSERM), Institute of Cardiovascular and Metabolic Diseases (I2MC), Rangueil, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Toulouse III University, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Department of Cardiology, University Hospital of Rangueil, Toulouse, France (J.P., O.L.); and INSERM-UMS 006-Microsurgery Facility, Toulouse, France (C.D., D.C.).
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Olivier Lairez
From the Institut National de la Santé et de la Recherche Médicale UMR1048 (INSERM), Institute of Cardiovascular and Metabolic Diseases (I2MC), Rangueil, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Toulouse III University, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Department of Cardiology, University Hospital of Rangueil, Toulouse, France (J.P., O.L.); and INSERM-UMS 006-Microsurgery Facility, Toulouse, France (C.D., D.C.).
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Florence Tortosa
From the Institut National de la Santé et de la Recherche Médicale UMR1048 (INSERM), Institute of Cardiovascular and Metabolic Diseases (I2MC), Rangueil, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Toulouse III University, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Department of Cardiology, University Hospital of Rangueil, Toulouse, France (J.P., O.L.); and INSERM-UMS 006-Microsurgery Facility, Toulouse, France (C.D., D.C.).
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Claire Vinel
From the Institut National de la Santé et de la Recherche Médicale UMR1048 (INSERM), Institute of Cardiovascular and Metabolic Diseases (I2MC), Rangueil, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Toulouse III University, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Department of Cardiology, University Hospital of Rangueil, Toulouse, France (J.P., O.L.); and INSERM-UMS 006-Microsurgery Facility, Toulouse, France (C.D., D.C.).
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Christine Delage
From the Institut National de la Santé et de la Recherche Médicale UMR1048 (INSERM), Institute of Cardiovascular and Metabolic Diseases (I2MC), Rangueil, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Toulouse III University, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Department of Cardiology, University Hospital of Rangueil, Toulouse, France (J.P., O.L.); and INSERM-UMS 006-Microsurgery Facility, Toulouse, France (C.D., D.C.).
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Denis Calise
From the Institut National de la Santé et de la Recherche Médicale UMR1048 (INSERM), Institute of Cardiovascular and Metabolic Diseases (I2MC), Rangueil, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Toulouse III University, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Department of Cardiology, University Hospital of Rangueil, Toulouse, France (J.P., O.L.); and INSERM-UMS 006-Microsurgery Facility, Toulouse, France (C.D., D.C.).
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Marianne Dutaur
From the Institut National de la Santé et de la Recherche Médicale UMR1048 (INSERM), Institute of Cardiovascular and Metabolic Diseases (I2MC), Rangueil, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Toulouse III University, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Department of Cardiology, University Hospital of Rangueil, Toulouse, France (J.P., O.L.); and INSERM-UMS 006-Microsurgery Facility, Toulouse, France (C.D., D.C.).
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Angelo Parini
From the Institut National de la Santé et de la Recherche Médicale UMR1048 (INSERM), Institute of Cardiovascular and Metabolic Diseases (I2MC), Rangueil, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Toulouse III University, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Department of Cardiology, University Hospital of Rangueil, Toulouse, France (J.P., O.L.); and INSERM-UMS 006-Microsurgery Facility, Toulouse, France (C.D., D.C.).
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Nathalie Pizzinat
From the Institut National de la Santé et de la Recherche Médicale UMR1048 (INSERM), Institute of Cardiovascular and Metabolic Diseases (I2MC), Rangueil, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Toulouse III University, Toulouse, France (F.L., V.D.-E., C.V., F.T., M.D., A.P., N.P.); Department of Cardiology, University Hospital of Rangueil, Toulouse, France (J.P., O.L.); and INSERM-UMS 006-Microsurgery Facility, Toulouse, France (C.D., D.C.).
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Abstract

Background—The mechanisms by which the heart adapts to chronic pressure overload, producing compensated hypertrophy and eventually heart failure (HF), are still not well defined. We aimed to investigate the involvement of T cells in the progression to HF using a transverse aortic constriction (TAC) model.

Methods and Results—Chronic HF was associated with accumulation of T lymphocytes and activated/effector CD4+ T cells within cardiac tissue. After TAC, enlarged heart mediastinal draining lymph nodes showed a high density of both CD4+ and CD8+ T-cell subsets. To investigate the role of T cells in HF, TAC was performed on mice deficient for recombination activating gene 2 expression (RAG2KO) lacking B and T lymphocytes. Compared with wild-type TAC mice, RAG2KO mice did not develop cardiac dilation and showed improved contractile function and blunted adverse remodeling. Reconstitution of the T-cell compartment into RAG2KO mice before TAC enhanced contractile dysfunction, fibrosis, collagen accumulation, and cross-linking. To determine the involvement of a specific T-cell subset, we performed TAC on mice lacking CD4+ (MHCIIKO) and CD8+ T-cell subsets (CD8KO). In contrast to CD8KO mice, MHCIIKO mice did not develop ventricular dilation and dysfunction. MHCIIKO mice also displayed very low fibrosis, collagen accumulation, and cross-linking within cardiac tissue. Interestingly, mice with transgenic CD4+ T-cell receptor specific for ovalbumin failed to develop HF and adverse remodeling.

Conclusions—These results demonstrate for the first time a crucial role of CD4+ T cells and specific antigen recognition in the progression from compensated cardiac hypertrophy to HF.

  • heart failure
  • lymphocytes
  • ventricular remodeling
  • Received March 25, 2013.
  • Accepted March 14, 2014.
  • © 2014 American Heart Association, Inc.

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May 27, 2014, Volume 129, Issue 21
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    CD4+ T Cells Promote the Transition From Hypertrophy to Heart Failure During Chronic Pressure OverloadCLINICAL PERSPECTIVE
    Fanny Laroumanie, Victorine Douin-Echinard, Joffrey Pozzo, Olivier Lairez, Florence Tortosa, Claire Vinel, Christine Delage, Denis Calise, Marianne Dutaur, Angelo Parini and Nathalie Pizzinat
    Circulation. 2014;129:2111-2124, originally published March 21, 2014
    https://doi.org/10.1161/CIRCULATIONAHA.113.007101

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    CD4+ T Cells Promote the Transition From Hypertrophy to Heart Failure During Chronic Pressure OverloadCLINICAL PERSPECTIVE
    Fanny Laroumanie, Victorine Douin-Echinard, Joffrey Pozzo, Olivier Lairez, Florence Tortosa, Claire Vinel, Christine Delage, Denis Calise, Marianne Dutaur, Angelo Parini and Nathalie Pizzinat
    Circulation. 2014;129:2111-2124, originally published March 21, 2014
    https://doi.org/10.1161/CIRCULATIONAHA.113.007101
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