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Left ventricular dysfunction and associated cellular injury in rats exposed to chronic intermittent hypoxia

¹Division of Pulmonary and Critical Care Medicine and ²Department of Physiology, University of Maryland, Baltimore, Maryland; ³Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada; and Departments of ⁴Internal Medicine and ⁵Physiology, University of Kentucky College of Medicine, Lexington, Kentucky

Submitted 16 March 2007 ; accepted in final form 5 November 2007

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 O₂ 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·min^–1·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 µm², P < 0.05) and cell length (CIH 148 ± 23 vs. HC 115 ± 16 µm, 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·min^–1·mg^–1, P < 0.05), and elevated expression of several remodeling gene markers, including c-fos, atrial natriuretic peptide, β-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.

obstructive sleep apnea; cardiac hypertrophy; apoptosis