Intermittent hypoxia induces early functional cardiovascular remodeling in mice.
BACKGROUND
Intermittent hypoxia, a hallmark of sleep apnea, is a major factor for hypertension and impaired vasoreactivity.


OBJECTIVE
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% Fi(O(2)), 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.


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.
Dematteis
Maurice
M
Laboratoire HP2, Institut Jean Roget, Faculté de Médecine de Grenoble, 38042 Grenoble Cedex 09, France. maurice.dematteis@ujf-grenoble.fr
Julien
Cécile
C
Guillermet
Christiane
C
Sturm
Nathalie
N
Lantuejoul
Sylvie
S
Mallaret
Michel
M
Lévy
Patrick
P
Gozal
Evelyne
E
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D002395:Catecholamines / Q000097:blood; D004195:Disease Models, Animal; D006339:Heart Rate; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D012891:Sleep Apnea Syndromes / Q000503:physiopathology*; D053773:Transforming Growth Factor beta1 / Q000097:blood; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation; D020257:Ventricular Remodeling
D002395:Catecholamines; D053773:Transforming Growth Factor beta1; D000109:Acetylcholine