The findings, published in the journal Cardiovascular Research, could help prevent heart disease as we grow older.
In earlier studies, researchers from University of Guelph in Canada found that heart attacks were worse for males than for females of similar age.
The study also uncovered a time-of-day effect: heart attacks in males were more severe during sleep.
This led to the idea that the circadian mechanism - tiny clocks in all of our body's cells which regulate our 24-hour day and night processes - might work differently in male and female hearts.
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"We think of these CLOCK mice as a genetic model of shift work," said Tami Martino, from University of Guelph.
"Surprisingly, ageing male CLOCK mice developed heart disease, but female CLOCK mice did not," said Martino.
Researchers discovered that female heart cells are actually different from those of males.
Cardiolipins in CLOCK male hearts look like those in humans with heart disease, Martino said.
The CLOCK males also had worse cardiac glucose and energy profiles. By contrast, CLOCK female hearts had a healthy cardiolipin profile and better energy, researchers said.
The findings may lead to clinical benefits for women and men, researchers added.
"Maintaining good circadian rhythms is important for achieving healthier and longer lives," Martino said.
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