Many doctors recommend their patients take heart drugs in the morning with their breakfast, but a new study from Canada suggests that one group of drugs, angiotensin-converting enzyme (ACE) inhibitors, works best when taken at bedtime because they reduce the effect of a hormone that is most active during sleep.

Lead author Tami A. Martino, a professor in the Department of Biomedical Sciences at the Unversity of Guelph in Ontario, told the press that:

“Heart drugs are often given to patients in the morning for convenience without considering biological rhythms or time-related risks of adverse effects.”

“But if they’re given at bedtime, it’s better,” she added.

Martino and colleagues wrote about their findings in a paper to be published in the Journal of the American College of Cardiology on 17 May.

For some diseases, the time of day or month of medication or surgery can make a difference to success. Asthma and arthritis pain, for example, respond differently when treatment is given at different times.

Martino and colleagues explained in their background information that evidence suggests the heart repairs or remodels itself primarily during sleep. And it’s well known that heart attacks and sudden cardiac deaths peak in the early morning, and that people who work nights have disturbed circadian rhythms and higher risk of heart disease.

But while studies have been done to show that timing of heart medication can alter diurnal patterns of blood pressure in patients with high blood pressure, little is known about how the timing of such medication affects heart remodeling.

The researchers decided to test ACE inhibitors because these drugs inhibit the activity of a natural hormone involved in heart repair. The levels of this hormone are highest at night, causing the heart to enlarge and increasing the risk of cardiac damage in heart patients.

For the study, Martino and colleagues used mice bred to have high blood pressure, and examined the effect of the short-acting ACE inhibitor, captopril, on the structure and function of the mice’s heart tissue, after the animals underwent surgery that put the heart under greater pressure, thus simulating the conditions that lead to heart failure.

The mice were then split into two groups: one was injected with ACE inhibitor and the other with placebo. Each group was further subdivided into two sets of mice: one set had the injection during wake time, and the other at sleep time. All groups were treated for 8 weeks, starting 1 week after surgery.

The results showed that the mice that received ACE inhibitor at sleep time had improved heart function and their hearts were less enlarged compared to the mice that had received the drug at wake time and the mice given the placebo.

These beneficial effects of the ACE inhibitor also correlated with diurnal changes in genetic expression of ACE in the heart.

However, the ACE inhibitor led to similar drops in blood pressure at both sleep and wake time, suggesting that the time of day differences were not due to blood pressure changes, wrote the authors.

They concluded that:

“The ACE inhibitor captopril benefited cardiovascular remodeling only when administered during sleep; wake-time captopril ACE inhibition was identical to that of placebo.”

They said the findings add weight to the idea that the heart and its blood vessels remodel during sleep time, and also shows the importance of diurnal timing for some cardiovascular drugs.

Martino said that giving the ACE inhibitor at sleep time fits in with the biological rhythm of the hormones.

“By targeting those hormones when they’re highest during sleep, you’re dropping their levels so they’re not doing so much damage,” she added.

Martino said doctors switching to bedtime use of ACE inhibitors should also consider a short-acting version, because it’s not necessary to have it last longer than the night, and this may help reduce the side effects.

She said other researchers are also looking at the possibility that other diseases may also be sensitive to biological rhythms for drug treatment, and gave the examples of insulin release in diabetes and chemotherapy in cancer patients.

“We are now starting to learn that biological and physiological rhythms play an important role in health and disease,” said Martino.

“The Primary Benefits of Angiotensin-Converting Enzyme Inhibition on Cardiac Remodeling Occur During Sleep Time in Murine Pressure Overload Hypertrophy.”
Martino, Tami A., Tata, Nazneen, Simpson, Jeremy A., Vanderlaan, Rachel, Dawood, Fayez, Kabir, M. Golam, Khaper, Neelam, Cifelli, Carlo, Podobed, Peter, Liu, Peter P., Husain, Mansoor, Heximer, Scott, Backx, Peter H., Sole, Michael J.
J Am Coll Cardiol, 17 May 2011; Vol 57, No 20.

Additional sources: University of Guelph,

Written by: Catharine Paddock, PhD