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Original Article

Circulating Dipeptidyl Peptidase IV Activity Correlates With Cardiac Dysfunction in Human and Experimental Heart FailureClinical Perspective

Leonardo dos Santos, Thiago A. Salles, Daniel F. Arruda-Junior, Luciene C.G. Campos, Alexandre C. Pereira, Ana Luiza T. Barreto, Ednei L. Antonio, Alfredo J. Mansur, Paulo J.F. Tucci, José E. Krieger, Adriana C.C. Girardi
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https://doi.org/10.1161/CIRCHEARTFAILURE.112.000057
Circulation: Heart Failure. 2013;6:1029-1038
Originally published September 17, 2013
Leonardo dos Santos
From the Heart Institute (InCor), University of São Paulo Medical School, Brazil (L.d.S., T.A.S., D.F.A.-J., L.C.G.C., A.C.P., A.L.T.B., A.J.M., J.E.K., A.C.C.G.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Brazil (L.d.S.); and Department of Physiology, Federal University of São Paulo University of São Paulo, Brazil (E.L.A., P.J.F.T.).
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Thiago A. Salles
From the Heart Institute (InCor), University of São Paulo Medical School, Brazil (L.d.S., T.A.S., D.F.A.-J., L.C.G.C., A.C.P., A.L.T.B., A.J.M., J.E.K., A.C.C.G.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Brazil (L.d.S.); and Department of Physiology, Federal University of São Paulo University of São Paulo, Brazil (E.L.A., P.J.F.T.).
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Daniel F. Arruda-Junior
From the Heart Institute (InCor), University of São Paulo Medical School, Brazil (L.d.S., T.A.S., D.F.A.-J., L.C.G.C., A.C.P., A.L.T.B., A.J.M., J.E.K., A.C.C.G.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Brazil (L.d.S.); and Department of Physiology, Federal University of São Paulo University of São Paulo, Brazil (E.L.A., P.J.F.T.).
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Luciene C.G. Campos
From the Heart Institute (InCor), University of São Paulo Medical School, Brazil (L.d.S., T.A.S., D.F.A.-J., L.C.G.C., A.C.P., A.L.T.B., A.J.M., J.E.K., A.C.C.G.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Brazil (L.d.S.); and Department of Physiology, Federal University of São Paulo University of São Paulo, Brazil (E.L.A., P.J.F.T.).
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Alexandre C. Pereira
From the Heart Institute (InCor), University of São Paulo Medical School, Brazil (L.d.S., T.A.S., D.F.A.-J., L.C.G.C., A.C.P., A.L.T.B., A.J.M., J.E.K., A.C.C.G.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Brazil (L.d.S.); and Department of Physiology, Federal University of São Paulo University of São Paulo, Brazil (E.L.A., P.J.F.T.).
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Ana Luiza T. Barreto
From the Heart Institute (InCor), University of São Paulo Medical School, Brazil (L.d.S., T.A.S., D.F.A.-J., L.C.G.C., A.C.P., A.L.T.B., A.J.M., J.E.K., A.C.C.G.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Brazil (L.d.S.); and Department of Physiology, Federal University of São Paulo University of São Paulo, Brazil (E.L.A., P.J.F.T.).
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Ednei L. Antonio
From the Heart Institute (InCor), University of São Paulo Medical School, Brazil (L.d.S., T.A.S., D.F.A.-J., L.C.G.C., A.C.P., A.L.T.B., A.J.M., J.E.K., A.C.C.G.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Brazil (L.d.S.); and Department of Physiology, Federal University of São Paulo University of São Paulo, Brazil (E.L.A., P.J.F.T.).
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Alfredo J. Mansur
From the Heart Institute (InCor), University of São Paulo Medical School, Brazil (L.d.S., T.A.S., D.F.A.-J., L.C.G.C., A.C.P., A.L.T.B., A.J.M., J.E.K., A.C.C.G.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Brazil (L.d.S.); and Department of Physiology, Federal University of São Paulo University of São Paulo, Brazil (E.L.A., P.J.F.T.).
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Paulo J.F. Tucci
From the Heart Institute (InCor), University of São Paulo Medical School, Brazil (L.d.S., T.A.S., D.F.A.-J., L.C.G.C., A.C.P., A.L.T.B., A.J.M., J.E.K., A.C.C.G.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Brazil (L.d.S.); and Department of Physiology, Federal University of São Paulo University of São Paulo, Brazil (E.L.A., P.J.F.T.).
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José E. Krieger
From the Heart Institute (InCor), University of São Paulo Medical School, Brazil (L.d.S., T.A.S., D.F.A.-J., L.C.G.C., A.C.P., A.L.T.B., A.J.M., J.E.K., A.C.C.G.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Brazil (L.d.S.); and Department of Physiology, Federal University of São Paulo University of São Paulo, Brazil (E.L.A., P.J.F.T.).
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Adriana C.C. Girardi
From the Heart Institute (InCor), University of São Paulo Medical School, Brazil (L.d.S., T.A.S., D.F.A.-J., L.C.G.C., A.C.P., A.L.T.B., A.J.M., J.E.K., A.C.C.G.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Brazil (L.d.S.); and Department of Physiology, Federal University of São Paulo University of São Paulo, Brazil (E.L.A., P.J.F.T.).
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Abstract

Background—The present study addresses the hypothesis that the activity of dipeptidyl peptidase IV (DPPIV), an enzyme that inactivates peptides that possess cardioprotective actions, correlates with adverse outcomes in heart failure (HF). The therapeutic potential of DPPIV inhibition in preventing cardiac dysfunction is also investigated.

Methods and Results—Measurements of DPPIV activity in blood samples obtained from 190 patients with HF and 42 controls demonstrated that patients with HF exhibited an increase of ≈130% in circulating DPPIV activity compared with healthy subjects. Furthermore, an inverse correlation was observed between serum DPPIV activity and left ventricular (LV) ejection fraction in patients with HF. Similarly, radiofrequency LV ablation-induced HF rats displayed higher DPPIV activity in the plasma (≈50%) and heart tissue (≈3.5-fold) compared with sham-operated rats. Moreover, positive correlations were observed between the plasma DPPIV activity and LV end-diastolic pressure and lung congestion. Two days after surgery, 1 group of LV ablation-induced HF rats was treated with the DPPIV inhibitor sitagliptin (40 mg/kg BID) for 6 weeks, whereas the remaining rats were administered water. Hemodynamic measurements demonstrated that radiofrequency LV-ablated rats treated with sitagliptin exhibited a significant attenuation of HF-related cardiac dysfunction, including LV end-diastolic pressure, systolic performance, and chamber stiffness. Sitagliptin treatment also attenuated cardiac remodeling and cardiomyocyte apoptosis and minimized pulmonary congestion.

Conclusions—Collectively, the results presented herein associate circulating DPPIV activity with poorer cardiovascular outcomes in human and experimental HF. Moreover, the results demonstrate that long-term DPPIV inhibition mitigates the development and progression of HF in rats.

  • dipeptidyl peptidase IV inhibitors
  • glucagon-like peptide 1
  • ventricular remodeling
  • water-electrolyte balance
  • Received July 25, 2012.
  • Accepted July 18, 2013.
  • © 2013 American Heart Association, Inc.
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Circulation: Heart Failure
September 2013, Volume 6, Issue 5
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    Circulating Dipeptidyl Peptidase IV Activity Correlates With Cardiac Dysfunction in Human and Experimental Heart FailureClinical Perspective
    Leonardo dos Santos, Thiago A. Salles, Daniel F. Arruda-Junior, Luciene C.G. Campos, Alexandre C. Pereira, Ana Luiza T. Barreto, Ednei L. Antonio, Alfredo J. Mansur, Paulo J.F. Tucci, José E. Krieger and Adriana C.C. Girardi
    Circulation: Heart Failure. 2013;6:1029-1038, originally published September 17, 2013
    https://doi.org/10.1161/CIRCHEARTFAILURE.112.000057

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    Circulating Dipeptidyl Peptidase IV Activity Correlates With Cardiac Dysfunction in Human and Experimental Heart FailureClinical Perspective
    Leonardo dos Santos, Thiago A. Salles, Daniel F. Arruda-Junior, Luciene C.G. Campos, Alexandre C. Pereira, Ana Luiza T. Barreto, Ednei L. Antonio, Alfredo J. Mansur, Paulo J.F. Tucci, José E. Krieger and Adriana C.C. Girardi
    Circulation: Heart Failure. 2013;6:1029-1038, originally published September 17, 2013
    https://doi.org/10.1161/CIRCHEARTFAILURE.112.000057
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