(PHILADELPHIA) – It has been known for
decades that heart
attacks and strokes occur most frequently in
the early-morning hours. Now, researchers at the University
of Pennsylvania School of Medicine have provided the first
evidence for the role of our body’s internal molecular clock
in controlling blood
pressure and a mechanism by which this occurs.
Published online next week in the Proceedings of the National
Academy of Sciences, this report points to the novel possibility
of modifying blood pressure and the early-morning risk of heart
Daily variation in blood pressure in normal mice
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The upswing in heart attacks tracks with rising blood pressure,
which undergoes a 24-hour, or circadian, rhythm. This rise in blood
pressure is amplified in patients with high
blood pressure. However,
scientists have debated as to whether this event signifies a role
for the molecular clock, or merely reflects the relationship of
clock time to stresses in our environment – such as awakening,
hurried dressing, and the rush to work.
“This study provides evidence that integrates both explanations
for the variation in blood pressure with clock time and, by inference,
the daily variation in heart attack and stroke,” explains
first author and postdoctoral fellow Annie M. Curtis, PhD.
The molecular clock is a complex set of genes located in a discrete
brain area that tightly regulate circadian rhythms in behavior,
temperature, and metabolism. Researchers now appreciate that this “master
clock” also interacts with clocks in almost all types of
Using mice in which the function of major clock genes have been
disrupted, the investigators found distinct and complimentary effects
on blood pressure and its circadian variation. What’s more,
genes relevant to the production and breakdown of catecholamines – the
hormones that equip mammals for “fight and flight” behavior
were under the control of the clock.
Catecholamines – norepinephrine and epinephrine – undergo
a daily variation, but also rise in response to stress. The investigators
wondered if they might provide a link between the two explanations
for the early morning rise in heart attacks.
Using a mouse model in which catecholamines and blood pressure
were made to surge, the researchers found that the rise in both
blood pressure and catecholamines depended on the time of the stress.
The greatest response occurred at a time that would correspond
to the early morning hours in humans.
However, the greater surprise was yet to come, say the investigators.
Deletion of a core clock gene completely abolished both the catecholamine
and blood pressure response to stress, irrespective of when the
stress was applied during the daily clock cycle. This effect was
specific to the catecholamines, as the stress response of another
hormone – a steroid – was unaltered.
“These results integrate for the first time the two leading
explanations for the diurnal variation
in blood pressure and reveal an unexpected role for a clock gene
in regulating the stress response,” says
senior author Garret
A. FitzGerald, MD, Director
of the Institute for Translational
Medicine and Therapeutics at
Penn. “They raise the novel possibility of modifying
blood pressure and consequently the early-morning risk of heart
attack and stroke by using drugs to ‘reset’ the molecular
clock.” Since blood pressure response (via rising catecholamines)
to stress in the early morning is tied to one’s internal
clock, tamping down the clock using drugs could be a treatment
for people with high blood pressure, whose upswing in pressure
is amplified in the morning anyway.
This study was funded by the National
Institutes of Health. Co-authors
in addition to FitzGerald are Anne M. Curtis, Yan Cheng, Shiv Kapoor,
Dermot Reilly, Tom S. Price, all from Penn.
PENN Medicine is a $2.9 billion enterprise
dedicated to the related missions of medical education, biomedical
research, and high-quality patient care. PENN Medicine consists
of the University of Pennsylvania School of Medicine (founded in
1765 as the nation's first medical school) and the University of
Pennsylvania Health System.
Penn's School of Medicine is ranked #2 in the nation for receipt
of NIH research funds; and ranked #3 in the nation in U.S. News
& World Report's most recent ranking of top research-oriented
medical schools. Supporting 1,400 fulltime faculty and 700 students,
the School of Medicine is recognized worldwide for its superior
education and training of the next generation of physician-scientists
and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals,
all of which have received numerous national patient-care honors [Hospital
of the University of Pennsylvania; Pennsylvania Hospital, the nation's
first hospital; and Penn Presbyterian Medical Center]; a faculty practice
plan; a primary-care provider network; two multispecialty satellite
facilities; and home care and hospice.