In a newly reported, first-ever finding, physicists from Boston University and physiologists from Boston’s Brigham and Women’s Hospital (BWH) have found that the body’s biological clock affects the patterns of heart-rate control in healthy individuals independent of sleep/wake cycle or other behavior influences.
Their analysis of the heartbeat dynamics of the healthy individuals in the study showed significant circadian rhythm, including a notable response at the internal circadian phase corresponding to 10 a.m., the time of day most often linked to adverse cardiac events in individuals with heart disease.
The BU/BWH team will report its findings in the Dec. 28 issue of the Proceedings of the National Academy of Sciences. Sponsored by grants from the National Institutes of Health, the institutional teams were led by Plamen Ivanov, a research associate in BU’s Center for Polymer Studies, who undertook the analysis of the data, and Steven Shea, director of BWH’s medical chronobiology program and associate professor of medicine at Harvard Medical School, who conducted the experimental part of the research.
Cardiac disease is the leading cause of death in the United States, accounting for 29 percent of the deaths from the nation’s 10 leading causes (including homicides and accidents), according to the latest statistics (2001) available from the National Center for Health Statistics.
When designing their study of this deadly disease, the BU/BWH team drew on seemingly disparate findings in epidemiology, cardiology, circadian biology, biomedical engineering, and physics to construct an approach that would assess heartbeat fluctuations in healthy individuals at different circadian phases. In addition, they choose to analyze the data from these individuals using tools from statistical physics that describe relationships between the frequencies of large and small events. With these tools, the researchers hoped to find whether underlying patterns in the heartbeat data of the study participants were affected by the circadian phases.
For more than a decade, researchers at the Center for Polymer Studies have applied statistical physics methods to investigations of cardiac dynamics, probing for hidden patterns. Previous statistical evaluations of heartbeat fluctuations by Ivanov and others have shown that those of healthy subjects exhibit a self-similar structure over a range of time scales, that is, the fluctuations found in a window of 10 beats will be statistically similar to those found in a heartbeat interval of 100 beats and or one of 1000 beats.
“These studies have demonstrated that this self-similar structure in the temporal order of heartbeat fluctuations changes with certain behaviors, such as sleep or wake, rest or exercise,” explains Ivanov. “Based on these observations, we hypothesized that these dynamic patterns will also change with circadian rhythm. This provided the impetus for the study design.”
Epidemiological studies, too, have shown a pattern to events associated with heartbeat irregularities such as myocardial infarction, stroke, angina, arrhythmias and sudden cardiac death. These events have been found to have a strong 24-hour day/night pattern and, intriguingly, have been found to occur most often around 10 a.m. Day/night patterns of disease severity are often associated with sleep/wake behavior but, the researchers hypothesized, they can also be linked to an internal body clock, the endogenous circadian pacemaker that controls much of our physiology, even when behaviors are unchanged. Body temperature, Shea notes, rises during the day and falls at night even when a person doesn’t sleep at night. The circadian cycle usually “resets” itself daily in response to certain external cues, most especially bright light, such as sunlight.
To remove any influence from the sleep/wake cycle, Shea and his team employed a “forced desynchrony” protocol on the five healthy volunteers who participated in the study. For 10 days, the participants lived in dimly lit rooms cut off from any outside stimuli or time cues. The researchers adjusted scheduled behaviors (sleeping periods, eating, and the like), gradually shifting the behavior patterns until the participants had a 28-hour day, about 19 hours awake and 9 hours asleep. This 28-hour sleep/wake schedule was sustained for seven “days,” while core body temperatures, used to mark participants’ internal circadian phases, continued to oscillate with an approximate 24-hour period, indicating their sleep/wake cycles had been experimentally separated from their circadian cycles.
Using heartbeat data gathered from the participants throughout the 10-day desynchrony, Ivanov and BU team members Kun Hu and Zhi Chen, research assistants in physics, estimated correlations in the heartbeat fluctuations according to a power law function quantified using a method known as a detrended fluctuation analysis (DFA). The DFA mathematically describes the fluctuations at different time scales in the heartbeat signal and produces a scaling exponent that characterizes the degree of correlation between heartbeat intervals. If, for example, the scaling exponent, known as á, equaled 0.5, the interval fluctuations showed no correlation; if á equaled 1.5, the interval fluctuations were considered to be without control, exhibiting a so-called random walk property. If, however, á fell between 0.5 and 1.5, the interval fluctuations were considered to be organized and physiologically controlled. Interestingly, research studies have associated á values progressing toward 1.5 with pathological conditions, such as congestive heart failure.
When the team analyzed wake period data, they found a striking correlation: á values changed according to the internal body clock time. At 2 a.m., the value was 0.8; at 5 p.m., it was 1.0. However, at 10 a.m., the time of day found to have the greatest incidence of cardiac incidents, the team found the value was 1.2, edging toward the value linked with congestive heart failure. The team likewise found strong circadian rhythms whether data were considered only from the awake period or only from the sleep period.
“We are tempted to speculate that if the same circadian effect occurs in people with diseased hearts, then this may contribute to the day/night pattern of cardiac events,” says BWH’s Shea. “But this was only a study on healthy subjects, and, therefore, we are a long way from making clinical recommendations. Further studies could, however, provide insight to the underlying cause of the disease — and to therapies that might work better by being timed to the specific phases of the body clock.”
Brigham and Women’s Hospital is a 735-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare System, an integrated health care delivery network. Internationally recognized as a leading academic health care institution, BWH is committed to excellence in patient care, medical research, and the training and education of health care professionals.
Scientists at Boston University’s Center for Polymer Studies, part of BU’s Department of Physics in the College and Graduate School of Arts and Sciences, research polymer systems at the microscopic level, focusing on describing the basic spatial configurations of polymer molecules so as to better predict the macroscopic behavior of polymers. Interdisciplinary science research at the Center includes studies of cardiac dynamics, the statistical mechanisms of Alzheimer’s disease, and simulations of liquid water. Boston University, with an enrollment of more than 29,000 in its 17 schools and colleges, is the fourth-largest independent university in the United States.