title: Left ventricular dysfunction and associated cellular injury in rats exposed to chronic intermittent hypoxia.
abstract: Obstructive sleep apnea (OSA) increases cardiovascular morbidity and mortality. We have reported that chronic intermittent hypoxia (CIH), a direct consequence during OSA, leads to left ventricular (LV) remodeling and dysfunction in rats. The present study is to determine LV myocardial cellular injury that is possibly associated with LV global dysfunction. Fifty-six rats were exposed either to CIH (nadir O(2) 4-5%) or sham (handled normoxic controls, HC), 8 h/day for 6 wk. At the end of the exposure, we studied LV global function by cardiac catheterization, and LV myocardial cellular injury by in vitro analyses. Compared with HC, CIH animals demonstrated elevations in mean arterial pressure and LV end-diastolic pressure, but reductions in cardiac output (CIH 141.3 +/- 33.1 vs. HC 184.4 +/- 21.2 ml x min(-1) x kg(-1), P < 0.01), maximal rate of LV pressure rise in systole (+dP/dt), and maximal rate of LV pressure fall in diastole (-dP/dt). CIH led to significant cell injury in the left myocardium, including elevated LV myocyte size, measured by cell surface area (CIH 3,564 +/- 354 vs. HC 2,628 +/- 242 microm(2), P < 0.05) and cell length (CIH 148 +/- 23 vs. HC 115 +/- 16 microm, P < 0.05), elevated terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-stained positive cell number (CIH 98 +/- 45 vs. HC 15 +/- 13, P < 0.01), elevated caspase-3 activity (906 +/- 249 vs. 2,275 +/- 1,169 pmol x min(-1) x mg(-1), P < 0.05), and elevated expression of several remodeling gene markers, including c-fos, atrial natriuretic peptide, beta-myosin heavy chain, and myosin light chain-2. However, there was no difference between groups in sarcomere contractility of isolated LV myocytes, or in LV collagen deposition on trichrome-stained slices. In conclusion, CIH-mediated LV global dysfunction is associated with myocyte hypertrophy and apoptosis at the cellular level.
authors.affiliation: Div. of Pulmonary and Critical Care Medicine, Univ. of Maryland, Baltimore, 685 West Baltimore St., MSTF 816, Baltimore, MD 21201, USA. Lchen@medicine.umaryland.edu
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Tracey X
authors.initials: TX
authors.lastname: Gan
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen-Izu
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Hasday
authors.forename: Morris
authors.initials: M
authors.lastname: Karmazyn
authors.forename: C William
authors.initials: CW
authors.lastname: Balke
authors.forename: Steven M
authors.initials: SM
authors.lastname: Scharf
mesh_terms: D000818:Animals; D017209:Apoptosis; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure; D001835:Body Weight; D024722:Cardiac Myosins / Q000235:genetics / Q000378:metabolism; D002302:Cardiac Output; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D053148:Caspase 3 / Q000378:metabolism; D048429:Cell Size; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D006984:Hypertrophy; D000860:Hypoxia / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012107:Research Design; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D017725:Ventricular Pressure; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: C000594638:MYH7 protein, rat; D018994:Myosin Light Chains; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; C107184:myosin light chain 2; D009320:Atrial Natriuretic Factor; D003094:Collagen; D053148:Caspase 3; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains