Human Induced Pluripotent Stem Cell–Derived Cardiomyocyte Patch in Rats With Heart Failure

Jordan J. Lancaster, Pablo Sanchez, Giuliana G. Repetti, Elizabeth B Juneman, Amitabh C. Pandey, Ikeotunye R. Chinyere, Talal Moukabary, Nicole LaHood, Sherry L. Daugherty, Steven Goldman

Research output: Contribution to journalArticle

Abstract

Background: To treat chronic heart failure (CHF), we developed a robust, easy to handle bioabsorbable tissue-engineered patch embedded with human neonatal fibroblasts and human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs). This patch was implanted on the epicardial surface of the heart covering the previously infarcted tissue. Methods: Sprague-Dawley rats (6-8 weeks old) underwent sham surgery (n = 12) or left coronary artery ligation (n = 45). CHF rats were randomized 3 weeks after ligation to CHF control with sham thoracotomy (n = 21), or a fibroblasts/hiPSC-CMs patch (n = 24) was implanted. All sham surgery rats also underwent a sham thoracotomy. At 3 weeks after randomization, hemodynamics, echocardiography, electrophysiologic, and cell survival studies were performed. Results: Patch-treated rats had decreased (P <.05) left ventricular-end diastolic pressure and the time constant of left ventricular relaxation (Tau), increased anterior wall thickness in diastole, and improved echocardiography-derived indices of diastolic function (E/e’ [ratio of early peak flow velocity to early peak LV velocity] and e’/a’ [ratio of early to late peak left ventricular velocity]). All rats remained in normal sinus rhythm, with no dysrhythmias. Rats treated with the patch showed improved electrical activity. Transplanted hiPSC-CMs were present at 7 days but not detected at 21 days after implantation. The patch increased (P <.05) gene expression of vascular endothelial growth factor, angiopoietin 1, gap junction α-1 protein (connexin 43), β-myosin heavy 7, and insulin growth factor-1 expression in the infarcted heart. Conclusions: Epicardial implantation of a fibroblasts/hiPSC-CMs patch electrically enhanced conduction, lowered left ventricular end-diastolic pressure, and improved diastolic function in rats with CHF. These changes were associated with increases in cytokine expression.

Original languageEnglish (US)
JournalAnnals of Thoracic Surgery
DOIs
StateAccepted/In press - Jan 1 2019

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Cardiac Myocytes
Heart Failure
Fibroblasts
Thoracotomy
Ligation
Echocardiography
Angiopoietin-1
Blood Pressure
Connexin 43
Connexins
Diastole
Myosins
Random Allocation
Vascular Endothelial Growth Factor A
Sprague Dawley Rats
Cell Survival
Intercellular Signaling Peptides and Proteins
Coronary Vessels
Hemodynamics
Insulin

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

Human Induced Pluripotent Stem Cell–Derived Cardiomyocyte Patch in Rats With Heart Failure. / Lancaster, Jordan J.; Sanchez, Pablo; Repetti, Giuliana G.; Juneman, Elizabeth B; Pandey, Amitabh C.; Chinyere, Ikeotunye R.; Moukabary, Talal; LaHood, Nicole; Daugherty, Sherry L.; Goldman, Steven.

In: Annals of Thoracic Surgery, 01.01.2019.

Research output: Contribution to journalArticle

Lancaster, Jordan J. ; Sanchez, Pablo ; Repetti, Giuliana G. ; Juneman, Elizabeth B ; Pandey, Amitabh C. ; Chinyere, Ikeotunye R. ; Moukabary, Talal ; LaHood, Nicole ; Daugherty, Sherry L. ; Goldman, Steven. / Human Induced Pluripotent Stem Cell–Derived Cardiomyocyte Patch in Rats With Heart Failure. In: Annals of Thoracic Surgery. 2019.
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abstract = "Background: To treat chronic heart failure (CHF), we developed a robust, easy to handle bioabsorbable tissue-engineered patch embedded with human neonatal fibroblasts and human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs). This patch was implanted on the epicardial surface of the heart covering the previously infarcted tissue. Methods: Sprague-Dawley rats (6-8 weeks old) underwent sham surgery (n = 12) or left coronary artery ligation (n = 45). CHF rats were randomized 3 weeks after ligation to CHF control with sham thoracotomy (n = 21), or a fibroblasts/hiPSC-CMs patch (n = 24) was implanted. All sham surgery rats also underwent a sham thoracotomy. At 3 weeks after randomization, hemodynamics, echocardiography, electrophysiologic, and cell survival studies were performed. Results: Patch-treated rats had decreased (P <.05) left ventricular-end diastolic pressure and the time constant of left ventricular relaxation (Tau), increased anterior wall thickness in diastole, and improved echocardiography-derived indices of diastolic function (E/e’ [ratio of early peak flow velocity to early peak LV velocity] and e’/a’ [ratio of early to late peak left ventricular velocity]). All rats remained in normal sinus rhythm, with no dysrhythmias. Rats treated with the patch showed improved electrical activity. Transplanted hiPSC-CMs were present at 7 days but not detected at 21 days after implantation. The patch increased (P <.05) gene expression of vascular endothelial growth factor, angiopoietin 1, gap junction α-1 protein (connexin 43), β-myosin heavy 7, and insulin growth factor-1 expression in the infarcted heart. Conclusions: Epicardial implantation of a fibroblasts/hiPSC-CMs patch electrically enhanced conduction, lowered left ventricular end-diastolic pressure, and improved diastolic function in rats with CHF. These changes were associated with increases in cytokine expression.",
author = "Lancaster, {Jordan J.} and Pablo Sanchez and Repetti, {Giuliana G.} and Juneman, {Elizabeth B} and Pandey, {Amitabh C.} and Chinyere, {Ikeotunye R.} and Talal Moukabary and Nicole LaHood and Daugherty, {Sherry L.} and Steven Goldman",
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T1 - Human Induced Pluripotent Stem Cell–Derived Cardiomyocyte Patch in Rats With Heart Failure

AU - Lancaster, Jordan J.

AU - Sanchez, Pablo

AU - Repetti, Giuliana G.

AU - Juneman, Elizabeth B

AU - Pandey, Amitabh C.

AU - Chinyere, Ikeotunye R.

AU - Moukabary, Talal

AU - LaHood, Nicole

AU - Daugherty, Sherry L.

AU - Goldman, Steven

PY - 2019/1/1

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N2 - Background: To treat chronic heart failure (CHF), we developed a robust, easy to handle bioabsorbable tissue-engineered patch embedded with human neonatal fibroblasts and human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs). This patch was implanted on the epicardial surface of the heart covering the previously infarcted tissue. Methods: Sprague-Dawley rats (6-8 weeks old) underwent sham surgery (n = 12) or left coronary artery ligation (n = 45). CHF rats were randomized 3 weeks after ligation to CHF control with sham thoracotomy (n = 21), or a fibroblasts/hiPSC-CMs patch (n = 24) was implanted. All sham surgery rats also underwent a sham thoracotomy. At 3 weeks after randomization, hemodynamics, echocardiography, electrophysiologic, and cell survival studies were performed. Results: Patch-treated rats had decreased (P <.05) left ventricular-end diastolic pressure and the time constant of left ventricular relaxation (Tau), increased anterior wall thickness in diastole, and improved echocardiography-derived indices of diastolic function (E/e’ [ratio of early peak flow velocity to early peak LV velocity] and e’/a’ [ratio of early to late peak left ventricular velocity]). All rats remained in normal sinus rhythm, with no dysrhythmias. Rats treated with the patch showed improved electrical activity. Transplanted hiPSC-CMs were present at 7 days but not detected at 21 days after implantation. The patch increased (P <.05) gene expression of vascular endothelial growth factor, angiopoietin 1, gap junction α-1 protein (connexin 43), β-myosin heavy 7, and insulin growth factor-1 expression in the infarcted heart. Conclusions: Epicardial implantation of a fibroblasts/hiPSC-CMs patch electrically enhanced conduction, lowered left ventricular end-diastolic pressure, and improved diastolic function in rats with CHF. These changes were associated with increases in cytokine expression.

AB - Background: To treat chronic heart failure (CHF), we developed a robust, easy to handle bioabsorbable tissue-engineered patch embedded with human neonatal fibroblasts and human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs). This patch was implanted on the epicardial surface of the heart covering the previously infarcted tissue. Methods: Sprague-Dawley rats (6-8 weeks old) underwent sham surgery (n = 12) or left coronary artery ligation (n = 45). CHF rats were randomized 3 weeks after ligation to CHF control with sham thoracotomy (n = 21), or a fibroblasts/hiPSC-CMs patch (n = 24) was implanted. All sham surgery rats also underwent a sham thoracotomy. At 3 weeks after randomization, hemodynamics, echocardiography, electrophysiologic, and cell survival studies were performed. Results: Patch-treated rats had decreased (P <.05) left ventricular-end diastolic pressure and the time constant of left ventricular relaxation (Tau), increased anterior wall thickness in diastole, and improved echocardiography-derived indices of diastolic function (E/e’ [ratio of early peak flow velocity to early peak LV velocity] and e’/a’ [ratio of early to late peak left ventricular velocity]). All rats remained in normal sinus rhythm, with no dysrhythmias. Rats treated with the patch showed improved electrical activity. Transplanted hiPSC-CMs were present at 7 days but not detected at 21 days after implantation. The patch increased (P <.05) gene expression of vascular endothelial growth factor, angiopoietin 1, gap junction α-1 protein (connexin 43), β-myosin heavy 7, and insulin growth factor-1 expression in the infarcted heart. Conclusions: Epicardial implantation of a fibroblasts/hiPSC-CMs patch electrically enhanced conduction, lowered left ventricular end-diastolic pressure, and improved diastolic function in rats with CHF. These changes were associated with increases in cytokine expression.

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