title: Activation of lymphocyte autophagy/apoptosis reflects haemodynamic inefficiency and functional aerobic impairment in patients with heart failure.
abstract: Lymphocytopenia is associated with an adverse prognosis in heart failure (HF). The present study investigated whether lymphocytopenia results from activated lymphocyte autophagy/apoptosis, which reflects haemodynamic inefficiency and functional aerobic impairment in patients with HF. One hundred and twenty-seven patients with HF were divided into three groups: HF with non- (lymphocytes ≥2000 cells/μl; n=45), mild (lymphocytes between ≥1500 cells/μl and <2000 cells/μl; n=39) and severe (lymphocytes <1500 cells/μl; n=43) lymphocytopenia. Lymphocyte autophagy/apoptosis, ventilatory/haemodynamic efficiencies and generic/disease-specific quality of life were analysed in these patients with HF and 35 normal counterparts. The results demonstrated that patients with HF with severe lymphocytopenia had (i) increased G-protein-coupled receptor kinase-2 (GRK-2) levels, (ii) lower mammalian target of rapamycin (mTOR) levels with higher lysosome-associated membrane protein-2 (LAMP-2) expression and Acridine Orange (AO) staining, (iii) lower mitochondrial transmembrane potential with higher caspase-3 activation and phosphatidylserine (PS) exposure, and (iv) greater extents of adrenaline (epinephrine)-induced apoptosis in lymphocytes, and higher plasma noradrenaline (norepinephrine)/adrenaline, myeloperoxidase and interleukin-6 concentrations than patients with HF without lymphocytopenia and normal counterparts did. Moreover, lymphocyte caspase-3 activation was an effect modifier, which modulated the correlation status between lymphocyte count and GRK-2 level. Lymphocyte count was positively correlated with peak cardiac output and peak oxygen consumption (VO2peak) in patients with HF. In addition, HF with lymphocytopenia was accompanied by lower Short Form-36 physical/mental component scores and increased Minnesota Living with Heart Failure Questionnaire scores. Therefore, we conclude that increased sympathetic activation and oxidative stress/pro-inflammatory status cause lymphocytopenia by activating programmed lymphocyte death in patients with HF. Moreover, a low lymphocyte count correlates with reduced haemodynamics and aerobic capacity, which reflects poor generic/disease-specific quality of life in patients with HF.
authors.affiliation: *Healthy Aging Research Center, Graduate Institute of Rehabilitation Science, Medical Collage, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Tzu-Pin
authors.initials: TP
authors.lastname: Weng
authors.affiliation: †Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Keelung, Taiwan.
authors.forename: Tieh-Cheng
authors.initials: TC
authors.lastname: Fu
authors.affiliation: ‡Heart Failure Center, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan.
authors.forename: Chao-Hung
authors.initials: CH
authors.lastname: Wang
authors.affiliation: †Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Keelung, Taiwan.
authors.forename: Chih-Chin
authors.initials: CC
authors.lastname: Hsu
authors.forename: Jong-Shyan
authors.initials: JS
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy / Q000502:physiology*; D002395:Catecholamines / Q000097:blood; D016207:Cytokines / Q000097:blood; D004921:Erythropoietin / Q000097:blood; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000097:blood; D006333:Heart Failure / Q000097:blood / Q000503:physiopathology*; D006439:Hemodynamics / Q000502:physiology*; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism / Q000502:physiology*; D008231:Lymphopenia / Q000097:blood / Q000503:physiopathology; D052119:Lysosomal-Associated Membrane Protein 2 / Q000097:blood; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008875:Middle Aged; D010101:Oxygen Consumption / Q000502:physiology*; D010545:Peroxides / Q000097:blood; D011788:Quality of Life; D012044:Regression Analysis; D011795:Surveys and Questionnaires; D058570:TOR Serine-Threonine Kinases / Q000097:blood
chemical_list: D002395:Catecholamines; D016207:Cytokines; C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; D010545:Peroxides; D004921:Erythropoietin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2