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Hiroyuki Muranaka
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Right arrow Cardiac - physiology
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J Thorac Cardiovasc Surg 2009;137:465-470
© 2009 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Chronic partial unloading restores β-adrenergic responsiveness and reverses receptor downregulation in failing rat hearts

Jian Wang, MDa, Masaki Tsukashita, MDa,*, Takeshi Nishina, MD, PhDa, Akira Marui, MD, PhDa, Eiji Yoshikawa, MDa, Hiroyuki Muranaka, MDa, Satoshi Matsuoka, MD, PhDb, Tadashi Ikeda, MD, PhDa

a Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
b Department of Physiology and Biophysics, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Received for publication March 6, 2008; revisions received July 15, 2008; accepted for publication August 19, 2008.

* Address for reprints: Masaki Tsukashita, MD, Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan. (Email: mtsuka{at}kuhp.kyoto-u.ac.jp).

Objectives: Mechanical unloading with a left ventricular assist device promotes "reverse remodeling," including restoration of β-adrenergic receptor signaling and function. We compared the effects of partial unloading and complete unloading on β-adrenergic responsiveness and gene expressions in failing rat hearts by use of heterotopic heart–lung or heart transplantation models.

Methods: Four weeks after ligation of the left anterior descending artery in Lewis rats, rats with heart failure were divided into 3 groups: infarcted hearts and lungs transplanted into the recipient rats (heart failure–partial unloading, n = 8); infarcted hearts transplanted into the recipient rats (heart failure–complete unloading, n = 7); infarcted (heart failure, n = 8) hearts without transplantation. Normal rats (n = 7) were used as controls. Papillary muscle function and gene expressions were studied at 2 or 4 weeks after transplantation.

Results: In 2-week models, baseline developed tension of papillary muscles significantly increased in heart failure–partial unloading and heart failure–complete unloading compared with heart failure (0.15 ± 0.07 and 0.12 ± 0.05 g/mm2 vs 0.02 ± 0.01 g/mm2, P < .05). However, in 4-week models, they decreased to 0.11 ± 0.03 and 0.10 ± 0.03 g/mm2. In 4-week but not in 2-week models, the increase from baseline in baseline developed tension produced by β-adrenergic stimulation (isoproterenol, 10–8 and 10–7 mol/L) was significantly increased in heart failure–partial unloading compared with heart failure–complete unloading and heart failure (P < .05). The mRNA expressions of brain natriuretic peptide and β1- and β2-adrenergic receptors were normalized in both 2- and 4-week models of heart failure–partial unloading.

Conclusions: Chronic partial unloading but not complete unloading improved β-adrenergic responsiveness and normalized brain natriuretic peptide and β1- and β2-adrenergic receptor mRNA expressions in the failing rat hearts.

Abbreviations and Acronyms ANOVA = analysis of variance; AR = adrenergic receptor; BNP = brain natriuretic peptide; DT = development tension; FAC = fractional area change; GAPDH = glyceraldehyde 3-phosphate dehydrogenase; HF = heart failure; HF-CU = heart failure–complete unloading; HF-PU = heart failure–partial unloading; LAD = left anterior descending; LV = left ventricular; LVAD = left ventricular assist device; LVDd = left ventricular end-diastolic dimension; LVEDA = left ventricular end-diastolic area; LVESA = left ventricular end-systolic area; MI = myocardial infarction; PCR = polymerase chain reaction; SERCA2a = sarco(endo)plasmic reticulum Ca2+-ATPase2a






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