Author + information
- Received July 9, 2010
- Revision received November 15, 2010
- Accepted November 18, 2010
- Published online May 17, 2011.
- Tami A. Martino, PhD*,
- Nazneen Tata, MSc, MBBChBAO‡,§,
- Jeremy A. Simpson, PhD†,
- Rachel Vanderlaan, BSc§,
- Fayez Dawood, DVM∥,
- M. Golam Kabir, MD§,
- Neelam Khaper, PhD¶,
- Carlo Cifelli, MSc‡,
- Peter Podobed, BSc*,
- Peter P. Liu, MD‡,§∥,
- Mansoor Husain, MD‡,§∥,
- Scott Heximer, PhD‡,§,
- Peter H. Backx, DVM, PhD‡,§∥ and
- Michael J. Sole, MD‡,§∥,* ()
- ↵*Reprint requests and correspondence:
Dr. Michael J. Sole, 4N-488 Toronto General Hospital, 585 University Avenue, Toronto, Ontario M5G 2N2, Canada
Objectives Our objective was to test the hypothesis that there is a significant diurnal variation for the therapeutic benefit of angiotensin-converting enzyme (ACE) inhibitors on pressure-overload cardiovascular hypertrophy.
Background Physiological and molecular processes exhibit diurnal rhythms that may affect efficacy of disease treatment (chronotherapy). Evidence suggests that the heart primarily remodels during sleep. Although a growing body of clinical and epidemiological evidence suggests that the timing of therapy, such as ACE inhibition, alters diurnal blood pressure patterns in patients with hypertension, the benefits of chronotherapy on myocardial and vascular remodeling have not been studied.
Methods We examined the effects of the short-acting ACE inhibitor, captopril, on the structure and function of cardiovascular tissue subjected to pressure overload by transverse aortic constriction (TAC) in mice. Captopril (15 mg/kg intraperitoneally) or placebo was administered at either murine sleep time or wake time for 8 weeks starting 1 week after surgery.
Results TAC mice given captopril at sleep time had improved cardiac function and significantly decreased heart: body weight ratios, myocyte cross-sectional areas, intramyocardial vascular medial wall thickness, and perivascular collagen versus TAC mice given captopril or placebo during wake time. Captopril induced similar drops in blood pressure at sleep or wake time, suggesting that time-of-day differences were not attributable to blood pressure changes. These beneficial effects of captopril were correlated with diurnal changes in ACE mRNA expression in the heart.
Conclusions The ACE inhibitor captopril benefited cardiovascular remodeling only when administered during sleep; wake-time captopril ACE inhibition was identical to that of placebo. These studies support the hypothesis that the heart (and vessels) remodel during sleep time and also illustrate the importance of diurnal timing for some cardiovascular therapies.
Supported by grants from Heart and Stroke Foundation of Ontario (485506, Dr. Martino), (T4479, Dr. Sole), and the A. Ephriam and Shirley Diamond Cardiomyopathy Fund (Dr. Sole). All other authors have reported that they have no relationships to disclose. Drs. Martino and Tata contributed equally to this work.
- Received July 9, 2010.
- Revision received November 15, 2010.
- Accepted November 18, 2010.
- American College of Cardiology Foundation