Disturbed diurnal rhythm alters gene expression and exacerbates cardiovascular disease with rescue by resynchronization.
Day/night rhythms are recognized as important to normal cardiovascular physiology and timing of adverse cardiovascular events; however, their significance in disease has not been determined. We demonstrate that day/night rhythms play a critical role in compensatory remodeling of cardiovascular tissue, and disruption exacerbates disease pathophysiology. We use a murine model of pressure overload cardiac hypertrophy (transverse aortic constriction) in a rhythm-disruptive 20-hour versus 24-hour environment. Echocardiography reveals increased left ventricular end-systolic and -diastolic dimensions and reduced contractility in rhythm-disturbed transverse aortic constriction animals. Furthermore, cardiomyocytes and vascular smooth muscle cells exhibit reduced hypertrophy, despite increased pressure load. Microarray and real-time PCR demonstrate altered gene cycling in transverse aortic constriction myocardium and hypothalamic suprachiasmatic nucleus. With rhythm disturbance, there is a consequent altered cellular clock mechanism (per2 and bmal), whereas key genes in hypertrophic pathways (ANF, BNP, ACE, and collagen) are downregulated paradoxical to the increased pressure. Phenotypic rescue, including reversal/attenuation of abnormal pathology and genes, only occurs when the external rhythm is allowed to correspond with the animals' innate 24-hour internal rhythm. Our study establishes the importance of diurnal rhythm as a vital determinant in heart disease. Disrupted rhythms contribute to progression of organ dysfunction; restoration of normal diurnal schedules appears to be important for effective treatment of disease.
Martino
Tami A
TA
Toronto General Research Institute, Division of Cardiology, University Health Network, Canada.
Tata
Nazneen
N
Belsham
Denise D
DD
Chalmers
Jennifer
J
Straume
Marty
M
Lee
Paul
P
Pribiag
Horia
H
Khaper
Neelam
N
Liu
Peter P
PP
Dawood
Fayez
F
Backx
Peter H
PH
Ralph
Martin R
MR
Sole
Michael J
MJ
D000818:Animals; D001683:Biological Clocks; D001921:Brain / Q000378:metabolism; D006332:Cardiomegaly / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology*; D002940:Circadian Rhythm; D004452:Echocardiography; D015870:Gene Expression; D020869:Gene Expression Profiling; D006973:Hypertension / Q000150:complications*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index; D020257:Ventricular Remodeling