麻豆传媒

SEATTLE -- Circadian rhythms in functioning of the heart and other organs impact both heart failure risk and efficacy of treatments for it, an expert argued.

A disrupted sleep schedule -- such that which occurs with shift work -- throws off the repair cycles for the heart and can boost risk or worsen disease, explained Michael Sole, MD, a physiologist at the University of Toronto.

But heart failure treatments that target remodeling -- such as ACE inhibitors and gene therapy -- appear to yield the greatest benefits when given at night while the heart is in that receptive mode, he pointed out in a featured lecture here at the Heart Failure Society of America meeting.

"If you take at least one of your antihypertensives at night when sleeping, you get a much better prognosis than if you take them all in the morning," he told attendees.

In particular, patients with limited tolerance of ACE inhibitors or angiotensin receptor blockers, such as due to rising creatinine, might be considered for a full dose of a short-acting agent at night with a relative "drug holiday" during the rest of the day, Sole suggested.

"Long-acting isn't always better," he said.

That's not a function of blood pressure effects, but of a more complex process.

In a mouse model study, injections of the short-acting ACE inhibitor captopril (Capoten) had largely the same impact on blood pressure lowering whether given during sleep hours versus during their active time when the lights were on.

However, the impact on remodeling was dramatically different.

Daytime dosing showed little difference from placebo in terms of fibrosis and hypertrophy in heart muscle cells.

Dosing at night, though, restored myocyte caliber and reduced fibrosis substantially compared with controls.

In humans, the study showed that hypertensive patients given most of their medications at night had substantially better event-free survival rates than those who took all their drugs in the morning (P<0.001).

The reason appears to be that the biological clock runs on a predictable, 24-hour schedule that anticipates and prepares the body for biological demands.

For example, cortisol, vascular resistance, platelet adhesiveness, blood viscosity, and catecholamines peak at around 6 a.m., followed by the sharpest rise in blood pressure 45 minutes later.

The highest blood pressure levels are reached by 6:30 pm, followed by a peak in cholesterol and triglycerides around 10 PM.

Light hitting the retina sets the master circadian clock, but virtually every cell in the body participates in feedback to coordinate hundreds or thousands of processes to occur at their optimal time of day.

A study from 2001 was one of the first to show rhythms in heart function, with cardiac power lower at night, oxygen consumption higher during the day, and a switch in preferred fuel between the two periods (glucose during the day versus oleate at night).

"Until these studies, we used to think housekeeping and repair processes were 24-hour," Sole said.

The same patterns can be seen in gene expression, he explained.

In a mouse study, sampling the heart every 3 hours over 24 hours showed that 13% of genes there varied in expression between day and night, with some most active at the transition period between the two, others in a cyclic pattern, and so on.

"The heart behaved as a genetically different organ during day versus night," Sole noted.

Expression of biomarkers also has shown diurnal variation. In one study, gene expression amplitude was up during the day in a third, up at night in another third, and spread across the full 24 hours in the rest.

Moving animals off a 24-hour clock to an artificially simulated 20-hour day was disastrous for their heart in another study.

The healthy mice on this "chronic jet lag" schedule showed vascular remodeling with a "tremendous" amount of fibrosis along with ventricular hypertrophy and worse cardiac function.

"Repair and renewal couldn't take place in these diurnally disturbed hours," Sole explained.

The effect reversed when the mice were put back into a 24-hour schedule.

In a study of hamsters with cardiomyopathy, disturbing their diurnal rhythm worsened their condition and markedly raised mortality.

"Shift work is a risk factor for cardiovascular disease and patients with cardiovascular disease shouldn't be on shift work," Sole concluded. "We should be interviewing patients about their day and sleep habits."

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