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Published ahead of print on October 25, 2007, doi:10.1164/rccm.200702-238OC

Am. J. Respir. Crit. Care Med., Volume 177, Number 2, January 2008, 227-235

A more recent version of this article appeared on January 15, 2008
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Submitted on February 12, 2007
Accepted on October 25, 2007

Intermittent Hypoxia Induces Early Functional Cardiovascular Remodeling in Mice

Maurice Dematteis1*, Cecile Julien2, Christiane Guillermet3, Nathalie Sturm3, Sylvie Lantuejoul4, Michel Mallaret5, Patrick Levy1, and Evelyne Gozal6

1 INSERM ERI17, Grenoble, France; Faculte de Medecine, Universite Joseph Fourier, Grenoble 1, IFR1, Grenoble, France; Laboratoires du Sommeil et EFCR, CHU, Hopital A. Michallon, Grenoble, France, 2 INSERM ERI17, Grenoble, France; Faculte de Medecine, Universite Joseph Fourier, Grenoble 1, IFR1, Grenoble, France; Laboratoire de Pharmacologie - CEIP, CHU, Hopital A. Michallon, Grenoble, France, 3 Departement de Pathologie, CHU, Hopital A. Michallon, Grenoble, France, 4 Departement de Pathologie, CHU, Hopital A. Michallon, Grenoble, France; Institut Albert Bonniot, INSERM U823/UJF, Grenoble, France, 5 Laboratoire de Pharmacologie - CEIP, CHU, Hopital A. Michallon, Grenoble, France, 6 Department of Pediatrics, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA

* To whom correspondence should be addressed. E-mail: maurice.dematteis{at}ujf-grenoble.fr.

Rationale: Intermittent hypoxia, a hallmark of sleep apnea, is a major factor for hypertension and impaired vasoreactivity. Examination of the temporal occurrence of these two outcomes should provide insight into mechanisms and early cardiovascular disease identification. Methods: Functional and structural cardiovascular alterations were assessed in C57BL6 mice exposed to intermittent hypoxia (21-4% FiO2, 30s cycle, 8h/day) or air for up to 35 days. Blood pressure, heart rate and urinary catecholamines were measured at day 1 and 14. Hindquarter vasoreactivity was assessed at day 14 and 35 including vasoconstriction to norepinephrine, endothelium and non-endothelium dependent vasodilation. Aorta, heart and hindquarter skeletal muscles were immunostained for vascular markers, PECAM-1 and collagen IV. Results: Hemodynamic alterations occurred from day 1, characterized by blood pressure surges with bradytachyarrhythmia driven by cyclic hypoxia. At day 14, blood pressure at normoxia was elevated, with predominant diastolic increase. With hypoxia, vasopressive catecholamines were elevated, blood pressure surged with a lower hypoxic threshold while heart rate fluctuations decreased. Histological alterations started from day 14, with decreased endothelial PECAM-1 expression in descending aorta and left heart. Impaired peripheral vasoreactivity occurred at day 35, including hypervasoconstriction to norepinephrine secondary to sympathetic hyperactivity, without changes in pre-postsynaptic alpha-adrenoceptors, endothelium and non-endothelium dependent vasodilation. Conclusion: Intermittent hypoxia induces sequential cardiovascular events suggesting increased chemoreflex and depressed baroreflex, resulting in sympathoadrenal hyperactivity, early hemodynamic alterations with proximal histological remodeling, and delayed changes in peripheral vasoreactivity. Such early alterations before overt cardiovascular disease strengthen the need for identifying at risk individuals for systematic treatment.
Key words: Sleep apnea - Blood pressure - Vasoconstriction - Histopathology




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