The Heart’s Circadian Rhythms Point to Potential Treatment Strategies
The morning is a dangerous time for the heart. As most cardiologists well know, events such as heart attacks, strokes, arrhythmias, and sudden cardiac death are all more likely to occur in the morning. Growing understanding of the circadian mechanisms that underlie these cardiac disease patterns is pointing to potential treatment strategies.
Although much of the work remains in the translational stage, clinical trials have shown that circadian-wise timing of the administration of blood pressure medications can help certain patients. At the same time, a growing body of evidence from animal studies shows that disruptions of circadian rhythms contribute to cardiovascular disease and may hamper recovery.
“We’ve known for the last couple of decades about the importance of circadian physiology for heart health,” said Tami A. Martino, PhD, director of the Center for Cardiovascular Investigations at the University of Guelph in Canada. “But clinical cardiology didn’t really pay attention to how you could apply it to benefit the treatment of patients.”
The circadian system helps humans stay in tune with the 24-hour light-dark cycle. About a dozen so-called clock genes regulate the expression of thousands of other genes that are differentially expressed at various times of day or night to meet the demands of the body during its active and sleeping hours.
A master clock residing in the hypothalamus within the central nervous system, called the suprachiasmatic nucleus, responds to light by the optic nerve and coordinates the expression of clock genes throughout the body, including in the heart and blood vessels. Disruptions in circadian rhythms triggered by jet lag, shift work, or sleep disturbances can desynchronize the expression of clock genes in the cardiovascular system and other parts of the body from the master clock, explained Guangrui Yang, MD, PhD, of the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania. Chronic clock disruption has been linked to metabolic syndrome, immune dysfunction, cancer, diabetes, and cardiovascular diseases, he noted.
“All these clocks are synchronized by the SCN [suprachiasmatic nucleus] every day, mainly by light cues,” Yang explained. “But after disruption, clocks in every organ will run their own speed.”
Clock genes influence blood pressure and heart rate rhythms in addition to endothelial function, platelet aggregation, and thrombus formation.
Chronotherapy has emerged to better time the administration of drugs based on the circadian patterns, which influence diseases, drug metabolism, and the interactions of drugs with their targets. Nearly half of all protein-coding genes have circadian-controlled expression patterns. More than half of the genes targeted by the 100 best-selling drugs in the United States, including medications used to treat hypertension and heart failure, target circadian-controlled genes.
“Drug efficiency, side effects, and pharmacokinetics have circadian variation,” said Yang.
Optimizing the timing of cardiovascular medications based on circadian cardiovascular patterns could boost their efficacy. In a recent review of the data, Roberto Manfredini, MD, professor of internal medicine at the University of Ferrara, Italy, said switching from a morning to evening administration of antihypertensive drugs can help certain high-risk subgroups of patients with elevated night-time blood pressure because of obstructive sleep apnea, type 2 diabetes mellitus, chronic kidney disease, a history of cardiovascular events, or morning-resistant hypertension.
“In my internal medicine ward, every day we use antihypertensive drugs with a chronotherapeutic approach, [it’s] easy and inexpensive, for patients with night hypertension [nondipping status secondary hypertension],” he said.
Other groups are beginning to look at optimal timing of other cardiovascular medications. For example, Martino and her colleagues used a mouse model of cardiac hypertrophy to study the best time to give the short-acting ACE-inhibitor captopril. They found that giving captopril at sleep time reduced heart weight and enlargement, but that the same drug given at wake time provided no benefit. This approach works because it targets the products of rhythmic genes and levels are highest at night, she explained. Indeed, many medications have short half-lives and may well benefit from timed dosage.
“Timing of drug therapy matters,” Martino said. “If you time drug therapies to the body’s physiological and molecular rhythms you can improve drug efficacy and sometimes reduce toxicity, and this can benefit patients.”
Evidence is also emerging that circadian disruption may hamper recovery in patients after an adverse cardiac event.
“The light, the noise, the nurses and doctors going in and out,” Yang explained. “The ICU environment is not good for these patients.”
Modern intensive care units and cardiac care units, which often have multibed rooms, lots of light, noisy machines, and frequent vitals checks, were not designed to maintain patients’ normal circadian rhythms, noted Martino.
“Contemporary medicine ignores the importance of undisturbed diurnal rhythms in the critically ill,” she said.
To better assess the effects of such disruptions on recovery after heart attack, Martino and her colleagues used a mouse model of myocardial infarction (MI) and housed the animals for a few days after the event in either normal day-night lighting conditions or altered lighting before returning both groups to their normal housing conditions.
“We found that short-term disruption, for just the first few days after MI, dramatically worsened their outcome,” Martino said. These mice ended up with greater infarct expansion, more ventricular dilation, and worse outcomes. Martino said this occurred because sleep and circadian rhythms were disrupted during the initial immune response to the injury. “The immune cells are not laying down the foundation for healing as they would if circadian rhythms are maintained during these critical first few days of healing,” she explained.
The data suggest that measures to mitigate circadian and sleep disruptions during recovery might help improve patients’ outcomes, but more research is needed to test how. For example, Martino suggested that physicians might try different types of lighting, find ways to reduce noise from machines, or minimize patient–staff interactions at night whenever possible.
“There are some things that can be done to minimize these effects,” she said. “If you can reduce the damage or increase the benefit over those first few days, [patients may] have a better overall healing process.”
Although many applications of circadian physiology in cardiology are still being studied, there are immediate implications for clinicians who can discuss with their patients the importance of good sleep and steps to avoid circadian disruption.
“There is an enormous opportunity to think about how to apply circadian biology to clinical medicine”; it has the potential to directly benefit the outcome of patients with cardiovascular (and other) diseases, Martino said. n
Circulation is available at http://circ.ahajournals.org.
- © 2016 American Heart Association, Inc.