TY - JOUR
T1 - Myocardial atrophy and chronic mechanical unloading of the failing human heart
T2 - Implications for cardiac assist device-induced myocardial recovery
AU - Diakos, Nikolaos A.
AU - Selzman, Craig H.
AU - Sachse, Frank B.
AU - Stehlik, Josef
AU - Kfoury, Abdallah G.
AU - Wever-Pinzon, Omar
AU - Catino, Anna
AU - Alharethi, Rami
AU - Reid, Bruce B.
AU - Miller, Dylan V.
AU - Salama, Mohamed
AU - Zaitsev, Alexey V.
AU - Shibayama, Junko
AU - Li, Hui
AU - Fang, James C.
AU - Li, Dean Y.
AU - Drakos, Stavros G.
N1 - Publisher Copyright:
© 2014 American College of Cardiology Foundation.
PY - 2014/10/14
Y1 - 2014/10/14
N2 - Background In animal models of heterotopic transplantation, mechanical unloading of the normal, nonhypertrophic heart results in atrophy. Primarily on the basis of these animal data, the notion that chronic left ventricular assist device (LVAD)-induced unloading will result in atrophy has dominated the clinical heart failure field, and anti-atrophic drugs have been used to enhance the cardiac recovery potential observed in some LVAD patients. However, whether unloading-induced atrophy in experimental normal heart models applies to failing and hypertrophic myocardium in heart failure patients unloaded by continuous-flow LVADs has not been studied.Objectives The study examined whether mechanical unloading by continuous-flow LVAD leads to myocardial atrophy.Methods We prospectively examined myocardial tissue and hemodynamic and echocardiographic data from 44 LVAD patients and 18 untransplanted normal donors.Results Cardiomyocyte size (cross-sectional area) decreased after LVAD unloading from 1,238 ± 81 μm2 to 1,011 ± 68 μm2 (p = 0.001), but not beyond that of normal donor hearts (682 ± 56 μm 2). Electron microscopy ultrastructural evaluation, cardiomyocyte glycogen content, and echocardiographic assessment of myocardial mass and left ventricular function also did not suggest myocardial atrophy. Consistent with these findings, t-tubule morphology, cytoplasmic penetration, and distance from the ryanodine receptor were not indicative of ongoing atrophic remodeling during LVAD unloading. Molecular analysis revealed no up-regulation of proatrophic genes and proteins of the ubiquitin proteasome system.Conclusions Structural, ultrastructural, microstructural, metabolic, molecular, and clinical functional data indicated that prolonged continuous-flow LVAD unloading does not induce hypertrophy regression to the point of atrophy and degeneration. These findings may be useful in designing future investigations that combine LVAD unloading and pharmaceutical therapies as a bridge to recovery of the failing heart.
AB - Background In animal models of heterotopic transplantation, mechanical unloading of the normal, nonhypertrophic heart results in atrophy. Primarily on the basis of these animal data, the notion that chronic left ventricular assist device (LVAD)-induced unloading will result in atrophy has dominated the clinical heart failure field, and anti-atrophic drugs have been used to enhance the cardiac recovery potential observed in some LVAD patients. However, whether unloading-induced atrophy in experimental normal heart models applies to failing and hypertrophic myocardium in heart failure patients unloaded by continuous-flow LVADs has not been studied.Objectives The study examined whether mechanical unloading by continuous-flow LVAD leads to myocardial atrophy.Methods We prospectively examined myocardial tissue and hemodynamic and echocardiographic data from 44 LVAD patients and 18 untransplanted normal donors.Results Cardiomyocyte size (cross-sectional area) decreased after LVAD unloading from 1,238 ± 81 μm2 to 1,011 ± 68 μm2 (p = 0.001), but not beyond that of normal donor hearts (682 ± 56 μm 2). Electron microscopy ultrastructural evaluation, cardiomyocyte glycogen content, and echocardiographic assessment of myocardial mass and left ventricular function also did not suggest myocardial atrophy. Consistent with these findings, t-tubule morphology, cytoplasmic penetration, and distance from the ryanodine receptor were not indicative of ongoing atrophic remodeling during LVAD unloading. Molecular analysis revealed no up-regulation of proatrophic genes and proteins of the ubiquitin proteasome system.Conclusions Structural, ultrastructural, microstructural, metabolic, molecular, and clinical functional data indicated that prolonged continuous-flow LVAD unloading does not induce hypertrophy regression to the point of atrophy and degeneration. These findings may be useful in designing future investigations that combine LVAD unloading and pharmaceutical therapies as a bridge to recovery of the failing heart.
KW - left ventricular assist device
KW - mechanical unloading
KW - myocardial atrophy
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U2 - 10.1016/j.jacc.2014.05.073
DO - 10.1016/j.jacc.2014.05.073
M3 - Article
C2 - 25301465
AN - SCOPUS:84908127009
SN - 0735-1097
VL - 64
SP - 1602
EP - 1612
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 15
ER -