Insights from complexity

science for the practice of
medicine
Robert A. Lindberg, MD
Darien, CT

Plexus Institute

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Complexity Science
 Other labels used:
– Chaos Theory
– Nonlinear Dynamics
– Science of Complex Adaptive Systems
– Systems Theory
 Dealswith the behavior and properties of
systems

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System definition

 A collectionof agents interconnected
around a common purpose

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System examples
 Weather system
 Phone system
 Internet
 Stock Market
 Central Nervous System
 Immune System
 Human Body

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Complex Dynamic System
Properties
Weather
 Agents obey Simple Rules
– Wind, water, thermodynamics, etc
 Continual Dynamic Interplay between all
the interconnected agents
 Net consequence cannot be forecast nor
engineered

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Weather patterns

U
N
I
T

TIME

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Complex Adaptive System
Stock Market
 Agents follow simple rules
– e.g. buy low, sell high
 Dynamic interplay between agents that have
the ability to learn and adapt
 Consequences cannot be forecast or
engineered

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Dow Jones Average

U
N
I
T

TIME

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Properties of Complex
Nonlinear Systems
 Simple Rules underlie complexity of system
 “Nonlinear” or variable
 Emergent order or stability created by the
dynamic interactions between the agents of
the system

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Relevance of Complexity
Science to Medicine
 Alternativemodel to the Mechanistic or
Reductionist Model
– Understand the whole by studying the parts
– The body is similar to a machine with independent parts
 Concept of the human body as a complex adaptive
system
 Systems embedded within systems
 The sum is greater than the parts

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Human Body = Complex
Adaptive System
 Comprised of many systems
– Central Nervous System
– Immune System
– Cardiovascular System
– G.I. System
– Etc.
 Systems embedded within systems

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Human Body Interacting with
Larger Systems
 Nature
 Ecosystems
 SolarCycles
 Micro-organisms
 Families, Organizations
 System embedded within systems

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Complexity Determinants

 Number of Interconnected Agents
and
 Number of Connections

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Signature of Complex System
behavior over time
 Waves,Rhythms, Oscillations, 1/f Noise,
Chaotic Resonance, Nonlinear Dynamics,
etc.

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Thermostat – Closed System

T
E
M
P

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Thermostat – Open System

T
E
M
P

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Simple vs Complex Systems

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Pattern of a Simple System:
two agents, one connection

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Pattern of a complex system:
many agents, many
connections

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Diurnal Thermostat System

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Circadian Body Temperature

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Circadian Body Temperature
wave on a wave

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Waves vs Particles

 Observing the pattern of a system’s “waves”
provides insight into it’s relative health and
degree of complexity
 Wave patterns suggest the number of agents
and the number of connections and their
relative responsiveness to each other

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Some examples of waves or
rhythms
 Heart rate
 Brainwaves
 Temperature curve
 Action potential of nerves, muscles
 Blood pressure
 Hormonal pulses
 Circadian rhythm

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Heart Rate Variability (HRV)
 AnIndependent Risk Factor for All Cause
Mortality
 Why?
– Represents a wave or rhythm indicative of the
degree of physiologic health of the human
system

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Normal Heart Rate Variability

Beats
per
minute

time
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Heart Rate Variability
 The Heart Rate cycles in a Wave like
pattern over time
 A reflection of the behavior of the
Cardiovascular System interacting and
connected to many other agents
 Its pattern has prognostic implications
 A signature of complex systems behavior

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Abnormal Heart Rate
Variability

Beats
Per
minute

time
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Chronotropic Response

Beats
per
minute
with
exercise

time
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Usefulness of impaired
chronotropic response to
exercise as a predictor of
 Chronotropic incompetence is a strong and
mortality
independent predictor of death, even after
accounting for angio severity of CAD
 384 pt’s for Thallium stress tests
 Dresing;Am J Cardiol 2000;86:602

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Prognostic implications of
chronotropic incompetence in the
Framingham Heart Study
 An attenuated heart rate response to
exercise is predictive of increased mortality
and coronary heart disease incidence
 1575 males, mean age 43, prospective
 Lauer;Circulation.1996;93:1520

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Effects of exercise training on
chronotropic incompetence in
pt’s with heart failure
 Exercise results in an increase in peak heart
rate and partial reversal of chronotropic
incompetence in patients with stable heart
failure
 Keteyian; Am Heart J. 1999;138:233

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Heart Rate Recovery

Beats
per
minute

time
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Heart-Rate Recovery
Immediately After Exercise as
a Predictor of Mortality
 A delayed decrease in the heart rate during
the first minute after graded exercise…is a
powerful and independent predictor of the
risk of death
 Cole; NEJM 1999;341:1351-7

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Heart Rate Recovery after
Submaximal Exercise Testing
as a Predictor of Mortality
 Healthy Cohorts, routine testing
 Heart rate recovery 2 minutes after ETT
 Reduced HR recovery a powerful
independent predictor of mortality in
healthy adults
 Cole; Annals of Int Med. 2000;132:552

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Heart rate variability

+

Chronotropic Heart rate
response recovery
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Heart Rate Variability

Beats
per
minute

time
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Normal Heart Rate Variability

rest exertion

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Decreased Heart Rate
Variability

rest exertion

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Decreased HRV and its
association with increased
mortality after acute MI
 MulticenterPost-Infarction research group
 Reduced HRV post MI poor prognosis
independent of traditional risk factors
 Kleiger. Am J Cardiol. 1987;59:256

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HRV as a predictor of
mortality in the Elderly
 Random sample of elderly over 65, # 347
followed for 10 yrs
 Prognostic power of traditional risk factors
compared
 24 hr HRV best predictor of death in elderly
subjects
 Circulation 1998;97:2031

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Reduced Heart Rate
Variability and Mortality Risk in
an Elderly Cohort
2 hour Holter Moniter analysis
 Estimation of HRV offers prognostic
information for all cause mortality beyond
that provided by evaluation of traditional
risk factors
 Circulation. 1994;90:878-883
 Framingham Heart Study

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HRV Components
 TheWave Model of HRV
 Amplitude
– Rate of Change
– Degree of Change
 Frequency
– Variation in frequency rate

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HRV Amplitude
-- degree of change

good bad
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HRV Amplitude
-- rate of change

good bad
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HRV Frequency

good

bad

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Cardiac Interbeat Interval
Dynamics From Childhood to
Senescence
 Healthy aging is associated with a loss of
complex variability in R-R intervals
 New methods of R-R interval variability
based on nonlinear dynamics may give
insight into heart rate dynamics
 Pikkujamsa;Circulation.1999;100:393

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Heritability of HRV
The Framingham Heart Study
 Holter moniter data, comparing siblings
 “Heritable factors may explain a substantial
proportion of the variance in HR and HRV”
 Singh;Circulation.1999;99:2251

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Association of Depression
With Reduced HRV in
Coronary Artery Disease
 Depressed patients with CAD have decreased
HRV compared with nondepressed CAD patients
even after adjusting for relevant covariates
 Decreased HRV may explain the increased risk for
cardiac mortality and morbidity in depressed
patients
 Carney;Am J Cardiol 1995;76:562

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HRV in healthy middle age
pts, post MI pts and heart
transplants
 HRV excellent predictor of death of any
cause or arrhythmic death
 Heart Transplant most reduced HRV
 Circulation. 1996;93:2142

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Association of hyperglycemia
with reduced HRV
 Framingham Heart Study
 HRV is inversely associated with plasma
glucose levels. It is reduced in both DM and
in subjects with impaired fasting glucose
 Does reduced HRV contribute to increased
cardiac mortality of DM and impaired
FBG?
 Am J Cardiol 2000;86:309

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Short and long term effects of
cigarette smoking on HRV
 Smoking results in decreased vagal cardiac
control leading to diminished HRV
 Hayano; Am J Cardiol 1990;65:84

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Decreased HRV associations
– a few examples
 Aging
 Diseases
– CHF, Parkinsons, DM, Cancer, Depression
 Syndromes
– Chronic Fatigue Syndrome, Sleep Apnea,
Septic Shock
 Lifestyle
– Smoking, Sedentary

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Reduced HRV precedes
 Arrhythmias – atrial and ventricular
 Cardiac mortality
 All cause mortality
 Manifest disease

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Altered Complexity and Correlation
Properties of R-R Interval Dynamics
Before Spontaneous Paroxysmal
Atrial Fibrillation
 A decrease in HRV precedes the onset of
AF in patients with no structural heart
disease
 Vikman;Circulation.1999;100:2079

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Low HRV in a 2 minute rhythm
strip predicts rsk of CHD &
mortality from several causes
 Middle aged men and women
 Low HRV predictive of increased mortality
rates…this relation could not be attributed
to cardiovascular risk factors or to
underlying disease
 Low HRV precedes manifest disease
 Dekker;Circulation.2000;102:1239

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Decomplexification in critical illness and
injury: Relationship between HRV,
severity of illness, and outcome
 135 pediatric ICU admissions, mean age 6.8
 Decomplexification of physiologic
dynamics is equivalent to loss of variability
or increased regularity
 The greater the severity of illness, the less
HRV was detected. Applied to all illnesses
 Crit Care Med 1998;26:352-357

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Multiple Organ Dysfunction
Syndrome
 Linked with progressive reduction in Heart
Rate Variability as the syndrome progresses
 HRV reflects trends and level of severity
 Correlation holds regardless of the inciting
event of MODS

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Uncoupling of biologic
oscillators: A hypothesis re the
pathogenesis of MODS
 Healthy organs behave as biologic
oscillators, coupled and maintained by a
communications network that includes
neural, humoral and cytokine components
 HRV is a reflection of the degree of
coupling between organ systems
 Godin; Crit Care Med;1996

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Coupling of biological
oscillators
Heart

CNS

Immune

Coupling
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MODS and HRV

 SIRS initiates disruption of communication
and uncoupling which if severe enough
leads to MODS
 MODS a consequence of the uncoupling of
organ systems as reflected by loss of
biologic oscillations or variability
 HRV decreases as SIRS and MODS unfolds

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Uncoupling of biologic
oscillators: A hypothesis re the
pathogenesis of MODS
 HRV decreases (organ isolation) with age
 HRV decreases (organ isolation) with SIRS
 Advanced age and SIRS means higher risk
for MODS (irreversible organ isolation)
 Crit Care Med 1996;24:1107

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Experimental human
endotoxemia increases
cardiac regularity
 Prospective, randomized, crossover trial
 Infusion of endotoxin into human volunteers
causes loss of HRV
 HRV is an indicator of coupling between biologic
oscillators(e.g. heart, brain, lung)
 MODS caused by an uncoupling of organ systems
 Crit Care Med 1996;24:1117

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Decreased HRV
 Impliesreduced interconnections
 Associated with reduced waves or rhythms
throughout, ie
– Temperature Variability
– Diurnal Rhythms
– Hormonal Pulses
– Gait, agility, CNS activity, EEG pattern

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Wave resonance - healthy
 Heart rate

 Brain

 Temperature

 Diurnal

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Wave resonance - unhealthy
 Heart

 Brain

 Temperature

 Diurnal

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HRV Implications
 HRV = Wave
 Wave = Signature of system dynamics
 System Dynamics = Complexity
 Complexity = Biologic Health/Resiliency

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Biologic Resiliency
 Biology is mutually supportive systems
 Systems embedded within systems
 The rich and responsive interconnections
between systems is key to robust health
 Wave patterns reflect the status of the
interconnections and the responsiveness of
the agents

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Implications of HRV
 Insights from wave patterns
 Pharmacology
 Lifestyle choices
 Influencing HRV with training
 Ubiquity of waves or rhythms
 Everything is connected to everything else

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HRV Implications
 Wave pattern implications
– Decrease complexity = poor health

– Increase complexity = good health

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HRV Implications
 Pharmacology
– Medications that can decrease HRV
 Amitryptiline, Anticholinergics, Anti-arryhthmics

– Medications that can increase HRV in CHF
 Beta blockers, spironolactone
– Testing of prospective new drugs

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HRV Implications
 Lifestyle choices
– Decrease HRV
 Smoking

 Sedentary

– Increase HRV
 Exercise
 Meditation or relaxation techniques

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HRV Implications
 Influencing HRV with training
– Sprinters have high HRV
– Ultra marathoners have low HRV
 Sprint training may have more of a health
benefit than endurance training

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HRV Implications
 Ubiquity of waves or rhythms at all levels
– Biochemical oscillation
– Cell cycles
– Organ system
– Organisms
– Biosphere

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HRV Implications
 Everything is connected to everything else

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Circadian (24 hr) Rhythm
an indicator of system health

6 am 12 noon 6 pm 12 pm
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Healthy Circadian Rhythm
“waves on waves”

6 am 12 noon 6 pm 12 pm
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Abnormal Circadian Rhythm -
less “waves on waves”

6 am 12 noon 6 pm 12 pm
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Heart Rate Variability

A risk factor for all cause mortality

Robert A. Lindberg, MD

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Effects of Spironolactone on
HRV and LV systolic function
in severe ischemic heart
failure
 In CHF pt’s on conventional medications,
the addition of spironolactone induces a
favorable sympathovagal balance
 Korkmaz; Am J Cardiol 2000;86:649

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Non-linear dynamics for
clinicians: chaos theory,
fractals, and complexity at the
 Normal HRV represents multiscale fractal
bedside
complexity of the heart rate
 Abnormal HRV represents loss of
multiscale fractal complexity
 Goldberger;Lancet.1996;347:1312

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Multifractality in human
heartbeat dynamics
 Physiological signals under healthy
conditions have a fractal temporal structure
 The healthy human heartbeat has fractal
scaling
 There is a loss of fractal scaling in
congestive heart failure
 Ivanov;Nature.1999;399:461

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Fractals
 An object composed of subunits that
resembles the larger scale structure, a
property known as self-similarity
 At each scale of magnification, the pattern
remains the same

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Classical vs Fractal Geometry
 Classical Geometry
– Smooth, regular, and integer dimensions (1, 2
and 3 for line, surface and volume respectively)
 Fractal Geometry
– Rough, irregular and non-integer, or fractional
dimensions

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Classical (Euclidian) vs
Fractal Line
 Classical: single scale and length

 Fractal: multiple scales, self-similar

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Examples of Fractal
Structures
 Trees, coral formations, clouds, coastlines,
mountain ranges, galaxies
 Arterial and venous trees, neurons,
tracheobronchial tree, His Purkinje
network, intestinal villi

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Examples of Non Fractal
Structures

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Fractal Structures

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Fractal Processes
 Fractal processes generate irregular
fluctuations on multiple time scales,
analogous to fractal objects that have
wrinkly structure on different length scales
 The variation over time is statistically self-
similar

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Examples of Fractal
Processes
 Weather patterns, Dow Jones average,
population dynamics
 Heart Rate, Respirations, Blood pressure,
WBC counts, temperature
 Demonstrate Self-Similar Dynamics

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Complex Nonlinear Systems
 A system consisting of a large and variable
number of component parts
 The components display marked variability
over time
 There is a high degree of connectivity and
interdependence between variables

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Complex nonlinear systems
are ubiquitous in nature
 Weather patterns
 Biosphere of our planet
 Stock market
 Ecosystem of a tropical rain forest
 Central nervous system
 Immune system

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Relevance of Complexity
Science to Medicine
 Concept of the human body as a complex
adaptive system
 Systems embedded within systems
 The sum is greater than the parts

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