TY - JOUR

T1 - Structural and functional cardiac profile after prolonged duration of mechanical unloading

T2 - potential implications for myocardial recovery

AU - Castillero, Estibaliz

AU - Ali, Ziad A.

AU - Akashi, Hirokazu

AU - Giangreco, Nicholas

AU - Wang, Catherine

AU - Stöhr, Eric J.

AU - Ji, Ruping

AU - Zhang, Xiaokan

AU - Kheysin, Nathaniel

AU - Park, Joo Eun S.

AU - Hegde, Sheetal

AU - Patel, Sanatkumar

AU - Stein, Samantha

AU - Cuenca, Carlos

AU - Leung, Diana

AU - Homma, Shunichi

AU - Tatonetti, Nicholas P.

AU - Topkara, Veli K.

AU - Takeda, Koji

AU - Colombo, Paolo C.

AU - Naka, Yoshifumi

AU - Sweeney, H. Lee

AU - Schulze, P. Christian

AU - George, Isaac

N1 - Funding Information: This work was supported by the National Center for Advancing Translational Sciences (Grant UL1-TR-000040), formerly the National Center for Research Resources (RR-024156) (to I. George). E. J. Stöhr received funding from the European Union’s Horizon 2020 Research and Innovation Program under Marie Skłodowska-Curie Grant Agreement 705219. Funding Information: P. C. Colombo is a recipient of a research grant from Abbott; he also serves as a consultant (with no honoraria) for the same company. None of the other authors has any conflicts of interest, financial or otherwise, to disclose. Funding Information: This work was supported by the National Center for Advancing Translational Sciences (Grant UL1-TR-000040), formerly the National Center for Research Resources (RR-024156) (to I. George). E. J. St?hr received funding from the European Union's Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie Grant Agreement 705219.

PY - 2018/11

Y1 - 2018/11

N2 - Clinical and experimental studies have suggested that the duration of left ventricular assist device (LVAD) support may affect remodeling of the failing heart. We aimed to 1) characterize the changes in Ca2+/calmodulin-dependent protein kinase type-IIδ (CaMKIIδ), growth signaling, structural proteins, fibrosis, apoptosis, and gene expression before and after LVAD support and 2) assess whether the duration of support correlated with improvement or worsening of reverse remodeling. Left ventricular apex tissue and serum pairs were collected in patients with dilated cardiomyopathy (n = 25, 23 men and 2 women) at LVAD implantation and after LVAD support at cardiac transplantation/LVAD explantation. Normal cardiac tissue was obtained from healthy hearts (n = 4) and normal serum from age-matched control hearts (n = 4). The duration of LVAD support ranged from 48 to 1,170 days (median duration: 270 days). LVAD support was associated with CaMKIIδ activation, increased nuclear myocyte enhancer factor 2, sustained histone deacetylase- 4 phosphorylation, increased circulating and cardiac myostatin (MSTN) and MSTN signaling mediated by SMAD2, ongoing structural protein dysregulation and sustained fibrosis and apoptosis (all P < 0.05). Increased CaMKIIδ phosphorylation, nuclear myocyte enhancer factor 2, and cardiac MSTN significantly correlated with the duration of support. Phosphorylation of SMAD2 and apoptosis decreased with a shorter duration of LVAD support but increased with a longer duration of LVAD support. Further study is needed to define the optimal duration of LVAD support in patients with dilated cardiomyopathy. NEW & NOTEWORTHY A long duration of left ventricular assist device support may be detrimental for myocardial recovery, based on myocardial tissue experiments in patients with prolonged support showing significantly worsened activation of Ca2+/calmodulin-dependent protein kinase-IIδ, increased nuclear myocyte enhancer factor 2, increased myostatin and its signaling by SMAD2, and apoptosis as well as sustained histone deacetylase-4 phosphorylation, structural protein dysregulation, and fibrosis.

AB - Clinical and experimental studies have suggested that the duration of left ventricular assist device (LVAD) support may affect remodeling of the failing heart. We aimed to 1) characterize the changes in Ca2+/calmodulin-dependent protein kinase type-IIδ (CaMKIIδ), growth signaling, structural proteins, fibrosis, apoptosis, and gene expression before and after LVAD support and 2) assess whether the duration of support correlated with improvement or worsening of reverse remodeling. Left ventricular apex tissue and serum pairs were collected in patients with dilated cardiomyopathy (n = 25, 23 men and 2 women) at LVAD implantation and after LVAD support at cardiac transplantation/LVAD explantation. Normal cardiac tissue was obtained from healthy hearts (n = 4) and normal serum from age-matched control hearts (n = 4). The duration of LVAD support ranged from 48 to 1,170 days (median duration: 270 days). LVAD support was associated with CaMKIIδ activation, increased nuclear myocyte enhancer factor 2, sustained histone deacetylase- 4 phosphorylation, increased circulating and cardiac myostatin (MSTN) and MSTN signaling mediated by SMAD2, ongoing structural protein dysregulation and sustained fibrosis and apoptosis (all P < 0.05). Increased CaMKIIδ phosphorylation, nuclear myocyte enhancer factor 2, and cardiac MSTN significantly correlated with the duration of support. Phosphorylation of SMAD2 and apoptosis decreased with a shorter duration of LVAD support but increased with a longer duration of LVAD support. Further study is needed to define the optimal duration of LVAD support in patients with dilated cardiomyopathy. NEW & NOTEWORTHY A long duration of left ventricular assist device support may be detrimental for myocardial recovery, based on myocardial tissue experiments in patients with prolonged support showing significantly worsened activation of Ca2+/calmodulin-dependent protein kinase-IIδ, increased nuclear myocyte enhancer factor 2, increased myostatin and its signaling by SMAD2, and apoptosis as well as sustained histone deacetylase-4 phosphorylation, structural protein dysregulation, and fibrosis.

KW - Heart failure

KW - Left ventricular assist device

KW - Mechanical support

KW - Reverse remodeling

UR - http://www.scopus.com/inward/record.url?scp=85060163239&partnerID=8YFLogxK

U2 - 10.1152/AJPHEART.00187.2018

DO - 10.1152/AJPHEART.00187.2018

M3 - Article

C2 - 30141986

AN - SCOPUS:85060163239

VL - 315

SP - H1463-H1476

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 5

ER -