The Primary Benefits of Angiotensin-Converting Enzyme Inhibition on Cardiac Remodeling Occur During Sleep Time in Murine Pressure Overload Hypertrophy
Key result
Sleep-time captopril improves cardiac function and reduces remodeling markers in murine pressure overload.
Why the study?
The benefits of chronotherapy on myocardial and vascular remodeling with ACE inhibition have not been studied despite evidence of diurnal rhythms affecting cardiovascular processes.
Does captopril administered at sleep time improve cardiac remodeling better than when administered at wake time or compared to placebo in mice with pressure overload?
Structured PICO
Does captopril administered at sleep time improve cardiac remodeling better than when administered at wake time or compared to placebo in mice with pressure overload?
P
Population
Mice subjected to pressure overload by transverse aortic constriction (TAC), treated for 8 weeks starting 1 week after surgery.
I
Intervention
Captopril 15 mg/kg administered intraperitoneally at murine sleep time for 8 weeks (starting 1 week after surgery)
C
Comparator
Captopril administered at murine wake time, or placebo
O
Outcome
Cardiac structure and function (including heart:body weight ratios, myocyte cross-sectional areas, intramyocardial vascular medial wall thickness, and perivascular collagen)surrogate
ACE inhibition with captopril in a murine model of pressure overload only attenuated cardiovascular remodeling when administered during sleep time, highlighting the potential importance of chronotherapy.
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“The sleep-time benefit of giving the ACE inhibitor correlates with the biological rhythm of this hormone. By targeting those hormones when they're highest during sleep, you're dropping their levels so they're not doing so much damage.”
“Earlier studies our group has worked on suggest that the heart repairs and renews itself during sleeping hours.”
Implication
Sleep-time captopril attenuated remodeling in pressure-overload mice; leaves open whether chronotherapy improves outcomes in human heart failure.
Abstract
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.
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Cite This Study
Martino et al. (2011) studied Murine pressure overload hypertrophy. Captopril vs. Placebo or wake-time captopril was evaluated on Cardiac function and structural remodeling markers (heart:body weight ratios, myocyte cross-sectional areas, intramyocardial vascular medial wall thickness, perivascular collagen). Captopril improved cardiac function and decreased cardiac remodeling markers in mice with pressure overload only when administered during sleep time.