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Israel Journal of Veterinary Medicine  Vol. 70 (4)  December 2015 3 Comparative and Evolutionary Medicine
Comparative and Evolutionary Medicine:
An Example from Cardiovascular Medicine
Natterson-Horowitz, B.
UCLA Division of Cardiology, David Gefen School of Medicine at UCLA, 650 Charles Young Drive South, A2-237 CHS,
Los Angeles, CA 90095, U.S.A.
*
Corresponding Author: Professor Barbara Natterson-Horowitz, M.D., UCLA Division of Cardiology, David Gefen School of Medicine at UCLA, 650
Charles Young Drive South, A2-237 CHS, Los Angeles, CA 90095, U.S.A. Email: bnatterson@mednet.ucla.edu
ABSTRACT
Te application of comparative methods to clinical problems is well known to veterinarians. Physicians, to
contrast, have poor awareness of the tremendous overlap in the pathology of animals and their human patients.
Tey remain unexposed to the potential for comparative and evolutionary approaches to generate novel
hypotheses and creative solutions to difcult human issues. Although the felds of human and animal medicine
are moving closer together through One Health and related initiatives, most of the insights gained through
these activities are in the areas of zoonoses, infectious diseases and public health. Physicians in other felds
of medicine are largely unaware of the value of a comparative and evolutionary approach. Demonstrations
of how comparative approaches can increase insights into human medical issues in non-infectious disease
felds will help advance collaboration between a wider range of physicians and veterinarians. Te power of a
comparative and evolutionary approach to spark unique hypotheses is provided from the feld of cardiovascular
medicine. A common cardiovascular condition afecting people, vasovagal syncope (VVS), has non-human
animal correlates and roots. Comparative analysis of VVS reveals insights into how and why this autonomic
response occurs. Tis example provides a demonstration of how this perspective can enhance clinician
understanding of high impact human concerns and spark new therapeutic approaches.
Keywords: One Health; Comparative Medicine; Cardiology; Vasovagal Syncope; Alarm Bradycardia
REVIEW
Te application of comparative methods lies at the heart
of the feld of veterinary medicine. Given the range of spe-
cies veterinarians encounter in clinical practice, comparative
exposure is a crucial component of veterinary education
and training. But the value of comparatively extends well
beyond practical educational and clinical benefts. Applying
a comparative perspective to any biomedical question can
generate novel hypotheses and spark creative solutions to
intractable challenges.
Unlike veterinary medicine, human medicine is not explic-
itly comparative. Physiology, pathophysiology and therapeutics
are taught in reference exclusively to Homo sapiens. Most
physicians are signifcantly unaware of the spontaneous oc-
currence of “human pathology” in non-human animals. Tis
leads to the erroneous assumption among many physicians
that many pathological conditions are uniquely human. Tis
medical form of human exceptionalism not only deprives
clinicians and physician-scientists of the hypothesis generat-
ing advantages of comparativity it obviates the possibility of
using an evolutionary approach to understand the origins and
etiology of pathological conditions. Recognition of the range of
non-human animals in whom “human” pathology occurs helps
expose the ancient roots of vulnerability to disease and can
help illuminate the evolutionary origins of human pathologies.
One example of how comparative knowledge can enhance
discovery comes from the feld of cardiology. A comparative
and evolutionary exploration of cardiac responses in a range of
Review Articles
Israel Journal of Veterinary Medicine  Vol. 70 (4)  December 2015 Natterson-Horowitz, B. 4
wild species is helping to illuminate the origins of a common
but puzzling clinical occurrence: vaso-vagal syncope (fainting).
Vaso-vagal syncope (VVS) is responsible for 3% of
emergency room visits and 6% of hospitalizations (1, 2).
One-third of all adults will have experienced VVS at least
once in their lives. Syncope has several causes, many of
them cardiac. Valvular heart disease, orthostatic hypoten-
sion and seizures may cause fainting. But it is vaso-vagal
syncope which leads to more fainting than any other cause
(3). Vaso-vagal fainting often occurs in the setting of extreme
adrenergic activation. VVS has been reported with highly
emotionally activating experiences including phlebotomy
and the site of blood, watching the birth of a child, intense
pain (i.e., long bone fracture), extreme fear or receiving ex-
tremely upsetting news (4, 5, 6). A specifc autonomic refex
is responsible for emotionally activated VVS. Te external
event, fear, grief, and/or pain, triggers a robust adrenergic
response (7). Instead of the expected fght/fight response
with consequent tachycardia and vasoconstriction, a sudden
withdrawal of sympathetic tone occurs which results in a
parasympathetically-mediated bradycardia and vasodilation.
Tis suite of autonomic responses results in a decrease in
blood pressure with consequent reduction in perfusion to the
central nervous system resulting in loss of consciousness (3).
Bradycardia in the face of adrenergically activating exter-
nal circumstances, which include threat, seems counterintui-
tive. From an evolutionary perspective, a robust fght/fight
response would seem to be vastly superior to the physiology
of fainting. In fact, sympathetically-mediated fght/fight
physiology is the more common autonomic response to
external threat, fear or anguish.
But the withdrawal of sympathetic stimulation and
consequent vagal dominance associated with VVS happens
to nearly every human. Te “heart drop” or woozy sensation
after a career-jeopardizing mistake or a near-miss between
your carful of kids and a truck, or stepping in front of a large
audience results from this bradycardia-vasodilation response
to external threat, pain, or anguish.
But why? What adaptive beneft might this seemingly
paradoxical response have had in the ancestral environ-
ment in which our mammalian autonomic nervous systems
evolved? Applying veterinary science, a comparative analysis
and an evolutionary perspective sheds light on this question.
Do non-human animals exhibit a slowed heart rate and
vasodilation responses to activating external stimuli? Do they
ever faint? And if they do, then why? What adaptive beneft
does this fainting physiology ofer?
A comparative look at VVS begins to shed light on
this question. External threat and fear trigger fght/fight
responses in mammals, reptiles, birds and fsh. But ‘alarm
bradycardia’, the sudden reduction in heart rate in response
to danger, fear, threat, is also found in the same broad range
of non-human animal species (8, 9, 10, 11, 12, 13, 14, 15, 16).
For example, white-tailed deer fawn responded to a variety of
threatening stimuli with marked bradycardia (10). Similarly
telemetry studies of the heart rates of willow grouse, wood-
chucks, rabbits and alligators have all demonstrated similar
bradycardic responses to perceived threat (8, 9, 12, 13). Te
slowed heart rate associated with alarm bradycardia has been
noted to be accompanied by reduced motion. Tis stillness
generates the hypothesis that alarm bradycardia provides
anti-predation protection for an animal when fght or fight
responses are unlikely to be successful (14, 15, 16).
Te epidemiology of alarm bradycardia and, in fact, VVS
seems to support this hypothesis. Alarm bradycardia is stron-
gest at the earliest phases of life, diminishing in intensity with
age fght or fight responses become more dominant. White-
tailed deer, for example, exhibit nearly exclusively bradycardic
responses to threat in the frst week of life. By the end of the
frst several weeks of life, however, they are much more likely
to respond with sympathetically modulated fight responses.
By 51 days of life, the response could not be elicited (10).
Tere are important comparative connections between
alarm bradycardia in young animals and human popula-
tions. Te sudden reduction in heart rate associated with
VVS is also seen with greater frequency and intensity in
young human life. One study published in 1993 looked at
how the heart rate of soon-to-be born babies was afected
by the sounding of sudden loud alarms. During the Gulf
War in 1991, the calm of a labor and delivery ward in Israel
was disrupted by the sounding of sudden loud alarms. Each
woman had a fetal heart monitor around her abdomen which
documented a dramatic plunge in fetal heart rates in response
to the loud noise suggesting alarm bradycardia is present
from the earliest stages of human life (17). Te potency of
this refex in young vertebrates further supports the hypoth-
esis that alarm bradycardia represents an anti-predation
physiology. Te youngest and most vulnerable of the species
may lack the strength and/or speed to escape or fght their
way out of danger. Te acute slowing of the heart rate and
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Israel Journal of Veterinary Medicine  Vol. 70 (4)  December 2015 5 Comparative and Evolutionary Medicine
associated stillness represents a third survival strategy: staying
quiet and still–hiding.
Trough this veterinary and evolutionarily-informed
analysis, VVS is not paradoxical at all. Rather, it represents
an autonomic legacy that has been keeping animals safe for
hundreds of millions of years.
Recognizing the linkage between alarm bradycardia and
the bradycardia of VVS leads to potential therapeutic inter-
ventions. It appears, for example, that a decrease in the alarm
bradycardic response is seen when animals are repeatedly ex-
posed‒and deconditioned–to the stress trigger. White-tailed
deer fawn, for example, responded with alarm bradycardia to
loud thunder only in the beginning of a storm. Successive
thunderstorms failed to elicit the response (10). Perhaps a
novel strategy to prevent syncope in a vulnerable population
with recurrent VVS would be to develop deconditioning
exercises targeting triggering stimuli. Or recognizing that
juvenile animals appear to ‘grow out’ of this response as they
age might help clinicians make challenging decisions about
permanent pacemakers and other medical devices.
As evidenced by the above example, putting comparative
knowledge into the hands of physicians allows for expanded
and evolutionarily informed perspectives on common and
enigmatic human pathologies. In the case of VVS the com-
parative analysis allows for the consideration of ‘why’ this
autonomic response emerges under high stress conditions. It
allows for a reframing of the traditional description of VVS
as representing a paradoxical response to stress to one which
points to an evolutionary past in which it was adaptive. Tis
points to therapeutic strategies based on the syndrome being
maladaptive rather than paradoxical.
Beyond the cardiovascular example ofered above, the
potential exists for comparative medicine to spark insights
and have a transformational afect on many felds of medicine.
Te connection and overlap between veterinary and human
syndromes is seen in felds ranging from psychiatry and pe-
diatrics to neurology and nephrology. Bringing comparative
perspectives to these and other felds of medicine will lead to
expanded perspectives and novel hypotheses. One Health is
an exciting idea which can and should span medicine in its
entirety. Demonstrating how comparative and evolutionary
insights do this in one feld should provide a model for how it
might be done in others. Given the longstanding and promi-
nent place comparative medicine has had in veterinary science,
veterinarians can and should emerge as leaders, teachers and
innovators in developing efective initiatives to excite their
physician colleagues about the power of a species-spanning
approach to medicine. Tis collaborative approach will help
physicians recognize the potential for efectively addressing
medical challenges in people by paying close attention to the
physiology and pathophysiology of non-human animals.
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Review Articles