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 systems waves

provides insight into its 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 pts 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
pts 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 exerciseis 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
ratesthis 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 pts 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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