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Published ahead of print on October 25, 2007, doi:10.1164/rccm.200702-238OC
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American Journal of Respiratory and Critical Care Medicine Vol 177. pp. 227-235, (2008)
© 2008 American Thoracic Society
doi: 10.1164/rccm.200702-238OC

Original Article

Intermittent Hypoxia Induces Early Functional Cardiovascular Remodeling in Mice

Maurice Dematteis1,2,3,*, Cécile Julien1,2,4,5,*, Christiane Guillermet6, Nathalie Sturm6, Sylvie Lantuejoul6,7, Michel Mallaret4, Patrick Lévy1,2,3,** and Evelyne Gozal5,8,**

1 INSERM ERI17, Grenoble, France; 2 Faculté de Médecine, IFR1, Université Joseph Fourier, Grenoble, France; 3 Laboratoires du Sommeil et EFCR, and 4 Laboratoire de Pharmacologie–CEIP, CHU, Hôpital A. Michallon, Grenoble, France; 5 Department of Pediatrics, KCHRI, University of Louisville, Louisville, Kentucky; 6 Département de Pathologie, CHU, Hôpital A. Michallon, Grenoble, France; 7 INSERM U823/UJF, Institut Albert Bonniot, Grenoble, France; and 8 Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky

Correspondence and requests for reprints should be addressed to Maurice Dematteis, M.D., Ph.D., Laboratoire HP2, Institut Jean Roget, Faculté de Médecine de Grenoble, 38042 Grenoble Cedex 09, France. 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.

Objectives: To examine the temporal occurrence of these two outcomes in order to 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, 30-s cycle, 8 h/d) or air for up to 35 days. Blood pressure, heart rate, and urinary catecholamines were measured at Days 1 and 14. Hindquarter vasoreactivity was assessed at Days 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.

Measurements and Main 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, whereas heart rate fluctuations decreased. Histologic 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- and postsynaptic {alpha}-adrenoceptors or in endothelium- and non–endothelium-dependent vasodilation.

Conclusions: Intermittent hypoxia induces sequential cardiovascular events suggesting increased chemoreflex and depressed baroreflex, resulting in sympathoadrenal hyperactivity, early hemodynamic alterations with proximal histologic 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


AT A GLANCE COMMENTARY

Current Scientific Knowledge on the Subject
Intermittent hypoxia in sleep apnea is a major factor for hypertension and impaired vasoreactivity. Understanding the development of these outcomes may condition the management of apneic patients at risk for cardiovascular complications.

What This Study Adds to the Field
Intermittent hypoxia induced early functional and histologic cardiovascular remodeling in mice. These results strengthen the need for early identification and treatment of apneic individuals at risk for cardiovascular complications.

 



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